Method for preparing cinepazide maleate

A technology of cinepazide maleate and piperazine, which is applied in the field of preparation of cinepazide maleate, can solve the problems of many by-products of disubstituted piperazine, strong toxicity of solvent anhydrous benzene, and difficult purification of products, etc. , to achieve the effects of less pollution of three wastes, high product purity and low cost

Inactive Publication Date: 2008-09-10
罗军 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] That is, the reaction of trans 3,4,5-trimethoxycinnamoyl chloride with 1-piperazine acetylpyrrolidine, and NaHCO 3 The acid-binding agent is reacted in anhydrous benzene to prepare cinepazide, which is then salted with maleic acid; the solvent anhydrous benzene used in this method is highly toxic and has been restricted in the pharmaceutical industry.
[0011] In the synthetic method reported in Chinese patent CN1631877A, the aqueous solution of inorganic alkali is used as the acid-binding agent, and the product yield is relatively low;
[0016] CN16

Method used

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  • Method for preparing cinepazide maleate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] The synthesis of chloroacetylpyrrolidine (II), reaction formula:

[0059]

[0060] Chloroacetyl chloride (135g) and dichloromethane (340ml) were added to a 1-liter reaction flask, cooled to -10°C in an ice-salt bath, and triethylamine (127g), pyrrolidine (85g) and dichloromethane (340ml) were added dropwise ) mixed solution, control the temperature below 5°C, and complete the addition in about 2 hours. Stir at 0-5°C for 1 hour. Stir for an additional 1 hour at room temperature. Suction filtration, the filter cake was washed with dichloromethane (510ml), and dried to obtain a brown filtrate. After the filtrate was washed with water (150ml×3), it was concentrated to obtain 158g of a brown oily substance, with a yield of 90%.

Embodiment 2

[0062] Synthesis of step (1) 1-piperazine acetylpyrrolidine (III):

[0063] In a 2000ml reaction flask, add piperazine (206g) and water (340ml), stir to dissolve. Add hydrochloric acid (300ml) with a weight concentration of 30%, after stirring, add dropwise 400 g of an aqueous solution of chloroacetylpyrrolidine with a weight concentration of 40% at room temperature, stir and react for 6 hours, then add NaOH to adjust the pH of the system to 11. (450ml×3) extraction, combined extracts, concentrated under reduced pressure at 60°C 0.09MPa until no distillate came out to obtain a brown oily substance, steam distilled until no piperazine was found in the concentrate, stopped distillation, added 300ml toluene to heat After reflux and water separation until no water came out, the solid was filtered and dried to obtain 187.9 g of a light yellow powder with a melting point of 64° C. and a yield of 90%.

[0064] Step (2): Synthesis of 3,4,5-trimethoxycinnamoyl chloride (IV):

[0065]...

Embodiment 3

[0074] Using the same method as in Example 2, wherein, in step (1), the reaction time is 6 hours, the alkaline substance adopts KOH, and the pH is adjusted to 13, the product obtained in step (1) is 190g, and the melting point is 64°C. Yield 91%.

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Abstract

The invention provides a method for preparing cinepazide maleate, comprising the following steps of: allowing chloride acid pyrrole , piperazine and Hydrochloric acid to react in a water solvent, adding alkaline substances to adjust PH value, and then collecting 1-piperazine acetyl pyrrole, allowing product to react with 3, 4 and 5 - trimethoxy chloride cinnamon in Acetic ester solvent, collecting Cinepazide free base in the reaction product and then salifying the free base with maleic acid to obtain cinepazide maleate. The cinepazide maleate obtained is heated to reflow in mixed solvent of alcohols and acetone, and then collecting cinepazide maleate with stable crystal form from the system. The melting point of the cinepazide maleate obtained is at a temperature of between 173 and 174 DEG C. The cinepazide maleate prepared in the method has a low cost, the method is simple to operate, is high in the yield, the product quality is stable and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of cinepazide maleate. Background technique [0002] Cinepazide maleate (molecular formula: C 26 h 35 N 3 o 9 ), the English name is Cinepazide Maleate, and the structural formula (I) is as follows: [0003] [0004] Cinepazide maleate is a new generation of piperazine drugs, which can improve brain metabolism, inhibit the release of excitatory transmitters, promote the release of GABA, mediate ion flow channels, stabilize cell membranes, block ischemia-reperfusion injury, and fully recover Blood circulation, activation of 5-HT neurons. Clinically widely used in the treatment of cardiovascular and cerebrovascular diseases. [0005] Due to the large dosage and clinical dosage of cinepazide maleate, it is necessary to establish a process method that is easy to operate, easy to control the reaction and suitable for industrial production. [0006] At present, existing patents disclose the preparation ...

Claims

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Application Information

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IPC IPC(8): C07D295/18A61P9/00A61P25/00
Inventor 李建其黄雷解鹏周峰张绍静毛中兴
Owner 罗军
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