Synthesis of the Brivaracetam Employing Asymmetric Photocatalysis and Continuous Flow Conditions

Marcelo S Franco; Rodrigo C Silva; Gabriel H S Rosa; Lara M Flores; Kleber T de Oliveira; Francisco F de Assis

doi:10.1021/acsomega.3c02134

Synthesis of the Brivaracetam Employing Asymmetric Photocatalysis and Continuous Flow Conditions

ACS Omega. 2023 Jun 14;8(25):23008-23016. doi: 10.1021/acsomega.3c02134. eCollection 2023 Jun 27.

Authors

Marcelo S Franco¹, Rodrigo C Silva², Gabriel H S Rosa², Lara M Flores¹, Kleber T de Oliveira², Francisco F de Assis¹

Affiliations

¹ Department of Chemistry, Universidade Federal de Santa Catarina, Campus Universitário Trindade, Florianópolis, Santa Catarina 88040-900, Brazil.
² Department of Chemistry, Universidade Federal de São Carlos, Rodovia Washington Luis km 235, São Carlos, São Paulo 13565-905, Brazil.

Abstract

An original total synthesis of the antiepileptic drug brivaracetam (BRV) is reported. The key step in the synthesis consists of an enantioselective photochemical Giese addition, promoted by visible-light and the chiral bifunctional photocatalyst Δ-RhS. Continuous flow conditions were employed to improve the efficiency and allow an easy scale-up of the enantioselective photochemical reaction step. The intermediate obtained from the photochemical step was converted into BRV by two different pathways, followed by one alkylation and amidation, thus giving the desired active pharmaceutical ingredients (API) in 44% overall yield, 9:1 diastereoisomeric ratio (dr) and >99:1 enantiomeric ratio (er).