1,2-Dichloroethane → 2-Fluoro-N-methoxy-N-methylnicotinamide

HRID 2178289Notes

Reaction equation

HRID 2178289 reaction equation
[F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:12][O:13][NH:14][CH3:15].CCN(C(C)C)C(C)C.C(Cl)CCl>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:1][C:2]1[C:7]([C:8]([N:14]([O:13][CH3:12])[CH3:15])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1

Participants

9

Reactant 4

HCID 111,2-DichloroethaneHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 81531DiisopropylethylamineHCID 960892-Fluoronicotinic acid

Product 1

HCID 534170672-Fluoro-N-methoxy-N-methylnicotinamideYield 62.1%

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
10 °C

Procedure

2-fluoropyridine-3-carboxylic acid (100 g, 708.7 mmol) was dissolved in THF (1.5 L). DMAP (86.58 g, 708.7 mmol) was added followed by N-methoxymethanamine hydrochloride (76.05 g, 779.6 mmol). The mixture was cooled to 10° C. then DIPEA (100.8 g, 135.8 mL, 779.6 mmol) was added followed by EDC (149.5 g, 779.6 mmol) portionwise. The mixture was stirred for 30 minutes, then warmed rapidly to ambient temp (22° C.) and stirred overnight. Lc/Ms after this time showed no acid remaining. The reaction mixture was diluted with ethyl acetate (1 L) and water (1.5 L). The mixture was stirred for 10 minutes then the organic phase was isolated. The aqueous was extracted with ethyl acetate (2×500 ml) and the combined organics washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified through a silica plug, eluting with 50-70% ethyl acetate/petrol. This afforded the title compound as a pale yellow oil (81 g, 62%); 1H NMR (CDCl3) 3.39 (3H, s), 3,68 (3H, brs), 7.29 (1H, m), 7.92 (1H, m), 8.32 (1H, m); MS ES (+) 184.9 (M+1).

Workup

  1. temperaturewarmed rapidly to ambient temp (22° C.)
  2. stirringstirred overnight
  3. stirringThe mixture was stirred for 10 minutes
  4. customthe organic phase was isolated
  5. extractionThe aqueous was extracted with ethyl acetate (2×500 ml)
  6. washthe combined organics washed with brine
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude was purified through a silica plug
  11. washeluting with 50-70% ethyl acetate/petrol

Sources & evidence

ORD record
ord-c8db549554df45a1b7a2cf6bccf05f27
Source dataset
uspto-grants-2015_06
Patent number
US09067932B2

Reaction notes

Loading…