Cesium carbonate → N-(4-(2-(2-(dimethylamino)acetamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 476370Notes

Reaction equation

HRID 476370 reaction equation
[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([NH2:6])=[O:5].Cl[C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([NH:23][C:24]([C:26]3([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[O:30])[CH2:28][CH2:27]3)=[O:25])=[C:18]([F:39])[CH:17]=2)[CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([NH:6][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([NH:23][C:24]([C:26]3([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)=[O:30])[CH2:28][CH2:27]3)=[O:25])=[C:18]([F:39])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:5]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 2301162-(Dimethylamino)acetamideHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86662871N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Product 1

HCID 54576084N-(4-(2-(2-(dimethylamino)acetamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 48%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

2-(Dimethylamino)acetamide (0.100 g, 0.974 mmol), N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.15 g, 0.325 mmol) (as prepared in Example 1), cesium carbonate (0.159 g, 0.487 mmol), and xantphos (0.018 g, 0.032 mmol) were combined in dry dioxane (2.5 mL) and argon was bubbled through the mixture for 5 minutes. Palladium acetate (5.47 mg, 0.024 mmol) was added and the solution was degassed for an additional 5 minutes. The reaction flask was fitted with a reflux condenser and a balloon of argon and heated at 100° C. for 15 hours. The mixture was cooled to room temperature and then diluted with ethyl acetate (75 mL) and water (45 mL). The water layer was removed and extracted again with ethyl acetate (25 mL). The combined organic layers were washed with brine (50 mL) and dried over magnesium sulfate. Evaporation of the solvent yielded a lavender-colored oil which was purified by silica gel chromatography (0 to 7% methanol in dichloromethane) to give N-(4-(2-(2-(dimethylamino)acetamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.0823 g, 48% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 9.97 (s, 1H), 9.79 (s, 1H), 8.20 (d, 1H), 8.09 (dd, 1H), 7.65 (d, 1H), 7.57 (m, 3H), 7.16 (m, 2H), 6.76 (dd, 1H), 3.06 (s, 2H), 2.25 (s, 6H), 1.63 (m, 2H), 1.57 (m, 2H); MS (ESI) ink: 528.2 (M+H+).

Workup

  1. customargon was bubbled through the mixture for 5 minutes
  2. customthe solution was degassed for an additional 5 minutes
  3. customThe reaction flask was fitted with a reflux condenser
  4. temperatureThe mixture was cooled to room temperature
  5. additiondiluted with ethyl acetate (75 mL) and water (45 mL)
  6. customThe water layer was removed
  7. extractionextracted again with ethyl acetate (25 mL)
  8. washThe combined organic layers were washed with brine (50 mL)
  9. dry with materialdried over magnesium sulfate
  10. customEvaporation of the solvent
  11. customyielded a lavender-colored oil which
  12. customwas purified by silica gel chromatography (0 to 7% methanol in dichloromethane)

Sources & evidence

ORD record
ord-2bbe862f8f8643ce90eccf4b7fc695b4
Source dataset
uspto-grants-2014_01
Patent number
US08637672B2

Reaction notes

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