Dimethylformamide → Ethyl 5-cyano-2-(difluoromethyl)nicotinate

HRID 241428Notes

Reaction equation

HRID 241428 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH:8]([F:10])[F:9])=[N:6][CH:7]=1.[CH3:16][N:17](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1(P([Pd](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:16]([C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH:8]([F:10])[F:9])=[N:6][CH:7]=1)#[N:17]

Participants

6

Reactant 2

HCID 6228DimethylformamideHCID 71059772HCID 71059772, compound

Product 1

HCID 71059720Ethyl 5-cyano-2-(difluoromethyl)nicotinate

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 178420554HCID 178420554, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

In a flask, dissolve ethyl 5-bromo-2-(difluoromethyl)pyridine-3-carboxylate (150 g, 536 mmol, 1.0 equiv) in DMF (1.5 L). Degas the resulting mixture by evacuating then backfilling the flask with nitrogen three times. Add zinc(II) cyanide (51 g, 434 mmol, 0.81 equiv), followed by tetrakis(triphenylphosphino)palladium (25.2 g, 21.8 mmol, 0.04 equiv). Heat the resulting suspension to an internal temperature of 100° C. for 3 h. Cool the mixture to room temperature; dilute with water (2 L); and extract with diethyl ether (3×2.5 L). Wash the combined organic phases with brine (3×2.5 L). Extract the combined aqueous phases with Et2O (2.5 L). Combine all organic phases, and dry over MgSO4. Remove the solids by filtration, and concentrate the filtrate under reduced pressure. Purify the resulting material by flash chromatography on silica gel (2 kg), eluting with a gradient of 1:1 DCM/isohexane to 100% DCM. Obtain the title compound as colorless oil, which solidifies on standing (114 g, 94.1%). MS (m/z) 227 (M+1).

Workup

  1. customDegas the resulting mixture
  2. customby evacuating
  3. temperatureCool the mixture to room temperature
  4. extractionand extract with diethyl ether (3×2.5 L)
  5. washWash the combined organic phases with brine (3×2.5 L)
  6. extractionExtract the combined aqueous phases with Et2O (2.5 L)
  7. dry with materialCombine all organic phases, and dry over MgSO4
  8. customRemove the solids
  9. filtrationby filtration
  10. concentrationconcentrate the filtrate under reduced pressure
  11. customPurify the resulting material by flash chromatography on silica gel (2 kg)
  12. washeluting with a gradient of 1:1 DCM/isohexane to 100% DCM

Sources & evidence

ORD record
ord-f0aa8abfe1ce40feb235911043a3a8b6
Source dataset
uspto-grants-2014_02
Patent number
US08648200B2

Reaction notes

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