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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 1050871
Notes
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Reaction equation

HRID 1050871 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]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

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 71575874
N-(2,5-difluoro-4-((2-propionamidopyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamide
Yield 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, 1 H), 10.52 (s, 1 H), 8.30 (dd, J=12.6, 7.2 Hz, 1 H), 8.18 (d, J=5.7 Hz, 1 H), 7.87 (d, J=7.9 Hz, 1 H), 7.68 (d, J=2.4 Hz, 1 H), 7.51-7.48 (m, 3 H), 7.35 (t, J=8.7 Hz, 2 H), 6.72 (dd, J=5.7, 2.4 Hz, 1 H), 6.55 (d, J=8.0 Hz, 1 H); 4.85 (m, 1 H), 2.34 (q, J=7.5 Hz, 2 H), 1.31 (d, J=6.0 Hz, 6 H), 0.99 (t, J=7.5 Hz, 3 H); 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-6078951735a8420084d9841e6ea06959
Source dataset
uspto-grants-2016_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09387202B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes