Triethylamine → 4-chloro-N-(2,5-difluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide

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Reaction Steps

A mixture of 4-chloro-N-(4-cyano-2,5-difluorobenzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (320 mg, 0.70 mmol) (Example 25), hydroxylamine hydrochloride (247 mg, 3.5 mmol), and triethylamine (488 uL, 3.5 mmol) was refluxed in 8 mL ethanol for 3 h. The reaction was concentrated and the residue was partitioned between ethyl acetate and sat. sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated. The crude intermediate was stirred in 5 mL triethylorthoformate with three drops of boron trifluoride etherate at room temperature overnight. The reaction was purified by flash chromatography on silica gel with 0 to 60% ethyl acetate in hexane to yield 4-chloro-N-(2,5-difluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (250 mg, 71%). 1H NMR (400 MHz, CDCl3) δ ppm 8.81 (s, 1H), 7.70-7.79 (m, 3H), 7.58 (dd, J=10.20, 5.92 Hz, 1H), 7.50 (d, J=8.56 Hz, 2H), 4.54 (d, J=15.60 Hz, 1H), 4.41 (d, J=15.60 Hz, 1H), 3.64 (td, J=7.93, 3.78 Hz, 2H), 3.14 (t, J=10.58 Hz, 1H), 2.52 (br. s., 1H), 1.58-1.74 (m, 3H), 1.45-1.53 (m, 2H), 1.02-1.26 (m, 4H). Analytical HPLC R.T.=22.92 min. MS [M+H]+=498. HRMS [M+H] calc'd 498.1066, found 498.1087. Chiral LC: R.T.=9.84 min., 99% ee. Optical rotation: [α]=−36.66°, CHCl3 (c=4.29 mg/mL).

Provenance & Evidence