Anisole → HCID 86713668, compound

HRID 1257238Notes

Reaction equation

HRID 1257238 reaction equation
[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([N:18](CC2C=CC(OC)=CC=2)[CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([Cl:43])[CH:37]=2)=[O:34])=[C:4]([F:44])[CH:3]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([Cl:43])[CH:37]=2)=[O:34])=[C:4]([F:44])[CH:3]=1

Participants

4

Reactant 2

HCID 7519AnisoleHCID 86713669HCID 86713669, compound

Product 1

HCID 86713668HCID 86713668, compoundYield 74.2%

Reagents, catalysts & solvents 1

HCID 6422Trifluoroacetic acidSolvent

Procedure

A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea (91 mg, 0.143 mmol) and anisole (77 mg, 0.713 mmol) was stirred in TFA (3 mL) at RT for 3 h. The mixture was concentrated to near-dryness, dissolved in EtOAc and treated with satd. NaHCO3. The layers were separated, the organic layer washed with brine and dried over Na2SO4. Solids precipitated, so THF, MeOH and DMF were added and the mixture was warmed to afford a clear solution, then filtered to remove salts. The filtrate was 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 neutralized with satd. NaHCO3, extracted with warm EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea (55 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 8.83 (s, 1H), 8.41 (s, 1H), 8.09 (d, J=8.6 Hz, 1H), 7.74 (s, 1H), 7.55 (d, J=10.9 Hz, 1H), 7.36 (s, 1H), 7.27 (dt, J=11.2, 2.1 Hz, 1H), 7.06-6.98 (m, 2H), 6.24 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.86 (d, J=4.8 Hz, 3H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 518.1 [M+H]+.

Workup

  1. concentrationThe mixture was concentrated to near-dryness
  2. dissolutiondissolved in EtOAc
  3. additiontreated with satd
  4. customThe layers were separated
  5. washthe organic layer washed with brine
  6. dry with materialdried over Na2SO4
  7. customSolids precipitated
  8. additionso THF, MeOH and DMF were added
  9. temperaturethe mixture was warmed
  10. customto afford a clear solution
  11. filtrationfiltered
  12. customto remove salts
  13. concentrationThe filtrate was concentrated to dryness
  14. custompurified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA)
  15. customThe organics were removed under reduced pressure
  16. extractionNaHCO3, extracted with warm EtOAc (2×)
  17. washthe combined organics were washed with brine
  18. dry with materialdried over Na2SO4
  19. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-225d0a1948f44f6cb956f7f28b779e98
Source dataset
uspto-grants-2013_06
Patent number
US08461179B1

Reaction notes

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