反応 #69792

反応方程式

4-iodo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole

barium hydroxide octahydrate

tributylamine

4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane

5-(tert-butyldimethylsilyloxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

→

title compound

(E)-1-(Tetrahydro-2H-pyran-2-yl)-3-(2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)vinyl)-1H-indazol-5-ol

溶媒

water

DMF

反応条件

後処理

1. 1
   その他Sparge with nitrogen
2. 2
   その他equipped with magnetic stirring, temperature probe, and condenser with septa for 10 minutes
3. 3
   その他continue sparging for 10 minutes
4. 4
   その他to sparge for an additional 0.5 hours
5. 5
   温度Cool the reaction mixture to below 40° C.
6. 6
   その他continue sparging for 10 minutes
7. 7
   その他Add 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride DCM complex (1.3 g, 1.56 mmol) to the reaction
8. 8
   その他continue sparging 0.5 hours
9. 9
   温度Heat the mixture at 95° C. under nitrogen for 3 hours
10. 10
    workup.ADDITIONDilute the mixture with EA
11. 11
    ろ過filter through a Celite® pad
12. 12
    洗浄Wash the pad with brine (400 mL)
13. 13
    その他separate the filtrate layers
14. 14
    洗浄Wash the organic layer with brine
15. 15
    抽出extract the combined aqueous layers with EA
16. 16
    濃縮concentrate to a brown oil
17. 17
    workup.DISSOLUTIONDissolve the oil in DCM (100 mL)
18. 18
    workup.ADDITIONadd to a silica gel pad
19. 19
    洗浄Elute the pad with eluent (50% EA in hexanes followed by 70% EA in hexanes)
20. 20
    その他to afford a light brown oil
21. 21
    その他Triturate with MTBE (100 mL)

実験手順

Sparge with nitrogen a mixture of 5-(tert-butyldimethylsilyloxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (14 g, 30.54 mmol) in DMF (150 mL) in a 500 mL 3-neck round bottom flask equipped with magnetic stirring, temperature probe, and condenser with septa for 10 minutes. To the resulting solution add tributylamine (TBA, 6.7 g, 36.1 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.0 g, 43.18 mmol) and continue sparging for 10 minutes. To the resulting mixture add bis(triphenylphosphine) palladium (II) chloride (0.45 g, 0.63 mmol) and continue to sparge for an additional 0.5 hours. Heat the mixture at 95-100° C. for 18 hours. Cool the reaction mixture to below 40° C. and charge with 4-iodo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole (9.8 g, 30.42 mmol). To the resulting mixture add barium hydroxide octahydrate (19.3 g, 60.3 mmol) and water (13 mL) and continue sparging for 10 minutes. Add 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride DCM complex (1.3 g, 1.56 mmol) to the reaction and continue sparging 0.5 hours. Heat the mixture at 95° C. under nitrogen for 3 hours. Dilute the mixture with EA and filter through a Celite® pad. Wash the pad with brine (400 mL) and separate the filtrate layers. Wash the organic layer with brine and extract the combined aqueous layers with EA. Combine the organic solutions and concentrate to a brown oil. Dissolve the oil in DCM (100 mL) and add to a silica gel pad. Elute the pad with eluent (50% EA in hexanes followed by 70% EA in hexanes) to afford a light brown oil. Triturate with MTBE (100 mL) to afford the title compound as a solid. Yield: 5 g (37%). MS (ES) m/z 439 [M+1]+.

出典