Synthesis of Suvorexant

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The Natural Science Foundation of Hebei Province

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    In order to explore the synthetic route of Suvorexant, clarify the physicochemical properties and spectral data of intermediates, lay the foundation for its industrial process, the synthetic method of Suvorexant is studied. The target compound is synthesized from 2-amino-5-methylbenzoic acid, followed by diazotization reaction, iodination reaction, Ullmann reaction, amidation reaction, deprotection reaction, nucleophilic substitution reaction. By optimizing the synthesis parameters, Suvorexant and intermediates can be directly obtained by using recrystallization method instead of column chromatography purification. The results show as follows: Hydrochloric acid aqueous solution is used as the solvent in the diazotization reaction and the iodination reaction, n (2-amino-5-methylbenzoic acid): n (sodium nitrite): n (potassium iodide) = 1: 1.2: 1.4, the yield is 92.31%; N, N-dimethylformamide is used as the solvent in the Ullmann reaction, n (compound 2): n (2H-1,2,3-triazole): n (copper iodide) = 1: 2: 0.05, the yield is 63.47%; Acetonitrile is used as the solvent in the deprotection reaction, n (compound 5): n (p-toluenesulfonic acid) = 1: 1.2, the yield is 93.02%; the total yield of the route is 47.99% after optimization, and the purity is 99.89%. The structure of the target compound is confirmed by 1H-NMR and 13C-NMR. The optimized route has advantage of mild reaction conditions, simple process and workup operation, and is suitable for industrial production.

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  • Received:February 27,2020
  • Revised:February 27,2020
  • Adopted:April 26,2022
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