p-Toluenesulfonic acid → N-(1-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)acetamide

HRID 591611Notes

Reaction equation

HRID 591611 reaction equation
[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=O.[NH2:19][C:20]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:21]=1[C:22]([NH2:24])=[O:23].CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+].C([O-])(O)=O.[Na+]>CC(N(C)C)=O.O>[CH3:32][O:31][C:25]1[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=[C:20]2[C:21]=1[C:22](=[O:23])[NH:24][C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]3[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]3)=[CH:5][CH:4]=1)=[N:19]2

Participants

8

Reactant 5

HCID 6101p-Toluenesulfonic acidHCID 516892Sodium BicarbonateHCID 203490162-Amino-4,6-dimethoxybenzamideHCID 23665763Sodium BisulfiteHCID 86662017N-(1-(4-formylphenyl)piperidin-4-yl)acetamide

Product 1

HCID 135939090N-(1-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)acetamideYield 29.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
155 °C

Procedure

A mixture of N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (0.280 g, 1.14 mmol), 2-amino-4,6-dimethoxybenzamide (0.224 g, 1.14 mmol), p-TsOH (0.022 g, 0.114 mmol), and NaHSO3 (0.125 g, 1.21 mmol) in DMA was heated at 155° C. for 6 hours. The reaction mixture was cooled, diluted with water (100 mL), basified with saturated NaHCO3, and extracted with ethyl acetate (3×150 mL). The organic phase was concentrated and purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/(92:7:1 CHCl3/MeOH/concentrated NH4OH) to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH. Further purification by reverse-phase HPLC, eluting with 10% to 90% CH3CN in H2O with 0.1% TFA, afforded the title compound as a yellow solid (0.140 g, 29%): 1H NMR (300 MHz, DMSO-d6): δ 11.74 (s, 1H), 8.08 (d, J=9.0 Hz, 2H), 7.83 (d, J=7.7 Hz, 1H), 7.01 (d, J=9.0 Hz, 2H), 6.68 (d, J=2.3 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 3.7-3.89 (m, 9H), 2.92-3.00 (m, 2H), 1.76-1.85 (m, 5H), 1.36-1.48 (m, 2H); APCI MS m/z 423 [M+H]+.

Workup

  1. temperatureThe reaction mixture was cooled
  2. extractionextracted with ethyl acetate (3×150 mL)
  3. concentrationThe organic phase was concentrated
  4. custompurified by flash chromatography on silica gel
  5. washeluting with 1:1 CH2Cl2/(92:7:1 CHCl3/MeOH/concentrated NH4OH) to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH
  6. customFurther purification by reverse-phase HPLC
  7. washeluting with 10% to 90% CH3CN in H2O with 0.1% TFA

Sources & evidence

ORD record
ord-18c4064f94b4437e8a19966b6dce8f9b
Source dataset
uspto-grants-2016_01
Patent number
US09238640B2

Reaction notes

Loading…