Acetic Acid → tert-Butyl 4-(2-chloroanilino)piperidine-1-carboxylate

HRID 1093536Notes

Reaction equation

HRID 1093536 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].[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].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:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[Cl:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 72402-ChloroanilineHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 5049666Sodium triacetoxyborohydride

Product 1

HCID 22557784tert-Butyl 4-(2-chloroanilino)piperidine-1-carboxylateYield 79.1%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 0.0025 mole) in dry 1,2-dichloroethane (5 mL) (under an atmosphere of nitrogen for 10 minutes) was added, 2-chloroaniline (0.352 g, 0.0027 mole), acetic acid (0.125 g, 0.00209 mole) and sodium triacetoxyborohydride (0.442 g, 0.00209 mole). The resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched in cold aqueous 1N NaOH solution and the product was extracted with dichloromethane. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was stirred with hexane. The hexane was then decanted and the residue was dried to afford 0.615 g (79%) of 4-(2-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a solid. 1H NMR (DMSO-d6): δ 7.6 (dd, 1H), 7.1 (t, 1H), 6.8 (d, 1H), 6.54 (t, 1H), 4.8 (d, 1H), 3.9 (d, 3H), 3.5 (m, 1H), 2.9 (bs, 2H), 1.8 (d, 2H), 1.4 (s, 9H), 1.3 (d, 1H). To a stirred, cooled (0° C.) solution of 4-(2-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.150 g, 0.00048 mole) in dioxane (0.5 mL) was added dioxane.HCl (1.5 mL). The stirring was continued at the same temperature for 10 minutes, then the mixture was gradually brought to ambient temperature with continued stirring for a further 15 minutes. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with dry ether and dried to afford 0.118 g (99%) of (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride.

Workup

  1. customThe reaction mixture was quenched in cold aqueous 1N NaOH solution
  2. extractionthe product was extracted with dichloromethane
  3. washThe organic layer was washed with brine solution
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. stirringThe resulting residue was stirred with hexane
  7. customThe hexane was then decanted
  8. customthe residue was dried

Sources & evidence

ORD record
ord-a74d60a8b86c4b369694392ea0183232
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Reaction notes

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