(4-Fluorophenyl)(pyridin-3-yl)methanone → (3-(4-(1H-Pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(4-fluorophenyl)(pyridin-3-yl)methanol

HRID 928834

반응식

HRID 928834 반응식
[Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)=[O:40])=[CH:35][CH:34]=1>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)([C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)[OH:40])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1

참가 물질

5

반응물 3

HCID 762660(4-Fluorophenyl)(pyridin-3-yl)methanoneHCID 867155963-(4-(1H-Pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline2회HCID 178418339Butyllithium

생성물 1

HCID 74220680(3-(4-(1H-Pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(4-fluorophenyl)(pyridin-3-yl)methanol

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매2회

실험 절차

A solution of n-BuLi (2.5 M in hexanes, 0.095 mL, 0.238 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (105.5 mg, 0.246 mmol, Intermediate 16) in dry THF (2.5 mL) in a dry ice-acetone bath. After 1.5 minutes, a solution of commercially available (4-fluorophenyl)(pyridin-3-yl)methanone (58.7 mg, 0.292 mmol) in dry THF (0.2 mL) was added dropwise. The reaction mixture was stirred for 5 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath. After 10 minutes, the mixture was warmed to room temperature and the reaction was quenched with methanol and water. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 10-50% EtOAc-Hexanes followed by 0-10% MeOH-DCM) to provide the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.50-8.48 (m, 1H), 8.43 (dd, J=4.8, 1.6 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.67-7.64 (m, 2H), 7.55-7.52 (m, 2H), 7.50 (dd, J=8.8, 2.2 Hz, 1H), 7.33 (d, J=8.6 Hz, 2H), 7.26-7.20 (m, 3H), 7.03-6.96 (m, 2H), 6.42-6.40 (m, 1H), 4.28 (s, 2H), 4.07 (s, 3H); MS m/e 551.2 [M+H]+.

후처리

  1. customthe reaction flask was placed into an ice-water bath
  2. waitAfter 10 minutes
  3. customthe reaction was quenched with methanol and water
  4. customThe mixture was partitioned between water and ethyl acetate
  5. extractionThe separated aqueous phase was further extracted with ethyl acetate
  6. dry with materialThe organic phase was dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude product was purified by flash column chromatography (silica gel, 10-50% EtOAc-Hexanes followed by 0-10% MeOH-DCM)

출처 및 근거

ORD 기록
ord-1dff49239aa34ffc8b074030fa3bf088
출처 데이터셋
uspto-grants-2016_03
특허 번호
US09290476B2

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