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Research and control method of impurity B control method in clopidogrel

A clopidogrel and pyridine technology, applied in the field of research and control of impurity B in clopidogrel, can solve problems such as rare research

Active Publication Date: 2009-11-25
CHINA RESOURCES SAIKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The literature on clopidogrel is quite rich, mainly focusing on the synthesis route and crystal form, for example, there are patents on the synthesis route of clopidogrel; there are patents on the crystal form of clopidogrel; on the control of clopidogrel impurities , published studies are relatively rare

Method used

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  • Research and control method of impurity B control method in clopidogrel
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  • Research and control method of impurity B control method in clopidogrel

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Embodiment 1, the preparation of 2-thienyl ethyl methyleneamine

[0027] Put 2-thienylethylamine (12.7 g, 0.1 mol) with a 3-thienyl ethylamine content of not more than 0.40% into the reaction flask, and add 36% formaldehyde aqueous solution (10 g, 0.12 mol) dropwise at room temperature under stirring. After dripping, reflux for 3h. Extracted with dichloromethane (150×3), combined extracts, washed with water (50ml), and concentrated to give 2-thienylmethylamine (12.8g, 92%) as light yellow oil.

Embodiment 2

[0028] Example two, preparation of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine

[0029] Put 2-thiopheneethylmethyleneamine (13.9 g, 0.1 mol), 6 mol / L hydrochloric acid (28 ml) into the reaction flask, and stir at room temperature for 6 h. Add sodium hydroxide solution to PH13, extract with dichloromethane (200ml×3), combine the extracts, wash with water (100ml), add anhydrous magnesium sulfate, dry and filter, recover dichloromethane from the filtrate to obtain a light yellow oil crude product (13.9 g, 100%) (literature yield 100%) was directly put into the next step reaction without purification.

Embodiment 3

[0030] Example 3, Preparation of 2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothiophene[3,2-c]pyridine-5)methyl acetate hydrochloride

[0031] Add 110g of acetonitrile, 11.3g of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 20.3g of α-bromo-o-chlorophenylacetic acid methyl ester and 13g of sodium bicarbonate into the reaction flask, and start stirring , and the temperature was raised to 80-85° C. for 5 hours. Cool to 20-25°C, filter, evaporate the filtrate to dryness, add 56g of ethyl acetate, stir, wash with saturated brine 4 times, cool to 5-10°C, add 6.5g of concentrated hydrochloric acid, keep the temperature constant. After the solid was fully separated out, it was suction filtered and dried to obtain methyl 2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothiophene[3,2-c]pyridine-5)acetate salt.

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Abstract

The invention relates to a research and control method of impurity B control method in clopidogrel, the method comprises the following steps: (1) preparing a batch or multiple batches of 2-thiophene ethylamine; (2) measuring the 3-thiophene ethylamine in (1) by a GC method; (3) selecting 2-thiophene ethylamine with 3-thiophene ethylamine content not more than 0.40% based on the step (2) as initial materials: (4) obtaining the clopidogrel with less impurity B, adopting the 2-thiophene ethylamine in the step (3) by the preparation of 2-thiophene ethyl methylene amine and the preparation of 4, 5, 6, 7-tetrahydrothieno[3, 2-c]pyridine.

Description

Technical field: [0001] The present invention relates to the research and control method of impurity B (CLPI-B) in clopidogrel, it is characterized in that through the research to CLPI-B in clopidogrel product, confirm the property of CLPI-B in clopidogrel; Pidogrel synthetic starting material quality control to prepare high-quality clopidogrel products. Background technique: [0002] Clopidogrel bisulfate is an anti-platelet aggregation agent, developed by Sanofi (Sanofi) company in France, and its trade name is Plavix. This product can inhibit platelet aggregation induced by ADP, and its action intensity and tolerance are higher than those of ticlopidine, which belongs to the same thienopyridine derivative, and has fewer side effects. It is clinically used to prevent atherosclerosis in patients with myocardial infarction, stroke or a history of peripheral arterial disease. Its structure is: [0003] [0004] Chemical name: Methyl S(+)-2-(2-chlorophenyl)-2-(4,5,6,7-te...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04G01N30/02A61P7/02A61P9/10
Inventor 邹江谢苏豪王龙山杨琰王文峰
Owner CHINA RESOURCES SAIKE PHARMA
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