Sodium hydride → (R/S)-(2-Cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-methyl-1-(pyrazin-2-yl-carbamoylmethyl)-pyrrolidinium bromide

Participants

Reaction Conditions

Reaction Steps

To a solution comprising (1R/S,3R)-3-hydroxy-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-pyrrolidinium bromide (Intermediate B) (0.317 g, 1.0 mmol) in DMF (3 ml) is added sodium hydride (0.08 g, of a 60% dispersion in oil, 2.0 mmol) in one portion. The suspension is stirred at 40° C. for 30 minutes and gas evolution is observed. Meanwhile, in a second reaction vessel, a solution of cyclohexyl-hydroxy-phenyl-acetic acid in DMF (3 ml) is treated with CDI (0.168 g, 1 mmol) in one portion. Gas evolution is observed and the reaction mixture is stirred at room temperature for 1 hour. The resulting CDI intermediate is added to the reaction vessel containing the sodium salt of (1R/S,3R)-3-hydroxy-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-pyrrolidinium bromide and the reaction mixture is stirred at 40° C. for 1 hour. The solvent is removed in vacuo and the residue is dissolved in water (10 ml) and the solution is acidified using 5% HBr (5 ml). The resulting oil precipitate is extracted with ethyl acetate (2×30 ml) and the combined organic portions are evaporated to dryness. The crude residue is purified using C-18 reverse phase column chromatography (eluent: water/1% TFA: acetonitrile/1% TFA) to yield the titled compound.

Provenance & Evidence