A solvent free tandem lactamization-decarboxylation route to (S)-Pregabalin lactam. (6th July 2022)

• Record Type: Journal Article
• Authors: Kumar Singh, Saurabh; Suresh, Muthiah; Bahadur Singh, Raj; Bandichhor, Rakeshwar; Ghosh, Partha
• Is Part Of: Tetrahedron letters. Volume 101(2022)
• Publication Date: 2022-07-06
• Subjects: γ-Lactam -- Decarboxylation -- Solvent-free -- Debenzylation of amide -- Pregabalin; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tetlet.2022.153903
• Languages: English
• ISSNs: 0040-4039

Abstract

Graphical abstract: Abstract: Herein we describe a novel lactamization-decarboxylation tandem reaction to form ( S )- N -benzyl-pregabalin lactam in solvent-free condensation of benzyl amine with ( S )-4-isobutyl α-ethylaceto γ–butyrolactone, 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.