Isobutyl chloroformate → (3,4-Difluoro-phenyl)-[(4-hydroxymethyl-2-methyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester

Participants

Reaction Steps

To a solution of [tert-butoxycarbonyl-(3,4-difluorophenyl)-amino]-acetic acid (5.74 g) in tetrahydrofuran (40 ml) at 0° C. was added triethylamine (3.2 ml) followed by isobutylchloroformate (2.9 ml) dropwise. After stirring for lhr, triethylamine (3.2 ml) was added followed by 4-(tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-phenylamine (5.0 g) in tetrahydrofuran (3 ml), and the reaction warmed to room temperature and then heated at 58° C. overnight. After cooling to 0° C., tetrabutylammonium fluoride (7.6 ml of a 1M solution in tetrahydrofuran) was added dropwise and the reaction warmed to room temperature. After 3 hrs, the solution was poured into ethyl acetate/water and the organic layer separated, washed with KHSO4 (10% solution in water), water and brine, dried (Na2SO4) and concentrated. Purification of the residue by silica gel chromatography (eluting with 3% methanol in dichloromethane) gave an orange solid. Recrystallisation from 2-propanol/isohexane gave the sub-title compound as white crystals (2.8 g).

Provenance & Evidence