1-Methyl-4-piperidone → N-(4-{trans-2-[(1-methylpiperidin-4-yl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride

HRID 922537Notes

Reaction equation

HRID 922537 reaction equation
[ClH:1].[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[CH:8][CH:7]=1.[CH3:25][N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.C1COCC1>[ClH:1].[ClH:1].[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([NH:2][C@@H:3]2[CH2:5][C@H:4]2[C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=3)=[CH:10][CH:11]=2)[CH2:28][CH2:27]1

Participants

7

Reactant 4

HCID 740491-Methyl-4-piperidoneHCID 516892Sodium Bicarbonate2×HCID 4311764Sodium borohydrideHCID 86729839N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride

Product 1

HCID 86729900N-(4-{trans-2-[(1-methylpiperidin-4-yl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochlorideYield 72.8%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (80 mg) in methanol (3 mL)/THF (3 mL) were added 1-methylpiperidin-4-one (33.0 mg) and sodium hydrogen carbonate (37.7 mg). The mixture was stirred at 60° C. for 2 hr, and ice-cooled to 0° C. and sodium borohydride (17.0 mg) was added. The mixture was stirred at room temperature for 2 hr, and ice-cooled to 0° C., and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate, ethyl acetate/methanol). 10% Hydrochloric acid methanol solution was added and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (40 mg).

Workup

  1. temperatureice-cooled to 0° C.
  2. stirringThe mixture was stirred at room temperature for 2 hr
  3. temperatureice-cooled to 0° C.
  4. extractionThe mixture was extracted with ethyl acetate
  5. washthe extract was washed with saturated brine
  6. dry with materialdried over anhydrous magnesium sulfate
  7. customThe solvent was evaporated under reduced pressure
  8. customThe residue was purified by silica gel column chromatography (hexane/ethyl acetate, ethyl acetate/methanol)
  9. addition10% Hydrochloric acid methanol solution was added
  10. customthe solvent was evaporated under reduced pressure
  11. customThe residue was recrystallized from methanol/diisopropyl ether

Sources & evidence

ORD record
ord-f42407001c464600a6c0363b297bc04a
Source dataset
uspto-grants-2016_03
Patent number
US09278931B2

Reaction notes

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