Method for synthesizing cinepazide

A synthesis method and technology of cinepazide are applied in the synthesis field of cinepazide, namely trans-1-[methyl]-4-piperazine, and can solve the problem of increasing reaction steps, harsh deprotection conditions and restricting application. etc., to achieve the effect of few reaction steps, high melting point and high yield

Inactive Publication Date: 2010-06-02
QILU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The formyl protection and deprotection piperazine adopted in this method increase the reaction steps, and the deprotection conditions are relatively harsh, which seriously limits the application of this method

Method used

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  • Method for synthesizing cinepazide
  • Method for synthesizing cinepazide
  • Method for synthesizing cinepazide

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preparation example Construction

[0014] A synthetic method of cinepazide, comprising the steps of:

[0015] a) 3,4,5-trimethoxycinnamic acid reacts with piperazine to obtain 3,4,5-trimethoxycinnamoylpiperazine;

[0016] b) reacting 3,4,5-trimethoxycinnamoylpiperazine with chloroacetylpyrrolidine to obtain cinepazide;

[0017] Optionally, cinepazide maleate is further reacted with maleic acid to form a salt to obtain cinepazide maleate.

[0018] The synthetic route is as follows:

[0019]

[0020] The piperazine is anhydrous piperazine, piperazine containing crystal water or piperazine containing free water, wherein anhydrous piperazine is preferred.

[0021] Wherein, in step a), 3,4,5-trimethoxycinnamic acid can be activated and reacted with piperazine to obtain 3,4,5-trimethoxycinnamoylpiperazine; 3,4,5-trimethoxycinnamic acid can also be The direct dehydration reaction of oxycinnamic acid and piperazine gives 3,4,5-trimethoxycinnamoylpiperazine.

[0022] More specifically, the preparation of step a) ...

Embodiment 1

[0045] Embodiment 1: the synthesis of cinepazide maleate:

[0046] 1) Synthesis of 3,4,5-trimethoxycinnamoylpiperazine

[0047] Dissolve 3,4,5-trimethoxycinnamic acid (50.0g, 0.210mol) in dichloromethane (250mL), add 2,4-dimethoxy-6-chloro-1,3,5-s Oxyzine (36.9 g, 0.210 mol), after complete dissolution, N-methylmorpholine (23.3 mL, 0.210 mol) was added. The stirring reaction was continued for 120 min. Dissolve piperazine (27.1g, 0.315mol) in dichloromethane (250mL), cool down to 0-10°C, add 3,4,5-trimethoxycinnamic acid active ester dropwise to piperazine, dropwise Afterwards, continue stirring reaction 30min. Stop responding. Extract with 2N hydrochloric acid (3×150 mL). The aqueous phase was adjusted to pH=10 with 6N sodium hydroxide solution. Extracted with dichloromethane (3×150 mL), combined organic phases, washed with saturated sodium chloride solution (1×150 mL), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 54.9 g of yellow oil, yield 8...

Embodiment 2

[0053] Embodiment 2: the synthesis of cinepazide

[0054] 1) Synthesis of 3,4,5-trimethoxycinnamoylpiperazine

[0055] Dissolve 3,4,5-trimethoxycinnamic acid (50.0 g, 0.210 mol) in dichloromethane (250 mL), add thionyl chloride (75 g, 0.630 mol) dropwise, heat to reflux for 2 h, and set aside. Dissolve piperazine hexahydrate (122g, 0.630mol) in methanol (150mL), add hydrobromic acid (67mL, 0.630mol), cool down to 0-10°C, add 3,4,5-trimethoxycinnamoyl chloride dropwise Add it to the piperazine solution, drop it, and stir at 50°C for 120 minutes. Stop responding. The reaction solution was extracted with water (2×150 mL), and adjusted to pH=10 with 6N sodium hydroxide solution. Extracted with dichloromethane (3×150 mL), combined organic phases, washed with saturated sodium chloride solution (1×150 mL), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 37.5 g of yellow oil, yield 58%. Leave to cure at room temperature.

[0056] 2) Synthesis of Cinepazid...

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Abstract

The invention relates to a method for synthesizing cinepazide. The method comprises: obtaining 3,4,5-trimethoxy cinnamoyl piperazine through the reaction of 3,4,5-trimethoxy cinnamic acid and piperazine; obtaining cinepazide through the reaction of 3,4,5-trimethoxy cinnamoyl piperazine and chloroacetyl pyrrolidine; and forming salts from cinepazide and maleic acid optionally. The method provided by the invention has the advantages of short route, simple operation, not high requirements for production equipment, environment-friendly reagents used, high reaction yield, high purity of obtained products and suitability for industrial scale production.

Description

technical field [0001] The invention relates to a synthesis method of cinepazide, i.e. trans-1-[(1-pyrrolidinecarbonyl)methyl]-4-(3,4,5-trimethoxycinnamoyl)piperazine, which belongs to the field of medicine and chemical industry . Background technique [0002] Cinepazide maleate, trans-1-[(1-pyrrolidinecarbonyl)methyl]-4-(3,4,5-trimethoxycinnamoyl)piperazine maleate, The structure looks like this: [0003] [0004] Cinepazide maleate is a cardiovascular drug that can prevent calcium ions from entering vascular smooth muscle cells across the membrane, causing smooth muscle relaxation, dilating blood vessels, relieving vasospasm, reducing vascular resistance, and increasing blood flow in the brain and heart. It is widely used clinically to treat various cardiovascular and cerebrovascular diseases. [0005] US Patent No. 3634411 introduces a preparation method of cinepazide and its maleate. The synthetic route is shown in the following formula. In this patent, the solve...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/18A61P9/00
Inventor 李洪伟林栋范传文张照珍朱屹东张明会王晶翼
Owner QILU PHARMA CO LTD
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