Potassium Carbonate → 2-[2-(4-[4-(1-benzofuran-5-yl)phenyl]-3-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione

HRID 525149

Reaktionsgleichung

Reaktionsgleichung von HRID 525149
[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][CH2:41][N:42]1[C:46](=[O:47])[C:45]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:44]2[C:43]1=[O:52]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:17](=[O:32])[N:18]([CH2:40][CH2:41][N:42]5[C:43](=[O:52])[C:44]6[C:45](=[CH:48][CH:49]=[CH:50][CH:51]=6)[C:46]5=[O:47])[N:19]=[C:20]4[CH2:21][C@@H:22]4[CH2:26][CH2:25][N:24]([C:27]([CH:29]5[CH2:30][CH2:31]5)=[O:28])[CH2:23]4)=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1

Komponenten

5

Edukt 3

HCID 11430Potassium CarbonateHCID 234274N-(2-Chloroethyl)phthalimideHCID 67376285Gsk2194069

Produkt 1

HCID 673759832-[2-(4-[4-(1-benzofuran-5-yl)phenyl]-3-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dioneAusbeute 33,8 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (300 mg, 0.699 mmol) in N,N-dimethylformamide (3 mL) in a 5 mL microwaveable vial was added potassium carbonate (300 mg, 2.1 mmol, 3 eq) and N-(2-chloroethyl)phthalimide (300 mg, 1.43 mmol, 2 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 90° C. Analysis by LC/MS displayed the reaction had progressed to 20% completion. The reaction was irradiated in the microwave at 185° C. for 60 min. Analysis by LC/MS displayed the reaction was complete. The reaction mixture was poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extracts were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 30-60% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the intermediate compound (142 mg, 33%). MS(ES)+ m/e 602.0 [M+H]+.

Aufarbeitung

  1. customThe vial was capped
  2. custompurged with nitrogen gas
  3. customThe reaction was irradiated in the microwave at 185° C. for 60 min
  4. additionThe reaction mixture was poured into a mixture of dichloromethane and water
  5. customThe organic layer was separated
  6. washThe aqueous layer was washed with dichloromethane
  7. washwashed 3× with a dilute brine solution
  8. customThe organic layer was separated
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customThe crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 30-60% acetonitrile w/0.1% TFA/water w/0.1% TFA)
  13. additionThe product fractions were neutralized with the addition of saturated aq sodium bicarbonate
  14. extractionextracted with dichloromethane
  15. dry with materialThe organic layer was dried over sodium sulfate
  16. filtrationfiltered
  17. concentrationconcentrated in vacuo

Quellen und Nachweise

ORD-Eintrag
ord-3b5e5dd809ef4289b9487d6e4f2c1224
Quelldatensatz
uspto-grants-2016_05
Patentnummer
US09340529B2

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