Reaction Steps
To a stirring solution of (2R,6S,13aS,14aR,16aS,Z)-2-(7-fluoro-3-(trifluoromethyl)quinoxalin-2-yloxy)-6-(5-methylisoxazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (5.13 g) and NMP (12.9 g) was added carbonyl diimidazole (1.83 g) as a solution in NMP (7.7 g). After 30 min, cyclopropylsulfonamide (1.81 g) was added to the reaction mixture as a solution in NMP (5.13 g). The solution was cooled to 5° C. and then DBU (4.0 g) was charged to the reaction mixture. The reaction was allowed to proceed for 15 h and then diluted with isopropyl acetate (IPAc) (33.5 g) and 2-methyltetrahydrofuran (33.5 g). The organic solution was washed with a 2.0 M aqueous solution of H3PO4 (51.3 g), a 5:3:1 solution of 2.0 M H3PO4, H2O, 10% aqueous solution of NaCl (total volume of 50 mL), water (5×25 g), and then concentrated to 25 mL by distillation. The organic solution was diluted with IPAc (25.0 g) and then concentrated back to 25 mL by distillation. This process was repeated three times. The concentrated product-containing solution was diluted with IPAc (108 g), filtered, and then concentrated again to 25 mL. The product-containing solution was distilled, maintaining a constant volume by the addition of ethanol (106 g). Ethanol (35 mL) was then added. Water (3.0 g) was then added to the product solution and the mixture was heated to 80° C. and then cooled to 20° C. over 12 h. The slurry was filtered and the cake was rinsed with ethanol (10 mL). The cake was dried under vacuum to provide the product (4.64 g, 79% yield) as a white, crystalline solid: 1H NMR (400 MHz, DMSO-D6) □ ppm 11.14 (s, 1H), 9.02 (s, 1H), 8.69 (d, J=6.7 Hz, 1H), 8.27 (dd, J=9.1, 5.9 Hz, 1H), 7.79 (dd, J=9.6, 2.3 Hz, 1H), 7.72 (td, J=8.7, 2.3 Hz, 1H), 6.09 (s, 1H), 5.95 (br s, 1H), 5.61 (q, J=8.5 Hz, 1H), 5.12 (t, J=9.5 Hz, 1H), 4.65 (d, J=11.7 Hz, 1H), 4.50 (t, J=8.2 Hz, 1H), 4.38-4.28 (m, 1H), 3.96 (dd, J=11.3, 2.4 Hz, 1H), 2.96-2.88 (m, 1H), 2.69-2.55 (m, 2H), 2.52-2.44 (m, 1H), 2.42 (s, 3H), 2.31 (q, J=8.7 Hz, 1H), 1.96 (q, J=11.4 Hz, 1H), 1.77-1.66 (m, 1H), 1.63-1.56 (m, 2H), 1.45-1.28 (m, 5H), 1.27-1.16 (m, 2H), 1.15-0.95 (m, 4H). LC-MS (ESI): m/z=792.2 [M+H].
