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

HRID 1776943Notes

Reaction equation

HRID 1776943 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 minutes. 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 in vacuo. The resulting 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 in vacuo. The resulting residue was purified using column chromatography (petroleum ether/EtOAc=20/1˜3/1) to provide 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), 6.63˜6.68 (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 in vacuo
  5. additionThe resulting 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 in vacuo
  12. customThe resulting residue was purified

Sources & evidence

ORD record
ord-f7e9778ee51c4409b688efc2fdd3e4eb
Source dataset
uspto-grants-2016_02
Patent number
US09265773B2

Reaction notes

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