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, 0.075 g, 0.225 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.045 g, 0.236 mmol) and N-methylmorpholine (0.052 mL, 0.473 mmol) were added sequentially to a solution of (1R,2S)-2-(cyclopropylmethyl-amino)-cyclopentanecarboxylic acid ethyl ester (0.048 g, 0.225 mmol) in N,N-dimethylformamide (3 mL) at 25° C. The reaction mixture was stirred at 25° C. for 16 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 (0.167 mL, 0.450 mmol) was added and the reaction mixture was heated to 60° C. for 1.5 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×75 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 purified by flash column chromatography (Analogix SuperFlash Column; 30-80% ethyl acetate in hexanes) to afford the desired product, (4aR,7aS)-N-[3-(1-cyclopropylmethyl-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (0.065 g, 0.135 mmol, 60%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 0.28-0.40 (m, 2H), 0.56-0.68 (m, 2H), 1.02-1.18 (m, 1H), 1.60-1.83 (m, 4H), 1.95-2.51 (m, 3H), 2.99-3.06 (m, 1H), 3.06 (d, 3H, J=3.3 Hz), 3.16-3.26 (m, 1H), 3.58-3.64 (m, 1H), 3.92 (q, 1H, J=7.7 Hz), 7.00 (s, 1H), 7.22 (d, 1H, J=8.4 Hz), 7.62-7.66 (m, 1H), 7.68-7.70 (m, 1H). LC-MS (ESI) calcd for C20H24N4O6S2 480.11, found 481.2 [M+H+].
