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

Participants

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 (141 mg, 0.235 mmol) and 4-methylmorpholine (57.0 μl, 0.52 mmol) in dioxane (4 mL) was added isobutyl chloroformate (31.0 μl, 0.24 mmol). After 1 h, the reaction mixture was added through a frit to a stirred solution of N′-hydroxy-4-methylbenzimidamide (38.8 mg, 0.258 mmol) in DMF (2 mL). After stirring at room temperature for 1 h, the reaction mixture was heated to 120° C. for 2 h. The reaction mixture was allowed to cool to room temperature, diluted with DCM (4 mL), washed with NaHCO3 (10 mL), split through a hydrophobic frit and evaporated. The crude material was purified by column chromatography (EA/isohexanes). The isolated material was taken up in DCM (2 mL), treated with TFA (2 mL) and allowed to stir for 2 h. The solvents were evaporated and the residue purified by preparative HPLC to afford 22 mg (14%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetic acid 363 as a white solid. LCMS-ESI (m/z) calculated for C35H29F3N4O6: 658; found 659 [M+H]+, tR=8.01 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 10.34 (s, 1H), 8.32-8.11 (m, 2H), 8.11-7.86 (m, 2H), 7.71-7.52 (m, 4H), 7.50-7.29 (m, 5H), 7.26-7.16 (m, 2H), 4.78 (s, 1H), 4.71 (s, 1H), 4.05 (s, 1H), 3.99 (s, 1H), 3.92-3.76 (m, 5H), 2.42 (s, 3H).

Provenance & Evidence