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STAUROSPORINE

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STAUROSPORINE

(+)-Staurosporine

Molecular FormulaC₂₈H₂₆N₄O₃
Average mass466.531 Da

(2S,3R,4R,6R)-3-Methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.1^2,6.0^7,28.0^8,13.0^15,19.0^20,27.0^21,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one

6,10-Epoxy-6H,16H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiazonin-16-one, 7,8,9,10,17,18-hexahydro-7-methoxy-6-methyl-8-(methylamino)-, (6S,7R,8R,10R)-
62996-74-1[RN]
AM-2282
Antibiotic 230
antibiotic am 2282
StaurosporineCAS Registry Number: 62996-74-1
CAS Name: (9S,10R,11R,13R)- 2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-11-(methylamino)-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3¢,2¢,1¢-lm]pyrrolo[3,4-j][1,7]benzodiazonin-1-one
Manufacturers’ Codes: AM-2282; CGP-39360
Molecular Formula: C28H26N4O3, Molecular Weight: 466.53
Percent Composition: C 72.09%, H 5.62%, N 12.01%, O 10.29%
Literature References: Protein kinase C inhibitor; alkaloid isolated from Streptomyces staurosporeus. Isoln: S. Omura et al., J. Antibiot.30, 275 (1977). Crystal and molecular structure: A. Furusaki et al., J. Chem. Soc. Chem. Commun.1978, 800; eidem,Bull. Chem. Soc. Jpn.55, 3681 (1982). Corrected stereochemistry: N. Funato et al., Tetrahedron Lett.35, 1251 (1994). Total synthesis: J. T. Link et al., J. Am. Chem. Soc.117, 552 (1995); idem et al., ibid.118, 2825 (1996). Biosynthetic studies: D. Meksuriyen, G. A. Cordell, J. Nat. Prod.51, 884, 893 (1988); S.-W. Yang et al., ibid.62 1551 (1999). HPLC determn in blood and pharmacokinetics in rats: L. R. Gurley et al., J. Chromatogr. B712, 211 (1998). Inhibition of protein kinase C: T. Tamaoki et al., Biochem. Biophys. Res. Commun.135, 397 (1986); of other protein kinases: U. T. Rüegg, G. M. Burgess, Trends Pharmacol. Sci.10, 218 (1989). Induction of apoptosis: E. Falcieri et al., Biochem. Biophys. Res. Commun.193, 19 (1993); R. Bertrand et al., Exp. Cell Res.211, 314 (1994); of tyrosine phosphorylation: D. Rasouly, P. Lazarovici, Eur. J. Pharmacol.269, 255 (1994).
Properties: Pale yellow needles from chloroform-methanol as the methanol solvate, mp 270° (dec) (Omura). Also reported as yellow crystals from methanol, mp 288-291° (Meksuriyen, Cordell). [a]D25 +35.0° (c = 1 in methanol); [a]D22 +56.1° (c = 0.14 in methanol). uv max (methanol): 241.0, 266.0, 292.5, 321.5, 335.0, 355.0, 372.5 nm (log e 4.25, 4.26, 4.53, 3.88, 3.96, 3.81, 3.85). Sol in DMSO, DMF. Slightly sol in chloroform, methanol.
Melting point: mp 270° (dec); mp 288-291° (Meksuriyen, Cordell)
Optical Rotation: [a]D25 +35.0° (c = 1 in methanol); [a]D22 +56.1° (c = 0.14 in methanol)
Absorption maximum: uv max (methanol): 241.0, 266.0, 292.5, 321.5, 335.0, 355.0, 372.5 nm (log e 4.25, 4.26, 4.53, 3.88, 3.96, 3.81, 3.85)
Derivative Type: Hydrochloride
Molecular Formula: C28H26N4O3.HCl, Molecular Weight: 502.99
Percent Composition: C 66.86%, H 5.41%, N 11.14%, O 9.54%, Cl 7.05%
Properties: LD50 in mice (mg/kg): 6.6 i.p. (Omura).
Toxicity data: LD50 in mice (mg/kg): 6.6 i.p. (Omura)
Use: Pharmacological tool to study signal transduction pathways, tyrosine phosphorylation and to induce apoptosis.
An indolocarbazole that is a potent protein kinase C inhibitor which enhances cAMP-mediated responses in human neuroblastoma cells. (Biochem Biophys Res Commun 1995;214(3):1114-20)

Staurosporine (antibiotic AM-2282 or STS) is a natural product originally isolated in 1977 from the bacterium Streptomyces staurosporeus.^[1] It was the first of over 50 alkaloids to be isolated with this type of bis-indole chemical structure. The chemical structure of staurosporine was elucidated by X-ray analysis of a single crystal and the absolute stereochemical configuration by the same method in 1994.^[2]

Staurosporine was discovered to have biological activities ranging from anti-fungal to anti-hypertensive.^[3] The interest in these activities resulted in a large investigative effort in chemistry and biology and the discovery of the potential for anti-cancer treatment.

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Synthesis Reference

Chikara Murakata, Toshimitsu Takiguchi, Shigeo Katsumata, Akira Mihara, Keiichi Takahashi, Hiromitsu Saito, Shiro Akinaga, Masami Okabe, Yutaka Saito, “Process for producing staurosporine derivatives.” U.S. Patent US5344926, issued December, 1990.

US5344926

SYN

CN 113122591

WO 2021127275

CN 110642872

WO 2020200945

CN 107603922

WO2006002422

PAPER

Journal of Antibiotics, 51(7), 679-682; 1998

PAPER

Journal of the American Chemical Society, 117(1), 552-3; 1995

PATENT

WO2006002422

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006002422

Preparation of Staurosporine Analogs

|00501 ] As will become apparent to a skilled artisan, many of the bridged epoxy diindolopyrrolo-hexahydrobenzodiazocines are commercially available as final compounds or modifiable intermediates. Staurosporine was originally isolated from the bacterium Streptomyces staurosporeus. (S.Omura et al. J.Antibiotics, 30, 275

1977).

[00502] Synthesis of 9, 12-epoxy staurosporine analogs:

NOTE: 2) 120°, 6) 120°,
Reactantsi 4, Reagents : 7, Catalysts. 2, Solvents 18,
Steps: 9, Stages: 11, Most stages in any one stept 2

[00503] Greater detail is provided in Tetrahedron Letters, 36(46), 8383-6,

1995.
[00504] Alternative synthesis of 9,12-epoxy staurosporine analogs:

NOTEt 1) stereoselective, 5) Raney nickel present,
Reactantsi 5, Reagentsi 6, Catalystsi 4, Solvents! 5,
Stepsi 7, stagest 9, Most stages in any one step: 2 [00505] Greater detail is provided in Organic Letters, 3(11), 1689-1692; 2001.
[00506]
[00507] Synthesis of 9, 13-epoxy staurosporine analogs:

NOTE: 1) STEREOSELECTIVE, 3) (92%/65%/95%/92%) , 4) 100% OVERALL (5.5:1,
ALPHA: BETA), 5) STEREOSELECTIVE, KEY STEP, 8) (97%/91%), 9) PHOTOCHEM.,
12) STEREOSELECTIVE KEY STEP, 14) (92%/81%/82%),
Reactants: 10, Reagents: 20, Catalysts: 5, Solvents: 9,
Steps: 17, Stages: 35, Most stages in any one step: 6

[00508] Whereas, a more thorough description of reagents, reaction conditions, and other pertinent syntheses are described Journal of the American Chemical Society, 117(1), 552-3; 1995. Additionally, syntheses on staurosporine and analogs thereof are described by S.J Danishefsky et al, J.Am.Chem.Soc, 118, 28251996 and J.L.Wood et al, J.Am.Chem.Soc, 118, 106561996.

Table 1 : Staurosporine Analogs

PATENT

https://patents.google.com/patent/WO2020200945A1/enEXAMPLES

A2 B2

Example 1Method for obtaining crude midostaurin B1 from crude staurosporine A1

A reactor was loaded with crude staurosporine A1 (1 mol) and DMF (7 L). The solution was cooled to 0°C and subsequently DIPEA (1.5 mol) was added. Benzoyl chloride (1.2 mol) was added while keeping the temperature within the range 0-5°C. After 30 minutes from the end of the addition, an aqueous 1 % ammonium chloride solution (15 L) was added while keeping the temperature within the range 0-5°C. After 1 hour from the end of the addition, the suspension was filtered and the panel was washed with plenty of water. The solid was dried for 6 hours at 40°C, obtaining crude midostaurin B1 with 95% yield. Example 2Method for obtaining purified midostaurin B2 from crude midostaurin B1 – reduction of 3-hydroxymidostaurin to midostaurin with triethylsilanei. TFA/TESii. NaHC0₃iii. Crystallizationin MeTHFiv. Crystallization

in EtOH/H₂0

B4 B2

A reactor was loaded with crude midostaurin B1 (1 mol) and DCM (10 L). The solution was cooled to 0°C and subsequently added with TES (1 mol) and TFA (0.50 L) in this order, while keeping the temperature within the range 0-5°C. At the end of the additions the solution was brought to 20°C. After 3 hours the solution was added with an aqueous 5% sodium bicarbonate solution (20 L). At the end of the development of gas the resulting two phases were separated and the aqueous phase was washed twice with DCM (10 L). The collected organic phases were concentrated at atmospheric pressure, added with 2-MeTHF (30 L) and two changes of solvent at atmospheric pressure were carried out. The solution was clarified by filtration at 75°C and the panel was washed with 2-MeTHF. The filtrate was transferred into another reactor and cooled at 0°C in 8 hours. After further 2 hours at 0°C the suspension was filtered and the panel was washed twice with 2-MeTHF. The solid was dried for 12 hours at 80°C and subsequently transferred into another reactor. Ethanol (7 L) was added and the mixture was heated at 75°C up to complete dissolution. Water (30 L) was added with a concurrent cooling to 20°C. The resulting suspension was filtered and the panel was washed with plenty of water. The solid was dried for 12 hours at 80°C, obtaining purified midostaurin B2 with 85% yield. Example 3Method for obtaining purified staurosporine A2 from crude staurosporine A1 – reduction of 3-hydroxystaurosporine to staurosporine with triethylsilane

A reactor was loaded with crude staurosporine A1 (1 mol) and DCM (10 L). The solution was cooled to 0°C and subsequently added with TES (1 mol) and TFA (0.50 L) in this order, while keeping the temperature within the range 0-5°C. After 1 hour from the end of the additions, the solution was added with MeOH (10 L) and, subsequently, with an aqueous 5% sodium bicarbonate solution (20 L). At the end of the development of gas the resulting two phases were separated and the aqueous phase was washed twice with DCM (10 L). The collected organic phases were concentrated at atmospheric pressure, added with 2-MeTHF (50 L) and two changes of solvent at atmospheric pressure were carried out. The warm solution was clarified by filtration at 75°C and the panel was washed with 2-MeTHF. The filtrate was transferred into another reactor and cooled at 0°C in 8 hours. After further 2 hours at 0°C the suspension was filtered and the panel was washed twice with 2-MeTHF. The solid was dried for 12 hours at 80°C, obtaining purified staurosporine A2 with 80% yield. Example 4Method for obtaining purified staurosporine A2 from crude staurosporine A1 – derivatization of 3-hydroxystaurosporine with trifluoroacetic acid and purification by crystallization

A reactor was loaded with crude staurosporine A1 (1 mol) and DCM (10 L). The mixture was cooled to 0°C and added with TFA (0.50 L), while keeping the temperature within the range 0-5°C. After 1 hour from the end of the addition, the solution was added with MeOH (10 L) and, subsequently, with an aqueous 5% sodium bicarbonate solution (20 L). At the end of the development of gas the resulting two phases were separated and the aqueous phase was washed twice with DCM (10 L). The collected organic phases were concentrated at atmospheric pressure, added with 2-MeTHF (50 L) and two changes of solvent at atmospheric pressure were carried out. The warm solution was clarified by filtration at 75°C and the panel was washed with 2-MeTHF. The filtrate was transferred into another reactor and cooled at 0°C in 8 hours. After further 2 hours at 0°C the suspension was filtered and the panel was washed twice with 2-MeTHF. The solid was dried for 12 hours at 80°C, obtaining purified staurosporine A2 with 80% yield. Example 5Method for obtaining purified midostaurin B2 from purified staurosporine A2 i. BzCI/DIPEAii. NH4CI/H2Oiii. Crystallizationin MeTHFiv. Crystallization

in EtOH/H₂0

A2 B2

A reactor was loaded with purified staurosporine A2 (1 mol) and DMF (7 L). The solution was cooled to 0°C and subsequently DIPEA (1.5 mol) was added. Benzoyl chloride (1.2 mol) was added while keeping the temperature within the range 0-5°C. After 30 minutes from the end of the addition, an aqueous 1 % ammonium chloride solution (15 L) was added while keeping the temperature within the range 0-5°C. After 1 hour from the end of the addition, the suspension was filtered and the panel was washed with plenty of water. The solid was dried for 6 hours at 40°C and subsequently transferred into another reactor. 2-MeTHF (30 L) was added and the suspension was heated under reflux up to complete dissolution. The solution was clarified by filtration at 75°C and the panel was washed with 2-MeTHF. The filtrate was transferred into another reactor and cooled at 0°C in 8 hours. After further 2 hours at 0°C the suspension was filtered and the panel was washed twice with 2-MeTHF. The solid was dried for 12 hours at 80°C and subsequently transferred into another reactor. Ethanol (7 L) was added and the mixture was heated at 75°C up to complete dissolution. Water (30 L) was added with a concurrent cooling to 20°C. The resulting suspension was filtered and the panel was washed with plenty of water. The solid was dried for 12 hours at 80°C, obtaining purified midostaurin B2 with 85% yield.
ClaimsHide Dependent
1) A process for the preparation of midostaurin with high purity, that is with a content of 3-hydroxymidostaurin impurities (III) and (IV) lower than 0.1%, comprising the treatment with strong organic or inorganic acids in a water-immiscible solvent and, optionally, also with reducing silanes.2) The process for the preparation of midostaurin according to claim 1 , comprising the treatment of crude midostaurin with a reducing silane in the presence of a strong organic or inorganic acid.3) The process for the preparation of midostaurin according to claim 1 , comprising the treatment of crude staurosporine with a strong organic or inorganic acid, optionally with the concomitant addition of a reducing silane.4) The process for the preparation of midostaurin according to claim 1 , 2 or 3, wherein the water-immiscible solvent is an aprotic polar water-immiscible solvent.5) The process for the preparation of midostaurin according to claim 4 wherein the water-immiscible solvent is dichloromethane, dichloroethane, methyl tetrahydrofuran or methylethylketone, preferably dichloromethane.6) The process for the preparation of midostaurin according to claim 1 , 2 or 3, wherein the strong acid is trifluoroacetic acid.7) The process for the preparation of midostaurin according to claim 1 , 2 or 3, wherein the reducing silane is triethylsilane.8) The process for the preparation of midostaturin according to anyone of the preceding claims, further comprising the benzoylation reaction of staurosporine to midostaurin characterized in that the benzoylation reaction is quenched with an aqueous solution having a slightly acid pH.9) The process for the preparation of midostaurin according to claim 8 wherein the aqueous solution having a slightly acid pH is an aqueous ammonium chloride solution.10) The process for the preparation of midostaurin according to anyone of the preceding claims, comprising the obtainment of purified midostaurin by crystallization from 2-MeTHF and its further isolation by:dissolving the crystallized midostaurin in a water-miscible polar solvent, adding waterisolating purified midostaurin as an amorphous solid obtained by filtering and drying, with a content of organic solvents < 50ppm. 11) The process for the preparation of purified midostaurin according to claim 10, wherein the polar s

Patent

Publication numberPriority datePublication dateAssigneeTitleJPS5247055B21973-12-041977-11-30US5093330A1987-06-151992-03-03Ciba-Geigy CorporationStaurosporine derivatives substituted at methylamino nitrogenEP0575955A11992-06-221993-12-29Kyowa Hakko Kogyo Co., Ltd.Process for producing staurosporine derivativesWO2006048296A12004-11-052006-05-11Novartis AgOrganic compoundsWO2011064355A12009-11-302011-06-03Novartis AgPolymorphous forms iii and iv of n-benzoyl staurosporineWO2018165071A12017-03-062018-09-13Teva Pharmaceutical Works Ltd.Solid state forms of midostaurin

Biological activities

The main biological activity of staurosporine is the inhibition of protein kinases through the prevention of ATP binding to the kinase. This is achieved through the stronger affinity of staurosporine to the ATP-binding site on the kinase. Staurosporine is a prototypical ATP-competitive kinase inhibitor in that it binds to many kinases with high affinity, though with little selectivity.^[4] Structural analysis of kinase pockets demonstrated that main chain atoms which are conserved in their relative positions to staurosporine contributes to staurosporine promiscuity.^[5] This lack of specificity has precluded its clinical use, but has made it a valuable research tool. In research, staurosporine is used to induce apoptosis. The mechanism of how it mediates this is not well understood. It has been found that one way in which staurosporine induces apoptosis is by activating caspase-3.^[6] At lower concentration, depending on the cell type, staurosporine induces specific cell cycle effects arresting cells either in G₁ or in G₂ phase of the cell cycle.^[7]

Chemistry family

Main article: Indolocarbazole

Staurosporine is an indolocarbazole. It belongs to the most frequently isolated group of indolocarbazoles: Indolo(2,3-a)carbazoles. Of these, Staurosporine falls within the most common subgroup, called Indolo(2,3-a)pyrrole(3,4-c)carbazoles. These fall into two classes – halogenated (chlorinated) and non-halogenated. Halogenated indolo(2,3-a)pyrrole(3,4-c)carbazoles have a fully oxidized C-7 carbon with only one indole nitrogen containing a β-glycosidic bond, while non-halogenated indolo(2,3-a)pyrrole(3,4-c)carbazoles have both indole nitrogens glycosylated, and a fully reduced C-7 carbon. Staurosporine is in the non-halogenated class.^[8]

Staurosporine is the precursor of the novel protein kinase inhibitor midostaurin (PKC412).^[9]^[10] Besides midostaurin, staurosporine is also used as a starting material in the commercial synthesis of K252c (also called staurosporine aglycone). In the natural biosynthetic pathway, K252c is a precursor of staurosporine.

Structure of an Indolo[2,3-a]pyrrole[3,4-c]carbazol

Biosynthesis

The biosynthesis of staurosporine starts with the amino acid L-tryptophan in its zwitterionic form. Tryptophan is converted to an imine by enzyme StaO which is an L-amino acid oxidase (that may be FAD dependent). The imine is acted upon by StaD to form an uncharacterized intermediate proposed to be the dimerization product between 2 imine molecules. Chromopyrrolic acid is the molecule formed from this intermediate after the loss of VioE (used in the biosynthesis of violacein – a natural product formed from a branch point in this pathway that also diverges to form rebeccamycin. An aryl aryl coupling thought to be catalyzed by a cytochrome P₄₅₀ enzyme to form an aromatic ring system occurs.^[8]

This is followed by a nucleophilic attack between the indole nitrogens resulting in cyclization and then decarboxylation assisted by StaC exclusively forming staurosporine aglycone or K252c. Glucose is transformed to NTP-L-ristoamine by StaA/B/E/J/I/K which is then added on to the staurosporine aglycone at 1 indole N by StaG. The StaN enzyme reorients the sugar by attaching it to the 2nd indole nitrogen into an unfavored conformation to form intermediated O-demethyl-N-demethyl-staurosporine. Lastly, O-methylation of the 4’amine by StaMA and N-methylation of the 3′-hydroxy by StaMB leads to the formation of staurosporine.^[8]

Research in clinical use

When encapsulated in liposome nanoparticle, staurosporine is shown to suppress tumors in vivo in a mouse model without the toxic side effects which have prohibited its use as an anti-cancer drug with high apoptotic activity. Researchers in UC San Diego Moores Cancer Center develop a platform technology of high drug-loading efficiency by manipulating the pH environment of the cells. When injected into the mouse glioblastoma model, staurosporine is found to accumulate primarily in the tumor via fluorescence confirmation, and the mice did not suffer weight loss compared to the control mice administered with the free compound, an indicator of reduced toxicity.^[11]^[12]

References

^ Omura S, Iwai Y, Hirano A, Nakagawa A, Awaya J, Tsuchiya H, Takahashi Y, Masuma R (1977). “A new alkaloid AM-2282 of Streptomyces origin taxonomy, fermentation, isolation and preliminary characterization”. J. Antibiot. 30 (4): 275–282. doi:10.7164/antibiotics.30.275. PMID 863788.
^ Funato N, Takayanagi H, Konda Y, Toda Y, Harigaya Y, Omura S (1994). “Absolute configuration of staurosporine by X-ray analysis”. Tetrahedron Lett. 35 (8): 1251–1254. doi:10.1016/0040-4039(94)88036-0.
^ [1] Rüegg UT, Burgess GM. (1989) Staurosporine, K-252 and UCN-01: potent but nonspecific inhibitors of protein kinases. Trends in Pharmacological Science 10 (6): 218-220.
^ Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP (2008). “A quantitative analysis of kinase inhibitor selectivity”. Nat. Biotechnol. 26 (1): 127–132. doi:10.1038/nbt1358. PMID 18183025. S2CID 205273598.
^ Tanramluk D, Schreyer A, Pitt WR, Blundell TL (2009). “On the origins of enzyme inhibitor selectivity and promiscuity: a case study of protein kinase binding to staurosporine”. Chemical Biology & Drug Design. 74 (1): 16–24. doi:10.1111/j.1747-0285.2009.00832.x. PMC 2737611. PMID 19519740.
^ Chae HJ, Kang JS, Byun JO, Han KS, Kim DU, Oh SM, Kim HM, Chae SW, Kim HR (2000). “Molecular mechanism of staurosporine-induced apoptosis in osteoblasts”. Pharmacological Research. 42 (4): 373–381. doi:10.1006/phrs.2000.0700. PMID 10987998.
^ Bruno S, Ardelt B, Skierski JS, Traganos F, Darzynkiewicz Z (1992). “Different effects of staurosporine, an inhibitor of protein kinases, on the cell cycle and chromatin structure of normal and leukemic lymphocytes”. Cancer Res. 52 (2): 470–473. PMID 1728418.
^ Jump up to:^a ^b ^c Ryan KS (2008). “Structural studies of rebeccamycin, staurosporine, and violacein biosynthetic enzymes” (PDF). Ph.D. Thesis. Massachusetts Institute of Technology. Archived from the original (PDF) on 2012-03-14.
^ Midostaurin product page, Fermentek
^ Wang, Y; Yin, OQ; Graf, P; Kisicki, JC; Schran, H (2008). “Dose- and Time-Dependent Pharmacokinetics of Midostaurin in Patients With Diabetes Mellitus”. J Clin Pharmacol. 48 (6): 763–775. doi:10.1177/0091270008318006. PMID 18508951. S2CID 26657407.
^ News Release (21 October 2013). “Study Identifies Safe Delivery System for Tricky Yet Highly Potent Anti-Cancer Compounds”. UC San Diego Health System. Retrieved 27 October 2013.
^ Mukthavaram, Rajesh; Jiang, Pengei; Saklecha, Rohit; Simbery, Dmitri; Bharati, Ila; Nomura, Natsuko; Chao, Ying; Pastorino, Sandra (2013). “High-efficiency liposomal encapsulation of a tyrosine kinase inhibitor leads to improved in vivo toxicity and tumor response profile”. International Journal of Nanomedicine. 8 (1): 3991–4006. doi:10.2147/IJN.S51949. PMC 3808212. PMID 24174874.

Clinical data


ATC code	none
Identifiers
show IUPAC name
CAS Number	62996-74-1
PubChem CID	44259
IUPHAR/BPS	346
DrugBank	DB02010
ChemSpider	40272
UNII	H88EPA0A3N
ChEBI	CHEBI:15738
ChEMBL	ChEMBL162
PDB ligand	STU (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID30911019 DTXSID6041131, DTXSID30911019
ECHA InfoCard	100.109.946
Chemical and physical data
Formula	C₂₈H₂₆N₄O₃
Molar mass	466.541 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI
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///////////STAUROSPORINE, AM-2282, CGP-39360

[H][C@]1(C[C@@]2([H])O[C@](C)(N3C4=CC=CC=C4C4=C5CNC(=O)C5=C5C6=CC=CC=C6N2C5=C34)[C@]1([H])OC)NC

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Alpha lipoic acid

December 7, 2021 2:09 am / Leave a comment

Alpha lipoic acid

(+)-Thioctic acid

Molecular FormulaC₈H₁₄O₂S₂
Average mass206.326 Da

5-[3-(1,2-Dithiolanyl)]pentanoic Acid
5-19-07-00237[Beilstein]
62-46-4[RN](+)-Thioctic acid, (+)-α-Lipoic acid, (3R)-1,2-Dithiolane-3-pentanoic acid
(R)-(+)-1,2-Dithiolane-3-pentanoic acid, (R)-(+)-lipoic acid, (R)-(+)-α-Lipoic acid
(R)-6,8-Dithiooctanoic acid, (R)-6,8-thioctic acid, (R)-Î±-Lipoic Acid, (R)-α-Lipoic Acid
1,2-Dithiolane-3-pentanoic acid, (3R)-
5-[(3R)-1,2-Dithiolan-3-yl]pentanoic acidd-Thioctic acid, (R)-(+)-alpha-Lipoic acid, (R)-(+)-Thioctic acid, Dexlipotam
Thioctic Acid
CAS Registry Number: 62-46-4
CAS Name: 1,2-Dithiolane-3-pentanoic acid
Additional Names: 1,2-dithiolane-3-valeric acid; 6,8-thioctic acid; a-lipoic acid; 5-(1,2-dithiolan-3-yl)valeric acid; 5-[3-(1,2-dithiolanyl)]pentanoic acid; d-[3-(1,2-dithiacyclopentyl)]pentanoic acid; protogen A; acetate replacing factor; pyruvate oxidation factor
Trademarks: Biletan (Gador); Thioctacid (Viatris); Thioctan (Katwijk); Tioctan (Fujisawa)
Molecular Formula: C8H14O2S2, Molecular Weight: 206.33
Percent Composition: C 46.57%, H 6.84%, O 15.51%, S 31.08%
Literature References: Growth factor for many bacteria and protozoa; prosthetic group, coenzyme, or substrate in plants, microorganisms, and animal tissues. Isoln of naturally occurring d-form: L. J. Reed et al.,Science114, 93 (1951); eidem,J. Am. Chem. Soc.75, 1267 (1953); Patterson et al.,ibid.76, 1823 (1954). Syntheses of dl-form: Bullock et al.,ibid.74, 1868, 3455 (1952); Hornberger et al.,ibid. 2382; Reed, US2980716 and US3049549 (1961, 1962 to Res. Corp.); Lewis, Raphael, J. Chem. Soc.1962, 4263; Ose et al.,US3223712 (1965 to Yamanouchi); J. Tsuji et al.,J. Org. Chem.43, 3606 (1978). Biosynthesis via linoleic acid: J. P. Carreau Methods Enzymol.62, 152-158 (1974). Enantioselective synthesis of d-form: P. C. Bulmanpage et al.,Chem. Commun.1986, 1408. Clinical study in treatment of Wilson’s disease: S. F. Gomes da Costa, Arzneim.-Forsch.20, 1210 (1970). Use in treatment of mushroom poisoning: R. Plotzker et al.,Am. J. Med. Sci.283, 79 (1982); J. P. Hanrahan, M. A. Gordon, J. Am. Med. Assoc.251, 1057 (1984). Reviews: Wagner, Folkers, Vitamins and Coenzymes (Interscience, New York, 1964) pp 244-263; Schmidt et al.,Angew. Chem. Int. Ed.4, 846 (1965); Schmidt et al.,Adv. Enzymol. Relat. Areas Mol. Biol.32, 423 (1969).
Derivative Type: Sodium salt
CAS Registry Number: 2319-84-8
Molecular Formula: C8H13NaO2S2, Molecular Weight: 228.31
Percent Composition: C 42.09%, H 5.74%, Na 10.07%, O 14.02%, S 28.09%
Properties: White powder, sol in water. pH of aq solns about 7.4.
Derivative Type:d-Form
CAS Registry Number: 1200-22-2
Properties: Crystals by vacuum sublimation (at 85-90° and 25 microns). mp 46-48° (microblock). [a]D23 +104° (c = 0.88 in benzene). uv max (methanol): 333 nm (e 150). pKa 5.4. Practically insol in water. Sol in fat solvents.Melting point: mp 46-48° (microblock)
pKa: pKa 5.4
Optical Rotation: [a]D23 +104° (c = 0.88 in benzene)
Absorption maximum: uv max (methanol): 333 nm (e 150)
Derivative Type:dl-Form
CAS Registry Number: 1077-28-7
Properties: Yellow needles from cyclohexane, mp 60-61°. bp 160-165°. uv spectrum: Calvin, Fed. Proc.13, 703 (1954). Practically insol in water. Sol in fat solvents. Forms a water-soluble sodium salt.
Melting point: mp 60-61°
Boiling point: bp 160-165°
Derivative Type:l-Form
CAS Registry Number: 1077-27-6
Properties: Crystals from cyclohexane, mp 45-47.5° (microblock). [a]D23 -113° (c = 1.88 in benzene). uv max (methanol): 330 nm (e 140).
Melting point: mp 45-47.5° (microblock)
Optical Rotation: [a]D23 -113° (c = 1.88 in benzene)
Absorption maximum: uv max (methanol): 330 nm (e 140)
Derivative Type: Ethylenediamine
Trademarks: Tioctidasi (ISI)
Therap-Cat: Treatment of liver disease; antidote to poisonous mushrooms (Amanita species).
Keywords: Hepatoprotectant.

Lipoic acid (LA), also known as α-lipoic acid, alpha-lipoic acid (ALA) and thioctic acid, is an organosulfur compound derived from caprylic acid (octanoic acid).^[3] ALA is made in animals normally, and is essential for aerobic metabolism. It is also manufactured and is available as a dietary supplement in some countries where it is marketed as an antioxidant, and is available as a pharmaceutical drug in other countries.^[3]

Physical and chemical properties

Lipoic acid (LA), also known as α-lipoic acid,^[3]^[4] alpha-lipoic acid (ALA), and thioctic acid^[5] is an organosulfur compound derived from octanoic acid.^[3] LA contains two sulfur atoms (at C6 and C8) connected by a disulfide bond and is thus considered to be oxidized although either sulfur atom can exist in higher oxidation states.^[3]

The carbon atom at C6 is chiral and the molecule exists as two enantiomers (R)-(+)-lipoic acid (RLA) and (S)-(-)-lipoic acid (SLA) and as a racemic mixture (R/S)-lipoic acid (R/S-LA).

LA appears physically as a yellow solid and structurally contains a terminal carboxylic acid and a terminal dithiolane ring.

For use in dietary supplement materials and compounding pharmacies, the USP has established an official monograph for R/S-LA.^[6]^[7]

Biological function

“Lipoate” is the conjugate base of lipoic acid, and the most prevalent form of LA under physiological conditions.^[3] Most endogenously produced RLA are not “free” because octanoic acid, the precursor to RLA, is bound to the enzyme complexes prior to enzymatic insertion of the sulfur atoms. As a cofactor, RLA is covalently attached by an amide bond to a terminal lysine residue of the enzyme’s lipoyl domains. One of the most studied roles of RLA is as a cofactor of the pyruvate dehydrogenase complex (PDC or PDHC), though it is a cofactor in other enzymatic systems as well (described below).^[3]

Only the (R)-(+)-enantiomer (RLA) exists in nature and is essential for aerobic metabolism because RLA is an essential cofactor of many enzyme complexes.^[3]

Biosynthesis and attachment

The precursor to lipoic acid, octanoic acid, is made via fatty acid biosynthesis in the form of octanoyl-acyl carrier protein.^[3] In eukaryotes, a second fatty acid biosynthetic pathway in mitochondria is used for this purpose.^[3] The octanoate is transferred as a thioester of acyl carrier protein from fatty acid biosynthesis to an amide of the lipoyl domain protein by an enzyme called an octanoyltransferase.^[3] Two hydrogens of octanoate are replaced with sulfur groups via a radical SAM mechanism, by lipoyl synthase.^[3] As a result, lipoic acid is synthesized attached to proteins and no free lipoic acid is produced. Lipoic acid can be removed whenever proteins are degraded and by action of the enzyme lipoamidase.^[8] Free lipoate can be used by some organisms as an enzyme called lipoate protein ligase that attaches it covalently to the correct protein. The ligase activity of this enzyme requires ATP.^[9]

Cellular transport

Along with sodium and the vitamins biotin (B7) and pantothenic acid (B5), lipoic acid enters cells through the SMVT (sodium-dependent multivitamin transporter). Each of the compounds transported by the SMVT is competitive with the others. For example research has shown that increasing intake of lipoic acid^[10] or pantothenic acid^[11] reduces the uptake of biotin and/or the activities of biotin-dependent enzymes.

Enzymatic activity

Lipoic acid is a cofactor for at least five enzyme systems.^[3] Two of these are in the citric acid cycle through which many organisms turn nutrients into energy. Lipoylated enzymes have lipoic acid attached to them covalently. The lipoyl group transfers acyl groups in 2-oxoacid dehydrogenase complexes, and methylamine group in the glycine cleavage complex or glycine dehydrogenase.^[3]

2-Oxoacid dehydrogenase transfer reactions occur by a similar mechanism in:

the pyruvate dehydrogenase complex
the α-ketoglutarate dehydrogenase or 2-oxoglutarate dehydrogenase complex
the branched-chain oxoacid dehydrogenase (BCDH) complex
the acetoin dehydrogenase complex.

The most-studied of these is the pyruvate dehydrogenase complex.^[3] These complexes have three central subunits: E1-3, which are the decarboxylase, lipoyl transferase, and dihydrolipoamide dehydrogenase, respectively. These complexes have a central E2 core and the other subunits surround this core to form the complex. In the gap between these two subunits, the lipoyl domain ferries intermediates between the active sites.^[3] The lipoyl domain itself is attached by a flexible linker to the E2 core and the number of lipoyl domains varies from one to three for a given organism. The number of domains has been experimentally varied and seems to have little effect on growth until over nine are added, although more than three decreased activity of the complex.^[12]

Lipoic acid serves as co-factor to the acetoin dehydrogenase complex catalyzing the conversion of acetoin (3-hydroxy-2-butanone) to acetaldehyde and acetyl coenzyme A.^[3]

The glycine cleavage system differs from the other complexes, and has a different nomenclature.^[3] In this system, the H protein is a free lipoyl domain with additional helices, the L protein is a dihydrolipoamide dehydrogenase, the P protein is the decarboxylase, and the T protein transfers the methylamine from lipoate to tetrahydrofolate (THF) yielding methylene-THF and ammonia. Methylene-THF is then used by serine hydroxymethyltransferase to synthesize serine from glycine. This system is part of plant photorespiration.^[13]

Biological sources and degradation

Lipoic acid is present in many foods in which it is bound to lysine in proteins,^[3] but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract.^[14] Naturally occurring lipoic acid is always covalently bound and not readily available from dietary sources.^[3] In addition, the amount of lipoic acid present in dietary sources is low. For instance, the purification of lipoic acid to determine its structure used an estimated 10 tons of liver residue, which yielded 30 mg of lipoic acid.^[15] As a result, all lipoic acid available as a supplement is chemically synthesized.

Baseline levels (prior to supplementation) of RLA and R-DHLA have not been detected in human plasma.^[16] RLA has been detected at 12.3−43.1 ng/mL following acid hydrolysis, which releases protein-bound lipoic acid. Enzymatic hydrolysis of protein bound lipoic acid released 1.4−11.6 ng/mL and <1-38.2 ng/mL using subtilisin and alcalase, respectively.^[17]^[18]^[19]

Digestive proteolytic enzymes cleave the R-lipoyllysine residue from the mitochondrial enzyme complexes derived from food but are unable to cleave the lipoic acid-L–lysine amide bond.^[20] Both synthetic lipoamide and (R)-lipoyl-L-lysine are rapidly cleaved by serum lipoamidases, which release free (R)-lipoic acid and either L-lysine or ammonia.^[3] Little is known about the degradation and utilization of aliphatic sulfides such as lipoic acid, except for cysteine.^[3]

Lipoic acid is metabolized in a variety of ways when given as a dietary supplement in mammals.^[3]^[21] Degradation to tetranorlipoic acid, oxidation of one or both of the sulfur atoms to the sulfoxide, and S-methylation of the sulfide were observed. Conjugation of unmodified lipoic acid to glycine was detected especially in mice.^[21] Degradation of lipoic acid is similar in humans, although it is not clear if the sulfur atoms become significantly oxidized.^[3]^[22] Apparently mammals are not capable of utilizing lipoic acid as a sulfur source.

Chemical synthesis

(R)-Lipoic acid (RLA, top) and (S)-lipoic acid (SLA, down). A 1:1 mixture (racemate) of (R)- and (S)-lipoic acid is called (RS)-lipoic acid or (±)-lipoic acid (R/S-LA).

SLA did not exist prior to chemical synthesis in 1952.^[23]^[24] SLA is produced in equal amounts with RLA during achiral manufacturing processes. The racemic form was more widely used clinically in Europe and Japan in the 1950s to 1960s despite the early recognition that the various forms of LA are not bioequivalent.^[25] The first synthetic procedures appeared for RLA and SLA in the mid-1950s.^[26]^[27]^[28]^[29] Advances in chiral chemistry led to more efficient technologies for manufacturing the single enantiomers by both classical resolution and asymmetric synthesis and the demand for RLA also grew at this time. In the 21st century, R/S-LA, RLA and SLA with high chemical and/or optical purities are available in industrial quantities. At the current time, most of the world supply of R/S-LA and RLA is manufactured in China and smaller amounts in Italy, Germany, and Japan. RLA is produced by modifications of a process first described by Georg Lang in a Ph.D. thesis and later patented by DeGussa.^[30]^[31] Although RLA is favored nutritionally due to its “vitamin-like” role in metabolism, both RLA and R/S-LA are widely available as dietary supplements. Both stereospecific and non-stereospecific reactions are known to occur in vivo and contribute to the mechanisms of action, but evidence to date indicates RLA may be the eutomer (the nutritionally and therapeutically preferred form).^[32]^[33]

Pharmacology

Pharmacokinetics

A 2007 human pharmacokinetic study of sodium RLA demonstrated the maximum concentration in plasma and bioavailability are significantly greater than the free acid form, and rivals plasma levels achieved by intravenous administration of the free acid form.^[34] Additionally, high plasma levels comparable to those in animal models where Nrf2 was activated were achieved.^[34]

The various forms of LA are not bioequivalent.^[25]^{[non-primary source needed]} Very few studies compare individual enantiomers with racemic lipoic acid. It is unclear if twice as much racemic lipoic acid can replace RLA.^[34]

The toxic dose of LA in cats is much lower than that in humans or dogs and produces hepatocellular toxicity.^[35]

Pharmacodynamics

The mechanism and action of lipoic acid when supplied externally to an organism is controversial. Lipoic acid in a cell seems primarily to induce the oxidative stress response rather than directly scavenge free radicals. This effect is specific for RLA.^[4] Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms.^[36] LA is able to scavenge reactive oxygen and reactive nitrogen species in a biochemical assay due to long incubation times, but there is little evidence this occurs within a cell or that radical scavenging contributes to the primary mechanisms of action of LA.^[4]^[37] The relatively good scavenging activity of LA toward hypochlorous acid (a bactericidal produced by neutrophils that may produce inflammation and tissue damage) is due to the strained conformation of the 5-membered dithiolane ring, which is lost upon reduction to DHLA. In cells, LA is reduced to dihydrolipoic acid, which is generally regarded as the more bioactive form of LA and the form responsible for most of the antioxidant effects and for lowering the redox activities of unbound iron and copper.^[38] This theory has been challenged due to the high level of reactivity of the two free sulfhydryls, low intracellular concentrations of DHLA as well as the rapid methylation of one or both sulfhydryls, rapid side-chain oxidation to shorter metabolites and rapid efflux from the cell. Although both DHLA and LA have been found inside cells after administration, most intracellular DHLA probably exists as mixed disulfides with various cysteine residues from cytosolic and mitochondrial proteins.^[32] Recent findings suggest therapeutic and anti-aging effects are due to modulation of signal transduction and gene transcription, which improve the antioxidant status of the cell. However, this likely occurs via pro-oxidant mechanisms, not by radical scavenging or reducing effects.^[4]^[37]^[39]

All the disulfide forms of LA (R/S-LA, RLA and SLA) can be reduced to DHLA although both tissue specific and stereoselective (preference for one enantiomer over the other) reductions have been reported in model systems. At least two cytosolic enzymes, glutathione reductase (GR) and thioredoxin reductase (Trx1), and two mitochondrial enzymes, lipoamide dehydrogenase and thioredoxin reductase (Trx2), reduce LA. SLA is stereoselectively reduced by cytosolic GR whereas Trx1, Trx2 and lipoamide dehydrogenase stereoselectively reduce RLA. (R)-(+)-lipoic acid is enzymatically or chemically reduced to (R)-(-)-dihydrolipoic acid whereas (S)-(-)-lipoic acid is reduced to (S)-(+)-dihydrolipoic acid.^[40]^[41]^[42]^[43]^[44]^[45]^[46] Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, thiol-disulfide exchange reactions.^[47]

RLA may function in vivo like a B-vitamin and at higher doses like plant-derived nutrients, such as curcumin, sulforaphane, resveratrol, and other nutritional substances that induce phase II detoxification enzymes, thus acting as cytoprotective agents.^[39]^[48] This stress response indirectly improves the antioxidant capacity of the cell.^[4]

The (S)-enantiomer of LA was shown to be toxic when administered to thiamine-deficient rats.^[49]^[50]

Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by competitive inhibition.^[51]^[52]^[53]^[54]^[55]

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Uses

R/S-LA and RLA are widely available as over-the-counter nutritional supplements in the United States in the form of capsules, tablets, and aqueous liquids, and have been marketed as antioxidants.^[3]

Although the body can synthesize LA, it can also be absorbed from the diet. Dietary supplementation in doses from 200–600 mg is likely to provide up to 1000 times the amount available from a regular diet. Gastrointestinal absorption is variable and decreases with the use of food. It is therefore recommended that dietary LA be taken 30–60 minutes before or at least 120 minutes after a meal. Maximum blood levels of LA are achieved 30–60 minutes after dietary supplementation, and it is thought to be largely metabolized in the liver.^[56]

In Germany, LA is approved as a drug for the treatment of diabetic neuropathy since 1966 and is available as a non-prescription pharmaceutical.^[57]

Clinical research

According to the American Cancer Society as of 2013, “there is no reliable scientific evidence at this time that lipoic acid prevents the development or spread of cancer”.^[58] As of 2015, intravenously administered ALA is unapproved anywhere in the world except Germany for diabetic neuropathy, but has been proven reasonably safe and effective in four clinical trials; however another large trial over four years found no difference from placebo.^[59] As of 2012, there was no good evidence alpha lipoic acid helps people with mitochondrial disorders.^[60] A 2018 review recommended ALA as an anti-obesity supplement with low dosage (< 600 mg/day) for a short period of time (<10 weeks); however, it is too expensive to be practical as a complementary therapy for obesity.^[61]

SYN

WO 0210151

DE 19709069; EP 0863125; US 6013833

A synthetic route based on the asymmetric reduction of oxo diesters has been reported. Meldrum’s acid (LII) was acylated by methyl adipoyl chloride (LI) in the presence of pyridine to produce the intermediate (LIII) which, upon alcoholysis with isobutanol, led to oxo diester (LIV). Enantioselective reduction of (LIV) by means of baker’s yeast furnished the (S)-hydroxy diester (LV). Alternatively, the analogous oxo diester (LVI) was prepared by acylation of methyl acetoacetate with methyl adipoyl chloride (LI), followed by deacetylation in the presence of ammonium hydroxide. Then, asymmetric chemical reduction of (LVI) by hydrogenation in the presence of the chiral catalyst Ru2Cl4[(S)-BINAP]2 provided the (S)-hydroxy diester (LVII). Regioselective reduction of either diester (LV) or (LVII) by means of NaBH4 in refluxing THF furnished dihydroxy ester (XLVIII). After conversion of (XLVIII) to the dimesylate (XLIX), displacement with potassium thioacetate afforded the bis(acetylthio) derivative (LVIII), which was further hydrolyzed with KOH to provide dihydrolipoic acid (LIX). In a related procedure, dihydrolipoic acid (LIX) was prepared by reaction of dimesylate (XLIX) with sodium disulfide, followed by reductive treatment with NaBH4 and NaOH. The title cyclic disulfide was then obtained by oxidation of the dithiol (LIX) using oxygen in the presence of FeCl3.

SYN

DE 10036516; WO 0210113

The key dihydroxy ester intermediate (XIII) was also obtained by asymmetric hydrogenation of hydroxy ketoester (XLIII) in the presence of (S)-BINAP-dichlororuthenium catalyst. The precursor hydroxy ketoester (XLIII) was prepared by two alternative procedures. In one method, the racemic dihydroxy ester (XLII) was selectively oxidized to (XLIII) by means of NaOCl. In another method, the unsaturated keto ester (XLIV) was epoxidized by means of sodium percarbonate, and the resultant epoxide (XLV) was then reduced to the hydroxy ketoester (XLIII) by catalytic hydrogenation over PtO2.

SYN

WO 0230919

Both enantiomers of racemic 8-chloro-6-hydroxyoctanoic acid (LX) were separated employing either (+)- or (-)-alpha-methylbenzylamine. Esterification of the (R)-(-)-enantiomer with HCl-MeOH provided the chloro hydroxy ester (LXI). Further chlorination of (LXI) with SOCl2 and pyridine proceeded with inversion of configuration at C-6 to furnish the (S)-dichloro derivative (LXII). The cyclic disulfide (L) was then prepared by treatment of chloride (LXII) with sulfur and sodium sulfide in boiling EtOH. Basic hydrolysis of the methyl ester group of (LXII) then afforded (R) alpha lipoic acid. The title compound was also obtained from the (S)-(+)-acid (LXIII). Reaction of hydroxy acid (LXIII) with methanesulfonyl chloride produced the chloro mesylate (LXIV), which was then cyclized to the target disulfide in the presence of sulfur and Na2S.

SYN

The reaction of the chiral dibenzoyloxy-dihydropyran (LXV) with H2SO4 and HgSO4 gives the unsaturated aldehyde (LXVI), which is condensed with the phosphorane (LXVII) to yield the hepatdienoic ester (LXVIII). The hydrogenation of (LXVIII) with H2 over Pd/C affords the heptanoic ester (LXIX), which is treated with Ts-Cl and pyridine to provide the tosyloxy derivative (LXX). The cyclization of (LXX) by means of K2CO3 gives the chiral epoxide (LXXI), which is condensed with vinylmagnesium bromide (LXXII) to yield 6(S)-hydroxy-8-nonenoic acid methyl ester (LXXIII). The oxidation of the terminal double bond of (LXXIII) with ozone affords the carbaldehyde (LXXIV), which is reduced with NaBH4 to provide 6(S),8-dihydroxyoctanoic acid methyl ester (XLVIII). The reaction of (XLVIII) with Ms-Cl and pyridine gives the dimesylate (XLIX), which is treated with Na2S2 to yield the lipoic acid methyl ester (L), which is hydrolyzed to the target acid with KOH in H2O.

SYN

DE 3629116; EP 0261336

Alkylation of the lithio-dianion of propargyl alcohol (XIII) with 6-bromo-1-hexene (XIV), followed by in situ reduction of the resultant disubstituted acetylene with lithium metal gave the allylic alcohol (XV). Asymmetric Sharpless epoxidation of (XV) using tert-butyl hydroperoxide in the presence of L-(+)-diisopropyl tartrate afforded the (S,S)-epoxy alcohol (XVI). This was reduced to the chiral diol (XVII) employing Red-Al?in THF. After formation of the bis-mesylate (XVIII), oxidative cleavage of the terminal double bond by means of NaIO4 in the presence of ruthenium catalyst furnished the carboxylic acid (XIX). The mesylate groups were finally displaced by sodium disulfide to produce the desired cyclic disulfide compound.

SYN

DE 19533881; EP 0763533; US 5731448

SYN

WO 9638437

A different strategy was based on the enantioselective oxidation of a cyclohexanone derivative by enzymic Baeyer-Villiger reaction. Keto ester (XXXVIII) was protected as the ethylene ketal (XXXIX) and subsequently reduced to alcohol (XL) using LiAlH4. Acetylation of alcohol (XL) to acetate (XLI), followed by acidic ketal hydrolysis afforded cyclohexanone (XLII) (9,10). The racemic ketone (XLII) was then subjected to oxidative cleavage by monooxigenase 2 obtained from Pseudomonas putida to furnish the (R)-lactone (XLIV) along with unreacted (S)-cyclohexanone (XLIII) (9-11). The use of cyclohexanone monooxigenase from Acinetobacter NCIMB 9871 has also been reported for this reaction (12). Methanolysis of lactone (XLIV) in the presence of NaOMe gave rise to the (R)-dihydroxy ester (XLV). Inversion of the configuration of (XLV) was accomplished by Mitsunobu coupling with p-nitrobenzoic acid (XLVI) to produce the (S)-p-nitrobenzoate ester (XLVII). Smooth hydrolysis of ester (XLVII) provided methyl (S)-6,8-dihydroxyoctanoate (XLVIII), which was processed through intermediates (XLIX) and (L), as for the isopropyl (X) (Scheme 29605101a) and ethyl (XXIX) (Scheme 29605103a) homologues, to afford the title compound.

SYN

Tetrahedron Lett 2001,42(29),4891

The olefinic diester (XXXVIII) was subjected to OsO4-catalyzed asymmetric dihydroxylation using hydroquinidine 1,4-phthalazinediyl diether [(DHQD)2-PHAL] as chiral ligand to afford diol (XXXIX). This was converted to the cyclic sulfate (XL) by treatment with SOCl2, followed by RuCl3-catalyzed NaIO4 oxidation of the intermediate sulfite. Regioselective reduction of sulfate (XL) at the alpha position with NaBH4 in DMA led to the (3S)-alcohol (XLI). Further selective reduction of the ethyl ester group of (XLI) was achieved by treatment with NaBH4-Et3N in MeOH-DMF, yielding the target intermediate dihydroxy ester (XIII).

SYN

1,6-Hexanediol (I) was protected as the mono-tetrahydropyranyl ether (II), and the free hydroxyl group was subsequently oxidized to aldehyde (III) under Swern conditions. Reformatskii reaction of aldehyde (III) with the organozinc reagent generated from ethyl bromoacetate yielded the racemic hydroxy ester (IV). The requisite (S)-enantiomer (VI) was obtained via oxidation of (IV) to oxo ester (V) using pyridinium chlorochromate, and then asymmetric hydrogenation in the presence of (S)-(-)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl dichlororuthenium complex. Oxo ester (V) was also prepared by SnCl2-catalyzed insertion of ethyl diazoacetate into aldehyde (III). The chiral hydroxy ester (VI) was then reduced to diol (VII) by means of NaBH4-CuSO4. After conversion of (VII) to the corresponding dimesylate (VIII), removal of the tetrahydropyranyl protecting group under acidic conditions gave alcohol (IX). This was sequentially oxidized with PCC to aldehyde, and then with Ag2O to furnish the target dimesylate acid intermediate (X).

SYN

Tetrahedron Asymmetry 2000,11(4),879

The intermediate 6(S)-hydroxy-8-nonenoic acid methyl ester (III) has been obtained by enantioselective allylation of 6-oxohexanoic acid methyl ester (I) with allyltributylstannane (II) catalyzed by the chiral catalyst (R)-BINOL/Ti(O-iPr)4 in refluxing dichloromethane (other BINOL/metal catalysts have also been studied).

SYN

Tetrahedron Lett 1985,26(21),2535

Aldehyde (II), prepared by ozonolysis of cyclohexene (I), was ketalized with (S,S)-2,4-pentanediol (III) to afford dioxane (IV). Titanium chloride-mediated coupling of acetal (IV) with the ketene acetal (V) afforded diastereoselectively adduct (VI), which was subsequently hydrolyzed to carboxylic acid (VII) by means of trifluoroacetic acid. Removal of the pentanediol moiety to furnish the (R)-alcohol (IX) was accomplished via Jones oxidation of the secondary alcohol (VII) to ketone (VIII), followed by beta-elimination in the presence of piperidinium acetate. Reduction of the free carboxyl group by borane-tetrahydrofuran complex gave diol (X), which was further converted to dimesylate (XI). Disulfide displacement of the mesylate groups provided (+)-lipoic acid isopropyl ester (XII), which was finally hydrolyzed to the title acid using K2CO3 in MeOH/H2O.

SYN

Tetrahedron Lett 1987,28(44),5313

A short synthetic strategy utilized the cyclic thioketal (XXXIII), derived from d-menthone (XXXII) and 1,3-propanedithiol, as the chiral template. Stereospecific oxidation of dithiane (XXXIII) employing NaIO4 produced sulfoxide (XXXIV). The carbanion generated from sulfoxide (XXXIV) was stereoselectively alkylated by 5-bromopentanoic acid (XXXV) in the presence of TMEDA to furnish the trans alkylated compound (XXXVI). Finally, acidic hydrolysis of (XXXVI) formed the intermediate mercapto sulfinic acid (XXXVII) which spontaneously cyclized to the desired dithiolane derivative.

SYN

Tetrahedron Lett 1987,28(19),2183

Diisopropylidene mannitol (I) was first converted into the dibutyltin derivative (II), which was subsequently mono-benzylated to (III). Acetylation of (III) with acetic anhydride in pyridine gave (IV). After acidic hydrolysis of the isopropylidene ketals of (IV), the resultant tetraol (V) was converted into tetramesylate (VI). Reductive elimination in (VI) with Zn and NaI produced diene (VII). The acetate group of (VII) was then hydrolyzed to (VIII) using NaOMe. Intermediate (VIII) was reacted with triethyl orthoacetate in the presence of propionic acid to generate the allyl vinyl ether (IX), which underwent a Claisen rearrangement to the diene-ester (X). Selective hydroboration-oxidation of the terminal double bond of (X) yielded the primary alcohol (XI). Subsequent benzyl group hydrogenolysis in (XI) furnished the target intermediate diol (XII).

SYN

Esterification of diisopropylidene mannitol (I) with benzoyl chloride in pyridine afforded dibenzoate (II). Hydrolysis of the isopropylidene ketals of (II) with aqueous HOAc gave tetraol (III), which was further converted to tetramesylate (IV) on treatment with methanesulfonyl chloride and pyridine. Reductive elimination of the mesylate groups of (IV) using Zn dust and NaI yielded diene (V). The benzoate esters of (V) were then removed by treatment with sodium methoxide. The resultant divinylglycol (VI) was reacted with dibutyltin oxide to produce the tin derivative (VII), which was converted to the target intermediate, themono-benzyl ether (VIII), by treatment with benzyl bromide in hot DMF.

SYN

Tetrahedron Lett 1989,30(42),5705

Alkylation of the dianion of octyl acetoacetate (XIII) with 4-iodobutyronitrile (XIV) provided the cyano keto ester (XV). Enantiospecific reduction of (XV) utilizing baker’s yeast gave rise to the desired (S)-hydroxy ester (XVI) in high enantiomeric excess. Subsequent ester group reduction in (XVI) by means of LiBH4 provided diol (XVII). The target dihydroxy ester (XII) was then obtained by alcoholysis of nitrile (XVII) under acidic conditions.

SYN

J Chem Soc Chem Commun 1995,(15),1563

SYN

Synthesis (Stuttgart) 1996,(5),594

Racemic tetrahydro-2-furylmethanol (I) was converted to tosylate (II), which was further displaced by KCN to yield nitrile (III). Basic hydrolysis of nitrile (III), followed by Fischer esterification of the resultant carboxylic acid (IV) provided ethyl ester (V). Enzymatic resolution of racemic ester (V) by means of the lipase from Candida cylindracea generated a mixture of the (R)-acid (VI) and the unreacted (S)-ester (VII), which were separated by column chromatography. The desired (S) ester (VII) was then reduced to alcohol (VIII) with LiAlH4 in cold Et2O. Regioselective opening of the cyclic ether (VIII) with iodotrimethylsilane in acetone furnished the acetonide of 6-iodo-1,3-hexanediol (IX). Alkylation of benzyl methyl malonate (X) with iodide (IX) provided malonate (XI). Hydrogenolysis of the benzyl ester group of (XI), followed by thermal decarboxylation led to ester (XII). The target dihydroxy ester precursor (XIII) was then obtained by acid-catalyzed hydrolysis of the acetonide function.

SYN

Synthesis (Stuttgart) 1996,(11),1289

Addition of vinylmagnesium bromide to 2-nitrocyclohexanone (XIV) afforded the nitro alcohol (XV). Ring cleavage of (XVI) in the presence of anhydrous CuSO4 absorbed on silica gel gave the nitro ketone (XVI). Nitro group hydrolysis in (XVI) by successive treatment with NaOMe and H2SO4 in MeOH furnished oxo ester (XVII) as the main product. This was enantiospecifically reduced with baker’s yeast to yield the (S)-alcohol (XVIII). Selective methyl ether cleavage with tetrabutylammonium iodide and BF3 provided the dihydroxy ester precursor (XIII).

SYN

An alternative route to (+)-lipoic acid used ethyl 4,6-di-O-acetyl-2,3-dideoxy-alpha-D-erythro-hexopyranoside (XX), prepared from triacetyl-D-glucal, as the chiral starting point. Deacetylation of (XX) with sodium methoxide under Zemplen conditions gave diol (XXI) which, after conventional benzylation, led to the 4,6-di-O-benzyl derivative (XXII). Ring opening of the cyclic acetal (XXII) with propanediol in the presence of boron trifluoride afforded the dithiane derivative (XXIII). The free hydroxyl group of (XXIII) was converted into xanthate (XXIV) by reaction with NaH and CS2, followed by methyl iodide. Reductive cleavage of the xanthate group by means of Bu3SnH and AIBN provided (XXV). Hydrolysis of the thioacetal function with HgO and BF3 provided aldehyde (XXVI). Chain homologation was performed by Wittig reaction of aldehyde (XXVI) with phosphorane (XXVII) to afford the unsaturated ester (XXVIII). Simultaneous double bond hydrogenation and benzyl ether cleavage in the presence of Raney nickel led to dihydroxy ester (XXIX). This was converted to the corresponding dimesylate (XXX), which was further cyclized to disulfide (XXXI) using the in situ generated sodium disulfide as in the precedent Schemes. Finally, basic hydrolysis of the ethyl ester (XXXI) yielded the title carboxylic acid.

Carbohydr Res 1986,148(1),51

SYN

J Carbohydr Chem 1990,9(2-3),307

SYN

J Chem Soc Chem Commun 1986,(18),1408

SYN

https://www.sciencedirect.com/science/article/abs/pii/S1381117713003342

References

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^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x ^y “Lipoic acid”. Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis. 1 January 2019. Retrieved 5 November 2019.
^ Jump up to:^a ^b ^c ^d ^e Shay, KP; Moreau, RF; Smith, EJ; Hagen, TM (June 2008). “Is alpha-lipoic acid a scavenger of reactive oxygen species in vivo? Evidence for its initiation of stress signaling pathways that promote endogenous antioxidant capacity”. IUBMB Life. 60 (6): 362–7. doi:10.1002/iub.40. PMID 18409172. S2CID 33008376.
^ Reljanovic, M; Reichel, G; Rett, K; Lobisch, M; et al. (September 1999). “Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): A two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy”. Free Radical Research. 31 (3): 171–9. doi:10.1080/10715769900300721. PMID 10499773.
^ USP32-NF27. p. 1042.
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^ Jiang, Y; Cronan, JE (2005). “Expression cloning and demonstration of Enterococcus faecalis lipoamidase (pyruvate dehydrogenase inactivase) as a Ser-Ser-Lys triad amidohydrolase”. Journal of Biological Chemistry. 280 (3): 2244–56. doi:10.1074/jbc.M408612200. PMID 15528186.
^ Cronan, JE; Zhao, X; Jiang, Y (2005). Poole, RK (ed.). Function, attachment and synthesis of lipoic acid in Escherichia coli. Advances in Microbial Physiology. 50. pp. 103–46. doi:10.1016/S0065-2911(05)50003-1. ISBN 9780120277506. PMID 16221579.
^ Zempleni, J.; Trusty, T. A.; Mock, D. M. (1997). “Lipoic acid reduces the activities of biotin-dependent carboxylases in rat liver”. The Journal of Nutrition. 127 (9): 1776–81. doi:10.1093/jn/127.9.1776. PMID 9278559.
^ Chirapu, S. R.; Rotter, C. J.; Miller, E. L.; Varma, M. V.; Dow, R. L.; Finn, M. G. (2013). “High specificity in response of the sodium-dependent multivitamin transporter to derivatives of pantothenic acid”. Current Topics in Medicinal Chemistry. 13 (7): 837–42. doi:10.2174/1568026611313070006. PMID 23578027.
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^ Fontanella, L (1955). “Preparation of optical antipodes of alpha-lipoic acid”. Il Farmaco; Edizione Scientifica. 10 (12): 1043–5. PMID 13294188.
^ Walton, E; Wagner, AF; Bachelor, FW; Peterson, LH; et al. (1955). “Synthesis of (+)-lipoic acid and its optical antipode”. Journal of the American Chemical Society. 77 (19): 5144–9. doi:10.1021/ja01624a057.
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^ Deguchi, Y; Miura, K (June 1964). “Studies on the synthesis of thioctic acid and its related compounds. XIV. Synthesis of (+)-thioctamide”. Yakugaku Zasshi. 84 (6): 562–3. doi:10.1248/yakushi1947.84.6_562. PMID 14207116.
^ Lang, G (1992). In Vitro Metabolism of a-Lipoic Acid Especially Taking Enantioselective Bio-transformation into Account (Ph.D. thesis). Münster, DE: University of Münster.
^ US patent 5281722, Blaschke, G; Scheidmantel, U & Bethge, H et al., “Preparation and use of salts of the pure enantiomers of alpha-lipoic acid”, issued 1994-01-25, assigned to DeGussa.
^ Jump up to:^a ^b Carlson, DA; Young, KL; Fischer, SJ; Ulrich, H. “Ch. 10: An Evaluation of the Stability and Pharmacokinetics of R-lipoic Acid and R-Dihydrolipoic Acid Dosage Forms in Plasma from Healthy Human Subjects”. Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects. pp. 235–70. In Packer & Patel 2008.
^ Packer, L; Kraemer, K; Rimbach, G (October 2001). “Molecular aspects of lipoic acid in the prevention of diabetes complications”. Nutrition. 17 (10): 888–95. doi:10.1016/S0899-9007(01)00658-X. PMID 11684397.
^ Jump up to:^a ^b ^c Carlson, DA; Smith, AR; Fischer, SJ; Young, KL; et al. (December 2007). “The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects” (PDF). Alternative Medicine Review. 12 (4): 343–51. PMID 18069903.
^ Hill, AS; Werner, JA; Rogers, QR; O’Neill, SL; et al. (April 2004). “Lipoic acid is 10 times more toxic in cats than reported in humans, dogs or rats”. Journal of Animal Physiology and Animal Nutrition. 88 (3–4): 150–6. doi:10.1111/j.1439-0396.2003.00472.x. PMID 15059240.
^ Packer, L; Witt, EH; Tritschler, HJ (August 1995). “Alpha-lipoic acid as a biological antioxidant”. Free Radical Biology and Medicine. 19 (2): 227–50. doi:10.1016/0891-5849(95)00017-R. PMID 7649494.
^ Jump up to:^a ^b Shay, KP; Moreau, RF; Smith, EJ; Smith, AR; et al. (October 2009). “Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential”. Biochimica et Biophysica Acta (BBA) – General Subjects. 1790 (10): 1149–60. doi:10.1016/j.bbagen.2009.07.026. PMC 2756298. PMID 19664690.
^ Haenen, GRMM; Bast, A (1991). “Scavenging of hypochlorous acid by lipoic acid”. Biochemical Pharmacology. 42 (11): 2244–6. doi:10.1016/0006-2952(91)90363-A. PMID 1659823.
^ Jump up to:^a ^b Shay, KP; Shenvi, S; Hagen, TM. “Ch. 14 Lipoic Acid as an Inducer of Phase II Detoxification Enzymes Through Activation of Nr-f2 Dependent Gene Expression”. Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects. pp. 349–71. In Packer & Patel 2008.
^ Arnér, ES; Nordberg, J; Holmgren, A (August 1996). “Efficient reduction of lipoamide and lipoic acid by mammalian thioredoxin reductase”. Biochemical and Biophysical Research Communications. 225 (1): 268–74. doi:10.1006/bbrc.1996.1165. PMID 8769129.
^ Biaglow, JE; Ayene, IS; Koch, CJ; Donahue, J; et al. (April 2003). “Radiation response of cells during altered protein thiol redox”. Radiation Research. 159 (4): 484–94. Bibcode:2003RadR..159..484B. doi:10.1667/0033-7587(2003)159[0484:RROCDA]2.0.CO;2. PMID 12643793.
^ Haramaki, N; Han, D; Handelman, GJ; Tritschler, HJ; et al. (1997). “Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid”. Free Radical Biology and Medicine. 22 (3): 535–42. doi:10.1016/S0891-5849(96)00400-5. PMID 8981046.
^ Constantinescu, A; Pick, U; Handelman, GJ; Haramaki, N; et al. (July 1995). “Reduction and transport of lipoic acid by human erythrocytes”. Biochemical Pharmacology. 50 (2): 253–61. doi:10.1016/0006-2952(95)00084-D. PMID 7632170.
^ May, JM; Qu, ZC; Nelson, DJ (June 2006). “Cellular disulfide-reducing capacity: An integrated measure of cell redox capacity”. Biochemical and Biophysical Research Communications. 344 (4): 1352–9. doi:10.1016/j.bbrc.2006.04.065. PMID 16650819.
^ Jones, W; Li, X; Qu, ZC; Perriott, L; et al. (July 2002). “Uptake, recycling, and antioxidant actions of alpha-lipoic acid in endothelial cells”. Free Radical Biology and Medicine. 33 (1): 83–93. doi:10.1016/S0891-5849(02)00862-6. PMID 12086686.
^ Schempp, H; Ulrich, H; Elstner, EF (1994). “Stereospecific reduction of R(+)-thioctic acid by porcine heart lipoamide dehydrogenase/diaphorase”. Zeitschrift für Naturforschung C. 49 (9–10): 691–2. doi:10.1515/znc-1994-9-1023. PMID 7945680.
^ Biewenga, GP; Haenen, GRMM; Bast, A (1997). “Ch. 1: An Overview of Lipoate Chemistry”. In Fuchs, J; Packer, L; Zimmer, G (eds.). Lipoic Acid In Health & Disease. CRC Press. pp. 1–32. ISBN 9780824700935.
^ Lii, CK; Liu, KL; Cheng, YP; Lin, AH; et al. (May 2010). “Sulforaphane and alpha-lipoic acid upregulate the expression of the pi class of glutathione S-transferase through c-jun and Nrf2 activation”. Journal of Nutrition. 140 (5): 885–92. doi:10.3945/jn.110.121418. PMID 20237067.
^ Gal, EM; Razevska, DE (August 1960). “Studies on the in vivo metabolism of lipoic acid. 1. The fate of DL-lipoic acid-S35 in normal and thiamine-deficient rats”. Archives of Biochemistry and Biophysics. 89 (2): 253–61. doi:10.1016/0003-9861(60)90051-5. PMID 13825981.
^ Gal, EM (July 1965). “Reversal of selective toxicity of (-)-alpha-lipoic acid by thiamine in thiamine-deficient rats”. Nature. 207 (996): 535. Bibcode:1965Natur.207..535G. doi:10.1038/207535a0. PMID 5328673. S2CID 4146866.
^ US patent 6271254, Ulrich, H; Weischer, CH & Engel, J et al., “Pharmaceutical compositions containing R-alpha-lipoic acid or S-alpha.-lipoic acid as active ingredient”, issued 2001-08-07, assigned to ASTA Pharma.
^ Kilic, F; Handelman, GJ; Serbinova, E; Packer, L; et al. (October 1995). “Modelling cortical cataractogenesis 17: In vitro effect of a-lipoic acid on glucose-induced lens membrane damage, a model of diabetic cataractogenesis”. Biochemistry and Molecular Biology International. 37 (2): 361–70. PMID 8673020.
^ Artwohl, M; Schmetterer, L; Rainer, G; et al. (September 2000). Modulation by antioxidants of endothelial apoptosis, proliferation, & associated gene/protein expression. 36th Annual Meeting of the European Association for the Study of Diabetes, 17–21 September 2000, Jerusalem, Israel. Diabetologia. 43 (Suppl 1) (published August 2000). Abs 274. PMID 11008622.
^ Streeper, RS; Henriksen, EJ; Jacob, S; Hokama, JY; et al. (July 1997). “Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle”. AJP: Endocrinology and Metabolism. 273 (1 Pt 1): E185–91. doi:10.1152/ajpendo.1997.273.1.E185. PMID 9252495.
^ Frölich, L; Götz, ME; Weinmüller, M; Youdim, MB; et al. (March 2004). “(r)-, but not (s)-alpha lipoic acid stimulates deficient brain pyruvate dehydrogenase complex in vascular dementia, but not in Alzheimer dementia”. Journal of Neural Transmission. 111 (3): 295–310. doi:10.1007/s00702-003-0043-5. PMID 14991456. S2CID 20214857.
^ McIlduff, Courtney E; Rutkove, Seward B (2011-01-01). “Critical appraisal of the use of alpha lipoic acid (thioctic acid) in the treatment of symptomatic diabetic polyneuropathy”. Therapeutics and Clinical Risk Management. 7: 377–385. doi:10.2147/TCRM.S11325. ISSN 1176-6336. PMC 3176171. PMID 21941444.
^ Ziegle, D.; Reljanovic, M; Mehnert, H; Gries, F. A. (1999). “α-Lipoic acid in the treatment of diabetic polyneuropathy in Germany”. Experimental and Clinical Endocrinology & Diabetes. 107 (7): 421–30. doi:10.1055/s-0029-1212132. PMID 10595592.
^ “Lipoic Acid”. American Cancer Society. November 2008. Retrieved 5 October 2013.
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^ Namazi, Nazli; Larijani, Bagher; Azadbakht, Leila (2018). “Alpha-lipoic acid supplement in obesity treatment: A systematic review and meta-analysis of clinical trials”. Clinical Nutrition. 37 (2): 419–428. doi:10.1016/j.clnu.2017.06.002. ISSN 0261-5614. PMID 28629898

Names



IUPAC name(R)-5-(1,2-Dithiolan-3-yl)pentanoic acid
Other namesα-Lipoic acid; Alpha lipoic acid; Thioctic acid; 6,8-Dithiooctanoic acid
Identifiers
CAS Number	1077-28-7 (racemate)1200-22-2 (R)
3D model (JSmol)	Interactive image
ChEBI	CHEBI:30314
ChEMBL	ChEMBL134342
ChemSpider	5886
DrugBank	DB00166
ECHA InfoCard	100.012.793
IUPHAR/BPS	4822
KEGG	C16241
MeSH	Lipoic+acid
PubChem CID	6112
UNII	73Y7P0K73Y (racemate)VLL71EBS9Z (R)
CompTox Dashboard (EPA)	DTXSID7025508
show InChI
show SMILES
Properties
Chemical formula	C₈H₁₄O₂S₂
Molar mass	206.32 g·mol⁻¹
Appearance	Yellow needle-like crystals
Melting point	60–62 °C (140–144 °F; 333–335 K)
Solubility in water	Very Slightly Soluble(0.24 g/L)^[1]
Solubility in ethanol 50 mg/mL	Soluble
Pharmacology
ATC code	A16AX01 (WHO)
Pharmacokinetics:
Bioavailability	30% (oral)^[2]
Related compounds
Related compounds	Lipoamide Asparagusic acid
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
verify (what is ?)
Infobox references

//////////Alpha lipoic acid, d-Thioctic acid, (R)-(+)-alpha-Lipoic acid, (R)-(+)-Thioctic acid, Dexlipotam,

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Acetaminosalol

November 29, 2021 9:28 am / Leave a comment

Acetaminosalol

Molecular FormulaC₁₅H₁₃NO₄
Average mass271.268 Da
ацетаминосалол [Russian] [INN], أسيتامينوسالول [Arabic] [INN], 醋氨沙洛 [Chinese] [INN]

(1E)-N-{4-[(2-Hydroxybenzoyl)oxy]phenyl}ethanimidic acid118-57-0[RN]
204-261-3[EINECS]
CAS Registry Number: 118-57-0
CAS Name: 2-Hydroxybenzoic acid 4-(acetylamino)phenyl ester
Additional Names:p-acetamidophenyl salicylate; acetylaminophenyl salicylate; acetyl-p-aminosalol; p-acetylaminophenol salicylic acid ester; phenetsal
Trademarks: Salophen (Bayer); Phenosal
Molecular Formula: C15H13NO4
Molecular Weight: 271.27
Percent Composition: C 66.41%, H 4.83%, N 5.16%, O 23.59%
Literature References: Prepn: Brewster, J. Am. Chem. Soc.40, 1136 (1918).
Properties: Crystals from hot ethanol, mp 187°. Practically insol in petr ether, cold water, more sol in warm water. Sol in alcohol, ether, benzene. Incompatible with alkalies and alkaline solns which dissolve it with decompn. The alkaline soln gradually becomes blue when boiled, the blue color being discharged upon continued boiling and again produced upon cooling and exposure to air.
Melting point: mp 187°
Therap-Cat: Analgesic; antipyretic; anti-inflammatory.
Therap-Cat-Vet: Analgesic; antipyretic.
Keywords: Analgesic (Non-Narcotic); Anti-inflammatory (Nonsteroidal); Salicylic Acid Derivatives; Antipyretic.

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Acetaminosalol is an organic compound with the chemical formula C₁₅H₁₃NO₄.

It is an esterification product of salicylic acid and paracetamol. It was marketed by Bayer under the brand name Salophen as an analgesic in the late 19th and early 20th centuries.

Action and uses

In a warm alkaline solution acetaminosalol is broken up into salicylic acid and paracetamol. It is decomposed in the intestines, even when given as an injection. It was used as a substitute for salicylic acid in acute rheumatism, and as an intestinal antiseptic. It was similarly effective and much safer than salol, another intestinal antiseptic commonly used at the time. The fact that it is tasteless renders it easy to administer.Advertisement for early 20th century Bayer products, including Salophen
SYNJournal of Organic Chemistry, 86(5), 4254-4261; 2021

Names

Preferred IUPAC name4-Acetamidophenyl 2-hydroxybenzoate
Identifiers
CAS Number	118-57-0
3D model (JSmol)	Interactive image Interactive image
ChEBI	CHEBI:250620
ChEMBL	ChEMBL92590
ChemSpider	1907
ECHA InfoCard	100.003.875
EC Number	204-261-3
MeSH	Salophen
PubChem CID	1984
UNII	O3J7H54KMD
CompTox Dashboard (EPA)	DTXSID7045865
show InChI
show SMILES
Properties
Chemical formula	C₁₅H₁₃NO₄
Molar mass	271.272 g·mol⁻¹
Density	1.327 g cm⁻³
log P	2.562
Acidity (pK_a)	7.874
Basicity (pK_b)	6.123
Hazards
Flash point	241.9 °C (467.4 °F; 515.0 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
verify (what is ?)
Infobox references

///////////////Acetaminosalol, nalgesic , Anti-inflammatory, Salicylic Acid Derivatives, Antipyretic, ацетаминосалол , أسيتامينوسالول , 醋氨沙洛 ,

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Dichlorquinazine

November 12, 2021 11:02 am / Leave a comment

CORRECT STR OF Dichlorquinazine

7-chloro-N-[1-[4-[2-[(7-chloroquinolin-4-yl)amino]propyl]piperazin-1-yl]propan-2-yl]quinolin-4-amine;methanesulfonic acid

1,4-Piperazinediethanamine, N,N’-bis(7-chloro-4-quinolinyl)-α,α’-dimethyl- (9CI)
Quinoline, 4,4-[1,4-piperazinediylbis[(1-methylethylene)imino]]bis[7-chloro- (7CI)
Quinoline, 4,4′-[1,4-piperazinediylbis[(1-methylethylene)imino]]bis[7-chloro- (8CI)
N¹,N⁴-Bis(7-chloro-4-quinolinyl)-α¹,α⁴-dimethyl-1,4-piperazinediethanamine
1,4-Bis[2-(7-chloro-4-quinolylamino)propyl]piperazine

Bis[(chloro-7”-quinolyl-4”)amino-2′-propyl]-1,4-piperazine
Dichlorquinazine
N,N’-Bis(7-chloro-4-quinolyl)-α,α’-dimethylpiperazine-1,4-diethylamine
NSC 129790
RP 12278
WR 3863

WRONG STRUCTURE

4,4'-(1,4-Piperazinediylbis((1-methylethylene)imino))bis(7-chloroquinoline).png

WRONG STRUCTURE

Dichlorquinazine

BRN 0867697
Dichlorquinazine
EINECS 234-130-6
NSC 129790
RP 12278
UNII-HT3GAD2SCM
WR 3863

cas 10547-40-7

C28H32Cl2N6, mw

523.5

7-chloro-N-[2-[4-[2-[(7-chloroquinolin-4-yl)amino]propan-2-yl]piperazin-1-yl]propan-2-yl]quinolin-4-amine

VARIANT

RN: 23256-65-7

Molecular Formula, C28-H32-Cl2-N6.C-H4-O3-S, Molecular Weight, 619.6144

RP-12278 mesylate
WR-3863 mesylate
Quinoline, 4,4′-(1,4-piperazinediylbis((1-methylethylene)imino))bis(7-chloro-, tetramethanesulfonate bis((7-chloro-4”-quinolyl)-2′-aminopropyl)-1,4-piperazine methanesulfonate

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PATENTS

BE 626239

4-(Chloro or alkoxy)quinolines are treated with a 1,4-bis(aminoalkyl)piperazine to give the title compds. which can be used as antiinflammatory agents and as amebicides. Thus, a mixt. of 16.3 g. 4-chloroquinoline, 10 g. 1,4-bis(3-aminopropyl)piperazine, 55 g. PhOH, and 0.2 g. NH₄Cl is heated 5 hrs. at 175°, poured into a mixt. of 500 ml. H₂O and 100 ml. NaOH (d. 1.33), filtered, the ppt. is treated with a mixt. of 80 ml. H₂O and 20 ml. NaOH, the mixt. filtered, and the ppt. washed with 500 ml. H₂O and dried to give 15.9 g. 1,4-bis[3-(4-quinolyl)aminopropyl]piperazine, m. 210°(MeOH-H₂O). Similarly prepd. are the following I: n, R, R¹, R², X, Y, m.p.; 2, H, H, H, MeO, H, 245° (HCONMe₂); 2, H, H, H, H, SO₂NMe₂, 271° (HCONMe₂); 2, H, H, H, H, CF₃, 293° (HCONMe₂); 3, Me, H, H, H, H, ∼100°; 3, Me, Ac, H, H, H, -(1); 3, Me, H, H, MeOH, 180° and 190°; 3, Me, Ac, H, MeO, H, -(2); 1, Me, H, Me, H, Cl, 264°; 2, H, H, H, Cl, H, 264° (BuOH); 1, Me, H, H, H, CF₃, 240° (MeCOEt); 2, H, H, H, H, MeO, 200° (EtOH); 2, H, H, Me, H, MeO, 216° (EtOH); 3, Me, H, H, H, MeO, 218° (CH₂Cl₂); (1) bis(acid maleate) m. 155° (iso-PrOH), (2) bis(acid maleate) m. 155° The following II were also prepd.: n, R, R¹, R², m.p.; 1, Me, A(R = R¹ = X = Y = H,Z =Cl), A(R = R¹ = X = Z = H,Y = Cl), 208-10° (HCONMe₂); 1, Me, A(R = R¹ = X = Y= H, Z = Cl), A(R = R¹ = X = Y = H,Z = MeO), 206-8° (HCONMe₂); 1, Me, A(R¹ = X = Y = H, R = 4-ClC₆H₄, Z = Cl), A(R = R¹ = X = Y = H,Z = Cl, 230-2° (HCONMe₂) The following III were prepd.: n, R, m, R¹, R², m.p.; 3, Me, 1, H, A(R = R¹ = X = Y = H, Z= Cl), 190-1° and 213-15°; 2, H, 2, H, A(R = X = Y = H, R¹ = Me, Z =Cl), 198° (PrOH); 3, Me, 2, H, A(R = R¹ = X = Y = H,Z = Cl), 160-2°; 1, Me, 1, H, A(R = R¹ = X = Y = H,Z = Cl), 178°; 1, Me, 1, Me, A(R¹ = X = Z = H,R = Me, Y =AcNH), 330° (decompn.) (EtOH); 2, H, 2, H, A(R¹ = X = Y = H,R = 4-ClC₆H₄,Z = Cl), 320-1° (HCONMe₂); 2, H, 2, H, A(R = Y = Z = H, R¹ = Me, X = Cl) 96° (iso-PrOH); 1, Me, 1, Me, A(R = R¹ = X = Z = H, Y = Cl), 220° and 246-8°; 1, Me, 1, Me, A(R¹ = X = Z = H, R = Me, Y = NH₂), 305° (EtOH-H₂O); 1, Me, 1, Me, A(R¹ = X = Z = H, R = Me, Y = MeO, 244° (EtOH) Also prepd. were (m.p. given): 1,4-bis[2-(7-chloro-4-quinolylamino)propyl]hexahydro-1,4-diazepine, 169°; 1-[5-(7-chloro-4-quinolylamino)-2-pentyl]-4-[2-(7-chloro-4-quinolylamino)propyl] piperazine, 210-12°(HCONMe₂); 1,4-bis[3-(7-chloro- 4-quinolylamino)propyl] hexahydro-1,4-diazepine, 186° (HCONMe₂). The following were prepd. (m.p. and optical rotation given):L(+)-1,4-bis[2-(7-chloro-4-quinolylamino)propyl]piperazine, 250-1°, [α]^23.5_D 382° ± 1° (c 4, 50:50 MeOH-H₂O); D(-)-1,4- bis[2-(7-chloro-4-quinolylamino)propyl] piperazine, 250-1°, [α]²⁵_D -382.5° ± 1° (c 4, 50:50 MeOH-H₂O); DL-1,4-bis[2-(7-chloro-4-quinolylamino)propyl]piperazine (IV), 266-8°, -; meso-1,4-bis [2-(7-chloro-4-quinolylamino)propyl] piperazine (V), 270-1° (HCONMe₂), -; equimol. mixt. of IV and V, 250-2°, -; 1,4-bis[2-(6-chloro-4-quinolylamino)propyl]piperazine-form A (VI-form A), 227° -; VI-form B, 110° and 245°, -. Also prepd. are the following intermediates of the general formula VII (R = H) (X, Y, Z, and m.p. given): OH, H, SO₂NMe₂, ∼288°; Cl, H,SO₂NMe₂, 170°; HO(CH₂)₃CHMeNH, H, H, 158° (EtOH); AcO(CH₂)₃CHMeNAc, H, H, -; HO(CH₂)₃CHMeNAc, H, H, -; MeSO₃(CH₂)₃CHMeNAc, H, H, -; N-(5-piperazino-2-pentyl)acetamido, H, H, -; HO(CH₂)₃CHMeNH, MeO, H, -; AcO(CH₂)₃CHMeNAc, MeO, H, -; HO(CH₂)₃CHMeNAc, MeO, H, -; MeSO₃(CH₂)₃CHMeNAc, MeO, H, -; N-(5-piperazino-2-pentyl)acetamido, MeO, H, -; Me(HOCH₂)CH, H, Cl, 210°; Me(ClCH₂)CH, H, Cl, 148-50°; Me(HOCH₂)CH, Cl, H, 192°; Me(ClCH₂)CH, Cl, H, 142°; Me(HOCH₂)CH, H, MeO, 170°; Me(ClCH₂)CH, H, MeO, 160°. Also prepd. were (m.p. given): VII (R = CO₂Et, X = OH, Y = H, Z = SO₂NMe₂), ∼335°; VII (R = CO₂H, X = OH, Y = H, Z = SO₂HMe₂), 310° (decompn.); 1,4-bis(2-oxopropyl)hexahydro-1,4-diazepine, -; 1,4-bis(2-oximinopropyl)hexahydro-1,4-diazepine, 180-1°; 1,4-bis(2-aminopropyl)hexahydro-1,4-diazepine, -; 1,4-bis(2-cyanoethyl)-hexahydro-1,4-diazepine, -. The following were prepd. (m.p. and optical rotation given): L(+)-4-(3-hydroxy-2-propylamino)-7-chloroquinoline, 223-4°, [α]²⁴_D 28.5° ± 2° (c 1, EtOH); L(+)-4-(3-chloro-2-propylamino)-7-chloroquinoline, 146-7°, [α]²⁴_D 103 ± 1° (c 2, EtOH); L(+)-4-(3-piperazino-2-propylamino)-7-chloroquinoline, 128-30°, [α]²³_D 139 ± 1° (c 2, EtOH); D(-)-4-(3-hydroxy-2-propylamino)-7-chloroquinoline, 223-4°, [α]²⁵_D – 31 ± 2° (c 1, EtOH); D(-)-4-(3-chloro-2-propylamino)-7-chloroquinoline, 147-8°, [α]²⁴_D -101 ± 1° (c 2, EtOH); D(-)-4-(3-piperazino-2-propylamino)-7-chloroquinoline, 131-2°, [α]²³_D -137 ± 1° (c 2, EtOH)

PATENT

FR CAM42 19631007.

Piperazines (I) are antiinflammatory and anthelmintic agents. A mixt. of 8.25 g. MeCH(NH₂)CH₂OH, 19.8 g. 4,6-dichloroquinoline, and 55 g. PhOH is heated to give 16.0 g. 6-chloro-4-[(3-hydroxy-2-propyl)-amino]quinoline (II), m. 192°. II (14.0 g.) is treated with a soln. of 10.6 g. SOCl₂ in 40 ml. CHCl₃ to give 12.5 g. 6-chloro-4-[(3-chloro-2-propyl)amino]quinoline (III), m. 142°. A mixt. of 13.2 g. 1-[2-(7-chloro-4-quinolylamino)propyl]piperazine, 11.0 g. III, 6.4 g. NaI, 2.3 g. anhyd. Et₃N, and 200 ml. AcEt is refluxed 18 hrs., the solvent is distd. in vacuo, and the residue is taken up in 100 ml. MeOH. The mixt. is made alk. with 110 ml. NaOH (d. 1.33), poured into 1000 ml. H₂O, and the ppt. that forms is filtered off, washed with H₂O, and recrystd. in HCONMe₂ to give 11.0 g. 1-[2-(7-chloro-4-quinolylamino)propyl]-4-[2-(6-chloro-4-quinolylamino)propyl]piperazine, m. 208-10°. Similarly prepd. are the following I (R, m, R¹, n, R², R³, R⁴, and m.p. given): H, 2, H, 2, H, MeO, H, 245°; H, 2, H, 2, H, H, SO₂NMe₂, 271°; H, 2, H, 2, H, H, CF₃, 293°; Me, 3, Me, 3, H, MeO, H, 180° and 190°; Me, 3, H, 1, H, H, Cl, 190-1° and 213-15°; H, 2, H, 2, H, Cl, H, 264°; Me, 1, Me, 1, H, H, CF₃, 240°; H, 2, H, 2, H, H, MeO, 200°; Me, 3, H, 2, H, H, Cl, 160-2°; Me, 1, H, 1, H, H, Cl, 178°; Me, 1, Me, 1, Me, AcNH, H, 330°; H, 2, H, 2, p-ClC₆H₄, H, Cl, 320-1°; Me, 1, Me, 1, H, Cl, H, 227° (form A); Me, 1, Me, 1, H, Cl, H, 110° and 245° (form B); H, 3, H, 3, H, H, Cl, 239-41°; Me, 1, Me, 1, Me, NH₂, H, 305°; Me, 1, Me, 1, Me, MeO, H, 244°; Me, 3, Me, 3, Me, 3, H, H, MeO, 218°; H, 3, H, 3, H, H, Cl, 240-2°. Also prepd. are (m.p. given): 1,4-bis[2-(7-chloro-4-quinolylamino)propyl]hexahydrodiazepine, 169°; 2,5-dimethyl-1,4-bis[2-(7-chloro-4-quinolylamino)propyl)piperazine, 264°; 1-[5-(7-chloro-4-quinolylamino [-2-pentyl]-4-[2-(7-chloro -4-quinolylamino)propyl]piperazine, 210-12°; 2,5-dimethyl-1,4-bis[3-(7-methoxy-4-quinolylamino)propyl]piperazine, 216°; 1,4-bis[3-(3-methyl-7-chloro-4-quinolylamino)propyl] piperazine, 198°; 1,4-bis[3-(7-chloro-4-quinolylamino)propyl]hexahydrodiazepine, 186°; 1-[2(7-chloro-4-quinolylamino)propyl]-4-[2-(7-methoxy-4-quinolylamino)propyl]piperazine, 206-8°; 1,4-bis[3-(3-methyl-5-chloro-4- quinolylamino)propyl]piperazine, 96°; 1 – [2 -[2 -(p – chlorophenyl)- 7- chloro- 4- quinolylamino]propyl] -4 – [2 – (7 – chloro – 4-quinolylamino)propyl]piperazine, 230-2°; L(+) 1,4-bis[2-(7-chloro-4-quinolylamino)propyl]piperazine, 250-1°, [α]^23.5_D + 382° ± 1° (c 4, 50/50 MeOH-H₂O); L(+)-7-chloro-4-(3-hydroxy-2-propylamino)quinoline, 223-4°, [α]²⁴_D 28.5° ± 2° (c 1, EtOH); L(+)-7-chloro-4-(3-chloro-2-propylamino)quinoline, 146-7°, [α]²⁴_D 103° + 1° (c 2, EtOH); L(+)-7-chloro-4-(3-piperazino-2-propylamino)quinoline 128-30°, [α]²³_D 139° ± 1° (c 2, EtOH); D(–)-1,4-bis[2-(7-chloro-4-quinolylamino)propyl]piperazine, 250-1°, [α]²⁵_D -382° ± 1° (c 4, 50:50 MeOH-H₂O); meso- 1,4 – bis [2 – (7 – chloro – 4 – quinolylamino)propyl] piperazine, 270-1°.

Patent Information

BE 612207

Publication Number	Title	Priority Date	Grant Date
US-2016045487-A1	Compositions and methods for treating neuropathy	2013-03-27
WO-2014160811-A1	Compositions and methods for treating neuropathy	2013-03-27
AU-2014234258-A1	Piperaquine microcapsules and compositions containing them	2013-03-22
AU-2014234258-B2	Piperaquine microcapsules and compositions containing them	2013-03-22	2019-02-14
CA-2907628-A1	Piperaquine microcapsules and compositions containing them	2013-03-22

Publication Number	Title	Priority Date	Grant Date
EP-2976069-A1	Piperaquine microcapsules and compositions containing them	2013-03-22
EP-2976069-B1	Piperaquine microcapsules and compositions containing them	2013-03-22	2020-05-06
US-2014322296-A1	Piperaquine microcapsules and compositions containing them	2013-03-22
US-2016045447-A1	Piperaquine microcapsules and compositions containing them	2013-03-22
US-9668979-B2	Piperaquine microcapsules and compositions containing them	2013-03-22	2017-06-06

Publication Number	Title	Priority Date	Grant Date
WO-2014147242-A1	Piperaquine microcapsules and compositions containing them	2013-03-22
AU-2009215107-A1	Treatments for neuropathy	2008-02-12
AU-2009215107-B2	Treatments for neuropathy	2008-02-12	2013-05-09
AU-2013203934-A1	Treatments for neuropathy	2008-02-12
CA-2714676-A1	Treatments for neuropathy	2008-02-12

Publication Number	Title	Priority Date	Grant Date
CA-2714676-C	Treatments for neuropathy	2008-02-12	2015-04-14
EP-2240177-A2	Treatments for neuropathy	2008-02-12
US-2009203735-A1	Treatments for neuropathy	2008-02-12
US-2011086878-A1	Treatments for Neuropathy	2008-02-12
US-2016058749-A1	Treatments for neuropathy	2008-02-12

////////////////Dichlorquinazine, BRN 0867697, Dichlorquinazine, EINECS 234-130-6, NSC 129790, RP 12278, UNII-HT3GAD2SCM, WR 3863

CC(C)(NC1=C2C=CC(=CC2=NC=C1)Cl)N3CCN(CC3)C(C)(C)NC4=C5C=CC(=CC5=NC=C4)Cl

WRONG

CC(CN1CCN(CC(C)Nc2ccnc3cc(Cl)ccc23)CC1)Nc4ccnc5cc(Cl)ccc45.CS(=O)(=O)O

AND

Clc1ccc2c(c1)nccc2NC(C)CN1CCN(CC(C)Nc2ccnc3cc(Cl)ccc32)CC1

CORRECT

NEW DRUG APPROVALS

ONETIME

$10.00

LERIGLITAZONE

November 9, 2021 10:44 am / Leave a comment

LERIGLITAZONE

C19H20N2O4S,

MW 372.4

Hydroxypioglitazone, CAS 146062-44-4

MIN 102, Hydroxy Pioglitazone (M-IV)лериглитазон [Russian] [INN]ليريغليتازون [Arabic] [INN]乐立格列酮 [Chinese] [INN]

5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione

Hydroxypioglitazone is a member of the class of thiazolidenediones that is the hydroxy derivative of pioglitazone. It has a role as a human xenobiotic metabolite. It is a member of thiazolidinediones, a member of pyridines and an aromatic ether. It derives from a pioglitazone.

OriginatorIDIBELL
DeveloperMinoryx Therapeutics
ClassNeuroprotectants; Phenyl ethers; Pyridines; Small molecules; Thiazolidinediones
Mechanism of ActionPeroxisome proliferator-activated receptor gamma agonists
Orphan Drug StatusYes – Adrenoleucodystrophy; Friedreich’s ataxia

Phase II/IIIAdrenoleucodystrophy
Phase IIFriedreich’s ataxia
PreclinicalCNS disorders

23 Sep 2020Leriglitazone receives Rare Pediatric Disease designation from the US FDA for X-linked adrenoleukodystrophy before September 2020
23 Sep 2020Minoryx Therapeutics licenses leriglitazone to Sperogenix Therapeutics in China, Hong Kong and Macau for X-linked adrenoleukodystrophy (X-ALD)
14 Sep 2020Minoryx Therapeutics completes the phase II FRAMES trial in Friedreich’s ataxia (In adolescents, In adults) in Spain, Germany, France and Belgium (PO) (NCT03917225)

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Leriglitazone (Hydroxypioglitazone), a metabolite of pioglitazone. Leriglitazone (Hydroxypioglitazone) PioOH is a PPARγ agonist, stabilizes the PPARγ activation function-2 (AF-2) co-activator binding surface and enhances co-activator binding, affording slightly better transcriptional efficacy. Leriglitazone (Hydroxypioglitazone) binds to the PPARγ C-terminal ligand-binding domain (LBD) with K_i of 1.2 μM，induces transcriptional efficacy of the PPARγ (LBD) with EC₅₀ of 680 nM.

Leriglitazone is under investigation in clinical trial NCT03917225 (A Clinical Study to Evaluate the Effect of MIN-102 on the Progression of Friedreich’s Ataxia in Male and Female Patients).

Treatment of X-Linked Adrenoleukodystrophy

PATENT

WO 9218501

WO 9322445

PAPER

Chemical & Pharmaceutical Bulletin (1995), 43(12), 2168-72

https://www.jstage.jst.go.jp/article/cpb1958/43/12/43_12_2168/_article

The metabolites of (±)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2, 4-thiazolidinedione (1, pioglitazone), which is a representative insulin-sensitizing agent, were synthesized to confirm their structures and for studies of their pharmacological properties. Of the metabolites identified, a compound hydroxylated at the 2-position of the ethoxy chain (3) and compounds oxygenated at the ethyl side chain attached to the pyridine ring (4, 5) were found to be active, although the potency was slightly lower than that of the parent compound.

PAPER

Journal of Medicinal Chemistry (1996), 39(26), 5053-5063.

https://pubs.acs.org/doi/10.1021/jm9605694

Pioglitazone (5-(4-(2-(5-ethyl-2-pyridyl)ethoxy)benzyl)-2,4-thiazolidinedione, 2) is a prototypical antidiabetic thiazolidinedione that had been evaluated for possible clinical development. Metabolites 6−9 have been identified after dosing of rats and dogs. Ketone 10 has not yet been identified as a metabolite but has been added to the list as a putative metabolite by analogy to alcohol 6 and ketone 7. We have developed improved syntheses of pioglitazone (2) metabolites 6−9 and the putative metabolite ketone 10. These entities have been compared in the KKA^y mouse model of human type-II diabetes to pioglitazone (2). Ketone 10 has proven to be the most potent of these thiazolidinediones in this in vivo assay. When 6−10 were compared in vitro in the 3T3-L1 cell line to 2, for their ability to augment insulin-stimulated lipogenesis, 10 was again the most potent compound with 6, 7, and 9 roughly equivalent to 2. These data suggest that metabolites 6, 7, and 9 are likely to contribute to the pharmacological activity of pioglitazone (2), as had been previously reported for ciglitazone (1).

PATENT

WO 2015150476

Compound 5-[4-[2-(5-(1 -hydroxyethyl)-2-pyridinyl)ethoxy]benzyl]-2,4-thiazolidinedione of formula (1 ) can be prepared according to Scheme 1 (see e.g. J.Med.Chem. 1996, 39(26),5053).

Scheme 1

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=6118BE930C610E7AA5FB6BD992B2A008.wapp1nC?docId=WO2015150476&tab=PCTDESCRIPTION

Scheme 2

Yet another method to prepare mixtures (c) – comprising compound (2) and (4) – and (d) – comprising compounds (3) and (5) – (scheme 3), includes the resolution of the racemic mixture VIII using the already described methods (chiral HPLC separation, enzymatic resolution, chiral resolution, etc) followed by double bond reduction in each of the enantiomers Villa and Vlllb.

Scheme 4

Compounds of formula (2), (3), (4) and (5) may be obtained from mixtures (c) and (d) (Scheme 45) by chiral HPLC separation. Alternatively, the desired enantiomerically pure compounds can be prepared by chiral synthetic procedures known to those skilled in the art (for example: asymmetric hydrogenolysis of the corresponding single isomer of compound VI).

HPLC Method

Column: Symmetry Shield RP-18, 5 μηη (4.6 x 250 mm); wavelength: 210 nm; flow: 1 mL/min; run time: 28 min; mobile phase-gradient: (t/%B): 0/10, 8/10, 12/60, 16/80, 20/80, 24/10, 28/10 [A: Water (potassium dihydrogen o-phosphate (pH~3)), B: Acetonitrile]

A mixture of compounds (2) and (4) (mixture (c)) and a mixture of compounds (3) and (5) (mixture (d)) were prepared according to Scheme 7.

Example 6: Preparation of diastereomeric mixtures D-1 and D-2 of M-IV:

Scheme 1 :

Ent-1 (VIII) Ent-2 (VIII)

Step 3 Step 3

MIV D-1 MIV D-2

Step 1 : Synthesis of compound VIII: HCI (48 ml, 2N) was added to a solution of compound VI (10 g, 0.024 mol) in methanol (200 ml) and the mixture was heated to reflux. After 4 h of reflux, the reaction mixture was cooled to r.t. and concentrated under reduced pressure to afford a yellow solid. The solid was suspended in water (70 ml) and neutralized using a saturated NaHC0₃ solution. The resulting pale yellow precipitate was collected by filtration and vacuum dried to afford compound VIII (7.5 g; 84% yield).

ES-MS [M+1]⁺: 371.0.

Step 2: Chiral prep. HPLC

Compound VIII (1 .0 g) was dissolved in a mixture containing equal volumes of acetonitrile, methanol and dichloromethane; injected (150 μΙ injections) in chiral prep-HPLC column (Chiralpak-IA 250 x 20 mm, 5 micron) and separated [Mobile phase- n-Hexane/0.05% Et₃N in EtOH (50:50); flow Rate: 18ml/min; run time: 60 min]. The fractions containing the enantiomers Villa and Vlllb were separately concentrated under reduced pressure to minimum volume and the respective residues were diluted with EtOAc (100 ml), followed by water (50 ml). The resultant organic phases were

dried over anhydrous Na₂S0₄ and concentrated to afford compounds Villa and Vlllb as off-white solids. Enantiomers Villa and Vlllb were isolated but the absolute configuration of each enantiomer has not been determined.

Compound Ent-1 (VIII): 250 mg (Yield: 50%); t_R (Chiral HPLC) = 14.8 min; ES-MS [M+1]⁺: 371 .0; ¹H NMR (400 MHz, DMSO-d₆): δ 12.5 (br S, 1 H), 8.47 (s, 1 H), 7.71 (s, 1 H), 7.67 (dd, J = 8.0, 2.0 Hz, 1 H), 7.53 (d , J = 9.2 Hz, 2H), 7.31 (d, J = 7.6 Hz, 1 H), 7.08 (d, J = 8.8 Hz, 2H), 5.25 (d, J = 4.0 Hz, 1 H), 4.74-4.76 (m, 1 H), 4.43 (dd, J = 6.8, 6.4 Hz, 2H), 3.18 (t, J = 6.4 Hz, 2H), 1.34 (d, J = 6.4 Hz, 3H).

Compound Ent-2 (VIII): 237 mg (Yield: 47%); t_R (Chiral HPLC) = 16.7 min; ES-MS [M+1]⁺: 371 .0; ¹H NMR (400 MHz, DMSO-d₆): δ 12.5 (br S, 1 H), 8.47 (s, 1 H), 7.71 (s, 1 H), 7.67 (dd, J = 8.0, 2.0 Hz, 1 H), 7.53 (d , J = 8.8 Hz, 2H), 7.31 (d, J = 8.0 Hz, 1 H), 7.08 (d, J = 9.2 Hz, 2H), 5.23 (d, J = 3.6Hz, 1 H), 4.75 (m, 1 H), 4.43 (dd, J = 6.8, 6.4 Hz, 2H), 3.18 (dd, J = 6.8, 6.4 Hz, 2H), 1 .34 (d, J = 6.4 Hz, 3H).

Synthesis of diastereomeric mixtures of M-IV

Synthesis of D-1 MIV

Step 3: A solution of NaBH₄ (77 mg, 2.02 mmol) in 0.1 N NaOH (2 ml) was added slowly to a stirred solution of compound Ent-1 (VIII) (250 mg, 0.675 mmol), dimethylglyoxime (32 mg, 0.27 mmol) and CoCI₂.6H₂0 (16 mg, 0.067 mmol) in a mixture of water (10 ml), THF (10 ml) and 1 M NaOH (0.5ml) solution at 10 °C, and the reaction mixture was stirred at r.t. for 1 h. After color of the reaction medium faded, additional quantity of NaBH₄ (26 mg, 0.675 mmol) and CoCI₂.6H₂0 (16 mg, 0.067 mmol) were added and stirring was continued at r.t. [additional quantities of CoC|₂ and NaBH₄ were added at 12 h intervals till the starting material was consumed, as monitored by LCMS]. After 90-96 h, the reaction mixture was neutralized with AcOH (pH~7); diluted with water (10 ml) and extracted in EtOAc (3 ^χ 50 ml). The combined organic extract was dried over anhydrous Na₂S0₄ and concentrated to afford crude compound which was purified by flash column chromatography (Si0₂; 4% methanol in CH₂CI₂) to afford diastereomeric mixture of MIV D-1 (125 mg) as off-white solid.

Synthesis of D-2 MIV

Step 3: A solution of NaBH₄ (72 mg, 1 .921 mmol) in 0.1 N NaOH (2 ml) was added slowly to a stirred solution of compound Ent-2 (VIII) (237 mg, 0.64 mmol), dimethylglyoxime (30 mg, 0.256 mmol) and CoCI₂.6H₂0 (15 mg, 0.064 mmol) in a mixture of water (10 ml), THF (10 ml), and 1 M NaOH (0.5ml) solution at 10 °C, and the

reaction mixture was stirred at r.t. for 1 h. After color of the reaction medium faded, additional quantity of NaBH₄ (24 mg, 0.64 mmol) and CoCI₂.6H₂0 (15 mg, 0.064 mmol) were added and stirring was continued at r.t. [additional quantities of CoCI₂.6H₂0 and NaBH₄ were added at 12 h intervals till the starting material was consumed, as monitored by LCMS]. After 96 h, the reaction mixture was neutralized with AcOH (pH~7); diluted with water (10 ml) and extracted in EtOAc (3 ^χ 50 ml). The combined organic extract was dried over anhydrous Na₂S0₄ and concentrated to afford crude compound, which was purified by flash column chromatography (Si0₂; 4% methanol in CH₂CI₂) to afford diastereomeric mixture of MIV D-2 (100 mg) as off-white solid.

MIV D-1 : yield: 125 mg (50%); t_R (Chiral HPLC) = 17.8, 14.7 min; ES-MS [M+1]⁺: 373.0, ¹H NMR (400 MHz, DMSO-d₆): δ 12.00 (br s, NH), 8.46 (d, J = 2.0 Hz, 1 H), 7.67 (dd, J = 8.0, 2.4 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.13 (d, J = 8.8Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.27 (d, J = 4.0 Hz, 1 H), 4.88-4.85 (m, 1 H), 4.76-4.74 (m, 1 H), 4.30 (t, J = 6.8 Hz, 2H), 3.30 (m, 1 H), 3.14 (dd, J = 6.8, 6.4 Hz, 2H), 3.08-3.02 (m, 1 H), 1 .34 (d, J = 6.4 Hz, 3H).

MIV D-2: yield: 100 mg (42%); t_R (Chiral HPLC) = 19.4, 16.5 min; ES-MS [M+1]⁺: 373.0; ¹H NMR (400 MHz, DMSO-d₆): δ 12.01 (br s, -NH), (d, J = 2.0 Hz, 1 H), 7.67 (dd, J = 8.0, 2.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.13 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.27 (d, J = 4.0 Hz, 1 H), 4.88-4.85 (m, 1 H), 4.76-4.74 (m, 1 H), 4.30 (dd, J = 6.8, 6.4 Hz, 2H), 3.30 (m, 1 H), 3.14 (dd, J = 6.8, 6.4 Hz, 2H), 3.08-3.02 (m, 1 H), 1.34 (d, J = 6.8 Hz, 3H).

Diastereomeric mixtures D-1 and D-2 of MIV correspond to mixtures (c) and (d) described above, but the specific diastereomers present in each diastereomeric mixture have not been assigned.

Example 7: in vitro ADME and toxicological characterization

Protocol: The assays performed include cytochrome P450 inhibition with the different isoforms, microsomal and hepatocyte stability, neurotoxicity in neural cells and hERG safety assays using a patch clamp electrophysiology measurement (FDA Draft Guidance for Industry. Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labelling Recommendations 2012, The European Medicines Agency (EMA) Guideline on the Investigation of Drug Interactions Adopted in 2012, Schroeder K et al. 2003 J Biomol Screen 8 (1 ); 50-64, Barter ZE et al. 2007

Curr Drug Metab 8 (1 ); 33-45, LeCluyse EL and Alexandre E 2010 Methods Mol Biol 640; 57-82). The results indicate a safe and favourable ADME profile for the compounds of the invention.

Example 8: The brain plasma ratios of Pioglitazone, MIV, Mill and Mil following oral dosing of a single administration of Pioglitazone at 4.5 mg/kg in male C57BL/6 mice.

The brain-plasma ratio was calculated based on levels of Pioglitazone, MIV, Mill and Mllin plasma and brain quantified at C max (maximal concentration) following oral dosing of a single administration of Pioglitazone at 4.5 mg/kg in male C57BL/6 mice. The percentage brain plasma ratio was 9, 13, 7 and 1 %, respectively, for Pioglitazone, Mil and Mill as shown in the Figure 4. Thus, active metabolites Mill and Mil crossed the BBB at much lower extent than Pioglitazone as it was predicted based on the physicochemical properties of the compounds (see Tablel ). In contrast, unexpectedly metabolite MIV crossed the BBB in a higher percentage than the parent compound Piolgitazone

The calculations of the both indexes (ClogP and QPIogBB) for Pioglitazone and its metabolites Mil and Mill are shown in Table 1 . For both indexes the 2 metabolites are lower than for pioglitazone, suggesting for Mil, and Mill a less favored penetration and distribution within CNS.

TABLE 1

PATENT

WO 2018116281

https://patents.google.com/patent/WO2018116281A1/enPioglitazone is a “dirty” drug which is converted to many metabolites in vivo. The metabolic pathway of pioglitazone after oral administration has been studied in several animal species and in humans and the metabolites have been described in the literature (see e.g. Sohda et al, Chem. Pharm. Bull., 1995, 43(12), 2168-2172) and Maeshiba et al, Arzneim.-Forsch/Drug Res, 1997, 47 (I), 29-35). At least six metabolites have been identified, named M-I to M-VI. Amongst these metabolites, M-II, M-III and M-IV show some pharmacological activity but are less active than Pioglitazone in diabetic preclinical models.

[0005] 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4- thiazolidinedione has the following structure:

[0006] Tanis et al. (J. Med. Chem. 39(26 ):5053-5063 (1996)) describe the synthesis of 5-[[4-[2-[5-( 1 -hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione as follows:Scheme 1

[0007] Tanis et al. describe that the intermediate 14 was obtained in a 27% yield by reacting compound 13 in an aqueous 37% formaldehyde at 170°C for 6 hours. In this process, 5-[[4- [2-[5-( 1 -hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione (compound 6 in Scheme 1) was obtained in a 2.47% overall yield.[0008] WO 2015/150476 Al describes the use of 5-[[4-[2-[5-(l-hydroxyethyl)-2- pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione, and its pharmaceutically acceptable salts, in the treatment of central nervous system (CNS) disorders. WO 2015/150476 Al describes that 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4- thiazolidinedione was prepared according to the process of Tanis et al. (supra) where the intermediate corresponding to compound 14 of Tanis et al. was prepared similarly at 160°C for 5 hours providing a 17% yield. The overall yield of 5-[[4-[2-[5-(l-hydroxyethyl)-2- pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione was about 1.5%.[0009] Due to the low yield of the intermediate 2-[5-(l-methoxymethoxy-ethyl)pyridine-2- yl]ethanol, the process step for preparing this intermediate is critical for the overall yield of the product, 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4- thiazolidinedione. In addition, the prior art process to obtain compound 14 is difficult to scale because the reaction is carried out in a pressure vessel at a very high temperature and it is a very dirty reaction.[0010] Accordingly, the processes described in the art afford the product 5-[[4-[2-[5-(l- hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione only in a very low overall yield and, therefore, they are not suitable for large scale synthesis. In addition, the prior art process employs CH₃OCH₂CI, a known carcinogen, for protecting the hydroxyl group in the key intermediate. There is a need for an improved process for synthesizing 5- [[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione, and its pharmaceutically acceptable salts.Formula I illustrated by Scheme 2:Scheme 2 r

deprotectionoptional saltformation

I (HCI salt)[0255] In another embodiment, the disclosure provides a process for preparing the compound of Formula I illustrated by Scheme 3 : Scheme 3C

Br. e

step ‘< step b step c

step step g

[0256] In another embodiment in Scheme 3, step c, the order of mixing of the reagents can be as follows: 1. n-BuLi, 2. ethylene oxide, and 3. Cul. This order of mixing is described in Example 2.[0257] In the step a, 2,5-dibromopyridine (1) is reacted with i-PrMgCl in THF and then further with acetaldehyde to obtain compound 2. The reaction mixture is preferably filtered over Celite^® after the reaction to remove most of the salts. In one embodiment, the addition of acetaldehyde is conducted at a temperature between -15°C and -10°C to control the exothermic reaction. [0258] In the step b, compound 2 is reacted with TBDMS-C1 in the presence of imidazole having DMF as a solvent. The crude product 3 is advantageously purified by a short plug filtration.[0259] In the step c, the hydroxyl protected compound 3 is reacted with ethylene oxide in the presence of n-BuLi and Cu(I)iodide while maintaining the reaction temperature, i.e., the reaction mixture temperature, below -20°C. In one embodiment, the reaction temperature is maintained below -55°C while adding n-BuLi and Cu(I)iodide into the reaction mixture. In another embodiment, the temperature of the reaction mixture is maintained below -55°C while adding n-BuLi, followed by ethylene oxide and then Cu(I)iodide into the reaction mixture. In another embodiment, the temperature of the reaction mixture is maintained below -55°C while adding n-BuLi into the reaction mixture, followed by ethylene oxide. In this embodiment, Cu(I)iodide is added then into the reaction mixture while the reaction mixture temperature is maintained below -20°C, and preferably below -55 °C. The reaction mixture is then allowed to slowly warm to room temperature after the addition of the reagents and stirred at room temperature, e.g., 20-25°C, overnight. This process is described in detail in Example 2. After the reaction, the complexed copper is advantageously removed by washing with 10% ammonia. The crude compound 4 can be purified by column chromatography to give >99% pure product with a yield of about 52%.[0260] The following examples are illustrative, but not limiting, of the methods of the present invention. Suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art in view of this disclosure are within the spirit and scope of the invention.ExamplesCOMPARATIVE EXAMPLE 1Synthesis of 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]- 2,4-thiazolidinedione (9a) according to the process described in WO 2015/150476 Al Scheme 4

8a 9a[0261] (a) Synthesis of l-(6-methyl-pyridin-3-yl)-ethanol (3a)[0262] LiHMDS (1.0 M in tetrahydrofuran, 463 ml, 0.463 mol) was added drop wise to a cooled solution of methyl 6-methylnicotinate (la) (20 g, 0.132 mol) and ethyl acetate (82 g, 0.927 mol) in dimethylformamide at -50°C; gradually raised the temperature to room temperature and stirred at the same temperature. After 1 h, the reaction mixture was cooled to 0°C; slowly diluted with 20% sulphuric acid and heated to reflux. After 4 h, the reaction mixture was cooled to room temperature, and further to 0°C and basified with potassium carbonate. The reaction medium was diluted with water and extracted in ethyl acetate (3×50 mL). Combined organic extract was dried over sodium sulphate and concentrated to afford crude l-(6-methylpyridin-3-yl)ethan-l-one (2a) (20.0 g) which was taken to the next step without any purification. ES-MS [M+l]+: 136.1.Sodium borohydride (2.3 g, 0.06 mol) was added in small portions over 30 min, to a solution of compound 2a (16.4 g, 0.121 mol) in ethanol (160 mL) at 0°C and the reaction mixture was stirred at same temperature. After 1 h, the reaction mixture was diluted with sodium bicarbonate solution (sat) (2×200 mL) and extracted with dichloromethane (2×500 mL). The combined organic extract was dried over anhydrous sodium sulphate and concentrated to afford a pale yellow oil, which was purified by flash column chromatography (5% methanol/dichloromethane) to afford compound 3a (17.0 g; 93% yield over 2 steps) as a pale yellow oil. ES-MS [M+l]⁺: 138.1. 1H NMR (400 MHz, CDC1₃): δ 8.35 (d, J = 2.0 Hz, 1H), 7.63 (dd, J = 8.0, 2.4 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 4.89 (q, J = 6.5 Hz, 1H), 3.30 (br s, 1H), 2.50 (s, 3H), 1.48 (d, J = 6.5 Hz, 3H).[0263] (b) Synthesis of 5-(l-methoxymethoxy-ethyl)-2-methyl-pyridine (4a):Compound 3a (15 g, 0.109 mol) was added, drop wise, to a cooled suspension of sodium hydride (6.56 g, 0.164 mol) in tetrahydrofurane (150 mL) and stirred at 0°C. After 30 min, chloromethyl methyl ether (13.2 g, 0.164 mol) was added drop wise while stirring and keeping the internal temperature around 0°C. After addition is over, the reaction mixture was stirred at the same temperature for 1 h. The reaction was quenched with ice cold water (80 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extract was dried over anhydrous sodium sulphate and concentrated to afford an orange color oil, which was purified by flash column chromatography (1% methanol/dichloromethane) to afford compound 4a (10.0 g; 51% yield) as a pale yellow oil. ES-MS [M+l]⁺: 182.2. 1H NMR (400 MHz, CDC1₃): δ 8.45 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 8.0, 2.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 4.75 (q, J = 6.4 Hz, 1H), 4.57 (ABq, 2H), 3.36 (s, 3H), 2.53 (s, 3H), 1.48 (d, J = 6.6 Hz, 3H).[0264] (c) Synthesis of 2-[5-(l-methoxymethoxy-ethyl)-pyridin-2-yl]-ethanol (5a):A mixture of compound 4a (7.0 g, 0.0386 mol) and 37% formaldehyde solution (5.8 g, 0.077 mol) was heated to 160°C in a sealed glass tube for 5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford a crude compound which was purified by flash column chromatography (1% methanol/dichloromethane) to afford compound 5 (1.2 g; 17% yield) as pale yellow oil. ES-MS [M+l]⁺: 212.1. 1H NMR (400 MHz, CDC1₃): δ 8.42 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.0, 2.4 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 4.72 (q, J = 6.6 Hz, 1H), 4.65 (t, J = 5.6 Hz, 1H), 4.52 (ABq, 2H), 3.73 (m, 2H), 3.24 (s, 3H), 2.86 (t, J = 7.2 Hz, 2H), 1.49 (d, J = 6.4 Hz, 3H).[0265] The total yield for compound 5a from compound la was 8% molar.[0266] (d) Synthesis of 4-{2-[5-(l-methoxymethoxy-ethyl)-pyridin-2-yl]-ethoxy}- benzaldehyde (6a): Methanesulphonylchloride (1.19 g, 0.01 mol) was added, drop wise, to a cooled suspension of compound 5a (1.7 g, 0.008 mol) and triethylamine (1.79 ml, 0.013 mol) in dichloromefhane (20 mL) at 0°C and stirred at same temperature for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic extract was dried over anhydrous sodium sulphate and concentrated to afford 2-(5-(l-(methoxymethoxy)ethyl)pyridin-2-yl)ethyl methanesulfonate (2.04 g; 88% yield) as a yellow oil, which was taken to next step without purification. ES-MS [M+l]⁺: 290.[0267] 2-(5-(l-(methoxymethoxy)ethyl)pyridin-2-yl)ethyl methanesulfonate was added (2.3 g, 0.008 mol) to a stirred suspension of 4-hydroxybenzaldehyde (1.65 g, 0.0137 mol) and potassium carbonate (1.86 g, 0.0137 mol) in mixture of toluene (25 mL) and ethanol (25 mL); stirred at 85°C for 5 h. After consumption of the starting materials, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extract was washed with water; dried over anhydrous sodium sulphate and concentrated to afford a crude dark yellow liquid. The crude was purified by flash column chromatography (1% methanol/dichloromethane) to afford compound 6a (1.5 g; 60% yield) as pale yellow liquid. ES-MS [M+l]⁺: 316.1.[0268] (e) Synthesis of 5-(4-{2-[5-(l-methoxymethoxy-ethyl)-pyridin-2-yl]-ethoxy}- benzylidene)-thiazolidine-2,4-dione (7a):Piperidine (80 mg, 0.95 mmol) was added to a solution of compound 6a (0.6 g, 1.9 mmol) and thiazolidine-2,4-dione (0.22 g, 1.9 mmol) in ethanol (15 mL) and the mixture was heated to reflux overnight. After 15 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford crude mixture, which was purified by flash column chromatography (2% methanol/dichloromethane) to afford compound 7 (500 mg; 64% yield) as a yellow solid. ES-MS [M+l]⁺: 415.1. 1H NMR (400 MHz, DMSO-d₆): δ 12.25 (br s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 8.0, 2.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.8 Hz, 2H), 4.73 (m, 1H), 4.60-4.40 (m, 4H), 4.22 (t, J = 6.2 Hz, 1H), 3.24 (s, 3H), 3.20 (t, J = 6.8 Hz, 2H), 1.41 (d, J = 6.0 Hz, 3H).[0269] (f) Synthesis of 5-(4-{2-[5-(l-hydroxy-ethyl)-pyridin-2-yl]-ethoxy}-benzyl)- thiazolidine-2,4-dione (9a): [0270] A solution of sodium borohydride (115 mg, 3.017 mmol) in 0.2N sodium hydroxide(1.2 mL) was added slowly to a stirred solution of compound 7 (0.5 g, 1.207 mmol), dimethylglyoxime (42 mg, 0.36 mmol) and C0CI₂.6H₂O (23 mg, 0.096 mmol) in a mixture of water (6 mL): tetrahydrofurane (6 mL) and 1M sodium hydroxide (1 mL) solution at 10°C and after addition, the reaction mixture was stirred at room temperature. After 1 h, the reaction color lightened and additional quantities of sodium borohydride (46 mg, 1.207 mmol) and C0CI₂.6H₂O (22 mg, 0.096 mmol) were added and stirring was continued at room temperature. After 12 h, the reaction was neutralized with acetic acid (pH~7); diluted with water (10 mL) and extracted in ethyl acetate (3×50 mL). The combined organic extract was dried over anhydrous sodium sulphate and concentrated to afford crude compound 8a, 5-(4- (2-(5-(l-(methoxymethoxy)ethyl)pyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione, (0.4 g) as pale yellow semi solid, which was taken to next step without purification. ES-MS [M+l]⁺: 417.5.[0271] 2N HC1 (2 mL) was added to a solution of compound 8a (0.4 g, 0.96 mmol) in methanol (20 ml) and the mixture was heated to reflux. After 4 h, the reaction mixture was cooled to room temperature and then concentrated under reduced pressure to afford a residue which was dissolved in water and the solution was neutralized using sodium bicarbonate solution (sat). The resulting white precipitate was collected by filtration to afford compound 9a (250 mg; 56% yield over 2 steps) as an off-white solid. ES-MS [M+l]+: 373.4. 1H NMR (400 MHz, DMSO-de): δ 12.00 (br s, -NH), 8.46 (d, J = 2.0 Hz, 1H), 7.66 (dd, J = 8.0, 2.4 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.25 (d, J = 4.4 Hz, 1H), 4.86 (m, 1H), 4.75 (m, 1H), 4.30 (t, J = 6.8 Hz, 2H), 3.30 (m, 1H), 3.14 (t, J = 6.4 Hz, 2H), 3.04 (m, 1H), 1.34 (d, J = 6.4 Hz, 3H).[0272] The overall yield of compound 9a was 1.5% molar.EXAMPLE 2Synthesis of 2-(5-(l-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)ethan-l-ol[0273] The synthesis of 2-(5-(l-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)ethan-l-ol was conducted according to the Scheme 5 using the reagents and solvents listed in Table 1 below: Scheme 5TBDMS-CI OTBDMS 1 . n-BuLi, <-55°C OTBDMSImidazole

DMF

[0274] The 1H-NMR spectra were recorded with Agilent MercuryPlus 300 NMR spectrometer.[0275] LC-MS data were obtained on an Agilent 1290 series with UV detector and HP 6130MSD mass detector using as column Waters XB ridge BEH XP (2.1 x 50 mm; 2.5 μιτι) and as eluent Ammonium acetate (10 mM); Water/ Methanol/ Acetonitrile.[0276] (a) l-(6-bromopyridin-3-yl)ethan-l-ol (2)[0277] A 20 L vessel was placed under nitrogen atmosphere and charged with tetrahydrofuran (5.5 L) and 2,5-dibromopyridine (1) (2000 g, 8.44 mol, 1.0 eq) (OxChem Corporation). The mixture was cooled to -10°C and isopropyl magnesium chloride (20% in THF, 6.02 L, 11.82 mol, 1.4 eq) (Rockwood Lithium) was added slowly over 1 h, keeping the reaction temperature below 5°C. After addition, the cooling bath was removed and the temperature was kept below 30°C (some additional cooling was needed to achieve this) and the reaction mixture was stirred overnight. After 16 h, a sample was taken; quenched with saturated aqueous ammonium chloride and extracted with methyl tert-buty\ ether (TBME). The TBME was evaporated under vacuum. 1H-NMR in deuterated chloroform showed complete conversion.[0278] The reaction mixture was cooled to -15°C and a solution of acetaldehyde (472 g,10.72 mol, 1.27 eq) (Acros) in tetrahydrofuran (200 mL) was added dropwise, while keeping temperature below -10°C. After the addition was complete, the cooling bath was removed and the temperature was allowed to rise to maximum of 5-8°C. After 1.5 h, a sample was taken and the reaction was quenched with aqueous ammonium chloride as described above. 1H-NMR showed the reaction was complete.[0279] Two batches were combined for work up.[0280] The reaction mixture was quenched by pouring the mixture into a solution of aqueous ammonium chloride (1 kg in 5 L water) and stirred for 15 min, filtered over Celite and rinsed thoroughly with toluene. The filtrate was transferred to a separation funnel and the obtained two layers system was separated. The aqueous layer was extracted with toluene (2 L). The combined organic layers were dried over sodium sulfate and filtered. Evaporation of the filtrate to dryness under vacuum yielded 3.49 kg (99%) of the desired crude material. ^XH NMR (300 MHz, CDC1₃): δ 8.30 (d, J = 2.5 Hz, 1H), 7.59 (dd, J = 8.0, 2.5 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 4,91 (q, J = 6.5 Hz, 1H), 1.49 (d, J = 6.5 Hz, 3H).[0281] (b) 2-bromo-5-(l-((tert-butyldimethylsilyl)oxy)ethyl)pyridine (3)[0282] A 50 L reactor under nitrogen atmosphere was charged with compound 2 (10.0 kg, around 49.5 mol) and DMF (16 L). The mixture was cooled to 10°C and imidazole (6.74 kg, 99 mol, 2.0 eq) (Apollo Scientific Ltd.) was added portion wise within 30 min. The mixture was cooled to 0°C and TBDMS-Cl (7.46 kg, 49.5 mol, 1.0 eq) (Fluorochem) was added portion wise within 5 h, keeping the temperature below 3°C. The mixture reaction temperature was allowed to reach room temperature and stirred overnig ht. H NMR of a sample showed complete conversion.[0283] The reaction mixture was transferred to a 100 L extraction-vessel and the product was extracted with heptane (2×7.5 L, 10 L). The combined heptane-layers were washed with water (2×6 L, 3 L) to remove small amounts of DMF, dried over sodium sulfate and evaporated under vacuum to give crude compound 3 (15.5 kg, 49.0 mol) in a 99.0% yield. This crude product was purified by a short plug filtration, using 10 kg silica/heptane and eluted with heptane (approx. 50 L). The product-fractions were combined and evaporated under vacuum to give 12.0 kg of purified compound 3 (38 mol) as a brown oil in a 76.8% molar yield. (Average yield for 3 experiments was 78%). HPLC-MS: Rt= 2.6 min, M+l=316.1 and 318.1; 1H NMR (300 MHz, CDC1₃): δ 8.55 (d, J = 2.2 Hz, 1H), 7.54 (dd, J = 8.2, 2.2 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 4,86 (q, J = 6.5 Hz, 1H), 1.40 (d, J = 6.5 Hz, 3H), 0.88 (s, 9H), 0.02 (d, J = 26 Hz, 2x3H).[0284] (c) 2-(5-(l-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)ethan-l-ol (4)[0285] The ethylene oxide solution in diethylether was prepared in advance. Diethylether(1.2 L) in a 3 L three-necked flask was cooled at -65 °C and ethylene oxide (462.3 g, 10.5 mol, 1.06 eq) (Linde) was added and stirred at -70°C. Alternatively, the ethylene oxide solution can be made at about -20°C and then added gradually to the reaction mixture having a temperature at about -60°C. [0286] To a solution of 2-bromo-5-(l-((ieri-butyldimethylsilyl)oxy)ethyl)pyridine (3) (3.13 kg, 9.90 mol, 1.0 eq) in diethylether (7.5 L) cooled at -59°C, n-butyllithium (4 L, 10.0 mol, 2.5M in hexanes, 1.01 eq) (Aldrich Chemistry) was added while keeping temperature between -58°C and -62°C. After addition, the mixture was stirred for 1 h while keeping temperature between -60°C and -68°C. The upfront prepared ethylene oxide solution was added at once to the reaction mixture, while temperature was around -62°C. Subsequently, copper(I) iodide (962.3 g, 5.05 mol, 0.51 eq) (Acros Organics) was added in portions of 120 g, every 10 min, keeping the temperature between -61°C and -63°C. Stirring was continued for 1 h after addition keeping temperature between -61°C and -63°C. The cooling bath was removed and allowing the temperature to rise to about 15°C and further to 25 °C with a water bath overnight.[0287] Workup: The reaction-mixture was poured into a solution of 1 kg ammonium- chloride in 5 L water and stirred for 30 min, then the layers were separated. The organic layer was washed with aqueous ammonium hydroxide (10%, 2.5 L, 4x) to remove Cu-complex (blue color disappeared). The combined organic layers were dried over sodium sulfate and evaporated to give 3.12 kg (max. 9.90 mol) crude compound 4 as a brown oil. The crude compound was purified over 20 kg silica (heptane/EtOAc) by eluting with 80 L heptane/EtOAc, 20 L EtOAc, 25 L EtOAc/MeOH 95/5, 25 L EtOAc/MeOH 9/1 and 10 L EtOAc/MeOH 8/2, to give 1.47 kg of purified compound 4 (5.22 mol) as a brown oil (with tendency to solidify) in a 52.7% average molar yield (HPLC-purity of 99.5%). (Average yield over 12 experiments 52%). HPLC-MS: Rt= 2.3 min, M+l=282.1; 1H NMR (300 MHz, CDC1₃): δ 8.42 (d, J = 2.1 Hz, 1H), 7.61 (dd, J = 8.3, 2.1 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 4,88 (q, J = 7.0 Hz, 1H), 4.01 (t, J=6.0 Hz, 2 H), 3.00 (t, J=6.0 Hz, 2 H), 1.41 (d, J =7.0 Hz, 3H), 0.90 (s, 9H), 0.02 (d, J = 26 Hz, 2x3H).[0288] Another 2.5% of the product was isolated by re -purifying impure product fraction.The total yield of compound 4 from compound 1 was 39.6% molar.EXAMPLE 3Synthesis of 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]- 2,4-thiazolidinedione hydrochloride (9) 2. Sodium bisulfiteethanol/water mixture

3. Addition 10% aqueous sodium hydroxide solution

until pH 12

from step e dimethylglyoxime7step g step f

step h[0289] The 1H-NMR spectra were recorded with a 400 MHz Avance Bruker NMR spectrometer. LC-MS data were obtained on a Agilent Technologies 6130 Quadrapole LC/MS using as column Agilent XDB-C18 and as eluent 0.1% formic acid (aq) and 0.05% formic acid in acetonitrile.[0290] Steps d and e: Synthesis of 4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]ethyl]-2- pyridinyl] ethoxy] -benzaldehyde (6)[0291] To a well stirred solution of 5-[[[(l,l-dimethylethyl)dimethylsilyl]-oxy]ethyl]-2- pyridineethanol (4) (obtained as described in Example 2) (1.91 kg) in toluene (8.6 L) at 5°C were added sodium hydroxide (30% aqueous, 2.79 L) and tetrabutylammonium bromide (7.2 g). p-Toluenesulfonyl chloride (1.62 kg) was next added in portions during 5 min. After the addition, the reaction mixture was allowed to reach room temperature in 0.5 h and stirred at this temperature for 18 h. Water (7.3 L) was then added and the mixture was mixed well. Once the solids were dissolved, the layers were allowed to settle and the organic layer was separated. This organic phase was washed with water (5.7 L, 2x), followed by washing with a solution of sodium chloride (57 g) in water (5.7 L). The solvents were concentrated at reduced pressure to an amount of 2.5 kg of a brown oil (compound 5).[0292] To this well stirred brown oil were added subsequently ethanol (7.8 L), water (0.86L), 4-hydroxybenzaldehyde (0.88 kg) and potassium carbonate (1.17 kg) and then the mixture was heated at 75 °C for 18 h. Then, the solvent was evaporated while adding toluene (7.7 L) during 6 h and then the reaction mixture was allowed to cool. At 30°C, water (7.6 L) was added, stirred until all solids were dissolved and the mixture was cooled to room temperature. The layers were allowed to settle and separated. The organic layer was washed with water (7.6 L). The first aqueous extract was extracted with toluene (2.8 L) and this organic extract was used to also extract the aqueous washing. The organic extracts were combined and concentrated under vacuum to give 3.49 kg of a black oil (crude title compound 6).[0293] 1.73 kg of this black oil was dissolved in ethanol (0.74 L) and added to a well stirred solution of sodium bisulfite (1.36 kg) in a mixture of water (3.27 L) and ethanol (0.74 L). The container of the black oil was rinsed with ethanol (0.37 L) twice and these two rinses were also added to the bisulfite reaction mixture. After 75 min, heptane (5.3 L) was added, well mixed for 5 min, and the layers were allowed to settle and separated. To the organic layer was added a solution of sodium bisulfite (0.55 kg) in water (2.65 L), and ethanol (1.06 L). After stirring for 30 min, the layers were allowed to settle and separated. The two bisulfide aqueous extracts were combined and flasks rinsed with water (2.12 L). Next, toluene (4.5 L) and heptane (4.5 L) were added, the mixture was well stirred and the pH was adjusted to 12 using sodium hydroxide (10% aq) (temperature became 32°C). After stirring for an additional 5 min, the layers were allowed to settle and separated at 30°C. The aqueous layer was extracted with a mixture of toluene (1.5 L) and heptane (3.0 L). The layers were separated and the organic layers were combined. The combined organic layers were washed with water (5 L, 2x) and concentrated under vacuum to give the purified title compound 6. This procedure was repeated with another 1.73 kg of the black oil (crude title compound 6) to give in total 2.77 kg of 4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]ethyl]-2- pyridinyl]ethoxy]-benzaldehyde (6) as brown oil which contained 24% m/m of toluene according to ¹H NMR (yield = 80%, calculated from compound 4 and corrected for residual toluene). [0294] 1H NMR (CDC1₃) δ: 0.00 (s, 3H), 0.09 (s, 3H), 0.91 (s, 9H), 1.44 (d, = 6 Hz, 3H),3.30 (t, = 7 Hz, 2H), 4.47 (t, = 7 Hz, 2H), 4.92 (q, = 6 Hz, 1H), 6.99 – 7.30 (m, 3H), 7.62- 7.67 (m, 1H), 7.80 – 7.85 (m, 2H), 8.5- 8.54 (m, 1H) and 9.88 (s, 1H).[0295] LC-MS; rt 7.5 min: ES: M⁺ 387, 386.[0296] Step f: Synthesis of (5Z)-5-[[4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]methylene]-2,4-thiazolidinedione (7)[0297] A solution of 4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]- ethoxy]-benzaldehyde (6) (2.75 kg, containing 24% m/m of toluene) and piperidine (6.0 g) in methanol (3.16 L) was concentrated at 40°C under reduced pressure. The residue was dissolved in methanol (10.4 L) and 2,4-thiazolidinedione (759 g) and piperidine (230 g) were added. The mixture was heated at 47°C. After 25 h, the reaction mixture was allowed to cool to room temperature. The mixture was kept at pH 5-6 by adjusting it with acetic acid, if necessary. After a night at room temperature, water (1.56 L) was added and the suspension was stirred at room temperature for additional 2 h. The solids were isolated by filtration, washed with methanol (1 L, 2x) and dried under vacuum to give crude compound 7 (1.65 kg). The crude compound was mixed with methanol (10 L) and dichloromethane (8.6 L) and heated at 32°C until all solids dissolved. Then, the solvents were removed by distillation until the temperature of the mixture reached 34°C at a pressure of 333 mbar. Then, it was allowed to cool to room temperature overnight and stirred at 2°C for additional 2 h. The solids were isolated by filtration, washed with methanol (0.5 L, 2x) and dried under vacuum to give title compound 7 (1.50 kg) (yield = 61%).[0298] 1H NMR (CDCI₃) δ 0.00 (s, 3H), 0.08 (s, 3H), 0.90 (s, 9H), 1.43 (d, = 6 Hz, 3H),3.32 (t, = 7 Hz, 2H), 4.48 (t, = 7 Hz, 2H), 4.92 (q, = 6 Hz, 1H), 6.95 – 7.00 (m, 2H), 7.24 – 7,28 (m, 1H), 7.38 – 7.42 (m, 2H), 7.67 (s, 1H), 7.69 – 7.73 (m, 1H) and 8.48 (d, = 3 Hz, 1H).[0299] LC-MS; rt 7.5 min: ES: M⁺ 487, 486, 485.[0300] Step g: Synthesis of 5-[[4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]ethyl]-2- pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione (8)[0301] To a stirred suspension of (5Z)-5-[[4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]- ethyl]-2-pyridinyl]ethoxy]phenyl]methylene]-2,4-thiazolidinedione (7) (10 g) in THF (10 mL) and sodium hydroxide (IN aq, 21 mL) was added of a solution of cobalt chloride (26 mg) and of dimethylglyoxime (930 mg) in THF (2.3 mL) and water (1.0 mL). Then the suspension was put under a nitrogen atmosphere by applying the sequence of vacuum and flushing with nitrogen (4x). Thereafter, the suspension was heated to 30°C. Then, a stock solution of sodium borohydride was prepared by dissolving sodium borohydride (2.7 g) in a mixture of water (15.8 mL) and a solution of sodium hydroxide (1 N aq, 3.5 mL), which was put under a nitrogen atmosphere by applying a sequence of vacuum and flushing with nitrogen (3x). This was added to the suspension of compound 7 at a rate of 4.5 mL/h. Simultaneously, nitrogen gas-saturated acetic acid was added to the suspension at a rate of 0.7 mL/h to maintain a pH of 10.0-10.5. After 1 h 30 min the rate of addition of the sodium borohydride solution and acetic acid were both reduced by half. Next, 3 h 45 min after start of addition, the addition of sodium borohydride and acetic acid were stopped. The mixture was allowed to cool down to room temperature and acetone (2.5 mL) was added over a period of 1 minute. After stirring the reaction mixture for 15 min acetic acid was added until the pH was 5.5-6.0 (about 3 mL required). Next, a mixture of ethyl acetate/toluene (1/3 v/v, 30 mL) was added, well mixed and layers were allowed to settle. The aqueous layer was separated and washed with ethyl acetate/toluene (1/3 v/v, 10 mL). Both organic extracts were pooled and water (40 mL) was added, well mixed and layers were allowed to settle. The pH of the aqueous layer was adjusted to 5.5-6 using saturated sodium hydrogen carbonate solution (aq) and again mixed with the organic layer. Layers were allowed to settle and the organic layer was separated and concentrated under vacuum to give 11.09 g of yellow oil (crude mixture containing title compound 8 and its borane complex). Several batches were combined for work up.33.1 g of the crude mixture containing title compound 8 and its borane complex (not corrected for residual solvents) was dissolved in toluene (30 mL) and filtered. The filtrate was submitted to column chromatography (silica gel, gradient of toluene to toluene/ethyl acetate 1/1) to give 30.0 g of mixture of 5-[[4-[2-[5-[[[(l,l- dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]methyl]-2,4- thiazolidinedione (8) and its borane complex as a slightly yellow oil (yield = 100% from compound 4, not corrected for residual solvents). [0303] 1H NMR (CDC1₃) δ: -0.03 – 0.10 (m, 6H), 0.87 – 0.93 (m, 9H), 1.42 (d, / = 6 Hz, 3H),3.05-3.71 (m, 4H), 4.30 – 4.51 (m, 3H), 4.87 – 4.94 (m, 1H), 6.82 – 6.88 (m, 2H), 7.10-7.92 (m, 5H), 8.49 (d, / = 3 Hz, 0.6H) and 8.72 (brs, 0.4H).[0304] LC-MS; rt 6.8 min: ES: M⁺ 489, 488, 487, M^“ 487, 486, 485; rt 8.1 min: ES M^“ 501,500, 499, 498, 485.[0305] Step h: Synthesis of 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]- methyl]-2,4-thiazolidinedione hydrochloride (9)[0306] To a stirred solution of the mixture of (5-[[4-[2-[5-[[[(l,l-dimethylethyl)- dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione and its borane complex (8) (5.17 g) in methanol (25.2 mL) at 22°C was added hydrochloric acid (30%, 2.75 mL) in about 5 min to give a temperature rise to 28°C. This solution was heated to 40 °C. Three hours after addition, the 11 g of volatiles were removed under reduced pressure. Then, acetonitrile (40.3 mL) was added and the mixture was heated at reflux for 0.5 h. Next, the suspension was allowed to cool down to room temperature and stirred for 1 h at room temperature. Solids were isolated by filtration, washed with a mixture of acetonitrile/water (20/1 v/v, 10 mL) and with acetonitrile (10 mL) and dried under vacuum at 40 °C to give 4.00 g of white solids (crude 9) (yield = 77%, not corrected for residual solvents).[0307] Purification of 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4- thiazolidinedione hydrochloride (9):[0308] The crude mixture of 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]- methyl]-2,4-thiazolidinedione hydrochloride (3.95 g, crude 9) was dissolved in methanol/water (7/2 v/v, 80 mL) by heating it to 49°C. To this solution was added washed norit (obtained by heating a suspension of norit (6 g) in methanol/water (7/2 v/v, 90 mL) at 45°C for 1 h, then isolating the norit by filtration and washing it twice with methanol/water (7/2 v/v, 30 mL) and drying it under vacuum at 40°C). Equipment was rinsed with methanol/water (7/2 v/v, 18 mL). After 0.5 h of stirring at 46°C, the warm suspension was filtered to remove the norit and filter was washed twice with methanol/water (7/2 v/v, 18 mL). The filtrate was concentrated under vacuum at a bath temperature of 60°C to a mass of 11.8 g (1 v of compound and 2 v of water). To the suspension was added butanone (19.7 mL, 5 v) and the mixture was heated at a bath temperature of 95°C. Under distillation at a constant volume, butanone (95 mL) was added. Next, heating was stopped and the suspension was allowed to reach room temperature in about 0.5 h. Subsequently it was stirred for 0.75 h at room temperature. The solids were isolated by filtration, washed with a mixture of butanone/water (95/5 v/v, 18 mL) and butanone (18 mL) and dried under vacuum at 40°C to give 3.57 g of compound 9 as white solids (yield = 91%).[0309] 1H NMR (DMSO-de): δ 12.00 (br s, -NH), 8.71 (d, = 2.0 Hz, 1H), 8.45 (dd, = 8.3,1.7 Hz, 1H), 7.98 (d, = 8.3 Hz, 1H), 7.15 (d, = 8.7 Hz, 2H), 6.88 (d, = 8.7 Hz, 2H), 5.57 (s, OH), 4.95 (q, = 6.5 Hz, 1H), 4.86 (dd, = 8.9, 4.4 Hz, 1H), 4.40 (t, = 6.3 Hz, 2H), 3.49 (t, = 6.2 Hz, 2H), 3.29 (dd, = 14.2, 4.4 Hz, 1H), 3.06 (dd, = 14.2, 9.0 Hz, 1H), 1.41 (d, = 6.5 Hz, 3H).[0310] LC-MS; rt 3.5 min: ES: M⁺ 374, 373, M^“ 372, 371.EXAMPLE 4Conditions tested in the preparation of compound 5 in the Step d[0311] The conditions described in Table 2 below were tested in the step d in the preparation of compound 5 from compound 4 providing a good yield of compound 5:Table 2Entry Reaction Conditions Amount of p-Ts-Cl / Eq1 Toluene/water/Bu₄NBr/NaOH 1.052 1.083 1.074 1.07+0.035 1.076 Et₃N / DCM 1.187 1.408 Pyridine / DCM 1.40 EXAMPLE 5Conditions tested in the preparation of compound 6 in the Step e[0312] The conditions described in Table 3 below were tested in the step e in the preparation of compound 6 from compound 5 providing a good yield of compound 6:Table 3

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021220250&tab=PCTDESCRIPTION&_cid=P12-KVRUVM-14535-1

Compound 1 is administered to the subject. The structure of 5-[[4-[2-[5-(l -hydroxy ethyljpyri din-2 – yl]ethoxy]phenyl]methyl]-l,3-thiazolidine-2,4-dione is:

[0047] The present disclosure encompasses the use of stereoisomers of 5-[[4-[2-[5-(l- hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-l,3-thiazolidine-2,4-dione. 5-[[4-[2-[5- (l-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-l,3-thiazolidine-2,4-dione has two asymmetric centers and thus four stereoisomers are possible as follows:

//////////LERIGLITAZONE, MIN 102 , лериглитазон , ليريغليتازون , 乐立格列酮 , Hydroxy Pioglitazone, M-IV, PHASE 2

CC(C1=CN=C(C=C1)CCOC2=CC=C(C=C2)CC3C(=O)NC(=O)S3)O

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DOCUSATE

1,4-Bis(2-ethylhexyl) sulfosuccinate

Molecular FormulaC₂₀H₃₈O₇S
Average mass422.577 Da

1,4-Bis[(2-ethylhexyl)oxy]-1,4-dioxobutane-2-sulfonic acid
10041-19-7[RN]
233-124-0[EINECS]

Docusate Sodium

Dioctyl sodium sulfosuccinate

Molecular FormulaC₂₀H₃₇NaO₇S
Average mass444.558 Da
216-684-0 [EINECS]
577-11-7 [RN]

sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate
CAS Registry Number: 577-11-7
CAS Name: Sulfobutanedioic acid 1,4-bis(2-ethylhexyl) ester sodium salt
Additional Names: sulfosuccinic acid 1,4-bis(2-ethylhexyl) ester S-sodium salt; bis(2-ethylhexyl)sodium sulfosuccinate; dioctyl sodium sulfosuccinate; sodium dioctyl sulfosuccinate; DSS
Trademarks: Aerosol OT (Cyanamid); Colace (Roberts); Comfolax (Searle); Coprola (Dunster); Dioctylal (Continental Pharma); Dioctyl (Medo); Diotilan (Chinoin); Disonate (Lannett); Doxinate (Hoechst); Doxol (Blair); Dulcivac (Harvey); Jamylène (Thaplix); Molatoc; Molcer (Wallace); Nevax; Regutol (Schering-Plough); Soliwax (Concept Pharm.); Velmol (Berlex); Waxsol (Norgine); Yal (Ritter)
Molecular Formula: C20H37NaO7S
Molecular Weight: 444.56
Percent Composition: C 54.03%, H 8.39%, Na 5.17%, O 25.19%, S 7.21%
Literature References: Prepn: Jaeger, US2028091; US2176423 (1936, 1939, both to Am. Cyanamid). Structure and wetting power: Caryl, Ind. Eng. Chem.33, 731 (1941). Comprehensive description: S. Ahuja, J. Cohen, Anal. Profiles Drug Subs.2, 199-219 (1973); 12, 713-720 (1983). For structure see Docusate calcium.
Properties: Available as wax-like solid, usually in rolls of tissue-thin material; also as 50-75% solns in various solvents. Soly in water (g/l): 15 (25°), 23 (40°), 30 (50°), 55 (70°). Sol in CCl4, petr ether, naphtha, xylene, dibutyl phthalate, liq petrolatum, acetone, alcohol, vegetable oils. Very sol in water + alcohol, water + water-miscible organic solvents. Stable in acid and neutral solns; hydrolyzes in alkaline solns.
Derivative Type: Docusate potassium
CAS Registry Number: 7491-09-0
Trademarks: Rectalad (Carter-Wallace)
Molecular Formula: C20H37KO7S
Molecular Weight: 460.67
Percent Composition: C 52.14%, H 8.10%, K 8.49%, O 24.31%, S 6.96%
NOTE: Ingredient of the laxative Peri-Colace (Roberts) which also contains casanthranol.Use: Sodium salt as pharmaceutic aid (surfactant); as wetting agent in industrial, pharmaceutical, cosmetic and food applications; dispersing and solubilizing agent in foods; adjuvant in tablet formation.
Therap-Cat: Stool softener.
Therap-Cat-Vet: Stool softener.
Keywords: Laxative/Cathartic.

Docusate Calcium
CAS Registry Number: 128-49-4
CAS Name: Sulfobutanedioic acid 1,4-bis(2-ethylhexyl)ester calcium salt
Additional Names: bis[2-ethylhexyl]calcium sulfosuccinate; calcium dioctyl sulfosuccinate; dioctyl calcium sulfosuccinate
Trademarks: Surfak (HMR)
Molecular Formula: C40H74CaO14S2
Molecular Weight: 883.22
Percent Composition: C 54.40%, H 8.44%, Ca 4.54%, O 25.36%, S 7.26%
Literature References: Prepd from dioctyl sodium sulfosuccinate dissolved in isopropanol and from calcium chloride dissolved in methanol: Klotz, US3035973 (1962 to Lloyd Brothers).
Properties: White precipitate. Sol in mineral and vegetable oils, liq polyethylene glycol. Practically insol in glycerol. Claimed to have greater surface-active wetting properties than the sodium salt.
NOTE: Ingredient of Doxidan (HMR) which also contains phenolphthalein.
Therap-Cat: Stool softener.
Keywords: Laxative/Cathartic.

Derivatives

free acid

Formula:C₂₀H₃₈O₇S
MW:422.58 g/mol
CAS-RN:10041-19-7
EINECS:233-124-0

calcium salt

Formula:C₄₀H₇₄CaO₁₄S₂
MW:883.23 g/mol
CAS-RN:128-49-4
EINECS:204-889-8

potassium salt

Formula:C₂₀H₃₇KO₇S
MW:460.67 g/mol
CAS-RN:7491-09-0
EINECS:231-308-5

SYN

CAS-RN	Formula	Chemical Name	CAS Index Name
141-02-6	C₂₀H₃₆O₄	bis(2-ethylhexyl) fumarate	2-Butenedioic acid (E)-, bis(2-ethylhexyl) ester
C₄H₄O₄	(E)-2-butenedioic acid
104-76-7	C₈H₁₈O	2-ethyl-1-hexanol	1-Hexanol, 2-ethyl-

SYN

https://scialert.net/fulltext/?doi=jas.2011.1396.1400

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SYN

Docusate is the common chemical and pharmaceutical name of the anionbis(2-ethylhexyl) sulfosuccinate, also commonly called dioctyl sulfosuccinate (DOSS).^[2]^[3]^[4]

Salts of this anion, especially docusate sodium, are widely used in medicine as laxatives and as stool softeners, by mouth or rectally.^[1] It is on the World Health Organization’s List of Essential Medicines.^[5]^[6] Some studies claim that docusate is not more effective than a placebo for improving constipation.^[7]^[8]^[9]^[10] Other docusate salts with medical use include those of calcium and potassium.^[11]^[1]^[2]

Docusate salts are also used as food additives, emulsifiers, dispersants, and wetting agents, among other uses.^[12]

History

Sodium docusate was patented in 1937 by Coleman R. Caryl and Alphons O. Jaeger for American Cyanamid,^[3] which commercialized it for many years as a detergent under the brand name Aerosol OT.

Its use for the treatment of constipation was first proposed in 1955 by James L. Wilson and David G. Dickinson,^[4] and quicky popularized under the name Doxinate.^[13]

Medical use

Constipation

The main medical use of docusate sodium is to treat constipation, acting as a laxative and stool softener. In painful anorectal conditions such as hemorrhoid and anal fissures, it can help avoid pain caused by straining during bowel movements.

When administered by mouth, a bowel movement often occurs in 1 to 3 days,^[1] while rectal use may be effective within 20 minutes.^[14]

Sodium docusate is recommended as a stool softener for children.^[1]

However, its effectiveness for constipation is poorly supported by evidence.^[7]^[8] Multiple studies have found docusate to be no more effective than a placebo for improving constipation.^[7]^[8]^[9]^[10] Others have found it to be less useful for the treatment of chronic constipation than psyllium.^[10]^[15]^[16]

The medication may be given to people who are receiving opioid medication, although prolonged use may cause irritation of the gastrointestinal tract.^[10]^[16]

Other medical uses

Docusate sodium, when used with ear syringing, may help with earwax removal, particularly in the case of impaction.^[17]

Sodium docusate is also used as a lubricant in the production of tablets and as an emulsifier in topical preparations and other suspensions.^[18]

Precautions and contraindications

Docusate sodium is approved and recommended as safe during pregnancy and breastfeeding.^[19]^[20]

Docusate is not recommended in people with appendicitis, acute abdomen, or ileus.^[16]

When taken by mouth it should be ingested with plenty of water.

Side effects

Side effects are uncommon and typically mild,^[1] and may include stomach pain, abdominal cramps or diarrhea,^[1] Efficacy decreases with long-term use, and may cause poor bowel function.^[11]

Serious allergic reactions may occur with the drug. The most severe side effect of docusate, although very rare, is rectal bleeding.^[21]

Interactions

Docusate might increase resorption of other drugs, for example, dantron (1,8-dihydroxyanthraquinone).^[16]

Mechanism of action

Docusate sodium works by allowing more water to be absorbed by the stool.^[11]^[22]

Docusate does not stay in the gastrointestinal tract, but is absorbed into the bloodstream and excreted via the gallbladder^[16] after undergoing extensive metabolism.

The effect of docusate may not necessarily be all due to its surfactant properties. Perfusion studies suggest that docusate inhibits fluid absorption or stimulates secretion in the portion of the small intestine known as the jejunum.

Pharmaceutical brand names

In the U.S., docusate sodium for pharmaceutical use is available under multiple brand names: Aqualax, Calube, Colace, Colace Micro-Enema, Correctol Softgel Extra Gentle, DC-240, Dialose, Diocto, Dioctocal, Dioctosoftez, Dioctyn, Dionex, Doc-Q-Lace, Docu Soft, Docucal, Doculax, Docusoft S, DOK, DOS, Doss-Relief, DSS, Dulcolax – Stool Softener (not to be confused with another drug marketed under the Dulcolax brand, bisacodyl, which is a stimulant laxative), Ex-Lax Stool Softener, Fleet Sof-Lax, Genasoft, Kasof, Laxa-basic, Modane Soft, Octycine-100, Pedia-Lax, Preferred Plus Pharmacy Stool Softener, Regulax SS, Sulfalax Calcium, Sur-Q-Lax, Surfak Stool Softener, and Therevac-SB. Generic preparations are also available.

In the UK, dioctyl sodium sulfosuccinate is sold under the brand name Docusol (Typharm Ltd) and DulcoEase (Boehringer Ingelheim).

In Australia, dioctyl sodium sulfosuccinate is sold as Coloxyl and Coloxyl with senna.

In India, preparations include Laxatin by Alembic, Doslax by Raptakos Laboratories, Cellubril by AstraZeneca, and Laxicon by Stadmed.

Other uses

Dioctyl sodium sulfosuccinate is used as a surfactant in a wide range of applications, often under the name Aerosol-OT.^[4]^[23] It is unusual in that it is able to form microemulsions without the use of co-surfactants, and it has a rich variety of aqueous-phase behavior including multiple liquid crystalline phases.^[24]

Food additive

Dioctyl sodium sulfosuccinate has been approved by the US FDA as a “generally recognized as safe” (GRAS) additive.^[25] It is used in a variety of food products, as a surface active agent, stabilizer, thickener, wetting agent, processing aid, solubilizing agent, emulsifier, and dispersant. The highest amount found in food products is 0.5% by weight, which include pasteurized cheese spreads, cream cheeses and salad dressings.^[26] The FDA also approved its use as a wetting agent or solubilizer for flavoring agents in carbonated and non-carbonated drinks at levels up to 10 parts per million.^[25]

Microencapsulation

Sodium docusate is the most widely used surfactant in reverse micelle encapsulation studies.^[27]

Non-medical brand names

As a surfactant, docusate sodium is or has been commercialized under many brand names, including DSSj Aerosol OT, Alphasol OT, Colace, Complemix, Coprol, Dioctylal, Dioctyl-Medo Forte, Diotilan, Diovac, Disonate, Doxinate, Doxol, Dulsivac, Molatoc, Molofac, Nevax, Norval, Regutol, Softili, Solusol, Sulfimel DOS, Vatsol OT, Velmol, and Waxsol^[28]

Chemistry

Structure and properties

The structural formula of the docusate anion is R−O−C(=O)−CH(SO−
3)−CH
2−C(=O)−O−R, where R is the 2-ethylhexyl groupH
3C−(CH
2)
3−C(−CH
2−CH
3)H−CH
2−. The conjugate acid can be described as the twofold carboxylate ester of sulfosuccinic acid with 2-ethylhexanol.

The compound is a white, wax-like, plastic solid, with an odor suggestive of octyl alcohol. It starts to decompose at about 220 °C.^[28]

Solubility of dioctyl sodium sulfosuccinate in water is 14 g/L at 25 °C, increasing to 55 g/L at 70 °C.^[28] Solubility is better in less polar solvents: 1:30 in ethanol, 1:1 in chloroform and diethylether, and practically unlimited in petroleum ether (25 °C). It also is highly soluble in glycerol, although this is a rather polar solvent. It is also highly soluble in xylene, oleic acid, acetone, diacetone alcohol, methanol, isopropanol, 2-butanol, methyl acetate, ethyl acetate, furfurol, and vegetable oils.^[28]

The ester groups are easily cleaved under basic conditions, but are stable against acids.^[16]

Synthesis

Sodium dioctyl sulfosuccinate can be obtained by treating dioctyl maleate with sodium bisulfite. The bisulfite anion adds to the double bond:−CH=CH− + HSO−
3 → −CH(−SO−
3)−CH
2−

Toxicity

Ingestion may cause the side effects described above, such as diarrhea, intestinal bloating, and occasionally cramping pains. Dioctyl sodium sulfosuccinate is not known to be carcinogenic, mutagenic, or teratogenic.^[29]

Marine species

Dioctyl sodium sulfosuccinate is of low toxicity for crustaceans such as the hermit crabClibanarius erythropus and the shrimp Crangon crangon. Toxicity for molluscs varies widely, with 48-hour LD₅₀ found between 5 mg/l for the common limpet and 100 mg/l for the common periwinkle. Various species of phytoplankton have an LD₅₀ around 8 mg/l.

In a 2010 study, dioctyl sodium sulfosuccinate exhibited higher toxicity against bacteria (Vibrio fischeri, Anabaena sp.) and algae (Pseudokirchneriella subcapitata) than did a number of fluorinated surfactants (PFOS, PFOA, or PFBS). Measuring bioluminescence inhibition of the bacteria and growth inhibition of the algae, the LD₅₀ were in the range of 43–75 mg/l. Combinations of the fluorinated compounds with dioctyl sodium sulfosuccinate showed mid to highly synergistic effects in most settings, meaning that such combinations are significantly more toxic than the individual substances.^[30]

Freshwater species

The substance is highly toxic for rainbow trout with a median lethal concentration (LC₅₀) of 0.56 mg/l after 48 hours for the pure substance. It is only slightly to moderately toxic for rainbow trout fingerlings, and slightly toxic for harlequin rasboras (LC₅₀ 27 mg/l of a 60% formulation after 48 hours).

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References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “Docusate Salts”. The American Society of Health-System Pharmacists. Archived from the original on 23 September 2015. Retrieved 11 August 2015.
^ Jump up to:^a ^b American Society of Health-System Pharmacists (15 August 2011). “Stool Softeners”. Archived from the original on 5 September 2015.
^ Jump up to:^a ^b US 2181087, Caryl CR, Jaeger AO, “Detergent composition”, issued 21 November 1939, assigned to American Cyanamid
^ Jump up to:^a ^b ^c Wilson JL, Dickinson DG (May 1955). “Use of dioctyl sodium sulfosuccinate (aerosol O.T.) for severe constipation”. Journal of the American Medical Association. 158 (4): 261–3. doi:10.1001/jama.1955.02960040019006a. PMID 14367076.
^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06.
^ “Docusate – Drug Usage Statistics”. ClinCalc. Retrieved 18 February 2021.
^ Jump up to:^a ^b ^c Fakheri RJ, Volpicelli FM (February 2019). “Things We Do for No Reason: Prescribing Docusate for Constipation in Hospitalized Adults”. Journal of Hospital Medicine. 14 (2): 110–113. doi:10.12788/jhm.3124. PMID 30785419.
^ Jump up to:^a ^b ^c “Dioctyl Sulfosuccinate or Docusate (Calcium or Sodium) for the Prevention or Management of Constipation: A Review of the Clinical Effectiveness”. CADTH Rapid Response Reports. 26 June 2014. PMID 25520993.
^ Jump up to:^a ^b Candy B, Jones L, Larkin PJ, Vickerstaff V, Tookman A, Stone P (May 2015). “Laxatives for the management of constipation in people receiving palliative care” (PDF). The Cochrane Database of Systematic Reviews. 13 (5): CD003448. doi:10.1002/14651858.CD003448.pub4. PMC 6956627. PMID 25967924.
^ Jump up to:^a ^b ^c ^d Ramkumar D, Rao SS (April 2005). “Efficacy and safety of traditional medical therapies for chronic constipation: systematic review”. The American Journal of Gastroenterology. 100 (4): 936–71. PMID 15784043.
^ Jump up to:^a ^b ^c 2013 Nurse’s Drug Handbook. Burlington, MA: Jones & Bartlett Learning. 2013. p. 366. ISBN 9781449642846.
^ Ash M, Ash I (2004). Handbook of preservatives. Endicott, N.Y.: Synapse information resources. p. 375. ISBN 9781890595661.
^ Friedman M (October 1956). “Dioctyl sodium sulfosuccinate (doxinate) in chronic functional constipation”. American Practitioner and Digest of Treatment. 7 (10): 1588–91. PMID 13362832.
^ “Docusate sodium”. 18 December 2004. Archived from the original on 21 July 2011. Retrieved 6 March 2019.
^ Portalatin M, Winstead N (March 2012). “Medical management of constipation”. Clinics in Colon and Rectal Surgery. 25 (1): 12–9. doi:10.1055/s-0032-1301754. PMC 3348737. PMID 23449608.
^ Jump up to:^a ^b ^c ^d ^e ^f Dinnendahl V, Fricke U, eds. (2010). Arzneistoff-Profile(in German). 2 (23 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
^ “How effective is docusate as a cerumenolytic agent?”. GlobalRPH.com. Archived from the original on 23 November 2010.
^ Jasek W, ed. (2008). Austria-Codex Stoffliste (in German) (41 ed.). Vienna: Österreichischer Apothekerverlag. p. 316. ISBN 978-3-85200-190-6.
^ Yaffe SJ (2011). Drugs in pregnancy and lactation : a reference guide to fetal and neonatal risk (9 ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 1651. ISBN 9781608317080.
^ Mahadevan U, Kane S (July 2006). “American gastroenterological association institute medical position statement on the use of gastrointestinal medications in pregnancy”. Gastroenterology. 131(1): 278–82. doi:10.1053/j.gastro.2006.04.048. PMID 16831610.
^ drugs.com: Docusate Archived 16 July 2010 at the Wayback Machine
^ Hamilton RJ (2013). Tarascon pocket pharmacopoeia : 2013 classic shirt-pocket edition (27 ed.). Burlington, Ma.: Jones & Bartlett Learning. p. 112. ISBN 9781449665869.
^ Whiffen AJ (1946). “Aerosol OT in the preparation of microscopic mounts of fungi”. Mycologia. 38: 346. doi:10.1080/00275514.1946.12024063. PMID 20983186.
^ Nave S, Eastoe J, Penfold J (November 2000). “What Is So Special about Aerosol-OT? 1. Aqueous Systems”. Langmuir. 16(23): 8733–8740. doi:10.1021/la000341q.
^ Jump up to:^a ^b “GRAS Notice Inventory Agency Response Letter GRAS Notice No. GRN 000006”. Center for Food Safety and Applied Nutrition. 20 July 1998. Archived from the original on 31 October 2017. Retrieved 24 January 2020.
^ “CFR – Code of Federal Regulations Title 21”. http://www.accessdata.fda.gov. Retrieved 29 January 2020.
^ Flynn PF (2004). “Multidimensional multinuclear solution NMR studies of encapsulated macromolecules”. Prog. Nucl. Magn. Reson. Spectrosc. 45 (1–2): 31–51. doi:10.1016/j.pnmrs.2004.04.003.
^ Jump up to:^a ^b ^c ^d Ahuja S, Cohen J (January 1973). “Dioctyl Sodium Sulfosuccinate”. InAnalytical Profiles of Drug Substances. Analytical Profiles of Drug Substances. 2. Academic Press. pp. 199–219. doi:10.1016/S0099-5428(08)60040-4. ISBN 9780122608025.
^ ScienceLab.com: Docusate sodium Material Safety Data Sheet Archived 2006-10-17 at the Wayback Machine
^ Rosal R, Rodea-Palomares I, Boltes K, Fernández-Piñas F, Leganés F, Petre A (September 2010). “Ecotoxicological assessment of surfactants in the aquatic environment: combined toxicity of docusate sodium with chlorinated pollutants”. Chemosphere. 81 (2): 288–93. Bibcode:2010Chmsp..81..288R. doi:10.1016/j.chemosphere.2010.05.050. PMID 20579683.

External links

“Docusate”. Drug Information Portal. U.S. National Library of Medicine.
“Docusate sodium”. Drug Information Portal. U.S. National Library of Medicine.
Stool Softeners at the N.I.H.PubMed Health resource.

Clinical data
Docusate sodium
Trade names	Colace, Ex-Lax Stool Softener, others
Other names	Dioctyl sulfosuccinate
AHFS/Drugs.com	Monograph
MedlinePlus	a601113
License data	USDailyMed: Docusate
Pregnancy category	AU: A
Routes of administration	By mouth, rectal
Drug class	Stool softener
ATC code	A06AA02 (WHO)
Legal status
Legal status	UK:General sales list (GSL, OTC)US:OTCIn general: Over-the-counter (OTC)
Pharmacokinetic data
Onset of action	12 hrs to 5 days^[1]
Duration of action	3 days^[1]
Identifiers
show IUPAC name
CAS Number	10041-19-7as salt: 577-11-7
PubChemCID	11339as salt: 23673837
DrugBank	DB11089as salt: DBSALT001500
ChemSpider	10862as salt: 10861
UNII	M7P27195AGas salt: F05Q2T2JA0
KEGG	as salt: D00305
ChEBI	CHEBI:534as salt: CHEBI:4674
ChEMBL	ChEMBL1477036as salt: ChEMBL1905872
E number	E480 (thickeners, …)
CompTox Dashboard (EPA)	DTXSID8022959
ECHA InfoCard	100.008.553
Chemical and physical data
Formula	C₂₀H₃₇O₇S
Molar mass	421.57 g·mol⁻¹
3D model (JSmol)	Interactive imageas salt: Interactive image
Density	1.1 g/cm³
Melting point	153 to 157 °C (307 to 315 °F) 173-179 °C
Solubility in water	1 in 70 parts mg/mL (20 °C)
show SMILES
show InChI

//////////DOCUSATE, Stool softener, Laxative, Cathartic,

CCCC(CC)COC(=O)CC(C(=O)OCC(CC)CCCC)S(=O)(=O)[O-].[Na+]

NEW DRUG APPROVALS

one time

$10.00

LIDOCAINE

October 26, 2021 9:16 am / Leave a comment

LIDOCAINE

CAS Registry Number: 137-58-6
CAS Name: 2-(Diethylamino)-N-(2,6-dimethylphenyl)acetamide
Additional Names: 2-diethylamino-2¢,6¢-acetoxylidide; w-diethylamino-2,6-dimethylacetanilide; lignocaine
Trademarks: Cuivasil (IDC); Lidoderm (Hind); LidoPosterine (Kade); Vagisil (Combe)
Molecular Formula: C14H22N2O
Molecular Weight: 234.34
Percent Composition: C 71.75%, H 9.46%, N 11.95%, O 6.83%
Literature References: Long-acting, membrane stabilizing agent against ventricular arrhythmia. Originally developed as a local anesthetic. Prepn: N. M. Löfgren, B. J. Lundqvist, US2441498 (1948 to Astra); A. D. H. Self, A. P. T. Easson, GB706409 (1954 to May & Baker); I. P. S. Hardie, E. S. Stern, GB758224 (1956 to J. F. Macfarlane & Co.); Zhuravlev, Nikolaev, Zh. Obshch. Khim.30, 1155 (1960). Toxicity studies: E. R. Smith, B. R. Duce, J. Pharmacol. Exp. Ther.179, 580 (1971); G. H. Kronberg et al.,J. Med. Chem.16, 739 (1973). Review of pharmacokinetics: N. L. Benowitz, W. Meister, Clin. Pharmacokinet.3, 177 (1978). Review of action as local anesthetic: Löfgren, Studies on Local Anesthetics: Xylocaine, A New Synthetic Drug (Hoeggstroms, Stockholm, 1948); Cooper, Pharm. J.171, 68 (1953). Reviews of anti-arrhythmic agents: J. L. Anderson et al.,Drugs15, 271 (1978); L. H. Opie, Lancet1, 861 (1980); E. Carmeliet, Ann. N.Y. Acad. Sci.427, 1 (1984). Comprehensive description: K. Groningsson et al.,Anal. Profiles Drug Subs.14, 207-243 (1985); M. F. Powell, ibid.15, 761-779 (1986). Review of use in treatment of postherpetic neuralgia: P. S. Davies, B. S. Galer, Drugs64, 937-947 (2004).Properties: Needles from benzene or alcohol, mp 68-69°. bp4 180-182°; bp2 159-160°. Insol in water. Sol in alcohol, ether, benzene, chloroform, oils. Partition coefficient (octanol/water, pH 7.4): 43.
Melting point: mp 68-69°
Boiling point: bp4 180-182°; bp2 159-160°
Log P: Partition coefficient (octanol/water, pH 7.4): 43
Derivative Type: Hydrochloride
CAS Registry Number: 73-78-9; 6108-05-0 (monohydrate)
Trademarks: Basicaina (Galenica); Batixim (So.Se.); Dynexan (Kreussler); Heweneural (Hevert); Licain (DeltaSelect); Lidesthesin (Ritsert); Lidofast (Angelini); Lidoject (Hexal); Lidrian (Baxter); Odontalg (Giovanardi); Sedagul (Wild); Xylocaine (AstraZeneca); Xylocard (AstraZeneca); Xylocitin (Jenapharm); Xyloneural (Strathmann)
Molecular Formula: C14H22N2O.HCl
Molecular Weight: 270.80
Percent Composition: C 62.09%, H 8.56%, N 10.34%, O 5.91%, Cl 13.09%
Properties: Crystals, mp 127-129°; monohydrate, mp 77-78°. Very sol in water, alcohol; sol in chloroform. Insol in ether. pH of 0.5% aq soln: 4.0-5.5. LD50 in mice (mg/kg): 292 orally (Smith, Duce); 105 i.p.; 19.5 i.v. (Kronberg).
Melting point: mp 127-129°; mp 77-78°
Toxicity data: LD50 in mice (mg/kg): 292 orally (Smith, Duce); 105 i.p.; 19.5 i.v. (Kronberg)
Therap-Cat: Anesthetic (local); antiarrhythmic (class IB).
Therap-Cat-Vet: Anesthetic (local).
Keywords: Anesthetic (Local); Antiarrhythmic.

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CLIP

Click to access Lidocaine.pdf

https://pubs.acs.org/doi/10.1021/ed076p1557

http://www.asianjournalofchemistry.co.in/User/ViewFreeArticle.aspx?ArticleID=19_7_12

PATENT

https://patents.google.com/patent/CN102070483B/en#:~:text=The%20method%20comprises%20the%20following,as%20solvent%20and%20carbonate%20isPreparation method of the present invention, it can be two-step approach, comprises the steps:1) 2,6-xylidine is dissolved in the acetone, adds carbonate then, the back that stirs drips chloroacetyl chloride, and 20～35 ℃ (room temperature) be stirring reaction 3h down; After-filtration is finished in reaction, and after filter cake was washed with water to filtrate and is neutrality, drying made intermediate chloracetyl-2, the 6-xylidine, and yield is about about 94%;
2) intermediate that step 1) is made is dissolved in the acetone, adds carbonate then, and the back that stirs drips diethylamine, back flow reaction 8h; After-filtration is finished in reaction, and filtrate is recrystallization, drying after removing solvent under reduced pressure, makes lignocaine.Wherein, in the step 1) 2, the mol ratio of 6-xylidine, chloroacetyl chloride and carbonate is 1: 1.2～1.7: 1.3～2.0, is preferably 1: 1.5: 1.6.
Step 2) intermediate chloracetyl-2 in, the mol ratio of 6-xylidine, diethylamine and carbonate is 1: 1.5～2.5: 1.2～2.0, is preferably 1: 2: 1.5.In addition, preparation method of the present invention owing to all be that solvent, carbonate are catalyzer with acetone in the two-step reaction, therefore can further optimize reaction process on the basis of two-step approach, namely the intermediate of Sheng Chenging needn’t pass through aftertreatment, prepares lignocaine by one kettle way.Described one kettle way comprises the steps: 2,6-xylidine is dissolved in the acetone, adds carbonate then, after stirring, drips chloroacetyl chloride, and 20～35 ℃ (room temperature) be reaction 3h down; After reaction is finished, without processing, directly drip diethylamine, back flow reaction 8h, after-filtration is finished in reaction, and filtrate is recrystallization, drying after removing solvent under reduced pressure, makes lignocaine.Wherein, described 2, the mol ratio of 6-xylidine, chloroacetyl chloride, diethylamine and carbonate is 1: 1.2～1.7: 1.5～2.5: 2.5～3.5, is preferably 1: 1.5: 2: 2.5.
In addition, preparation method of the present invention adopts TLC monitoring reaction progress, and the developping agent of TLC is sherwood oil: ethyl acetate (V/V)=3: 1.The invention has the advantages that, the method synthesis technique for preparing lignocaine of the present invention is simple, do not need in the intermediate aftertreatment first pickling numerous and diverse step of alkali cleaning again, avoided unnecessary loss, therefore the yield of the intermediate that makes of the inventive method and lignocaine is all higher, and the lignocaine purity that makes is good, reaches more than 99%, has favorable industrial application prospect; In addition, the inventive method uses acetone to make solvent, and this solvent is nontoxic substantially non-stimulated, and can recycle, and is environmentally friendly.
EmbodimentBelow further specify the present invention by specific embodiment, but be not used for limiting the scope of the invention.
Embodiment 1 two-step approach prepares lignocaine1) intermediate chloracetyl-2, the preparation of 6-xylidineAdd 102g 2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, adds 200g salt of wormwood again, and mechanical stirring evenly back drips 100mL chloroacetyl chloride (1.5h drips off), (20 ℃) stirring reaction 3h under the room temperature; Reaction finishes the back suction filtration, and filter cake is washed with water to filtrate and is neutral, and under 100 ℃ of temperature dry 1 hour then, make the 156g white powder, be intermediate chloracetyl-2,6-xylidine, yield are 94%, fusing point is 145.0～147.0 ℃.2) preparation of lignocaineAdd 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, and the dissolving back adds 112g salt of wormwood, drips the 60g diethylamine fast, back flow reaction 8h; Reaction finishes the back suction filtration, and filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, uses 150mL sherwood oil recrystallization then, suction filtration, vacuum-drying 6h under 40 ℃ of temperature makes the 90g white powder, is lignocaine, yield is 95%, and fusing point is 67.0～68.0 ℃, and content is 99.05%.
Embodiment 2 two-step approachs prepare lignocaine1) intermediate chloracetyl-2, the preparation of 6-xylidineAdd 102g 2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, adds 163g salt of wormwood again, and mechanical stirring evenly back drips 80mL chloroacetyl chloride (1.5h drips off), (20 ℃) stirring reaction 3h under the room temperature; Reaction finishes the back suction filtration, and filter cake is washed with water to filtrate and is neutral, and under 100 ℃ of temperature dry 1 hour then, make the 136g white powder, be intermediate chloracetyl-2,6-xylidine, yield are 82%, fusing point is 145～146 ℃.
2) preparation of lignocaineAdd 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, and the dissolving back adds 90g salt of wormwood, drips the 45g diethylamine fast, back flow reaction 8h; Reaction finishes the back suction filtration, and filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, uses 150mL sherwood oil recrystallization then, suction filtration, vacuum-drying 6h under 40 ℃ of temperature makes the 84g white powder, is lignocaine, yield is 89%, and fusing point is 66～67 ℃, and content is 99.15%.
Embodiment 3 two-step approachs prepare lignocaine1) intermediate chloracetyl-2, the preparation of 6-xylidineAdd 102g 2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, adds 250g salt of wormwood again, and mechanical stirring evenly back drips 113mL chloroacetyl chloride (1.5h drips off), (20 ℃) stirring reaction 3h under the room temperature; Reaction finishes the back suction filtration, and filter cake is washed with water to filtrate and is neutral, and under 100 ℃ of temperature dry 1 hour then, make the 150g white powder, be intermediate chloracetyl-2,6-xylidine, yield are 90%, fusing point is 147～148 ℃.
2) preparation of lignocaineAdd 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, and the dissolving back adds 150g salt of wormwood, drips the 75g diethylamine fast, back flow reaction 8h; Reaction finishes the back suction filtration, and filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, uses 150mL sherwood oil recrystallization then, suction filtration, vacuum-drying 6h under 40 ℃ of temperature makes the 88g white powder, is lignocaine, yield is 93%, and fusing point is 68～69 ℃, and content is 98.75%.
Embodiment 4 one kettle ways prepare lignocaineIn the 5000mL there-necked flask, add 305g 2, the 6-xylidine, make solvent with 2000mL acetone, add 700g salt of wormwood again, mechanical stirring evenly back slowly drips 230mL chloroacetyl chloride (1.5h drips off), room temperature (35 ℃) is stirring reaction 3h down, and TLC point plate (use sherwood oil: ethyl acetate (V/V)=3: 1 is made developping agent) demonstration reacts completely; Dropwise 5 50g diethylamine then, the back back flow reaction 8h that stirs, TLC monitoring (developping agent is the same) shows and reacts completely; The reaction solution suction filtration, filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, gets light yellow solid, uses sherwood oil recrystallization secondary then, makes 482g white lignocaine crystal, and total recovery is 82%, and fusing point is 68.0～69.0 ℃, and content is 99.75%.
Comparative example 1 existing method prepares lignocaine1) intermediate chloracetyl-2, the preparation of 6-xylidineIn the 1000mL there-necked flask, with 102g 2, the 6-xylidine is dissolved in the 400mL glacial acetic acid, stirs slowly to add the 100mL chloroacetyl chloride down, is heated to 45 ℃, adds 200g solid sodium acetate (containing crystal water) then, reaction 2h; After reaction finished, ice bath was cooled to below 10 ℃, suction filtration, filter cake is washed with water to filtrate and is neutral, and drying is 1 hour under 100 ℃ of temperature, makes the 111g white powder, be intermediate chloracetyl-2,6-xylidine, yield are that 67% fusing point is 145.0～148.0 ℃.
2) preparation of lignocaineAdd 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL toluene, and the dissolving back drips 60g diethylamine, back flow reaction 3.5h fast; After reaction finished, ice bath was cooled to 5 ℃, suction filtration, filtrate is used the 3mol/L hcl as extraction agent, and the acid solution that extraction is obtained is cooled to 10 ℃ then, stirs slowly to add 6mol/L KOH solution down, be alkalescence (pH8～9) to solution, with pentane extraction, organic layer was after washing, Anhydrous potassium carbonate drying after ice bath was cooled to 20 ℃, vapor bath is steamed and is desolventized, make the 74g white powder, be lignocaine, yield is 78%, fusing point is 66.0～67.0 ℃, and content is 97.15%.Embodiment 1 compares with comparative example 1, its intermediate chloracetyl-2, and the yield of 6-xylidine obviously improves, and reaches 94%, and the total recovery of final product lignocaine also is significantly improved, and the content of lignocaine is brought up to about 99%.Embodiment 4 compares with comparative example 1, and the total recovery of lignocaine is significantly improved, and reach 82%, and content is brought up to more than 99%.
Though above with a general description of the specific embodiments, the present invention is described in detail, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
CLIPhttps://www.cerritos.edu/chemistry/chem_212/Documents/Lab/10_lidocaine.pdf

Procedure: (1st week)A: Synthesis of 2,6-Dimethylaniline via Reduction of 2,6-Dimethylnitrobenzene 1. Dissolve1.0 g of 2,6-dimethylnitrobenzene in 10 mL of glacial acetic acid in a 50 mL Erlenmeyer flask. 2. In a 25 mL flask, dissolve 4.6 grams of SnCl2 · 2H2O in 8 mL of concentrated HCl, inside the fume hood. 3. Add the SnCl2 solution in one portion to the nitroxylene solution, magnetically swirl and mix, and let the mixture stand for 15 minutes. 4. Cool the mixture and collect the crystalline salt (dimethylaniline in the salt form: C6H5NH3 +Cl- ) in a Buchner funnel. 5. Transfer the moist crystals to an Erlenmeyer flask, add 5-10 mL of water, and make the solution strongly basic (to remove the acid and change C6H5NH3 +Clback intoC6H5NH2) by adding 30% KOH solution (12 to 17 mL required). 6. After cooling extract with three 10 mL portions of ether, rinse the ether extracts twice with 10 mL of water, and dry over K2CO3. 7. Evaporate the dried and filtered solution to an oil, transfer and rinse into a 50 mL Erlenmeyer flask, complete evaporation, weigh, and calculate the %yield of 2,6-dimethylaniline.
B: Synthesis of α-Chloro-2,6-dimethylacetanilide (prepare for a steam bath ahead of time) 1. For every 7 grams (from this step on, you need to calculate proportionally how much you need to add according to the actual weight that you got) of dimethylaniline from the previous step, add 50 mL of glacial acetic acid, and 7.2 g (or 5.2 mL) of chloroacetyl chloride, in that order. 2. Warm the solution on a steam bath to (40–50)ºC, remove, and add a solution of 1 gram of sodium acetate in 100 mL of water. 3. Cool the mixture and collect the product in a Buchner funnel. 4. Transfer the product to a disk of medium–sized filter paper, finely divide it with a spatula, and let air dry until the next laboratory period. 5. Upon drying, measure the mass and the melting point. Also, calculate the % yield.
B: Synthesis of α-Chloro-2,6-dimethylacetanilide (prepare for a steam bath ahead of time) 1. For every 7 grams (from this step on, you need to calculate proportionally how much you need to add according to the actual weight that you got) of dimethylaniline from the previous step, add 50 mL of glacial acetic acid, and 7.2 g (or 5.2 mL) of chloroacetyl chloride, in that order. 2. Warm the solution on a steam bath to (40–50)ºC, remove, and add a solution of 1 gram of sodium acetate in 100 mL of water. 3. Cool the mixture and collect the product in a Buchner funnel. 4. Transfer the product to a disk of medium–sized filter paper, finely divide it with a spatula, and let air dry until the next laboratory period. 5. Upon drying, measure the mass and the melting point. Also, calculate the % yield.
D. Synthesis of the bisulfate salt of lidocaine 1. Dissolve the lidocaine in ether (10 mL per gram of lidocaine) and add 2 mL of 2.2 M sulfuric acid in ethanol per gram of lidocaine. 2. Stir and scratch with a glass rod to mix and induce crystallization. 3. Dilute the mixture with an equal volume of acetone to aid filtration and collect the salt in a small Buchner funnel. 4. Rinse the solid on the funnel with a few milliliters of acetone and air dry and weigh the product. 5. Calculate the % yield of this step. *** Overall % Yield The overall % YCLIPhttp://home.sandiego.edu/~khuong/chem302L/Handouts/Lidocaine_handout_Su07.pdfSynthetic Strategy Lidocaine will be prepared via a three-step linear synthesis starting from 2,6-dimethylnitrobenzene. The reduction of 2,6-dimethylnitrobenzene 1 with three equivalents of stannous chloride (SnCl2) yields the ammonium salt 2. It is very important that the reaction mixture is strongly acidic during this reaction because the reduction of nitrobenzene using different reducing reagents and conditions can afford a variety of functional groups: nitroso, hydroxylamine (zinc dust, pH 4), azoxy (sodium arsenite), azo (zinc, weakly basic), or hydrazo (zinc, strongly basic). In industrial settings, often iron or tin with hydrochloric acid is used instead of stannous chloride because iron and tin are cheaper, but the reduction takes much longer. In the workup portion of the reaction, the ammonium salt 2 is reacted with an aqueous potassium hydroxide solution, liberating the free 2,6-dimethylaniline 3 in an acid-base reaction.

The reaction of 3 with the bifunctional α-chloroacetyl chloride leads to α-chloro-2,6-dimethylacetanilide 4. A slight excess of the acid chloride is used to ensure the complete conversion of the amine to the amide. The formation of the amide is a result of the significantly higher reactivity (~106 times) of the acyl chloride over the alkyl chloride. The addition of sodium acetate solution avoids the formation of HCl which would protonate unreacted 3 causing it to co-precipitate with the desired product 4.

In the last step, diethylamine performs a nucleophilic substitution (SN2) on the remaining alkyl chloride. Diethylamine serves both as a nucleophile to form lidocaine 5, and as acid scavenger, leading to formation of NH2Et2 + Cl- in this reaction. Since diethylamine is not a very strong nucleophile, it is used in excess here to improve the yield and speed up the reaction. The unreacted amine is later removed by extraction with water. The aqueous extraction of lidocaine with acid separates the unreacted chloroanilide 4 and the lidocaine. After addition of a strong base like aqueous potassium hydroxide, crude lidocaine is obtained.

Procedure Synthesis of 2,6-dimethylaniline (3) Dissolve 15 g of SnCl2•2H2O in 27 mL of concentrated hydrochloric acid. If necessary, heat the mixture gently. Add this solution in one portion to a solution of 3 mL of 2,6-dimethylnitrobenzene in 34 mL of glacial acetic acid. Swirl the resulting mixture and then allow it to stand for 15 minutes before placing the mixture in an ice bath. Collect the formed precipitate by vacuum filtration. Place the wet precipitate obtained above in a beaker and add 20 mL of water. Neutralize the acidic mixture by carefully adding an 8 M aqueous potassium hydroxide with continuous stirring until basic to litmus. Place the mixture in an ice bath. Upon cooling to room temperature, extract the mixture three times with diethyl ether. Combine the organic layers and wash them twice with water and once with brine. Dry the organic layer over anhydrous potassium carbonate. Decant away from the drying agent and evaporate the diethyl ether from a dry, preweighed flask using a rotary evaporator. The oily residue will be your crude product 3. Obtain and record the following information: 1. crude product description (co2. crude weight/percent yieldSynthesis of α-chloro-2,6-dimethylacetanilide (4) Dissolve 3 in 17 mL of glacial acetic acid. Add 1.1 equivalents (based on the moles of 3) of α-chloroacetyl chloride to this solution. Heat the solution to 40-50 o C for ten minutes to complete the reaction. Upon cooling, add a solution of ~3.3 g sodium acetate trihydrate in 67 mL water and then place the resulting mixture in an ice bath. Collect the precipitate by vacuum filtration. Rinse the filter cake with copious amounts of water in order to remove the acetic acid. It is important that the product be completely free of acetic acid after this step (why?). The pH of the individual water rinses can be checked with litmus paper to determine if the product is acid free. Allow for the product to air-dry on a watch glass until the next meeting. There is a reasonable chance that you will not obtain a precipitate as described above. If this is the case, you can try “seeding” using a small sample of authentic product from a classmate. If this does not work, check the TLC to be sure that you have formed product and devise an extractive workup that will separate the unreacted aniline 3 from the desired product 4. (Make sure you understand how to do this even if you obtain a precipitate in the first place). After the aqueous workup and following removal of solvent, you should obtain a solid. If not, check the TLC, using a sample of authentic product from a classmate as a standard. If the product appears relatively pure, you can continue even though the material is not a solid. Obtain and record the following information: 1. crude product description (color, physical state, etc.) 2. crude weight/percent yield 3. mp (if a solid)
4. TLC analysis 5. IR (check for presence of amide functional group) Synthesis of lidocaine; α-(N,N-diethylamino)-2,6-dimethylacetanilide (5). In a round bottom flask, dissolve α-chloro-2,6-dimethylacetanilide 4 in 17 mL of toluene. Before continuing, spot several (4 to 5) TLC plates in advance with this solution of 4. Provide three lanes and spot the 4 on the “SM” and “CO-SPOT” lanes. You will use these plates to monitor the progress of this reaction. Add three equivalents of diethylamine to the round bottom flask, and reflux the mixture vigorously until the reaction is complete. The amount of time required for complete reaction depends on many factors but it will likely take anywhere from more than a few minutes up to several hours. If the reaction is not complete when your lab period ends, you can stopper the reaction and reflux it for additional time at the next period. Usually a white precipitate forms during the reflux. Upon cooling, transfer the reaction mixture to a separatory funnel and extract the mixture three times with water. Next, extract the organic layer with two portions of 3 M hydrochloric acid. Cool the combined acidic aqueous extracts in an ice bath and then add 8 M aqueous potassium hydroxide slowly until the mixture is strongly basic again. The formation of a thin, dark yellow oily layer on top or a white solid is observed at this point. Place the mixture in an ice bath. Once the mixture is chilled, try to initiate the crystallization of the final product if no solid has formed at this point. Collect the obtained precipitate by filtration using a Büchner funnel. Wash it with twice with water and then press it as dry as possible. Obtain and record the following information: 1. crude product description (color, physical state, etc.) 2. crude weight/percent yield 3. TLC analysis Recrystallize the crude product from hexanes. Regardless of the final physical state of your product (solid or oil), obtain and record the following: 1. pure product description (color, physical state, etc.) 2. pure product weight/percent yield 3. overall (three-step) percent yield (from starting material 1) 4. TLC analysis 5. melting point (if a solid) 6. IR 7. 1 H and 13C NMR spectra of lidocaine will be given to you. Turn in a sample of your final product.

¹H NMR

13C NMR

IR KBR

Lidocaine is an antiarrhythmic medicine and also serves as a local anaesthetic drug. It is utilized in topical application to relieve pain, burning and itching sensation caused from skin inflammations. This drug is mainly used for minor surgeries. Figure 1 shows the ¹H NMR spectrum of 200 mM lidocaine in CDCl₃.

Proton NMR spectrum of 200 mM lidocaine in CDCl3.

Figure 1. Proton NMR spectrum of 200 mM lidocaine in CDCl₃.

¹H NMR Relaxation

Figures 2, 3 and 4 show the relaxation time measurements. It can be seen that the relaxation times are shortest for the CH₂ protons and longest for the CH protons. The first data point amplitude increases with the number of protons for the related peak.

Proton T1 relaxation time measurement of 200 mM lidocaine in CDCl3.

Figure 2. Proton T₁ relaxation time measurement of 200 mM lidocaine in CDCl₃.

Proton T2 relaxation time measurement of 200 mM lidocaine in CDCl3.

Figure 3. Proton T₂ relaxation time measurement of 200 mM lidocaine in CDCl₃.

COSY spectrum of 200 mM lidocaine in CDCl3.

Figure 4. COSY spectrum of 200 mM lidocaine in CDCl₃. The cross-peaks and corresponding exchanging protons are labeled by colour-coded arrows and ellipses.

2D COSY

Figure 4 shows the 2D COSY spectrum where two spin systems (6,7,8) to (10,11) can be clearly seen. For instance, the methyl groups at 10 and 11 positions bond to aromatic protons at 6 and 8 positions, while the methyl groups at 16 and 17 positions bond to the ethylene groups at 14 and 15 positions. No coupling occurs at positions (6,7,8) to (16,17) or (14,15).

2D Homonuclear J-Resolved Spectroscopy

The chemical shift in the 2D homonuclear j-resolved spectrum appears along the direct (f₂) direction and the effects of coupling between protons appear along the indirect (f₁) dimension. This enables the assignment of chemical shifts of multiplets and may help in measuring unresolved couplings. Also, a decoupled 1D proton spectrum is produced by the projection along the f1 dimension. The 2D homonuclear j-resolved spectrum of lidocaine, plus the 1D proton spectrum (blue line) are shown in Figure 5.

Homonuclear j-resolved spectrum of 200 mM lidocaine in CDCl3

Figure 5. Homonuclear j-resolved spectrum of 200 mM lidocaine in CDCl₃. The multiplet splitting frequencies for different couplings are colour- coded.

The projection which is vertical reveals how the multiplets disintegrate into a single peak, which makes the 1D spectrum more simplified. Peak multiplicities are produced by vertical traces from peaks in the 2D spectrum and help in determining the frequencies of proton-proton coupling. When coupling frequencies are compared between different peaks, information can be obtained regarding which peaks are bonded to each other. Also, Information regarding the coupling strength can be obtained from the size of the coupling frequencies. These couplings substantiate the results of the COSY experiment.

However, in this experiment, the effects of second order coupling appear in the f1 direction as additional peaks which are equidistant from the coupling partners detached from the zero frequency in the f1 dimension. These peaks provide proof of second order coupling partners, but are generally considered as artifacts. Figure 6 shows these coupling partners and additional peaks marked by colour-coded arrows and ellipses.

Homonuclear j-resolved spectrum of 200 mM lidocaine in CDCl3 showing the extra peaks due to strong couplings.

Figure 6. Homonuclear j-resolved spectrum of 200 mM lidocaine in CDCl₃ showing the extra peaks due to strong couplings.

1D ¹³C Spectra

Figure 7 shows the ¹³C NMR spectra of 1 M lidocaine in CDCl₃. Since the 1D Carbon experiment is highly susceptible to the ¹³C nuclei in the specimen, it easily and clearly resolves 9 resonances. In this experiment, only carbons coupled to protons are seen.

Carbon spectra of 1 M lidocaine in CDCl3.

Figure 7. Carbon spectra of 1 M lidocaine in CDCl₃.

Given the fact that the DEPT spectra do not display the peaks at 170 and 135ppm, they must be part of quaternary carbons. The DEPT-135 and the DEPT-45 experiments provide signals of CH_3,CH₂ and CH groups, while the DEPT-90 experiment provides only the signal of CH groups. However, in DEPT-135 the CH₂ groups occur as negative peaks. It can thus be summed up that the peaks between 45 and 60ppm belong to ethylene groups; the peaks between 10 and 20ppm are part of the methyl groups; and the peaks between 125 and 130ppm belong to methyne groups. A similar study can be carried out on the C and CH peaks.

Heteronuclear Correlation

The Heteronuclear Correlation (HETCOR) experiment identifies the proton signal that appears along the indirect dimension and the carbon signal along the direct dimension. Figure 8 shows the HETCOR spectrum of 1 M lidocaine in CDCl₃. in the 2D spectrum, the peaks reveal which proton is attached to which carbon. This experiment helps in resolving assignment uncertainty from the ID carbon spectra.

HETCOR spectrum of 1 M lidocaine in CDCl3.

Figure 8. HETCOR spectrum of 1 M lidocaine in CDCl₃.

Heteronuclear Multiple Quantum Coherence

Heteronuclear Multiple Quantum Coherence (HMQC) is similar to the HETCOR experiment and is utilized to associate proton resonances to the carbons that are coupled directly to those protons. But in the HMQC experiment, the proton signal appears along the direct dimension and the carbon signal along the indirect dimension. Figure 9 shows the HMQC spectrum of 1 M lidocaine in CDCl₃. In the 2D spectrum, the peaks show which proton is attached to which carbon. For conclusive peak assignment, a similar study with the HETCOR spectrum can be carried out.

HMQC spectrum of 1 M lidocaine in CDCl3.

Figure 9. HMQC spectrum of 1 M lidocaine in CDCl₃.

Heteronuclear Multiple Bond Correlation

The Heteronuclear Multiple Bond Correlation (HMBC) experiment can be employed to achieve long-range correlations of proton and carbon via two or three bond couplings. Similar to the HMQC experiment, the proton signal appears along the direct dimension and the carbon signal along the indirect dimension. Figure 10 shows the HMBC spectrum of 1 M lidocaine in CDCl₃.

HMBC spectrum of 1 M lidocaine in CDCl3, with some of the long-range couplings marked.

Figure 10. HMBC spectrum of 1 M lidocaine in CDCl₃, with some of the long-range couplings marked.

The couplings amid the molecular positions appear analogous to the couplings seen in the COSY spectrum; however, the HMBC also displays couplings to quaternary carbons, which are not seen either in HMQC or COSY experiments. In addition, there is a correlation between protons and carbons. This is attributed to three-bond bonding from 14 and 15 and vice versa, as shown in light green in Figure 1.

SYN

Synthesis of lidocaine T. J. Reilly (1999). “The Preparation of Lidocaine”. J. Chem. Ed. 76 (11): 1557.

CLIP

The Present Synthesis Of Lidocaine Begins With 2,6-Dimethylnitrobenzene (1). This Compound Can Be Made From 1,3-Dimethylbenzene, Also Known As M-Xylene, Which Is More Difficult To Make. Luckily,

This problem has been solved!

See the answer

REFER TO THE SCHEME FOR THE SYNTHESIS OF LIDOCAINE SHOWN BELOW © NH, CI q NH2 avec NO2 SnCl2/ HCI CH3COOH KOH CH3COOH 2 3 1 2

The present synthesis of lidocaine begins with 2,6-dimethylnitrobenzene (1). This compound can be made from 1,3-dimethylbenzene, also known as m-xylene, which is more difficult to make. Luckily, m-xylene is commercially available, so a synthesis of 1 from m-xylene is a practical alternative if one wants to begin the synthesis of lidocaine with m-xylene. Suppose you want to prepare 1 from m-xylene. Show with chemical equations the reagents that you would use, and the possible isomers that would result.

2. The practical transformation of 1 into 3 is carried out by the following scheme:

1 in glacial CH3COOH + SnCl2 in conc. HCI vacuum filtration 2 as a solid precipitate dissolve in aq. KOH to pH > 10 3+ impuri

Suppose you dissolve the solid precipitate of 2 in water, but forget to include the KOH in the second step above. What would happen after the extraction with ether? Give your answer in terms of what would be found in the ether layer, and in the aqueous layer.

3. Suppose you’re out of acetic acid (CH₃COOH) and decide to use ethanol (CH₃ CH₂OH) as the solvent in the transformation of 3 into 4. Would this be a wise choice, and why?

4.The amide 4 has a nitrogen attached to the benzene ring, and a chlorine attached to a primary carbon. Yet, it doesn’t react with itself in a nucleophilic displacement. Why is the nitrogen in the amide not nucleophilic? Give your answer in terms of the resonance forms of amides in general:

5. In the reaction below, what factors come into play to favor attack of the aniline 3 on the carbonyl carbon of the acid chloride (carbon 1 in red), rather than at the a-carbon (carbon 2 in red)?

6. Before carrying out the transformation below, compound 4 and the glassware used must be oven-dried. What would happen if the reaction was attempted using wet 4?

7.In the reaction below, what factors come into play to favor attack of diethylamine on the a-carbon (carbon 1 in red), rather than on the amide C=O carbon (carbon 2 in red)?

8. In the reaction below, why does the amine nitrogen (#1 in red) undergo protonation with H₂SO₄ preferentially over the amide nitrogen (#2 in red)? In other words, why is nitrogen 1 basic, but nitrogen 2 is not?

9.Lidocaine and other drugs containing amino groups are usually marketed as their hydrochloride or hydrogen sulfate salts, rather than as “free amines.” Provide two reasons why this practice makes sense.

10.Although lidocaine is marketed as its hydrochloride salt, it doesn’t exhibit the same level of physiological activity as the free amine. The free amine is more lipophilic and diffuses across a neuron cell membrane more rapidly than the ionic salt, resulting in a more rapid onset of anesthesia. Therefore, sodium bicarbonate (NaHCO₃) is added to a solution of lidocaine prior to injection. How does the addition of sodium bicarbonate promote a faster anesthetic effect?

CLIP

Click to access LidocaineRemoteHandout.pdf

CLIP

Lidocaine, also known as lignocaine and sold under the brand name Xylocaine among others, is a local anesthetic of the amino amide type. It is also used to treat ventricular tachycardia.^[7]^[8] When used for local anaesthesia or in nerve blocks, lidocaine typically begins working within several minutes and lasts for half an hour to three hours.^[8]^[9] Lidocaine mixtures may also be applied directly to the skin or mucous membranes to numb the area.^[8] It is often used mixed with a small amount of adrenaline (epinephrine) to prolong its local effects and to decrease bleeding.^[8]

If injected intravenously, it may cause cerebral effects such as confusion, changes in vision, numbness, tingling, and vomiting.^[7] It can cause low blood pressure and an irregular heart rate.^[7] There are concerns that injecting it into a joint can cause problems with the cartilage.^[8] It appears to be generally safe for use in pregnancy.^[7] A lower dose may be required in those with liver problems.^[7] It is generally safe to use in those allergic to tetracaine or benzocaine.^[8] Lidocaine is an antiarrhythmic medication of the class Ib type.^[7] This means it works by blocking sodium channels and thus decreasing the rate of contractions of the heart.^[7] When injected near nerves, the nerves cannot conduct signals to or from the brain.^[8]

Lidocaine was discovered in 1946 and went on sale in 1948.^[10] It is on the World Health Organization’s List of Essential Medicines.^[11] It is available as a generic medication.^[8]^[12] In 2018, it was the 233rd most commonly prescribed medication in the United States, with more than 2 million prescriptions.^[13]^[14]

Medical uses

Local numbing agent

The efficacy profile of lidocaine as a local anaesthetic is characterized by a rapid onset of action and intermediate duration of efficacy. Therefore, lidocaine is suitable for infiltration, block, and surface anaesthesia. Longer-acting substances such as bupivacaine are sometimes given preference for spinal and epidural anaesthesias; lidocaine, though, has the advantage of a rapid onset of action. Adrenaline vasoconstricts arteries, reducing bleeding and also delaying the resorption of lidocaine, almost doubling the duration of anaesthesia.

Lidocaine is one of the most commonly used local anaesthetics in dentistry. It can be administered in multiple ways, most often as a nerve block or infiltration, depending on the type of treatment carried out and the area of the mouth worked on.^[15]

For surface anaesthesia, several formulations can be used for endoscopies, before intubations, etc. Buffering the pH of lidocaine makes local numbing less painful.^[16] Lidocaine drops can be used on the eyes for short ophthalmic procedures. There is tentative evidence for topical lidocaine for neuropathic pain and skin graft donor site pain.^[17]^[18] As a local numbing agent, it is used for the treatment of premature ejaculation.^[19]

An adhesive transdermal patch containing a 5% concentration of lidocaine in a hydrogel bandage, is approved by the US FDA for reducing nerve pain caused by shingles.^[20] The transdermal patch is also used for pain from other causes, such as compressed nerves and persistent nerve pain after some surgeries.

Heart arrhythmia

Lidocaine is also the most important class-1b antiarrhythmic drug; it is used intravenously for the treatment of ventricular arrhythmias (for acute myocardial infarction, digoxin poisoning, cardioversion, or cardiac catheterization) if amiodarone is not available or contraindicated. Lidocaine should be given for this indication after defibrillation, CPR, and vasopressors have been initiated. A routine preventive dose is no longer recommended after a myocardial infarction as the overall benefit is not convincing.^[21]

Epilepsy

A 2013 review on treatment for neonatal seizures recommended intravenous lidocaine as a second-line treatment, if phenobarbital fails to stop seizures.^[22]

Other

Intravenous lidocaine infusions are also used to treat chronic pain and acute surgical pain as an opiate sparing technique. The quality of evidence for this use is poor so it is difficult to compare it to placebo or an epidural.^[23]

Inhaled lidocaine can be used as a cough suppressor acting peripherally to reduce the cough reflex. This application can be implemented as a safety and comfort measure for patients who have to be intubated, as it reduces the incidence of coughing and any tracheal damage it might cause when emerging from anaesthesia.^[24]

Lidocaine, along with ethanol, ammonia, and acetic acid, may also help in treating jellyfish stings, both numbing the affected area and preventing further nematocyst discharge.^[25]^[26]

For gastritis, drinking a viscous lidocaine formulation may help with the pain.^[27]

Adverse effects

Adverse drug reactions (ADRs) are rare when lidocaine is used as a local anesthetic and is administered correctly. Most ADRs associated with lidocaine for anesthesia relate to administration technique (resulting in systemic exposure) or pharmacological effects of anesthesia, and allergic reactions only rarely occur.^[28] Systemic exposure to excessive quantities of lidocaine mainly result in central nervous system (CNS) and cardiovascular effects – CNS effects usually occur at lower blood plasma concentrations and additional cardiovascular effects present at higher concentrations, though cardiovascular collapse may also occur with low concentrations. ADRs by system are:

CNS excitation: nervousness, agitation, anxiety, apprehension, tingling around the mouth (circumoral paraesthesia), headache, hyperesthesia, tremor, dizziness, pupillary changes, psychosis, euphoria, hallucinations, and seizures
CNS depression with increasingly heavier exposure: drowsiness, lethargy, slurred speech, hypoesthesia, confusion, disorientation, loss of consciousness, respiratory depression and apnoea.
Cardiovascular: hypotension, bradycardia, arrhythmias, flushing, venous insufficiency, increased defibrillator threshold, edema, and/or cardiac arrest – some of which may be due to hypoxemia secondary to respiratory depression.^[29]
Respiratory: bronchospasm, dyspnea, respiratory depression or arrest
Gastrointestinal: metallic taste, nausea, vomiting
Ears: tinnitus
Eyes: local burning, conjunctival hyperemia, corneal epithelial changes/ulceration, diplopia, visual changes (opacification)
Skin: itching, depigmentation, rash, urticaria, edema, angioedema, bruising, inflammation of the vein at the injection site, irritation of the skin when applied topically
Blood: methemoglobinemia
Allergy

ADRs associated with the use of intravenous lidocaine are similar to toxic effects from systemic exposure above. These are dose-related and more frequent at high infusion rates (≥3 mg/min). Common ADRs include: headache, dizziness, drowsiness, confusion, visual disturbances, tinnitus, tremor, and/or paraesthesia. Infrequent ADRs associated with the use of lidocaine include: hypotension, bradycardia, arrhythmias, cardiac arrest, muscle twitching, seizures, coma, and/or respiratory depression.^[29]

It is generally safe to use lidocaine with vasoconstrictor such as adrenaline, including in regions such as the nose, ears, fingers, and toes.^[30] While concerns of tissue death if used in these areas have been raised, evidence does not support these concerns.^[30]

Interactions

Any drugs that are also ligands of CYP3A4 and CYP1A2 can potentially increase serum levels and potential for toxicity or decrease serum levels and the efficacy, depending on whether they induce or inhibit the enzymes, respectively. Drugs that may increase the chance of methemoglobinemia should also be considered carefully. Dronedarone and liposomal morphine are both absolutely a contraindication, as they may increase the serum levels, but hundreds of other drugs require monitoring for interaction.^[31]

Contraindications

Absolute contraindications for the use of lidocaine include:

Heart block, second or third degree (without pacemaker)
Severe sinoatrial block (without pacemaker)
Serious adverse drug reaction to lidocaine or amide local anesthetics
Hypersensitivity to corn and corn-related products (corn-derived dextrose is used in the mixed injections)
Concurrent treatment with quinidine, flecainide, disopyramide, procainamide (class I antiarrhythmic agents)
Prior use of amiodarone hydrochloride
Adams-Stokes syndrome^[32]
Wolff-Parkinson-White syndrome^[32]
Lidocaine viscous is not recommended by the FDA to treat teething pain in children and infants.^[33]

Exercise caution in patients with any of these:

Hypotension not due to arrhythmia
Bradycardia
Accelerated idioventricular rhythm
Elderly patients
Ehlers-Danlos Syndrome
Pseudocholinesterase deficiency
Intra-articular infusion (this is not an approved indication and can cause chondrolysis)
Porphyria, especially acute intermittent porphyria; lidocaine has been classified as porphyrogenic because of the hepatic enzymes it induces,^[34] although clinical evidence suggests it is not.^[35] Bupivacaine is a safe alternative in this case.
Impaired liver function – people with lowered hepatic function may have an adverse reaction with repeated administration of lidocaine because the drug is metabolized by the liver. Adverse reactions may include neurological symptoms (e.g. dizziness, nausea, muscle twitches, vomiting, or seizures).^[36]

Overdosage

Overdoses of lidocaine may result from excessive administration by topical or parenteral routes, accidental oral ingestion of topical preparations by children (who are more susceptible to overdose), accidental intravenous (rather than subcutaneous, intrathecal, or paracervical) injection, or from prolonged use of subcutaneous infiltration anesthesia during cosmetic surgery.

Such overdoses have often led to severe toxicity or death in both children and adults. Lidocaine and its two major metabolites may be quantified in blood, plasma, or serum to confirm the diagnosis in potential poisoning victims or to assist forensic investigation in a case of fatal overdose.

Lidocaine is often given intravenously as an antiarrhythmic agent in critical cardiac-care situations.^[37] Treatment with intravenous lipid emulsions (used for parenteral feeding) to reverse the effects of local anaesthetic toxicity is becoming more common.^[38]

Postarthroscopic glenohumeral chondrolysis

Lidocaine in large amounts may be toxic to cartilage and intra-articular infusions can lead to postarthroscopic glenohumeral chondrolysis.^[39]

Pharmacology

Mechanism of action

Lidocaine alters signal conduction in neurons by prolonging the inactivation of the fast voltage-gated Na⁺ channels in the neuronal cell membrane responsible for action potential propagation.^[40] With sufficient blockage, the voltage-gated sodium channels will not open and an action potential will not be generated. Careful titration allows for a high degree of selectivity in the blockage of sensory neurons, whereas higher concentrations also affect other types of neurons.

The same principle applies for this drug’s actions in the heart. Blocking sodium channels in the conduction system, as well as the muscle cells of the heart, raises the depolarization threshold, making the heart less likely to initiate or conduct early action potentials that may cause an arrhythmia.^[41]

Pharmacokinetics

When used as an injectable it typically begins working within four minutes and lasts for half an hour to three hours.^[8]^[9] Lidocaine is about 95% metabolized (dealkylated) in the liver mainly by CYP3A4 to the pharmacologically active metabolites monoethylglycinexylidide (MEGX) and then subsequently to the inactive glycine xylidide. MEGX has a longer half-life than lidocaine, but also is a less potent sodium channel blocker.^[42] The volume of distribution is 1.1 L/kg to 2.1 L/kg, but congestive heart failure can decrease it. About 60% to 80% circulates bound to the protein alpha₁ acid glycoprotein. The oral bioavailability is 35% and the topical bioavailability is 3%.

The elimination half-life of lidocaine is biphasic and around 90 min to 120 min in most patients. This may be prolonged in patients with hepatic impairment (average 343 min) or congestive heart failure (average 136 min).^[43] Lidocaine is excreted in the urine (90% as metabolites and 10% as unchanged drug).^[44]

History

Lidocaine, the first amino amide–type local anesthetic, was first synthesized under the name ‘xylocaine’ by Swedish chemist Nils Löfgren in 1943.^[45]^[46]^[47] His colleague Bengt Lundqvist performed the first injection anesthesia experiments on himself.^[45] It was first marketed in 1949.

Society and culture

Dosage forms

Lidocaine, usually in the form of its hydrochloride salt, is available in various forms including many topical formulations and solutions for injection or infusion.^[48] It is also available as a transdermal patch, which is applied directly to the skin.

Lidocaine hydrochloride 2% epinephrine 1:80,000 solution for injection in a cartridge
Lidocaine hydrochloride 1% solution for injection
Topical lidocaine spray
2% viscous lidocaine

Names

Lidocaine is the International Nonproprietary Name (INN), British Approved Name (BAN), and Australian Approved Name (AAN),^[49] while lignocaine is the former BAN^{[citation needed]} and AAN. Both the old and new names will be displayed on the product label in Australia until at least 2023.^[50]

Xylocaine is a brand name.

Recreational use

As of 2021, lidocaine is not listed by the World Anti-Doping Agency as a substance whose use is banned in sport.^[51] It is used as an adjuvant, adulterant, and diluent to street drugs such as cocaine and heroin.^[52] It is one of the three common ingredients in site enhancement oil used by bodybuilders.^[53]

Adulterant in cocaine

Lidocaine is often added to cocaine as a diluent.^[54]^[55] Cocaine and lidocaine both numb the gums when applied. This gives the user the impression of high-quality cocaine, when in actuality the user is receiving a diluted product.^[56]

Compendial status

Veterinary use

It is a component of the veterinary drug Tributame along with embutramide and chloroquine used to carry out euthanasia on horses and dogs.^[58]^[59]

References

^ “Lidocaine”. Merriam-Webster Dictionary.
^ “Lidocaine”. Dictionary.com Unabridged. Random House.
^ “Poisons Standard February 2021”. Federal Register of Legislation. 1 January 2021. Retrieved 11 April 2021.
^ “Lidocaine Hydrochloride Injection BP 1% w/v – Summary of Product Characteristics (SmPC)”. (emc). 29 June 2020. Retrieved 11 April 2021.
^ “Xylocaine MPF- lidocaine hydrochloride injection, solution Xylocaine- lidocaine hydrochloride injection, solution Xylocaine- lidocaine hydrochloride,epinephrine bitartrate injection, solution”. DailyMed. Retrieved 11 April 2021.
^ “Ztlido- lidocaine patch”. DailyMed. Retrieved 11 April 2021.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k “Lidocaine Hydrochloride (Antiarrhythmic)”. The American Society of Health-System Pharmacists. Archivedfrom the original on 2015-08-10. Retrieved Aug 26, 2015.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j “Lidocaine Hydrochloride (Local)”. The American Society of Health-System Pharmacists. Archived from the original on 2015-09-06. Retrieved Aug 26, 2015.
^ Jump up to:^a ^b ^c J. P. Nolan; P. J. F. Baskett (1997). “Analgesia and anaesthesia”. In David Skinner; Andrew Swain; Rodney Peyton; Colin Robertson (eds.). Cambridge Textbook of Accident and Emergency Medicine. Project co-ordinator, Fiona Whinster. Cambridge, UK: Cambridge University Press. p. 194. ISBN 9780521433792. Archived from the original on 2017-09-08.
^ Scriabine, Alexander (1999). “Discovery and development of major drugs currently in use”. In Ralph Landau; Basil Achilladelis; Alexander Scriabine (eds.). Pharmaceutical Innovation: Revolutionizing Human Health. Philadelphia: Chemical Heritage Press. p. 211. ISBN 9780941901215. Archived from the original on 2017-09-08.
^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06.
^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 22. ISBN 9781284057560.
^ “The Top 300 of 2021”. ClinCalc. Retrieved 18 February 2021.
^ “Lidocaine – Drug Usage Statistics”. ClinCalc. Retrieved 18 February 2021.
^ “Local anaesthetic drugs”.
^ Cepeda MS, Tzortzopoulou A, Thackrey M, Hudcova J, Arora Gandhi P, Schumann R (December 2010). Tzortzopoulou A (ed.). “Adjusting the pH of lidocaine for reducing pain on injection”. The Cochrane Database of Systematic Reviews (12): CD006581. doi:10.1002/14651858.CD006581.pub2. PMID 21154371.(Retracted, see doi:10.1002/14651858.cd006581.pub3. If this is an intentional citation to a retracted paper, please replace{{Retracted}} with {{Retracted|intentional=yes}}.)
^ Derry S, Wiffen PJ, Moore RA, Quinlan J (July 2014). Derry S (ed.). “Topical lidocaine for neuropathic pain in adults”. The Cochrane Database of Systematic Reviews. 7 (7): CD010958. doi:10.1002/14651858.CD010958.pub2. PMC 6540846. PMID 25058164.
^ Sinha S, Schreiner AJ, Biernaskie J, Nickerson D, Gabriel VA (November 2017). “Treating pain on skin graft donor sites: Review and clinical recommendations”. The Journal of Trauma and Acute Care Surgery. 83 (5): 954–964. doi:10.1097/TA.0000000000001615. PMID 28598907. S2CID 44520644.
^ “Lidocaine/prilocaine spray for premature ejaculation”. Drug and Therapeutics Bulletin. 55 (4): 45–48. April 2017. doi:10.1136/dtb.2017.4.0469. PMID 28408390. S2CID 19110955.
^ Kumar M, Chawla R, Goyal M (2015). “Topical anesthesia”. Journal of Anaesthesiology Clinical Pharmacology. 31 (4): 450–6. doi:10.4103/0970-9185.169049. PMC 4676230. PMID 26702198.
^ Martí-Carvajal AJ, Simancas-Racines D, Anand V, Bangdiwala S (August 2015). “Prophylactic lidocaine for myocardial infarction”. The Cochrane Database of Systematic Reviews. 8 (8): CD008553. doi:10.1002/14651858.CD008553.pub2. PMC 8454263. PMID 26295202.
^ Slaughter LA, Patel AD, Slaughter JL (March 2013). “Pharmacological treatment of neonatal seizures: a systematic review”. Journal of Child Neurology. 28 (3): 351–64. doi:10.1177/0883073812470734. PMC 3805825. PMID 23318696.
^ Weibel S, Jelting Y, Pace NL, Helf A, Eberhart LH, Hahnenkamp K, et al. (June 2018). “Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery in adults”. The Cochrane Database of Systematic Reviews. 2018 (6): CD009642. doi:10.1002/14651858.cd009642.pub3. PMC 6513586. PMID 29864216.
^ Biller JA (2007). “Airway obstruction, bronchospasm, and cough”. In Berger AM, Shuster JL, Von Roenn JH (eds.). Principles and practice of palliative care and supportive oncology. Hagerstwon, MD: Lippincott Williams & Wilkins. pp. 297–307. ISBN 978-0-7817-9595-1. Inhaled lidocaine is used to suppress cough during bronchoscopy. Animal studies and a few human studies suggest that lidocaine has an antitussive effect…
^ Birsa LM, Verity PG, Lee RF (May 2010). “Evaluation of the effects of various chemicals on discharge of and pain caused by jellyfish nematocysts”. Comp. Biochem. Physiol. C. 151 (4): 426–30. doi:10.1016/j.cbpc.2010.01.007. PMID 20116454.
^ Morabito R, Marino A, Dossena S, La Spada G (Jun 2014). “Nematocyst discharge in Pelagia noctiluca (Cnidaria, Scyphozoa) oral arms can be affected by lidocaine, ethanol, ammonia and acetic acid”. Toxicon. 83: 52–8. doi:10.1016/j.toxicon.2014.03.002. PMID 24637105.
^ James G. Adams (2012). “32”. Emergency Medicine: Clinical Essentials. Elsevier Health Sciences. ISBN 9781455733941. Archived from the original on 2017-09-08.
^ Jackson D, Chen AH, Bennett CR (October 1994). “Identifying true lidocaine allergy”. J Am Dent Assoc. 125 (10): 1362–6. doi:10.14219/jada.archive.1994.0180. PMID 7844301.
^ Jump up to:^a ^b Australian Medicines Handbook. Adelaide, S. Aust: Australian Medicines Handbook Pty Ltd. 2006. ISBN 978-0-9757919-2-9.^{[page needed]}
^ Jump up to:^a ^b Nielsen LJ, Lumholt P, Hölmich LR (October 2014). “[Local anaesthesia with vasoconstrictor is safe to use in areas with end-arteries in fingers, toes, noses and ears]”. Ugeskrift for Laeger. 176(44). PMID 25354008.
^ “Lidocaine”. Epocrates. Archived from the original on 2014-04-22.
^ Jump up to:^a ^b “Lidocaine Hydrochloride and 5% Dextrose Injection”. Safety Labeling Changes. FDA Center for Drug Evaluation and Research (CDER). January 2014. Archived from the original on 2013-04-03.
^ “Lidocaine Viscous: Drug Safety Communication – Boxed Warning Required – Should Not Be Used to Treat Teething Pain”. FDA Center for Drug Evaluation and Research (CDER). June 2014. Archived from the original on 2014-07-14.
^ “Table 96–4. Drugs and Porphyria” (PDF). Merck Manual. Merck & Company, Inc. 2011. Archived from the original on 2014-04-20.
^ “Lidocaine – N01BB02”. Drug porphyrinogenicity monograph. The Norwegian Porphyria Centre and the Swedish Porphyria Centre. Archived from the original on 2014-04-20. strong clinical evidence points to lidocaine as probably not porphyrinogenic
^ Khan, M. Gabriel (2007). Cardiac Drug Therapy (7th ed.). Totowa, NJ: Humana Press. ISBN 9781597452380.
^ Baselt R (2008). Disposition of Toxic Drugs and Chemicals in Man(8th ed.). Foster City, CA: Biomedical Publications. pp. 840–4. ISBN 978-0-9626523-7-0.
^ Picard J, Ward SC, Zumpe R, Meek T, Barlow J, Harrop-Griffiths W (February 2009). “Guidelines and the adoption of ‘lipid rescue’ therapy for local anaesthetic toxicity”. Anaesthesia. 64 (2): 122–5. doi:10.1111/j.1365-2044.2008.05816.x. PMID 19143686. S2CID 25581037.
^ Gulihar A, Robati S, Twaij H, Salih A, Taylor GJ (December 2015). “Articular cartilage and local anaesthetic: A systematic review of the current literature”. Journal of Orthopaedics. 12 (Suppl 2): S200-10. doi:10.1016/j.jor.2015.10.005. PMC 4796530. PMID 27047224.
^ Carterall, William A. (2001). “Molecular mechanisms of gating and drug block of sodium channels”. Sodium Channels and Neuronal Hyperexcitability. Novartis Foundation Symposia. 241. pp. 206–225. doi:10.1002/0470846682.ch14. ISBN 9780470846681.
^ Sheu SS, Lederer WJ (Oct 1985). “Lidocaine’s negative inotropic and antiarrhythmic actions. Dependence on shortening of action potential duration and reduction of intracellular sodium activity”. Circulation Research. 57 (4): 578–90. doi:10.1161/01.res.57.4.578. PMID 2412723.
^ Lewin NA, Nelson LH (2006). “Chapter 61: Antidysrhythmics”. In Flomenbaum N, Goldfrank LR, Hoffman RL, Howland MD, Lewin NA, Nelson LH (eds.). Goldfrank’s Toxicologic Emergencies(8th ed.). New York: McGraw-Hill. pp. 963–4. ISBN 978-0-07-143763-9.
^ Thomson PD, Melmon KL, Richardson JA, Cohn K, Steinbrunn W, Cudihee R, Rowland M (April 1973). “Lidocaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans”. Ann. Intern. Med. 78 (4): 499–508. doi:10.7326/0003-4819-78-4-499. PMID 4694036.
^ Collinsworth KA, Kalman SM, Harrison DC (1974). “The clinical pharmacology of lidocaine as an antiarrhythymic drug”. Circulation. 50 (6): 1217–30. doi:10.1161/01.CIR.50.6.1217. PMID 4609637.
^ Jump up to:^a ^b Löfgren N (1948). Studies on local anesthetics: Xylocaine: a new synthetic drug (Inaugural dissertation). Stockholm, Sweden: Ivar Heggstroms. OCLC 646046738.^{[page needed]}
^ Löfgren N, Lundqvist B (1946). “Studies on local anaesthetics II”. Svensk Kemisk Tidskrift. 58: 206–17.
^ Wildsmith JAW (2011). “Lidocaine: A more complex story than ‘simple’ chemistry suggests” (PDF). The Proceedings of the History of Anaesthesia Society. 43: 9–16. Archived (PDF) from the original on 2014-04-22.
^ “Lidocaine international forms and names”. Drugs.com. Retrieved 29 October 2017.
^ “Lidocaine Ingredient Summary”. Therapeutic Goods Administration. Retrieved 20 September 2018.
^ “Updating medicine ingredient names – list of affected ingredients”. Therapeutic Goods Administration. 24 June 2019. Retrieved 16 February 2020.
^ “The 2021 Prohibited List International Standard” (PDF). The World Anti-Doping Code. World Anti-Doping Agency (WADA). 1 January 2021. Archived from the original (PDF) on 13 May 2021. Retrieved 18 May 2021.
^ “New York Drug Threat Assessment”. National Drug Intelligence Center. November 2002. Archived from the original on 2012-08-12.
^ Pupka A, Sikora J, Mauricz J, Cios D, Płonek T (2009). “[The usage of synthol in the body building]”. Polimery W Medycynie. 39(1): 63–5. PMID 19580174.
^ Bernardo NP; Siqueira MEPB; De Paiva MJN; Maia PP (2003). “Caffeine and other adulterants in seizures of street cocaine in Brazil”. International Journal of Drug Policy. 14 (4): 331–4. doi:10.1016/S0955-3959(03)00083-5.
^ “UNITED STATES of America, Plaintiff-Appellee, v. Luis A. CUELLO, Alvaro Bastides-Benitez, John Doe, a/k/a Hugo Hurtado, and Alvaro Carvajal, Defendants-Appellants”. Docket No. 78-5314. United States Court of Appeals, Fifth Circuit. 1979-07-25. Archived from the original on 2012-05-24.
^ Winterman, Denise (2010-09-07). “How cutting drugs became big business”. BBC News Online. BBC News Magazine. Archivedfrom the original on 2 February 2017. Retrieved 20 January 2017.
^ “Revision Bulletin: Lidocaine and Prilocaine Cream–Revision to Related Compounds Test”. The United States Pharmacopeial Convention. November 30, 2007. Archived from the original on May 1, 2013.
^ Peterson, Michael E.; Talcott, Patricia A. (2013-08-07). Small Animal Toxicology. Elsevier Health Sciences. ISBN 978-0323241984. Archived from the original on 2017-09-08.
^ “FDA Freedom of Information Summary – Tributame” (PDF). Archived from the original (PDF) on 2015-05-18.

External links

“Lidocaine”. Drug Information Portal. U.S. National Library of Medicine.
“Lidocaine Transdermal Patch”. MedlinePlus.
US patent 2441498, Nils Magnus Loefgren & Bengt Josef Lundqvist, “Alkyl glycinanilides”, published 1948-05-11, issued 1948-05-11, assigned to ASTRA APOTEKARNES KEM FAB

Chemical and physical data
IUPAC name2-(diethylamino)- N-(2,6-dimethylphenyl)acetamide
CAS Number	137-58-6as HCl: 73-78-9
PubChem CID	3676as HCl: 6314
IUPHAR/BPS	2623
DrugBank	DB00281as HCl: DBSALT001508
ChemSpider	3548as HCl: 6075
UNII	98PI200987as HCl: EC2CNF7XFP
KEGG	D00358as HCl: D02086
ChEBI	CHEBI:6456as HCl: CHEBI:50512
ChEMBL	ChEMBL79as HCl: ChEMBL541521
PDB ligand	LQZ (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID1045166
ECHA InfoCard	100.004.821
Formula	C₁₄H₂₂N₂O
Molar mass	234.343 g·mol⁻¹
3D model (JSmol)	Interactive image
Melting point	68 °C (154 °F)
show SMILES
show InChI

////////LIDOCAINE, lignocaine

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Divalproex sodium

October 26, 2021 2:47 am / Leave a comment

Divalproex

44089

WeightAverage: 144.2114
Chemical FormulaC₈H₁₆O₂

UNII614OI1Z5WI, CAS number99-66-1, 76584-70-8

2-propylpentanoic acid, DIVALPROEX SODIUM, 76584-70-8, Valproate semisodium, Epival, Depakote, Sodium divalproate, Semisodium Valproate, Abbott 50711, ValdisovalValproic Acid
CAS Registry Number: 99-66-1
CAS Name: 2-Propylpentanoic acid
Additional Names: 2-propylvaleric acid; di-n-propylacetic acid
Trademarks: Convulex (Pharmacia); Depakene (Abbott)
Molecular Formula: C8H16O2
Molecular Weight: 144.21
Percent Composition: C 66.63%, H 11.18%, O 22.19%
Literature References: Antiepileptic; increases levels of g-aminobutyric acid (GABA) in the brain. Prepn: B. S. Burton, Am. Chem. J.3, 385 (1882); E. Oberreit, Ber.29, 1998 (1896); M. Tiffeneau, Y. Deux, Compte Rend.212, 105 (1941). Anticonvulsant activity: H. Meunier et al.,Therapie18, 435 (1963). Toxicity data: Jenner et al.,Food Cosmet. Toxicol.2, 327 (1964). Comprehensive description: Z. L. Chang, Anal. Profiles Drug Subs.8, 529-556 (1979). Review of teratogenicity studies: H. Nau et al.,Pharmacol. Toxicol.69, 310-321 (1991); R. Alsdorf, D. F. Wyszynski, Expert Opin. Drug Safety4, 345-353 (2005). Review of pharmacology and clinical experience in epilepsy: E. M. Rimmer, A. Richens, Pharmacotherapy5, 171-184 (1985); in psychiatric disease: D. R. P. Guay, ibid.15, 631-647 (1995); in migraine prophylaxis: C. E. Shelton, J. F. Connelly, Ann. Pharmacother.30, 865-866 (1996). Review of pharmacodynamics and mechanisms of action: W. Löscher, Prog. Neurobiol.58, 31-59 (1999).
Properties: Colorless liquid with characteristic odor. bp 219.5°. nD24.5 1.425. d40 0.9215. pKa 4.6. Very sol in organic solvents. Soly in water: 1.3 mg/ml. LD50 orally in rats: 670 mg/kg (Jenner).
Boiling point: bp 219.5°
pKa: pKa 4.6
Index of refraction:nD24.5 1.425
Density: d40 0.9215
Toxicity data: LD50 orally in rats: 670 mg/kg (Jenner)
Derivative Type: Sodium salt (1:1)
CAS Registry Number: 1069-66-5
Additional Names: Sodium valproate
Trademarks: Depacon (Abbott); Depakin (Sanofi-Synthelabo); Dépakine (Sanofi-Aventis); Epilim (Sanofi-Aventis); Ergenyl (Sanofi-Synthelabo); Leptilan (Dolorgiet); Orfiril (Desitin)
Molecular Formula: C8H15NaO2
Molecular Weight: 166.19
Percent Composition: C 57.82%, H 9.10%, Na 13.83%, O 19.25%
Properties: White, odorless, crystalline, deliquescent powder. pKa 4.8. Hygroscopic. One gram is sol in 0.4 ml water; 1.5 ml ethanol; 5 ml methanol. Practically insol in common organic solvents. LD50 orally in mice: 1700 mg/kg (Meunier).
pKa: pKa 4.8
Toxicity data: LD50 orally in mice: 1700 mg/kg (Meunier)
Derivative Type: Sodium salt (2:1)
CAS Registry Number: 76584-70-8
Additional Names: Sodium hydrogen bis(2-propylpentanoate); divalproex sodium; valproate semisodium
Manufacturers’ Codes: Abbott 50711
Trademarks: Depakote (Abbott); Valcote (Abbott)
Molecular Formula: C16H31NaO4
Molecular Weight: 310.40
Percent Composition: C 61.91%, H 10.07%, Na 7.41%, O 20.62%
Derivative Type: Magnesium salt
Trademarks: Depamag (Sigma-Tau)
Molecular Formula: C16H30MgO4
Molecular Weight: 310.71
Percent Composition: C 61.85%, H 9.73%, Mg 7.82%, O 20.60%
Therap-Cat: Anticonvulsant; antimanic; antimigraine.Keywords: Anticonvulsant; Antimigraine; Antimanic.

Synthesis Reference

Daniel Aubert, Francis Blanc, Henri Desmolin, Michel Morre, Lucette Sindely, “Valproic acid preparations.” U.S. Patent US5017613, issued January, 1965.

US5017613

Patent

https://patents.google.com/patent/WO2007004238A2/enDivalproex sodium is one of the most widely used epileptic agents presently available in the market. Both the constituents, valproic acid and sodium valproate themselves have also been used for the treatment of epileptic seizures and convulsions. But their utility has remained restricted since valproic acid is a liquid and is difficult to formulate for an oral dosage form whereas sodium valproate is a hygroscopic solid with poor stability characteristics. Divalproex sodium is an oligomer having 1:1 molar ratio of valproic acid and sodium valproate containing 4 to 6 units. The relevant prior art includes US 4,988,731 (’73I) relates to a non-hygroscopic stable sodium hydrogen divalproate oligomer. Its probable structure is shown in Fig 1

Fig 1 – Divalproex sodiumWhere M is a about 2.As can be seen from the displayed structure, one mole each of the valproic acid forms coordinate bonds with the sodium of the sodium valproate molecule, and the valproate ion is ionically bonded to the sodium atom. The structure is thus consistent with the unique characteristic of the compound. However the preferred mode of representing Divalproex sodium is by reference to single compound of the formula{(CH₃CH₂CH₂)₂CHCO₂} {(CH₃CH₂CH₂)₂CHCO₂}Na, HThe said patent also describes two alternative processes for the preparation of the oligomer. According to one aspect, the oligomer is produced by dissolving sodium valproate and valproic acid in equimolar amount in acetone and crystallizing from chilled acetone at around O⁰C. Alternatively Divalproex sodium can be isolated from a two component liquid medium, which includes acetone where in half equivalent of NaOH to the valproic acid present, preferable as a solution in an acetone miscible solvent eg. water. The new compound can be recovered from the liquid phase by evaporating the solvent(s) and, if desired, the new compound can be recrystallized, for instance from acetonitrile or others or the material may be spay-dried, lyophilized or purified by chromatography.US ‘731 claims yield of 90% of theory.Drawbacks of the above mentioned reported methods for the preparation of Divalproex sodium described in US 4988731 are difficult to reproduce on a large scale and provides inconsistent yields and the material obtained is not always free flowing in nature. The process involves the crystallization of a 1:1 mixture of valproic acid and sodium valproate from a chilled solution of acetone, followed by washing with chilled acetone. Divalproex sodium is as such fairly soluble in acetone at temperatures above 1O⁰C and extreme care has to be. taken while performing washing with chilled acetone as any rise in temperature would lead to the loss of yield. This problem actually comes to the fore while scaling up the process during commercialization since during centrifugation of the large volume the temperature of the mixture rises and acetone has to be cooled below O⁰C, which require large amount of liquid nitrogen or dry ice. Moreover it was also observed that due to the cooled nature of the solvent, the isolated Divalproex sodium absorbs considerable amount of moisture and therefore requires longer time to dry eventually leading to longer time cycle for the otherwise simple single step process. Also the high moisture content in the recovered acetone makes it unsuitable for reuse. Alternatively, to avoid absorption of water, the centrifugation had to be carried out under a blanket of dry nitrogen gas. These additional infrastructural loads add to input costs eventually making the otherwise single step low cost process becoming uncompetitive and economically unviable.Similarly the other process involves the addition of half molar equivalent of sodium hydroxide dissolved in water to valproic acid and the solvent has to be evaporated to obtain crude product, which has to be recrystallized to get Divalprox of the desired specification. The process is operationally tedious and requires the reduction in the level of water in the reaction mass via evaporation of the solvent followed by re- crystallization from acetonitrile making the process lengthy and economically unviable. There is therefore a need for operationally making this single step process more efficient and high yieldingExample I:To lOOg of Valproic acid with stirring at 20-30⁰C, powdered NaOH ( 13g; half molar) is added & the resulting reaction mixture is stirred at 40-50⁰C for 1 hr. Then acetonitrile(600ml) is added to obtain clear solution at 40-50⁰C and the solution is charcoalized at 40-50⁰C followed by filtration at 40-50⁰C through hyflo-bed. The resultant reaction mixture was stirred at 10-20⁰C for 2-3 hr. The solid , thus obtained, was filtered and product was dried at 40-45⁰C for 10-12 hr. (102.25g, 95%)Example II;To lOOg of Valproic acid with stirring at 20-30⁰C, powdered NaOH (13g; half molar) is added & the resulting reaction mixture is stirred at 30-40⁰C for 1 hr. Then acetone (600ml) is added to obtain clear solution at 30-40⁰C and the material is charcoalized at 30-40⁰C followed by filtration through hyflo-bed. The resultant reaction solution was stirred at -5°C to -1O⁰C for 2-3 hr. The solid , thus obtained, was filtered and product was dried at 40-45⁰C for 10-12 hr. ( 55g, 51.11%) Example III:To a solution of Valproic acid (10Og) in dichloromethane (200ml) at 20-30⁰C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 30- 40⁰C for 1 hr to get clear solution. Then acetonitrile (600ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-5⁰C for 2-3 hr followed by filtration. The product was dried at 40-45⁰C for 10-12 hr. (10Og; 93%)Example IV:To a solution of Valproic acid (10Og) in diisopropyl ether(200ml) at 20-30⁰C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 40-50⁰C for 1 hr to get clear solution. Then acetonitrile (800ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-5⁰C for 2-3 hr followed by filtration. The product was dried at 40-45⁰C for 10-12 hr. (104g; 96.65%)Example V:To a solution of Valproic acid (10Og) in methyl tertiary butyl ether(200ml) at 20- 30⁰C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 40-50⁰C for 1 hr to get clear solution. Then acetonitrile (800ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-5⁰C for 2-3 hr followed by filtration. The product was dried at 40-45⁰C for 10-12 hr. (102g;94.79%)Example VI:To a solution of Valproic acid (10Og) in toluene (200ml) at 20-30⁰C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 40-50⁰C for 1 hr to get clear solution. Then acetonitrile (800ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-5⁰C for 2-3 hr followed by filtration. The product was dried at 40-45⁰C for 10-12 hr. (101g; 93.87%)Example VII: A mixture of sodium valproate (6Og) and valproic acid (52.04g) was taken in acetonitrile (800ml) and heated at reflux to obtain a clear solution, which was filtered through hyflo-bed to remove suspended particles. Then the solution was stirred at 10- 20⁰C for 2-3 hr. The solid, thus obtained, was filtered and washed with acetonitrile (100ml). The product was dried at 40-45⁰C for 10-12 hr. (105g ; 93.75%)Example VIII;To a solution of valproic acid (10Og) in methanol (200ml) at 20-30⁰C₅ caustic (13g; half molar) is added & the reaction mixture is stirred at 20-30⁰C for 1 hr. Then the methanol was recovered at reduced pressure and acetonitrile (600ml) is added to it with stirring. The reaction mixture was further stirred at 0-5⁰C for 2-3 hr. The solid, thus obtained, is filtered, washed with acetonitrile (100ml) and product was dried at 40-45°C for 10-12 hr.(102g; ~ 95%) Example IX:To a solution of valproic acid (10Og) in methanol (200ml) at 20-30⁰C, caustic (13g; half molar) is added & the reaction mixture is stirred at 20-30⁰C for 1 hr. Then the methanol was recovered at reduced pressure and acetone (600ml) is added to it with stirring. The reaction mixture was further stirred at -5°C to -1O⁰C for 2-3 hr. The solid, thus obtained, is filtered, washed with chilled acetone (100ml) and product was dried at 40-45⁰C for 10-12 hr.(54g; ~ 50.11%)Example X:To a solution of valproic acid (10Og) in ethanol (200ml) at 20-30⁰C, caustic (13g; half molar) is added & the reaction mixture is stirred at 20-30⁰C for 1 hr. Then the ethanol was recovered at reduced pressure and acetonitrile (600ml) is added to it with stirring.The reaction mixture was further stirred at 0-5⁰C for 2-3 hr. The solid, thus obtained, is filtered, washed with acetonitrile (100ml) and product was dried at 40-45⁰C for 10-12 hr.(101g; ~ 93.87%)Example XI: To a solution of valproic acid (10Og) in ethanol (200ml) at 20-30°C, caustic (13g; half molar) is added & the reaction mixture is stirred at 20-30⁰C for 1 hr. Then the ethanol was recovered at reduced pressure and acetone (600ml) is added to it with stirring. The reaction mixture was further stirred at -5°C to -10⁰C for 2-3 hr. The solid, thus obtained, is filtered, washed with chilled acetone (100ml) and product was dried at 40-45⁰C for 10-12 hr.(55g; ~ 51%)ADVANTAGES:> The process is high yielding. > The process produces Divalproex sodium with improved flowability.> The process produces Divalproex sodium that is non-hygroscopic and more stable.> The process is industrially feasible, precise, reproducible and does not require sophisticated infrastructure.

Divalproex Sodium is a stable coordination compound comprised of sodium valproate and valproic acid with anticonvulsant and antiepileptic activities. Divalproex dissociates to the valproate ion in the gastrointestinal tract. This agent binds to and inhibits gamma-aminobutyric acid (GABA) transaminase and its anticonvulsant activity may be exerted by increasing brain concentration of GABA and by inhibiting enzymes that catabolize GABA or block the reuptake of GABA into glia and nerve endings. Divalproex may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels.

Valproate semisodium is a mixture of valproic acid and its sodium salt in a 1:1 molar ratio. It is used for the management and treatment of seizure disorders, mania, and prophylactic treatment of migraine headache. It has a role as an antimanic drug, an anticonvulsant and a GABA agent. It contains a valproic acid and a sodium valproate.

Divalproex sodium, valproate sodium, and valproic acid, are all similar medications that are used by the body as valproic acid. Therefore, the term valproic acid will be used to represent all of these medications in this discussion.

Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches.^[2] They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures.^[2] They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.^[2]

Common side effects of valproate include nausea, vomiting, sleepiness, and dry mouth.^[2] Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended.^[2] Other serious risks include pancreatitis and an increased suicide risk.^[2] Valproate is known to cause serious abnormalities in babies if taken during pregnancy,^[2]^[3] and as such it is not typically recommended for women of childbearing age who have migraines.^[2]

Valproate’s precise mechanism of action is unclear.^[2]^[4] Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, and inhibiting histone deacetylases.^[5]^[6] Valproic acid is a branched short-chain fatty acid (SCFA) made from valeric acid.^[5]

Valproate was first made in 1881 and came into medical use in 1962.^[7] It is on the World Health Organization’s List of Essential Medicines^[8] and is available as a generic medication.^[2] It is marketed under the brand names Depakote, among others.^[2] In 2018, it was the 131st most commonly prescribed medication in the United States, with more than 5 million prescriptions.^[9]^[10]

Terminology

Valproic acid (VPA) is an organic weak acid. The conjugate base is valproate. The sodium salt of the acid is sodium valproate and a coordination complex of the two is known as valproate semisodium.^[11]

Medical uses

It is used primarily to treat epilepsy and bipolar disorder. It is also used to prevent migraine headaches.^[12]

Epilepsy

Valproate has a broad spectrum of anticonvulsant activity, although it is primarily used as a first-line treatment for tonic–clonic seizures, absence seizures and myoclonic seizures and as a second-line treatment for partial seizures and infantile spasms.^[12]^[13] It has also been successfully given intravenously to treat status epilepticus.^[14]^[15]

Mental illness

Bipolar disorder

Valproate products are also used to treat manic or mixed episodes of bipolar disorder.^[16]^[17]

Schizophrenia

A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:^[18]

There is limited evidence that adding valproate to antipsychotics may be effective for overall response and also for specific symptoms, especially in terms of excitement and aggression. Valproate was associated with a number of adverse events among which sedation and dizziness appeared more frequently than in the control groups.^[18]

showOutcomeFindings in wordsFindings in numbersQuality of evidence

Dopamine dysregulation syndrome

Based upon five case reports, valproic acid may have efficacy in controlling the symptoms of the dopamine dysregulation syndrome that arise from the treatment of Parkinson’s disease with levodopa.^[19]^[20]^[21]

Migraines

Valproate is also used to prevent migraine headaches. Because this medication can be potentially harmful to the fetus, valproate should be considered for those able to become pregnant only after the risks have been discussed.^[22]

Other

The medication has been tested in the treatment of AIDS and cancer, owing to its histone-deacetylase-inhibiting effects.^[23]

Contraindications

Contraindications include:

Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related.^[24]
Known hypersensitivity to valproate or any of the ingredients used in the preparation^[24]
Urea cycle disorders^[24]
Hepatic porphyria^[24]
Hepatotoxicity^[24]
Mitochondrial disease^[24]
Pancreatitis^[24]
Porphyria^[25]

Adverse effects

Most common adverse effects include:^[22]

Nausea (22%)
Drowsiness (19%)
Dizziness (12%)
Vomiting (12%)
Weakness (10%)

Serious adverse effects include:^[22]

Bleeding
Low blood platelets
Encephalopathy
Suicidal behavior and thoughts
Low body temperature

Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.^[22]

There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.^[26]^[27]^[28]^[29] Valproic acid can also cause mydriasis, a dilation of the pupils.^[30] There is evidence that shows valproic acid may increase the chance of polycystic ovary syndrome (PCOS) in women with epilepsy or bipolar disorder. Studies have shown this risk of PCOS is higher in women with epilepsy compared to those with bipolar disorder.^[31] Weight gain is also possible.^[32]

Pregnancy

Valproate causes birth defects;^[33] exposure during pregnancy is associated with about three times as many major abnormalities as usual, mainly spina bifida with the risks being related to the strength of medication used and use of more than one drug.^[34]^[35] More rarely, with several other defects, including a “valproate syndrome”.^[36] Characteristics of this valproate syndrome include facial features that tend to evolve with age, including a triangle-shaped forehead, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth.^[37] While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.^[38]

Children of mothers taking valproate during pregnancy are at risk for lower IQs.^[39]^[40]^[41] Maternal valproate use during pregnancy increased the probability of autism in the offspring compared to mothers not taking valproate from 1.5% to 4.4%.^[42] A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.^[43] The normal incidence for autism in the general population is estimated at less than one percent.^[44] A 2009 study found that the 3-year-old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.^[45]^[46]^[47]

Sodium valproate has been associated with paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy.^[48]^[49]

Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate.^[50] Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although valproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have worse outcomes for the fetus than exposure to valproate). Studies have shown that taking folic acid supplements can reduce the risk of congenital neural tube defects.^[22] The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in the European Union, and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available.^[51]

Elderly

Valproate in elderly people with dementia caused increased sleepiness. More people stopped the medication for this reason. Additional side effects of weight loss and decreased food intake were also associated with one-half of people who become sleepy.^[22]

Overdose and toxicity

Form	Lower limit	Upper limit	Unit
Total (including protein bound)	50^[52]	125^[52]	µg/mL or mg/l
350^[53]	700^[53]	μmol/L
Free	6^[52]	22^[52]	µg/mL or mg/l
35^[53]	70^[53]	μmol/L

Excessive amounts of valproic acid can result in sleepiness, tremor, stupor, respiratory depression, coma, metabolic acidosis, and death.^[54] In general, serum or plasma valproic acid concentrations are in a range of 20–100 mg/l during controlled therapy, but may reach 150–1500 mg/l following acute poisoning. Monitoring of the serum level is often accomplished using commercial immunoassay techniques, although some laboratories employ gas or liquid chromatography.^[55] In contrast to other antiepileptic drugs, at present there is little favorable evidence for salivary therapeutic drug monitoring. Salivary levels of valproic acid correlate poorly with serum levels, partly due to valproate’s weak acid property (pKa of 4.9).^[56]

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.^[57]^[58] Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored.^[22] Supplemental L-carnitine is indicated in patients having an acute overdose^[59]^[60] and also prophylactically^[59] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly^[61] than L-carnitine.

Interactions

Valproate inhibits CYP2C9, glucuronyl transferase, and epoxide hydrolase and is highly protein bound and hence may interact with drugs that are substrates for any of these enzymes or are highly protein bound themselves.^[24] It may also potentiate the CNS depressant effects of alcohol.^[24] It should not be given in conjunction with other antiepileptics due to the potential for reduced clearance of other antiepileptics (including carbamazepine, lamotrigine, phenytoin and phenobarbitone) and itself.^[24] It may also interact with:^[22]^[24]^[62]

Aspirin: may increase valproate concentrations. May also interfere with valproate’s metabolism.
Benzodiazepines: may cause CNS depression and there are possible pharmacokinetic interactions.
Carbapenem antibiotics: reduce valproate levels, potentially leading to seizures.
Cimetidine: inhibits valproate’s metabolism in the liver, leading to increased valproate concentrations.
Erythromycin: inhibits valproate’s metabolism in the liver, leading to increased valproate concentrations.
Ethosuximide: valproate may increase ethosuximide concentrations and lead to toxicity.
Felbamate: may increase plasma concentrations of valproate.
Mefloquine: may increase valproate metabolism combined with the direct epileptogenic effects of mefloquine.
Oral contraceptives: may reduce plasma concentrations of valproate.
Primidone: may accelerate metabolism of valproate, leading to a decline of serum levels and potential breakthrough seizure.
Rifampicin: increases the clearance of valproate, leading to decreased valproate concentrations
Warfarin: valproate may increase free warfarin concentration and prolong bleeding time.
Zidovudine: valproate may increase zidovudine serum concentration and lead to toxicity.

Pharmacology

Pharmacodynamics

Although the mechanism of action of valproate is not fully understood,^[24] traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA).^[24] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.^[24] In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic neurotransmitter, GABA, possibly by inhibiting GABA degradative enzymes, such as GABA transaminase, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells.^[24]

Prevention of neurotransmitter-induced hyperexcitability of nerve cells, via Kv7.2 channel and AKAP5, may also contribute to its mechanism.^[63] Also, it has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.^[64]

It also has histone-deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid. Intermediate molecules mediating these effects include VEGF, BDNF, and GDNF.^[65]^[66]

Endocrine actions

Valproic acid has been found to be an antagonist of the androgen and progesterone receptors, and hence as a nonsteroidal antiandrogen and antiprogestogen, at concentrations much lower than therapeutic serum levels.^[67] In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.^[68] These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.^[67]^[68]

Valproic acid has been found to directly stimulate androgen biosynthesis in the gonads via inhibition of histone deacetylases and has been associated with hyperandrogenism in women and increased 4-androstenedione levels in men.^[69]^[70] High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.^[70]

Pharmacokinetics

Some metabolites of valproic acid. Glucuronidation and β-oxidation are the main metabolic pathways; ω-oxidation metabolites are considered hepatotoxic.^[71]^[72] Details see text.

Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut.^[71] When in the bloodstream, 80–90% of the substance are bound to plasma proteins, mainly albumin. Protein binding is saturable: it decreases with increasing valproate concentration, low albumin concentrations, the patient’s age, additional use of other drugs such as aspirin, as well as liver and kidney impairment.^[73]^[74] Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10% of blood plasma concentrations.^[71]

The vast majority of valproate metabolism occurs in the liver.^[75] Valproate is known to be metabolized by the cytochrome P450 enzymes CYP2A6, CYP2B6, CYP2C9, and CYP3A5.^[75] It is also known to be metabolized by the UDP-glucuronosyltransferase enzymes UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15.^[75] Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image):^[75]

via glucuronidation (30–50%): valproic acid β-O-glucuronide
via beta oxidation (>40%): 2E-ene-valproic acid, 2Z-ene-valproic acid, 3-hydroxyvalproic acid, 3-oxovalproic acid
via omega oxidation: 5-hydroxyvalproic acid, 2-propyl-glutaric acid
some others: 3E-ene-valproic acid, 3Z-ene-valproic acid, 4-ene-valproic acid, 4-hydroxyvalproic acid

All in all, over 20 metabolites are known.^[71]

In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as the glucuronide conjugate.^[75] The other major pathway in the metabolism of valproate is mitochondrial beta oxidation, which typically accounts for over 40% of an administered dose.^[75] Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms.^[75] Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine.^[75] Only a small amount is excreted via the faeces.^[71] Elimination half-life is 16±3 hours and can decrease to 4–9 hours when combined with enzyme inducers.^[71]^[74]

Chemistry

Valproic acid is a branched short-chain fatty acid and the 2-n–propyl derivative of valeric acid.^[5]

History

Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.^[76] Valproic acid is a carboxylic acid, a clear liquid at room temperature. For many decades, its only use was in laboratories as a “metabolically inert” solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for antiseizure activity. He found it prevented pentylenetetrazol-induced convulsions in laboratory rats.^[77] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.^[78] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.^[79]

Society and culture

Valproate is available as a generic medication.^[2]

Approval status

Indications	FDA-labelled indication?^[1]	TGA-labelled indication?^[12]	MHRA-labelled indication?^[80]	Literature support
Epilepsy	Yes	Yes	Yes	Limited (depends on the seizure type; it can help with certain kinds of seizures: drug-resistant epilepsy, partial and absence seizures, can be used against glioblastoma and other tumors both to improve survival and treat seizures, and against tonic–clonic seizures and status epilepticus).^[81]^[82]^[83]^[84]
Bipolar mania	Yes	Yes	Yes	Limited.^[85]
Bipolar depression	No	No	No	Moderate.^[86]
Bipolar maintenance	No	No	No	Limited.^[87]
Migraine prophylaxis	Yes	Yes (accepted)	No	Limited.
Acute migraine management	No	No	No	Only negative results.^[88]
Schizophrenia	No	No	No	Weak evidence.^[89]
Agitation in dementia	No	No	No	Weak evidence. Not recommended for agitation in people with dementia.^[90] Increased rate of adverse effects, including a risk of serious adverse effects.^[90]
Fragile X syndrome	Yes (orphan)	No	No	Limited.^[66]
Familial adenomatous polyposis	Yes (orphan)	No	No	Limited.
Chronic pain & fibromyalgia	No	No	No	Limited.^[91]
Alcohol hallucinosis	No	No	No	One randomised double-blind placebo-controlled trial.^[92]
Intractable hiccups	No	No	No	Limited, five case reports support its efficacy, however.^[93]
Non-epileptic myoclonus	No	No	No	Limited, three case reports support its efficacy, however.^[94]
Cluster headaches	No	No	No	Limited, two case reports support its efficacy.^[95]
West syndrome	No	No	No	A prospective clinical trial supported its efficacy in treating infantile spasms.^[96]
HIV infection eradication	No	No	No	Double-blind placebo-controlled trials have been negative.^[97]^[98]^[99]
Myelodysplastic syndrome	No	No	No	Several clinical trials have confirmed its efficacy as a monotherapy,^[100] as an adjunct to tretinoin^[100] and as an adjunct to hydralazine.^[101]
Acute myeloid leukaemia	No	No	No	Two clinical trials have confirmed its efficacy in this indication as both a monotherapy and as an adjunct to tretinoin.^[102]^[103]^[104]
Cervical cancer	No	No	No	One clinical trial supports its use here.^[105]
Malignant melanoma	No	No	No	One phase II study has seemed to discount its efficacy.^[106]
Breast cancer	No	No	No	A phase II study has supported its efficacy.^[107]
Impulse control disorder	No	No	No	Limited.^[108]^[109]

Off-label uses

In 2012, pharmaceutical company Abbott paid $1.6 billion in fines to US federal and state governments for illegal promotion of off-label uses for Depakote, including the sedation of elderly nursing home residents.^[110]^[111]

Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.^[112]^[113]

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Formulations

Clinical data


Other names	valproate sodium (USAN US)
License data	US DailyMed: Valproate_sodium
Identifiers
show IUPAC name
CAS Number	1069-66-5
PubChem CID	16760703
DrugBank	DBSALT001257
ChemSpider	13428
UNII	5VOM6GYJ0D
KEGG	D00710
ChEBI	CHEBI:9925
ChEMBL	ChEMBL433
CompTox Dashboard (EPA)	DTXSID6023733
ECHA InfoCard	100.002.525
Chemical and physical data
Formula	C₈H₁₅NaO₂
Molar mass	166.196 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI
(verify)

Clinical data
Trade names	Depakote, others
Other names	semisodium valproate, divalproex sodium (USAN US)
License data	US DailyMed: Divalproex_sodium
Identifiers
show IUPAC name
CAS Number	76584-70-8
PubChem CID	23663956
DrugBank	DBSALT000185
ChemSpider	48337
UNII	644VL95AO6
KEGG	D00304
ChEBI	CHEBI:4667
ChEMBL	ChEMBL2105613
CompTox Dashboard (EPA)	DTXSID6023733
ECHA InfoCard	100.002.525
Chemical and physical data
Formula	C₁₆H₃₁NaO₄
Molar mass	310.410 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI

Valproate exists in two main molecular variants: sodium valproate and valproic acid without sodium (often implied by simply valproate). A mixture between these two is termed semisodium valproate. It is unclear whether there is any difference in efficacy between these variants, except from the fact that about 10% more mass of sodium valproate is needed than valproic acid without sodium to compensate for the sodium itself.^[114]

Brand names of valproic acid

Branded products include:

Absenor (Orion Corporation Finland)
Convulex (G.L. Pharma GmbH Austria)
Depakene (Abbott Laboratories in US and Canada)^[115]
Depakine (Sanofi Aventis France)
Depakine (Sanofi Synthelabo Romania)
Depalept (Sanofi Aventis Israel)
Deprakine (Sanofi Aventis Finland)
Encorate (Sun Pharmaceuticals India)
Epival (Abbott Laboratories US and Canada)
Epilim (Sanofi Synthelabo Australia and South Africa)
Stavzor (Noven Pharmaceuticals Inc.)
Valcote (Abbott Laboratories Argentina)
Valpakine (Sanofi Aventis Brazil)
Orfiril (Desitin Arzneimittel GmbH Norway)

Brand names of sodium valproate

Portugal

Tablets – Diplexil-R by Bial.

United States

Intravenous injection – Depacon by Abbott Laboratories.
Syrup – Depakene by Abbott Laboratories. (Note Depakene capsules are valproic acid).
Depakote tablets are a mixture of sodium valproate and valproic acid.
Tablets – Eliaxim by Bial.

Australia

Epilim Crushable Tablets Sanofi^[116]
Epilim Sugar Free Liquid Sanofi^[116]
Epilim Syrup Sanofi^[116]
Epilim Tablets Sanofi^[116]
Sodium Valproate Sandoz Tablets Sanofi
Valpro Tablets Alphapharm
Valproate Winthrop Tablets Sanofi
Valprease tablets Sigma

New Zealand

Epilim by Sanofi-Aventis

All the above formulations are Pharmac-subsidised.^[117]

UK

Depakote Tablets (as in USA)
Tablets – Orlept by Wockhardt and Epilim by Sanofi
Oral solution – Orlept Sugar Free by Wockhardt and Epilim by Sanofi
Syrup – Epilim by Sanofi-Aventis
Intravenous injection – Epilim Intravenous by Sanofi
Extended release tablets – Epilim Chrono by Sanofi is a combination of sodium valproate and valproic acid in a 2.3:1 ratio.
Enteric-coated tablets – Epilim EC200 by Sanofi is a 200-mg sodium valproate enteric-coated tablet.

UK only

Capsules – Episenta prolonged release by Beacon
Sachets – Episenta prolonged release by Beacon
Intravenous solution for injection – Episenta solution for injection by Beacon

Germany, Switzerland, Norway, Finland, Sweden

Tablets – Orfiril by Desitin Pharmaceuticals
Intravenous injection – Orfiril IV by Desitin Pharmaceuticals

South Africa

Syrup – Convulex by Byk Madaus^[118]
Tablets – Epilim by Sanofi-synthelabo

Malaysia

Tablets – Epilim by Sanofi-Aventis

Romania

Companies are SANOFI-AVENTIS FRANCE, GEROT PHARMAZEUTIKA GMBH and DESITIN ARZNEIMITTEL GMBH
Types are Syrup, Extended release mini tablets, Gastric resistant coated tablets, Gastric resistant soft capsules, Extended release capsules, Extended release tablets and Extended release coated tablets

Canada

Intravenous injection – Epival or Epiject by Abbott Laboratories.
Syrup – Depakene by Abbott Laboratories its generic formulations include Apo-Valproic and ratio-Valproic.

Japan

Tablets – Depakene by Kyowa Hakko Kirin
Extended release tablets – Depakene-R by Kyowa Hakko Kogyo and Selenica-R by Kowa
Syrup – Depakene by Kyowa Hakko Kogyo

Europe

In much of Europe, Dépakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.

Taiwan

Tablets (white round tablet) – Depakine (Chinese: 帝拔癲; pinyin: di-ba-dian) by Sanofi Winthrop Industrie (France)

Iran

Tablets – Epival 200 (enteric coated tablet) and Epival 500 (extended release tablet) by Iran Najo
Slow release tablets – Depakine Chrono by Sanofi Winthrop Industrie (France)

Israel

Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above. Manufactured and distributed by Sanofi-Aventis.

India, Russia and CIS countries

Valparin Chrono by Torrent Pharmaceuticals India
Valprol CR by Intas Pharmaceutical (India)
Encorate Chrono by Sun Pharmaceutical (India)
Serven Chrono by Leeven APL Biotech (India)

Brand names of valproate semisodium

Brazil – Depakote by Abbott Laboratories and Torval CR by Torrent do Brasil
Canada – Epival by Abbott Laboratories
Mexico – Epival and Epival ER (extended release) by Abbott Laboratories
United Kingdom – Depakote (for psychiatric conditions) and Epilim (for epilepsy) by Sanofi-Aventis and generics
United States – Depakote and Depakote ER (extended release) by Abbott Laboratories and generics^[22]
India – Valance and Valance OD by Abbott Healthcare Pvt Ltd, Divalid ER by Linux laboratories Pvt Ltd, Valex ER by Sigmund Promedica, Dicorate by Sun Pharma
Germany – Ergenyl Chrono by Sanofi-Aventis and generics
Chile – Valcote and Valcote ER by Abbott Laboratories
France and other European countries — Depakote
Peru – Divalprax by AC Farma Laboratories
China – Diprate OD

References

^ Jump up to:^a ^b ^c ^d “Depakene, Stavzor (valproic acid) dosing, indications, interactions, adverse effects, and more”. Medscape Reference. WebMD. Archived from the original on 21 February 2014. Retrieved 13 February 2014.
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^ Rocca A, Minucci S, Tosti G, Croci D, Contegno F, Ballarini M, Nolè F, Munzone E, Salmaggi A, Goldhirsch A, Pelicci PG, Testori A (2009). “A phase I-II study of the histone deacetylase inhibitor valproic acid plus chemoimmunotherapy in patients with advanced melanoma”. Br. J. Cancer. 100 (1): 28–36. doi:10.1038/sj.bjc.6604817. PMC 2634690. PMID 19127265.
^ Munster P, Marchion D, Bicaku E, Lacevic M, Kim J, Centeno B, Daud A, Neuger A, Minton S, Sullivan D (2009). “Clinical and biological effects of valproic acid as a histone deacetylase inhibitor on tumor and surrogate tissues: phase I/II trial of valproic acid and epirubicin/FEC” (PDF). Clin. Cancer Res. 15 (7): 2488–96. doi:10.1158/1078-0432.CCR-08-1930. PMID 19318486. S2CID 3230087.
^ Hicks CW, Pandya MM, Itin I, Fernandez HH (2011). “Valproate for the treatment of medication-induced impulse-control disorders in three patients with Parkinson’s disease”. Parkinsonism Relat. Disord. 17 (5): 379–81. doi:10.1016/j.parkreldis.2011.03.003. PMID 21459656.
^ Sriram A, Ward HE, Hassan A, Iyer S, Foote KD, Rodriguez RL, McFarland NR, Okun MS (2013). “Valproate as a treatment for dopamine dysregulation syndrome (DDS) in Parkinson’s disease”. J. Neurol. 260 (2): 521–7. doi:10.1007/s00415-012-6669-1. PMID 23007193. S2CID 21544457.
^ Aizenman, N. C. (7 May 2012). “Abbott Laboratories to pay $1.6 billion over illegal marketing of Depakote”. Washington Post. Retrieved 27 June 2018.
^ Schmidt, Michael; Thomas, Katie (8 May 2012). “Abbott settles marketing lawsuit”. New York Times. Retrieved 27 June 2018.
^ Gervain J, Vines BW, Chen LM, Seo RJ, Hensch TK, Werker JF, Young AH (2013). “Valproate reopens critical-period learning of absolute pitch”. Frontiers in Systems Neuroscience. 7: 102. doi:10.3389/fnsys.2013.00102. PMC 3848041. PMID 24348349.
^ Thomson, Helen. “Learning drugs reawaken grown-up brain’s inner child”. New Scientist. New Scientist Ltd. Retrieved 8 May2021.
^ David Taylor; Carol Paton; Shitij Kapur (2009). The Maudsley Prescribing Guidelines, Tenth Edition (10, revised ed.). CRC Press. p. 124. ISBN 9780203092835.
^ “Depakene- valproic acid capsule, liquid filled”. DailyMed. 19 September 2019. Retrieved 14 April 2020.
^ Jump up to:^a ^b ^c ^d “Australian product information epilim (sodium valproate) crushable tablets, enteric-coated tablets, syrup, liquid” (PDF). TGA eBS. 15 April 2020. Retrieved 15 April 2020.
^ “Sodium valproate — Pharmaceutical Schedule”. Pharmaceutical Management Agency. Archived from the originalon 4 March 2016. Retrieved 22 June 2014.
^ South African Electronic Package Inserts: Convulex

External links

“Valproic acid”. Drug Information Portal. U.S. National Library of Medicine.
“Valproate sodium”. Drug Information Portal. U.S. National Library of Medicine.
“Divalproex sodium”. Drug Information Portal. U.S. National Library of Medicine.

Clinical data


Trade names	Depakote, Epilim, Convulex, others
Other names	Valproic acid; Sodium valproate (sodium); Valproate semisodium (semisodium); 2-Propylvaleric acid
AHFS/Drugs.com	Monograph
MedlinePlus	a682412
License data	US DailyMed: Valproic_acidUS FDA: Valproic%20acid
Pregnancy category	AU: D
Routes of administration	By mouth, intravenous
ATC code	N03AG01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)CA: ℞-onlyUK: POM (Prescription only)US: ℞-only
Pharmacokinetic data
Bioavailability	Rapid absorption
Protein binding	80–90%^[1]
Metabolism	Liver—glucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%
Elimination half-life	9–16 hours^[1]
Excretion	Urine (30–50%)^[1]
Identifiers
show IUPAC name
CAS Number	99-66-1
PubChem CID	3121
IUPHAR/BPS	7009
DrugBank	DB00313
ChemSpider	3009
UNII	614OI1Z5WI
KEGG	D00399
ChEBI	CHEBI:39867
ChEMBL	ChEMBL109
NIAID ChemDB	057177
CompTox Dashboard (EPA)	DTXSID6023733
ECHA InfoCard	100.002.525
Chemical and physical data
Formula	C₈H₁₆O₂
Molar mass	144.214 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI
(verify)

Patent

Publication numberPriority datePublication dateAssigneeTitleCA1144558A *1979-10-221983-04-12Francis E. FischerProcess for making sodium hydrogen divalproateUS4988731A *1979-08-201991-01-29Abbott LaboratoriesSodium hydrogen divalproate oligomerUS5212326A *1979-08-201993-05-18Abbott LaboratoriesSodium hydrogen divalproate oligomerWO2001032595A1 *1999-11-022001-05-10Cilag AgMethod for producing compounds of the valproinic acidUS20030018215A1 *2001-06-292003-01-23Procos S.P.A.Process for the preparation of sodium divalproatePublication numberPriority datePublication dateAssigneeTitleUS20110040122A1 *2009-08-112011-02-17Sci Pharmtech, Inc.Method for preparing metal salt of valproic acidCN102942467A *2012-10-172013-02-27山东方明药业集团股份有限公司Preparation method of divalproex sodiumCN103183600A *2011-12-302013-07-03北大方正集团有限公司Method for preparing divalproex sodium

////// divalproex, Anticonvulsant, Antimigraine, Antimanic, valproic acid, sodium valproate

CCCC(CCC)C(O)=O

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FAROPENEM

October 21, 2021 8:46 am / Leave a comment

Molecular FormulaC₁₂H₁₅NO₅S
Average mass285.316 Da

Faropenem

7086

(+)-(5R,6S)-6-((1R)-1-Hydroxyethyl)-7-oxo-3-((2R)-tetrahydro-2-furyl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid

(5R,6S)-6-[(1R)-1-Hydroxyethyl]-7-oxo-3-[(2R)-tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
(5R,6S)-6-[(1R)-1-Hydroxyethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
106560-14-9[RN]
4-Thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2R)-tetrahydro-2-furanyl]-, (5R,6S)-
6α-[(R)-1-hydroxyethyl]-2-[(R)-tetrahydrofuran-2-yl]pen-2-em-3-carboxylic acid
4-Oxofenretinide
4-Oxo-N-(4-hydroxyphenyl)retinamide
6α-[(1R)-1-hydroxyethyl]-2-[(2R)-tetrahydrofuran-2-yl]-2,3-didehydropenam-3-carboxylic acid
7305146 [Beilstein]
FaropenemCAS Registry Number: 106560-14-9
CAS Name: (5R,6S)-6-[(1R)-1-Hydroxyethyl]-7-oxo-3-[(2R)-tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Additional Names: fropenem; (5R,6S,8R,2¢R)-2-(2¢-tetrahydrofuryl)-6-hydroxyethylpenem-3-carboxylate
Molecular Formula: C12H15NO5S
Molecular Weight: 285.32
Percent Composition: C 50.51%, H 5.30%, N 4.91%, O 28.04%, S 11.24%
Literature References: Orally active, b-lactamase stable, penem antibiotic.Prepn: M. Ishiguro et al.,EP199446; eidem,US4997829 (1986, 1991 both to Suntory); eidem,J. Antibiot.41, 1685 (1988).Pharmacokinetics: A. Tsuji et al.,Drug Metab. Dispos.18, 245 (1990). In vitro antimicrobial spectrum: J. M. Woodcock et al.,J. Antimicrob. Chemother.39, 35 (1997). b-Lactamase stability: A. Dalhoff et al., Chemotherapy (Basel)49, 229 (2003).HPLC determn in plasma: R. V. S. Nirogi et al., Arzneim.-Forsch.55, 762 (2005). Clinical trial in urinary tract infections: S. Arakawa et al.,Nishinihon J. Urol.56, 300 (1994); in bacterial sinusitis: R. Siegert et al., Eur. Arch. Otorhinolaryngol.260, 186 (2003).
Derivative Type: Sodium salt
CAS Registry Number: 122547-49-3
Additional Names: Furopenem
Manufacturers’ Codes: ALP-201; SUN-5555; SY-5555; WY-49605
Trademarks: Farom (Daiichi)
Molecular Formula: C12H15NNaO5S
Molecular Weight: 308.31
Percent Composition: C 46.75%, H 4.90%, N 4.54%, Na 7.46%, O 25.95%, S 10.40%
Properties: [a]D22 +60° (c = 0.10).
Optical Rotation: [a]D22 +60° (c = 0.10)
Derivative Type: Daloxate
CAS Registry Number: 141702-36-5
CAS Name: (5R,6S)-6-[(1R)-1-Hydroxyethyl]-7-oxo-3-[(2R)-tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester
Additional Names: faropenem medoxomil
Manufacturers’ Codes: Bay-56-6854; SUN-208
Trademarks: Orapem (Replidyne)
Molecular Formula: C17H19NO8S
Molecular Weight: 397.40
Percent Composition: C 51.38%, H 4.82%, N 3.52%, O 32.21%, S 8.07%
Literature References: Prepn: H. Iwata et al., WO9203442; eidem, US5830889 (1992, 1998 both to Suntory).
Properties: Pale yellow crystals.
Therap-Cat: Antibacterial (antibiotics).
Keywords: Antibacterial (Antibiotics); ?Lactams; Penems.

Faropenem is an orally active beta-lactam antibiotic belonging to the penem group.^[1] It is resistant to some forms of extended-spectrum beta-lactamase.^[2] It is available for oral use.^[3]

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Forms

Faropenem was developed by Daiichi Asubio Pharma, which markets it in two forms.

The sodium salt faropenem sodium, available under the trade name Farom, has been marketed in Japan since 1997. (CID 636379 from PubChem)
The prodrug form faropenem medoxomil^[4] (also known as faropenem daloxate) has been licensed from Daiichi Asubio Pharma by Replidyne, which plans to market it in conjunction with Forest Pharmaceuticals. The trade name proposed for the product was Orapem, but company officials recently announced this name was rejected by the FDA.^[5]

Clinical use

As of 8 September 2015, Faropenem has yet to receive marketing approval in the United States, and was submitted for consideration by the United States Food and Drug Administration (FDA) on 20 December 2005. The new drug application dossier submitted included these proposed indications:

acute bacterial sinusitis
community-acquired pneumonia
acute exacerbations of chronic bronchitis
uncomplicated skin and skin structure infections
urinary tract infections

History

The FDA refused to approve faropenem, an antibiotic manufactured by Louisville-based Replidyne. The FDA said the drug was “nonapprovable”, but did not refer to specific safety concerns about the product. The company will have to conduct new studies and clinical trials, lasting an estimated two more years, to prove the drug treats community-acquired pneumonia, bacterial sinusitis, chronic bronchitis, and skin infections.^{[citation needed]}

In India it is available as Farobact 200/300ER CIPLA.

PATENT

https://patents.google.com/patent/WO2008035153A2/enFaropenem is an orally active β-lactam antibiotic belonging to the penem group. Faropenem is chemically known as 6-(l-hydroxyethyl)-7-oxo-3-(oxolan-2-yl)-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid. The known forms of Faropenem are Faropenem sodium and the prodrug form, FaropenemMedoxomil (also known as Faropenem Daloxate). In view of the importance of the compound of the formula (I), several synthetic procedures to prepare the compound have been reported.US 4,997,829 provides process for the preparation of faropenem according to the following scheme. The process is exemplified with the allyl protected carboxyl group. One of the process involves the reaction of A- acetoxyazetidinone with tetrahydrothiofuroic acid, condensation with allyl glyoxalate in refluxing benzene, chlorination with thionyl chloride, reaction of triphenylphosphine with lutidine in hot THF, cyclization in refluxing toluene, deprotection of silyl protecting group with tetrabutylammonium fluoride, treating with triphenylphosphine and, treating with sodium 2-ethylhexanoate and (PP^)₄Pd to result faropenem sodium. The process exemplified utilizes benzene as solvent, which is not environmentally acceptable. Tetrabutylammonium fluoride was used as desilylating agent that is expensive. Even though the description teaches that optically active compounds can be employed, the examples utilized the dl-compound of tetrahydrothiofuroic acid further requiring resolution.

Methods are provided for the synthesis of series of penem compounds in J Antibiotics 1988, 41(11), 1685-1693. The provided methods utilize sulfonylazetidinone as the starting materials. As one of the procedures gives lesser yield, another procedure was adopted which uses silver salts.Japanese patent, JP2949363 describes a process for deallylation and salt formation with an alkali metal salt of carboxylic acid in the presence of a catalytic amount of palladium complex for the preparation of faropenem.EP410727 describes a process for removing allyl group from a penem compound using cyclic 1,3-diketone such as dimedone.The yield and quality of the final product is always less in the above prior art methods. With the continued research, the present inventors have undertaken extensive studies for developing a process for the preparation of compound of formula (I), which is commercially viable, involves simple techniques such as crystallizations, with improved yields and quality of the product, and with lesser reaction time. None of the prior art suggests or teaches the techniques provided herein.The process is shown in Scheme-I as given below:

One-pot process for the preparation of Faropenem sodium:Sodium salt of R(+)-tetrahydrofuran-2-thiocarboxylic acid (67 g) in aqueous acetone was added slowly to a solution of AOSA (100 g) in acetone (200 mL) and stirred for 3 h at pH 8.0 to 8.5 using sodium bicarbonate solution.After completion of the reaction, the product was extracted with toluene. The combined toluene layer was washed with saturated sodium bicarbonate solution and brine solution. Toluene was removed under vacuum completely and the mass obtained, 3-(l’-tert-butyldimethylsilyloxyethyl)-4-(2′- tetrahydrofuranoylthio)-2-azetidinone was directly taken for next step.3-(r-tert-Butyldimethylsilyloxyethyl)-4-(2′-tetrahydrofuranoylthio)-2- azetidinone obtained was dissolved in toluene (1000 mL) and cooled to -10 to -5 °C under nitrogen. Triethylamine (124 mL) was added to it followed by allyl oxalyl chloride (82 g) at -10 to- 5 ⁰C for 2 h. After completion of the reaction, cold water was added to the mass and washed with dilute hydrochloric acid and sodium bicarbonate solution. Toluene layer was separated and washed with purified water. The toluene layer containing compound of formula (VI) was concentrated under vacuum at 50 to 60 °C and taken for next step as such.Compound of formula (VI) (150 g) was dissolved in triethyl phosphite (150 mL), heated to 60 ⁰C and stirred under nitrogen atmosphere. Toluene (3000 mL) was added, heated to 100 to 110 °C and stirred for 20- 24 h. Toluene was distilled under vacuum completely. Product obtained, allyl (1 ‘R,2″R,5R,6S)-6-(l ⁵-tert-butyldimethylsilyloxyethyl)-2-(2″-tetrahydrofuranyl) penem-3-carboxylate (VII) was directly taken for next step.Compound (VII) obtained was dissolved in DMF (700 mL) at 30 °C.Ammonium hydrogen difluoride (80 g) and NMP (210 mL) were added and stirred at room temperature for 25 to 35 h. The reaction mass was quenched into a mixture of water-ethyl acetate and stirred at room temperature. The ethyl acetate layer was separated and the aqueous layer extracted with ethyl acetate. ^■ The combined ethyl acetate layer was washed with water followed by saturated sodium bicarbonate solution. The ethyl acetate layer was charcoal treated. The ethyl acetate layer containing allyl (l’R,2″R,5R,6S)-6-(l’-hydroxyethyl)-2-(2″- tetrahydrofuranyl)penem-3-carboxylate (XII) was partially distilled and taken for the next step.The ethyl acetate layer containing compound of formula (XII), Pd/C, sodium bicarbonate and purified water (1000 mL) were taken in an autoclave and maintained 5 to 10 kg pressure of hydrogen gas for 2-5 h. After completion of the reaction the Pd/C was filtered off and ethyl acetate layer separated. The pH of the mass was adjusted to 1.5 and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate twice. The combined ethyl acetate layer was carbon treated. Sodium-2-ethylhexanoate in ethyl acetate was added slowly and stirred. The precipitated title compound was filtered under vacuum, washed with acetone and dried. Dry weight of the product: 65-75 g.Example 9Purification of Faropenem sodiumCrude Faropenem sodium (50 g) was dissolved in purified water (200 mL) at 25-30 ⁰C. The solution was charcoalised. Acetone (1500 mL) was added. The reaction mass was stirred further for 10 min. The precipitated solid was cooled to 0 —2 °C then filtered, washed with acetone and dried at room temperature. Weight of pure Faropenem sodium is 43 to 46 g (Purity 99.95%).Example 9aPurification of Faropenem sodiumCrude Faropenem sodium (50 g) was dissolved in purified water (200 mL) at 25-30 °C. Acetone (150O mL) was added. The reaction mass was stirred further for 10 min. The precipitated solid was cooled to 0-2 °C then filtered, washed with acetone and dried at room temperature. Weight of pure Faropenem sodium is 43 to 46 g (Purity 99.95%).

PATENT

https://patents.google.com/patent/CN103880864B/enFaropenem sodium is developed by Japanese Suntory companies, and first penemss antibiosis in listing in 1997 Element, it are similar to the several carbapenem antibiotics for listing, strong with has a broad antifungal spectrum, antibacterial activity, to beta-lactamase Stably, the features such as also having good action to extended spectrumβ-lactamase producing strains, citrobacter, enterococcus and anaerobe etc.. It is first orally active, penems antibiotics stable to beta-lactamase in the world so far.Its structural formula As follows：
Report about Faropenem sodium preparation method is a lot, mainly has several as follows：1st, J. Antibiotics 1988, the method that reports in 41,1685, see below row reaction equation:
Acyl group substitution reaction is carried out in the basic conditions with 4-AA and three beneze methane thiols and obtains thio trityl as protecting group Aza cyclo-butanone, then when 2-TETRAHYDROFUROYL chlorine is connected with lactams, using silver nitrate as condensing agent, but nitric acid Silver is expensive, and cost is too high, while the silver chloride for generating is difficult to filter, is not suitable for large-scale production.2nd, the classical preparation method of United States Patent (USP) US4997829 report：There is acyl with (R) tetrahydrofuran -2- thiocarboxylic acids Base substitution reaction generates thioesters, then through condensation, chlorine replacement, intramolecular Witting cyclization, slough hydroxyl protecting group and carboxylic Base protection group obtains product, and this synthetic route yield is very low, while side chain is thio-compoundss, abnormal smells from the patient is extremely smelly, and prepares complexity, There is-fixed harm to human body and environment.It is also required in chloro building-up process using pungent thionyl chloride, these factors are all It is unfavorable for industrialized production
3rd, the method that reports in Chinese patent CN1314691 is as follows：
Said method route is shorter, is produced using one kettle way, more convenient.But said method is related to some other salt such as acetate using heavy metal palladium in last operation The deprotecting regent of compound and triphenyl phosphorus together as pi-allyl, metal palladium reagent is expensive, while triphenyl phosphorus are most More difficult removing in step afterwards, increases operation difficulty, affects product quality.Allyloxy is used easily to produce as protection group simultaneously A kind of double bond olefinic polymerization species impurity of life, affects product quality, reduces yield.Embodiment one(R) tetrahydrofuran -2- thiocarboxylic acids (198g, 1.5 mol) are put in 3L reaction bulbs, plus 1 mol/L hydrogen-oxygens Change sodium body lotion (I.5 L) to be adjusted at 5 DEG C of pH 9- 10,0-, Deca 4AA（287g, 1. 0mo l) acetone (1 L) Solution, drop are finished, and are adjusted to pH 8 or so, 2 h of room temperature reaction with 1 mol/L sodium hydroxide. and add water (500 ml) dilution, second Acetoacetic ester (600 ml x3) is extracted, and merges organic layer, successively with 5 % sodium bicarbonate solutions (300 ml x 2) and water (300 m1 x 2) is washed, and anhydrous sodium sulphate is dried, and is filtered, and filtrate concentrates, and obtains pale yellow oil (about 360 g), directly Input the next step.Embodiment twoThe mixing of concentrated solution as obtained above, triethylamine (l70g, 1.7 mol) and dichloromethane (1.5 L), 0-5 DEG C Deca chlorine oxalic acid is finished to p-Nitrobenzyl (414.1 g, 1 .7 mo l), drop, and equality of temperature reacts 2 h, and add water (1 L) dilution, Extracted with dichloromethane (500 ml x 4), merge organic layer, molten with water (300m1 x 2) and 5 % sodium bicarbonate successively Liquid (300 m1 x 2) is washed, anhydrous sodium sulfate drying, is filtered, and concentration obtains pale yellow oil (about 530g), direct plunges into The next step..Embodiment threeAbove-mentioned gained grease, dimethylbenzene (4L) and NSC 5284 (500ml) are mixed, heating reflux reaction 5h , reduce pressure and boil off dimethylbenzene and NSC 5284, residue ethyl acetate-hexane (1：5,1 L) recrystallization, obtain yellowish Color solid (334.3g, 61%, in terms of 4AA).Example IVAbove-mentioned solid (0.60 mol of 330g.) is dissolved in methanol (2 L), adds 1.0M hydrochloric acid (0.4 L), adds palladium carbon （15.0 g）, hydrogen is passed through, 40 DEG C of stirrings, response time are 16 h, and the pressure of system is 4atm, after reaction terminates, crosses and filters Catalyst is removed, is concentrated.Embodiment fiveThe product obtained after above-mentioned concentration is dissolved in tetrahydrofuran 600ml, the 2 ethyl hexanoic acid sodium of 100.0g is added Tetrahydrofuran（200ml）And water（200 ml）Mixed solution, 2 h are stirred at room temperature, have faint yellow solid generate, filter, be method Faropenem crude product 147.0g.Embodiment sixBy above-mentioned solid deionized water（2200ml）Acetone is slowly added under dissolved solution, stirring to start to become to solution Muddiness, when about adding acetone 750ml, solution starts to become cloudy, and stops adding, and continues stirring and allows its crystallize overnight, sucking filtration, acetone Washing, dries, and obtains the Faropenem sodium fine work 125.0g of white.

Syn

AU 8654460; EP 0199446; JP 1994128267; US 4997829

This compound is prepared by several related ways: 1) The reaction of silylated azetidinone (I) with tetrahydrofuran-2-thiocarboxylic acid (II) by means of NaOH in THF – water gives the azetidinone thioester (III), which is condensed with allyl glyoxylate in refluxing benzene yielding the hydroxyester (IV). The reaction of (IV) with SOCl2 affords the chloroester (V), which by reaction with triphenylphosphine by means of lutidine in hot THF is converted into the phosphoranylidene derivative (VI). The elimination of the silyl protecting group of (VI) with tetrabutylammonium fluoride gives the azetidinone (VII), which is cyclized in refluxing toluene yielding the (5R,6S)-6-[1(R)-hydroxyethyl]-2-[2(R)-tetrahydrofuryl]penem-3-carboxyli c acid allyl ester (VIII). Finally, this compound is hydrolyzed with triphenylphosphine, sodium 2-ethylhexanoate and Pd-tetrakis(triphenylphosphine). 2) The condensation of the silver salt of protected azetidinone (IX) with tetrahydrofuran-2(R)-carbonyl chloride (X) also yields the phosphoranylidene salt (VI). 3) Phosphoranylidene ester (VI) can also be cyclized first in refluxing benzene yielding the silylated penem ester (XI), which is deprotected with tetrabutylammonium fluoride to (VIII). 4) The hydrolysis of allyl ester (VIII) to the final product can also be performed with paladium tetrakis(triphenylphosphine) and sodium 4-(methoxycarbonyl)-5,5-dimethylcyclohexane-1,3-dione enolate in several different solvents such as methyl acetate, ethylacetate, tetrahydrofuran, dioxane, sec-butanol, acetonitrile, acetone, 2-butanone, 1,2-dichloroethane, chlorobenzene, toluene, or ethylene glycol dimethyl ether. 5) The preceding hydrolysis can also be performed with triphenylphosphine and paladium tetrakis(triphenylphosphine) with sodium propionate, sodium acetate or sodium lactate in tetrahydrofuran or acetone.

Treatment of the silylated azetidinone (I) with tritylmercaptan affords the tritylsulfanyl-azetidinone (II), which is converted into the silver salt (III) by reaction with AgNO3. Compound (III) is coupled with tetrahydrofuran-2(R)-carbonyl chloride (IV) — obtained by treatment of carboxylic acid (V) with thionyl chloride — providing the azetidinone thioester (VI). Coupling of azetidinone (VI) with allyl oxalyl chloride (VII) in CH2Cl2 by means of Et3N, followed by intramolecular Wittig cyclization by means of triethyl phosphite in refluxing xylene, affords penem (VIII). Alternatively, compound (VIII) can also be obtained as follows: Substitution of phenyl sulfonyl group of azetidinone (X) by tritylmercaptan by means of NaOH in acetone/water provides tritylsulfanyl-azetidinone (XI), which is condensed with allyl oxalyl chloride (VII) by means of DIEA in CH2Cl2 to give the oxalyl amide (XII). Compound (XII) is then treated with AgNO3 and pyridine in acetonitrile, providing the silver mercaptide (XIII), which is acylated with tetrahydrofuran-2(R)-carbonyl chloride (IV) in acetonitrile to afford the penem precursor (XIV). Penem (VIII) is obtained by intramolecular Wittig cyclization of (XIV) with P(OEt)3 in refluxing xylene. Finally, faropenem sodium can be obtained by removal of the tbdms protecting group of (VIII) by means of either Et3N tris(hydrogen fluoride) in ethyl acetate or tetrabutylammonium fluoride (TBAF) and HOAc in THF to give compound (IX). This is followed by allyl ester group removal of (IX), which can be performed under several different conditions: i) triphenylphosphine, sodium 2-ethylhexanoate and palladium tetrakis(triphenylphosphine); ii) palladium tetrakis(triphenylphosphine) and sodium 4-(methoxycarbonyl)-5,5-dimethylcyclohexane-1,3-dione enolate in several different solvents such as methyl acetate, ethyl acetate, tetrahydrofuran, dioxane, sec-butanol, acetonitrile, acetone, 2-butanone, 1,2-dichloroethane, chlorobenzene, toluene or ethylene glycol dimethyl ether; iii) triphenylphosphine and palladium tetrakis(triphenylphosphine) with sodium propionate, sodium acetate or sodium lactate in tetrahydrofuran or acetone; or iv) palladium acetate in the presence of P(OBu)3 and sodium propionate in THF.

Treatment of the silylated azetidinone (I) with tritylmercaptan affords the tritylsulfanylazetidinone (II), which by reaction with AgNO3 is converted into the silver salt (III). Compound (III) is coupled with tetrahydrofuran-2(R)-carbonyl chloride (IV) ?obtained by treatment of carboxylic acid (V) with thionyl chloride ?to provide the azetidinone thioester (VI). Alternatively, compound (VI) can be obtained by condensation of tetrahydrofuran-2(R)-thiocarboxylic S-acid (VII) ?obtained by treatment of carboxylic acid (V) with hydrogen sulfide ?with silylated azetidinones (I) or (VIII) by means of NaOH in THF/water. Condensation of azetidinone thioester (VI) with allyl glyoxylate (IX) in refluxing benzene gives the hydroxy ester (X), which is treated with SOCl2 to yield the chloro ester (XI). Reaction of compound (XI) with triphenylphosphine and lutidine in hot THF provides the phosphoranylidene derivative (XII), which is converted into (5R,6S)-6-[1(R)-hydroxyethyl]-2-[2(R)-tetrahydrofuryl]penem-3-carboxylic acid allyl ester, faropenem allyl ester (XIII) by removal of the silyl protecting group with tetrabutylammonium fluoride, followed by cyclization in refluxing toluene. Compound (XII) can also be obtained by condensation of the silver salt of protected azetidinone (XIV) with tetrahydrofuran-2(R)-carbonyl chloride (V).

Alternatively, faropenem allyl ester (XIII) can also be prepared by cyclization of compound (XII) in refluxing benzene to yield silylated penem allyl ester (XV), which is then deprotected with either tetrabutylammonium fluoride in AcOH or triethylamine tris(hydrogen fluoride) in methyl isobutyl ketone or toluene. Penem (XV) can also be synthesized by several related ways: a) By coupling of azetidinone (VI) with allyl oxalyl chloride (XVI) in CH2Cl2 by means of Et3N, followed by intramolecular Wittig cyclization by means of triethyl phosphite in refluxing xylene. b) Substitution of phenyl sulfonyl group of azetidinone (VIII) by tritylmercaptan by means of NaOH in acetone/water provides tritylsulfanyl-azetidinone (II), which is condensed with allyl oxalyl chloride (XVI) by means of DIEA in CH2Cl2 to give the oxalyl amide (XVII). Compound (XVII) is then treated with AgNO3 and pyridine in acetonitrile to provide the silver mercaptide (XVIII), which is acylated with tetrahydrofuran-2(R)-carbonyl chloride (IV) in acetonitrile to afford the penem precursor (XIX). Finally, compound (XV) is obtained by intramolecular Wittig cyclization of (XX) with P(OEt)3 in refluxing xylene.

Hydrolysis of faropenem allyl ester (XIII) to faropenem sodium (XX) can be performed under several different conditions: i) triphenylphosphine, sodium 2-ethylhexanoate and palladium tetrakis(triphenylphosphine); ii) palladium tetrakis(triphenylphosphine) and sodium 4-(methoxycarbonyl)- 5,5-dimethylcyclohexane-1,3-dione enolate in several different solvents such as methyl acetate, ethyl acetate, tetrahydrofuran, dioxane, sec-butanol, acetonitrile, acetone, 2-butanone, 1,2-dichloroethane, chlorobenzene, toluene, or ethylene glycol dimethyl ether; iii) triphenylphosphine and palladium tetrakis(triphenylphosphine) with sodium propionate, sodium acetate or sodium lactate in tetrahydrofuran or acetone; and iv) palladium acetate in the presence of P(OBu)3 and sodium propionate in THF. Finally, faropenem daloxate can be directly obtained from faropenem sodium (XX) by esterification with 4-(iodomethyl)-5-methyl-1,3-dioxol-2-one (XXI) in DMF.

PATENT

https://patents.google.com/patent/CN103059046A/enFaropenem (Faropenem), chemistry (5R, 6S)-6-[(1R)-hydroxyethyl by name]-2-[(2R)-and tetrahydrofuran (THF)] penem-3-carboxylic acid list sodium salt, by the first exploitation listing in 1997 years of Japanese Suntory company.This medicine is a kind of atypical beta-lactam penems antibiotics, has very strong anti-microbial activity, especially to the anti-microbial activities of the anerobes such as the gram positive organisms such as golden Portugal bacterium, penicillin-fast streptococcus pneumoniae, streptococcus faecium and bacteroides fragilis apparently higher than existing cynnematin, anti-gram-negative bacteria is active similar to oral cephalosporin, and is stable to various β-lactamases.Various clinical studyes show that this medical instrument has clinical effectiveness good, safe, the advantage that renal toxicity and neurotoxicity are little.Its structural formula is as follows:
For synthesizing of Faropenem, existing many reports in the prior art, for example CN101125857A has reported following synthetic route:
Take (3R, 4R)-3-[(R)-1-tert-butyl dimethyl silica ethyl]-4-[(R)-and acetoxyl group] nitrogen heterocyclic din-2-ketone is as starting raw material, and warp gets intermediate compound I with R-(+)-sulfo-tetrahydrofuran (THF)-2-formic acid condensation; Intermediate compound I is carried out acylation reaction with monoene propoxy-oxalyl chloride under the catalysis of alkali, get intermediate II; Intermediate II cyclization under the effect of triethyl-phosphite gets intermediate III; Intermediate III is sloughed hydroxyl protecting group through the effect of tetrabutylammonium, gets intermediate compound IV; Intermediate compound IV decarboxylize protecting group under [four (triphenylphosphine)] palladium and triphenylphosphine effect gets Faropenem.Find that after deliberation the method for the present synthetic Faropenem of reporting is all similar with the disclosed method of above-mentioned CN101125857A, all need remove in two steps the protecting group of hydroxyl and carboxyl, reaction scheme is longer.When removing above-mentioned protecting group, need to use a large amount of tetrabutylammonium and [four (triphenylphosphine)] palladium and triphenylphosphine; these reagent costs are high, toxicity is large; be unfavorable for large industrial production; and can introduce the heavy metal palladium; so that the heavy metal remnants in the Faropenem exceed standard, be not suitable for the production of bulk drug.And when adopting aforesaid method deprotection base, the yield in per step only can reach 60%-75%, has further increased production cost.Embodiment 6The preparation of FaropenemWith intermediate 3(364.5g, 0.8mol) use the 700mL acetic acid ethyl dissolution, to open and stir, 0 ℃ of lower dropping with the 36g trifluoroacetic acid after the dilution of 100mL ethyl acetate dripped off in 1 hour, 0 ℃ of lower reaction 2h that continues.Stopped reaction stirs the sodium bicarbonate aqueous solution of lower dropping 5%, until reaction solution pH is neutral.Emit water layer from the reactor lower end, discard.In reactor, add gradually the ethanolic soln of sodium bicarbonate, until till no longer including solid and separating out.Suction filtration, filter cake gets white solid powder 230g(productive rate 93.7% with acetone-water (10:3, v/v) recrystallization), M.P. 163-164 ℃, detect through HPLC, purity is 99.8%Reference examples 1(5R, 6S)-6-[(R)-1-hydroxyethyl]-2-[(R)-and the 2-TETRAHYDROFUROYL sulfenyl] preparation of penem-3-carboxylic acid propyleneWith (5R, 6S)-6-[(R)-the 1-tert-butyl dimethyl silica ethyl]-2-[(R)-and the 2-TETRAHYDROFUROYL sulfenyl] penem-3-carboxylic acid propylene (150g, 0.342mol) and ammonium bifluoride (59.5g, 1.025mmol) add successively among the 400mL DMF, 55～60 ℃ were reacted 5 hours, stopped reaction, suction filtration, filtrate adds water 800ml, uses ethyl acetate extraction, and organic phase is washed with 5% sodium hydrogen carbonate solution, anhydrous sodium sulfate drying, concentrated, gained incarnadine oily matter gets yellow solid 73g through the petrol ether/ethyl acetate recrystallization, yield 66%.Reference examples 2The preparation of Faropenem(the 5R that reference examples 1 is prepared, 6S)-6-[(R)-the 1-hydroxyethyl]-2-[(R)-and the 2-TETRAHYDROFUROYL sulfenyl] penem-3-carboxylic acid propylene (73g, 0.224mol), 6.5g triphenylphosphine, 6.5g [four (triphenylphosphine)] palladium adds among the 500mL methylene dichloride l successively, the ethyl acetate solution that adds the 2 ethyl hexanoic acid sodium preparation of 500mL 0.5M, stirring at room 1 hour, stopped reaction adds 15mL water in reaction solution, stir 30min, suction filtration, this solid is dissolved in the 100mL water again, adds decolorizing with activated carbon 30min, filter, filtrate adds in the 500mL acetone, place crystallization, get Faropenem 66g, yield 96%.Find that by contrast the total recovery that two steps of reference examples remove hydroxyl and carboxyl-protecting group only has about 63.4%, and single stage method of the present invention removes the yield of hydroxyl and carboxyl-protecting group and can reach more than 90%.Preparation method of the present invention can the one-step removal hydroxyl and carboxyl on protecting group, shortened the production cycle, the deprotecting regent cost is low, toxicity is little, can not cause heavy metal remaining, and have higher reaction yield, is fit to very much the industrial production of raw material medicine.

Patent

Publication numberPriority datePublication dateAssigneeTitleCN1939924A *2006-09-082007-04-04鲁南制药集团股份有限公司Industrial production of Fallopeinan sodiumWO2008035153A2 *2006-08-022008-03-27Orchid Chemicals & Pharmaceuticals LimitedProcess for the preparation of beta-lactam antibioticCN103059046A *2013-01-282013-04-24苏州二叶制药有限公司Preparation method of faropenemFamily To Family CitationsCN100522975C *2007-08-232009-08-05东北制药集团公司沈阳第一制药厂Method for preparing faropenemPublication numberPriority datePublication dateAssigneeTitleCN1884284A *2005-06-212006-12-27浙江金华康恩贝生物制药有限公司Process for the preparation of sodium faropenemCN1939924A *2006-09-082007-04-04鲁南制药集团股份有限公司Industrial production of Fallopeinan sodiumCN101125857A *2007-08-232008-02-20东北制药集团公司沈阳第一制药厂Method for preparing faropenemWO2008035153A2 *2006-08-022008-03-27Orchid Chemicals & Pharmaceuticals LimitedProcess for the preparation of beta-lactam antibiotic

Publication numberPriority datePublication dateAssigneeTitle

EP0410727A1 *1989-07-261991-01-30Suntory LimitedProcesses for removing allyl groupsUS4997829A *1985-03-091991-03-05Suntory LimitedPenem compounds, and use thereofEP0574940A1 *1992-06-181993-12-22Tanabe Seiyaku Co., Ltd.Method for removing the protecting group for carboxyl groupWO2007039885A1 *2005-10-052007-04-12Ranbaxy Laboratories LimitedA process for the preparation of faropenemFamily To Family Citations
Publication numberPriority datePublication dateAssigneeTitleCN102964357A *2012-11-112013-03-13苏州二叶制药有限公司Faropenem sodium and tablet thereofCN103059046A *2013-01-282013-04-24苏州二叶制药有限公司Preparation method of faropenemCN103880864A *2014-03-252014-06-25江苏正大清江制药有限公司Method for synthesizing faropenem sodiumCN104086516A *2014-07-182014-10-08成都樵枫科技发展有限公司Synthetic method of R-(+)-sulfotetrahydrofuran-2-formic acidCN101941981B *2009-07-032015-01-21湖南华纳大药厂有限公司Catalyst composition and method for preparing faropenem sodiumCN106860405A *2015-12-142017-06-20山东新时代药业有限公司A kind of faropenem sodium granules and preparation method thereofCN108840877A *2018-06-122018-11-20赤峰迪生药业有限责任公司A kind of preparation method of oxygen cephalosporin intermediate

References

^ Critchley IA, Brown SD, Traczewski MM, Tillotson GS, Janjic N (December 2007). “National and regional assessment of antimicrobial resistance among community-acquired respiratory tract pathogens identified in a 2005-2006 U.S. Faropenem surveillance study”. Antimicrob. Agents Chemother. 51 (12): 4382–9. doi:10.1128/AAC.00971-07. PMC 2168020. PMID 17908940.
^ Mushtaq S, Hope R, Warner M, Livermore DM (May 2007). “Activity of faropenem against cephalosporin-resistant Enterobacteriaceae”. J. Antimicrob. Chemother. 59 (5): 1025–30. doi:10.1093/jac/dkm063. PMID 17353220.
^ Milazzo I, Blandino G, Caccamo F, Musumeci R, Nicoletti G, Speciale A (March 2003). “Faropenem, a new oral penem: antibacterial activity against selected anaerobic and fastidious periodontal isolates”. J. Antimicrob. Chemother. 51 (3): 721–5. doi:10.1093/jac/dkg120. PMID 12615878.
^ Gettig JP, Crank CW, Philbrick AH (January 2008). “Faropenem medoxomil”. Ann Pharmacother. 42 (1): 80–90. doi:10.1345/aph.1G232. PMID 18094341. Archived from the original on 2013-02-03.
^ (Q1 06 Investor Conf Call)(CID 6918218 from PubChem)

External links

DrugBank website

Clinical data

AHFS/Drugs.com	International Drug Names
Routes of administration	Oral
ATC code	J01DI03 (WHO)
Identifiers
CAS Number	106560-14-9
PubChem CID	65894
ChemSpider	59303
UNII	F52Y83BGH3
ChEBI	CHEBI:51257
ChEMBL	ChEMBL556262
CompTox Dashboard (EPA)	DTXSID0046430
Chemical and physical data
Formula	C₁₂H₁₅NO₅S
Molar mass	285.31 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI
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///////////Faropenem, ALP-201, SUN-5555, SY-5555, WY-49605, ANTIBACTERIALS, DIICHI, Daiichi Asubio Pharma

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AUR 101

October 20, 2021 2:55 am / Leave a comment

AUR 101

AUR101-201

ANTIINNFLAMATORY

AUR-101, a ROR gamma inverse agonist for autoimmune disorders like psoriasis

AUR-101 is an ROR-gammaT inverse agonist in phase II clinical development at Aurigene for the treatment of patients with moderate-to-severe chronic plaque-type psoriasis.

DrugsAUR 101 (Primary)
IndicationsPlaque psoriasis
FocusAdverse reactions; First in man
AcronymsINDUS
SponsorsAurigene Discovery Technologies

OriginatorAurigene Discovery Technologies
ClassAntipsoriatics; Small molecules
Mechanism of ActionNuclear receptor subfamily 1 group F member 3 inverse agonists

Phase IIPsoriasis

28 Aug 2021No recent reports of development identified for phase-I development in Psoriasis(In volunteers) in Australia (PO, Tablet)
23 Apr 2021Aurigene Discovery Technologies plans a phase II INDUS-3 trial for Psoriasis in USA (PO) in May 2021 (NCT04855721)
15 Apr 2021Aurigene Discovery Technologies completes a phase II trial in Psoriasis in India (PO) (NCT04207801)
CDSCO
https://www.cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2018/UploadCTApprovals/Aurigene20.pdf
NCT04207801

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AURIGENE ANNOUNCES FIRST PATIENT DOSED WITH AUR101 IN PHASE II STUDY IN PATIENTS WITH MODERATE TO SEVERE PSORIASIS

https://www.aurigene.com/aurigene-announces-first-patient-dosed-with-aur101-in-phase-ii-study-in-patients-with-moderate-to-severe-psoriasis/

PRESS RELEASE

Aurigene Announces First Patient Dosed with AUR101 in Phase II Study in Patients with Moderate to Severe Psoriasis

Bangalore, February 17, 2020 — Aurigene, a development stage biotechnology company, today announced dose administration for the first patient in INDUS-2, a Phase II double blind placebo-controlled three-arm study of AUR101 in patients with moderate to severe psoriasis. AUR101 is an oral small molecule inverse agonist of RORγ and has shown desirable pharmacodynamic modulation of IL-17 and acceptable safety in a completed Phase I human study conducted in Australia.

“The initiation of this Phase II study under a US FDA IND represents a significant milestone for Aurigene, as it marks the first program which Aurigene has led from the bench side to the clinic all by itself,” said Murali Ramachandra, PhD, Chief Executive Officer of Aurigene. “We look forward to producing important clinical data by the end of 2020 to guide our future development plans and demonstrating Aurigene’s unique expertise in conducting Proof-of-Concept studies in a quality and fast-paced manner.”

About AUR101-201 and the Phase II Study of AUR101 in Patients with Moderate to Severe Psoriasis

The purpose of the Phase II multi-center, blinded, placebo-controlled, three-arm study is to evaluate the clinical activity of AUR101 in patients with moderate to severe psoriasis. In two of the arms, AUR101 will be administered twice daily, at 400 mg PO BID and 600 mg PO BID, for 12 weeks. Patients in the third arm will receive matched blinded placebo in a double dummy fashion. The trial is listed at clinicaltrials.gov with identifier NCT04207801.

About Aurigene

Aurigene is a development stage biotech company engaged in discovery and clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases and a wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY,NYSE: RDY). Aurigene is focused on precision- oncology, oral immune checkpoint inhibitors, and the Th-17 pathway. Aurigene currently has several programs from its pipeline in clinical development. Aurigene has also submitted an IND to DCGI, India for a Phase IIb/III trial of CA-170, a dual inhibitor of PD-L1 and VISTA, in non-squamous NSCLC. Additionally, Aurigene has multiple compounds at different stages of pre-clinical development. Aurigene has partnered with many large and mid-pharma companies in the United States and Europe and has 15 programs currently in clinical development. For more information, please visit Aurigene’s website at https://www.aurigene.com/.

CLIP

Signalling of multiple interleukin (IL)-17 family cytokines via IL-17 receptor A drives psoriasis-related inflammatory pathways

https://onlinelibrary.wiley.com/doi/10.1111/bjd.20090

M.A.X. Tollenaere,J. Hebsgaard,D.A. Ewald,P. Lovato,S. Garcet,X. Li,S.D. Pilger,M.L. Tiirikainen,M. Bertelsen,J.G. Krueger,H. Norsgaard,First published: 01 April 2021 https://doi.org/10.1111/bjd.20090Citations: 2Funding sources LEO Pharma A/S funded this study.Conflicts of interest M.A.X.T., J.H., D.A.E., P.L., S.D.P., M.L.T., M.B. and H.N. are employees of LEO Pharma. J.G.K. received grants paid to his institution from Novartis, Pfizer, Amgen, Lilly, Boehringer, Innovaderm, BMS, Janssen, AbbVie, Paraxel, LEO Pharma, Vitae, Akros, Regeneron, Allergan, Novan, Biogen MA, Sienna, UCB, Celgene, Botanix, Incyte, Avillion and Exicure; and personal fees from Novartis, Pfizer, Amgen, Lilly, Boehringer, Biogen Idec, AbbVie, LEO Pharma, Escalier, Valeant, Aurigene, Allergan, Asana, UCB, Sienna, Celgene, Nimbus, Menlo, Aristea, Sanofi, Sun Pharma, Almirall, Arena and BMS.Data Availability Statement The gene array dataset described in this publication has been deposited in NCBI’s Gene Expression Omnibus and is accessible through GEO Series accession number GSE158448 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE158448).

CLOP

https://www.drugdiscoverychemistry.com/Anti-Inflammatories/16

10:35 Small Molecule Inhibitors of RORgamma and IRAK4 for the Treatment of Autoimmune Disorders

Susanta_Samajdar Susanta Samajdar, Ph.D., Director, Medicinal Chemistry, Aurigene Discovery Technologies Limited

Although biologics such as anti-TNFα antibody are fairly successful in the treatment of autoimmune disorders, there is significant unmet need due to heterogeneity in diseases and lack of response to established therapies in some patients. While biologics typically target one cytokine signaling pathway, small molecule therapeutics directed towards intracellular target(s) can interfere in the signaling from multiple cytokines potentially leading to improved response. Development of small molecule oral inhibitors of IRAK4 and RORgamma to target TLR/IL-R and Th17 pathway respectively will be discussed.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=IN214955226&_fid=MY224223530

2448/CHE/2015 15.05.2015 IN

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015083130&_cid=P21-KUYVWP-43720-1

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=AU208432398&_cid=P22-KUY2P5-62097-3

This application claims the benefit of Indian provisional application number 5641/CHE/2013 filed on 06^th December 2013 which hereby incorporated by reference.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016185342&_fid=AU208432398

KOTRABASAIAH UJJINAMATADA, Ravi
PANDIT, Chetan

2049005-13-0

2-Quinolinecarboxamide, 6-(2,6-dimethyl-4-pyrimidinyl)-N-[[4-(ethylsulfonyl)phenyl]methyl]-5,6,7,8-tetrahydro-6-methyl-5-oxo-, (6S)-

Molecular Weight492.59, C₂₆ H₂₈ N₄ O₄ S

EXAMPLE

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015101928&_cid=P21-KUYVWP-43720-1

CLIP

https://www.sciencedirect.com/science/article/abs/pii/S0223523419301011

2013239366 CA 170

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///////////////////////AUR 101, AURIGENE, ROR, IL-17, PHASE 2, CDSCO, Ravi Ujjinamatada, KOTRABASAIAH UJJINAMATADA Ravi, PANDIT Chetan, AUR101-201, plaque-type psoriasis

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Fig. 1:	Synthesis of Trihexyltetradecylphosphonium octylsulfosuccinate [P_{6, 6, 6, 14}][docusate]

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