Isobutyryl chloride → Ethyl 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinate

HRID 241430Notes

Reaction equation

HRID 241430 reaction equation
Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([CH:10]([F:12])[F:11])=[N:8][CH:9]=1.CCN(C(C)C)C(C)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>C(Cl)Cl>[F:11][CH:10]([F:12])[C:7]1[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][C:4]([CH2:3][NH:2][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:9][N:8]=1

Participants

5

Reactant 3

HCID 62325Isobutyryl chlorideHCID 81531DiisopropylethylamineHCID 71059730Ethyl 5-(aminomethyl)-2-(difluoromethyl)nicotinate hydrochloride

Product 1

HCID 71059744Ethyl 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinateYield 73.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

In a thermally controlled reactor stir a mixture of ethyl 5-(aminomethyl)-2-(difluoromethyl)pyridine-3-carboxylate hydrochloride (198 g, 742.4 mmol, 1.0 equiv), DCM (3040 mL), and DIPEA (520 mL, 2.98 mol, 4 equiv), then add a solution of isobutyryl chloride (95 mL, 903 mmol, 1.2 equiv) at such a rate so that the internal temperature is held between 18° C. and 22° C. Stir for 90 min. Extract the reaction mixture with NaHCO3 (sat., 1 L). Add water (1 L) and DCM (1 L), and filter the resulting suspension through diatomaceous earth. 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 slurrying with iso-hexane:Et2O [1:1, 1 L]. Collect the solids by filtration, wash with cold iso-hexanes (500 ml), and dry under vacuum at 50° C. to give the title compound as an off-white crystalline powder (164 g). MS (m/z) 301 (M+1).

Workup

  1. customis held between 18° C. and 22° C
  2. stirringStir for 90 min
  3. extractionExtract the reaction mixture with NaHCO3 (sat., 1 L)
  4. filtrationAdd water (1 L) and DCM (1 L), and filter the resulting suspension through diatomaceous earth
  5. dry with materialCombine all organic phases, and dry over MgSO4
  6. customRemove the solids
  7. filtrationby filtration
  8. concentrationconcentrate the filtrate under reduced pressure
  9. customPurify the resulting material
  10. customCollect the solids
  11. filtrationby filtration
  12. washwash with cold iso-hexanes (500 ml)
  13. customdry under vacuum at 50° C.

Sources & evidence

ORD record
ord-4f8fb5fe7e6446c4ac83758fda5afa03
Source dataset
uspto-grants-2014_02
Patent number
US08648200B2

Reaction notes

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