p-Toluenesulfonic acid → 6-amino-2-(4-(2-hydroxy ethoxy)-3,5-dimethyl phenyl)-3H-quinazolin-4-one

HRID 555532

Reaction equation

HRID 555532 reaction equation
[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[O:14]([CH2:22][CH2:23][O:24][C:25]1[C:32]([CH3:33])=[CH:31][C:28]([CH:29]=O)=[CH:27][C:26]=1[CH3:34])[Si](C(C)(C)C)(C)C.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.CN(C=O)C.CO.[Pd]>[NH2:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:29]([C:28]1[CH:31]=[C:32]([CH3:33])[C:25]([O:24][CH2:23][CH2:22][OH:14])=[C:26]([CH3:34])[CH:27]=1)[NH:6][C:4]2=[O:5]

Participants

9

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 976652-Amino-5-nitrobenzamideHCID 23665763Sodium BisulfiteHCID 866219154-(2-(Tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylbenzaldehyde

Product 1

HCID 1363988506-amino-2-(4-(2-hydroxy ethoxy)-3,5-dimethyl phenyl)-3H-quinazolin-4-oneYield 42%

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
150 °C

Procedure

To a solution of 2-amino-5-nitro-benzamide (680 mg, 3.75 mmol) and 4-[2-(tert-butyidimethylsilanoxy)ethoxy]-3,5-dimethylbenzaldehyde (1.16 g, 3.75 mmol) in N,N-dimethyl acetamide (35 mL), NaHSO3 (736 mg, 4.14 mmol) and p-TSA (71 mg, 0.375 mmol) were added and the reaction mixture was heated at 150° C. for 5 h. The solvent was evaporated under reduced pressure. The residue was diluted with water and the solids were filtered off to give crude product (590 mg, 44%). To a solution of above crude product (490 mg, 1.38 mmol) in DMF (20 mL) and MeOH (20 mL), Pd—C (100 mg, 10%) was added and the reaction mixture was hydrogenated for 4 h at room temperature at 30 psi H2. The reaction mixture was filtered and the solvent was evaporated to give crude product. The crude was purified by column chromatography (silica gel 230-400 mesh; 4% methanol in CH2Cl2 as eluent) to give 6-amino-2-(4-(2-hydroxy ethoxy)-3,5-dimethyl phenyl)-3H-quinazolin-4-one (190 mg, 42% yield). To a solution of 6-amino-2-(4-(2-hydroxy ethoxy)-3,5-dimethyl phenyl)-3H-quinazolin-4-one (95 mg, 0.29 mmol) in pyridine (5 mL), acetic anhydride (108 mg, 0.73 mmol) was added and the mixture was stirred for 16 h at room temperature. The solvent was removed and the solids were dissolved in a mixture of MeOH (10 mL) and THF (10 mL) (compound was partially soluble). Then K2CO3 (100 mg, 0.73 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. The solvent was removed and the crude was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent) to give N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide (65 mg, 60%). Selected data: MS (ES) m/z: 368.09; MP>300° C.

Workup

  1. customThe solvent was evaporated under reduced pressure
  2. additionThe residue was diluted with water
  3. filtrationthe solids were filtered off
  4. customto give crude product (590 mg, 44%)
  5. filtrationThe reaction mixture was filtered
  6. customthe solvent was evaporated
  7. customto give crude product
  8. customThe crude was purified by column chromatography (silica gel 230-400 mesh; 4% methanol in CH2Cl2 as eluent)

Sources & evidence

ORD record
ord-988e8ec2adb843a2b1740d7083460d63
Source dataset
uspto-grants-2011_11
Patent number
US08053440B2

Linked notes

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