Benzenamine, 3,5-bis(trifluoromethyl)- → 3-Cyclobutyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid (3,5-bis-trifluoromethylphenyl)-amide

HRID 2068247Notes

Reaction equation

HRID 2068247 reaction equation
[Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11].C[O:22][C:23]([C:25]1([CH:39]2[CH2:42][CH2:41][CH2:40]2)[CH2:29][C:28](=[O:30])[N:27]([C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:26]1)=O.[NH4+].[Cl-]>C1COCC1>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:9]=[C:10]([NH:11][C:23]([C:25]2([CH:39]3[CH2:40][CH2:41][CH2:42]3)[CH2:29][C:28](=[O:30])[N:27]([C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:38])[CH2:26]2)=[O:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1

Participants

6

Reactant 4

HCID 9480Benzenamine, 3,5-bis(trifluoromethyl)-HCID 25517Ammonium ChlorideHCID 582188223-Cyclobutyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl esterHCID 178418339Butyllithium

Product 1

HCID 510340083-Cyclobutyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid (3,5-bis-trifluoromethylphenyl)-amideYield 1.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

n-BuLi (2.5 M solution in hexanes, 1.13 mL, 2.82 mmol) was added to a solution of 3,5-bis-trifluoromethylaniline (437 μL, 2.82 mmol) in THF (5 mL) at room temperature. The resulting dark brown colored solution was stirred for 10 min at room temperature. A solution of 3-cyclobutyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step a, 283 mg, 0.94 mmol) in THF (3 mL) was added and stirred for 30 min at 100° C. in a sealed vial. Saturated aqueous NH4Cl solution (10 mL) was added, extracted with EtOAc (3×25 mL). The combined organic layer was washed with water (40 mL), brine (40 mL), dried (Na2SO4) and evaporated. The reaction mixture was then purified by automated flash chromatography (SiO2, 20→70% EtOAc/hexanes). Selected fractions were combined and concentrated under reduced pressure. The obtained product was further purified twice by preparative HPLC (5→90% gradient of MeCN—H2O with 0.1% TFA) to obtain the desired product 3-cyclobutyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid (3,5-bis-trifluoromethylphenyl)-amide (7 mg, 1.5% yield). LC-MS: Rt (retention time): 3.17 min, MS: (ES) m/z 499.1 (M+H+). 1H NMR (400 MHz, CDCl3) δ8.08 (s, 3H), 7.63 (s, 1H), 7.12-7.16 (m, 1H), 7.04-7.09 (m, 2H), 4.18 (d, 1H, J=8.5 Hz), 3.58 (d, 1H, J=8.5 Hz), 3.18 (d, 1H, J=17 Hz), 2.8 (d, 1H, J=17 Hz), 2.2 (s, 3H), 2.17 (s, 3H), 1.85-2.0 (m, 2H), 0.68-0.8 (m, 1H), 0.5-0.62 (m, 2H), 0.15-0.2 (m, 2H).

Workup

  1. additionwas added
  2. stirringstirred for 30 min at 100° C. in a sealed vial
  3. extractionextracted with EtOAc (3×25 mL)
  4. washThe combined organic layer was washed with water (40 mL), brine (40 mL)
  5. dry with materialdried (Na2SO4)
  6. customevaporated
  7. customThe reaction mixture was then purified by automated flash chromatography (SiO2, 20→70% EtOAc/hexanes)
  8. concentrationconcentrated under reduced pressure
  9. customThe obtained product was further purified twice by preparative HPLC (5→90% gradient of MeCN—H2O with 0.1% TFA)

Sources & evidence

ORD record
ord-caf34b7069ce47778cf692cf9983e5ac
Source dataset
uspto-grants-2012_10
Patent number
US08293925B2

Reaction notes

Loading…