Acetic Acid → HCID 86650654, compound

HRID 1969445Notes

Reaction equation

HRID 1969445 reaction equation
CC(O)=O.COC1CCC(OC)O1.[F:14][C:15]([F:20])([F:19])[C:16](O)=O.FC1C=CC=CC=1C1N(C2C=CC(OC(F)F)=CC=2)C(=O)C(NC2C=CC(OC(F)F)=CC=2)=C1.[F:55][CH:56]([F:78])[O:57][C:58]1[CH:63]=[CH:62][C:61]([N:64]2[CH:68]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=3[F:75])[CH2:67][C:66](=O)[C:65]2=[O:77])=[CH:60][CH:59]=1.[CH3:79][C:80]([NH2:92])([C:82]1[CH:87]=[CH:86][CH:85]=C(C(F)(F)F)[N:83]=1)[CH3:81]>C1COCC1.C1(C)C=CC=CC=1.O>[CH3:79][C:80]([NH:92][C:66]1[C:65](=[O:77])[N:64]([C:61]2[CH:62]=[CH:63][C:58]([O:57][CH:56]([F:78])[F:55])=[CH:59][CH:60]=2)[CH:68]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=2[F:75])[CH:67]=1)([C:82]1[CH:87]=[CH:86][CH:85]=[C:16]([C:15]([F:20])([F:19])[F:14])[N:83]=1)[CH3:81]

Participants

10

Reactant 6

HCID 176Acetic Acid2×HCID 6422Trifluoroacetic acidHCID 790982,5-DimethoxytetrahydrofuranHCID 573469902-[6-(Trifluoromethyl)pyridin-2-yl]propan-2-amineHCID 58129455HCID 58129455, compoundHCID 66909183HCID 66909183, compound2×

Product 1

HCID 86650654HCID 86650654, compoundYield 50%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
35 °C

Procedure

Add HOAc (2.1 mL, 36.5 mmol), 2,5-dimethoxytetrahydrofuran (1.8 mL, 13.7 mmol), water (10 mL), and trifluoroacetic acid (1.4 mL, 18.3 mmol) sequentially to a solution of (±)-5-(2-fluoro-phenyl)-1-(4-difluoromethoxy-phenyl)-3-(4-difluoromethoxy-phenylamino)-1,5-dihydro-pyrrol-2-one (4.35 g, 9.13 mmol) in THF (38 mL). Heat the reaction mixture to 35° C. for 22 hours. Observe significant formation of (±)-1-(4-difluoromethoxy-phenyl)-5-(2-fluoro-phenyl)-pyrrolidine-2,3-dione (LC-MS ESI m/z: 336 (M+H)+, Tr=3.38 min., method 1). Cool the reaction mixture to room temperature and add toluene (100 mL) in a single portion. Wash the mixture with water and then pH 7 buffer. Separate layers and observe that the aqueous layer is pH=7. Filter through sodium sulfate and add HOAc (1.05 mL, 18.3 mmol) and 1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamine (2.24 g, 11.0 mmol) to the toluene solution containing 1-(4-difluoromethoxy-phenyl)-5-(2-fluoro-phenyl)-pyrrolidine-2,3-dione. Heat to 55° C. for 18 hours. Concentrate the reaction mixture and purify by silica gel chromatography (5-25% EtOAc-hexane) to yield the title compound (2.36 g, 50%) as an oil, LC-MS ESI m/z: 522 (M+H)+, Tr=5.15 min., method 1.

Workup

  1. temperatureCool the reaction mixture to room temperature
  2. washWash the mixture with water
  3. filtrationFilter through sodium sulfate
  4. temperatureHeat to 55° C. for 18 hours
  5. concentrationConcentrate the reaction mixture
  6. custompurify by silica gel chromatography (5-25% EtOAc-hexane)

Sources & evidence

ORD record
ord-2b0cc04e69cd40829ddeff7026e35117
Source dataset
uspto-grants-2013_04
Patent number
US08426448B2

Reaction notes

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