反应 #1707990

反应方程式

dimethoxyethane

3-{3-tert-butylsulfanyl-5-hydroxy-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester

5-bromo-2-ethoxypyridine

potassium carbonate

→

desired product

收率 80.2%

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

收率 80.2%

溶剂

water

Methyl tert-butyl ether

反应条件

后处理

1. 1
   其他in a 50 L reaction flask under nitrogen
2. 2
   其他The mixture was sparged with nitrogen for 30 minutes
3. 3
   其他to remove
4. 4
   workup.DISSOLUTIONdissolved oxygen gas
5. 5
   workup.ADDITIONtetrakis(triphenylphosphine)palladium(0) (59.15 g) was added
6. 6
   温度the reaction was cooled to 40° C.
7. 7
   workup.ADDITIONwater (6.6 L) was added
8. 8
   workup.ADDITIONEthyl acetate (6.6 L) was added
9. 9
   workup.STIRRINGthe mixture was agitated for 20 minutes
10. 10
    其他to separate over 1.5 hours
11. 11
    其他The aqueous layer was separated
12. 12
    workup.ADDITIONadditional water (6.6 L) was added to the organic layer
13. 13
    workup.STIRRINGThe mixture was agitated for 2 minutes
14. 14
    其他to separate over 1 hour, with additional ethyl acetate (1.4 L)
15. 15
    workup.ADDITIONadded
16. 16
    其他phase separation
17. 17
    其他The aqueous layer was separated
18. 18
    workup.ADDITIONEthyl acetate (5.0 L) was added to the combined aqueous layer
19. 19
    workup.STIRRINGthe mixture was agitated for 3 minutes
20. 20
    其他to separate over 2 minutes
21. 21
    其他The aqueous layer was separated
22. 22
    workup.ADDITIONtreated with activated carbon, Novit Neutral (446.43 g)
23. 23
    workup.STIRRINGThe mixture was stirred for 17 hours at room temperature
24. 24
    过滤filtered through a 1-2″ pad of Celite
25. 25
    洗涤The reaction flask was rinsed twice with ethyl acetate (1.25 L)
26. 26
    过滤filtered through the pad of Celite
27. 27
    浓缩the filtrate was concentrated
28. 28
    其他to give the crude material
29. 29
    workup.STIRRINGthe mixture was agitated for 1.5 hours
30. 30
    过滤filtered
31. 31
    洗涤The flask was rinsed with methyl tert-butyl ether (1 L) three times
32. 32
    过滤filtered through the filter cake
33. 33
    其他The isolated solids were dried in a drying oven at 25° C. under vacuum for 3 days

实验过程

To a stirring mixture of dimethoxyethane (16.5 L) and water (6.6 L) in a 50 L reaction flask under nitrogen was added 3-{3-tert-butylsulfanyl-5-hydroxy-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester (1652.19 g), 5-bromo-2-ethoxypyridine (650.30 g), and potassium carbonate (605.03 g). The mixture was sparged with nitrogen for 30 minutes to remove dissolved oxygen gas, and then tetrakis(triphenylphosphine)palladium(0) (59.15 g) was added, and the reaction mixture was heated to 65-85° C. over 2 hours and stirred at 65-85° C. under nitrogen for 19 hours. Once no starting material was seen by tlc analysis, the reaction was cooled to 40° C. and water (6.6 L) was added. Ethyl acetate (6.6 L) was added, and the mixture was agitated for 20 minutes and then allowed to separate over 1.5 hours. The aqueous layer was separated, and additional water (6.6 L) was added to the organic layer. The mixture was agitated for 2 minutes and then allowed to separate over 1 hour, with additional ethyl acetate (1.4 L) added to facilitate phase separation. The aqueous layer was separated, and the two aqueous layers were combined. Ethyl acetate (5.0 L) was added to the combined aqueous layer, and the mixture was agitated for 3 minutes and allowed to separate over 2 minutes. The aqueous layer was separated, and the two organic layers were combined and treated with activated carbon, Novit Neutral (446.43 g). The mixture was stirred for 17 hours at room temperature, and then filtered through a 1-2″ pad of Celite. The reaction flask was rinsed twice with ethyl acetate (1.25 L) and filtered through the pad of Celite, and the filtrate was concentrated to give the crude material. Methyl tert-butyl ether (8.2 L) was added to the solids, and the mixture was agitated for 1.5 hours and filtered. The flask was rinsed with methyl tert-butyl ether (1 L) three times and then filtered through the filter cake. The isolated solids were dried in a drying oven at 25° C. under vacuum for 3 days to give the desired product (1314 g).

来源