4-Chloro-5-fluoroquinazoline → N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine

HRID 1864185Notes

Reaction equation

HRID 1864185 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[NH2:17]>CC(O)C>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[CH:4][N:3]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1

Participants

4

Reactant 2

HCID 119744454-Chloro-5-fluoroquinazolineHCID 167812123-Chloro-4-(2-pyridylmethoxy)aniline

Product 1

HCID 57444972N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amineYield 48%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Procedure

4-Chloro-5-fluoroquinazoline (6.75 g) was added to a stirred solution of 3-chloro-4-(2-pyridylmethoxy)aniline (9.27 g, obtained as described in Example 15-21 (note u) of WO 96/15118) in IPA (200 ml), and the solution was stirred and heated at reflux for 8 hours. The solution was allowed to cool to ambient temperature overnight and the precipitated solid was filtered off, washed with acetone and dried. The solid was added to 50% aqueous methanol (400 ml) and the mixture was heated on a steam bath until the entire solid had dissolved. The solution was basified by careful addition of aqueous ammonia (0.880), and the mixture was concentrated to remove methanol. Water (300 ml) was added and the mixture was extracted with DCM (600 ml). The extract washed with water, and brine, and dried. The solvent was removed by evaporation to give a solid, which was re-precipitated from a mixture of ethyl acetate, tetrahydrofuran and isohexane to give N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine as a beige solid (6.75 g, 48%); NMR spectrum (DMSO-d6) 5.3 (s, 2H), 7.2-7.3 (d, 1H), 7.35-7.5 (m, 2H), 7.5-7.65 (m, 3H), 7.8-7.95 (m, 3H), 8.55 (s, 1H), 8.55-8.6 (d, 1H), 9.1-9.2 (bs, 1H); Mass spectrum MH+ 381.

Workup

  1. temperatureheated
  2. temperatureat reflux for 8 hours
  3. filtrationthe precipitated solid was filtered off
  4. washwashed with acetone
  5. customdried
  6. additionThe solid was added to 50% aqueous methanol (400 ml)
  7. temperaturethe mixture was heated on a steam bath until the entire solid
  8. dissolutionhad dissolved
  9. additionThe solution was basified by careful addition of aqueous ammonia (0.880)
  10. concentrationthe mixture was concentrated
  11. customto remove methanol
  12. additionWater (300 ml) was added
  13. extractionthe mixture was extracted with DCM (600 ml)
  14. washThe extract washed with water, and brine
  15. customdried
  16. customThe solvent was removed by evaporation
  17. customto give a solid, which
  18. customwas re-precipitated from a mixture of ethyl acetate, tetrahydrofuran and isohexane

Sources & evidence

ORD record
ord-272da55dae644f3fabf184f35a8a182e
Source dataset
uspto-grants-2009_12
Patent number
US07625908B2

Reaction notes

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