Reaction #577441

Reaction equation

4-fluoro-3-methylbenzoyl chloride

(±)-2-[1-(2-amino-2-methyl-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-quinazolin-4-one

triethylamine

→

(±)-3-benzyl-7-chloro-2-{1-[2-(4-fluoro-3-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-imidazol-1-yl]-2-methyl-propyl}-3H-quinazolin-4-one

Yield 43.0%

Solvents

dichloromethane

Conditions

Workup

1. 1
   Otherevaporated under reduced pressure to a crude white solid
2. 2
   workup.ADDITIONThe resultant solid was treated with glacial acetic acid (10 mL)
3. 3
   Temperaturethe resultant suspention was heated
4. 4
   Temperatureat reflux for 48 hours
5. 5
   Otherthen evaporated under reduced pressure to a crude oil
6. 6
   OtherThe oil was quenched with saturated aqueous sodium bicarbonate (10 mL) and brine (5 mL)
7. 7
   ExtractionThe aqueous layer was extracted with dichloromethane (2×5 mL)
8. 8
   Dryingthe combined extracts were dried over magnesium sulfate
9. 9
   Filtrationfiltered
10. 10
    Concentrationconcentrated under reduced pressure
11. 11
    OtherThe residue was purified by silica gel chromatography (5-10% ethyl acetate/hexanes)

Procedure

To a solution of (±)-2-[1-(2-amino-2-methyl-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-quinazolin-4-one (250 mg, 0.61 mmol) in dichloromethane (10 mL) was added triethylamine (295 μL, 2.12 mmol), followed by 4-fluoro-3-methylbenzoyl chloride (105 mg, 0.61 mmol). The resultant solution was stirred at ambient temperature for 2 hours, then evaporated under reduced pressure to a crude white solid. The resultant solid was treated with glacial acetic acid (10 mL) then the resultant suspention was heated at reflux for 48 hours. The reaction was cooled to ambient temperature then evaporated under reduced pressure to a crude oil. The oil was quenched with saturated aqueous sodium bicarbonate (10 mL) and brine (5 mL). The aqueous layer was extracted with dichloromethane (2×5 mL) and the combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-10% ethyl acetate/hexanes) to furnish (±)-3-benzyl-7-chloro-2-{1-[2-(4-fluoro-3-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-imidazol-1-yl]-2-methyl-propyl}-3H-quinazolin-4-one (138 mg, 43%) as a white solid: LCMS 531 (M++H)

Source