Hydrochloric Acid → 6-Chloro-5-(4-(1-hydroxy-2-methylpropan-2-yl)phenyl)-1H-indazole-3-carboxylic acid

HRID 1054821Notes

Reaction equation

HRID 1054821 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][C:43]=1[Cl:44])[NH:40][N:39]=[C:38]2[C:45]([OH:47])=[O:46].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.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].O.CCO>[Cl:44][C:43]1[CH:42]=[C:41]2[C:37]([C:38]([C:45]([OH:47])=[O:46])=[N:39][NH:40]2)=[CH:36][C:35]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[CH:4][CH:3]=1

Participants

11

Reactant 6

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2734316Bis(neopentyl glycolato)diboronHCID 128051244-Bromo-beta,beta-dimethylbenzeneethanolHCID 866987915-bromo-6-chloro-1H-indazole-3-carboxylic acid

Product 1

HCID 866988136-Chloro-5-(4-(1-hydroxy-2-methylpropan-2-yl)phenyl)-1H-indazole-3-carboxylic acidYield 20.2%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst2×HCID 702EthanolSolventHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
130 °C

Procedure

A suspension of 2-(4-bromophenyl)-2-methylpropan-1-ol (168 mg, 0.73 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (275 mg, 0.81 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 0.037 mmol) and potassium acetate (216 mg, 2.20 mmol) in 1,4-dioxane (2 mL) was sealed in a pressure tube and heated to 130° C. for 1 hour. To the mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg, 0.018 mmol), 2 N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol) and EtOH (2 mL). The reaction mixture was sealed and heated to 130° C. for 1 hour. Water (3 mL) was added to the reaction mixture, followed by 1 N HCl solution to adjust the pH to 2. The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material 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); 90.0% H2O/10.0% MeCN linear to 70.0% H2O/30.0% MeCN in 8.5 min, 70.0% H2O/30.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 9.0 to 10.0 min. Flow: 25 mL/min) to afford the title compound (25.1 mg, 20% yield). MS (ES+) 345.1 (M+H)+. Retention time=1.59 minutes (Column: Waters XBridge dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH 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 sealed in a pressure tube
  2. customThe reaction mixture was sealed
  3. temperatureheated to 130° C. for 1 hour
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted with EtOAc (3×5 mL)
  6. dry with materialThe combined organic layers were dried over Na2SO4
  7. concentrationconcentrated in vacuo
  8. customThe crude material 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); 90.0% H2O/10.0% MeCN linear to 70.0% H2O/30.0% MeCN in 8.5 min, 70.0% H2O/30.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 9.0 to 10.0 min. Flow: 25 mL/min)

Sources & evidence

ORD record
ord-2e43ad33a1914928997458385b3ac59b
Source dataset
uspto-grants-2016_07
Patent number
US09394285B2

Reaction notes

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