Synthesis of the Brivaracetam Employing Asymmetric Photocatalysis and Continuous Flow Conditions

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).

Highly Enantioselective Lewis Acid Catalyzed Conjugate Addition of Imidazo[1,2-a]pyridines to α,β-Unsaturated 2-Acylimidazoles under Mild Conditions

“…The solvent was removed under vacuum, and the crude product was purified by flash chromatography on silica gel (EtOAc/hexane) to produce α,β-unsaturated alkenes 1a – i . The NMR spectra of the compounds corroborate the data found in the literature, 25 with exception of compounds 1d and 1h that have not been described so far.…”

“…A huge variety of asymmetric catalysts have been devised for promoting enantioselective conjugate addition reactions, and our main focus was to employ a catalytic system with a strong background of elevated enantioselectivity associated with low catalyst loading. Recently, we have reported a new enantioselective synthesis of the active pharmaceutical ingredient (API) brivaracetam, using a “chiral-at-metal” catalyst developed by Meggers’ group . In several works reported, − including ours, this catalyst demonstrated very good levels of stereoinduction, so we decided to evaluate if it would suit our purposes in this work.…”

“…Recently, we have reported a new enantioselective synthesis of the active pharmaceutical ingredient (API) brivaracetam, using a “chiral-at-metal” catalyst developed by Meggers’ group. 14 In several works reported, 15 − 20 including ours, this catalyst demonstrated very good levels of stereoinduction, so we decided to evaluate if it would suit our purposes in this work.…”

Continuous flow reactions in the preparation of active pharmaceutical ingredients and fine chemicals

“…Subsequently, an alternative strategy to prepare the antiepileptic API brivaracetam ( 79 ), used in the treatment of drug-resistant epilepsy, 85 was described by de Assis group with our collaboration. 86 The key step in the synthesis involved a continuous enantioselective visible-light mediated Giese addition between 75 and 76 , promoted by the chiral rhodium photocatalyst 77 , affording intermediate 78 in 98% yield and an enantiomeric ratio of 96 : 4 (Scheme 17). The scale up of this protocol was also carried out at 5 mmol, affording 1.7 g of the desired compound without almost any loss in yield and enantioselectivity (94% yield and 94 : 6 e.r.).…”

Recent advances in catalytic asymmetric synthesis

“…Accordingly, the development of a practical synthetic process for Brivaracetam has been in demand and attracting considerable interest. In 2023, de Assis and coworkers reported the first application of asymmetric photocatalysis in continuous flow for the enantioselective synthesis of Brivaracetam ( Figure 13B ) ( Franco et al, 2023 ) The key step in this synthesis is the enantioselective photochemical Giese 1,4-addition of BocNHCH 2 radical, generated from Hantzsch ester 13-B2 , to n -hex-2-enoylimidazole 13-B1 , promoted by visible-light and chiral bifunctional Rh photocatalyst Δ-RhS , to give the key intermediate 13B ( de Assis et al, 2018 ). The key parameters for this photocatalysis were investigated and optimized in batch reactions to afford the key intermediate 13B with 99% yield and 96% e. e. The reaction conditions were further tuned for the continuous flow process and the reaction with a flow rate of 1.0 mL/min and 4% catalytic loading of photocatalyst Δ-RhS at 40°C afforded 13B in 95% yield and 95% e.e.…”