Potassium Carbonate → (R)-5-oxo-1-(2-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid ethyl ester

HRID 882815

Reaction equation

HRID 882815 reaction equation
[O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1.CN(C=O)C.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O>[CH2:10]([O:9][C:7]([C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:26])([F:27])[F:28])=[O:8])[CH3:11]

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 2855718-Crown-6HCID 643508ethyl (2R)-5-oxopyrrolidine-2-carboxylateHCID 86647367DMF 1-(bromomethyl)-2-(trifluoromethyl)benzene

Product 1

HCID 66644833(R)-5-oxo-1-(2-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid ethyl esterYield 14.7%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

To the solution of (R)-ethyl 5-oxo-pyrrolidine-2-carboxylate (D-pyroglutamic acid ethyl ester; 99% pure; 1403 mg, 8.84 mmol) in 20 ml of DMF 1-(bromomethyl)-2-(trifluoromethyl)benzene (96% pure; 2200 mg, 8.84 mmol), K2CO3 (3660 mg, 26.5 mmol) and a small amount of each KI and 18-crown-6 were added, and the mixture was heated at 80° C. for 6 h. Subsequently the mixture was poured into water and extracted three times with MTBE. The organic layer was washed with brine, dried over MgSO4 and the solvent removed under reduced pressure. Chromatography on silica gel using dichloromethane and dichloromethane/MeOH (99:1) resulted in (R)-5-oxo-1-(2-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid ethyl ester (410 mg, ESI-MS [M+H]+=316.1; yield: 12%), which was hydrolyzed to the corresponding carboxylate by stiffing overnight at room temperature in a solution of 15 ml ethanol and 1.56 mL 2N NaOH (aq). Evaporation of the solvent, followed by addition of water to the residue, extraction with ethyl acetate, subsequent acidification of the aqueous layer to pH 3 using concentrated HCl, extraction with dichloromethane, drying of the combined organic layers with MgSO4 and removal of the solvent under reduced pressure led to the desired product as a white foam.

Workup

  1. extractionextracted three times with MTBE
  2. washThe organic layer was washed with brine
  3. dry with materialdried over MgSO4
  4. customthe solvent removed under reduced pressure

Sources & evidence

ORD record
ord-fb2c2e1e851f42a09a3ea87761e8ba55
Source dataset
uspto-grants-2012_08
Patent number
US08236798B2

Linked notes

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