Ethanol → N-[3-(4-hydroxy-1-isopentyl-2-oxo-5,6,7,8,9,9a-hexahydro-4aH-cyclohepta[b]pyridin-3-yl)-1,1-dioxo-4H-1$l^{6},2,4-benzothiadiazin-7-yl]methanesulfonamide

Participants

Reaction Conditions

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, 0.200 g, 0.600 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.121 g, 0.630 mmol) and N-methylmorpholine (0.139 mL, 1.26 mmol) were added sequentially to a solution of cis-2-(3-methyl-butylamino)-cycloheptanecarboxylic acid methyl ester (0.144 g, 0.600 mmol) in N,N-dimethylformamide (7 mL) at 25° C. The reaction mixture was stirred at 25° C. for 1 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 (5 mL) at 25° C. A 21% w/w solution of sodium ethoxide in ethanol (0.448 mL, 1.20 mmol) was added and the reaction mixture was heated to 60° C. for 2 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; 25-80% ethyl acetate in hexanes) to afford the desired product, N-{3-[4-hydroxy-1-(3-methyl-butyl)-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 (0.186 g, 0.354 mmol, 59%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 0.98-1.01 (m, 6H), 1.41-2.24 (m, 15H), 2.75-3.01 (m, 1H), 3.05-3.09 (m, 1H), 3.06 (d, 3H, J=3.9 Hz), 3.41-3.52 (m, 1H), 3.96-4.09 (m, 1H), 7.16-7.23 (m, 1H), 7.62-7.66 (m, 1H), 7.69-7.71 (m, 1H). LC-MS (ESI) calcd for C23H32N4O6S2 524.18, found 525.4 [M+H+].

Provenance & Evidence