Ammonium Chloride → 5-(Tert-butyl-dimethyl-silanyloxy)-4-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentanoic acid methyl ester

Participants

Reaction Conditions

Reaction Steps

To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl(methyl)carbamate (91.0 g, 242.6 mmol) in DCM (750 mL) was added TMSOTf (87.8 mL, 485.2 mmol) at 0° C. The mixture was stirred for 1 h, and then poured into saturated aq. NH4Cl (1 L) and CH2Cl2 (1 L) (Note: water (700 mL) was added to dissolve salts). The organic layer was then washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was re-dissolved in THF (300 mL) and DIEA (84.5 mL, 485.2 mmol). To this THF solution was added a pre-stirred solution of 4-nitrophenylchloroformate (56.3 g, 279.0 mmol), 2-chloro-3-fluorobenzylamine (46.5 g, 291.1 mmol), and DIEA (50.7 mL, 291.1 mmol) in THF (1.1 L) at 0° C. The reaction mixture was stirred for 2 h allowing the reaction to gradually warm to 24° C. at which point the LCMS analysis revealed reaction completion. The mixture was concentrated under reduced pressure and purified on silica gel column using a mixture of hexanes and EtOAc to give 5-(tert-butyl-dimethyl-silanyloxy)-4-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentanoic acid methyl ester (73.1 g, 65% over two steps). LRMS (M+H+) m/z 461.1.

Provenance & Evidence