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Improved cinepazide maleate preparation method

A technology of cinepazide maleate and preparation steps is applied in the field of preparation of 1-[methyl]-4-piperazine maleate, and can solve production danger, excessive usage and blockage of condenser tubes and other problems, to achieve the effect of high melting point and stable crystal form

Active Publication Date: 2009-12-23
BEIJING SIHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] In the embodiment 2) of CN 1631877A, 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 in the reaction is greatly excessive, the actual operation is difficult; CN 1631877A narrates CA 51 : 7436i literature synthesis compound (III), the use of vacuum distillation to purify the product, the condensation tube blockage is very easy to occur in the 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, 0=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 to a preparation method of cinepazide maleate. Preparation of chloroacetylpyrrolidine; Preparation of 1-[(1-tetrahydropyrrolecarbonyl)methyl]piperazine; Preparation of 3,4,5-trimethoxycinnamoyl chloride; 1-[(1-Pyrrolidinecarbonyl ) methyl]-4-(3,4,5-trimethoxycinnamoyl)piperazine; 1-[(1-pyrrolidinecarbonyl)methyl]-4-(3,4,5-trimethoxy Preparation of base cinnamoyl) piperazine maleate; purification of cinepazide maleate and preparation of stable crystal form; characterized in that: the solvent used in the preparation step of cinepazide maleate stable crystal form One or any combination of chloroform and acetone. The product prepared by the preparation method of cinepazide maleate has a melting point of 170-175°C. The product prepared by the method for preparing cinepazide maleate provided by the invention has high melting point and stable crystal form, and is suitable for industrial scale production.

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 prevent 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 clinica...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/06A61K31/496A61P9/10
Inventor 王雪松车冯升
Owner BEIJING SIHUAN PHARMA
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