Preparation method of cinepazide maleate

Abstract

The invention relates to a preparation method of cinepazide maleate, comprising the following steps: taking (E)-3, 4, 5-trimethoxy cinnamate as a raw material, preparing and obtaining (E)-3, 4, 5-trimethoxy cinnamoyl piperazine by activating carboxyl with an activated agent and then reacting with piperazine anhydrous as a compound, and reacting the (E)-3, 4, 5-trimethoxy cinnamoyl piperazine with chloracetyl pyrrolidine to prepare cinepazide free alkali which becomes salt after adding maleic acid. The preparation of the chloracetyl pyrrolidine adopts a solventless method. Since the solventless method is adopted for preparing the chloracetyl pyrrolidine, the preparation method prevents from using an organic solvent with larger toxicity and low boiling point, has high safety, is environment-friendly, and simplifies the production condition and process. The cinepazide maleate crystal with the melting point of 170 DEG C to 175 DEG C is obtained by adopting an alcohol-butanone mixed solvent, has high melting point and stable crystal form and is suitable for industrial production on large scale.

Description

【Technical field】 [0001] The invention belongs to the technical field of medicine and chemical industry, and relates to a preparation method of cinepazide maleate. 【Background technique】 [0002] The chemical name of cinepazide maleate is (E)-1-{4-[(3',4',5'-trimethoxycinnamoyl)]-1-piperazine}acetylpyrrolidinium butene Diacid salt, the molecular formula is: C 26 h 35 N 3 o 9 , the English name is Cinepazide Maleate, and its structural formula is: [0003] [0004] Cinepazide maleate is a peripheral vasodilator. Cinepazide maleate blocks the reabsorption of adenosine by cells and inhibits the activity of adenosine deaminase, blocks the inactivation process of adenosine, delays the metabolic process of adenosine, thereby increasing the concentration of endogenous adenosine in the lesion , enhance the biological effect of endogenous adenosine; have weak calcium ion blocking effect, can antagonize calcium ion overload, significantly dilate blood vessels, have good antis...

AI Technical Summary

Problems solved by technology

[0014] In summary, both synthetic route one and synthetic route two have adopted (E)-3,4,5-trimethoxycinnamoyl chloride as a key intermediate, because a large amount of thionyl chloride is needed for the synthesis of this intermediate, The requirements for equipment are relatively high, and the environment is not friendly; and (E)-3,4,5-trimethoxycinnamoyl chloride is easy to hydrolyze and has poor stability, so it is not suitable for long-term storage, which limits its industrial application to a certain extent

Among them, synthetic route one is the route with the most public reports, which is relatively mature, but in the post-treatment process of preparing N-[(1-tetrahydropyrrolecarbonyl) methyl] piperazine, multiple vacuum vacuum distillation or steam Distillation, because piperazine is very easy to crystallize during the distillation operation, thereby blocking the condenser tube, the risk is high during mass production, which brings difficulties to actual operation; and all react under reflux conditions, resulting in relatively high bis-substituted piperazine by-products Many, making the product difficult to purify

The disadvantage of the third synthetic route is that the compound N-[(1-tetrahydropyrrolecarbonyl)methyl]piperazine reacts with chloroacetyl chloride to produce an amide that is extremely unstable and easily decomposes during post-treatment

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