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Preparation method of cinepazide maleate

A technology of piperazine and hydrochloride, which is applied in the field of preparation of pharmaceutical compounds, can solve the problems of large quantities, difficulties in extraction and crystallization of compound III, and achieve the effects of simple operation process, good crystal form, and simplified operation process

Inactive Publication Date: 2011-01-26
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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  • Preparation method of cinepazide maleate
  • Preparation method of cinepazide maleate
  • Preparation method of cinepazide maleate

Examples

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Embodiment 1

[0036] 1.1. Preparation of chloroacetylpyrrolidine

[0037] 22.6g (0.2moL) of chloroacetyl chloride was added to 70mL of dichloromethane, cooled to -10°C; under stirring, 14.21g (0.2moL) of tetrahydropyrrole, 22.26g (0.22moL) of triethylamine in 20mL of dichloromethane were added dropwise. Chloromethane solution, the temperature is controlled below -5°C, and after the addition is completed, the reaction is continued at room temperature for 1 h. It was washed three times with 30 mL of water, dried over anhydrous sodium sulfate, filtered, concentrated to near dryness, and placed at room temperature to obtain 25.51 g of the product with a yield of 86.45%.

[0038] 1.2. Preparation of 1-[(1-pyrrolidinecarbonyl)methyl]piperazine dihydrochloride (V)

[0039] 31.8 g (0.2 mol) of piperazine dihydrochloride and 38.8 g (0.2 mol) of piperazine hexahydrate were added to 100 mL of absolute ethanol, and heated to reflux until completely dissolved. Under stirring, a solution of 29.51 g (0....

Embodiment 2

[0051] 2.1, the preparation of 3,4,5-trimethoxycinnamic acid phosphoric anhydride

[0052] 7.14g (0.03mol) 3,4,5-trimethoxycinnamic acid was suspended in 70mL dichloromethane solution, stirred for 10min, and 9.12mL (0.066mol) triethylamine was added. The temperature was lowered to 10° C., and under stirring, 4.78 mL (0.033 mol) of diethyl chlorophosphate in 30 mL of dichloromethane solution was added dropwise within 0.5 h, and the stirring reaction was continued for 1 h after the drop was completed. spare. or dropwise

[0053] 2.2. Preparation of 1-[(1-pyrrolidinylcarbonyl)methyl]piperazine in dichloromethane solution

[0054] Suspend 8.1g (0.03moL) 1-[(1-pyrrolidinylcarbonyl)methyl]piperazine dihydrochloride in 20mL dichloromethane, add 10.1g (0.1mol) triethylamine, stir at room temperature for 1h, filter A solid came out; the solid was washed with 10 mL of dichloromethane and combined with the filtrate to give a solution of 1-[(1-pyrrolidinylcarbonyl)methyl]piperazine in ...

Embodiment 3

[0059] 3.1, the preparation of 3,4,5-trimethoxycinnamic acid sulfonic anhydride

[0060] 11.91g (0.05mol) of 3,4,5-trimethoxycinnamic acid was suspended in 10mL of ethyl acetate, and 7.6g of triethylamine was added dropwise with stirring to obtain a transparent solution; cooled to -10°C, 10.6g was added dropwise (0.06 mol) benzenesulfonyl chloride in 20 mL of ethyl acetate solution, stirred at 0°C for 2 h and at room temperature for 1 h; filtered to obtain crude 3,4,5-trimethoxycinnamic acid benzenesulfonic anhydride.

[0061] 3.2, the preparation of cinepazide maleate

[0062] 13.5g (0.05mol) 1-[(1-pyrrolidinecarbonyl)methyl]piperazine dihydrochloride (V) was suspended in 200mL dichloromethane, and 20.2g (0.2mol) triethylamine was added dropwise at room temperature , and continue to stir for 0.5h after the addition. Within 1 h, the crude 3,4,5-trimethoxycinnamic acid benzenesulfonic anhydride obtained in step 3.1 was added in three portions, and the reaction was stirred at ...

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Abstract

The invention relates to a preparation method of cinepazide maleate, comprising the steps of: reacting 3,4,5-trimethoxycinnamic acid with a chlorination agent, diethyl phosphorochloridate and benzene sulfonyl chloride to prepare a corresponding acyl active matter of the 3,4,5-trimethoxycinnamic acid; reacting the acyl active matter of the 3,4,5-trimethoxycinnamic acid with 1-[(1-pyrrolidine carbonyl) methyl] piperazine dihydrochloride to prepare 1-[(1-pyrrolidine carbonyl) methyl]-4-(3,4,5-trimethoxyphenyl) piperazine; and separating the 1-[(1-pyrrolidine carbonyl) methyl]-4-(3,4,5-trimethoxyphenyl) piperazine to salify with maleic acid so as to prepare cinepazide maleate, or directly salifying with the maleic acid in an ethanol or acetone solution and then crystallizing to prepare the cinepazide maleate with high melting point and stable crystal form, wherein the 1-[(1-pyrrolidine carbonyl) methyl] piperazine dihydrochloride can be prepared through reacting chloracetyl pyrrolidine with the dihydrochloride mixture of the piperazine and piperazine in proportion of 1:1 in lower alcohol, and introducing hydrogen chloride. The process has the advantages of simple operation and high yield.

Description

technical field [0001] The present invention relates to the preparation of a medicinal compound, in particular to a medicinal cinepazide maleate for treating cardiovascular and cerebrovascular diseases: 1-[(1-pyrrolidinecarbonyl)methyl]-4-(3,4, The invention relates to a preparation method of 5-trimethoxycinnamoyl) piperazine maleate, belonging to the technical field of medicine. Background technique [0002] The molecular formula of 1-[(1-pyrrolidinylcarbonyl)methyl]-4-(3,4,5-trimethoxycinnamoyl)piperazine maleate (cinmepazide maleate) is C26H35N302 , structural formula (I) sees following structural formula, common name is cinepazide maleate, English name is Cinepazide Maleate. [0003] [0004] Structural formula of cinepazide maleate [0005] Cinepazide maleate has the dual effect of enhancing adenosine and cAMP and blocking calcium ion channels. It is mainly used for the treatment of the following diseases clinically: 1. Cerebrovascular diseases, such as cerebral ar...

Claims

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Application Information

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IPC IPC(8): C07D295/185
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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