Toluene → 3(S)-[(3-chloro-4-cyanophenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 660113Notes

Reaction equation

HRID 660113 reaction equation
C1(C)C=CC=CC=1.[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[Cl:29][C:30]1[CH:37]=[C:36](F)[CH:35]=[CH:34][C:31]=1[C:32]#[N:33].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C(OCC)C.O.O1CCCC1>[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][C@H:17]([N:20]([C:36]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:29])[CH:37]=2)[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]

Participants

8

Reactant 4

HCID 1140TolueneHCID 1090002-Chloro-4-fluorobenzonitrileHCID 2724254Sodium bis(trimethylsilyl)amideHCID 666570713(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 666572273(S)-[(3-chloro-4-cyanophenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl esterYield 77.7%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Procedure

To an anhydrous toluene solution containing 3(S)-[(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.6 mmol) and 2-chloro-4-fluorobenzonitrile (0.30 g, 1.9 mmol) was added a 1.45 ml tetrahydrofuran solution containing sodium bis(trimethylsilyl)amide (1.1 M) using a syringe. The mixture was heated under reflux under a nitrogen atmosphere for 8 hours and cooled to room temperature. Water was added to the reaction solution, and extraction with diethyl ether was conducted. After drying over sodium sulfate and concentration under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 0.56 g of white amorphous solid 3(S)-[(3-chloro-4-cyanophenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.

Workup

  1. temperatureThe mixture was heated
  2. temperatureunder reflux under a nitrogen atmosphere for 8 hours
  3. dry with materialAfter drying over sodium sulfate and concentration under reduced pressure
  4. customthe residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1)
  5. concentrationThe purified product was concentrated to dryness under reduced pressure

Sources & evidence

ORD record
ord-8c6ae82f150c4dfe87ee400a79c1ad7a
Source dataset
uspto-grants-2011_12
Patent number
US08084442B2

Reaction notes

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