Reaction Steps
(3R)-2,3,4,7-Tetrahydro-3-isobutyl-4-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-8H-[1,4]oxazino[2,3-f]quinolin-8-one (Compound 155, Structure 17 of Scheme III, where R1, R3, R4, R5, R7, R8=H, R2=trifluoromethyl, R6=isobutyl, R=CH2CF2), and (2R)-1,2,3,6-tetrahydro-2-isobutyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-f]quinolin-7-one (Structure 18 of Scheme III, where R1, R3, R4, R5, R7=H, R=trifluoromethyl, R6=isobutyl, R13=CH2CF3): This compound was prepared by treatment of (3R)-7-amino-3,4-dihydro-3-isobutyl-4-trifluoroethyl-2H-1,4-benzoxazine (0.13 g, 0.45 mmol) and ethyl-4,4,4-trifluoroacetoacetate (0.25 g, 1.4 mmol) in 6 mL toluene heated at reflux for 3 h, followed by removal of solvent and treatment with 3 mL concentrated H2SO4 heated to 95° C. for 1 h. The mixture was poured into water (100 mL), neutralized with 6N NaOH, and extracted with chloroform (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The baseline impurities and were removed and partial purification achieved by flash chromatography (95:5 CH2Cl2:MeOH). Further purification by HPLC (Kromasil, 0.5″ semi-prep column, 70% MeOH/water at 3 mL/min) afforded 5.0 mg (3%) of Compound 155, and recrystallization of the other impure fractions (ethyl acetate:hexanes) afforded 17 mg (9%) of (2R)-1,2,3,6-tetrahydro-2-isobutyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, the regioisomer of Compound 155. Data for Compound 155: 1H NMR (500 MHz, CDCl3) δ 12.0–12.4 (v broad s, 1H), 7.15 (s, 1H), 7.13 (d, J=9.0, 1H), 7.01 (d, J=9.0, 1H), 4.34 (d, J=11, 1H), 3.99 (broad d, J=10, 1H), 3.75–3.85 (m, 1H), 3.65–3.75 (m, 1H), 3.35–3.40 (m, 1H), 1.70–1.80 (m, 1H), 1.40–1.50 (m, 1H), 1.30–1.40 (m, 1H), 0.95 (d, J=6.5, 3H), 0.93 (d, J=7.0, 3H).
