Potassium Carbonate → 6-Chloro-5-(4-isopropoxyphenyl)-1H-indazole-3-carboxylic acid

HRID 1054806Notes

Reaction equation

HRID 1054806 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].[CH:15]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([CH3:17])[CH3:16].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].ClCCl>[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:22]1[CH:23]=[CH:24][C:19]([O:18][CH:15]([CH3:17])[CH3:16])=[CH:20][CH:21]=1

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 36987264-Isopropoxybenzeneboronic acidHCID 866987915-bromo-6-chloro-1H-indazole-3-carboxylic acid

Product 1

HCID 866987986-Chloro-5-(4-isopropoxyphenyl)-1H-indazole-3-carboxylic acidYield 11%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 702EthanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol), 4-isopropoxyphenylboronic acid (68.6 mg, 0.38 mmol), and 2 N aqueous potassium carbonate solution (1.1 mL, 2.2 mmol) in toluene (1.6 mL) and EtOH (2.4 mL) was degassed with N2 and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (29.4 mg, 0.036 mmol) under N2. The reaction mixture was sealed in a pressure tube and heated to 110° C. for 1 hour. The cooled reaction mixture was acidified to pH 5 and concentrated in vacuo. The resulting solid was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 50.0% H2O/50.0% MeCN in 10.5 min, 50.0% H2O/50.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 11.0 to 12.0 min. Flow: 25 mL/min) to give the title compound (13.0 mg, 11% yield). MS (ES+) 331.1 (M+H)+. Retention time=3.05 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).

Workup

  1. customwas degassed with N2
  2. customThe reaction mixture was sealed in a pressure tube
  3. customThe cooled reaction mixture
  4. concentrationconcentrated in vacuo
  5. customThe resulting solid was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 50.0% H2O/50.0% MeCN in 10.5 min, 50.0% H2O/50.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 11.0 to 12.0 min. Flow: 25 mL/min)

Sources & evidence

ORD record
ord-14296b46093b41bd868b1d1077372c16
Source dataset
uspto-grants-2016_07
Patent number
US09394285B2

Reaction notes

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