Hydroxylamine → 3-(4-{4-Methyl-5-[2-(trifluoromethyl)phenyl]-4h-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-5-(4,4,4-trifluorobutyl)-1,2,4-oxadiazole

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Reaction Steps

A solution of nitrile 1-F (0.56 g, 1.6 mmol) and hydroxylamine (50% aqueous, 4 ml) in ethanol (40 ml) was heated at 80° C. for 18 h. The resulting mixture was cooled to room temperature and concentrated in vacuo. The solid was stripped from toluene and dried under reduced pressure. A portion of the resulting white powder (0.050 g, 0.13 mmol) was added to a pre-stirred solution of 5,5,5-trifluoropentanoic acid (0.058 g, 0.37 mmol) and 1,1′-carbonyldiimidazole (0.050 g, 0.31 mmol) in methylene chloride (1 ml). The resulting mixture was stirred at room temperature for 24 h, then concentrated. The solid was resuspended in DMF and heated to 10° C. under a nitrogen atmosphere for 2 h. The crude product was purified by Gilson reverse phase chromatography eluting with a 10-90% CH3CN (0.1% TFA)/water (0.1% TFA) gradient. Solvent was removed in vacuo and the product free based from methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4 and the solvent removed to yield 1-G as a white powder. MS (ESI+)=514.34 (M+1); 1H NMR (500 MHz, CDCl3): δ 7.86-7.83 (m, 1 H), 7.73-7.69 (m, 2 H), 7.56 (s, 1 H), 3.51 (s, 3 H), 2.99 (t, 2 H), 2.30-2.22 (m, 8 H), 2.17-2.09 (m, 8 H).

Provenance & Evidence