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

HRID 1838004Notes

Reaction equation

HRID 1838004 reaction equation
[OH:1][C@H:2]([C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.[CH2:28]=O.C[O-].[Na+].[BH4-].[Na+].[OH-].[Na+]>CO.O>[OH:1][C@H:2]([C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:11]=[CH:12][C:13]([NH:16][CH3:28])=[CH:14][CH:15]=1

Participants

8

Reactant 5

HCID 712FormaldehydeHCID 14798Sodium HydroxideHCID 4311764Sodium borohydrideHCID 10271018(+/-)-(4R*,5R*)-5-[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]-4-(4-aminophenyl)-1-methylpyrrolidin-2-oneHCID 10942334Sodium Methoxide

Product 1

HCID 59066505(+/-)-(4R*,5R*)-5-[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]methyl-4-[4-(methylamino)phenyl]pyrrolidin-2-oneYield 76%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

A mixture of (±)-(4R*,5R*)-5-[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]-4-(4-aminophenyl)-1-methylpyrrolidin-2-one (Example 17, 105 mg, 0.30 mmol), paraformaldehyde (13 mg, 0.42 mmol) and sodium methoxide (81 mg, 1.5 mmol) in methanol (1 mL) was stirred overnight. After adding sodium borohydride (12 mg, 0.30 mmol) the reaction mixture was heated at the reflux temperature for 1 h, then treated with a 1M NaOH solution (1 mL). The resulting mixture was stirred for 10 min, diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The organic layer was washed with a saturated NaCl solution, dried (Na2SO4) and concentrated under reduced pressure to give a yellow solid. The crude product was sequentially triturated with EtOAc, Et2O and hexane to provide (±)-(4R*,5R*)-5-[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]methyl-4-[4-(methylamino)phenyl]pyrrolidin-2-one (89 mg, 76%) as a white solid: TLC (EtOAc) Rf 0.34; mp: 212° C.

Workup

  1. temperaturewas heated at the reflux temperature for 1 h
  2. stirringThe resulting mixture was stirred for 10 min
  3. extractionextracted with EtOAc (2×10 mL)
  4. washThe organic layer was washed with a saturated NaCl solution
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated under reduced pressure
  7. customto give a yellow solid
  8. customThe crude product was sequentially triturated with EtOAc, Et2O and hexane

Sources & evidence

ORD record
ord-c6815c49241c4635b7951d4532b033ca
Source dataset
uspto-grants-2004_08
Patent number
US06784167B2

Reaction notes

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