Toluene → 1-(2,2-Difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid

To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.999 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2,2-difluoroethyl trifluoromethanesulfonate (428 mg, 1.998 mmol) in N,N-dimethylformamide (4 ml) at −35° C. under argon was added sodium hydride (80 mg, 1.998 mmol). The reaction mixture was warmed to 0° C. over 2 hours, quenched with water (10 ml) and extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (15 ml), water (10 ml×2) and brine (15 ml). The organic layer was dried (magnesium sulfate), filtered and evaporated. The residue was purified by silica gel chromatography eluting with 10-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg). LC/MS [M+H]+=265. (ii) 1,1-dimethylethyl 1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.757 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) added. The solution was stirred at room temperature for 2 hours. The solvent was evaporated and the residue co-evaporated with toluene (×2) to give 1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (0.757 mmol) which was used in the next step. LC/MS [M+H]+=209.