Acetic Acid → HCID 66909235, compound

HRID 1969444Notes

Reaction equation

HRID 1969444 reaction equation
C(O)(=O)C.COC1CCC(OC)O1.FC(F)(F)C(O)=O.[F:21][C:22]([F:54])([F:53])[O:23][C:24]1[CH:25]=[C:26]([CH:30]2[N:34]([C:35]3[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=3)[C:33](=[O:43])[C:32](NC3C=CC(C#N)=CC=3)=[CH:31]2)[CH:27]=[CH:28][CH:29]=1.O=C1C(=O)[CH2:59][CH:58]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64](OC(F)(F)F)[CH:63]=2)[N:57]1C1C=CC(C#N)=CC=1.C[C@@H](N)C1C=CC=CC=1>C1(C)C=CC=CC=1.C1COCC1.O>[O:43]=[C:33]1[C:32]([NH:57][C@@H:58]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH3:59])=[CH:31][C@@H:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:22]([F:21])([F:54])[F:53])[CH:25]=2)[N:34]1[C:35]1[CH:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=1

Participants

10

Reactant 6

HCID 176Acetic AcidHCID 6422Trifluoroacetic acidHCID 790982,5-DimethoxytetrahydrofuranHCID 6431891-Phenethylamine, (+)-HCID 66909199HCID 66909199, compoundHCID 66909220HCID 66909220, compound

Product 1

HCID 66909235HCID 66909235, compoundYield 26%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
40 °C

Procedure

Add acetic acid (6.32 mL, 110 mmol), 2,5-dimethoxytetrahydrofuran (10.7 mL, 82.8 mmol), water (25 mL), and trifluoroacetic acid (4.2 mL, 55.2 mmol) sequentially to a mixture of (±)-4-[5-(3-trifluoromethoxy-phenyl)-2-oxo-3-(4-cyano-phenylamino)-2,5-dihydro-pyrrol-1-yl]-benzonitrile (12.7 g, 27.6 mmol) and THF (83 mL). Heat the reaction mixture to 40° C. for 18 hours. Observe significant formation of (±)-4-[2,3-dioxo-5-(3-trifluoromethoxy-phenyl)-pyrrolidin-1-yl]-benzonitrile (LC-MS ESI m/z: 361 (M+H)+, Tr=2.34 min., method 2). Cool the reaction mixture to room temperature and add toluene (150 mL) in a single portion. Wash the mixture with water and then with brine. Dry over sodium sulfate, filter and add (R)-(+)-α-methyl benzylamine (7.1 mL, 55.2 mmol). Stir the solution at 45° C. for 1.75 hours. Concentrate the reaction mixture and purify by silica gel chromatography (15% EtOAc-hexane) to yield 4-[(S)-2-oxo-3-((R)-1-phenyl-ethylamino)-5-(3-trifluoromethoxy-phenyl)-2,5-dihydro-pyrrol-1-yl]-benzonitrile (3.34 g, 26%) as a red oil, LC-MS ESI m/z: 464 (M+H)+, Tr=3.09 min., method 2 and 4-[(R)-2-oxo-3-((R)-1-phenyl-ethylamino)-5-(3-trifluoromethoxy-phenyl)-2,5-dihydro-pyrrol-1-yl]-benzonitrile (4.05 g, 32%) as a foam, LC-MS ESI m/z: 464 (M+H)+, Tr=3.04 min., method 2.

Workup

  1. temperatureCool the reaction mixture to room temperature
  2. washWash the mixture with water
  3. dry with materialDry over sodium sulfate
  4. filtrationfilter
  5. concentrationConcentrate the reaction mixture
  6. custompurify by silica gel chromatography (15% EtOAc-hexane)

Sources & evidence

ORD record
ord-3cf73513a272479984529878ac5c12cc
Source dataset
uspto-grants-2013_04
Patent number
US08426448B2

Reaction notes

Loading…