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Improved synthetic method of cinepazide maleate

A technology of cinepazide maleate and a synthesis method, which is applied in the synthesis field of -1{4-]-1-piperazine} acetylpyrrolidine maleate and can meet the requirements of production conditions and equipment High, unfavorable industrial production, easy to block pipelines and other problems, to achieve the effect of low cost, easy operation, simple reaction equipment

Inactive Publication Date: 2014-03-26
凌沛学
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, this method uses vacuum distillation or steam distillation in the product purification process, which has higher requirements on production conditions and equipment. Excessive piperazine is easy to block the pipeline during distillation, which is easy to cause safety accidents and is not conducive to industrial production.

Method used

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preparation example Construction

[0014] An improved preparation method of cinepazide maleate, comprising the following steps: 1: preparation of chloroacetylpyrrolidine; step 2: preparation of 1-piperazine acetylpyrrolidine; step 3: 3, 4, Preparation of 5-trimethoxycinnamoyl chloride; step 4: preparation of cinepazide free base; step 5: preparation of cinepazide maleate. In the preparation process of step 1 and step 4, the feeding method of dripping alkaline raw materials was adopted; in step 2, triethylamine was used as the acid-binding agent, and the post-treatment method of removing piperazine by layered extraction was adopted, also Or use potassium carbonate as an acid-binding agent and use acetone crystallization to remove piperazine.

[0015]

[0016] In the preparation method of step 2, different acid-binding agents adopt different methods to remove excess piperazine.

[0017] As an optimized solution, when organic bases such as organic amines or pyridines are used as acid-binding agents for the rea...

Embodiment 1

[0037] Embodiment 1: the synthesis of cinepazide maleate

[0038] Step 1: Preparation of Chloroacetylpyrrolidine

[0039] Put chloroacetyl chloride (3.7kg, 33mol) and dichloromethane (21.5kg) into a 50L reaction kettle in turn, stir and cool down to -10~0°C, slowly add tetrahydropyrrole (2.15kg, 30mol), triethyl Amine (3.12kg, 33mol) in dichloromethane (2.5kg) solution, the temperature is controlled not to exceed 0°C during the dropwise addition, after the drop is completed, react at 0°C for 0.5h, raise the temperature to reflux and continue stirring for 2h, cool down to room temperature, and react The solution was washed with water and saturated NaCl successively, dried over anhydrous sodium sulfate, the filtrate was concentrated, dichloromethane was recovered, and the residue solidified at room temperature to give 2 (3.7kg, yield 83.9%), Mp43-45°C.

[0040] Step 2: Preparation of 1-piperazine acetylpyrrolidine

[0041] Put anhydrous piperazine (8.2kg, 95.2mol) and absolute...

Embodiment 2

[0049] Embodiment 2: the synthesis of cinepazide maleate

[0050] Step 1: Preparation of Chloroacetylpyrrolidine

[0051] Put chloroacetyl chloride (3.7kg, 33mol) and dichloromethane (21.5kg) into a 50L reaction kettle in turn, stir and cool down to -10~0°C, slowly add tetrahydropyrrole (2.15kg, 30mol), triethyl Amine (3.12kg, 33mol) in dichloromethane (2.5kg) solution, the temperature is controlled not to exceed 0°C during the dropwise addition, after the drop is completed, react at 0°C for 0.5h, raise the temperature to reflux and continue stirring for 2h, cool down to room temperature, and react The solution was washed with water and saturated NaCl successively, dried over anhydrous sodium sulfate, the filtrate was concentrated, dichloromethane was recovered, and the residue solidified at room temperature to give 2 (3.7kg, yield 83.9%), Mp43-45°C.

[0052] Step 2: Preparation of 1-piperazine acetylpyrrolidine

[0053] Put anhydrous piperazine (8.2kg, 95.2mol), triethylami...

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Abstract

The invention relates to an improved synthetic method of cinepazide maleate. The synthetic method sequentially comprises the following steps: 1, preparation of chloracetyl pyrrolidine; 2, preparation of 1-piperazine acetyl pyrrolidine; 3, preparation of 3, 4, 5-trimethoxyl cinnamoyl chloride; 4, preparation of cinepazide free alkali; 5, preparation of cinepazide maleate. The synthetic method is characterized in that in the preparation processes of steps 1 and 4, a feeding manner of dropping an alkaline raw material is adopted; in the step 2, by taking triethylamine as an acid-binding agent, a post-treatment method for removing piperazine by layered extraction is adopted, or by taking potassium carbonate as an acid-binding agent, a method for removing piperazine by acetone crystallization is adopted. The invention provides the improved synthetic method of cinepazide maleate, which is simple to operate, economic and applicable and can be used for industrialized production easily by changing the feeding sequence and the post-treatment method.

Description

technical field [0001] The present invention relates to (E)-1{4-(3', 4', 5'-trimethoxycinnamoyl)]-1-piperazine} acetylpyrrolidine maleate (cinepezil maleate Special) synthetic method, belongs to the field of medicine and chemical industry. Background technique [0002] Cinepazide maleate, its English name is Cinepazide Maleate, its chemical name is (E)-1{4-(3',4',5'-trimethoxycinnamoyl)]-1-piperazine}acetyl Pyrrolidine maleate, the structural formula is as follows: [0003] [0004] Cinepazide maleate is a calcium channel blocker that blocks 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, thereby improving microcirculation; reducing blood viscosity, protecting ischemic o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/185
CPCC07D295/192
Inventor 刘文涛郑德强毋立华王长斌孙利民张玲索栋李帅任文杰郭新艳凌沛学
Owner 凌沛学
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