Method for preparing ozagrel intermediate (E)-4-(methyl imidazolyl) methyl cinnamate

Abstract

The invention discloses a method for preparing an ozagrel intermediate (E)-4-(methyl imidazolyl) methyl cinnamate, which comprises the following steps of: (1) sodium imidazolide preparation: (1.1) dissolving sodium hydroxides in deionized water, and after the sodium hydroxides is completely dissolved, stirring the obtained product and adding imidazolide to the obtained product; (1.2) putting the solution obtained in the step (1.1) into a reaction kettle and uniformly mixing to obtain a stand-by material; and (1.3) adding toluene to the stand-by material obtained in the step (1.2), then adding acetone to the obtained mixture to obtain an acetone solution; and (2) (E)-4-(imidazolyl-methyl) methyl cinnamate preparation: (2.1) adding methyl 3-(4-bromomethyl) cinnamate to the acetone solution, and after reaction, carrying out depressurized evaporation on the obtained product to remove acetone from the material; and (2.2) adding deionized water to the material subjected to acetone evaporation in the step (2.1), and stirring the obtained mixture to crystallize, thereby obtaining the (E)-4-(imidazolyl-methyl) methyl cinnamate. By using the method disclosed by the invention, the shortages existing in the prior art can be overcome, and the production cost of the intermediate is greatly reduced.

Description

technical field [0001] The invention relates to medicines, and relates to a preparation method of ozagrel intermediate (E)-4-(imidazolylmethyl) cinnamic acid methyl ester. Background technique [0002] Ozagrel is an antithrombotic drug, a potent thrombosynthetic enzyme inhibitor. Because the drug has a good preventive effect on cerebral infarction caused by blocking the middle cerebral artery, it is mainly used for the treatment of acute thrombotic cerebral infarction and the movement disorder associated with cerebral infarction. At the same time, ozagrel hydrochloride can also be used for bronchial asthma and Angina treatment etc. Because this drug has broad application prospects, in order to reduce the use cost of patients, some pharmaceutical companies in my country are also working hard to produce this drug in order to achieve the purpose of high product quality and low production cost. However, the quality of the intermediate (E)-4-(imidazolylmethyl)methyl cinnamate i...

AI Technical Summary

Problems solved by technology

However, the quality of the intermediate (E)-4-(imidazolylmethyl)methyl cinnamate in the preparation process directly affects the curative effect of the ozagrel drug, and the reported preparation methods of the intermediate all exist Insufficient: for example: adopt imidazole and methyl p-bromomethyl cinnamate reaction to produce (E)-4-(imidazolylmethyl) methyl cinnamate through N-alkylation, the impurity in this method reaction is generally all in 10-15%, the process of removing impurities is relatively complicated, and it is difficult to achieve high purity. At the same time, the yield of this method is generally about 75%, which is low, and the reaction temperature is difficult to control; Methyl bromomethyl cinnamate reacts with N-acetylimidazole under the protection of nitrogen to generate imidazolium bromide, which is then hydrolyzed by sodium carbonate to obtain (E)-4-(imidazolylmethyl)methyl cinnamate. This method is complex to operate, the reaction time is longer, the yield is lower, and it is still difficult to reduce the production cost.