4-Methylmorpholine → N-{3-[1-(allyl-cyclobutyl-amino)-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[1,2,4]thiadiazin-7-yl}-methanesulfonamide

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Reaction Steps

2-(N′-Allyl-N′-cyclobutyl-hydrazino)-cycloheptanecarboxylic acid methyl ester (0.60 g, 2.16 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 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, 0.72 mg, 2.16 mmol) was added followed by N-methylmorpholine (0.50 mL, 4.54 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.44 mg, 2.27 mmol) was added and the mixture was stirred at 25° C. for 16 h. The reaction was quenched via addition of saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined and washed with brine (20 mL). The resulting solution was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The oil was dissolved in ethanol (20 mL). A 21% w/w solution of sodium ethoxide in ethanol (2.42 mL, 6.48 mmol) was added. The reaction was heated at reflux for 16 h. The reaction was quenched via the addition of saturated aqueous ammonium chloride solution (40 mL). The mixture was extracted with ethyl acetate (3×40 mL). The organic layer was further washed with saturated sodium bicarbonate solution (2×20 mL), aqueous saturated brine solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a clear oil. Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-5% methanol in dichloromethane) afford the desired product, N-{3-[1-(allyl-cyclobutyl-amino)-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[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.39 g, 0.69 mmol, 32%) as a white powder. 1H NMR (400 MHz, CDCl3) δ: 1.38-2.14 (17H, m), 2.90-3.05 (3H, m), 3.14-3.97 (4H, m), 5.09-5.95 (3H, m), 7.16-8.02 (3H, m). LC-MS (ESI) calcd for C25H33N5O6S2 563.69, found 564.5 [M+H+].

Provenance & Evidence