Citric Acid → 2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid

HRID 932114Notes

Reaction equation

HRID 932114 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]([C:24](=[O:27])[CH2:25][CH3:26])[CH2:22][CH3:23])[C:11](=[O:28])[C@:10]([CH2:30][C:31]([OH:33])=[O:32])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[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]([CH:24]([OH:27])[CH2:25][CH3:26])[CH2:22][CH3:23])[C:11](=[O:28])[C@:10]([CH2:30][C:31]([OH:33])=[O:32])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 3

HCID 311Citric AcidHCID 4311764Sodium borohydride2×HCID 585738322-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-4-oxohexan-3-yl)piperidin-3-yl)acetic acid

Product 1

HCID 680004752-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-4-oxohexan-3-yl)piperidin-3-yl)acetic acid (0.038 g, 0.077 mmol; Example 158, Step B) in a mixture of THF and methanol (4:1, 5 mL) was added sodium borohydride (9 mg, 0.24 mmol) at 0° C. Then the reaction was allowed to warm to room temperature. After being stirred at room temperature for 1.5 h, another 2 eq. of sodium borohydride were added and stirred for another 0.5 h. The reaction was acidified (10% citric acid) and extracted (2×EtOAc). The combined organic layers were washed (sat. aq. NaCl solution), dried (MgSO4), and concentrated under reduced pressure. The crude material was purified by reverse phase preparatory HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution) to give the title compound as the first eluting fraction as a white solid after lyophilization.

Workup

  1. stirringstirred for another 0.5 h
  2. extractionextracted (2×EtOAc)
  3. washThe combined organic layers were washed (sat. aq. NaCl solution)
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated under reduced pressure
  6. customThe crude material was purified by reverse phase preparatory HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution)

Sources & evidence

ORD record
ord-e1c0315ab4594542ba7e968d7b47437a
Source dataset
uspto-grants-2016_03
Patent number
US09296736B2

Reaction notes

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