Trimethylacetamide → N-((5-((2-isobutyramidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)pivalamide

HRID 626551Notes

Reaction equation

HRID 626551 reaction equation
[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[NH2:14][C:15]1[N:20]=[C:19]([CH3:21])[C:18]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:24]=2)=[CH:17][CH:16]=1>ClCCCl.C1COCC1>[C:30]([NH:29][C:25]1[CH:24]=[C:23]([O:22][C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])=[N:20][C:19]=2[CH3:21])[CH:28]=[CH:27][N:26]=1)(=[O:34])[CH:31]([CH3:32])[CH3:33]

Participants

6

Reactant 3

HCID 12957TrimethylacetamideHCID 65578Oxalyl chlorideHCID 90409610N-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)isobutyramide

Product 1

HCID 86272747N-((5-((2-isobutyramidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)pivalamideYield 43.7%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 2,2,2-trimethylacetamide (0.046 g, 0.454 mmol) in DCE (2 mL) was treated with oxalyl chloride (0.040 mL, 0.454 mmol), stirred at RT for 0.5 h, then heated at 75° C. for 1 h. The mixture was cooled to RT, added to a solution of N-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)isobutyramide (0.10 g, 0.349 mmol) and TEA (0.1 mL, 0.70 mmol) in THF (2 mL) and stirred at RT for 1 h. The mixture was concentrated to dryness, the residue treated with EtOAc, washed with brine, dried over Na2SO4 and concentrated to dryness. The material was treated with EtOAc, allowed to stand at RT overnight and the resulting solid collected via filtration and dried to afford N-((5-((2-isobutyramidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)pivalamide (63 mg, 42%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 10.50 (s, 1H), 10.42 (br s, 1H), 8.18 (d, J=5.7 Hz, 1H), 7.92 (m, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 6.66 (dd, J=5.7, 2.4 Hz, 1H), 2.69 (m, 1H), 2.24 (s, 3H), 1.22 (s, 9H), 1.02 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 414.2 (M+H+).

Workup

  1. temperatureheated at 75° C. for 1 h
  2. temperatureThe mixture was cooled to RT
  3. stirringstirred at RT for 1 h
  4. concentrationThe mixture was concentrated to dryness
  5. additionthe residue treated with EtOAc
  6. washwashed with brine
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated to dryness
  9. additionThe material was treated with EtOAc
  10. waitto stand at RT overnight
  11. filtrationthe resulting solid collected via filtration
  12. customdried

Sources & evidence

ORD record
ord-36c542539aeb44e18a9a04e6b65ad261
Source dataset
uspto-grants-2016_04
Patent number
US09309224B2

Reaction notes

Loading…