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Method for preparing sulfate or hydrochloride of (S)-clopidogrel

A technology of clopidogrel and sulfate, applied in the field of preparation of sulfate or hydrochloride, which can solve the problems of reduced yield, large product loss, and increased product loss

Active Publication Date: 2014-01-01
ZHEJIANG MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] U.S. Patent US200424012 uses roughly the same steps to prepare (S)-clopidogrel hydrogen sulfate, the difference is that the racemate of clopidogrel hydrogen sulfate is obtained by using racemized raw materials in the reaction, and finally uses (+)-10 -Camphorsulfonic acid is separated to obtain (S)-clopidogrel hydrogen sulfate. The purity of the product obtained by this method is better, but (+)-10-camphorsulfonic acid cannot be recovered, and the cost is relatively high
[0009] U.S. Patent US2007225320 discloses another method for preparing (S)-clopidogrel bisulfate with higher purity. The method can improve the solubility of impurities in water, which is conducive to improving the purity of the finally obtained (S)-clopidogrel bisulfate, but the addition of methanol also increases the loss of products and reduces the yield
European patent EP200732023 extracts (S)-clopidogrel under the condition of pH 2.4-2.7, which can improve the purity of the product, but also has the disadvantage of large product loss
[0010] Another commonly used method to improve product purity is to convert (S)-clopidogrel into hydrochloride and sulfate salts for crystallization and separation (such as US2004132765 and WO2006130852), and then add alkali to neutralize to obtain a product with improved purity (S)-clopidogrel, and then react with sulfuric acid to obtain (S)-clopidogrel sulfate or hydrochloride, these steps are conducive to improving the purity of the final product, but there are also disadvantages of greater product loss

Method used

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  • Method for preparing sulfate or hydrochloride of (S)-clopidogrel

Examples

Experimental program
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Effect test

Embodiment 1

[0066] Add 500L water and 400L cyclohexane to the hydrochloride of 100kg (S)-(+)-α-(2-thienylethylamino)-α-(2-chlorophenyl)methyl acetate, mix the The system was heated to 40°C, and then a commercially available 37% aqueous solution of formaldehyde was added dropwise, wherein, in terms of molar mass, formaldehyde: (S)-(+)-α-(2-thiopheneethylamino)-α- (2-Chlorophenyl) methyl acetate hydrochloride = 5: 1, the dropping time is 1h. After reacting for 6 hours, it was detected that the reaction was complete, and the reaction solution was cooled to room temperature, and separated to obtain an aqueous phase and a first organic phase. Add about 400L of new cyclohexane to the water phase, then adjust the pH of the water phase to 7.5-8, perform extraction, separate the second organic phase, and combine the first and second organic phases. The combined organic phases were washed successively with water, saturated sodium bisulfite, and water, and then the solvent was removed under reduced...

Embodiment 2

[0081] Add 500L water and 400L cyclohexane to the hydrochloride of 100kg (S)-(+)-α-(2-thienylethylamino)-α-(2-chlorophenyl)methyl acetate, mix the The system was heated to 40°C, and then commercially available 37% formaldehyde aqueous solution was added dropwise thereto, wherein, in terms of molar mass, formaldehyde: (S)-(+)-α-(2-thiopheneethylamino)-α- (2-Chlorophenyl) methyl acetate hydrochloride = 5: 1, the dropping time is 1h. After reacting for 6 hours, it was detected that the reaction was complete, and the reaction solution was cooled to room temperature, then the pH of the aqueous phase was adjusted to 7-8, and the organic phase was separated. The obtained organic phase was washed successively with water, saturated sodium bisulfite, and water, and then the solvent was removed under reduced pressure to obtain an oily solid. Dissolve the oily solid in 330L of a mixture of acetone and methanol (volume ratio 10:1), add activated carbon, filter, and cool the filtrate to -5...

Embodiment 3～12

[0084] The operation steps of embodiment 3~12 are as follows:

[0085] Add water and an organic solvent to (S)-(+)-α-(2-thienylethylamino)-α-(2-chlorophenyl)acetic acid methyl ester hydrochloride (indicated by III in the table), Heat the mixed system to T°C, and then add commercially available 37% formaldehyde aqueous solution to it, wherein, in terms of molar mass, formaldehyde: (S)-(+)-α-(2-thiopheneethylamino)- Hydrochloride of methyl α-(2-chlorophenyl)acetate=n:1. After reacting for t hours, it was detected that the reaction was complete, and the reaction solution was cooled to room temperature, then the pH of the aqueous phase was adjusted to 6.5-8, and the organic phase was separated. The organic phase is detected by HPLC, and compared with the standard sample, the HPLC purity of the free base of (S)-clopidogrel is A 1 %, impurity content is A 2 %, wherein, Table 2 is various parameters in the reaction process.

[0086] The reaction parameter of table 2 embodiment 3~...

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Abstract

The invention discloses a method for preparing sulfate or hydrochloride of (S)-clopidogrel. The method comprises the steps as follows: (1), under the condition of existence of an organic solvent insoluble with water, an aqueous solution of formaldehyde is added to hydrochloride or sulfate of (S)-(+)-alpha-(2-thiophene ethylamino)-alpha-(2-chlorphenyl) methyl acetate for a cyclization reaction, and (S)-clopidogrel is obtained through postprocessing after the reaction is completely performed; and (2), (S)-clopidogrel obtained in the step (1) is dissolved in a solvent, sulfuric acid or hydrochloric acid is added for a salt forming reaction, and sulfate or hydrochloride of (S)-clopidogrel is obtained through postprocessing after the reaction is completely performed. According to the method, the step (1) is performed in a two-phase system, so that impurities are effectively reduced, and the purity and the yield of (S)-clopidogrel are improved; and meanwhile, the purification steps are simplified with the reduction of the impurity content, and industrialization operation is facilitated.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of (S)-clopidogrel sulfate or hydrochloride. Background technique [0002] Clopidogrel is a platelet aggregation inhibitor, which has better anti-platelet aggregation effect than aspirin, and has less side effects on the gastrointestinal tract. There is a chiral center in the clopidogrel molecule, which has two optical Among the isomers, (S)-clopidogrel is much more active than (R)-clopidogrel, and it is generally used in the form of its sulfate salt clinically. [0003] (S)-Clopidogrel bisulfate (Clopidogrel bisulfate) is the sulfate salt of clopidogrel, its structure is shown in formula (I), and its trade name is Plavix, which was approved by the FDA on November 17, 1997 Treatment of post-myocardial infarction, post-stroke and established peripheral arterial disease (PAD). [0004] [0005] Sanofi disclosed the racemate of clopidogrel for the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 陈为人亚罗米尔·托曼鲍继胜廖腾火生
Owner ZHEJIANG MENOVO PHARMA