Cesium carbonate → N-(5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide

HRID 2279055Notes

Reaction equation

HRID 2279055 reaction equation
Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]([CH3:35])[C:32]([NH2:34])=[O:33].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]>[CH3:30][N:31]([CH3:35])[C:32](=[O:33])[NH:34][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 11737N,N-DimethylureaHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 90426999N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide

Product 1

HCID 90427123N-(5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamideYield 65.3%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

A mixture of Example C1 (0.150 g, 0.359 mmol), N,N-dimethyl urea (0.190 g, 2.154 mmol), Cs2CO3 (0.292 g, 0.897 mmol) and Xantphos (0.062 g, 0.108 mmol) in dioxane (7 mL) was sparged with Ar, treated Pd2(dba)3 (0.043 g, 0.047 mmol), sparged again with Ar and heated at 100° C. overnight. The mixture was cooled to RT, treated with aqueous saturated NaHCO3, and extracted with EtOAc (3×). The combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The yellowish solid was re-purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue neutralized with satd. NaHCO3 and extracted with EtOAc (3×). The combined organics were dried over Na2SO4, concentrated to dryness and dried in vacuo. The residue was dissolved in 4:1 MeCN/water, frozen and lyophilized overnight to afford N-(5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (110 mg, 54%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1 H), 8.90 (s, 1 H), 8.20 (d, J=2.5 Hz, 1 H), 8.10 (J=5.7 Hz, 1 H), 8.06 (d, J=9.0 Hz, 1 H), 7.69 (dd, J=9.0, 2.9 Hz, 1 H), 7.37 (d, J=2.4 Hz, 1 H), 6.60 (dd, J=5.7, 2.4 Hz, 1 H), 3.93-3.77 (m, 5 H), 3.47-3.35 (m, 4 H), 2.87 (s, 6 H), 1.76-1.65 (m, 2 H), 1.62-1.56 (m, 2H); MS (ESI) m/z: 470.2 (M+H+).

Workup

  1. customsparged again with Ar
  2. temperatureThe mixture was cooled to RT
  3. additiontreated with aqueous saturated NaHCO3
  4. extractionextracted with EtOAc (3×)
  5. dry with materialThe combined organics were dried over Na2SO4
  6. concentrationconcentrated to dryness
  7. custompurified via silica gel chromatography (MeOH/DCM)
  8. customThe yellowish solid was re-purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA)
  9. customThe organics were removed under reduced pressure
  10. extractionNaHCO3 and extracted with EtOAc (3×)
  11. dry with materialThe combined organics were dried over Na2SO4
  12. concentrationconcentrated to dryness
  13. customdried in vacuo
  14. dissolutionThe residue was dissolved in 4:1 MeCN/water
  15. temperaturefrozen

Sources & evidence

ORD record
ord-23f5103126b04aa3a8282de8e937877c
Source dataset
uspto-grants-2015_09
Patent number
US09133183B2

Reaction notes

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