Water → N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramide

HRID 626552Notes

Reaction equation

HRID 626552 reaction equation
[C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)[C:8](Cl)=[O:9].[NH2:13][C:14]1[N:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=2)=[CH:16][CH:15]=1.O>ClCCCl.C1COCC1>[C:28]([NH:27][C:23]1[CH:22]=[C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:8]([NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[O:9])=[N:19][CH:18]=2)[CH:26]=[CH:25][N:24]=1)(=[O:30])[CH3:29]

Participants

7

Reactant 4

HCID 962WaterHCID 65578Oxalyl chlorideHCID 68424IsobutyramideHCID 90410482N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)acetamide

Product 1

HCID 86272749N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramideYield 31%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of isobutyramide (0.071 g, 0.819 mmol) in DCE (3 mL) was treated with oxalyl chloride (0.104 g, 0.819 mmol), stirred at RT for 1 h, then heated at 75° C. for 1 h. The mixture was cooled to RT, treated with a solution of Example A2 (0.1 g, 0.409 mmol) and TEA (0.124 g, 1.228 mmol) in THF (3 mL) and stirred at RT for 1 h. The mixture was treated with water, extracted with 10% MeOH/DCM (1×), then DCM (1×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The residue was treated with EtOAc, sonicated and the resulting solid collected via filtration. The solid was re-suspended in EtOAc, sonicated and again collected via filtration and dried to afford N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramide (45 mg, 31%). 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 10.85 (s, 1H), 10.56 (s, 1H), 8.24 (d, J=2.9 Hz, 1H), 8.18 (d, J=5.7 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 6.68 (dd, J=5.7, 2.4 Hz, 1H), 2.68-2.66 (m, 1H), 2.03 (s, 3H), 1.09 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 358.2 (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. extractionextracted with 10% MeOH/DCM (1×)
  5. washDCM (1×) and the combined organics were washed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated to dryness
  8. additionThe residue was treated with EtOAc
  9. customsonicated
  10. filtrationthe resulting solid collected via filtration
  11. customsonicated
  12. filtrationagain collected via filtration
  13. customdried

Sources & evidence

ORD record
ord-2045cb188d6d4f3ea8e90a64fe6bf0b6
Source dataset
uspto-grants-2016_04
Patent number
US09309224B2

Reaction notes

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