Sodium hydride → N-(4-bromo-2,6-difluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine

HRID 577375Notes

Reaction equation

HRID 577375 reaction equation
[H-].[Na+].[Br:3][C:4]1[CH:10]=[C:9]([F:11])[C:7]([NH2:8])=[C:6]([F:12])[CH:5]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CN(C=O)C>[Br:3][C:4]1[CH:10]=[C:9]([F:11])[C:7]([NH:8][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:6]([F:12])[CH:5]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 6101914-Bromo-2,6-difluoroanilineHCID 117822304-Chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline

Product 1

HCID 5329046N-(4-bromo-2,6-difluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amineYield 70.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Under argon, sodium hydride (60%, 372 mg, 9.3 mmol) was added to a solution of 4-bromo-2,6-difluoroaniline (1.67 g, 8.08 mmol) in DMF. After stirring for 30 minutes at ambient temperature, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (1.3 g, 4.04 mmol) was added and stirring was continued for a further 20 hours. The mixture was poured onto water (130 ml) and extracted with ethyl acetate. The organic layers were washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography on silica, eluting with methylene chloride/methanol (95/5) followed by methylene chloride/methanol containing ammonia (1%) (90/10). The fractions containing the expected product were combined and evaporated. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum at 50° C. to give 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (1.4 g, 70%).

Workup

  1. stirringstirring
  2. waitwas continued for a further 20 hours
  3. additionThe mixture was poured onto water (130 ml)
  4. extractionextracted with ethyl acetate
  5. washThe organic layers were washed with water, brine
  6. dry with materialdried (MgSO4)
  7. customthe volatiles were removed by evaporation
  8. customThe residue was purified by column chromatography on silica
  9. washeluting with methylene chloride/methanol (95/5)
  10. additioncontaining ammonia (1%) (90/10)
  11. additionThe fractions containing the expected product
  12. customevaporated
  13. customThe residue was triturated with ether
  14. filtrationcollected by filtration
  15. washwashed with ether
  16. customdried under vacuum at 50° C.

Sources & evidence

ORD record
ord-27052ed7fd4743f7b38cb938a260d2cb
Source dataset
uspto-grants-2015_05
Patent number
US09040548B2

Reaction notes

Loading…