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Preparation method of high-purity sarpogrelate hydrochloride

A technology of sagrelate hydrochloride and crystallization temperature, which is applied in the field of preparation of 5-HT2 receptor blocker sarcogrelate hydrochloride, can solve the problems of not mentioning the control of single impurity content and the inability to obtain high purity

Active Publication Date: 2014-12-17
深圳万乐药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And the alkane of C2-C10, the ketone of C3-C10, the carboxylate of C2-C10, the halogenated alkane of C1-C10, aromatic hydrocarbon or aromatic hydrocarbon derivative are very little to the solubility of sarcogrelate hydrochloride at room temperature to reflux temperature and should not be alone As the recrystallization solvent of sargrelor hydrochloride, high-purity products cannot be obtained even if water is used as the recrystallization solvent or the organic solvent contains more than 5% water
Existing literature does not mention the issue of individual impurity content control

Method used

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  • Preparation method of high-purity sarpogrelate hydrochloride
  • Preparation method of high-purity sarpogrelate hydrochloride
  • Preparation method of high-purity sarpogrelate hydrochloride

Examples

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Embodiment 1

[0019] Example 1 Preparation of Crude Sagrelate Hydrochloride

[0020] 1-Dimethylamino-3-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]-2-propanol hydrochloride 13.7g into a 250ml single-neck bottle, and then add water 25ml, stir to dissolve. Adjust the pH value to 9-14 with 20% sodium hydroxide aqueous solution, extract with 30 ml of toluene, and concentrate the organic layer under reduced pressure at 50° C. until there is no leakage of 0 liquid to obtain a brown oil. Then add 30g of tetrahydrofuran, stir to dissolve, add 4.5g of succinic anhydride, stir and heat to reflux, reflux for 1 to 4 hours, then concentrate the reaction solution at 40°C under reduced pressure to dryness; add 25g of ethyl acetate to the residue and stir After dissolving, add dropwise saturated hydrogen chloride ethyl acetate solution to adjust the PH value to below 1, and stir for 50-60 min. Centrifugal suction filtration, a crude wet product of sargresil hydrochloride was obtained. Dry at 45~55℃ under reduced ...

Embodiment 2

[0021] Example 2 Purification of Crude Sagrexate Hydrochloride

[0022] Take 5g of crude sargrelate hydrochloride, add 20ml of methyl ethyl ketone, stir and warm to dissolve, reflux for 20-30 minutes, cool to 25-35°C, keep stirring for 40-60 minutes, filter, and rinse the filter cake with a small amount of methyl ethyl ketone to obtain a white loose The solid was dried under reduced pressure at 55-65°C for 24 hours to obtain 4.6 g of sargrelate hydrochloride, with a yield of 92%, HPLC purity of 99.9%, and a maximum single impurity content of 0.04%.

Embodiment 3

[0023] Example 3 Purification of Crude Sagrelate Hydrochloride

[0024] Take 5g of crude sargrelate hydrochloride, add 30ml of methyl ethyl ketone, stir and warm to dissolve, reflux for 20-30 minutes, cool to 25-35°C, keep stirring for 40-60 minutes, filter, and rinse the filter cake with a small amount of methyl ethyl ketone to obtain a white loose The solid was dried under reduced pressure at 55-65°C for 24 hours to obtain sargrelate hydrochloride 4.55, yield 91%, HPLC purity 99.7%, and maximum single impurity content 0.05%.

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Abstract

The invention provides a preparation method of high-purity sarpogrelate hydrochloride. The method comprises the following steps of: carrying out alkali dissociation on 1-dimethylamino-3-[2-[2-(3-methoxyphenyl)ethyl]phenoxy-2-propanol hydrochloride which is taken as a raw material, reacting the dissociated 1-dimethylamino-3-[2-[2-(3-methoxyphenyl)ethyl]phenoxy-2-propanol hydrochloride with succinic anhydride to obtain an ester, acidifying the ester to obtain a sarpogrelate hydrochloride crude product, and purifying the sarpogrelate hydrochloride crude product by using butanone as a recrystallization solvent to obtain the sarpogrelate hydrochloride, wherein the purity of the obtained sarpogrelate hydrochloride is higher than 9.9%, the any individual impurity of the obtained sarpogrelate hydrochloride is less than 0.1%, and the yield of the obtained sarpogrelate hydrochloride is higher than 90%. The preparation method adopts the single solvent for recrystallization, which facilitates solvent recovery, so that the preparation method is suitable for industrial production.

Description

Technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of 5-HT2 receptor blocker sargresil hydrochloride. Background technique [0002] Sagrelate hydrochloride tablets were first marketed in Japan in 1993, and their trade name is Anplag. It is a 5-HT2 receptor blocker that can inhibit platelet aggregation, inhibit vasoconstriction, have antithrombotic effects and improve microcirculation. Its indications are to improve ischemic symptoms such as ulcers, pain and cold sensation caused by chronic arterial occlusive disease. The chemical name of sagrelate hydrochloride is 2-(dimethylamino)-1-{[2-(3-methoxyphenyl)phenoxy]methyl}ethylsuccinic acid monoester hydrochloride, which The structural formula is: [0003] [0004] The synthetic route disclosed in the Journal of Medicinal Chemistry (J. Med. Chem, 1990, 33: 1818-1823) is: [0005] [0006] The raw material medicine of sargrelate hydrochloride used to prepare sargresi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C213/10C07C213/06C07C219/06
Inventor 肖阳张广明刘立力袁庆
Owner 深圳万乐药业有限公司
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