Diisopropylethylamine → 2-(4-fluorophenyl)-N-methyl-5-(3-((1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclopropyl)carbamoyl)phenyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridine-3-carboxamide

2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (23 mg, 0.062 mmol) was added to stirring solution of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoic acid (20 mg, 0.041 mmol), N-ethyl-N-isopropylpropan-2-amine (0.022 mL, 0.12 mmol) and 1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclopropanamine hydrochloride (18 mg, 0.10 mmol) in DMF (1 mL) at rt. The mixture was allowed to stir at rt for 1 h. Then, separately an additional amount of the amine: 1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclopropanamine hydrochloride (18 mg, 0.10 mmol) was taken up in 2 mL of a 1:1 mixture of DMF: N-ethyl-N-isopropylpropan-2-amine and then concentrated. The resulting residue along with additional 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoic acid (20 mg, 0.041 mmol), N-ethyl-N-isopropylpropan-2-amine (0.022 mL, 0.12 mmol), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (23 mg, 0.062 mmol) was added to the original reaction mixture and the mixture was allowed to stir for 1 h at rt. The crude 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: 30-70% 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 2.3 mg, and its estimated purity by LCMS analysis was 99%. 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: 2.77 min; M+H: 609. 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. retention time: 3.81 min; M+H: 609. Proton NMR was acquired in deuterated DMSO. 1H NMR (500 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.42-8.33 (m, 1H), 8.00-7.90 (m, 4H), 7.70-7.56 (m, 3H), 7.39-7.30 (m, 2H), 6.65-6.58 (m, 1H), 4.25-4.11 (m, 2H), 2.83-2.75 (m, 3H), 2.52 (s, 3H), 1.48-1.42 (m, 2H), 1.37-1.30 (m, 2H).

1. concentrationN-ethyl-N-isopropylpropan-2-amine and then concentrated
2. stirringto stir for 1 h at rt
3. customThe crude mixture was purified via preparative LC/MS with the following conditions
4. waitGradient: 30-70% B over 20 minutes
5. customa 5-minute hold
6. additionFractions containing the desired product
7. customdried via centrifugal evaporation
8. custom40° C.
9. waitGradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes
10. customa 0.5-minute hold
11. custom40° C.
12. waitGradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes
13. customa 0.5-minute hold

ORD record

ord-67bd08f4c15a44aaa0bf244ea33b624f

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08962651B2