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Short Paper | Regular issue | Vol 102, No. 11, 2021, pp.2197-2206
Published online, 23rd August, 2021
DOI: 10.3987/COM-21-14527
New Synthesis of Lumateperone Tosylate

Cong Sun, Yongjun Mao,* Bo Li, Zhiyong Xu, Shun Jiang, Linlin Kang, and Han Wang

*College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201620, China

Abstract

A new and practical synthesis of lumateperone tosylate is developed. The intermediate, ethyl (4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido-[4,3-b]indole-2-carboxylate (12), is prepared on kilograms scale in 31% overall yield and >99% ee. (6bR,10aS)-3-Methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline hydrochloride (16-HCl) is obtained through reductamination reaction, palladium catalyzed cyclization and ester hydrolysis in 60% yield over 3 steps and >98% purity. Lumateperone tosylate is produced on 20 g scale in 65% yield over 2 steps and >99% purity (HPLC). Purification methods of the intermediates and the final product involved in the route are developed.