Preparation process of ozagrel intermediate methyl (E)-4-(imidazolylmethyl) cinnamate

Abstract

The invention discloses a preparation process of an ozagrel intermediate methyl (E)-4-(imidazolylmethyl) cinnamate. The preparation process comprises the following steps: (1) preparing imidazolium salt: putting DMF (dimethyl formamide) in a reaction kettle, putting potassium hydroxide and imidazole, stirring the materials to react, then adding potassium carbonate, stirring the materials for hours and removing water generated by a reaction system, thus obtaining a DMF solution of imidazolium salt; (2) preparing methyl (E)-4-(imidazolylmethyl) cinnamate: dissolving methyl p-bromomethyl cinnamate in DMF and dropwise adding the solution to the DMF solution of imidazolium salt; adding deionized water and stirring the materials for crystallization, thus obtaining methyl (E)-4-(imidazolylmethyl) cinnamate. The preparation process has the beneficial effects that the appearance of obtained methyl (E)-4-(imidazolylmethyl) cinnamate is obviously changed and methyl (E)-4-(imidazolylmethyl) cinnamate becomes an off-white solid, thus being beneficial to improving the quality of ozagrel; the production cycle is substantially shortened and the material cost is reduced.

Description

technical field [0001] The invention relates to the technical field of preparation of ozagrel intermediates, in particular to a preparation process of ozagrel intermediate (E)-4-(imidazolylmethyl)methyl cinnamate. Background technique [0002] Ozagrel is an antithrombotic drug with a powerful thrombosynthetic enzyme inhibitor, mainly used for the treatment of acute thrombotic cerebral infarction and the movement disorder associated with cerebral infarction; it can also be used for the treatment of bronchial asthma and angina pectoris. Because this drug has broad application prospects, in order to reduce the cost of patients, many pharmaceutical companies are also researching this drug in order to achieve the purpose of high product quality and low cost of raw materials. Because the quality of its key intermediate (E)-4-(imidazolylmethyl)methyl cinnamate directly affects the quality of ozagrel in the preparation process, and the reported preparation methods of this intermedia...

AI Technical Summary

Problems solved by technology

Because the quality of its key intermediate (E)-4-(imidazolylmethyl)methyl cinnamate directly affects the quality of ozagrel in the preparation process, and the preparation methods of the intermediate that have been reported all have deficiencies

For example, using imidazole and methyl p-bromomethyl cinnamate to react through N-alkylation to produce (E)-4-(imidazolylmethyl) methyl cinnamate, the impurities in this method are generally in the range of 10- 15%, the process of removing impurities is relatively complicated, and it is difficult to achieve high purity

Simultaneously, the productive rate of this method is generally about 75% lower; And temperature is more difficult to control in the reaction

Another method is to adopt to prepare imidazolium salt first, and then react with methyl p-bromomethyl cinnamate to generate (E)-4-(imidazolylmethyl) methyl cinnamate, but its imidazolium salt preparation process is loaded down with trivial details, and the period is long , the product has many impurities and dark color, which will affect the cycle and cost of preparing ozagrel

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