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Production method of (-)-(R)- clopidogrel (-)-(R)-camphorsulfonate racemisation

A technology of camphorsulfonate and production method, which is applied in the field of drug synthesis, can solve the problems of unfavorable industrial production, complex reaction, high cost, etc., and achieve the effects of stable quality, simple preparation method and improved yield

Active Publication Date: 2009-06-24
TIANJIN CENT PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The racemization embodiment mentioned in U.S. Patent US2005 / 0049275 is that (-)-(R)-camphorsulfonate mother liquor of (-)-(R)-clopidogrel is carried out racemization with potassium tert-butoxide Rotation, the cost is too high, not conducive to large-scale industrial production
The embodiment of racemization mentioned in the world patent WO2006 / 042481 is to hydrolyze (-)-(R)-camphorsulfonate mother liquor of (-)-(R)-clopidogrel with KOH, and then react with CH 3 I esterification obtains racemic clopidogrel free base, the cost is too high, the reaction is complicated, and the yield is low

Method used

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  • Production method of (-)-(R)- clopidogrel (-)-(R)-camphorsulfonate racemisation

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Effect test

Embodiment 2

[0034]Add 32.1g (0.1mol) of racemic clopidogrel free base, 320ml of acetone (10 times) into the reaction flask, stir until completely dissolved, add 18.6g (0.08mol) (-)-(R)-camphorsulfonic acid ( 0.8 times), react at 30°C for 1 hour, crystallize at 0°C for 12 hours, heat up to 50°C, hold for 2 hours, crystallize at 0°C for 2 hours, filter, rinse with acetone to obtain (+)-(S)-chlorine Pidogrel (-)-(R)-camphorsulfonate 22.0 g, HPLC 99%, melting point 161-163°C, [α]=+24.7°, yield 39.67%.

Embodiment 3

[0036] Preparation of (+)-(S)-Clopidogrel Sulfate

[0037] (+)-(S)-clopidogrel (-)-(R)-camphorsulfonate 22.0 g (0.040 mol) in Reference Example 2, 176 ml of ethyl acetate and 176 ml of water were added to the reaction flask, saturated with NaHCO 3 The aqueous solution was adjusted to neutral pH, the ethyl acetate layer was separated, the aqueous layer was extracted with 50 ml of ethyl acetate, the ethyl acetate layers were combined, washed with 50 ml of saturated aqueous NaCl solution, and anhydrous MgSO 4 Dry, concentrate to dryness under reduced pressure to obtain 12.5 g of (+)-(S)-clopidogrel free base oil, add 62.5 ml of isopropanol (5 times), and dropwise add 2.6 ml of concentrated sulfuric acid (1.3 times) at 10°C , crystallized at 0°C for 8 hours, filtered and rinsed with acetone to obtain (+)-(S)-clopidogrel sulfate 16.4g, HPLC 99.3%, melting point 183-184°C, [α]=55.8°, yield 97.55%.

preparation Embodiment 1

[0039] Racemized (-)-(R)-clopidogrel (-)-(R)-camphorsulfonate mother liquor

[0040] About 350 ml of the (-)-(R)-clopidogrel (-)-(R)-camphorsulfonate mother liquor remaining in Reference Example 2 was concentrated to dryness under reduced pressure to obtain 23.3 g of pale yellow oil, and 116.5 ml was added. Methanol (5 times) was stirred until dissolved, 11.7g (weight ratio 1:0.5) sodium methoxide was added, reacted at 30°C for 1 hour, 100ml of ethyl acetate and 100ml of water were added, the organic layer was separated, and the aqueous layer was extracted with 50ml of ethyl acetate , the organic layers were combined, washed with saturated aqueous NaCl, anhydrous MgSO 4 Dry, concentrate to dryness under reduced pressure to obtain 18.4 g of racemic clopidogrel free base oil, add 92 ml of isopropanol (5 times), add 3.9 ml of concentrated sulfuric acid (1.3 times) dropwise at 10 °C, and crystallize 8 at 0 °C hour, filtered, rinsed with acetone to obtain 18.9 g of racemic clopido...

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Abstract

The invention discloses a racemization production method of (-)-(R)-clopidogrel(-)-(R)-camphorsulfonate. The racemization production method comprises the following steps: allowing (-)-(R)-camphorsulfonate mother liquor concentrate of (-)-(R)-clopidogrel to react with sodium methylate in methanol, which replaces expensive tertiary butyl alcohol and potassium tertbutoxide in U.S. patents; and then extracting and condensing with ethyl acetate, and salifying in isopropyl alcohol to obtain clopidogrel sulfate with high quality and high yield. The racemization production method of the (-)-(R)-clopidogrel(-)-(R)-camphorsulfonate is characterized by convenient industrial operation, stable quality and high yield, and is more favorable for large-scale industrialized production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and relates to a production method for the racemization of (-)-(R)-clopidogrel (-)-(R)-camphorsulfonate. Background technique [0002] Clopidogrel, chemical name (S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester, is A platelet inhibitor, which was successfully researched and developed by the French company Sanofi in 1986. Its sulfate is used clinically. The chemical structure of the trade name is Plavix: [0003] [0004] Relevant surveys including developed and developing countries show that ischemic heart disease and cerebrovascular disease have become the main causes of human death. In my country, especially cerebrovascular disease, the prevalence rate is as high as 490 per 100,000 people. Studies have shown that atherosclerosis is the underlying cause of these diseases, and platelet inhibitors are effective against atherosclerotic thr...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61P7/02
Inventor 孟庆礼杨冠宇宋风武张艳雪
Owner TIANJIN CENT PHARM CO LTD
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