Sodium hydride → 4-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-nitroquinazoline

HRID 1023288Notes

Reaction equation

HRID 1023288 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28](F)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:18]=[CH:19][CH:20]=1>O1CCCC1>[Br:14][C:15]1[CH:16]=[C:17]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:11][CH2:10][CH2:9][CH2:8][CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:18]=[CH:19][CH:20]=1

Participants

5

Reactant 3

HCID 24758Sodium hydride2×HCID 10761182N-(3-Bromophenyl)-7-fluoro-6-nitroquinazolin-4-amineHCID 155406773-(1-Methylpiperidin-4-yl)propan-1-ol

Product 1

HCID 155406764-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-nitroquinazoline

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
65 °C

Procedure

To a solution of 1.45 g of 3-(1-methylpiperidin-4-yl)propan-1-ol in 40 ml of tetrahydrofuran are added 360 mg of sodium hydride. The white suspension formed is stirred for 15 minutes at 65° C., cooled and mixed with 1.45 g of 4-[(3-bromophenyl)amino]-7-fluoro-6-nitroquinazoline, whereupon the mixture suddenly turns dark red. The reaction mixture is stirred first for 10 minutes at ambient temperature, then for 45 minutes at 65° C. As the reaction is not yet complete, a further 150 mg of sodium hydride are added and the mixture is stirred for a further 45 minutes at 65° C. The solvent is distilled off using a rotary evaporator and the brown residue is stirred with 50 ml of ice water. The aqueous phase is extracted with methylene chloride. The combined extracts are washed with water, dried over sodium sulfate and concentrated by evaporation. The crude product is purified by chromatography over a silica gel column with methylene chloride/methanol/concentrated ammonia solution (90:10:0.05). Yield: 1.30 g of (65% of theory); Rf value: 0.28 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1); mass spectrum (ESI+): m/z=500, 502 [M+H]+.

Workup

  1. customThe white suspension formed
  2. temperaturecooled
  3. stirringThe reaction mixture is stirred first for 10 minutes at ambient temperature
  4. waitfor 45 minutes at 65° C
  5. stirringthe mixture is stirred for a further 45 minutes at 65° C
  6. distillationThe solvent is distilled off
  7. customa rotary evaporator
  8. stirringthe brown residue is stirred with 50 ml of ice water
  9. extractionThe aqueous phase is extracted with methylene chloride
  10. washThe combined extracts are washed with water
  11. dry with materialdried over sodium sulfate
  12. concentrationconcentrated by evaporation
  13. customThe crude product is purified by chromatography over a silica gel column with methylene chloride/methanol/concentrated ammonia solution (90:10:0.05)

Sources & evidence

ORD record
ord-348dfd1091d74662a35cf9602823618d
Source dataset
uspto-grants-2014_05
Patent number
US08722694B2

Reaction notes

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