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

HRID 338462Notes

Reaction equation

HRID 338462 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].[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[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:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:15][CH3:16])=[CH:19][CH:20]=1

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 27343514-Ethoxyphenylboronic acidHCID 866987915-bromo-6-chloro-1H-indazole-3-carboxylic acid

Product 1

HCID 866987976-Chloro-5-(4-ethoxyphenyl)-1H-indazole-3-carboxylic acidYield 5%

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-ethoxyphenylboronic acid (63.2 mg, 0.38 mmol), and 2N aqueous potassium carbonate solution (1.10 mL, 2.18 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 Sunfire C18 19×100, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); 80.0% H2O/20.0% MeCN linear to 40.0% H2O/60.0% MeCN in 10.5 min, 40.0% H2O/60.0% 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 (5.3 mg, 5% yield). MS (ES+) 317.1 (M+H)+. Retention time=2.91 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 Sunfire C18 19×100, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); 80.0% H2O/20.0% MeCN linear to 40.0% H2O/60.0% MeCN in 10.5 min, 40.0% H2O/60.0% 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-bc93db20c5c3422eb343de47301ca21e
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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