Triethylamine → Ethyl 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinate

HRID 241441Notes

Reaction equation

HRID 241441 reaction equation
Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]([CH:11]([F:13])[F:12])=[N:9][CH:10]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C(Cl)Cl>[F:12][CH:11]([F:13])[C:8]1[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:5]([CH2:4][NH:3][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:10][N:9]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 62325Isobutyryl chlorideHCID 86674201Ethyl 5-(aminomethyl)-2-(difluoromethyl)pyridine-3-carboxylate dihydrochloride

Product 1

HCID 71059744Ethyl 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinateYield 77%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Cool a mixture of ethyl 5-(aminomethyl)-2-(difluoromethyl)pyridine-3-carboxylate dihydrochloride (29.8 g, 111.8 mmol, 1.0 equiv), DCM (510 mL), and triethylamine (59.2 mL, 424.6 mmol, 3.8 equiv) to 0° C., then add a solution of isobutyryl chloride (15.3 mL, 145.3 mmol, 1.3 equiv) in DCM (23 mL) drop wise over 20 min. Stir overnight while allowing the mixture to warm to room temperature. Remove the solid precipitate by filtration, and rinse the filter with EtOAc (500 mL). Concentrate the filtrate under reduced pressure; filter the concentrate to remove the solids; and rinse the solids with EtOAc. Concentrate the filtrate under reduced pressure to give a yellow oil. Subject this crude material to silica gel chromatography eluting with a gradient of 40-90% EtOAc/hexanes gradient, to give the title compound as a light yellow crystalline solid (25.8 g, 77% yield). ES/MS (m/z) 301 (M+1).

Workup

  1. temperatureCool
  2. customRemove the solid precipitate
  3. filtrationby filtration
  4. washrinse the
  5. filtrationfilter with EtOAc (500 mL)
  6. concentrationConcentrate the filtrate under reduced pressure
  7. filtrationfilter the
  8. concentrationconcentrate
  9. customto remove the solids
  10. washand rinse the solids with EtOAc
  11. concentrationConcentrate the filtrate under reduced pressure
  12. customto give a yellow oil
  13. washeluting with a gradient of 40-90% EtOAc/hexanes gradient

Sources & evidence

ORD record
ord-6da8dc3c62d340669ebf0dde28cb8623
Source dataset
uspto-grants-2014_02
Patent number
US08648200B2

Reaction notes

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