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

HRID 1469796Notes

Reaction equation

HRID 1469796 reaction equation
C(O[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([CH:21]([F:23])[F:22])=[C:14]([CH:20]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])(C)(C)C.CCN(C(C)C)[CH:27]([CH3:29])[CH3:28].C(Cl)(=O)C(C)C>Cl.CCO.CCOC(C)=O>[F:23][CH:21]([F:22])[C:13]1[N:12]=[CH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[CH:27]([CH3:29])[CH3:28])=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]

Participants

7

Reactant 3

HCID 62325Isobutyryl chlorideHCID 81531DiisopropylethylamineHCID 71059899Ethyl 5-(((tert-butoxycarbonyl)amino)methyl)-2-(difluoromethyl)nicotinate

Product 1

HCID 71059744Ethyl 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinateYield 44.1%

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidSolventHCID 702EthanolSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of ethyl 5-(((tert-butoxycarbonyl)amino)methyl)-2-(difluoromethyl)nicotinate (500 mg, 1.51 mmol) in HCl in EtOH (2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated and the concentrate was dissolved in DMF (2 mL). The solution was treated with DIPEA (464 mg, 3.60 mmol) and isobutyryl chloride (115 mg, 1.08 mmol) at rt. The reaction mixture was stirred for 2 h before it was diluted with EtOAc and was washed with H2O and brine. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.75 (s, 1H), 8.48 (t, 1H), 8.14 (s, 1H), 7.59-7.24 (t, J=54 Hz, 1H), 4.39-4.32 (m, 4H), 2.44 (m, 1H), 1.35-1.29 (t, J=6.9 Hz, 3H), 1.04-1.02 (d, J=6.9 Hz, 6H); MS [M+H]+: 301.36.

Workup

  1. concentrationThe reaction mixture was concentrated
  2. dissolutionthe concentrate was dissolved in DMF (2 mL)
  3. washwas washed with H2O and brine
  4. customThe organic layer was separated
  5. customdried
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by column chromatography

Sources & evidence

ORD record
ord-0db722cccb0445588862f4315928c95e
Source dataset
uspto-grants-2015_04
Patent number
US09006257B2

Reaction notes

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