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

HRID 591791Notes

Reaction equation

HRID 591791 reaction equation
[CH:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:17])[CH3:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:39][C:40]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[C:45]([O:51][CH3:52])[C:41]=1[C:42]([NH2:44])=[O:43]>CC(N(C)C)=O>[CH3:52][O:51][C:45]1[CH:46]=[C:47]([O:49][CH3:50])[CH:48]=[C:40]2[C:41]=1[C:42](=[O:43])[NH:44][C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]3[CH2:13][CH2:12][CH:11]([N:14]([CH:18]([CH3:19])[CH3:20])[C:15](=[O:17])[CH3:16])[CH2:10][CH2:9]3)=[CH:21][CH:22]=1)=[N:39]2

Participants

6

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 203490162-Amino-4,6-dimethoxybenzamideHCID 23665763Sodium BisulfiteHCID 86662036N-(1-(4-formylbenzyl)piperidin-4-yl)-N-isopropylacetamide

Product 1

HCID 136348044N-(1-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)benzyl)piperidin-4-yl)-N-isopropylacetamideYield 56%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
130 °C

Procedure

A mixture of N-(1-(4-formylbenzyl)piperidin-4-yl)-N-isopropylacetamide (0.770 g, 2.5 mmol), NaHSO3 (0.350 g, 3.3 mmol), and p-TsOH (0.100 g, 0.51 mmol) was added to a solution of 2-amino-4,6-dimethoxybenzamide (0.500 g, 2.5 mmol) in DMA (20 mL). The reaction was stirred at 130° C. for 5 hours and concentrated in vacuo. The residue was diluted with H2O and saturated NaHCO3, then extracted with CH2Cl2. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 1% to 10% MeOH/CH2Cl2, afforded the title compound (0.670 g, 56%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 12.02 (s, 1H), 8.13 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 6.74 (d, J=1.9 Hz, 1H), 6.54 (d, J=2.0 Hz, 1H), 3.85-3.95 (m, 7H), 3.43-3.71 (m, 3H), 2.55-3.00 (m, 3H), 1.97-2.09 (m, 5H), 1.70-1.77 (m, 1H), 1.58-1.61 (m, 1H), 1.25-1.30 (m, 4H), 1.11-1.13 (m, 3H). ESI MS m/z 479 [M+H]+.

Workup

  1. concentrationconcentrated in vacuo
  2. additionThe residue was diluted with H2O and saturated NaHCO3
  3. extractionextracted with CH2Cl2
  4. washThe organics were washed with brine
  5. dry with materialdried over anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customPurification by flash chromatography on silica gel
  9. washeluting with 1% to 10% MeOH/CH2Cl2

Sources & evidence

ORD record
ord-8865fe937a89492391ea031b04072bb4
Source dataset
uspto-grants-2016_01
Patent number
US09238640B2

Reaction notes

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