反应详情

tert-Butyl N-(diphenylmethylene)-2-nitro-3-(trifluoromethoxy)-L-phenylalaninate (118) Trifluoroacetic acid (6 mL, 80 mmol) was added to a solution of 2-[(tert-butoxycarbonyl)amino]-3-(trifluoromethoxy)benzoic acid (117) (7.254 g, 22.58 mmol) in dichloromethane (40 mL). The mixture was stirred at RT for 2 h. The volatiles were removed in vacuo to provide 2-amino-3-(trifluoromethoxy)benzoic acid, which was dissolved in trifluoroacetic acid (30 mL). After addition of NaBO3.4H2O (18.3 g, 113 mmol), the mixture was stirred and heated at reflux for 18 h. The reaction mixture was cooled to RT, poured into water and extracted with Et2O. The combined extracts were dried, filtered and concentrated in vacuo to yield 2-nitro-3-(trifluoromethoxy)benzoic acid, which was then dissolved in THF (8.5 mL) and cooled to 0° C. Sodium borohydride (99%, 2.40 g, 62.8 mmol) was added in two portions; after gas evolution had subsided, boron trifluoride dimethyl etherate (98%, 5.89 mL, 62.9 mmol) was added drop-wise at 0° C., and the reaction mixture was stirred for 30 min at 0° C. The reaction was allowed to warm to RT over 18 h, then recooled in an ice bath and treated with saturated aqueous ammonium chloride solution until no additional gas evolution was observed. The mixture was partitioned between EtOAc (30 mL) and water (10 mL), and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide [2-nitro-3-(trifluoromethoxy)phenyl]methanol. This crude residue was dissolved in Et2O (150 mL). The mixture was cooled to 0° C. and phosphorus tribromide (97%, 3.68 mL, 37.9 mmol) was added. The mixture was allowed to warm to RT over 18 h, then poured onto ice water. The layers were separated and the aqueous layer was extracted with Et2O. The combined extracts were washed with water, dried, filtered and concentrated in vacuo to yielding 1-(bromomethyl)-2-nitro-3-(trifluoromethoxy)benzene. This crude residue was converted to the title compound using the general procedure outlined in Example 12 to afford the product as a yellow oil (3.67 g, 32%). LCMS m/z 515.5 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 3.20-3.31 (m, 2H), 4.23 (dd, J=8.2, 5.1 Hz, 1H), 6.68 (br d, J=7.2 Hz, 2H), 7.25-7.43 (m, 9H), 7.59-7.62 (m, 2H).

1. customThe volatiles were removed in vacuo