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

Participants

Reaction Steps

2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (33 mg, 0.087 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-methoxybenzoic acid (30 mg, 0.058 mmol), N-ethyl-N-isopropylpropan-2-amine (0.030 mL, 0.17 mmol) and 2-(1,2,4-oxadiazol-3-yl)propan-2-amine hydrochloride (14 mg, 0.087 mmol) in DMF (1 mL) at rt. The mixture was allowed to stir at rt for 30 min. The crude reaction mixture was then 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: 25-100% B over 20 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 material was further 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 methanol:water with 20-mM ammonium acetate; Gradient: 0-100% B over 20 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 10.7 mg, and its estimated purity by LCMS analysis was 97%. 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. retention time: 3.12 min; M+H: 626. 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; MobilePhase 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. retention time: 4.00 min; M+H: 626. Proton NMR was acquired in deuterated DMSO. 1H NMR (500 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.67 (s, 1H), 8.53-8.46 (m, 1H), 8.08-8.01 (m, 2H), 7.88 (s, 1H), 7.72 (s, 1H), 7.62-7.57 (m, 1H), 7.40 (s, 2H), 7.35-7.29 (m, 1H), 4.03 (s, 3H), 3.04-2.96 (m, 2H), 2.83-2.69 (m, 5H), 1.72 (s, 6H).

Provenance & Evidence