反应详情

To a crude solution of intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜666 mL, ˜121.5 mmol) was added 2.0 M methylamine (95 mL, 190 mmol, in THF) and T3P (50 wt % solution in EtOAc, 96.6 mL, 152 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 300 ml of 1N NaOH and 400 mL of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×500 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 75L Biotage™ column, eluting with gradients of 5%, 8%, 10%, 15% MeOH/CH2Cl2 with 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (18.9 g, 48% yield). Rf=0.35 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C17H23ClN2O2, 322.2, found, 323.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ 7.47-7.45 (m, 2H), 7.33 (dd, J=7.9, 1.7 Hz, 1H) 5.94 (brs, 1H), 5.67 (brs, 1H), 3.75 (s, 3H), 2.85 (d, J=4.9 Hz, 3H), 2.86-2.73 (m, 3H), 2.62-2.56 (m, 4H), 2.54-2.47 (m, 2H), 1.84-1.76 (m 4H); 100 MHz 13C NMR (CDCl3) δ 177.6, 146.0, 135.5, 134.0, 130.8, 126.3, 123.6, 74.3, 56.8, 54.3, 41.1, 33.3, 26.9, 23.7.

1. customThe resulting reaction mixture
2. customthe layers were separated
3. extractionThe aqueous layer was subjected to EtOAc extraction (2×500 ml) again
4. dry with materialthe combined organic layers were dried over MgSO4
5. customevaporated
6. customThe residue was purified by flash column chromatography
7. washeluting with gradients of 5%, 8%, 10%, 15% MeOH/CH2Cl2 with 0.25% NH4OH
8. additionThe product containing fractions
9. customwere collected
10. concentrationconcentrated under reduced pressure