3-(Trifluoromethyl)aniline → HCID 178515979, compound

HRID 49227Notes

Reaction equation

HRID 49227 reaction equation
Cl[C:2]1[N:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19]C)=[CH:17][CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.ClC1N=CC(CC2C=NC(Cl)=CC=2)=C2C=1C=CC=N2.[F:40][C:41]([F:50])([F:49])[C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45].Cl.O1CCOCC1>C([O-])([O-])=O.[Na+].[Na+].C(O)C.CCOC(C)=O.O1CCOCC1>[F:40][C:41]([F:49])([F:50])[C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH:45][C:2]1[N:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2

Participants

9

Reactant 4

HCID 73753-(Trifluoromethyl)anilineHCID 204431481,4-Dioxane hydrochlorideHCID 20636428HCID 20636428, compoundHCID 206364295-Chloro-8-[(6-methoxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine

Product 1

HCID 178515979HCID 178515979, compound

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 8857Ethyl AcetateSolventHCID 10340Sodium CarbonateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
70 °C

Procedure

Under a N2 atmosphere, 146 mg (0.5 mmol) of 5-chloro-8-[(6-methoxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine (contains a little 5-chloro-8-[(6-chloro-pyridin-3-yl)-methyl]-[1,6]naphthyridine as an impurity) in 2.0 ml of tbutanol/dioxane 1:5 are mixed with 160 mg (1 mmol) of 3-trifluoromethyl-aniline and 0.12 ml of 4 N HCl/dioxane and stirred for 14 h at 70° C. The cooled reaction mixture is dissolved in diluted Na2CO3 solution and EtOAc whilst adding ethanol. The water phase is separated and extracted twice with EtOAc. The organic phases are dried (Na2SO4) and concentrated by evaporation. The resulting oil is separated by reversed phase medium-pressure chromatography (water/-acetonitrile/TFA). The fractions are partially concentrated by evaporation, then solid NaHCO3 is added to the aqueous residue. Extraction with 3 portions of EtOAc, drying (Na2SO4) and concentration by evaporation yields 5-(3-trifluoromethyl-anilino)-8-[(6-hydroxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine 36a (FAB-MS: (M+H)+=397; HPLC(gradient20-100) tRet=8.5); 5-(3-trifluoromethyl-anilino)-8-[(6-methoxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine 36b (FAB-MS: (M+H)+=411; HPLC(gradient20-100) tRet=10.0) and 5-(3-trifluoromethyl-anilino)-8-[(6-chloro-pyridin-3-yl)-methyl]-[1,6]naphthyridine 36c (FAB-MS: (M+H)+=415; HPLC(gradient20-100) tRet=1.5).

Workup

  1. customThe cooled reaction mixture
  2. customThe water phase is separated
  3. extractionextracted twice with EtOAc
  4. dry with materialThe organic phases are dried (Na2SO4)
  5. concentrationconcentrated by evaporation
  6. customThe resulting oil is separated by reversed phase medium-pressure chromatography (water/-acetonitrile/TFA)
  7. concentrationThe fractions are partially concentrated by evaporation
  8. additionsolid NaHCO3 is added to the aqueous residue
  9. extractionExtraction with 3 portions of EtOAc
  10. customdrying
  11. concentration(Na2SO4) and concentration
  12. customby evaporation

Sources & evidence

ORD record
ord-4a59824031b542bcaf608c8f61be01a2
Source dataset
uspto-grants-2004_03
Patent number
US06706731B2

Reaction notes

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