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

HRID 1054820Notes

Reaction equation

HRID 1054820 reaction equation
CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.Br[C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][C:45]=1[Cl:46])[NH:42][N:41]=[C:40]2[C:47]([OH:49])=[O:48].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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:46][C:45]1[CH:44]=[C:43]2[C:39]([C:40]([C:47]([OH:49])=[O:48])=[N:41][NH:42]2)=[CH:38][C:37]=1[C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1

Participants

10

Reactant 5

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2734316Bis(neopentyl glycolato)diboronHCID 213638774-(4-Bromophenyl)-1-methylpiperidineHCID 866987915-bromo-6-chloro-1H-indazole-3-carboxylic acid

Product 1

HCID 866988126-Chloro-5-(4-(1-methylpiperidin-4-yl)phenyl)-1H-indazole-3-carboxylic acidYield 10.1%

Reagents, catalysts & solvents 4

HCID 178418807HCID 178418807, compoundCatalyst2×HCID 702EthanolSolventHCID 1140TolueneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (92.0 mg, 0.27 mmol), oven dried potassium acetate (116 mg, 1.18 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (22 mg, 0.027 mmol) and 4-(4-bromophenyl)-1-methylpiperidine (65 mg, 0.26 mmol) in 1,4-dioxane (2.6 mL) was degassed with N2 for 10 minutes, sealed in a pressure tube, and heated to 100° C. for 2 hours. The cooled reaction mixture was filtered through cotton and concentrated in vacuo to give a dark solid. To the dark solid was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (59.8 mg, 0.22 mmol), 2 N aqueous potassium carbonate solution (0.4 mL, 0.87 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (18 mg, 0.022 mmol). The reaction mixture was diluted with degassed toluene (0.8 mL) and EtOH (0.8 mL), sealed in a pressure tube and heated at 100° C. for 1.5 hours then 75° C. for an additional 16 hours. The cooled reaction mixture was concentrated in vacuo. The resulting dark 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 0% H2O/100% MeCN in 8.5 min, HOLD at 0% H2O/100% MeCN to 10.0 min. Flow: 25 mL/min) to give the title compound (8.2 mg, 9% yield). MS (ES+) 370.2 (M+H)+. Retention time=2.00 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 for 10 minutes
  2. customsealed in a pressure tube
  3. customThe cooled reaction mixture
  4. filtrationwas filtered through cotton
  5. concentrationconcentrated in vacuo
  6. customto give a dark solid
  7. customsealed in a pressure tube
  8. temperatureheated at 100° C. for 1.5 hours
  9. customThe cooled reaction mixture
  10. concentrationwas concentrated in vacuo
  11. customThe resulting dark 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 0% H2O/100% MeCN in 8.5 min, HOLD at 0% H2O/100% MeCN to 10.0 min. Flow: 25 mL/min)

Sources & evidence

ORD record
ord-6921e3bee37649a0b9d68a4ad1ed3ee7
Source dataset
uspto-grants-2016_07
Patent number
US09394285B2

Reaction notes

Loading…