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 931961노트

반응식

HRID 931961 반응식
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

참가 물질

7

반응물 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

생성물 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

시약·촉매·용매 3

HCID 10219390chromium (VI) trioxide촉매HCID 180Acetone용매HCID 962Water용매2회

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온도
55 °C

실험 절차

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].

후처리

  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

출처 및 근거

ORD 기록
ord-b947331526c3410fa087ba6711404794
출처 데이터셋
uspto-grants-2016_03
특허 번호
US09296736B2

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