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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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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 LIFE SCIENCES 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 PLUS year tenure till date June 2021, 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, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, 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 33 lakh plus views on New Drug Approvals Blog in 233 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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Tixagevimab


(Heavy chain)
QMQLVQSGPE VKKPGTSVKV SCKASGFTFM SSAVQWVRQA RGQRLEWIGW IVIGSGNTNY
AQKFQERVTI TRDMSTSTAY MELSSLRSED TAVYYCAAPY CSSISCNDGF DIWGQGTMVT
VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL
QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKR VEPKSCDKTH TCPPCPAPEF
EGGPSVFLFP PKPKDTLYIT REPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE
QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKALPASIEK TISKAKGQPR EPQVYTLPPS
REEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSKLTVDK
SRWQQGNVFS CSVMHEALHN HYTQKSLSLS PGK
(Light chain)
EIVLTQSPGT LSLSPGERAT LSCRASQSVS SSYLAWYQQK PGQAPRLLIY GASSRATGIP
DRFSGSGSGT DFTLTISRLE PEDFAVYYCQ HYGSSRGWTF GQGTKVEIKR TVAAPSVFIF
PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST
LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC
(Disulfide bridge: H22-H96, H101-H106, H150-H206, H216-L216, H232-H’232, H235-H’235, H267-H327, H373-H431, H’22-H’96, H’101-H’106, H’150-H’206, H’226-L’216, H’267-H’327, H’373-H’431, L23-L89, L136-L196, L’23-L’89, L’136-L’196)

Tixagevimab

FDA 2021, 2021/12/8

ANTI VIRAL, CORONA VIRUS, PEPTIDE

Monoclonal antibody
Treatment and prevention of SARS-CoV-2 infection

FormulaC6488H10034N1746O2038S50
CAS2420564-02-7
Mol weight146704.817
  • 2196
  • AZD-8895
  • AZD8895
  • COV2-2196
  • Tixagevimab
  • Tixagevimab [INN]
  • UNII-F0LZ415Z3B
  • WHO 11776
  • OriginatorVanderbilt University
  • DeveloperAstraZeneca; INSERM; National Institute of Allergy and Infectious Diseases
  • ClassAntivirals; Monoclonal antibodies
  • Mechanism of ActionVirus internalisation inhibitors
  • RegisteredCOVID 2019 infections
  • 24 Dec 2021Pharmacodynamics data from a preclinical trial in COVID-2019 infections released by AstraZeneca
  • 16 Dec 2021Pharmacodynamics data from a preclinical trial in COVID-2019 infections released by AstraZeneca
  • 10 Dec 2021Registered for COVID-2019 infections (In the elderly, Prevention, In adults) in USA (IM) – Emergency Use Authorization

Tixagevimab/cilgavimab is a combination of two human monoclonal antibodiestixagevimab (AZD8895) and cilgavimab (AZD1061) targeted against the surface spike protein of SARS-CoV-2[4][5] used to prevent COVID-19. It is being developed by British-Swedish multinational pharmaceutical and biotechnology company AstraZeneca.[6][7] It is co-packaged and given as two separate consecutive intramuscular injections (one injection per monoclonal antibody, given in immediate succession).[2]

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Development

In 2020, researchers at Vanderbilt University Medical Center discovered particularly potent monoclonal antibodies, isolated from COVID-19 patients infected with a SARS-CoV-2 circulating at that time. Initially designated COV2-2196 and COV2-2130, antibody engineering was used to transfer their SARS-CoV-2 binding specificity to IgG scaffolds that would last longer in the body, and these engineered antibodies were named AZD8895 and AZD1061, respectively (and the combination was called AZD7442).[8]

To evaluate the antibodies’ potential as monoclonal antibody based prophylaxis (prevention), the ‘Provent’ clinical trial enrolled 5,000 high risk but not yet infected individuals and monitored them for 15 months.[9][10] The trial reported that those receiving the cocktail showed a 77% reduction in symptomatic COVID-19 and that there were no severe cases or deaths. AstraZeneca also found that the antibody cocktail “neutralizes recent emergent SARS-CoV-2 viral variants, including the Delta variant“.[7]

In contrast to pre-exposure prophylaxis, the Storm Chaser study of already-exposed people (post-exposure prophylaxis) did not meet its primary endpoint, which was prevention of symptomatic COVID-19 in people already exposed. AZD7442 was administered to 1,000 volunteers who had recently been exposed to COVID.[9]

Regulatory review

In October 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of tixagevimab/cilgavimab, which is being developed by AstraZeneca AB, for the prevention of COVID-19 in adults.[11]

Also in October 2021, AstraZeneca requested Emergency Use Authorization for tixagevimab/cilgavimab to prevent COVID-19 from the U.S. Food and Drug Administration (FDA).[12][13]

Emergency use authorization

On 14 November 2021, Bahrain granted emergency use authorization.[14]

On 8 December 2021, the U.S. Food and Drug Administration (FDA) granted emergency use authorization of this combination to prevent COVID-19 (before exposure) in people with weakened immunity or who cannot be fully vaccinated due to a history of severe reaction to coronavirus vaccines.[15] The FDA issued an emergency use authorization (EUA) for AstraZeneca’s Evusheld (tixagevimab co-packaged with cilgavimab and administered together) for the pre-exposure prophylaxis (prevention) of COVID-19 in certain people aged 12 years of age and older weighing at least 40 kilograms (88 lb).[2] The product is only authorized for those individuals who are not currently infected with the SARS-CoV-2 virus and who have not recently been exposed to an individual infected with SARS-CoV-2.[2]

References

  1. ^ “Evusheld- azd7442 kit”DailyMed. Retrieved 4 January 2022.
  2. Jump up to:a b c d “Coronavirus (COVID-19) Update: FDA Authorizes New Long-Acting Monoclonal Antibodies for Pre-exposure Prevention of COVID-19 in Certain Individuals”U.S. Food and Drug Administration (FDA) (Press release). 8 December 2021. Retrieved 9 December 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ O’Shaughnessy, Jacqueline A. (20 December 2021). “Re: Emergency Use Authorization 104” (PDF). Food and Drug Administration. Letter to AstraZeneca Pharmaceuticals LP | Attention: Stacey Cromer Berman, PhD. Archived from the original on 29 December 2021. Retrieved 18 January 2022.
  4. ^ “IUPHAR/BPS Guide to PHARMACOLOGY”IUPHAR. 27 December 2021. Retrieved 27 December 2021.
  5. ^ “IUPHAR/BPS Guide to PHARMACOLOGY”IUPHAR. 27 December 2021. Retrieved 27 December 2021.
  6. ^ Ray, Siladitya (21 August 2021). “AstraZeneca’s Covid-19 Antibody Therapy Effective In Preventing Symptoms Among High-Risk Groups, Trial Finds”ForbesISSN 0015-6914Archived from the original on 21 August 2021. Retrieved 18 January 2022.
  7. Jump up to:a b Goriainoff, Anthony O. (20 August 2021). “AstraZeneca Says AZD7442 Antibody Phase 3 Trial Met Primary Endpoint in Preventing Covid-19”MarketWatchArchived from the original on 21 August 2021. Retrieved 18 January 2022.
  8. ^ Dong J, Zost SJ, Greaney AJ, Starr TN, Dingens AS, Chen EC, et al. (October 2021). “Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail”. Nature Microbiology6 (10): 1233–1244. doi:10.1038/s41564-021-00972-2ISSN 2058-5276PMC 8543371. PMID 34548634.
  9. Jump up to:a b Haridy, Rich (23 August 2021). “”Game-changing” antibody cocktail prevents COVID-19 in the chronically ill”New Atlas. Retrieved 23 August 2021.
  10. ^ “AZD7442 PROVENT Phase III prophylaxis trial met primary endpoint in preventing COVID-19”AstraZeneca (Press release). 20 August 2021. Retrieved 15 October 2021.
  11. ^ “EMA starts rolling review of Evusheld (tixagevimab and cilgavimab)”European Medicines Agency. 14 October 2021. Retrieved 15 October 2021.
  12. ^ “AZD7442 request for Emergency Use Authorization for COVID-19 prophylaxis filed in US”AstraZeneca US (Press release). 5 October 2021. Retrieved 15 October 2021.
  13. ^ “AZD7442 request for Emergency Use Authorization for COVID-19 prophylaxis filed in US”AstraZeneca (Press release). 5 October 2021. Retrieved 15 October 2021.
  14. ^ Abd-Alaziz, Moaz; Elhamy, Ahmad (14 November 2021). Macfie, Nick (ed.). “Bahrain authorizes AstraZeneca’s anti-COVID drug for emergency use”ReutersArchived from the original on 23 November 2021. Retrieved 18 January 2022.
  15. ^ Mishra, Manas; Satija, Bhanvi (8 December 2021). Dasgupta, Shounak (ed.). “U.S. FDA authorizes use of AstraZeneca COVID-19 antibody cocktail”ReutersArchived from the original on 13 January 2022. Retrieved 18 January 2022.

“Tixagevimab”Drug Information Portal. U.S. National Library of Medicine.

  • “Cilgavimab”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT04625972 for “Phase III Double-blind, Placebo-controlled Study of AZD7442 for Post-exposure Prophylaxis of COVID-19 in Adults (STORM CHASER)” at ClinicalTrials.gov
  • Clinical trial number NCT04625725 for “Phase III Double-blind, Placebo-controlled Study of AZD7442 for Pre-exposure Prophylaxis of COVID-19 in Adult. (PROVENT)” at ClinicalTrials.gov
Tixagevimab (teal, right) and cilgavimab (purple, left) binding the spike protein RBD. From PDB7L7E.
Combination of
TixagevimabMonoclonal antibody
CilgavimabMonoclonal antibody
Clinical data
Trade namesEvusheld
Other namesAZD7442
License dataUS DailyMedTixagevimab
Routes of
administration
Intramuscular
ATC codeJ06BD03 (WHO)
Legal status
Legal statusUS: ℞-only via emergency use authorization[1][2][3]
Identifiers
KEGGD12262
Clinical data
Drug classAntiviral
ATC codeNone
Identifiers
CAS Number2420564-02-7
DrugBankDB16394
UNIIF0LZ415Z3B
KEGGD11993
Chemical and physical data
FormulaC6488H10034N1746O2038S50
Molar mass146706.82 g·mol−1
Clinical data
Drug classAntiviral
ATC codeNone
Identifiers
CAS Number2420563-99-9
DrugBankDB16393
UNII1KUR4BN70F
KEGGD11994
Chemical and physical data
FormulaC6626H10218N1750O2078S44
Molar mass149053.44 g·mol−1

/////////////////Tixagevimab, ANTI VIRAL, CORONA VIRUS, PEPTIDE, Monoclonal antibody,  SARS-CoV-2 , WHO 11776, 2196, AZD-8895, AZD 8895, COV2-2196, COVID 19

NEW DRUG APPROVALS

ONE TIME

$10.00

Daridorexant


Nemorexant.svg
ChemSpider 2D Image | [(2S)-2-(5-Chloro-4-methyl-1H-benzimidazol-2-yl)-2-methyl-1-pyrrolidinyl][5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone | C23H23ClN6O2

Daridorexant

  • Molecular FormulaC23H23ClN6O2
  • Average mass450.921 Da

[(2S)-2-(5-Chloro-4-methyl-1H-benzimidazol-2-yl)-2-methyl-1-pyrrolidinyl][5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone
1505484-82-1[RN]
Methanone, [(2S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-2-methyl-1-pyrrolidinyl][5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]-
ACT-541468, , Nemorexant

FDA APPROVED 2022, 1/7/2022, To treat insomnia,

Quviviq
img

Daridorexant HCl
CAS#: 1792993-84-0 (HCl)
Chemical Formula: C23H24Cl2N6O2
Molecular Weight: 487.39
Elemental Analysis: C, 56.68; H, 4.96; Cl, 14.55; N, 17.24; O, 6.57

 Methanone, ((2S)-2-(6-chloro-7-methyl-1H-benzimidazol-2-yl)-2-methyl-1-pyrrolidinyl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)-, hydrochloride (1:1)

Daridorexant HCl; Daridorexant hydrochloride; ACT541468A; ACT 541468A; ACT-541468A; ACT541468 hydrochloride; ACT 541468 hydrochloride; ACT-541468 hydrochloride

Daridorexant HCl is used in the treat of Insomnia Disorder in Adult Patients

Daridorexant, sold under the brand name Quviviq, is a medication used for the treatment of insomnia.[1] Daridorexant is a dual orexin receptor antagonist (DORA) which was originated by Actelion Pharmaceuticals and is under development by Idorsia Pharmaceuticals.[3][4] It acts as a selective dual antagonist of the orexin receptors OX1 and OX2.[3][4] The medication has a relatively short elimination half-life of 6 to 10 hours.[2] As of April 2020, daridorexant has passed its first phase III clinical trial for the treatment of insomnia.[3]Daridorexant was approved for medical use in the United States in January 2022.[1][5][6]

Daridorexant, formerly known as nemorexant, is a selective dual orexin receptor antagonist used to treat insomnia. Insomnia is characterized by difficulties with sleep onset and/or sleep maintenance and impairment of daytime functioning. It chronically affects the person’s daily functioning and long-term health effects, as insomnia is often associated with comorbidities such as hypertension, diabetes, and depression. Conventional treatments for insomnia include drugs targeting gamma-aminobutyric acid type-A (GABA-A), serotonin, histamine, or melatonin receptors; however, undesirable side effects are frequently reported, such as next-morning residual sleepiness, motor incoordination, falls, memory and cognitive impairment. Novel drugs that target orexin receptors gained increasing attention after discovering the role of orexin signalling pathway in wakefulness and almorexant, an orexin receptor antagonist that improved sleep. Daridorexant was designed via an intensive drug discovery program to improve the potency and maximize the duration of action while minimizing next-morning residual activity.1

Daridorexant works on orexin receptors OX1R and OX2R to block the binding of orexins, which are wake-promoting neuropeptides and endogenous ligands to these receptors. Daridorexant reduces overactive wakefulness: in the investigational trials, daridorexant reportedly improved sleep and daytime functioning in patients with insomnia.1 It was approved by the FDA on January 10, 2022, under the name QUVIVIQ.6 as the second orexin receptor antagonist approved to treat insomnia following suvorexant.2

QUVIVIQ

  • Generic Name: daridorexant tablets
  • Brand Name: Quviviq

QUVIVIQ contains daridorexant, an orexin receptor antagonist. The chemical name of daridorexant hydrochloride is (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5- methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride. The molecular formula is C23H23N6O2Cl * HCl. The molecular weight is 487.38 g/mol.

The structural formula is:

QUVIVIQ (daridorexant) Structural Formula - Illustration

Daridorexant hydrochloride is a white to light yellowish powder that is very slightly soluble in water.

QUVIVIQ tablets are intended for oral administration. Each film-coated tablet contains 27 mg or 54 mg of daridorexant hydrochloride equivalent to 25 mg or 50 mg of daridorexant, respectively. The inactive ingredients are croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, povidone, and silicon dioxide.

In addition, the film coating contains the following inactive ingredients: glycerin, hypromellose, iron oxide black, iron oxide red, microcrystalline cellulose, talc, titanium dioxide, and, in the 50 mg tablet only, iron oxide yellow.

Dosage Forms And Strengths

QUVIVIQ (daridorexant) tablets are available as:

25 mg: light purple, arc-triangle shaped, film-coated tablet debossed with “25” on one side and “i” (Idorsia logo) on the other side, containing 25 mg daridorexant.

50 mg: light orange, arc-triangle shaped, film-coated tablet debossed with “50” on one side and “i” (Idorsia logo) on the other side, containing 50 mg daridorexant.

QUVIVIQ tablets are available as:

25 mg, light purple, arc-triangle shaped film-coated tablets debossed with “25” on one side, and “i” on the other side. NDC 80491-7825-3, bottle of 30 with child-resistant closure

50 mg: light orange, arc-triangle shaped film-coated tablets debossed with “50” on one side, and “i” on the other side. NDC 80491-7850-3, bottle of 30 with child-resistant closure

SYN

https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202000453

Since its discovery in 1998, the orexin system has been of interest to the research community as a potential therapeutic target for the treatment of sleep/wake disorders. Herein we describe our efforts leading to the identification of daridorexant, which successfully finished two pivotal phase 3 clinical trials for the treatment of insomnia disorders.

image

Step 3. Amide (S7) (1000 g, 2.13 mmol) was dissolved in EtOH (5 L) and 32% aqueous HCl (500 mL) was added at 23 °C. The solution was filtered through a Whatman filter (5 µm). The filtrate was heated to 75 °C for 4h. The resulting suspension was cooled to 0 °C and filtered. The product was dried under reduced pressure to yield 93 x HCl (922 g, 89%) as a white solid.

LC-MS B: tR = 0.78 min; [M+H]+ = 451.19, mp 280 °C.

1H NMR (500 MHz, D6-DMSO) δ: 15.05- 15.65 (m, 1 H), 8.06 (s, 2 H), 7.79 (s, 1 H), 7.75 (d, J = 8.9 Hz, 2 H), 7.66 (m, 1 H), 7.57 (d, J = 8.7 Hz, 1 H), 7.15 (dd, J1 = 2.9 Hz, J2 = 8.9 Hz, 1 H), 4.06-4.10 (m, 1 H), 3.92 (s, 3 H), 3.35 (s, 1 H), 2.78 (s, 3 H), 2.54-2.67 (m, 1 H), 2.23-2.31 (m, 1 H), 2.06-2.20 (m, 2 H), 1.97 (s, 3 H),

13C NMR (125 MHz, D6-DMSO) δ: 166.2, 159.3, 158.6, 136.5, 132.7, 131.9, 130.4, 130.3, 129.4, 126.8, 124.5, 123.4, 116.4, 113.7, 113.0, 61.6, 56.8, 49.7, 41.1, 23.9, 20.2, 15.7.

SYN

https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.201900618

Abstract

DORA explorers: The orexin system plays an important role in regulating the sleep-wake cycle. Herein we report our optimization efforts toward a novel dual orexin receptor antagonist (DORA) with improved properties over compound 6. Replacing the oxadiazole by a triazole resulted in compounds (e. g. compound 33) with improved properties, such as higher intrinsic metabolic stability, lower plasma protein binding, higher brain free fraction, and increased solubility. Further optimization was needed to decrease the compounds P-glycoprotein susceptibility. Our work led to the identification of compound 42, a potent, brain-penetrating DORA with improved in vivo efficacy in dogs compared with compound 6.

image

Abstract

The orexin system is responsible for regulating the sleep-wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}methanone (6), a compound which emerged from our in-house research program. Compound 6 was shown to be a potent, brain-penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (fu brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above-mentioned shortcomings resulted in the identification of (4-chloro-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-methyl-2-[5-(2-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone (42), a DORA with improved in vivo efficacy compared to 6.

PAT

WO 2015083071

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015083071

Reference Example 1

1) Synthesis of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid

2-lodo-5-methoxy benzoic acid (15.0 g; 53.9 mmol) is dissolved in anhydrous DMF (45 ml) followed by the addition of 1 H-1 ,2,3-triazole (7.452 g; 108 mmol) and cesium carbonate (35.155 g; 108 mmol). By the addition of cesium carbonate the temperature of the reaction mixture increases to 40°C and gas evolved from the reaction mixture. Copper(l)iodide (514 mg; 2.7 mmol) is added. This triggers a strongly exothermic reaction and the temperature of the reaction mixture reaches 70°C within a few seconds. Stirring is continued for 30 minutes. Then the DMF is evaporated under reduced pressure followed by the addition of water (170 ml) and EtOAc (90 ml). The mixture is vigorously stirred and by the addition of citric acid monohydrate the pH is adjusted to 3-4. The precipitate is filtered off and washed with water and EtOAc and discarded. The filtrate is poured into a separation funnel and the phases are separated. The water phase is extracted again with EtOAc. The combined organic layers are dried over MgS04, filtered and the solvent is evaporated to give 7.1 g of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid as a white powder of 94% purity (6 % impurity is the regioisomerically N1-linked triazolo-derivative); tR [min] = 0.60; [M+H]+ = 220.21

2) Synthesis of (S)-1 -(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid

2-Methyl-L-proline hydrochloride (99.7 g; 602 mmol) is dissolved in a 1/1-mixture of MeCN and water (800 ml) and triethylamine (254 ml; 1810 mmol) is added. The temperature of the reaction mixture slightly rises. The reaction mixture is cooled to 10°C to 15°C followed by careful addition of a solution of Boc20 (145 g; 662 mmol) in MeCN (200 ml) over 10 minutes.

Stirring at RT is continued for 2 hours. The MeCN is evaporated under reduced pressure and aq. NaOH solution (2M; 250 ml) is added to the residual aq. part of the reaction mixture. The water layer is washed with Et20 (2x 300 ml) then cooled to 0°C followed by slow and careful addition of aq. HCI (25%) to adjust the pH to 2. During this procedure a suspension forms.

The precipitate is filtered off and dried at HV to give 1 10.9 g of the title compound as a beige powder; tR [min] = 0.68; [M+H]+ = 230.14

3) Synthesis of (S)-tert-butyl 2-((2-amino-4-chloro-3-methylphenyl)carbamoyl)-2-

(S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (60 g; 262 mmol) and HATU (100 g; 264 mmol) is suspended in DCM (600 ml) followed by the addition of DIPEA (84.6 g; 654 mmol) and 6-chloro-2,3-diaminotoluene (41 g; 262 mmol). The reaction mixture is stirred at rt for 14 hours then concentrated under reduced pressure and to the residue is added water followed by the extraction of the product with EtOAc (3x). The combined organic layers are washed with brine, dried over MgS04, filtered and the solvent is evaporated under

reduced pressure to give 185 g of the title compound as a dark brownish oil, which is used in the next step without further purification; tR [min] = 0.89; [M+H]+ = 368.01

4) Synthesis of (S)-tert-butyl 2-(5-chloro-4-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylpyrrolidine-1 -carboxylate

(S)-tert-butyl 2-((2-amino-4-chloro-3-methylphenyl)carbamoyl)-2-methylpyrrolidine-1-carboxylate (185 g; 427 mmol) are dissolved in AcOH (100%; 611 ml), heated to 100°C and stirring continued for 90 minutes. The AcOH is evaporated under reduced pressure and the residue is dissolved in DCM followed by careful addition of saturated sodium bicarbonate solution. The phases are separated, the aq. phase is extracted once more with DCM, the combined aq. phases are dried over MgS04, filtered and the solvent is evaporated under reduced pressure to give 142.92 g of the title compound as a dark brown oil which is used in the next step without further purification; tR [min] = 0.69; [M+H]+ = 350.04

5) Synthesis of (S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1 H-benzo[d]imidazole hydrochloride

(S)-tert-butyl 2-(5-chloro-4-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylpyrrolidine-1-carboxylate (355.53 g; 1.02 mol) are dissolved in dioxane (750 ml) followed by careful addition of HCI solution in dioxane (4M; 750 ml; 3.05 mol). The reaction mixture is stirred for 3 hours followed by the addition of Et20 (800 ml) which triggered precipitation of the product. The solid is filtered off and dried at high vacuum to give 298.84 g of the title compound as a redish powder; tR [min] = 0.59; [M+H]+ = 250.23

6) Synthesis of [(S)-2-(5-chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-pyrrolidin-1- -(5-methoxy-2-[1,2,3]triazol-2-yl-phenyl)-methanone

(S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1 H-benzo[d]imidazole hydrochloride (62.8 g; 121 mmol) is dissolved in DCM (750 ml) followed by the addition of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (62.8 g; 121 mmol) and DIPEA (103 ml; 603 mmol). Stirring is continued for 10 minutes followed by the addition of HATU (47 g; 124 mmol). The reaction mixture is stirred for 16 hours at RT. The solvents are evaporated under reduced pressure and the residue is dissolved in EtOAc (1000 ml) and washed with water (3x 750 ml). The organic phase is dried over MgS04, filtered and the solvent is evaporated under reduced pressure. The residue is purified by CC with EtOAc / hexane = 2 / 1to give 36.68 g of the title compound as an amorphous white powder. tR [min] = 0.73; [M+H]+ = 450.96

Table 1 : Characterisation data for COMPOUND as free base in amorphous form

II. Preparation of crystalline forms of COMPOUND

Example 1 :

Preparation of seeding material of COMPOUND hydrochloride in crystalline Form 1

10 mg COMPOUND is mixed with 0.2 mL 0.1 M aq. HCI and 0.8 mL EtOH. The solvent is fully evaporated and 0.05 mL isopropanol is added. Alternatively 0.05 mL methyl-isobutylketone can be added. The sample is stored closed at room temperature for 4 days and crystalline material of COMPOUND hydrochloride in crystalline Form 1 is obtained. This material can be used as seeding material for further crystallization of COMPOUND hydrochloride in crystalline Form 1.

Example 2: Preparation and characterization of COMPOUND hydrochloride in crystalline form 1

5g COMPOUND is mixed with 0.9 mL 1 M aq. HCI and 20 mL EtOH. The solvent is evaporated and 25 mL isopropanol is added. Seeds of COMPOUND hydrochloride are added and the sample is allowed to stand at room temperature. After about 2 days the suspension is filtered and the solid residue is dried at reduced pressure (2 mbar for 1 hour) and allowed to equilibrate open for 2 hours at 24°C/46% relative humidity. The obtained solid is COMPOUND hydrochloride in crystalline Form 1

Table 2: Characterisation data for COMPOUND hydrochloride in crystalline form 1

PAT

WO 2018202689

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018202689

Examples

Reference Example 1

Synthesis of 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid

4,5-dibromo-2-(4-methoxy-2-nitrophenyl)-2H-1,2,3-triazole

4- Fluoro-3-nitroanisole (3.44 g, 1 eq.), 4,5-dibromo-2/-/-1 ,2,3-triazole (4.56 g, 1 eq.)1, K2C03 (2.78 g, 1 eq.) and DMF (30 mL) are heated to 1 10 °C for 32 h. The reaction mixture is cooled to 22 °C and treated with water (70 mL). The resulting suspension is filtered, washed with water (15 mL). The product is slurried in isopropanol (40 mL), filtered and dried under reduced pressure to yield a white solid. Yield: 6.42 g, 84%. Purity: 100% a/a (LC-MS method 2). 1H NMR (400 MHz, CDCI3) δ: 7.71 (d, J = 8.9 Hz, 1 H), 7.47 (d, J = 2.8 Hz, 1 H), 7.25 (dd, Ji = 2.8 Hz, J2 = 8.9 Hz, 1 H), 3.97 (s, 3 H).

1 X. Wang, L. Zhang, D. Krishnamurthy, C. H. Senanayake, P. Wipf Organic Letters 2010 12 (20), 4632-4635.

5- methoxy-2-(2H-1 ,2,3-triazol-2-yl)aniline

4, 5-Dibromo-2-(4-methoxy-2-nitrophenyl)-2/-/-1 ,2,3-triazole (2 g, 1 eq.), sodium acetate (1.3 g, 3 eq.), and 10% Pd/C 50% water wet (0.3 g) is suspended in EtOAc (10 mL). The mixture is heated to 50 °C and set under hydrogen until conversion is complete. The reaction mixture is filtered over Celite. The filtrate is washed with 1 N NaOH (10 mL) and water (15 mL). The organic layer is concentrated under reduced pressure to yield an oil. Yield: 0.95 g, 94%. Purity: 96% a/a (LC-MS method 2). 1H NMR (400 MHz, DMSO) <5: 8.05 (s, 2 H), 7.53 (d, J = 8.9 Hz, 1 H), 6.49 (d, J = 2.7 Hz, 1 H), 6.30 (dd, Ji = 2.7 Hz, J2 = 8.9 Hz, 1 H), 5.94 (s, 2 H), 3.74 (s, 3 H).

5-methoxy-2-(2H-1,2,3-triazol-2-yl)aniline monosulfate

5-Methoxy-2-(2/-/-1 ,2,3-triazol-2-yl)aniline (455 g, 1 eq ) is dissolved in isopropanol (3 L). To the solution is added cone. H2SO4 (235 g, 1 eq.) below 40 °C. The suspension is cooled to

20 °C and filtered. The cake is washed with isopropanol (700 mL) and TBME (1.5 L). The product is dried to obtain a white solid. Yield: 627 g, 91 %. Purity: 100% a/a (LC-MS method 2).

2-(2-iodo-4-methoxyphenyl)-2H-1,2,3-triazole

5-Methoxy-2-(2/-/-1 ,2,3-triazol-2-yl)aniline monosulfate (200 g, 1 eq.) is dissolved in 2 M aq. H2SO4 soln. (1.4 L) and cooled to -5 °C. To the solution is added a solution of sodium nitrite (62 g, 1.3 eq.) in water (600 mL) at -5 to 0 °C. The mixture is stirred at 0 °C for 30 min and then added to a preheated mixture of Kl (161 g, 1.4 eq.) in water (700 mL) at 65 °C. The resulting solution is stirred at 60 °C for 20 min, cooled to 20 °C and treated with a soln. of sulfamic acid (27 g, 0.4 eq.) in water (120 mL). The mixture is extracted with isopropyl acetate (2 L). The organic layer is washed with a mixture of 2 N NaOH (500 mL) and 40% NaHS03 soln. (100 mL), and a mixture of 1 N HCI (50 mL) and water (500 mL). The organic layer is concentrated to dryness. The residue is dissolved in isopropanol (700 mL) and cooled to 0 °C. The resulting suspension is filtered. The solid is dried under reduced pressure. Yield: 164 g, 79%. Purity: 100% a/a (LC-MS method 2). 1H NMR (400 MHz, DMSO) <5: 8.08 (s, 2 H), 7.57 (d, J = 2.8 Hz, 1 H), 7.43 (d, J = 8.8 Hz, 1 H), 7.13 (dd, Ji = 2.8 Hz, J2 = 8.8 Hz, 1 H), 3.85 (s, 3 H).

5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid

2-(2-lodo-4-methoxyphenyl)-2/-/-1 ,2,3-triazole (200 g, 1 eq.) is dissolved in THF (2 L) and cooled to 0 °C. 2 M iPrMgCI soln. in THF (350 mL, 1.05 eq.) is added at 0 °C. The mixture is cooled to -20 °C and C02 (gas) is bubbled into the solution over 30 min until the exothermicity is ceased. To the mixture is added 2 N HCI (600 mL) at 8 °C and concentrated under reduced pressure to remove 2.4 L solvent. The residue is extracted with TBME (1.6 L). The organic layer is washed with 1 N HCI (200 mL) and extracted with 1 N NaOH (600 mL and 200 mL). The aq. layer is filtered over charcoal (15 g), diluted with water (200 mL) and treated with 32% HCI (160 mL). The resulting suspension is filtered and washed with water (200 mL). Yield: 127 g, 87%. Purity: 100% a/a (LC-MS method 2); MP: 130 °C (DSC goldpan). The obtained product may be re-crystallized from toluene (MP: 130.9 °C) or water (MP: 130 °C).

Table Ref 1 : Characterisation data for 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid in crystalline form 2 (recrystallization from toluene)

Technique Data Summary Remarks

XRPD Crystalline see Fig. 8

Reference Example 2

Synthesis of 4-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid

4,5-Dibromo-2-(5-methyl-2-nitrophenyl)-2H-1 ,2,3-triazole

3- Fluoro-4-nitrotoluene (1367 g, 1 eq.), 4,5-dibromo-2/-/-1 ,2,3-triazole (1999 g, 1 eq.), K2C03 (1340 g, 1.1 eq.) and DMF (1 1 L) is heated to 75 °C for 15 h. The reaction mixture is cooled to 22 °C and treated with water (18 L). The resulting suspension is filtered, washed with water (4 L). The product is washed with isopropanol (5 L), and dried under reduced pressure to yield a white solid. Yield: 281 1 g, 88%. Purity: 100% a/a (LC-MS method 2). 1H NMR (400 MHz, DMSO) <5: 8.10 (d, J = 8.3 Hz, 1 H), 7.86 (d, J = 1.0 Hz, 1 H), 7.66 (dd, J1 = 0.9 Hz, J2 = 8.3 Hz, 1 H), 2.51 (s, 3 H).

4- Methyl-2-(2H-1 ,2,3-triazol-2-yl)aniline

4, 5-Dibromo-2-(5-methyl-2-nitrophenyl)-2/-/-1 ,2,3-triazole (205 g, 1 eq.), sodium acetate (149 g, 3.2 eq.), and 5% Pd/C 50% water wet (37.8 g) is suspended in EtOAc (0.8 L). The mixture is heated to 40-50 °C and set under hydrogen (2 bar) until conversion is complete. The reaction mixture is filtered over Celite. The filtrate is washed with water (300 mL), 2N NaOH (300 ml_+250 mL) and water (300 mL). The organic layer is concentrated under reduced pressure to yield a yellow oil. Yield: 132 g, 90%. Purity: 100% a/a (LC-MS method 2). 1H NMR (400 MHz, DMSO) <5: 8.09 (s, 2 H), 7.48 (d, J = 1.3 Hz, 1 H), 6.98 (dd, J1 = 1.8 Hz, J2 = 8.3 Hz, 1 H), 6.85 (d, J = 8.2 Hz, 1 H), 5.79 (s, 2 H), 2.23 (s, 3 H).

4-Methyl-2-(2H-1,2,3-triazol-2-yl)aniline monosulfate

4-Methyl-2-(2/-/-1 ,2,3-triazol-2-yl) aniline (199 g, 1 eq ) is dissolved in isopropanol (1.7 L). To the solution is added cone. H2SO4 (118 g, 1.05 eq.) below 40 °C. The suspension is cooled to 20 °C and filtered. The cake is washed with isopropanol (500 mL). The product is dried to obtain a white solid. Yield: 278 g, 89%. Purity: 100% a/a (LC-MS method 2). 1H NMR (400 MHz, DMSO) <5: 8.21 (s, 2 H), 7.70 (s, 1 H), 7.23 (s, 2 H), 2.35 (s, 3 H).

2-(2-iodo-5-methylphenyl)-2H-1 ,2,3-triazole

4-Methyl-2-(2/-/-1 ,2,3-triazol-2-yl)aniline monosulfate (1553 g, 1 eq.) is dissolved in 1 M aq. H2S04 Soln. (1 1 L) and cooled to -5 °C. To the solution is added a solution of sodium nitrite (433 g, 1.1 eq.) in water (4 L) at -5 to 0 °C. The mixture is stirred at 0 °C for 30 min and then added to a preheated mixture of potassium iodide (1325 g, 1.4 eq.) in water (4 L) at 55-70 °C. The resulting solution is stirred at 60 °C for 20 min, cooled to 20 °C and treated with a soln. of sulfamic acid (220 g, 0.4 eq.) in water (900 mL). The mixture is extracted with isopropyl acetate (13 L). The organic layer is washed with a mixture of 2 N NaOH (3.5 L) and 40% NaHSOs soln. (330 g), and a mixture of 1 N HCI (280 mL) and water (3.5 L). The

organic layer is concentrated to dryness. Yield: 1580 g, 97%. Purity: 91 % a/a (LC-MS method 2). 1 H NMR (400 MHz, CDCI3) <5: 7.90 (s, 2 H), 7.87 (d, J = 8.1 Hz, 1 H), 7.34 (d, J = 1 .6 Hz, 1 H), 7.03-7.06 (m, 1 H), 2.40 (s, 3 H).

The crude product, together with a second batch (141 1 g) is purified by distillation on a short path distillation equipment at 120 °C jacket temperature, feeding tank (70 °C), cooling finger (20 °C) and at a pressure of 0.004 mbar. Yield: 2544 g (78%), Purity: 100 % a/a ()LC-MS method 2).

4-Methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid

2-(2-lodo-5-methylphenyl)-2/-/-1 ,2,3-triazole (1250 g, 1 eq.) is dissolved in THF (13 L) and cooled to 0 °C. 2 M iPrMgCI soln. in THF (2.2 L, 1 eq.) is added at 0 °C. The mixture is cooled to -25 °C and CO2 (gas) is bubbled into the solution over 60 min until the exothermicity is ceased. To the mixture is added 2 N HCI (5 L) at 4 °C and concentrated under reduced pressure to remove 14.5 L solvent. The residue is extracted with TBME (10 L). The organic layer is extracted with 1 N NaOH (6 L and 3 L). The aq. layer is filtered over charcoal (15 g), diluted with water (200 mL) and treated with 32% HCI (1 .23 L). The resulting suspension is filtered and washed with water (5 L). Yield: 796 g, 89%. Purity: 100% a/a (LC-MS method 2); MP: 125 °C (DSC goldpan).

The following examples illustrate the invention.

Example 1 :

Example 1.1: Crystalline 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt (potassium 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoate)

2-Bromo-5-methoxybenzoic acid (21 .5 g, 0.093 mol, 1 eq.) copper (I) iodide (0.886 g, 0.05 eq.), and K2CO3 powder (32.2 g, 2.5 eq.) were suspended in dioxane (600 mL) and water (8.4 mL). To the mixture were added 1 H-1 ,2,3-triazole (10.8 mL, 2 eq.) and trans-/V,/V-dimethylcyclohexane-1 ,2-diamine (1 .32 g, 0.1 eq.). The mixture was heated at reflux for 3.5 h. IPC showed full conversion. The ratio of the desired N(2) to the regioisomeric Λ/(1 ) isomer was 84: 16. The mixture was cooled to 40 °C and filtered. The cake was washed with dioxane (100 mL). The solid was dried to obtain 50.6 g of a blue solid. The ratio of N{2) to Λ/(1 ) isomer of was 98.6: 1 .4.

Table 1 : Characterisation data for 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt in crystalline form 1

Example 1.2: Crystalline 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid

The solid of Example 1.1 was dissolved in water (300 mL). TBME (200 mL) and 32% aq. HCI (35 mL) was added. The aq. layer was separated and discarded. The organic layer was washed with a mixture of 2N aq. HCI (100 mL) and 32% aq. HCI (20 mL). The organic layer was washed with 1 N aq. HCI (50 mL). The organic layer was extracted with 1 N aq. NaOH (200 mL). The aq. layer was heated to 45 °C and traces of TBME were removed under reduced pressure. To the aq. layer was added at 45 °C 32% aq. HCI (20 mL). At a pH of 6 optionally seed crystals were added. The resulting suspension was filtered at 40 °C. The cake was washed with water (30 mL). The product was dried at 60 °C and 5 mbar. Yield: 12.4 g, 61 %. Purity: 100% a/a, tR 0.63 min. Seed crystals may be obtained by careful crystallization according to the above procedure.

MP: 80 °C (DSC).

1H NMR (400 MHz, DMSO) & 3.87 (s, 3 H), 7.26 (m, 2 H), 7.64 (d, J = 8.7 Hz, 1 H), 8.02 (s, 2 H), 13.01-13.22 (br, 1 H).

Table 2: Characterisation data for 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid in crystalline form 1

Example 1.3: Crystalline 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt

5-Methoxy-2-(2/-/-1 ,2,3-triazol-2-yl)benzoic acid, e.g. obtained according to the procedure of Reference Example 1 (5 g, 0.0228 mol) and KHCO3 (1.61 g, 0.7 eq) were suspended in dioxane (100 mL) and water (1 mL). The mixture was heated at reflux for 40 min. The mixture was cooled to 20 °C and filtered. Yield: 2.56 g, 44%. 1H NMR (400 MHz, D20) & 3.80 (s, 3 H), 7.04 (m, 2 H), 7.46 (d, J = 8.7 Hz, 1 H), 7.82 (s, 2 H). MP: 279.5°C (DSC shows additionally a broad endothermic event at about 153 °C to 203 °C which may be attributed to endothermic desolvations; melting is immediately followed by exothermic degradation).

Table 3: Characterisation data for 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt in crystalline form 2

Example 1.4: Crystalline 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt

In an alternative procedure, 2-Bromo-5-methoxybenzoic acid (20 g, 0.086 mol, 1 eq.) copper (I) iodide (0.824 g, 0.05 eq.), and K2C03 powder (26.9 g, 2.25 eq.) were suspended in dioxane (494 mL). To the mixture was added 1 H-1 ,2,3-triazole (12 g, 2 eq.). The mixture was heated at reflux for 1 h. To the mixture was added water (12.5 g, 8 eq.). The mixture was heated at reflux for 2 h. Solvent (100 mL) was removed by distillation. The residue was cooled to 45 °C in 8 min, filtered and washed with dioxane (50 mL).

XRPD corresponds to crystalline form 1 (see Fig. 1 , Example 1.1 ).

Example 1.5: Crystalline 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid

The solid of Example 1.4 was dissolved in water (200 mL). The mixture was heated to 50 °C and 20% aq. H2SO4 (40 mL) was added to adjust the pH to 5. The mixture was filtered over Celite. The filtrate was treated at 45 °C with 20% aq. H2S04 (40 mL). At pH 3 seeds (obtained for example using the procedure of reference example 1 ) were added. The suspension was stirred at 45 °C and filtered. The product was washed with water (20 mL) and dried at 60 °C and 10 mbar to yield a white solid. Yield: 10.8 g, 57%. Purity: 100% a/a, tR 0.63 min.

Characterisation of 5-methoxy-2-(2/-/-1 ,2,3-triazol-2-yl)benzoic acid obtained according to Example 1.5:

XRPD corresponds to crystalline form 1 (see Fig. 2, Example 1.2).

Example 2:

Example 2.1: Crystalline 4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt (potassium 4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoate)

2-Bromo-4-methylbenzoic acid (20 g, 0.093 mol, 1 eq.) copper (I) iodide (0.886 g, 0.05 eq.), and K2CO3 powder (32.2 g, 2.5 eq.) were suspended in dioxane (300 mL) and water (10.1 mL). To the mixture was added 1 A7-1 ,2,3-triazole (10.8 mL, 2 eq.) and trans-Λ/,ΛΑ-

dimethylcyclohexane-1 ,2-diamine (1 .32 g, 0.1 eq.). The mixture was heated at reflux for 4 h. IPC showed a conversion of 98.5%. The ratio of the desired N(2) to the regioisomeric Λ/(1 ) isomer was 75:25. The mixture was concentrated at normal pressure and external temperature of 130 °C. Solvent (100 mL) was removed. To the residue was added dioxane (100 mL) and the mixture was cooled to 45 °C and filtered. The cake was washed with dioxane (80 mL). The solid was dried to obtain 48.8 g of a blue solid. The ratio of N(2) to Λ/(1 ) isomer was 98.7: 1 .3.

Table 4: Characterisation data for 4-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid potassium salt in crystalline form 1

Example 2.2: Crystalline 4-methyl-2-(2H-1,2,3-triazol-2-yl) benzoic acid

The solid of Example 2.1 was dissolved in water (300 mL) and filtered. To the filtrate were added TBME (200 mL) and 32% aq. HCI (30 mL). The aq. layer was separated and discarded. The organic layer was washed with a mixture of 2N aq. HCI (100 mL) and 32% aq. HCI (10 mL). The organic layer was washed with 1 N aq. HCI (50 mL). The organic layer was extracted with 1 N aq. NaOH (200 mL). The aq. layer was heated to 45 °C and traces of TBME were removed under reduced pressure. To the aq. layer was added at 45 °C 32% aq. HCI (20 mL). At a pH of 6 seed crystals (obtained for example using the procedure of reference example 2) were added. The resulting suspension was filtered at 40 °C. The cake was washed with water (30 mL). The product was dried at 60 °C and 5 mbar. Yield: 1 1 .7 g, 62%. Purity: 100% a/a. tR 0.66 min.

MP: 125 °C (DSC).

1H NMR (400 MHz, DMSO) & 2.44 (s, 3 H), 7.41 (d, J = 7.9 Hz, 1 H), 7.56 (s, 1 H), 7.68 (d, J = 7.9 Hz, 1 H), 8.06 (s, 2 H), 12.53-13.26 (br, 1 H)

Table 5: Characterisation data for 4-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid in crystalline form 1

Technique Data Summary Remarks

XRPD Crystalline see Fig. 5

Example 2.3: Crystalline 4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt

4-Methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (5 g, 0.0246 mol) and KHC03 (1 .74 g , 0.7 eq) were suspended in dioxane ( 100 mL) and water (1 mL). The mixture was heated at reflux for 40 min. The mixture was cooled to 20 °C and filtered. Yield: 2.47 g, 42% . MP: 277 °C (DSC Alupan) 1 H NMR (400 MHz, D20) & 2.32 (s, 3 H), 7.28 (d, J = 7.9 Hz, 1 H), 7.39 (m, 2 H), 7.84 (s, 2 H).

MP: 276.8 °C (DSC shows additionally a broad endothermic event at about 140 °C to 208 °C which may be attributed to endothermic desolvations; melting is immediately followed by exothermic degradation).

XRPD corresponds to crystalline form 1 (see Fig. 4, Example 2.1 ).

Reference Example 3:

Reference Example 3.1: Crystalline 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid sodium salt (sodium 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoate)

2-Bromo-5-methylbenzoic acid (20 g, 0.093 mol, 1 eq. ) copper (I) iodide (0.886 g, 0.05 eq.), Na2CC>3 powder (24.6 g, 2.5 eq.) were suspended in dioxane (300 mL) and water (10.1 mL). To the mixture was added 1 /-/-1 ,2,3-triazole ( 10.8 mL, 2 eq.) and 8-hydroxy quinoline ( 1 .35 g, 0.1 eq.). The mixture was heated at reflux for 5 h. IPC showed a conversion of >99%. The ratio of the desired N(2) to the regioisomeric Λ/(1 ) isomer was 78:22. The mixture was concentrated at normal pressure and external temperature of 135 °C. Solvent (100 mL) was removed. To the residue was added dioxane (100 mL) and the mixture was cooled to 45 °C and filtered. The cake was washed with dioxane (80 mL). The solid was dried to obtain 36.2 g of a yellow solid. The ratio of N(2) to Λ/( 1 ) isomer of was 99: 1 .

Table 6: Characterisation data for 5-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid sodium salt in crystalline form 1

Reference Example 3.2: Crystalline 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid

The solid obtaind in Reference Example 3.1 was dissolved in water (300 mL) and filtered. To the filtrate was added TBME (200 mL) and 32% aq. HCI (30 mL) was added. The aq. layer was separated and discarded. The organic layer was washed with 1 N aq. HCI ( 100 mL). The organic layer was washed with 1 N aq. HCI (50 mL). The organic layer was extracted with 1 N aq. NaOH (200 mL). The aq. layer was heated to 45 °C and traces of TBME were removed

under reduced pressure. To the aq. layer was added at 45 °C 32% aq. HCI (20 mL). At a pH of 6 seed crystals (obtained for example using the procedure of Reference example 2) were added. The resulting suspension was filtered at 40 °C. The cake was washed with water (30 mL). The product was dried at 60 °C and 5 mbar. Yield: 12.1 g, 64%. Purity: 100% a/a. tR 0.67 min.

MP: 173 °C (DSC)

1 H NMR (400 MHz, DMSO) & 2.42 (s, 3 H), 7.50-7.52 (m, 1 H), 7.58 (s, 1 H), 7.63 (m, 1 H), 8.05 (s, 2 H), 13.01 (s, 1 H).

Table 7: Characterisation data for 5-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid in crystalline form 1

Reference Example 3.3: Crystalline 5-methyl-2-(2H-1,2,3-triazol-2-yl) benzoic acid sodium salt

5-Methyl-2-(2/-/-1 ,2,3-triazol-2-yl)benzoic acid (5 g, 0.0246 mol) and Na2C03 (1 .05 g, 0.4 eq) were suspended in dioxane ( 100 mL) and water (1 mL). The mixture was heated at reflux for 40 min. The mixture was cooled to 20 °C and filtered. Yield: 2.79 g, 50%. MP: 341 °C (DSC Alupan) 1 H NMR (400 MHz, D20) & 2.32 (s, 3 H), 7.30 (m, 2 H), 7.43 (m, 1 H), 7.83 (s, 2 H).

XRPD corresponds to crystalline form 1 (see Fig. 6, Reference Example 3.1 ).

Reference Example 3.4: 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid potassium salt

2-Bromo-5-methylbenzoic acid (20 g, 0.093 mol, 1 eq. ) copper (I) iodide (0.886 g, 0.05 eq.), and K2CO3 powder (32.1 g, 2.5 eq.) were suspended in dioxane (600 mL). To the mixture was added 1 /-/-1 ,2,3-triazole ( 10.8 mL, 2 eq.) and 8-hydroxy quinoline ( 1 .35 g, 0.1 eq.). The mixture was heated at reflux for 4 h. IPC showed a conversion of >94%. The ratio of the desired N(2) to the regioisomeric Λ/( 1 ) isomer was 78:22. The mixture was cooled to 35 °C and filtered. The cake was washed with dioxane (100 mL). The products were dissolved in water and a LC-MS was recorded. The ratio of N(2) to Λ/(1 ) isomer of was 83: 17.

Reference Example 4.1: Methyl (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl) benzoyl)-2-methylpyrrolidine-2-carboxylate

5-Methoxy-2-(2/-/-1 ,2,3-triazol-2-yl) benzoic acid (100 g, 0.46 mol) was suspended in DCM (650 mL) and DMF (10 mL) at 20 °C. To this suspension was added oxalyl chloride (51 mL, 0.59 mol) over a period of 30 min. LC-MS showed 60% conversion to acid chloride intermediate. Oxalyl chloride (17.6 mL, 0.45 eq.) was added dropwise. LC-MS showed full conversion to acid chloride intermediate.

Methyl (S)-2-methylpyrrolidine-2-carboxylate hydrochloride (84 g, 0.47 mol) was suspended in DCM (800 mL) in a second flask. The suspension was cooled to 10 °C. Triethylamine (200 mL, 1.41 mol) was added over 15 min. The acid chloride solution was added to the reaction mixture at 10-20 °C over at least 15 min. The reaction mixture was washed with 1 M HCI (500 mL), 1 N NaOH (500 mL) and water (500 mL). The organic layer was concentrated to dryness to give a light-yellow solid as product. Yield: 157 g, 100%, 99% a/a (LC-MS), M+1 =345. 1H NMR (400 MHz, DMSO) δ: 8.06 (s, 2 H), 7.79 (d, J = 8.9 Hz, 1 H), 7.21 (dd, J1 = 2.9 Hz, J2 = 8.9 Hz, 1 H), 6.85 (d, J = 1.9 Hz, 1 H), 3.89 (s, 3 H), 3.66 (s, 3 H), 3.29 (m, 1 H), 3.03 (m, 1 H), 2.08 (m, 1 H), 1.82 (m, 3 H), 1.50 (s, 3 H).

Reference Example 4.2: (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl) benzoyl)-2-methylpyrrolidine-2-carboxylic acid

Methyl (S)-1-(5-methoxy-2-(2/-/-1 ,2,3-triazol-2-yl) benzoyl)-2-methylpyrrolidine-2-carboxylate (157 g, 0.46 mol) was dissolved in MeOH (750 mL) at 20 °C. To this solution was added 16% NaOH (300 mL). The resulting solution was heated up to 80 °C and stirred for 60 min. Solvent was distilled off under reduced pressure (850 mL). The residue was taken up in DCM (1500 mL) and water (450 ml) at 20 °C. 32% HCI (200 mL) was added. Layers were separated and the organic layer was washed with water (450 mL). The organic layer was concentrated to the minimum stirring volume under reduced pressure. Toluene (750 mL) was added and solvent was further distilled under vacuum (150 mL distilled). The mixture was cooled to 20 °C and stirred for 15 min. The suspension was filtered at 20 °C. The cake was rinsed with toluene (150 mL) and then dried under reduced pressure at 50 °C to give a white solid as product. Yield: 128 g, 85%, 94% a/a (LC-MS), M+1 =331. Melting point: 178 °C (DSC). 1H NMR (400 MHz, DMSO) δ: 12.3 (s, 1 H), 8.04 (s, 2 H), 7.79 (d, 1 H), 7.20 (dd, J1 = 2.8 Hz, J2 = 8.9 Hz, 1 H), 6.84 (m, 1 H), 3.88 (s, 3 H), 3.29 (m, 1 H), 2.99 (m, 1 H), 2.1 1 (m, 1 H), 1.81 (m, 3 H), 1.47 (s, 3 H).

Reference Example 4.3: (S)-N-(2-amino-4-chloro-3-methylphenyl)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl) benzoyl)-2 methylpyrrolidine-2-carboxamide

(S)-1-(5-Methoxy-2-(2/-/-1 ,2,3-triazol-2-yl) benzoyl)-2-methylpyrrolidine-2-carboxylic acid (128 g, 0.39 mol) was suspended in DCM (850 mL) and DMF (6 mL) at 20 °C. To this suspension was added oxalyl chloride (39 mL, 0.45 mol) over a period of 30 min. 4-Chloro-3-methylbenzene-1 ,2-diamine hydrochloride (75 g, 0.39 mol) was suspended in DCM (1300 mL) in a second flask. The suspension was cooled down to 10 °C. Triethylamine (180 mL, 1.27 mol) was added. The acid chloride solution was added to the reaction mixture at 10-20 °C over at least 15 min. Water (650 mL) was added to the reaction mixture. Layers were separated and the organic phase was concentrated under reduced pressure (1900 mL distilled out). TBME (1000 mL) was added and solvent was further distilled under vacuum (400 mL distilled). The mixture was finally cooled down to 20 °C and stirred for 15 min. The resulting suspension was filtered off at 20 °C. The cake was rinsed with TBME (250 mL) and then dried under reduced pressure at 50 °C to give a white solid as product. Yield: 145 g, 80%, 97% a/a (LC-MS), M+1=469. Melting point: 185 °C (DSC). 1H NMR (400 MHz, DMSO) δ: 9.10-9.14 (m, 1 H), 7.88-8.12 (m, 2 H), 7.81-7.82 (m, 1 H), 7.38-7.44 (m, 1 H), 7.21 (dd, J1 = 2.7 Hz, J2 = 8.9 Hz, 1 H), 6.84 (d, J = 7.8 Hz, 1 H), 6.64 (d, J = 8.3 Hz, 1 H), 5.01 (brs, 2 H), 3.88 (s, 3 H), 3.61-3.73 (m, 1 H), 3.14-3.26 (m, 1 H), 2.25-2.30 (m, 1 H), 2.13 (s, 3 H), 1.97 (m, 3 H), 1.47-1.61 (m, 3 H).

Reference Example 4.4: (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl) (5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride

(S)-/V-(2-amino-4-chloro-3-methylphenyl)-1-(5-methoxy-2-(2H-1 ,2,3-triazol-2-yl) benzoyl)-2 methylpyrrolidine-2-carboxamide (145 g, 0.31 mol) was dissolved in isopropanol (870 mL) at 20 °C. To this solution was added carefully 5-6 N HCI in isopropanol (260 mL) over 10 min. the reaction mixture was then heated up to 90 °C and stirred for 4 hours. Water (28 mL) was added and the reaction mixture was stirred for an additional one hour. The reaction mixture was cooled to 20 °C. A light brown suspension was obtained which was filtered. The cake was rinsed with isopropanol (220 mL). The solid was finally dried under reduced pressure at 60 °C to give a beige solid. Yield: 133 g, 88%, 100% a/a (LC-MS), M+1 =451. Melting point: 277 °C (DSC). Ή NMR (400 MHz, DMSO) δ: 8.06 (s, 2 H), 7.76 (d, J = 8.9 Hz, 1 H), 7.63 (d, J = 8.8 Hz, 2 H), 7.55 (m, 1 H), 7.16 (dd, J1 = 2.7 Hz, J2 = 8.9 Hz, 1 H), 3.98 (m, 1 H), 3.90 (s, 3 H), 3.33 (m, 2H), 3.32 (m, 1 H), 2.74 (s, 3 H), 2.55 (m, 1 H), 2.23 (m, 1 H), 2.10 (m, 2 H), 1.95 (s, 3 H).

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Clinical data
Trade namesQuviviq
Other namesNemorexant; ACT-541468
License dataUS DailyMedDaridorexant
Routes of
administration
By mouth
Drug classOrexin antagonist
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Pharmacokinetic data
Elimination half-life6–10 hours[2]
Identifiers
showIUPAC name
CAS Number1505484-82-1
PubChem CID91801202
DrugBankDB15031
ChemSpider64854514
UNIILMQ24G57E9
KEGGD11886
PDB ligandNS2 (PDBeRCSB PDB)
Chemical and physical data
FormulaC23H23ClN6O2
Molar mass450.93 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

REF

References

  1. Jump up to:a b c https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214985s000lbl.pdf
  2. Jump up to:a b Muehlan C, Vaillant C, Zenklusen I, Kraehenbuehl S, Dingemanse J (November 2020). “Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders”. Expert Opin Drug Metab Toxicol16 (11): 1063–1078. doi:10.1080/17425255.2020.1817380PMID 32901578.
  3. Jump up to:a b c “Daridorexant – Idorsia Pharmaceuticals – AdisInsight”.
  4. Jump up to:a b Equihua-Benítez AC, Guzmán-Vásquez K, Drucker-Colín R (July 2017). “Understanding sleep-wake mechanisms and drug discovery”. Expert Opin Drug Discov12 (7): 643–657. doi:10.1080/17460441.2017.1329818PMID 28511597.
  5. ^ “Daridorexant: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 11 January 2022.
  6. ^ “Idorsia receives US FDA approval of Quviviq (daridorexant)” (Press release). Idorsia Pharmaceuticals. 10 January 2022. Retrieved 11 January 2022 – via GlobeNewswire.
  • “Daridorexant”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03545191 for “Study to Assess the Efficacy and Safety of ACT-541468 in Adult and Elderly Subjects With Insomnia Disorder” at ClinicalTrials.gov
  • Clinical trial number NCT03575104 for “Study to Assess the Efficacy and Safety of ACT-541468 in Adult and Elderly Subjects Suffering From Difficulties to Sleep” at ClinicalTrials.gov
  • Clinical trial number NCT03679884 for “Study to Assess the Long Term Safety and Tolerability of ACT-541468 in Adult and Elderly Subjects Suffering From Difficulties to Sleep” at ClinicalTrials.gov

///////////////Daridorexant, Quviviq, FDA 2022, APPROVALS 2022, INSOMNIA,  ACT541468A, ACT 541468A. ACT-541468A, ACT541468, FDA 2022, APPROVALS 2022

O=C(N1[C@](C)(C2=NC3=CC=C(Cl)C(C)=C3N2)CCC1)C4=CC(OC)=CC=C4N5N=CC=N5.[H]Cl

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$10.00

TAUROLIDINE


ChemSpider 2D Image | Taurolidine | C7H16N4O4S2
Taurolidine.png

TAUROLIDINE

  • Molecular FormulaC7H16N4O4S2
  • Average mass284.356 Da

19388-87-5[RN]
243-016-5[EINECS]
2H-1,2,4-Thiadiazine, 4,4′-methylenebis[tetrahydro-, 1,1,1′,1′-tetraoxide
4,4′-methanediylbis(1,2,4-thiadiazinane) 1,1,1′,1′-tetraoxide
UNII-8OBZ1M4V3V 
тауролидин 
توروليدين 
牛磺利定 
NMR https://www.apexbt.com/downloader/document/C4559/NMR-2.pdf
MS https://www.apexbt.com/downloader/document/C4559/MS-2.pdf
Taurolidine 
CAS Registry Number: 19388-87-5 
CAS Name: 4,4¢-Methylenebis(tetrahydro-1,2,4-thiadiazine) 1,1,1¢,1¢-tetraoxide 
Additional Names: 4,4¢-methylenebis(perhydro-1,2,4-thiadiazine 1,1-dioxide); bis(1,1-dioxoperhydro-1,2,4-thiadiazin-4-yl)methane 
Trademarks: Drainasept (Geistlich); Taurolin (HMR); Tauroflex (Geistlich) 
Molecular Formula: C7H16N4O4S2, Molecular Weight: 284.36 
Percent Composition: C 29.57%, H 5.67%, N 19.70%, O 22.51%, S 22.55% 
Literature References: Broad spectrum, synthetic formaldehyde carrier formed by the condensation of two molecules of taurine and three molecules of formaldehyde. Prepn: FR1458701; R. W. Pfirrmann, US3423408 (1966, 1969 both to Ed. Geistlich Söhne). Antibacterial activity in mice: M. K. Browne et al.,J. Appl. Bacteriol.41, 363 (1976). Anti-endotoxin activity in lab animals: R. W. Pfirrmann, G. B. Leslie, ibid.46, 97 (1979). Mechanism of action: E. Myers et al.,ibid.48, 89 (1980). HPLC determn of metabolites in plasma: A. D. Woolfson et al.,Int. J. Pharm.49, 135 (1989). Pharmacokinetics: C. Steinbach-Lebbin et al.,Arzneim.-Forsch.32, 1542 (1982). Metabolism in humans: B. I. Knight et al.,Br. J. Clin. Pharmacol.12, 695 (1981). Clinical trials in peritonitis: M. K. Browne et al.,Surg. Gynecol. Obstet.146, 721 (1978); G. Wesch et al.,Fortschr. Med.101, 545 (1983); in wound sepsis: A. K. Halsall et al.,Pharmatherapeutica2, 673 (1981); in pleural infection: A. A. Conlan et al.,S. Afr. Med. J.64, 653 (1983). 
Properties: White crystals, mp 154-158°. Sol in water. 
Melting point: mp 154-158° 
Therap-Cat: Antibacterial. 
Keywords: Antibacterial (Synthetic).

Taurolidine is an antimicrobial that is used to try to prevent infections in catheters.[1] Side effects and the induction of bacterial resistance is uncommon.[1] It is also being studied as a treatment for cancer.[2]

It is derived from the endogenous amino acid taurine. Taurolidine’s putative mechanism of action is based on a chemical reaction. During the metabolism of taurolidine to taurinamide and ultimately taurine and water, methylol groups are liberated that chemically react with the mureins in the bacterial cell wall and with the amino and hydroxyl groups of endotoxins and exotoxins. This results in denaturing of the complex polysaccharide and lipopolysaccharide components of the bacterial cell wall and of the endotoxin and in the inactivation of susceptible exotoxins.[3]

PATENT

https://patents.google.com/patent/WO2012070066A1/en

Taurolidine is an antibacterial drug and also has antiendotoxic substance, which is used as an antiseptic solution in surgery for washing out the abdominal cavity and it also prevents septic shock. It is commercially sold as Taurolidine (Formula I). The present invention relates to a process for the preparation of Taurolidine which provides significant advantages over the existing processes.

Figure imgf000002_0001

Formula I

The current process for the preparation of Taurolidine is depicted in Scheme 1

Figure imgf000003_0001

Formula II

Figure imgf000003_0002

Formula IVFormula IThe present inventors thus propose an industrially viable procedure for isolation of Taurolidine in substantially pure form.Taurolidine is dissolved in a suitable solvent to obtain a clear solution. The product starts to precipitate and an anti solvent is added optionally to maximize the precipitation procedure. The solvents employed for the purification are non -aqueous aprotic solvents comprising DMSO, DMAc, DMF, Acetonitirle, DMSO being the most preferred solvent. The antisolvents employed are toluene, ethyl acetate, dichloromethane, ether; toluene being the most preferred.Taurolidine obtained by the instant procedure has purity greater than or equal to 99.5 %. The process of the invention is illustrated by the following examples to obtain Taurolidine. Example ICbz-Taurine sodium salt (Formula II)To 1000ml of water in the RBF charge 192gm of (3.0 eq) of sodium hydroxide under cooling followed by 200gm of Taurine and dissolve it until clear solution is obtained. Cool to 0°C to 5°C, and Charge 50% CBZ-C1 in toluene at 0°C to 5°C. After completion of addition, maintain at room temperature for 14h. Separate the toluene layer and wash the aqueous layer with 2x200ml of ethyl acetate. Add slowly 27gm of sodium hydroxide in 60ml of water to the aqueous layer and adjust pH to 12- 14. Cool to 0°C to 5°C and a white solid separates from the solution. Filter the solid and dry the solid at 60 -70 °C. Weight of the solid: 320 gExample 2Cbz-Taurinamide (Formula III)To a clean dry flask charge 1500ml of toluene and charge 320gm of Formula II and cool to 0°C to 5°C. Charge 308 gm of PC15 slowly at 0°C to 5°C for 2hrs. Maintain at 0°C to 5°C up to completion of reaction. Quench the RM into another flask containing 2 ltr of water at 0°C to 5°C. Separate the organic layer, wash and extract the aqueous layer with toluene. Dry the organic layer with sodium sulphate and cool to 0°C to 5°C. Purge ammonia gas into the reaction mass till the reaction is complete. Filter the solid and dissolve the solid in 21tr of water and extract the aqueous layer with 2x600ml of ethyl acetate. Dry the organic layer with sodium sulphate and concentrate it under reduced pressure to obtain a white solid. Weight of the solid: 150 gExample 3Taurinamide Succinate (Formula IV)Take a suspension of 100 g of Cbz-Taurinamide in 1000 ml methanol, and 10% Pd/C (1 .0 g) and subject to hydrogenation at 45-50 psi. Upon completion of the reaction filter the catalyst and add succinic acid (1 .0 eq) to the solvent and distill off the solvent under vacuum to provide the title compound in about 90% yield as a white solid.Example 4Taurolidine (Formula I)To a solution of 100 g Taurinamide succinate in water is added sat sodium bicarbonate solution and pH adjusted to 7-8. To the solution was added formaldehyde (50 ml) and allowed to stir for 4 h. The solid obtained was filtered and washed with water to give Taurolidine. The title compound was obtained in about 70% yield and about 98% purity.Example 5Purification of TaurolidineTaurolidine (100 g) was dissolved in DMSO (400 ml) and a clear solution is obtained and a precipitate is obtained immediately. The solid is filtered and washed with toluene and dried to give a white solid in 40 % yield. The product obtained was >99.5% pure.Example 6Purification of TaurolidineTaurolidine (100 g) was dissolved in DMSO (400 ml) and a clear solution is obtained and a precipitate is obtained immediately. To the solution, toluene (1000 ml) is added. The solid is filtered and washed with toluene and dried to give a white solid in 70 % yield. The product obtained was >99.5% pure by HPLC and passed elemental analysis within 0.4% of the theoretical values.Example 7Purification of TaurolidineTaurolidine (100 g) was dissolved in DMAc (800 ml) and to the solution, toluene (1000 ml) is added. The solid is filtered and washed with toluene and dried to give a white solid in 70% yield.

PATENT

WO/2022/007713

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022007713&_cid=P12-KYJIDL-52672-1Taurolidine (English name Taurolidine, chemical name is 4,4′-methylenebis[tetrahydro-2H-1,2,4-thiadiazine] 1,1,1′,1′-tetraoxide , the molecular formula is C 7 H 16 N 4 O 4 S 2 ) is a derivative of the amino acid taurine, and its structure is as follows:

Taurolidine has anti-endotoxin, anti-bacterial and anti-adherent properties. In terms of bacteria, taurolidine can chemically react with cell walls, endotoxins and exotoxins to inhibit microbial adhesion and play an antibacterial role. In addition, in terms of anti-tumor, taurolidine can induce cytotoxicity of tumor cells by inducing apoptosis, autophagy and necrosis. The extent to which these processes are involved may vary with the type of tumor cell. Until July 2020, there were more than 260 foreign literature searches on taurolidine research reports, most of which focused on the exploration of the effect of taurolidine on tumor-related signaling pathways, while the application of taurolidine in antiviral activity was not yet available. See research reports. 
PATENThttps://patents.google.com/patent/CN101274921B/en
Taurolidine synthetic operation step:1. the preparation of tauryl villaumite hydrochlorate 
In being housed, ventpipe, escape pipe, thermometer and churned mechanically 300ml four-necked bottle add Mercaptamine 25g, 200ml methylene dichloride and 32ml dehydrated alcohol, under ice-water bath (below the 10 ℃) mechanical stirring, feed dry appropriate chlorine, reaction begins and heat release immediately, the thick solid of adularescent generates, and temperature remains on below 50 ℃ and stirs, reaction 5h.The whole process HCl gas and the monochloroethane gas of alkali lye absorption reaction process.Stop logical chlorine after reacting end, get yellow mercury oxide, suction filtration is used washed with dichloromethane four times, and vacuum-drying gets white solid 50g, 152~154 ℃ of fusing points.2. the preparation of tauryl azide salt hydrochlorate 
The reaction flask ice-water bath of containing 45ml water is cooled to-15 ℃, adds NaN 3(2g), after stirring is molten entirely, add slightly pinkiness of tauryl villaumite hydrochlorate (9g) solution in batches, the water-bath of 20 minutes recession deicings, room temperature continues stirring 60 minutes.3. the preparation of tauryl amine hydrochlorate 
Above-mentioned reaction solution is joined in the 500ml autoclave, add 0.5g 5%Pd/C, feed hydrogen, pressure is 7Mpa, stirring at room 6h.Turn off hydrogen, pour out reaction solution, elimination Pd/C gets colourless reaction solution.The reaction solution that takes a morsel adds in the nuclear-magnetism pipe, adds deuterated reagent D 2O, with 1HNMR determines the transformation efficiency of hydrogenation reaction.Two kinds of CH of tauryl amine hydrochlorate 21The HNMR peak is 3.29~3.31 and 3.40~3.42ppm place, and two kinds of CH of reactant tauryl azide salt hydrochlorate 21The HNMR peak is 3.37~3.38 and 3.82~3.84ppm place.Determine that with the peak height ratio of two kinds of compounds the 4th step added the amount of formaldehyde.4. the preparation of taurolidine 
With the above-mentioned reaction solution that removes by filter Pd/C, add 5g NaHCO 3, be stirred to molten entirely, frozen water cooling, stir slowly splash into down formaldehyde solution (37%, 2ml), have milky white precipitate to produce after 30 minutes, continue to stir 1h, suction filtration, filter cake is washed 3 times with frozen water.Vacuum-drying gets white powdery solid 2.3g, 170~174 ℃ of fusing points.Embodiment 2:Making with extra care of taurolidine:The above-mentioned taurolidine white powder 5~10g that obtains adds 50~200ml acetonitrile, and heating for dissolving removes by filter a small amount of insolubles, concentrates, and cooling below 10 ℃ gets white powder 5~10g, 172~174 ℃ of fusing points.Embodiment 3:Proton nmr spectra ( 1H-NMR) data are as follows:1HNMR(DMSO-D6,TMS7.26-7.28(t,2H,NH),4.09-4.10(d,4H,N-CH 2),3.53(s,2H,N-CH 2-N),3.28-3.29(t,4H,N-CH 2-CH 2),2.96-2.97(t,4H,S-CH 2-CH 2)。The infrared absorption spectrum data are as follows:IR (KBr compressing tablet cm -1): 3425,3263,1633,1450,1404,1317,1278,1228,1160,1134,1073,1026,993,958,924,830,757,667,532,511.See Fig. 3.The ultimate analysis analytical value:C, 29.04%, N, 18.55%, H, 5.85%; Calculated value: C, 29.57%, N, 19.71%, H, 5.67%Embodiment 4:Taurolidine formulation optimizing injection type of the present invention, as: infusion solution, injection liquid, freeze-dried powder injection or powder ampoule agent for injection etc., more preferably infusion solution.The preparation of infusion solution[prescription 1] taurolidine 10.0~30.0gPVP 40.0~80.0gNaCl 2~5gAdd water to 1000ml[method for making] takes by weighing taurolidine, is dissolved in water, and stirs, and adds the PVP dissolving, and adjust pH to 7.0 is crossed the moisture film of 0.22 μ m, packing, and 121 ℃ of sterilizations 20 minutes, promptly.[prescription 2] taurolidine 10.0~30.0gCitric acid 0.1~1.0gLemon enzyme sodium 10.0~20.0gAdd water to 1000ml[method for making] takes by weighing taurolidine, is dissolved in water, stir, and the dissolving of adding citric acid sodium, adjust pH to 7.0, the moisture film of mistake 0.22 μ m, packing was sterilized 20 minutes for 121 ℃, promptly. 
PATENThttps://patents.google.com/patent/US8952148B2/en

Figure US08952148-20150210-C00002

Example ICbz-Taurine Sodium Salt (Formula II)To 1000 ml of water in the RBF charge 192 gm of (3.0 eq) of sodium hydroxide under cooling followed by 200 gm of Taurine and dissolve it until clear solution is obtained. Cool to 0° C. to 5° C., and Charge 50% CBZ-Cl in toluene at 0° C. to 5° C. After completion of addition, maintain at room temperature for 14 h. Separate the toluene layer and wash the aqueous layer with 2×200 ml of ethyl acetate. Add slowly 27 gm of sodium hydroxide in 60 ml of water to the aqueous layer and adjust pH to 12-14. Cool to 0° C. to 5° C. and a white solid separates from the solution. Filter the solid and dry the solid at 60-70° C. Weight of the solid: 320 g

Example 2Cbz-Taurinamide (Formula III)To a clean dry flask charge 1500 ml of toluene and charge 320 gm of Formula II and cool to 0° C. to 5° C. Charge 308 gm of PClslowly at 0° C. to 5° C. for 2 hrs. Maintain at 0° C. to 5° C. up to completion of reaction. Quench the RM into another flask containing 2 ltr of water at 0° C. to 5° C. Separate the organic layer, wash and extract the aqueous layer with toluene. Dry the organic layer with sodium sulphate and cool to 0° C. to 5° C. Purge ammonia gas into the reaction mass till the reaction is complete. Filter the solid and dissolve the solid in 2 ltr of water and extract the aqueous layer with 2×600 ml of ethyl acetate. Dry the organic layer with sodium sulphate and concentrate it under reduced pressure to obtain a white solid. Weight of the solid: 150 g

Example 3Taurinamide Succinate (Formula IV)Take a suspension of 100 g of Cbz-Taurinamide in 1000 ml methanol, and 10% Pd/C (1.0 g) and subject to hydrogenation at 45-50 psi. Upon completion of the reaction filter the catalyst and add succinic acid (1.0 eq) to the solvent and distill off the solvent under vacuum to provide the title compound in about 90% yield as a white solid.

Example 4Taurolidine (Formula I)To a solution of 100 g Taurinamide succinate in water is added sat sodium bicarbonate solution and pH adjusted to 7-8. To the solution was added formaldehyde (50 ml) and allowed to stir for 4 h. The solid obtained was filtered and washed with water to give Taurolidine. The title compound was obtained in about 70% yield and about 98% purity.

Example 5Purification of TaurolidineTaurolidine (100 g) was dissolved in DMSO (400 ml) and a clear solution is obtained and a precipitate is obtained immediately. The solid is filtered and washed with toluene and dried to give a white solid in 40% yield. The product obtained was >99.5% pure.

Example 6Purification of TaurolidineTaurolidine (100 g) was dissolved in DMSO (400 ml) and a clear solution is obtained and a precipitate is obtained immediately. To the solution, toluene (1000 ml) is added. The solid is filtered and washed with toluene and dried to give a white solid in 70% yield. The product obtained was >99.5% pure by HPLC and passed elemental analysis within 0.4% of the theoretical values.

Example 7Purification of TaurolidineTaurolidine (100 g) was dissolved in DMAc (800 ml) and to the solution, toluene (1000 ml) is added. The solid is filtered and washed with toluene and dried to give a white solid in 70% yield. 

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Medical uses

Taurolidine is an antimicrobial agent used in an effort to prevent catheter infections. It however is not approved for this use in the United States as of 2011.[4]

  • Catheter lock solution in home parenteral nutrition (HPN) or total parenteral nutrition (TPN): catheter-related blood stream infections (CRBSI) remains the most common serious complication associated with long-term parenteral nutrition. The use of taurolidine as a catheter lock solution shows a reduction of CRBSI.[1][5] The overall quality of the evidence however is not strong enough to justify routine use.[1][5]
  • Catheter lock solution: Taurolidine decreases the adherence of bacteria and fungi to host cells by destructing the fimbriae and flagella and thus prevent the biofilm formation.[6][7] Taurolidine is the active ingredient of antimicrobial catheter lock solutions for the prevention and treatment of catheter related bloodstream infections (CRBSIs) and is suitable for use in all catheter based vascular access devices.[8][1] Bacterial resistance against taurolidine has never been observed in various studies.[9][10]
  • The use of a taurolidine lock solution may decrease the risk of catheter infection in children with cancer but the evidence is tentative.[11]

Side effects

No systemic side effects have been identified. The safety of taurolidine has also been confirmed in clinical studies with long-term intravenous administration of high doses (up to 20 grams daily). In the body, taurolidine is metabolized rapidly via the metabolites taurultam and methylol taurinamide, which also have a bactericidal action, to taurine, an endogenous aminosulphonic acid, carbon dioxide and water. Therefore, no toxic effects are known or expected in the event of accidental injection. Burning sensation while instilling, numbness, erythema, facial flushing, headache, epistaxis, and nausea have been reported.[12]

Toxicology

Taurolidine has a relatively low acute and subacute toxicity.[1] Intravenous injection of 5 grams taurolidine into humans over 0.5–2 hours produce only burning sensation while instilling, numbness, and erythema at the injection sites.[12] For treatment of peritonitis, taurolidine was administered by peritoneal lavage, intraperitoneal instillation or intravenous infusion, or by a combination thereof. The total daily dose ranged widely from 0.5 to 50 g. The total cumulative dose ranged from 0.5 to 721 g. In those patients who received intravenous taurolidine, the daily intravenous dose was usually 15 to 30 g but several patients received up to 40 g/day. Total daily doses of up to 40 g and total cumulative doses exceeding 300 g were safe and well tolerated.[12][13][14][15][16]

Pharmacology

  • Metabolism: Taurolidine and taurultam are quickly metabolized to taurinamide, taurine, carbon dioxide and water. Taurolidine exists in equilibrium with taurultam and N-methylol-taurultam in aqueous solution.[17]
  • Pharmacokinetic (elimination): The half-life of the terminal elimination phase of taurultam is about 1.5 hours, and of the taurinamide metabolite about 6 hours. 25% of the taurolidine dose applied is renally eliminated as taurinamide and/or taurine.[13][14][18]

Mechanism of action

Following administration of taurolidine, the antimicrobial and antiendotoxin activity of the taurolidine molecule is conferred by the release of three active methylol (hydroxymethyl) groups as taurolidine is rapidly metabolized by hydrolysis via methylol taurultam to methylol taurinamide and taurine. These labile N-methylol derivatives of taurultam and taurinamide react with the bacterial cell-wall resulting in lysis of the bacteria, and by inter- and intramolecular cross-linking of the lipopolysaccharide-protein complex, neutralization of the bacterial endotoxins which is enhanced by enzymatic activation. This mechanism of action is accelerated and maximised when taurolidine is pre-warmed to 37 °C (99 °F). Microbes are killed and the resulting toxins are inactivated; the destruction time in vitro is 30 minutes.[19]

The chemical mode of action of taurolidine via its reactive methylol groups confers greater potency in vivo than indicated by in vitro minimum inhibitory concentration (MIC) values, and also appears to preclude susceptibility to resistance mechanisms.[14]

Taurolidine binding to lipopolysaccharides (LPS) prevents microbial adherence to host epithelial cells, thereby prevents microbial invasion of uninfected host cells. Although the mechanism underlying its antineoplastic activity has not been fully elucidated, it may be related to this agent’s anti-adherence property.[6][7] Taurolidine has been shown to block interleukin 1 (IL-1) and tumour necrosis factor (TNF) in human peripheral blood mononuclear cells (PBMC).[20] In addition, taurolidine also promotes apoptosis by inducing various apoptotic factors and suppresses the production of vascular endothelial growth factor (VEGF), a protein that plays an important role in angiogenesis.[21]

Taurolidine is highly active against the common infecting pathogens associated with peritonitis and catheter sepsis, this activity extends across a wide-spectrum of aerobic and anaerobic bacteria and fungi (with no diminution of effect in the presence of biological fluids, e.g. blood, serum, pus).[15][16][22]

Chemical properties

The chemical name for taurolidine is 4,4′-Methylene-bis(1,2,4-thiadiazinane)-1,1,1’,1′-tetraoxide.

It is a white to off white odourless crystalline powder. It is practically insoluble in chloroform, slightly soluble in boiling acetone, ethanol, methanol, and ethyl acetate, sparingly soluble in water 8 at 20° and ethyl alcohol, soluble in dilute hydrochloric acid, and dilute sodium hydroxide, and freely soluble in N,N-dimethylformamide (at 60 °C).

History

Taurolidine was first synthesized in the laboratories of Geistlich Pharma AG, Switzerland in 1972. Clinical trials begun in 1975 in patients with severe peritonitis.

Research

Taurolidine demonstrates some anti-tumor properties, with positive results seen in early-stage clinical investigations using the drug to treat gastrointestinal malignancies and tumors of the central nervous system.[23] More recently, it has been found to exert antineoplastic activity. Taurolidine induces cancer cell death through a variety of mechanisms. Even now, all the antineoplastic pathways it employs are not completely elucidated. It has been shown to enhance apoptosis, inhibit angiogenesis, reduce tumor adherence, downregulate pro-inflammatory cytokine release, and stimulate anticancer immune regulation following surgical trauma. Apoptosis is activated through both a mitochondrial cytochrome-c-dependent mechanism and an extrinsic direct pathway. A lot of in vitro and animal data support taurolidine’s tumoricidal action.[24][25][26] Taurolidine has been used as an antimicrobial agent in the clinical setting since the 1970s and thus far appears nontoxic. The nontoxic nature of taurolidine makes it a favorable option compared with current chemotherapeutic regimens. Few published clinical studies exist evaluating the role of taurolidine as a chemotherapeutic agent. The literature lacks a gold-standard level 1 randomized clinical trial to evaluate taurolidine’s potential antineoplastic benefits. However, these trials are currently underway. Such randomized control studies are vital to clarify the role of taurolidine in modern cancer treatment.[21][2]

References

  1. Jump up to:a b c d e f Liu Y, Zhang AQ, Cao L, Xia HT, Ma JJ (2013). “Taurolidine lock solutions for the prevention of catheter-related bloodstream infections: a systematic review and meta-analysis of randomized controlled trials”PLOS ONE8 (11): e79417. Bibcode:2013PLoSO…879417Ldoi:10.1371/journal.pone.0079417PMC 3836857PMID 24278133.
  2. Jump up to:a b Neary PM, Hallihan P, Wang JH, Pfirrmann RW, Bouchier-Hayes DJ, Redmond HP (April 2010). “The evolving role of taurolidine in cancer therapy”. Annals of Surgical Oncology17 (4): 1135–43. doi:10.1245/s10434-009-0867-9PMID 20039217S2CID 23807182.
  3. ^ Waser PG, Sibler E (1986). “Taurolidine: A new concept in antimicrobial chemotherapy”. In Harms AF (ed.). Innovative Approaches in Drug Research. Elsevier Science Publishers. pp. 155–169.
  4. ^ O’Grady NP, Alexander M, Burns LA, Dellinger EP, Garland J, Heard SO, et al. (May 2011). “Guidelines for the prevention of intravascular catheter-related infections”Clinical Infectious Diseases52 (9): e162-93. doi:10.1093/cid/cir257PMC 3106269PMID 21460264.
  5. Jump up to:a b Bradshaw JH, Puntis JW (August 2008). “Taurolidine and catheter-related bloodstream infection: a systematic review of the literature”. Journal of Pediatric Gastroenterology and Nutrition47 (2): 179–86. doi:10.1097/MPG.0b013e318162c428PMID 18664870S2CID 19136945.
  6. Jump up to:a b Gorman SP, McCafferty DF, Woolfson AD, Jones DS (April 1987). “Reduced adherence of micro-organisms to human mucosal epithelial cells following treatment with Taurolin, a novel antimicrobial agent”. The Journal of Applied Bacteriology62 (4): 315–20. doi:10.1111/j.1365-2672.1987.tb04926.xPMID 3298185.
  7. Jump up to:a b Blenkharn JI (July 1989). “Anti-adherence properties of taurolidine and noxythiolin”. Journal of Chemotherapy1 (4 Suppl): 233–4. PMID 16312382.
  8. ^ Liu H, Liu H, Deng J, Chen L, Yuan L, Wu Y (2014). “Preventing catheter-related bacteremia with taurolidine-citrate catheter locks: a systematic review and meta-analysis”Blood Purification37 (3): 179–87. doi:10.1159/000360271PMID 24777144.
  9. ^ Olthof ED, Rentenaar RJ, Rijs AJ, Wanten GJ (August 2013). “Absence of microbial adaptation to taurolidine in patients on home parenteral nutrition who develop catheter related bloodstream infections and use taurolidine locks”. Clinical Nutrition32 (4): 538–42. doi:10.1016/j.clnu.2012.11.014PMID 23267744.
  10. Jump up to:a b Torres-Viera C, Thauvin-Eliopoulos C, Souli M, DeGirolami P, Farris MG, Wennersten CB, et al. (June 2000). “Activities of taurolidine in vitro and in experimental enterococcal endocarditis”Antimicrobial Agents and Chemotherapy44 (6): 1720–4. doi:10.1128/aac.44.6.1720-1724.2000PMC 89943PMID 10817739.
  11. ^ Simon A, Bode U, Beutel K (July 2006). “Diagnosis and treatment of catheter-related infections in paediatric oncology: an update”Clinical Microbiology and Infection12 (7): 606–20. doi:10.1111/j.1469-0691.2006.01416.xPMID 16774556.
  12. Jump up to:a b c Gong L, Greenberg HE, Perhach JL, Waldman SA, Kraft WK (June 2007). “The pharmacokinetics of taurolidine metabolites in healthy volunteers”Journal of Clinical Pharmacology47 (6): 697–703. doi:10.1177/0091270007299929PMID 17395893S2CID 31059736.
  13. Jump up to:a b Knight BI, Skellern GG, Browne MK, Pfirrmann RW (November 1981). “Peritoneal absorption of the antibacterial and antiendotoxin taurolin in peritonitis”British Journal of Clinical Pharmacology12 (5): 695–9. doi:10.1111/j.1365-2125.1981.tb01292.xPMC 1401955PMID 7332737.
  14. Jump up to:a b c Stendel R, Scheurer L, Schlatterer K, Stalder U, Pfirrmann RW, Fiss I, et al. (2007). “Pharmacokinetics of taurolidine following repeated intravenous infusions measured by HPLC-ESI-MS/MS of the derivatives taurultame and taurinamide in glioblastoma patients”. Clinical Pharmacokinetics46 (6): 513–24. doi:10.2165/00003088-200746060-00005PMID 17518510S2CID 33321671.
  15. Jump up to:a b Browne MK, MacKenzie M, Doyle PJ (May 1978). “C controlled trial of taurolin in established bacterial peritonitis”. Surgery, Gynecology & Obstetrics146 (5): 721–4. PMID 347606.
  16. Jump up to:a b Browne MK (1981). “The treatment of peritonitis by an antiseptic – taurolin”. Pharmatherapeutica2 (8): 517–22. PMID 7255507.
  17. Jump up to:a b Knight BI, Skellern GG, Browne MK, Pfirrmann RW (September 1981). “The characterisation and quantitation by high-performance liquid chromatography of the metabolites of taurolin”British Journal of Clinical Pharmacology12 (3): 439–40. doi:10.1111/j.1365-2125.1981.tb01245.xPMC 1401804PMID 7295478.
  18. ^ Browne MK, Leslie GB, Pfirrmann RW (December 1976). “Taurolin, a new chemotherapeutic agent”. The Journal of Applied Bacteriology41 (3): 363–8. doi:10.1111/j.1365-2672.1976.tb00647.xPMID 828157.
  19. ^ Braumann C, Pfirrman RW, et al. (2013). “Taurolidine, an Effective Multimodal Antimicrobial Drug Versus Traditional Antiseptics and Antibiotics”. In Willy C (ed.). Antiseptics in Surgery – Update 2013. Lindqvist Book Publishing. pp. 119–125.
  20. ^ Bedrosian I, Sofia RD, Wolff SM, Dinarello CA (November 1991). “Taurolidine, an analogue of the amino acid taurine, suppresses interleukin 1 and tumor necrosis factor synthesis in human peripheral blood mononuclear cells”. Cytokine3 (6): 568–75. doi:10.1016/1043-4666(91)90483-tPMID 1790304.
  21. Jump up to:a b Jacobi CA, Menenakos C, Braumann C (October 2005). “Taurolidine–a new drug with anti-tumor and anti-angiogenic effects”. Anti-Cancer Drugs16 (9): 917–21. doi:10.1097/01.cad.0000176502.40810.b0PMID 16162968S2CID 33876185.
  22. Jump up to:a b Nösner K, Focht J (1994). “In-vitro Wirksamkeit von Taurolidin und 9 Antibiotika gegen klinische Isolate aus chirurgischem Einsendegut sowie gegen Pilze”. Chirurgische Gastroenterologie10 (Suppl 2): 10.
  23. ^ Stendel R, Picht T, Schilling A, Heidenreich J, Loddenkemper C, Jänisch W, Brock M (2004-04-01). “Treatment of glioblastoma with intravenous taurolidine. First clinical experience”. Anticancer Research24 (2C): 1143–7. PMID 15154639.
  24. ^ Calabresi P, Goulette FA, Darnowski JW (September 2001). “Taurolidine: cytotoxic and mechanistic evaluation of a novel antineoplastic agent”. Cancer Research61 (18): 6816–21. PMID 11559556.
  25. ^ Clarke NW, Wang JH, et al. (2005). “Taurolidine inhibits colorectal adenocarcinoma metastases in vivo and in vitro by inducing apoptosis”. Ir J Med Sci174 (Supplement 3): 1.
  26. ^ Stendel R, Scheurer L, Stoltenburg-Didinger G, Brock M, Möhler H (2003-06-01). “Enhancement of Fas-ligand-mediated programmed cell death by taurolidine”. Anticancer Research23 (3B): 2309–14. PMID 12894508.
Clinical data
ATC codeB05CA05 (WHO)
Identifiers
showIUPAC name
CAS Number19388-87-5
ChemSpider27486
UNII8OBZ1M4V3V
CompTox Dashboard (EPA)DTXSID00173001 
ECHA InfoCard100.039.090 
Chemical and physical data
FormulaC7H16N4O4S2
Molar mass284.35 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

////////////////////TAUROLIDINE, UNII-8OBZ1M4V3V, тауролидин  ,توروليدين , 牛磺利定  ,

C1CS(=O)(=O)NCN1CN2CCS(=O)(=O)NC2

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Anthony crasto is now Consultant Glenmark Lifesciences at Glenmark Life Sciences!


I’m happy to share that I’m starting a new position as Consultant Glenmark Lifesciences at Glenmark Life Sciences!
17th Jan 2022, A new innings

I retired 16th Jan 2022 at 58 yrs from Glenmark . completed 16 yrs 2 months

30 plus years in the field of Process research

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DIPYRIDAMOLE


Dipyridamole.svg
ChemSpider 2D Image | Dipyridamole | C24H40N8O4

Dipyridamole

  • Molecular FormulaC24H40N8O4
  • Average mass504.626 Da

2,2′,2”,2”’-{[4,8-Di(piperidin-1-yl)pyrimido[5,4-d]pyrimidine-2,6-diyl]dinitrilo}tetraethanol
200-374-7[EINECS]
58-32-2[RN]
Ethanol, 2,2′,2”,2”’-[(4,8-di-1-piperidinylpyrimido[5,4-d]pyrimidine-2,6-diyl)dinitrilo]tetrakis-
дипиридамол [Russian] [INN]
ديبيريدامول [Arabic] [INN]
双嘧达莫 [Chinese] [INN]
0068373 [Beilstein]
DipyridamoleCAS Registry Number: 58-32-2 
CAS Name: 2,2¢,2¢¢,2¢¢¢-[(4,8-Di-1-piperidinylpyrimido[5,4-d]pyrimidine-2,6-diyl)dinitrilo]tetrakisethanol 
Additional Names: 2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido-[5,4-d]pyrimidine 
Manufacturers’ Codes: NSC-515776; RA-8 
Trademarks: Anginal (Yamanouchi); Cardoxin (RAFA); Cleridium (Marcofina); Coridil (Delalande); Coronarine (NEGMA); Curantyl (Berlin-Chemie); Dipyridan (Hokuriku); Gulliostin (Taiyo); Natyl (Interdelta); Peridamol (Boehringer, Ing.); Persantine (Boehringer, Ing.); Piroan (Towa Yakuhin); Prandiol (Bottu); Protangix (Lefrancq) 
Molecular Formula: C24H40N8O4 
Molecular Weight: 504.63 
Percent Composition: C 57.12%, H 7.99%, N 22.21%, O 12.68% 
Literature References: Phosphodiesterase inhibitor that reduces platelet aggregation; also acts as a coronary vasodilator. Prepn: GB807826; F. G. Fischer, et al.,US3031450 (1959, 1962 both to Thomae). Activity studies: Saraf, Seth, Indian J. Physiol. Pharmacol.15, 135 (1971). Toxicological study: F. Takenaka et al.,Arzneim.-Forsch.22, 892 (1972). Symposium on pharmacology and clinical experience as antithrombotic: Thromb. Res.60, Suppl. 12, 1-99 (1990). Review of use as pharmacological stress agent in echocardiography: M. B. Buchalter et al.,Postgrad. Med. J.66, 531-535 (1990); in 201Tl cardiac imaging: S. G. Beer et al.,Am. J. Cardiol.67, Suppl., 18D-26D (1991). 
Properties: Deep yellow needles from ethyl acetate, mp 163°. Bitter taste. Slightly sol in H2O; sol in dil acid having a pH of 3.3 or below; very sol in methanol, ethanol, chloroform; not too sol in acetone, benzene, ethyl acetate. Solns are yellow and show strong blue-green fluorescence. LD50 in rats: 8.4 g/kg orally; 208 mg/kg i.v. (Takenaka).Melting point: mp 163° 
Toxicity data: LD50 in rats: 8.4 g/kg orally; 208 mg/kg i.v. (Takenaka) 
Derivative Type: Combination with aspirin 
Trademarks: Aggrenox (Boehringer, Ing.) 
Literature References: Review of pharmacology and clinical efficacy in secondary prevention of stroke: P. S. Hervey, K. L. Goa, Drugs58, 469-475 (1999). 
Therap-Cat: Antithrombotic; diagnostic aid (cardiac stress testing). 
Keywords: Antithrombotic; Diagnostic Aid; Phosphodiesterase Inhibitor.

Dipyridamole (trademarked as Persantine and others) is a nucleoside transport inhibitor and a PDE3 inhibitor medication that inhibits blood clot formation[3] when given chronically and causes blood vessel dilation when given at high doses over a short time.

PATENT

https://patents.google.com/patent/WO2011151640A1/enDipyridamole, represented by structural formula (I), possesses platelet aggregation inhibiting, anti-thrombotic and vasodilator properties and it is marketed as an anti-platelet therapy for the treatment and prevention of disorders such as thrombo-embolisms.

Figure imgf000002_0001

A process for the preparation of dipyridamole, disclosed in patent US 3031450, involves the reaction of 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine (see Scheme 1). The preparation of 2,6-dichloro-4,8-dipiperidino- pyrimido(5,4-d)pyrimidine is also reported in US 3031450 and is incorporated herein by reference. The reaction to prepare dipyridamole does not employ an additional reaction solvent and is a neat mixture of the two reactants carried out at a very high temperature of 190 to 195°C. The process also involves a cumbersome work-up to isolate dipyridamole, since the crude product obtained is a pasty mass which needs decantation of the mother liquor and further purification. This decantation process is not practical on commercial scale.

Figure imgf000003_0001

2,6-dichloro-4,8-dipiperidino- dipyridamole (Ί) pyflmido(5,4-d)pyrimidineScheme 1A similar process for the production of dipyridamole is described in patent DD 117456 wherein the reaction conditions exemplified are heating 2,6-dichloro-4,8-dipiperidino- pyrimido(5,4-d)pyrimidine and diethanolamine at 155 to 160°C under vacuum. However, this process again requires a high temperature which leads to the formation of impurities.A process for the preparation and purification of dipyridamole is disclosed in patent DE 1812918, wherein 2,6-dicMoro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine and diethanolamine are heated to 150 to 200°C. After completion of the reaction, the reaction mixture is dissolved in chloroform, which is further separated into an upper layer of diethanolamine and its hydrochloride and a chloroform solution. The chloroform solution obtained is separated and reduced to dryness after stirring with water. This process also requires a high temperature which can lead to the formation of impurities. In addition, the solvent used for the isolation of dipyridamole, chloroform, is inconvenient as it is a restricted solvent and its permitted limit in the final marketed dipyridamole is very low.A similar process, wherein dipyridamole is manufactured by the reaction of diethanolamine with 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine is disclosed in patent RO 104718. However, this process again requires high temperatures of 180 to 200°C which leads to the formation of impurities and, consequently, the yield of the final product is very low (58%) with a purity of less than 98%.A process is disclosed in patent DD 115670, wherein the purification of dipyridamole involves refluxing it in butyl acetate, AcOBu, for 2 hours in the presence of an equal amount of silica gel or column chromatography on silica gel at 60-100°C. However, purification by column chromatography is not economical and not feasible on industrial scale. Moreover, this purification process only removes one specific impurity, 2,4,6-tris- (diethanolamino) – 8 -pip eridino-pyrimido (5,4-d)pyrimidine .The processes described above to prepare dipyridamole do not employ an additional reaction solvent but involve neat mixtures of the two reactants, 2,6-dichloro-4,8- dipiperidino-pyrimido(5,4-d)pyrimidine and diethanolamine, which are heated at very high temperatures. The use of neat reaction mixtures and/ or high temperatures means that it is very difficult to control the levels of impurities formed.Another process for the preparation of dipyridamole, disclosed in patent application WO 2007/080463, involves reacting diethanolamine with 2,6-dichloro-4,8-dipiperidino- pyrimido(5,4-d)pyrimidine in a solvent selected from the group consisting of l-methyl-2- pyrrolidinone, sulpholane and polyethylene glycol. However, the exemplified reaction temperatures are very high at 190 to 200°C and the HPLC purity of the crude dipyridamole is reported to be only 90-94%. A purification method is disclosed using first a ketonic solvent and then an alcohol and water. Even though the process disclosed in this patent application uses a solvent in the reaction, the temperature of reaction is still very high and the purification in ketonic solvent is reported at high temperature (100 to 120°C). The HPLC purity after purification is reported as only 99.0-99.5%.As discussed above, all the processes disclosed in the prior art for the preparation of dipyridamole suffer from serious disadvantages with respect to commercial production. The prior art synthetic and purification processes employ high temperatures in the preparation of dipyridamole which leads to inefficiency and high processing costs. The high temperatures also lead to higher levels of impurities being formed during manufacture with the consequence that further cumbersome and expensive purification procedures are required.The high quality dipyridamole prepared by the processes according to the present invention can be used for the preparation of a pharmaceutical composition to use in the manufacture of a medicament for anti-platelet therapy. A preferred embodiment of the present invention, illustrated in Scheme 2, provides a process for the preparation of dipyridamole comprising reacting 2,6-dichloro-4,8- dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine at 113-115°C. This reaction temperature is significantly lower than that used in the prior art processes to prepare dipyridamole.

Figure imgf000014_0001

Another preferred embodiment of the present invention, illustrated in Scheme 3, also provides a process for the preparation of dipyridamole by the reaction of 2,6-dichloro-4,8- dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine in dimethylsulfoxide at 120- 125°C to afford the mono-substituted intermediate, 2-chloro-6-diethanolamino-4,8- dipiperidino-pyrimido(5,4-d)pyrimidine, which is isolated and then further converted to dipyridamole by heating in diethanolamine at 113-115°C.Although the solvent used in this preferred embodiment of the present invention is preferably dimethylsulfoxide (DMSO), other solvents can alternatively be used. Preferred alternative solvents are other polar aprotic solvents, such as dimethylformamide (DMF), dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP). Alternatively, hydrocarbon solvents can be used. Preferred hydrocarbon solvents are aromatic hydrocarbon solvents such as toluene or xylene.

Figure imgf000015_0001
Figure imgf000015_0002

Example 1Preparation of crude dipyridamoleDiethanolamine (10 vol) and 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine (1 eq) were mixed at 25-30°C, stirred for 10 minutes and then heated at 113-115°C for 45-48 hours. After completion of the reaction, the mixture was cooled to 75-80°C. Ethanol (5 vol) was added at 75-80°C and the mixture was stirred at 75-80°C for 10 minutes. Toluene (10 vol) was added at 70-75°C and the mixture was stirred at 70-75°C for 15 minutes. Purified water (15 vol) was added at 70-75°C and the mixture was stirred at 60-65°C for 30 minutes. The mixture was then cooled and stirred at 25-30°C for 30 minutes. The precipitated solid was filtered and washed with purified water (2 x 5 vol) before drying at 75-80°C under reduced pressure afforded crude dipyridamole as a yellow crystalline solid. Yield (w/w) = 80-85%Yield (molar) = 58-62%HPLC purity > 98%Example 2Stage 1: Preparation of 2-chloro-6-diemanolamino-4,8-dipiperidino-pyrimido(5,4-d) pyrimidineDiethanolamine (3 eq) and 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine (1 eq) were added to dimefhylsulfoxide (10 vol) at 25-30°C, stirred for 10 minutes and then heated at 120-125°C for 4-5 hours. After completion of the reaction, the reaction mixture was cooled to 55-60°C. Acetone (5 vol) was added at 55-60°C and the mixture was stirred at 55-60°C for 10 minutes. Purified water (15 vol) was added at 55-60°C and the mixture was stirred at 50-55°C for 15 minutes. The mixture was cooled to 25-30°C and stirred at 25-30°C for 30 minutes. The precipitated solid was filtered, washed with purified water (2 x 5 vol) and dried at 75-80°C under reduced pressure to afford crude 2-chloro-6- diethanolamino-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine as a yellow crystalline solid. Yield (w/w) = 110-120%Yield (molar) = 93-100%HPLC purity > 96%Stage 2: Preparation of crude dipyridamoleDiethanolamine (10 vol) and 2-chloro-6-diemanolamino-4,8-dipiperidino-pyrimido(5,4-d) pyrimidine (1 eq) were mixed at 25-30°C, stirred for 10 minutes and then heated at 113- 115°C for 45-48 hours. After completion of the reaction, the mixture was cooled to 75- 80°C. Ethanol (5 vol) was added and the mixture was stirred at 75-80°C for 10 minutes. Toluene (10 vol) was added and the mixture was stirred at 70-75°C for 15 minutes. Purified water (15 vol) was added and the mixture was stirred at 60-65°C for 30 minutes. The mixture was then cooled to 25-30°C and stirred for 30 minutes. The precipitated solid was filtered, washed with purified water (2 x 5 vol) and dried at 75-80°C under reduced pressure to afford crude dipyridamole as a yellow crystalline solid.Yield (w/w) = 95-97%Yield (molar) = 82-84%HPLC purity > 98%Example 3Crystallization of crude dipyridamoleCrude dipyridamole (1 eq) and diefhanolamine (8 vol) were stirred together at 25-30°C for 10 minutes and then heated to about 80°C for 10 minutes. The clear solution was cooled to 75-80°C, ethanol (5 vol) was added and the mixture was stirred at 75-80°C for 10 minutes. Toluene (10 vol) was added and the mixture was stirred at 70-75°C for 15 minutes. The mixture was cooled to 25-30°C, stirred at 25-30°C for 10 minutes and filtered. The filtrate was heated to 70-75°C for 10 minutes, purified water (15 vol) was added and the mixture was stirred at 60-65°C for 30 minutes before cooling to 25-30°C with stirring for 30 minutes. The precipitated solid was filtered, washed with purified water (2 x 5 vol) and dried at 75-80°C under reduced pressure to afford dipyridamole as a yellow crystalline solid.Yield (w/w and molar) = 90-95%HPLC purity > 99.9% 
PATENT 
https://patents.google.com/patent/WO2007080463A1/enDipyridamole which is chemically known as 4,8-Bis(piperidino)-N,N,N’,N’- tetra(2-hydroxyethyl)pyrimido[5,4-d]pyrimidine-2,6-diamine is a platelet adhesion inhibitor. It is useful in anti-platelet therapy and it is marketed as Persantin ® by Boehringer Ingelheim.The platelet aggregation inhibiting properties, anti-thrombotic and vasodilator properties of Dipyridamole is reported in US patent 3031450 which also describe a process for its preparation by reacting 2-chloro-6-diethanolamino-4, 8-dipiperidyl- pyrimido-pyrimidine with diethanolamine.German patent 117456 describes the process for the production of Dipyridamole from 2,6-dichloro-4,8-dipiperidinopyrimido[5,4-d]pyrimidine and diethanolamine at 130 to 200° C under vacuum. German patent 1812918 describes the process for the preparation and purification of Dipyridamole. According to this patent 2,6-dichloro-4,8,- dipiperidinopyrimido[5,4-d]pyrimidine and diethanolamine are heated to 150 to 2000C to obtain Dipyridamole. This is characterized by the fact that after the completion of the reaction, the reaction mixture is dissolved in chloroform, which is further separated into the upper layer of diethanolamine and its hydrochloride and the chloroform solution. Thus obtained chloroform solution is reduced to dryness after stirring with water.RO 104718 Bl describes a process where Dipyridamole is manufactured and purified by reaction of diethanolamine with 2,6-dichloro-4,8-dipiperidinopyrimido[5,4- d]pyrimidine. In this process the yield is very low (58%) and purity is only 98%.Another patent DDl 15670 Z describes a process for the purification of Dipyridamole by refluxing it in AcOBu for 2 h in the presence of an equal amount of silica gel or by column chromatography on silica gel at 60-1000C. The purification by column chromatography is not economical and feasible at industrial scale.All the above mentioned prior art are neat reaction in which it is difficult to control the impurity and is not easy to scale up. In the prior art process the obtained product is pasty which needs decanting the mother liquor and further purification.We focused our research to develop an improved and efficient process for the preparation and purification of Dipyridamole of formula (I) which will overcome the above mentioned prior art problems and will produce Dipyridamole in substantially good yield, high purity and with no mixture of solvents.Objectives of the InventionThe main objective of the present invention is to provide an improved process for the preparation and purification of compound of formula (I), which gives better purity and high yield of the product. Another objective of the present invention is to provide a process for the preparation and purification of compound of formula (I), which would be easy to scale up and implement at industrial level.Yet another objective of the present invention is to provide a process for the preparation and purification of compound of formula (I), which avoids, use of hazardous gas (SO2) and corrosive chemicals like HCl, H2SO4, acetic acid, NaOH, NH3 etc.Summary of the InventionAccordingly, the present invention provides a process for the preparation ofDipyridamole of formula (I) comprising reacting 2,6-Dichloro-4,8- dipiperidinopyrimido- (5,4-d)pyrimidine (DDH) of formula (II) with Diethanolamine (DEA) of formula (III) using a solvent. This process can be represented by the scheme given below:

Figure imgf000004_0001

(II) (III) (I)The obtained wet or optionally dried crude Dipyridamole is purified by using ketonic solvent and aqueous alcoholic solvent or mixture thereof.Description of the InventionIn an embodiment of the present invention the solvent is selected from the group consisting of l-Methyl-2-pyrrolidinone, Sulpholane and Polyethylene glycol, preferably l-Methyl-2-pyrrolidinone (NMP). In another embodiment of the present invention, the polyethylene glycol used is PEG-20Q or PEG-400, preferably PEG-400.In yet another embodiment of the present invention, the reaction is carried out at a temperature of about 25° C to reflux temperature, preferably at a temperature of about 150° C to 2000C.In still another embodiment of the present invention the starting material of this invention is prepared according to the literature available in the prior art.In yet another embodiment the ketonic solvent is acetone, methyl ethyl ketone, methyl vinyl ketone or methyl isobutyl ketone (MIBK), preferably MIBK.In yet another embodiment the alcoholic solvent is selected from the group having Ci to C4 alkanol preferably isopropyl alcohol (IPA) or methanol.The present invention is illustrated with the following examples, which should not be construed for limiting the scope of the invention.Example 1Preparation of Dipyridamole (Crude)250 mL of l-Methyl-2-pyrrolidinone (NMP), 50g of 2,6-Dichloro-4,8 dipiperidinopyrimido(5,4-d)pyrimidine (DDH) and 136g of Diethanolamine (DEA) were charged into a 2.0 L four-necked RBF at 25-35 0C. The reaction mass was heated to 190 – 2000C and maintained for 1.5 to 2.5 hrs under stirring. The reaction mass was cooled to 25-350C and 450 mL of purified water was charged slowly into it and stirred for lhr. The solid reaction mass was filtered and washed with 500ml-purified water and dried the solid under vacuum at 50-550C for 8 to 10 hrs to get 55-60 g of crude Dipyridamole of 90-94% HPLC purity.Purification Of DipyridamoleMethyl isobutyl ketone (750 ml) and 50 g of Dipyridamole (crude) were charged into a clean 2.0 L four-necked RBF at 25-3O0C and heated to 100-1200C. It was stirred to dissolve and cooled to 25-350C and stirred for 30-60 min. The solid was Filtered and washed with 100 ml MIBK. The product was dried at 45-50 0C under vacuum. The obtained material was further purified as follows:Isopropyl alcohol (200 mL) and 40-45 g of Dipyridamole were charged into a clean 1.0 lit four-necked RBF at 25-350C. It was heated to 60-650C. Carbon (Ig) was added at 30-350C and filtered through celite and washed with 50 mL IPA. Water (500 mL) was charged slowly and stirred for 30 min. The solid was filtered and washed with a mixture of IPA : Water (1 :2) and dried the product at 45-50 0C under vacuum to obtain 43-5Og of Dipyridamole having HPLC purity 99.0 – 99.5%Example 2Sulpholane (15 mL), 5.0g of 2,6-Dichloro-4,8-dipiperidinopyrimido(5,4-d) pyrimidine (DDH) and 8.6g Diethanolamine (DEA) were charged into 100 mL four- necked RBF at 25-35°C. It was heated to 190-2000C and stirred for 2-3 hrs. The reaction mass was cooled to 25-35°C and 45 mL of water was added into it. The reaction mass was stirred. The solid was filtered and washed with water. The solid was purified with MIBK,IPA-Water as given in example 1.Example 3Polyethylene glycol-400 (15 mL), 5g of 2,6-Dichloro-4,8-dipiperidinopyrimido (5,4-d) pyrimidine (DDH) and 8.6 gm Diethanolamine (DEA) were charged into 10OmL four necked RBF at 25-35°C. The reaction mass was heated to 190-2000C and maintained for 2-3 hrs. The mixture was cooled to 25-350C. Water (45 mL) was added to the reaction mixture and stirred. The solid was filtered and washed with water. The solid was purified with MIBK,IPA- Water as given in example 1.Example 4 (Azeotrophic removal of water in MIBK purification)Preparation of Dipyridamole (Crude*) l-Methyl-2-pyrrolidinone (150 mL), 50g of 2,6-Dichloro-4,8-dipiperidinopyrimido(5,4-d)pyrimidine (DDH) and 136g Diethanolamine (DEA) was charged into a 2.0 L four-necked RBF at 25-35 0C. The reaction mass was stirred & heated to 190 – 2000C and stirring was continued for 1.5 to 2.5 hrs. The reaction mass was cooled to 25-350C and 450 mL of purified water was charged slowly into it and stirred for lhr. The solid reaction mass was filtered and washed with 500ml-purified water to obtain 110-13Og of wet crude Dipyridamole.Purification Of DipyridamoleMethyl isobutyl ketone (750 ml) and 65 g of Dipyridamole (wet crude) were charged into a clean 2.0 L four-necked RBF at 25-3O0C and heated to 100-1200C followed by azeotrophic separation of water. It was cooled to 25-350C and stirred for30-60 min. The solid was filtered and washed with 100 ml MIBK. The product was dried at 45-50 0C under vacuum. The obtained material was further purified as follows:Isopropyl alcohol (200 mL) and 45-48 g of Dipyridamole were charged into a clean 1.0 L four-necked RBF at 25-350C. It was heated to 60-650C and stirred to dissolve. Carbon (Ig) was added at 30-350C and filtered through celite and washed with 50 mL IPA. Water (500 mL) was charged slowly and stirred for 30 min. The solid was filtered and washed with a mixture of IPA : Water (1:2) and dried the product at 45-50 0C under vacuum to obtain 43-5Og of Dipyridamole having HPLC purity 99.0-99.5%Purification with Methaanol-waterMethanol (200 mL) and 45-48 g of Dipyridamole were charged into a clean 1.0 L four-necked RBF at 25-350C. It was heated to 60-650C and stirred to dissolve. Carbon (Ig) was added at 30-350C and filtered through celite and washed with 50 mL methanol. Water (500 mL) was charged slowly and stirred for 30 min. The solid was filtered and washed with a mixture of methanol : Water (1 :2) and dried the product at 45-50 0C under vacuum to obtain 45g of Dipyridamole having HPLC purity 99%. 
PATENThttps://patents.google.com/patent/CN108069972A/enEmbodiment 1Weigh urea 120g(2mol), ethylene glycol 62g(1mol)120 DEG C are heated in a kettle, in Catalyzed by p-Toluenesulfonic Acid Effect is lower to carry out step(1)Reaction, generate compound 3;Then 2,3- diamino succinic acid 37g is weighed(0.25mol)With step The compound 3 generated in rapid 1 carries out the reaction generation compound 5 of step 2,220 DEG C, reaction time 3h of reaction temperature, catalyst For the nickel-base catalyst of support type, catalyst is filtered out after the completion of reaction;Exist in phosphorus oxychloride, phosphorus trichloride and lead to chlorine In the case of, compound 5 carries out chlorination reaction generation compound 6,110 DEG C of reaction temperature, reaction time 30h;Weigh piperidines 85g (1mol)Step is carried out with compound(4)Reaction, after reaction liquid hydrolysis, cooling filtering, be dried to obtain compound 9;Claim Take 105g(1mol)Diethanol amine and compound 9 carry out step(6)Reaction, 220 DEG C of reaction temperature, reaction time 3h fills 1.5 MPa of Hydrogen Vapor Pressure, catalyst are the crude product of the nickel-base catalyst, after reaction cold filtration of support type, and crude product passes through It is refining to obtain Dipyridamole finished product, quality 62.10g, purity 99.21%, product yield 48.74%(Yield is with 2,3- diamino fourths Diacid is calculating benchmark).Embodiment 2Weigh urea 120g(2mol), ethylene glycol 62g(1mol)120 DEG C are heated in a kettle, in Catalyzed by p-Toluenesulfonic Acid Effect is lower to carry out step(1)Reaction, generate compound 3;Then 2,3- diamino succinic acid 30g is weighed(0.2mol)With step The compound 3 generated in rapid 1 carries out the reaction generation compound 5 of step 2,220 DEG C, reaction time 3h of reaction temperature, catalyst For the nickel-base catalyst of support type, catalyst is filtered out after the completion of reaction;Exist in phosphorus oxychloride, phosphorus trichloride and lead to chlorine In the case of, compound 5 carries out chlorination reaction generation compound 6,110 DEG C of reaction temperature, reaction time 30h;Weigh piperidines 85g (1mol)Step is carried out with compound(4)Reaction, after reaction liquid hydrolysis, cooling filtering, be dried to obtain compound 9;Claim Take 105g(1mol)Diethanol amine and compound 9 carry out step(6)Reaction, 220 DEG C of reaction temperature, reaction time 3h fills 1.5 MPa of Hydrogen Vapor Pressure, catalyst are the crude product of the nickel-base catalyst, after reaction cold filtration of support type, and crude product passes through It is refining to obtain Dipyridamole finished product, quality 50.34g, purity 99.3%, product yield 49.53%(Yield is with 2,3- diamino fourth two Acid is calculating benchmark).Embodiment 3Other steps are the same as embodiment 2, step(6)In reaction temperature for 240 DEG C, product yield 50.31%.Comparative example 1Weigh urea 36g(0.6mol), ethyl acetoacetate 26g(0.2mol), add in ethanol-hydrogen chloride liquid(30% hydrochloric acid:95% second Alcohol=1:4)Then 200ml, drying and dehydrating after stirring add in sodium hydroxide solution and are warming up to 95 DEG C, then cool to 75 DEG C, add Hydrochloric acid adjusts PH=1, cold filtration, the 6- methyluracils of washing filtering;Nitric acid is added in reaction pot, is cooled to less than 10 DEG C, Stirring adds in 6- methyluracils, be warming up to 30 DEG C of heat preservations 1 it is small when the nitro whey liquid that filters;Take a policy powder in water, stirring After dissolving plus nitro whey liquid, temperature control keep the temperature 30min at 35 DEG C, add the static 3h of hydrochloric acid, stir 2h, filtration drying obtains amino breast Clear liquid;Again weigh urea 36g and add in reaction kettle with amino whey liquid, stirring is warming up to 100 DEG C of heat preservation 20min, cools to 90 DEG C add in 2mol/L sodium hydroxide solution, be warming up to 100 DEG C heat preservation dissolving 1h.Cool to 40 DEG C, filter tetrahydroxy pyrimidine- [4,5d] and pyrimidine sodium salt, adds water, 60 DEG C of heat preservation 30min add hydrochloric acid to adjust PH=4, is cooled to 15 DEG C of filterings, washing, dries 2,4,6,8- tetrahydroxys pyrimidine-[4,5d] and pyrimidine;Tetrahydroxy object, phosphorus oxychloride, phosphorus trichloride are added in reaction kettle, is stirred, 10 DEG C of similarly hereinafter chlorine are warming up to 110 DEG C of reflux for 24 hours, be cooled to 15 DEG C of filterings, washing, dry 2,4,6,8- tetrachloro-pyrimidines- [4,5d] and pyrimidine;Acetone, tetrachloride are sequentially added, piperidines-acetone mixture, 30 DEG C of heat preservations are added dropwise in 20 DEG C of heat preservation 30min 1h, adds water to stir 1h, and filtration drying obtains 2,6- bis- chloro- 4,8 ,-two piperidines-pyrimidine(Dichloride);Weigh diethanol amine 63g with Dichloride is mixed, and is warming up to 200 DEG C of heat preservation 15min, is cooled to less than 25 DEG C plus acetone and stirs 30min, then 30 DEG C 4h is kept the temperature, filtration drying obtains Dipyridamole crude product, then carries out refined Dipyridamole finished product 13.53, purity 98.5%, yield 13.21%(Using ethyl acetoacetate as calculating standard).It is found by being compared with comparative example:The method of the production Dipyridamole of the present invention is short with synthetic route, into The characteristics of product high income, production cost is low. 

SYN

GB 807826 U.S. Patent 3,031,450

File:Dipyridamole synthesis.png

SYN

SYN

R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006

Dipyridamole

Dipyridamole, 2,2′,2″,2′″-[(4,8-dipiperidinopirimido[5,4-d]pirimidin-2,6-diyl)-diimino]-tetraethanol (19.4.13), is easily synthesized from 5-nitroorotic acid (19.4.8), easily obtained, in turn, by nitrating of 2,4-dihydroxy-6-methylpyrimidine, which is usually synthesized by the condensation of urea with acetoacetic ether. Reduction of the nitro group in 5-nitroorotic acid by various reducing agents gives 5-aminoorotic acid (19.4.9), which is reacted with urea or with potassium cyanide to give 2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine (19.4.10). This undergoes a reaction with a mixture of phosphorous oxychloride and phosphorous pentachloride, which forms 2,4,6,8- tetra-chloropyrimido[5,4-d]pyrimidine (19.4.11). Reacting the resulting tetrachloride with piperidine replaces the chlorine atoms at C4 and C8 of the heterocyclic system with piperidine, giving 2,6-dichloropyrimido-4,8-dipiperidino[5,4-d]pyrimidine (19.4.12). Reacting the resulting product with diethanolamine gives dipyridamole (19.4.13) [32,33].

Dipyridamole increases coronary blood circulation, increases oxygen flow to the myocardium, potentiates adenosine activity, and impedes its metabolization. It inhibits aggregation of thrombocytes, blocks phosphodiesterase, increases microcirculation, and inhibits the formation of thrombocytes.

It is used for chronic coronary insufficiency, as well as for preventing and treating thrombosis. Synonyms of this drug are anginal, curantyl, stenocor, thrompresantin, and many others.SYN

Chemical Synthesis

Dipyridamole, 2,2′,2”,2”’-[(4,8-dipiperidinopirimido[5,4-d]pirimidin-2,6- diyl)-diimino]-tetraethanol (19.4.13), is easily synthesized from 5-nitroorotic acid (19.4.8), easily obtained, in turn, by nitrating of 2,4-dihydroxy-6-methylpyrimidine, which is usually synthesized by the condensation of urea with acetoacetic ether. Reduction of the nitro group in 5-nitroorotic acid by various reducing agents gives 5-aminoorotic acid (19.4.9), which is reacted with urea or with potassium cyanide to give 2,4,6,8- tetrahydroxypyrimido[5,4-d]pyrimidine (19.4.10). This undergoes a reaction with a mixture of phosphorous oxychloride and phosphorous pentachloride, which forms 2,4,6,8- tetrachloropyrimido[ 5,4-d]pyrimidine (19.4.11). Reacting the resulting tetrachloride with piperidine replaces the chlorine atoms at C4 and C8 of the heterocyclic system with piperidine, giving 2,6-dichloropyrimido-4,8-dipiperidino[5,4-d]pyrimidine (19.4.12). Reacting the resulting product with diethanolamine gives dipyridamole (19.4.13).

 clipA general outline of the procedure for synthesizing dipyridamole is shown in Scheme 1. Reaction of the pyrimidino pyrimidine-2,4,6,8- tetraol (1) with a mixture of phosphorous oxychloride and phosphorous pentachloride gives the tetrachloro derivative (2). The halogens at the peri positions 4 and 8 are more reactive to substitution than are the remaining halogen pairs 2 and 6, which are in effect the two positions of the pyrimidines. Thus, reaction with piperidine at ambient temperature gives the 4, 8 diamine (3). Subsequent reaction with bis-2-hydroxy ethylamine under more strenuous conditions gives dipyridamole (4) [12, 13].12. F.G. Fischer, J. Roch, and A. Kottler, U.S. Patent 3, 031, 450 (1962). 13. D. Lednicer and L.A. Mitscher, The Organic Chemistry of Drug Synthessis Volume 1, John Wiley and Sons, New York, p. 428 (1977). 

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Medical uses

Stroke

A combination of dipyridamole and aspirin (acetylsalicylic acid/dipyridamole) is FDA-approved for the secondary prevention of stroke and has a bleeding risk equal to that of aspirin use alone.[4] Dipyridamole absorption is pH-dependent and concomitant treatment with gastric acid suppressors (such as a proton pump inhibitor) will inhibit the absorption of liquid and plain tablets.[7][8] Modified release preparations are buffered and absorption is not affected.[9][10]

However, it is not licensed as monotherapy for stroke prophylaxis, although a Cochrane review suggested that dipyridamole may reduce the risk of further vascular events in patients presenting after cerebral ischemia.[11]

A triple therapy of aspirinclopidogrel, and dipyridamole has been investigated, but this combination led to an increase in adverse bleeding events.[12]

  • Vasodilation occurs in healthy arteries, whereas stenosed arteries remain narrowed. This creates a “steal” phenomenon where the coronary blood supply will increase to the dilated healthy vessels compared to the stenosed arteries which can then be detected by clinical symptoms of chest pain, electrocardiogram and echocardiography when it causes ischemia.
  • Flow heterogeneity (a necessary precursor to ischemia) can be detected with gamma cameras and SPECT using nuclear imaging agents such as Thallium-201, Tc99mTetrofosmin and Tc99mSestamibi. However, relative differences in perfusion do not necessarily imply any absolute decrease in blood supply in the tissue supplied by a stenosed artery.

Other uses

Dipyridamole also has non-medicinal uses in a laboratory context, such as the inhibition of cardiovirus growth in cell culture.[citation needed]

Drug interactions

Due to its action as a phosphodiesterase inhibitor, dipyridamole is likely to potentiate the effects of adenosine. This occurs by blocking the nucleoside transporter (ENT1) through which adenosine enters erythrocyte and endothelial cells.[13]

According to Association of Anaesthetists of Great Britain and Ireland 2016 guidelines, dipyridamole is considered to not cause risk of bleeding when receiving neuroaxial anaesthesia and deep nerve blocks. It does not therefore require cessation prior to anaesthesia with these techniques, and can continue to be taken with nerve block catheters in place.[14]

Overdose

Dipyridamole overdose can be treated with aminophylline[2]: 6  or caffeine which reverses its dilating effect on the blood vessels. Symptomatic treatment is recommended, possibly including a vasopressor drug. Gastric lavage should be considered. Since dipyridamole is highly protein bound, dialysis is not likely to be of benefit.

Mechanisms of action

Dipyridamole has two known effects, acting via different mechanisms of action:

Experimental studies[

Dipyridamole is currently undergoing repurposing for treatment of ocular surface disorders. These include pterygium and dry eye disease. The first report of topical dipyridamole’s benefit in treating pterygium was published in 2014.[15] A subsequent report of outcomes in 25 patients using topical dipyridamole was presented in 2016.[16]

See also

References

  1. ^ Nielsen-Kudsk, F; Pedersen, AK (May 1979). “Pharmacokinetics of Dipyridamole”. Acta Pharmacologica et Toxicologica44 (5): 391–9. doi:10.1111/j.1600-0773.1979.tb02350.xPMID 474151.
  2. Jump up to:a b “Aggrenox (aspirin/extended-release dipyridamole) Capsules. Full Prescribing Information” (PDF). Boehringer Ingelheim Pharmaceuticals, Inc. Retrieved 1 December 2016.
  3. ^ “Dipyridamole” at Dorland’s Medical Dictionary
  4. Jump up to:a b c Brown DG, Wilkerson EC, Love WE (March 2015). “A review of traditional and novel oral anticoagulant and antiplatelet therapy for dermatologists and dermatologic surgeons”. Journal of the American Academy of Dermatology72 (3): 524–34. doi:10.1016/j.jaad.2014.10.027PMID 25486915.
  5. ^ Dixon BS, Beck GJ, Vazquez MA, et al. (2009). “Effect of dipyridamole plus aspirin on hemodialysis graft patency”N Engl J Med360 (21): 2191–2201. doi:10.1056/nejmoa0805840PMC 3929400PMID 19458364.
  6. ^ Dipyridamole in the laboratory: Fata-Hartley, Cori L.; Ann C. Palmenberg (2005). “Dipyridamole reversibly inhibits mengovirus RNA replication”Journal of Virology79 (17): 11062–11070. doi:10.1128/JVI.79.17.11062-11070.2005PMC 1193570PMID 16103157.
  7. ^ Russell TL, Berardi RR, Barnett JL, O’Sullivan TL, Wagner JG, Dressman JB. pH-related changes in the absorption of “dipyridamole” in the elderly. Pharm Res (1994) 11 136–43.
  8. ^ Derendorf H, VanderMaelen CP, Brickl R-S, MacGregor TR, Eisert W. “Dipyridamole” bioavailability in subjects with reduced gastric acidity. J Clin Pharmacol (2005) 45, 845–50.
  9. ^ “Archived copy”. Archived from the original on 2009-07-05. Retrieved 2010-02-06.
  10. ^ Stockley, Ivan (2009). Stockley’s Drug Interactions. The Pharmaceutical Press. ISBN 978-0-85369-424-3.
  11. ^ De Schryver EL, Algra A, van Gijn J (2007). Algra A (ed.). “Dipyridamole for preventing stroke and other vascular events in patients with vascular disease”Cochrane Database of Systematic Reviews (2): CD001820. doi:10.1002/14651858.CD001820.pub3PMID 17636684.
  12. ^ Sprigg N, Gray LJ, England T, et al. (2008). Berger JS (ed.). “A randomised controlled trial of triple antiplatelet therapy (aspirin, clopidogrel and dipyridamole) in the secondary prevention of stroke: safety, tolerability and feasibility”PLOS ONE3 (8): e2852. Bibcode:2008PLoSO…3.2852Sdoi:10.1371/journal.pone.0002852PMC 2481397PMID 18682741.
  13. ^ Gamboa A, Abraham R, Diedrich A, Shibao C, Paranjape SY, Farley G, et al. Role of adenosine and nitric oxide on the mechanisms of action of dipyridamole. Stroke. 2005;36(10):2170-2175.
  14. ^ AAGBI Guidelines Neuraxial and Coagulation June 2016
  15. ^ Carlock, Beth H.; Bienstock, Carol A.; Rogosnitzky, Moshe (2014-03-25). “Pterygium: Nonsurgical Treatment Using Topical Dipyridamole – A Case Report”Case Reports in Ophthalmology5 (1): 98–103. doi:10.1159/000362113ISSN 1663-2699PMC 3995373PMID 24761148.
  16. ^ “Topical Dipyridamole for Treatment of Pterygium and Associated Dry Eye Symptoms: Analysis of User-Reported Outcomes”ResearchGate. Retrieved 2019-05-19.
Clinical data
Trade namesPersantine, others
AHFS/Drugs.comMonograph
MedlinePlusa682830
Pregnancy
category
B
Routes of
administration
By mouthIV
ATC codeB01AC07 (WHO)
Legal status
Legal statusUK: POM (Prescription only)US: ℞-only
Pharmacokinetic data
Bioavailability37–66%[1]
Protein binding~99%
MetabolismLiver (glucuronidation)[2]
Elimination half-lifeα phase: 40 min,
β phase: 10 hours
ExcretionBiliary (95%), urine (negligible)
Identifiers
showIUPAC name
CAS Number58-32-2 
PubChem CID3108
IUPHAR/BPS4807
DrugBankDB00975 
ChemSpider2997 
UNII64ALC7F90C
KEGGD00302 
ChEBICHEBI:4653 
ChEMBLChEMBL932 
CompTox Dashboard (EPA)DTXSID6040668 
ECHA InfoCard100.000.340 
Chemical and physical data
FormulaC24H40N8O4
Molar mass504.636 g·mol−1
3D model (JSmol)Interactive image
hideSMILESOCCN(CCO)C(N=C1N2CCCCC2)=NC3=C1N=C(N(CCO)CCO)N=C3N4CCCCC4
showInChI
  (verify)

Patent

Publication numberPriority datePublication dateAssigneeTitleUS3031450A1959-04-301962-04-24Thomae Gmbh Dr KSubstituted pyrimido-[5, 4-d]-pyrimidinesDE1812918A11968-04-251969-11-06Dresden Arzneimittel2,6-Bis (diethanolamino-4,8-dipiperidino-pyrimido (5,4-d)-pyrimidine – purification by simple procedure giving good yieldsDD115670A11974-02-191975-10-12DD117456A11975-02-131976-01-12DE2927539A1 *1979-07-071981-01-08Margineanu Dan Axente Dipl IngBis:di:ethanol-amino-di:piperidino-pyrimido-pyrimidine prepn. – from methyl acetoacetate and urea via amino-orotic acidRO104718B11989-08-091994-09-30Medicamente DePRODUCTION METHOD OF PURE 2,6-bis-(DIETHANOL AMIDE)-4,8-DI- PIPERIDINE-PYRIMIDO-(5,4-d)-PYRIMIDINEWO2007080463A12006-01-122007-07-19Orchid Chemicals & Pharmaceuticals LimitedAn improved process for the preparation of dipyridamoleFamily To Family CitationsDE115670C *JPS5191295A *1975-02-051976-08-10Jipiridamooruno kairyoseizohoJPS5757038B2 *1977-09-301982-12-02Yamanouchi Pharma Co LtdJPS57209291A *1981-06-171982-12-22Kyowa Hakko Kogyo Co LtdPurification of dipyridamoleUS6232312B1 *1995-06-072001-05-15Cell Pathways, Inc.Method for treating patient having precancerous lesions with a combination of pyrimidopyrimidine derivatives and esters and amides of substituted indenyl acetic acidesCN1425461A *2003-01-032003-06-25贵州益佰制药股份有限公司Injection preparation for resisting platelet aggregation and its producing methodCN1634085A *2004-11-242005-07-06崔晓廷Injectio of aspirin and dipyridamole and its preparing process 

Non-Patent

TitleCURTIN, NICOLA J. ET AL: “Resistance-Modifying Agents of Pyrimido[5,4-d]pyrimidine Modulators of Antitumor Drug Activity. Synthesis and Structure-Activity Relationships for Nucleoside Transport Inhibition and Binding to .alpha.1-Acid Glycoprotein”, JOURNAL OF MEDICINAL CHEMISTRY , 47(20), 4905-4922 CODEN: JMCMAR; ISSN: 0022-2623, 26 August 2004 (2004-08-26), XP002651697 * 

 

CN104710431B *2015-03-182017-03-01常州康普药业有限公司A kind of purifying process of dipyridamoleCN107782805B *2016-08-252021-02-02亚宝药业集团股份有限公司HPLC analysis method for key intermediate impurity synthesized by dipyridamoleCN106380471B *2016-08-312018-11-06广州市桐晖药业有限公司A kind of preparation method of DipyridamoleCN108069972A *2016-11-162018-05-25湖南尔康制药股份有限公司A kind of production method of Dipyridamole bulk pharmaceutical chemicalsCN106946887B *2017-03-242019-05-28大连万福制药有限公司A kind of preparation method introducing catalyst optimization synthesis Dipyridamole

/////////////////Dipyridamole, дипиридамол , ديبيريدامول , 双嘧达莫 , 0068373 , NSC-515776, RA-8

OCCN(CCO)C(N=C1N2CCCCC2)=NC3=C1N=C(N(CCO)CCO)N=C3N4CCCCC4

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Racecadotril


Racecadotril2DCSD.svg
ChemSpider 2D Image | Racecadotril | C21H23NO4S
Racecadotril.png
STR1

Racecadotril

  • Molecular FormulaC21H23NO4S
  • Average mass385.477 Da

(±)-Acetorphan
(RS)-Benzyl N-[3-(acetylthio)-2-benzylpropanoyl]glycinate
2-{[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]amino}acetic acid (phenylmethyl) ester7378
76K53XP4TO
81110-73-8[RN]
Benzyl N-[3-(acetylsulfanyl)-2-benzylpropanoyl]glycinate [ACD/IUPAC Name] 
Cadotril
Dexecadotril[INN]
Glycine, N-[3-(acetylthio)-1-oxo-2-(phenylmethyl)propyl]-, phenylmethyl ester
Hidrasec [Trade name] 
рацекадотрил[Russian][INN]
راسيكادوتريل[Arabic][INN]
消旋卡多曲[Chinese][INN]
RacecadotrilCAS Registry Number: 81110-73-8 
CAS Name:N-[2-[(Acetylthio)methyl]-1-oxo-3-phenylpropyl]glycine phenylmethyl ester 
Additional Names:N-[(R,S)-3-acetylthio-2-benzylpropanoyl]glycine benzyl ester; acetorphan 
Trademarks: Hidrasec (GSK); Tiorfan (Bioprojet) 
Molecular Formula: C21H23NO4S, Molecular Weight: 385.48 
Percent Composition: C 65.43%, H 6.01%, N 3.63%, O 16.60%, S 8.32% 
Literature References: Antisecretory enkephalinase inhibitor. Prepn: B. Roques et al.,EP38758 (1981); eidem,US4513009 (1985 to Bioprojet). Pharmacology: J.-M. Lecomte et al.,J. Pharmacol. Exp. Ther.237, 937 (1986). Effect on intestinal transit: J. F. Bergmann et al.,Aliment. Pharmacol. Ther.6, 305 (1992). Clinical trial in acute diarrhea: P. Baumer et al.,Gut33, 753 (1992); in children: E. Salazar-Lindo et al.,N. Engl. J. Med.343, 463 (2000). Symposium on pharmacology and clinical experience: Aliment. Pharmacol. Ther.13, Suppl. 6, 1-32 (1999). Review of clinical development: J.-C. Schwartz, Int. J. Antimicrob. Agents14, 75-79 (2000); J. M. Lecomte, ibid. 81-87. 
Properties: White crystals from ether mp 89°., Melting point: mp 89° 
Derivative Type: (S)-Form 
CAS Registry Number: 112573-73-6 
Additional Names: Ecadotril; sinorphan 
Manufacturers’ Codes: Bay-y-7432 
Molecular Formula: C21H23NO4S, Molecular Weight: 385.48 
Percent Composition: C 65.43%, H 6.01%, N 3.63%, O 16.60%, S 8.32% 
Literature References: Prepn: P. Duhamel et al.,EP318377eidem,US5208255 (1989, 1993 both to Bioprojet); and pharmacology: B. Giros et al.,J. Pharmacol. Exp. Ther.243, 666 (1987). Clinical effect on plasma ANP levels in CHF: J. C. Kahn et al.,Lancet335, 118 (1990); on renal function: F. Schmitt et al.,Am. J. Physiol.267, F20 (1994). Clinical trial in heart failure: C. M. O’Connor et al.,Am. Heart J.138, 1140 (1999); J. G. F. Cleland, K. Swedberg, Lancet351, 1657 (1998). 
Properties: mp 71°. [a]D25 -24.1° (c = 1.3 in methanol). LD50 i.v. in mice: >100 mg/kg (Duhamel, 1993). 
Melting point: mp 71° 
Optical Rotation: [a]D25 -24.1° (c = 1.3 in methanol) 
Toxicity data: LD50 i.v. in mice: >100 mg/kg (Duhamel, 1993) 
Therap-Cat: Antidiarrheal. 
Keywords: Antidiarrheal; Neutral Endopeptidase Inhibitor.

Racecadotril is an anti-secretory enkephalinase inhibitor useful in the treatment of diarrhea.Racecadotril has been investigated for the basic science and treatment of Diarrhea, Acute Diarrhea, and Acute Gastroenteritis.

Racecadotril, also known as acetorphan, is an antidiarrheal medication which acts as a peripheral enkephalinase inhibitor.[3] Unlike other opioid medications used to treat diarrhea, which reduce intestinal motility, racecadotril has an antisecretory effect — it reduces the secretion of water and electrolytes into the intestine.[3] It is available in France (where it was first introduced in ~1990) and other European countries (including Germany, Italy, the United Kingdom, Spain, Portugal, Poland, Finland, Russia and the Czech Republic) as well as most of South America and some South East Asian countries (including China, India and Thailand), but not in the United States. It is sold under the tradename Hidrasec, among others.[4] Thiorphan is the active metabolite of racecadotril, which exerts the bulk of its inhibitory actions on enkephalinases.[5]

Medical uses

Racecadotril is used for the treatment of acute diarrhea in children and adults and has better tolerability than loperamide, as it causes less constipation and flatulence.[6][7] Several guidelines have recommended racecadotril use in addition to oral rehydration treatment in children with acute diarrhea.[8]

Contraindications

Racecadotril has no contraindications apart from known hypersensitivity to the substance.[9][10]

There is insufficient data for the therapy of chronic diarrhea, for patients with renal or hepatic failure, and for children under three months. Additional contraindications for the children’s formulation are hereditary fructose intoleranceglucose-galactose malabsorption and saccharase deficiency, as it contains sugar.[7][9]

Racecadotril (CAS NO.: 81110-73-8), with its systematic name of Glycine, N-(2-((acetylthio)methyl)-1-oxo-3-phenylpropyl)-, phenylmethyl ester, (+-)-, could be produced through many synthetic methods.

Following is one of the synthesis routes: 2-Benzylacrylic acid (I) reacts with SOCl2 in hot toluene to afford the acyl chloride (II), which is condensed with N-tosylglycine benzyl ester (III) in the presence of TEA in toluene to yield the corresponding amide (IV). Finally, this compound is condensed with thioacetic acid by heating at 80 °C to afford the target acylthio compound.

 

Racecadotril is a neutral endopeptidase inhibitor used as antidiarrheal in the treatment of chronic cardiac insufficiency and is available under the brand names Hidrasec and Tiorfan. Racecadotril is chemically known as N-[2-[(acetylthio) methyl]- l-oxo-3-phenylpropyl] glycine phenyl methyl ester, (herein after referred by its generic name racecadotril) and represented by the formula (I).

Figure imgf000002_0001

U.S. Patent No. US 4,513,009 describes amino acid derivatives including racecadotril, a pharmaceutical composition and a method of treatment.

The US’009 patent also discloses a process for the preparation of racecadotril which is illustrated by below scheme:

Figure imgf000003_0001

U.S. Patent No. US 6,835,851 B2 discloses a process for the preparation of racecadotril which is illustrated by scheme below:

Figure imgf000003_0002

European Patent No. EP 0501870B 1 discloses a process for the preparation of racec

Figure imgf000004_0001

Racecadotril

The use of coupling agents like hydroxyl benzotriazole (HOBT) and dicyclohexyl amine carbodiimide (DCC) generally induces the formation of side products such as dicyclohexylurea. These side products do lead to major problems, wherein purification by chromatography may be contemplated, but the side products are extremely difficult to remove on an industrial scale.

Consequently, efforts have been made to replace the peptidic coupling step

so as to avoid the formation of side products associated with the use of the coupling agents. Thus, it appears that, even if the preparation of N-(mercaptoacyl)amino acid derivatives from .alpha.-substituted acrylic acids by Michael addition of a thio acid and conversion of acid to acid chloride by using thionyl chloride and then coupling of an amino ester may be advantageous on a laboratory scale, such reactions are difficult to adapt on an industrial use.

The aforementioned processes described above involves expensive reagents such as hydroxyl benzotriazole (HOBT) and dicyclohexyl amine carbodiimide (DCC) and hazardous reagent like thionyl chloride thus rendering the processes expensive and not feasible on industrial scale.

SYNTHESIS BY WORLDDRUGTRACKER

STR1

Patent

https://www.google.com/patents/WO2013098826A1?cl=en

EXAMPLES

Example-1: Preparation of Racecadotril (I):

Step A) Preparation of 2-acetyIsulfanyI methyI-3-phenyI propionic acid (IV)

16.2 g of 2-benzylacrylic acid and 12.3 ml of thioacetic acid were were charged into a clean and dry R.B.flask and stirred at about 30°C for about 1 hour. The reaction mixture was heated to about 60°C and stirred for about 4 hours.The excess of thioacetic acid was distilled off completely to afford the title compound as residue. Yield: 23.8 g. Step B) Preparation of Racecadotril crude (la)

23.8 g. of 2-acetyl sulfanylmethyl-3-phenyl-propionic acid (IV), 200ml of methylene chloride and 16.7 ml of triethylamine were charged into a clean and dry R.B.flask. 10. 5 ml of ethylchloroformate was added at about -5°C. The resultant reaction mixture was stirred at about 0°C for about 30 min. 33.7 g of glycine benzyl ester p-tosyalte (II), 14 ml of triethylamine and 100ml of methylene chloride was added as a mixture to the reaction mass at about 0°C. Then the resultant reaction mixture was stirred at about 0°C for about 1 hr. followed by at about 30°C for about 30 min. After completion of the reaction as determined by TLC, the reaction mass was washed with 65 ml of distilled water, 65 ml 4% sodium bicarbonate solution and followed by 65 ml distilled water. The organic and aqueous phases were separated and the solvent was distilled completely, 2 x 50 ml Isopropyl alcohol was charged and again distilled off the solvent completely to give residue. The residue

obtained was triturated with a mixture of isopropyl alcohol 4 ml) and n-hexane (94 ml) at about 5°C to the title compound as crude. Yield: 34 g.

ExampIe-2: Purification of Racecadotril (Crude):

34 g. of crude Racecadotril and 35 ml of 20 % v/v aqueous .methanol were charged in a clean and dry R.B.flask and heated to about 65°C. 3g. of SP.carbon was charged and stirred at about 65°C for about 10 min. The reaction suspension was stirred at about 65°C for about 10 min. The reaction suspension was filtered on hyflow bed (diatomous earth) and washed the hyflow bed with 30 ml of aqueous methanol. The filtrate obtained was cooled to about 0°C for about 30 min. The solid separated was filtered and the solid obtained washed with 60 ml of precooled aqueous methanol to afford the pure racecadotril (I).

Yield: 29 g.; Purity by HPLC: 99.5 area %; The overall yield is 75.3%.

PATENT

https://www.google.com/patents/CN104356036A?cl=en

Example 1

The 40. 0g Racecadotril dissolved in 200ml of absolute ethanol and water bath heated to 40 ° C, and stir until the whole solution, stirring was stopped, the solution was placed in 15 ° C water bath was allowed to stand, when starting When there is precipitation of crystals, and then placed under the 0 ° C crystallization, after filtration, to 45 ° C under hot air drying cycle 6 hours to obtain 29. 2g, purity 99.6% of Racecadotril a polymorph crystals.

  reflection angle X-ray powder diffraction pattern 20 at 4.3 °, 8.7 °, 13.2 °, 16.8 °, 17.8 ° and 20.0 ° at the show X-ray powder diffraction peaks. In 1135. 19CHT1,1551. 46CHT1,1644. 73CHT1,1687. 57CHT1, 1731. 35CHT1 and 3289. 20CHT1 displayed at an infrared absorption peak.

Clips

US 20020055645

PATENT

CN 104356036 A

Racecadotril, chemical name N_ [(R, S) -3- acetyl-mercapto-2-benzyl-propionyl)] glycine benzyl ester, is a neprilysin inhibitor, selectively, reversible inhibition of neprilysin, so that the inner protection from degradation of endogenous enkephalins, prolong the physiological activity of endogenous enkephalins in the digestive tract, mainly used in clinical treatment of children and adults with acute diarrhea. Its structural formula is as follows:

Figure CN104356036AD00031

 Racecadotril as enkephalinase inhibitors, developed in France in 1993 Bioprojet listed acute diarrhea treatment, trade name Tiorfan.

In W02011116490A1, US5945548 and CN101768095A and other documents, documented racecadotril the synthesis process, but did not report the crystal form; therefore the present inventors have not reported Racecadotril crystalline polymorph conduct further

Example 1

[0032] The 40. 0g Racecadotril dissolved in 200ml of absolute ethanol and water bath heated to 40 ° C, and stir until the whole solution, stirring was stopped, the solution was placed in 15 ° C water bath was allowed to stand, when starting When there is precipitation of crystals, and then placed under the 0 ° C crystallization, after filtration, to 45 ° C under hot air drying cycle 6 hours to obtain 29. 2g, purity 99.6% of Racecadotril a polymorph crystals.

[0033] reflection angle X-ray powder diffraction pattern 20 at 4.3 °, 8.7 °, 13.2 °, 16.8 °, 17.8 ° and 20.0 ° at the show X-ray powder diffraction peaks. In 1135. 19CHT1,1551. 46CHT1,1644. 73CHT1,1687. 57CHT1, 1731. 35CHT1 and 3289. 20CHT1 displayed at an infrared absorption peak.

SYN

EP 0038758

Alternatively, the condensation of dimethyl malonate (VI) with benzaldehyde (VII) by means of piperidine in refluxing toluene gives dimethyl benzylidenemalonate (VIII), which is reduced with H2 over Pd/C in toluene to yield the corresponding benzyl derivative (IX). The hydrolysis of (IX) with NaOH in water affords the benzylmalonic acid (X). Alternatively, intermediate (X) can also be obtained starting from diethyl malonate (XI), which is condensed with with benzaldehyde (VII) by means of piperidine in refluxing toluene to give diethyl benzylidenemalonate (XII). Reduction of (XII) with H2 over Pd/C in toluene yields the corresponding benzyl derivative (XIII), which is then hydrolized with NaOH in water. The monodecarboxylation of (X) and its condensation with paraformaldehyde and diethylamine in refluxing ethyl acetate provides 2-benzylacrylic acid (XIV), which is condensed with thioacetic acid (V) by heating at 70 C to afford 2-(acetylsulfanylmethyl)-3-phenylpropionic acid (XV). Finally, this compound is condensed with N-tosylglycine benzyl ester (XVI) by means of HOBt, DCC and TEA in THF.

SYN

EP 0729936

Reaction of benzaldehyde (I) with dimethyl malonate (II) in refluxing toluene in the presence of piperidine and HOAc provides dimethyl benzylidene malonate (III), which is then hydrogenated over Pd/C to afford dimethyl benzyl malonate (IV). Reduction of (IV) with LiAlH4 in refluxing THF furnishes 2-benzyl-1,3-propanediol (V), which is then subjected to reaction with vinyl acetate (VI) by means of Novozym 435 enzyme to yield diacetate (VII). Enantioselective removal of one acetyl group from (VII) by treatment with Pseudomonas fluorescens Lipase in acetone/phosphate buffer (pH = 7) at 30 C gives 3-acetoxy-2(S)-benzyl-propanol (S)-(VIII), which is then oxidized by means of Jones reagent in acetone/isopropanol to provide carboxylic acid (R)-(IX). The hydrolysis of (IX) with LiOH in THF/H2O gives 2(R)-benzyl-3-hydroxypropanoic acid (R)-(X). Alternatively, intermediate (X) can also be synthesized as follows: Condensation of benzaldehyde (I) with methyl acrylate (XV) by means of diaza-1,4-bicyclo[2.2.2.]octane affords methyl beta-hydroxy-alpha-methylene-benzenepropanoate (XVI), which is then subjected to hydrolysis with KOH in MeOH/H2O to yield carboxylic acid (XVII). Treatment of (XVII) with p-toluenesulfonic acid in refluxing HOAc gives (E)-2-(acetoxymethyl)-3-phenylpropionic acid (XVIII), which is finally converted into (X) by enantioselective hydrogenation in the presence of S-Binap and ruthenium catalyst [CodRu(all)2]. Derivative (R)-(X) is then converted into 3-(acetylsulfanyl)-2(S)-benzylpropionic acid (XI) by means of a Mitsunobu reaction with thioacetic acid, diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPh3). Compound (XI) is then subjected to optical purification by formation and isolation of the corresponding salt with (-)-ephedrine and subsequent hydrolysis with HCl to furnish enantiomerically pure (S)-(XII). Finally, carboxylic acid (S)-(XII) is converted into ecadotril by its coupling with benzyl glycinate (XIV), either by means of Et3N, DCC and HOBt in CHCl3, or by first reaction with thionyl chloride to give acid chloride (S)-(XIII) and subsequent coupling with glycinate (XIV) by means of Et3N in CH2Cl2.

SYN

The reaction of 2-benzylacrylic acid (I) with SOCl2 in hot toluene gives the acyl chloride (II), which is condensed with N-tosylglycine benzyl ester (III) by means of TEA in toluene to yield the corresponding amide (IV). Finally, this compound is condensed with thioacetic acid by heating at 80 C to afford the target acylthio compound.

FR 2816309; US 2002055645
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Side effects

The most common adverse effect is headache, which occurs in 1–2% of patients.[7] Rashes occur in fewer than 1% of patients. Other described skin reactions include itching, urticariaangioedemaerythema multiforme, and erythema nodosum.[9][10]

Overdose

No cases of overdose are known. Adults have tolerated 20-fold therapeutic doses without ill effects.[10]

Interactions

No interactions in humans have been described. Combining racecadotril with an ACE inhibitor can theoretically increase the risk for angioedema.[9][10]

Racecadotril and its main metabolites neither inhibit nor induce the liver enzymes CYP1A2CYP2C9CYP2C19CYP2D6, and CYP3A4. They also do not induce UGT enzymes.[10] This means that racecadotril has a low potential for pharmacokinetic interactions.

Pharmacology

Mechanism of action

Enkephalins are peptides produced by the body that act on opioid receptors with preference for the δ subtype.[11] Activation of δ receptors inhibits the enzyme adenylyl cyclase, decreasing intracellular levels of the messenger molecule cAMP.[7]

The active metabolite of racecadotril, thiorphan, inhibits enkephalinase enzymes in the intestinal epithelium with an IC50 of 6.1 nM, protecting enkephalins from being broken down by these enzymes. (Racecadotril itself is much less potent at 4500 nM.)[7][8] This reduces diarrhea related hypersecretion in the small intestine without influencing basal secretion. Racecadotril also has no influence on the time substances, bacteria or virus particles stay in the intestine.[10]

Pharmacokinetics

Some metabolites of racecadotril.
top left: precursor to the active metabolite
top right: active metabolite
bottom row: inactive metabolites

Racecadotril is rapidly absorbed after oral administration and reaches Cmax within 60 minutes. Food delays Cmax by 60 to 90 minutes but does not affect the overall bioavailability. Racecadotril is rapidly and effectively metabolized to the moderately active S-acetylthiorphan the main active metabolite thiorphan, of which 90% are bound to blood plasma proteins. In therapeutic doses, racecadotril does not pass the blood–brain barrier. Inhibition of enkephalinases starts 30 minutes after administration, reaches its maximum (75–90% inhibition with a therapeutic dose) two hours after administration, and lasts for eight hours. The elimination half-life, measured from enkephalinase inhibition, is three hours.[7][8][9]

Thiorphan is further metabolized to inactive metabolites such as the methyl thioether and the methyl sulfoxide. Both active and inactive metabolites are excreted, mostly via the kidney (81.4%), and to a lesser extent via the feces (8%).[10]

Society and culture

Brand names

In both France and Portugal it is sold as Tiorfan and in Italy as Tiorfix. In India it is available as Redotril and Enuff.[4]

See also

References

  1. ^ https://www.ema.europa.eu/documents/psusa/racecadotril-list-nationally-authorised-medicinal-products-psusa/00002602/202003_en.pdf
  2. Jump up to:a b c d “SPC-DOC_PL 39418-0003.PDF” (PDF). Medicines and Healthcare Products Regulatory Agency. Bioprojet Europe Ltd. 26 December 2012. Retrieved 7 May 2014.
  3. Jump up to:a b Matheson AJ, Noble S (April 2000). “Racecadotril”. Drugs59 (4): 829–35, discussion 836–7. doi:10.2165/00003495-200059040-00010PMID 10804038.
  4. Jump up to:a b Brayfield, A, ed. (13 December 2013). “Racecadotril”Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 6 May 2014.
  5. ^ Spillantini MG, Geppetti P, Fanciullacci M, Michelacci S, Lecomte JM, Sicuteri F (June 1986). “In vivo ‘enkephalinase’ inhibition by acetorphan in human plasma and CSF”. European Journal of Pharmacology125 (1): 147–50. doi:10.1016/0014-2999(86)90094-4PMID 3015640.
  6. ^ Fischbach, Wolfgang; Andresen, Viola; Eberlin, Marion; Mueck, Tobias; Layer, Peter (2016). “A Comprehensive Comparison of the Efficacy and Tolerability of Racecadotril with Other Treatments of Acute Diarrhea in Adults”Frontiers in Medicine3: 44. doi:10.3389/fmed.2016.00044ISSN 2296-858XPMC 5064048PMID 27790616.
  7. Jump up to:a b c d e f Dinnendahl, V; Fricke, U, eds. (1982). Arzneistoff-Profile (in German). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
  8. Jump up to:a b c Eberlin, Marion; Mück, Thomas; Michel, Martin C. (2012). “A Comprehensive Review of the Pharmacodynamics, Pharmacokinetics, and Clinical Effects of the Neutral Endopeptidase Inhibitor Racecadotril”Frontiers in Pharmacology3: 93. doi:10.3389/fphar.2012.00093ISSN 1663-9812PMC 3362754PMID 22661949.
  9. Jump up to:a b c d e Mediq.ch: racecadotril. Accessed 2019-12-30.
  10. Jump up to:a b c d e f g Haberfeld, H, ed. (2019). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Hidrasec 100 mg-Hartkapseln.
  11. ^ Cumming, P (2019). “A Survey of Molecular Imaging of Opioid Receptors”Molecules24 (22): 4190. doi:10.3390/molecules24224190PMC 6891617PMID 31752279.
Clinical data
Trade namesHidrasec, Tiorfan, Zedott, others
Other namesBenzyl 2-[3-(acetylthio)-2-benzylpropanamido]acetate
AHFS/Drugs.comInternational Drug Names
Routes of
administration
By mouth
ATC codeA07XA04 (WHO)
Legal status
Legal statusUK: POM (Prescription only)EU: Rx-only [1]
Pharmacokinetic data
Protein binding90% (active metabolite thiorphan)[2]
MetabolismLiver-mediated[2]
Onset of action30 min
Elimination half-life3 hours[2]
ExcretionUrine (81.4%), feces (8%)[2]
Identifiers
showIUPAC name
CAS Number81110-73-8 
PubChem CID107751
DrugBankDB11696
ChemSpider96913 
UNII76K53XP4TO
KEGGD08464
ChEMBLChEMBL2103772 
CompTox Dashboard (EPA)DTXSID8045513 
ECHA InfoCard100.214.352 
Chemical and physical data
FormulaC21H23NO4S
Molar mass385.48 g·mol−1
3D model (JSmol)Interactive image
ChiralityRacemic mixture
Melting point89 °C (192 °F)
showSMILES
showInChI
  (what is this?)  (verify)
https://i0.wp.com/www.frontiersin.org/files/Articles/27281/fphar-03-00093-HTML/image_m/fphar-03-00093-g001.jpg
CN101103960A *Jul 14, 2006Jan 16, 2008海南盛科生命科学研究院Dry mixed suspension containing racecadotril and preparation method thereof
CN101768095A *Dec 26, 2008Jul 7, 2010山东齐都药业有限公司Preparation method of racecadotril
WO2001097803A1 *Jun 20, 2001Dec 27, 2001Laboratoire GlaxosmithklinePharmaceutical preparations comprising racecadotril (acetorphan)
WO2013098826A1 *Dec 26, 2011Jul 4, 2013Symed Labs Limited“a process for the preparation of n-[2-[(acetylthio) methyl]-1-oxo-3-phenylpropyl] glycine phenyl methyl ester and intermediates thereof”
Reference
Reference
CN101103960A *Jul 14, 2006Jan 16, 2008海南盛科生命科学研究院Dry mixed suspension containing racecadotril and preparation method thereof
CN101768095A *Dec 26, 2008Jul 7, 2010山东齐都药业有限公司Preparation method of racecadotril
WO2001097803A1 *Jun 20, 2001Dec 27, 2001Laboratoire GlaxosmithklinePharmaceutical preparations comprising racecadotril (acetorphan)
WO2013098826A1 *Dec 26, 2011Jul 4, 2013Symed Labs Limited“a process for the preparation of n-[2-[(acetylthio) methyl]-1-oxo-3-phenylpropyl] glycine phenyl methyl ester and intermediates thereof”
1*金庆平 等: “神经内肽酶抑制剂消旋卡多曲(Racecadotril)的合成工艺研究“, 《中国现代应用药学杂志》, vol. 20, no. 7, 31 August 2003 (2003-08-31)
Reference
Citing PatentFiling datePublication dateApplicantTitle
US6013829 *Feb 4, 1997Jan 11, 2000Societe Civile BioprojetProcess for the asymmetric synthesis of S-acyl derivatives of 2-mercaptomethyl -3- phenyl propanoic acid, application to the synthesis of N-(mercaptoacyl) amino acid derivatives
US20040009956 *Apr 29, 2003Jan 15, 2004Dehua PeiInhibition of protein tyrosine phosphatases and SH2 domains by a neutral phosphotyrosine mimetic
1*MOHAMED A.O. ET AL.: ‘Stability-indicating methods for the determination of racecadotril in the presence of its degradation products‘ BIOSCIENCE TRENDS vol. 3, no. 6, 2009, pages 247 – 252, XP055074337
CN104356036A *Nov 7, 2014Feb 18, 2015山东齐都药业有限公司Alpha crystal form of racecadotril and preparation method of alpha crystal form

///////////Racecadotril, рацекадотрил , راسيكادوتريل , 消旋卡多曲 , Antidiarrheal, Neutral Endopeptidase Inhibitor, Cadotril, Dexecadotril , 

CC(=O)SCC(CC1=CC=CC=C1)C(=O)NCC(=O)OCC1=CC=CC=C1

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CEFADROXIL


Cefadroxil.svg
ChemSpider 2D Image | Cefadroxil | C16H17N3O5S

CEFADROXIL

  • Molecular FormulaC16H17N3O5S
  • Average mass363.388 Da

(6R,7R)-7-{[(2R)-2-Amino-2-(4-hydroxyphenyl)acetyl]amino}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
256-555-6[EINECS]
50370-12-2[RN]
5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7-(((2R)-amino(4-hydroxyphenyl)acetyl)amino)-3-methyl-8-oxo-, (6R,7R)-
5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-, (6R,7R)-
цефадроксил [Russian] [INN]
سيفادروكسيل [Arabic] [INN]
头孢羟氨苄 [Chinese] [INN]

ChemSpider 2D Image | Cephos | C16H19N3O6S

Cephos

  • Molecular FormulaC16H19N3O6S
  • Average mass381.404 Da

5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-, (6R,7R)-, monohydrate
66592-87-8[RN]
(6R,7R)-7-{[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrate
(6R,7R)-7-{[(2R)-2-Amino-2-(4-hydroxyphenyl)acetyl]amino}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrate (1:1)

Product Ingredients

INGREDIENTUNIICASINCHI KEY
Cefadroxil hemihydrateJ9CMF6461M119922-85-9AJAMDISMDZXITN-QXBGZBSVSA-N
Cefadroxil monohydrate280111G16066592-87-8NBFNMSULHIODTC-CYJZLJNKSA-N
Cefadroxil sodiumSSZ6380I0I42284-83-3GQOVFIUWRATNJC-CYJZLJNKSA-M

CefadroxilCAS Registry Number: 66592-87-8 
CAS Name: (6R,7R)-7-[[(2R)-Amino-(4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohydrate 
Additional Names: 7-[D-(-)-a-amino-a-(4-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate; p-hydroxycephalexine monohydrate 
Manufacturers’ Codes: BL-S578; MJF-11567-3 
Trademarks: Baxan (BMS); Bidocef (BMS); Cefa-Drops (Fort Dodge); Cefamox (BMS); Ceforal (Farmoffer); Cephos (CT); Duracef (BMS); Duricef (BMS); Kefroxil (Torre); Oracéfal (BMS); Sedral (BMS); Ultracef (BMS) 
Molecular Formula: C16H17N3O5S.H2O 
Molecular Weight: 381.40 
Percent Composition: C 50.39%, H 5.02%, N 11.02%, O 25.17%, S 8.41% 
Literature References: Semi-synthetic cephalosporin antibiotic. Prepn: NL6812382; L. B. Crast, Jr., US3489752 (1969, 1970 both to Bristol-Myers); T. Takahashi et al.,DE2216113eidem,US3816253 (1972, 1974, both to Takeda). Prepn of crystalline monohydrate: D. Bouzard et al.,US4504657 (1985 to Bristol-Myers). Antimicrobial activity: R. E. Buck, K. E. Price, Antimicrob. Agents Chemother.11, 324 (1977). Pharmacology: M. Pfeffer et al.,ibid. 331; A. I. Hartstein et al.,ibid.12, 93 (1977). Review:J. Antimicrob. Chemother.10, Suppl. B, 1-162 (1982). Series of articles on clinical trials in respiratory tract infections: Drugs32, Suppl. 3, 1-56 (1986).Properties: White crystals, mp 197° (dec). 
Melting point: mp 197° (dec) 
Therap-Cat: Antibacterial. 
Therap-Cat-Vet: Antibacterial. 
Keywords: Antibacterial (Antibiotics); ?Lactams; Cephalosporins.

Cefadroxil is a cephalosporin antibiotic used in the treatment of various bacterial infections, such as urinary tract infections, skin and skin structure infections, and tonsillitis.

Cefadroxil (formerly trademarked as Duricef) is a broad-spectrum antibiotic of the cephalosporin type, effective in Gram-positive and Gram-negative bacterial infections. It is a bactericidal antibiotic.

It was patented in 1967 and approved for medical use in 1978.[1]

DURICEF (cefadroxil) is a semisynthetic cephalosporin antibiotic intended for oral administration. It is a white to yellowish-white crystalline powder. It is soluble in water and it is acid- stable. It is chemically designated as 5-Thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[amino(4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-, monohydrate[6R- [6α,7β(R*)]]-. It has the formula C16H17N3O5S•H20 and the molecular weight of 381.40. It has the following structural formula:

DURICEF (cefadroxil monohydrate) structural formula illustration

DURICEF (cefadroxil) film-coated tablets, 1 g, contain the following inactive ingredients: microcrystalline cellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol, polysorbate 80, simethicone emulsion, and titanium dioxide.

DURICEF (cefadroxil) for Oral Suspension contains the following inactive ingredients: FD&C Yellow No. 6, flavors (natural and artificial), polysorbate 80, sodium benzoate, sucrose, and xanthan gum.

DURICEF (cefadroxil) capsules contain the following inactive ingredients: D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40, gelatin, magnesium stearate, and titanium dioxide.

SYN

a) : IR spectrum of pure cefadroxil drug. 

IR spectrum of pure cefadroxil drug.

Synthesis Reference

Leonardo Marsili, “Substantially anhydrous crystalline cefadroxil and method for producing it.” U.S. Patent US5329001, issued April, 1978.

US5329001

SYN

Antibiotics

R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006

Cefadroxil

Cefadroxil, [6R-[6α,7β(R)]]-3-methyl-8-oxo-7-[[amino(4-hydroxyphenyl) acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (32.1.2.14), is an analog of cephalexin and differs only in the presence of a hydroxyl group in the fourth position of the phenyl ring of phenylglycine, and is synthesized by a scheme analogous to the scheme of cephradin synthesis [90–96].

Cefadroxil has a broad spectrum of antimicrobial action; it is active with respect to Gram-positive and Gram-negative microorganisms. Like all of the other drugs described above, it acts as a bactericide by disrupting the process of restoring the membranes of bacteria. Synonyms of this drug are bidocef, cefadril, duracef, ultracef, and others.SYN

Cefadroxil

  • ATC:J01DA09
  • MW:363.39 g/mol
  • CAS-RN:50370-12-2
  • InChI Key:BOEGTKLJZSQCCD-UEKVPHQBSA-N
  • InChI:InChI=1S/C16H17N3O5S/c1-7-6-25-15-11(14(22)19(15)12(7)16(23)24)18-13(21)10(17)8-2-4-9(20)5-3-8/h2-5,10-11,15,20H,6,17H2,1H3,(H,18,21)(H,23,24)/t10-,11-,15-/m1/s1
  • EINECS:256-555-6
  • LD50:>1.5 g/kg (M, i.v.); >10 g/kg (M, p.o.);
    >1 g/kg (R, i.v.); >10 g/kg (R, p.o.);
    >2 g/kg (dog, p.o.)

 

Synthesis

Substances

CAS-RNFormulaChemical NameCAS Index Name
22252-43-3C8H10N2O3S7-amino-3-deacetoxycephalosporanic acid5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-amino-3-methyl-8-oxo-, (6R-trans)-
53487-89-1C13H15NO5d(–)-4-hydroxy-N-(2-methoxycarbonyl-1-methylethenyl)phenylglycineBenzeneacetic acid, 4-hydroxy-α-[(3-methoxy-1-methyl-3-oxo-1-propenyl)amino]-, (R)-

PATENT

 Seo, Dae-Won; WO 2005042543

https://patents.google.com/patent/WO2005042543A1/enOral cephalosporin antibiotics, including cefprozil, cefatrizine, and cefadroxii, commonly have a 4-hydroxyphenylglycine group, as represented by the following formula:

Figure imgf000002_0001

The compound of the above formula is cefprozil when A is -C=CH-CH3, cefatrizine when A is 1 H-1 ,2,3-triazole-4-yl-thiomethyl, and cefadroxii when A is -CH3. Conventionally, there have been known various processes for preparing oral cephalosporin antibiotics, such as cefprozil, cefatrizine, and cefadroxii, by reacting reactive derivatives of 4-hydroxyphenylglycine with 3-cephem compounds. For example, U.S. Patent No. 3,985,741 discloses a process for preparing a cefadroxii, which includes reacting 4-hydroxyphenylglycine and ethylchloroformate inN-methylmorpholine to obtain an anhydride, followed by reaction with7-amino-deacetoxy-cephalosporanic acid (7-ADCA). However, the yield and quality of the product are poor. U.S. Patent Nos. 4,520,022, 4,591 ,641 , and 4,661 ,590 disclose a condensation reaction between 4-hydroxyphenylglycine with a protected amino group and a cephem compound in the presence of Λ/.Λ/’-dicyclohexylcarbodimide. However,Λ/,Λ/’-dicyclohexylurea produced after the condensation reaction is not easily removed, which restricts industrial applications. U.S. Patent No. 4,336,376 discloses a process for preparing a cefadroxii, which includes reacting a 4-hydroxyphenylglycine salt having a protected amino group with trimethylsilyl-2-oxazolidinone to protect a 4-hydroxyl group followed by reaction with acylchloride to obtain a 4-hydroxyphenylglycine anhydride and then reaction with 7-ADCA. However, silylation is prerequisite and these reactions are annoying, and thus, this process is not suitable for industrial application. U.S. Patent No. 4,708,825 discloses a technique of reacting4-hydroxyphenylglycine having a substituted amino group with thionyl chloride using a gaseous hydrogen chloride to obtain a 4-hydroxyphenylglycyl chloride hydrochloride followed by reaction with a cephem compound. However, handling property of the thionyl chloride and the gaseous hydrogen chloride is poor, and thus, this technique is not suitable for industrial application. U.S. Patent Nos. 3,925,418, 4,243,819, and 4,464,307 disclose a process for producing 4-hydroxyphenylglycine using excess phosgene. However, difficulty in handling of highly toxic phosgene, removal of excess residual phosgene, and control of reaction conditions renders mass production difficult. As a process for preparing a reactive anhydride of 4-hydroxyphenylglycine, there are reported a method for the preparation of acid chloride using phosphorus pentachloride, phosphorus oxychloride, or thionyl chloride, and a method for the preparation of active ester using imidazole, mercaptobenzothiazole, or hydroxybenzotriazole. However, an acid chloride of 4-hydroxyphenylglycine has poor reactivity due to a hydroxyl group and an active ester of 4-hydroxyphenylglycine has poor reactivity and involves a side reaction. In addition, Korean Patent Laid-Open Publication Nos. 2002-69431 , 2002-69432, 2002-69437, and 2002-69440 disclose a process for preparing a pivaloyl or succinimide derivative of 4-hydroxyphenylglycine and a process for preparing a cephem compound such as cefprozil using the pivaloyl or succinimide derivative of 4-hydroxyphenylglycine. Meanwhile, there have been known various preparation processes for 3-(Z)-propenyl cephem derivative which is a compound useful as an intermediate for preparation of cefprozil which is an oral cephalosporin antibiotic. WO93/16084 discloses a process of selectively separating a 3-(Z)-propenyl cephem compound by means of a hydrochloride, metal, or tertiary amine salt of7-amino-3-(1-propen-1-yl)-3-cephem-carboxylic acid or by adsorption chromatography. However, there is a disadvantage in that separation and purification are cost-ineffective. U.K. Patent No. 2,135,305 discloses a process for preparing cefprozil from a4-hydroxyphenylglycine compound with a t-butoxycarbonyl-protected amino group and a cephem compound with a benzhydryl-protected carboxyl group. However, incorporation of a 3-propenyl group after acylation lowers reaction efficiency and high-performance liquid chromatography is required for isomer separation, which render industrial application difficult. U.S. Patent No. 4,727,070 discloses a technique of removing an E-isomer cefprozil from a mixture of 27E cefprozil, which includes incorporating an active group such as sodium imidazolidinone into the mixture of 2VE cefprozil by reaction of the mixture of 27E cefprozil with acetone followed by deprotection. However, purification by chromatography incurs enormous costs. In view of the above problems, Korean Patent Laid-Open Publication No.2002-80838 discloses a process for preparing a 3-(Z)-propenyl cephem compound by reacting a phosphoranylidene cephem compound with acetaldehyde in a mixed solvent essentially consisting of ether in the presence of a base. According to a disclosure in this patent document, ether is essentially used. In this respect, in the case of using methylenechloride or tetrahydrofuran, even when other reaction conditions, for example, reaction temperature, reaction duration, base, catalyst, and the like are adjusted, it is very difficult to adjust the content of the Z-isomer to more than 83%.DETAILED DESCRIPTION OF THE INVENTION Technical Goal of the Invention The present invention provides a process for simply preparing a cephalosporin antibiotic in high yield and purity using a novel reactive intermediate, i.e., a 4-hydroxyphenylglycine derivative. The present invention also provides a novel reactive intermediate, i.e., a 4-hydroxyphenylglycine derivative which is used in simply preparing a cephalosphorin antibiotic in high yield and purity, and a preparation process thereof. While searching for a process for stereospecifically preparing a novel3-(Z)-propenyl cephem derivative, the present inventors found that use of a mixed solvent including methylenechloride, isopropylalcohol, and water in a predetermined ratio can stereospecifically and efficiently produce the 3-(Z)-propenyl cephem derivative, which is in contrary to the disclosure in Korean Patent Laid-Open Publication No. 2002-80838. Therefore, the present invention also provides a process for stereospecifically preparing a 3-(Z)-propenyl cephem derivative using a mixed solvent including methylenechloride, isopropylalcohol, and water in a predetermined ratio.

Figure imgf000007_0002
Figure imgf000009_0003
Figure imgf000012_0002

 Example 9 Preparation of7-r2-amino-2-(4-hvdroxyphenyl)acetamido1-3-methyl-3-cephem-4-carboxylic acid(cefadroxii) The reaction solution obtained in step A of Example 1 was cooled to -40 °C and a solution obtained by dissolving 6.21 g (0.029mol) of 7-amino-3-methyl-3-cephem-4-carboxylic acid in 40 ml of methylenechloride, 10 ml of water, and 6.5 g of triethylamine was gradually dropwise added thereto for 1 hour. Then, the reaction mixture was incubated at the same temperature for 2 hours and cooled to 0°C to obtain an insoluble solid. The insoluble solid was filtered. A filtrate was sent to a reactor and then stirred for 1 hour after addition of 20 ml of 6N HCI. The reaction solution was adjusted to pH of 3.2 by addition of 10% NaOH, stirred at0°C for 2 hours, and filtered to give 9.1g (83%) of the titled compound as a white solid. H-NMR( δ , D20-d2) : 1.79(3H, d, 8.6Hz, -CH3), 3.22(1 H, d, 18Hz, 2-H),3.55(1 H. d. 18Hz, 2-H), 5.15(1 H, d, 4.6Hz, 6-H), 5.66(1 H, d, 4.6Hz, 7-H), 6.91 (2H, d,8.0Hz, phenyl-H), 7.38(2H, d, 8.0Hz, phenyl-H)

PAPER

Deshmukh, J. H.; Asian Journal of Chemistry 2010, V22(3), P1760-1768 

Journal of the Chinese Chemical Society (Weinheim, Germany), 66(12), 1649-1657; 2019

Journal of the Indian Chemical Society, 93(6), 593-598; 2016

 Biotechnology Letters, 34(9), 1719-1724; 2012

PATENT

WO 2011113486

By Gupta, Niranjan Lal et alFrom Indian, 184842, 30 Sep 2000

PAPER

European Journal of Organic Chemistry, (10), 1817-1820; 2001

PAPER

 Organic Letters, 2(18), 2829-2831; 2000

The cephalosporin antibiotic Cefadroxil can be epimerized at the α-carbon of its amino acid side chain using pyridoxal as the mediator. By clathration with 2,7-dihydroxynaphthalene, the desired diastereomer can be selectively withdrawn from the equilibrating mixture of epimers. In this way, an asymmetric transformation of Cefadroxil can be accomplished. This opens the possibility of the production of Cefadroxil starting from racemic p-hydroxyphenylglycine, in contrast to the current industrial synthesis that employs the d-amino acid in enantiopure form.

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Medical use

Cefadroxil is a first-generation cephalosporin antibacterial drug that is the para-hydroxy derivative of cephalexin, and is used similarly in the treatment of mild to moderate susceptible infections such as the bacterium Streptococcus pyogenes, causing the disease popularly called strep throat or streptococcal tonsillitisurinary tract infectionreproductive tract infection, and skin infections.

Cefadroxil is used as an antibiotic prophylaxis before dental procedures, for patients allergic to penicillins.

Spectrum of bacterial resistance and susceptibility

Cefadroxil has a broad spectrum of activity and has been effective in treating bacteria responsible for causing tonsillitis, and infections of the skin and urinary tract. The following represents MIC susceptibility data for a few medically significant microorganisms.[2]

  • Escherichia coli: 8 μg/ml
  • Staphylococcus aureus: 1 – 2 μg/ml
  • Streptococcus pneumoniae: ≤1 – >16 μg/ml

Side effects

The most common side effects of cefadroxil are diarrhea (which, less commonly, may be bloody), nauseaupset stomach, and vomiting. Other side effects include[3] rasheshives, and itching.

Pharmacokinetics

Cefadroxil is almost completely absorbed from the gastrointestinal tract. After doses of 500 mg and 1 g by mouth, peak plasma concentrations of about 16 and 30 micrograms/ml, respectively, are obtained after 1.5 to 2.0 hours. Although peak concentrations are similar to those of cefalexin, plasma concentrations are more sustained. Dosage with food does not appear to affect the absorption of cefadroxil. About 20% of cefadroxil is reported to be bound to plasma proteins. Its plasma half-life is about 1.5 hours and is prolonged in patients with renal impairment.

Cefadroxil is widely distributed to body tissues and fluids. It crosses the placenta and appears in breast milk. More than 90% of a dose of cefadroxil may be excreted unchanged in the urine within 24 hours by glomerular filtration and tubular secretion; peak urinary concentrations of 1.8 mg/ml have been reported after a dose of 500 mg. Cefadroxil is removed by haemodialysis.

Dosage

Cefadroxil is given by mouth, and doses are expressed in terms of the anhydrous substance; 1.04 g of cefadroxil monohydrate is equivalent to about 1 g of anhydrous cefadroxil.

Veterinary use

It can be used for treating infected wounds on animals. Usually in powder form mixed with water, it has a color and smell similar to Tang. Given orally to animals, the amount is dependent on their weight and severity of infection.

References

  1. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 493. ISBN 9783527607495.
  2. ^ “Cefadroxil, Free Acid Susceptibility and Minimum Inhibitory Concentration (MIC) Data” (PDF).
  3. ^ “Cefadroxil side effects”. Drugs.
Clinical data
Trade namesDuricef
AHFS/Drugs.comMonograph
MedlinePlusa682730
Routes of
administration
Oral
ATC codeJ01DB05 (WHO)
Legal status
Legal statusIn general: ℞ (Prescription only)
Pharmacokinetic data
Protein bindingplasma protein
Metabolismunknown
Elimination half-life1.5 hours
Identifiers
showIUPAC name
CAS Number66592-87-8 
PubChem CID47964
DrugBankDB01140 
ChemSpider43629 
UNII280111G160
KEGGD02353 
ChEBICHEBI:53667 
ChEMBLChEMBL1644 
CompTox Dashboard (EPA)DTXSID8022749 
ECHA InfoCard100.051.397 
Chemical and physical data
FormulaC16H17N3O5S
Molar mass363.39 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (what is this?)  (verify)

////////////CEFADROXIL, цефадроксил , سيفادروكسيل , 头孢羟氨苄 , BL-S578; MJF-11567-3, BL S578, MJF 11567-3

[H][C@]12SCC(C)=C(N1C(=O)[C@H]2NC(=O)[C@H](N)C1=CC=C(O)C=C1)C(O)=O

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Cabergoline


Cabergoline.svg
ChemSpider 2D Image | Cabaser | C26H37N5O2
Cabergoline

Cabergoline

Cabaser

  • Molecular FormulaC26H37N5O2
  • Average mass451.604 Da

1-Ethyl-3-(3′-dimethylaminopropyl)-3-(6′-allylergoline-8’β-carbonyl)urea
5860
81409-90-7[RN]
(6aR,9R,10aR)-N-[3-(dimethylamino)propyl]-N-(ethylcarbamoyl)-7-prop-2-en-1-yl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide
(8b)-N-[3-(Dimethylamino)propyl]-N-[(ethylamino)carbonyl]-6-(2-propenyl)ergoline-8-carboxamide
(8β)-6-Allyl-N-[3-(dimethylamino)propyl]-N-(ethylcarbamoyl)ergoline-8-carboxamide
Ergoline-8-carboxamide, N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl]-6-(2-propen-1-yl)-, (8β)-
ergoline-8-carboxamide, N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl]-6-(2-propenyl)-, (8β)-
KE6167600, LL60K9J05T, UNII-LL60K9J05T, 
каберголин 
كابارغولين 

卡麦角林, 

  • FCE 21336
  • FCE-21336

Cabergoline 
CAS Registry Number: 81409-90-7 
CAS Name:(8b)-N-[3-(Dimethylamino)propyl]-N-[(ethylamino)carbonyl]-6-(2-propenyl)ergoline-8-carboxamide 
Additional Names: 1-ethyl-3-(3¢-dimethylaminopropyl)-3-(6¢-allylergoline-8¢b-carbonyl)urea; 1-[(6-allylergoline-8b-yl)carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea 
Manufacturers’ Codes: FCE-21336 
Trademarks: Dostinex (Pharmacia & Upjohn) 
Molecular Formula: C26H37N5O2, Molecular Weight: 451.60 
Percent Composition: C 69.15%, H 8.26%, N 15.51%, O 7.09% 
Literature References: Dopamine D2-receptor agonist. Prepn: P. Salvati et al.,BE888243eidem,US4526892 (1981, 1985 both to Farmitalia Carlo Erba). Prepn and bioactivity: E. Brambilla et al.,Eur. J. Med. Chem.24, 421 (1989). Clinical pharmacology: C. Ferrari et al.,J. Clin. Endocrinol. Metab.63, 941 (1986). Veterinary trial as abortifacient in dogs: K. Post et al.,Theriogenology29, 1233 (1988). Clinical evaluation to prevent puerperal lactation: G. B. Melis et al.,Obstet. Gynecol.71, 311 (1988); in hyperprolactinemic disorders: C. Ferrari et al.,J. Clin. Endocrinol. Metab.68, 1201 (1989). Clinical trial in Parkinson’s disease: J. T. Hutton et al.,Neurology46, 1062 (1996). 
Properties: White crystals from diethyl ether, mp 102-104°. Sol in ethyl alcohol, chloroform, DMF; slightly sol in 0.1 N HCl; very slightly sol in n-hexane. Insol in water. LD50 orally in male mice: >400 mg/kg (Brambilla). 
Melting point: mp 102-104° 
Toxicity data: Sol in ethyl alcohol, chloroform, DMF; slightly sol in 0.1 N HCl; very slightly sol in n-hexane. Insol in water. LD50 orally in male mice: >400 mg/kg (Brambilla) 

2D chemical structure of 85329-89-1

Cabergoline diphosphate
85329-89-1 
Derivative Type: Diphosphate 
CAS Registry Number: 85329-89-1, Molecular Formula: C26H37N5O2.2H3PO4, Molecular Weight: 647.59 
Percent Composition: C 48.22%, H 6.69%, N 10.81%, O 24.71%, P 9.57% 
Properties: mp 153-155°., Melting point: mp 153-155° 
Therap-Cat: Prolactin inhibitor; antiparkinsonian. 
Therap-Cat-Vet: Prolactin inhibitor. 
Keywords: Antiparkinsonian; Dopamine Receptor Agonist; Prolactin Inhibitor.

Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levelsprolactinomasParkinson’s disease, and for other indications. It is taken by mouth.

Cabergoline is an ergot derivative and a potent dopamine D2 receptor agonist.[1]

Cabergoline was patented in 1980 and approved for medical use in 1993.[2]

Cabergoline is a dopamine receptor agonist used for the treatment of hyperprolactinemic conditions due to various causes.

Cabergoline, an ergot derivative, is a long-acting dopamine agonist and prolactin inhibitor. It is used to treat hyperprolactinemic disorders and Parkinsonian Syndrome. Cabergoline possesses potent agonist activity on dopamine D2 receptors.

Synthesis Reference

US4526892

PAPER

https://www.researchgate.net/publication/11103403_A_Practical_Synthesis_of_Cabergoline

N-[[(5R,8R,10R)-6-Allylergolin-8-yl]carbonyl]-N-[3-(di-methylamino)propyl]-N′-ethylurea (1). Compound 11 (40.13g, 72.7 mmol), H2O (200 mL), and 1 M aqueous hydrochloric acid(182 mL, 182 mmol) were combined and heated to 80 °C for 1 h.EtOAc (300 mL) was added to the light yellow solution. The pHwas adjusted to 10 with concentrated NH4OH (30 mL). Theorganic phase was separated and extracted with H2O(2×100mL). The aqueous layer was extracted with EtOAc (1 ×100 mL),and the combined organic layer was dried over Na2SO4, filtered,and concentrated to an amorphous solid. Cabergoline wasisolated in 94% yield (55% chemical yield overall from 8in highpurity (99 area % by HPLC): 1H NMR (CDCl3)δ1.18 (t, J)7.1 Hz, 3H), 1.76 (m, 2H), 1.85 (m, 2H), 2.23 (s, 6H), 2.34 (m,2H), 2.53-2.84 (m, 4H), 2.98 (m, 1H), 3.17 (m, 1H), 3.29-3.44(m, 4H), 3.55 (m, 1H), 3.83 (m, 2H), 5.19 (d, J)10.2 Hz, 1H),5.25 (d, J)16.8 Hz, 1H), 5.95 (m, 1H), 6.87 (m, 2H), 7.14 (m,2H), 8.88 (s, 1H), 9.45 (s, 1H); 13C NMR (100 MHz, CDCl3)δ14.7, 26.61, 31.31, 35.41, 40.04, 42.23, 43.21, 44.93, 55.61, 56.10,63.74, 108.7, 111.58, 113.10, 117.88, 118.36, 122.98, 126.02,132.67, 133.31, 133.83, 177.89.
1H AND 13 NMR IN CDCl3file:///C:/Users/Inspiron/Downloads/jo0203847_si_001.pdf

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in dmso d6

SYN

DOI: 10.1016/0223-5234(89)90087-1

File:Cabergoline synthesis.png

PATENT

https://patents.google.com/patent/EP1720869B1/en

  • 6-Allyl-N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl]-ergoline-8β-carboxamide – international non-proprietary name cabergoline – of formula (I)is a potent dopamine agonist and is useful as anti-Parkinson drug and as prolactin inhibitor (Eur. J. Med. Chem. 1989, 24, 421-426 and United States Patent 5,382,669 ).
  • [0003]
    Cabergoline (I) was firstly prepared according to United States Patent 4,526,892 by reaction of 6-allyl-ergoline-8β-carboxylic acid (II) with 1-[3-(dimethylamino)propyl)-3-ethylcarbodiimide (EDC) (Scheme 1).
  • [0004]
    In this case both regioisomers (I) and (III) were obtained and the yield of the isolated cabergoline (I) is only approx. 21% as a consequence of isolation difficulties, considering that the yield of compound (II) prepared from (XIII) according to the state of the art is 70%.
  • [0005]
    Eur. J. Med. Chem. 1989, 24, 421-426 describes another method for the preparation of Cabergoline (I), which is based on the direct reaction of 6-allyl-N-[3-(dimethylamino)propyl]-ergoline-8β-carboxamide (IV) with ethyl isocyanate (EtNCO) (Scheme 2).
  • [0006]
    Since this reaction leads to equilibrium, it requires the use of a large excess of ethyl isocyanate (up to 40 equivalents) for reasonable conversion and must be conducted at above 100°C in toluene for several hours. The use of large quantities of toxic ethyl isocyanate under drastic reaction conditions presents a serious hazard for the large-scale preparation of cabergoline (I). In addition, conversion to (I) is incomplete and competitive acylation of the indole nitrogen forming compounds (V) and (VI) occurs. This side reaction complicates the product purification and reduces the yield, which is only approx. 58%, considering that the yield of compound (IV) prepared from (XIII) according to the state of the art is 72%.
  • [0007]
    The method proposed in United States Patent 5,382,669 and Syn. Lett. 1995, 605-606 showed that catalysis by copper salts in the presence of phosphine ligands permitted the ethyl isocyanate reaction to be run at room temperature with only 3 equivalents of ethyl isocyanate. However, despite of moderation in reaction conditions the conversion and the ratio of cabergoline (I) and the byproducts (V and VI) are not much different from the uncatalyzed thermal reaction. The yield is only approx. 48% and 57%, considering that the yield of compound (IV) prepared from (XIII) according to the state of the art is 72%.
  • [0008]
    J. Org. Chem. 2002, 67, 7147-7150 describes an ethyl isocyanate-free method for the production of cabergoline (I) that solves the problem of completing acylation of indole nitrogen, too.
  • [0009]
    The first step is the protection of indole nitrogen of amide (IV) preferably as tert-butyl carbamate (VII).
  • [0010]
    Extension of the amide side chain is done by deprotonation of compound (VII) with sodium hexamethyldisilazide (NaHMDS) followed by trapping the anion with phenyl chloroformate (PhOCOCl) to yield the phenyl carbamate (VTII).
  • [0011]
    Reaction of compound (VII) with ethylamine hydrochloride (EtNH2xHCl) gives BOC-cabergoline (IX) but also generates the ethylamide (X). The deprotection is done from the mixture of (IX) and (X) with 1N aqueous hydrochloric acid. The purified cabergoline (I) is then isolated by basification followed by chromatography on silica. (Scheme 3).
  • [0012]
    In this approach the deprotonating step requires special cold reactor and strictly anhydrous circumstances. These requirements can hardly be satisfied in the course of large-scale preparation and the yield is only approx. 52%, considering that the yield of compound (VII) prepared from (XIII) according to the state of the art is 66%.
  • [0013]
    According to US 2002/0177709 A1 Patent Application cabergoline (I) may be prepared by silylating amide (IV) with a silylating agent (e.g. trimethylsilyl trifluoromethane sulfonate – TMSOTf), reacting the obtained product (XI) with ethyl isocyanate (EtNCO) followed by desilylation of intermediate (XII) (Scheme 4).
  • [0014]
    The disadvantage of this process is, that the silylating step requires strictly anhydrous circumstances. Otherwise, the reaction with ethyl isocyanate runs too long (24 hours) raising the safety hazard in the course of large-scale preparation and the yield is approx. 65%, considering that the yield of compound (IV) prepared from (XIII) according to the state of the art is 72%.
  • [0015]
    Several crystalline forms of Cabergoline (I) are known.
  • [0016]
    IL Farmaco 1995, 50 (3), 175-178 describes the preparation of crystalline form I. This solvated anhydrate product is crystallized from diethyl ether.
  • [0017]
    WO 01/70740 A1 Patent Application describes a new process for the preparation of crystalline form I from the new crystalline form V. The form V – which is toluene solvate – is prepared from the mixture of the purified cabergoline (I) with toluene and diethyl ether by a long-lasting complicated process, at low reaction temperature, and the yield is only 45%. The crystalline form I is prepared by drying the form V in vacuum.
  • [0018]
    WO 01/72746-A1 Patent Application describes the preparation of crystalline form VII from the crystalline form L By this process the suspension of form I in n-heptane or 1,4-dioxane is stirred for 48 hours, and then the suspension was filtered to obtain the crystalline form VII. The yield is 45.2%.
  • [0019]
    WO 01/72747 A1 Patent Application describes the crystalline form II and a process for its preparation with approx. 70% yield by stirring the cabergoline (I) for several days in an organic solvent (eg. diethyl ether) at low temperature.
  • [0020]
    Xenobiotica 1993, 23(12), 1377-1389, describes a comparison of the disposition and urinary metabolic pattern of 14C-cabergoline after single oral administration to rat, monkey and man. Among the potential metabolites of cabergoline a compound identified as FCE 27392 is disclosed, which corresponds to intermediate XIX of the preparation process of cabergoline according to the present invention.

The reaction procedure is shown in Scheme 5.

Figure imgb0006

EXAMPLE 5Synthesis of 6-allyl-N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl]-ergoline-8β-carboxamide (I) (Cabergoline).

  • [0077]
    To a suspension of 9.0 g (21.87 mmol) N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl)-ergoline-8β-carboxamide (XIX) in 250 ml of toluene 0.5 g of tetrakis(triphenylphosphine)palladium(0) and 5 ml of allyl acetate was added, and the reaction mixture was stirred at ambient temperature for 2 hours. The resulting mixture was washed with 100 ml of water. The organic layer was dried over anhydrous sodium sulphate. The dried solution was concentrated in vacuum and the product was purified on a silica plug to give 9.1 g (92.3%) of the title compound.
    1H NMR (DMSO-d6, TMS, 500MHz) δ 1.10 (t, 3H, J=7.2Hz, CONHCH2CH 3); 1.47 (q, 1H, J=12.4Hz, Hβ-9); 1.62-1.72 (m, 2H, CONCH2CH 2CH2N(CH3)2); 2.15 (s, 6H, CONCH2CH2CH2N(CH 3)2); 2.20-2.30 (m, 2H, CONHCH2CH2CH 2N(CH3)2); 2.32-2.40 (m, 2H, H-5, Hβ-7); 2.54 (dd, 1H, J=14.3Hz, 11.2Hz, Hα-4); 2.68-2.84 (m, 2H, Hα-9, H-10); 3.08 (ddd, 1H, J=11.3Hz, 3.1Hz, 1.8Hz, Hα-7); 3.14-3.22 (m, 2H, CONHCH 2CH3); 3.26 (dd, 1H, J=14.7Hz, 7.3Hz, Hx-N(6)CH 2CH=CH2); 3.28-3.38 (m, 2H, Hβ-4, H-8); 3.48 (dd, 1H, J=14.7Hz, 5.8Hz, Hy-N(6)CH 2CH=CH2); 3.58-3.68 (m, 2H, CONCH 2CH2CH2N(CH3)2); 5.15 (d, 1H, J=10.3Hz, Hx-N(6)CH2CH=CH 2); 5.24 (d, 1H, J=17.2Hz, Hy-N(6)CH2CH=CH 2); 5.88-5.98 (m, 1H, N(6)CH2CH=CH2); 6.75 (d, 1H, J=7.0Hz, H-12); 6.97 (s, 1H, H-2); 7.01 (t, 1H, J=7.5Hz, H-13); 7.13 (d, 1H, J=8.0Hz, H-14); 9.04 (t, 1H, J=5.0Hz, CONHCH2CH3); 10.60 (s, 1H, N(1)H).

EXAMPLE 6Production of amorphous form of Cabergoline (I)

  • [0078]
     
  1. a) 10 g of chromatographically purified oily Cabergoline (I) was dissolved in 50 ml of acetone. The solution was concentrated in vacuum at 25-30°C to approx. 15 g. The obtained oily residue was dissolved in 40 ml of acetone, and the solution was concentrated in vacuum at 25-30°C to approx. 12 g. The obtained oily residue was dissolved in 30 ml of acetone again, and the solution was concentrated in vacuum at 25-30°C to 10 g. The obtained solid Cabergoline (I) was dried in vacuum at 25-30°C to solvent-free, to give 9.8 g (98%) of the title compound.
  2. b) The same as in Example 6a, but employing methyl acetate as solvent, 9.85 g (98.5%) of the title compound was obtained.
  3. c) The same as in Example 6a, but employing dichloromethane as solvent, 9.82 g (982%) of the title compound was obtained.

Patent

Publication numberPriority datePublication dateAssigneeTitleFamily To Family CitationsGB9205439D0 *1992-03-121992-04-22Erba Carlo SpaProcess for the synthesis of ergoline derivativesUS6696568B2 *2001-04-162004-02-24Finetech Ltd.Process and intermediates for production of cabergoline and related compoundsJP2004525187A *2001-04-162004-08-19フイネテク・リミテツドMethods and intermediates for the preparation of cabergoline and related compounds 
Publication numberPriority datePublication dateAssigneeTitleFamily To Family CitationsEP1620101A4 *2003-05-082008-07-09Ivax Pharmaceuticals SroPolymorphs of cabergolineEP1925616A1 *2006-10-262008-05-28LEK Pharmaceuticals D.D.Process for the preparation of crystal forms of cabergoline via stable solvates of cabergolineWO2008104956A2 *2007-02-282008-09-04Ranbaxy Laboratories LimitedProcess for the preparation of amorphous cabergolineEP2083008A1 *2007-12-072009-07-29Axxonis Pharma AGErgoline derivatives as selective radical scavengers for neuronsWO2011154827A2 *2010-06-112011-12-15Rhodes TechnologiesTransition metal-catalyzed processes for the preparation of n-allyl compounds and use thereofCA2876321A1 *2012-06-222013-12-27Map Pharmaceuticals, Inc.Novel cabergoline derivatives 
SYNBE 0894060; JP 58038282This compound can be obtained by two differents ways: 1) By condensation of 6-allyl-N-[3-(dimethylamino)propyl]ergolin-8-beta-caboxamide (I) with ethyl isocyanate (II) in refluxing toluene. 2) By condensation of 6-allylergolin-8-beta-carboxylic acid (III) with N-ethyl-N’-[3-(dimethylamino)propyl]carbodiimide (IV) in refluxing THF.

SYN

J Label Compd Radiopharm 1991,29(5),519

The synthesis of tritiated cabergoline by two similar routes has been described: 1) The acylation of 6-nor-dihydrolysergic acid methyl ester (I) with propargyl bromide yields the corresponding 6-propargyl derivative (II), which is hydrogenated with tritium gas over Pd/C in the presence of quinoline to give the ditritiated 6-allyl derivative (III). This compound is treated with 3-(dimethylamino)propylamine at 120 C, yielding the amide (IV), which is finally treated with ethyl isocyanate. 2) The reaction of the propargyl derivative (II) with 3-(dimethylamino)propylamine as before gives the amide (V). The reaction of (V) with ethyl isocyanate gives compound (VI), which is then hydrogenated with tritium as before.

SYNThe synthesis of [14C]-cabergoline has also been described: The reaction of 6-allylergoline-8beta-carboxylic acid methyl ester (I) with hydrazine in refluxing methanol gives the hydrazide (II), which by reaction with NaNO2-HCl in water is converted to the amine (III). The reaction of (III) again with NaNO2-HCl in water, followed by reaction with SnCl2, affords the chloro derivative (IV), which is condensed with [14C]-CNK in refluxing ethanol-water yielding the nitrile (V). Hydrolysis of (V) with NaOH in refluxing ethanol affords the acid (VI), which is finally condensed with N-ethyl-N’-[3-(dimethylamino)propyl]carbodiimide in DMF.

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Medical uses

Cabergoline is frequently used as a first-line agent in the management of prolactinomas due to its higher affinity for D2 receptor sites, less severe side effects, and more convenient dosing schedule than the older bromocriptine, though in pregnancy bromocriptine is often still chosen since there is less data on safety in pregnancy for cabergoline.

Off-label

It has at times been used as an adjunct to SSRI antidepressants as there is some evidence that it counteracts certain side effects of those drugs, such as reduced libido and anorgasmia. It also has been suggested that it has a possible recreational use in reducing or eliminating the male refractory period, thereby allowing men to experience multiple ejaculatory orgasms in rapid succession, and at least two scientific studies support those speculations.[6][7]: e28–e33  Additionally, a systematic review and meta-analysis concluded that prophylactic treatment with cabergoline reduces the incidence, but not the severity, of ovarian hyperstimulation syndrome (OHSS), without compromising pregnancy outcomes, in females undergoing stimulated cycles of in vitro fertilization (IVF).[8] Also, a study on rats found that cabergoline reduces voluntary alcohol consumption, possibly by increasing GDNF expression in the ventral tegmental area.[9] It may be used in the treatment of restless legs syndrome.[citation needed]

Pregnancy and lactation

Relatively little is known about the effects of this medication during pregnancy and lactation. In some cases the related bromocriptine may be an alternative when pregnancy is expected.[citation needed]

  • Pregnancy: available preliminary data indicates a somewhat increased rate of congenital abnormalities in patients who became pregnant while treated with cabergoline.[citation needed]. However, one study concluded that “foetal exposure to cabergoline through early pregnancy does not induce any increase in the risk of miscarriage or foetal malformation.”[10]
  • Lactation: In rats cabergoline was found in the maternal milk. Since it is not known if this effect also occurs in humans, breastfeeding is usually not recommended if/when treatment with cabergoline is necessary.
  • Lactation suppression: In some countries cabergoline (Dostinex) is sometimes used as a lactation suppressant. It is also used in veterinary medicine to treat false pregnancy in dogs.

Contraindications

Side effects

Side effects are mostly dose dependent. Much more severe side effects are reported for treatment of Parkinson’s disease and (off-label treatment) for restless leg syndrome which both typically require very high doses. The side effects are considered mild when used for treatment of hyperprolactinemia and other endocrine disorders or gynecologic indications where the typical dose is one hundredth to one tenth that for Parkinson’s disease.[citation needed]

Cabergoline requires slow dose titration (2–4 weeks for hyperprolactinemia, often much longer for other conditions) to minimise side effects. The extremely long bioavailability of the medication may complicate dosing regimens during titration and require particular precautions.

Cabergoline is considered the best tolerable option for hyperprolactinemia treatment although the newer and less tested quinagolide may offer similarly favourable side effect profile with quicker titration times.

Approximately 200 patients with newly diagnosed Parkinson’s disease participated in a clinical study of cabergoline monotherapy.[11] Seventy-six (76) percent reported at least one side effect. These side effects were chiefly mild or moderate:

In a combination study with 2,000 patients also treated with levodopa, the incidence and severity of side effects was comparable to monotherapy. Encountered side effects required a termination of cabergoline treatment in 15% of patients. Additional side effects were infrequent cases of hematological side effects, and an occasional increase in liver enzymes or serum creatinine without signs or symptoms.

As with other ergot derivatives, pleuritisexudative pleura disease, pleura fibrosislung fibrosis, and pericarditis are seen. These side effects are noted in less than 2% of patients. They require immediate termination of treatment. Clinical improvement and normalization of X-ray findings are normally seen soon after cabergoline withdrawal. It appears that the dose typically used for treatment of hyperprolactinemia is too low to cause this type of side effects.

Valvular heart disease

In two studies published in the New England Journal of Medicine on January 4, 2007, cabergoline was implicated along with pergolide in causing valvular heart disease.[12][13] As a result of this, the FDA removed pergolide from the U.S. market on March 29, 2007.[14] Since cabergoline is not approved in the U.S. for Parkinson’s Disease, but for hyperprolactinemia, the drug remains on the market. The lower doses required for treatment of hyperprolactinemia have been found to be not associated with clinically significant valvular heart disease or cardiac valve regurgitation.[15][16]

Interactions

No interactions were noted with levodopa or selegiline. The drug should not be combined with other ergot derivatives. Dopamine antagonists such as antipsychotics and metoclopramide counteract some effects of cabergoline. The use of antihypertensive drugs should be intensively monitored because excessive hypotension may result from the combination.

Pharmacology

Pharmacodynamics

SiteAffinity
(Ki [nM])
Efficacy
(Emax [%])
Action
D1214–32,000??
D2S0.5–0.62102Full agonist
D2L0.9575Partial agonist
D30.80–1.086Partial agonist
D45649Partial agonist
D522??
5-HT1A1.9–2093Partial agonist
5-HT1B479102Full agonist
5-HT1D8.768Partial agonist
5-HT2A4.6–6.294Partial agonist
5-HT2B1.2–9.4123Full agonist
5-HT2C5.8–69296Partial agonist
5-HT3>10,000
5-HT43,000??
5-HT61,300??
5-HT72.5?Antagonist
α1A288–>10,0000Silent antagonist
α1B60–1,000??
α1D166??
α2A12–1320Silent antagonist
α2B17–720Silent antagonist
α2C22–3640Silent antagonist
α2D3.6??
H11,380??
M1>10,000
SERT>10,000
Notes: All sites are human except α2D-adrenergic, which is rat (no human counterpart).[17] Negligible affinity (>10,000 nM) for various other receptors (β1 and β2-adrenergicadenosineGABAglutamateglycinenicotinic acetylcholineopioidprostanoid).[18] Sources: [17][19][20][18][21]

Cabergoline is a long-acting dopamine D2 receptor agonistIn-vitro rat studies show a direct inhibitory effect of cabergoline on the prolactin secretion in the lactotroph cells of the pituitary gland and cabergoline decreases serum prolactin levels in reserpinized rats.[citation needed] Although cabergoline is commonly described principally as a D2 receptor agonist, it also possesses significant affinity for the dopamine D3, and D4serotonin 5-HT1A5-HT2A5-HT2B, and 5-HT2C, and α2-adrenergic receptors, as well as moderate/low affinity for the dopamine D1, serotonin 5-HT7, and α1-adrenergic receptors.[17][18][22] Cabergoline functions as an partial or full agonist at all of these receptors except for the 5-HT7, α1-adrenergic, and α2-adrenergic receptors, where it acts as an antagonist.[19][20][18] Cabergoline has been associated with cardiac valvulopathy due to activation of 5-HT2B receptors.[23]

Pharmacokinetics

Following a single oral dose, resorption of cabergoline from the gastrointestinal (GI) tract is highly variable, typically occurring within 0.5 to 4 hours. Ingestion with food does not alter its absorption rate. Human bioavailability has not been determined since the drug is intended for oral use only. In mice and rats the absolute bioavailability has been determined to be 30 and 63 percent, respectively. Cabergoline is rapidly and extensively metabolized in the liver and excreted in bile and to a lesser extent in urine. All metabolites are less active than the parental drug or inactive altogether. The human elimination half-life is estimated to be 63 to 68 hours in patients with Parkinson’s disease and 79 to 115 hours in patients with pituitary tumors. Average elimination half-life is 80 hours.

The therapeutic effect in treatment of hyperprolactinemia will typically persist for at least 4 weeks after cessation of treatment.

History

Cabergoline was first synthesized by scientists working for the Italian drug company Farmitalia-Carlo Erba in Milan who were experimenting with semisynthetic derivatives of the ergot alkaloids, and a patent application was filed in 1980.[24][25][26] The first publication was a scientific abstract at the Society for Neuroscience meeting in 1991.[27][28]

Farmitalia-Carlo Erba was acquired by Pharmacia in 1993,[29] which in turn was acquired by Pfizer in 2003.[30]

Cabergoline was first marketed in The Netherlands as Dostinex in 1992.[24] The drug was approved by the FDA on December 23, 1996.[31] It went generic in late 2005 following US patent expiration.[32]

Society and culture

Brand names

Brand names of cabergoline include Cabaser, Dostinex, Galastop (veterinary), and Kelactin (veterinary), among others.[33]

Research

Cabergoline was studied in one person with Cushing’s disease, to lower adrenocorticotropic hormone (ACTH) levels and cause regression of ACTH-producing pituitary adenomas.[34]

References

  1. ^ J. Elks; C. R. Ganellin (1990). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 204–.
  2. ^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 533. ISBN 9783527607495.
  3. ^ UK electronic Medicines Compendium Dostinex Tablets Last Updated on eMC Dec 23, 2013
  4. ^ Sayyah-Melli, M; Tehrani-Gadim, S; Dastranj-Tabrizi, A; Gatrehsamani, F; Morteza, G; Ouladesahebmadarek, E; Farzadi, L; Kazemi-Shishvan, M (2009). “Comparison of the effect of gonadotropin-releasing hormone agonist and dopamine receptor agonist on uterine myoma growth. Histologic, sonographic, and intra-operative changes”. Saudi Medical Journal30 (8): 1024–33. PMID 19668882.
  5. ^ Sankaran, S.; Manyonda, I. (2008). “Medical management of fibroids”. Best Practice & Research Clinical Obstetrics & Gynaecology22 (4): 655–76. doi:10.1016/j.bpobgyn.2008.03.001PMID 18468953http://www.britishfibroidtrust.org.uk/journals/bft_Sankaran.pdf
  6. ^ Krüger TH, Haake P, Haverkamp J, et al. (December 2003). “Effects of acute prolactin manipulation on sexual drive and function in males”. Journal of Endocrinology179 (3): 357–65. CiteSeerX 10.1.1.484.4005doi:10.1677/joe.0.1790357PMID 14656205.
  7. ^ Hollander, Adam B.; Pastuszak, Alexander W.; Lipshultz, Larry I. (2016). “Cabergoline in the Treatment of Male Orgasmic Disorder—A Retrospective Pilot Analysis”Journal of Sexual Medicine4 (4): e28–e33. doi:10.1016/j.esxm.2015.09.001PMC 4822480PMID 26944776.
  8. ^ Youssef MA, van Wely M, Hassan MA, et al. (March 2010). “Can dopamine agonists reduce the incidence and severity of OHSS in IVF/ICSI treatment cycles? A systematic review and meta-analysis”Hum Reprod Update16 (5): 459–66. doi:10.1093/humupd/dmq006PMID 20354100.
  9. ^ Carnicella, S.; Ahmadiantehrani, S.; He, D. Y.; Nielsen, C. K.; Bartlett, S. E.; Janak, P. H.; Ron, D. (2009). “Cabergoline Decreases Alcohol Drinking and Seeking Behaviors Via Glial Cell Line-Derived Neurotrophic Factor”Biological Psychiatry66 (2): 146–153. doi:10.1016/j.biopsych.2008.12.022PMC 2895406PMID 19232578.
  10. ^ Colao, A; Abs R.; et al. (January 2008). “Pregnancy outcomes following cabergoline treatment: extended results from a 12-year observational study”. Clinical Endocrinology68 (1): 66–71. doi:10.1111/j.1365-2265.2007.03000.xPMID 17760883S2CID 38408935.
  11. ^ Rinne, U. K.; Bracco, F.; Chouza, C.; Dupont, E.; Gershanik, O.; Masso, J. F. M.; Montastruc, J. L.; Marsden, C. D.; Dubini, A.; Orlando, N.; Grimaldi, R. (1997-02-01). “Cabergoline in the treatment of early parkinson’s disease: Results of the first year of treatment in a double-blind comparison of cabergoline and levodopa”Neurology48 (2): 363–368. doi:10.1212/WNL.48.2.363ISSN 0028-3878PMID 9040722S2CID 34955541.
  12. ^ Schade, Rene; Andersohn, Frank; Suissa, Samy; Haverkamp, Wilhelm; Garbe, Edeltraut (2007-01-04). “Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation”. New England Journal of Medicine356 (1): 29–38. doi:10.1056/NEJMoa062222PMID 17202453.
  13. ^ Zanettini, Renzo; Antonini, Angelo; Gatto, Gemma; Gentile, Rosa; Tesei, Silvana; Pezzoli, Gianna (2007-01-04). “Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease”. New England Journal of Medicine356 (1): 39–46. doi:10.1056/NEJMoa054830PMID 17202454.
  14. ^ “Food and Drug Administration Public Health Advisory”Food and Drug Administration. 2007-03-29. Archived from the original on 2007-04-08. Retrieved 2007-04-27.
  15. ^ Bogazzi, F.; Buralli, S.; Manetti, L.; Raffaelli, V.; Cigni, T.; Lombardi, M.; Boresi, F.; Taddei, S.; Salvetti, A. (2008). “Treatment with low doses of cabergoline is not associated with increased prevalence of cardiac valve regurgitation in patients with hyperprolactinaemia”. International Journal of Clinical Practice62 (12): 1864–9. doi:10.1111/j.1742-1241.2008.01779.xPMID 18462372S2CID 7822137.
  16. ^ Wakil, A.; Rigby, A. S; Clark, A. L; Kallvikbacka-Bennett, A.; Atkin, S. L (2008). “Low dose cabergoline for hyperprolactinaemia is not associated with clinically significant valvular heart disease”European Journal of Endocrinology159 (4): R11–4. doi:10.1530/EJE-08-0365PMID 18625690.
  17. Jump up to:a b c Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (November 2002). “Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes”. J Pharmacol Exp Ther303 (2): 791–804. doi:10.1124/jpet.102.039867PMID 12388666S2CID 6200455.
  18. Jump up to:a b c d Sharif NA, McLaughlin MA, Kelly CR, Katoli P, Drace C, Husain S, Crosson C, Toris C, Zhan GL, Camras C (March 2009). “Cabergoline: Pharmacology, ocular hypotensive studies in multiple species, and aqueous humor dynamic modulation in the Cynomolgus monkey eyes”. Experimental Eye Research88 (3): 386–97. doi:10.1016/j.exer.2008.10.003PMID 18992242.
  19. Jump up to:a b Newman-Tancredi A, Cussac D, Audinot V, Nicolas JP, De Ceuninck F, Boutin JA, Millan MJ (November 2002). “Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor”. J Pharmacol Exp Ther303 (2): 805–14. doi:10.1124/jpet.102.039875PMID 12388667S2CID 35238120.
  20. Jump up to:a b Newman-Tancredi A, Cussac D, Quentric Y, Touzard M, Verrièle L, Carpentier N, Millan MJ (November 2002). “Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT(1) and 5-HT(2), receptor subtypes”. J Pharmacol Exp Ther303 (2): 815–22. doi:10.1124/jpet.102.039883PMID 12388668S2CID 19260572.
  21. ^ https://web.archive.org/web/20210413033753/https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Cabergoline&doQuery=Submit+Query
  22. ^ National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Jul 24]. ChapelHill (NC): University of North Carolina. 1998-2013. Available from: “Archived copy”. Archived from the original on 2013-11-08. Retrieved 2014-03-04.
  23. ^ Cavero I, Guillon JM (2014). “Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy”. J Pharmacol Toxicol Methods69 (2): 150–61. doi:10.1016/j.vascn.2013.12.004PMID 24361689.
  24. Jump up to:a b Council regulation (EEC) no 1768/92 in the matter of Application No SPC/GB94/012 for a Supplementary Protection Certificate in the name of Farmitalia Carlo Erba S. r. l.
  25. ^ Espace record: GB 202074566
  26. ^ US Patent 4526892 – Dimethylaminoalkyl-3-(ergoline-8′.beta.carbonyl)-ureas
  27. ^ Fariello, RG (1998). “Pharmacodynamic and pharmacokinetic features of cabergoline. Rationale for use in Parkinson’s disease”. Drugs55 (Suppl 1): 10–6. doi:10.2165/00003495-199855001-00002PMID 9483165S2CID 46973281.
  28. ^ Carfagna N, Caccia C, Buonamici M, Cervini MA, Cavanus S, Fornaretto MG, Damiani D, Fariello RG (1991). “Biochemical and pharmacological studies on cabergoline, a new putative antiparkinsonian drug”. Soc Neurosci Abs17: 1075.
  29. ^ Staff. News: Farmitalia bought by Kabi Pharmacia[permanent dead link]. Ann Oncol (1993) 4 (5): 345.
  30. ^ Staff, CNN/Money. April 16, 2003 It’s official: Pfizer buys Pharmacia
  31. ^ FDA approval history
  32. ^ “Drugs@FDA: FDA Approved Drug Products – ANDA 076310”http://www.accessdata.fda.gov. FDA.gov. Retrieved 14 December 2018.
  33. ^ “Cabergoline Uses, Side Effects & Warnings”. Archived from the original on 2015-12-30.
  34. ^ Miyoshi, T.; et al. (2004). “Effect of cabergoline treatment on Cushing’s disease caused by aberrant adrenocorticotropin-secreting macroadenoma”. Journal of Endocrinological Investigation27 (11): 1055–1059. doi:10.1007/bf03345309PMID 15754738S2CID 6660262.
Clinical data
Trade namesDostinex, others
AHFS/Drugs.comMonograph
License dataUS FDACABERGOLINE
Routes of
administration
Oral
ATC codeG02CB03 (WHON04BC06 (WHO)
Legal status
Legal statusUS: ℞-only
Pharmacokinetic data
BioavailabilityFirst-pass effect seen; absolute bioavailability unknown
Protein bindingModerately bound (40–42%); concentration-independent
MetabolismHepatic, predominately via hydrolysis of the acylurea bond or the urea moiety
Elimination half-life63–69 hours (estimated)
ExcretionUrine (22%), feces (60%)
Identifiers
showIUPAC name
CAS Number81409-90-7 
PubChem CID54746
IUPHAR/BPS37
DrugBankDB00248 
ChemSpider49452 
UNIILL60K9J05T
KEGGD00987 
ChEBICHEBI:3286 
ChEMBLChEMBL1201087 
CompTox Dashboard (EPA)DTXSID6022719 
ECHA InfoCard100.155.380 
Chemical and physical data
FormulaC26H37N5O2
Molar mass451.615 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (what is this?)  (verify)

////////////////Cabergoline, UNII-LL60K9J05T, каберголин , كابارغولين ,卡麦角林 ,  FCE-21336

[H][C@@]12CC3=CNC4=CC=CC(=C34)[C@@]1([H])C[C@H](CN2CC=C)C(=O)N(CCCN(C)C)C(=O)NCC

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Zuclopenthixol


Zuclopenthixol.svg
ChemSpider 2D Image | Zuclopenthixol | C22H25ClN2OS

Zuclopenthixol

Clopenthixol

  • Molecular FormulaC22H25ClN2OS
  • Average mass400.965 Da

53772-83-1 [RN],

  • N05AF05

1-​Piperazineethanol, 4-​[(3Z)​-​3-​(2-​chloro-​9H-​thioxanthen-​9-​ylidene)​propyl]​-
5443
2-{4-[(3Z)-3-(2-Chloro-9H-thioxanthen-9-ylidene)propyl]piperazin-1-yl}ethanol
258-758-5[EINECS]
Z)-Clopenthixol
1-piperazineethanol, 4-(3-(2-chloro-9h-thioxanthen-9-ylidene)propyl)-
1-Piperazineethanol, 4-(3-(2-chlorothioxanthen-9-ylidene)propyl)-
1-Piperazineethanol, 4-[(3Z)-3-(2-chloro-9H-thioxanthen-9-ylidene)propyl]-

  • 1-Piperazineethanol, 4-[3-(2-chloro-9H-thioxanthen-9-ylidene)propyl]-, (Z)-
  • 4-[(3Z)-3-(2-Chloro-9H-thioxanthen-9-ylidene)propyl]-1-piperazineethanol
  • 9H-Thioxanthene, 1-piperazineethanol deriv.
  • (Z)-Clopenthixol
  • Acuphase
  • Cisordinol
  • Clopixol
  • Clopixol depo
  • Zuclopenthixol
  • cis-(Z)-Clopenthixol
  • cis-Clopenthixol
  • α-Clopenthixol

Product Ingredients

INGREDIENTUNIICASINCHI KEY
Zuclopenthixol acetate349S2ZHF0585721-05-7OXAUOBQMCDIVPQ-IOXNKQMXSA-N
Zuclopenthixol decanoateTSS9KIZ5OG64053-00-5QRUAPADZILXULG-WKIKZPBSSA-N
Zuclopenthixol dihydrochloride7042692VYN58045-23-1LPWNZMIBFHMYMX-MHKBYHAFSA-N
2D chemical structure of 58045-23-1

Zuclopenthixol hydrochloride
58045-23-1, MW: 473.8933

ZUCLOPENTHIXOL DECANOATE, CLOPENTHIXOL DECANOATE, CIS-

64053-00-5, Molecular Formula, C32-H43-Cl-N2-O2-S, Molecular Weight, 555.2227

Zuclopenthixol acetate.png

Zuclopenthixol acetate

85721-05-7, C24H27ClN2O2S, 443.0ClopenthixolCAS Registry Number: 982-24-1 
CAS Name: 4-[3-(2-Chloro-9H-thioxanthen-9-ylidene)propyl]-1-piperazineethanol 
Additional Names: 2-chloro-9-[3-[4-(2-hydroxyethyl)-1-piperazinyl]propylidene]thiaxanthene 
Molecular Formula: C22H25ClN2OS 
Molecular Weight: 400.96 
Percent Composition: C 65.90%, H 6.28%, Cl 8.84%, N 6.99%, O 3.99%, S 8.00% 
Literature References: Thioxanthene neuroleptic. Prepn (configuration not specified): BE585338; P. V. Petersen et al.,US3116291 (1960, 1963 both to Kefalas A/S). Prepn of the pharmacologically active cis-isomer: BE816855; N. Lassen, US3996211 (1974, 1976 both to Kefalas A/S). Pharmacology: Cazzullo, Andreola, Acta Neurol.20, 162 (1965); Weissman, Mod. Probl. Pharmacopsychiatry2, 15 (1969); Moeller Nielsen, ibid. 23. Metabolism: Khan, Acta Pharmacol. Toxicol.27, 202 (1969). HPLC determn of isomers in serum: T. Aaes-Jorgensen, J. Chromatogr.188, 239 (1980). Series of articles on pharmacology and clinical studies: Acta Psychiatr. Scand.64, Suppl. 294, 1-77 (1981). 
Properties: Colorless syrup. Sparingly sol in ether. Readily sol in methanol. 
Derivative Type: Dihydrochloride 
CAS Registry Number: 633-59-0 
Manufacturers’ Codes: AY-62021; N-746 
Trademarks: Ciatyl (Troponwerke); Sordenac (Lundbeck); Sordinol (Ayerst) 
Molecular Formula: C22H25ClN2OS.2HCl 
Molecular Weight: 473.89 
Percent Composition: C 55.76%, H 5.74%, Cl 22.44%, N 5.91%, O 3.38%, S 6.77% 
Properties: Crystals from ethanol, mp 250-260° (dec). Freely sol in water; sparingly sol in alcohol. Practically insol in other organic solvents. LD50 in male mice (mg/kg): 111 i.v. (Lassen). 
Melting point: mp 250-260° (dec) 
Toxicity data: LD50 in male mice (mg/kg): 111 i.v. (Lassen) 

Derivative Type:cis(Z)-Form 
CAS Registry Number: 53772-83-1 
Additional Names: a-Clopenthixol; zuclopenthixol 
Properties: Crystals, mp 84-85°. 
Melting point: mp 84-85° 

Derivative Type:cis(Z)-Form dihydrochloride 
CAS Registry Number: 58045-23-1 
Trademarks: Cisordinol (Lundbeck); Clopixol (HMR) 
Properties: Crystals, mp 250-260° (dec). LD50 in male mice (mg/kg): 105 i.v. (Lassen). 
Melting point: mp 250-260° (dec) 
Toxicity data: LD50 in male mice (mg/kg): 105 i.v. (Lassen) 
Therap-Cat: Antipsychotic. 
Keywords: Antipsychotic; Thioxanthenes. 
Zuclopenthixol is an antipsychotic indicated for the management of schizophrenia. The acuphase formulation is indicated for initial treatment of acute psychosis or exacerbation of psychosis, while the depot formulation is best for maintenance.Zuclopenthixol, also known as Zuclopentixol or Zuclopenthixolum, is an antipsychotic agent. Zuclopenthixol is a thioxanthene-based neuroleptic with therapeutic actions similar to the phenothiazine antipsychotics. It is an antagonist at D1 and D2 dopamine receptors. Major brands of zuclopenthixol are Cisordinol, Acuphase, and Clopixol. This drug is a liquid. This compound belongs to the thioxanthenes. These are organic polycyclic compounds containing a thioxanthene moiety, which is an aromatic tricycle derived from xanthene by replacing the oxygen atom with a sulfur atom. Known drug targets of zuclopenthixol include 5-hydroxytryptamine receptor 2A, D(1B) dopamine receptor, D(2) dopamine receptor, D(1A) dopamine receptor, and alpha-1A adrenergic receptor. It is known that zuclopenthixol is metabolized by Cytochrome P450 2D6. Zuclopenthixol was approved for use in Canada in 2011, but is not approved for use in the United States.

Zuclopenthixol (brand names CisordinolClopixol and others), also known as zuclopentixol, is a medication used to treat schizophrenia and other psychoses. It is classed, pharmacologically, as a typical antipsychotic. Chemically it is a thioxanthene. It is the cisisomer of clopenthixol (Sordinol, Ciatyl).[1] Clopenthixol was introduced in 1961, while zuclopenthixol was introduced in 1978.

Zuclopenthixol is a D1 and D2 antagonist, α1-adrenergic and 5-HT2 antagonist.[2] While it is approved for use in Australia, Canada, Ireland, India, New Zealand, Singapore, South Africa and the UK it is not approved for use in the United States.[3][4]

Medical uses

Available forms

Zuclopenthixol is available in three major preparations:

  • As zuclopenthixol decanoate (Clopixol DepotCisordinol Depot), it is a long-acting intramuscular injection. Its main use is as a long-acting injection given every two or three weeks to people with schizophrenia who have a poor compliance with medication and suffer frequent relapses of illness.[5] There is some evidence it may be more helpful in managing aggressive behaviour.[6]
  • As zuclopenthixol acetate (Clopixol-AcuphaseCisordinol-Acutard), it is a shorter-acting intramuscular injection used in the acute sedation of psychotic inpatients. The effect peaks at 48–72 hours providing 2–3 days of sedation.[7]
  • As zuclopenthixol dihydrochloride (ClopixolCisordinol), it is a tablet used in the treatment of schizophrenia in those who are compliant with oral medication.[8]

It is also used in the treatment of acute bipolar mania.

Dosing

As a long-acting injection, zuclopenthixol decanoate comes in a 200 mg and 500 mg ampoule. Doses can vary from 50 mg weekly to the maximum licensed dose of 600 mg weekly. In general, the lowest effective dose to prevent relapse is preferred. The interval may be shorter as a patient starts on the medication before extending to 3 weekly intervals subsequently. The dose should be reviewed and reduced if side effects occur, though in the short-term an anticholinergic medication benztropine may be helpful for tremor and stiffness, while diazepam may be helpful for akathisia. 100 mg of zuclopenthixol decanoate is roughly equivalent to 20 mg of flupentixol decanoate or 12.5 mg of fluphenazine decanoate.

In acutely psychotic and agitated inpatients, 50 – 200 mg of zuclopenthixol acetate may be given for a calming effect over the subsequent three days, with a maximum dose of 400 mg in total to be given. As it is a long-acting medication, care must be taken not to give an excessive dose.

In oral form zuclopenthixol is available in 10, 25 and 40 mg tablets, with a dose range of 20–60 mg daily.

Side effects

Chronic administration of zuclopenthixol (30 mg/kg/day for two years) in rats resulted in small, but significant, increases in the incidence of thyroid parafollicular carcinomas and, in females, of mammary adenocarcinomas and of pancreatic islet cell adenomas and carcinomas. An increase in the incidence of mammary adenocarcinomas is a common finding for D2 antagonists which increase prolactin secretion when administered to rats. An increase in the incidence of pancreatic islet cell tumours has been observed for some other D2 antagonists. The physiological differences between rats and humans with regard to prolactin make the clinical significance of these findings unclear.

Withdrawal syndrome: Abrupt cessation of therapy may cause acute withdrawal symptoms (eg, nausea, vomiting, or insomnia). Symptoms usually begin in 1 to 4 days of withdrawal and subside within 1 to 2 weeks.[1][2]

Other permanent side effects are similar to many other typical antipsychotics, namely extrapyramidal symptoms as a result of dopamine blockade in subcortical areas of the brain. This may result in symptoms similar to those seen in Parkinson’s disease and include a restlessness and inability to sit still known as akathisia, a slow tremor and stiffness of the limbs.[8] Zuclopenthixol is thought to be more sedating than the related flupentixol, though possibly less likely to induce extrapyramidal symptoms than other typical depots.[5] As with other dopamine antagonists, zuclopenthixol may sometimes elevate prolactin levels; this may occasionally result in amenorrhoea or galactorrhoea in severe cases. Neuroleptic malignant syndrome is a rare but potentially fatal side effect. Any unexpected deterioration in mental state with confusion and muscle stiffness should be seen by a physician.

Zuclopenthixol decanoate induces a transient dose-dependent sedation. However, if the patient is switched to maintenance treatment with zuclopenthixol decanoate from oral zuclopenthixol or from i.m. zuclopenthixol acetate the sedation will be no problem. Tolerance to the unspecific sedative effect develops rapidly.[9]

SYN

Journal of the American Chemical Society (2019), 141(6), 2251-2256

https://pubs.acs.org/doi/10.1021/jacs.8b13907

Synthesis of Clopenthixol (4d)

Inside a nitrogen-filled glovebox, an oven-dried glass culture tube (Fischer Scientific part #14- 959-35A), equipped with a magnetic stirring bar, was charged with 2-chloro-9H-thioxanthen-9- one (245 mg, 1.0 mmol, 1 equiv), copper(II) acetate (0.91 mg, 0.0050 mmol, 0.0050 equiv), racBINAP (3.2 mg, 0.0050 mmol, 0.0050 equiv), and THF (1.0 mL). The tube was then fitted tightly with a Teflon-lined blow-out screw cap (Kimble-Chase part #73808-15425). The reaction tube was removed from the glovebox, and the mixture was stirred rapidly for 5 min. A balloon, connected to a 6 mL plastic syringe head, was filled with allene gas until its size was roughly 6 cm in diameter. A needle was attached to the head of the syringe. The reaction tube was evacuated by piercing the septum with a needle connected to a Schlenk line. Immediately after, the allene contained in the balloon was used to refill the reaction tube by piercing the septum with the needle. The balloon decreased to roughly half its original diameter during the refill process. The needle and balloon were left attached, and dimethoxy(methyl)silane (250 uL, 2.0 mmol, 2.0 equiv) was added to the reaction mixture using a 1 mL plastic syringe. The solution was then stirred overnight at rt. At this point, the flask was quickly evacuated by piercing the septum with a needle connected to a Schlenk line, and the headspace was refilled with dry nitrogen. This process was repeated a total of three times. THF (1 mL) solution containing 4e (367 mg, 1.2 mmol, 1.2 equiv), triphenylphosphine (11.5 mg, 0.044 mmol, 0.044 equiv), racDTBM-SEGPHOS (26.8 mg, 0.044 mmol, 0.044 equiv), and copper(II) acetate (3.6 mg, 0.040 mmol, 0.040 equiv) was added to the reaction mixture using a 1 mL plastic syringe. The reaction tube was heated to 40 °C by submersion in an oil bath overnight. After cooling to rt, the cap was removed and 4 M HCl in dioxane was slowly added to the reaction mixture (2.0 mL, WARNING: VIGOROUS HYDROGEN GAS EVOLUTION). The color of the reaction mixture turned to deep red, and after stirring for approximately 30 min, a tan precipitate evolved. After an additional 1 h, diethyl ether (10 mL) was added and the solids collected by filtration (950 mg). By LC/MS analysis, this solid contains mostly 4c (as the hydrochloride) with a trace amount of triphenylphosphine oxide. The entire solid was suspended in dry acetonitrile (1.0 mL) in another dry reaction tube, equipped with a magnetic stirring bar. Potassium carbonate (552 mg, 4 mmol) was added to the tube, which was then capped and placed under a nitrogen atmosphere using a needle connected to a Schlenk line. 2-bromoethanol (142 uL, 2 mmol) was added to the reaction mixture using a glass microsyringe, and the mixture was left to stir overnight at rt. After this time, the cap was removed, and the solution was diluted with water (10 mL). The mixture was extracted with dichloromethane (3 x 10 mL), and the combined organic phases was concentrated with the aid of a rotary evaporator. The mixture was purified by reverse phase preparative HPLC (C18 column, MeCN/water) to yield a 1.1:1 Z/E mixture of 4d as a yellow foamy solid (217 mg, 54% overall yield). The identity of 4d was confirmed by LC/MS analysis against a commercially available standard (Cayman Chemical) and by comparison of 1H NMR to the literature. 13 For further structural confirmation, a portion of 4d was repurified by HPLC to obtain pure (Z)-4d, the biologically active isomer, whose spectra have not been reported in the literature. 1H NMR (400 MHz, CDCl3) δ 7.43 (dd, J = 14.5, 6.2 Hz, 3H), 7.27 (q, J = 8.2 Hz, 4H), 7.17 (d, J = 8.3 Hz, 1H), 5.89 (t, J = 7.1 Hz, 1H), 3.60 (t, J = 5.4 Hz, 2H), 2.62 (t, J = 7.2 Hz, 2H), 2.58–2.35 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 140.2, 135.7, 133.4, 133.2, 132.7, 130.9, 130.4, 128.6, 127.3, 126.9, 126.8, 126.7, 126.2, 125.6, 59.2, 58.3, 57.7, 53.1, 52.8, 27.3.

SYN

Chemical Engineering & Technology (2016), 39(10), 1821-1827.  

https://onlinelibrary.wiley.com/doi/10.1002/ceat.201500673

SYN

European Journal of Pharmaceutics and Biopharmaceutics (2012), 82(2), 437-456.

https://www.sciencedirect.com/science/article/abs/pii/S0939641112002263?

SYN

Organic Process Research & Development (2013), 17(9), 1142-1148.

https://pubs.acs.org/doi/10.1021/op400069e

SUN

CN 103214453 

https://patents.google.com/patent/CN103214453A/enDiuril ton (Clopenthixol), chemistry 2-chloro-9-[3 ‘ by name-(N ‘-the 2-hydroxyethyl piperazine-N)-allyl group]-thioxanthene, this product is a kind of Thiaxanthene derivative, has significant antipsycholic action and special sedative effect, is particularly useful for the schizophrenia patient.Its activeconstituents is its alpha-isomer, i.e. zuclopenthixol (structural formula is seen Fig. 1); Have the stereotypy effect that anti-Ritalin causes, and the effect of anti-Apomorphine is arranged, this product energy rejection condition avoiding reaction and catalepsy are stronger 10 times than chlorpromazine.A little less than the cholinolytic effect, and antihistamine effect is strong.Zuclopenthixol is applicable to that treatment has psychosis, class Paranoia-illusion type schizophrenia, hebephrenia, the manic and anxiety periodic psychosis of anxiety and illusion symptom; The uneasiness that mental element causes, excitement, psychiatric disorder, the encephalatrophy process, post-traumatic psychosis, the proverb of trembling are absurd etc.Be particularly useful for elderly patients.Recorded the quality standard of zuclopenthixol sheet, zuclopenthixol dihydrochloride, Ciatyl Depot and zuclopenthixol acetic ester etc. in the British Pharmacopoeia, wherein the zuclopenthixol quality standard has stipulated that its content should be 95%-105%.But in actual industrial production, guarantee that zuclopenthixol reaches pharmaceutically acceptable purity, and β-isomer (structural formula is seen Fig. 2) content being limited in 5%, is a very thing of difficulty.About the preparation method of zuclopenthixol, mainly containing of bibliographical information is following several:As if the general separation of having described diuril ton isomer can be undertaken by the fractional crystallization of dihydrochloride among the BE585338A of nineteen fifty-nine application, and still, this separation method yield is extremely low, and complicated operation does not also have actual industrial use.Described the preparation method of diuril ton isomer mixture among the US3116291, wherein alpha-isomer is that the content of zuclopenthixol is 30%-35%.Obtain purer zuclopenthixol by diuril ton alkali being carried out fractional separation in the literary composition with ether organic solvent, but, instructed crystallization to come the purifying zuclopenthixol can not obtain good result, especially in isomer mixture, had under the situation of a large amount of impurity existence by diuril ton alkali.Embodiment 1: the preparation of diuril ton base1) preparation of 2-chloro-9-allyl group-9-thioxanthene alcohol100.00g (0.405mol) 2-chloro-9-thioxanthone is dissolved in the 600mL tetrahydrofuran (THF), 20 ℃ of-30 ℃ of stirrings, add magnesium powder 26g then, iodine 1g, splash into chlorallylene 65g (0.855mol), 40 ℃-50 ℃ are reacted 2h down, and the cooling back drips 20% sodium chloride aqueous solution 1000ml in reaction solution, stir 10min, filter insolubles, use dichloromethane extraction then 2 times, each 500ml, merge organic phase, water 500ml washing is told organic layer, dry after-filtration, filtrate is concentrated except that desolvating, obtain 105.40g2-chloro-9-allyl group-9-thioxanthene alcohol.2) preparation of 2-chloro-9-(2-propenylidene) thioxanthene100.00g (0.346mol) 2-chloro-9-allyl group-9-thioxanthene alcohol is dissolved in the 100ml toluene, solution is heated to 40 ℃, the Acetyl Chloride 98Min. of 1.34g (0.017mol) is dissolved in the diacetyl oxide of 41.19g (0.403mol) and drops in the above-mentioned solution, temperature is controlled at about 40 ℃, dropwise, it is complete until the TLC monitoring reaction that heating makes temperature of reaction rise to 50 ℃ of-55 ℃ of reactions, and concentrating under reduced pressure steams solvent, obtains 94.01g2-chloro-9-(2-propenylidene) thioxanthene.3) preparation of clopenthixol baseN-(2-hydroxyethyl) piperazine of getting 90.00g (0.332mol) 2-chloro-9-(2-propenylidene) thioxanthene and 215.21g (1.65mol) adds in the 1L four-hole boiling flask, stirs and is warming up to 100 ℃ of reactions, and TLC monitors to reacting completely.Vacuum oil pump concentrating under reduced pressure excessive N-(2-hydroxyethyl) piperazine, temperature is controlled at 100 ℃-135 ℃, and oil pump vacuum tightness is at 0.2-1mmHg.Distillation finishes, and adds the benzene of 400ml and the water of 100ml in gained oily matter, and 70 ℃ are stirred 15min, and separatory is used the water washing organic phase of 100ml again, and simultaneous temperature is controlled at 60 ℃-70 ℃, separatory; With organic phase concentrate resistates.This resistates is dissolved in the 300ml methylene dichloride, after add 10% hydrochloric acid soln and transfer pH to 2-3, stirring 10min, separatory, water discard dichloromethane extraction liquid with the dichloromethane extraction of 150ml; Above-mentioned water adds ammoniacal liquor and regulates pH=9-10, extract with methylene dichloride (300ml * 2) after stirring 10min, merge organic phase, use anhydrous sodium sulfate drying, suction filtration, filtrate decompression concentrate 109.32g diuril ton base, isomer proportion α/β is that 45/55 (the HPLC area normalization method: analytical column is 4.6 * 250mmAgilent C18 post, moving phase is acetonitrile: methyl alcohol: phosphoric acid buffer=20: 30: 50, flow velocity are 1mL/min; With this understanding, the retention time of zuclopenthixol is 12min, and the retention time of β-isomer is 16min).Embodiment 2: the preparation of zuclopenthixol Chlorodracylic acid ester 2HCl100.00g (0.250mol) α/β-diuril ton is dissolved in the ethyl acetate of 500ml, under 40 ℃ of conditions, drips the 100ml ethyl acetate that is dissolved with 52.48g (0.30mol) parachlorobenzoyl chloride, dropwise the back back flow reaction, complete until the TLC monitoring reaction.Remove the 300ml solvent under reduced pressure, be cooled to 4 ℃, remove by filter precipitation.Mother liquor is heated to 40 ℃, drips the concentrated hydrochloric acid aqueous solution of 12.50g (0.125mol) 37%, react about 1h after, cool off, have solid to separate out, filter 56.27g zuclopenthixol Chlorodracylic acid ester 2HCl.Purity (HPLC is the same) is 97.11%, and productive rate is 36.82%.Embodiment 3: the preparation of zuclopenthixol2HCl is dissolved in the methanol aqueous solution of 300ml80% with 45.25g (0.074mol) zuclopenthixol Chlorodracylic acid ester, adds the potassium hydroxide of 16.83mol (0.30mol) then.With mixture heating up to 50 ℃, insulation reaction 1h.Underpressure distillation removes and desolvates, and with toluene (200ml * 2) and water extraction, merges organic phase, and concentrating under reduced pressure is removed toluene; Residue obtainedly carry out recrystallization with hexanaphthene, the 25.51g dried crystals.Purity is 99.7%, and productive rate is 86.17%. 1H?NMR(CDCl 3,400MHz),δ:7.10-7.46(7H,m),5.98(1H,t),3.41(2H,t),2.46-2.52(14H,m)。Embodiment 4: the preparation of Ciatyl Depot 2HClThe zuclopenthixol of 50.00g (0.125mol) is dissolved in the methylene dichloride of 500ml, and to wherein dripping 28.60g (0.150mol) decanoyl chloride, back flow reaction is complete to the TLC monitoring reaction after dropwising under the room temperature.Underpressure distillation removes and desolvates, and adds the ethyl acetate of 300ml in residue, drips the ethyl acetate solution that contains hydrogenchloride again, is transferred to 3-4 until pH.After the cooling, filter, vacuum-drying gets 70.63g Ciatyl Depot 2HCl.Productive rate is 90.12%.Embodiment 5: the preparation of Ciatyl DepotThe Ciatyl Depot 2HCl of 60g (0.0957mol) is suspended in the t-butyl methyl ether of 400ml, drips water (250ml) solution of 13.22g (0.0957mol) salt of wormwood, stirring reaction 0.5h.Two are separated, and use 100ml water washing organic phase again, use the anhydrous sodium sulfate drying organic phase, filter, and organic solvent is removed in underpressure distillation, get the 51.29g Ciatyl Depot.Productive rate is 96.58%. 1H?NMR(CDCl 3,400MHz),δ:7.12-7.50(7H,m),5.90(1H,t),4.35(2H,t),3.41(2H,t),2.97(2H,t),2.32-2.57(10H,m),2.06(2H,t),1.64(2H,m),1.30(12H,m),0.88(3H,t)。

SYN

https://patents.google.com/patent/WO2017121755A1/enPreparation of ZU3:9-(3-(4-(2-hydroxyethyl)piperazinyl)propylidene)-thioxanthene

Figure imgf000033_0001

ZU3To a solution of 9-oxothioxanthene (1.0 equiv.) in THF at reflux were added a solution of cyclopropylmagnesium bromide in THF (1.0 equiv.) and stirred during 2 hours. The mixture was cooled down at room temperature and a solution of hydrogen bromide in acetic acid (4 eq.) was added and stirred at room temperature. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography to obtain 9- (3bromopropylidene)thioxanthene in 30% yield.Then, to a solution of 9-(3bromopropylidene)thioxanthene in acetonitrile at reflux was added N-(2-hydroxyethyl)piperazine (1,5 eq.), potassium iodide (0.1 eq.) and potassium carbonate (3 eq.). The mixture was stirred at reflux then concentrated in vacuo and purified by silica gel column chromatography to afford ZU3 with 98% purity (HPLC). HPLC analysis (BEH C18 type, mobile phase: H20/ acetonitrile (HCOOH 0.1%)) : tR = 1.68 min. Preparation of ZUf:l-(3-(9H-thioxanthen-9-ylidene)propyl)piperidine-4-carboxylic acid), ZU4 (9-(3-(4- (ethylacetate) iperidine)propylidene)-thioxanthene

Figure imgf000034_0001

To a solution of 9-(3-bromopropylidene)thioxanthene in acetonitrile at reflux was added N-ethylacetate piperidine (1,5 eq.), potassium iodide (0.1 eq.) and potassium carbonate (3 eq.). The mixture was stirred at reflux then concentrated in vacuo and purified by silica gel column chromatography to afford ZU4 as a brown oil with a purity of 97% in HPLC analysis HPLC analysis (BEH C18 type, mobile phase: H20/acetonitrile (HCOOH 0.1%)) : tR = 2.07 min.The compound ZU4 was stirred during 2 hours at reflux in a mixture of THF and a solution of NaOH in water. After phase separation, the aqueous layer was extracted twice by diethyl ether. The global organic layer was, then, washed by a saturated solution of NaCl, dried over MgSC^, filtered and concentrated in vacuo to afford ZUf HPLC analysis (BEH CI 8 type, mobile phase: H20/acetonitrile (HCOOH 0.1%)) : tR = 2.24 min.Preparation of ZU5:(Z)-2-(4-(3-(2-chloro-9H-thioxanthen-9-ylidene)propyl)piperazin-l-yl)ethylacetate

Figure imgf000035_0001

To a solution of ZU (4-[3-(2-chloro-9H-thioxanthen-9-ylidene)propyl]-l- piperazineethanol) (leq.) in dichloromethane was added acetic anhydride (1.5 eq.), 4- dimethylaminopyridine (0,1 eq.) and trimethylamine (1 eq.). The mixture was stirred at room temperature and then concentrated in vacuo to afford ZU5 as a yellow oil with 97% of purity (HPLC). HPLC analysis {BEH C18 type, mobile phase: H20/acetonitrile (HCOOH 0.1%)): tR = 2.44 minPreparation of ZUe and ZU6:l-(3-(9H-xanthen-9-ylidene)propyl)piperidine-4-carboxylic acidand eth -(3-(9H-xanthen-9-ylidene)propyl)piperidine-4-carboxylate

Figure imgf000036_0001

To a solution of 9-oxoxanthene (1.0 equiv.) in THF at reflux were added a solution of cyclopropylmagnesium bromide in THF (1.0 equiv.) and stirred during 2 hours. The mixture was cooled down at room temperature and a solution of hydrogen bromide in acetic acid (4 eq.) was added and stirred at room temperature. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography to obtain 9- (3bromopropylidene)-oxoxanthene.Then, to a solution of 9-(3bromopropylidene)-oxoxanthene in acetonitrile at reflux was added Ethyl 4-piperidinecarboxylate (1,5 eq.), potassium iodide (0.1 eq.) and potassium carbonate (3 eq.). The mixture was stirred at reflux then concentrated in vacuo and purified by silica gel column chromatography to obtain ZU6 ZU6 is then dissolved in a mixture of THF and a solution of NaOH in water. After phase separation, the aqueous layer was extracted twice by diethyl ether. The global organic layer was, then, washed by a saturated solution of NaCl, dried over MgSC^, filtered and concentrated in vacuo to afford ZUe as a white solid with a purity up to 97% in HPLC. Preparation of ZUc:(Z)-2-(4-(3-(2-(trifluoromethyl)-9H-thioxanthen-9-ylidene)propyl)piperazin-l-yl) ethanamine

Figure imgf000037_0001

EtOH, reflux, 2hPurification withHCI buffer

Figure imgf000037_0002

To a solution of ZU1 (2-[4-[3-[2-(trifiuoromethyl)thioxanthen-9- ylidene]propyl]piperidin-l-yl] ethanol) (leq.) in THF was added diethylazodicarboxylate, phtalimide and triphenylphosphine. The solution was stirred at room temperature during 3 hours and then concentrated in vacuo. The crude oil was then dissolved in ethanol, hydrazine was added and the mixture was stirred at reflux during 2 hours. The crude product obtained after concentration was purified via a reversed phase chromatography using HCI as buffer to afford the compound ZUc as an hydrochloride salt (orange solid). [M+H]+ (ESI+) : 434. HPLC analysis (BEH C18 type, mobile phase: H20/acetonitrile (HCOOH 0.1%)): tR = 2.04 min Preparation of ZUd:(Z)-l-(2-fluoroethyl)-4-(3-(2-(trifluoromethyl)-9H-thioxanthen-9-ylidene)propyl) iperazine

Figure imgf000038_0001

To a solution of flupenthixol in dichloromethane was added at -10°C diethylamino sulfur trifluoride. The mixture was then stirred at room temperature. The crude product was purified via a reversed phase chromatography using HC1 as buffer to afford the compound ZUd as a hydrochloride salt (orange solid) with 97% purity in HPLC. HPLC analysis (BEH C18 type, mobile phase: H20/acetonitrile (HCOOH 0.1%)): tR = 3.59 min.Compounds ZU, ZUa, ZUb, ZU1, ZU2The following compounds can be easily found in commerce: 

Figure imgf000039_0001

Example 2: Ebselen oxide derivatives

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Pharmacology

Pharmacodynamics

Cisordinol 10 mg tablet

Zuclopenthixol antagonises both dopamine D1 and D2 receptors, α1-adrenoceptors and 5-HT2 receptors with a high affinity, but has no affinity for cholinergic muscarine receptors. It weakly antagonises the histamine (H1) receptor but has no α2-adrenoceptor blocking activity[citation needed].

Evidence from in vitro work and clinical sources (i.e. therapeutic drug monitoring databases) suggests that both CYP2D6 and CYP3A4 play important roles in zuclopenthixol metabolism.[11]

Pharmacokinetics

History

Zuclopenthixol was introduced by Lundbeck in 1978.[22]

References

  1. ^ Sneader, Walter (2005). Drug discovery: a history. New York: Wiley. p. 410. ISBN 0-471-89980-1.
  2. ^ Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics Life sciences 1984 Apr 16;34(16):1529-40.
  3. ^ Green, Alan I.; Noordsy, Douglas L.; Brunette, Mary F.; O’Keefe, Christopher (2008). “Substance abuse and schizophrenia: Pharmacotherapeutic intervention”Journal of Substance Abuse Treatment34 (1): 61–71. doi:10.1016/j.jsat.2007.01.008ISSN 0740-5472PMC 2930488PMID 17574793.
  4. ^ Sweetman, Sean C., ed. (2009). “Anxiolytic Sedatives Hypnotics and Antipsychotics”. Martindale: The complete drug reference (36th ed.). London: Pharmaceutical Press. pp. 1040–1. ISBN 978-0-85369-840-1.
  5. Jump up to:a b da Silva Freire Coutinho E, Fenton M, Quraishi SN (1999). “Zuclopenthixol decanoate for schizophrenia”The Cochrane Database of Systematic Reviews. John Wiley and Sons, Ltd. (2): CD001164. doi:10.1002/14651858.CD001164PMC 7032616PMID 10796607. Retrieved 2007-06-12.
  6. ^ Haessler F, Glaser T, Beneke M, Pap AF, Bodenschatz R, Reis O (2007). “Zuclopenthixol in adults with intellectual disabilities and aggressive behaviours”British Journal of Psychiatry190 (5): 447–448. doi:10.1192/bjp.bp.105.016535PMID 17470962.
  7. ^ Lundbeck P/L (1991). “Clopixol Acuphase 50 mg/mL Injection Clopixol Acuphase 100 mg / 2 mL Injection”. Lundbeck P/L. Retrieved 2007-06-12.
  8. Jump up to:a b Bryan, Edward J.; Purcell, Marie Ann; Kumar, Ajit (16 November 2017). “Zuclopenthixol dihydrochloride for schizophrenia”The Cochrane Database of Systematic Reviews2017 (11): CD005474. doi:10.1002/14651858.CD005474.pub2ISSN 1469-493XPMC 6486001PMID 29144549.
  9. ^ “Summary of Product Characteristics” (PDF).
  10. Jump up to:a b c d e “TGA eBS – Product and Consumer Medicine Information Licence”.
  11. ^ Davies SJ, Westin AA, Castberg I, Lewis G, Lennard MS, Taylor S, Spigset O (2010). “Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies”. Acta Psychiatrica Scandinavica122 (6): 445–453. doi:10.1111/j.1600-0447.2010.01619.xPMID 20946203S2CID 41869401.
  12. ^ Parent M, Toussaint C, Gilson H (1983). “Long-term treatment of chronic psychotics with bromperidol decanoate: clinical and pharmacokinetic evaluation”. Current Therapeutic Research34 (1): 1–6.
  13. Jump up to:a b Jørgensen A, Overø KF (1980). “Clopenthixol and flupenthixol depot preparations in outpatient schizophrenics. III. Serum levels”. Acta Psychiatrica Scandinavica. Supplementum279: 41–54. doi:10.1111/j.1600-0447.1980.tb07082.xPMID 6931472.
  14. Jump up to:a b Reynolds JE (1993). “Anxiolytic sedatives, hypnotics and neuroleptics.”. Martindale: The Extra Pharmacopoeia (30th ed.). London: Pharmaceutical Press. pp. 364–623.
  15. ^ Ereshefsky L, Saklad SR, Jann MW, Davis CM, Richards A, Seidel DR (May 1984). “Future of depot neuroleptic therapy: pharmacokinetic and pharmacodynamic approaches”. The Journal of Clinical Psychiatry45 (5 Pt 2): 50–9. PMID 6143748.
  16. Jump up to:a b Curry SH, Whelpton R, de Schepper PJ, Vranckx S, Schiff AA (April 1979). “Kinetics of fluphenazine after fluphenazine dihydrochloride, enanthate and decanoate administration to man”British Journal of Clinical Pharmacology7 (4): 325–31. doi:10.1111/j.1365-2125.1979.tb00941.xPMC 1429660PMID 444352.
  17. ^ Young D, Ereshefsky L, Saklad SR, Jann MW, Garcia N (1984). Explaining the pharmacokinetics of fluphenazine through computer simulations. (Abstract.). 19th Annual Midyear Clinical Meeting of the American Society of Hospital Pharmacists. Dallas, Texas.
  18. ^ Janssen PA, Niemegeers CJ, Schellekens KH, Lenaerts FM, Verbruggen FJ, van Nueten JM, et al. (November 1970). “The pharmacology of fluspirilene (R 6218), a potent, long-acting and injectable neuroleptic drug”. Arzneimittel-Forschung20 (11): 1689–98. PMID 4992598.
  19. ^ Beresford R, Ward A (January 1987). “Haloperidol decanoate. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in psychosis”. Drugs33 (1): 31–49. doi:10.2165/00003495-198733010-00002PMID 3545764.
  20. ^ Reyntigens AJ, Heykants JJ, Woestenborghs RJ, Gelders YG, Aerts TJ (1982). “Pharmacokinetics of haloperidol decanoate. A 2-year follow-up”. International Pharmacopsychiatry17 (4): 238–46. doi:10.1159/000468580PMID 7185768.
  21. ^ Larsson M, Axelsson R, Forsman A (1984). “On the pharmacokinetics of perphenazine: a clinical study of perphenazine enanthate and decanoate”. Current Therapeutic Research36 (6): 1071–88.
  22. ^ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia. Elsevier. pp. 1102–. ISBN 978-0-8155-1856-3.
  1. Product information for Zuclopenthixol (CLOPIXOL), provided by the Therapeutic Goods Administration — https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05705-3
Clinical data
Trade namesClopixol
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
AU: C
Routes of
administration
OralIM
Drug classTypical antipsychotic
ATC codeN05AF05 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)UK: POM (Prescription only)In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability49% (oral)
Protein binding98%
MetabolismHepatic (CYP2D6 and CYP3A4-mediated)
Elimination half-life20 hours (oral), 19 days (IM)
ExcretionFeces
Identifiers
showIUPAC name
CAS Number53772-83-1 
85721-05-7 (acetate)
64053-00-5 (decanoate)
PubChem CID5311507
DrugBankDB01624 
ChemSpider4470984 
UNII47ISU063SG
KEGGD03556 
ChEBICHEBI:51364 
ChEMBLChEMBL53904 
CompTox Dashboard (EPA)DTXSID3048233 
ECHA InfoCard100.053.398 
Chemical and physical data
FormulaC22H25ClN2OS
Molar mass400.97 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
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/////////zuclopenthixol, N05AF05, Clopenthixol, CisordinolClopixol

OCCN1CCN(CC\C=C2\C3=C(SC4=C2C=C(Cl)C=C4)C=CC=C3)CC1

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