反应详情

DIPEA (3.47 mL, 19.88 mmol) was added to a stirred slurry of crude 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (4.35 g, 13.3 mmol) and (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (3.01 g, 13.25 mmol) in acetonitrile (80 mL) and the reaction was stirred at rt overnight. The reaction was concentrated to dryness and purified by BIOTAGE® Horizon (160 g SiO2, 10-20% EtOAc/hexanes). The fractions containing the desired product were allowed to stand for 3d. Some fractions had crashed large crystals (collected 240 mg, pure desired product by 1H NMR). All fractions containing the desired product were collected and concentrated to a yellow solidified foam which was slurried with Et2O (˜40 mL). The white solid that formed was collected by filtration and rinsed with Et2O to yield (1R,3S,5R)-3-(2-(6-bromonaphthalen-2-yl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (3.24 g). LC-MS retention time 2.760 min; m/z 472, 474.02 (1:1) (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 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 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 mHz, MeOD) d ppm 8.61 (br s, 1H), 8.17 (s, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.00 (d, J=8.9 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.71 (dd, J=8.6, 1.8 Hz, 1H), 5.75-5.66 (m, 1H), 5.61-5.46 (m, 1H), 4.34-4.26 (m, 1H), 3.46 (br s, 1H), 2.69-2.59 (m, 1H), 2.55-2.44 (m, 1H), 1.73 (br s, 1H), 1.54-1.43 (m, 9H), 0.88 (br s, 1H), 0.59-0.53 (m, 1H).

1. concentrationThe reaction was concentrated to dryness
2. custompurified by BIOTAGE® Horizon (160 g SiO2, 10-20% EtOAc/hexanes)
3. additionThe fractions containing the desired product
4. customcrystals (collected 240 mg, pure desired product by 1H NMR)
5. additionAll fractions containing the desired product
6. customwere collected
7. concentrationconcentrated to a yellow solidified foam which
8. customThe white solid that formed
9. filtrationwas collected by filtration
10. washrinsed with Et2O