Synthesis of 4-Aryl-2-pyrrolidones and β-Aryl-γ-amino-butyric Acid (GABA) Analogues by Heck Arylation of 3-Pyrrolines with Arenediazonium Tetrafluoroborates. Synthesis of (±)-Rolipram on a Multigram Scale and Chromatographic Resolution by Semipreparative Chiral Simulated Moving Bed Chromatography

Abstract

We report herein a new, practical, and economic synthesis of the phosphodiesterase inhibitor Rolipram on a multigram scale as well as the synthesis of new 4-aryl pyrrolidones and beta-aryl-gamma-amino butyric acids (GABA derivatives) employing an efficient Heck-Matsuda arylation of 3-pyrroline with aryldiazonium tetrafluoroborates. Racemic Rolipram was resolved into its enantiomers using chiral simulated moving bed chromatography having the low-cost microcrystalline cellulose triacetate as a chiral stationary phase.

Transition metals in organic synthesis: Highlights for the year 2005

“…Both palladium and rhodium were used as catalysts [410]. Tetraarylphosphonium halides [411] and aryl diazonium tetrafluoroborates [412], in a synthesis of rolipram [413] and tosylates and mesylates derived from 1,3-dicarbonyl compounds [414] were used in place of halides and triflates. Halides and triflates of heterocyclic ring systems, such as 3-bromoquinoline-2-ones [177] and 7-bromo-pyrido[2,3-b]pyrazine [185] were used in Heck reactions.…”

Synthesis of Single‐enantiomer Bioactive Molecules: A Brief Overview

“…The method was also used for the synthesis of new 4-aryl pyrrolidones and β-aryl-γ-amino butyric acids (GABA derivatives) employing an efficient Heck-Matsuda arylation of 3-pyrroline with aryldiazonium tetrafluoroborates (Scheme 40). 72 A simple liquid chromatographic method was developed by Nagarjuna et al 73 for the separation and quantification of voriconazole 136, a triazole antifungal, effective for serious and invasive fungal infections. The separation was achieved on Chiralcel-OD using a mobile phase consisting of n-hexane and ethanol in the ratio 9:1 (v/v) with a flow rate of 1.0 mL min -1 and detected at 254 nm (Fig.…”

“…Racemic rolipram, a phosphodiesterase inhibitor, was resolved into its enantiomers using chiral simulated moving bed chromatography (SMBC) having microcrystalline cellulose triacetate as a chiral stationary phase. The method was also used for the synthesis of new 4‐aryl pyrrolidones and β ‐aryl‐ γ ‐amino butyric acids (GABA derivatives) employing an efficient Heck‐Matsuda arylation of 3‐pyrroline with aryldiazonium tetrafluoroborates (Scheme ) …”

Synthesis of γ‐Aminobutyric Acid Analogs

“…[96]. The synthesis of a wide range of baclofen analogs has also been described including the phosphonic analog, phaclofen [97], iodobaclofen [98], heterocyclic analogs [99,100], hydroxysaclofen [101,102], homologs [103][104][105][106], pyrolidinone analogs [107], and conformationally restricted derivatives [108,109]. A highly efficient three-step synthesis of the phosphonic analog of baclofen, (AE)-phaclofen (114a) [110] and its a,a-difluoro analog (114b) has been reported (Scheme 14.32) [111].…”