Diisopropylethylamine → 5-[2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridin-5-yl]-2-methoxy-N-[2-(1,2,4-oxadiazol-3-yl)propan-2-yl]pyridine-3-carboxamide

Participants

Reaction Steps

N-ethyl-N-isopropylpropan-2-amine (67 μl, 0.39 mmol) was added to stirring solution of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridin-5-yl)-2-methoxynicotinic acid (25 mg, 0.048 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (28 mg, 0.072 mmol) and 2-(1,2,4-oxadiazol-3-yl)propan-2-amine hydrochloride (7.9 mg, 0.048 mmol) in DMF (1) at rt. The mixture was allowed to stir at rt for 1 h. LCMS shows complete reaction. The solution was filtered and then the crude material was purified via preparative LC/MS with the following conditions: Column:Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 20-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.2 mg, and its estimated purity by LCMS analysis was 96%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column:Waters BEH C18, 2.0×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40° C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min. Rt: 3.14 min, M+H=627. Injection 2 conditions: Column:Waters BEH C18, 2.0×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10 mM ammonium acetate; Temperature: 40° C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min. Rt: 4.05 min, M+H=627. Proton NMR was acquired in deuterated DMSO. 1H NMR (500 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.70 (s, 1H), 8.49 (d, J=4.6 Hz, 1H), 8.43 (d, J=2.4 Hz, 1H), 8.10 (d, J=2.4 Hz, 1H), 8.08-8.02 (m, 2H), 7.98 (s, 1H), 7.41 (t, J=8.9 Hz, 2H), 4.10 (s, 3H), 3.04-2.98 (m, 2H), 2.81 (d, J=4.6 Hz, 3H), 2.80-2.74 (m, 2H), 1.73 (s, 6H).

Provenance & Evidence