Reaction Steps
Charge a flask with (7R,8aR)-(4-bromo-2-nitro-phenyl)-(hexahydro-pyrrolo[2,1-c][1,4]oxazin-7-yl)-amine (50.9 g, 0.149 mol), (E)-2-((3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (57.5 g, 0.163 mol), triphenylphosphine (10.1 g, 39 mmol) and sodium methoxide (19.7 g, 0.346 mol) in tetrahydrofuran (1 L) and methanol (500 mL). Bubble nitrogen through the mixture for 30 min. Add palladium (II) acetate (3.00 g, 13 mmol) and bubble nitrogen through the mixture for an additional 30 min. Heat at reflux (60° C.) under nitrogen for 16 h. Cool to room temperature, filter through diatomaceous earth and concentrate in vacuo to obtain a solid. Dissolve in 1:1 ethyl acetate/brine (2 L) and pass through a pad of diatomaceous earth. Wash the pad with 1:1 ethyl acetate/brine (2×1 L) and then with 10% methanol in dichloromethane (4×1 L). Separate the layers and combine the organic phases. Dry the organic portion over sodium sulfate, filter, and concentrate to obtain an oil. Dissolve the oil in dichloromethane and pass through a silica gel pad. Rinse the pad with dichloromethane until higher Rf TLC component is removed. Elute with 1% methanol in dichloromethane and concentrate in vacuo to obtain a foam. Dissolve in ethyl acetate (2 L) and concentrate to approximately 200 mL. Add hexanes (1.5 L) and allow the suspension to stand at room temperature for one hour. Collect the orange solid by filtration and dry at 50° C./20 mm Hg to obtain the title compound (53 g, 73%). [α]D20−26 (c=1.0 in DMSO). 1H NMR (400 MHz, DMSO-d6) δ 1.08 (m, 1H), 2.02 (m, 1H), 2.17 (m, 1H), 2.41 (m, 2H), 2.88 (m, 1H), 3.17 (m, 1H), 3.40 (m, 1H), 3.73 (d, 1H), 3.82 (d, 1H), 4.12 (m, 1H), 5.02 (broad s, 1H), 5.59 (broad s, 1H), 6.60 (d, 1H), 6.81 (m, 2H), 6.96 (s, 1H), 7.05 (m, 2H), 7.28 (t, 1H), 7.38 (t, 1H), 7.60 (m, 2H), 7.84 (s, 1H), 8.05 (d, 1H). LC-MS m/z 458.3 [M+H]+.
