Potassium Carbonate → (2S)-tert-butyl 3-methyl-2-(4-(5-(2'-methyl-2-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)phenethylamino)butanoate

HRID 572595

반응식

HRID 572595 반응식
[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25](O)[CH3:26])=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][C:9]=1[C:28]([F:31])([F:30])[F:29].CCN(C(C)C)C(C)C.S(Cl)(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:52][C@@H:53]([CH:61]([CH3:63])[CH3:62])[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55]>C(Cl)Cl.C([O-])(O)=O.[Na+].O>[CH3:62][CH:61]([CH3:63])[C@H:53]([NH:52][CH2:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])=[C:9]([C:28]([F:31])([F:29])[F:30])[CH:10]=3)[O:18][N:17]=2)=[CH:24][CH:23]=1)[C:54]([O:56][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:55]

참가 물질

9

반응물 5

HCID 11430Potassium CarbonateHCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 114626tert-Butyl L-valinateHCID 66652855(4-(5-(2'-Methyl-2-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol

생성물 1

HCID 66652979(2S)-tert-butyl 3-methyl-2-(4-(5-(2'-methyl-2-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)phenethylamino)butanoate수율 74.2%

시약·촉매·용매 3

HCID 962Water용매HCID 6344Dichloromethane용매3회HCID 516892Sodium Bicarbonate용매

반응 조건

온도
0 °C

실험 절차

To (4-(5-(2′-methyl-2-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol (84 mg; 0.2 mmol) in DCM (2 mL) was added DIEA (71 μL; 0.4 mmol) and mesyl chloride (17 μL; 0.22 mmol), at 0° C. The resulting mixture was stirred at 0° C. for 10 minutes, allowed to warm to RT and stirred for 2 hours. The mixture was diluted with DCM (20 mL) and saturated aqueous NaHCO3 solution was added. The aqueous layer was extracted with DCM (3×20 mL), the combined organic fractions were dried (MgSO4), filtered and the solvent removed in vacuo. The crude residue was all used in the next step without further purification. It was dissolved in dioxan (2 mL). Potassium carbonate (165 mg, 1.2 mmol) and (S)-tert-butyl 2-amino-3-methylbutanoate (104 mg; 0.60 mmol) were added. The mixture was heated at 130° C. for 72 hours, diluted with DCM (5 mL) and water (5 mL). The aqueous layer was extracted with DCM (3×20 mL), the combined organic fractions were dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by flash chromatography eluting with petrol containing increasing amounts of EtOAc to give the title compound as a colourless gum (86 mg; 72%). 1H NMR (CDCl3, 400 MHz) δ 8.63 (1H, s), 8.39 (1H, dd, J=8.0, 1.7 Hz), 8.12 (2H, d, J=8.1 Hz), 7.47 (1H, d, J=8.0 Hz), 7.43-7.21 (5H, m), 7.16 (1H, d, J=7.6 Hz), 2.99-2.68 (5H, m), 2.07 (3H, s), 1.94-1.79 (1H, m), 1.46 (9H, s), 0.94 (6H, dd, J=6.8, 3.7 Hz). LC/MS (Method B): 580 (M+H)+. HPLC (Method D) Rt 3.7 min (Purity: 94.9%).

후처리

  1. customat 0° C
  2. temperatureto warm to RT
  3. stirringstirred for 2 hours
  4. additionwas added
  5. extractionThe aqueous layer was extracted with DCM (3×20 mL)
  6. dry with materialthe combined organic fractions were dried (MgSO4)
  7. filtrationfiltered
  8. customthe solvent removed in vacuo
  9. customall used in the next step without further purification
  10. dissolutionIt was dissolved in dioxan (2 mL)
  11. temperatureThe mixture was heated at 130° C. for 72 hours
  12. extractionThe aqueous layer was extracted with DCM (3×20 mL)
  13. dry with materialthe combined organic fractions were dried (MgSO4)
  14. filtrationfiltered
  15. customthe solvent removed in vacuo
  16. customThe residue was purified by flash chromatography
  17. washeluting with petrol containing
  18. temperatureincreasing amounts of EtOAc

출처 및 근거

ORD 기록
ord-64cd1781f11349748ad48173f762f3e0
출처 데이터셋
uspto-grants-2015_05
특허 번호
US09029405B2

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