Tributylphosphine → HCID 22625100, compound

HRID 279531Notes

Reaction equation

HRID 279531 reaction equation
[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:30][C:31]1[CH:50]=[CH:49][C:34]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][C:42](O)=[C:43]([O:46][CH3:47])[CH:44]=3)[N:39]=[CH:38][N:37]=2)=[C:33]([F:51])[CH:32]=1.C(P(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:30][C:31]1[CH:50]=[CH:49][C:34]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][C:42]([O:1][CH2:2][CH2:3][CH2:4][N:5]4[CH:6]=[CH:7][C:8](=[O:11])[CH:9]=[CH:10]4)=[C:43]([O:46][CH3:47])[CH:44]=3)[N:39]=[CH:38][N:37]=2)=[C:33]([F:51])[CH:32]=1

Participants

6

Reactant 4

HCID 13831TributylphosphineHCID 730421,1'-(Azodicarbonyl)dipiperidineHCID 22624886HCID 22624886, compoundHCID 1355137204-(4-Chloro-2-fluorophenylamino)-7-hydroxy-6-methoxyquinazoline

Product 1

HCID 22625100HCID 22625100, compoundYield 11.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
5 °C

Procedure

1-(3-Hydroxypropyl)-1,4-dihydro-4-pyridone (220 mg, 1.44 mmol) in methylene chloride (4 ml) followed by 1,1′-(Azodicarbonyl)dipiperidine (720 mg, 2.86 mmol) were added to a stirred solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (300 mg, 0.94 mmol), (prepared as described for the starting material in Example 15), and tributylphosphine (0.69 ml, 2.8 mmol) in methylene chloride (20 ml) under nitrogen at 5° C. The mixture was stirred at 5° C. for 3 hours, allowed to warm to ambient temperature and stirred for a further 18 hours. The solvent was removed by evaporation and the residue partitioned between ethyl acetate and water. The organic phase was separated, dried (MgSO4), and solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/triethylamine mixtures (100/0/0 increasing to 70/30/0.5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-[3-(4-oxo-1,4-dihydro-1-pyridyl)propoxy]quinazoline (48 mg, 11%).

Workup

  1. custom(prepared
  2. customat 5° C
  3. temperatureto warm to ambient temperature
  4. stirringstirred for a further 18 hours
  5. customThe solvent was removed by evaporation
  6. customthe residue partitioned between ethyl acetate and water
  7. customThe organic phase was separated
  8. dry with materialdried (MgSO4), and solvent
  9. customremoved by evaporation
  10. customThe residue was purified by column chromatography
  11. washeluting with methylene chloride/methanol/triethylamine mixtures (100/0/0 increasing to 70/30/0.5)

Sources & evidence

ORD record
ord-8f6bf82bfac2486b9326c3af198441fe
Source dataset
uspto-grants-2002_03
Patent number
US06362336B1

Reaction notes

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