Trifluoroacetic acid → (4S)-4-Phenyl-L-proline

Participants

Reaction Steps

To a suspension of CuBr: ##STR10## (27.02 g, 0.13143 mole) in dry ether (600 ml) was added phenyllithium (111.58 ml, 2.355 molar solution, 0.2629 mole) dropwise keeping the inside temperature between -20° to -15° C. At the end of the addition a bright clear yellow solution was obtained which was stirred at that temperature for another 15 minutes. A solution of Title D tosylate acid (23.0 g, 0.597 mole) in THF (dry, 300 ml) was added to the diphenyl copper lithium solution at -15° C. and the reaction mixture was stirred at that temperature for 2 hours and 1 hour at 0° C. and allowed to come to ambient temperature (1 hour) followed by 1 hour at ambient temperature. It was cooled in an ice bath and saturated ammonium chloride solution (200 ml) was added to it with vigorous stirring and left overnight at room temperature. The pH of the solution was raised from 11 to 12 by adding 10% NaOH solution, and the solution was then extracted with ether. The blue aqueous phase was acidified with 10% KHSO4 to a pH of ~1 to 2 with cooling and stirring and and the solution was then extracted with ethyl acetate (4×100 ml). The combined organic phase was washed with water (2×50 ml) and brine (2×50 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent on a rotavap gave 15.5 g (89%) of crude phenyl substituted material, namely, N-t-butoxycarbonyl-4-phenylproline, as heavy white crystals. The above crude material was dissolved in chloroform (50 ml) and trifluoroacetic acid (50 ml) was added to it, and the mixture stirred at room temperature for 1 hour and the solvent evaporated on a rotavap. Toluene (100 ml) was added to the residue and evaporated again on a rotavap. The residue was dissolved in 500 ml water (pH ~1) and the pH of the solution was brought to 6.3 by adding 10% NaOH solution. The precipitate was dissolved in 2 liters hot water and ~2 g of charcoal was added to it and boiled for 5 minutes, filtered and concentrated to a volume of ~500 ml. It was kept in the refrigerator overnight to complete the crystallization. It was filtered, washed with water (50 ml), acetonitrile (100 ml), and ether (100 ml) and air dried to give 6 g of title compound, m.p. >300° C.

Provenance & Evidence