Acetic Acid → tert-Butyl 4-((2-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate

HRID 1093534Notes

Reaction equation

HRID 1093534 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:16]([F:15])([F:24])[F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 69222-(Trifluoromethyl)anilineHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 5049666Sodium triacetoxyborohydride

Product 1

HCID 66591750tert-Butyl 4-((2-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylateYield 307.8%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.0001 mole) in dry 1,2-dichloroethane (7 mL) under an atmosphere of nitrogen for 10 minutes, was added 2-trifluoromethylaniline (0.161 g, 0.0001 mole), acetic acid (0.06 g, 0.0001 mole) and sodium triacetoxyborohydride (1.05 g, 0.0005 mole). The stirring was continued at ambient temperature for 14 hours. The reaction mixture was then quenched in cold aqueous 1N NaOH solution and the product extracted with ether. The ether layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to get the crude product as transparent viscous liquid. Purification by column chromatography using silica gel 60-120 mesh (2% ethyl acetate in hexane) afforded 0.106 g (31%) of 4-(2-trifluoromethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (DMSO-d6): δ 7.4 (t, 2H), 7.0 (d, 1H), 6.7 (t, 1H), 3.9 (m, 2H), 2.9 (m, 2H), 1.9 (m, 2H), 1.4 (s, 9H). To a solution of 4-(2-trifluoromethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.106 g, 0.000307 mole) in dioxane (0.5 mL) which was cooled to 0° C., was added, dioxane.HCl (2.5 mL) and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was gradually brought to ambient temperature and stirring was continued for 15 minutes. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with dry ether to afford 0.04 g (41%) of piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine dihydrochloride. 1H NMR (DMSO-d6): δ 7.41 (t, 2H), 7.0 (d, 2H), 6.75 (t, 1H), 4.8 (d, 1H), 3.7 (bs, 1H), 3.3 (bs, 1H), 3.0 (m, 2H), 2.1 (m, 2H), 1.7 (m, 2H).

Workup

  1. customThe reaction mixture was then quenched in cold aqueous 1N NaOH solution
  2. extractionthe product extracted with ether
  3. washThe ether layer was washed with brine solution
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customto get the crude product as transparent viscous liquid
  7. customPurification by column chromatography

Sources & evidence

ORD record
ord-383065801e624b088cf81e1bceced4f3
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Reaction notes

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