Citric Acid → 6-Chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-carboxylic acid

HRID 338465Notes

Reaction equation

HRID 338465 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].CC1(C)COB([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29]([OH:34])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)OC1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>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]>[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:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])=[CH:26][CH:27]=1

Participants

8

Reactant 4

HCID 311Citric AcidHCID 11430Potassium CarbonateHCID 866987915-bromo-6-chloro-1H-indazole-3-carboxylic acidHCID 866987994'-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-[1,1'-biphenyl]-2-ol

Product 1

HCID 866988006-Chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-indazole-3-carboxylic acidYield 22%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 702EthanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (900 mg, 3.27 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (360 mg, 0.49 mmol) was purged with N2. To this mixture was added 4′-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-[1,1′-biphenyl]-2-ol (922 mg, 3.27 mmol) in toluene (5.0 mL) and EtOH (15.0 mL), followed by 2N aqueous potassium carbonate solution (6.0 mL, 12 mmol). The reaction mixture was heated to 100° C. for 48 hours, cooled to room temperature and poured into 1N aqueous citric acid (15 mL). The aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase chromatography (C-18 column, 10-40% MeCN/water) to give the title compound (258 mg, 22% yield) as a solid. MS (ES+) 365.0 (M+H)+. 1H NMR (500 MHz, CD3OD) δ 8.18 (s, 1H), 7.82 (s, 1H), 7.68 (d, 2H), 7.50 (d, 2H), 7.36 (d, 1H), 7.19 (dt, 1H), 6.97-6.92 (m, 2H).

Workup

  1. customwas purged with N2
  2. temperaturecooled to room temperature
  3. extractionThe aqueous layer was extracted with EtOAc (3×25 mL)
  4. dry with materialThe combined organic layers were dried over Na2SO4
  5. concentrationconcentrated in vacuo
  6. customThe crude material was purified by reverse phase chromatography (C-18 column, 10-40% MeCN/water)

Sources & evidence

ORD record
ord-00e3dbe3d0784140a13911e4083c47f3
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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