Formamide → HCID 71584842, compound

HRID 1257275Notes

Reaction equation

HRID 1257275 reaction equation
Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([CH3:41])=[CH:17][C:18]([F:40])=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH2:32][N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)[CH:26]=4)=[O:23])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[CH:42]([NH2:44])=[O:43].C([O-])([O-])=O.[K+].[K+]>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+]>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:44][CH:42]=[O:43])[CH:11]=2)[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH2:32][N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH:26]=3)=[O:23])[C:18]([F:40])=[CH:17][C:16]=2[CH3:41])[C:8]1=[O:14])[CH3:13]

Participants

6

Reactant 3

HCID 713FormamideHCID 11430Potassium CarbonateHCID 86761879HCID 86761879, compound

Product 1

HCID 71584842HCID 71584842, compoundYield 44%

Reagents, catalysts & solvents 2

HCID 25112666BrettPhos PalladacycleCatalystHCID 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-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (0.120 g, 0.207 mmol), formamide (0.041 ml, 1.033 mmol) and K2CO3 (0.057 g, 0.413 mmol) in dioxane (3 mL) was sparged with Ar, treated with BrettPhos Palladacycle (8.05 mg, 10.33 μmol), sparged again with Ar, and heated to 100° C. for 1 h. The mixture was cooled to RT, treated with EtOAc and satd. NaHCO3, filtered to remove insoluble material and the layers separated. The organic layer was washed with brine, dried over MgSO4 and concentrated to dryness. The material was treated with a small amount of DCM, allowed to stand at RT, and the resulting solid collected via filtration and dried. The filtrate was concentrated to dryness, layered with a small amount of DCM and allowed to stand at RT overnight. The resulting solid was collected via filtration and combined with the above-isolated solid to afford N-(1-ethyl-3-(4-fluoro-5-(3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)ureido)-2-methylphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide (53 mg, 44% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.38 (m, 1H), 9.05 (s, 1H), 8.69 (d, J=18.4 Hz, 1H), 8.44 (s, 1H), 8.21 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.43 (dd, J=6.5, 2.8 Hz, 1H), 7.30 (ddd, J=8.9, 4.4, 2.8 Hz, 1H), 7.16 (d, J=12.2 Hz, 1H), 7.05 (t, J=9.3 Hz, 1H), 6.96 (s, 1H), 4.19 (m, 2H), 3.42 (s, 2H), 2.41-2.19 (m, 8H), 2.10 (s, 3H), 2.07 (s, 3H), 1.24 (m, 3H); MS (ESI) m/z: 590.2 [M+H]+.

Workup

  1. customwas sparged with Ar
  2. customsparged again with Ar
  3. temperatureThe mixture was cooled to RT
  4. additiontreated with EtOAc
  5. filtrationNaHCO3, filtered
  6. customto remove insoluble material
  7. customthe layers separated
  8. washThe organic layer was washed with brine
  9. dry with materialdried over MgSO4
  10. concentrationconcentrated to dryness
  11. additionThe material was treated with a small amount of DCM
  12. customto stand at RT
  13. filtrationthe resulting solid collected via filtration
  14. customdried
  15. concentrationThe filtrate was concentrated to dryness
  16. filtrationThe resulting solid was collected via filtration

Sources & evidence

ORD record
ord-dbb96143807449998a8657d82bc53ca4
Source dataset
uspto-grants-2013_06
Patent number
US08461179B1

Reaction notes

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