Methanamine, N-methoxy-, hydrochloride (1:1) → N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide

HRID 241445Notes

Reaction equation

HRID 241445 reaction equation
[F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([C:9](O)=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH3:18][O:17][N:16]([CH3:15])[C:9]([C:6]1[CH:7]=[N:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)=[O:10]

Participants

7

Reactant 4

HCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 27775516-(Trifluoromethyl)nicotinic acid

Product 1

HCID 23116945N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamideYield 93.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

Dissolve 6-(trifluoromethyl)pyridine-3-carboxylic acid (0.949 g, 4.767 mmol) in DMF (10 mL) and add N,O-dimethylhydroxylamine hydrochloride (0.590 g, 5.959 mmol), and DIPEA (1.67 mL, 9.534 mmol), followed by BOP (2.259 g, 5.005 mmol). Stir the resulting mixture for about 60 hours. Pour reaction mixture into water (200 mL). Extract with EtOAc (4×75 mL). Wash the combined organic extracts with a saturated sodium chloride aqueous solution (5×75 mL). Dry the organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Dissolve the residue in EtOAc (100 mL). Sequentially wash the residue in EtOAc with a saturated NaHCO3 aqueous solution (50 mL) to remove any residual acid starting material, followed by water (2×50 mL), and then a saturated sodium chloride aqueous solution (2×50 mL). Dry the organic layer over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to give the title compound as a clear liquid (1.04 g, 93% yield). 1H NMR (400.43 MHz, d6-DMSO) δ 8.90 (d, J=2.0 Hz, 1H), 8.25-8.23 (m, 1H), 7.96 (dd, J=0.7, 8.1 Hz, 1H), 3.52 (s, 3H), 3.27 (s, 3H).

Workup

  1. additionPour
  2. extractionExtract with EtOAc (4×75 mL)
  3. washWash the combined organic extracts with a saturated sodium chloride aqueous solution (5×75 mL)
  4. dry with materialDry the organic extracts over sodium sulfate
  5. filtrationfilter
  6. customcollect the filtrate
  7. concentrationand concentrate the filtrate under reduced pressure
  8. dissolutionDissolve the residue in EtOAc (100 mL)
  9. washSequentially wash the residue in EtOAc with a saturated NaHCO3 aqueous solution (50 mL)
  10. customto remove any residual acid
  11. dry with materialDry the organic layer over sodium sulfate
  12. filtrationfilter
  13. customcollect the filtrate
  14. concentrationand concentrate the filtrate under reduced pressure

Sources & evidence

ORD record
ord-7b43010e70f94a9fb6b8e5561e7bbe8a
Source dataset
uspto-grants-2014_02
Patent number
US08648200B2

Reaction notes

Loading…