Reaction Steps
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1 g, 0.299 mmol) was dissolved in anhydrous N,N-dimethylformamide (1.5 mL). cis-2-(4-Fluoro-benzylamino)-cycloheptanecarboxylic acid methyl ester (0.084 g, 0.299 mmol) was added followed by a 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.314 mL, 0.314 mmol). The mixture stirred at 25° C. for 1.5 h. Triethylamine (0.122 mL, 0.897 mmol) was added and the mixture stirred at 50° C. for 16 h. Upon cooling, the mixture was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The product was extracted into ethyl acetate (100 mL). The organic layer was filtered to remove the N,N′-dicyclohexylurea precipitate and then further washed with 1.0 M aqueous hydrochloric acid solution (50 mL), saturated aqueous brine solution (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; column 1: 50-70% ethyl acetate in hexanes; column 2: 1-5% methanol in dichloromethane) afforded the desired product, N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,8,9,9a-octahydro-1H-cyclohepta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.049 g, 0.087 mmol, 29%), as a pale yellow powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.23-1.38 (3H, m), 1.46-1.73 (6H, m), 1.93-2.02 (1H, m), 2.72-2.80 (1H, m), 2.98 (3H, s), 3.03 (1H, s), 4.07 (1H, d, J=14.9 Hz), 5.01 (1H, d, J=15.5 Hz), 7.12 (2H, t, J=9.1 Hz), 7.18-7.25 (1H, m), 7.33-7.37 (3H, m), 7.43 (1H, s), 7.51-7.56 (1H, m), 9.81 (1H, s). LC-MS (ESI) calcd for C25H27FN4O6S2 562.14, found 563.2 [M+H+].
