Propionamide → N-(2,5-difluoro-4-(2-propionamidopyridin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 476373

Reaction equation

HRID 476373 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.[C:33]([NH2:37])(=[O:36])[CH2:34][CH3:35].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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[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:33](=[O:36])[CH2:34][CH3:35])[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 6578PropionamideHCID 10796Cesium carbonateHCID 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 54576300N-(2,5-difluoro-4-(2-propionamidopyridin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 60.7%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

N-(4-(2-Chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 0.43 mmol) (as prepared in Example 1), propionamide (95 mg, 1.30 mmol), xantphos (25 mg, 0.043 mmol), and cesium carbonate (280 mg, 0.86 mmol) were dissolved in dry dioxane (3 mL) and argon was bubbled through the mixture for 10 minutes. Pd2(dba)3 (20 mg, 0.022 mmol) was then added, and the solution was degassed for an additional 10 minutes. The flask was fitted with a balloon of N2 and slowly heated to 100° C. and stirred overnight. The reaction mixture was cooled to room temperature and diluted with a 4:1 mixture of ethyl acetate and THF (60 mL) and water (40 mL). The organic layer was separated and washed with brine and the aqueous layer was back extracted with the ethyl acetate/THF solution, which was then extracted with brine. The combined organic layers were dried over sodium sulfate and evaporated and the residue was purified by silica gel chromatography to give N-(2,5-difluoro-4-(2-propionamidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (130 mg, 60.7% yield). 1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 10.52 (s, 1H), 9.79 (s, 1H), 8.19 (d, 5.6 Hz, 1H), 8.10-8.05 (m, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.59-7.53 (m, 3H), 7.16 (t, J=8.8 Hz, 2H), 6.74-6.72 (m, 1H), 2.33 (q, 0.7=7.2 Hz, 2H), 1.64-1.55 (m, 4H), 0.99 (t, J=7.2 Hz, 3H).

Workup

  1. customargon was bubbled through the mixture for 10 minutes
  2. customthe solution was degassed for an additional 10 minutes
  3. customThe flask was fitted with a balloon of N2
  4. temperatureThe reaction mixture was cooled to room temperature
  5. additiondiluted with a 4:1 mixture of ethyl acetate and THF (60 mL) and water (40 mL)
  6. customThe organic layer was separated
  7. washwashed with brine
  8. extractionthe aqueous layer was back extracted with the ethyl acetate/THF solution, which
  9. extractionwas then extracted with brine
  10. dry with materialThe combined organic layers were dried over sodium sulfate
  11. customevaporated
  12. customthe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-243ed066297d4ac5ae2af67a5c0075c4
Source dataset
uspto-grants-2014_01
Patent number
US08637672B2

Linked notes

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