Trifluoroacetic acid → 5-[2-(Methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine

HRID 1864353Notes

Reaction equation

HRID 1864353 reaction equation
[H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][OH:7].F[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[C:22]([CH3:34])[CH:21]=1)=[N:12][CH:13]=[N:14]2.C(O)(C(F)(F)F)=O>CC(N(C)C)=O>[CH3:3][NH:4][CH2:5][CH2:6][O:7][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[C:22]([CH3:34])[CH:21]=1)=[N:12][CH:13]=[N:14]2

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 80162-(Methylamino)ethanolHCID 24758Sodium hydrideHCID 690241975-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine

Product 1

HCID 690582265-[2-(Methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amineYield 34.4%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Procedure

Sodium hydride (60% dispersion in mineral oil, 28 mg, 0.69 mmol) was suspended in DMA (10 ml) and N-methylethanolamine (56 μl, 0.69 mmol) was added under an atmosphere of nitrogen. The mixture was stirred for 20 minutes at ambient temperature, and 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (obtained as described in Example 103, preparation of starting materials, 100 mg, 0.28 mmol) was added. The mixture was heated under an atmosphere of nitrogen at 110° C. for 1 hour, then at 125° C. for 14 hours. The mixture was cooled to ambient temperature, and acidified with TFA. The mixture was concentrated in vacuo, and the residue purified by reverse-phase HPLC, eluting with 5 to 50% acetonitrile in H2O. The appropriate fractions were evaporated to a volume such that all of the acetonitrile had been removed. The resulting aqueous solution was basified with concentrated aqueous ammonia, and extracted with DCM (4×20 ml). The combined extracts were filtered through a silicone-treated filter paper, and concentrated in vacuo to give 5-[2-(methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine as a yellow solid (40 mg, 34%); NMR Spectrum (CDCl3, 400 MHz) 2.20 (s, 3H), 2.44 (s, 3H), 2.49 (s, 3H), 3.12 (t, 2H), 4.25 (t, 2H), 6.80 (d, 1H), 6.83 (d, 1H), 7.00 (d, 1H), 7.04 (dd, 1H), 7.39 (d, 1H), 7.55 (dd, 1H), 7.61 (dd, 1H), 7.68 (d, 1H), 8.19 (d, 1H), 8.56 (s, 1H), 10.26 (s, 1H); Mass spectrum MH+ 416.0

Workup

  1. temperatureThe mixture was heated under an atmosphere of nitrogen at 110° C. for 1 hour
  2. waitat 125° C. for 14 hours
  3. temperatureThe mixture was cooled to ambient temperature
  4. concentrationThe mixture was concentrated in vacuo
  5. customthe residue purified by reverse-phase HPLC
  6. washeluting with 5 to 50% acetonitrile in H2O
  7. customThe appropriate fractions were evaporated to a volume such that all of the acetonitrile
  8. customhad been removed
  9. extractionextracted with DCM (4×20 ml)
  10. filtrationThe combined extracts were filtered through a silicone-
  11. additiontreated
  12. filtrationfilter paper
  13. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-6b5037e4438548d2b88e516832fb1fc5
Source dataset
uspto-grants-2009_12
Patent number
US07625908B2

Reaction notes

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