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Method for preparing cinepazide maleate

A technology of cinepazide maleate and piperazine, which is applied in the field of preparation of pharmaceutical compounds, can solve the problems of compound III extraction and crystallization difficulties, large quantities, etc., and achieve the effect of good crystal form, simple operation process and high product purity

Inactive Publication Date: 2009-07-29
SHIJIANGZHUANG ZHIHENG PHARMACY TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In the process of preparing 1-[(1-pyrrolidinecarbonyl) methyl] piperazine (III) by the reaction of chloroacetylpyrrolidine and piperazine, an excessive amount of anhydrous piperazine and chloroacetylpyrrolidine are required to react. After the reaction finishes, adopt Steam distillation reclaims excess piperazine; in addition, compound III is difficult to extract and crystallize, requiring a large amount of organic solvent

Method used

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  • Method for preparing cinepazide maleate
  • Method for preparing cinepazide maleate
  • Method for preparing cinepazide maleate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 1.1, the preparation of chloroacetylpyrrolidine

[0038] Add 22.6g (0.2moL) of chloroacetyl chloride into 70mL of dichloromethane, cool to -10°C; add dropwise 14.21g (0.2moL) of tetrahydropyrrole, 22.26g (0.22moL) of triethylamine in 20mL of di Chloromethane solution, the temperature is controlled below -5°C, after the addition is complete, the reaction is continued at room temperature for 1 h. Washed with 30mL water three times, dried over anhydrous sodium sulfate, filtered, concentrated to near dryness, and left at room temperature to obtain 25.51g of the product with a yield of 86.45%.

[0039] 1.2, Preparation of 1-[(1-pyrrolidinecarbonyl)methyl]piperazine dihydrochloride (V)

[0040] Add 31.8g (0.2mol) of piperazine dihydrochloride and 38.8g (0.2mol) of piperazine hexahydrate into 100mL of absolute ethanol, heat to reflux until fully dissolved. Under stirring, a 70 mL ethanol solution of 29.51 g (0.2 mol) of chloroacetylpyrrolidine was added dropwise, and the dro...

Embodiment 2

[0052] 2.1 Preparation of 3,4,5-trimethoxycinnamic phosphoric anhydride

[0053] Suspend 7.14g (0.03mol) of 3,4,5-trimethoxycinnamic acid in 70mL of dichloromethane solution, stir for 10min, and add 9.12mL (0.066mol) of triethylamine. Cool down to 10°C and add dropwise 4.78mL (0.033mol) of diethyl chlorophosphate in 30mL of dichloromethane solution within 0.5h under stirring, and continue to stir for 1h after the dropwise reaction. spare. or drip

[0054] 2.2. Preparation of 1-[(1-pyrrolidinecarbonyl)methyl]piperazine in dichloromethane

[0055] Suspend 8.1g (0.03moL) of 1-[(1-pyrrolidinecarbonyl)methyl]piperazine dihydrochloride in 20mL of dichloromethane, add 10.1g (0.1mol) of triethylamine, stir at room temperature for 1h, and filter A solid was obtained; the solid was washed with 10 mL of dichloromethane, and combined with the filtrate to obtain a dichloromethane solution of 1-[(1-pyrrolidinecarbonyl)methyl]piperazine.

[0056] 2.3, the preparation of cinepazide maleat...

Embodiment 3

[0060] 3.1 Preparation of 3,4,5-trimethoxycinnamic sulfonic anhydride

[0061] Suspend 11.91g (0.05mol) of 3,4,5-trimethoxycinnamic acid in 10mL of ethyl acetate, and dropwise add 7.6g of triethylamine under stirring to obtain a transparent solution; cool down to -10°C, and dropwise add 10.6g (0.06mol) 20 mL of ethyl acetate solution of benzenesulfonyl chloride, stirred at 0°C for 2 hours, and stirred at room temperature for 1 hour; filtered to obtain crude 3,4,5-trimethoxycinnamic acid benzenesulfonic anhydride.

[0062] 3.2, the preparation of cinepazide maleate

[0063] Suspend 13.5g (0.05mol) of 1-[(1-pyrrolidinecarbonyl)methyl]piperazine dihydrochloride (V) in 200mL of dichloromethane, and add 20.2g (0.2mol) of triethylamine dropwise at room temperature , Continue stirring for 0.5h after addition. Within 1 h, the crude 3,4,5-trimethoxycinnamic acid benzenesulfonic anhydride prepared in Step 3.1 was added in 3 times, and stirred at room temperature for 3 h. The reaction...

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Abstract

The invention relates to a preparation method of cinepazide maleate, comprising the following steps: 3, 4, 5-trimethoxycinnamylic acid reacts with chlorinating agent, chloro diethyl phosphate and benzenesulfonyl chloride for preparing corresponding acyl active matters of the 3, 4, 5-trimethoxycinnamylic acid. The acyl active matters react with 1-[(1-pyrrolidine carbonyl) methyl] piperazine double hydrochloride for preparing 1-[(1-pyrrolidine carbonyl) methyl]-4-(3, 4, 5-trimethoxycinnamylic acid acyl) piperazine which is separated and forms salt with maleic acid for preparing cinepazide maleate or can be directly used in ethanol or acetone solution for forming salt with maleic acid. And after the crystallization, the cinepazide maleate with high melting point and stable crystal form is prepared. Chloroacetyl pyrrole perimidine reacts with mixture of piperazine and double hydrochloride of the piperazine with the ratio of 1 to 1 in lower alcohol, and then the chlorine hydride is pumped in to obtain the 1-[(1-pyrrolidine carbonyl) methyl] piperazine double hydrochloride. The process has the advantages of simple operation and high yield.

Description

technical field [0001] The present invention relates to the preparation of a pharmaceutical compound, in particular to a drug for treating cardiovascular and cerebrovascular diseases, cinepazide maleate: 1-[(1-pyrrolidinecarbonyl)methyl]-4-(3,4, The invention discloses a preparation method of 5-trimethoxycinnamoyl)piperazine maleate, which belongs to the technical field of medicine. Background technique [0002] The molecular formula of 1-[(1-pyrrolidinecarbonyl)methyl]-4-(3,4,5-trimethoxycinnamoyl)piperazine maleate (cinepazide maleate) is C26H35N302 , structural formula (I) sees following structural formula, common name is cinepazide maleate, and English name is Cinepazide Maleate. [0003] [0004] Structural formula of cinepazide maleate [0005] Cinepazide maleate has the dual effects of increasing the efficiency of adenosine and cAMP and blocking calcium ion channels. It is mainly used for the treatment of the following diseases in clinical practice: 1. Cerebrovas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/185C07F9/14C07C309/78C07C303/22A61P9/00
Inventor 付德才李志伟路翠罗刘畅康钰王颖
Owner SHIJIANGZHUANG ZHIHENG PHARMACY TECH CO LTD
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