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Novel method for preparing clopidogrel and slat thereof

A clopidogrel and new method technology, applied in the field of preparation of clopidogrel, can solve the problems of complex reaction, low total yield and purity, and achieve easy purification, improved yield and purity, and improved conversion rate and optical purity. Effect

Inactive Publication Date: 2010-07-28
无锡好芳德药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The above route has the problems of complex reaction, low total yield and purity

Method used

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  • Novel method for preparing clopidogrel and slat thereof
  • Novel method for preparing clopidogrel and slat thereof
  • Novel method for preparing clopidogrel and slat thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1: the preparation of (S)-(+)-o-chlorophenylglycine (III)

[0031] In a 250mL single-port reaction equipped with magnetic stirring, add 10.0g (0.0539mol) o-chlorophenylglycine and 13.8g (0.0595mol) D-camphorsulfonic acid, then add 100mL water and heat to 65°C to dissolve , kept stirring for 0.5 hours and then lowered to 45°C for filtration. The filtrate was lowered to -10°C for 6 hours, filtered, and the filter cake was washed with isopropanol (15 mL×2). The mother liquor was concentrated to 50 mL, recrystallized at -10°C, filtered, washed and combined to obtain white solids, and dried to obtain 9.8 g of the product with a purity of 99%, e.e=95%. The solid was added into 30 mL of water, heated to dissolve, frozen to crystallize, filtered, washed with 10 mL of water, and dried to obtain 9.0 g of refined product with a purity of 99.5%, e.e=99%. The two mother liquors were combined and concentrated to dryness to obtain impure (R)-(+)-o-chlorophenylglycine camp...

Embodiment 2

[0037] Example 2: Preparation of (S)-(+)-α-(2-thienylethylamino)-(2-chlorophenyl)acetic acid hydrochloride (IV)

[0038] Take 18.6g (0.1mol) of (S)-(+)-o-chlorophenylglycine and add it to a 250mL three-neck reaction flask with magnetic stirring, then add 100mL of anhydrous acetonitrile to dissolve, and then add 21g (0.25mol) of bicarbonate Sodium and 42g (0.15mol) α-thiophenethanol p-toluenesulfonate, start stirring, and raise the temperature to 80°C for 48 hours. After filtration, the filtrate was concentrated to obtain an oil; the filter cake was washed with ethyl acetate (50 mL×3). Dissolve the previously obtained oil in ethyl acetate as washing liquid, and pass hydrogen chloride gas for 20 minutes under rapid stirring, and a large amount of white solids will precipitate out. After stopping the flow of hydrogen chloride gas, cool to 0°C and keep warm for 2 hours to filter, and filter the cake with a small amount of diethyl ether. washing. The mother liquor was concentrate...

Embodiment 3

[0039] Embodiment 3: Preparation of α-thiophene ethanol p-toluenesulfonate (VII)

[0040] Take 12.7g (0.1mol) of α-thiophene ethanol and put it into a 250mL single-port reaction with magnetic stirring, add 25mL of dichloromethane and 21mL (0.15mol) of triethylamine, and cool to 0°C. Another 21g (0.12mol) of p-toluenesulfonic acid was dissolved in 40mL of dichloromethane, and the solution was slowly dropped into the reaction flask. After dripping, rise to 35°C and react for 5 hours. TLC detects that α-thiophene ethanol disappears, then adds 0.9g sodium bicarbonate and 20mL water, and stirs for another hour. After TLC detects that excess p-toluenesulfonyl chloride is hydrolyzed, cool to room temperature, and then 30 mL of water was added, stirred for 10 minutes, and the organic phase was washed once with saturated brine after liquid separation. The organic phase was dried over anhydrous sodium sulfate, concentrated, and cooled to obtain 26.8 g of a tan solid with a content of 9...

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Abstract

The invention discloses a novel method for preparing a clopidogrel compound, which comprises the following steps: taking a compound shown in Formula (II) as a raw material, obtaining a compound shown in Formula (III) through optical resolution, obtaining a compound shown in Formula (IV) through substitution reaction of the compound shown in Formula (III), further obtaining a compound shown in Formula (V) by acetifying the compound shown in Formula (IV) to be salt, obtaining the final product, i.e. the lopidogrel compound shown in Formula (VI), through Mannich cyclization, and then generating salt by mixing the compound shown in Formula (VI) and sulfuric acid for reaction to obtain the target product (I). The method of the invention for preparing the clopidogrel compound has the advantages of readily available raw materials, low price, mild reaction condition, simple operation and high total yield, and is a novel integrated synthesis method applicable for industrial production of clopidogrel.

Description

technical field [0001] The invention relates to the technical field of chemical industry and pharmacy, in particular to a new preparation method of clopidogrel. Background technique [0002] Clopidogrel is an anti-platelet coagulation agent drug developed by Sanofi Pharmaceutical Company of France (Sanofi). It is a platelet aggregation inhibitor that selectively inhibits the interaction between adenosine diphosphate (ADP) and its platelet receptor Binding and secondary ADP-mediated activation of the glycoprotein GPIIb / IIIa complex, while clopidogrel can also inhibit platelet aggregation induced by other agonists by blocking the expansion of platelet activation caused by ADP release. Clopidogrel has two configurations, of which only (S)-clopidogrel shows platelet aggregation inhibitory activity, while (R)-clopidogrel is inactive, and (R)-clopidogrel is well tolerated It is 1 / 40 of (S)-clopidogrel. At present, there are not many commonly used drugs for anti-platelet aggregat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
Inventor 沈立新袁利刘福双周燕
Owner 无锡好芳德药业有限公司
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