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

HRID 1854767Notes

Reaction equation

HRID 1854767 reaction equation
C(N(C(C)C)C(C)C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:42][C:20]3=[N:21][C:22]([CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[C:23]([C:25]4[CH:26]=[N:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=4)[C:30](O)=[O:31])[CH:24]=[C:19]3[C:18]=2[C:43](=[O:46])[NH:44][CH3:45])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[O:72]1[CH:76]=[N:75][C:74]([C:77]([NH2:80])([CH3:79])[CH3:78])=[N:73]1>CN(C=O)C>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:42][C:20]3=[N:21][C:22]([CH2:36][CH2:37][C:38]([F:40])([F:41])[F:39])=[C:23]([C:25]4[CH:33]=[C:29]([C:30]([NH:80][C:77]([C:74]5[N:75]=[CH:76][O:72][N:73]=5)([CH3:79])[CH3:78])=[O:31])[C:28]([O:34][CH3:35])=[N:27][CH:26]=4)[CH:24]=[C:19]3[C:18]=2[C:43](=[O:46])[NH:44][CH3:45])=[CH:13][CH:12]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 866747552-(1,2,4-Oxadiazol-3-yl)propan-2-amine hydrochlorideHCID 90402530HCID 90402530, compound

Product 1

HCID 854719425-[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

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

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).

Workup

  1. customreaction
  2. filtrationThe solution was filtered
  3. customthe crude material was purified via preparative LC/MS with the following conditions
  4. waitGradient: 20-100% B over 15 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

Sources & evidence

ORD record
ord-ca7da8e36a4a41e7888a5ba972c1d443
Source dataset
uspto-grants-2015_02
Patent number
US08962651B2

Reaction notes

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