Preparation method of racecadotril intermediate 2-(benzyl acrylamide) benzyl acetate

Abstract

The invention discloses a preparation method of racecadotril intermediate 2-(benzyl acrylamide) benzyl acetate, which comprises the following steps of: (1) taking 2-benzyl acrylic acid halide to react with glycinate so as to prepare 2-(benzyl acrylamide) acetic acid for standby; and (2) taking the 2-(benzyl acrylamide) acetic acid to be subjected to the catalytic esterification reaction with benzyl alcohol so as to prepare the 2-(benzyl acrylamide) benzyl acetate. In the step (1), the reaction between the 2-benzyl acrylic acid halide and the glycinate is carried out in a mixed phase of an organic solvent and an aqueous phase, and the reaction between the 2-benzyl acrylic acid halide and the glycinate is carried out in the presence of an acid-binding agent; in the step (2), the molar ratio of the 2-(benzyl acrylamide) acetic acid to the benzyl alcohol is 1:1.5-2, the catalyst is sodium toluenesulfonate or N,N-dimethylamino pyridine, and the use amount of the catalyst is 1%-2% of the molar weight of the 2-(benzyl acrylamide) acetic acid. With the adoption of the preparation method of the racecadotril intermediate 2-(benzyl acrylamide) benzyl acetate, the defects of the prior art can be overcome, and thus, the pollution is lowered, and the manufacture cost is lowered.

Description

technical field [0001] The invention relates to medicines, and relates to a preparation method of racecadotril intermediate 2-(benzylacrylamide) benzyl acetate. Background technique [0002] Because racecadotril acts on peripheral enkephalins, it does not affect the activity of enkephalinases in the central nervous system, and has no obvious effect on gastrointestinal motility or intestinal secretion. It is effective and safe to take, and can be combined with food. Taken together, therefore, it is especially suitable for the treatment of acute diarrhea in infants and children. [0003] At present, the drug is one of the first-choice drugs for the treatment of acute diarrhea in children in many medical institutions. Since the amount of racecadotril is increasing, many countries are studying its preparation method. However, there are few public reports on it, and there are few reports on its intermediate 2-(benzylacrylamide) benzyl acetate. U.S. Patent No. 6,835,851 disclos...

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However, there are few public reports on it, and there are few reports on its intermediate 2-(benzylacrylamide) benzyl acetate

U.S. Patent No. 6,835,851 discloses the preparation method of racecadotril in detail. When preparing its intermediate 2-(benzylacrylamide) benzyl acetate, a large amount of reaction by-products released during the preparation of acid chlorides are sulfur dioxide gas. , because sulfur dioxide gas is a poisonous substance, it seriously pollutes the environment; at the same time, a large amount of sulfur oxychloride is removed by distillation, and a large amount of toluene containing thionyl chloride produced in this process is difficult to handle, which greatly increases the manufacturing cost; and acid chloride and Glycine benzyl ester p-toluenesulfonic acid reaction is to remove p-toluenesulfonic acid under the action of triethylamine, and then use triethylamine as an acid-binding agent to react with acid chloride. During this process, a large amount of p-methanesulfonic acid triethyl Amine salts are difficult to handle, easy to pollute the environment, and glycine p-toluene iodate is expensive, which will eventually lead to extremely high product prices, and the yield of this intermediate is lower than 68%.

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