反应详情

2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (23 mg, 0.059 mmol) was added to stirring solution of 2-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridin-5-yl)benzoic acid (20 mg, 0.040 mmol), N-ethyl-N-isopropylpropan-2-amine (0.021 mL, 0.12 mmol) and 2-(1,2,4-oxadiazol-3-yl)propan-2-amine hydrochloride (10 mg, 0.059 mmol) in DMF (1 mL) at rt. The mixture was allowed to stir at rt for 30 min. The crude reaction mixture 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 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: 50-90% B over 30 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 acetonitrile:water with 20-mM ammonium acetate; Gradient: 40-80% B over 40 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 7.7 mg, and its estimated purity by LCMS analysis was 100%. 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: 3.04 min; M+H: 614. 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: 4.03 min; M+H: 614. Proton NMR was acquired in deuterated DMSO. 1H NMR (500 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.85 (s, 1H), 8.55-8.48 (m, 1H), 8.08-8.01 (m, 2H), 7.93 (s, 1H), 7.66-7.59 (m, 1H), 7.57-7.51 (m, 1H), 7.46-7.37 (m, 3H), 3.04-2.96 (m, 2H), 2.85-2.69 (m, J=3.7 Hz, 5H), 1.68 (s, 6H).

1. customThe crude reaction mixture
2. customwas purified via preparative LC/MS with the following conditions
3. waitGradient: 20-100% B over 20 minutes
4. customa 5-minute hold
5. additionFractions containing the desired product
6. customdried via centrifugal evaporation
7. customThe material was further purified via preparative LC/MS with the following conditions
8. waitGradient: 50-90% B over 30 minutes
9. customa 5-minute hold
10. additionFractions containing the desired product
11. customdried via centrifugal evaporation
12. customThe material was further purified via preparative LC/MS with the following conditions
13. waitGradient: 40-80% B over 40 minutes
14. customa 5-minute hold
15. additionFractions containing the desired product
16. customdried via centrifugal evaporation
17. custom40° C.
18. waitGradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes
19. customa 0.5-minute hold
20. custom40° C.
21. waitGradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes
22. customa 0.5-minute hold