2,6-Lutidine → (3S,5R,6S)-3-Allyl-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one

HRID 1846977Notes

Reaction equation

HRID 1846977 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C@@H:9]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[CH2:10][C@:11]([CH3:24])([CH2:21][CH:22]=[CH2:23])[C:12]([NH:14][C@@H:15]([CH:18]2[CH2:20][CH2:19]2)[CH2:16][OH:17])=[O:13])=[CH:4][C:3]=1[F:33].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.N1C(C)=CC=CC=1C.C(=O)(O)[O-].[Na+]>ClCCl.O.ClCCCl>[CH2:21]([C@@:11]1([CH3:24])[CH2:10][C@H:9]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:33])[CH:4]=2)[N:14]([C@@H:15]([CH:18]2[CH2:20][CH2:19]2)[CH2:16][OH:17])[C:12]1=[O:13])[CH:22]=[CH2:23]

Participants

8

Reactant 4

HCID 79372,6-LutidineHCID 77773Toluene-p-sulphonic anhydrideHCID 516892Sodium BicarbonateHCID 86731824(2S)-2-((2R)-3-(4-Chloro-3-fluorophenyl)-2-(3-chlorophenyl)-3-hydroxypropyl)-N-((S)-1-cyclopropyl-2-hydroxyethyl)-2-methylpent-4-enamide

Product 1

HCID 86731826(3S,5R,6S)-3-Allyl-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

A solution of (2S)-2-((2R)-3-(4-chloro-3-fluorophenyl)-2-(3-chlorophenyl)-3-hydroxypropyl)-N—((S)-1-cyclopropyl-2-hydroxyethyl)-2-methylpent-4-enamide (40.2 g, 81 mmol, Example 4, Step F) in dichloromethane (80 mL) was added p-toluenesulfonic anhydride (66.3 g, 203 mmol) in dichloromethane (220 mL) at 0° C., and the reaction mixture was stirred for 10 minutes at same the temperature. 2,6-Lutidine (43.6 mL, 374 mmol, Aldrich, St. Louis, Mo.) was added dropwise via addition funnel at 0° C. The reaction mixture was slowly warmed to room temperature, and then it was stirred at reflux. After 24 hours, sodium bicarbonate (68.3 g, 814 mmol) in water (600 mL) and 1,2-dichloroethane (300 mL) were added in succession. The reaction mixture was heated at reflux for an hour and then cooled to room temperature. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with 1 N hydrochloric acid, water, and brine, then concentrated under reduced pressure. The residue was purified by flash chromatography (1.5 kg SiO2 column, gradient elution of 10% to 50% ethyl acetate in hexanes) to provide the title compound as a white solid.

Workup

  1. stirringit was stirred
  2. temperatureat reflux
  3. waitAfter 24 hours
  4. temperatureThe reaction mixture was heated
  5. temperatureat reflux for an hour
  6. temperaturecooled to room temperature
  7. customThe layers were separated
  8. extractionthe aqueous layer was extracted with dichloromethane
  9. washThe combined organic layer was washed with 1 N hydrochloric acid, water, and brine
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was purified by flash chromatography (1.5 kg SiO2 column, gradient elution of 10% to 50% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-b94d68e0f7e944e987007bcacdcd2f14
Source dataset
uspto-grants-2015_02
Patent number
US08952036B2

Reaction notes

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