Sodium hydride → (S)-tert-butyl 2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate

HRID 931887Notes

Reaction equation

HRID 931887 reaction equation
Cl[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:25]([CH2:33][CH3:34])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].[NH4+].[Cl-:36]>CN(C=O)C>[Cl:36][C:3]1[CH:4]=[C:5]([C@H:8]2[CH2:9][CH2:10][C:11](=[O:21])[N:12]([C@@H:25]([CH2:33][CH3:34])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:13]2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:6]=[CH:7][CH:2]=1

Participants

6

Reactant 4

HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 13124118tert-Butyl 2-bromobutanoateHCID 67999914(5R,6S)-5,6-bis(4-chlorophenyl)piperidin-2-one

Product 1

HCID 68001176(S)-tert-butyl 2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 13.5 g (42.2 mmol) of (5R,6S)-5,6-bis(4-chlorophenyl)piperidin-2-one (Example 1, Step E) in 140 mL of DMF was added 4.22 g (105 mmol) of a dispersion of 60% sodium hydride in mineral oil at 0° C. After being stirred for 20 min, tert-butyl 2-bromobutanoate (28.2 g, 126 mmol) was added at 0° C. and the resulting solution was stirred at 25° C. for 1.5 h until completion of the reaction. Then sat. aq. NH4Cl solution was added and the mixture was extracted with ethylacetate. The combined organic layers were washed with water and sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 20 to 50% EtOAc/hexanes, gradient elution) provided tert-butyl (2S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-1-piperidinyl)butanoate as the faster eluting minor isomer:

Workup

  1. stirringthe resulting solution was stirred at 25° C. for 1.5 h until completion of the reaction
  2. extractionthe mixture was extracted with ethylacetate
  3. washThe combined organic layers were washed with water and sat. NaCl solution
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationthe filtrate was concentrated under reduced pressure
  7. customPurification of the residue by flash chromatography on silica gel (eluent: 20 to 50% EtOAc/hexanes, gradient elution)

Sources & evidence

ORD record
ord-504c2b8c8f524fa78e657ab3c64d57a3
Source dataset
uspto-grants-2016_03
Patent number
US09296736B2

Reaction notes

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