反应详情

To a 100 mL dry round bottom flask was added 73 mg (3.0 mmol) of magnesium powder, a couple of I2 crystals, and 5 mL of dry diethyl ether, and the mixture was allowed to stir under argon. 4-Bromomethyl-2,6-dichloropyridine (723 mg, 3.0 mmol) in 10 mL of diethyl ether was added dropwise through a dropping funnel and the resulting mixture was heated to reflux for 1 hour. 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (278 mg, 1.0 mmol) (Example 1) in diethyl ether (5 mL) was carefully added dropwise through a dropping funnel and the mixture was allowed to stir to reflux temperature for 4 hours and then overnight (16 hours) at room temperature. The reaction was quenched with the addition of 3 mL of aqueous NH4Cl solution, and the resulting mixture was extracted with three 30 mL portions of EtOAc, washed with H2O (10 mL) and brine (10 mL), and the organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using an EtOAc-hexanes gradient. Combined product fractions were concentrated in vacuo to afford the desired product which was further purified by preparative-HPLC using a gradient of 80%-100% (CH3CN-water) in 15 minutes and a flow rate of 20 mL/min to afford 76 mg of the title compound (17.2% yield) as a yellowish liquid.

1. customTo a 100 mL dry round bottom flask
2. temperaturethe resulting mixture was heated
3. temperatureto reflux for 1 hour
4. stirringto stir
5. temperatureto reflux temperature for 4 hours
6. customovernight (16 hours)
7. customat room temperature
8. customThe reaction was quenched with the addition of 3 mL of aqueous NH4Cl solution
9. extractionthe resulting mixture was extracted with three 30 mL portions of EtOAc
10. washwashed with H2O (10 mL) and brine (10 mL)
11. dry with materialthe organic phase was dried over Na2SO4
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customThe residue was purified by flash chromatography on silica gel using an EtOAc-hexanes gradient
15. concentrationCombined product fractions were concentrated in vacuo