6-bromo-4-chloro-N,N-diethyl-3-phenoxyquinolin-2-amine → (4-Chloro-2-(diethylamino)-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol

HRID 520849Notes

Reaction equation

HRID 520849 reaction equation
[Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[C:10]2[Cl:29].[CH3:30][N:31]1[C:35]([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[O:37])=[CH:34][N:33]=[CH:32]1>C1COCC1>[Cl:29][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:36]([C:35]3[N:31]([CH3:30])[CH:32]=[N:33][CH:34]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[OH:37])[CH:8]=2)[N:13]=[C:12]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1

Participants

5

Reactant 3

HCID 867154626-bromo-4-chloro-N,N-diethyl-3-phenoxyquinolin-2-amine2×HCID 86715605(1-Methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanone2×HCID 178418339Butyllithium

Product 1

HCID 118005465(4-Chloro-2-(diethylamino)-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of n-BuLi (2.5 M in hexanes, 0.49 mL, 1.2 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-N,N-diethyl-3-phenoxyquinolin-2-amine (0.500 g, 1.23 mmol, Intermediate 5: step d) in dry THF (20.5 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanone (230.9 mg, 1.233 mmol, Intermediate 6: step b) in dry THF (1.5 mL) was added dropwise. The reaction was stirred for 2 minutes, then moved into an ice bath for 7 minutes, and finally allowed to warm to ambient temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water/brine and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 100% EtOAc), followed by reverse phase chromatography (ACN/H20+0.05% TFA). Product fractions were basified with saturated aqueous sodium bicarbonate and extracted with DCM, before being dried (Na2SO4), filtered, and concentrated to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.54 (d, J=3.9 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.84 (dd, J=9.5, 7.7 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.32 (dd, J=14.1, 5.4 Hz, 3H), 7.05 (t, J=7.3 Hz, 1H), 6.93 (s, 1H), 6.79 (d, J=7.8 Hz, 2H), 6.22 (d, J=1.1 Hz, 1H), 3.51 (q, J=14.6, 7.3 Hz, 4H), 3.25 (s, 3H), 1.05 (t, J=7.0 Hz, 6H); MS m/e 514.3 [M+H]+.

Workup

  1. waitmoved into an ice bath for 7 minutes
  2. customThe reaction was quenched with saturated aqueous ammonium chloride
  3. customThe mixture was partitioned between water/brine and dichloromethane
  4. extractionThe separated aqueous phase was further extracted with dichloromethane
  5. dry with materialThe organic phase was dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product was purified by flash column chromatography (silica gel, 100% EtOAc)
  9. extractionextracted with DCM
  10. dry with materialbefore being dried (Na2SO4)
  11. filtrationfiltered
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-69893b7cba024678b9d3e4d2876e4dcb
Source dataset
uspto-grants-2016_05
Patent number
US09328095B2

Reaction notes

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