Triphenylphosphine → 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline

HRID 916448Notes

Reaction equation

HRID 916448 reaction equation
[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36]O)[CH2:31][CH2:30]1)(=[O:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:25])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]

Participants

6

Reactant 4

HCID 11776Triphenylphosphine2×HCID 75555Diisopropyl diazene-1,2-dicarboxylate2×HCID 47396291-Acetyl-4-(2-hydroxyethyl)piperazine2×HCID 1355308324-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-ol

Product 1

HCID 117522547-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolineYield 17.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline (300 mg, 0.88 mmol), (prepared as described for the starting material in Example 7), 2-(4-acetylpiperazin-1-yl)ethanol (183 mg, 1.06 mmol) and triphenylphosphine (278 mg, 1.06 mmol) were stirred together in dichloromethane (10 ml) and the mixture cooled in an ice/water bath. Diisopropyl azodicarboxylate (209 μl, 1.06 mmol) was added and the mixture stirred for 1.5 hours. A further one mole equivalent of 2-(4-acetylpiperazin-1-yl)ethanol (172 mg, 1 mmol), triphenylphosphine (262 mg, 1 mmol) and diisopropyl azodicarboxylate (197 μl, 1 mmol) were added and the mixture stirred for a further 1 hour. The volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give a crude solid that was further purified by preparative HPLC to give 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (75 mg, 17%).

Workup

  1. temperaturethe mixture cooled in an ice/water bath
  2. stirringthe mixture stirred for a further 1 hour
  3. customThe volatiles were removed under vacuum
  4. customthe residue was purified by column chromatography
  5. washeluting with methylene chloride/methanol (95/5)
  6. customto give a crude solid that
  7. customwas further purified by preparative HPLC

Sources & evidence

ORD record
ord-562d29b7470e4580aa09a5db664fa379
Source dataset
uspto-grants-2007_09
Patent number
US07268230B2

Reaction notes

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