Methanamine, N-methoxy-, hydrochloride (1:1) → 4-chloro-2-(2-chloro-phenylamino)-N-methoxy-N-methyl-benzamide

HRID 1887802Notes

Reaction equation

HRID 1887802 reaction equation
[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:3]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.Cl.[CH3:44][NH:45][O:46][CH3:47].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:45]([O:46][CH3:47])[CH3:44])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:3]=1

Participants

7

Reactant 5

HCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)2×HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 2733179PyBroPHCID 134005684-Chloro-2-(2-chloro-phenylamino)-benzoic acid

Product 1

HCID 866757654-chloro-2-(2-chloro-phenylamino)-N-methoxy-N-methyl-benzamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

In a 500 mL round bottom flask, 4-chloro-2-(2-chloro-phenylamino)-benzoic acid (1.15 g, 4.08 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP, 2.28 g, 4.89 mmol), N,O-dimethylhydroxylamine hydrochloride (0.80 g, 8.2 mmol) and N,N-diisopropylethylamine (7.5 mL, 42.9 mmol) were added to dichloromethane (60.0 mL). The mixture was stirred at room temperature overnight. LCMS the next day indicated a mixture of starting material and product. The reaction was further charged with N,O-dimethylhydroxylamine hydrochloride (1.61 g, 16.5 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 1.86 g, 4.89 mmol) and the mixture was stirred overnight at room temperature. LCMS the next day showed complete consumption of starting material. The reaction mixture was poured into ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water and brine. The organic layer was dried, filtered and concentrated. The crude was purified by flash chromatography using 0-15% ethyl acetate-hexanes to give 4-chloro-2-(2-chloro-phenylamino)-N-methoxy-N-methyl-benzamide as an orange oil. 1H NMR (DMSO-d6) δ ppm 8.03 (s, 1H) 7.39-7.58 (m, 2H) 7.20-7.37 (m, 2H) 6.92-7.17 (m, 3H) 3.52 (s, 3H) 3.24 (s, 3H). MS calcd. for C15H14Cl2N2O2 [(M+H)+] 326.0, obsd. 324.9, [(M-C2H6NO2)+] 265.0, obsd. 264.0.

Workup

  1. additiona mixture of starting material and product
  2. stirringthe mixture was stirred overnight at room temperature
  3. customconsumption of starting material
  4. additionThe reaction mixture was poured into ethyl acetate
  5. washThe organic layer was washed with saturated sodium bicarbonate, water and brine
  6. customThe organic layer was dried
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude was purified by flash chromatography

Sources & evidence

ORD record
ord-a81088562c0d49a5b568cab1c6b9d3ac
Source dataset
uspto-grants-2013_08
Patent number
US08501732B2

Reaction notes

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