Aniline → methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2,5-difluorobenzoate

Participants

Reaction Steps

To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (300 mg, 0.64 mmol) in methylene chloride (5 mL), DIPEA (Aldrich, 2.57 mmol, 0.45 ml) was added followed by diphenylphosphinic chloride (Aldrich, 1.93 mmol, 0.37 ml). The mixture was stirred for 5 min. and 4-amino-2,5-difluoro-benzoic acid methyl ester (Prepared by methylation of the corresponding acid. 201 mg, 0.76 mmol) was added and the mixture was stirred overnight. The reaction was quenched with 10% sodium carbonate (6 mL) and the mixture was stirred for 15 min. The organic layer was separated and the solvent was reduced to about 3 ml. The solution was loaded onto a 40 g silica gel column and eluted with 2% EtOAc/CH2Cl2 to give a mixture of the desired product and aniline. The crude was again chromatographed on a reverse phase column and eluted with 50-95% acetonitrile/water to give a white solid. 82 mg. (ES+) m/z Calcd: [(M+H)+]: 636. found: 636.

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