Reacción #47967

Ecuación de reacción

thionyl chloride

ethylmagnesium bromide

N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-N′-(2,2,2-trifluoroethyl)urea

5,6-difluoro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one

triethylamine

→

4-ethyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one

Disolventes

THF

Condiciones de reacción

Tratamiento posterior

1. 1
   workup.WAITAfter 30 minutes at −78° C.
2. 2
   workup.WAITAfter 1 h at −78° C.
3. 3
   Otrothe reaction mixture was quenched with saturated NH4Cl
4. 4
   Temperaturawarmed to room temperature
5. 5
   ExtracciónThe reaction mixture was extracted three times with EtOAc
6. 6
   Lavadowashed with brine
7. 7
   SecadoThe organic layer was dried over NaSO4
8. 8
   Filtraciónfiltered
9. 9
   Concentraciónconcentrated in vacuo
10. 10
    OtroPurification by flash chromatography (1×14 cm silica gel, linear gradient 0-50% EtOAc:hexane)

Procedimiento

To a solution of 1.5 g (3.987 mmol) N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (open form) and 5,6-difluoro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (closed form) in 8 ml THF was added 2.0 mL (19.933 mmol) triethylamine. After 1 h at 80° C., the reaction mixture was cooled to −78° C. To this solution was added 0.498 mL (4.186 mmol) thionyl chloride. After 30 minutes at −78° C., 5 mL (12.358 mmol) ethylmagnesium bromide (3.0M solution in diethyl ether) was added dropwise. After 1 h at −78° C., the reaction mixture was quenched with saturated NH4Cl and warmed to room temperature. The reaction mixture was extracted three times with EtOAc and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 0-50% EtOAc:hexane) afforded 4-ethyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. Chiral Separation (ChiralPak AD column, 5 cm×50 cm, 20μ, 10-40% ethanol/hexane, modifier: DEA 1 mL/L, 60 mins) afforded 350 mg of the second isomer.

Fuente