Dichloromethane → 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2-(1-methylethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

HRID 525138

反応式

HRID 525138 の反応式
[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+].I[CH:40]([CH3:42])[CH3:41].ClCCl>CN(C)C=O.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:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:30][CH2:31]6)=[O:28])[CH2:23]5)=[N:19][N:18]([CH:40]([CH3:42])[CH3:41])[C:17]4=[O:32])=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1

参加物

7

反応物 4

HCID 6344DichloromethaneHCID 6362Isopropyl iodideHCID 11430Potassium CarbonateHCID 67376285Gsk2194069

生成物 1

HCID 682614704-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2-(1-methylethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one収率 27.3%

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 6228Dimethylformamide溶媒

反応条件

温度
80 °C

実験手順

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 (60 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (60 mg, 0.434 mmol, 3.1 eq) and 2-iodopropane (34 mg, 0.200 mmol, 1.4 eq). The vial was capped and purged with nitrogen gas, and the reaction was stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction had progressed only 15%. To the reaction mixture was added another equivalent of 2-iodopropane and the solution was irradiated in the microwave at 160° C. for 30 min. Analysis by LC/MS displayed the reaction had progressed to 35% completion. The reaction mixture was subjected to several iterations of microwave conditions, increasing the reaction temperature and reaction time, until the final conditions of 180° C. for 3 h was reached. It was determined via analysis by LC/MS that the reaction had proceeded to 90% completion. 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 extractions 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; 25-65% 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 title compound (18 mg, 27%). MS(ES)+ m/e 471.3 [M+H]+.

後処理

  1. customThe vial was capped
  2. custompurged with nitrogen gas
  3. additionTo the reaction mixture was added another equivalent of 2-iodopropane
  4. customthe solution was irradiated in the microwave at 160° C. for 30 min
  5. temperatureincreasing
  6. customthe reaction temperature and reaction time
  7. waituntil the final conditions of 180° C. for 3 h was reached
  8. customThe organic layer was separated
  9. washThe aqueous layer was washed with dichloromethane
  10. extractionThe organic extractions
  11. washwashed 3× with a dilute brine solution
  12. customThe organic layer was separated
  13. dry with materialdried over sodium sulfate
  14. filtrationfiltered
  15. concentrationconcentrated in vacuo
  16. customThe crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 25-65% acetonitrile w/0.1% TFA/water w/0.1% TFA)
  17. additionThe product fractions were neutralized with the addition of saturated aq sodium bicarbonate
  18. extractionextracted with dichloromethane
  19. dry with materialThe organic layer was dried over sodium sulfate
  20. filtrationfiltered
  21. concentrationconcentrated in vacuo

出典と根拠

ORDレコード
ord-c5c4df1f72304221ade0a2dd3d38f947
出典データセット
uspto-grants-2016_05
特許番号
US09340529B2

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