反应详情

温度

-30 °C

In a 1500 mL four necked flask (with mechanical stirrer) 22 g (84.2 mmol) ethyl N-benzyl-3-oxo-4-piperidine-carboxylate (from the HCl-salt by aq.Na2CO3/CH2Cl2-extraction) and 43.5 mL (252 mmol) DIPEA were dissolved in 300 mL DCM. The amber solution was cooled to −20° C. to −30° C. 28.5 g (101 mmol) trifluoromethanesulfonic anhydride were added drop wise over a period of 45 min. The dark brown solution was stirred for 2 h at −20° C./−30° C. 300 mL water and 300 mL 10% Na2CO3 aq. was added and the mixture was stirred for 15 min at 5-10° C. The organic layer was separated and the aqueous layer was extracted twice with 150 mL DCM. The combined organic layers were dried over Na2SO4 and filtered. The filtrate was evaporated to dryness and dissolved in 500 mL dioxane. 15.8 g (101 mmol) 4-chlorophenylboronic acid, 93 mL Na2CO3 aq. (2M) and 3.8 g (3.36 mmol) tetrakis(triphenylphosphine)palladium(0) was added and the mixture was heated to reflux over night. After cooling to room temperature, the mixture was diluted with 400 g ice-water and extracted twice with 400 mL ethyl acetate. The organic layers were extracted once with 500 mL brine. After drying over Na2SO4 the filtrate was evaporated to dryness. The black oil was absorbed on 60 g isolute HM-N and purified by column chromatography to yield 14.6 g (48%) of the title compound as viscous yellow oil. MS (m/e): 356.3 [(M+H)+].

1. temperatureThe amber solution was cooled to −20° C. to −30° C
2. stirringthe mixture was stirred for 15 min at 5-10° C
3. customThe organic layer was separated
4. extractionthe aqueous layer was extracted twice with 150 mL DCM
5. dry with materialThe combined organic layers were dried over Na2SO4
6. filtrationfiltered
7. customThe filtrate was evaporated to dryness
8. dissolutiondissolved in 500 mL dioxane
9. temperaturethe mixture was heated
10. temperatureto reflux over night
11. temperatureAfter cooling to room temperature
12. extractionextracted twice with 400 mL ethyl acetate
13. extractionThe organic layers were extracted once with 500 mL brine
14. dry with materialAfter drying over Na2SO4 the filtrate
15. customwas evaporated to dryness
16. customThe black oil was absorbed on 60 g
17. custompurified by column chromatography