Reaction Steps
2-(4-Fluoro-benzylamino)-cyclohex-3-enecarboxylic acid methyl ester (0.051 g, 0.19 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.065 g, 0.19 mmol) was added followed by N-methylmorpholine (0.05 mL, 0.43 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.041 g, 0.21 mmol) was added and the mixture was stirred at 25° C. for 3 h. The solution was diluted with ethyl acetate (25 mL) and washed with 1.0 M aqueous hydrochloric acid solution (2×25 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The oil was dissolved in ethanol (4 mL) and a 21% w/w solution of sodium ethoxide in ethanol (0.3 mL, 0.8 mmol) was added, and the reaction mixture was heated to 60° C. for 2 h. Upon cooling to 25° C., the reaction mixture was acidified to pH 2-3 with 2.0 M aqueous hydrochloric acid solution, upon which the product precipitated while stirring. The solid was collected by vacuum filtration and purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-95% in 9 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,4a,5,6,8a-hexahydro-quinolin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.025 g, 0.046 mmol, 25%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.65-2.24 (4H, m), 3.04 (3H, s), 4.10-4.21 (1H, m), 5.01 (1H, d, J=16.0 Hz), 5.45 (1H, d, J=10.0 Hz), 5.86 (1H, d, J=8.8 Hz), 7.16 (2H, dd, J=8.8 Hz), 7.42 (2H, m), 7.51 (1H, m), 7.57 (12H, m), 10.20 (1H, s). LC-MS (ESI) calcd for C24H23FN4O6S2 546.10, found 547.3 [M+H+].
