Formamide → HCID 71584878, compound

HRID 1257279Notes

Reaction equation

HRID 1257279 reaction equation
[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)=[CH:6][C:5]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:27]=2)=[O:24])=[C:4]([F:40])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:47]([NH2:49])=[O:48].CCOC(C)=O>O1CCOCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:40])[C:5]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:27]=2)=[O:24])=[CH:6][C:7]=1[C:8]1[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]2[C:16]([CH:17]=1)=[CH:15][N:14]=[C:13]([NH:49][CH:47]=[O:48])[CH:12]=2

Participants

8

Reactant 4

HCID 713FormamideHCID 8857Ethyl AcetateHCID 11430Potassium CarbonateHCID 86713694HCID 86713694, compound

Product 1

HCID 71584878HCID 71584878, compoundYield 21%

Reagents, catalysts & solvents 3

HCID 25112666BrettPhos PalladacycleCatalystHCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)phenyl)urea (155 mg, 0.263 mmol), K2CO3 (73 mg, 0.570 mmol) and formamide (59 mg, 1.317 mmol) in dioxane (3 mL) was sparged with Ar, treated with BrettPhos Palladacycle (10 mg, 13 μmol) and heated at 100° C. for 2 h. The mixture was cooled to RT, treated with EtOAc, DMF and 50% satd. NaHCO3 and the solid collected via filtration. The layers of the filtrate were separated, the organics layer washed with brine, dried over Na2SO4, concentrated to dryness, combined with the isolated solid 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 for 1 h. The resulting solid was collected via filtration, dried and re-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 extracted with EtOAc (3×). The combined organics were dried over Na2SO4 and concentrated to dryness to afford N-(3-(2-chloro-4-fluoro-5-(3-(4-fluoro-3-(morpholinomethyl)phenyl)ureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide (33 mg, 20% yield). MS (ESI) m/z: 597.2 [M+H]+.

Workup

  1. customwas sparged with Ar
  2. temperatureThe mixture was cooled to RT
  3. filtrationNaHCO3 and the solid collected via filtration
  4. customThe layers of the filtrate were separated
  5. washthe organics 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
  13. customre-purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA)
  14. customThe organics were removed under reduced pressure
  15. additionthe aqueous residue treated with satd
  16. extractionNaHCO3 and extracted with EtOAc (3×)
  17. dry with materialThe combined organics were dried over Na2SO4
  18. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-f71b5fc5858141508d684aa47e026c3a
Source dataset
uspto-grants-2013_06
Patent number
US08461179B1

Reaction notes

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