Methyl iodide → [(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester

HRID 587407Notes

Reaction equation

HRID 587407 reaction equation
[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH2:11][N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:32]>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[N:7]([C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH2:11][N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9]1)[CH3:32])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 58303063[(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

Product 1

HCID 58303101[(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
60 °C

Procedure

A mixture of 5.7 g (14.1 mmol) [(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester, 676 mg (17 mmol) NaH (55%) in DMF was stirred for 20 minutes at room temperature and 1 h at 60° C. 3 g (21 mmol) iodomethane in DMF was added and the mixture was stirred at 60° C. for 1 h and evaporated. The residue was taken up in ethyl acetate and water, the organic layer washed with brine and back-extracted with ethyl acetate. The combined organic layers were dried with Na2SO4, filtered off and evaporated. The residue was taken up on isolute and subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 2.67 g (45%) of the title compound as light yellow oil. MS m/e: 419.2 [M+H]+.

Workup

  1. stirringthe mixture was stirred at 60° C. for 1 h
  2. customevaporated
  3. washwater, the organic layer washed with brine
  4. extractionback-extracted with ethyl acetate
  5. dry with materialThe combined organic layers were dried with Na2SO4
  6. filtrationfiltered off
  7. customevaporated
  8. customformed from ethyl acetate and heptane
  9. customto yield
  10. customafter evaporation of the product
  11. additioncontaining fractions 2.67 g (45%) of the title compound as light yellow oil

Sources & evidence

ORD record
ord-2d827ed3da7b4d55bfb622c0d9f30c1b
Source dataset
uspto-grants-2016_01
Patent number
US09226916B2

Reaction notes

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