Pyridine → N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide

HRID 1049315Notes

Reaction equation

HRID 1049315 reaction equation
[F:1][C:2]([F:12])([F:11])[C:3]1([CH2:6][CH2:7][C:8]([NH2:10])=[O:9])[CH2:5][CH2:4]1.C(Cl)(=O)[C:14](Cl)=[O:15].[CH3:19][N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=3)[CH:28]=[CH:27][N:26]=2)[CH:22]=[N:21]1.N1C=CC=CC=1>ClCCCl.C1COCC1>[CH3:19][N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([NH:38][C:14]([NH:10][C:8](=[O:9])[CH2:7][CH2:6][C:3]4([C:2]([F:11])([F:12])[F:1])[CH2:5][CH2:4]4)=[O:15])=[N:36][CH:37]=3)[CH:28]=[CH:27][N:26]=2)[CH:22]=[N:21]1

Participants

7

Reactant 4

HCID 1049PyridineHCID 65578Oxalyl chlorideHCID 593227775-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-amineHCID 904035533-(1-(Trifluoromethyl)cyclopropyl)propanamide

Product 1

HCID 90403202N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamideYield 55.2%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A suspension of Example B2 (0.081 g, 0.449 mmol) in DCE (6 mL) was treated with oxalyl chloride (0.039 mL, 0.449 mmol), stirred at RT for 0.5 h, then heated to 83° C. for 3 h. The mixture was cooled to RT, added drop-wise to a solution of Example A2 (0.10 g, 0.374 mmol) and pyridine (0.151 mL, 1.871 mmol) in THF (6 mL) and stirred at RT for 1 h. The mixture was treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN, sonicated for 5 min and the resulting solid collected via filtration and dried to afford N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide (98 mg, 55%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 10.89 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27-8.25 (m, 2H), 8.08 (d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.73 (dd, J=9.0, 2.9 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.70 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.57 (t, J=8.0 Hz, 2H), 1.87 (t, J=8.0 Hz, 2H), 0.91 (m, 2H), 0.78 (m, 2H); MS (ESI) m/z: 475.1 (M+H+).

Workup

  1. temperatureheated to 83° C. for 3 h
  2. temperatureThe mixture was cooled to RT
  3. stirringstirred at RT for 1 h
  4. additionThe mixture was treated with satd
  5. extractionNaHCO3, extracted with EtOAc (3×)
  6. dry with materialthe combined organics were dried over Na2SO4
  7. concentrationconcentrated to dryness
  8. additionThe material was treated with MeCN
  9. customsonicated for 5 min
  10. filtrationthe resulting solid collected via filtration
  11. customdried

Sources & evidence

ORD record
ord-d09763a557874a3d9ca7617f45bc105e
Source dataset
uspto-grants-2016_07
Patent number
US09382228B2

Reaction notes

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