Pyridine → N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramide

HRID 1049329Notes

Reaction equation

HRID 1049329 reaction equation
[C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)[C:8](Cl)=[O:9].[CH3:13][N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=3)[CH:22]=[CH:21][N:20]=2)[CH:16]=[N:15]1.N1C=CC=CC=1>ClCCCl.C1COCC1>[CH3:13][N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:8]([NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[O:9])=[N:30][CH:31]=3)[CH:22]=[CH:21][N:20]=2)[CH:16]=[N:15]1

Participants

7

Reactant 4

HCID 1049PyridineHCID 65578Oxalyl chlorideHCID 68424IsobutyramideHCID 593227775-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-amine

Product 1

HCID 86268064N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramideYield 42%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A suspension of Example B7 (0.059 g, 0.673 mmol) in DCE (4 mL) was treated with oxalyl chloride (0.059 mL, 0.673 mmol), stirred at RT for 1 h, warmed to 80° C. for 2.5 h, cooled to RT and added drop-wise to a solution of Example A2 (0.15 g, 0.561 mmol) in THF (4 mL) and pyridine (0.226 mL, 2.81 mmol). The mixture was stirred at RT overnight, treated with satd. Na2CO3, extracted with EtOAc (4×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The resulting material was dissolved in MeCN/H2O, frozen and lyophilized to afford N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramide (89 mg, 42%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 10.85 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.26-8.25 (m, 2H), 8.09 (d, J=9.0 Hz, 1H), 7.96 (d, J=0.7 Hz, 1H), 7.73 (dd, J=9.0, 3.0 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 6.70 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.43 (m, 1H), 1.09 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 381.1 (M+H+).

Workup

  1. temperaturewarmed to 80° C. for 2.5 h
  2. temperaturecooled to RT
  3. stirringThe mixture was stirred at RT overnight
  4. additiontreated with satd
  5. extractionNa2CO3, extracted with EtOAc (4×)
  6. dry with materialthe combined organics were dried over Na2SO4
  7. concentrationconcentrated to dryness
  8. custompurified via silica gel chromatography (MeOH/DCM)
  9. dissolutionThe resulting material was dissolved in MeCN/H2O
  10. temperaturefrozen

Sources & evidence

ORD record
ord-2a1298ae5c6f451b9e538171484f4b10
Source dataset
uspto-grants-2016_07
Patent number
US09382228B2

Reaction notes

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