Formamide → 4(1H)-Quinazolinone

Participants

Reaction Conditions

Reaction Steps

The intermediate 4-piperazinyl-7-(2-piperidylethoxy)quinazoline was prepared using the procedures as generally described in Scheme 1 as follows: Step A To the ethanol solution (15 mL) of 2-amino-4-fluorobenzoic acid (840 mg, 5.41 mmol) was added thionyl chloride (1.18 mL, 16.23 mmol) and the resulting suspension was refluxed overnight. The solvent was evaporated to the residue added EtOAc, washed with 10% NaOH solution, dried, filtered and evaporated to afford desired ethyl ester as a solid 981 mg, 82%). MS (ES) 184(M+H) Step B: To the formamide (6 mL) solution of ethyl-2-amino-4-fluorobenzoate (811 mg, 4.43 mmol) added ammonium formate (0.450 g, 7.14 mmol) and the reaction mixture was heated at 140° C. overnight. After cooling added water and ethyl acetate. The layers were separated, the EtOAc layer was dried, filtered and evaporated to give desired quinazolinone (1 g, quantitative). MS (ES) 165 (M+H) Step C: To the DMF solution (3 mL) of 1-piperidineethanol (0.689 mL, 5.18 mmol) at 0° C. added sodium hydride (0.518 g, 12.95 mmol) and the mixture was stirred for 30 min. To this cold solution added DMF solution (3 mL) of intermediate quinazolinone (0.284 g, 1.73 mmol, from Step B) and the mixture was heated at 75° C. overnight. The solvent was evaporated and the residue purified by RP-HPLC to afford desired product as a creamy solid (0.459 g, 97%) Step D: A mixture of 7-(2-piperidylethoxy)-4-quinazolinone (0.459 g, 1.68 mmol), from Step C) and POCl3 (5 mL) was heated at 75° C. overnight. After cooling excess POCl3 was removed by evaporation and the residue azeotroped with toluene to afford intermediate, 4-chloro-7-(2-piperidylethoxy)quinazoline (600 mg, 95%) Step E: To the isopropanol solution (10 mL) of 4-chloroquinazoline (0.615 g, 2.11 mmol, from Step D) added piperazine (0.727 g, 8.44 mmol) and heated the reaction for 4 h at 100° C. The solvent was evaporated and the residue purified by RP-HPLC to afford 4-piperazinyl-7-(2-piperidylethoxy)quinazoline as a white solid (0.630 g, 87%).

Provenance & Evidence