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A preparation method of clopidogrel hydrogen sulfate type II

A technology of clopidogrel bisulfate and clopidogrel free base, applied in the direction of organic chemistry, can solve the problems of large solvent usage, high cost, cumbersome operation, etc., save time for solvent concentration, improve recycling, The effect of reducing the generation of waste liquid

Active Publication Date: 2019-06-11
WUHAN WUYAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the process is relatively simple and the yield is high, the obtained clopidogrel has low purity and poor stability
[0008] Method using o-chlorophenylglycine methyl tartrate as raw material: Patent CN201410700458.8 reports the method of preparing S-clopidogrel bisulfate by using o-chlorophenylglycine methyl tartrate. The amount is large, the process is complicated, the cost is high, and the yield is low
[0009] Method using S-o-chlorophenylglycine methyl ester as raw material: Patent CN201410478320.8 reports a method for preparing S-clopidogrel hydrogen sulfate with S-o-chlorophenylglycine methyl ester and 2-thiopheneacetaldehyde. To a large number of dangerous chemicals, the operation is relatively cumbersome, the product has many impurities, and it is difficult to apply on a large scale

Method used

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  • A preparation method of clopidogrel hydrogen sulfate type II
  • A preparation method of clopidogrel hydrogen sulfate type II
  • A preparation method of clopidogrel hydrogen sulfate type II

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0115] From o-chloromandelic acid to type II clopidogrel bisulfate, the specific preparation method is as follows:

[0116] The first step: the preparation of R-o-chloromandelic acid methyl ester

[0117] Add 200.0g of o-chloromandelic acid, 397.5g of dichloromethane, and 51.6g of methanol into a 1L three-necked flask, stir and dissolve at 15-25°C, slowly pour 20.0g of concentrated sulfuric acid, heat up to 42°C, keep warm in a water bath for 3 hours, and cool to room temperature, washed with purified water, separated the organic phase, and washed with 5% NaHCO 3 Adjust the organic layer to neutral, wash the organic phase with water, and dry over anhydrous sodium sulfate. Suction filtration to obtain R-o-chloromandelic acid methyl ester solution, the yield was determined by external standard method: 96.3%, and the purity: 99.57%. 1 H-NMR (400MHz, CD 3 OD), δ: 3.314 (3H, d), 5.605 (1H, s), 7.274-7.340 (2H, dd), 7.370-7.422 (1H, m), 7.480-7.523 (1H, m).

[0118] The second s...

Embodiment 2

[0132] Investigate the impact of solvent feed ratio and reaction temperature on product purity and yield in the preparation process of R-o-chloromandelic acid methyl ester, see Table 1, Table 2. Others are the same as embodiment 1.

[0133] The influence of table 1 solvent charging ratio on product yield and purity

[0134]

[0135] As seen from Table 1, in above-mentioned six groups of experiments, under the situation that temperature of reaction, reaction time, concentration temperature, concentration time are constant, the mol ratio of R-o-chloromandelic acid, methyl alcohol, organic solvent, the vitriol oil is 1: When 1.5:4.3:0.2, the product yield purity that obtains is the highest.

[0136] The impact of table 2 reaction temperature on product yield and purity

[0137]

[0138] It can be seen from Table 2 that in the above six groups of experiments, when the feed ratio, reaction time, concentration temperature and concentration time are constant, the product yiel...

Embodiment 3

[0140] Investigate the impact of catalyst consumption, temperature of reaction and reaction time in the process of 2-benzenesulfonic acid group-2 (2-chlorophenyl) methyl acetate preparation, product purity and yield, see table 3, table 4, table 5

[0141] The influence of table 3 catalyst (DMAP) charging ratio on product yield and purity

[0142]

[0143]

[0144] As seen from Table 3, in above-mentioned seven groups of experiments, under the situation that temperature of reaction, dropwise addition time, reaction time, concentration time are constant, methyl mandelate: organic base: catalyst: the mol ratio of benzenesulfonyl chloride is 1: When 1:0.075:1.0, the product yield and purity obtained are the highest.

[0145] The impact of table 4 benzenesulfonyl chloride charging ratio on product yield and purity

[0146]

[0147] As can be seen from Table 4, in the above-mentioned 4 groups of experiments, under the situation that temperature of reaction, dripping time, ...

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Abstract

The invention discloses a preparation method of clopidogrel hydrogen sulfate type II. According to the method, clopidogrel hydrogen sulfate type II is prepared by taking clopidogrel free alkali as a raw material, and a preparation method of clopidogrel free alkali comprises the following steps: (1) preparing a reaction mixed solution of R-chloromandelic acid methyl ester by the reaction of R-chloromandelic acid and methanol in an organic solvent and in the presence of a catalyst; (2) mixing the reaction mixed solution of R-chloromandelic acid methyl ester with an organic base and a catalyst, reacting in the presence of benzenesulfonyl chloride to obtain a reaction mixed solution of methyl 2-benzenesulfonyl-2-chlorophenylacetate; (3) mixing the reaction mixed solution of methyl 2-benzenesulfonyl-2-chlorophenylacetate obtained in the step (2) with 4,5,6,7-Tetrahydrothieno[3,2,c] pyridine hydrochloride and potassium carbonate for reaction to obtain the clopidogrel free alkali. According to the method, the solvent does not need to be supplemented in the last two steps, the solvent is directly used, and the reaction liquid concentration time is saved.

Description

technical field [0001] The application relates to a preparation method of type II clopidogrel bisulfate, which belongs to the field of pharmaceutical technology. Background technique [0002] Clopidogrel bisulfate (Clopidogrel bisulfate), chemical name (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridyl-5( 4H) - Methyl acetate hydrogen sulfate. [0003] The structural formula of S-clopidogrel bisulfate is as follows: [0004] [0005] Clopidogrel is a second-generation adenosine diphosphate receptor antagonist. It is an inactive prodrug that enters the body and is oxidized by liver cytochrome P450 mixed function oxidase (CYP450 enzyme) to become an active metabolite. The active product has an activated sulfhydryl group that can form a disulfide bond with the cysteine ​​residue of P2Y12 (the receptor for adenosine diphosphate), irreversibly blocking the binding of adenosine diphosphate to its receptor, thereby blocking ADP Activates the whole process of platelet ...

Claims

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Application Information

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IPC IPC(8): C07D495/04
Inventor 赵涛涛艾娇张伟皮金红张琦谢国范吴鸣
Owner WUHAN WUYAO PHARMA
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