4-Methylmorpholine → 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzyl)benzamido) acetic acid

Participants

Reaction Conditions

Reaction Steps

To a stirring solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid INT-37 (129 mg, 0.22 mmol) and 4-methylmorpholine (52.0 μL, 0.47 mmol) in dioxane (2 mL) was added isobutyl chloroformate (28.0 μL, 0.22 mmol). After 1 h, the reaction mixture was added to a stirring solution of N′-hydroxybenzimidamide (32.0 mg, 0.24 mmol) in DMF (2 mL). After a further 1 h, the reaction mixture was heated to 120° C. for 1 h. The reaction mixture was allowed to cool to room temperature then poured onto citric acid (50 mL, 0.1 M aqueous solution) and extracted with EA(2×20 mL). The combined organic extracts were washed with NaHCO3 (20 mL), dried over MgSO4 and the solvents evaporated. The crude material was purified by column chromatography (EA/isohexanes). The isolated material was dissolved in DCM (2 mL) and treated with TFA (2 mL). After 2 h, the solvents were concentrated and the residue purified by preparative HPLC to afford 19 mg (14%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzyl)benzamido) acetic acid 368 as a white solid. LCMS-ESI (m/z) calculated for C34H27F3N4O6: 644; found 645 [M+H]+, tR=7.56 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 10.34 (s, 1H), 8.22-8.16 (m, 2H), 8.15-8.08 (m, 2H), 7.81-7.49 (m, 7H), 7.49-7.29 (m, 3H), 7.29-7.05 (m, 2H), 4.78 (s, 1H), 4.71 (s, 1H), 4.05 (s, 1H), 3.98 (s, 1H), 3.91-3.77 (s, 5H).

Provenance & Evidence