Sodium hydride → (S)-Methyl 2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate

HRID 1048305Notes

Reaction equation

HRID 1048305 reaction equation
[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[H-].[Na+].Br[CH:29]([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:29]([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31])[C:5]1=[O:24])[CH:2]=[CH2:3]

Participants

6

Reactant 4

HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 95577Butanoic acid, 2-bromo-, methyl esterHCID 58574008(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

Product 1

HCID 58573915(S)-Methyl 2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 71, Step D) (4.00 g, 10.7 mmol) in 45 mL of DMF was added a dispersion of 60% sodium hydride in mineral oil (1.71 g, 42.7 mmol) at 0° C. After being stirred for 20 min, methyl 2-bromobutanoate (6.15 mL, 53.4 mmol) was added at 0° C. and the resulting solution was stirred at 25° C. for 12 h until completion of the reaction. Then sat. aq. NH4Cl solution was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and sat. aq. 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: 0 to 100% MTBE/hexanes, gradient elution), followed by separation of individual stereoisomers by chiral SFC (flowrate: 65 mL/min on a ChiralPak ®AD-H column (Diacel Inc., Fort Lee, N.J.) using 3:1 heptanes/IPA (0.1% DEA)/CO2 as the eluent) provided the title compound as the faster eluting isomer.

Workup

  1. stirringthe resulting solution was stirred at 25° C. for 12 h until completion of the reaction
  2. extractionthe mixture was extracted with ethyl acetate
  3. washThe combined organic layers were washed with water and sat. aq. 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: 0 to 100% MTBE/hexanes, gradient elution)
  8. customfollowed by separation of individual stereoisomers by chiral SFC (flowrate

Sources & evidence

ORD record
ord-3ffaa63ad159425ab4364dcce2d95e91
Source dataset
uspto-grants-2013_10
Patent number
US08569341B2

Reaction notes

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