Sodium Bicarbonate → 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol

HRID 595544Notes

Reaction equation

HRID 595544 reaction equation
C(OC([N:8]1[C:16]2[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)=O)(C)(C)C.[Cl:21][C:22]1[N:27]=[C:26](I)[C:25]([OH:29])=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:22]1[N:27]=[C:26]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:25]([OH:29])=[CH:24][CH:23]=1

Participants

8

Reactant 3

HCID 516892Sodium BicarbonateHCID 234331586-Chloro-2-iodo-3-hydroxypyridineHCID 44118245(1-(tert-Butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid

Product 1

HCID 867262926-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-olYield 76.5%

Reagents, catalysts & solvents 4

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

A mixture of (1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid (5 g, 18.0 mmol), 6-chloro-2-iodopyridin-3-ol (3.82 g, 15.0 mol) and NaHCO3 (3.78 g, 45.0 mol) in 1,4-dioxane (76 mL) and water (7 mL) was stirred at room temperature for 15 min. Then Pd(PPh3)2Cl2 (527 mg, 0.75 mmol) was added under nitrogen atmosphere, and the mixture was heated at 100° C. under N2 for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), filtered and concentrated. The residue was diluted with H2O (60 mL) and EtOAc (30 mL), and the layer was separated, the aqueous layer was extracted with EtOAc (3*30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE/EtOAc=20/1˜3/1) to give 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol (3 g, yield: 76.5%). 1H-NMR (MeOD, 400 MHz) δ 7.36 (s, 1H), 7.23˜7.27 (m, 2H), 7.03˜7.11 (m, 2H), 6.6˜36.68 (m, 1H). MS (M+H)+: 263/265.

Workup

  1. temperaturethe mixture was heated at 100° C. under N2 for 16 hours
  2. temperatureThe reaction mixture was cooled to room temperature
  3. filtrationfiltered
  4. concentrationconcentrated
  5. additionThe residue was diluted with H2O (60 mL) and EtOAc (30 mL)
  6. customthe layer was separated
  7. extractionthe aqueous layer was extracted with EtOAc (3*30 mL)
  8. washThe combined organic layers were washed with brine (50 mL)
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe residue was purified by column chromatography (PE/EtOAc=20/1˜3/1)

Sources & evidence

ORD record
ord-5e1cefd3f7484e24aa880bf619b9fda5
Source dataset
uspto-grants-2016_01
Patent number
US09242998B2

Reaction notes

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