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Oxime derivatives containing thienopyridine, preparation method and application thereof

A technology of pyridine and tetrahydrothiophene, which is applied in the field of medicine and can solve problems such as weak alkalinity, difficult purification, and limitations

Inactive Publication Date: 2009-04-08
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since clopidogrel is an oily substance with a very weak alkalinity, it needs to be mixed with a strong acid to form a salt, but it is unstable in the presence of moisture, so that the free base is precipitated, and there are certain difficulties in purification.
And because of its strong acidity, it is subject to certain restrictions in preparation

Method used

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  • Oxime derivatives containing thienopyridine, preparation method and application thereof
  • Oxime derivatives containing thienopyridine, preparation method and application thereof
  • Oxime derivatives containing thienopyridine, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0087] Intermediate III-2

[0088]

[0089]Add 16.4g of 3-carboxy-5-methylbenzaldehyde into a reaction flask equipped with stirring, a condenser, and a thermometer, dissolve it with 45mL of anhydrous methanol, and add 11.2g of potassium hydroxide while stirring. Add 8.4 g of hydroxylammonium oxymethyl hydrochloride in batches to the reaction system. After the addition was complete, the reaction was continued at 35°C for 6.5h (the plate showed that the reaction was complete). Evaporate anhydrous methanol to dryness, wash the reaction liquid with 3×50mL water, extract with chloroform, fully dry over anhydrous sodium sulfate, filter, and evaporate chloroform under reduced pressure to obtain an off-white solid (HPLC: 98.3%). Rf = 0.32 [single site, developing solvent: v (dichloromethane): v (methanol) = 6: 1].

Embodiment 3

[0091] Intermediate III-3

[0092]

[0093] Add 14.8g of 2-methyl-4-ethylbenzaldehyde into a reaction flask equipped with stirring, a condenser and a thermometer, dissolve it with 40mL of anhydrous methanol, and add 9.0g of sodium hydroxide while stirring. Add 9.8 g of oxyethyl hydroxylammonium hydrochloride to the reaction system in batches. After the addition was complete, the reaction was continued at 55°C for 6h (the plate showed that the reaction was complete). Evaporate anhydrous methanol to dryness, wash the reaction solution with 3×50mL water, extract with dichloromethane, fully dry over anhydrous sodium sulfate, filter, and evaporate dichloromethane under reduced pressure to obtain a white solid (HPLC: 99.2%). Rf = 0.40 [single site, developing solvent: v (dichloromethane): v (methanol) = 6: 1].

[0094] Reference Example 4:

[0095] Intermediate III-4

[0096]

[0097] Add 12.4g of 2-fluorobenzaldehyde into a reaction flask equipped with stirring, a conde...

Embodiment 7

[0107] Intermediate III-7

[0108]

[0109] Add 15.9 g of 2-fluoro-3-chlorobenzaldehyde into a reaction flask equipped with stirring, a condenser, and a thermometer, dissolve it with 20 mL of acetone, and add 15.8 g of pyridine while stirring. Add 6.9 g of hydroxylammonium hydrochloride to the reaction system in batches. After the addition was completed, the reaction was continued for 6.5 h under reflux (the plate showed that the reaction was complete). The acetone was evaporated to dryness, the reaction solution was washed with 3×20 mL of water, extracted with chloroform, fully dried over anhydrous sodium sulfate, filtered, and the chloroform was evaporated under reduced pressure to obtain a white solid (HPLC: 99.8%). Rf = 0.32 [single site, developing solvent: v (dichloromethane): v (methanol) = 6: 1].

[0110] Reference Example 8:

[0111] Intermediate III-8

[0112]

[0113] Add 21.9g of 2-chloro-4-bromobenzaldehyde into the reaction flask equipped with stirrin...

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Abstract

The invention pertains to the technical field of medicaments for preventing platelet aggregation and provides an oxime derivative which contains thienopyridine and has a structure as shown in the general formula (I), and pharmaceutically acceptable salt thereof, wherein, m equals to 1 and 2 and n equals to 0 and 1; R <1 >, R <2> and R <3> collectively or individually refer to hydrogen, C1-C6 straight-chain or branched-chain alkyl, C3-C6 naphthenic base, halogen, hydroxyl, carboxyl, amino, amido, cyano, nitryl, C1-C4 alkoxy, substituted phenyl and substituted heterocyclic radical; and R<4> refers to hydrogen, C1-C4 straight-chain or branched-chain alkyl as defined in the Instruction in details. In addition, the invention also relates to a preparation method of the compounds and discloses medicament combinations of which the compound or the pharmaceutically acceptable salt of the compound is taken as active ingredient and the application of such medicament combinations as drugs for preventing platelet aggregation.

Description

technical field [0001] The present invention belongs to the technical field of medicine, and more specifically, relates to a class of compounds with anti-platelet aggregation and their preparation methods, pharmaceutical compositions containing them and their use as anti-platelet drugs. Background technique [0002] In recent years, the incidence of thromboembolic diseases, mainly coronary thrombosis and cerebral thrombosis, has been on the rise, seriously endangering human health. Platelet aggregation is a key link in the normal coagulation mechanism, and the adhesion, aggregation, and release reactions of platelets lead to thrombus formation. Therefore, drugs that inhibit platelet aggregation play an important role in the treatment of thrombosis have always been a research hotspot. [0003] Clinically, aspirin is widely used as an antiplatelet aggregation drug. Although aspirin can be tolerated by most people, sometimes even a small dose may cause gastrointestinal discom...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/4365A61P7/02A61P9/10
Inventor 刘颖刘登科刘默张士俊成碟金丽媛杨妙帅军徐为人刘昌孝
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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