Sulfuric Acid → Methyl (3S,4R)-1-benzyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylate

HRID 587345Notes

Reaction equation

HRID 587345 reaction equation
[CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6]1)=[O:4].C[O-].[Na+].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CO.C(OC)(C)(C)C>[CH3:1][O:2][C:3]([C@H:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][N:7]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:6]1)=[O:4]

Participants

7

Reactant 4

HCID 1118Sulfuric AcidHCID 10340Sodium CarbonateHCID 10942334Sodium Methoxide2×HCID 67233768(3R,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester

Product 1

HCID 59131036Methyl (3S,4R)-1-benzyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylateYield 86.4%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 15413tert-Butyl methyl etherSolvent

Procedure

To a solution of (3R,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester (72.74 g, 220.5 mmol) in methanol (730 mL) was added sodium methylate solution (5.4 M methanol, 81.7 mL, 441.1 mmol). The reaction mixture was stirred for 116 h at ambient temperature (after 17.5 h further sodium methylate solution (5.4 M in methanol, 20.4 mL, 110.3 mmol) was added). It was set to pH=1 by addition of sulfuric acid (26.13 mL, 463.1 mmol) and stirred at 60° C. for 19 h. The resulting suspension was cooled to 0° C., tert-butylmethylether (1.6 L) was added and the solution was set to pH=9 with aqueous sodium carbonate (1 M, 440 mL). The aqueous layer was separated and extracted with further tert-butylmethylether (410 mL). The organic layers were washed with brine (310 mL), combined and dried over sodium sulfate. Concentration and filtration over silicagel (heptane: ethyl acetate=80:20) afforded the title compound (62.82 g, 86%) as a light yellow oil. MS m/e: 330.3/332.3 [M+H]+.

Workup

  1. stirringstirred at 60° C. for 19 h
  2. temperatureThe resulting suspension was cooled to 0° C.
  3. customThe aqueous layer was separated
  4. extractionextracted with further tert-butylmethylether (410 mL)
  5. washThe organic layers were washed with brine (310 mL)
  6. dry with materialdried over sodium sulfate
  7. concentrationConcentration and filtration over silicagel (heptane: ethyl acetate=80:20)

Sources & evidence

ORD record
ord-58458a3dca7b4fc2b89c54ad352c330d
Source dataset
uspto-grants-2016_01
Patent number
US09226916B2

Reaction notes

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