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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 generates compound (III), the product is processed by the operation method of steam distillation, because the use amount of raw material piperazine is greatly excessive in the reaction, the actual operation is difficult; CN1631877A narrates CA51: 7436i document In the synthesis of compound (III), the product is purified by vacuum distillation, which is prone to clogging of the condenser tube during operation, and the danger of mass production:

Method used

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  • Improved cinepazide maleate preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Step 1, the preparation of chloroacetylpyrrolidine

[0054] Add 700 grams of chloroacetyl chloride into 2000 milliliters of chloroform, cool down to -10 to -5 °C under stirring, slowly add dropwise a solution of 440 grams of tetrahydropyrrole and 690 grams of triethylamine dissolved in 2000 milliliters of chloroform, and the addition is complete. Stir to return to room temperature, continue to react for 1 hour, add 300 ml × 3 water, wash and extract, dry over anhydrous sodium sulfate, evaporate the solvent to obtain a light green transparent liquid, solidify at room temperature, weighing 732 g, yield 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, the preparation of 1-[(1-tetrahydropyrrolecarbonyl)methyl]piperazine

[0056] Add 1020 grams of anhydrous potassium carbonate and 1830 grams of anhydrous piperazine into 4500 milliliters of absolute ethanol, stir and reflux...

Embodiment 2

[0067] Step 1, the preparation of chloroacetylpyrrolidine

[0068] Add 700 grams of chloroacetyl chloride into 2000 milliliters of chloroform, cool down to -10 to -5 °C under stirring, slowly add dropwise a solution of 440 grams of tetrahydropyrrole and 690 grams of triethylamine dissolved in 2000 milliliters of chloroform, and the addition is complete. Stir to return to room temperature, continue to react for 1 hour, wash and extract with 300 ml × 3 water, dry over anhydrous sodium sulfate, evaporate the solvent to obtain a light green transparent liquid, solidify at room temperature, weigh 732 g, yield 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, the preparation of 1-[(1-tetrahydropyrrolecarbonyl)methyl]piperazine

[0070] Add 1020 grams of anhydrous potassium carbonate and 1830 grams of anhydrous piperazine into 4500 milliliters of absolute ethanol, stir and reflux, add...

Embodiment 3

[0081] Step 1, the preparation of chloroacetylpyrrolidine

[0082] Add 700 grams of chloroacetyl chloride into 2000 milliliters of chloroform, cool down to -10 to -5 °C under stirring, slowly add dropwise a solution of 440 grams of tetrahydropyrrole and 690 grams of triethylamine dissolved in 2000 milliliters of chloroform, and the addition is complete. Stir to return to room temperature, continue to react for 1 hour, wash and extract with 300 ml × 3 water, dry over anhydrous sodium sulfate, evaporate the solvent to obtain a light green transparent liquid, solidify at room temperature, weigh 732 g, yield 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, the preparation of 1-[(1-tetrahydropyrrolecarbonyl)methyl]piperazine

[0084] Add 1020 grams of anhydrous potassium carbonate and 1830 grams of anhydrous piperazine into 4500 milliliters of absolute ethanol, stir and reflux, a...

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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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