p-Toluenesulfonic acid → 2-(4-((3R,5S)-4-Acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

HRID 591644Notes

Reaction equation

HRID 591644 reaction equation
[C:1]([N:4]1[CH:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH:5]1[CH3:19])(=[O:3])[CH3:2].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:36][C:37]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([O:48][CH3:49])[C:38]=1[C:39]([NH2:41])=[O:40]>CC(N(C)C)=O.O>[C:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:18]=[CH:17][C:14]([C:15]3[NH:41][C:39](=[O:40])[C:38]4[C:37](=[CH:45][C:44]([O:46][CH3:47])=[CH:43][C:42]=4[O:48][CH3:49])[N:36]=3)=[CH:13][CH:12]=2)[CH2:6][C@H:5]1[CH3:19])(=[O:3])[CH3:2]

Participants

7

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 203490162-Amino-4,6-dimethoxybenzamideHCID 23665763Sodium BisulfiteHCID 866620144-(4-Acetyl-3,5-dimethylpiperazin-1-yl)benzaldehyde

Product 1

HCID 1359391162-(4-((3R,5S)-4-Acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneYield 46%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 4-(4-acetyl-3,5-dimethylpiperazin-1-yl)benzaldehyde (0.580 g, 2.20 mmol), NaHSO3 (0.260 g, 2.40 mmol), and p-TsOH (0.039 g, 0.20 mmol) was added to a solution of 2-amino-4,6-dimethoxybenzamide (0.400 g, 2.20 mmol) in DMA (15 mL). The reaction was stirred at 120° C. for 4 hours and then cooled to room temperature overnight. The mixture was diluted with H2O and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 10% MeOH/CH2Cl2, afforded the title compound (0.400 g, 46%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 11.78 (br s, 1H), 8.10 (d, J=8.9 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H), 6.68 (d, J=2.3 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 4.01-4.64 (m, 2H), 3.71-3.95 (m, 8H), 2.87-3.07 (m, 2H), 2.06 (s, 3H), 1.25 (d, J=6.2 Hz, 6H). ESI MS m/z 437 [M+H]+.

Workup

  1. temperaturecooled to room temperature overnight
  2. extractionextracted with EtOAc
  3. washThe organics were washed with brine
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification by flash chromatography on silica gel
  8. washeluting with 2% to 10% MeOH/CH2Cl2

Sources & evidence

ORD record
ord-4bff2de075e04250b32ae1f1b6b58ae7
Source dataset
uspto-grants-2016_01
Patent number
US09238640B2

Reaction notes

Loading…