Acetic Anhydride → 1-(3-((4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(hydroxy)methyl)azetidin-1-yl)ethanone

Participants

Reaction Conditions

Reaction Steps

To a flask containing crude azetidin-3-yl(4-chloro-2-methoxy-3-(4-(trifluoromethyl)-benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol and 6-(azetidin-3-yl(2,6-dimethylpyridin-3-yl)(hydroxy)methyl)-4-chloro-3-(4-(trifluoromethyl)benzyl)-quinolin-2-ol (630 mg, 1.16 mmol, Example 126) was added DCM (20 mL) which gave a suspension at room temperature. Triethylamine (1 mL, 6.9 mmol) was added, followed by acetic anhydride (0.30 mL, 3 mmol) and the initial suspension became homogeneous after about 2 minutes. The mixture was heated to 40° C. for 4 hours then quenched with brine and extracted with DCM (3×25 mL). The combined organics were dried over MgSO4, filtered and concentrated to dryness. The residue was purified by FCC (5% MeOH-EtOAc increasing to 10% MeOH) to provide the title compound as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.26 (dd, J=4.1, 2.0 Hz, 2H), 7.81-7.71 (m, 4H), 7.53 (d, J=8.2 Hz, 4H), 7.46-7.37 (m, 6H), 7.25-7.17 (m, 2H), 4.45-4.33 (m, 5H), 4.30-4.07 (m, 4H), 4.04 (d, J=1.3 Hz, 5H), 4.01-3.97 (m, 1H), 3.85 (t, J=8.6 Hz, 1H), 3.77-3.59 (m, 3H), 2.49 (d, J=1.6 Hz, 6H), 2.18 (s, 6H), 1.83 (d, J=13.7 Hz, 6H); MS (ESI): mass calcd. Chemical Formula: C31H29ClF3N3O3, Exact Mass: 583.2. m/z found 583.9 [M+H]+. 1-(3-((4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(hydroxy)methyl)azetidin-1-yl)ethanone was purified by chiral SFC (Stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm, Mobile phase: 75% CO2, 25% i-PrOH (0.3% iPrNH2)) to give two enantiomers. The first eluting enantiomer was Example 87b and the second eluting enantiomer was Example 87c.

Provenance & Evidence