Potassium Carbonate → 6-Chloro-5-(4-(2-hydroxypropan-2-yl)phenyl)-1H-indazole-3-carboxylic acid

HRID 338466Notes

Reaction equation

HRID 338466 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 591660132-(4-(Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-olHCID 866987915-bromo-6-chloro-1H-indazole-3-carboxylic acid

Product 1

HCID 866988016-Chloro-5-(4-(2-hydroxypropan-2-yl)phenyl)-1H-indazole-3-carboxylic acidYield 35.3%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 702EthanolSolventHCID 1140TolueneSolvent

Procedure

To a mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol) and 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propan-2-ol (114 mg, 0.44 mmol) in toluene (1.5 mL) and EtOH (1.5 mL) was added 2N aqueous potassium carbonate solution (0.7 mL, 1.4 mmol). The reaction mixture was degassed with N2 for 10 minutes, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.0 mg, 0.018 mmol), and heated to reflux for 16 hours. After cooling to room temperature, the reaction was quenched with 1N NaOH (1 mL). The mixture was stirred for 30 minutes, acidified with 1N HCl to pH 5 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase chromatography (Biotage C18 column, 0-40% MeCN/water) to give the title compound (42 mg, 35% yield) as a solid. MS (ES−) 329.1 (M−H)+. 1H NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 7.74 (s, 1H), 7.55 (d, J=8.20 Hz, 2H), 7.37 (d, J=8.20 Hz, 2H), 1.57 (s, 6H).

Workup

  1. customThe reaction mixture was degassed with N2 for 10 minutes
  2. temperatureheated
  3. temperatureto reflux for 16 hours
  4. customthe reaction was quenched with 1N NaOH (1 mL)
  5. extractionextracted with EtOAc
  6. washThe organic layer was washed with brine
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated in vacuo
  9. customThe crude material was purified by reverse phase chromatography (Biotage C18 column, 0-40% MeCN/water)

Sources & evidence

ORD record
ord-beda717375644a90911b27318e28bbc0
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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