Acetic Anhydride → 1-(3-(1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-hydroxyprop-2-yn-1-yl)azetidin-1-yl)ethanone

Participants

Reaction Conditions

Reaction Steps

To a flask containing crude 1-(azetidin-3-yl)-1-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)-benzyl)quinolin-6-yl)prop-2-yn-1-ol (130 mg, 0.28 mmol, Example 16) was added DCM (10 mL) followed by Et3N (0.2 mL, 1.44 mmol) and acetic anhydride (0.1 mL, 1.06 mmol) at room temperature. The mixture was heated to 40° C. for 2 hours and then quenched with a solution of saturated aqueous NaHCO3. The aqueous portion was extracted with DCM (3×35 mL) and the combined organics were dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel using (5% MeOH-DCM) provided the title compound as an off white amorphous solid. 1H NMR (500 MHz, CD3OD) δ 8.44 (d, J=1.9 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.91-7.82 (m, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 4.40 (s, 2H), 4.36-4.18 (m, 1H), 4.16-4.01 (m, 4H containing a singlet at 4.07), 4.05-3.98 (m, 1H), 3.93-3.80 (m, 1H), 3.28 (s, 1H), 3.24-3.09 (m, 1H), 1.85 (d, J=3.3 Hz, 3H); MS (ESI): mass calcd. for C26H22ClF3N2O3, 502.1, m/z found 503.2 [M+H]+. 1-(3-(1-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-hydroxyprop-2-yn-1-yl)azetidin-1-yl)ethanone was purified by chiral SFC: (Stationary phase: CHIRALPAK AD-H, 5 μm, 250×20 mm), Mobile phase: 70% CO2, 30% MeOH), to give 2 enantiomers. The first eluting enantiomer was Example 7b and the second eluting enantiomer was Example 7c.

Provenance & Evidence