Method for preparing clopidogrel and salts thereof

A technology of clopidogrel salt and clopidogrel, which is applied in the field of medicine and chemical industry, can solve the problems of difficulty in purifying the target product, affecting the purity of the target product, and low melting point of the compound, and achieves a product with mild process conditions, good quality, and abundant sources. Effect

Active Publication Date: 2008-12-31
江苏八巨药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

3. Selection of racemization method for invalid enantiomers
[0011] Chinese patent application (02803998.X) uses structural formula d and structural formula e as raw materials to prepare clopidogrel. Although the method has fewer steps and a short process route, the price of raw materials is higher, and the structural formula is d. The point is low, it is difficult to purify the target product, which seriously affects the purity of the target product

Method used

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  • Method for preparing clopidogrel and salts thereof
  • Method for preparing clopidogrel and salts thereof
  • Method for preparing clopidogrel and salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Add 400g of methanol and 193g of o-chlorophenylglycine to the reaction bottle, add 220g of concentrated sulfuric acid dropwise to the material under stirring, drop it in about 0.5-1.0 hours, heat to reflux, and keep warm for 20 hours under reflux. After the reaction, methanol was evaporated. When the internal temperature reached 85°C, after cooling down to room temperature, 400g crushed ice and 800g chloroform were added, and sodium hydroxide was added dropwise under stirring to adjust the pH value to 8.5. The chloroform was extracted twice and incorporated into the chloroform layer, the chloroform layer was washed twice with water, and dried by adding anhydrous magnesium sulfate. The dried chloroform layer was distilled under reduced pressure until no chloroform came out to obtain a red oily product o-chlorophenylglycine methyl ester (II), 165 g, content 97.2%.

[0045] In another reaction bottle, drop into 800g acetonitrile, 165g o-chlorophenylglycine methyl ester pre...

Embodiment 2

[0051] The preparation process of o-chlorophenylglycine methyl ester (II) is the same as that of Example 1, and will not be repeated.

[0052] Add 500g butanone, 165g of the above-prepared o-chlorophenylglycine methyl ester, 140g oxalic acid and 50g salicylaldehyde into the reaction flask, heat up to 80°C, drop in 148g (+) tartaric acid, and keep stirring for 6 hours. Cool down to room temperature and filter. The filter cake was recrystallized with 2.5 times the weight of methanol, cooled to 0°C and filtered to obtain 125 g of (+) o-chlorophenylglycine methyl ester tartrate in the form of white crystals, [α]D / 20=85°. Raise the temperature of the butanone mother liquor to 100°C, keep it warm for 0.5 hours, cool down to 80°C, add 72g (+) tartaric acid, repeat the above resolution steps, and obtain 74g of (+) o-chlorophenylglycine methyl ester tartrate. The mother liquor can continue to repeat Use it, or save it for the next batch to apply.

[0053] Put 64g of thiophenethanol a...

Embodiment 3

[0058] The preparation process of o-chlorophenylglycine methyl ester (II) is the same as that of Example 1, and will not be repeated.

[0059] 400g of acetone, 165g of o-chlorophenylglycine methyl ester prepared above, 80g of formic acid and 60g of salicylaldehyde were added to the reaction flask, the temperature was raised to 75°C, 103g (+) tartaric acid was dropped, and the mixture was incubated and stirred for 10 hours. Cool down to room temperature and filter. The filter cake was recrystallized with 2.5 times the weight of methanol, cooled to 0°C and filtered to obtain 126 g of (+) o-chlorophenylglycine methyl ester tartrate in the form of white crystals, [α]D / 20=85°. Raise the temperature of the acetone mother liquor to 110°C, keep it warm for 0.5 hours, cool down to 75°C, add 50g of (+) tartaric acid, and repeat the above separation steps to obtain 72g of (+) o-chlorophenylglycine methyl ester tartrate. The mother liquor can be reused , and can also be reserved for the ...

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Abstract

The invention provides a preparation method for clopidogrel and the salts of clopidogrel, belonging to the field of medical and chemical technology. The invention solves the problems of more reaction steps, long technical route, high cost and low purity of the existing preparation method for clopidogrel. The preparation method for clopidogrel comprises the following steps: a. synchronous resolution and racemization; b. preparation of (plus) alpha-(2 - thiophene triethylamine yl) -2 - (2 - chlorophenyl) methyl acetate; c. preparation of target product clopidogrel through cyclization reaction. The clopidogrel can generate medicinal salt with acids in a solvent. The preparation method for clopidogrel and the salts of clopidogrel has simple technology, easy operation, lower costs and higher product purity.

Description

technical field [0001] The present invention relates to the preparation method of platelet inhibitory agent and antithrombotic agent, more specifically, relates to clopidogrel [(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3, The invention discloses a preparation method of 2-c]pyridine-5(4H)-acetic acid methyl ester] and a pharmaceutically acceptable salt thereof; it belongs to the technical field of medicine and chemical industry. Background technique [0002] Clopidogrel, chemical name (S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester, English The name is methyl(+)-(S)-α-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate, and the structural formula (I) is shown below. [0003] [0004] It is a platelet aggregation inhibitor, which irreversibly inhibits the aggregation of platelets by selectively binding to the ADP receptor coupled with adenylate cyclase on the surface of platelets, and can reduce the formation of thrombus in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04A61P7/02
Inventor 徐斌徐汉青孙守湘冯庆梅徐强陈恬陈孟哲
Owner 江苏八巨药业有限公司
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