Synthesis of Suvorexant

Abstract

In order to explore the synthetic route of Suvorexant, simplify experimental process and clarify the physicochemical properties and spectral data of intermediates, the synthetic method of Suvorexant was studied. The target compound was synthesized from 2-amino-5-methylbenzoic acid, followed by diazotization reaction, iodination reaction, Ullmann reaction, amidation reaction, deprotection reaction, and 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(2- iodine -5-methylbenzoic acid)∶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((R)5- methyl -4-(5- methyl -2-(2H-1,2,3- triazol -2- yl) benzoyl) -1,4- diaza -1- carboxylic acid tert-butyl ester)∶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 1</sup>H-NMR and 13</sup>C-NMR. The optimized route has advantages of mild reaction conditions and simple process and workup operation, which is suitable for industrial production.

Keywords

• organic synthesis chemistry; suvorexant; insomnia; orexin receptor antagonist; ullmann reaction