p-Toluenesulfonic acid monohydrate → 8-Chloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one

HRID 591776Notes

Reaction equation

HRID 591776 reaction equation
[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:29])[C:20]=1[O:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:16]=O.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[Cl:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:16]([C:15]1[CH:14]=[C:13]([CH3:12])[C:20]([O:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:19]([CH3:29])[CH:18]=1)[NH:6][C:4]2=[O:5]

Participants

6

Reactant 4

HCID 521998p-Toluenesulfonic acid monohydrateHCID 141004282-Amino-3-chlorobenzamideHCID 23665763Sodium BisulfiteHCID 289325703,5-Dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde

Product 1

HCID 1363480098-Chloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
140 °C

Procedure

To a solution of 2-amino-3-chloro-benzamide (0.85 g, 5.00 mmol) and 3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (1.23 g, 5.00 mmol) in N,N-dimethylacetamide (20 mL) were added sodium hydrogen sulfite (58.5 wt %, 1.37 g, 7.50 mmol) and p-toluenesulfonic acid monohydrate (3.80 g, 20.0 mmol). The reaction mixture was stirred at 140° C. for 16 hours under nitrogen, then cooled to room temperature. Solvent was evaporated under reduced pressure. Water (100 mL) was added, and the mixture was neutralized, to pH approximately 8 with 2 N aqueous NaOH solution. The separated solid was filtered, washed with water (50 mL), and dried under vacuum. Crude compound was purified by the Simpliflash system (0-5% methanol in CH2Cl2 and then 5% 7.0 M ammonia in methanol and CH2Cl2 as eluent) to give the title compound as a brown solid. Yield: 0.49 g (25%). MP 216-217° C. 1H NMR (400 MHz, DMSO-d6): δ 8.07 (d, J=7.81 Hz, 1H), 8.01-7.87 (m, 3H), 7.43 (t, J=7.81 Hz, 1H), 3.89 (t, J=5.85 Hz, 2H), 2.81 (t, J=5.85 Hz, 2H), 2.53 (br s, 4H), 2.30 (s, 6H), 1.75-1.60 (m, 4H). MS (ES+) m/z 398.11 (100%), 400.13 (40%).

Workup

  1. temperaturecooled to room temperature
  2. customSolvent was evaporated under reduced pressure
  3. additionWater (100 mL) was added
  4. filtrationThe separated solid was filtered
  5. washwashed with water (50 mL)
  6. customdried under vacuum
  7. customCrude compound was purified by the Simpliflash system (0-5% methanol in CH2Cl2

Sources & evidence

ORD record
ord-80ad8f4cecc04780ab9e61d4598124c2
Source dataset
uspto-grants-2016_01
Patent number
US09238640B2

Reaction notes

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