Sodium hydride → Ethyl 6-chloro-2-((4-chloro-2-methoxyphenoxy)methyl)-4-phenylquinoline-3-carboxylate

HRID 538744

Reaction equation

HRID 538744 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([O:33][CH3:34])[CH:27]=1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][O:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][C:28]=1[O:33][CH3:34])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 280504-ChloroguaiacolHCID 14417743Ethyl 6-chloro-2-(chloromethyl)-4-phenyl-3-quinolinecarboxylate

Product 1

HCID 46189884Ethyl 6-chloro-2-((4-chloro-2-methoxyphenoxy)methyl)-4-phenylquinoline-3-carboxylate

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of ethyl 6-chloro-2-(chloromethyl)-4-phenylquinoline-3-carboxylate (718 mg, 2.0 mmol) in dry N,N-dimethylformamide (3.0 ml) at room temperature was added 4-chloro-2-methoxyphenol (0.301 ml, 2.2 mmol) followed by sodium hydride (88.0 mg of a 60% oil dispersion, 2.2 mol). The mixture was stirred at room temperature for 18 hours, then the reaction mixture was diluted with ethyl acetate and poured into a separatory funnel. The organic phase was washed with saturated sodium bicarbonate and water (2×), then brine. The organic phase was separated, and the solvent removed under reduced pressure to provide a viscous oil. Upon sitting at room temperature overnight a solid formed, to which a mixture of 10% ethyl acetate/hexanes was added, and the resulting solid filtered off. The solid was washed with 20% ethyl acetate/hexanes and dried under reduced pressure to provide ethyl 6-chloro-2-((4-chloro-2-methoxyphenoxy)methyl)-4-phenylquinoline-3-carboxylate then provided PT-011 (558 mg, 58%) as a light yellow powder. TLC Rf=0.38 in 30% ethyl cetate:hexanes on a glass backed silica gel plate. 1H NMR (CDCl3, 400 MHz) δ 8.08 (d, 1H, J=8.9 Hz); 7.69 (dd, 1H, J=8.9, 2.3 Hz); 7.58 (d, 1H, J=2.3 Hz); 7.48-7.52 (m, 3H); 7.36-7.30 (m, 2H); 6.95-6.92 (app d, 1H, J=8.6 Hz); 6.75 (s, 1H); 6.78-6.70 (m, 1H); 5.50 (s, 2H); 3.90 (q, 2H, J=7.0 Hz); 3.80 (s, 3H); 0.82 (t, 3H, J=7.0 Hz). LC MS (CI) shows M+H 482.

Workup

  1. additionpoured into a separatory funnel
  2. washThe organic phase was washed with saturated sodium bicarbonate and water (2×)
  3. customThe organic phase was separated
  4. customthe solvent removed under reduced pressure
  5. customto provide a viscous oil
  6. waitUpon sitting at room temperature overnight
  7. customa solid formed, to which
  8. additionwas added
  9. filtrationthe resulting solid filtered off
  10. washThe solid was washed with 20% ethyl acetate/hexanes
  11. customdried under reduced pressure

Sources & evidence

ORD record
ord-c343140874804466ac681a81266c5a40
Source dataset
uspto-grants-2014_10
Patent number
US08865739B2

Linked notes

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