Methanamine, N-methoxy-, hydrochloride (1:1) → N-methoxy-N-methyl-2-phenylamino-6-trifluoromethyl-nicotinamide

HRID 1887819Notes

Reaction equation

HRID 1887819 reaction equation
[C:1]1([NH:7][C:8]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:22][NH:23][O:24][CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:25][O:24][N:23]([CH3:22])[C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:8]=1[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1

Participants

7

Reactant 4

HCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 708171352-Phenylamino-6-trifluoromethyl-nicotinic acid

Product 1

HCID 86672055N-methoxy-N-methyl-2-phenylamino-6-trifluoromethyl-nicotinamideYield 96%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

In a 1 L pear-shaped flask, 2-phenylamino-6-trifluoromethyl-nicotinic acid (6.2 g, 22.0 mmol) was combined with DMF (120 mL) to give a dark brown solution. N,O-dimethylhydroxyl-amine hydrochloride (2.79 g, 28.6 mmol) and HBTU (13.3 g, 35.2 mmol) were added. N,N-diisopropylethylamine (8.88 g, 12 mL, 68.7 mmol) was added. The reaction mixture was stirred at 25° C. for 4 hr. The reaction mixture was diluted with methylene chloride (400 mL), washed with saturated NH4Cl (1×300 mL), saturated NaHCO3 (1×300 mL), and brine (1×200 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo to give 20.5 g of crude product as a brown oil. The crude material was purified by flash chromatography (silica gel, 250 g, 10% to 35% ethyl acetate-hexanes). Fractions containing the desired product were concentrated, treated with ether and concentrated again to give N-methoxy-N-methyl-2-phenylamino-6-trifluoromethyl-nicotinamide (6.86 g, 96%) as a brown oil which solidified on standing overnight at room temperature. 1H NMR (DMSO-d6) δ ppm 8.85 (s, 1H) 7.93 (d, J=7.5 Hz, 1H) 7.64 (d, J=7.8 Hz, 2H) 7.14-7.48 (m, 3H) 6.78-7.14 (m, 1H) 3.55 (s, 3H) 3.31 (s, 3H). MS calcd. for C15H14F3N3O2 [(M+H)+] 326.0, obsd. 326.0.

Workup

  1. customto give a dark brown solution
  2. washwashed with saturated NH4Cl (1×300 mL), saturated NaHCO3 (1×300 mL), and brine (1×200 mL)
  3. dry with materialThe organic phase was dried over Na2SO4
  4. concentrationconcentrated in vacuo
  5. customto give 20.5 g of crude product as a brown oil
  6. customThe crude material was purified by flash chromatography (silica gel, 250 g, 10% to 35% ethyl acetate-hexanes)
  7. additionFractions containing the desired product
  8. concentrationwere concentrated
  9. additiontreated with ether
  10. concentrationconcentrated again

Sources & evidence

ORD record
ord-7b261149188f47c4bdbb1bba5021f6ce
Source dataset
uspto-grants-2013_08
Patent number
US08501732B2

Reaction notes

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