(4-Fluorophenyl)(1-methyl-1H-imidazol-5-yl)methanone → (3-(4-(1H-Pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(4-fluorophenyl)(1-methyl-1H-imidazol-5-yl)methanol

HRID 926649Notes

Reaction equation

HRID 926649 reaction equation
[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[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=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[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=3)[OH:40])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1

Participants

5

Reactant 3

HCID 71711558(4-Fluorophenyl)(1-methyl-1H-imidazol-5-yl)methanone2×HCID 867155963-(4-(1H-Pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline2×HCID 178418339Butyllithium

Product 1

HCID 74220746(3-(4-(1H-Pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(4-fluorophenyl)(1-methyl-1H-imidazol-5-yl)methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of n-BuLi (2.5 M in hexanes, 0.07 mL, 0.175 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (75.8 mg, 0.177 mmol, Intermediate 10) in dry THF (3 mL) in a dry ice-acetone bath. After 1 minute, a solution of (4-fluorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (37.8 mg, 0.185 mmol, Intermediate 89: step b) in dry THF (0.6 mL) was added dropwise. The reaction mixture was stirred for 5 minutes in a dry ice-acetone bath, then 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, 0-50% EtOAc-Hexanes) to provide the title compound as a clear foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (d, J=2.1 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.57-7.50 (m, 3H), 7.35 (d, J=8.6 Hz, 2H), 7.34-7.29 (m, 2H), 7.25 (s, 1H), 7.04-6.96 (m, 2H), 6.45-6.40 (m, 1H), 6.30 (s, 1H), 4.30 (s, 2H), 4.08 (s, 3H), 3.34 (s, 3H); MS m/e 554.1 [M+H]+.

Workup

  1. customthe reaction was quenched with methanol and water
  2. customThe mixture was partitioned between water and ethyl acetate
  3. extractionThe separated aqueous phase was further extracted with ethyl acetate
  4. dry with materialThe organic phase was dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude product was purified by flash column chromatography (silica gel, 0-50% EtOAc-Hexanes)

Sources & evidence

ORD record
ord-c3341a7ad3b64a71accec900e61d3088
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

Loading…