Oxalyl chloride → N-methyl-4-((6-(3-(1-(trifluoromethyl)cyclobutanecarbonyl)ureido)pyridin-3-yl)oxy)picolinamide

HRID 626582Notes

Reaction equation

HRID 626582 reaction equation
[F:1][C:2]([F:11])([F:10])[C:3]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4]1.[C:12](Cl)(=[O:16])C(Cl)=O.[NH2:18][C:19]1[N:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32]([NH:34][CH3:35])=[O:33])[CH:27]=2)=[CH:21][CH:20]=1.CC[N:38](C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C.O1CCOCC1.CCOC(C)=O.[Ag]OC#N>[CH3:35][NH:34][C:32](=[O:33])[C:28]1[CH:27]=[C:26]([O:25][C:22]2[CH:23]=[N:24][C:19]([NH:18][C:12]([NH:38][C:7]([C:3]3([C:2]([F:1])([F:11])[F:10])[CH2:4][CH2:5][CH2:6]3)=[O:9])=[O:16])=[CH:20][CH:21]=2)[CH:31]=[CH:30][N:29]=1

Participants

10

Reactant 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 27828381-(Trifluoromethyl)cyclobutanecarboxylic acidHCID 904105404-((6-aminopyridin-3-yl)oxy)-N-methylpicolinamide

Product 1

HCID 86274905N-methyl-4-((6-(3-(1-(trifluoromethyl)cyclobutanecarbonyl)ureido)pyridin-3-yl)oxy)picolinamideYield 72.3%

Reagents, catalysts & solvents 5

HCID 6228DimethylformamideCatalystHCID 178513473HCID 178513473, compoundCatalystHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

A solution of 1-trifluoromethyl-cyclobutane-1-carboxylic acid (0.413 g, 2.457 mmol) in DCM (8 mL) was treated with oxalyl chloride (0.179 mL, 2.047 mmol) and DMF (1 drop), stirred for at RT for 2 h, treated with silver cyanate (0.982 g, 6.55 mmol), stirred at RT for 1 h, treated with a solution of 4-((6-aminopyridin-3-yl)oxy)-N-methylpicolinamide (0.2 g, 0.819 mmol) and DIEA (0.858 mL, 4.91 mmol) in dioxane (8 mL) and stirred at RT overnight. The mixture was diluted with EtOAc, the solids removed via filtration through diatomaceous earth and washed with EtOAc. The filtrate was washed with satd. NaHCO3, water, then 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-methyl-4-((6-(3-(1-(trifluoromethyl)cyclobutanecarbonyl)ureido)pyridin-3-yl)oxy)picolinamide (0.259 g, 72%). 1H NMR (400 MHz, DMSO-d6): δ 11.16 (br s, 1H), 10.87 (s, 1H), 8.79 (d, J=5.1 Hz, 1H), 8.53 (d, J=5.6 Hz, 1H), 8.32 (d, J=2.9 Hz, 1H), 8.08 (d, J=9.1 Hz, 1H), 7.81 (dd, J=9.0, 2.9 Hz, 1H), 7.41 (d, J=2.6 Hz, 1H), 7.19 (dd, J=5.6, 2.7 Hz, 1H), 2.78 (d, J=4.8 Hz, 3H), 2.67 (t, J=10.5 Hz, 2H), 2.41 (m, 2H), 1.90-1.87 (m, 2H); MS (ESI) m/z: 438.2 (M+H+).

Workup

  1. stirringstirred at RT for 1 h
  2. stirringstirred at RT overnight
  3. customthe solids removed via filtration through diatomaceous earth
  4. washwashed with EtOAc
  5. washThe filtrate was washed with satd
  6. extractionNaHCO3, water, then brine and the combined aqueous washes were back-extracted with EtOAc
  7. dry with materialThe combined organics were dried over Na2SO4
  8. concentrationconcentrated to dryness
  9. custompurified by silica gel chromatography (EtOAc/DCM)

Sources & evidence

ORD record
ord-df6594acb818441a9d873ce572bfee4f
Source dataset
uspto-grants-2016_04
Patent number
US09309224B2

Reaction notes

Loading…