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

HRID 1054810Notes

Reaction equation

HRID 1054810 reaction equation
CC1(C)COB(B2OCC(C)(C)CO2)OC1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]2([OH:28])[CH2:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.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+]>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].ClCCl>[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:18]1[CH:23]=[CH:22][C:21]([C:24]2([OH:28])[CH2:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1

Participants

8

Reactant 5

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2734316Bis(neopentyl glycolato)diboronHCID 120954191-(4-Bromophenyl)cyclobutanolHCID 866987915-bromo-6-chloro-1H-indazole-3-carboxylic acid

Product 1

HCID 866988026-Chloro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indazole-3-carboxylic acidYield 11.4%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalyst2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (800 mg, 2.34 mmol), 1-(4-bromophenyl)cyclobutanol (500 mg, 2.20 mmol), potassium acetate (1.0 g, 10 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (136 mg, 0.17 mmol) in 1,4-dioxane (12 mL) was degassed with N2 for 5 minutes, and subjected to microwave irradiation at 115° C. for 1 hour. The cooled reaction mixture was filtered through a cotton plug and concentrated in vacuo. The resulting dark solid was dissolved in 1:1 toluene/EtOH (10 mL) and to this solution was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (551 mg, 2.00 mmol) followed by 2 N aqueous potassium carbonate solution (4.0 mL, 8.0 mmol). The reaction mixture was degassed with N2, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (98.0 mg, 0.12 mmol) under N2, and heated in a sealed pressure tube to 110° C. for 3 hours. The cooled reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (20 mL) and 2 N citric acid solution (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase chromatography (Biotage C18 column, 20-60% MeCN/water) to give the title compound (78 mg, 10% yield) as a solid. MS (ES−) 341.5 (M−H)+. 1H NMR (500 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.88 (s, 1H), 7.59 (d, J=8.05 Hz, 2H), 7.42 (d, J=8.05 Hz, 2H), 5.55 (br. s, 1H), 2.39-2.46 (m, 2H), 2.23-2.35 (m, 2H), 1.89-2.01 (m, 1H), 1.64-1.76 (m, 1H).

Workup

  1. customwas degassed with N2 for 5 minutes
  2. customirradiation at 115° C. for 1 hour
  3. customThe cooled reaction mixture
  4. filtrationwas filtered through a cotton plug
  5. concentrationconcentrated in vacuo
  6. dissolutionThe resulting dark solid was dissolved in 1:1 toluene/EtOH (10 mL) and to this solution
  7. customThe reaction mixture was degassed with N2
  8. customThe cooled reaction mixture
  9. concentrationwas concentrated in vacuo
  10. customthe residue was partitioned between EtOAc (20 mL) and 2 N citric acid solution (20 mL)
  11. customThe layers were separated
  12. extractionthe aqueous layer was extracted with EtOAc
  13. dry with materialThe combined organic layers were dried over Na2SO4
  14. concentrationconcentrated in vacuo
  15. customThe crude material was purified by reverse phase chromatography (Biotage C18 column, 20-60% MeCN/water)

Sources & evidence

ORD record
ord-2a28584d26a94dac851aacfb26917af6
Source dataset
uspto-grants-2016_07
Patent number
US09394285B2

Reaction notes

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