Methyl chloroacetate → methyl (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)acetate

HRID 525140

반응식

HRID 525140 반응식
[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][C:41]([O:43][CH3:44])=[O:42]>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][C:41]([O:43][CH3:44])=[O:42])[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

참가 물질

5

반응물 3

HCID 7295Methyl chloroacetateHCID 11430Potassium CarbonateHCID 67376285Gsk2194069

생성물 1

HCID 68261353methyl (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)acetate수율 57.7%

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

반응 조건

온도
80 °C

실험 절차

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 (55 mg, 0.128 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (60 mg, 0.434 mmol, 3.3 eq) and methyl chloroacetate (25 mg, 0.227 mmol, 1.7 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction had gone to completion. The reaction mixture was cooled to room temperature and 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; 20-55% 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 (37 mg, 57%). MS(ES)+ m/e 501.1 [M+H]+.

후처리

  1. customThe vial was capped
  2. custompurged with nitrogen gas
  3. temperatureThe reaction mixture was cooled to room temperature
  4. additionpoured 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; 20-55% 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

출처 및 근거

ORD 기록
ord-a2b3d73dcb7f43e9ae471e64b3c97ef3
출처 데이터셋
uspto-grants-2016_05
특허 번호
US09340529B2

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