4-Methylmorpholine → (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-(1H-tetrazol-5-yl)phenylcarbamoyl)pyrrolidine

Participants

Reaction Conditions

Reaction Steps

Vilsmeier reagent was prepared by treatment of DMF (0.72 ml, 9.25 mmol) in dichloromethane (40 ml) under argon with oxalylchloride (0.72 ml, 8.3 mmol) at -20° C. for 30 minutes (2S,4S)-4-Acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-carboxypyrrolidine (3 g, 8.1 mmol) in dichloromethane (10 ml) was added, followed by N-methylmorpholine (1.1 ml, 10.1 mmol) and stirring continued at -20° C. for 45 minutes. Formation of the acid chloride was found to be incomplete so a further (0.4 ml, 4.6 mmol) oxalylchloride was added and the mixture stirred at -20° C. for 30 minutes. The solvent was removed to give a brown solid which was azeotroped with toluene. The solid was dissolved in dichloromethane (50 ml) and cooled to -20° C. under an atmosphere of argon. A mixture of 3-(1H-tetrazol-5-yl)aniline (1.5 g; 9.3 mmol) and N-methylmorpholine (2.5 ml, 22.9 mmol) in DMF (4 ml) was added and the mixture allowed to warm to ambient temperature over 20 hours. After dilution with dichloromethane (30 mls) the mixture was washed with aqueous 1N HCl solution and brine (50 ml), dried (MgSO4) and the solvent removed by evaporation to give a brown gum. This was purified by flash chromatography on silica, eluting with a gradient of dichloromethane; glacial acetic acid (100:3) to dichloromethane: ethylacetate: glacial acetic acid (40:60:3) and azeotroped with toluene to give (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-(1H-tetrazol-5-yl)phenylcarbamoyl)pyrrolidine as a pale yellow solid (3 g).

Provenance & Evidence