Ethylene Glycol → 3(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 2408861Notes

Reaction equation

HRID 2408861 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=1[F:22].C(O)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:19]2[CH:18]=[CH:17][C:16]([F:22])=[C:15]([Cl:14])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 174Ethylene GlycolHCID 62657Potassium Phosphate, TribasicHCID 854071tert-butyl (3S)-3-aminopyrrolidine-1-carboxylateHCID 27246052-Chloro-1-fluoro-4-iodobenzene

Product 1

HCID 666570713(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl esterYield 62.7%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 3776IsopropanolSolvent

Procedure

To a 50 ml of isopropyl alcohol solution containing 15.0 g of 3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (80.5 mmol) and 24.8 g of 2-chloro-1-fluoro-4-iodobenzene (96.7 mmol) were added 1.54 g of copper (I) iodide (8.1 mmol), 9.0 ml of ethylene glycol (10.1 mmol) and 34.2 g of potassium phosphate (161 mmol), and heated under reflux under a nitrogen atmosphere for 46 hours. The reaction solution was cooled to room temperature and filtered using Celite. The substance remained in the filter was washed with ethyl acetate and the filtrate was concentrated under reduced pressure together with the washings, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether to thereby obtain 15.9 g of white powdery 3(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester.

Workup

  1. temperatureheated
  2. temperatureunder reflux under a nitrogen atmosphere for 46 hours
  3. filtrationfiltered
  4. washwas washed with ethyl acetate
  5. concentrationthe filtrate was concentrated under reduced pressure together with the washings
  6. customthe residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1)
  7. distillationThe solvent was distilled off under reduced pressure
  8. customthe residue was recrystallized from diethyl ether

Sources & evidence

ORD record
ord-8be51f52efab4a549637f9eb40eb86e2
Source dataset
uspto-grants-2014_08
Patent number
US08815871B2

Reaction notes

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