Cesium carbonate → N-(2,5-difluoro-4-((2-pivalamidopyridin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 476387Notes

Reaction equation

HRID 476387 reaction equation
Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:33][C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36].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.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:32][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:37][C:35](=[O:36])[C:34]([CH3:39])([CH3:38])[CH3:33])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:23])[CH2:21][CH2:20]1)=[O:18]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 12957TrimethylacetamideHCID 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 54576513N-(2,5-difluoro-4-((2-pivalamidopyridin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 40.2%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (160 mg, 0.34 mmol) (as prepared in Example 1), 2,2-dimethyl-propionamide (100 mg, 1 mmol), xantphos (40 mg, 0.068 mmol), and cesium carbonate (222 mg, 0.68 mmol) were dissolved in dry dioxane (2 mL) and argon was bubbled through the mixture for 10 minutes. Pd(OAc)2 (8 mg, 0.034 mmol) was then added, and the solution was degassed for an additional 10 minutes. The mixture was heated to 100° C. and stirred overnight. The reaction mixture was cooled to RT and diluted with EtOAc (20 mL) and water (15 mL). The organic layer was separated and washed with brine. The aqueous layer was extracted with EtOAc and the extracts were washed with brine. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by prep-TLC to give N-(2,5-difluoro-4-((2-pivalamidopyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (72 mg, 40% yield). 1H-NMR (400 MHz, DMSO-d6): δ 8.19-8.17 (m, 2H), 7.69 (s, 1H), 7.53-7.51 (m, 2H), 7.24 (br t, J=7.2 Hz, 1H), 7.10-7.05 (m, 2H), 6.73 (brs, 1H), 1.73-1.69 (m, 4H), 1.27 (s, 9H); MS (ESI); m/z 527.3 [M+H]+.

Workup

  1. customargon was bubbled through the mixture for 10 minutes
  2. customthe solution was degassed for an additional 10 minutes
  3. temperatureThe reaction mixture was cooled to RT
  4. additiondiluted with EtOAc (20 mL) and water (15 mL)
  5. customThe organic layer was separated
  6. washwashed with brine
  7. extractionThe aqueous layer was extracted with EtOAc
  8. washthe extracts were washed with brine
  9. dry with materialThe combined organic layers were dried over sodium sulfate
  10. concentrationconcentrated in vacuo
  11. customThe residue was purified by prep-TLC

Sources & evidence

ORD record
ord-5a55bd82ae904c21aa011e28d9e824cf
Source dataset
uspto-grants-2014_01
Patent number
US08637672B2

Reaction notes

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