Diisopropylethylamine → 3-Diethylcarbamoyl-pyrrolidine-1-carboxylic acid 2,2,2-trichloro-ethyl ester

HRID 489916

Reaction equation

HRID 489916 reaction equation
CO[C:3]([CH:5]1[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)=[O:4].Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19].ClC([O-])=O.[CH:30]([N:33](CC)[CH:34](C)[CH3:35])(C)[CH3:31]>Cl.O1CCOCC1.ClCCl.CO.ClCCl>[Cl:23][C:22]([Cl:25])([Cl:24])[CH2:21][O:20][C:18]([N:7]1[CH2:8][CH2:9][CH:5]([C:3](=[O:4])[N:33]([CH2:34][CH3:35])[CH2:30][CH3:31])[CH2:6]1)=[O:19]

Participants

9

Reactant 4

HCID 81531DiisopropylethylamineHCID 870632,2,2-Trichloroethyl chloroformateHCID 4610751Methyl 1-benzylpyrrolidine-3-carboxylateHCID 21226386Carbonochloridate2×

Product 1

HCID 696945863-Diethylcarbamoyl-pyrrolidine-1-carboxylic acid 2,2,2-trichloro-ethyl esterYield 60%

Reagents, catalysts & solvents 4

HCID 313Hydrochloric AcidSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolventHCID 21226129Dichloromethane methanolSolvent

Procedure

A solution of 1-benzyl-pyrrolidine-3-carboxylic acid methyl ester (109.6 mg, 0.5 mmol) in 2N hydrochloric acid (3 mL) and dioxane (1 mL) was heated to 80-90° C. for 1 h. The solvent was evaporated under vacuum and the residue redissolved in dioxane/methanol/toluene and evaporated under vacuum. The residue was then heated under reflux in chloroform containing an excess of thionyl chloride for 1 h and then the solvent was evaporated under vacuum. The residue was dissolved in anhydrous dichloromethane (5 mL) and diethylamine (300 μL) was added. After 20 minutes the solvent was evaporated and the residue dissolved in dichloromethane, washed with dilute sodium hydroxide, dried over anhydrous sodium sulfate and evaporated under vacuum. This material was dissolved in anhydrous acetonitrile (2 mL) and 2,2,2-trichloroethyl chloroformate (1.1 eq, 76 μL) was added at room temperature. After 1.5 h a further aliquot of the chloroformate (0.52 eq., 36 μL) was added. After 30 minutes thin layer chromatography (5% methanol-dichloromethane) indicated that the reaction was still incomplete so a further aliquot of the chloroformate (0.52 eq., 36 μL) and N,N-diisopropylethylamine (0.2 eq., 20 μL) was added. After 1 h the reaction was diluted with dichloromethane, washed with dilute sodium hydroxide, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel eluting with 40:1 dichloromethane-methanol to give 3-diethylcarbamoyl-pyrrolidine-1-carboxylic acid 2,2,2-trichloro-ethyl ester (102.2 mg, 60%)

Workup

  1. customThe solvent was evaporated under vacuum
  2. dissolutionthe residue redissolved in dioxane/methanol/toluene
  3. customevaporated under vacuum
  4. temperatureThe residue was then heated
  5. temperatureunder reflux in chloroform containing an excess of thionyl chloride for 1 h
  6. customthe solvent was evaporated under vacuum
  7. dissolutionThe residue was dissolved in anhydrous dichloromethane (5 mL)
  8. additiondiethylamine (300 μL) was added
  9. customAfter 20 minutes the solvent was evaporated
  10. dissolutionthe residue dissolved in dichloromethane
  11. washwashed with dilute sodium hydroxide
  12. dry with materialdried over anhydrous sodium sulfate
  13. customevaporated under vacuum
  14. dissolutionThis material was dissolved in anhydrous acetonitrile (2 mL)
  15. additionwas added
  16. washwashed with dilute sodium hydroxide
  17. dry with materialdried over anhydrous sodium sulfate
  18. customevaporated under vacuum
  19. customThe residue was purified by chromatography on silica gel eluting with 40:1 dichloromethane-methanol

Sources & evidence

ORD record
ord-9123d12be485434bb6c250a49f6b55ab
Source dataset
uspto-grants-2005_12
Patent number
US06979741B2

Linked notes

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