2-Pyrrolidone → (+/-)-(4R*,5R*)-5-[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]-4-(4-hydroxy-phenyl)-1-methylpyrrolidin-2-one

HRID 1838006Notes

Reaction equation

HRID 1838006 reaction equation
C([BH-](CC)CC)C.[Li+].ClC1C=C(C=CC=1)[O:13][CH2:14][C@@H:15]1[N:19]([CH3:20])[C:18](=[O:21])[CH2:17][C@@H:16]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([C@@H]1N(C)C(=O)C[C@@H]1C1C=CC=CC=1)=[O:32].[C:46]1([C:52]2[S:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[Li]CCCC.N1CCCC1=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[OH:13][C@H:14]([C:54]1[S:53][C:52]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[CH:56][CH:55]=1)[C@@H:15]1[N:19]([CH3:20])[C:18](=[O:21])[CH2:17][C@@H:16]1[C:22]1[CH:23]=[CH:24][C:25]([OH:32])=[CH:26][CH:27]=1

Participants

10

Reactant 7

HCID 120252-PyrrolidoneHCID 699992-PhenylthiopheneHCID 2724141Tetrabutylammonium FluorideHCID 13825985(-)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-oneHCID 23664628LithiumtriethylborohydrideHCID 69891684(+/-)-(4R* 5R*)-5-[(3-chlorophenoxy)methyl]-1-methyl-4-phenylpyrrolidin-2-oneHCID 178418339Butyllithium

Product 1

HCID 10271085(+/-)-(4R*,5R*)-5-[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]-4-(4-hydroxy-phenyl)-1-methylpyrrolidin-2-oneYield 82%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

Intermediate Y was reduced with lithium triethylborohydride using the method described as Method 2 in the preparation of Intermediate T. The resulting alcohol was then subjected to Swern oxidation using the procedure described as Method 1 in the preparation of Intermediate Z, followed by a reaction of the resulting aldehyde with 2-phenylthiophene and n-BuLi in a manner analogous to that of Example 3a. The resulting product, (±)-(4R*,5R*)-5[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]-1-methyl-4-[4-tert-butyldimethylsilyloxy)phenyl]pyrrolidin-2-one (0.050 g, 0.10 mmol), was dissolved in THF (1 mL) under Ar, a solution of TBAF (1M in THF, 0.11 mL, 0.11 mmol) was added, and the resulting solution was stirred for 4 min. The reaction was treated with water and a saturated NH4Cl solution, then extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (EtOAc) to yield (±)-(4R*,5R*)-5-[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]-4-(4-hydroxy-phenyl)-1-methylpyrrolidin-2-one (31 mg, 82%) as a white powder: mp 248-249° C.; TLC (EtOAc) Rf 0.37.

Workup

  1. extractiona saturated NH4Cl solution, then extracted with EtOAc
  2. dry with materialThe combined organic layers were dried (MgSO4)
  3. concentrationconcentrated under reduced pressure
  4. customThe crude product was purified by flash chromatography (EtOAc)

Sources & evidence

ORD record
ord-b051b5e042ad4ce395e355c926caf709
Source dataset
uspto-grants-2004_08
Patent number
US06784167B2

Reaction notes

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