Acetaldehyde → 3-Acetyl-2-chloropyridine

온도

-78 °C

To a solution of 2-chloropyridine (XI) (31.0 kg, 273 mol) in dry THF (275 L) cooled to −78° C. under nitrogen was added LDA (113 L, 1220 mol) dropwise while maintaining the temperature at −78° C. and stirred for 5 hours. Acetaldehyde (16 L, 463 mol) was then added and the reaction was stirred at −78° C. for another 5 hours before warming to 0° C. and adding water (310 L) to quench the reaction. The solution was stirred for 50 min and then warmed to room temperature. The solution was extracted 3×EtOAc (279 L) by adding EtOAc, stirring for 50 min, allowing to stand for 50 min, separating the layers and then repeating twice. The combined EtOAc was concentrated under vacuum to a volume of 300-500 L. To the crude 1-(2-chloropyridin-3-yl)ethanol (XII) was added DCM (705 L) followed by an aqueous solution of KBr (3.3 Kg, 27.7 mol) dissolved in water (33 L). The solution was cooled to 0° C. before adding TEMPO (1.7 Kg, 10.9 mol) and then stirred for 50 min. In a second container, water (980 L) was added followed by KHCO3 (268 Kg, 2677 mol) and 10% aqueous NaClO (233 L, 313 mol). This aqueous mixture was then added dropwise to the TEMPO mixture. This combined mixture was stirred at 0° C. for 5 hours. To this mixture was added dropwise Na2S2O3.7H2O (22.5 Kg, 90 mol) in water (107 L) with stirring for 50 min at 0° C. The mixture was allowed to warm to room temperature and the organic phase was separated. The aqueous phase was extracted 2×DCM (353 L) by adding DCM, stirring for 50 min, allowing to stand for 50 min, separating the layers and then repeating. The combined organic layers were washed with aqueous 25% NaCl (274 L) and concentrated under vacuum to give crude 1-(2-chloropyridin-3-yl)ethanone (XIII) which was used for the next step without additional purification.

1. stirringthe reaction was stirred at −78° C. for another 5 hours
2. temperaturebefore warming to 0° C.
3. customto quench
4. customthe reaction
5. stirringThe solution was stirred for 50 min
6. temperaturewarmed to room temperature
7. extractionThe solution was extracted 3×EtOAc (279 L)
8. additionby adding EtOAc
9. stirringstirring for 50 min
10. waitto stand for 50 min
11. customseparating the layers
12. concentrationThe combined EtOAc was concentrated under vacuum to a volume of 300-500 L
13. additionTo the crude 1-(2-chloropyridin-3-yl)ethanol (XII) was added DCM (705 L)
14. temperatureThe solution was cooled to 0° C.
15. stirringstirred for 50 min
16. stirringThis combined mixture was stirred at 0° C. for 5 hours
17. stirringwith stirring for 50 min at 0° C
18. temperatureto warm to room temperature
19. customthe organic phase was separated
20. extractionThe aqueous phase was extracted 2×DCM (353 L)
21. additionby adding DCM
22. stirringstirring for 50 min
23. waitto stand for 50 min
24. customseparating the layers
25. washThe combined organic layers were washed with aqueous 25% NaCl (274 L)
26. concentrationconcentrated under vacuum

ORD 기록

ord-1fc702aa7d6340279d13e5ad2241c7d5

출처 데이터셋

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US09233104B2