Acetamide → HCID 71585134, compound

HRID 1257234Notes

Reaction equation

HRID 1257234 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]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=2)=[O:24])=[C:4]([F:34])[CH:3]=1.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+].[C:83]([NH2:86])(=[O:85])[CH3:84]>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].C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:34])[C:5]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[C:28]([F:33])[CH:29]=[C:30]([F:32])[CH:31]=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:86][C:83](=[O:85])[CH3:84])[CH:12]=2

Participants

8

Reactant 4

HCID 178AcetamideHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86713665HCID 86713665, compound

Product 1

HCID 71585134HCID 71585134, compoundYield 4.8%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolventHCID 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-(3,5-difluorophenyl)urea (178 mg, 0.351 mmol), Xantphos (20.30 mg, 0.035 mmol), Cs2CO3 (229 mg, 0.702 mmol) and acetamide (104 mg, 1.754 mmol) in dioxane (3.5 mL) was sparged with Ar for 10 min, treated with Pd2(dba)3 (16.07 mg, 0.018 mmol) and heated at 100° C. overnight. The mixture was cooled to RT, treated with THF, the solids removed via filtration through diatomaceous earth and rinsed well with THF. The filtrate was washed with brine (3×), dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex). The material was suspended in 4:1 MeCN/H2O, frozen and lyophilized; the resulting solid was triturated with MTBE, collected via filtration and dried to afford N-(3-(2-chloro-5-(3-(3,5-difluorophenyl)ureido)-4-fluorophenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide (9 mg, 4.8% yield). 1H NMR (500 MHz, DMSO-d6): δ 10.86 (s, 1H), 9.48 (s, 1H), 8.89 (s, 1H), 8.74 (s, 1H), 8.29 (s, 1H), 8.17 (d, J=8.5 Hz, 1H), 8.01 (s, 1H), 7.63 (d, J=10.9 Hz, 1H), 7.17 (m, 2H), 6.84-6.83 (m, 1H), 4.22 (q, J=7.2 Hz, 2H), 2.17 (s, 3H), 1.27 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 530.1 [M+H]+.

Workup

  1. customwas sparged with Ar for 10 min
  2. temperatureThe mixture was cooled to RT
  3. customthe solids removed via filtration through diatomaceous earth
  4. washrinsed well with THF
  5. washThe filtrate was washed with brine (3×)
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated to dryness
  8. custompurified via silica gel chromatography (EtOAc/Hex)
  9. temperaturefrozen
  10. customthe resulting solid was triturated with MTBE
  11. filtrationcollected via filtration
  12. customdried

Sources & evidence

ORD record
ord-69fd2eae56cb43c5b05bc2916daf64fc
Source dataset
uspto-grants-2013_06
Patent number
US08461179B1

Reaction notes

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