HCID 86713636, compound → HCID 89606307, compound

HRID 1257259Notes

Reaction equation

HRID 1257259 reaction equation
[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[CH2:17]([N:19]1[C:28]2[C:23](=[CH:24][N:25]=[C:26]([NH:29][CH3:30])[CH:27]=2)[CH:22]=[C:21]([C:31]2[C:32]([F:45])=[CH:33][C:34]([F:44])=[C:35]([NH:37][C:38](=O)[O:39]C(C)=C)[CH:36]=2)[C:20]1=[O:46])[CH3:18]>O1CCOCC1.CN1CCCC1>[CH2:17]([N:19]1[C:28]2[C:23](=[CH:24][N:25]=[C:26]([NH:29][CH3:30])[CH:27]=2)[CH:22]=[C:21]([C:31]2[C:32]([F:45])=[CH:33][C:34]([F:44])=[C:35]([NH:37][C:38]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[C:3]([CH2:9][N:10]4[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]4)[CH:4]=3)=[O:39])[CH:36]=2)[C:20]1=[O:46])[CH3:18]

Participants

5

Reactant 2

HCID 86713636HCID 86713636, compoundHCID 131730623HCID 131730623, compound

Product 1

HCID 89606307HCID 89606307, compoundYield 31%

Reagents, catalysts & solvents 2

HCID 84541-MethylpyrrolidineCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of Example D2 (0.060 g, 0.269 mmol) and prop-1-en-2-yl (5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)carbamate (0.086 g, 0.208 mmol) in dioxane (2 mL) was treated with 1-methylpyrrolidine (2 drops) and heated at 80° C. overnight. The mixture was concentrated to dryness, treated with EtOAc and the resulting solid collected via filtration 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, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over MgSO4 and concentrated to dryness to afford 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (37 mg, 31% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1H), 8.94 (s, 1H), 8.86 (t, J=8.5 Hz, 1H), 8.59 (s, 1H), 7.93 (dd, J=6.5, 2.8 Hz, 1H), 7.76 (m, 2H), 7.62 (s, 1H), 7.13 (t, J=9.5 Hz, 2H), 6.25 (s, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.55 (s, 2H), 3.08 (d, J=4.9 Hz, 3H), 2.50 (br s, 4H), 2.30 (br s, 4H), 2.10 (s, 3H), 1.18 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 580.2 [M+H]+.

Workup

  1. concentrationThe mixture was concentrated to dryness
  2. additiontreated with EtOAc
  3. filtrationthe resulting solid collected via filtration
  4. custompurified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA)
  5. customThe organics were removed under reduced pressure
  6. additionthe aqueous residue treated with satd
  7. extractionNaHCO3, extracted with EtOAc (2×)
  8. washthe combined organics were washed with brine
  9. dry with materialdried over MgSO4
  10. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-67a57937fd074f14bda85c21c71becb0
Source dataset
uspto-grants-2013_06
Patent number
US08461179B1

Reaction notes

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