Synthesis of Antiepileptic Drug (R)-Lacosamide and Chronic Pain Reliever (S)-Lacosamide from Chiral Glycine Enolate Equivalent.

Abstract

A short enantioselective and azide-free synthesis of antiepileptic drug (R)-lacosamide and pain reliever (S)-lacosamide on a large scale has been articulated from an uncommon chiral synthon "glycine enolate equivalent of 4-benzyl-N-glycinyl oxazolidinone". Evans' asymmetric alkylation using N-(N-Boc-glycinyl) oxazolidinone was standardized to ensure the stereoselective formation of (Z)-enolate for a diastereofacial selection in the C-alkylation process of chiral glycine enolate equivalent with different alkyl halides such as methyl iodide, methoxymethyl chloride, benzyl bromide, p-NO2C6H4CH2Br, allyl bromide, and p-OCH3C6H4CH2Br in the presence of lithium diisopropyl amide at -78 °C in THF. This optimized asymmetric C-alkylation method with methoxymethyl chloride on lithium-mediated (Z)-enolate of (4S/4R)-4-benzyl-N-glycinyl oxazolidinones was extended following other subsequent reactions to produce the final lacosamides with no racemization in ∼36 to 45% overall yields from commercially available 4-benzyl-2-oxazolidinone and N-Boc-glycine.