Improved cinepazide maleate preparation method

A technology of cinepazide maleate and piperazine, which is applied in the field of preparation of 1-[methyl]-4-piperazine maleate, and can solve the problems of large volume, low solubility and practical operation difficulties, etc. problem, to achieve the effect of high melting point and stable crystal shape

Active Publication Date: 2006-12-13
BEIJING SIHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In step 5) of CN1631877A, after cinepazide reacts with maleic acid to generate cinepazide maleate, it is recrystallized with absolute ethanol, although the product with a melting point of 171-173°C is obtained, but cinnamon maleate The solubility of pazide in absolute ethanol is small, and the volume is very large when recrystallized, which is not conducive to large-scale production:
[0014] In the embodiment 2) of CN1631877A, after the reaction

Method used

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  • Improved cinepazide maleate preparation method
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  • Improved cinepazide maleate preparation method

Examples

Experimental program
Comparison scheme
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Example Embodiment

[0052] Example 1:

[0053] Step 1. Preparation of chloroacetylpyrrolidine

[0054] Add 700 g of chloroacetyl chloride to 2000 ml of chloroform, cool to -10~-5℃ under stirring, slowly add dropwise a solution of 440 g of tetrahydropyrrole and 690 g of triethylamine dissolved in 2000 ml of chloroform. After the addition, Stir and return to room temperature, continue the reaction for 1 hour, add 300 ml×3 water, wash and extract, dry with anhydrous sodium sulfate, and distill off the solvent to obtain a light green transparent liquid, which is solidified at room temperature, weighs 732 grams, and the yield is 80.2%. 1 HNMR(CDCl 3 ): δ1.85(m, 2H, -CH 2 -), δ1.96(m, 2H, -CH 2 -), δ3.48[m, 4H, (-CH 2 -N) 2 ], δ3.99(s, 2H, O=C-CH 2 -Cl).

[0055] Step 2. Preparation of 1-[(1-tetrahydropyrrolecarbonyl)methyl]piperazine

[0056] Add 1020 g of anhydrous potassium carbonate and 1830 g of anhydrous piperazine to 4500 ml of anhydrous ethanol, stir and reflux, and add dropwise a solution of 630 g...

Example Embodiment

[0066] Example 2:

[0067] Step 1. Preparation of chloroacetylpyrrolidine

[0068] Add 700 g of chloroacetyl chloride to 2000 ml of chloroform, cool to -10~-5℃ under stirring, slowly add dropwise a solution of 440 g of tetrahydropyrrole and 690 g of triethylamine dissolved in 2000 ml of chloroform. After the addition, Stir and return to room temperature, continue the reaction for 1 hour, wash and extract with 300 ml×3 water, dry with anhydrous sodium sulfate, and distill off the solvent to obtain a light green transparent liquid, which is solidified at room temperature, weighs 732 grams, and the yield is 80.2%. 1 HNMR(CDCl 3 ): δ1.85(m, 2H, -CH 2 -), δ1.96(m, 2H, -CH 2 -), δ3.48[m, 4H, (-CH 2 -N) 2 ], δ3.99(s, 2H, O=C-CH 2 -Cl).

[0069] Step 2. Preparation of 1-[(1-tetrahydropyrrolecarbonyl)methyl]piperazine

[0070] Add 1020 g of anhydrous potassium carbonate and 1830 g of anhydrous piperazine to 4500 ml of anhydrous ethanol, stir and reflux, add dropwise a solution of 630 g of ch...

Example Embodiment

[0080] Example 3:

[0081] Step 1. Preparation of chloroacetylpyrrolidine

[0082] Add 700 g of chloroacetyl chloride to 2000 ml of chloroform, cool to -10~-5°C under stirring, and slowly add dropwise a solution of 440 g of tetrahydropyrrole and 690 g of triethylamine dissolved in 2000 ml of chloroform. After the addition, Stir and return to room temperature, continue the reaction for 1 hour, wash and extract with 300 ml×3 water, dry with anhydrous sodium sulfate, and distill off the solvent to obtain a light green transparent liquid, which is solidified at room temperature, weighs 732 grams, and the yield is 80.2%. 1 HNMR(CDCl 3 ): δ1.85(m, 2H, -CH 2 -), δ1.96(m, 2H, -CH 2 -), δ3.48[m, 4H, (-CH 2 -N) 2 ], δ3.99(s, 2H, O=C-CH 2 -Cl).

[0083] Step 2. Preparation of 1-[(1-tetrahydropyrrolecarbonyl)methyl]piperazine

[0084] Add 1020 g of anhydrous potassium carbonate and 1830 g of anhydrous piperazine to 4500 ml of anhydrous ethanol, stir and reflux, add dropwise a solution of 630 ...

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Abstract

The invention relates the preparing method of maleic acid cinprazole. The method comprises the following steps: preparing chloracetyl pyrrolyl; preparing 1- [(1- pyrrolidine carbonyl) methyl] ethyleneamine; preparing 3, 4, 5- trimethoxyl cinnamomum cassia acyl; preparing 1- [(1- pyrrolidine carbonyl) methyl]-4- 3, 4, 5- trimethoxyl cinnamomum cassia acyl) ethyleneamine; preparing 1-[(1- pyrrolidine carbonyl) methyl]-4- 3, 4, 5- trimethoxyl cinnamomum cassia acyl) ethyleneamine maleate; preparing the purification of maleic acid cinprazole. The invention has the character that the solvent is one of chloroform and acetone. The fusing point of the product is 170-175Deg.C. The product has the advantages of high fusing point and stable crystal shape.

Description

technical field [0001] The present invention relates to 1-[(1-tetrahydropyrrolecarbonyl)methyl]-4-(3,4,5-trimethoxycinnamoyl)piperazine maleate (cinepazide maleate) method of preparation. Background technique [0002] 1-[(1-tetrahydropyrrolecarbonyl)methyl]-4-(3,4,5-trimethoxycinnamoyl)piperazine maleate has the following molecular structure [0003] [0004] and formula C 26 h 35 N 3 o 9 , the common name is cinepazide maleate, and the English name is Cinepazide Maleate, which is a calcium channel blocker that can block Ca 2+ Transmembrane into vascular smooth muscle cells to cause smooth muscle relaxation, dilate blood vessels, relieve vasospasm, reduce vascular resistance, increase brain and heart blood flow; enhance the effect of adenosine and cyclic adenosine monophosphate; improve the flexibility and deformation of red blood cells through Capillary capacity, improve microcirculation; reduce blood viscosity, protect ischemic organs. It is mainly used clinicall...

Claims

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Application Information

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IPC IPC(8): C07D401/06A61K31/496A61P9/10
Inventor 王雪松
Owner BEIJING SIHUAN PHARMA
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