Hydrochloric Acid → HCID 68520616, compound

Participants

Reaction Steps

A mixture of 2-amino-N-(isopropylcarbamoylmethyl)-5-(3-piperidin-1-ylpropoxy)benzamide (INTERMEDIATE VII.1) (1.40 g, 3.72 mmol) and ethyl 3-chlorobenzimidate*HCl (INTERMEDIATE III.1) (2.46 g, 11.16 mmol) in anhydrous ethanol (20 mL) was heated to 80° C. in a sealed pressure tube for 16 h. This was then cooled and concentrated in vacuo. The crude residue was partitioned between dichloromethane:2-propanol (3:1 [v/v], 80 mL) and water (50 mL) and the aqueous extracted with additional dichloromethane:2-propanol (3:1 [v/v], 3×80 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The amber oil thus obtained was purified by chromatography on silica gel with dichloromethane:methanol:NH4OH (aq.) (170:29:1, v/v) as eluent to afford a sticky light yellow solid (1.74 g). This was further purified by recrystallization from ethanol:hexane to afford a white solid (410 mg, 0.82 mmol, 22%). A second crop was obtained as follows: the filtrate was concentrated in vacuo and the crude oil partitioned between 1N HCl (aq.) (20 mL) and ethyl acetate (10 mL) and washed with additional ethyl acetate (10 mL). The aqueous phase was basified with 3N NaOH (aq.) to give a white precipitate which was collected by filtration and washed with cold water. The residue was recrystallized from 90% ethanol (aq.) giving additional product as a white solid (254 mg, 0.52 mmol, 14%). Both batches were combined to afford 2-[2-(3-chlorophenyl)-4-oxo-6-(3-piperidin-1-ylpropoxy)-4H-quinazolin-3-yl]-N-isopropylacetamide (664 mg, 1.34 mmol, 36%). 2-[2-(3-Chlorophenyl)-4-oxo-6-(3-piperidin-1-ylpropoxy)-4H-quinazolin-3-yl]-N-isopropylacetamide was treated with 4N HCl in methanol (4 mL, prepared by the addition of AcCl (4 mmol) to methanol (10 mL) dropwise at 0° C.) and concentrated in vacuo. The resultant crystalline white solid was triturated with cold diethyl ether, collected by filtration and dried in vacuo giving 2-[2-(3-chlorophenyl)-4-oxo-6-(3-piperidin-1-ylpropoxy)-4H-quinazolin-3-yl]-N-isopropylacetamide hydrochloride (EXAMPLE 3a) (743 mg, 1.39 mmol, 37%).

Provenance & Evidence