Racemization and enantiomer separation of clopidogrel

Details Racemization and enantiomer separation of clopidogrel Racemization and enantiomer separation of clopidogrel

2003-03-19

2004-10-05

Seaman, D. Margaret (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S077000

Reexamination Certificate

active

06800759

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the stereochemistry of clopidogrel.
BACKGROUND OF THE INVENTION
Atherosclerosis is the buildup of plaque in the wall of the arteries leading to a thickening and a reduction in elasticity of the arteries. Atherosclerosis results from injury to the inside layer of the artery. The injury is caused by common activities and diseases such as high cholesterol, high blood pressure, smoking and infection.
Plaques form on the inner walls of the artery at these sites of injury. The plaques are mainly composed of fatty tissue and smooth muscle cells. The formation of plaque often leads to blood clotting due to platelet aggregation at the site of the injury. This clotting may result in a reduction or elimination of blood flow to vital organs, causing heart attacks or other serious conditions. The plaque may also rupture and send a blood clot through the artery, referred to as an embolus, which if deposited in a smaller blood vessel may completely block blood flow.
Antiplatelet activity is desirable in fighting the often fatal results of atherosclerosis. Clopidogrel is an inhibitor of induced platelet aggregation which acts by inhibiting the binding of adenosine diphosphate to its receptor. Clopidogrel is metabolized by the liver into active form. Its antiplatelet activity is extended in that it stops any platelet activity even up to ten days after administration.
The chemical name of clopidogrel is methyl (+)-(S)-∝-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate. It has the following structure:
Clopidogrel is disclosed in U.S. Pat. Nos. 4,529,596 (EP 99802, JP 59027895), 6,258,961, 5,036,156 (EP 420706, JP 3120286), 6,080,875 (EP 971915, JP 2001513806), 6,180,793 (EP 981529, JP 2001525829), FR 2769313, all of which are incorporated herein by reference for their disclosure and preparation of clopidogrel. U.S. Pat. No. 4,529,596 discloses a racemic mixture of clopidogrel and processes for preparing such mixture. U.S. Pat. No. 5,036,156 discloses a method for preparing an intermediate in the synthesis of clopidogrel, 2-chloro-&agr;-bromophenylacetic acid, and a process for condensing its methyl ester with tetrahydrothienopyridine. FR 2769313 discloses an intermediate in the synthesis of clopidogrel, (R)-2-benzenesulfonyloxy-2-(2-chlorophenyl)acetic acid methyl ester, and processes for its preparation. FR 2769313 further discloses converting the ester to clopidogrel by nucleophilic substitution with tetrahydrothienopyridine. U.S. Pat. No. 5,036,156 discloses preparation of pyridine drivatives by reacting a benzaldehyde with tribromomethane and potassium hydroxide in water and in the presence of an inert solvent.
Clopidogrel's platelet inhibiting activity makes it an effective drug for reducing the incidence of ischemic strokes, heart attacks or claudication due to vascular diseases such as atherosclerosis. By inhibiting platelet aggregation, clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart attacks. U.S. Pat. No. 5,576,328 describes a method of preventing the occurrence of a secondary ischemic event by administration of clopidogrel, and is incorporated herein by reference.
Recent studies have shown that clopidogrel is more effective in blocking platelet aggregation than aspirin and is much gentler on the gastrointestinal tract. Clopidogrel is more effective than aspirin even at much lower dosage. A dosage of 75 mg of base equivalent has been shown to be more effective than a dosage of 325 mg of aspirin. In addition to being more effective, clopidogrel produces much less gastrointestinal bleeding than aspirin.
Clopidogrel is administered as its bisulfate (syn. hydrogensulfate) salt. Clopidogrel bisulfate has an empirical formula of C
16
H
16
Cl NO
2
S.H
2
SO
4
. It is currently being marketed as PLAVIX® tablets, which contain about 98 mg clopidogrel bisulfate, which is the equivalent of 75 mg clopidogrel base. PLAVIX® 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.
U.S. Pat. No. 6,080,875 (EP 971915, JP 2001513806), incorporated herein by reference, prepares (S) clopidogrel by reaction of sodium 2-thienylglycidate with (S) 2-chloro phenyl glycine in the presence of cyanoborohydride.
U.S. Pat. No. 6,180,793 (EP 981,529, JP 2001525819) and related publications WO 98/51681, WO 98/51682 and WO/51689, incorporated herein by reference, prepare the (S) enantiomer by methods that control the chirality of the intermediates used in the synthesis of clopiodogrel to reduce formation of the (R) enantiomer. U.S. Pat. No. 6,180,793 and the related art disclose processes for synthesizing (S) clopidogrel by reaction of an activated form of 2-thiophene ethanol with (S)-2-chlorophenyl glycineamide, (S)-2-chlorophenyl-&agr;-amino acetonitrile or (S)2-chlorophenyl glycine methyl ester. After condensation, the resulting compound is cyclicized, hydrolyzed and esterified.
WO 98/39286, incorporated herein by reference, discloses a racemization process for phenyl glycine esters. A mixture of enantiomers of phenyl glycine ester is treated with a carbonyl compound in the presence of a carboxylic acid and a single enantiomer of an N-protected &agr;-amino acid as resolving agent. The formation of an imino intermediate causes the racemization of the starting product and the precipitation of a single diastereomeric salt. After hydrolysis of the salt, an enantiomer of phenyl glycine ester is obtained.
U.S. Pat. No. 4,847,265 (EP 291459, JP 63203684) discloses methods for separating one enantiomer of clopidogrel from another by selective crystallization of the camphor sulfonate of the (S) enantiomer. The '265 patent discloses crystallizing the (S) enantiomer from dimethylformamide (“DMF”), ketones, and alcohols, though crystallization with acetone is primarily disclosed. U.S. Pat. No. 5,132,435 (EP 465358, JP 3055819), U.S. Pat. Nos. 6,215,005 and 6,258,961, incorporated herein by reference, also disclose separating the (S) enantiomer of clopidogrel by crystallization of the camphor sulfonate from acetone.
U.S. Pat. No. 5,204,469 (EP 466569, JP 4230387) discloses an enantioselective process for synthesis of clopidogrel through reaction of (+)-2-chloro phenylglycine and an activated form of 2-thiophene ethanol followed by cyclization with formaldehyde.
WO 00/27840 (EP 1129087) discloses using a base to racemize an amide intermediate used in the synthesis of clopidogrel. The process of WO 00/27840 requires going through an amide intermediate, which is not always used in preparing clopidogrel, as illustrated by Examples 1 and 2 of the present invention. It is advantageous to prepare clopidogrel, and then racemize clopidogrel rather than the intermediate, and to skip the necessary conversion of the amide intermediate to an ester as required in WO 00/27840. WO 02/059128 also generally discloses racemization of an intermediate of clopidogrel and clopidogrel with an equimolar amount of a base, though an actual example is not provided regarding racemization of clopidogrel.
A problem with the preparation of clopidogrel is the presence of a therapeutically inactive enantiomer, the (R) enantiomer. The presence of the (R) enantiomer results in contamination of the main product, and reduces the yield by being a waste product. There is a need in the art to prepare the (S) enantiomer of clopidogrel substantially free of the (R) enantiomer in a facile manner suitable on an industrial scale.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for preparing (S) clopidogrel free base or a pharmaceutically acceptable salt thereof comprising the steps of reacting a mixture of (R) and (S) clopidogrel free base with levorotatory camphor sulfonic acid in a mixture of a C
5
to a C
12
hydrocarbon and a suitable co-so

Affiliated with

Also associated with

Rating

Racemization and enantiomer separation of clopidogrel does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Racemization and enantiomer separation of clopidogrel, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Racemization and enantiomer separation of clopidogrel will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3328690