Cyclobutanone → 5-{2-(4-Tert-butylphenyl)-2-[5-(1-hydroxycyclobutyl)-6-methoxypyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one

HRID 70674Notes

Reaction equation

HRID 70674 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5](/[C:10](/[C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)=[CH:11]/[C@@H:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])[C:15](=[O:28])[CH2:14][CH2:13]2)=[N:6][C:7]=1[O:8][CH3:9].C([Li])CCC.[C:44]1(=[O:48])[CH2:47][CH2:46][CH2:45]1.[Cl-].[NH4+]>O1CCCC1>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([C:10]([C:5]2[CH:4]=[CH:3][C:2]([C:44]3([OH:48])[CH2:47][CH2:46][CH2:45]3)=[C:7]([O:8][CH3:9])[N:6]=2)=[CH:11][CH:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])[C:15](=[O:28])[CH2:14][CH2:13]2)=[CH:34][CH:33]=1)([CH3:38])([CH3:36])[CH3:37]

Participants

6

Reactant 4

HCID 14496CyclobutanoneHCID 25517Ammonium ChlorideHCID 67397955(5R)-5-[(E)-2-(5-bromo-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-oneHCID 178418339Butyllithium

Product 1

HCID 674003365-{2-(4-Tert-butylphenyl)-2-[5-(1-hydroxycyclobutyl)-6-methoxypyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

(5R)-5-[(E)-2-(5-Bromo-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-42(1) (100 mg) was dissolved in tetrahydrofuran (5 mL), and n-butyllithium was added at −78° C. After stirring for 30 minutes, cyclobutanone was added dropwise. The mixture was stirred for further 30 minutes and then an ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give 5-{2-(4-tert-butylphenyl)-2-[5-(1-hydroxycyclobutyl)-6-methoxypyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (EZ mixture) (35 mg).

Workup

  1. stirringThe mixture was stirred for further 30 minutes
  2. extractionfollowed by extraction with ethyl acetate
  3. dry with materialThe organic layer was dried over sodium sulfate
  4. customthe solvent was evaporated under reduced pressure
  5. customThe residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1)

Sources & evidence

ORD record
ord-a4584d7375584cad916d184117a0df8e
Source dataset
uspto-grants-2014_09
Patent number
US08822503B2

Reaction notes

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