Hydrochloric Acid → (22S,23S)-3alpha,7alpha-dihydroxy-22,23-methylene-5beta-cholan-24-oic acid

HRID 1640451Notes

Reaction equation

HRID 1640451 reaction equation
[N+](=CC(OCC)=O)=[N-].O[C@@H]1CC[C@@]2(C)[C@H](C[C@@H](O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCC(OC)=O)C1.[CH3:38][C@@H:39]([CH2:43][C@H:44]([C@@H:46]1[C@:63]2([CH3:64])[C@H:49]([C@H:50]3[C@H:60]([CH2:61][C@@H:62]2O)[C@:58]2([CH3:59])[C@@H:53]([CH2:54][C@H:55]([OH:66])[CH2:56][CH2:57]2)[C@@H:52](CC)[C@H:51]3[OH:69])[CH2:48][CH2:47]1)[CH3:45])[C:40]([O-:42])=[O:41].[OH-].[Na+].Cl>C(Cl)Cl.CCO.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Rh+2].[Rh+2].O>[OH:66][C@@H:55]1[CH2:56][CH2:57][C@@:58]2([CH3:59])[C@H:53]([CH2:52][C@@H:51]([OH:69])[C@@H:50]3[C@@H:60]2[CH2:61][CH2:62][C@@:63]2([CH3:64])[C@H:49]3[CH2:48][CH2:47][C@@H:46]2[C@H:44]([CH3:45])[C@@H:43]2[CH2:38][C@@H:39]2[C:40]([OH:42])=[O:41])[CH2:54]1.[OH:66][C@@H:55]1[CH2:56][CH2:57][C@@:58]2([CH3:59])[C@H:53]([CH2:52][C@@H:51]([OH:69])[C@@H:50]3[C@@H:60]2[CH2:61][CH2:62][C@@:63]2([CH3:64])[C@H:49]3[CH2:48][CH2:47][C@@H:46]2[C@H:44]([CH3:45])[C@H:43]2[CH2:38][C@H:39]2[C:40]([OH:42])=[O:41])[CH2:54]1

Participants

11

Reactant 5

HCID 313Hydrochloric AcidHCID 12192Ethyl diazoacetateHCID 14798Sodium HydroxideHCID 11069533Methyl chenodeoxycholateHCID 13172944223(S)-methyl-3alpha,7alpha,12alpha-trihydroxy-6alpha-ethyl-5beta-cholan-24-oate2×

Product 2

HCID 11165617(22S,23S)-3alpha,7alpha-dihydroxy-22,23-methylene-5beta-cholan-24-oic acidYield 15%HCID 11258221HCID 11258221, compoundYield 11.5%

Reagents, catalysts & solvents 4

HCID 152122Dirhodium tetraacetateCatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

Ethyl diazoacetate (0.478 g, 1.19 mmol) in dry CH2Cl2 (15 mL) was slowly added dropwise to a stirred suspension of 3α,7α-diacetoxy-5-norcholan-22,23-ene (1) (0.6 g, 1.39 mmol) in the presence of dirhodium (II) tetraacetate (9 mg, 0.02 mmol) in dry CH2Cl2(15 mL) under nitrogen at room temperature. The reaction mixture was filtered and washed with H2O (20 mL), dried (Na2SO4), and evaporated under vacuum, thus affording a mixture of the four diastereoisomeric esters 2. The esters 2 were successively dissolved in EtOH (15 mL) and treated with a solution of 10 N NaOH (10 mL) at reflux for 4 h, cooled, poured onto cold H2O (50 mL), acidified with 2 N HCl, and extracted with EtOAc (3×15 mL). The organic phase was washed with brine (10 mL), dried (Na2SO4), and concentrated under vacuum. The residue was chromatographated on silica gel. Elution with CH2Cl2/MeOH 96/4 with AcOH 0.1% afforded 0.087 g (15% yeld) of (22S,23S)-3α,7α-dihydroxy-22,23-methylene-5β-cholan-24-oic acid (Io5) and 0.065 g (11.5% yield) of (22R,23R)-3α,7α-dihydroxy-22,23-methylene-5β-cholan-24-oic acid (Iq5). Elution with CH2Cl2/MeOH 95.5/4.5 with 0.1% AcOH afforded 0.18 g (32% yield) of (22S,23R)-3α,7α-dihydroxy-22,23-methylene-5β-cholan-24-oic acid (Ip5) and 0.15 g (26.7% yield) of (22R,23S)-3α,7α-dihydroxy-22,23-methylene-5β-cholan-24-oic acid (Ir5) as white solids.

Workup

  1. filtrationThe reaction mixture was filtered
  2. washwashed with H2O (20 mL)
  3. dry with materialdried (Na2SO4)
  4. customevaporated under vacuum
  5. customthus affording
  6. temperatureat reflux for 4 h
  7. temperaturecooled
  8. extractionextracted with EtOAc (3×15 mL)
  9. washThe organic phase was washed with brine (10 mL)
  10. dry with materialdried (Na2SO4)
  11. concentrationconcentrated under vacuum
  12. washElution with CH2Cl2/MeOH 96/4 with AcOH 0.1%

Sources & evidence

ORD record
ord-072f2d4e6e314d3cb297d1a5d99d4d02
Source dataset
uspto-grants-2012_02
Patent number
US08114862B2

Reaction notes

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