Diisopropylamine → 7-bromo-3-chloro-8-fluoro-5H-chromeno[2,3-c]pyridin-5-one

HRID 335897Notes

Reaction equation

HRID 335897 reaction equation
C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[C:15]([F:35])=[CH:16][C:17]([O:27][C:28]2[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[C:18]([CH:26]=1)[C:19](N(CC)CC)=[O:20]>C1COCC1>[Br:13][C:14]1[CH:26]=[C:18]2[C:17](=[CH:16][C:15]=1[F:35])[O:27][C:28]1[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][C:33]=1[C:19]2=[O:20]

Participants

5

Reactant 3

HCID 7912DiisopropylamineHCID 866584835-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethyl-4-fluorobenzamideHCID 178418339Butyllithium

Product 1

HCID 866584847-bromo-3-chloro-8-fluoro-5H-chromeno[2,3-c]pyridin-5-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

n-Butyl lithium (3.14 mL, 7.84 mmol) was added to a solution of diisopropylamine (1.341 mL, 9.41 mmol) in THF (40 mL) at −78° C. The resulting solution was stirred at 0° C. for 15 minutes before being added dropwise via cannula to a solution of 5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethyl-4-fluorobenzamide (2.1 g, 5.23 mmol) in THF (40.0 mL) cooled to −78° C. under positive pressure. The resulting solution was stirred 3 hours at −78° C. before being quenched with saturated ammonium chloride (100 mL). The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were washed with saturated aqueous NH4Cl, water, saturated aqueous NaCl, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by dissolving in a minimal amount of CH2Cl2 and filtering through a pad of silica gel by eluting with 1:10 EtOAc in hexane, to provide 7-bromo-3-chloro-8-fluoro-5H-chromeno[2,3-c]pyridin-5-one as a off-white solid. MS m/z=330.0 [M+H].

Workup

  1. temperaturecooled to −78° C. under positive pressure
  2. stirringThe resulting solution was stirred 3 hours at −78° C.
  3. custombefore being quenched with saturated ammonium chloride (100 mL)
  4. additionThe reaction mixture was diluted with water (50 mL)
  5. extractionextracted with EtOAc (3×75 mL)
  6. washThe combined organic extracts were washed with saturated aqueous NH4Cl, water, saturated aqueous NaCl
  7. dry with materialdried over sodium sulfate
  8. filtrationThe solution was filtered
  9. concentrationconcentrated in vacuo
  10. customto give the crude material
  11. customThe crude material was purified
  12. dissolutionby dissolving in a minimal amount of CH2Cl2
  13. filtrationfiltering through a pad of silica gel
  14. washby eluting with 1:10 EtOAc in hexane

Sources & evidence

ORD record
ord-7fe3be45658144e6a9df8bacbf083bbd
Source dataset
uspto-grants-2014_11
Patent number
US08883782B2

Reaction notes

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