A kind of preparation method of raw material Suvorexan

Abstract

The invention discloses a preparation method of raw drug suvorexant. The preparation method comprises the following step of generating S1 condensation acylation reaction by virtue of an intermediate I and an intermediate II in the presence of a condensing agent so as to generate an intermediate III, wherein the condensing agent is selected from one or combination of more than two of ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-carbonyldiimidazole, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole and tri(2,6-dimethoxyphenyl)bismuth. By adopting the proper condensing agent or condensing agent combination in the S1 condensation acylation reaction in the preparation method, and the yield in the prior art can be achieved at a reaction temperature of about 25 DEG C, and the condensing agent and intermediate products are simply separated, so that the energy saving and the consumption reduction in the large-scale industrial production are promoted.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for preparing a raw material drug Suvorexan. Background technique [0002] Suvorexant, English name Suvorexant, also known as MK-4305, is a dual orexin receptor antagonist newly developed by Merck, which can help patients improve sleep by blocking orexin that makes it difficult to fall asleep. At present, Phase III clinical research has been completed, and the research found that it can reduce the sleep initiation time, improve the sleep quality of patients, have few side effects, and is suitable for long-term treatment. [0003] The background technology section of CN103923068A describes in detail the preparation route and corresponding technical defects of Suwo Leisheng, and further discloses the following synthetic route: [0004] [0005] However, the above-mentioned technical solution has the following defects: DMF, methylene chloride and acetone are resp...

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Problems solved by technology

[0005] However, the above-mentioned technical solution has the following defects: DMF, methylene chloride and acetone are respectively used as organic solvents in Examples 13-15 of the patent disclosure specification, and the reaction temperature of the condensation acylation reaction in Example 13 is 50 ° C, and the yield is relatively high , the reaction temperature of the condensation acylation reaction in Examples 14-15 is 30°C, and the yield is slightly lower on the basis of Example 13

The carboxylic acid of condensation acylation reaction is a weak acylating agent, and triethylamine reacts with carboxylic acid to generate amide which affects its affinity, which is unfavorable for ensuring the yield of this step; the acylation reaction temperature in the patent publication embodiment 19 is 75°C, the reaction temperature is higher, and the impurities formed by side reactions are more, so the yield is low, which is 93.02%

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