4-Methylmorpholine → 4-(4-Chlorophenyl)-4-dimethylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester

HRID 409563Notes

Reaction equation

HRID 409563 reaction equation
[C:1]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:24][N:25]1CCOC[CH2:26]1.C1C=CC2N(O)N=NC=2C=1.Cl.CNC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([C:14](=[O:15])[N:25]([CH3:26])[CH3:24])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]

Participants

8

Reactant 6

HCID 79724-MethylmorpholineHCID 10473Dimethylamine, hydrochlorideHCID 14798Sodium HydroxideHCID 757711-HydroxybenzotriazoleHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 248288571-(Tert-butoxycarbonyl)-4-(4-chlorophenyl)piperidine-4-carboxylic acid

Product 1

HCID 596621944-(4-Chlorophenyl)-4-dimethylcarbamoyl-piperidine-1-carboxylic acid tert-butyl esterYield 94%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

N-Boc-4-(4-chlorophenyl)-4-piperidine carboxylic acid Compound 2-1 (5.96 g, 18 mmol, Arch Chemical) was dissolved in DMF (175 mL) and chilled in an ice bath temp. To the solution was added N-methylmorpholine (5.76 mL, 53 mmol), HOBt (1.18 g, 8.8 mmol), dimethylamine hydrochloride (1.41 g, 18 mmol), and HBTU (10.0 g, 26 mmol). The solution was allowed to warm overnight to rt, poured into 1N sodium hydroxide solution (100 mL), and extracted with EtOAc (3×75 mL). The combined organic layers were washed with 1N NaOH (2×), 1N hydrochloric acid solution (2×), and brine (3×); and dried over Na2SO4 and concentrated to give Compound 2-2 (6.1 g, 17 mmol, 94%) as a white solid. 1H NMR (300 MHz, CDCl3,) δ 7.32 (d, J=9 Hz, 2H), 7.17 (d, J=9 Hz, 2H), 4.2-3.8 (br m, 2H), 3.0-2.6 (br m, 2H), 2.96 (s, 3H), 2.80 (s, 3H), 2.25 (m, 2H), 2.1-1.7 (br m, 2H), 1.45 (s, 9H).

Workup

  1. temperaturechilled in an ice bath temp
  2. temperatureto warm overnight to rt
  3. extractionextracted with EtOAc (3×75 mL)
  4. washThe combined organic layers were washed with 1N NaOH (2×), 1N hydrochloric acid solution (2×), and brine (3×)
  5. dry with materialand dried over Na2SO4
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-264bf82e45024151afc10a4bafeb4e79
Source dataset
uspto-grants-2014_06
Patent number
US08759342B2

Reaction notes

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