Ammonium Chloride → Benzyl 1-benzyl-3-(2-(tert-butoxy)-2-oxoethyl)-4-methylpyrrolidine-3-carboxylate

HRID 445993Notes

Reaction equation

HRID 445993 reaction equation
[CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].CCCCCC.O1CCCC1.Br[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46].[Cl-].[NH4+]>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[C:10]([CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

8

Reactant 4

HCID 25517Ammonium ChlorideHCID 79177tert-Butyl bromoacetateHCID 86605466Lithium diisopropylamide hexane tetrahydrofuranHCID 86678243Benzyl (3RS,4SR)-1-benzyl-4-methylpyrrolidine-3-carboxylate

Product 1

HCID 86678244Benzyl 1-benzyl-3-(2-(tert-butoxy)-2-oxoethyl)-4-methylpyrrolidine-3-carboxylateYield 14.5%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-70 °C

Procedure

Benzyl (3RS,4SR)-1-benzyl-4-methylpyrrolidine-3-carboxylate obtained in Example 1f (30 g, 97.4 mmol) was dissolved in tetrahydrofuran (300 ml), which was cooled to −70° C. with stirring under nitrogen. A 1.11M lithium diisopropylamide/n-hexane-tetrahydrofuran solution (105 ml, 116 mmol) was added dropwise over 20 minutes so that the internal temperature did not exceed −64.3° C. The mixture was stirred at −70° C. for 1 hour, and tetrahydrofuran (30 ml) and tert-butyl bromoacetate (26.6 g, 136 mmol) were then added dropwise over 10 minutes so that the internal temperature did not exceed −60° C. The reaction mixture was stirred at −70° C. for further one hour, and a saturated aqueous ammonium chloride solution was then added to the reaction mixture. Immediately thereafter, the reaction mixture was diluted with water and ethyl acetate was added. The organic layer was washed with brine and a 5 N aqueous hydrochloric acid solution, and then dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane). The residue was further purified by NH silica gel column chromatography (elution solvent: heptane/ethyl acetate=98/2) to give the title compound (6 g, yield: 14.5%).

Workup

  1. customdid not exceed −64.3° C
  2. stirringThe mixture was stirred at −70° C. for 1 hour
  3. customdid not exceed −60° C
  4. stirringThe reaction mixture was stirred at −70° C. for further one hour
  5. additionwas added
  6. washThe organic layer was washed with brine
  7. dry with materiala 5 N aqueous hydrochloric acid solution, and then dried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane)
  11. customThe residue was further purified by NH silica gel column chromatography (elution solvent: heptane/ethyl acetate=98/2)

Sources & evidence

ORD record
ord-6eb98e50d9ae47718c371eb41a903878
Source dataset
uspto-grants-2013_07
Patent number
US08476301B2

Reaction notes

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