1-[2-(2-Hydroxyethoxy)ethyl]piperazine → 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{2-[2-(1-piperazinyl)-ethoxy]ethoxy)-3-quinolinecarbonitrile

HRID 1837354Notes

Reaction equation

HRID 1837354 reaction equation
[Na].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:26]#[N:27].[N:28]1([CH2:34][CH2:35][O:36][CH2:37][CH2:38][OH:39])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:26]#[N:27]

Participants

4

Reactant 3

HCID 1394361-[2-(2-Hydroxyethoxy)ethyl]piperazineHCID 5360545SodiumHCID 114861534-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile

Product 1

HCID 104601024-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{2-[2-(1-piperazinyl)-ethoxy]ethoxy)-3-quinolinecarbonitrile

Conditions

Temperature
120 °C

Procedure

A mixture of sodium (50 mg, 2.2 mmol) in 1 mL of 2-[2-(1-piperazinyl)ethoxy]ethanol is heated at 120° C. for 2 hours. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (150 mg, 0.38 mmol) is added and the reaction mixture is heated at 140-145° C. for 2 hours, then cooled to room temperature. The reaction mixture is partitioned between saturated sodium bicarbonate and ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 3% methanol in dichloromethane to 1% ammonium hydroxide and 30% methanol in dichloromethane followed by recrystallization from acetone and hexane to provide 124 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{2-[2-(1-piperazinyl)-ethoxy]ethoxy)-3-quinolinecarbonitrile, mp 88-90° C.

Workup

  1. temperaturethe reaction mixture is heated at 140-145° C. for 2 hours
  2. temperaturecooled to room temperature
  3. customThe reaction mixture is partitioned between saturated sodium bicarbonate and ethyl acetate
  4. dry with materialThe organic layer is dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue is purified by flash column chromatography
  8. washeluting with a gradient of 3% methanol in dichloromethane to 1% ammonium hydroxide and 30% methanol in dichloromethane
  9. customfollowed by recrystallization from acetone and hexane

Sources & evidence

ORD record
ord-528d8a2078a94c878a1a524dbed2cb81
Source dataset
uspto-grants-2004_08
Patent number
US06780996B2

Reaction notes

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