Triphenylphosphine → 4-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline hydrochloride

HRID 1384574Notes

Reaction equation

HRID 1384574 reaction equation
N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:54]1[CH:59]=[CH:58][C:57]([CH2:60][CH2:61]O)=[CH:56][CH:55]=1>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:61][CH2:60][C:57]4[CH:58]=[CH:59][N:54]=[CH:55][CH:56]=4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1

Participants

6

Reactant 4

HCID 11776TriphenylphosphineHCID 729214-PyridineethanolHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 1355137204-(4-Chloro-2-fluorophenylamino)-7-hydroxy-6-methoxyquinazoline

Product 1

HCID 226250054-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline hydrochlorideYield 54.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Diethyl azodicarboxylate (315 μl, 2 mmol) was added dropwise to a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (319.5 mg, 1 mmol), (prepared as described for the starting material in Example 24), triphenylphosphine (524 mg, 2 mmol) and 2-(4-pyridyl)ethanol (160 mg, 1.25 mmol), (Zhur. Obshchei. Khim. 1958, 28, 103-110), in methylene chloride (7 ml). The mixture was stirred for 1 hour at ambient temperature and the solvent was removed by evaporation. The residue was triturated with ether, the solid collected by filtration and purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (85/10/5). The purified solid product was dissolved in a mixture of methylene chloride (50 ml) and methanol (50 ml) and 5M hydrochloric acid in isopropanol (0.5 ml) was added. After diluting with isopropanol (20 ml), the mixture was concentrated by evaporation. The precipitated solid was collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline hydrochloride (125 mg, 25%). m.p. 189-191° C. 1H NMR Spectrum: (DMSOd6; CF3COOD) 3.55(t, 2H); 3.99(s, 3H); 4.64(t, 2H); 7.46(s, 1H); 7.48(d, 1H); 7.62(t, 1H); 7.67(dd, 1H); 8.16(d, 2H); 8.17(s, 1H); 8.88(s, 1H); 8.94(d, 1H) MS-ESI: 425 [MH]+

Workup

  1. custom(prepared
  2. customthe solvent was removed by evaporation
  3. customThe residue was triturated with ether
  4. filtrationthe solid collected by filtration
  5. custompurified by column chromatography
  6. washeluting with methylene chloride/acetonitrile/methanol (85/10/5)
  7. dissolutionThe purified solid product was dissolved in a mixture of methylene chloride (50 ml) and methanol (50 ml) and 5M hydrochloric acid in isopropanol (0.5 ml)
  8. additionwas added
  9. additionAfter diluting with isopropanol (20 ml)
  10. concentrationthe mixture was concentrated by evaporation
  11. filtrationThe precipitated solid was collected by filtration
  12. customdried under vacuum

Sources & evidence

ORD record
ord-eae72a55b1b14e22bacd97b7cfbf0804
Source dataset
uspto-grants-2001_07
Patent number
US06258951B1

Reaction notes

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