Tempo → 3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-2-hydroxypropanoic acid

HRID 931980Notes

Reaction equation

HRID 931980 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]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][CH:29]([OH:32])[CH2:30][OH:31])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CC1(C)N([O])C(C)(C)CCC1.Cl([O-])=[O:45].[Na+]>C(#N)C.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[OH-].[Na+].O>[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]([CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:11](=[O:26])[C@:10]([CH2:28][CH:29]([OH:32])[C:30]([OH:45])=[O:31])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 3

HCID 2724126TempoHCID 23668197Sodium ChloriteHCID 58573209(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one

Product 1

HCID 585736883-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-2-hydroxypropanoic acid

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 6342AcetonitrileSolventHCID 20215742Sodium phosphate sodium hydroxideSolvent

Conditions

Temperature
35 °C

Procedure

A mixture of 142 mg (0.30 mmol) of (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one (Example 81, Step A) and 28 mg (0.18 mmol) of TEMPO in a mixture of acetonitrile (6 mL) and sodium phosphate-sodium hydroxide buffer (pH 6.7, 4.5 mL) at 35° C. was treated simultaneously with a solution of 105 mg (1.16 mmol) of sodium chlorite in water (1.2 mL) and a solution of 106 μL (0.07 mmol) of bleach solution (ca. 0.7 N) in water (0.6 mL) over 10 min. The resulting dark orange solution was stirred at 35° C. for 1.75 h, and then was partitioned between 1 N HCl and EtOAc (3×). The combined organic layers were dried 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 60% MeCN in water to 80% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound (mixture of alcohol epimers) as a white solid.

Workup

  1. customwas partitioned between 1 N HCl and EtOAc (3×)
  2. dry with materialThe combined organic layers were dried over Na2SO4
  3. filtrationfiltered
  4. concentrationthe filtrate was concentrated
  5. customPurification of the residue by reversed phase prep
  6. washHPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 60% MeCN in water to 80% MeCN in water over a 30 min period, where both solvents

Sources & evidence

ORD record
ord-02e887e91f6a402294ccfc10dad525bc
Source dataset
uspto-grants-2016_03
Patent number
US09296736B2

Reaction notes

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