Cesium carbonate → N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

HRID 1050863노트

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HRID 1050863 반응식
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:20](=[O:35])[N:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH:37]1([C:40]([NH2:42])=[O:41])[CH2:39][CH2:38]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.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]>[CH:37]1([C:40]([NH:42][C:2]2[CH:7]=[C:6]([O:8][C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]4[C:20](=[O:35])[N:21]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)[CH:22]=[CH:23][C:24]=4[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[O:41])[CH2:39][CH2:38]1

참가 물질

7

반응물 4

HCID 10796Cesium carbonateHCID 80376CyclopropanecarboxamideHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86703361N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

생성물 1

HCID 71575771N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide수율 30.1%

시약·촉매·용매 2

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 312751,4-Dioxane용매

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온도
100 °C

실험 절차

A mixture of N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.100 g, 0.194 mmol, see: Example 1), cyclopropanecarboxamide (0.033 g, 0.388 mmol), Cs2CO3 (0.095 g, 0.291 μmol) and Xantphos (5.05 mg, 8.72 μmol) in dioxane (2 mL) was sparged with argon, treated with Pd2(dba)3 (2.66 mg, 2.91 μmol), sparged again with argon, then fitted with a reflux condensor capped with an argon-filled balloon and heated to 100° C. overnight. The mixture was cooled to RT and partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (33 mg, 30% yield) as a solid. MS (ESI) m/z: 565.2 (M+H+).

후처리

  1. customwas sparged with argon
  2. customsparged again with argon
  3. customfitted with a reflux condensor
  4. customcapped with an argon-
  5. additionfilled balloon
  6. temperatureThe mixture was cooled to RT
  7. custompartitioned between water and EtOAc
  8. washThe organic layer was washed with brine
  9. dry with materialdried over MgSO4
  10. concentrationconcentrated to dryness
  11. custompurified via silica gel chromatography (EtOAc/Hex)

출처 및 근거

ORD 기록
ord-1e05ba3d482c47e9be4fbe0267faab78
출처 데이터셋
uspto-grants-2016_07
특허 번호
US09387202B2

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