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Synthesis of cinepazide maleate

A technology of cinepazide maleate and a synthesis method, applied in the field of medicine, can solve problems such as long steps and low yield, and achieve the effects of mild reaction conditions, shortening reaction steps, and reducing equipment requirements

Inactive Publication Date: 2009-08-19
DALIAN UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has longer steps and lower yield

Method used

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  • Synthesis of cinepazide maleate
  • Synthesis of cinepazide maleate
  • Synthesis of cinepazide maleate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 1) Preparation of cinepazide free base

[0038] Reaction formula:

[0039]

[0040] operating:

[0041] 1.20g (0.005mol) of trans 3,4,5-trimethoxycinnamic acid, 1.01g (2mol.eq.) of triethylamine, and 20ml of dichloromethane were stirred and dissolved at -10°C, and 0.65g ( 1.2mol.eq.) 5ml dichloromethane solution of ethyl chloroformate, keep stirring and react for 1 hour (TLC follows the reaction process, methanol is the developing solvent), then slowly drop 0.99g (1.0mol.eq.) 1-[ A solution of (1-tetrahydropyrrolecarbonyl)methyl]piperazine in 10 ml of dichloromethane was incubated and stirred for 3 hours (TLC followed the progress of the reaction, methanol was the developing solvent). After the reaction is complete, the reaction solution is acidified with 10% HCl to PH=1~2, and the organic layer is separated; the acid layer is washed with dichloromethane 10ml*2 times and then basified with 20% sodium hydroxide to PH=12~14, and then Extract 20ml*4 times with dichloromethan...

Embodiment 2

[0053] Reaction formula:

[0054]

[0055] operating:

[0056] 1.20g (0.005mol) of trans 3,4,5-trimethoxycinnamic acid, 1.01g (2mol.eq.) of triethylamine, and 20ml of dichloromethane were stirred and dissolved at 20°C, and 0.65g (1.2 mol.eq.) 5ml dichloromethane solution of ethyl chloroformate, keep stirring and react for 1 hour (TLC follows the reaction process, methanol is the developing solvent), then slowly drop 0.99g(1.0mol.eq.)1-[( A solution of 1-tetrahydropyrrolecarbonyl)methyl]piperazine in 10 ml of dichloromethane was incubated and stirred for 3 hours (TLC followed the progress of the reaction, methanol was the developing solvent). After the reaction is complete, the reaction solution is acidified with 10% HCl to PH=1~2, and the organic layer is separated; the acid layer is washed with dichloromethane 10ml*2 times and then basified with 20% sodium hydroxide to PH=12~14, and then Extract 20ml*4 times with dichloromethane, and then wash with saturated sodium bicarbonate ...

Embodiment 3

[0061] Reaction formula:

[0062]

[0063] operating:

[0064]1.20g (0.005mol) of trans 3,4,5-trimethoxycinnamic acid, 1.01g (2mol.eq.) of triethylamine, 20ml of dichloromethane were stirred and dissolved at -10°C, and 0.57g ( 1.2mol.eq.) 5ml dichloromethane solution of methyl chloroformate, keep warm and stir and react for 1 hour (TLC follows the reaction process, methanol is the developing solvent), then slowly drop 0.99g (1.0mol.eq.) 1-[ A solution of (1-tetrahydropyrrolecarbonyl)methyl]piperazine in 10 ml of dichloromethane was incubated and stirred for 3 hours (TLC followed the reaction process, methanol was the developing solvent). After the reaction is completed, the reaction solution is acidified with 10% HCl to PH=1~2, and the organic layer is separated; the acid layer is washed with dichloromethane 10ml*2 times and then basified with 20% sodium hydroxide to PH=12~14, and then Extract 20ml*4 times with dichloromethane, then wash 30ml*2 times with saturated sodium bicarb...

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Abstract

A synthetic method of cinepazide maleate belongs to the pharmaceutical technical field. The synthetic method is characterized in that trans-3,4,5-trimethoxycinnamic acid is taken as a raw material, and a carboxy activator is employed to synthesize by a 'one pot' method to obtain cinepazide free alkali in the presence of organic base. The used activator is any one of alkyl chloroformate, methylsulfonyl chloride, benzene sulfonyl chloride, p-methylsufonyl chloride, diphenylphosphinyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, N,N-dicyclohexylcarbodiimide(DCC) and carbonyldiimidazole (CDI); ethyl chlorocarbonate is preferred, the reaction temperature is minus 10 DEG C and a solvent is dichloromethane. The cinepazide maleate is obtained after salifying the free alkali. The synthetic method has the effects and benefits of simplifying production conditions and procedure, avoiding application of a reactive intermediate trans-3,4,5-trimethoxycinnamoyl chloride, reducing environmental hazards and reducing equipment requirements; and providing a new synthetic route which is simple and easily controlled, has mild reaction conditions, is environment-friendly and applicable to large-scale industrial production.

Description

Technical field [0001] The present invention relates to trans-1-[(pyrrolidinecarbonyl)methyl]-4-(3,4,5-trimethoxycinnamoyl)piperazine maleate (cinepazide maleate) A synthetic method of belongs to the field of medical technology. Background technique [0002] The chemical name of cinepazide maleate is: trans-1-[(pyrrolidinecarbonyl)methyl]-4-(3,4,5-trimethoxycinnamoyl)piperazine maleate ( Molecular formula: C 26 H 35 N 3 O 2 ), English name: CinepazideMaleate, chemical structure (I) is as follows: [0003] [0004] Cinepazide maleate is a calcium channel blocker that prevents Ca 2+ Transmembrane enters the vascular smooth muscle cells, relaxes the vascular smooth muscle, dilates the cerebrovascular, coronary and peripheral blood vessels, thereby alleviating vasospasm, reducing vascular resistance, and increasing blood flow. It can enhance the effects of adenosine and cyclic adenosine monophosphate (cAMP) and reduce oxygen consumption. This product can inhibit cAMP phosphodiester...

Claims

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Application Information

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IPC IPC(8): C07D295/185A61P9/00A61P9/10A61P7/02
Inventor 孟庆伟刘华祥都健张成海陈祥麟于翔董述祥郝雅男
Owner DALIAN UNIV OF TECH
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