Propionamide → N-(2,5-difluoro-4-((2-propionamidopyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamide

HRID 1411155Notes

Reaction equation

HRID 1411155 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:20](=[O:36])[N:21]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH:26]([CH3:28])[CH3:27])=[O:18])=[C:11]([F:37])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:44]([NH2:48])(=[O:47])[CH2:45][CH3:46].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]>[F:37][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:48][C:44](=[O:47])[CH2:45][CH3:46])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1[C:20](=[O:36])[N:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH:26]([CH3:28])[CH3:27])=[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 86703364N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamide

Product 1

HCID 71575874N-(2,5-difluoro-4-((2-propionamidopyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamideYield 49.4%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
90 °C

Procedure

N-(4-((2-Chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamide (180 mg, 0.340 mmol), Cs2CO3 (400 mg, 1.228 mmol), propionamide (200 mg, 2.74 mmol) and Xantphos (20 mg, 0.035 mmol) were combined in dioxane (10 mL), sparged with argon under sonication, treated with Pd2(dba)3 (15 mg, 0.016 mmol) and heated to 90° C. overnight. The solids were collected by filtration and washed with DCM and MeCN. The filtrate was evaporated and the residue purified by silica gel chromatography (0-100% EtOAc/DCM) to provide N-(2,5-difluoro-4-((2-propionamidopyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamide (95 mg, 49.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 10.52 (s, 1H), 8.30 (dd, J=12.6, 7.2 Hz, 1H), 8.18 (d, J=5.7 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.51-7.48 (m, 3H), 7.35 (t, J=8.7 Hz, 2H), 6.72 (dd, J=5.7, 2.4 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H); 4.85 (m, 1H), 2.34 (q, J=7.5 Hz, 2H), 1.31 (d, J=6.0 Hz, 6H), 0.99 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 567.1 (M+H+).

Workup

  1. customsparged with argon under sonication
  2. filtrationThe solids were collected by filtration
  3. washwashed with DCM and MeCN
  4. customThe filtrate was evaporated
  5. customthe residue purified by silica gel chromatography (0-100% EtOAc/DCM)

Sources & evidence

ORD record
ord-b0ac709ea4fd4bbfbb6167b8f59f7301
Source dataset
uspto-grants-2014_12
Patent number
US08921565B2

Reaction notes

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