First Preparative Enantiomer Resolution of Pirlindole, a Potent Antidepressant Drug

Abstract

Pirlindole is an antidepressant drug. It acts principally as reversible inhibitor of monoamine oxidase‐A (RIMA) and appears relatively potent in comparison with reference drugs. Pirlindole possesses stereogenic center but is generally used as racemate. In this work, the first preparative resolution of its enantiomeric couple is described. Whereas selective crystallization of salts of chiral acid failed, two asymmetric synthetic pathways were also examined; however, without success. Finally separation and isolation of enantiomers of pirlindole was completed by using the derivatization method coupled with preparative HPLC. Optical purity of each isomer was determined by chiral HPLC. The specific rotation of each antipode was also determined.

Efficient Asymmetric Synthesis of N-[(1R)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-pyridinecarboxamide for Treatment of Human Papillomavirus Infections

“…Therefore, our efforts shifted to an approach based on asymmetric reduction directed with a chiral auxiliary. For this approach, we focused on chiral benzyl amines that are known surrogates for the amino group and available on scale at low cost . Liégeois and co-workers used ( S )- and ( R )-α-methylbenzylamines in their efforts towards synthesis of pirlindole from a 6-methyl tetrahydrocarbazolone via reductive amination, although the stereoselectivity was not verified 14a…”

The Use of Phosphite‐Type Ligands in the Ir‐Catalyzed Asymmetric Hydrogenation of Heterocyclic Compounds

“…2,31 Ir-catalyzed asymmetric hydrogenation of carbazole 5 in the presence of ligands L2 and L4 showed complete conversion in 20 h using [Ir(COD)Cl] 2 (1 mol%) as a precatalyst, while phosphites L1 and L3 were less effective (Table 4, entries 1-4). The reaction constitutes a new one-step approach to enantiomerically enriched form of the antidepressant drug pirlindole (8-methyl-2,3,3a,4,5,6-hexahydro-Hl-pyrazino[3,2,1-j,k]carbazole (6)).…”

“…The reaction constitutes a new one-step approach to enantiomerically enriched form of the antidepressant drug pirlindole (8-methyl-2,3,3a,4,5,6-hexahydro-Hl-pyrazino[3,2,1-j,k]carbazole (6)). 2,31 Ir-catalyzed asymmetric hydrogenation of carbazole 5 in the presence of ligands L2 and L4 showed complete conversion in 20 h using [Ir(COD)Cl] 2 (1 mol%) as a precatalyst, while phosphites L1 and L3 were less effective ( Table 4, entries 1-4). In all these cases enantioselectivities were low.…”

“…1 However, use of the traditional achiral direct cyclization reactions combined with diastereomeric resolution strategies is not efficient for preparation of these compounds in enantiomerically pure form. 2 Direct catalytic asymmetric hydrogenation of readily available heteroaromatic precursors can constitute the most convenient route to enantiomerically pure chiral heterocyclic compounds. 3 However, in comparison with asymmetric hydrogenation of unsaturated olefins, ketones, and imines, enantioselective hydrogenation of heterocyclic compounds remains a challenging task.…”