2-fluoro-3-(trifluoromethoxy)aniline

反応条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (1.83 g, 8.07 mmol) in dry THF (45 mL) at −20° C. under nitrogen atmosphere was added triethylamine (3.32 mL, 23.8 mmol) followed by ethylchloroformate (0.775 mL, 8.07 mmol) dropwise. The reaction mixture was stirred at −20° C. for 90 min and a solution of 2-fluoro-3-(trifluoromethoxy)aniline (prepared as described in Part C, 1.5 g, 7.69 mmol) in dry THF (5 mL) was added. The reaction mixture was further stirred at −20° C. for 1 h, warmed up to RT and stirred at 65° C. for 16 h until completion of the reaction. The reaction mixture was diluted with EtOAC, washed with a saturated aqueous solution of NaHCO3 (×3) and brine, dried (phase separator) and concentrated under reduced pressure. The crude residue was purified via flash column chromatography on silica gel (EtOAc/c-hexane 1:1) to give the desired material as a colorless oil. MS: 427 [M+Na]+, 304.9 [MH−Boc]+; tR (HPLC conditions c): 5.23 min. The reaction mixture was further stirred at −20° C. for 1 h warmed up to RT stirred at 65° C. for 16 h until completion of the reaction The reaction mixture was diluted with EtOAC washed with a saturated aqueous solution of NaHCO3 (×3) and brine dried (phase separator) concentrated under reduced pressure The crude residue was purified via flash column chromatography on silica gel (EtOAc/c-hexane 1:1)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (1R,3S,5S)-5-(tetrahydro-pyran-2-yloxymethyl)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (100 mg, 0.29 mmol) in dry CH2Cl2 (1 mL) under argon at 0° C. was added 1-chloro-N,N,2-trimethylpropenylamine (58 μL, 0.44 mmol) and the reaction mixture was stirred at 0° C. for 1.5 h. 2-Fluoro-3-(trifluoromethoxy)aniline (86 mg, 0.44 mmol) was added, followed by DIPEA (100 μL, 0.59 mmol) and the mixture was stirred at RT overnight. Then poured into water and extracted with CH2Cl2 (×2), the organics were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (eluent: c-hexane to c-hexane/EtOAc 85:15). TLC, Rf (c-hexane/EtOAc 2:1)=0.45; MS (UPLC/MS): 519.3 [M+H]+, 536.3 [M+NH4]+, 517.4 [M−H]−, 563.3 [M−HCOO]−; tR (HPLC conditions f): 2.51 min. the mixture was stirred at RT overnight extracted with CH2Cl2 (×2) the organics were dried (Na2SO4) filtered concentrated The crude residue was purified by flash column chromatography on silica gel (eluent: c-hexane to c-hexane/EtOAc 85:15) 2.51 min.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (prepared as described in Scheme B25, 1.00 g, 3.80 mmol) in CH2Cl2 (10 mL) at 0° C. under nitrogen atmosphere was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (609 mg, 4.56 mmol) and the mixture was stirred at this temperature for 1 h. 2-Fluoro-3-(trifluoromethoxy)aniline (0.815 mg, 4.18 mmol) was then added, followed by DIPEA (1.327 mL, 7.60 mmol) and the mixture was stirred at RT for 1 h. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:0 to 1:1) to give (2S,3S,4S)-4-fluoro-2-(2-fluoro-3-trifluoromethoxy-phenylcarbamoyl)-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-d6) 2:1 mixture of rotamers δ (ppm): 10.15 (m, 1H), 7.87 (m, 1/3H), 7.77 (m, 2/3H), 7.31 (m, 2H), 5.29-5.11 (m, 1H), 4.76 (d, 1/3H), 4.70 (d, 2/3H), 4.29 (m, 1H), 3.80-3.53 (m, 2H), 3.39 (m, 3H), 1.39 (s, 3H), 1.31 (s, 6H). MS (UPLC-MS): 441 [M+H]+; tR (HPLC conditions f): 2.14 min. the mixture was stirred at RT for 1 h The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:0 to 1:1)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-fluoro-3-(trifluoromethoxy)aniline (1.0 g, 5.13 mmol) dissolved in DMF (2 mL) at 0° C. was slowly added a solution of cold N-bromosuccinimide (0.91 g, 5.13 mmol) dissolved in DMF (6 mL) over 5 min. The reaction mixture was stirred at 0° C. for 1 h, extracted with EtOAc (125 mL) and washed with water (3×25 mL). The combined aqueous layers were extracted with EtOAc (75 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated to produce the title compound as a dark colored liquid (1.27 g, 90% yield). (m/z): [M+H]+ calcd for C7H4BrF4NO 273.94. found 273.8. extracted with EtOAc (125 mL) washed with water (3×25 mL) The combined aqueous layers were extracted with EtOAc (75 mL) The combined organic layers were washed with brine (25 mL) dried over sodium sulfate filtered concentrated