Acetone cardice → (3-(4-(1H-Pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)bis(1,2-dimethyl-1H-imidazol-5-yl)methanol

HRID 926579

반응식

HRID 926579 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.[CH3:32][N:33]1[C:37]([C:38]([C:40]2[N:44]([CH3:45])[C:43]([CH3:46])=[N:42][CH:41]=2)=[O:39])=[CH:36][N:35]=[C:34]1[CH3:47].C(=O)=O.CC(C)=O>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:38]([C:37]3[N:33]([CH3:32])[C:34]([CH3:47])=[N:35][CH:36]=3)([C:40]3[N:44]([CH3:45])[C:43]([CH3:46])=[N:42][CH:41]=3)[OH:39])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1

참가 물질

6

반응물 4

HCID 18522661Acetone cardiceHCID 867155963-(4-(1H-Pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline2회HCID 118006325bis(1,2-dimethyl-1H-imidazol-5-yl)methanone2회HCID 178418339Butyllithium

생성물 1

HCID 118006127(3-(4-(1H-Pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)bis(1,2-dimethyl-1H-imidazol-5-yl)methanol

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매2회

실험 절차

n-BuLi (1.63 M in hexane, 0.124 mL, 0.203 mmol) was added dropwise under argon at ˜−70° C. to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (81.6 mg, 0.19 mmol, Intermediate 10) in THF (1.9 mL). After 2 additional minutes, an opaque milky suspension of bis(1,2-dimethyl-1H-imidazol-5-yl)methanone (42.4 mg, 0.194 mmol, Intermediate 11) in LaCl3-2LiCl (0.5 M in THF, 0.381 mL, 0.19 mmol) and THF (2.5 mL) was added rapidly dropwise over 1.5 minutes. The resulting yellow slurry was stirred in the dry ice/acetone bath for 10 minutes, and was then transferred to an ice bath and stirred overnight as the bath warmed to room temperature. The reaction was then quenched with 5 M aqueous NH4Cl (0.06 mL) and diluted with DCM (˜5 mL) and MeOH (˜2 mL), and the suspension was partitioned with 0.75 M aqueous tetrasodium EDTA (4 mL) and 9:1 DCM/MeOH (10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by C18 HPLC (20% to 100% CH3CN gradient with 0.1% TFA throughout) and the lyophilisate neutralized with 9:1 DCM/MeOH) and 2 M aqueous K2CO3. The organic layer was dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound as a colorless film. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.86 (d, J=2.53 Hz, 1H), 7.63-7.70 (m, 2H), 7.58 (d, J=8.59 Hz, 2H), 7.38 (d, J=8.59 Hz, 2H), 7.37 (m, 1H), 6.42 (t, J=1.99 Hz, 1H), 6.14 (s, 2H), 5.82 (br. s., 1H), 4.29 (s, 2H), 4.08 (s, 3H), 3.38 (s, 6H), 2.26 (s, 6H); MS m/e 568.3 [M+H]+.

후처리

  1. additionwas added rapidly dropwise over 1.5 minutes
  2. customwas then transferred to an ice bath
  3. customThe reaction was then quenched with 5 M aqueous NH4Cl (0.06 mL)
  4. additiondiluted with DCM (˜5 mL) and MeOH (˜2 mL)
  5. customthe suspension was partitioned with 0.75 M aqueous tetrasodium EDTA (4 mL) and 9:1 DCM/MeOH (10 mL)
  6. dry with materialThe organic layer was dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by C18 HPLC (20% to 100% CH3CN gradient with 0.1% TFA throughout)
  10. dry with materialThe organic layer was dried (Na2SO4)
  11. filtrationfiltered
  12. concentrationconcentrated to dryness

출처 및 근거

ORD 기록
ord-5fefa040ca1e450c90451996a6ca388f
출처 데이터셋
uspto-grants-2016_03
특허 번호
US09284308B2

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