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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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RG 7604,Taselisib


Taselisib skeletal.svgChemSpider 2D Image | Taselisib | C24H28N8O2  Taselisib.png

  • Molecular FormulaC24H28N8O2
  • Average mass460.531 Da

RG7604,Taselisib

GDC-0032, GDC0032;GDC 0032, RO5537381

1282512-48-4 [RN]
1H-Pyrazole-1-acetamide, 4-[5,6-dihydro-2-[3-methyl-1-(1-methylethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-d][1,4]benzoxazepin-9-yl]-α,α-dimethyl-
UNII:L08J2O299M
10.1021/jm4003632
2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide
2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2–4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide
POLYMORPHS almost A to Z, US9266903
Taselisib (GDC-0032) is an experimental cancer drug in development by Roche. Molecule is a complex heterocycle with no chiral centres, hazardous materials are used in synthesis, preparation of impurities is a challenge. Taselisib is in phase III with Roche , clinical trials for treatment of metastatic breast cancer and non-small cell lung cancer

Taselisib (GDC-0032) is an experimental cancer drug in development by Roche. It is a small molecule inhibitor targeting phosphoinositide 3-kinase subtype PIK3CA.[1]

Taselisib is in phase III with Roche , clinical trials for treatment of metastatic breast cancer and non-small cell lung cancer.[2]

Taselisib is a phosphatidylinositol 3-kinase (PI3Kalpha) inhibitor in phase III clinical studies at Roche for the treatment of postmenopausal women with histologically or cytologically confirmed locally advanced or metastatic estrogen-receptor positive (ER+) breast cancer.

Taselisib is an orally bioavailable inhibitor of the class I phosphatidylinositol 3-kinase (PI3K) alpha isoform (PIK3CA), with potential antineoplastic activity. Taselisib selectively inhibits PIK3CA and its mutant forms in the PI3K/Akt/mTOR pathway, which may result in tumor cell apoptosis and growth inhibition in PIK3CA-expressing tumor cells. By specifically targeting class I PI3K alpha, this agent may be more efficacious and less toxic than pan PI3K inhibitors. Dysregulation of the PI3K/Akt/mTOR pathway is frequently found in solid tumors and causes increased tumor cell growth, survival, and resistance to both chemotherapy and radiotherapy. PIK3CA, which encodes the p110-alpha catalytic subunit of the class I PI3K, is mutated in a variety of cancer cell types and plays a key role in cancer cell growth and invasion.

str1

PRODUCT PATENT

WO 2011036280

Inventors Nicole BlaquiereSteven DoDanette DudleyAdrian J. FolkesRobert HealdTimothy HeffronMark JonesAleksandr KolesnikovChudi NdubakuAlan G. OliveroStephen PriceSteven StabenLan WangLess «
Applicant F. Hoffmann-La Roche Ag

https://encrypted.google.com/patents/WO2011036280A1?cl=en

Discovery of 2-(3-(2-(1-Isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (GDC-0032): A -sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity
J Med Chem 2013, 56(11): 4597

Condensation of 4-bromo-2-hydroxybenzaldehyde  with glyoxal  in the presence of NH3 in MeOH gives 5-bromo-2-(1H-imidazol-2-yl)phenol

Which upon annulation with 1,2-dibromoethane  in the presence of Cs2CO3 in DMF at 90 °C yields 9-bromo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine .

Iodination of oxazepine  with NIS in DMF provides 9-bromo-2,3-diiodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine,

Which upon mono-deiodination by means of EtMgBr in THF at -15 °C affords 9-bromo-2-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine .

Amidation of iodide  with CO in the presence of PdCl2(PPh3)2 and HMDS in DMF at 70 °C produces the intermediate,

Which upon reaction with N,N-dimethylacetamide dimethyl acetal  in the presence of DME at 65 °C furnishes intermediate . Intramolecular cyclization of this compound with isopropylamine hydrochloride  in AcOH generates triazole derivative,

Which upon Suzuki coupling with dioxaborolane derivative in the presence of Pd(PPh3)4 and KOAc in CH3CN/H2O at 120 °C yields the target compound Taselisib.

Genentech BioOncology® logo

Taselisib has been used in trials studying the treatment and basic science of LYMPHOMA, Breast Cancer, Ovarian Cancer, Solid Neoplasm, and HER2/Neu Negative, among others.

Solubility (25°C)

In vitro DMSO 70 mg/mL warmed (151.99 mM)
Water Insoluble
Ethanol Insoluble warmed

Biological Activity

Description Taselisib (GDC 0032) is a potent, next-generation β isoform-sparing PI3K inhibitor targeting PI3Kα/δ/γ with Ki of 0.29 nM/0.12 nM/0.97nM, >10 fold selective over PI3Kβ.
Features A beta isoform-sparing PI3K inhibitor.
Targets
PI3Kδ [1]
(Cell-free assay)
PI3Kα [1]
(Cell-free assay)
PI3Kγ [1]
(Cell-free assay)
PI3Kβ [1]
(Cell-free assay)
C2β [1]
(Cell-free assay)
View More
0.12 nM(Ki) 0.29 nM(Ki) 0.97 nM(Ki) 9.1 nM(Ki) 292 nM
In vitro GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3Kα, δ, and γ isoforms, with 30 fold less inhibition of the PI3K β isoform relative to the PI3Kα isoform. Preclinical data show that GDC-0032 has increased activity against PI3Kα isoform (PIK3CA) mutant and HER2-amplified cancer cell lines. GDC-0032 inhibits MCF7-neo/HER2 cells proliferation with IC50 of 2.5 nM. [1]
Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human MOLM16 cells Proliferation assay 72 h Antiproliferative activity against human MOLM16 cells after 72 hrs by Cell Titer-Blue assay 22727640
In vivo GDC-0032 pharmacokinetics is approximately dose proportional and time independent with a mean t1/2 of 40 hours. The combination of GDC-0032 enhances activity of fulvestrant resulting in tumor regressions and tumor growth delay (91% tumor growth inhibition (TGI)). In addition, the combination of GDC-0032 with tamoxifen enhances the efficacy of tamoxifen in vivo (102%TGI for GDC-0032). [1]

PATENT

WO 2014140073

The invention relates to methods of making the PI3K inhibitor I (GDC-0032), named as 2-(4-(2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,2- d][l,4]oxazepin-9-yl)-lH-pyrazol-l-yl)-2-methylpropanamide, having the structure:

Figure imgf000003_0001

and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof.

Another aspect of the invention includes novel intermediates useful for preparing GDC- 0032 and having the structures:

Figure imgf000003_0002
Figure imgf000004_0001
Figure imgf000005_0001

The following Schemes 1-15 illustrate the chemical reactions, processes, methodology for the synthesis of GDC-0032, Formula I, and certain intermediates and reagents. Scheme 1:

Figure imgf000010_0001
Figure imgf000010_0002

Scheme 1 shows the synthesis of intermediate isopropylhydrazine hydrochloride 4 from Boc-hydrazine 1. Condensation of 1 with acetone and magnesium sulfate gave Boc-hydrazone, tert-butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 (Example 1). Palladium-catalyzed hydrogenation of 2 in acetic acid and methanol gave Boc-isopropyl-hydrazine 3 (Example 2) which was treated in situ with hydrogen chloride gas to give 4 (Example 3).

Alternatively, the double bond of 2 can be reduced with a hydride reagent such as sodium cyanoborohydride (Example 2).

Scheme 2:

Figure imgf000010_0003

Scheme 2 shows the synthesis of l-isopropyl-3-methyl-lH-l,2,4-triazole 7 from methyl acetimidate hydrochloride 5 and isopropylhydrazine hydrochloride 4. Reaction of 5 and 4 in triethylamine and methanol followed by cyclization of condensation product, N’- isopropylacetohydrazonamide 6 (Example 4) with triethyl orthoformate (triethoxymethane) gave 7 (Example 5). Alternatively, 4 and acetamidine can be reacted to give 6.

Or, 4 can be reacted with acetonitrile and an acid to form the corresponding salt of 6. Scheme 3:

Figure imgf000011_0001

0 K2C03, H20, MTBE w

Scheme 3 shows the synthesis of intermediate, 2-chloro-N-methoxy-N-methylacetamide 10. Reaction of 2-chloroacetyl chloride 8 and Ν,Ο-dimethylhydroxylamine hydrochloride 9 in aqueous potassium carbonate and methyl, tert-butyl ether (MTBE) gave 10 (Example 6).

Scheme 4:

Figure imgf000011_0002

Scheme 4 shows the synthesis of intermediate 4-bromo-2-fluorobenzimidamide hydrochloride 12 formed by reaction of 4-bromo-2-fluorobenzonitrile 11 with lithium hexamethyldisilazide (LiHMDS) in tetrahydrofuran (Example 7). Alternatively, 11 is treated with hydrogen chloride in an alcohol, such as ethanol, to form the imidate, ethyl 4-bromo-2- fluorobenzimidate hydrochloride, followed by ammonia in an alcohol, such as ethanol, to form 12 (Example 7).

Scheme 5:

Figure imgf000012_0001

Scheme 5 shows the synthesis of 5-(2-(4-bromo-2-fluorophenyl)-lH-imidazol-4-yl)-l- isopropyl-3 -methyl- lH-l,2,4-triazole V from l-isopropyl-3-methyl-lH-l,2,4-triazole 7.

Deprotonation of 7 with n-butyllithium and acylation with 2-chloro-N-methoxy-N- methylacetamide 10 gave intermediate 2-chloro-l-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5- yl)ethanone 13 (Example 8). Cyclization of 13 with 4-bromo-2-fluorobenzimidamide hydrochloride 12 and potassium hydrogen carbonate in water and THF (tetrahydrofuran) formed the imidazole V (Example 9).

Scheme 6:

Figure imgf000012_0002

Scheme 6 shows the synthesis of 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5- yl)-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III from V. Alkylation of the imidazole nitrogen of V with a 2-hydroxyethylation reagent such as, l,3-dioxolan-2-one, gave 2-(2-(4- bromo-2-fluorophenyl)-4-( 1 -isopropyl-3-methyl- 1 H- 1 ,2,4-triazol-5 -yl)- 1 H-imidazol- 1 – yl)ethanol 14 (Example 10). Cyclization of 14 with an aqueous basic reagent, such as methyltributylammonium chloride in aqueous potassium hydroxide, gave III, which can be cystallized from ethanol and water (Example 11). Scheme 7:

Figure imgf000013_0001

IV

Scheme 7 shows the synthesis of ethyl 2-(4-bromo-lH-pyrazol-l-yl)-2-methylpropanoate IV starting from 2-bromo-2-methylpropanoic acid 15. Alkylation of pyrazole with 15 gave 2- methyl-2-(lH-pyrazol-l-yl)propanoic acid 16 (Example 12). Esterification of 16 with sulfuric acid in ethanol gave ethyl 2-methyl-2-(lH-pyrazol-l-yl)propanoate 17 (Example 13).

Regiospecific bromination of 17 with N-bromosuccinimide (NBS) gave IV (Example 14). Alternatively, 16 was treated in situ with a brominating reagent such as l,3-dibromo-5,5- dimethylhydantoin (DBDMH) to give 2-(4-bromo-lH-pyrazol-l-yl)-2-methylpropanoic acid which was esterified to give IV, where R is ethyl. Other esters can also be prepared, such as methyl, iso-propyl, or any alkyl, benzyl or aryl ester.

Scheme 8:

Figure imgf000014_0001

Scheme 8 shows an alternative synthesis of ethyl 2-(4-bromo-lH-pyrazol-l-yl)-2- methylpropanoate IV starting from ethyl 2-bromo-2-methylpropanoate 18. Alkylation of pyrazole with 18 in the presence of a base such as sodium tert-butyloxide or cesium carbonate gave a mixture of ethyl 2-methyl-2-(lH-pyrazol-l-yl)propanoate 17 and ethyl 2-methyl-3-(lH- pyrazol-l-yl)propanoate 19. Bromination of the mixture with l,3-dibromo-5,5- dimethylimidazolidine-2,4-dione (DBDMH) gave a mixture containing IV, ethyl 3-(4-bromo- lH-pyrazol-l-yl)-2-methylpropanoate 20, and 4-bromo-lH-pyrazole 21 which was treated with a strong base under anhydrous conditions, such as lithium hexamethyldisilazide in tetrahydrofuran. Acidification with hydrochloric acid gave IV.

Scheme 9:

Pd(O) catalyst

Figure imgf000015_0001

KOAc, EtOH

Figure imgf000015_0002

Scheme 9 shows the synthesis of 2-(4-(2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)- 5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepin-9-yl)-lH-pyrazol-l-yl)-2-methylpropanamide, GDC-0032, 1 from ethyl 2-(4-bromo- 1 H-pyrazol- 1 -yl)-2-methylpropanoate IV (CAS Registry Number: 1040377-17-0, WO 2008/088881) and 9-bromo-2-(l-isopropyl-3-methyl-lH- 1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III (CAS Registry Number: 1282514-63-9, US 2012/0245144, US 8242104). Other esters besides ethyl can also be used which can be hydrolyzed with aqueous base, such as methyl, iso-propyl, or any alkyl, benzyl or aryl ester. In a one-pot Miyaura Borylation /Suzuki, Buchwald system, ethyl 2-(4-bromo-lH- pyrazol-l-yl)-2-methylpropanoate IV is reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(l,3,2- dioxaborolane), CAS Reg. No. 73183-34-3, also referred to as B2Pin2, and a palladium catalyst such as XPhos (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, CAS Reg. No. 564483- 18-7), with a salt such as potassium acetate, in a solvent such as ethanol, at about 75 °C to form the intermediate ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol- l-yl)propanoate 22 (Example 15, CAS Registry Number: 1201657-32-0, US 8242104, US 8263633, WO 2009/150240).

Figure imgf000016_0001

XPhos ligandIntermediate 22 can be isolated or reacted in situ (one pot) with III to form 23.

A variety of low valent, Pd(II) and Pd(0) palladium catalysts can be used during the Suzuki coupling step to form 23 (Example 16) from 22 and III, including PdCl2(PPh3)2, Pd(t- Bu)3, PdCl2 dppf CH2C12, Pd(PPh3)4, Pd(OAc)/PPh3, Cl2Pd[(Pet3)]2, Pd(DIPHOS)2, Cl2Pd(Bipy), [PdCl(Ph2PCH2PPh2)]2, Cl2Pd[P(o-tol)3]2, Pd2(dba)3/P(o-tol)3, Pd2(dba)/P(furyl)3,

Cl2Pd[P(furyl)3]2, Cl2Pd(PMePh2)2, Cl2Pd[P(4-F-Ph)3]2, Cl2Pd[P(C6F6)3]2, Cl2Pd[P(2-COOH- Ph)(Ph)2]2, Cl2Pd[P(4-COOH-Ph)(Ph)2]2, and encapsulated catalysts Pd EnCat™ 30, Pd EnCat™ TPP30, and Pd(II)EnCat™ BINAP30 (US 2004/0254066).

The ester group of 23 is saponified with an aqueous basic reagent such as lithium hydroxide, to give 2-(4-(2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)- IH-pyrazol- 1 -yl)-2-methylpropanoic acid II (Example 17). Intermediate 23 can be isolated or further reacted in situ with the aqueous basic reagent to form II. The carboxylic acid group of II is activated with an acyl activating reagent such as di(lH-imidazol-l-yl)methanone (carbonyl diimidazole, CDI) or Ν,Ν,Ν’,Ν’-tetramethyl- 0-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (HATU), and then reacted with an alcoholic ammonia reagent, such as ammonia dissolved in methanol, ethanol, or isopropanol, aqueous ammonium hydroxide, aqueous ammonium chloride, or ammonia dissolved in THF, to give I (Example 18).

A variety of solid adsorbent palladium scavengers can be used to remove palladium after the Suzuki coupling step to form compound I. Exemplary embodiments of palladium scavengers include FLORISIL®, SILIABOND®Thiol, and SILIABOND® Thiourea. Other palladium scavengers include silica gel, controlled-pore glass (TosoHaas), and derivatized low crosslinked polystyrene QUADRAPURE™ AEA, QUADRAPURE™ IMDAZ, QUADRAPURE™ MPA, QUADRAPURE™ TU (Reaxa Ltd., Sigma-Aldrich Chemical Co.).

Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000017_0003

Scheme 10 shows the synthesis of 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5- yl)-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III from 4-bromo-2-fluorobenzonitrile 11. Addition of hydroxylamine to the nitrile of 11 gave 4-bromo-2-fluoro-N-hydroxybenzimidamide 24. Michael addition of 24 to ethyl propiolate gave ethyl 3-(4-bromo-2- fluorobenzimidamidooxy)acrylate 25. Heating 25 in a high-boiling solvent such as toluene, xylene, ethylbenzene, or diphenyl oxide gave cyclized imidazole, ethyl 2-(4-bromo-2- fluorophenyl)-lH-imidazole-4-carboxylate 26, along with by-product pyrimidine, 2-(4-bromo-2- fluorophenyl)pyrimidin-4-ol. Alternatively, 25 can be cyclized to 26 with catalytic Lewis acids such as Cu(I) or Cu(II) salts. Alkylation of 26 with a 2-hydroxyethylation reagent, such as 1,3- dioxolan-2-one, in a base, such as N-methylimidazole or cesium carbonate, gave ethyl 2-(4- bromo-2-fluorophenyl)-l-(2-hydroxyethyl)-lH-imidazole-4-carboxylate 27. Ring-cyclization of 27 with an aqueous basic reagent, such as potassium hydroxide, lithium hydroxide, and methyl tributylammonium hydrochloride, gave 9-bromo-5,6-dihydrobenzo[f]imidazo[l,2- d][l,4]oxazepine-2-carboxylic acid 28. Addition of acetamidine to 28 with triphenylphosphine gave 9-bromo-N-(l-iminoethyl)-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2- carboxamide 29. Ring-cyclization of 29 with isopropylhydrazine hydrochloride 4 in acetic acid gave 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,2- d][l,4]oxazepine III.

Alternatively, 28 can be reacted with N’-isopropylacetohydrazonamide 6 to give III (Scheme 12).

Scheme 11 :

Figure imgf000018_0001

Scheme 11 shows the synthesis of 5-(2-(4-bromo-2-fluorophenyl)-lH-imidazol-4-yl)-l- isopropyl-3 -methyl- lH-l ,2,4-triazole V from 4-bromo-2-fluorobenzimidamide hydrochloride 12. 3-Chloro-2-oxopropanoic acid and 12 are reacted with base to give 2-(4-bromo-2-fluorophenyl)- lH-imidazole-4-carboxylic acid 30. Alternatively, 3-bromo-2-oxopropanoic acid can be reacted with 12 to give 30. Reaction of 30 with N’-isopropylacetohydrazonamide 6 and coupling reagent HBTU (N,N,N’,N’-tetramethyl-0-(lH-benzotriazol-l-yl)uronium hexafluorophosphate, O- (Benzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate, CAS Ref. No. 94790- 37-1) in DMF gives intermediate, 2-(4-bromo-2-fluorophenyl)-N-(l-(2- isopropylhydrazinyl)ethylidene)-lH-imidazole-4-carboxamide 31 which need not be isolated and cyclizes upon heating to give V.

Alternatively, 5-(2-(4-chloro-2-fluorophenyl)-lH-imidazol-4-yl)-l-isopropyl-3-methyl- lH-l,2,4-triazole 44, the chloro version of V, can be prepared from 4-chloro-2-fluorobenzonitrile 38 (Scheme 15) Scheme 12:

Figure imgf000019_0001

Scheme 12 shows an alternative synthesis of 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III from 4-bromo-2- fluorobenzonitrile 11. Alkylation of 11 with tert-butyl 2-hydroxyethylcarbamate gives tert-butyl 2-(5-bromo-2-cyanophenoxy)ethylcarbamate 32. Cyclization of 32 under acidic conditions, such as hydrochloric acid in ethanol, gives 8-bromo-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33. It will be noted that 33 has an alternative tautomeric form where the double bond is inside the oxazepine ring. Formation of the imidazole ring occurs by reaction of 3-bromo-2- oxopropanoic acid (X = Br, R = OH), or other 3-halo-2-oxopropanoic acid or ester (R = alkyl), and 33 to give 9-bromo-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxylic acid 28. Coupling of 28 with N’-isopropylacetohydrazonamide 6 and a coupling reagent such as HBTU, HATU or CDI in DMF gives intermediate, 9-bromo-N-(l-(2-isopropylhydrazinyl)ethylidene)- 5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxamide 34, which need not be isolated and forms 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III upon heating.

Alternatively, N’-isopropylacetohydrazonamide 6 is used as monohydrochloride salt, which has to be set free under the reaction conditions with an appropriate base, such as K2CO3. Scheme 13:

Figure imgf000020_0001

Scheme 13 shows an alternative synthesis of 8-bromo-3,4-dihydrobenzo[f][l,4]oxazepin- 5(2H)-imine 33 from 4-bromo-2-fluorobenzonitrile 11. Reaction of 11 with sodium methoxide in methanol gives methyl 4-bromo-2-fluorobenzimidate 35. Alkylation of 35 with 2- aminoethanol gives 4-bromo-2-fluoro-N-(2-hydroxyethyl)benzimidamide 36, followed by cyclization to 33.

Scheme 14:

Figure imgf000020_0002

37

11

Scheme 14 shows another alternative synthesis of 8-bromo-3,4- dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33 from 4-bromo-2-fluorobenzonitrile 11. Reaction of 11 with 2-aminoethanol and potassium tert-butoxide displaces fluorine to give 2-(2- aminoethoxy)-4-bromobenzonitrile hydrochloride 37. Ring closure of 37 with

trimethylaluminum gave 33. Alternatively, other trialkylaluminum reagents can be used, or magnesium alkoxide reagents such as magnesium ethoxide (magnesium bisethoxide, CAS Reg. No. 2414-98-4) to cyclize 37 to 33.

Figure imgf000021_0001
Figure imgf000021_0002

Scheme 15 shows the synthesis of 5-(2-(4-chloro-2-fluorophenyl)-lH-imidazol-4-yl)-l- isopropyl-3 -methyl- lH-l,2,4-triazole 44 from 4-chloro-2-fluorobenzonitrile 38. Addition of hydroxylamine to the nitrile of 38 gave 4-chloro-2-fluoro-N-hydroxybenzimidamide 39.

Michael addition of 39 to ethyl propiolate gave ethyl 3-(4-chloro-2- fluorobenzimidamidooxy)acrylate 40. Heating 40 in diphenyl oxide gave cyclized imidazole, ethyl 2-(4-chloro-2-fluorophenyl)-lH-imidazole-4-carboxylate 41. Saponification of the ester of 41 with aqueous sodium hydroxide in tetrahydrofuran gave 2-(4-chloro-2-fluorophenyl)-lH- imidazole-4-carboxylic acid 42. Reaction of 42 with N’-isopropylacetohydrazonamide 6 and coupling reagent HBTU in DMF gives intermediate, 2-(4-chloro-2-fluorophenyl)-N-(l-(2- isopropylhydrazinyl)ethylidene)-lH-imidazole-4-carboxamide 43 which cyclizes upon heating to give 44.

EXAMPLES

Example 1 tert-butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2

To a solution of tert-butyl hydrazinecarboxylate 1 (CAS Reg. No. 870-46-2) (25.1 g, 0.190 mol) in acetone (185 mL) was added the magnesium sulfate (6 g) and 12 drops acetic acid (Wu et al (2012) Jour. Med. Chem. 55(6):2724-2736; WO 2007/056170; Zawadzki et al (2003) Polish Jour. Chem. 77(3):315-319). The mixture was heated to reflux for 2.5 h and cooled to rt and filtered. The filtrate was concentrated to give tert-butyl 2-(propan-2- ylidene)hydrazinecarboxylate 2 (CAS Reg. No. 16689-34-2) as an off-white solid (32 g, 98%) (used in the next step without further purification). LC-MS [M+H]+ = 172.9, RT = 2.11 min. 1H NMR 300 MHz (CDC13) d 7.35 (br s, 1H, NH), 2.04 (s, 3H), 1.82 (s, 3H), 1.54 (s, 9H); 13C NMR 300 MHz (CDC13) d 152.9, 149.7, 80.7, 28.1, 25.3, 15.9. Example 2 tert-butyl 2-isopropylhydrazinecarboxylate 3

tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 was reduced with palladium catalyst on carbon with hydrogen gas in acetic acid and methanol to give tert-butyl 2- isopropylhydrazinecarboxylate 3 (CAS Reg. No. 16689-35-3).

Alternatively, tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 (0.51 g, 3.0 mmol) was dissolved in 20 mL of THF, treated with NaB¾CN (0.19 g, 3.0 mmol) and a few mg of bromocresol green, followed by a solution of p-toluenesulfonic acid (0.57 g, 3.0 mmol) in 1.5 mL of THF which was added dropwise over approximately 1 h to maintain the reaction pH between 3.5-5.0. After stirring at room temperature for an additional hour, the solvent was removed by rotary evaporation, and the residue was partitioned between EtOAc (30 mL) and brine. The organic phase was extracted with sat. NaHCC>3, 20 mL and brine, evaporated to a residue and dissolved in 10 mL of ethanol. The ethanolic solution was treated with 3.6 mL of 1M NaOH solution (3.6 mmol) and left to stir at rt for 30 min. The solvent was removed by rotary evaporation and the residue was taken up into ethyl acetate and extracted with water. The organic layer was evaporated under reduced pressure and the residue was purified by column chromatography using 5 % MeOH in DCM as eluent to collect tert-butyl 2- isopropylhydrazinecarboxylate 3 (0.4 g, 77 % yield): mp = 47-49 °C; Rf = 0.44 (5 % MeOH in DCM); IH NMR 300 MHz (CDC13) d 6.03 (s, N-H, IH), 3.92 (s, N-H, IH), 3.14 (m, IH), 1.46 (s, 9H), 1.02 (d, 6H, J = 6 Hz); 13C NMR 300 MHz (CDC13) d 157.2, 80.8, 51.2, 28.7, 21.0.

Example 3 isopropylhydrazine hydrochloride 4

tert-butyl 2-isopropylhydrazinecarboxylate 3 was treated with hydrochloric acid to remove the Boc protecting group and give 4 (CAS Reg. No. 16726-41-3).

Example 4 N’-isopropylacetohydrazonamide 6

Methyl acetimidate hydrochloride 5 (CAS Reg. No. 14777-27-6), isopropylhydrazine hydrochloride 4, and triethylamine were reacted in methanol to give 6 (CAS Reg. No. 73479-06- 8).

Example 5 l-isopropyl-3 -methyl- lH-l,2,4-triazole 7

N’-isopropylacetohydrazonamide 6 was treated with triethylorthoformate in ethanol, followed by triethylamine and tetrahydrofuran to give 7 (CAS Reg. No. 1401305-30-3). Example 6 2-chloro-N-methoxy-N-methylacetamide 10

To a solution of 21.2 kg potassium carbonate K2CO3 (153.7 mol, 3.0 eq) in 30 L H20 was added, Ν,Ο-dimethylhydroxylamine 9 (CAS Reg. No. 1117-97-1) (5.0 kg, 51.3 mol, 1.0 eq) at 15-20 °C. The reaction was stirred at rt for 30min and 30 L methyl tert-butyl ether (TBME) was added. After stirred for 30min, the mixture was cooled to 5°C, and 11.6 kg of 2-Chloroacetyl chloride 8 (CAS Reg. No. 79-04-9 (102.7 mol, 2.0 eq) were added slowly. The reaction was stirred at rt overnight. Organics were separated from aqueous, and aqueous was extracted with TBME (30 L). The combined organics were washed with H20 (50 L), brine (50 L) and dried over Na2S04. Filtered and concentrated under vacuum afforded 5.1 kg of 2-chloro-N-methoxy- N-methylacetamide 10 (CAS Reg. No. 67442-07-3) as a white solid.

Example 7 4-bromo-2-fluorobenzimidamide hydrochloride 12

To 35.0 L of lithium hexamethyldisilazide LiHMDS (35.0 mol, 1.4 eq, 1.0 M in THF) under N2 was added a THF solution of 4-Bromo-2-fluorobenzonitrile 11 (CAS Reg. No. 105942- 08-3) (5.0 kg in 10 L THF) at 10 °C, the mixture was stirred at rt for 3h. Cooled to -20°C and 8.3 L of HCl-EtOH (6.6 M) were added. The mixture was stirred at -10 °C for additional lh, filtered. The wet cake was washed with EA (10 L) and H20 (6 L). Drying in vacuo yielded 5.8 kg 4- bromo-2-fluorobenzimidamide hydrochloride 12 (CAS Reg. No. 1187927-25-8) as an off-white solid.

Alternatively, to a 200-L vessel was charged 4-bromo-2-fluorobenzonitrile 11 (10 kg, 50.00 mol, 1.00 equiv) and ethanol (100 L) followed by purging 40 kg Hydrogen chloride (g) at – 10 °C with stirring (Scheme 4). The resulting solution was allowed to react for an additional 36 h at 10 °C. The reaction progress was monitored by TLC until 11 was consumed completely. The resulting mixture was concentrated under vacuum while maintaining the temperature below 60 °C. The volume was concentrated to 10-15 L before 60 L MTBE was added to precipitate the product. The precipitates were collected by filtration to afford in 12 k g of ethyl 4-bromo-2- fluorobenzimidate hydrochloride 12 as a white solid. (Yield: 85%). 1H NMR δ 7.88-7.67 (m), 4.89 (br s), 4.68 (q), 3.33 (m), 1.61 (t). MS M+l: 245.9, 248.0.

To a 200L vessel, was charged ethyl 4-bromo-2-fluorobenzimidate hydrochloride (12.5 k g, 44mol, 1.00 equiv, 99%) and ethanol (125 L) followed by purging NH3 (g) at -5 °C for 12 h. The resulting solution was stirred at 30 °C for an additional 24 h. The reaction progress was monitored by TLC until SM was consumed completely. The precipitates were filtered and the filtrate was concentrated under vacuum. The product was precipitated and collected by filtration to afford 6.1 kg (54.5%) of 4-bromo-2-fluorobenzamidine hydrochloride 12 as a white solid. 1H NMR δ 9.60 (br), 7.91-7.64 (m), 3.40 (s), 2.50 (m). MS M+l: 216.9, 219.9.

Example 8 2-chloro-l-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)ethanone 13

To a 10L four necked flask was charged l-Isopropyl-3-methyl-lH-l,2,4-triazole 7 (400 g) in THF (2.5 L). The resulting solution was cooled to -40 °C and 2.5 M n-butyllithium BuLi in n- hexanes (1.41 L) was added while keeping the internal temp, below -20°C. The resulting yellow suspension was stirred at -40°C for 1 hour before being transferred. To a 20L flask was charged 2-chloro-N-methoxy-N-methylacetamide 10 (485 g) in THF (4 L). The resulting solution was cooled to -40 °C at which point a white suspension was obtained, and to this was added the solution of lithiated triazole 7 keeping the internal temp, below -20°C. At this point a yellow orange solution was obtained which was stirred at – 30°C for lhour. Propionic acid (520 mL) was added keeping the internal temp, below -20°C. The resulting off-white to yellowish suspension was warmed to -5 °C over 30 minutes. Citric acid (200 g) in water (0.8 L) was added and after stirring for 5 minutes a clear biphasic mixture was obtained. At this point stirring was stopped and the bottom aqueous layer was removed. The organic phase was washed with 20w% K3PO4 solution (1 L), 20w% K2HP04 solution (2 L), and 20w% NaCl solution (1 L). The organics was reduced to ca 4L via distillation under vacuum to afford 2-chloro-l-(l-isopropyl-3- methyl-lH-l,2,4-triazol-5-yl)ethanone 13 as a dark amber liquid which was used “as is” in the next step.

Example 9 5-(2-(4-bromo-2-fluorophenyl)- lH-imidazol-4-yl)-l -isopropyl-3-methyl- lH-l,2,4-triazole V

To a 10 L four- neck flask were charged with THF (5.6 L), 4-bromo-2- fluorobenzimidamide hydrochloride 12 (567 g), KHCO3 (567 g) and water (1.15 L). The resulting white suspension was heated to 60°C over 2 hours. At this point a hazy solution was obtained to which was added a solution of 2-Chloro-l-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5- yl)ethanone 13 in THF (2 L). This solution was stirred at 60-65 °C for 24 hours. Then the aqueous bottom layer was removed. The organic layer was concentrated under vacuum. The residue was slurried in a mixture of MIBK (1.25 L) and toluene (0.7 L), and the precipitated product was filtered giving 552 g of 5-(2-(4-bromo-2-fluorophenyl)-lH-imidazol-4-yl)-l- isopropyl-3 -methyl- lH-l,2,4-triazole V (98.0% purity, 254 nm) as a brown solid Example 10 2-(2-(4-bromo-2-fluorophenyl)-4-(l-isopropyl-3-methyl-lH-l,2,4-triazol- 5-yl)- 1 H-imidazol- 1 -yl)ethanol 14

5-(2-(4-Bromo-2-fluorophenyl)-lH-imidazol-4-yl)-l-isopropyl-3-methyl-lH- 1,2,4- triazole V (2.75 kg, 7.55 mol) was added to a solution of 3-dioxolan-2-one (ethylene carbonate, 3.99 kg, 45.3 mol) inN-methylimidazole (12 L) at 50 °C. The suspension was heated at 80°C for 7 h until the reaction was judged complete by HPLC. The solution of 14 was cooled to 35 °C and used directly in the subsequent cyclization.

Example 11 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepine III

To a solution of 2-(2-(4-Bromo-2-fluorophenyl)-4-(l-isopropyl-3-methyl-lH-l,2,4- triazol-5-yl)-l H-imidazol- l-yl)ethanol (7.55 mmol) 14 inN-methylimidazole(12 L) at 35 °C was added methyl tributylammonium chloride (115 g, 0.453 mol), toluene (27.5 L) and 35% potassium hydroxide solution (10.6 kg, 25 mol in 22 L of water). The biphasic solution was stirred vigorously at 65 °C for 18 h when it was judged complete by HPLC. Stirring was stopped but heating was continued and the bottom aqueous layer was removed. Added isopropyl acetate (13.8 L) and the organic phase was washed twice with water (13.8 L and 27.5 L). The solvent was removed via vacuum distillation and after 30 L had been removed, isopropanol (67.6 L) was added. Vacuum distillation was resumed until an additional 30 L of solvent had been removed. Added additional isopropanol (28.8 L) and continued vacuum distillation until the volume was reduced by 42 L. Added isopropanol (4L) and the temperature was increased to >50 °C. Added water (28 L) such that the internal temperature was maintained above 50 °C, then heated to 75 °C to obtain a clear solution. The mixture was allowed to cool slowly and the product crystallized out of solution. The resulting suspension was cooled to 0 °C, held for 1 h then filtered and the cake was washed with water (5.5 L). The cake was dried at 45 °C under a nitrogen sweep to give III as a tan solid (3.30 kg, 71.6 wt %, 80.6% yield).

Example 12 2-methyl-2-(lH-pyrazol-l-yl)propanoic acid 16

2-Bromo-2-methylpropanoic acid 15 and pyrazole were reacted in triethylamine and 2- methyltetrahydrofuran to give 16.

Example 13 ethyl 2-methyl-2-(lH-pyrazol-l-yl)propanoate 17

2-Methyl-2-(lH-pyrazol-l-yl)propanoic acid 16 was treated with sulfuric acid in ethanol to give 17. Alternatively, pyrazole (10 g, 147 mmol, 1.0 eq.) was dissolved in DMF (500 ml) at room temperature (Scheme 8). 2-Bromoisobutyrate 18 (22 ml, 147 mmol, 1.0 eq.), cesium carbonate CS2CO3 (53 g, 162 mmol, 1.1 eq) and catalytic sodium iodide Nal (2.2 g, 15 mmol, 0.1, eq) were added to the mixture that was then heated to 60 °C for 24 hr. Reaction was followed by 1H NMR and pyrazole was not detected after 24 hr. The reaction mixture was quenched with a saturated solution of NaHCC>3 (200 ml) and ethyl acetate EtOAc (150 ml) was added and organics were separated from aqueous. Organics were dried over Na2S04, filtered and concentrated under vacuum to afford an oil which was purified by flash chromatography to give 17.

Example 14 Ethyl 2-(4-bromo-lH-pyrazol-l-yl)-2-methylpropanoate IV

Method A: Ethyl 2-methyl-2-(lH-pyrazol-l-yl)propanoate 17 was reacted with N- bromosuccinimide (NBS) in 2-methyltetrahydrofuran to give IV (CAS Reg. No. 1040377-17-0).

Method B: Ethyl 2-bromo-2-methylpropanoate 18 and pyrazole were reacted with sodium tert-butoxide in dimethylformamide (DMF) to give a mixture of ethyl 2-methyl-2-(lH- pyrazol-l-yl)propanoate 17 and ethyl 2-methyl-3-(lH-pyrazol-l-yl)propanoate 19 which was treated with l,3-dibromo-5,5-dimethylimidazolidine-2,4-dione to give a mixture of IV, ethyl 3- (4-bromo-lH-pyrazol-l-yl)-2-methylpropanoate 20, and 4-bromo-lH-pyrazole 21. The mixture was treated with a catalytic amount of lithium hexamethyldisilazide in tetrahydrofuran followed by acidification with hydrochloric acid to give IV.

Example 15 ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)propanoate 22

To a 50 L glass reactor was charged ethyl 2-(4-bromo-lH-pyrazol-l-yl)-2- methylpropanoate IV (1.00 kg, 3.85 mol, 1.00 equiv), potassium acetate, KOAc (0.47 kg, 4.79 mol 1.25 equiv), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(l,3,2-dioxaborolane),

bis(pinacolato)diboron, B2Pin2 (1.22 kg, 4.79 mol, 1.25 equiv) and ethanol (10 L, 10 vol) and the mixture was stirred until a clear solution was obtained. The solution was vacuum/degassed 3x with nitrogen. To this mixture was charged XPhos ligand (0.023 kg, 0.048 mol, 1.0 mol ) and the Pd precatalyst (0.018 kg, 0.022 mol, 0.5 mol ) resulting in a homogeneous orange solution. The solution was vacuum/degassed once with nitrogen. The internal temperature of the reaction was set to 75 °C and the reaction was sampled every 30 min once the set temperature was reached and was monitored by LC (IPC method: XTerra MS Boronic). After 5 h, conversion to 22 (CAS Reg. No. 1201657-32-0) was almost complete, with 1.3% IV remaining. Example 16 ethyl 2-(4-(2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)- IH-pyrazol- 1 -yl)-2-methylpropanoate 23

Ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)propanoate 22 and 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III were reacted under Suzuki conditions with palladium catalyst, in isopropanol and aqueous phosphate buffer to give 23.

A 1M solution of K3PO4 (1.60 kg in 7.6 L of water, 7.54 mol, 2.00 equiv) was charged to the above reaction mixture from Example 15, followed by the addition of a solution of III in THF (1.33 kg in 5.0 L, 3.43 mol, 0.90 equiv) over 2 min. The reaction mixture was warmed to 75 °C (internal temperature) over 45 min and stirred for 13 h at 75 °C, then analyzed by HPLC (III not detected) showing the formation of 23.

Example 17 2-(4-(2-( 1 -isopropyl-3-methyl- 1 H- 1 ,2,4-triazol-5-yl)-5 ,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)- IH-pyrazol- 1 -yl)-2-methylpropanoic acid II

Ethyl 2-(4-(2-(l -isopropyl-3 -methyl- 1 H- 1 ,2,4-triazol-5-yl)-5 ,6- dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepin-9-yl)-lH-pyrazol-l-yl)-2-methylpropanoate 23 was treated with aqueous lithium hydroxide to give II.

The ester saponification reaction was initiated with the addition of 3.5 M aqueous LiOH (0.74 kg in 5.0 L, 17.64 mol, 5 equiv) to the reaction mixture from Example 16 and allowed to warm to 75 °C. The mixture was sampled every 30 min (IPC method: XTerra MS Boronic) and the saponification was complete after 4.5 h (with less than 0.3% 23 remaining). The reaction mixture was concentrated via distillation to approximately half volume (starting vol = 37 L; final vol = 19 L) to remove EtOH and THF, resulting in tan-brown slurry. Water (5 L, 5 vol) was charged to the mixture and then distilled (starting vol = 25 L; final vol = 21 L). The temperature was set at 60 °C (jacket control) and then charged with isopropyl acetate, IP Ac (4 L, 4 vol). The biphasic mixture was stirred a minimum of 5 min and then the layers allowed to separate for a minimum of 5 min. The bottom aqueous layer was removed into a clean carboy and the organics were collected into a second carboy. The extraction process was repeated a total of four times, until the organic layer was visibly clear. The aqueous mixture was transferred back to the reactor and then cooled to 15 °C. A 6 M solution of HC1 (6.4 L, 38.40 mol, 10 equiv) was charged slowly until a final pH = 1 was obtained. The heterogeneous mixture was then filtered. The resulting solids were washed twice with 5 L (2 x 5 vol) of water. The filter was then heated to 80 °C and the vacuum set to -10 Psi (with nitrogen bleed) and the solids were dried for 24 h (KF = 2.0 % H20) to give 1.54 kg (95% corrected yield) of II as a white solid; 98% wt, 97.3 % pure.

Example 18 2-(4-(2-( 1 -isopropyl-3-methyl- 1 H- 1 ,2,4-triazol-5-yl)-5 ,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)- lH-pyrazol- 1 -yl)-2-methylpropanamide I (GDC-0032)

2-(4-(2-(l-Isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,2- d][l,4]oxazepin-9-yl)-lH-pyrazol-l-yl)-2-methylpropanoic acid II was treated with di(lH- imidazol-l-yl)methanone (carbonyldiimidazole, CDI) in tetrahydrofuran followed by methanolic ammonia to give crude I.

Solid II (1.44 kg, 3.12 mol, 1.00 equiv) was transferred into a 20 L bottle and then THF

(10 L, 7 vol) was charged. The slurry was transferred under reduced pressure into a second 50 L reactor and additional THF (5 L, 3 vol) was added for the rinse. The internal temperature of the slurry was set to 22 °C and Γ1 -carbonyldiimidazole, CDI (0.76 Kg, 5.12 mol, 1.50 equiv) was charged to the mixture and a clear solution was observed after 5 min. The reaction mixture was sampled every 30 min and analyzed by HPLC (IPC: XTerra MS Boronic method) which showed almost complete conversion to the acyl-imidazole intermediate and 1.2% remaining II after 30 min. An additional portion of CDI (0.07 kg, 0.15 mol, 0.14 equiv) was added, and the reaction mixture was stirred for 1 h and then analyzed by HPLC (IPC: XTerra MS Boronic method) which showed 0.8% remaining II.

Into a second 50-L reactor, was added NH3/MeOH (1.5 L, 10.5 mol, 3.37 equiv) and THF

(5 L, 3 vol). The acyl-imidazole intermediate was transferred to a second reactor under reduced pressure (transfer time -10 min). The internal temperature was then set to 45 °C and the volume of solvent was distilled down from 35 L to 12 L. Water (6 L, 4 vol) was then added to the mixture that was further distilled from 18 L to 11 L. Finally, another portion of water (6 L, 4 vol) was added and the solvents were distilled one last time from 17 L to 14 L, until no more THF was coming out. The reaction was then cooled down to 10 °C (internal temperature). The white slurry was filtered and the filter cake was washed with water (2 x 6 L, 2 x 4 vol). The solids were then dried at 80 °C (jacket temp) in the Aurora filter for 24 h (KF = 1.5 % H20) under vacuum to give 1.25 kg crude I, GDC-0032 (84% corrected yield, 96% wt, 97.3 % pure by HPLC) as a white solid.

A slurry of crude I (1.15 kg, 2.50 moles) in MeOH (6 L, 5 vol) was prepared and then charged to a 50 L glass reactor. Additional MeOH (24 L, 21 vol) was added to the mixture, which was then heated to 65 °C. A homogenous mixture was obtained. Si-thiol (Silicycle, Inc., 0.23 kg, 20% wt) was added to the solution via the addition port and the mixture was stirred for 3 hours. It was then filtered warm via the Aurora filter (jacket temperature = 60 °C, polish filtered and transferred directly into a second 50 L reactor with reduced pressure. The solution was then heated back to 65 °C internal temperature (IT). The homogeneous solution was cooled down to 54 °C and I seeds (12 g, 1 % wt) in MeOH (50 mL) were added with reduced pressure applied to the reactor. The mixture was then cooled down to 20 °C over 16 hours. The solids were then filtered via the Aurora filter and dried at 80 °C for 72 hours to give 921 g, 80% yield of I as a methanoate solvate (form A by XRPD,) and transferred to a pre-weighed charge-point bag.

In an isolator, the solids were slurred in IP Ac (8 L, 7 vol) and transferred to a clean 10 L reactor. The mixture was stirred for 1 h at 60 °C (IT). The solids were then filtered via the Aurora system and dried at 80 °C (jacket) for 96 h. A sample of I was removed and analyzed by GC (IP Ac = 1 %). To attempt more efficient drying, the API was transferred to two glass trays in an isolator and sealed with a drying bag before being dried in a vacuum oven set at 100 °C for 16 h. GC (IPC: Q12690V2) showed 1 % solvent was still present. The process afforded 760 g (68% corrected yield, 68% wt, 99.9 % purity by LC) of a white solid (form B by XRPD).

Crude I (340.7 g) was charged to a 2-1 . 1 1 DPI · bottle and slurried with 0.81 ,

isoamylalcohol (I A A). The slurry was transferred to a 20 L reactor and diluted with 6.7 L round- bottom flask (22 vol total). The white slurry was heated until a solution was observed (internal temperature rose to 118 °C and then cooled to 109 °C). The solution was polish filtered (0.2 μ .Μ filter). A flask was equipped with overhead stirring and the filtrate was slurried in isoamyl alcohol (344 ml ., 21 vol). The mixture was warmed to 95 °C (internal) until the solids dissolved. A slurry of charcoal (10 wt%, 0.16g) and silicycle thiol (10 wt%, 0.16g) in isoamyl alcohol (1 vol, 1 6 ml . ) was charged and the mixture was stirred at 90-95 °C for 1 h and then filtered (over Celite® pad). The clear amber colored solution was cooled to 73 °C (seeding temp range = 70 ±5 °C) and a GDC-0032 I seed (10 wt%, 0.16g) was added. The temperature of the heating mantle was turned off and the mixture was allowed to cool to room temperature overnight with stirrin (200 rpni). After 17 hr, the white solids were filtered starting with slow gravity filtration and then vacuum was applied. The solids were suction dried for 20 min with mixing until a free flowing powder was obtained. ( rude weight prior to oven drying = 16 g. The solids were oven- dried at 100 °C for 24 h and then sampled for testing. Drying continued at 100 °C for another 24 hr. I l l NMR (DMSO d6) δ 8.38 (t), 8.01 (s), 7.87 (s), 7.44, 7.46 (d), 7.36 (s), 7.18 (br s), 6.81

(br s), 5.82 (m), 3.99 (s), 2.50 (s), 2.26 (s), 1.75 (s), 1.48, 1.46 (d).

Purified 2-(4-(2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)- lH-pyrazol- 1 -yl)-2-methylpropanamide I (GDC-0032) was dry granulation formulated in tablet form by the roller compaction method (He et al (2007) Jour, of Pharm. Sci., 96(5):1342-1355) with excipients including lactose, microcrystalline cellulose (AVICEL® PH 01, FMC BioPolymer, 50 μΜ particle),

croscarmellose sodium (Ac-Di-Sol®, FMC BioPolymer), and magnesium stearate.

Example 19 4-bromo-2-fluoro-N-hydroxybenzimidamide 24

To a solution of 4-Bromo-2-fluorobenzonitrile 11 (800 g, 4 mol, 1 eq), hydroxylamine hydrochloride (695 g, 10 mol, 2.5 eq) in MeOH (2 L, 2.5 vol) was added Et3N (485 g, 4.8 mol, 1.2 eq), then the mixture was stirred at 60 °C for 40 min and checked by HPLC (no nitrile remaining). Reaction was then quenched by H20 (30 L), and lots of off-white solid was separated out, and then filtered, the filter cake was washed with water (10 L x 2) and 1350 g wet 4-bromo-2-fluoro-N-hydroxybenzimidamide 24 was obtained with 96% purity.

Example 20 ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25

To a solution of 4-Bromo-2-fluoro-N-hydroxybenzimidamide 24 (800 g, 3.43 mol, 1 eq) and Amberlyst® A21 (20 wt%, 160 g) in PhMe (12 L, 15 vol) was added ethyl propiolate (471 g, 4.8 mol, 1.4 eq) at 10 °C. The reaction was stirred at 50 °C overnight and checked by LC-MS (ca 14A% of starting material 24 was left). Reaction was then filtered and the filtrate was concentrated under vacuum, and 1015 g ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25 was obtained as a yellow oil with 84.9% LC purity (yield: 89%).

Example 21 ethyl 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4-carboxylate 26

A solution of ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25 (300 g, 0.91 mol, 1 eq) in diphenyl oxide (900 mL, 3 vol) was stirred at 190 °C under N2 for 1 h and checked by LC-MS (no 25 remaining). Cooled the mixture to rt and TBME (600 mL, 2 vol of 25) was added, and then PE (1.8 L, 6 vol of 25) was dropwise added to separate out solids. The mixture was stirred at rt for 20 min, and filtered to give 160 g wet cake. The wet cake was washed with PE (1 L) and dried to afford 120 g ethyl 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4-carboxylate 26 with 92% LC purity as brown solids. Example 22 ethyl 2-(4-bromo-2-fluorophenyl)- 1 -(2-hydroxyethyl)- 1 H-imidazole-4- carboxylate 27

Ethyl 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4-carboxylate 26 and l,3-dioxolan-2- one and N-methylimidazole were reacted to give 27.

Example 23 9-bromo-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxylic acid 28

Ethyl 2-(4-bromo-2-fluorophenyl)-l -(2-hydroxyethyl)- lH-imidazole-4-carboxylate 27, potassium hydroxide and methyl tributylammonium hydrochloride were reacted at 65 °C, cooled, and concentrated. The mixture was dissolved in ethanol and water to crystallize 28.

Example 24 9-bromo-N-(l-iminoethyl)-5,6-dihydrobenzo[f]imidazo[l,2- d] [ 1 ,4]oxazepine-2-carboxamide 29

9-Bromo-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxylic acid 28, triphenylphosphine, and acetamidine were reacted to give 29.

Example 25 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III

9-Bromo-N-( 1 -iminoethyl)-5 ,6-dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepine-2- carboxamide 29 was reacted with isopropylhydrazine hydrochloride 4 in acetic acid to give III.

Example 26 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4-carboxylic acid 30

3-Chloro-2-oxopropanoic acid and 4-bromo-2-fluorobenzimidamide hydrochloride 12 are reacted with base to give 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4-carboxylic acid 30.

Alternatively, to a solution of ethyl 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4- carboxylate 26 (1350 g, 4.3 mol) in THF (8.1 L, 6 vol) and H20 (4 L, 3 vol) was added NaOH (520 g, 13 mol, 3 eq), and the reaction was stirred at 65 °C for 48 h till it completed (checked by LC-MS). Adjust the mixture with 2 M HC1 to pH = 5, and product was separated out as a yellow solid, filtered to give 2.2 kg wet cake, the wet cake was washed with H20 (1.5 L), DCM (1.5 L x 3), PE (1 L), and dried to afford 970 g pure 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4- carboxylic acid 30 (Scheme 10). Example 27 5-(2-(4-bromo-2-fluorophenyl)-lH-imidazol-4-yl)-l-isopropyl-3-methyl- lH-l,2,4-triazole V

Reaction of 30 with N’-isopropylacetohydrazonamide 6 and coupling reagent HBTU in DMF gives intermediate, 2-(4-bromo-2-fluorophenyl)-N-(l-(2-isopropylhydrazinyl)ethylidene)- lH-imidazole-4-carboxamide 31 which cyclizes upon heating to give V.

Example 28 tert-butyl 2-hydroxyethylcarbamate gives tert-butyl 2-(5-bromo-2- cyanophenoxy)ethylcarbamate 32

Alkylation of 4-bromo-2-fluorobenzonitrile 11 with tert-butyl 2-hydroxyethylcarbamate gives 32.

Example 29 8-bromo-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33

Cyclization of tert-butyl 2-hydroxyethylcarbamate gives tert-butyl 2-(5-bromo-2- cyanophenoxy)ethylcarbamate 32 under acidic conditions, such as hydrochloric acid in ethanol, gives 33.

Example 30 9-bromo-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxylic acid 28

Reaction of 3-bromo-2-oxopropanoic acid and 8-bromo-3,4- dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33 gives 28 (CAS Reg. No. 1282516-74-8).

Example 31 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepine III

Coupling of 28 with N’-isopropylacetohydrazonamide 6 and coupling reagent HBTU in

DMF gives intermediate, 9-bromo-N-(l-(2-isopropylhydrazinyl)ethylidene)-5,6- dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxamide 34, which forms III upon heating.

Example 32 methyl 4-bromo-2-fluorobenzimidate 35

Reaction of 4-bromo-2-fluorobenzonitrile 11 with sodium methoxide in methanol gives 35.

Example 33 8-bromo-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33

Alkylation of methyl 4-bromo-2-fluorobenzimidate 35 with 2-aminoethanol gives 4- bromo-2-fluoro-N-(2-hydroxyethyl)benzimidamide 36, followed by cyclization to 33 (Scheme 13). Alternatively, reaction of 11 with 2- aminoethanol and potassium tert-butoxide displaces fluorine to give 2-(2-aminoethoxy)-4-bromobenzonitrile hydrochloride 37. Ring closure of 37 with trimethylaluminum gave 33 (Scheme 14). A solution of 11 (10 g, 50 mmol) and 2- aminoethanol (3.1 mL, 50.8 mmol) in 2-methyltetrahydrofuran (80 mL) was cooled to 0 °C and a solution of 1M potassium tert-butoxide in tetrahydrofuran (55 mL, 55 mmol) was slowly added while maintaining the solution temperature below 5 °C. The reaction was stirred at 0 °C for 30 min until judged complete by HPLC at which point it was warmed to 25 °C. A solution of 0.5M HC1 in isopropanol (100 mL, 50 mmol) was added and the desired HC1 salt 3 crystallized directly from the solution. The solid was collected by filtration and dried under vacuum with a nitrogen bleed to give 2-(2-aminoethoxy)-4-bromobenzonitrile hydrochloride 37 as a white solid. (12.1 g, 87 % yield).

To a flask was charged 37 (9.00 g, 32.4 mmol) and toluene (90.0 ml). The suspension was cooled to 0 °C and was added trimethylaluminum (1.8 equiv., 58.4 mmol, 2M in toluene) drop-wise over 30 minutes. The suspension was then stirred at room temperature for 1 h and then warmed to 100 °C. After 5 h, the solution was cooled to 0 °C and quenched with aqueous NaOH (2N, 90.0 ml). The suspension was extracted with EtOAc (4 x 90 ml) and the combined extracts were dried over then filtered through Celite®. The solution was concentrated and the residue triturated with EtOAc to afford 8-bromo-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33 (6.26 g, 26.0 mmol, 80% yield) as white crystalline solid.

Example 34 4-chloro-2-fluoro-N-hydroxybenzimidamide 39

To a solution of 4-chloro-2-fluorobenzonitrile 38 (400 g, 2.58 mol, 1.0 eq),

hydroxylamine hydrochloride (448 g, 6.45 mol, 2.5 eq) in MeOH (1 L, 2.5 vol) was added Et3N (313 g, 3.1 mol, 1.2 eq), then the mixture was stirred at 60 °C for 40 min and checked by HPLC (no nitrile remaining). Reaction was then quenched by H20 (10 L), and lots of off-white solid was separated out, and then filtered, the filter cake was washed with water (10 L x 2) and 378 g 4-chloro-2-fluoro-N-hydroxybenzimidamide 39 was obtained with 93% purity (Scheme 15).

Example 35 ethyl 3-(4-chloro-2-fluorobenzimidamidooxy)acrylate 40

To a solution of 4-chloro-2-fluoro-N-hydroxybenzimidamide 39 (378 g, 2 mol, 1.0 eq) and Amberlyst® A21 (20 wt%, 75.6 g) in toluene PhMe (5.6 L, 15 vol) was added ethyl propiolate (275 g, 2.8 mol, 1.4 eq) at 30 °C. The reaction was stirred at 30 °C overnight and checked by LC-MS. Reaction was then filtered and the filtrate was concentrated under vacuum, and 550 g ethyl 3-(4-chloro-2-fluorobenzimidamidooxy)acrylate 40 was obtained as a yellow oil with 83% LC purity (Scheme 15).

Example 36 ethyl 2-(4-chloro-2-fluorophenyl)-lH-imidazole-4-carboxylate 41

A solution of ethyl 3-(4-chloro-2-fluorobenzimidamidooxy)acrylate 40 (550 g, 1.9 mol, 1.0 eq, 83% LC purity) in diphenyl oxide (1.65 L, 3 vol) was stirred at 190 °C under N2 for 1 h and checked by LC-MS (no 40 remaining). Cooled the mixture to rt and PE (10 L) was added dropwise. The mixture was stirred at rt for 20 min, and filtered to give 400 g wet cake, after purified by chromatography on silica gel (PE / EA=1 / 5) to get 175 g pure ethyl 2-(4-chloro-2- fluorophenyl)-lH-imidazole-4-carboxylate 41 with 98% LC purity (Scheme 15).

Example 37 2-(4-chloro-2-fluorophenyl)-lH-imidazole-4-carboxylic acid 42

To a solution of ethyl 2-(4-chloro-2-fluorophenyl)-lH-imidazole-4-carboxylate 41 (175 g, 4.3 mol) in THF (1 L, 6 vol) and H20 (500 mL, 3 vol) was added NaOH (78 g, 1.95 mol, 3.0 eq), and the reaction was stirred at 65 °C for 48 h till it completed (checked by LC-MS). Adjust the mixture with 2 N HC1 to pH = 5, and product was separated out as a yellow solid, filtered to give 210 g wet cake, the wet cake was washed with H20 (300 mL), DCM (3 x 300 mL), PE (500 mL), and dried to afford 110 g pure 2-(4-chloro-2-fluorophenyl)-lH-imidazole-4-carboxylic acid 42 (CAS Reg. No. 1260649-87-3) (Scheme 15 ). I l l NMR (DMSO d6) δ: 12.8 (br s), 8.0, 7.9 (br s), 7.46, 7.4 (m).

PATENT

US 2014275523

SYNTHESIS

Taselisib_药物数据_原料药API_CCIS-CHEM化学平台科研物资一站式采购平台 …

化学试剂

参考文献:

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CLIP

http://www.ccis-chem.com/goods.php?id=194272

商品规格

Taselisib

Taselisib是罗氏集团及其下属公司Genentech和Chugai研发,目前治疗绝经后妇女雌激素受体阳性(ER +)乳腺癌和非小细胞肺癌(NSCLC)的三期临床研究均在进行中。

基本信息更新时间:2016-02-01

药品名称:
Taselisib
研发代码:
GDC-0032; RG-7604
商品名称:
作用机制:
PI3K inhibitor; Cytochrome P450 CYP3A4 Inhibitors
适应症:
乳腺癌,非小细胞肺癌
研发阶段:
临床三期 (进行中)
研发公司:
罗氏 (原研)

化学信息更新时间:2015-08-27

分子量 460.53
分子式 C24H28N8O2
CAS号 1282512-48-4 (Taselisib);
化学名称 1H-Pyrazole-1-acetamide, 4-[5,6-dihydro-2-[3-methyl-1-(1-methylethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-d][1,4]benzoxazepin-9-yl]-a,a-dimethyl-
Fudosteine药品(游离态)参数:
MW HD HA FRB* PSA* cLogP*
460.53 2 10 5 119 2.548±1.034

化学合成路线及相关杂质更新时间:2015-12-15

参考文献:J. Med. Chem. 2013, 56, 4597−4610

参考文献:WO2014140073A1

PAPER

J Med Chem 2013, 56(11): 4597

Discovery of 2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2–4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): A β-Sparing Phosphoinositide 3-Kinase Inhibitor with High Unbound Exposure and Robust in Vivo Antitumor Activity

Departments of Discovery Chemistry, Drug Metabolism and Pharmacokinetics, §Translational Oncology, and Biochemical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
 Argenta Discovery, 8-9 Spire Green Centre, Flex Meadow, Harlow, Essex, CM19 5TR, United Kingdom
J. Med. Chem.201356 (11), pp 4597–4610
DOI: 10.1021/jm4003632
*Phone: 650-225-2923 (C.O.N.); +1-(650)-467-3214 (T.P.H.). E-mail: chudin@gene.com (C.O.N.); theffron@gene.com (T.P.H.).
Abstract Image

Dysfunctional signaling through the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway leads to uncontrolled tumor proliferation. In the course of the discovery of novel benzoxepin PI3K inhibitors, we observed a strong dependency of in vivo antitumor activity on the free-drug exposure. By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepin compounds that showed improved unbound drug exposure and effectively suppressed growth of tumors in a mouse xenograft model at low drug dose levels. One of these compounds, GDC-0032 (11l), was progressed to clinical trials and is currently under phase I evaluation as a potential treatment for human malignancies.

2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2–4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (11l)

1H NMR (500 MHz, DMSO) δ 8.42 (s, 1H), 8.37 (d, J = 8.3 Hz, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.46 (dd, J = 8.3, 1.8 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.22 (s, 1H), 6.87 (s, 1H), 5.90–5.73 (m, 1H), 4.62–4.42 (m, 4H), 2.50 (dt, J = 3.6, 1.7 Hz, 5H), 2.26 (s, 3H), 1.74 (s, 6H), 1.47 (d, J = 6.5 Hz, 6H). 13C NMR (126 MHz, DMSO) δ 173.78, 158.24, 155.88, 147.31, 143.94, 136.64, 134.60, 130.26, 129.88, 126.42, 123.62, 120.32, 119.31, 116.17, 115.26, 68.31, 64.48, 49.89, 49.70, 40.06, 39.97, 39.89, 39.80, 39.72, 39.63, 39.56, 39.47, 39.30, 39.13, 38.96, 25.47, 22.34, 13.82. HRMS (ESI+): m/z (M + H+) calcd: 461.2413, found: 461.2427. Melting point: 259 °C.
POLYMORPHS almost A to Z
GDC-0032, also known as taselisib, RG7604, or the IUPAC name: 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide, has potent PI3K activity (Ndubaku et al (2013) J. Med. Chem. 56(11):4597-4610; WO 2013/182668; WO 2011/036280; U.S. Pat. No. 8,242,104; U.S. Pat. No. 8,343,955) and is being studied in patients with locally advanced or metastatic solid tumors (Juric et al “GDC-0032, a beta isoform-sparing PI3K inhibitor: Results of a first-in-human phase Ia dose escalation study”, 2013 (Apr. 7) Abs LB-64 American Association for Cancer Research Annual Meeting).

the invention relates to polymorph forms of the PI3K inhibitor I (taselisib, GDC-0032, RG7604, CAS Reg. No. 1282512-48-4, Genentech, Inc.), named as 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide, having the structure:

Figure US09266903-20160223-C00001

and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof.

Publication numberPriority datePublication dateAssigneeTitle
WO2011036280A12009-09-282011-03-31F. Hoffmann-La Roche AgBenzoxazepin pi3k inhibitor compounds and methods of use
WO2014140073A12013-03-132014-09-18F. Hoffmann-La Roche AgProcess for making benzoxazepin compounds

References

Patent ID

Patent Title

Submitted Date

Granted Date

US9670228 BENZOXAZEPIN PI3K INHIBITOR COMPOUNDS AND METHODS OF USE
2016-12-05
US9546178 BENZOXAZEPIN PI3K INHIBITOR COMPOUNDS AND METHODS OF USE
2015-11-03
2016-02-25
US9303043 PROCESS FOR MAKING BENZOXAZEPIN COMPOUNDS
2014-03-12
2014-09-18
US8785626 Benzoxazepin PI3K inhibitor compounds and methods of use
2013-10-07
2014-07-22
US2016135446 CELL STABILIZATION
2014-06-13
2016-05-19
Patent ID

Patent Title

Submitted Date

Granted Date

US2016375033 METHODS OF TREATMENT WITH TASELISIB
2016-06-28
US2016045515 MUTANT SELECTIVITY AND COMBINATIONS OF A PHOSPHOINOSITIDE 3-KINASE INHIBITOR COMPOUND AND CHEMOTHERAPEUTIC AGENTS FOR THE TREATMENT OF CANCER
2015-07-06
2016-02-18
US2016117439 SUPERIOR BIOINFORMATICS PROCESS FOR IDENTIFYING AT RISK SUBJECT POPULATIONS
2015-10-26
2016-04-28
US2017096492 DOSAGE AND ADMINISTRATION OF ANTI-IGF-1R, ANTI-ErbB3 BISPECIFIC ANTIBODIES, USES THEREOF AND METHODS OF TREATMENT THEREWITH
2016-08-19
US9481690 Polymorphs of 2-(4-(2-(1-(isopropyl-3-methyl-1H-1, 2, 4, triazol-5-yl)-5, 6-dihydrobenzo[f] imidazo[1, 2-d][1, 4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide, methods of production, and pharmaceutical uses thereof
2016-01-08
2016-11-01
Patent ID

Patent Title

Submitted Date

Granted Date

US9266903 POLYMORPHS OF 2-(4-(2-(1-ISOPROPYL-3-METHYL-1H-1, 2, 4-TRIAZOL-5-YL)-5, 6-DIHYDROBENZO[F]IMIDAZO[1, 2-D][1, 4]OXAZEPIN-9-YL)-1H-PYRAZOL-1-YL)-2-METHYLPROPANAMIDE, METHODS OF PRODUCTION, AND PHARMACEUTICAL USES THEREOF
2014-12-15
2015-06-18
US2016279142 COMBINATIONS OF A PHOSPHOINOSITIDE 3-KINASE INHIBITOR COMPOUND AND A CDK4/6 INHIBITOR COMPOUND FOR THE TREATMENT OF CANCER
2016-03-24
2016-09-29
US2016117443 BIOINFORMATICS PROCESS FOR IDENTIFYING AT RISK SUBJECT POPULATIONS
2015-10-26
2016-04-28
Patent ID

Patent Title

Submitted Date

Granted Date

US2016220537 COMPOSITIONS TO IMPROVE THE THERAPEUTIC BENEFIT OF BISANTRENE AND ANALOGS AND DERIVATIVES THEREOF
2014-07-25
2016-08-04
US2016113932 TREATMENT OF CANCERS USING PI3 KINASE ISOFORM MODULATORS
2014-05-30
2016-04-28
US2014113879 BLOCK COPOLYMERS FOR STABLE MICELLES
2013-09-16
2014-04-24
US2014114051 BLOCK COPOLYMERS FOR STABLE MICELLES
2013-09-16
2014-04-24
US2014127271 BLOCK COPOLYMERS FOR STABLE MICELLES
2013-09-16
2014-05-08
Patent ID

Patent Title

Submitted Date

Granted Date

US9555030 THERAPEUTIC USES OF SELECTED PYRAZOLOPYRIMIDINE COMPOUNDS WITH ANTI-MER TYROSINE KINASE ACTIVITY
2015-04-03
2015-10-15
US9555031 THERAPEUTIC USES OF SELECTED PYRROLOPYRIMIDINE COMPOUNDS WITH ANTI-MER TYROSINE KINASE ACTIVITY
2015-04-03
2015-10-15
US9649309 THERAPEUTIC USES OF SELECTED PYRIMIDINE COMPOUNDS WITH ANTI-MER TYROSINE KINASE ACTIVITY
2015-04-03
2015-10-15
US2015258080 THERAPEUTIC COMBINATIONS WITH ESTROGEN RECEPTOR MODULATORS
2015-03-12
2015-09-17
US2016166546 COMBINATORIAL METHODS TO IMPROVE THE THERAPEUTIC BENEFIT OF BISANTRENE AND ANALOGS AND DERIVATIVES THEREOF
2014-07-25
2016-06-16
Patent ID

Patent Title

Submitted Date

Granted Date

US2016346408 IRON STABILIZED MICELLES AS MAGNETIC CONTRAST AGENTS
2016-05-26
US2016264732 BLOCK COPOLYMERS FOR STABLE MICELLES
2016-03-10
2016-09-15
US2016220569 CDK4/6 Inhibitor Dosage Formulations For The Protection Of Hematopoietic Stem And Progenitor Cells During Chemotherapy
2016-02-03
2016-08-04
US2015320754 COMBINATION THERAPIES
2015-04-15
2015-11-12
US2015320755 COMBINATION THERAPIES
2015-04-15
2015-11-12
Patent ID

Patent Title

Submitted Date

Granted Date

US8242104 Benzoxazepin P13K inhibitor compounds and methods of use
2011-03-31
2012-08-14
US2017182043 Anti-Neoplastic Combinations and Dosing Regimens using CDK4/6 Inhibitor Compounds to Treat RB-Positive Tumors
2017-03-13
US2017246171 Treatment Of RB-Negative Tumors Using Topoisomerase Inhibitors In Combination With Cyclin Dependent Kinase 4/6 Inhibitors
2017-03-13
US2017136043 THERAPEUTIC USES OF SELECTED PYRROLOPYRIMIDINE COMPOUNDS WITH ANTI-MER TYROSINE KINASE ACTIVITY
2017-01-30
US2017135960 AGGREGATING MICROPARTICLES FOR MEDICAL THERAPY
2016-11-11
Patent ID

Patent Title

Submitted Date

Granted Date

US9603850 MERTK-SPECIFIC PYRAZOLOPYRIMIDINE COMPOUNDS
2015-04-03
2015-10-15
US9198918 BENZOXAZEPIN PI3K INHIBITOR COMPOUNDS AND METHODS OF USE
2014-06-05
2014-09-25
US2014377258 Treatment Of Cancers Using PI3 Kinase Isoform Modulators
2014-05-30
2014-12-25
US2015283142 TREATMENT OF CANCERS USING PI3 KINASE ISOFORM MODULATORS
2013-11-01
2015-10-08
US8586574 Benzoxazepin PI3K inhibitor compounds and methods of use
2012-11-20
2013-11-19
Patent ID

Patent Title

Submitted Date

Granted Date

US2017121421 ANTIBODY CONJUGATES COMPRISING TOLL-LIKE RECEPTOR AGONIST
2016-10-25
US9643980 Benzoxazepin oxazolidinone compounds and methods of use
2016-07-01
2017-05-09
US9650393 BENZOXAZEPIN OXAZOLIDINONE COMPOUNDS AND METHODS OF USE
2016-07-01
US2015291606 MERTK-SPECIFIC PYRROLOPYRIMIDINE COMPOUNDS
2015-04-03
2015-10-15
US2015291609 MERTK-SPECIFIC PYRIMIDINE COMPOUNDS
2015-04-03
2015-10-15
Taselisib
Taselisib skeletal.svg
Clinical data
ATC code
  • None
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
Formula C24H28N8O2
Molar mass 460.54 g·mol−1
3D model (JSmol)

Taselisib

(GDC-0032, RG7604)

BREAST
  • PHASE II,
  • III

This compound and its uses are investigational and have not been approved by the US Food and Drug Administration. Efficacy and safety have not been established. The information presented should not be construed as a recommendation for use. The relevance of findings in preclinical studies to humans is currently being evaluated.

Taselisib, a PI3K inhibitor

Taselisib, an investigational PI3K inhibitor, is currently in clinical development based on its potential selectivity for the PI3Kα isoform.1,2 Preclinical data have shown that taselisib induced growth inhibition in PI3Kα-mutant cell lines.Taselisib continues to be investigated in ongoing clinical studies.

1Taselisib is an investigational PI3K inhibitor currently being studied for its potential to selectively inhibit the PI3Kα isoform.1,2

2Taselisib is designed to bind to the ATP-binding pocket of PI3Kα to potentially prevent subsequent downstream signaling.1

3In preclinical studies, taselisib induced growth inhibition in PI3Kα-mutant xenograft mouse models.1 Taselisib continues to be investigated in ongoing clinical studies.

References

  1. Lopez S, Schwab CL, Cocco E, et al. Taselisib, a selective inhibitor of PIK3CA, is highly effective on PIK3CA-mutated and HER2/neu amplified uterine serous carcinoma in vitro and in vivo. Gynecol Oncol.2014;135:312-317. PMID: 25172762
  2. Ndubaku CO, Heffron TP, Staben ST, et al. Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): a β-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity. J Med Chem. 2013;56:4597-4610. PMID: 23662903

//////////////////RG7604, Taselisib, PHASE 3,  metastatic breast cancer,  non-small cell lung cancer, RO5537381, Roche

CC1=NN(C(=N1)C2=CN3CCOC4=C(C3=N2)C=CC(=C4)C5=CN(N=C5)C(C)(C)C(=O)N)C(C)C

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Alatrofloxacin Mesylate


 

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Alatrofloxacin mesylate.png

Alatrofloxacin Mesylate

Chemical Names: Alatrofloxacin mesylate; UNII-2IXX802851; 146961-77-5; Alatrofloxacin mesylate [USAN]; 157605-25-9; 2IXX802851
Molecular Formula: C27H29F3N6O8S
Molecular Weight: 654.618 g/mol
CAS No. 146961-76-4 (Alatrofloxacin );
157605-25-9 (Alatrofloxacin Mesylate);
Chemical Name (1α, 5α, 6α)-L-alanyl-N-[3-[6-carboxy-8-(2,4-difluorophenyl)-3-fluoro-5,8-dihydro-5-oxo-1,8-naphthyridine-2-yl]-3-azabicyclo[3.1.0]hex-6-yl]-L-alaninamide, monomethanesulfonate

Research Code:CP-116517-27; CP-116517,    Trade Name:Trovan I.V.®          MOA:Quinolone antibiotic            Indication:Life- or limb-threatening infections caused by susceptible strains          Status:Withdrawn    Company:Pfizer (Originator)

Alatrofloxacin (Trovan IV) is a fluoroquinolone antibiotic developed by Pfizer, delivered as a mesylate salt.[1]

Trovafloxacin and alatrofloxacin were both withdrawn from the U.S. market in 2001

Alatrofloxacin mesylate was first approved by the U.S. Food and Drug Administration (FDA) on Dec 18, 1997. It was developed and marketed as Trovan I.V. ® by Pfizer in the US.

Alatrofloxacin mesylate is a fluoronaphthyridone related to the fluoroquinolones with in vitro activity against a wide range of gram-negative and gram-positive aerobic and anaerobic microorganisms. The bactericidal action of alatrofloxacin results from inhibition of DNA gyrase and topoisomerase IV. Trovan I.V.® is indicated for the treatment of patients initiating therapy in in-patient health care facilities (i.e., hospitals and long term nursing care facilities) with serious, life- or limb-threatening infections caused by susceptible strains of the designated microorganisms in the conditions listed below.

Trovan I.V.® is available as injection solution for intravenous use, containing 7.86 mg/ml of Alatrofloxacin mesylate. The recommended starting dose is 200 mg or 300 mg administered intravenously.

Alatrofloxacin mesylate was withdrawn from the U.S. market in 2001.

Image result for Alatrofloxacin mesylate

Alatrofloxacin mesilate

    • Synonyms:CP 116517, CP 116517-27
    • ATC:J01MA
  • Use:antibiotic, prodrug of trovafloxacin
  • Chemical name:l-Alanyl-N-[(1α,5α,6α)-3-[6-carboxy-8-(2,4-difluorophenyl)-3-fluoro-5,8-dihydro-5-oxo-1,8-naphthyridin-2-yl]-3-azabicyclo[3.1.0]hex-6-yl]-l-alaninamide monomethanesulfonate
  • Formula:C26H25F3N6O5 • CH4O3S
  • MW:654.62 g/mol
  • CAS-RN:146961-77-5

Derivatives

base

  • Formula:C26H25F3N6O5
  • MW:558.52 g/mol
  • CAS-RN:146961-76-4

Substance Classes

Synthesis Path

Substances Referenced in Synthesis Path

CAS-RN Formula Chemical Name CAS Index Name
27317-69-7 C11H20N2O5 Ntert-butoxycarbonyl-l-alanyl-l-alanine L-Alanine, N-[(1,1-dimethylethoxy)carbonyl]-L-alanyl-
186772-86-1 C33H37F3N6O7 N-[(1,1-dimethylethoxy)carbonyl]-l-alanyl-N-[(1α,5α,6α)-3-[8-(2,4-difluorophenyl)-6-(ethoxycarbonyl)-3-fluoro-5,8-dihydro-5-oxo-1,8-naphthyridin-2-yl]-3-azabicyclo[3.1.0]hex-6-yl]-l-alaninamide L-Alaninamide, N-[(1,1-dimethylethoxy)carbonyl]-L-alanyl-N-[(1α,5α,6α)-3-[8-(2,4-difluorophenyl)-6-(ethoxycarbonyl)-3-fluoro-5,8-dihydro-5-oxo-1,8-naphthyridin-2-yl]-3-azabicyclo[3.1.0]hex-6-yl]-
171176-56-0 C22H19F3N4O3 ethyl (1α,5α,6α)-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 1,8-Naphthyridine-3-carboxylic acid, 7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-, ethyl ester, (1α,5α,6α)-
134575-66-9 C27H27F3N4O5 ethyl (1α,5α,6α)-1-(2,4-difluorophenyl)-7-[6-[[(1,1-dimethylethoxy)carbonyl]amino]-3-azabicyclo[3.1.0]hex-3-yl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 1,8-Naphthyridine-3-carboxylic acid, 1-(2,4-difluorophenyl)-7-[6-[[(1,1-dimethylethoxy)carbonyl]amino]-3-azabicyclo[3.1.0]hex-3-yl]-6-fluoro-1,4-dihydro-4-oxo-, ethyl ester, (1α,5α,6α)-
75-75-2 CH4O3S methanesulfonic acid Methanesulfonic acid

Trade Names

Country Trade Name Vendor Annotation
D TROVAN Pfizer wfm
F Turvel Pfizer wfm
GB Turvel Pfizer wfm
I Turvel Pfizer wfm
USA Trovan Pfizer wfm

(wfm = withdrawn from market)

Formulations

  • vial 200 mg/40 ml, 300 mg/60 ml (5 mg/ml) (as mesilate)

References

    • US 5 164 402 (Pfizer; 17.11.1992; appl. 4.2.1991; WO-prior. 16.8.1989).
    • US 5 229 396 (Pfizer; 20.7.1993; appl. 24.7.1992).
    • WO 9 700 268 (Pfizer; appl. 27.3.1996; USA-prior. 15.6.1995).
    • US 5 763 454 (Pfizer; 9.6.1998; appl. 21.5.1997; WO-prior. 6.6.1995).
  • polymorphs:

    • US 6 080 756 (Pfizer; 27.6.2000; appl. 30.1.1998; WO-prior. 5.7.1996).

References
“Center for Drug Evaluation and Research – Application Number: 020759/020760 – Chemistry Review(s)” (PDF). Food and Drug Administration. Retrieved 29 August 2014.

Alatrofloxacin
Alatrofloxacin.svg
Clinical data
AHFS/Drugs.com Micromedex Detailed Consumer Information
MedlinePlus a605016
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
Intravenous
ATC code
  • none
Legal status
Legal status
  • Withdrawn
Pharmacokinetic data
Bioavailability N/A
Protein binding 76% (trovafloxacin)
Metabolism Quickly hydrolyzed to trovafloxacin
Elimination half-life 9 to 12 hours (trovafloxacin)
Excretion Fecal and renal(trovafloxacin)
Identifiers
CAS Number
ChemSpider
UNII
ChEMBL
Chemical and physical data
Formula C26H25F3N6O5
Molar mass 558.509 g/mol
3D model (JSmol)

/////////////////

Chenodeoxycholic acid, ケノデオキシコール酸


Skeletal formula of chenodeoxycholic acid

ChemSpider 2D Image | chenodeoxycholic acid | C24H40O4Chenodeoxycholic acid.png

Chenodeoxycholic acid

Chenodiol

  • Molecular FormulaC24H40O4
  • Average mass392.572
UNII-0GEI24LG0J
ケノデオキシコール酸
474-25-9 [RN]
chenodeoxycholic acid [JP15] [Wiki]
(+)-chenodeoxycholic acid
(3a,5b,7a)-3,7-dihydroxy-cholan-24-oic acid
(3α,5β,7α,8ξ,20R)-3,7-Dihydroxycholan-24-säure[German] [ACD/IUPAC Name]
(4R)-4-[(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-Dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid
0GEI24LG0J
17b-(1-Methyl-3-carboxypropyl)etiocholane-3a,7a-diol
207-481-8[EINECS]
3a,7a-dihydroxy-5b-cholan-24-oic acid
3a,7a-dihydroxy-5b-cholanic acid; anthropodesoxycholic acid; gallodesoxycholic acid; 17b-(1-methyl-3-carboxypropyl)etiocholane-3a,7a-diol; chenic acid; chenodeoxycholic acid; CDC
Chenodeoxycholate;
Chenodeoxycholic acid;
3alpha,7alpha-Dihydroxy-5beta-cholanic acid;
Chenodiol

Synthesis ReferenceHenry Francis Frost, Fritz Fabian, Christopher James Sharpe, William Arthur Jones, “Process for preparing chenodeoxycholic acid.” U.S. Patent US4022806, issued October, 1974. US4022806

First ref 

  • By Windaus, A.; Bohne, A.; Schwarzkopf, E.
  • From Z. physiol. Chem. (1924), 140, 177-85
  • By Wieland, Heinrich; Reverey, Gustav
  • From Z. physiol. Chem. (1924), 140, 186-202.  

Title: Chenodiol
CAS Registry Number: 474-25-9
CAS Name: (3a,5b,7a)-3,7-Dihydroxycholan-24-oic acid
Additional Names: 3a,7a-dihydroxy-5b-cholanic acid; anthropodesoxycholic acid; gallodesoxycholic acid; 17b-(1-methyl-3-carboxypropyl)etiocholane-3a,7a-diol; chenic acid; chenodeoxycholic acid; CDC
Trademarks: Chendol (CP Pharm.); Chenocol (Astellas); Chenofalk (Falk); Chenossil (Sanofi-Aventis); Cholanorm (Grñenthal); Fluibil (Zambon)
Molecular Formula: C24H40O4
Molecular Weight: 392.57
Percent Composition: C 73.43%, H 10.27%, O 16.30%
Literature References: A major bile acid in many vertebrates, occurring as the N-glycine and/or N-taurine conjugate. With other bile acids, forms mixed micelles with lecithin in bile which solubilize cholesterol and thus facilitates its excretion. Facilitates fat absorption in the small intestine by micellar solubilization of fatty acids and monoglycerides. Has cathartic properties since it induces fluid secretion from large intestine. Main constituent of the bile of hens, geese and other fowl; occurs in appreciable amounts in the bile of hamster, hog, guinea pig, bear and man. Epimeric with ursodiol, q.v. Isoln: Windhaus et al.,Z. Physiol. Chem.140, 177 (1924); Wieland, Reveney, ibid. 186. Configuration: Lettré, Ber.68, 766 (1935). Prepn from cholic acid: Fieser, Rajagopalan, J. Am. Chem. Soc.72, 5530 (1950); Hauser et al.,Helv. Chim. Acta43, 1595 (1960); Hofmann, Acta Chem. Scand.17, 173 (1963). Alternate prepns: Sato, Ikekawa, J. Org. Chem.24, 1367 (1959); T. Iida, F. C. Chang, ibid.46, 2786 (1981). Stereoselective total synthesis: T. Kametani et al.,J. Am. Chem. Soc.103, 2890 (1981). Asymmetric total synthesis of (+)-form:eidem,J. Org. Chem.47, 2331 (1982). Dissolution of cholesterol gallstones: Danzinger et al.,N. Engl. J. Med.286, 1 (1972); Bell et al.,LancetII, 1213 (1972). Use in long-term treatment of cerebrotendinous xanthomatosis: V. M. Berginer et al.,N. Engl. J. Med.311, 1649 (1984). Monograph on bile acids: The Bile Acids, 2 vols., P. P. Nair, D. Kritchevsky, Eds. (Plenum Press, New York, 1971, 1973). Review of pharmacology and therapeutic use of chenodeoxycholic acid: J. H. Iser, A. Sali, Drugs21, 90-119 (1981). Effect on cholesterol and bile acid metabolism: G. S. Tint et al.,Gastroenterology91, 1007 (1986).
Properties: Needles from ethyl acetate + heptane, mp 119°. [a]D20 +11.5° (dioxane). Freely sol in methanol, alc, acetone, acetic acid; more sol in ether and ethyl acetate than deoxycholic acid. Practically insol in water, petr ether, benzene. High solvent power for alkali soaps, but does not form “choleic” acid addition compds as does deoxycholic acid. Forms beautiful cryst salts of Na, K and Ba. While the acid is tasteless, the Na salt tastes slightly sweet at first, then bitter.
Melting point: mp 119°
Optical Rotation: [a]D20 +11.5° (dioxane)
Derivative Type: Diformate
Molecular Formula: C25H40O6
Molecular Weight: 436.58
Percent Composition: C 68.78%, H 9.23%, O 21.99%
Properties: Clusters of needles from alc; mp with slight effervescence at 137°, upon further heating solidifies again, and finally melts around 172°.
Melting point: mp with slight effervescence at 137°
Derivative Type: Methyl ester
Molecular Formula: C25H42O4
Molecular Weight: 406.60
Percent Composition: C 73.85%, H 10.41%, O 15.74%
Properties: Fine needles from benzene + heptane, mp 90-91°. [a]D25 +20°.
Melting point: mp 90-91°
Optical Rotation: [a]D25 +20°
Therap-Cat: Anticholelithogenic.
Keywords: Cholelitholytic Agent.
SPECIFIC ROTATION
+13.23 °   ethanol ,  589.3 nm;  21 °C, Yonemura, Sadatomo; Journal of Biochemistry 1926, Vol6, Pg287-96
+12.5 °  chloroform, 589.3 nm; 17 °C  Plattner, Pl. A.; Helvetica Chimica Acta 1944, Vol27, Pg748-57
MP
Chenodeoxycholic acid (or Chenodiol) is an epimer of ursodeoxycholic acid (DB01586). Chenodeoxycholic acid is a bile acid naturally found in the body. It works by dissolving the cholesterol that makes gallstones and inhibiting production of cholesterol in the liver and absorption in the intestines, which helps to decrease the formation of gallstones. It can also reduce the amount of other bile acids that can be harmful to liver cells when levels are elevated.

Chenodeoxycholic acid (also known as chenodesoxycholic acidchenocholic acid and 3α,7α-dihydroxy-5β-cholan-24-oic acid) is a bile acid. It occurs as a white crystalline substance insoluble in water but soluble in alcohol and acetic acid, with melting point at 165–167 °C. Salts of this carboxylic acid are called chenodeoxycholates. Chenodeoxycholic acid is one of the main bile acids produced by the liver.[1]

It was first isolated from the bile of the domestic goose, which gives it the “cheno” portion of its name (Greek: χήν = goose).[2]

Chenodeoxycholic acid and cholic acid are the two primary bile acids in humans. Some other mammals have muricholic acid or deoxycholic acid rather than chenodeoxycholic acid.[1]

Chenodeoxycholic acid is synthesized in the liver from cholesterol by a process which involves several enzymatic steps.[1] Like other bile acids, it can be conjugated in the liver with taurine or glycine, forming taurochenodeoxycholate or glycochenodeoxycholate. Conjugation results in a lower pKa. This means the conjugated bile acids are ionized at the usual pH in the intestine and will stay in the gastrointestinal tract until reaching the ileum where most will be reabsorbed. Bile acids form micelles which facilitate lipid digestion. After absorption, they are taken up by the liver and resecreted, so undergoing an enterohepatic circulation. Unabsorbed chenodeoxycholic acid can be metabolised by bacteria in the colon to form the secondary bile acid known as lithocholic acid.

Chenodeoxycholic acid is the most potent natural bile acid at stimulating the nuclear bile acid receptor, farnesoid X receptor (FXR).[3]The transcription of many genes is activated by FXR.

Indication

Chenodiol is indicated for patients with radiolucent stones in well-opacifying gallbladders, in whom selective surgery would be undertaken except for the presence of increased surgical risk due to systemic disease or age. Chenodiol will not dissolve calcified (radiopaque) or radiolucent bile pigment stones.

Associated Conditions

Pharmacodynamics

It acts by reducing levels of cholesterol in the bile, helping gallstones that are made predominantly of cholesterol to dissolve. Chenodeoxycholic acid is ineffective with stones of a high calcium or bile acid content.

Mechanism of action

Chenodiol suppresses hepatic synthesis of both cholesterol and cholic acid, gradually replacing the latter and its metabolite, deoxycholic acid in an expanded bile acid pool. These actions contribute to biliary cholesterol desaturation and gradual dissolution of radiolucent cholesterol gallstones in the presence of a gall-bladder visualized by oral cholecystography. Bile acids may also bind the the bile acid receptor (FXR) which regulates the synthesis and transport of bile acids.

EMA

On 16 December 2014, orphan designation (EU/3/14/1406) was granted by the European Commission to Sigma-Tau Pharma Ltd, United Kingdom, for chenodeoxycholic acid for the treatment of inborn errors in primary bile acid synthesis.

The sponsorship was transferred to sigma-tau Arzneimittel GmbH, Germany, in May 2015.

Chenodeoxycholic acid has been authorised in the EU as Chenodeoxycholic acid sigma-tau since 10 April 2017.

The name of the product changed to Chenodeoxycholic acid Leadiant in May 2017.

The sponsorship was transferred to Leadiant GmbH, Germany, in June 2017.

On 16 February 2017, the Committee for Orphan Medicinal Products (COMP) concluded its review of the designation EU/3/14/1406 for Chenodeoxycholic acid sigma-tau (chenodeoxycholic acid) as an orphan medicinal product for the treatment of inborn errors in primary bile acid synthesis. The COMP assessed whether, at the time of marketing authorisation, the medicinal product still met the criteria for orphan designation. The Committee looked at the seriousness and prevalence of the condition, and the existence of other methods of treatment. As other methods of treatment are authorised in the European Union (EU), the COMP also considered whether the medicine is of significant benefit to patients with inborn errors in primary bile acid synthesis. The COMP recommended that the orphan designation of the medicine be maintained1.


1 The maintenance of the orphan designation at time of marketing authorisation would, except in specific situations, give an orphan medicinal product 10 years of market exclusivity in the EU. This means that in the 10 years after its authorisation similar products with the same therapeutic indication cannot be placed on the market.

http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2015/02/WC500183233.pdf

Therapeutic applications

Chenodeoxycholic acid has been used as medical therapy to dissolve gallstones.[4]

Chenodeoxycholic acid can be used in the treatment of cerebrotendineous xanthomatosis.[5]

The Australian biotechnology company Giaconda has tested a treatment for Hepatitis C infection that combines chenodeoxycholic acid with bezafibrate.[6]

As diarrhea is a complication of chenodeoxycholic acid therapy, it has also been used to treat constipation.[7][8]

In supramolecular chemistrymolecular tweezers based on a chenodeoxycholic acid scaffold is a urea receptor that can contain anionsin its binding pocket in order of affinity: H2PO4 (dihydrogen phosphate) > Cl > Br > I reflecting their basicities (tetrabutylammonium counter ion).[9]

Molecular tweezer based on chenodeoxycholic acid
PAPER
1H and 13C NMR characterization and stereochemical assignments of bile acids in aqueous media
Lipids (2005), 40, (10), 1031-1041.
https://onlinelibrary.wiley.com/doi/abs/10.1007/s11745-005-1466-1

PAPER

Improved Chemical Synthesis, X-Ray Crystallographic Analysis, and NMR Characterization of (22R)-/(22S)-Hydroxy Epimers of Bile Acids
Lipids (2014), 49, (11), 1169-1180.

Improved Chemical Synthesis, X‐Ray Crystallographic Analysis, and NMR Characterization of (22R)‐/(22S)‐Hydroxy Epimers of Bile Acids

PAPER

A Practical and Eco-friendly Synthesis of Oxo-bile Acids

By Han, Young Taek and Yun, HwayoungFrom Organic Preparations and Procedures International, 48(1), 55-61; 2016

DOI:10.1080/00304948.2016.1127101

General Procedure

An aqueous solution of 0.2 M NaBrO3 (1.5 equiv. per hydroxy group) was added dropwise to a slurry of bile acid (1 equiv.) and ceric ammonium nitrate (0.05 equiv.) in 20% aqueous acetonitrile (0.2 M) at 80°C over 20 min. The bile acid slowly dissolved in a few minutes, and then the color of the reaction mixture changed to orange. The reaction mixture was stirred at the same temperature and the progress of the reaction was monitored by TLC on silica gel (1:20 MeOH-CH2Cl2) until disappearance of the starting material and partially oxidized intermediates. It was then cooled in an ice bath and quenched with aqueous Na2S2O3 solution. Water was added slowly to the resulting white suspension until no more oxo-bile acid precipitated. The white solid was collected, washed with water until the filtrate was colorless, and then dried in vacuo at 50°C. Methyl 3,7α-Diacetoxy-12-oxo-5β-cholanoate(3),21 was obtained in 92% yield (275 mg) as a white solid from 300 mg (0.590 mmol) of 2 via the general procedure. mp. 176-178°C, lit.22 mp. 178-179°C, IR (thin film, neat): 2947 (m), 2873 (s), 1736 (w), 1706 (w), 1436 (s), 1365 (m) cm-1; 1H-NMR (400 MHz, CDCl3): δ 4.96 (m, 1H, 7-CH), 4.55 (m, 1H, 3-CH), 3.64 (s, 3H), 2.49 (t, 1H, J = 12.6 Hz), 2.41-0.80 (m, 23H), 2.01 (s, 3H), 2.00 (s, 3H), 1.01 (s, 3H, 18-CH3), 1.00 (s, 3H, 19-CH3), 0.83 (d, 3H, J = 6.6 Hz, 21-CH3); 13C-NMR (CDCl3, 100 MHz): δ 214.0 (12-C), 174.6 (24-C), 170.7 (C = O), 170.2 (C = O), 73.5 (3-C), 70.5 (7-C), 57.1 (13-C), 53.1 (14-C), 51.5 (CH3O), 46.3 (17-C), 40.5 (5-C), 37.9 (11-C), 37.8 (4-C), 37.6 (8-C), 35.54 (9-C), 35.52 (20-C), 34.9 (1-C), 34.5 (10-C), 31.3 (6-C), 31.2 (22-C), 30.4 (23-C), 27.4 (16-C), 26.5 (2-C), 23.8 (15-C), 22.1 (19-C), 21.51 (CH3CO2), 21.46 (CH3CO2), 18.6 (21-C), 11.5 (18-C); LR-MS (FABC) m/z 505 (M+H +). HR-MS (FABC): Calcd for C29H45O7 (M+H +): 505.3165. Found 505.3161.

next step

R:KOH, R:N2H4

NOTE STARTING  IS BILE ACID AS BELOW

Cholan-24-oic acid, 3,7-bis(acetyloxy)-12-oxo-, methyl ester, (3α,5β,7α)-

  • 5β-Cholan-24-oic acid, 3α,7α-dihydroxy-12-oxo-, methyl ester, diacetate (8CI)
  • 5β-Cholanic acid, 3α,7α-dihydroxy-12-oxo-, methyl ester, diacetate (6CI,7CI)
  • 3α,7α-Diacetoxy-12-oxo-5β-cholan-24-oic acid methyl ester
  • Methyl 3α,7α-diacetoxy-12-oxo-5β-cholan-24-oate
  • Methyl 3α,7α-diacetoxy-12-oxo-5β-cholanate
CAS 28535-81-1
C29 H44 O7  504.66
Cholan-24-oic acid, 3,7-bis(acetyloxy)-12-oxo-, methyl ester, (3α,5β,7α)-

PAPER

https://pubs.acs.org/doi/pdf/10.1021/jo01091a623

Journal of Organic Chemistry
Volume24
Pages1367-8
Journal
1959

DOI:10.1021/jo01091a623

Chenodeoxycholic acid (V). Five hundred mg. of the above ester IV was hydrolyzed with 80 ml. of ethanolic 5% potassium hydroxide for 4 hr. After partial concentration of the volume and addition of water, the reaction product was acidified with hydrochloric acid. The resulting precipitate was collected, dried, and crystallized from ethyl acetate. A quantitative crop (400 mg.) of prisms melting at 143- 145° were obtained. Recrystallization from the same solvent yielded a product of m.p. 145-146°, [ ]2 +10.7° (dioxane). Anal. Caled, for C24H40O4: C, 73.43; H, 10.27. Found: C, 73.49; H, 10.31.

NOTE I IS BILE ACID

Cholan-24-oic acid, 3,7-bis(acetyloxy)-12-oxo-, methyl ester, (3α,5β,7α)-

  • 5β-Cholan-24-oic acid, 3α,7α-dihydroxy-12-oxo-, methyl ester, diacetate (8CI)
  • 5β-Cholanic acid, 3α,7α-dihydroxy-12-oxo-, methyl ester, diacetate (6CI,7CI)
  • 3α,7α-Diacetoxy-12-oxo-5β-cholan-24-oic acid methyl ester
  • Methyl 3α,7α-diacetoxy-12-oxo-5β-cholan-24-oate
  • Methyl 3α,7α-diacetoxy-12-oxo-5β-cholanate
CAS 28535-81-1
C29 H44 O7  504.66
Cholan-24-oic acid, 3,7-bis(acetyloxy)-12-oxo-, methyl ester, (3α,5β,7α)-

PATENT

https://patents.google.com/patent/CN102060902A/en

chenodeoxycholic acid (3 α, 7 α – dihydroxy _5 β – cholestane-24-oic acid) Chenodeoxycholic Ac id (referred to as CDCA), clinically used to correct dissolving cholesterol calculi and bile saturation drugs, the main function is to reduce the cholesterol in the bile saturation, large doses can inhibit the synthesis of cholesterol CDCA and increasing bile gallstone patients cholesterol level in a non-saturated, thereby preventing the formation of cholesterol gallstones of cholesterol and promote stone dissolve and fall off. It also has significant anti-asthmatic, anti-inflammatory, antitussive and expectorant effects.

[0003] Synthesis of chenodeoxycholic acid or ursodeoxycholic acid (3 α, 7β_ -5β_ dihydroxy-cholestane-24-oic acid, ursodeoxycholic Acid, referred UDCA), a key intermediate. Ursodeoxycholic acid is the main active ingredient of precious Chinese medicine bear bile, used in a variety of clinical hepatobiliary disease and dyspepsia. Currently we bear bile resources are scarce, mainly used synthetic chemical ursodeoxycholic acid as a clinical treatment. Therefore, the preparation of chenodeoxycholic acid is also important for the preparation of ursodeoxycholic acid.

[0004] CDCA mainly come from poultry or livestock bile extraction. Traditional extraction process complicated operation, low yield, (pharmaceutical industry, 1987,18 (9), 416; Chinese Journal of Biochemical Pharmaceutics, 1996,17 (1), 17; Applied Technology, 1998, (4), 9; CN1850846A ) can not meet the needs of modern industry. Chemical synthesis of chenodeoxycholic acid have also been reported (Japanese Journal of Chemistry 1955,76 (3), 297 -J Org Chem 1982,47 (2): 2331; Journal of Biochemical Pharmaceutics 1987,1,6 -, Tap Chi Duoc ^ oc2004 , 44 (1), 11; CN1869043A), but lower yield widespread pollution major problem, especially in the oxidation reaction is often used to expensive, and polluting agents.Therefore, to reduce pollution, reduce environmental hazards, streamline operations, improve yield, reduce costs, important for the synthesis of chenodeoxycholic acid.

 Figure CN102060902AD00041

n particular by the following steps:

(1) Preparation of cholate: bile acid in alcohol, concentrated hydrochloric acid as catalyst, at reflux, cooling and crystallization, filtration, and washed with methanol.

[0008] (2) Preparation of 3α, 7α- diacetyl hydroxy -12α- cholate: bile acid ester was dissolved in dichloromethane and triethylamine was added with stirring acetic anhydride and the catalyst N, N- dimethyl pyridine, methylene chloride was distilled off, poured into water, filtered to give 3α, 7α- diacetyl -12 α – hydroxy cholate.

[0009] (3) 3α, 7α- diacetyl -12– Preparation oxo chenodeoxycholic acid ester: Take 3 α, 7 α – diacetyl -12 α – hydroxy cholate dissolved in ethyl acetate and methanol, bromide and tetrabutylammonium bromide as catalyst, and acetic acid was added dropwise under stirring hypochlorite, the organic solvent was distilled off and filtered, to give 12-oxo-3,7-diacetyl Chenodeoxy cholate.

[0010] (4) i2 – Preparation oxo chenodeoxycholic acid: 3,7-diacetyl-12-oxo-chenodeoxycholic acid ester added ethanol – sodium hydroxide solution, at reflux.PH adjusted with hydrochloric acid value of the reaction system acidic, ethanol was distilled off, and filtered to give 12- oxo crude chenodeoxycholic acid, fine recrystallization.

[0011] Preparation of chenodeoxycholic acid (5): 12- oxo take chenodeoxycholic acid, ethylene glycol and solid sodium hydroxide, hydrated corpus, refluxed for 2 hours, gradually warming evaporated partially hydrated corpus, continue to heat up to 150 ° C, continued to reflux, cooled to room temperature, poured into water, adjusting the PH with hydrochloric acid, the white precipitate was filtered, washed with water to give crude chenodeoxycholic acid, recrystallization

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[0012] Step (1): cholic acid to alcohol weight to volume ratio of 1: 2 ~ 5, the volume ratio of concentrated hydrochloric acid to alcohol is 10 wide: 100, 5-5 hours reflux time was 0.5.

[0013] Step (2): cholate: acetic anhydride molar ratio = 1: 2 ~ 5, the reaction temperature, time; Tl2O hours; cholate was added per mole of N, N- dimethylpyridine wide 5g.

[0014] Step (; 3): The hypochlorite is sodium hypochlorite or calcium hypochlorite; bromide is sodium bromide, potassium bromide and the like.

[0015] Step (4): recrystallization from a solvent with an alcohol such: as methanol or ethanol.

[0016] Step (5): recrystallization solvent is a water-miscible organic solvents, such as: methanol, ethanol, acetonitrile, acetone and the like.

[0017] Step (cholate was used ¾ of methyl cholate, ethyl cholate, cholic acid or cholic acid propyl ester; Step (3) used as 3 [alpha], 7 α – diacetyl -12 α – hydroxy cholate as 3 α, 7 α – diacetyl -12 α – hydroxy methyl cholate, 3 α, 7α- diacetyl -12 α – hydroxy bile acid ethyl ester, 3 α, 7α- diacetyl yl -12 α – hydroxy acid or ester 3α, 7α- diacetyl -12 α – hydroxy acid ester.

[0018] The invention has the advantages: in cholic acid as raw materials, and the choice of bromide tetrabutylammonium bromide as catalyst, in a non-polluting oxidizing agent is hypochlorite, Intermediate 3 α, 7 α – Diacetyl _12_ oxo chenodeoxycholic acid ester yield of 90% or more, thereby improving the yield of the final product of chenodeoxycholic acid, 99% yield, low cost and no pollution, very convenient for industrial production. detailed description

[0019] The present invention will be better described, for example is as follows:

(1) Preparation of methyl cholate: bile acid 5. lg, 15ml of anhydrous methanol, heating the whole solution. Refluxed for 3 hours, was added 0. 4ml concentrated hydrochloric acid, the reaction was stopped after 30min, after slow cooling, and filtered to give methyl cholate 5. 05g, 95% yield. 1HNMR (CDCl3):. Δ 0. 70 (s, 3H, 18- CH3), 0.90 (s, 3H, 19- CH3), 0.98 (d, 3H, 21-CH3), 3 50 (m, 1H, 3 β -H), 3. 67 (s, 3H, OCH3), 3. 87 (s, 1H, 7 β -H), 3. 99 (s, 1H, 12 β -H).

[0020] (2) Preparation of 3α, 7α- methyl cholate diacetyl-hydroxy -12α-: bile acid methyl ester 4. 71g (Ilmmol) IOOml was placed in a flask, was added methylene chloride 30ml, triethylamine 3 . Chiu 1, stirred at room temperature, was added dropwise acetic anhydride 2. 7ml (28. 6mmo 1), followed by addition of 20mg N, N- dimethylpyridine catalyst, the reaction time of 7 hours, methylene chloride was distilled off, into the water, filtered to give a white solid. The crude product was recrystallized from methanol to give white crystals 4. 05g, yield 67.2%. 1H NMR (CDCl3) δ: 4.90 (m, 1H, 7 β -H), 4. 59 (s, 1H, 3 β -H), 4 01 (s, 1H, 12 β -H), 3 67.. (s, 3Η, OCH3), 2. 08 (s, 3Η, CH3CO), 2. 02 (s, 3Η, CH3CO), 0. 98 (s, 3Η, 21-CH3), 0. 93 (s, 3Η , 19-CH3), 0.69 (s, 3Η, 18_CH3).

[0021] (3) 3α, 7α – 12-oxo-diacetyl chenodeoxycholic acid methyl ester prepared: Take 3 α, 7 α – diacetyl -12 α- hydroxy methyl cholate 1.917 g ( 3. 79mmol) was placed in a 50ml round bottom flask, 12ml of ethyl acetate was added, 5ml methanol, stirring at room temperature, was added 0. 25g 0. Ig of potassium bromide and tetrabutylammonium bromide. Was added dropwise a solution of acetic acid and 6g of sodium hypochlorite (7%) (5.62mmol), for 10 hours. Methanol was distilled off under reduced pressure and ethyl acetate, filtered, washed with water, and dried to give crude 1.915g, 1.75g as a white solid after recrystallization from methanol, yield 91.2%. 1H bandit R (CDCl3) δ:.. 4. 99 (d, 1H, 7 β-H), 4 60 (m, 1H, 3 β-H), 3 67 (s, 3H, OCH3), 2. 07 (s, 6H, CH3CO), 1. 03 (s, 6H, I8-CH3 and 19-CH3), 0. 82 (d, 3H, 21-CH3) ο

[0022] (4) 12- oxo chenodeoxycholic acid Preparation: Take 3 α, 7 α – diacetyl _12_ oxo chenodeoxycholic acid methyl ester 1. 56g, was dissolved in 30ml 95% ethanol was added 3. 2g of sodium hydroxide, heated at reflux for 5 hours. PH adjusted with hydrochloric acid value of the reaction system, most of the ethanol was distilled off, filtered, washed with water, and dried to give a white solid 12- oxo-1 crude chenodeoxycholic acid, recrystallized from methanol ^ g 1. 25g, yield rate of 96%. Tun bandit R (CDCl3) δ:. 3.96 (d, 1H, 7 β-H), 3 47 (m, 1H, 3 β-H), 1.03 (s, 3H, 19_CH3), 0.89 (s, 3H, 18_CH3 ), 0 · 70 (d, 3 H, 21_CH3).

[0023] Preparation of chenodeoxycholic acid (5): 12- oxo take chenodeoxycholic acid 0. 9g, 15ml ethylene glycol was added solid sodium hydroxide and 1. 5g, 15ml hydrated corpus (80%) , 120 ° C reflux for 2 hours, change return device is a distillation apparatus, was gradually warmed evaporated amount hydrated corpus, continue to heat up to 150 ° C, continuing reflux for 4h, cooled to room temperature, poured into water, adjusted with HCl of PH3, white precipitated, was filtered cake was washed with water, and dried to give crude chenodeoxycholic acid 0. 92g, recrystallized from methanol to give 0. 86g, 99 (s, 1H, C00H).

Paper

https://pubs.acs.org/doi/abs/10.1021/ja01168a045

Reactions of 2-Arylcyclohexanones. IV. Michael Addition of Malonic Ester to 2-Phenyl-Δ2-cyclohexenone

J. Am. Chem. Soc.195072 (12), pp 5529–5530
DOI: 10.1021/ja01168a045
Publication Date: December 1950
PAPER
Hauser et al., Helv. Chim. Acta 43, 1595 (1960);
Paper

The Preparation of Chenodeoxycholic Acid and Its Glycine and Taurine Conjugates.Hofmann, Alan F.

Pages: 173-186.
DOI number: 10.3891/acta.chem.scand.17-0173
Download as: PDF DjVu
PAPER
Sato, Ikekawa, J. Org. Chem. 24, 1367 (1959)

Preparation of Chenodeoxycholic Acid

J. Org. Chem.195924 (9), pp 1367–1368
DOI: 10.1021/jo01091a623
Publication Date: September 1959
PAPER
J. Org. Chem. 47, 2331 (1982)

Further studies on the synthesis of thienamycin: a facile and stereoselective synthesis of a bicyclic .beta.-keto ester by 1,3-dipolar cycloaddition

J. Org. Chem.198247 (12), pp 2328–2331
DOI: 10.1021/jo00133a019
PAPER
PATENT

Chenodeoxycholic acid (3α, 7α- -5β- dihydroxy-cholestane acid) Chenodeoxycholic Acid (referred to as CDCA), a medicine for treating gallstones. 1848 first discovered in goose bile, 1924, known as the CDCA. By reducing cholesterol absorption, synthesis, the bile cholesterol decreased, thereby suppressing cholesterol gallstone formation and promote dissolution, and can reduce cholesterol saturation.

Chenodeoxycholic acid addition pharmaceutically itself, but also as the preparation of ursodeoxycholic acid (3α, 7β- -5β- dihydroxy bile acid, abbreviated UDCA) starting material. Ursodeoxycholic acid is the main active ingredient contained bile valuable medicine, in clinical treatment of various gastrointestinal diseases and bladder diseases. But the limited sources of bear bile medicine, and contrary to the principles of animal protection. So, dwindling source of natural bear bile, can not meet the medical requirements. Therefore, the preparation of chenodeoxycholic acid is also of great significance for further preparation of ursodeoxycholic acid.

CDCA bile extracted mainly from poultry or animal bile extraction methods in the past as it involves toxic chemicals (animal biological pharmacy, 1981, People’s Medical Publishing House, P259; pharmaceutical industry, 1987,18 (2): 75-76; ) or unsafe to use a large amount of organic solvent (Chinese Journal of biochemical Pharmaceutics, 1996,17 (1): 17; application technology, 1998,4: 9-10; US Patent, 3,965,131; US Patent, 4,331,607; USPatent, 4,163,017), can not be meet the requirements of modern industry, CDCA and low purity prepared costly.

PATENT

https://patents.google.com/patent/WO2007069814A1/en

Chenodeoxycholic acid is generally contained in bile of cow, swine, bear, or poultry such as chicken or goose, as well as in bile of human. Chenodeoxycholic acid is used as starting material for the preparation of ursodeoxycholic acid which is effective to alleviate biliary system diseases, hyperlipidemia, cholelithiasis, and chronic liver diseases, and a typical process for preparing ursodeoxycholic acid known in the art is as follows.

A typical process for preparing chenodeoxycholic acid comprises the steps of: esterifying cholic acid (3α,7α,12θ!-trihydroxy cholic acid) with methyl; protecting the hydroxyl group of 3α and Ia position by acetylating them with anhydrous acetic acid; oxidizing the hydroxyl group of 12α position to carbonyl group by using chromic acid, and then removing the carbonyl group by Wolff-kichner reduction reaction; hydrolyzing and deprotecting the obtained product to yield chenodeoxycholic acid. The above process requires the reaction to be maintained at a high temperature of more than 200 °C , and the supply of raw material may be interrupted by bovine spongiform encephalopathy, etc. Bile ,of poultry contains chenodeoxycholic acid, lithocholic acid, and a small amount of cholic acid. Thus, the process for separating chenodeoxycholic acid from poultry is well known in the art, but is not economically reasonable due to the supply decrease of raw material and low yield [see, Windhaus et al, I Physiol. Chem., 140, 177-185 (1924)].

US Patent No. 4,186,143 disclosed a process for purely separating and purifying chenodeoxycholic acid from chenodeoxycholic acid mixture derived from natural swine bile. This process comprises the major steps of: pre-treatment to remove 3ohydroxy-6- oxo-5/3-cholic acid by saponification of bile; esterification of bile acid; acetylation of bile acid ester; removal of intermediate product by using non-polar organic solvent; crystallization of acetylated ester of formula I; deprotection; and production of the compound of formula I by using crystallization in organic solvent. However, this patent does not describe HPLC content for acetylated ester of formula I, and the purity of the final product is very low since the specific rotatory power is [ofo25 +13.8° (c=l, CHCl3), and the melting point is 119-121 °C [STD: [α]D 25 +15.2°(c=l, CHCl3), melting point 127- 129 “C]. Also, the crystallization for purifying the final product requires a very long time (i.e., 16-48 hours), and the entire process is complex as eight (8) steps. Thus, when purifying the compound of formula I by using the above process, the yield of the final product becomes low, and the reaction time is as long as 12 days. Therefore, the process is not economically reasonable.

Step 6: Deprotection and crystallization of chenodeoxycholic acid

To 220ml of water were added 24.5g of chenodeoxycholic acid-diacetate-ester and 29.5g of sodium hydroxide, and then the solution was stirred with reflux for 4 hours. To the solution was added 370ml of water. The solution’s pH is adjusted to 2.0-3.0 by using 59ml of hydrochloric acid. Then, the solution was stirred at 35-45 °C for 1 hour, and then filtered. The filtered material was washed with 24.5ml of water and dried in vacuum at 70 °C to obtain 19.5g of pure chenodeoxycholic acid, m.p.: 160-161 °C, [α]o25 +13.0°(c=l, CHCl3).

Step 8: Production of the compound of formula I

The reaction solution was extracted by using ethyl acetate, and aqueous layer was discarded therefrom. Ethyl acetate layer in the solution was washed with 6% saline, and the solution was distilled to about 90ml. This solution was cooled, kept cool for one day after adding 90ml of hexane, and filtered. Thus filtered material was washed with 20ml of hexane, and dried in vacuum at 60 °C to produce 12.7g of chenodeoxycholic acid. m.p. 142-1450C; [α]D 25 +13.0°(c=l, CHCl3). INDUSTRIAL APPLICABILITY The present invention can purify chenodeoxycholic acid of formula I from swine bile solid in high yield and purity. Also, the present invention is suitable for industrial purification by reducing the purification time.

PATENT

https://patents.google.com/patent/CN102060902A/en

chenodeoxycholic acid (3 α, 7 α – dihydroxy _5 β – cholestane-24-oic acid) Chenodeoxycholic Ac id (referred to as CDCA), clinically used to correct dissolving cholesterol calculi and bile saturation drugs, the main function is to reduce the cholesterol in the bile saturation, large doses can inhibit the synthesis of cholesterol CDCA and increasing bile gallstone patients cholesterol level in a non-saturated, thereby preventing the formation of cholesterol gallstones of cholesterol and promote stone dissolve and fall off. It also has significant anti-asthmatic, anti-inflammatory, antitussive and expectorant effects.

[0003] Synthesis of chenodeoxycholic acid or ursodeoxycholic acid (3 α, 7β_ -5β_ dihydroxy-cholestane-24-oic acid, ursodeoxycholic Acid, referred UDCA), a key intermediate. Ursodeoxycholic acid is the main active ingredient of precious Chinese medicine bear bile, used in a variety of clinical hepatobiliary disease and dyspepsia. Currently we bear bile resources are scarce, mainly used synthetic chemical ursodeoxycholic acid as a clinical treatment. Therefore, the preparation of chenodeoxycholic acid is also important for the preparation of ursodeoxycholic acid.

[0004] CDCA mainly come from poultry or livestock bile extraction. Traditional extraction process complicated operation, low yield, (pharmaceutical industry, 1987,18 (9), 416; Chinese Journal of Biochemical Pharmaceutics, 1996,17 (1), 17; Applied Technology, 1998, (4), 9; CN1850846A ) can not meet the needs of modern industry. Chemical synthesis of chenodeoxycholic acid have also been reported (Japanese Journal of Chemistry 1955,76 (3), 297 -J Org Chem 1982,47 (2): 2331; Journal of Biochemical Pharmaceutics 1987,1,6 -, Tap Chi Duoc ^ oc2004 , 44 (1), 11; CN1869043A), but lower yield widespread pollution major problem, especially in the oxidation reaction is often used to expensive, and polluting agents.Therefore, to reduce pollution, reduce environmental hazards, streamline operations, improve yield, reduce costs, important for the synthesis of chenodeoxycholic acid.

 Preparation of chenodeoxycholic acid.

[0007]

Figure CN102060902AD00041
Preparation of chenodeoxycholic acid (5): 12- oxo take chenodeoxycholic acid 0. 9g, 15ml ethylene glycol was added solid sodium hydroxide and 1. 5g, 15ml hydrated corpus (80%) , 120 ° C reflux for 2 hours, change return device is a distillation apparatus, was gradually warmed evaporated amount hydrated corpus, continue to heat up to 150 ° C, continuing reflux for 4h, cooled to room temperature, poured into water, adjusted with HCl of PH3, white precipitated, was filtered cake was washed with water, and dried to give crude chenodeoxycholic acid 0. 92g, recrystallized from methanol to give 0. 86g, 99% yield. .. 1HnMR (CD3SOCD3) S: 0.60 (s, 3H, 18- CH3), 0 90 (s, 3H, 19_CH3), 0.95 (d, 3H, 21-CH3), 3 47 (s, IH, 3 β – H), 3. 96 (s, 1H, 7 β -H), 11. 94 (s, 1H, C00H).
PATENT

Cholic acid esters prepared by (1) Weigh 50 g of cholic acid, dissolved in 150 ml of anhydrous methanol was added 5 ml of concentrated hydrochloric acid was refluxed for 30 minutes, cooled slowly into the freezer, the available capacity methyl cholate It was 95%.

(2) hydroxy -12α- diacetyl – Preparation of methyl cholate methyl cholate weighed 50 g, was dissolved in 100 ml of pyridine was purified, dissolved completely, 100 ml of acetic anhydride was stirred at room temperature for 3 to 4 hours, poured into 500 ml of water, a white precipitate in the refrigerator, filtered the next day, diacetyl -12α- available hydroxy – methyl cholate, yield 40%.

(3) 3α, 7α–diacetoxy-12-oxo – Preparation of methyl cholanic acid prepared above was weighed 25 g of crude product, dissolved in 250 ml of acetone, filtered to remove insolubles, the stirring conditions , the Jones reagent was slowly added, at room temperature for 30 minutes, filtered, water was added to the filtrate precipitated white precipitate was filtered available 3α, 7α–diacetoxy-12-oxo – methyl-cholanic acid. The yield was 100%.

(4) 12- oxo – Preparation of chenodeoxycholic acid in ethanol 10% – sodium hydroxide solution and saponified for 1 hour at room temperature, the solution was acidified, poured into water to give 12- oxo – chenodeoxycholic acid , 100% yield.Recrystallized in absolute ethanol.

Preparation of chenodeoxycholic acid (5) was weighed 12- oxo – chenodeoxycholic acid, 20 grams, was added 300 ml of ethylene glycol and 30 g of solid sodium hydroxide and 300 ml of hydrazine hydrate (85%), 100 ℃ refluxed for 2 hours, warming gradually raised to 130. ℃, generated by hydrazine hydrate was distilled off, continue to heat up to 185 ~ 190 ℃, continued reflux for 4 hours, cooled to a lower temperature, poured into water and heat, PH adjusted with hydrochloric acid (20%) 3, a white precipitate was filtered cake was washed with water to give chenodeoxycholic acid.

(6) Purification of chenodeoxycholic acid obtained weighed amount of chenodeoxycholic acid, dissolved with a small amount of ethanol, was impregnated on a silica gel column petroleum ether, liquid flow linear velocity by column chromatography 1 ~ 5cm / control points, with petroleum ether: acetone = 2, begins to elute, detected by TLC chromatography therebetween, Junichi appearance of spots to be chenodeoxycholic acid appears to start collecting the eluate until no Chenodeoxy acid spots, distillation under reduced pressure and dried to give pure higher chenodeoxycholic acid.

PATENTS

Publication numberPriority datePublication dateAssigneeTitle
WO2007069814A1 *2005-12-122007-06-21Daewoong Pharmaceutical Co., Ltd.Purification process for chenodeoxycholic acid
WO2007078039A1 *2005-12-302007-07-12Daewoong Pharmaceutical Co., Ltd.Purification process for chenodeoxycholic acid
CN100484952C2005-12-132009-05-06山东博尔德生物科技有限公司Method for producing high-purity chenodeoxy cholic acid from poultry and livestock bile
CN102060902A *2011-01-212011-05-18郑州大学Chenodeoxycholic acid synthesis method
CN102286051A *2011-08-152011-12-21上海华震科技有限公司A method for separating chenodeoxycholic acid and ursodeoxycholic acid
CN102690856A *2012-05-302012-09-26绵阳劲柏生物科技有限责任公司Process using microbial solution to prepare free bile acid
CN102703556A *2012-05-302012-10-03绵阳劲柏生物科技有限责任公司Method for separating chenodeoxycholic acid from duck bile by using macroporous resin
CN101830956B2008-11-192012-11-21毕小升Preparation method for separating and purifying chenodeoxycholic acid in porcine bile paste or leftovers
CN102827234A *2012-08-302012-12-19苏州天绿生物制药有限公司Method for separating and purifying chenodeoxycholic acid from duck gall
CN103360454A *2013-05-062013-10-23广西大学Method for separating and purifying chenodeoxycholic acid from goose bile
US3919266A1972-09-211975-11-11Intellectual Property Dev CorpProduction of bile acids
FR2429224A1 *1978-06-191980-01-18Canada Packers LtdChenodeoxycholic acid recovery from porcine bile – useful for dissolving gall stones in vivo
JPS60181096A *1984-02-281985-09-14Tokyo Tanabe Co LtdPurification of bile acid
EP0386538A21989-03-061990-09-12ERREGIERRE INDUSTRIA CHIMICA SpaProcess for preparing high purity 3-alpha-7-beta-dihydroxycholanic acid
JPH03227998A *1990-02-021991-10-08Showa Denko KkMethod for purifying chenodeoxycholic acid
CN1528779A *2003-09-292004-09-15华东理工大学Method for preparing cheodexycholic acid
Family To Family Citations
GB1450939A *1973-12-191976-09-29Intellectual Property
US4186143A *1977-06-201980-01-29Canada Packers LimitedChenodeoxycholic acid recovery process
KR100658512B1 *2005-12-302006-12-11주식회사 대웅제약Purification process for chenodeoxycholic acid

References

  1. Jump up to:a b c Russell DW (2003). “The enzymes, regulation, and genetics of bile acid synthesis”Annu. Rev. Biochem72: 137–74. doi:10.1146/annurev.biochem.72.121801.161712PMID 12543708.
  2. Jump up^ Carey MC (December 1975). “Editorial: Cheno and urso: what the goose and the bear have in common”. N. Engl. J. Med293 (24): 1255–7. doi:10.1056/NEJM197512112932412PMID 1186807.
  3. Jump up^ Parks DJ, Blanchard SG, Bledsoe RK, et al. (May 1999). “Bile acids: natural ligands for an orphan nuclear receptor”Science284 (5418): 1365–8. doi:10.1126/science.284.5418.1365PMID 10334993.
  4. Jump up^ Thistle JL, Hofmann AF (September 1973). “Efficacy and specificity of chenodeoxycholic acid therapy for dissolving gallstones”N. Engl. J. Med289 (13): 655–9. doi:10.1056/NEJM197309272891303PMID 4580472.
  5. Jump up^ Berginer VM, Salen G, Shefer S (December 1984). “Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid”N. Engl. J. Med311 (26): 1649–52. doi:10.1056/NEJM198412273112601PMID 6504105.
  6. Jump up^ Giaconda. “Press release”. Retrieved 5 April 2014.
  7. Jump up^ Bazzoli F, Malavolti M, Petronelli A, Barbara L, Roda E (1983). “Treatment of constipation with chenodeoxycholic acid”. J. Int. Med. Res11 (2): 120–3. PMID 6852359.
  8. Jump up^ Rao AS, Wong BS, Camilleri M, et al. (November 2010). “Chenodeoxycholate in females with irritable bowel syndrome-constipation: a pharmacodynamic and pharmacogenetic analysis”Gastroenterology139 (5): 1549–58, 1558.e1. doi:10.1053/j.gastro.2010.07.052PMC 3189402Freely accessiblePMID 20691689.
  9. Jump up^ Ki Soo Kim, Hong-Seok Kim Molecular Tweezer Based on Chenodeoxycholic Acid:Synthesis, Anion Binding Properties. Bulletin of the Korean Society 1411-1413 2004 Article ArchivedSeptember 27, 2007, at the Wayback Machine.
Chenodeoxycholic acid
Skeletal formula of chenodeoxycholic acid
Ball-and-stick model of the chenodeoxycholic acid molecule
Names
IUPAC names

chenodiol
OR
3α,7α-dihydroxy-5β-cholanic acid
OR
5β-cholanic acid-3α,7α-diol
OR
(R)-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.006.803
EC Number 207-481-8
KEGG
PubChem CID
UNII
Properties
C24H40O4
Molar mass 392.57 g/mol
Melting point 165 to 167 °C (329 to 333 °F; 438 to 440 K)
Pharmacology
A05AA01 (WHO)
License data
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
No verify (what is YesNo ?)
Infobox references

////////////////////Chenodeoxycholic acid,  ケノデオキシコール酸 , orphan designation

[H][C@@]1(CC[C@@]2([H])[C@]3([H])[C@H](O)C[C@]4([H])C[C@H](O)CC[C@]4(C)[C@@]3([H])CC[C@]12C)[C@H](C)CCC(O)=O

FDA and USDA announce key step to advance collaborative efforts to streamline produce safety requirements for farmers


DRUG REGULATORY AFFAIRS INTERNATIONAL

Image result for FDA and USDA announce key step to advance collaborative efforts to streamline produce safety requirements for farmers
As part of the U.S. Food and Drug Administration and the U.S. Department of Agriculture’s ongoing effort to make the oversight of food safety stronger and more efficient, the FDA and the USDA today announced the alignment of the USDA Harmonized Good Agricultural Practices Audit Program (USDA H-GAP) with the requirements of the FDA Food Safety Modernization Act’s (FSMA’s) Produce Safety Rule.
The new step is part of an ongoing effort to streamline produce safety requirements for farmers. The joint announcement was made by Agriculture Secretary Sonny Perdue and FDA Commissioner Scott Gottlieb, M.D., during a visit by the Secretary to the FDA’s White Oak campus in Silver Spring, Md.

june 5, 2018

Image result for FDA and USDA announce key step to advance collaborative efforts to streamline produce safety requirements for farmers

Release

As part of the U.S. Food and Drug Administration and the U.S. Department of Agriculture’s ongoing effort…

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Penciclovir


Penciclovir2DCSD.svgChemSpider 2D Image | Penciclovir | C10H15N5O3

Penciclovir

  • Molecular FormulaC10H15N5O3
  • Average mass253.258 Da

Cas 39809-25-1
97845-62-0 (Na salt)

Launched – 1996 PERRIGO, Herpes labialis

2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)butyl]-6H-purin-6-one
2-Amino-9-[4-hydroxy-3-(hydroxymethyl)butyl]-1,9-dihydro-6H-purin-6-one
2-Amino-9-[4-hydroxy-3-(hydroxyméthyl)butyl]-1,9-dihydro-6H-purin-6-one
359HUE8FJC

BRL-39123; penciclovir; BRL 39123A; penciclovir sodium; Denavir; Vectavir; Euraxvir; Fenivir

Penciclovir [USAN:INN:BAN]

  • BRL 39123
  • BRL-39123
  • CCRIS 9213
  • Denavir
  • HSDB 8123
  • Penciclovir
  • Penciclovirum
  • Penciclovirum [INN-Latin]
  • UNII-359HUE8FJC
Title: Penciclovir
CAS Registry Number: 39809-25-1
CAS Name: 2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)butyl]-6H-purin-6-one
Additional Names: 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]guanine; PCV
Manufacturers’ Codes: BRL-39123
Trademarks: Denavir (SKB); Vectavir (SKB)
Molecular Formula: C10H15N5O3
Molecular Weight: 253.26
Percent Composition: C 47.42%, H 5.97%, N 27.65%, O 18.95%
Literature References: Carba analog of ganciclovir, q.v., active against several herpes viruses. Prepn: U. K. Pandit et al., Synth. Commun. 2, 345 (1972); R. L. Jarvest, M. R. Harnden, US 5075445 (1991 to Beecham). Synthesis: M. R. Harnden et al., J. Med. Chem. 30, 1636 (1987); J. Hannah et al., J. Heterocycl. Chem. 26, 1261 (1989). Crystal and molecular structures: M. R. Harnden et al., Nucleosides Nucleotides 9, 499 (1990). In vitro activity of enantiomers in comparison with acyclovir, q.v.: G. Abele et al.,Antiviral Chem. Chemother. 2, 163 (1991); against herpes simplex viruses: A. Weinberg et al., Antimicrob. Agents Chemother. 36,2037 (1992). Clinical pharmacokinetics: S. E. Fowles et al., Eur. J. Clin. Pharmacol. 43, 513 (1992). HPLC determn in plasma and urine: J. R. McMeekin et al., Anal. Proc. 29, 178 (1992). Review of development and antiviral activity: M. R. Harnden, Drugs Future14, 347-358 (1989).
Properties: White crystalline solid from water, (monohydrate), mp 275-277°; also reported as colorless matted needles, mp 272-275°. uv max (in water): 253 nm (e 11500). uv max (aq 0.01N NaOH): 215, 268 nm (e 18140, 10710). Sol in water (20°): 1.7 mg/ml, pH 7.
Melting point: mp 275-277°; mp 272-275°
Absorption maximum: uv max (in water): 253 nm (e 11500); uv max (aq 0.01N NaOH): 215, 268 nm (e 18140, 10710)
Derivative Type: Sodium salt
Manufacturers’ Codes: BRL-39123A
Properties: Occurs as monohydrate, stable crystalline solid. Sol in water (20°): >200 mg/ml. 30 mg/ml soln has pH 11.
Therap-Cat: Antiviral.
Keywords: Antiviral; Purines/Pyrimidinones.
Penciclovir is a guanosine analogue antiviral drug used for the treatment of various herpesvirus infections. It is a nucleoside analoguewhich exhibits low toxicity and good selectivity. Because penciclovir is absorbed poorly when given orally (by mouth) it is more often used as a topical treatment. It is the active ingredient in the cold sore medications Denavir (NDC 0135-0315-52), Vectavir and Fenivir. Famciclovir is a prodrug of penciclovir with improved oral bioavailability.

Penciclovir was approved for medical use in 1996.[2]

Developed and launched by SmithKline Beecham (SB; now GlaxoSmithKline) and now marketed in the US by Prestium Pharma and ex-US by Novartis, penciclovir (Vectavir; Fenivir; Denavir; Euraxvir) is a 1% topical cream indicated for the treatment of recurrent herpes labialis (cold sores) in adults and children 12 years of age and older

APPROVALS

THE US

In September 1996, the compound was approved by the US FDA for cold sore treatment , and was launched in the US in 1997.

EUROPE

In December 1995, SB filed for European approvals of the drug . In  1997, the drug was approved in Belgium  Iceland Denmark  Norway  Ireland . In January 2003, the drug was launched in Sweden . In May 2007, the drug was launched in Portugal .

JAPAN

In December 1995, SB filed for Japanese approval of the drug .

CHINA

In September 1999, the compound was approved in China

FDA

https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020629s016lbl.pdf

Chemically, penciclovir is known as 9-[4-hydroxy-3-(hydroxymethyl)butyl] guanine. Its molecular formula is C10H15N5O3; its molecular weight is 253.26. It is a synthetic acyclic guanine derivative

Penciclovir is a white to pale yellow solid. At 20°C it has a solubility of 0.2 mg/mL in methanol, 1.3 mg/mL in propylene glycol, and 1.7 mg/mL in water. In aqueous buffer (pH 2) the solubility is 10.0 mg/mL. Penciclovir is not hygroscopic. Its partition coefficient in n-octanol/water at pH 7.5 is 0.024 (logP = -1.62).

Medical use

In herpes labialis, the duration of healing, pain and detectable virus is reduced by up to one day,[3] compared with the total duration of 2–3 weeks of disease presentation.

Mechanism of action

Penciclovir is inactive in its initial form. Within a virally infected cell a viral thymidine kinase adds a phosphate group to the penciclovir molecule; this is the rate-limiting step in the activation of penciclovir. Cellular (human) kinases then add two more phosphate groups, producing the active penciclovir triphosphate. This activated form inhibits viral DNA polymerase, thus impairing the ability of the virus to replicate within the cell.

The selectivity of penciclovir may be attributed to two factors. First, cellular thymidine kinases phosphorylate the parent form significantly less rapidly than does the viral thymidine kinase, so the active triphosphate is present at much higher concentrations in virally infected cells than in uninfected cells. Second, the activated drug binds to viral DNA polymerase with a much higher affinity than to human DNA polymerases. As a result, penciclovir exhibits negligible cytotoxicity to healthy cells.

The structure and mode of action of penciclovir are very similar to that of other nucleoside analogues, such as the more widely used aciclovir. A difference between aciclovir and penciclovir is that the active triphosphate form of penciclovir persists within the cell for a much longer time than the activated form of aciclovir, so the concentration within the cell of penciclovir will be higher given equivalent cellular doses.

SYN

Choudary, B.M.; Geen, G.R.; Grinter, T.J.; MacBeath, F.S.; Parratt, M.J.
Influence of remote structure upon regioselectivity in the N-alkylation of 2-amino-6-chloropurine: Application to the synthesis of penciclovir
Nucleosides Nucleotides 1994, 13(4): 979

PATENT

US 6573378

PATENT

CN 102070636

PAPER

https://www.tandfonline.com/doi/abs/10.1081/SCC-120026312?journalCode=lsyc20Selective and Practical Synthesis of Penciclovir

Pages 3897-3905 | Received 01 May 2003, Published online: 19 Aug 2006

9-[4-Hydroxy-3-(hydroxymethyl)butyl]guanine
(Penciclovir)[3a,b] (1)
………………………as a colorless crystalline solid: m.p. 268.4–269.2C [Lit.[3a,b]
275–277C]. UV (H2O) max 252 and 273 (sh) nm [Lit[3a,b] 253 and 270
(sh) nm].

1HNMR (DMSO-d6) 1.42 (pseudo septet, 1H, J¼7 Hz, H-30),
1.69 (pseudo q, 2H, J¼7 Hz, H-20), 3.37 (ddd, 2H, J¼11, 7 and 7 Hz)
and 3.41 (ddd, 2H, J¼11, 7 and 7 Hz) (CH2OH), 3.98 (t, 2H, J¼7 Hz,
H-10), 4.42 (t, 2H, J¼7 Hz, OH), 6.42 (br s, 2H, NH2), 7.67 (s, 1H, H-8),
10.50 (br s, 1H, H-1).

The 1HNMR spectrum is in good agreement with
the literature data.[3a,b]

3 (a) Harnden, M.R.; Jarvest, R.L.Tetrahedron Lett. 1985, 26, 4265–4268;

(b) Harnden, M.R.;Jarvest, R.L.; Bacon, T.H.; Boyd, M.R. J. Med. Chem. 1987, 30,1636–1642;

PAPER

Improved industrial syntheses of penciclovir and famciclovir using N2-acetyl-7-benzylguanine and a cyclic side chain precursor.

The synthesis of penciclovir by two related ways has been reported: 1) The reaction of 2-(hydroxymethyl)butane-1,4-diol (I) with formaldehyde (or an aldehyde such as trimethylacetaldehyde) (II) by means of H2SO4 (or p-toluenesulfonic acid, TsOH) gives the dioxane (III), which by reaction first with methanesulfonyl chloride and triethylamine and then with NaI in acetone affords the corresponding 5-(2-iodoethyl)-1,3-dioxane (IV). The reaction of (IV) with 2-amino-6-chloropurine (V) by means of K2CO3 in DMF gives the corresponding condensation product (VI), which is finally hydrolyzed and deprotected with refluxing 2M aqueous HCl. 2) The reaction of triol (I) with 2,2-dimethoxypropane (VII) by means of TsOH gives the corresponding 1,3-dioxane (VIII), which by reaction with triphenylphosphine and CBr4 is converted to the 5-(2-bromoethyl) derivative (IX). The reaction of (IX) with the purine (V) by means of K2CO3 as before affords the corresponding condensation product (X), which is hydrolyzed and deprotected with 2M HCl as before.
AND
This compound has been obtained by two similar ways: 1) The reaction of 6-chloropurine-2-amine (I) with 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (II) by means of K2CO3 in DMF gives the expected condensation product (III), which is methanolized with HCl/methanol yielding 2-[2-(2-amino-6-methoxypurin-9-yl)ethyl]malonic acid dimethyl ester (IV). The reduction of (IV) with NaBH4 in tert-butanol/methanol affords the corresponding diol (V), which is finally converted into pecnciclovir by hydrolysis with 2N NaOH. 2) The reaction of purine (I) with 3-bromopropane-1,1,1-tricarboxylic acid triethyl ester (VI) by means ofK2CO3 in DMF gives the expected condensation product (VII), which is partially decarboxylated with sodium methoxide in methanol yielding 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonic acid diethyl ester (VIII). The reduction of (VIII) with NaBH4 in tert-butanol/methanol followed by acetylation with acetic anhydride affords the corresponding diol diacetate (IX), which is finally converted into penciclovir by hydrlysis with 2N HCl.
AND
A synthesis of famciclovir that corresponds to that previously published and studies on its oral bioavailability in rats and mice, identifying famciclovir as the preferred prodrug of BRL-39123 (penciclovir), have been published.
AND
The reaction of purine (I) with 3-bromopropane-1,1,1-tricarboxylic acid triethyl ester (II) by means ofK2CO3 in DMF gives the expected condensation product (III), which is partially decarboxylated with sodium methoxide in methanol yielding 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonic acid diethyl ester (IV). The reduction of (IV) with NaBH4 in tert-butanol/methanol followed by acetylation with acetic anhydride affords the corresponding diol diacetate (V), which is finally converted into famciclovir by reductive dechlorination with H2 over Pd/C in ethyl acetate/triethylamine.
PAPER
Synth Commun 1972,2345-351
This compound has been obtained by two similar ways: 1) The reaction of 6-chloropurine-2-amine (I) with 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (II) by means of K2CO3 in DMF gives the expected condensation product (III), which is methanolized with HCl/methanol yielding 2-[2-(2-amino-6-methoxypurin-9-yl)ethyl]malonic acid dimethyl ester (IV). The reduction of (IV) with NaBH4 in tert-butanol/methanol affords the corresponding diol (V), which is finally converted into pecnciclovir by hydrolysis with 2N NaOH. 2) The reaction of purine (I) with 3-bromopropane-1,1,1-tricarboxylic acid triethyl ester (VI) by means ofK2CO3 in DMF gives the expected condensation product (VII), which is partially decarboxylated with sodium methoxide in methanol yielding 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonic acid diethyl ester (VIII). The reduction of (VIII) with NaBH4 in tert-butanol/methanol followed by acetylation with acetic anhydride affords the corresponding diol diacetate (IX), which is finally converted into penciclovir by hydrlysis with 2N HCl.
PAPER
Tetrahedron Lett 1985,264265-68
This compound has been obtained by two similar ways: 1) The reaction of 6-chloropurine-2-amine (I) with 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (II) by means of K2CO3 in DMF gives the expected condensation product (III), which is methanolized with HCl/methanol yielding 2-[2-(2-amino-6-methoxypurin-9-yl)ethyl]malonic acid dimethyl ester (IV). The reduction of (IV) with NaBH4 in tert-butanol/methanol affords the corresponding diol (V), which is finally converted into pecnciclovir by hydrolysis with 2N NaOH. 2) The reaction of purine (I) with 3-bromopropane-1,1,1-tricarboxylic acid triethyl ester (VI) by means ofK2CO3 in DMF gives the expected condensation product (VII), which is partially decarboxylated with sodium methoxide in methanol yielding 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonic acid diethyl ester (VIII). The reduction of (VIII) with NaBH4 in tert-butanol/methanol followed by acetylation with acetic anhydride affords the corresponding diol diacetate (IX), which is finally converted into penciclovir by hydrlysis with 2N HCl.
PAPER
J Med Chem 1987,301636-42
PAPER
Journal of Zhejiang University SCIENCE A 2013 Vol.14 No.10 P.760-766

10.1631/jzus.A1300238

Accelerated effect on Mitsunobu reaction via bis-N-tert-butoxycarbonylation protection of 2-amino-6-chloropurine and its application in a novel synthesis of penciclovir

Author(s):  Li-yan Dai, Qiu-long Shi, Jing Zhang, Xiao-zhong Wang, Ying-qi Chen
Affiliation(s):  . Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China
Corresponding email(s):   dailiyan@zju.edu.cn
Key Words:  2-amino-6-chloropurine, Mitsunobu reaction, bis-Boc protection, Penciclovir (PCV)
1.  Introduction
 Numerous nucleoside analogues in which the sugar residues have been replaced by acylic side-chains have been found to exhibit high antiviral activity (De Clercq, 1991). Purine derivatives (Fig. 1), in the majority N9 position, represent a plurality of important active substances endowed with antiviral activity. This group of compounds includes acyclovir (ACV) 1 (Schaeffer et al., 1978), ganciclovir (GCV) 2 (Ogilvie et al., 1982; Martin et al., 1983), penciclovir (PCV) 3 (Harnden et al., 19851987; Harnden and Jarvest, 1987), and famciclovir (FCV) 4 (Geen et al., 1992), and so on. Since Schaeffer et al. (1978) discovered that acyclovir is a promising anti-herpes virus agent, several groups have undertaken intensive studies to develop still more potent and effective acylic nucleoside analogues (Ashton et al., 1982; Smith et al., 1982; Martin et al., 1983). As a result, penciclovir (PCV) 3 and its pro-drug famciclovir (FCV) 4 were found to be potent and highly selective antiviral agents against both the herpes simplex virus (HSV) and the vari-cella-zoster virus (VZV) (Tippie et al., 1984). It was also reported that 3 exhibits anti hepatitis B virus (HBV) and duck hepatitis B virus (DHBV) activity (Korba and Boyd, 1996; Shaw et al., 1994).
Fig.1
Purine derivatives

To synthesize 3 and 4, 2-amino-6-chloropurine (ACP) is commonly used as a starting material, coupling with alkyl halide side chains (Geen et al., 1990; Geen et al., 1992; Kim et al., 1998; Brand et al., 1999; Toyokuni et al., 2003). However, considering its isomerization at N7 and N9 positions under acidic or alkaline conditions, the most challengeable issue is the selectivity of a N-alkylation at the N7 or N9 position of ACP. Normally, alkylation takes place at the N9 position as well as at the N7 position of the purine moiety, and the N9/N7 ratio is usually less than 6:1 (Kim et al., 1998). Accordingly, to improve this ratio, several approaches have been reported, mainly involving changing the structure of the side chains (Geen et al., 1992) and modification of the ACP (Brand et al., 1999). For example, as reported by Zheng et al. (2004) (Fig. 2), a side chain 6 was synthesized and separated readily at 0 °C. After coupling 6 with 2-amino-6-chloropurine 7, the ratio of the product 9-isomer purine (8a) and the 7-isomer purine (8b) could reach about 10:1. However, the reaction temperature must be strictly controlled as 6 decomposes easily even at room temperature and then an extra careful column chromatography separation procedure would be required to obtain pure 8a. Thus, finding a more practical and efficient method, which could avoid the formation of N7-alkylated compound and shorten the synthetic steps to obtain ACP, becomes attractive.

Fig.2
Synthesis of penciclovir (PCV) with conventional method

The Mitsunobu reaction might be an alternative (potential) approach (Mitsunobu, 1981; Swamy et al., 2009). This reaction has become a very popular chemical transformation due to its mildness, occurring under essentially neutral conditions, and its stereospecificity, proceeding with complete Walden inversion of stereochemistry (Mitsunobu, 1981). Moreover, it permits C-O, C-S, C-N, or C-C bonds formed by the condensation of an acidic component with a primary or a secondary alcohol. Actually, some literature has already reported successful Mitsunobu coupling of ACP and adenine with allylic and benzylic alcohol, showing a good N9 selectivity (Yang et al., 2005; Kitade et al., 2006; Yin et al., 2006). However, a poor to modest yield (20%–50%) and a limited substrate scope were observed. In order to improve these yields, Lu et al. (2007) developed a modified Mitsunobu method to couple purine with alcohols in a higher temperature (70 °C), along with two rounds of the Mitsunobu reaction; yet its long reaction procedure and poor atom economy weaken its potential. The poor solubility of ACP or its derivatives in THF, the preferred solvent for Mitsunobu reactions, is likely the primary reason for these defects being observed.

A possible process to improve the solubility of ACP is to make use of the tert-butoxycarbonyl group (Boc), which can serve as the protection of the exocylic amino groups functionality and increase the lipophilicity of the base portion of the purine. Another advantage of the Boc protection group is that its acidolytic removal is less sensitive to steric factors and can also be removed under neutral conditions (Hwu et al., 1996; Siro et al., 1998). In contrast, a few studies have recently been reported that apply the Boc group in the protection of nucleobase (Sikchi and Hultin, 2006; Porcheddu et al., 2008). As described by Porcheddu et al. (2008), solubility of nucleobases, including guanine, was increased in some organic solvents after protected by Boc groups. In addition, some results in our previous study (Yang et al., 2011) demonstrated a very good improvement in coupling purine derivatives under Mitsunobu conditions. Thus, it could be safer to presume that protecting amino groups of ACP with Boc would be an ideal way for its application in the synthesis of PCV 3 and offer similar results as shown under Mitsunobu conditions.

In this study, we firstly synthesized a bis-Boc protected ACP, namely, bis-Boc-2-amino-6-chloropurine 9 (Fig. 3) and investigated its solubility in several different Mitsunobu solvents, then coupling bis-Boc-2-amino-6-chloropurine 9 with a large scope of alcohols confirmed its good reactivity for a Mitsunobu reaction and successfully developed a new and efficient method for the preparation of PCV using Mitsunobu coupling reaction as the key step.

Fig.3
Synthesis of bis-Boc-6-chloropurine 9
a: 2-amino-6-chloropurine, 4,4-dimethylaminopyridine (DMAP), THF and Boc2O, 25 °C, N2; b: MeOH, NaHCO3, 55 °C

2.  Experimental
2.1.  General
 Acetic ether and hexane, used for extraction and chromatography, were distilled. Absolute anhydrous THF used in the Mitsunobu reactions were prepared by distillation over a drying agent (Na/benzophenone). All other reagents were purchased and used without further purification. Thin-layer chromatography (TLC) analyses were conducted on the Merck Kieselgel 60 F254 plates. Flash chromatography was performed using a silica gel Merck 60 (particle size 0.040–0.063 mm). All 1H NMR and 13C NMR spectra were recorded on the BRUKER AVANCE DX500 (BRUKER AVANCE, Germany), using CDCl3 or d6-DMSO as solvent at room temperature. Chemical shifts are given in 10−6 relative to tetramethylsilane (TMS) and the coupling constants J are given in Hz. TMS served as an internal standard (δ=0) for 1H NMR, and CDCl3 was used as an internal standard (δ=77.0×10−6) for 13C NMR. Melting points (mp) were obtained on a Melting Point WRR (Shanghai Precision & Scientific Instrument Co., Ltd., China).
2.2.  Bis-Boc-2-amino-6-chloropurine (9)
 1. t-Butyl-2-[bis(t-butoxycarbonyl)amino]-6-chloro-9H-purine-9-carboxylate (9a)

To a 250 ml N2-flushed flask with dry THF (100 ml), equipped with a magnetic stir bar, 2-amino-6-chloropurine (2.0 g, 11.8 mmol) and DMAP (0.14 g, 1.18 mmol) were added. Boc2O (10.3 g, 47.2 mmol) was added to the stirred suspension under an N2atmosphere, then the reaction mixture was stirred for 6 h at room temperature (TLC analysis indicated the disappearance of 2-mino-6-chloropurine). The excess amount of THF was removed, and the crude product was dissolved in AcOEt (400 ml), washed with HCl aqueous (2 mol/L, 1×30 ml) and brine (2×50 ml), dried with Na2SO4 and concentrated in vacuo to give a white solid (5.2 g, 94.5%). mp 51–52 °C; 1H NMR (500 MHz, CDCl3): δ=1.47 (s, 18H, C(CH3)3), 1.69 (s, 9H, C(CH3)3), 8.58 (s, 1H, CH); 13C NMR (125 MHz, CDCl3δ=153.8, 152.0, 151.8, 150.6, 145.5, 144.7, 130.8, 88.0, 83.9, 28.0.

2. Bis-Boc-2-amino-6-chloropurine (9)

A solution of the white solid obtained above (14 g, 30 mmol) in MeOH (400 ml) was added to saturated NaHCO3 aqueous (200 ml), then the turbid solution was stirred at 55 °C for 2 h, at which point clean conversion to bis-Boc protected adenine was observed by TLC. After evaporation of MeOH, the residue mixture was cooled, added 5 mol/L hydrochloric acid to get pH=7 (approximate). A large amount of white solid formed, the reaction mixture was filtrated and then dried under a vacuum to give a white solid 9 (10.5 g, 95.5%). mp 101.3–103.3 °C; 1H NMR (500 MHz, CDCl3): δ=1.50 (s, 18H, C(CH3)3), 8.41 (s, 1H, CH); 13C NMR (125 MHz, CDCl3δ=153.5, 151.9, 151.6, 151.3, 145.6, 128.5, 82.7, 28.5.

2.3.  5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxane (5)

2-hydroxymethyl-1,4-butanediol 11 (8.10 g, 67.4 mmol) and 2,2-dimethoxypropane (13 ml, 105.7 mmol) were dissolved in dry THF (20 ml). The mixture was stirred and p-toluenesulfonic acid monohydrate (0.64 g, 3.4 mmol) was added, the clear solution was stirred at room temperature for 12 h, triethylamine (10 ml) was added to quench the reaction, and the solution was stirred for 30 min. Then solvents were removed to leave a colorless liquid, the residue was subject to column chromatography on silica gel eluted with 2:1 EtOAc/hexane to give a colorless liquid 5 (6.2 g, 61.5%), R f=0.46 (2:1 EtOAc/hexane). 1H NMR (500 MHz, CDCl3): δ=3.99 (dd, 2H, Heq. J 1=11.80 Hz, J 2=4.45 Hz, CH2); 3.80 (t, 2H, J=6.71 Hz, CH2), 3.34 (dd, 2H, Hax. J 1=11.80 Hz, J 2=8.11 Hz, CH2), 1.90–1.98 (m, 2H, CH and OH), 1.62 (q, 2H, J=6.85 Hz, CH2 ); 13C NMR (125 MHz, CDCl3): δ=100.5, 69.8, 60.4, 31.9, 30.3, 21.2.

2.4.  Bis-Boc-2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl] purine (12)

Bis-Boc-2-amino-6-chloropurine 9 (1.0 equivalent) was added to a solution of the side chain 5 (1.1 equivalent) and phosphine reagent (1.1 equivalent) in anhydrous THF under N2 atmosphere at 0 °C, the resulting solution was treated with di-p-nitrobenzyl azocarboxylate (DNAD) (1.1 equivalent) dropwise and the reaction mixture was continued at room temperature for 8 h, then the solvent was evaporated and the residue dissolved in cyclohexane. The triphenylphosphane oxide precipitated and was filtered off and then the filtrate evaporated under reduced pressure. The product was purified by a column chromatography on silica gel to obtain the pure products as a white solid. mp>280 °C (dec); 1H NMR (500 MHz, CDCl3): δ=8.36 (s, 1H, CH), 4.02 (t, 2H, J=7.23 Hz, CH2), 3.79 (dd, 2H, Heq. J 1=11.57 Hz, J 2=4.46 Hz, CH2), 3.56 (dd, 2H, Hax. J 1=11.57 Hz, J 2=8.77 Hz, CH2), 1.67 (q, 2H, J=7.22 Hz, CH2), 1.53–1.61 (m, 1H, CH), 1.47 (s, 18H, C(CH3)3), 1.39 (s, 3H, CH3), 1.36 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3): δ=154.3, 151.7, 151.5, 151.1, 128.0, 104.8, 81.7, 71.5, 50.8, 33.7, 28.6, 26.2, 25.7.

2.5.  2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl) ethyl]purine (8a)

A mixture of compound 12 (2.56 g, 5.0 mmol), 2,6-dimethyl pyridine (1.18 ml, 10 mmol) and dry DCM (20 ml) was stirred at 0 °C, then TBTMS-OTf was added dropwise; after the addition, the reaction mixture was stirred at room temperature until TLC showed that compound 12 had completely disappeared. Then 30 ml saturated ammonium chloride solution was added, separated the organic layer, extracted with DCM (2×20 ml), combined and washed by saturated NaCl (2×40 ml), dried with anhydrous sodium sulfate and evaporated to give a white solid (1.21 g, 78%). mp 125–126 °C; 1H NMR (500 MHz, CDCl3): δ=8.07 (s, 1H, CH) , 6.99 (s, 2H, NH2), 4.12 (t, 2H, J=7.31 Hz, CH2), 3.82 (dd, 2H, 4′-Heq, J 1=11.79 Hz, J 2=4.50 Hz, CH2), 3.53 (dd, 2H, 4′-Hax, J 1=11.79 Hz, J 2=8.80 Hz, CH2), 1.74 (q, 2H, J=7.30 Hz, CH2), 1.53–1.65 (m, 1H, CH), 1.36 (s, 3H, CH3), 1.31 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3): δ=159.94, 150.31, 150.26, 141.84, 132.11, 100.52, 68.14, 52.90, 31.32, 26.84, 26.05.

2.6.  9-[4-hydroxy-3-(hydroxymethyl)butyl] guanine (PCV 3)

Compound 12 (5.12 g, 10 mmol) was dissolved in THF (20 ml) hydrochloric acid (2 mol/L, 20 ml). The mixture was stirred for 2 h at 70 °C, and then slowly warmed to reflux for 2 h. After evaporation of the THF under reduced vacuum, 10% aqueous NaOH solution was added to neutralize the residual liquid, and a large amount of off-white solid formed, filtered, washed with acetone and then water, and dried under vacuum to give an off-white solid 3 (2.07 g, 82%). mp 274.6–276.9 °C.

3.  Results and discussion
 To begin with, bis-Boc-2-amino-6-chloropurine 9 was synthesized from 2-amino-6-chloropurine 7 in high yield followed by Subhakar’s procedure (Dey and Garner, 2000). The solubility of bis-Boc-2-amino-6-chloropurine 9 was investigated and the results are shown in Table 1. Unlike 2-amino-6-chloropurine 7, known for its notorious insolubility in most common solvents, the solubility of 9 in DCM, methylbenzene, acetonitrile, and especially in THF was increased dramatically.

Table 1

Mole fraction solubility x of bis-Boc-2-amino-6-chloropurine 9 in different Mitsunobu solvents

T (K) (±0.05 K) Solubility x a (%)


THFb DCMb Methylbenzeneb Acetonitrileb
273.15 0.1141 0.0493 0.0213 0.0150
278.15 0.1191 0.0552 0.0253 0.0178
283.15 0.1251 0.0613 0.0303 0.0210
288.15 0.1299 0.0664 0.0349 0.0244
293.15 0.1352 0.0734 0.0405 0.0288
298.15 0.1399 0.0809 0.0470 0.0347
303.15 0.1463 0.0894 0.0544 0.0417
308.15 0.1523 0.0983 0.0634 0.0501
313.15 0.1581 0.1081 0.0734 0.0617
  • a: the solubility of bis-Boc-2-amino-6-chloropurine 9 was measured by our previous method with temperature ranging from 273.15 K to 313.15 K (Wang et al., 2008) at atmospheric pressure. The laser monitoring observation technique was used to determine the disappearance of the solid phase in a solid and liquid mixture

b: all the solvents were further purified by distillation in dry agent (Na/benzophenone) and the sample bis-boc-2-amino-6-chloropurine 9 was dried in vacuum for over 2 d

As shown in Table 1, THF, which is the most common solvent in Mitsunobu reaction, has great solubility for bis-Boc-2-amino-6-chloropurine 9. Afterwards, the best solvent THF was taken for coupling 9 with a number of alcohols under normal Mitsunobu conditions to investigate its reactivity. The results were illustrated in Table 2. We clearly learned that bis-Boc-2-amino-6-chloropurine 9, as an excellent nucleophilic precursor, was able to react with a large number of alcohols, including primary alcohol, secondary alcohol, allyl alcohol, benzyl alcohol, etc., with high N9 selectivity and yields. Moreover, tert-Butyl alcohol still could not react with a protected purine as in the previous study (Yang et al., 2011), owing to its steric hindrance in tertiary carbon.

Table 2

Investigation of the reactivity of bis-Boc-2-amino-6-chloropurine 9 with different alcohols

Entry Alcohol Product Isolated yield (%)
1 10a 90.2
2 10b 86.6
3 10c 83.3
4 10d 84.8
5 10e 86.4
6 10f 81.2
7 10g 81.5
8 10h 80.7
9 10i 0
  • a): a mixture of 9 (1.0 equivalent), alcohol (1.1 equivalent) and phosphine reagent (1.1 equivalent) in anhydrous THF stirring under N2 atmosphere at 0 °C, then treated with azo-reagent DNAD (1.1 equivalent) warmed to room temperature; b): the mixture of the products from procedure a, THF (20 ml) and aqueous hydrochloric acid (2 mol/L, 20 ml) was refluxed for 2 h at 70 °C
  • According to the research results above, it is more reasonable and assuring to prepare PCV via a Mitsunobu reaction. This novel method for the preparation of PCV is indicated in Fig. 4. First, the side chain of 5-(2-hydroxyethyl)-2,2-dimethyl-1,3 -dioxane 5 was achieved through the commercially available starting material 2-hydroxymethyl-1,4-butanediol 11 reacting with 2,2-dimethoxypropane catalyzed by p-toluenesulfonic acid. The free –OH group of compound 5 is not necessary to be converted to the other leaving group such as chlorine, tosylate or methanesulphonate, which is always taken as a necessary step in the previous method or many other previous studies for the preparation of PVC till now (Harnden and Jarvest, 1985; Harnden et al., 1987; Zheng et al., 2004), making the synthesis of the side chain part of our method much more convenient and practical.
Fig.4
Synthesis of penciclovir (PCV) with new method
a: 2,2-dimethoxypropane, p-toluenesulfonic acid, THF; b: 1.1 equivalent of the side chain 5, 1.1 equivalent of PPh3, and 1.1 equivalent of azodicarboxylate reagent at rt. in THF; c: TBDMS-OTf, DCM; d: aqueous hydrochloric acid (2 mol/L), THF; e: aqueous hydrochloric acid (2 mol/L)

Our next objective was the synthesis of PCV. As was expected, bis-Boc-2-amino-6-chloropurine 9 combined with the side chain 5(1.1 equivalent) under normal Mitsunobu conditions successfully obtained the desired N9-alkylated compound 12 in 92% yield without the undesired N7 alkylation by-product being formed. Importantly, the reaction conditions were significantly milder than those reported in recent studies (Geen et al., 19901992; Kim et al., 1998; Brand et al., 1999; Toyokuni et al., 2003), requiring only 1.1 equivalent of each of the alcohol, PPh3 and DNAD, and proceeding to completion within 60 min at room temperature. This is mainly due to the enhanced solubility of the compound 9 as mentioned above. By process c in Fig. 4, compound 8a was obtained under neutral conditions. It is 1H and 13C NMR spectra further indicated that no 7-isomer purine (8b) was formed. Subsequently, we could obtain PCV 3 in an acid condition as procedure e; or directly starting from 12, where hydrolytic dechlorination and deprotection step(s) were accomplished in one pot under mild acid conditions (2mol/L, hydrochloric acid in THF at room temperature) to afford the target PCV 3 in 80%–85% yield (process d). The overall yield of PCV from 11 was 44.5% higher than that in previous study (16%) (Zheng et al., 2004).

4.  Conclusions
 In this study, ACP was protected with a bis-Boc carbamate group and showed a significant increase of solubility in the favorite Mitsunobu solvents. Coupling bis-Boc-2-amino-6-chloropurine 9 with different alcohols indicated a higher N9 selectivity and good reactivity in a Mitsunobu reaction. The results provided a convenient and practical protocol to prepare PCV from ACP, avoiding the presence of undesired N7 by-product and requiring only a few synthetic steps with higher yields.

References

[1] Ashton, W.T., Karkas, J.D., Field, A.K., Tolman, R.L., 1982. Activation by thymidine kinase and potent antiherpetic activity of 2’-nor-2’-deoxyguanosine (2’NDG). Biochemical and Biophysical Research Communications, 108(4):1716-1721.
[2] Brand, B., Reese, C.B., Song, Q., Visintin, C., 1999. Convenient syntheses of 9-[4-hydroxy-3-(hydroxymethyl)butyl] guanine (penciclovir) and 9-[4-acetoxy-3-(acetoxymethyl) butyl]-2-amino-9H-purine (famciclovir). Tetrahedron, 55(16):5239-5252.
[3] De Clercq, E., 1991. Broad-spectrum anti-DNA virus and anti-retrovirus activity of phosphonylmethoxyalkylpurines and pyrimidines. Biochemical Pharmacology, 42(5):963-972.
[4] Dey, S., Garner, P., 2000. Synthesis of tert-butoxycarbonyl (Boc)-protected purines. The Journal of Organic Chemistry, 65(22):7697-7699.
[5] Geen, G.R., Grinter, T.J., Kincey, P.M., Jarvest, R.L., 1990. The effect of the C-6 substituent on the regioselectivity of N-alkylation of 2-aminopurines. Tetrahedron, 46(19):6903-6914.
[6] Geen, G.R., Kincey, P.M., Choudary, B.M., 1992. Regiospecific Michael additions with 2-aminopurines. Tetrahedron Letters, 33(32):4609-4612.
[7] Harnden, M.R., Jarvest, R.L., 1985. An improved synthesis of the antiviral acyclonucleoside 9-(4-hydroxy-3-hydroxymethylbut-1-yl) guanine. Tetrahedron Letters, 26(35):4265-4268.
[8] Harnden, M.R., Jarvest, R.L., Bacon, T.H., Boyd, M.R., 1987. Synthesis and antiviral activity of 9-[4-hydroxy-3-(hydroxymethyl) but-1-yl] purines. Journal of Medicinal Chemistry, 30(9):1636-1642.
[9] Hwu, J.R., Jain, M.L., Tsay, S.C., Hakimelahi, G.H., 1996. Ceric ammonium nitrate in the deprotection of tert-butoxycarbonyl group. Tetrahedron Letters, 37(12):2035-2038.
[10] Kim, D.K., Lee, N., Kim, Y.W., Chang, K.Y., Kim, J.S., Im, G.J., Choi, W.S., Jung, I.H., Kim, T.S., Hwang, Y.Y., 1998. Synthesis and evaluation of 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonylo-xybut-1-yl) purines as potential prodrugs of penciclovir. Journal of Medicinal Chemistry, 41(18):3435-3441.
[11] Kitade, Y., Ando, T., Yamaguchi, T., Hori, A., Nakanishi, M., Ueno, Y., 2006. 4’-fluorinated carbocyclic nucleosides: synthesis and inhibitory activity against S-adenosyl-l-homocysteine hydrolase. Bioorganic & Medicinal Chemistry, 14(16):5578-5583.
[12] Korba, B.E., Boyd, M.R., 1996. Penciclovir is a selective inhibitor of hepatitis B virus replication in cultured human hepatoblastoma cells. Antimicrobial Agents and Chemotherapy, 40(13):1282-1284.
[13] Lu, W., Sengupta, S., Petersen, J.L., Akhmedov, N.G., Shi, X., 2007. Mitsunobu coupling of nucleobases and alcohols: an efficient, practical synthesis for novel nonsugar carbon nucleosides. Journal of Organic Chemistry, 72(13):5012-5015.
[14] Martin, J.C., Dvorak, C.A., Smee, D.F., Matthews, T.R., Verheyden, J.P.H., 1983. 9-(1,3-dihydroxy-2-propoxymethyl) guanine: a new potent and selective antiherpes agent. Journal of Medicinal Chemistry, 26(5):759-761.
[15] Mitsunobu, O., 1981. The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products. Synthesis, 1981(1):1-28.
[16] Ogilvie, K.K., Cheriyan, U.O., Radatus, B.K., Smith, K.O., Galloway, K.S., Kennell, W.L., 1982. Biologically active acyclonucleoside analogues. II. The synthesis of 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl] guanine (BIOLF-62). Canadian Journal of Chemistry, 60(24):3005-3010.
[17] Porcheddu, A., Giacomelli, G., Piredda, I., Carta, M., Nieddu, G., 2008. A Practical and efficient approach to PNA monomers compatible with Fmoc-mediated solid-phase synthesis protocols. European Journal of Organic Chemistry, 2008(34):5786-5797.
[18] Schaeffer, H.J., Beauchamp, L., Miranda, P.D., Elion, G.B., Bauer, D.J., Collins, P., 1978. 9-(2-hydroxyethoxymethyl) guanine activity against viruses of the herpes group. Nature, 272(5654):583-585.
[19] Shaw, T., Amor, P., Civitico, G., Boyd, M., Locarnini, S., 1994. In vitro antiviral activity of penciclovir, a novel purine nucleoside, against duck hepatitis B virus. Antimicrobial Agents and Chemotherapy, 38(4):719-723.
[20] Smith, K.O., Galloway, K.S., Kennell, W.L., Ogilvie, K.K., Radatus, B.K., 1982. A new nucleoside analog, 9-[[2-hydroxy-1-(hydroxymethyl)ethoxyl]methyl] guanine, highly active in vitro against herpes simplex virus types 1 and 2. Antimicrobial Agents and Chemotherapy, 22(1):55-61.
[21] Tippie, M.A., Martin, J.C., Smee, D.F., Matthews, T.R., Verheyden, J.P.M., 1984. Antiherpes simplex virus activity of 9-[4-hydroxy-3-(hydroxymethyl)-1-butyl] guanine. Nucleosides and Nucleotides, 3(5):525-535.
[22] Toyokuni, T., Walsh, J.C., Namavari, M., Shinde, S.S., Moore, J.R., Barrio, J.R., Satyamurthy, N., 2003. Selective and practical synthesis of penciclovir. Synthetic Communications, 33(22):3897-3905.
[23] Sikchi, S.A., Hultin, P.G., 2006. Solventless protocol for efficient Bis-N-Boc protection of adenosine, cytidine, and guanosine derivatives. Journal of Organic Chemistry, 71(16):5888-5891.
[24] Siro, J.G., Martin, J., Garcia-Navio, J.L., Remuinan, M.J., Vaquero, J.J., 1998. Easy microwave assisted deprotection of N-Boc derivatives. Synlett, 1998(2):147-148.
[25] Swamy, K.C.K., Kumar, N.N.B., Balaraman, E., Kumar, K.V.P.P., 2009. Mitsunobu and related reactions: advances and applications. Chemical Reviews, 109(6):2551-2651.
[26] Wang, L., Dai, L.Y., Lei, M., Chen, Y., 2008. Solubility of hexamethylenetetramine in a pure water, methanol, acetic acid, and ethanol+water mixture from (299.38 to 340.35) K. Journal of Chemical & Engineering Data, 53(12):2907-2909.
[27] Yang, J., Dai, L., Wang, X., Chen, Y., 2011. Di-p-nitrobenzyl azodicarboxylate (DNAD): an alternative azo-reagent for the Mitsunobu reaction. Tetrahedron, 67(7):1456-1462.
[28] Yang, M.M., Schneller, S.W., Korba, B., 2005. 5’-homoneplanocin a inhibits hepatitis B and hepatitis C. Journal of Medicinal Chemistry, 48(15):5043-5046.
[29] Yin, X.Q., Li, W.K., Schneller, S.W., 2006. An efficient Mitsunobu coupling to adenine-derived carbocyclic nucleosides. Tetrahedron Letters, 47(52):9187-9189.
[30] Zheng, Q.H., Wang, J.Q., Liu, X., Fei, X.S., Mock, B.H., Glick-Wilson, B.E., Sullivan, M.L., Raikwar, S.P., Gardner, T.A., Kao, C.H., 2004. An improved total synthesis of PET HSV-tk gene reporter probe 9-(4-[18F] fluoro-3-hydroxymethylbutyl) guanine ([18F]FHBG). Synthetic Communications, 34(4):689-704.
PAPER
Image result for penciclovir synthesis

SYN

EP 0141927; ES 8602791; ES 8603887; ES 8603888; JP 1994293764; US 5075445

This compound has been obtained by two similar ways: 1) The reaction of 6-chloropurine-2-amine (I) with 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (II) by means of K2CO3 in DMF gives the expected condensation product (III), which is methanolized with HCl/methanol yielding 2-[2-(2-amino-6-methoxypurin-9-yl)ethyl]malonic acid dimethyl ester (IV). The reduction of (IV) with NaBH4 in tert-butanol/methanol affords the corresponding diol (V), which is finally converted into pecnciclovir by hydrolysis with 2N NaOH. 2) The reaction of purine (I) with 3-bromopropane-1,1,1-tricarboxylic acid triethyl ester (VI) by means ofK2CO3 in DMF gives the expected condensation product (VII), which is partially decarboxylated with sodium methoxide in methanol yielding 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]malonic acid diethyl ester (VIII). The reduction of (VIII) with NaBH4 in tert-butanol/methanol followed by acetylation with acetic anhydride affords the corresponding diol diacetate (IX), which is finally converted into penciclovir by hydrlysis with 2N HCl.

References

  1. Jump up^ “Penciclovir”Merriam-Webster Dictionary. Retrieved 2016-01-22.
  2. Jump up^ Long, Sarah S.; Pickering, Larry K.; Prober, Charles G. (2012). Principles and Practice of Pediatric Infectious Disease. Elsevier Health Sciences. p. 1502. ISBN 1437727026.
  3. Jump up^ Farmaceutiska Specialiteter i Sverige – the Swedish official drug catalog. [http://www.fass.se Fass.se –> Vectavir. Retrieved on August 12, 2009. Translated from “Tiden för läkning, smärta och påvisbart virus förkortas med upp till ett dygn.”
Penciclovir
Penciclovir2DCSD.svg
Clinical data
Pronunciation /ˌpɛnˈsklˌvɪər/[1]
Trade names Denavir
AHFS/Drugs.com Monograph
MedlinePlus a697027
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
Routes of
administration
Topical
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 1.5% (oral), negligible (topical)
Protein binding <20%
Metabolism Viral thymidine kinase
Elimination half-life 2.2–2.3 hours
Excretion Renal
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.189.687 Edit this at Wikidata
Chemical and physical data
Formula C10H15N5O3
Molar mass 253.258 g/mol
3D model (JSmol)

/////////////Penciclovir, BRL-39123,  BRL 39123A, penciclovir sodium, Denavir, Vectavir, Euraxvir, Fenivir,

C1=NC2=C(N1CCC(CO)CO)NC(=NC2=O)N

Doxepin, ドキセピン


Doxepin2DACS.svgDB01142.png

Doxepin

1668-19-5 
1229-29-4 (hydrochloride), 4698-39-9 ((E)-isomer); 25127-31-5 ((Z)-isomer)

Launched – 1964

1-Propanamine, 3-dibenz(b,e)oxepin-11(6H)-ylidene-N,N-dimethyl-
1-Propanamine, 3-dibenz[b,e]oxepin-11(6H)-ylidene-N,N-dimethyl-, (3Z)-
3-(Dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine
N,N-Dimethyldibenz[b,e]oxepin-D11(6H),g-propylamine
(3Z)-3-(Dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine
Doxepin Hydrochloride 3U9A0FE9N5 1229-29-4

NSC-108160
P-3693A
SO-101

Aponal
Quitaxon
Silenor
Sinequan
Sinquan
Xepin
Zonalon

USP

USP32/pub/data/v32270/usp32nf27s0_m28110

N,N-Dimethyldibenz[b,e]oxepin-D11(6H),-propylamine hydrochloride [1229-29-4; 4698-39-9 ((E)-isomer); 25127-31-5 ((Z)-isomer)].

» Doxepin Hydrochloride, an (E) and (Z) geometric isomer mixture, contains the equivalent of not less than 98.0 percent and not more than 102.0 percent of doxepin (C19H21NO·HCl), calculated on the dried basisIt contains not less than 13.6 percent and not more than 18.1 percent of the (Z)-isomer, and not less than 81.4 percent and not more than 88.2 percent of the (E)-isomer.
Title: Doxepin
CAS Registry Number: 1668-19-5
CAS Name: 3-Dibenz[b,e]oxepin-11(6H)-ylidene-N,N-dimethyl-1-propanamine
Additional Names:N,N-dimethyldibenz[b,e]oxepin-D11(6H),g-propylamine; 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin
Manufacturers’ Codes: P-3693A
Molecular Formula: C19H21NO
Molecular Weight: 279.38
Percent Composition: C 81.68%, H 7.58%, N 5.01%, O 5.73%
Literature References: Prepn of mixture of cis- and trans-isomers: K. Stach, F. Bickelhaupt, Monatsh. Chem.93, 896 (1962); F. Bickelhaupt et al.,ibid.95, 485 (1964); NL6407758; K. Stach, US3438981 (1965, 1969 both to Boehringer Mann.); and separation and activity of isomers: B. M. Bloom, J. R. Tretter, BE641498eidem,US3420851 (1964, 1969 both to Pfizer). Pharmacology: A. Ribbentrop, W. Schaumann, Arzneim.-Forsch.15, 863 (1965). Metabolism in animals: D. C. Hobbs, Biochem. Pharmacol.18, 1941 (1969). Determn in plasma by GC/MS: T. P. Davis et al.,J. Chromatogr.273, 436 (1983); by HPLC: T. Emm, L. J. Lesko, ibid.419,445 (1987). Clinical study in depression: K. Rickels et al.,Arch. Gen. Psychiatry42, 134 (1985). Comparative clinical trial with cimetidine, q.v., in treatment of ulcer: R. K. Shrivastava et al.,Clin. Ther.7, 181 (1985). Review of pharmacology and therapeutic efficacy: R. M. Pinder et al.,Drugs13, 161 (1977).
Properties: Oily liq consisting of a mixture of cis- and trans-isomers. bp0.03 154-157°, bp0.2 260-270°. LD50 in mice, rats (mg/kg): 26, 16 i.v.; 79, 182 i.p.; 135, 147 orally (Ribbentrop, Schaumann).
Boiling point: bp0.03 154-157°; bp0.2 260-270°
Toxicity data: LD50 in mice, rats (mg/kg): 26, 16 i.v.; 79, 182 i.p.; 135, 147 orally (Ribbentrop, Schaumann)
Derivative Type: Hydrochloride
CAS Registry Number: 1229-29-4
Trademarks: Adapin (Lotus); Aponal (Boehringer, Mann.); Curatin (Pfizer); Quitaxon (Boehringer, Mann.); Sinequan (Pfizer)
Molecular Formula: C19H21NO.HCl
Molecular Weight: 315.84
Percent Composition: C 72.25%, H 7.02%, N 4.43%, O 5.07%, Cl 11.22%
Properties: Crystals, mp 184-186°, 188-189°.
Melting point: mp 184-186°, 188-189°
Derivative Type: Maleate
Properties: Crystals, mp 161-164°, 168-169°.
Melting point: mp 161-164°, 168-169°
Derivative Type:trans-Form hydrochloride
CAS Registry Number: 3607-18-9
Properties: mp 192-193°.
Melting point: mp 192-193°
Derivative Type:cis-Form hydrochloride
CAS Registry Number: 25127-31-5
Additional Names: Cidoxepin hydrochloride
Manufacturers’ Codes: P-4599
Properties: Crystals, mp 209-210.5°.
Melting point: mp 209-210.5°
Therap-Cat: Antidepressant.
Therap-Cat-Vet: Antipruritic.
Keywords: Antidepressant; Tricyclics.
US FDA
NDA 22-036 Silenor (doxepin HCl) Tablets Somaxon Pharmaceuticals, Inc
Introduction: Doxepin Hydrochloride has been marketed by Pfizer since 1969 for the treatment of depression, anxiety, and psychotic depressive disorders. It is available, under the tradename Sinequan®, as 10-, 25-, 50-, 75-, 100-, and 150 mg capsules and 10 mg/mL oral concentrate. In the current NDA, Somaxon proposes to market doxepin, under the tradename Silenor™, for treatment of insomnia. The product will be available as 1-, 3-, and 6 mg tablets. Silenor Tablets will be packaged in 30-, 100- and 500-count HDPE bottles, 4-count blister packs (physician sample), and 30-count blister packs.
Drug Substance: The active ingredient, Doxepin Hydrochloride, USP, [chemical name: 3- dibenz[b,e]oxepin- 11(6H)ylidene-N,N-dimethyl-1-propanamine hydrochloride] is a member of the tricyclic class of antidepressants. It is a well characterized small molecule with molecular formula C19H21O•HCl and molecular weight 315.84. Doxepin hydrochloride is readily soluble in water. The active moiety, doxepin, exists as an approximately mixture of E- and Zisomers. The relative amounts of the two geometric isomers are controlled through drug substance specification. The drug substance CMC information is referenced to DMF . The DMF was reviewed and found to be inadequate to support this NDA. Subsequently, the DMF holder provided adequate responses to the c

DESCRIPTION

SINEQUAN® (doxepin hydrochloride) is one of a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds. The molecular formula of the compound is C19H21NO•HCl having a molecular weight of 316. It is a white crystalline solid readily soluble in water, lower alcohols and chloroform.

Inert ingredients for the capsule formulations are: hard gelatin capsules (which may contain Blue 1, Red 3, Red 40, Yellow 10, and other inert ingredients); magnesium stearate; sodium lauryl sulfate; starch.

Inert ingredients for the oral concentrate formulation are: glycerin; methylparaben; peppermint oil; propylparaben; water.

Chemistry

SINEQUAN (doxepin HCl) is a dibenzoxepin derivative and is the first of a family of tricyclic psychotherapeutic agents. Specifically, it is an isomeric mixture of: 1-Propanamine, 3-dibenz[b,e]oxepin-11(6H)ylidene-N,N-dimethyl-, hydrochloride.

SINEQUAN® (doxepin HCl) Structural Formula Illustration

For Consumers

WHAT ARE THE POSSIBLE SIDE EFFECTS OF DOXEPIN (SINEQUAN) (SINEQUAN)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Synthesis Reference

Luigi Schioppi, Brian Talmadge Dorsey, Michael Skinner, John Carter, Robert Mansbach, Philip Jochelson, Roberta L. Rogowski, Cara Casseday, Meredith Perry, Bryan Knox, “LOW-DOSE DOXEPIN FORMULATIONS AND METHODS OF MAKING AND USING THE SAME.” U.S. Patent US20090074862, issued March 19, 2009.

US20090074862

File:Doxepin synthesis.png

DOI: 10.1007/BF00904459

DOI: 10.1007/BF00901313 US 3420851

DE 1232161

SYN 2

Synth Commun 1989, 19(19): 3349, US 3438981

 Doxepin hydrochloride pk_prod_list.xml_prod_list_card_pr?p_tsearch=A&p_id=91437

Condensation of dibenzo-oxepinone (I) with 3-(dimethylamino)propylmagnesium chloride (II), followed by a dehydration of the resultant tertiary alcohol with hot HCl gives the target 3-(dimethylamino)propylidene derivative.

SYN 3

 Doxepin hydrochloride pk_prod_list.xml_prod_list_card_pr?p_tsearch=A&p_id=91437

Chlorination of 2-(phenoxymethyl)benzoic acid (I) with SOCl2 at 50 °C gives 2-(phenoxymethyl)benzoyl chloride (II), which undergoes cyclization in the presence of FeCl3 in toluene to furnish dibenzo[b,e]oxepin-11-one (III)

Grignard reaction of intermediate (III) with tert-butyl 3-chloropropyl ether (IV) using Mg  in refluxing THF or Et2O  provides 11-(3-tert-butoxypropyl)-6,11-dihydrodibenzo[b,e]oxepin-11-ol (V), which upon elimination by means of HCl  in refluxing EtOH  affords alkene (VI).

Treatment of tert-butyl ether (VI) with SOCl2 in refluxing  toluene gives 11-(3-chloropropylidene)-6,11-dihydrodibenzo[b,e]oxepine (VII), which is then coupled with dimethylamine (VIII)  in the presence of Ni(OAc)2, PPh3 and K2CO3 in DMF  or in EtOH at 100 °C  to furnish doxepin (VII) .

Finally, treatment of tertiary amine (VII) with HCl at 140 °C yields the target doxepin hydrochloride .

US 2014309437, CN 102924424

Doxepin is a dibenzoxepin-derivative tricyclic antidepressant (TCA). Structurally similar to phenothiazines, TCAs contain a tricyclic ring system with an alkyl amine substituent on the central ring. In non-depressed individuals, doxepin does not affect mood or arousal, but may cause sedation. In depressed individuals, doxepin exerts a positive effect on mood. TCAs are potent inhibitors of serotonin and norepinephrine reuptake. Tertiary amine TCAs, such as doxepin and amitriptyline, are more potent inhibitors of serotonin reuptake than secondary amine TCAs, such as nortriptyline and desipramine. TCAs also down-regulate cerebral cortical β-adrenergic receptors and sensitize post-synaptic serotonergic receptors with chronic use. The antidepressant effects of TCAs are thought to be due to an overall increase in serotonergic neurotransmission. TCAs also block histamine H1 receptors, α1-adrenergic receptors and muscarinic receptors, which accounts for their sedative, hypotensive and anticholinergic effects (e.g. blurred vision, dry mouth, constipation, urinary retention), respectively. Doxepin has less sedative and anticholinergic effects than amitriptyline. See toxicity section below for a complete listing of side effects. When orally administered, doxepin may be used to treat depression and insomnia. Unlabeled indications of oral doxepin also include chronic and neuropathic pain, and anxiety. Doxepin may also be used as a second line agent to treat idiopathic urticaria. As a topical agent, doxepin may be used relieve itching in patients with certain types of eczema. It may be used for the management of moderate pruritus in adult patients with atopic dermatitis or lichen simplex chronicus

Doxepin is a tricyclic antidepressant (TCA) used as a pill to treat major depressive disorderanxiety disorders, chronic hives, and for short-term help with trouble remaining asleep after going to bed (a form of insomnia).[8][7][9] As a cream it is used for short term treatment of itchiness due to atopic dermatitis or lichen simplex chronicus.[10]

At doses used to treat depression, doxepin appears to inhibit the reuptake of serotonin and norepinephrine and to have antihistamineadrenergic and serotonin receptor antagonistic, and anticholinergic activities; at low doses used to treat insomnia it appears to be selective for the histamine H1 receptor.[11]

It was introduced under the brand names Quitaxon and Aponal by Boehringer, which discovered it, and as Sinequan by Pfizer,[12] and has subsequently been marketed under many other names worldwide.[2]

Medical uses

Doxepin is used as a pill to treat major depressive disorderanxiety disorders, chronic hives, and for short-term help with trouble remaining asleep after going to bed (a form of insomnia).[8][7][9] As a cream it is used for short term treatment of itchiness to due atopic dermatitis or lichen simplex chronicus.[10]

In 2016 the American College of Physicians advised that insomnia be treated first by treating comorbid conditions, then with cognitive behavioral therapy and behavioral changes, and then with drugs; doxepin was among those recommended for short term help maintaining sleep, on the basis of weak evidence.[13][14] The 2017 American Academy of Sleep Medicine recommendations focused on treatment with drugs were similar.[13] A 2015 AHRQ review of treatments for insomnia had similar findings.[15]

A 2010 review found that topical doxepin is useful to treat itchiness.[16]

A 2010 review of treatments for chronic hives found that doxepin had been superseded by better drugs but was still sometimes useful as a second line treatment.[17]

Chemistry

Doxepin is a tricyclic compound, specifically a dibenzoxepin, and possesses three rings fused together with a side chain attached in its chemical structure.[38] It is the only TCA with a dibenzoxepin ring system to have been marketed.[64] Doxepin is a tertiary amine TCA, with its side chaindemethylated metabolite nordoxepin being a secondary amine.[40][41] Other tertiary amine TCAs include amitriptylineimipramineclomipraminedosulepin (dothiepin), and trimipramine.[65][66] Doxepin is a mixture of (E) and (Z) stereoisomers (the latter being known as cidoxepin or cis-doxepin) and is used commercially in a ratio of approximately 85:15.[3][67] The chemical name of doxepin is (E/Z)-3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine[38][68] and its free base form has a chemical formula of C19H21NO with a molecular weight of 279.376 g/mol.[68] The drug is used commercially almost exclusively as the hydrochloride salt; the free base has been used rarely.[3][69] The CAS Registry Number of the free base is 1668-19-5 and of the hydrochloride is 1229-29-4.[3][69]

Image result for synthesis doxepin

Image result for synthesis doxepin

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https://www.sciencedirect.com/science/article/pii/S0040402007016079

Image result for synthesis doxepin

History

Doxepin was discovered in Germany in 1963 and was introduced in the United States as an antidepressant in 1969.[38] It was subsequently approved at very low doses in the United States for the treatment of insomnia in 2010.[44][69]

Society and culture

Generic names

Doxepin is the generic name of the drug in English and German and its INN and BAN, while doxepin hydrochloride is its USANUSPBANM, and JAN.[3][69][70][2] Its generic name in Spanish and Italian and its DCIT are doxepina, in French and its DCF are doxépine, and in Latin is doxepinum.[2]

The cis or (Z) stereoisomer of doxepin is known as cidoxepin, and this is its INN while cidoxepin hydrochloride is its USAN.[3]

Brand names

It was introduced under the brand names Quitaxon and Aponal by Boehringer and as Sinequan by Pfizer.[12]

As of October 2017, doxepin is marketed under many brand names worldwide: Adnor, Anten, Antidoxe, Colian, Dofu, Doneurin, Dospin, Doxal, Doxepini, Doxesom, Doxiderm, Flake, Gilex, Ichderm, Li Ke Ning, Mareen, Noctaderm, Oxpin, Patoderm, Prudoxin, Qualiquan, Quitaxon, Sagalon, Silenor, Sinepin, Sinequan, Sinequan, Sinquan, and Zonalon.[2] It is also marketed as a combination drug with levomenthol under the brand name Doxure.[2]

Approvals

The oral formulations of doxepin are FDA-approved for the treatment of depression and sleep-maintenance insomnia and its topical formulations are FDA-approved the short-term management for some itchy skin conditions.[71] Whereas in Australia and the United Kingdom, the only licensed indication(s) is/are in the treatment of major depression and pruritus in eczema, respectively.[20][72]

Research

Antihistamine

As of 2017 there was no good evidence that topical doxepin was useful to treat localized neuropathic pain.[73] Cidoxepin is under development by Elorac, Inc. for the treatment of chronic urticaria (hives).[74] As of 2017, it is in phase II clinical trials for this indication.[74] The drug was also under investigation for the treatment of allergic rhinitisatopic dermatitis, and contact dermatitis, but development for these indications was discontinued.[74]

Headache

Doxepin was under development by Winston Pharmaceuticals in an intranasal formulation for the treatment of headache.[75] As of August 2015, it was in phase II clinical trials for this indication.[75]

PATENT

https://patents.google.com/patent/US9486437B2/en

Doxepin:

Doxepin HCl is a tricyclic compound currently approved and available for treatment of depression and anxiety. Doxepin has the following structure:

Figure US09486437-20161108-C00001

For all compounds disclosed herein, unless otherwise indicated, where a carbon-carbon double bond is depicted, both the cis and trans stereoisomers, as well as mixtures thereof are encompassed.

Doxepin belongs to a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds, and is currently approved and prescribed for use as an antidepressant to treat depression and anxiety. Doxepin has a well-established safety profile, having been prescribed for over 35 years.

Doxepin, unlike most FDA approved products for the treatment of insomnia, is not a Schedule IV controlled substance. U.S. Pat. Nos. 5,502,047 and 6,211,229, the entire contents of which are incorporated herein by reference, describe the use of doxepin for the treatment chronic and non-chronic (e.g., transient/short term) insomnias at dosages far below those used to treat depression.

It is contemplated that doxepin for use in the methods described herein can be obtained from any suitable source or made by any suitable method. As mentioned, doxepin is approved and available in higher doses (75-300 milligrams) for the treatment of depression and anxiety. Doxepin HCl is available commercially and may be obtained in capsule form from a number of sources. Doxepin is marketed under the commercial name SINEQUAN® and in generic form, and can be obtained in the United States generally from pharmacies in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg dosage, and in liquid concentrate form at 10 mg/mL. Doxepin HCl can be obtained from Plantex Ltd. Chemical Industries (Hakadar Street, Industrial Zone, P.O. Box 160, Netanya 42101, Israel), Sifavitor S.p.A. (Via Livelli 1—Frazione, Mairano, Italy), or from Dipharma S.p.A. (20021 Baranzate di Bollate, Milano, Italy). Also, doxepin is commercially available from PharmacyRx (NZ) (2820 1st Avenue, Castlegar, B.C., Canada) in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg. Furthermore, Doxepin HCl is available in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg and in a 10 mg/ml liquid concentrate from CVS Online Pharmacy Store (CVS.com).

Also, doxepin can be prepared according to the method described in U.S. Pat. No. 3,438,981, which is incorporated herein by reference in its entirety. It should be noted and understood that although many of the embodiments described herein specifically refer to “doxepin,” other doxepin-related compounds can also be used, including, for example, pharmaceutically acceptable salts, prodrugs, metabolites, in-situ salts of doxepin formed after administration, and solid state forms, including polymorphs and hydrates.

Metabolites:

In addition, doxepin metabolites can be prepared and used. By way of illustration, some examples of metabolites of doxepin can include, but are not limited to, desmethyldoxepin, hydroxydoxepin, hydroxyl-N-desmethyldoxepin, doxepin N-oxide, N-acetyl-N-desmethyldoxepin, N-desmethyl-N-formyldoxepin, quaternary ammonium-linked glucuronide, 2-O-glucuronyldoxepin, didesmethyldoxepin, 3-O-glucuronyldoxepin, or N-acetyldidesmethyldoxepin. The metabolites of doxepin can be obtained or made by any suitable method, including the methods described above for doxepin.

Desmethyldoxepin has the following structure:

Figure US09486437-20161108-C00002

Desmethyldoxepin is commercially available as a forensic standard. For example, it can be obtained from Cambridge Isotope Laboratories, Inc. (50 Frontage Road, Andover, Mass.). Desmethyldoxepin for use in the methods discussed herein can be prepared by any suitable procedure. For example, desmethyldoxepin can be prepared from 3-methylaminopropyl triphenylphosphonium bromide hydrobromide and 6,11-dihydrodibenz(b,e)oxepin-11-one according to the method taught in U.S. Pat. No. 3,509,175, which is incorporated herein by reference in its entirety.

Hydroxydoxepin has the following structure:

Figure US09486437-20161108-C00003

2-Hydroxydoxepin can be prepared by any suitable method, including as taught by Shu et al. (Drug Metabolism and Disposition (1990) 18:735-741), which is incorporated herein by reference in its entirety.

Hydroxyl-N-desmethyldoxepin has the following structure:

Figure US09486437-20161108-C00004

2-Hydroxy-N-desmethyldoxepin can be prepared any suitable method.

Doxepin N-oxide has the following structure:

Figure US09486437-20161108-C00005

Doxepin N-oxide can be prepared by any suitable method. For example, doxepin N-oxide can be prepared as taught by Hobbs (Biochem Pharmacol (1969) 18:1941-1954), which is hereby incorporated by reference in its entirety.

N-acetyl-N-desmethyldoxepin has the following structure:

Figure US09486437-20161108-C00006

N-acetyl-N-desmethyldoxepin can be prepared by any suitable means. For example, (E)-N-acetyl-N-desmethyldoxepin has been produced in filamentous fungus incubated with doxepin as taught by Moody et al. (Drug Metabolism and Disposition (1999) 27:1157-1164), hereby incorporated by reference in its entirety.

N-desmethyl-N-formyldoxepin has the following structure:

Figure US09486437-20161108-C00007

N-desmethyl-N-formyldoxepin can be prepared by any suitable means. For example, (E)-N-desmethyl-N-formyldoxepin has been produced in filamentous fungus incubated with doxepin as taught by Moody et al. (Drug Metabolism and Disposition (1999) 27:1157-1164), hereby incorporated by reference in its entirety.

N-acetyldidesmethyldoxepin has the following structure:

Figure US09486437-20161108-C00008

N-acetyldidesmethyldoxepin can be prepared by any suitable means. For example, (E)-N-acetyldidesmethyldoxepin has been produced in filamentous fungus incubated with doxepin as taught by Moody et al. (Drug Metabolism and Disposition (1999) 27:1157-1164), hereby incorporated by reference in its entirety.

Didesmethyldoxepin has the following structure:

Figure US09486437-20161108-C00009

Didesmethyldoxepin can be prepared by any suitable means. For example, (Z)- and (E)-didesmethyldoxepin have been isolated from plasma and cerebrospinal fluid of depressed patients taking doxepin, as taught by Deuschle et al. (Psychopharmacology (1997) 131:19-22), hereby incorporated by reference in its entirety.

3-O-glucuronyldoxepin has the following structure:

Figure US09486437-20161108-C00010

3-O-glucuronyldoxepin can be prepared by any suitable means. For example, (E)-3-O-glucuronyldoxepin has been isolated from the bile of rats given doxepin, as described by Shu et al. (Drug Metabolism and Disposition (1990) 18:1096-1099), hereby incorporated by reference in its entirety.

2-O-glucuronyldoxepin has the following structure:

Figure US09486437-20161108-C00011

2-O-glucuronyldoxepin can be prepared by any suitable means. For example, (E)-2-O-glucuronyldoxepin has been isolated from the bile of rats given doxepin, and also in the urine of humans given doxepin, as described by Shu et al. (Drug Metabolism and Disposition (1990) 18:1096-1099), hereby incorporated by reference in its entirety.

Quaternary ammonium-linked glucuronide of doxepin (doxepin N+-glucuronide) has the following structure:

Figure US09486437-20161108-C00012

N+-glucuronide can be obtained by any suitable means. For example, doxepin N+-glucuronide can be prepared as taught by Luo et al. (Drug Metabolism and Disposition, (1991) 19:722-724), hereby incorporated by reference in its entirety.

PATENT

https://patents.google.com/patent/CN105330638A/en

 doxepin hydrochloride, the chemical name is N, N- dimethyl-3-dibenzo (b, e) _ oxepin -11 (6H) -1-propanamine salt subunit cistron iso the mixture body configuration. CAS Number 1229-29-4 thereof, of the formula

[0003]

Figure CN105330638AD00061

[0004] Doxepin hydrochloride is a drug for the treatment of depression and anxiety neurosis that act to inhibit the central nervous system serotonin and norepinephrine reuptake, such that these two synaptic cleft neurotransmitter concentration increased and antidepressant effect, but also has anti-anxiety and sedative effects. Doxepin hydrochloride oral absorption, bioavailability of 13-45%, half-life (Shu 1/2) is 8-12 hours, to apparent volume of distribution (1) ^ 9-33171.Primarily metabolized in the liver to active metabolites thereof demethylation.Metabolite excretion from the kidney, elderly patients decline of metabolism and excretion ability of this product

[0005] Chinese Patent CN102924486A discloses a method for preparing a hydrochloride of doxepin. The method comprises the coupling reaction CN, i.e., the use of Ni (0Α〇) 2 / ΡΡ1 ^ φ to the amine-based compound. Although Ni catalyst the reaction step (OAc) 2 is more readily available and inexpensive, but the low yield of this step, and low product purity.

SUMMARY

[0006] Accordingly, the present invention provides a method of o-toluic acid synthesized multi doxepin hydrochloride, the higher the yield and purity of the obtained product was purified by this method.

[0007] – o-methylbenzoate method for the synthesis of doxepin hydrochloride, comprising the steps of:

[0008] (1) o-methylbenzoic acid with N- halosuccinimide benzylation halogenation reaction occurs in an acetonitrile solvent in the light conditions, to give o-halo-methylbenzoic acid (Compound J), the following reaction formula,

[0009]

Figure CN105330638AD00071

[0010] (2) Compound J celite load cesium fluoride intramolecular substitution reaction, to give phthalide (Compound H) in an acetonitrile solvent and as a catalyst, the following reaction formula,

[0011]

Figure CN105330638AD00072

[0012] (3) The phenol compound J with sodium methoxide in an alcohol solvent substitution reaction, to give a compound I, the following reaction formula,

[0013]

Figure CN105330638AD00073

[0014] (4) The cyclization reaction of Compound I in a solvent in the catalytic DMS0 anhydrous aluminum chloride to give 6, 11-dihydro-dibenzo [b, e] oxepin -11- one (compound A), the following reaction formula,

[0015]

Figure CN105330638AD00074

[0016] (5) 6, 11-dihydro-dibenzo [b, e] oxepin-11-one (Compound A) and 3-chloropropyl alkyl tert-butyl ether (compound B) is added magnesium powder and with THF and / or a nucleophilic addition of anhydrous diethyl ether under the conditions of the reaction solvent to give the hydroxy compound (compound C), the following reaction formula,

[0017]

Figure CN105330638AD00081

[0018] (6) heating elimination reaction to give an olefin compound (Compound D) in a strong base in an alcoholic solvent to the hydroxy compound, the following reaction formula,

[0019]

Figure CN105330638AD00082

[0020] (7) to the olefinic compound in the nucleophilic substitution reaction of a hydrogen halide acid, to give halide (Compound E), the following reaction formula,

Figure CN105330638AD00083

[0022] wherein the compound E X is a C1, Br, or a a I;

[0023] (8) the halide with dimethylamine in a solvent under an organic lithium compound is added in ether to nucleophilic substitution reaction to yield doxepin (Compound F.), The following reaction formula,

[0024]

Figure CN105330638AD00091

[0025] (9) the doxepin neutralization reaction with hydrochloric acid to give sulfasalazine (Compound G), the following reaction formula,

Figure CN105330638AD00092

Example 1

[0043] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 10 ° C, under stirring for 4h. A known separation method, separation of o-bromomethyl-benzoic acid. This compound is named J.

[0044] placed in a 20L reaction container, Compound J, diatomaceous earth in an amount of 0.05 to load cesium fluoride (compound J as a mass basis), acetonitrile in an amount of 2.5 (in Compound J 1 is a mass basis), and the temperature was adjusted to 30 ° C, with stirring under reflux for 20h adjustment. Then, a known means for separating the reaction phthalide.

After [0045] placed in a 20L reaction vessel phthalide, 3 an amount of sodium methoxide in ethanol solvent (total mass of phenol phthalide and 1 meter), the reaction solution temperature adjusted to 50 ° C, was added dropwise start phenol was 1.05 mass (in mass was 1 meter phthalide), dropwise over lh. After the dropwise addition, the reaction temperature after 5h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.

[0046] The above compound I, in an amount of 10% anhydrous aluminum chloride (mass of Compound I was 100% basis), the amount of DMS0 3 (mass basis Compound I 1) into a reaction vessel , the temperature was adjusted to 95 ° C. The reaction time is to be 12h. Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.

[0047] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.1-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2 times the mass 6, 11-dihydro-dibenzo [b, e] oxepin-11-one magnesium in , taking all of fifths THF (5 to 6 times by mass, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) and heated to 35 ° C and allowed to react. After the reaction started, the remaining 3/5 of THF was added dropwise.Was added dropwise to the system to be completed into hydrogen, reflux. After a total reaction 5h, the reaction was stopped. After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.

[0048] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 1.5 times the mass of hydroxy compound class of sodium hydroxide (concentration l〇wt mass%), was heated to 65 ° C, 2h elimination reaction after the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.

[0049] placed in a 20L reaction vessel of the olefin compound, in an aqueous solution plus 1 times the mass of the olefinic compound hydrochloride (concentration of 5wt%), and heated to 50 ° C, so that a nucleophilic substitution reaction . The reaction time is to be after 4h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.

[0050] placed in a 20L reaction vessel above halide, 0.1 times the mass of methyl lithium halides to 2 times the mass of the halide in diethyl ether, heated to 40 ° C, so that the nucleophilic substitution reaction. The reaction time is to be after 5h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.

[0051] 20L is placed in a pressure reactor above doxepin, 1.05 times the mass of material in the doxepin hydrochloride (concentration of 30wt%), the control pressure to 3 ~ 4MPa, and heated to 130 ° C , and among the responses. Time after to be reacted for 20 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. In this embodiment overall yield 37.9%, measured by HPLC obtaining 99.2% purity.

[0052] Example 2

[0053] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 20 ° C, under stirring for 2h. A known separation method, separation of o-toluic acid halide.

[0054] placed in a 20L reaction container, Compound J, an amount of load of cesium fluoride Celite ~ 0.05 0.15 (in mass Compound J is 1 meter), in an amount of 2.5 to 8 acetonitrile (compound J as a mass basis), and the temperature was adjusted to 30 ~ 50 ° C, 12 ~ 20h at reflux with stirring under regulation. Then, a known means for separating the reaction phthalide.

After [0055] phthalide placed in 20L reaction vessel, an amount of sodium methoxide in 10 ethanol solvent (total mass of phenol phthalide and 1 meter), adjusting the temperature of the reaction solution was 60 ° C, was added dropwise start phenol was 1.15 mass (in mass was 1 meter phthalide), dropwise over lh.After the dropwise addition, the reaction temperature after 5h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.

[0056] The above compound I, in an amount of 40% anhydrous aluminum chloride (mass of Compound I was 100% basis), in an amount of DMS0 8 (in compound I is a mass basis) into a reaction vessel , the temperature was adjusted to 105 ° C. The reaction time is to be for 6h. Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.

[0057] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.5-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2.4 times the mass in 6, 11-dihydro-dibenzo [b, e] oxepin-11-one of magnesium, taking all fifths THF (5 to 7 times the mass in 6, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) is to make, and heated to 40 ° C reaction.After the reaction started, the remaining 3/5 of THF was added dropwise. Was added dropwise to the system to be completed into hydrogen, reflux. When the total reaction 2h, the reaction was stopped. After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.

[0058] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 5 times the mass of hydroxy compound class of sodium hydroxide (concentration of 70wt%), was heated to 80 ° C, the reaction was stopped after the elimination reaction LH, cooling, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.

[0059] placed in a 20L reaction vessel of the olefin compound, in an aqueous solution of 2 times the mass of the olefinic compound added hydrobromic acid (concentration of 30wt%), and heated to 60 ° C, so that nucleophilic Substitution reaction. The reaction time is to be after the 1. 5h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.

[0060] placed in a 20L reaction vessel above halide, 0.8 times the mass of phenyl lithium halide to 8 times the mass of the halide in diethyl ether, heated to 50 ° C, so that the nucleophilic substitution reaction. The reaction time is to be after 2h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.

[0061] 20L is placed in a pressure reactor above doxepin, 1.2 times the mass of material in the doxepin hydrochloride (concentration of 38wt%), the control pressure to 3 ~ 4MPa, and heated to 150 ° C , and among the responses. Time after to be reacted for 16 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. In this embodiment overall yield 39.7%, measured by HPLC obtaining 99.4% purity.

[0062] Example 3

[0063] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 15 ° C, under stirring for 3h. A known separation method, separation of o-bromomethyl-benzoic acid.

[0064] placed in a 20L reaction container, Compound J, an amount of load of cesium fluoride Celite ~ 0.05 0.15 (in mass Compound J is 1 meter), in an amount of 2.5 to 8 acetonitrile (compound J as a mass basis), and the temperature was adjusted to 30 ~ 50 ° C, 12 ~ 20h at reflux with stirring under regulation. Then, a known means for separating the reaction phthalide.

After [0065] phthalide placed in 20L reaction vessel, an amount of sodium methoxide in ethanol solvent 6 (total mass of phenol phthalide and 1 meter), adjusting the temperature of the reaction solution was 55 ° C, was added dropwise start phenol was 1.10 mass (in mass was 1 meter phthalide), dropwise over lh.After the dropwise addition, the reaction temperature after 3. 5h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.

[0066] Anhydrous aluminum above compound I, in an amount of 25% of the chloride (compound I mass is 100% basis), in an amount of DMS0 6. 5 (in compound I is a mass basis) into the reaction vessel temperature is adjusted to 100 ° C. The reaction time is to be 9h. Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.

[0067] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.3-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2.2 times the mass in 6, 11-dihydro-dibenzo [b, e] oxepin-11-one of magnesium, taking all fifths THF (5 to 7 times the mass in 6, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) is to make, and heated to 38 ° C reaction.After the reaction started, the remaining 3/5 of THF was added dropwise. Was added dropwise to the system to be completed into hydrogen, refluxed for 2h. After a total reaction 3. 5h, the reaction was stopped. After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.

[0068] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 3-hydroxysteroid times the mass of the compound of sodium hydroxide (concentration of 40wt%), and heated to 75 ° C, 1. 5h the reaction stopped after elimination the reaction was cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.

[0069] placed in a 20L reaction vessel of the olefin compound, an aqueous solution of 1.5-fold increase in the mass of hydroiodic olefinic compounds (concentration of 18wt%), was heated to 55 ° C, so nucleophilic substitution reaction. The reaction time is to be after 2h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.

[0070] placed in a 20L reaction vessel above halide, 0.4 times the mass of the halide in n-butyllithium, in diethyl ether five times the mass of halide and heated to 45 ° C, so that a nucleophilic substitution reaction . The reaction time is to be 3. After 5h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.

[0071] 20L is placed in a pressure reactor above doxepin, 1.12 times the mass of material in the doxepin hydrochloride (concentration of 34wt%), the control pressure to 3 ~ 4MPa, and heated to 140 ° C , and among the responses. Time after to be reacted for 18 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. In this embodiment overall yield 40.2%, measured by HPLC obtaining 99.5% purity.

[0072] Example 4

[0073] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 15 ° C, under stirring for 4h. A known separation method, separation of o-toluic acid halide.

[0074] placed in a 20L reaction container, Compound J, an amount of load of cesium fluoride Celite ~ 0.05 0.15 (in mass Compound J is 1 meter), in an amount of 2.5 to 8 acetonitrile (compound J as a mass basis), and the temperature was adjusted to 30 ~ 50 ° C, 12 ~ 20h at reflux with stirring under regulation. Then, a known means for separating the reaction phthalide.

After [0075] phthalide placed in 20L reaction vessel, 5 an amount of sodium methoxide in ethanol solvent (total mass of phenol phthalide and 1 meter), adjusting the temperature of the reaction solution was 55 ° C, was added dropwise start phenol was 1.15 mass (in mass was 1 meter phthalide), dropwise over lh.After the dropwise addition, the reaction temperature after 5h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.

[0076] The above compound I, in an amount of 25% anhydrous aluminum chloride (mass of Compound I was 100% basis), in an amount of DMS0 8 (in compound I is a mass basis) into a reaction vessel , the temperature was adjusted to 100 ° C. The reaction time is to be 12h. Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.

[0077] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.3-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2.4 times the mass in 6, 11-dihydro-dibenzo [b, e] oxepin-11-one of magnesium, taking all fifths THF (5 to 7 times the mass in 6, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) is to make, and heated to 40 ° C reaction.After the reaction started, the remaining 3/5 of THF was added dropwise. Was added dropwise to the system to be completed into hydrogen, reflux. When the total reaction 2h, the reaction was stopped. After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.

[0078] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 5 times the mass of hydroxy compound class of sodium hydroxide (concentration of 70wt%), was heated to 80 ° C, the reaction was stopped after the elimination reaction LH, cooling, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.

[0079] placed in a 20L reaction vessel of the olefin compound, an aqueous solution of 1.5-fold increase in the mass of hydroiodic olefinic compounds (concentration of 30wt%), and heated to 60 ° C, so nucleophilic substitution reaction. The reaction time is to be after the 1. 5h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.

[0080] placed in a 20L reaction vessel above halide, 0.8 times in mass n-butyl lithium halide, eight times the mass of the halide in diethyl ether, heated to 50 ° C, so that a nucleophilic substitution reaction . The reaction time is to be after 2h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.

[0081] 20L is placed in a pressure reactor above doxepin, 1.2 times the mass of material in the doxepin hydrochloride (concentration of 38wt%), the control pressure to 3 ~ 4MPa, and heated to 150 ° C , and among the responses. Time after to be reacted for 16 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. In this embodiment overall yield 41.6%, measured by HPLC obtaining 99.7% purity.

[0082] Example 5

[0083] placed in a 20L reaction vessel acetonitrile, o-methylbenzoic acid, N- bromosuccinimide, using a water bath temperature controlled at 15 ° C, the reaction 2. 5h under stirring. A known separation method, separation of o-bromomethyl-benzoic acid.

[0084] placed in a 20L reaction vessel o-bromomethyl benzoic acid, diatomaceous earth in an amount of load of cesium fluoride 0.05 ~ 0.15 (in mass Compound J is 1 meter), in an amount of 2. 5-8 acetonitrile (compound J as a mass basis), and the temperature was adjusted to 30 ~ 50 ° C, 12 ~ 20h at reflux with stirring under regulation. Then, a known means for separating the reaction phthalide.

After [0085] phthalide placed in 20L reaction vessel, 5 an amount of sodium methoxide in ethanol solvent (total mass of phenol phthalide and 1 meter), adjusting the temperature of the reaction solution was 55 ° C, was added dropwise start was 1.08 mass of phenol (mass was phthalide 1 meter), dropwise over lh.After the dropwise addition, the reaction temperature after 3h using known separation methods, to give o-methyl benzyl phenyl ether, this compound is named I.

[0086] Anhydrous aluminum above compound I, in an amount of 25% of the chloride (compound I mass is 100% basis), in an amount of DMS0 5 (in compound I is a mass basis) into a reaction vessel , the temperature was adjusted to 100 ° C.The reaction time is to be 8h. Using known separation means for separating the 6, 11-dihydro-dibenzo [b, e] oxepin-11-one.

[0087] placement 6, 11-dihydro-dibenzo in a reaction vessel and 20L [b, e] oxepin-11-one, 1.2-dihydro-fold of the mole of diphenyl at 6, 11 and [ b, e] oxepin-11-one 3-chloropropyl alkyl tert-butyl ether, 2.2 times the mass in 6, 11-dihydro-dibenzo [b, e] oxepin-11-one of magnesium, taking all fifths THF (5 to 7 times the mass in 6, 11-dihydro-dibenzo [b, e] THF oxepin-11-one) is to make, and heated to 38 ° C reaction.After the reaction started, the remaining 3/5 of THF was added dropwise. Was added dropwise to the system to be completed into hydrogen, reflux. When the total reaction 2h, the reaction was stopped. After the system was cooled and then poured into saturated ammonium chloride solution, extracted twice with ethyl acetate was added, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to give hydroxy compound.

[0088] placed in a 20L reaction vessel above hydroxy compound, an ethanol solution of 2 times the mass of hydroxy compound class of sodium hydroxide (concentration of 40wt%), was heated to 70 ° C, the reaction was stopped after the elimination reaction 2h, cooling, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the olefinic compounds.

[0089] placed in a 20L reaction vessel of the olefin compound, an aqueous solution of 1.5-fold increase in the mass of hydroiodic olefinic compounds (concentration of 15wt%), and heated to 50 ° C, so nucleophilic substitution reaction. The reaction time is to be after 4h, the reaction was stopped, cooled, the solvent was distilled off more of the obtained crude product was crystallized from acetonitrile to give the halides.

[0090] placed in a 20L reaction vessel above halide, 0.4 times the mass of the halide in n-butyl lithium, 2 to 8 times the mass of the halide in diethyl ether, heated to 45 ° C, so that nucleophilic Substitution reaction. The reaction time is to be after 3h, the reaction was stopped, reaction was complete and extracted with ethylacetate three times, dried over anhydrous sodium sulfate 5h, the resulting crude product was recrystallized from acetonitrile to obtain doxepin.

[0091] 20L is placed in a pressure reactor above doxepin, 1.12 times the mass of material in the doxepin hydrochloride (mass concentration 37. 6wt%), the control pressure to 3 ~ 4MPa, heated to 140 ° C, allowing the reaction among. Time after to be reacted for 20 h, cooled to room temperature and should be finished by filtration, and dried to give doxepin hydrochloride. In this embodiment overall yield 43.9%, measured by HPLC obtaining 99.9% purity.

PATENTS

CN102924424A *2012-09-042013-02-13苏州弘森药业有限公司Method for synthesizing doxepin hydrochloride
CN105061386A *2015-08-172015-11-18苏州黄河制药有限公司Method for synthesizing doxepin hydrochloride by utilizing phthalic anhydride as raw material
Doxepin
Doxepin2DACS.svg
Doxepin-3RZE-2011-ball-and-stick.png
Clinical data
Trade names Sinequan, many others[2]
Synonyms NSC-108160[3]
AHFS/Drugs.com Monograph
MedlinePlus a682390
License data
Pregnancy
category
  • AU: C
  • US: B (No risk in non-human studies)
Routes of
administration
By mouthtopicalintravenousintramuscular injection[1]
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 13–45% (mean 29%)[5][6]
Protein binding 76%[7]
Metabolism Hepatic (CYP2D6CYP2C19)[4][5]
Metabolites Nordoxepin, glucuronide conjugates[4]
Elimination half-life Doxepin: 8–24 hours (mean 17 hours)[7]
Nordoxepin: 31 hours[7]
Excretion Urine: ~50%[4][5]
Feces: minor[5]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C19H21NO
Molar mass 279.376 g/mol
3D model (JSmol)
  1. Virtanen R, Iisalo E, Irjala K: Protein binding of doxepin and desmethyldoxepin. Acta Pharmacol Toxicol (Copenh). 1982 Aug;51(2):159-64. [PubMed:7113722]
  2. Virtanen R, Scheinin M, Iisalo E: Single dose pharmacokinetics of doxepin in healthy volunteers. Acta Pharmacol Toxicol (Copenh). 1980 Nov;47(5):371-6. [PubMed:7293791]
  3. Negro-Alvarez JM, Carreno-Rojo A, Funes-Vera E, Garcia-Canovas A, Abellan-Aleman AF, Rubio del Barrio R: Pharmacologic therapy for urticaria. Allergol Immunopathol (Madr). 1997 Jan-Feb;25(1):36-51. [PubMed:9111875]
  4. Sansone RA, Sansone LA: Pain, pain, go away: antidepressants and pain management. Psychiatry (Edgmont). 2008 Dec;5(12):16-9. [PubMed:19724772]
  5. Kirchheiner J, Meineke I, Muller G, Roots I, Brockmoller J: Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers. Pharmacogenetics. 2002 Oct;12(7):571-80. [PubMed:12360109]
  6. ZONALON® (doxepin hydrochloride) CREAM, 5% [Link]
  7. FDA Label: SilenorTM (doxepin) tablets for oral administration [Link]

//////////////Doxepin, ドキセピン , NSC-108160  , P-3693A  , SO-101

[H]C(CCN(C)C)=C1C2=CC=CC=C2COC2=CC=CC=C12

Doxepin Hydrochloride
usp32nf27s0_m28120
Click to View Image

C19H21NO·HCl 315.84

1-Propanamine, 3-dibenz[b,e]oxepin-11(6H)ylidene-N,N-dimethyl-, hydrochloride.
N,N-Dimethyldibenz[b,e]oxepin-D11(6H),-propylamine hydrochloride [1229-29-4; 4698-39-9 ((E)-isomer); 25127-31-5 ((Z)-isomer)].
» Doxepin Hydrochloride, an (E) and (Z) geometric isomer mixture, contains the equivalent of not less than 98.0 percent and not more than 102.0 percent of doxepin (C19H21NO·HCl), calculated on the dried basis. It contains not less than 13.6 percent and not more than 18.1 percent of the (Z)-isomer, and not less than 81.4 percent and not more than 88.2 percent of the (E)-isomer.
Packaging and storage— Preserve in well-closed containers.

Identification—

B: The retention time of the major peak in the chromatogram of the Assay preparation corresponds that in the chromatogram of the Standard preparation, as obtained in the Assay.
C: A solution (1 in 100) in a mixture of water and alcohol (1:1) meets the requirements of the test for Chloride 191 in amine hydrochlorides.
Loss on drying 731 Dry it in vacuum at 60 for 3 hours: it loses not more than 0.5% of its weight.
Residue on ignition 281: not more than 0.2%.
Heavy metals, Method II 231: 0.002%.

Related compounds—

Diluted phosphoric acid— Prepare a mixture of water and phosphoric acid (10:1), and mix well.
Buffer— Dissolve 1.42 g of dibasic sodium phosphate in 1 L of water, adjust with Diluted phosphoric acid to a pH of 7.7, and mix.
Mobile phase— Prepare a filtered and degassed mixture of methanol, Buffer, and acetonitrile (50:30:20). Make adjustments if necessary (see System Suitabilityunder Chromatography 621).
Diluent— Prepare a mixture of Mobile phase and 2 N sodium hydroxide (1000:2).
Standard solution— Dissolve accurately weighed quantities of USP Doxepin Hydrochloride RSUSP Doxepin Related Compound A RSUSP Doxepin Related Compound B RS, and USP Doxepin Related Compound C RS in Diluent to obtain a solution having a known concentration of about 0.001 mg of doxepin hydrochloride, doxepin related compound A, and doxepin related compound B each per mL, and 0.002 mg per mL of doxepin related compound C. [NOTE—Sonication for about 1 minute may be used to aid the initial dissolution of the compounds.]
Test solution— Dissolve an accurately weighed quantity of Doxepin Hydrochloride in Diluent to obtain a final solution having a known concentration of about 1 mg per mL.

Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a 215-nm detector and a 4.6-mm × 25-cm column that contains 5-µm packing L1. The flow rate is about 1 mL per minute. The column temperature is maintained at 30. Chromatograph about 20 µL of the Standard solution, and record the peak areas as directed for Procedure: the resolution, R, between doxepin related compound A and doxepin related compound C is not less than 1.5; the resolution between doxepin related compound C and doxepin related compound B is not less than 1.5; and the signal-to-noise ratio for all the peaks is not less than 10. [NOTE—Use the approximate relative retention times given in Table 1 for the purpose of peak identification. The doxepin related compound C peak will be the largest peak in the Standard solution chromatogram.]

Table 1
Name Relative
Retention
Time
(RRT)
Limit (%)
Doxepin related compound A 0.48 0.10
Doxepin related compound C 0.55 0.20
Doxepin related compound B 0.63 0.10
Doxepin hydrochloride 1.0
Unknown impurity 0.10 each

Procedure— Inject a volume (about 20 µL) of the Test solution into the chromatograph, record the chromatogram for up to 2.2 times the retention time of doxepin, and measure the peak responses. Calculate the percentage of each individual doxepin related compound in the portion of Doxepin Hydrochloride taken by the formula:

100(rU / rS)(CS / CT)

in which rU is the individual peak response for each doxepin related compound obtained from the Test solution; rS is the response of the corresponding peak in theStandard solution; CS is the concentration, in mg per mL, of each doxepin related compound in the Standard solution; and CT is the concentration, in mg per mL, of Doxepin Hydrochloride in the Test solution. The related substance limits are listed in Table 1[NOTE—Discard any peak with a relative retention time less than 0.25. This method is not intended to resolve the E- and Z-isomers of doxepin hydrochloride. Minor variations in the mobile phase composition could result in a shoulder in the trailing edge of doxepin. In cases where there may be separation, both the E- and Z-isomers should be used in the appropriate calculations.] Use the response of the doxepin peak obtained from the Standard solution and the concentration of doxepin hydrochloride in the Standard solution to calculate the percentage of unknown individual impurities.

Assay—

Mobile phase— Prepare a mixture of 0.2 M monobasic sodium phosphate buffer and methanol (7:3), adjust with 2 N phosphoric acid to a pH of 2.5, filter, and degas. Make adjustments if necessary (see System Suitability under Chromatography 621).
Standard preparation— Dissolve an accurately weighed quantity of USP Doxepin Hydrochloride RS in Mobile phase, and dilute quantitatively and stepwise with Mobile phase to obtain a solution having a known concentration of about 100 µg per mL.
Assay preparation— Transfer about 50 mg of Doxepin Hydrochloride, accurately weighed, to a 100-mL volumetric flask. Add about 70 mL of Mobile phase, and sonicate to dissolve. Dilute with Mobile phase to volume, and mix. Pipet 10.0 mL of this solution into a 50-mL volumetric flask, and dilute with Mobile phase to volume.
Chromatographic system— The liquid chromatograph is equipped with a 254-nm detector and a 4-mm × 12.5-cm column, heated to 50, that contains packing L7. The flow rate is about 1 mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed under Procedure: the resolution between the (E)- and (Z)-isomers is not less than 1.5, the tailing factor for each analyte peak is not more than 2.0, and the relative standard deviation for replicate injections is not more than 2.0%.

Procedure— Separately inject equal volumes (about 20 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of C19H21NO·HCl in the portion of Doxepin Hydrochloride taken by the formula:

0.5C[(rU(Z) + rU(E)) / (rS(Z) + rS(E))]

in which C is the concentration, in µg per mL, of USP Doxepin Hydrochloride RS in the Standard preparation, and rU(Z) and rU(E) are the respective peak responses of the (Z)- and (E)-isomers obtained from the Assay preparation, and rS(Z) and rS(E) are the respective peak responses of the (Z)- and (E)-isomers obtained from the Standard preparation. Calculate the percentage of the (Z)-isomer in the Assay preparation taken by the formula:

(rU(Z) / rS(Z))(WS / WT)(PZ)

in which WS is the weight, in mg, of USP Doxepin Hydrochloride RS in the Standard preparationWT is the weight, in mg, in the portion of Doxepin Hydrochloride taken, and PZ is the labeled percentage of (Z)-isomer in USP Doxepin Hydrochloride RS. Similarly calculate the percentage of (E)-isomer in the Assay preparationtaken by the formula:

(rU(E) / rS(E))(WS / WT)(PE)

in which PE is the labeled percentage of (E)-isomer in USP Doxepin Hydrochloride RS.

Auxiliary Information— Please check for your question in the FAQs before contacting USP.

Topic/Question Contact Expert Committee
Monograph Ravi Ravichandran, Ph.D.
Senior Scientist
1-301-816-8330
(MDPP05) Monograph Development-Psychiatrics and Psychoactives
Reference Standards Lili Wang, Technical Services Scientist
1-301-816-8129
RSTech@usp.org
USP32–NF27 Page 2206

Pharmacopeial Forum: Volume No. 32(2) Page 330

Chromatographic Column—

Chromatographic columns text is not derived from, and not part of, USP 32 or NF 27.

ONC201 disrupts mitochondrial function and kills breast cancer cells, reveals study — Med-Chemist


TRAIL, a member of the TNF family of ligands, causes caspase-dependent apoptosis through activation of its receptors, death receptor 4 and DR5.ONC201 was originally identified as a small molecule that inhibits both Akt and ERK, resulting in dephosphorylation of Foxo3a and thereby induces TRAIL transcription.Recently, two independent groups, Wafik El Deiry at Fox Chase and…

via ONC201 disrupts mitochondrial function and kills breast cancer cells, reveals study — Med-Chemist

FDA approves new treatment Xeljanz (tofacitinib) for moderately to severely active ulcerative colitis


The U.S. Food and Drug Administration today expanded the approval of Xeljanz (tofacitinib) to include adults with moderately to severely active ulcerative colitis. Xeljanz is the first oral medication approved for chronic use in this indication. Other FDA-approved treatments for the chronic treatment of moderately to severely active ulcerative colitis must be administered through an intravenous infusion or subcutaneous injection.

May 30, 2018

Release

The U.S. Food and Drug Administration today expanded the approval of Xeljanz (tofacitinib) to include adults with moderately to severely active ulcerative colitis. Xeljanz is the first oral medication approved for chronic use in this indication. Other FDA-approved treatments for the chronic treatment of moderately to severely active ulcerative colitis must be administered through an intravenous infusion or subcutaneous injection.

“New treatments are needed for patients with moderately to severely active ulcerative colitis,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research. “Today’s approval provides an alternative therapy for a debilitating disease with limited treatment options.”

Ulcerative colitis is a chronic, inflammatory bowel disease affecting the colon. Patients experience recurrent flares of abdominal pain and bloody diarrhea. Other symptoms include fatigue, weight loss and fever. More than 900,000 patients are affected in the U.S., many of them experiencing moderately to severely active ulcerative colitis, and there is currently no cure.

The efficacy of Xeljanz for the treatment of moderately to severely active ulcerative colitis was demonstrated in three controlled clinical trials. This included two 8-week placebo-controlled trials that demonstrated that 10 mg of Xeljanz given twice daily induces remission in 17 to 18 percent of patients by week eight. In a placebo-controlled trial among patients who achieved a clinical response by week eight, Xeljanz, at a 5 mg or 10 mg dose given twice daily, was effective in inducing remission by week 52 in 34 percent and 41 percent of patients, respectively. Among patients who achieved remission after 8 weeks of treatment, 35 percent and 47 percent achieved sustained corticosteroid-free remission when treated with 5 mg and 10 mg, respectively.

The safety of chronic use of Xeljanz for ulcerative colitis was studied in the 52-week placebo- controlled trial. Additional supportive safety information was collected from patients who received treatment in an open-label long-term study.

The most common adverse events associated with Xeljanz treatment for ulcerative colitis were diarrhea, elevated cholesterol levels, headache, herpes zoster (shingles), increased blood creatine phosphokinase, nasopharyngitis (common cold), rash and upper respiratory tract infection.

Less common serious adverse events included malignancy and serious infections such as opportunistic infections. Xeljanz has a boxed warning for serious infections and malignancy. Patients treated with Xeljanz are at increased risk for developing serious infections that may lead to hospitalization or death. Lymphoma and other malignancies have been observed in patients treated with Xeljanz.

Use of Xeljanz in combination with biological therapies for ulcerative colitis or with potent immunosuppressants, such as azathioprine and cyclosporine, is not recommended.

Xeljanz, made by Pfizer Labs, was previously approved in 2012 for rheumatoid arthritis and in 2017 for psoriatic arthritis.

/////////////Xeljanz, tofacitinib, pfizer, fda 2017, psoriatic arthritis, ulcerative colitis

Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite


STR4

SR1

SR2

Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.8b00565

Pronay Das†ab, Palak Babbar†c, Nipun Malhotra†c, Manmohan Sharmac , Goraknath R. Jachakab , Rajesh G. Gonnadebd, Dhanasekaran Shanmugambe, Karl Harlosf , Manickam Yogavelc , Amit Sharmac *, and D. Srinivasa Reddyab* †All three have contributed equally to this work.
aOrganic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
b Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India
cMolecular Medicine Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi 110067, India dCenter for Material Characterization, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
e Biochemical Sciences Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
fDivision of Structural Biology, Welcome Trust Centre for Human Genetics, The Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
J. Med. Chem., Just Accepted Manuscript
DOI: 10.1021/acs.jmedchem.8b00565
Publication Date (Web): May 21, 2018
Copyright © 2018 American Chemical Society
The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral centre anti-malarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme- and structure-based assays.
We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency where changes at C3 are sensed by rotameric flipping of Glutamate332.
Given that scores of anti-malarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of anti-microbial drug development.
Cladosporin (12) displays exquisite selectivity for the parasite lysyl-tRNA synthetase over human enzyme. This species specific selectivity of cladosporin has been previously described through comprehensive sequence alignment, where the residues val329 and ser346 seem to be sterically crucial for accommodating the methyl moiety of THP ring10. The structural features of compound 12 clearly indicate the presence of three stereocenters, and therefore 2n (n=3) i.e., eight stereoisomers are possible (Fig.1). Till date, only one asymmetric total synthesis of cladosporin13 has been achieved which was followed by another report of formal syntheses14. Here, we have developed a general chemical synthesis route to synthetically access all the eight possible stereoisomers of compound 12.
cladosporin (compound 12) (0.052 g) as a white solid with a yield of 54 %. Melting point: 171-173 °C; [α]25 D = -15.75 (c = 0.6, EtOH); IR υmax(film): cm-1 3416, 3022, 1656, 1218; 1H NMR (400 MHz, CDCl3): δ 11.06 (s, 1H), 7.47 (br. s., 1H), 6.29 (s, 1H), 6.16 (s, 1H), 4.68 (t, J = 9.8 Hz, 1H), 4.12 (s, 1H), 4.01 (s, 1H), 2.89 – 2.75 (m, 2H), 2.00 – 1.94 (m, 1H), 1.87 – 1.81 (m, 1H), 1.70 – 1.63 (m, 4H), 1.35 (d, J = 6.1 Hz, 2H), 1.23 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 169.9, 164.3, 163.1, 141.8, 106.7, 102.0, 101.5, 76.3, 68.0, 66.6, 39.3, 33.6, 30.9, 18.9, 18.1; HRMS calculated for C16H21O5 [M + H]+ 293.1384, observed 293.1379.
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Dr. D. Srinivasa Reddy has been appointed as an editor of Bioorganic & Medicinl Chemistry Letters, Elsevier Publications. Congratulation Sir !

Click here for details. https://www.journals.elsevier.com/bioorganic-and-medicinal-chemistry-letters

The research interests of his group lie in issues related to application of oriented organic synthesis, in particular total synthesis of biologically active natural products, medicinal chemistry and crop protection. This team has been credited with having accomplished total synthesis of more than 25 natural products with impressive biological activities. “Some of our recent achievements include identification of potential leads, like antibiotic compound based on hunanamycin natural product for treating food infections, anti-diabetic molecule in collaboration with an industry partner and  anti-TB compound using a strategy called ‘re-purposing of a drug scaffold’,” said Reddy.

A total of two awardees out of four were from CSIR institutes. In addition to Reddy, Rajan Shankarnarayanan, CSIR – CCMB, Hyderabad (basic sciences), also was conferred with the award. Vikram Mathews, CMC, Vellore (medical research) and Prof Ashish Suri, AIIMS, New Delhi (clinical research), were the others to receive the awards.

With more than 80 scientific publications and 35 patents, Reddy is one of the most prominent scientists in the city and has already been honoured with the Shanti Swarup Bhatnagar prize in chemical sciences. Reddy is also a nominated member of the scientific body of Indian Pharmacopoeia, government of India and was  elected as a fellow of the Telangana and Maharashtra Academies of Sciences in addition to the National Academy of Sciences, India (NASI).

//////////CLADOSPORIN, NCL, CSIR, SRINIVASA REDDY, PUNE, MALARIA

FDA Approves Tavalisse (fostamatinib disodium hexahydrate) for Chronic Immune Thrombocytopenia — Med-Chemist


Rigel Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) approved Tavalisse (fostamatinib disodium hexahydrate) for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. Tavalisse is an oral spleen tyrosine kinase (SYK) inhibitor that targets the underlying autoimmune cause of the…

via FDA Approves Tavalisse (fostamatinib disodium hexahydrate) for Chronic Immune Thrombocytopenia — Med-Chemist

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