Specification
IMPROVED PROCESS FOR PREPARING CLOPIDOGREL
CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. provisional application Serial No. 60/925,231, filed April 18,2007, hereby incorporated by reference.
FIELD OF THE INVENTION The present invention relates to a process for the preparation of optically pure clopidogrel camphorsulfonic acid salt, in a high yield, which is useful in the synthesis of clopidogrel for the treatment of peripheral arterial diseases.
BACKGROUND OF THE INVENTION Clopidogrel ("CLD"), methyl (+)-(S)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4fl)-acetate of formula (I),
(Formula Removed)
is an inhibitor of adenosine diphosphate (ADP)-induced platelet aggregation which is effective in treating peripheral arterial diseases such as stroke, thrombosis and embolism, as well as coronary arterial diseases such as stroke, thrombosis, embolism, and myocardial infarction. Similar properties are displayed by the less potent racemic mixture (see U.S. Patent No. 4,847,265).
Clopidogrel is administered as its bisulfate (hydrogen sulfate) salt. Clopidogrel bisulfate has an empirical formula of C16H16CINO2S.H2SO4. It is currently being marketed as PLAVLX® tablets, which contain about 98 mg clopidogrel bisulfate, which is the equivalent of 75 mg clopidogrel base. PLAVDC® is a white to off-white powder that is practically insoluble in water at neutral pH but highly soluble at acidic pH. It dissolves freely in methanol, somewhat in methylene chloride, and poorly in ethyl ether.
The enantiomer (S) clopidogrel is particularly preferred since it is the pharmaceutically active compound. The enantiomerically enriched compound can be
EM 095041820 US
prepared by means of enantioselective synthesis or starting from a racemic mixture of enantionmers in conjunction with a resolution process.
Various methods for preparing clopidogrel are described in US Patent Nos. 4,847,265, 5,204,469, 6,080,875,6,495,691, 6,573,381, 6,635,763, 5,132,435, WO2005/104663, and WO 2006/137628.
US Patent No. 5,132,435 describes a process for the preparation of the (R) and (S) enantiomers of methyl a-(4,5,6,7-tetrahydro-5-thieno[3,2-c]-pyridyl (2-chlorophenyl-) acetate. For example, methyl l-chloro-(2-chlorophenyl) acetate is coupled with 4,5,6,7-tetrahydrothieno[3,2-c]pyridine in the form of a base or salt to obtain a racemic methyl a-(4,5,6,7-tetrahydro-5-thieno[3,2-c]-pyridyl (2-chlorophenyl-) acetate in the presence of an acid acceptor, e.g. an alkali metal carbonate or bicarbonate, and optionally under phase transfer conditions to obtain the desired racemic clopidogrel base, which has been isolated as clopidogrel hydrochloride salt. The isolated racemic clopidogrel hydrochloride can further be resolved with camphorsulfonic acid in acetone.
The process described in U.S. Patent No. 5,132,435 requires the isolation of racemic clopidogrel hydrochloride salt (an additional step), resulting in longer reaction cycle time (more than 75 hours) and low yield (33%-39%).
WO 2005/104663 also describes a process for the preparation of racemic clopidogrel. WO 2005/104663 describes a process for resolution of racemic clopidogrel and conversion to hydrogen sulfate salt of clopidogrel via crystalline Forms I and n. The process describes formation of racemic clopidogrel base by coupling 4,5,6,7-tetrahydrothieno(3,2-c)pyridine with methyl-l-halo-(2-chlorophenyl) acetate at room temperature in a solvent, e.g. water and/or dichloroethane in the presence of organic or inorganic bases, e.g. sodium carbonate. Subsequently, resolving the racemic clopidogrel base to provide methyl-(S)-(+)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl acetate using anhydrous levo-camphor-10-sulphonic acid in a mixture of solvents selected from combination of polar and non-polar/weakly polar solvents like acetone : chloromethane, acetone : toluene, and acetone : cyclohexane. This process also requires isolating the racemic clopidogrel hydrogen sulfate salt prior to resolution, which give rise to longer reaction cycle time and low yield.
US Patent Nos. 4,529,596, 4,847,265, 5,036,156, 5,189,170 and WO 2006/0137628 refer to various methods of preparing racemic clopidogrel or clopidogrel. These processes also involve the formation of clopidogrel acid salt before its resolution
with levorotatory camphosulphonic acid, which leads to an increase of additional reaction steps, e.g. formation of acid salt and making of free base, thereby increasing (1) the amount of solvents and reagents consumed, (2) reaction cycle time, (3) laborious work ups and separations and (4) effluent load; ultimately results in formation of clopidogrel in poor yield.
US Patent No. 6,737,411 and US Publication No. 2005/0059696 describe the preparation of clopidogrel hydrogen sulfate.
The present invention provides an improved process for preparing clopidogrel that allows one to obtain an enantiomerically pure or enantiomerically enriched product without the need of laborious procedures and separations.
SUMMARY OF THE INVENTION In one embodiment the present invention encompasses a process for preparing (-)-10-camphosulphonic acid salt of methyl (+)-(5)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate ("CLD-CSA") of formula II comprising: (a) reacting 4,5,6,7-tetrahydrothieno (3,2-c) pyridine hydrochloride ("formula III") with o-chlorophenyl-α-bromo methyl acetate ("formula IV") in the presence of an acid acceptor to produce (±)-methyl a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H) -acetate; (b) reacting in-situ(±)-methyl α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H) -acetate ("clopidogrel racemate") with (-)-10-camphosulphonic acid to afford (-)-10-camphosulphonic acid salt of methyl (+)-(5)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate of formula II. Preferably, the reaction in step (a) is carried out in a biphasic solvent system optionally under phase transfer conditions. The biphasic (two-phase) system is preferably composed of water and water-immiscible organic solvent mixture.
(Scheme Removed)
In another embodiment, the invention encompasses a process for preparing (S)-clopidogrel (-)-10-camphosulphonic acid salt ("CLD-CSA") comprising: (a) combining (R) clopidogrel or a mixture of (R) and (S) clopidogrel ("formula VI") with a base to obtain a racemic mixture of (R) and (S) clopidogrel further enriched with (S) clopidogrel ("formula VII"); and (b) reacting the racemic mixture of (R) and (S) clopidogrel further enriched with (S) clopidogrel ("formula VII") with levorotatory camphorsulphonic acid, to provide (S)-clopidogrel (-)-10-camphosulphonic acid salt ("formula II"), wherein steps (a) and (b) are carried out without an intermediate step of reacting the racemic mixture of (R) and (S) clopidogrel with sulfuric acid. Preferably, prior to step (a), the process comprises preparing (R) clopidogrel or a mixture of (R) and (S) clopidogrel ("formula VI") comprising combining mother liquor of (R) clopidogrel (-)-10-camphosulphonic acid salt or a mixture of (R) and (S) clopidogrel (-)-10-camphosulphonic acid salt ("formula V") with a base in an organic solvent to obtain (R) clopidogrel or a mixture of (R) and (S) clopidogrel ("formula VI").
(Scheme Removed)
In another embodiment, the invention encompasses a process for the preparation of a pharmaceutically acceptable salt of (S)-clopidogrel from CLD-CSA salt of formula II via conventional techniques. Preferably, the salt is bisulfate.
In another embodiment, the present invention encompasses a process for preparing clopidogrel camphosulfonate comprising: combining 4,5,6,7-tetrahydrothieno-(3,2-c)pyridine hydrochloride, toluene, N,N-dimethyl formamide ("DMF"), o-chlorophenyl-α-bromo methyl acetate to obtain a reaction mixture containing (±) clopidogrel; and converting the (±) clopidogrel to clopidogrel camphosulfonate without the recovery of (±) clopidogrel. Preferably, the process further comprises adding tetrabutylammonium hydrogen sulphate and/or a base to the combination of 4,5,6,7-tetrahydrothieno-(3,2-c)pyridine hydrochloride, toluene, DMF, and o-chlorophenyl-α-bromo methyl acetate.
In another embodiment, the present invention encompasses a process for preparing (S)-clopidogrel bisulfate comprising: (a) reacting 4,5,6,7-tetrahydrothieno (3,2-c) pyridine hydrochloride with o-chlorophenyl-α-bromo methyl acetate in the presence of an acid acceptor to produce (±)-methyl a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate; (b) reacting in-situ (±)-methyl
Documents
Application Documents
| # |
Name |
Date |
| 1 |
5511-delnp-2009-Correspondence-Others (19-11-2009).pdf |
2009-11-19 |
| 1 |
5511-DELNP-2009_EXAMREPORT.pdf |
2016-06-30 |
| 2 |
5511-delnp-2009-Assignment (19-11-2009).pdf |
2009-11-19 |
| 2 |
5511-delnp-2009-abstract.pdf |
2011-08-21 |
| 3 |
5511-delnp-2009-pct-304.pdf |
2011-08-21 |
| 3 |
5511-delnp-2009-claims.pdf |
2011-08-21 |
| 4 |
5511-delnp-2009-correspondence-others.pdf |
2011-08-21 |
| 4 |
5511-delnp-2009-gpa.pdf |
2011-08-21 |
| 5 |
5511-delnp-2009-form-5.pdf |
2011-08-21 |
| 5 |
5511-delnp-2009-description (complete).pdf |
2011-08-21 |
| 6 |
5511-delnp-2009-form-3.pdf |
2011-08-21 |
| 6 |
5511-delnp-2009-form-1.pdf |
2011-08-21 |
| 7 |
5511-delnp-2009-form-2.pdf |
2011-08-21 |
| 7 |
5511-delnp-2009-form-18.pdf |
2011-08-21 |
| 8 |
5511-delnp-2009-form-2.pdf |
2011-08-21 |
| 8 |
5511-delnp-2009-form-18.pdf |
2011-08-21 |
| 9 |
5511-delnp-2009-form-3.pdf |
2011-08-21 |
| 9 |
5511-delnp-2009-form-1.pdf |
2011-08-21 |
| 10 |
5511-delnp-2009-description (complete).pdf |
2011-08-21 |
| 10 |
5511-delnp-2009-form-5.pdf |
2011-08-21 |
| 11 |
5511-delnp-2009-correspondence-others.pdf |
2011-08-21 |
| 11 |
5511-delnp-2009-gpa.pdf |
2011-08-21 |
| 12 |
5511-delnp-2009-pct-304.pdf |
2011-08-21 |
| 12 |
5511-delnp-2009-claims.pdf |
2011-08-21 |
| 13 |
5511-delnp-2009-Assignment (19-11-2009).pdf |
2009-11-19 |
| 13 |
5511-delnp-2009-abstract.pdf |
2011-08-21 |
| 14 |
5511-DELNP-2009_EXAMREPORT.pdf |
2016-06-30 |
| 14 |
5511-delnp-2009-Correspondence-Others (19-11-2009).pdf |
2009-11-19 |