Pyridine → N-((6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide

HRID 1049342Notes

Reaction equation

HRID 1049342 reaction equation
[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[CH3:14][C:15]1[N:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[CH:30]=2)[CH:24]=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>ClCCCl.C1COCC1>[CH3:14][C:15]1[N:20]=[C:19]([NH:21][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])[CH:18]=[CH:17][C:16]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[CH:30]=2)[CH:24]=1

Participants

8

Reactant 5

HCID 1049PyridineHCID 12957TrimethylacetamideHCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 904036286-Methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine

Product 1

HCID 90403221N-((6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamideYield 18%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A suspension of 2,2,2-trimethylacetamide (0.086 g, 0.850 mmol) in DCE (3.5 mL) was treated drop-wise with oxalyl chloride (0.074 mL, 0.850 mmol), stirred at RT for 0.5 h, then warmed to 85° C. for 1 h. The solution was cooled to RT, added drop-wise to a solution of Example A7 (0.2 g, 0.708 mmol) and pyridine (0.069 mL, 0.850 mmol) in THF (3.5 mL) and stirred at RT for 2.5 days. Satd. NaHCO3 was added, the mixture extracted with EtOAc (4×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The white solid was dissolved in MeOH, treated with water until a precipitate formed and the solid was collected via filtration, dissolved in MeCN/H2O, frozen and lyophilized to afford N-((6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (51 mg, 18%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 10.41 (s, 1H), 8.55 (d, J=5.7 Hz, 1H), 7.93-7.91 (m, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.5 Hz, 1H), 6.97-6.95 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 1.20 (s, 9H); MS (ESI) m/z: 410.2 (M+H+).

Workup

  1. temperaturewarmed to 85° C. for 1 h
  2. temperatureThe solution was cooled to RT
  3. stirringstirred at RT for 2.5 days
  4. extractionthe mixture extracted with EtOAc (4×)
  5. dry with materialthe combined organics were dried over Na2SO4
  6. concentrationconcentrated to dryness
  7. custompurified via silica gel chromatography (MeOH/DCM)
  8. dissolutionThe white solid was dissolved in MeOH
  9. additiontreated with water until a precipitate
  10. customformed
  11. filtrationthe solid was collected via filtration
  12. dissolutiondissolved in MeCN/H2O
  13. temperaturefrozen

Sources & evidence

ORD record
ord-0175bd0979df46aaab6e161c4e2d123f
Source dataset
uspto-grants-2016_07
Patent number
US09382228B2

Reaction notes

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