Cesium carbonate → HCID 71584877, compound

HRID 1430570Notes

Reaction equation

HRID 1430570 reaction equation
Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([CH3:34])=[CH:17][C:18]([F:33])=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=4)=[O:23])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:41][N:42]([CH3:46])[C:43]([NH2:45])=[O:44].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].CN(C=O)C.CCOC(C)=O.O>[F:32][C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[NH:21][C:19]2[C:18]([F:33])=[CH:17][C:16]([CH3:34])=[C:15]([C:7]3[C:8](=[O:14])[N:9]([CH2:12][CH3:13])[C:10]4[C:5]([CH:6]=3)=[CH:4][N:3]=[C:2]([NH:45][C:43](=[O:44])[N:42]([CH3:46])[CH3:41])[CH:11]=4)[CH:20]=2)[CH:30]=[C:29]([F:31])[CH:28]=1

Participants

10

Reactant 4

HCID 10796Cesium carbonateHCID 11737N,N-DimethylureaHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86713696HCID 86713696, compound

Product 1

HCID 71584877HCID 71584877, compoundYield 5.7%

Reagents, catalysts & solvents 5

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3,5-difluorophenyl)urea (287 mg, 0.589 mmol), Cs2CO3 (576 mg, 1.768 mmol), N,N-dimethylurea (260 mg, 2.95 mmol) and Xantphos (102 mg, 0.177 mmol) in dioxane (5 mL) was sparged with Ar, treated with Pd2(dba)3 (81 mg, 0.088 mmol) and heated at 100° C. overnight. The mixture was cooled to RT, treated with water, EtOAc and DMF and the solids removed via filtration through diatomaceous earth. The layers of the filtrate were separated, the organic layer washed with brine, dried over Na2SO4, concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue treated with satd. NaHCO3 and stirred overnight. The resulting solid was collected via filtration and dried to afford 3-(3-(5-(3-(3,5-difluorophenyl)ureido)-4-fluoro-2-methylphenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (18 mg, 5% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H), 9.17 (s, 1H), 8.65 (m, 2H), 8.01 (s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.86 (s, 1H), 7.20-7.11 (m, 3H), 6.78 (m, 1H), 4.18 (q, J=7.1 Hz, 2H), 2.97 (s, 6H), 2.08 (s, 3H), 1.24 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 539.2 [M+H]+.

Workup

  1. customwas sparged with Ar
  2. temperatureThe mixture was cooled to RT
  3. customthe solids removed via filtration through diatomaceous earth
  4. customThe layers of the filtrate were separated
  5. washthe organic layer washed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated to dryness
  8. custompurified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA)
  9. customThe organics were removed under reduced pressure
  10. additionthe aqueous residue treated with satd
  11. filtrationThe resulting solid was collected via filtration
  12. customdried

Sources & evidence

ORD record
ord-00d10feb42774741955a1ea9e0c825c3
Source dataset
uspto-grants-2015_01
Patent number
US08940756B2

Reaction notes

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