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, 0.100 g, 0.300 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.060 g, 0.315 mmol) and N-methylmorpholine (0.070 mL, 0.630 mmol) were added sequentially to a solution of cis-2-(3,3-dimethyl-butylamino)-cycloheptanecarboxylic acid methyl ester (0.076 g, 0.300 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were washed with saturated aqueous brine solution (100 mL), dried over sodium sulfate, filtered, and were concentrated in vacuo. The residue was dissolved in ethanol (4 mL) at 25° C. A 21% w/w solution of sodium ethoxide in ethanol (0.244 mL, 0.600 mmol) was added and the reaction mixture was heated to 60° C. for 2 h. After cooling to 25° C. and stirring for 16 h, the reaction mixture was slowly added to 1.0 M aqueous hydrochloric acid solution (50 mL) at 0° C. The resulting precipitate was collected by filtration and dried in vacuo, then was triturated with a small amount of methanol (ca. 0.5 mL) to afford the desired product, N-{3-[1-(3,3-dimethyl-butyl)-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 (0.096 g, 0.178 mmol, 59%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.01 (s, 9H), 1.41-2.25 (m, 12H), 2.72-3.00 (m, 1H), 3.06 (d, 3H, J=3.6 Hz), 3.06-3.33 (m, 1H), 3.40-3.50 (m, 1H), 3.94-4.10 (m, 1H), 7.02 (d, 1H, J=18.0 Hz), 7.20 (dd, 1H, J1=22.7 Hz, J2=13.4 Hz), 7.64 (t, 1H, J=7.5 Hz), 7.69 (d, 1H, J=7.7 Hz). LC-MS (ESI) calcd for C24H34N4O6S2 538.19, found 539.4 [M+H+].
