New synthesis of β-aryl-GABA drugs

Abstract

A new synthetic method for the preparation of β-aryl-GABA drugs is reported. The key step for the construction of α,β-unsaturated-β-aryl-γ-lactam derivatives relies on a novel cascade radical reaction. An N-propargyl aryl amide was rapidly constructed starting from an aryl carboxylic acid and propargyl amine. Protection of the amide N–H with a Boc group, followed by a cascade radical aryl migration reaction, produced the key intermediate, an unsaturated β-aryl-γ-lactam. Further catalytic hydrogenation and deprotection gave rolipram. Meanwhile, coupling of the glycine methyl ester and propargyl bromide, followed by benzoylation gave the radical precursor. The radical reaction resulted in the production of the unsaturated β-aryl-γ-lactam with the glycine moiety. After aminolysis reactions, phenylpiracetam and phenylpiracetam hydrazide were produced, respectively. This synthetic protocol provides a general and simple approach for preparing racemates or chiral forms of β-aryl-GABA drugs and analogues.