Cesium carbonate → 1,1-Dimethyl-3-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea

HRID 626523Notes

Reaction equation

HRID 626523 reaction equation
Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:19][N:20]([CH3:24])[C:21]([NH2:23])=[O:22].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]>[CH3:19][N:20]([CH3:24])[C:21]([NH:23][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1)=[O:22]

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 904036213-((2-Chloropyridin-4-yl)oxy)-2-methyl-6-nitropyridine

Product 1

HCID 904098671,1-Dimethyl-3-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

A solution of Example A3 (8.0 g, 30 mmol) in dioxane (150 mL) was sparged with Ar under sonication for 20 min, treated with N,N-dimethylurea (10.6 g, 120 mmol), XANTPHOS (3.48 g, 6.02 mmol), and Cs2CO3 (1.226 g, 3.76 mmol), sparged with Ar under sonication for 30 min, treated with Pd2(dba)3 (2.76 g, 3.01 mmol), sparged again with Ar under sonication for 30 min and heated at 100° C. overnight. The mixture was cooled to RT and diluted with EtOAc. The solids were removed via filtration through diatomaceous earth and washed with EtOAc. The filtrates were concentrated to dryness. The residue was partitioned into EtOAc and water. The aqueous layer was back-extracted with EtOAc (3×) and the combined organics were dried (Na2SO4) and concentrated. MeCN was added and the mixture was sonicated. The solids were collected by filtration to provide 1,1-dimethyl-3-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea, crop 1. The filtrate was concentrated to dryness. Fresh MeCN was added and the mixture was again sonicated. The solids were collected by filtration to provide 1,1-dimethyl-3-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea, crop 2. The filtrate was concentrated in vacuo and purified via silica gel chromatography (MeOH/EtOAc) to afford 1,1-dimethyl-3-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea, crop 3. Crops 1-3 of 1,1-dimethyl-3-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea were combined (5.2 g, 54%). MS (ESI) m/z: 288.1 (M+H+).

Workup

  1. customsparged with Ar under sonication for 30 min
  2. customsparged again with Ar under sonication for 30 min
  3. temperatureThe mixture was cooled to RT
  4. additiondiluted with EtOAc
  5. customThe solids were removed via filtration through diatomaceous earth
  6. washwashed with EtOAc
  7. concentrationThe filtrates were concentrated to dryness
  8. customThe residue was partitioned into EtOAc and water
  9. extractionThe aqueous layer was back-extracted with EtOAc (3×)
  10. dry with materialthe combined organics were dried (Na2SO4)
  11. concentrationconcentrated
  12. additionMeCN was added
  13. customthe mixture was sonicated
  14. filtrationThe solids were collected by filtration

Sources & evidence

ORD record
ord-9809e4a8077b45dfbadc0e1286206477
Source dataset
uspto-grants-2016_04
Patent number
US09309224B2

Reaction notes

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