反应详情

A sample of 2.25 g (5.5 mmol) of 3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]-1-(diphenylmethyl)azetidine(Step 2 of Preparation 14) was dissolved in 15 mL of THF and 1.1 mL (10 mmole) of 1-chloroethyl chloroformate was added. The solution was stirred at room temperature. After 2 h, the solution was concentrated under reduced pressure and the residue was dried under high vacuum for 1 h. The residue was dissolved in 20 mL of CH3OH and heated to reflux for 6 h. The solution was concentrated and the residue was partitioned between 100 mL ether and 50 mL of 1:1 saturated Na2CO3 solution-1M NaOH. The aqueous layer was washed with 3 portions of 100 mL ether, and the combined organic extracts were washed with NaHCO3, then brine, then concentrated. The oily residue was applied to a silica gel column packed in 20% ethyl acetate-hexane and the column was washed with 5 column volumes of 20% ethyl acetate-hexane, then with CH2Cl2, with 10% CH3OH in CH2Cl2 and finally with 80:20:2 CH2Cl2—CH3OH-ammonium hydroxide. Homogenous fractions were concentrated to afford the title compound, which was not further purified but was used directly in the next step; Mass Spectrum: m/e=244 (M+1).

1. concentrationthe solution was concentrated under reduced pressure
2. customthe residue was dried under high vacuum for 1 h
3. dissolutionThe residue was dissolved in 20 mL of CH3OH
4. temperatureheated
5. temperatureto reflux for 6 h
6. concentrationThe solution was concentrated
7. customthe residue was partitioned between 100 mL ether and 50 mL of 1:1 saturated Na2CO3 solution-1M NaOH
8. washThe aqueous layer was washed with 3 portions of 100 mL ether
9. washthe combined organic extracts were washed with NaHCO3
10. concentrationbrine, then concentrated
11. washthe column was washed with 5 column volumes of 20% ethyl acetate-hexane
12. concentrationHomogenous fractions were concentrated