Sodium Carbonate → 5-(2-chloropyridin-3-yl)-1H-indazole

HRID 2284557

Reaction equation

HRID 2284557 reaction equation
C([N:8]1[C:16]2[C:11](=[CH:12][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)(OC(C)(C)C)=O.Br[C:27]1[C:28]([Cl:33])=[N:29][CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.O>[Cl:33][C:28]1[C:27]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][N:9]=[CH:10]3)=[CH:32][CH:31]=[CH:30][N:29]=1

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 312751,4-DioxaneHCID 6933243-Bromo-2-chloropyridineHCID 18525862tert-Butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate

Product 1

HCID 867154695-(2-chloropyridin-3-yl)-1H-indazoleYield 50%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 22728543Water ethylacetateSolvent

Conditions

Temperature
100 °C

Procedure

A single necked round bottom flask equipped with a magnetic stir bar was charged with 1-Boc-indazole-5-boronic acid pinacol ester (3.0 g, 8.7 mmol), 3-bromo-2-chloropyridine (2.0 g, 10.4 mmol), Pd(PPh3)4 (1 g, 0.86 mmol) and 2M aq. Na2CO3 (10 mL, 20 mmol) and 1,4-dioxane under nitrogen atmosphere. The reaction flask was fitted with a reflux condenser containing three-way stopcock equipped with argon filled balloon. The reaction contents were stirred and air was removed from the closed reaction system by vacuum and back filled with argon. Following three cycles of degassing, the reaction mixture was heated at 100° C. (oil-bath) under argon. Initial clear heterogeneous reaction mixture turned to clear biphasic off-yellow solution. After 12 h with no additional change in the proportion of the product, as analyzed by LC/MS, the reaction mixture was cooled to room temperature. Upon concentration of the reaction mixture, EtOAc/water (200 mL/100 mL) was transferred to the concentrate and stirred for 30 min. The organic layer was separated and the aqueous layer extracted with EtOAc (2×75 mL). MgSO4 and Celite® were added to combined organic layers, stirred for 20 min and the contents suction filtered. The filter cake was washed with EtOAc (100 mL) and the combined filtrates concentrated by rotary evaporator under vacuum. The crude concentrate was dissolved in 1% MeOH/CH2Cl2 and absorbed on silica gel (20g) by evaporating the solvent followed by drying. Subsequent purification by flash silica gel column purification of the dry powder (Combiflash® companion System® with RediSep® silica gel column 120 g, 30-70% EtOAc/hexanes eluting solvent) provided 5-(2-chloropyridin-3-yl)-1H-indazole (1.0 g, 50%) as a white crystalline solid after concentration of the desired product fractions. 1H NMR (DMSO-d6): δ 13.2 (s, 1H), 8.41 (dd, 1H, J=1.8 and 4.7 Hz), 8.13 (s, 1H), 7.90 (dd, 1H, J=1.7 and 4.7 Hz), 7.84 (s, 1H), 7.62 (d, 1H, J=8.8 Hz), 7.51 (dd, 1H, J=4.7 and 7.3 Hz), 7.42 (dd, 1H, J=1.4 and 8.5 Hz). LCMS: 95%, MS (m/e) 230 (MH+).

Workup

  1. customA single necked round bottom flask equipped with a magnetic stir bar
  2. customThe reaction flask was fitted with a reflux condenser
  3. additioncontaining three-way stopcock
  4. customequipped with argon filled balloon
  5. customThe reaction contents
  6. customair was removed from the closed reaction system by vacuum
  7. additionback filled with argon
  8. customof degassing
  9. customInitial clear heterogeneous reaction mixture
  10. temperaturethe reaction mixture was cooled to room temperature
  11. concentrationconcentrate
  12. stirringstirred for 30 min
  13. customThe organic layer was separated
  14. extractionthe aqueous layer extracted with EtOAc (2×75 mL)
  15. additionMgSO4 and Celite® were added
  16. stirringstirred for 20 min
  17. filtrationthe contents suction filtered
  18. washThe filter cake was washed with EtOAc (100 mL)
  19. concentrationthe combined filtrates concentrated by rotary evaporator under vacuum
  20. concentrationThe crude concentrate
  21. dissolutionwas dissolved in 1% MeOH/CH2Cl2
  22. customabsorbed on silica gel (20g)
  23. customby evaporating the solvent
  24. customby drying
  25. customSubsequent purification
  26. customby flash silica gel column purification of the dry powder (Combiflash® companion System® with RediSep® silica gel column 120 g, 30-70% EtOAc/hexanes eluting solvent)

Sources & evidence

ORD record
ord-648319d49ba74b619eb3f0871219b5ed
Source dataset
uspto-grants-2015_09
Patent number
US09145433B2

Linked notes

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