p-Toluenesulfonic acid monohydrate → 2-(3,5-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-difluoroquinazolin-4(3H)-one

HRID 591770Notes

Reaction equation

HRID 591770 reaction equation
[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:30])[C:21]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH:17]=O.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:30][C:20]1[CH:19]=[C:16]([C:17]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[F:12])[N:1]=2)[CH:15]=[C:14]([CH3:13])[C:21]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1

Participants

6

Reactant 4

HCID 521998p-Toluenesulfonic acid monohydrateHCID 23665763Sodium BisulfiteHCID 289325703,5-Dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehydeHCID 594419592-Amino-4,6-difluorobenzamide

Product 1

HCID 1363480212-(3,5-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-difluoroquinazolin-4(3H)-one

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
145 °C

Procedure

To a solution of 2-amino-4,6-difluoro-benzamide (0.80 g, 4.60 mmol) and 3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (1.14 g, 4.60 mmol) in N,N-dimethylacetamide (60 mL) were added sodium hydrogen sulfite (58.5 wt %, 1.25 g, 6.9 mmol) and p-toluenesulfonic acid monohydrate (3.50 g, 18.4 mmol). The reaction mixture was stirred at 145° C. for 16 hours under nitrogen atmosphere, then cooled to room temperature. Solvent was evaporated under reduced pressure. Water (50 mL) was added, followed by saturated aqueous sodium bicarbonate solution (15 mL). The mixture was extracted with CH2Cl2 (2×100 mL) and washed with water. The organic phase was evaporated and the residue was washed with hexane/ether (90:10, 100 mL). The solid was filtered and dried under vacuum to give the title compound as a brown solid. Yield: 1.48 g (80%). MP 234-235° C. 1H NMR (400 MHz, DMSO-d6): δ 12.36 (s, 1H), 7.90 (s, 1H), 7.32 (m, 2H), 3.91 (t, J=4 Hz, 2H), 2.83 (t, J=4 Hz, 2H), 2.55 (s, 4H), 2.31 (s, 6H), 1.70 (s, 4H).

Workup

  1. temperaturecooled to room temperature
  2. customSolvent was evaporated under reduced pressure
  3. additionWater (50 mL) was added
  4. extractionThe mixture was extracted with CH2Cl2 (2×100 mL)
  5. washwashed with water
  6. customThe organic phase was evaporated
  7. washthe residue was washed with hexane/ether (90:10, 100 mL)
  8. filtrationThe solid was filtered
  9. customdried under vacuum

Sources & evidence

ORD record
ord-e82d4e8abc30492e92eb20ed647db7d6
Source dataset
uspto-grants-2016_01
Patent number
US09238640B2

Reaction notes

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