4-Methylmorpholine → N-[3-[1-[(4-fluorophenyl)methyl]-4-hydroxy-3-isopentyl-3-methyl-6-oxo-2H-pyridin-5-yl]-1,1-dioxo-4H-1$l^{6},2,4-benzothiadiazin-7-yl]methanesulfonamide

Participants

Reaction Conditions

Reaction Steps

A solution of 2-[(4-fluoro-benzylamino)-methyl]-2,5-dimethyl-hexanoic acid ethyl ester (93 mg, 0.30 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (100 mg, 0.30 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60 mg, 0.315 mmol) in anhydrous N,N-dimethyformamide (4 mL) was treated with N-methyl morpholine (0.069 mL, 0.63 mmol). The reaction was stirred under a nitrogen environment at 25° C. for 1 h, quenched with a 1.0 M aqueous hydrochloric acid solution (50 mL), extracted with ethyl acetate (2×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was dissolved in ethanol (5 mL) and treated with a 60% oil dispersion of sodium hydride (48 mg, 2.0 mmol). The reaction was heated at 60° C. under a nitrogen environment for 1.5 h. The reaction mixture was allowed to cool to 25° C., quenched with a 0.5 M aqueous hydrochloric acid solution (50 mL), extracted with ethyl acetate (2×50 mL), washed with brine (50 mL), dried with sodium sulfate, filtered, and concentrated in vacuo. The crude resin was purified by flash column chromatography (ISCO RediSep column, 0 to 100% ethyl acetate in hexanes) to afford the desired product, N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-5-methyl-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}methanesulfonamide (67 mg, 38%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 0.81 (t, 6H, J=7.0 Hz), 0.87-1.04 (m, 3H), 1.14 (s, 3H), 1.23-1.56 (m, 4H), 3.06 (s, 3H), 3.15 (q, 2H, J=11.4 Hz), 4.62 (dd, 2H, J1=115.3 Hz, J2=14.7, Hz), 7.03-7.10 (m, 2H), 7.18-7.30 (m, 3H), 7.62-7.71 (m, 2H). LC-MS (ESI) calculated for C26H31FN4O6S2: 578.6, found 579.2 [M+H+].

Provenance & Evidence