3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline → (3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloroquinolin-6-yl)(2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol

HRID 926645

반응식

HRID 926645 반응식
[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Li]CCCC.[CH3:31][C:32]1[C:37]([C:38]([C:40]2[N:44]([CH3:45])[N:43]=[N:42][CH:41]=2)=[O:39])=[CH:36][CH:35]=[C:34]([CH3:46])[N:33]=1>C1COCC1>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:38]([C:37]3[C:32]([CH3:31])=[N:33][C:34]([CH3:46])=[CH:35][CH:36]=3)([C:40]3[N:44]([CH3:45])[N:43]=[N:42][CH:41]=3)[OH:39])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1

참가 물질

5

반응물 3

HCID 867155943-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline2회HCID 86715642(2,6-Dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone2회HCID 178418339Butyllithium

생성물 1

HCID 118006215(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloroquinolin-6-yl)(2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매2회

반응 조건

온도
-45 °C

실험 절차

6-Bromo-2,4-dichloro-3-phenylquinoline (2.00 g, 4.62 mmol, Intermediate 3: step c) was dissolved in THF (250 mL) in a dry round bottom flask under an N2 atmosphere, then cooled to −45° C. in a dry ice acetone bath. n-BuLi (1.6 M in hexanes, 3.18 mL, 5.08 mmol) was then added dropwise via syringe over approximately 2 minutes and the resulting mixture was allowed to stir at that temperature for an additional 2 minutes. (2,6-Dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (1.10 g, 5.08 mmol, Intermediate 19: step b) in THF (15 mL) was then added to the reaction vessel via cannula over approximately 5 minutes. The reaction solution was stirred at −78° C. for approximately 5 minutes, then the dry ice bath was removed and replaced with an ice water bath and stirred at 0° C. for approximately 1 hour. The reaction was then quenched with a saturated, aqueous NH4Cl solution, then transferred to a separatory funnel with EtOAc. The organic phase was separated, then the aqueous layer was back extracted with EtOAc and the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/(10% of a 2 M NH3 MeOH in DCM)) then further purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. For C30H25Cl2N7O, 570.5. m/z found, 570.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.27-8.22 (m, 1H), 8.07-8.02 (m, 1H), 7.84-7.77 (m, 1H), 7.73-7.67 (m, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.18-7.13 (m, 2H), 7.04-6.98 (m, 3H), 6.86 (d, J=8.2 Hz, 1H), 6.76 (d, J=8.1 Hz, 1H), 5.91 (d, J=1.9 Hz, 1H), 4.51 (s, 2H), 3.94 (s, 3H), 2.40 (s, 3H), 2.32 (s, 3H).

후처리

  1. stirringThe reaction solution was stirred at −78° C. for approximately 5 minutes
  2. customthe dry ice bath was removed
  3. customreplaced with an ice water bath
  4. stirringstirred at 0° C. for approximately 1 hour
  5. customThe reaction was then quenched with a saturated, aqueous NH4Cl solution
  6. customtransferred to a separatory funnel with EtOAc
  7. customThe organic phase was separated
  8. extractionthe aqueous layer was back extracted with EtOAc
  9. dry with materialthe combined organic phases were dried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe crude product was purified by flash column chromatography (silica gel, 0-10% DCM/(10% of a 2 M NH3 MeOH in DCM))
  13. customthen further purified via reverse phase chromatography

출처 및 근거

ORD 기록
ord-f23492744cbf4989bdcb85dae24f8f0f
출처 데이터셋
uspto-grants-2016_03
특허 번호
US09284308B2

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