Reacción #69792

Ecuación de reacción

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

Disolventes

water

DMF

Condiciones de reacción

Tratamiento posterior

1. 1
   OtroSparge with nitrogen
2. 2
   Otroequipped with magnetic stirring, temperature probe, and condenser with septa for 10 minutes
3. 3
   Otrocontinue sparging for 10 minutes
4. 4
   Otroto sparge for an additional 0.5 hours
5. 5
   TemperaturaCool the reaction mixture to below 40° C.
6. 6
   Otrocontinue sparging for 10 minutes
7. 7
   OtroAdd 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride DCM complex (1.3 g, 1.56 mmol) to the reaction
8. 8
   Otrocontinue sparging 0.5 hours
9. 9
   TemperaturaHeat the mixture at 95° C. under nitrogen for 3 hours
10. 10
    workup.ADDITIONDilute the mixture with EA
11. 11
    Filtraciónfilter through a Celite® pad
12. 12
    LavadoWash the pad with brine (400 mL)
13. 13
    Otroseparate the filtrate layers
14. 14
    LavadoWash the organic layer with brine
15. 15
    Extracciónextract the combined aqueous layers with EA
16. 16
    Concentraciónconcentrate 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
    LavadoElute the pad with eluent (50% EA in hexanes followed by 70% EA in hexanes)
20. 20
    Otroto afford a light brown oil
21. 21
    OtroTriturate with MTBE (100 mL)

Procedimiento

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]+.

Fuente