反应详情

温度

35 °C

3-{3-tert-Butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-hydroxy-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester (1313.2 g) was dissolved in acetonitrile (20.0 L) in a 50 L reaction flask under nitrogen, and the mixture was stirred and heated to 30-40° C. Cesium carbonate (2118.67 g) was added, followed by 2-chloro-5-methylpyridine hydrochloride (497.17 g), and the temperature was increased to 70-80° C. over 2 hours. After heating at 70-80° C. for 4 hours, no starting material was seen by tlc analysis, and the mixture was cooled to 55° C. and concentrated. The residue was dissolved in dichloromethane (2 L) and water (2 L) and transferred to a flask containing dichloromethane (4 L) and water (4 L). The original flask was rinsed twice with dichloromethane (2 L) and water (2 L), and the combined material was then diluted with an additional 3 L of dichloromethane and 6 L water to a total volume of 13 L of dichloromethane and 16 L of water. The mixture was agitated for 10 minutes and allowed to separate over 10 minutes. The organic layer was separated, and additional dichloromethane (9 L) was added to the aqueous layer. The mixture was agitated for 6 minutes and allowed to separate over 5 minutes. The organic layer was separated, and the two organic layers were combined and treated with activated carbon, Novit Neutral (433.07 g) and silica gel, thiol derivatized (91.17 g). The mixture was stirred for 17 hours at room temperature, and then filtered through a 1-2″ pad of Celite. The flask was rinsed with dichloromethane (2.6 L) and filtered through the pad of Celite, and the filtrate was concentrated to give the crude material. Ethanol (9.2 L) was added to the solids, and the mixture was stirred slowly for 17 hours and filtered. The isolated solids were dried in a drying oven at 45° C. under vacuum for 2 days to give the desired product (1459.4 g).

1. temperaturethe temperature was increased to 70-80° C. over 2 hours
2. temperatureAfter heating at 70-80° C. for 4 hours
3. temperaturethe mixture was cooled to 55° C.
4. concentrationconcentrated
5. dissolutionThe residue was dissolved in dichloromethane (2 L)
6. customwater (2 L) and transferred to a flask
7. additioncontaining dichloromethane (4 L) and water (4 L)
8. washThe original flask was rinsed twice with dichloromethane (2 L) and water (2 L)
9. additionthe combined material was then diluted with an additional 3 L of dichloromethane and 6 L water to a total volume of 13 L of dichloromethane and 16 L of water
10. stirringThe mixture was agitated for 10 minutes
11. customto separate over 10 minutes
12. customThe organic layer was separated
13. additionadditional dichloromethane (9 L) was added to the aqueous layer
14. stirringThe mixture was agitated for 6 minutes
15. customto separate over 5 minutes
16. customThe organic layer was separated
17. additiontreated with activated carbon, Novit Neutral (433.07 g) and silica gel, thiol
18. stirringThe mixture was stirred for 17 hours at room temperature
19. filtrationfiltered through a 1-2″ pad of Celite
20. washThe flask was rinsed with dichloromethane (2.6 L)
21. filtrationfiltered through the pad of Celite
22. concentrationthe filtrate was concentrated
23. customto give the crude material
24. stirringthe mixture was stirred slowly for 17 hours
25. filtrationfiltered
26. customThe isolated solids were dried in a drying oven at 45° C. under vacuum for 2 days