Tributylphosphine → HCID 22625100, compound

HRID 1384544Notes

Reaction equation

HRID 1384544 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%). m.p. >250° C. 1H NMR Spectrum: (DMSOd6) 3.56(m, 2H); 4.00(s, 3H); 3.54(t, 2H); 4.38(t, 2H); 7.42(d, 1H); 7.5-7.65(m, 5H); 8.43(s, 1H); 8.65-8.75(m, 4H) MS-ESI: 455 [MH]+

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-1b31813133154a15aa91332ac9bc1d83
Source dataset
uspto-grants-2001_07
Patent number
US06258951B1

Reaction notes

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