تفاعل #69792

معادلة التفاعل

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

المذيبات

water

DMF

ظروف التفاعل

المعالجة

1. 1
   أخرىSparge with nitrogen
2. 2
   أخرىequipped with magnetic stirring, temperature probe, and condenser with septa for 10 minutes
3. 3
   أخرىcontinue sparging for 10 minutes
4. 4
   أخرىto sparge for an additional 0.5 hours
5. 5
   درجة الحرارةCool the reaction mixture to below 40° C.
6. 6
   أخرىcontinue sparging for 10 minutes
7. 7
   أخرىAdd 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride DCM complex (1.3 g, 1.56 mmol) to the reaction
8. 8
   أخرىcontinue sparging 0.5 hours
9. 9
   درجة الحرارةHeat the mixture at 95° C. under nitrogen for 3 hours
10. 10
    workup.ADDITIONDilute the mixture with EA
11. 11
    ترشيحfilter through a Celite® pad
12. 12
    غسيلWash the pad with brine (400 mL)
13. 13
    أخرىseparate the filtrate layers
14. 14
    غسيلWash the organic layer with brine
15. 15
    استخلاصextract the combined aqueous layers with EA
16. 16
    تركيزconcentrate 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
    غسيلElute the pad with eluent (50% EA in hexanes followed by 70% EA in hexanes)
20. 20
    أخرىto afford a light brown oil
21. 21
    أخرىTriturate with MTBE (100 mL)

الإجراء التجريبي

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]+.

المصدر