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

HRID 591641Notes

Reaction equation

HRID 591641 reaction equation
[CH2:1]([N:3]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[C:4](=[O:6])[CH3:5])[CH3:2].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:37][C:38]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[C:43]([O:49][CH3:50])[C:39]=1[C:40]([NH2:42])=[O:41]>CC(N(C)C)=O.O>[CH3:50][O:49][C:43]1[CH:44]=[C:45]([O:47][CH3:48])[CH:46]=[C:38]2[C:39]=1[C:40](=[O:41])[NH:42][C:19]([C:16]1[CH:15]=[CH:14][C:13]([N:10]3[CH2:9][CH2:8][CH:7]([N:3]([CH2:1][CH3:2])[C:4](=[O:6])[CH3:5])[CH2:12][CH2:11]3)=[CH:18][CH:17]=1)=[N:37]2

Participants

7

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 203490162-Amino-4,6-dimethoxybenzamideHCID 23665763Sodium BisulfiteHCID 86662019N-ethyl-N-(1-(4-formylphenyl)piperidin-4-yl)acetamide

Product 1

HCID 135939115N-(1-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-N-ethylacetamideYield 55.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
150 °C

Procedure

A mixture of N-ethyl-N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (0.385 g, 1.40 mmol), NaHSO3 (0.162 g, 1.50 mmol), and p-TsOH (0.024 g, 0.12 mmol) were added to a solution of 2-amino-4,6-dimethoxybenzamide (0.250 g, 1.20 mmol) in DMA (10 mL). The reaction was stirred at 150° 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 (0.300 g, 55%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): mixture of rotamers δ 11.76 (s, 1H), 8.08 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 6.67 (d, J=2.0 Hz, 1H), 6.46 (d, J=2.0 Hz, 1H), 4.29-4.33 (m, 0.5H), 3.99-4.03 (m, 2H), 3.88 (s, 3H), 3.83 (5, 3H), 3.12-3.25 (m, 2H), 2.81-2.93 (m, 2H), 2.07 (s, 1.5H), 2.01 (s, 1.5H), 1.59-1.74 (m, 4.5H), 1.10 (t, J=6.7 Hz, 1.5H), 0.99 (t, J=6.7 Hz, 1.5H). ESI MS m/z 451 [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-8e181b92dc9b48ddb4f1ec2664ee8da0
Source dataset
uspto-grants-2016_01
Patent number
US09238640B2

Reaction notes

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