A kind of preparation method of clopidogrel hydrogen sulfate crystal form ii

A technology for clopidogrel hydrogen sulfate and clopidogrel free base is applied in the directions of organic chemistry, organic chemistry and the like, and can solve the problems of complex clopidogrel hydrogen sulfate process, harsh reaction conditions and high impurity content

Active Publication Date: 2020-05-26
HUNAN DINUO PHARMA
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Problems solved by technology

[0009] The invention provides a preparation method of clopidogrel hydrogen sulfate crystal form II, which aims to solve the problems of complex process, harsh reaction conditions and high impurity content of clopidogrel hydrogen sulfate, reduce cost input, and prepare clopidogrel hydrogen sulfate at one time A high-purity clopidogrel bisulfate crystal type II, the reaction process is safe and environmentally friendly

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  • A kind of preparation method of clopidogrel hydrogen sulfate crystal form ii
  • A kind of preparation method of clopidogrel hydrogen sulfate crystal form ii
  • A kind of preparation method of clopidogrel hydrogen sulfate crystal form ii

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preparation example Construction

[0040] The present invention provides a kind of preparation method of clopidogrel bisulfate crystal form II, which comprises the following steps:

[0041] S1. Preparation of (+) o-chlorophenylglycine methyl ester

[0042] Add extractant, water, and inorganic base into the reaction vessel, stir to dissolve, then add (+) o-chlorophenylglycine methyl ester tartrate, separate the liquid after the reaction is complete, and extract the water layer with the extractant. The organic layers were combined, dried with a desiccant, centrifuged, and the filtrate was taken to reclaim the extractant under reduced pressure to obtain (+) o-chlorophenylglycine methyl ester. The reaction process is as follows:

[0043]

[0044] In certain embodiments of the present invention, the inorganic base is selected from dipotassium hydrogen phosphate, sodium sulfate, sodium carbonate, potassium carbonate, or disodium hydrogen phosphate. The inorganic base is used as an acid-binding agent in the prepar...

Embodiment 1

[0076] Add 300ml of dichloromethane, 160ml of water, and 80g of sodium carbonate into the three-necked flask, stir to dissolve, then add 140g of (+) o-chlorophenylglycine methyl ester tartrate, separate the liquids after the reaction is complete, and extract the water layer with 50ml of dichloromethane Three times, the organic layers were combined, dried with anhydrous sodium sulfate, centrifuged, and the filtrate was taken to recover dichloromethane under reduced pressure to obtain (+) o-chlorophenylglycine methyl ester.

[0077] Add 600ml of acetonitrile and 140g of dipotassium hydrogen phosphate to the three-necked flask, mix with (+) o-chlorophenylglycine methyl ester obtained in the previous step, and stir at 20°C for 1 hour. Then add 170 g of 2-(2-thienyl)ethanol p-toluenesulfonate, then raise the temperature to 48° C., and keep the temperature for reaction. Centrifuge after the reaction, collect the mother liquor into the reaction vessel, add appropriate amount of hydro...

Embodiment 2

[0098] Add 300ml of dichloromethane, 160ml of water, and 80g of sodium carbonate into the three-necked flask, stir to dissolve, then add 140g of (+) o-chlorophenylglycine methyl ester tartrate, separate the liquids after the reaction is complete, and extract the water layer with 50ml of dichloromethane Three times, the organic layers were combined, dried with anhydrous sodium sulfate, centrifuged, and the filtrate was taken to recover dichloromethane under reduced pressure to obtain (+) o-chlorophenylglycine methyl ester.

[0099] Add 600ml of acetonitrile and 140g of dipotassium hydrogen phosphate to the three-necked flask, mix with (+) o-chlorophenylglycine methyl ester obtained in the previous step, and stir at 30°C for 1 hour. Then add 170 g of 2-(2-thienyl)ethanol p-toluenesulfonate, then raise the temperature to 52° C., and keep the temperature for reaction. Centrifuge after the reaction, collect the mother liquor into the reaction vessel, add appropriate amount of hydro...

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Abstract

The invention discloses a preparation method of a clopidogrel hydrogen sulfate crystal form II. The method includes: preparation of (+)o-chlorophenylglycine methyl ester; preparation of (+)alpha-(2-thiophene ethylamino)-alpha-(2-chlorphenyl)methyl acetate hydrochloride; preparation of (+)clopidogrel free alkali; preparation of (+)clopidogrel camphorsulfonic acid double salt; hydrolysis of (+)clopidogrel camphorsulfonic acid double salt; and preparation of clopidogrel hydrogen sulfate. The preparation method of the clopidogrel hydrogen sulfate crystal form II provided by the invention optimizesthe synthesis process of clopidogrel hydrogen sulfate, selects cheap and easily available materials, adopts mild reaction conditions, and can achieve safe and environment-friendly production of a high-purity product.

Description

technical field [0001] The invention relates to a preparation method of clopidogrel hydrogen sulfate crystal form II, which belongs to the technical field of medicinal chemical crystallization. Background technique [0002] Clopidogrel bisulfate is an anti-platelet aggregation drug developed by the French company Sanlfi-Aventis in 1986. It irreversibly inhibits platelet aggregation by selectively binding to the ADP receptor coupled to adenylate cyclase on the surface of platelets. , to reduce the formation of blood clots in blood vessels. The drug has remarkable clinical curative effect, few side effects, and high tolerance. It has gradually replaced aspirinidine and has become the first-line drug for the treatment of thrombotic diseases. The product was first launched in the United States and the United Kingdom in 1998, and entered China in 2001. At present, the main domestic manufacturers of clopidogrel bisulfate preparations include Sanofi (Hangzhou) Pharmaceutical Co.,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04
CPCC07B2200/13C07D495/04
Inventor 刘倩
Owner HUNAN DINUO PHARMA
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