Bromomethylcyclopropane → (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)piperidin-2-one

HRID 931954Notes

Reaction equation

HRID 931954 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])[C:11](=[O:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:28][CH:29]1[CH2:31][CH2:30]1.CC(C)([O-])C.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][O:23][CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:11](=[O:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 81503BromomethylcyclopropaneHCID 23676156Sodium t-butoxideHCID 58573362(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one

Product 1

HCID 58573287(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)piperidin-2-one

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 1.48 g (3.77 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (Example 68, Step A) and bromomethylcyclopropane (0.828 mL, 7.54 mmol) in DMF (20 mL) was added sodium t-butoxide (0.544 g, 5.66 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h and then warmed to rt. Then the reaction was stirred at rt for 14 h. The reaction was quenched with sat. aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water and sat. aq. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: 20%-40% EtOAc/Hexanes, gradient elution) provided the title compound as a colorless oil.

Workup

  1. temperaturewarmed to rt
  2. stirringThen the reaction was stirred at rt for 14 h
  3. customThe reaction was quenched with sat. aqueous NH4Cl solution
  4. extractionextracted with EtOAc
  5. washThe combined organic layers were washed with water and sat. aq. NaCl solution
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationthe filtrate was concentrated under reduced pressure
  9. customPurification by flash chromatography on silica gel (eluent: 20%-40% EtOAc/Hexanes, gradient elution)

Sources & evidence

ORD record
ord-64bd22eb9c4545b08e92f2573456b6b0
Source dataset
uspto-grants-2016_03
Patent number
US09296736B2

Reaction notes

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