Trimethylacetamide → N-isopropyl-4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)picolinamide

HRID 626585Notes

Reaction equation

HRID 626585 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]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH:23]=2)=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>ClCCCl.O1CCOCC1.CCOC(C)=O>[CH:31]([NH:30][C:28](=[O:29])[C:24]1[CH:23]=[C:22]([O:21][C:18]2[CH:19]=[N:20][C:15]([NH:14][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])=[CH:16][CH:17]=2)[CH:27]=[CH:26][N:25]=1)([CH3:33])[CH3:32]

Participants

8

Reactant 4

HCID 12957TrimethylacetamideHCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 904106474-((6-aminopyridin-3-yl)oxy)-N-isopropylpicolinamide

Product 1

HCID 86274906N-isopropyl-4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)picolinamideYield 82.2%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A suspension of 2,2,2-trimethylacetamide (0.149 g, 1.469 mmol) in DCE (4 mL) was treated with oxalyl chloride (0.129 mL, 1.469 mmol), heated at 80° C. for 1 h, cooled to RT, added drop-wise to a solution of 4-((6-aminopyridin-3-yl)oxy)-N-isopropylpicolinamide (0.2 g, 0.734 mmol) and DIEA (0.641 mL, 3.67 mmol) in dioxane (4 mL) and stirred at RT overnight. The mixture was diluted with EtOAc, washed with satd. NaHCO3, water, and brine, and the combined aqueous washes were back-extracted with EtOAc. The combined organics were dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (EtOAc/DCM) to afford N-isopropyl-4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)picolinamide (0.241 g, 82%). 1H NMR (400 MHz, DMSO-d6): δ 11.24 (s, 1H), 10.45 (s, 1H), 8.50-8.49 (m, 2H), 8.30 (d, J=2.9 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.78 (dd, J=9.0, 2.9 Hz, 1H), 7.40 (d, J=2.6 Hz, 1H), 7.21 (dd, J=5.6, 2.7 Hz, 1H), 4.05-4.04 (m, 1H), 1.21 (s, 9H), 1.15 (d, J=6.5 Hz, 6H); MS (ESI) m/z: 400.2 (M+H+).

Workup

  1. temperaturecooled to RT
  2. washwashed with satd
  3. extractionNaHCO3, water, and brine, and the combined aqueous washes were back-extracted with EtOAc
  4. dry with materialThe combined organics were dried over Na2SO4
  5. concentrationconcentrated to dryness
  6. custompurified by silica gel chromatography (EtOAc/DCM)

Sources & evidence

ORD record
ord-13ca4698ae7342ceb1f5c1c3ee186791
Source dataset
uspto-grants-2016_04
Patent number
US09309224B2

Reaction notes

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