Methyl Chloride → N-Boc-pyrrolidine

HRID 1185653Notes

Reaction equation

HRID 1185653 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1C1NC(C2C=CC(C3C=CN=C(OCC4C=CC=CC=4)C=3)=CC=2)=CN=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CCl.[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 6327Methyl ChlorideHCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 666202502-{5-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 643455N-Boc-pyrrolidineYield 270.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 2-{5-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.530 g) in DMF (5.0 mL) at 0° C. was added 60% sodium hydride (0.047 g). After stirring for 5 minutes, 2-(trimethylsilyl)ethoxy]methyl chloride was added and reaction mixture stirred for 2 hours. Saturated ammonium chloride was added and mixture was extracted with ethyl acetate (2×). Organic layer was washed with 5% lithium chloride solution (2×), brine and dried (MgSO4). Concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexanes) to give 245-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.495 g). LCMS-ESI+: calc'd for C36H47N4O4Si: 627.87 (M+H+). Found: 627.1 (M−1-H+). A mixture of 245-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.495 g) and 10% Pd/C (0.023 g) in ethanol (5.5 mL) was stirred under hydrogen atmosphere for 1 hour. Reaction mixture was filtered through a pad of Celite, which was washed with methanol. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0 to 10% methanol/ethyl acetate) to give 2-[5-[4-(2-Oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.3027 g): LCMS-ESI+: calc'd for C29H41N4O4Si: 537.47 (M+H+). Found: 537.0 (M+H+).

Workup

  1. customreaction mixture
  2. stirringstirred for 2 hours
  3. extractionmixture was extracted with ethyl acetate (2×)
  4. washOrganic layer was washed with 5% lithium chloride solution (2×), brine
  5. dry with materialdried (MgSO4)
  6. concentrationConcentrated
  7. custompurified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-e68489cd1ee04e838e91433b3e7e9dc9
Source dataset
uspto-grants-2014_03
Patent number
US08669234B2

Reaction notes

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