Acetic Acid → HCID 86650655, compound

HRID 1969446Notes

Reaction equation

HRID 1969446 reaction equation
[C:1]([OH:4])(=O)[CH3:2].C[O:6][CH:7]1[CH2:11][CH2:10][CH:9](OC)O1.[F:14][C:15]([F:20])([F:19])C(O)=O.[F:21][C:22]([F:59])([F:58])[C:23]1[CH:24]=[C:25](C2N(C3C=CC(OC(F)(F)F)=CC=3)C(=O)C(NC3C=CC(OC(F)(F)F)=CC=3)=C2)[CH:26]=[CH:27][CH:28]=1.FC(F)(F)OC1C=[CH:67][C:66]([N:69]2C(C3C=CC=C(C(F)(F)F)C=3)CC(=O)C2=O)=[CH:65][CH:64]=1.C(OC(C)C)(=O)C.[CH3:95][C:96]([NH2:108])([C:98]1[CH:103]=[CH:102][CH:101]=[C:100]([C:104]([F:107])([F:106])[F:105])[N:99]=1)[CH3:97].C(=O)(O)[O-].[Na+]>C1COCC1.O.C1(C)C=CC=CC=1>[CH3:97][C:96]([NH:108][C:11]1[C:7](=[O:6])[N:69]([C:66]2[CH:67]=[CH:2][C:1]([O:4][C:15]([F:20])([F:19])[F:14])=[CH:64][CH:65]=2)[CH:9]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:58])[F:59])[CH:24]=2)[CH:10]=1)([C:98]1[CH:103]=[CH:102][CH:101]=[C:100]([C:104]([F:106])([F:107])[F:105])[N:99]=1)[CH3:95]

Participants

12

Reactant 8

HCID 176Acetic Acid2×HCID 6422Trifluoroacetic acidHCID 7915Isopropyl AcetateHCID 790982,5-DimethoxytetrahydrofuranHCID 516892Sodium BicarbonateHCID 573469902-[6-(Trifluoromethyl)pyridin-2-yl]propan-2-amineHCID 57951133HCID 57951133, compoundHCID 86650656HCID 86650656, compound2×

Product 1

HCID 86650655HCID 86650655, compoundYield 63%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
35 °C

Procedure

Add acetic acid (3.6 mL, 63.2 mmol), 2,5-dimethoxytetrahydrofuran (3.1 mL, 23.7 mmol), and trifluoroacetic acid (2.4 mL, 31.6 mmol) sequentially to a solution of (±) 5-(3-trifluoromethyl-phenyl)-1-(4-trifluoromethoxy-phenyl)-3-(4-trifluoromethoxy-phenylamino)-1,5-dihydro-pyrrol-2-one (8.89 g, 15.8 mmol) in THF (12 mL) and water (3 mL). Heat the reaction mixture to 35° C. for 72 hours. Observe significant formation of (±)-1-(4-trifluoromethoxy-phenyl)-5-(3-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione (LC-MS ESI m/z: 404 (M+H)+, Tr=2.61 min., method 2). Cool the reaction mixture to room temperature and add toluene (20 mL) and isopropyl acetate (10 mL). Wash the mixture with saturated sodium bicarbonate solution and then brine. Filter through sodium sulfate. Add acetic acid (7.6 mL, 126 mmol) and 1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamine (4.89 g, 24.0 mmol) to the solution containing (±)-1-(4-trifluoromethoxy-phenyl)-5-(3-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione. Heat to 55° C. for 1.5 hours. Pour reaction mixture into saturated sodium bicarbonate solution and separate phases. Dry over sodium sulfate, filter and concentrated under reduced pressure. Purify by silica gel chromatography (10-50% EtOAc-hexane) to yield the title compound (5.89 g, 63%) as an oil, LC-MS ESI m/z: 588 (M−H)−, Tr=3.55. min., method 2.

Workup

  1. temperatureCool the reaction mixture to room temperature
  2. washWash the mixture with saturated sodium bicarbonate solution
  3. filtrationFilter through sodium sulfate
  4. temperatureHeat to 55° C. for 1.5 hours
  5. additionPour
  6. customseparate phases
  7. dry with materialDry over sodium sulfate
  8. filtrationfilter
  9. concentrationconcentrated under reduced pressure
  10. customPurify by silica gel chromatography (10-50% EtOAc-hexane)

Sources & evidence

ORD record
ord-43c20135a39e4f3294fc5a8505e544e6
Source dataset
uspto-grants-2013_04
Patent number
US08426448B2

Reaction notes

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