Reaktion #1707990

Reaktionsgleichung

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

Ausbeute 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

Ausbeute 80.2%

Lösungsmittel

water

Methyl tert-butyl ether

Reaktionsbedingungen

Aufarbeitung

1. 1
   Sonstigein a 50 L reaction flask under nitrogen
2. 2
   SonstigeThe mixture was sparged with nitrogen for 30 minutes
3. 3
   Sonstigeto remove
4. 4
   workup.DISSOLUTIONdissolved oxygen gas
5. 5
   workup.ADDITIONtetrakis(triphenylphosphine)palladium(0) (59.15 g) was added
6. 6
   Temperaturthe 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
    Sonstigeto separate over 1.5 hours
11. 11
    SonstigeThe 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
    Sonstigeto separate over 1 hour, with additional ethyl acetate (1.4 L)
15. 15
    workup.ADDITIONadded
16. 16
    Sonstigephase separation
17. 17
    SonstigeThe 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
    Sonstigeto separate over 2 minutes
21. 21
    SonstigeThe 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
    Filtrationfiltered through a 1-2″ pad of Celite
25. 25
    WaschenThe reaction flask was rinsed twice with ethyl acetate (1.25 L)
26. 26
    Filtrationfiltered through the pad of Celite
27. 27
    Einengenthe filtrate was concentrated
28. 28
    Sonstigeto give the crude material
29. 29
    workup.STIRRINGthe mixture was agitated for 1.5 hours
30. 30
    Filtrationfiltered
31. 31
    WaschenThe flask was rinsed with methyl tert-butyl ether (1 L) three times
32. 32
    Filtrationfiltered through the filter cake
33. 33
    SonstigeThe isolated solids were dried in a drying oven at 25° C. under vacuum for 3 days

Vorschrift

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).

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