Synthetic method for intermediate of suvorexant as anti-insomnia medicament

Abstract

The invention relates to a synthetic method for an intermediate of suvorexant as an anti-insomnia medicament. The synthetic method is characterized in that 4-methyl-2-hydrazinobenzoic acid hydrochloride is taken as a starting raw material, and reacts with glyoxal to generate dihydrazone; then dihydrazone is subjected to cyclization under the action of copper trifluoromethanesulfonate to obtain a key intermediate 5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoic acid of the suvorexant as the anti-insomnia medicament. The synthetic method disclosed by the invention has the advantages of low price of raw materials, short reaction step, simpleness and convenience in operation, no isomers difficult to separate, high content of products and easiness for industrial production; meanwhile, a ring-closing by-product 4-methyl-2-carboxy anilide is separated in a form of forming hydrochloride, and is a raw materials for synthesizing the starting raw material 4-methyl-2-hydrazinobenzoic acid, so that organic materials can be recycled, and further the total synthetic cost is lower; in addition, by recovering treatment, solvent can be used indiscriminately, economy, environment friendliness and important application value are realized.

Description

Technical field [0001] The invention relates to a synthetic method of an anti-insomnia drug intermediate, in particular to a synthetic method of an anti-insomnia drug Suvorexan intermediate. Background technique [0002] Suvorexant is an anti-insomnia drug newly developed by Merck Pharmaceuticals in the United States. It was approved by the Food and Drug Administration (FDA) in August 2014 for marketing under the brand name Belsomra. Suvorexant is an Orexin (orexin) receptor antagonist that can affect the signal transduction of the Orexin pathway. Orexin is a small molecule neuropeptide related to the regulation of sleep-wake cycle. Among the insomnia drugs approved by the FDA, Orexin receptor antagonists are the only one. Based on 3 clinical trials, the FDA recognized Suvorexant as effective, and the total number of subjects in these trials exceeded 500. Studies have shown that compared with subjects taking a placebo, those taking the drug fall asleep faster and wake up less ...

AI Technical Summary

Problems solved by technology

The problems of these routes are mainly: the production cost of iodide is relatively high, and the price of raw materials is expensive; there are many reaction impurities, especially the product at the triazole-1 position is similar to the product properties, and it must be formed through salt formation, crystallization, acidification, recrystallization Multiple operations are very cumbersome and difficult to monitor; since the docking of this intermediate and another fragment is the final product, in order to ensure that the API single and total impurities of the product are qualified, the content must be more than 99.5%. The cost of such a standard is very high, so there are certain difficulties in the application and industrial production of this route

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