Triphenylphosphine → 4-(4-Chloro-2-fluoroanilino)-7-(3-(imidazol-1-yl)propoxy)-6-methoxyquinazoline hydrochloride

HRID 1384597Notes

Reaction equation

HRID 1384597 reaction equation
N(C(OCC)=O)=NC(OCC)=O.[OH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Cl:22][C:23]1[CH:42]=[CH:41][C:26]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34](O)=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[C:25]([F:43])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[ClH:22].[Cl:22][C:23]1[CH:42]=[CH:41][C:26]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:13][CH2:14][CH2:15][CH2:16][N:17]4[CH:21]=[CH:20][N:19]=[CH:18]4)=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[C:25]([F:43])[CH:24]=1

Participants

6

Reactant 4

HCID 11776TriphenylphosphineHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 47122713-(1H-imidazol-1-yl)propan-1-olHCID 1355137204-(4-Chloro-2-fluorophenylamino)-7-hydroxy-6-methoxyquinazoline

Product 1

HCID 226250634-(4-Chloro-2-fluoroanilino)-7-(3-(imidazol-1-yl)propoxy)-6-methoxyquinazoline hydrochlorideYield 79.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Diethyl azodicarboxylate (295 μl, 1.8 mmol) was added dropwise to a solution of 1-(3-hydroxypropyl)imidazole (102 mg, 0.81 mmol), (EP 0060696 A1), 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.62 mmol), (prepared as described for the starting material in Example 24), and triphenylphosphine (492 mg, 1.8 mmol) in methylene chloride (4 ml) and the mixture stirred for 2 hours at ambient temperature. The solvent was removed by evaporation and the residue was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (60/35/5). The purified solid was dissolved in methylene chloride/methanol and 5M ethereal hydrogen chloride (2 ml) was added. The volatiles were removed by evaporation, the solid residue was suspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-(3-(imidazol-1-yl)propoxy)-6-methoxyquinazoline hydrochloride (114 mg, 36%). 1H NMR Spectrum: (DMSOd6; CF3COOD) 2.5(m, 2H); 3.99(s, 3H); 4.32(t, 2H); 4.45(t, 2H); 7.39(s, 1H); 7.45(dd, 1H); 7.61(t, 1H); 7.66(dd, 1H); 7.71(s, 1H); 7.84(s, 1H); 8.19(s, 1H); 8.77(s, 1H); 9.20(s, 1H) MS-ESI: 428 [MH]+

Workup

  1. custom(prepared
  2. customThe solvent was removed by evaporation
  3. customthe residue was purified by column chromatography
  4. washeluting with methylene chloride/acetonitrile/methanol (60/35/5)
  5. dissolutionThe purified solid was dissolved in methylene chloride/methanol
  6. addition5M ethereal hydrogen chloride (2 ml) was added
  7. customThe volatiles were removed by evaporation
  8. filtrationcollected by filtration
  9. washwashed with ether
  10. customdried under vacuum

Sources & evidence

ORD record
ord-87e0a30e130c477da403d00d4346c78f
Source dataset
uspto-grants-2001_07
Patent number
US06258951B1

Reaction notes

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