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

HRID 595645Notes

Reaction equation

HRID 595645 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 72,026.297%

Reagents, catalysts & solvents 4

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

Conditions

Temperature
90 °C

Procedure

To a solution of (1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid (126 g, 0.45 mol) and 6-chloro-2-iodopyridin-3-ol (96 g, 0.37 mmol) in 1,4-dioxane (1.8 L) and water (0.2 L) were added Pd(PPh3)2Cl2 (13.2 g, 18.6 mmol) and NaHCO3 (94.8 g, 1.13 mol) under nitrogen atmosphere, and the mixture was heated at 90° C. under N2 for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (900 mL), filtered and concentrated. The residue was diluted with H2O (400 mL) and EtOAc (800 mL), and the layer was separated, the aqueous layer was extracted with EtOAc (3*400 mL). The combined organic layers were washed with brine (800 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 (70 g, yield: 70.1%). 1H-NMR (MeOD, 400 MHz) δ 7.36 (s, 1H), 7.23˜7.27 (m, 2H), 7.03˜7.11 (m, 2H), 6.63˜6.68 (m, 1H). MS (M+H)+: 263 (M+H).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. filtrationfiltered
  3. concentrationconcentrated
  4. additionThe residue was diluted with H2O (400 mL) and EtOAc (800 mL)
  5. customthe layer was separated
  6. extractionthe aqueous layer was extracted with EtOAc (3*400 mL)
  7. washThe combined organic layers were washed with brine (800 mL)
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue was purified by column chromatography (PE:EtOAc=20:1˜3:1)

Sources & evidence

ORD record
ord-8ee2406763c54b50b3b4ce7c1ba3809b
Source dataset
uspto-grants-2016_01
Patent number
US09243002B2

Reaction notes

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