Herein we describe a novel lactamization-decarboxylation tandem reaction to form (S)-N-benzyl-prega-balin lactam in solvent-free condensation of benzyl amine with (S)-4-isobutyl a-ethylaceto y-butyrolac-tone, obtained in two steps from commercially available starting material. Triflic acid-mediated debenzylation in the same pot gave (S)-pregabalin lactam, which constitutes a formal synthesis of the anticonvulsant and anxiolytic drug pregabalin. Isolation of the lactamization intermediates indicates that the initially formed kinetic hydroxyamide is in equilibrium with lactone and the formation of amino acid precedes lactamization. (C) 2022 Elsevier Ltd. All rights reserved.
Key words
Decarboxylation/Solvent-free/Debenzylation of amide/Pregabalin/GAMMA-AMINO-ACIDS/ENANTIOSELECTIVE SYNTHESIS/RADICAL CYCLIZATION/CONCISE SYNTHESIS/PREGABALIN/LACTONES/DISCOVERY/ANALOGS
NSTL
Elsevier