Process development of a selective serotonin reuptake inhibitor (1) is described. The synthesis features Nishiyama catalyst-mediated asymmetric cyclopropanation of vinyl indole 2 with ethyldiazoacetate to install the trans-disubstituted cyclopropane. The active pharmaceutical ingredient (1) was prepared in 13 chemical steps with 9 isolations and proceeded in an overall yield of 34%.
A practical synthesis of 3-((1S, 2S)-2-dimethylaminomethylcyclopropyl)-1H-indole-5-carbonitrile hydrochloride (1), a selective serotonin reuptake inhibitor (SSRI), is described. The process to prepare 1 was demonstrated on laboratory scale and highlights an enantioselective Simmons−Smith cyclopropanation of allylic alcohol 3 using Charette’s chiral dioxaborolane ligand. The improved synthesis enabled production of 1 in 8 chemical steps (5 isolations) in an overall yield of 38%.
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