反应详情

A solution of (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (55 g, 0.156 mol) in acetonitrile (1.2 L) was cooled to 0° C., NaH (19.2 g, 0.48 mol, 60% in oil) was added in portions, then the mixture was stirred at rt for 1 hr. The mixture was cooled to −20° C. and bromoacetonitrile (57.7 g, 0.48 mol) was added dropwise. After 0.5 hr, additional NaH (19.2 g, 0.48 mol, 60% in oil) and bromoacetonitrile (57.7 g, 0.48 mol) was added. TLC showed 80% of the starting material was reacted. The reaction was quenched with saturated NH4Cl solution (200 mL), water (1 L) was added. Acetonitrile was removed by reduced pressure, CH2Cl2 (1 L) was added, the aqueous layer was back extracted with CH2Cl2 (3×500 mL), dried over Na2SO4 and concentrated in vacuo to give the crude (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate (90 g), which was used for the next step without further purification.

1. temperatureThe mixture was cooled to −20° C.
2. waitAfter 0.5 hr
3. customwas reacted
4. customThe reaction was quenched with saturated NH4Cl solution (200 mL), water (1 L)
5. additionwas added
6. customAcetonitrile was removed by reduced pressure, CH2Cl2 (1 L)
7. additionwas added
8. extractionthe aqueous layer was back extracted with CH2Cl2 (3×500 mL)
9. dry with materialdried over Na2SO4
10. concentrationconcentrated in vacuo