Sulfuric Acid → 2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)acetic acid

HRID 1048273Notes

Reaction equation

HRID 1048273 reaction equation
S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:17]([CH2:26][CH:27]3[CH2:29][CH2:28]3)[C:16](=[O:30])[C:15]([CH2:38][CH2:39][OH:40])([CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:14]2)[CH:10]=[CH:11][CH:12]=1.CC(C)=[O:43].OS(O)(=O)=O.O=[Cr](=O)=O>O.CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:17]([CH2:26][CH:27]3[CH2:28][CH2:29]3)[C:16](=[O:30])[C@:15]([CH2:38][C:39]([OH:43])=[O:40])([CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:14]2)[CH:10]=[CH:11][CH:12]=1

Participants

7

Reactant 3

HCID 1118Sulfuric AcidHCID 58573627(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-hydroxyethyl)-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-2-oneHCID 131709961Jones' reagent

Product 1

HCID 565911512-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)acetic acid

Reagents, catalysts & solvents 3

HCID 10219390chromium (VI) trioxideCatalystHCID 180AcetoneSolventHCID 962WaterSolvent2×

Conditions

Temperature
55 °C

Procedure

An ice-cooled solution of 2.05 g (20.5 mmol) of chromium(VI) oxide in water (4 mL) was treated with 1.75 mL (32.7 mmol) of sulfuric acid via syringe. The mixture was diluted with additional water (4 mL) and stored at 0° C. at prior to use. In a separate flask, 105 mg (0.21 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-hydroxyethyl)-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-2-one (Example 69, Step D, mixture of diastereomers) was dissolved in acetone (20 mL) and then treated with Jones reagent (see above) slowly via pipette at room temperature. After 30 min, the resulting dark red solution was heated at 55° C. for an additional 17.5 h. The reaction was concentrated under reduced pressure, then was diluted with water and extracted with ethyl acetate (4×). The organic layers were over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 40% MeCN in water to 55% MeCN in water over a 35 min period, where both solvents contain 0.1% TFA) provided the title compound (single enantiomer) as a white solid. [Note that the desired C-3 (3S) epimer is the less polar epimer and elutes off second].

Workup

  1. customstored at 0° C.
  2. concentrationThe reaction was concentrated under reduced pressure
  3. additionwas diluted with water
  4. extractionextracted with ethyl acetate (4×)
  5. filtrationfiltered
  6. concentrationthe filtrate was concentrated
  7. customPurification of the residue by reversed phase prep
  8. washHPLC (Sunfire Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 40% MeCN in water to 55% MeCN in water over a 35 min period, where both solvents

Sources & evidence

ORD record
ord-67ab651adf0c42d8966b3bd51f4aba97
Source dataset
uspto-grants-2013_10
Patent number
US08569341B2

Reaction notes

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