Synthetic Approaches toward the Synthesis of Brivaracetam: An Antiepileptic Drug

Abstract

Epilepsy is a chronic neurological disorder in the brain, affecting individuals of all age groups. Nearly 1% of the world population is affected by seizure disorder, of which 80% of the patients are observed in underdeveloped and developing countries. The predominant treatment option for epilepsy includes an antiepileptic drug named brivaracetam. This drug emerged as an unusual success of rational drug discovery in clinical development by exhibiting magnificent affinity toward synaptic vesicle glycoprotein as compared to conventional drug levetiracetam and piracetam. Given its efficiency in limiting the progression of epilepsy, this drug has drawn considerable attention of researchers to devise novel routes of its synthesis. The present review encapsulates the reported literature on synthetic strategies for brivaracetam, which will assist medicinal chemists in the further progress of its synthesis.

Stereodivergent Synthesis of Enantioenriched 2-Pyrrolidones via Diastereoselective Hydrogenation of α,β-Unsaturated γ-Lactams

“…at room temperature and under atmospheric pressure of hydrogen, syn -product 6a was obtained as the major diastereomer with >99% conversion and 88:12 dr within 2 h (entry 1). This result demonstrated that, compared to the previous strategy for Pd/C catalyzed hydrogenation of 1 , furnishing the primary amide to N -tosyl amide did induce remote chirality control of the hydrogenation, which improved the diastereoselectivity considerably. The reaction of compound 5a under the same conditions (entry 2) showed that the exocyclic carboxylic acid moiety could also induce remote chirality control to generate 7a as the major diastereomer, albeit with a lower dr (83:17).…”

“…Various synthetic strategies for brivaracetam have been reported in due course (Scheme a) . In the initial studies, the target enantiomer of brivaracetam was usually obtained via the separation of racemic mixtures by chiral HPLC …”

“…Various synthetic strategies for brivaracetam have been reported in due course (Scheme 1a). 7 In the initial studies, the target enantiomer of brivaracetam was usually obtained via the separation of racemic mixtures by chiral HPLC. 8 Afterward, as the (2S)-ethyl chiral moiety could be obtained from commercially available (S)-2-aminobutanamide, research was intended to focus on constructing the chiral γ-lactam core.…”

Lewis Base‐Catalysed Enantioselective Radical Conjugate Addition for the Synthesis of Enantioenriched Pyrrolidinones

“…The methyl‐substituted pyrrolidinone 3 z was obtained in good yield and enantioselectivity. Variation of the alkyl chain was well accepted, which permitted the synthesis of 3 aa and 3 ab , structural derivatives of brivaracetam [18] and pregabalin , [19] thus highlighting the potential of the protocol to access biologically relevant scaffolds. A thioether moiety was well tolerated ( 3 ac ), while alicyclic‐substituted esters resulted in enhanced enantioselectivity (products 3 ad and 3 ae ).…”

Enantioselective Synthesis of α-Chiral Amides by Catalytic Hydrogenation with Iridium N,P-Complexes

“…Amides bearing a stereogenic center in the α-position are frequently observed architectures in pharmaceuticals, natural products, and their intermediates. 1 For example, aliskiren 2 and captopril 3 are commonly prescribed pharmaceuticals for the treatment of hypertension, whereas brivaracetam 4 and levetiracetam 5 exhibit anticonvulsant properties for the treatment of epilepsy (Figure 1 ). The synthesis of such chiral motifs is therefore of high interest in organic synthesis.…”