HCID 86713636, compound → HCID 71584786, compound

HRID 1430554Notes

Reaction equation

HRID 1430554 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.[NH2:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([C:31]3[C:32]([CH3:45])=[CH:33][C:34]([F:44])=[C:35]([NH:37][C:38](=O)[O:39]C(C)=C)[CH:36]=3)[C:24](=[O:30])[N:25]2[CH2:28][CH3:29])=[CH:20][N:19]=1>O1CCOCC1.CN1CCCC1.CS(C)=O>[NH2:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([C:31]3[C:32]([CH3:45])=[CH:33][C:34]([F:44])=[C:35]([NH:37][C:38]([NH:6][C:5]4[CH:7]=[CH:8][C:2]([F:1])=[C:3]([CH2:9][N:10]5[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]5)[CH:4]=4)=[O:39])[CH:36]=3)[C:24](=[O:30])[N:25]2[CH2:28][CH3:29])=[CH:20][N:19]=1

Participants

6

Reactant 2

HCID 86713636HCID 86713636, compoundHCID 131730624HCID 131730624, compound

Product 1

HCID 71584786HCID 71584786, compoundYield 22%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideCatalystHCID 84541-MethylpyrrolidineCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of Example D2 (0.100 g, 0.448 mmol) and prop-1-en-2-yl (5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)carbamate (0.142 g, 0.358 mmol) in dioxane (3 mL) was treated with 1-methylpyrrolidine (3 drops) and heated at 80° C. overnight. The mixture was treated with DMSO (2 drops) and heated at 80° C. for an additional 24 h. The mixture was cooled to RT, 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, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over MgSO4 and concentrated to dryness to afford 1-(5-(7-amino-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 (44 mg, 22% yield). 1H NMR (400 MHz, pyridine-d5): δ 9.87 (s, 1H), 8.89 (s, 1H), 8.71 (m, 1H), 8.60 (s, 1H), 7.97 (dd, J=6.5, 2.8 Hz, 1H), 7.79 (dt, J=8.7, 3.6 Hz, 1H), 7.64 (s, 1H), 7.26 (s, 2H), 7.15 (t, J=9.2 Hz, 1H), 7.07 (d, J=12.0 Hz, 1H), 6.56 (s, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.58 (s, 2H), 2.53 (s, 4H), 2.30 (m, 7H), 2.13 (s, 3H), 1.16 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 562.2 [M+H]+.

Workup

  1. temperatureheated at 80° C. for an additional 24 h
  2. temperatureThe mixture was cooled to RT
  3. concentrationconcentrated to dryness
  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-4b4fd1c989b845039a68c91d03feeb7f
Source dataset
uspto-grants-2015_01
Patent number
US08940756B2

Reaction notes

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