反应详情

温度

-78 °C

A solution of 0.985 g (4.0 mmole) of finely powdered CeCl3 (Strem Chemical Co.) in 10 mL anhydrous THF was stirred at room temperature under N2. After 1 h, the solution was cooled to −78° C. in a dry ice-acetone bath and 2.5 mL of a 1.6M solution of methyllithium in ether was added dropwise at such a rate that the solids remained dispersed. After 30 minutes, a solution of 0.485 g (1.1 mmole) of methyl {1-[(3-chlorophenyl)(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)acetate in 5 mL of THF was added and the solution was left stirring at −78° C. for 1 h. The reaction was quenched by addition of 0.1 mL of methanol, diluted with 40 mL of ether and allowed to warm to −10° C. Then aqueous NH4Cl solution was added dropwise until the cerium salts precipitated onto the surface of the flask. The supernatant was decanted and the solids were triturated with two 20 mL portions of dichloromethane and two 20 mL portions of ether. The combined organic extracts were washed with saturated aqueous NH4Cl solution and brine, dried over Na2SO4 and concentrated to afford the title compound as a mixture of 4 diastereomers. The mixture was purified by flash chromatography on silica gel using a step gradient of 3 column volumes each of 1%, then 2%, then 4%, then 6% ethyl acetate-hexane to afford two diastereomers of the title compound. The enantiomers of the faster diastereomer were separated by chromatography on an AD column chiral using 6% isopropanol in heptane.

1. additionremained dispersed
2. waitAfter 30 minutes
3. waitthe solution was left
4. customThe reaction was quenched by addition of 0.1 mL of methanol
5. additiondiluted with 40 mL of ether
6. temperatureto warm to −10° C
7. additionThen aqueous NH4Cl solution was added dropwise until the cerium salts
8. customprecipitated onto the surface of the flask
9. customThe supernatant was decanted
10. customthe solids were triturated with two 20 mL portions of dichloromethane and two 20 mL portions of ether
11. washThe combined organic extracts were washed with saturated aqueous NH4Cl solution and brine
12. dry with materialdried over Na2SO4
13. concentrationconcentrated