Ethanol → cis-N-{3-[1-(4-fluoro-benzyl)-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-1lambda6-benzo[1,4]thiazin-7-yl}-methanesulfonamide

Participants

Reaction Conditions

Reaction Steps

(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (prepared as described in Example 25 h, 0.365 g, 1.10 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.223 g, 1.16 mmol) and N-methylmorpholine (0.256 mL, 2.33 mmol) were added sequentially to a solution of cis-2-(4-fluoro-benzylamino)-cycloheptanecarboxylic acid methyl ester (prepared as described in Example 2b, 0.310 g, 1.10 mmol) in N,N-dimethylformamide (6 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 (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 (30 mL) at 25° C. A 21% w/w solution of sodium ethoxide in ethanol (1.44 mL, 4.44 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; 30-100% ethyl acetate in hexanes) to afford cis-N-{3-[1-(4-fluoro-benzyl)-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[1,4]thiazin-7-yl}-methanesulfonamide (0.340 g, 0.610 mmol, 55%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: (1:1 mixture of tautomers) 0.86-0.90 (m), 1.15-1.19 (m), 1.27-1.36 (m), 1.46-1.66 (m), 2.01-2.05 (m), 3.06 (s), 3.31 (s), 3.50-3.54 (m), 3.98-4.41 (1H, m), 4.26-4.33 (m), 4.95-5.05 (m), 5.52 (d, J=16.1 Hz), 5.61 (d, J=15.9 Hz), 5.69 (d, J=15.4 Hz), 5.89 (d, J=16.4 Hz), 7.15-7.26 (m), 7.40-7.41 (m), 7.48-7.51 (m), 7.57-7.61 (m), 10.14 (s), 10.18 (s). LC-MS (ESI) calcd for C26H28FN3O6S2 561.14, found 562.4 [M+H+].

Provenance & Evidence