Chemo-Enzymatic Synthesis of Brivaracetam via Lipase-Catalyzed Desymmetrization

A scalable chemo-enzymatic process for Brivaracetam preparation has been developed, featuring lipase-catalyzed desymmetrization of 2-propylpropane-1,3-diol (21) using commercially available lipase from Burkholderia cepacia (BCL). The reaction in DIPE at −20 °C with 20% w/w enzyme loading delivered chiral alcohol 22 in 83% isolated yield and >90% enantiomeric excess (e.e.). This intermediate was efficiently converted to the key chiral building block, (R)-3-n-propyllactone (KSM-I, 1), through a concise three-step sequence involving selective tosylation of the primary hydroxyl group, nucleophilic substitution with NaCN in the presence of catalytic NaI to form nitrile 24, and subsequent intramolecular lactonization under basic conditions. The enzyme demonstrated excellent recyclability, and the chiral lactone’s synthetic utility was validated by enriching the chiral purity of intermediate 27 to >99% e.e via crystallization, resulting in Brivaracetam with 99% chiral purity. This sustainable, cost-efficient route highlights the commercial viability of the enantiomerically enriched intermediate, 1 (90% e.e) for API manufacturing.