Reaction Steps
(7-Iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 24b, 0.959 g, 2.62 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.527 g, 2.75 mmol) and N-methylmorpholine (0.605 mL, 5.50 mmol) were added sequentially to a solution of cis-2-(4-fluoro-benzylamino)-cycloheptanecarboxylic acid methyl ester (prepared as described in Example 2b, 0.732 g, 2.62 mmol) in N,N-dimethylformamide (20 mL) at 25° C. The reaction mixture was stirred at 25° C. for 3 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethanol (60 mL) at 25° C. A 21% w/w solution of sodium ethoxide in ethanol (3.40 mL, 10.4 mmol) was added and the reaction mixture was heated to 60° C. for 1 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep Column; 10-70% ethyl acetate in hexanes) to afford the desired product, 1-(4-fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1,4a,5,6,7,8,9,9a-octahydro-cyclohepta[b]pyridin-2-one (0.534 g, 0.891 mmol, 34%) as a beige foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.25-1.42 (2H, m), 1.50-1.57 (3H, m), 1.76-1.98 (1H, m), 1.93 (3H, s), 3.30 (1H, bs), 3.55-3.59 (1H, m), 4.27 (1H, d, J=15.1 Hz), 5.02 (1H, d, J=14.9 Hz), 7.11-7.18 (2H, m), 7.25-7.29 (1H, m), 7.30-7.32 (1H, m), 7.39-7.42 (2H, m), 7.91-7.96 (1H, m), 8.02 (1H, s). LC-MS (ESI) calcd for C24H23FIN3O4S 595.04, found 596.2 [M+H+].
