Method for preparing cinepazide free alkali

A technology of free base and piperazine, applied in the field of synthesis of cinepazide free base, can solve the problems of increasing investment in industrialized equipment, speeding up equipment depreciation, and high equipment requirements, and achieving stable product quality, enhanced nucleophilicity, environmental protection less pollution

Inactive Publication Date: 2011-02-23
HAINAN KANGHONG MEDICAL TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the post-treatment process, excess thionyl chloride is removed by distillation, which requires high equipment and serious corrosion, which increases the investment in industrial equipment and accelerates depreciation of equipment.

Method used

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  • Method for preparing cinepazide free alkali
  • Method for preparing cinepazide free alkali
  • Method for preparing cinepazide free alkali

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Mix 5.1g (0.02mol) of methyl 3,4,5-trimethoxycinnamate and 5.16g (0.06mol) of anhydrous piperazine in a 100ml single-necked bottle, add 5ml of dry N,N-dimethylformamide , stirred, and under a water bath, 2.2 g (0.06 mol) of NaH (65%) was added, and after adding, no bubbles were generated. Heat to reflux for 10 hours. Stop heating, and add 20ml of water dropwise under ice bath. Adjust the pH to 1-2 with 4M hydrochloric acid aqueous solution, and extract the aqueous phase with dichloromethane (20ml*3). Under the ice bath of the water phase, adjust the pH to about 12 with NaOH, extract with dichloromethane (25ml*3), combine the organic phases, extract with saturated aqueous sodium carbonate solution (15ml*2), and concentrate the organic phase to obtain 3.67g of light yellow oil, which is Cinepazide intermediate (60% yield).

Embodiment 2

[0020] Mix 5.1g (0.02mol) of methyl 3,4,5-trimethoxycinnamate and 7.89g 1-piperazineacetylpyrrolidine (0.04mol) in a 100ml single-necked bottle, add 5ml of dry N,N-di Methylformamide was stirred, and under a water bath, 2.2 g (0.06 mol) of NaH (65%) was added. After the addition, no bubbles were generated. Heat to reflux for 10 hours. Stop heating, and add 20ml of water dropwise under ice bath. 4M hydrochloric acid aqueous solution was used to adjust the pH to 1-2, and the aqueous phase was extracted with dichloromethane (20ml*3). Under the ice bath of the water phase, adjust the pH to about 12 with NaOH, extract with dichloromethane (25ml*3), combine the organic phases, extract with aqueous acetic acid (acetic acid: water = 15:100) (15ml*2), concentrate the organic phase to obtain shallow 4.58 g of reddish-brown oily substance is cinepazide free base (yield 55%).

Embodiment 3

[0022] Mix 8.2g (0.025mol) of benzyl 3,4,5-trimethoxycinnamate and 9.9g 1-piperazineacetylpyrrolidine (0.05mol) in a 100ml single-necked bottle, stir and add NaH (65%) 2.95g (0.08mol), slowly heated until the solid dissolved. Keep the temperature t=105~110°C for 8 hours, stop heating, add 20ml of water dropwise under ice bath. 4M hydrochloric acid aqueous solution was used to adjust the pH to 1-2, and the aqueous phase was extracted with dichloromethane (20ml*3). The aqueous phase was placed in an ice bath, adjusted to about PH=12 with sodium hydroxide, extracted with dichloromethane (25ml*3), combined with the organic phase, extracted with aqueous acetic acid (acetic acid: water = 15:100) (15ml*2), concentrated the organic phase Obtained 4.35 g of a light reddish-brown oily substance, which was cinepazide free base (yield 41%).

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Abstract

The invention discloses a method for preparing cinepazide maleate, which is characterized by comprising the following step of: performing ammonolysis on 3,4,5-trimethoxy cinnamic acid ester and piperazin or piperazin derivative in the presence of strong base to obtain cinepazide free alkali.

Description

[0001] Technical field: the present invention relates to the synthetic method of cinepazide free base. It belongs to the field of medical technology. Background technique: [0002] The chemical name of cinepazide is: trans-{(1-pyrrolidinecarbonyl)methyl}-4-(3,4,5-trimethoxycinnamoyl)-piperazine. Its salt, cinepazide maleate, is a peripheral vasodilator, clinically used to treat cardiovascular and cerebrovascular diseases. [0003] Patent document 1 (US 3634411) reported the synthetic route of cinepazide the earliest, as figure 1 Shown: with trans-3,4,5-trimethoxycinnamoyl chloride (II) and 1-piperazine acetylpyrrolidine (III) as raw materials, anhydrous toluene as solvent, NaHCO 3 As an acid-binding agent, an acylation reaction occurs to produce cinepazide. Subsequent patent documents JP2180876A, CN1631877A, CN1876646A, CN1246310C, CN101260092A and Xu Juan and Wang Lin [Chinese Journal of New Drugs, 2003, 12(8): 625-626] all adopted similar synthesis methods. [0004] Pate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/185
Inventor 葛亚伯洪建辉孙公保
Owner HAINAN KANGHONG MEDICAL TECH DEV
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