反应详情

Hunig's base (2.3 mL, 13.1 mmol) was added to a stirred mixture of 2-bromo-1-(4-bromophenyl)ethanone (3.64 g, 13.1 mmol) and (2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (3.0 g, 13 mmol) in dry acetonitrile (150 mL) and stirred at rt for 16 h. The solvent was removed by rotary evaporation and the residue was taken up in EtOAc and washed with water, sat′d NaHCO3 soln, brine, and dried (Na2SO4). The resulting ester was taken up in xylene (150 mL) and treated with NH4OAc (15.1 g, 196 mmol) in a sealed pressure vessel which was immersed in an oil bath at 140° C. and stirred for 2 h. The solvent was removed by rotary evaporation under high vacuum and the residue was taken up in EtOAc and washed with sat′d NaHCO3 soln, brine, and dried (Na2SO4), filtered and concentrated. The crude product was purified with a Thompson 300 g silica gel cartridge (gradient elution 3% B to 100% B over 4.5 L and hold 0.5 L B; Solvent B=ethyl acetate and Solvent A=hexanes) to yield (2S,4S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (3.5 g, 59%) as a foam. For purpose of characterization, approximately 25 mg was dissolved in methanol (2 mL) and subject to prep HPLC (gradient 0-100% B over a 25 min at 40 ml/min) on a PHENOMENEX® Luna column (30×100 mm, 10u); Solvent B=95% CH3CN-5% H2O-10 mM NH4OAc and A=5% CH3CN-95% H2O-10 mM NH4OAc. LC-MS retention time 3.06 min; calcd. for C19H25BrN3O2: 408.11 m/z. found 408.16 [M+H]. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.62 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.6 Hz, 2H), 7.38 (s, 1H), 4.84-4.81 (m, 1H), 3.79 (t, J=8.6 Hz, 1H), 3.17 (t, J=10.4 Hz, 1H), 2.50-2.45 (m, 1H), 2.36-2.31 (m, 1H), 1.76-1.69 (m, 1H), 1.45/1.20 (s, 9H), 1.14 (d, J=6.1 Hz, 3H).

1. customThe solvent was removed by rotary evaporation
2. washwashed with water
3. dry with materialbrine, and dried (Na2SO4)
4. customwas immersed in an oil bath at 140° C.
5. stirringstirred for 2 h
6. customThe solvent was removed by rotary evaporation under high vacuum
7. washwashed with sat′d NaHCO3 soln
8. dry with materialbrine, and dried (Na2SO4)
9. filtrationfiltered
10. concentrationconcentrated
11. customThe crude product was purified with a Thompson 300 g silica gel cartridge (gradient elution 3% B to 100% B over 4.5 L and hold 0.5 L B; Solvent B=ethyl acetate and Solvent A=hexanes)