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Method for preparing clopidogrel

A clopidogrel and ortho-chlorine technology, applied in the chemical field, can solve the problem of high cost and achieve the effects of low production cost, good environmental protection and mild reaction conditions

Inactive Publication Date: 2010-09-29
SHANGYU JINGXIN PHARMA
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

This route has mild reaction conditions and good environmental protection, but the optical purity of the final product clopidogrel is only 90%, which needs to be purified again, and the cost is also high

Method used

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  • Method for preparing clopidogrel
  • Method for preparing clopidogrel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] a) Synthesis of R, S-methyl o-chloromandelic acid (Ⅲ)

[0026] Put 20.5g of R,S-o-chloromandelic acid (0.11mol), 130ml of methanol and 4g of concentrated sulfuric acid into the reaction flask, raise the temperature to 60-65°C, and keep the reaction temperature for 3h. After the reaction is completed, the methanol is recovered to dryness, 100 ml of dichloromethane and 40 ml of potassium carbonate aqueous solution (15%) are added to the oily residue, washed with water, allowed to stand, and the organic layer is separated for use in the next reaction.

[0027] b) Synthesis of the compound 2-benzenesulfonate-2 (2-chlorophenyl) methyl acetate (Ⅳ)

[0028] Add 30g tri-n-propylamine (0.21mol) to the dichloromethane solution of R,S-methyl o-chloromandelic acid prepared in step a), stir, cool to 0~5℃ with chilled brine, slowly add 25g benzene dropwise Sulfonyl chloride (0.14mol), incubate the reaction for about 3h until the reaction is complete. After that, add 10ml of 30% hydrochlor...

Embodiment 2

[0034] a) Synthesis of R, S-methyl o-chloromandelic acid (Ⅲ)

[0035] This step is the same as in Example 1

[0036] b) Synthesis of the compound 2-tosylate-2(2-chlorophenyl) methyl acetate (Ⅳ)

[0037] Add 25 g of triethylamine (0.25 mol) to the R, S-methyl o-chloromandelic acid obtained from the above reaction, stir, pass chilled salt water to cool to 0~5℃, and start to add p-35 g toluenesulfonyl chloride solution (0.18 mol), the reaction is incubated for 3h, and the end of the reaction is controlled by TLC. After that, add the hydrochloric acid aqueous solution, stir and wash, stand still, separate into layers, and wash the oil layer to pH 6-7. After completion, the dichloromethane was recovered to obtain 36 g of oil (0.10 mol), the cumulative molar yield of the two-step reaction was 92%, and the liquid content of the product was 97.9%.

[0038] c) Synthesis of R, S-clopidogrel (Ⅴ)

[0039] Add 100ml of butyl acetate, 94g of potassium carbonate aqueous solution (30%), and 30g of t...

Embodiment 3

[0043] a) Synthesis of R, S-methyl o-chloromandelic acid (Ⅲ)

[0044] This step is the same as in Example 1

[0045] b) Synthesis of the compound 2-tosylate-2(2-chlorophenyl) methyl acetate (Ⅳ)

[0046] This step is the same as in Example 2

[0047] c) Synthesis of R, S-clopidogrel (Ⅴ)

[0048] Add 100 ml of chloroform, 94 g of potassium carbonate aqueous solution (30%), and 30 g of thiophenepyridine hydrochloride (0.17 mol) to the formula IV obtained from the above reaction, stir at 20-30°C for 1 hour, and then heat up to 50°C for 6 hours. After finishing, let stand, separate into layers, wash the oil layer with water, separate the oil layer, distill and recover the chloroform to dryness, obtain 29.3g R, S-clopidogrel (0.091mol), the molar yield is 90.1%

[0049] d) Synthesis of S-clopidogrel (Ⅰ)

[0050] To 29.3g of R,S-clopidogrel free base (0.091mol) prepared in step c) was added 100ml of acetone and 50ml of methyl tert-butyl ether and 23g of L-camphorsulfonic acid (0.099mol). The t...

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Abstract

The invention relates to a method for preparing clopidogrel. The conventional synthetic methods have the disadvantages of poor environmental protection, disadvantageous industrial production, low optical purity of final products and high cost. The technical scheme adopted by the invention comprises the following steps of: performing a reaction on a compound, namely, R,S-o-chloromandelic acid and methanol to produce R,S-chloromandelic acid methyl ester; performing the reaction on the R,S-chloromandelic acid methyl ester and benzene sulfonyl chloride under the action of an alkaline catalyst to produce 2-benzenesulfonic acyloxy-2(2-chlorphenyl) methyl acetate; performing an SN2 substitution reaction on the 2-benzenesulfonic acyloxy-2(2-chlorphenyl) methyl acetate and 4,5,6,7-tetrahydro-thiophene pyridine hydrochloride under an alkaline condition to produce R,S-clopidogrel free alkali; resolving the R,S-clopidogrel free alkali in resolving solvent by using a resolving agent; and dissociating the resolved R,S-clopidogrel free alkali to prepare the clopidogrel. In a synthetic route of the invention, reaction conditions are temperate, used reaction substrates are environmentally friendly, reaction yield in each step is high, the optical purity of a final product is up to over 99.5 percent, and pollution-free production can be realized.

Description

Technical field [0001] The invention relates to the field of chemistry, in particular to a preparation method of clopidogrel. Background technique [0002] Clopidogrel (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-2chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate, a platelet inhibitor, produced by France Sano The Philippine (Sanofi) company successfully researched and developed in 1986, its sulfate is clinically used, and its trade name is Plavix. The structural formula of clopidogrel is as follows: [0003] [0004] There are many synthetic methods for clopidogrel. US Patent US5036156 reports that methyl α-bromo(2-chloro)phenylacetate is substituted with 4,5,6,7-tetrahydrothieno[3,2-c]pyridine for SN2 The reaction generates (±)-clopidogrel, which is then resolved with (-)-camphorsulfonic acid in acetone to obtain (+)-clopidogrel. This route has a relatively...

Claims

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Application Information

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IPC IPC(8): C07D495/04
Inventor 梁水东丁卫东张永塘
Owner SHANGYU JINGXIN PHARMA
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