CA2567806A1 - Rapid resolution process of clopidogrel base and a process for preparation of clopidogrel bisulfate polymorph - form i - Google Patents
Rapid resolution process of clopidogrel base and a process for preparation of clopidogrel bisulfate polymorph - form i Download PDFInfo
- Publication number
- CA2567806A1 CA2567806A1 CA002567806A CA2567806A CA2567806A1 CA 2567806 A1 CA2567806 A1 CA 2567806A1 CA 002567806 A CA002567806 A CA 002567806A CA 2567806 A CA2567806 A CA 2567806A CA 2567806 A1 CA2567806 A1 CA 2567806A1
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- CA
- Canada
- Prior art keywords
- clopidogrel
- aliphatic
- ether
- methyl
- base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a rapid resolution process of racemic clopidogrel base followed by conversion of the resolved (S) isomer to crystalline Clopidogrel bisulfate Form I. The invention also discloses novel racemization process of the unwanted (R) isomer of clopidogrel base. The invention further discloses an improved process for preparation of acid addition salts of clopidogrel.
Claims (21)
1. A process for rapid resolution of methyl (~) .alpha.-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate comprising;
a) treating methyl (~) .alpha.-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate using levo rotatory camphor-10- sulfonic acid in a mixture of aliphatic ketone and aliphatic ether under stirring for a duration ranging from 2-12 hours within a temperature range of 0-70°C to obtain (S)-(+)-clopidogrel camphor sulphonate salt;
b) purifying the (S)-(+)-clopidogrel camphor sulphonate salt using an aliphatic ketone solvent to obtain purified (S)-(+)- clopidogrel camphor sulphonate salt; and c) converting the obtained methyl (S)-(+)-clopidogrel camphor sulphonate salt into (S)-(+)-clopidogrel base by treating with lower chlorinated hydrocarbon and aqueous base.
a) treating methyl (~) .alpha.-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate using levo rotatory camphor-10- sulfonic acid in a mixture of aliphatic ketone and aliphatic ether under stirring for a duration ranging from 2-12 hours within a temperature range of 0-70°C to obtain (S)-(+)-clopidogrel camphor sulphonate salt;
b) purifying the (S)-(+)-clopidogrel camphor sulphonate salt using an aliphatic ketone solvent to obtain purified (S)-(+)- clopidogrel camphor sulphonate salt; and c) converting the obtained methyl (S)-(+)-clopidogrel camphor sulphonate salt into (S)-(+)-clopidogrel base by treating with lower chlorinated hydrocarbon and aqueous base.
2. The process as claimed in claim 1, wherein the aliphatic ketone is selected from a group consisting of acetone, 2-butanone, 3-pentanone, methyl iso-butyl ketone.
3. The process as claimed in claim 1, wherein the aliphatic ether is selected from the group consisting of di-ethyl ether, di-isopropyl ether and methyl-tert- butyl ether.
4. The process as claimed in 1, wherein said aliphatic ketone and aliphatic ether is in a proportion of 1:1 to 1:9.
5. The process as claimed in 1, wherein said aliphatic ketone and aliphatic ether is in a proportion of 1:1.
6. The process as claimed in claim 1, wherein the stirring is carried out for a duration ranging from 6 to 12 hours.
7. The process claimed in claim 1, wherein said temperature ranges from 25°C-55°C.
8. The process as claimed in claim 1, wherein said lower chlorinated hydrocarbon is methylene dichloride.
9. The process as claimed in claim 1, wherein said aqueous base is sodium bicarbonate.
10. An improved process for the preparation of (S)-(+)-Clopidogrel bisulfate Form I, said process comprising:
a. condensing 4,5,6,7-Tetrahydrothieno[3,2-c]pyridine hydrochloride with .alpha.-bromo-2-chlorophenyl acetic acid methyl ester in dimethyl formamide (DMF) at a temperature ranging from 80°C-85°C in presence of an inorganic base, extracting with lower chlorinated hydrocarbon to obtain methyl (~) .alpha.-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate;
b. treating methyl (~) .alpha.-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate with levo rotatory camphor-10-sulphonic acid in a mixture of aliphatic ketone and aliphatic ether under stirring for a duration ranging from 2-12 hours within a temperature of range of 0°C-70°C to obtain (S)-(+)-Clopidogrel camphor sulphonate salt;
c. purifying the (S)-(+)-Clopidogrel camphor sulfonate salt using an aliphatic ketone solvent to obtain purified (S)-(+)-clopidogrel camphor sulphonate salt;
d. converting said purified (S)-(+) Clopidogrel camphor sulfonate salt into (S)-(+)-Clopidogrel base by treating with a lower chlorinated hydrocarbon and an aqueous base; and e. converting said (S)-(+)-Clopidogrel free base into (S)-(+)-Clopidogrel bisulfate Form I by dissolving said (S)-(+)-Clopidogrel free base in a C1-C5 carboxylic acid followed by adding sulfuric acid and an antisolvent selected from a group of aliphatic ether within a temperature range 0-25°C with stirring for a suitable time duration of 12-48 hours followed by filtering to obtain (S)-(+)-Clopidogrel bisulphate Form I.
a. condensing 4,5,6,7-Tetrahydrothieno[3,2-c]pyridine hydrochloride with .alpha.-bromo-2-chlorophenyl acetic acid methyl ester in dimethyl formamide (DMF) at a temperature ranging from 80°C-85°C in presence of an inorganic base, extracting with lower chlorinated hydrocarbon to obtain methyl (~) .alpha.-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate;
b. treating methyl (~) .alpha.-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate with levo rotatory camphor-10-sulphonic acid in a mixture of aliphatic ketone and aliphatic ether under stirring for a duration ranging from 2-12 hours within a temperature of range of 0°C-70°C to obtain (S)-(+)-Clopidogrel camphor sulphonate salt;
c. purifying the (S)-(+)-Clopidogrel camphor sulfonate salt using an aliphatic ketone solvent to obtain purified (S)-(+)-clopidogrel camphor sulphonate salt;
d. converting said purified (S)-(+) Clopidogrel camphor sulfonate salt into (S)-(+)-Clopidogrel base by treating with a lower chlorinated hydrocarbon and an aqueous base; and e. converting said (S)-(+)-Clopidogrel free base into (S)-(+)-Clopidogrel bisulfate Form I by dissolving said (S)-(+)-Clopidogrel free base in a C1-C5 carboxylic acid followed by adding sulfuric acid and an antisolvent selected from a group of aliphatic ether within a temperature range 0-25°C with stirring for a suitable time duration of 12-48 hours followed by filtering to obtain (S)-(+)-Clopidogrel bisulphate Form I.
11. The process as claimed in Claim 10, wherein said inorganic base is potassium carbonate.
12. The process as claimed in Claim 10, wherein said lower chlorinated hydrocarbon is methylene dichloride.
13. The process as claimed in claim 10, wherein said aliphatic ketone is selected from a group consisting of acetone, 2-butanone, 3-pentanone, methyl-iso-butyl ketone.
14. The process as claimed in claim 10, wherein the aliphatic ether is selected from the group consisting of di-ethyl ether, di-isopropyl ether and methyl-tert-butyl ether.
15. The process as claimed in 10, wherein said aliphatic ketone and aliphatic ether is in a proportion of 1:1 to 1:9.
16. The process as claimed in 10, wherein said aliphatic ketone and aliphatic ether is in a proportion of 1:1.
17. The process as claimed in claim 10(b), wherein said stirring is carried out for a duration ranging from 6 to 12 hours.
18. The process as claimed in claim 10, wherein said aqueous base is sodium bicarbonate.
19. The process as claimed in claim 10, wherein said C1-C5 carboxylic acid is glacial acetic acid.
20. The process as claimed in claim 10(e), wherein said suitable time duration is 16 hours.
21. The process as claimed in claim 10, wherein said (S)-(+)-Clopidogrel bisulphate Form I is in crystalline form.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2005/000048 WO2006087729A1 (en) | 2005-02-15 | 2005-02-15 | Rapid resolution process for clopidogrel base and a process for preparation of clopidogrel bisulfate polymorph - form i |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2567806A1 true CA2567806A1 (en) | 2006-08-24 |
| CA2567806C CA2567806C (en) | 2011-04-26 |
Family
ID=36644897
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2567806A Expired - Fee Related CA2567806C (en) | 2005-02-15 | 2005-02-15 | Rapid resolution process of clopidogrel base and a process for preparation of clopidogrel bisulfate polymorph - form i |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1848720A1 (en) |
| AU (1) | AU2005327776A1 (en) |
| CA (1) | CA2567806C (en) |
| WO (1) | WO2006087729A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL382055A1 (en) * | 2007-03-23 | 2008-09-29 | Koźluk Tomasz Nobilus Ent | Production method of crystalline form of clopidogrel 1 hydrogen sulphate |
| WO2008146249A1 (en) * | 2007-05-30 | 2008-12-04 | Wockhardt Research Centre | Processes for the preparation of clopidogrel |
| EP2107061A1 (en) | 2008-04-02 | 2009-10-07 | Krka Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of optically enriched clopidogrel |
| WO2011042804A2 (en) | 2009-10-08 | 2011-04-14 | Jubliant Life Sciences Limited | An improved process for the preparation of clopidogrel hydrogen sulfate form i |
| KR101710922B1 (en) | 2015-06-03 | 2017-02-28 | 경동제약 주식회사 | Method for preparing crystalline form I of Clopidogrel hydrogen sulfate |
| CN107383055A (en) * | 2017-08-03 | 2017-11-24 | 江苏汉斯通药业有限公司 | The synthetic method of bisulfate clopidogrel |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2623810B2 (en) * | 1987-02-17 | 1992-01-24 | Sanofi Sa | ALPHA SALTS- (TETRAHYDRO-4,5,6,7 THIENO (3,2-C) PYRIDYL-5) (2-CHLORO-PHENYL) -THETHYL ACETATE DEXTROGYRE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| FR2779726B1 (en) * | 1998-06-15 | 2001-05-18 | Sanofi Sa | POLYMORPHIC FORM OF CLOPIDOGREL HYDROGENOSULFATE |
| IL166593A0 (en) * | 2002-08-02 | 2006-01-15 | Racemization and enantiomer separation of clopidogrel | |
| US6800759B2 (en) * | 2002-08-02 | 2004-10-05 | Teva Pharmaceutical Industries Ltd. | Racemization and enantiomer separation of clopidogrel |
| EP1606231A1 (en) * | 2003-02-03 | 2005-12-21 | Nadkarni, Sunil Sadanand | Process for preparation of clopidogrel, its salts and pharmaceutical compositions |
-
2005
- 2005-02-15 AU AU2005327776A patent/AU2005327776A1/en not_active Abandoned
- 2005-02-15 WO PCT/IN2005/000048 patent/WO2006087729A1/en active Application Filing
- 2005-02-15 EP EP05747156A patent/EP1848720A1/en not_active Withdrawn
- 2005-02-15 CA CA2567806A patent/CA2567806C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2567806C (en) | 2011-04-26 |
| WO2006087729A1 (en) | 2006-08-24 |
| EP1848720A1 (en) | 2007-10-31 |
| AU2005327776A1 (en) | 2006-08-24 |
| WO2006087729B1 (en) | 2006-11-09 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20140217 |