Synthesis of Trifluoromethyl-Phenyl-Benzoxazine Derivative

Example 81

[Figure (not displayed)]

The mixture of compound 86-1 (70 mg, 0.22 mmol, 1 eq), HATU (126.2 mg, 0.33 mmol, 1.5 eq) and DIEA (85.8 mg, 0.66 mmol, 0.11 mL, 3 eq) in DCM (2 mL) was stirred at 25° C. for 1 hr, Then 2-aminoethanol (16.2 mg, 0.26 mmol, 16.0 uL, 1.2 eq) was added at the mixture and the mixture was stirred for another 1 hr. LC-MS showed the desired compound was detected. The reaction mixture was diluted with H₂O (10 mL) and the mixture was extracted with EA (10 mL*3). The combined organic phase was washed with brine (10 mL*3), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC. The title compound (36 mg, 0.10 mmol, 45.2% yield) was obtained as white solid. LCMS (ESI): RT=0.898 min, mass calcd for C₂₀H₁₆F₃NO₂ 359.34, m/z found 360.1 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (br t, J=5.5 Hz, 1H), 8.58 (d, J=1.5 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.98-7.89 (m, 3H), 7.81 (d, J=8.8 Hz, 1H), 7.77-7.67 (m, 3H), 7.59 (dd, J=1.0, 7.0 Hz, 1H), 4.78 (br s, 1H), 3.61-3.51 (m, 2H), 3.45-3.39 (m, 2H).