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Preparation method of intermediate for leukemia treatment medicines

An intermediate and leukemia technology, which is applied in the field of preparation of intermediates for treating leukemia drugs, can solve the problems of high production cost and low yield, and achieve the effects of uniform particle size distribution, high yield, and good catalytic effect

Inactive Publication Date: 2019-01-04
邹永旗
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to overcome the defects of low yield and high production cost in the prior art, and provide a method for preparing an intermediate for treating leukemia. Reaction of 6-methoxy 7-fluoro-quinoline-3-carbonitrile and 2,4-dichloro-5-methoxyaniline to produce intermediate 4-(2,4-dichloro-5- Methoxyaniline)-7-fluoro-6-methoxyquinoline-3-carbonitrile, the yield is as high as 90.2%, and the process is green and environmentally friendly; the acidic ionic liquid loaded on silica gel can be removed from the reaction system by simple filtration, and can be recycled

Method used

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  • Preparation method of intermediate for leukemia treatment medicines
  • Preparation method of intermediate for leukemia treatment medicines
  • Preparation method of intermediate for leukemia treatment medicines

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Preparation of silica-supported acidic ionic liquids:

[0034] 1) Disperse 5.0g of nano-silica in 100ml of chloroform and stir evenly, then add 2.74g of N-[3-(triethoxysilyl)propyl]-4,5-dihydroimidazole for reflux reaction for more than 12h, and cool down to Filter at room temperature, rinse with ammonia water and acetone in turn, and dry to obtain dihydroimidazole-modified silica gel;

[0035] 2) Put 5.0 g of dihydroimidazole-modified silica gel and 1.36 g of 1,4-butane sultone in 200 ml of acetone to react at room temperature for 24 hours, then add 1.14 g of trifluoroacetic acid or 1.50 g of trifluoromethanesulfonic acid or p-toluene 1.72 g of sulfonic acid was refluxed for 2-3 days, cooled to room temperature, filtered, washed with n-heptane and dried to obtain an acidic ionic liquid supported on silica gel.

[0036] The silica-supported acidic ionic liquids prepared from trifluoroacetic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid are respectively...

Embodiment 2

[0038] With the prepared IL / TFA@SiO 2 、IL / TfO@SiO 2 and IL / Ts@SiO 2 As a catalyst for catalytic performance evaluation:

[0039] Add 4-chloro-6-methoxy 7-fluoro-quinoline-3-carbonitrile (4.72g, 20mmol), 2,4-dichloro-5-methoxyaniline (4.61g, 24mmol) into the reaction flask ), stirred and dissolved in 80ml dimethyl sulfoxide, then added catalyst (0.50g, ~10.6wt%) to stir and disperse evenly, heated to 90-100°C for reaction, HPLC detection, 4-chloro-6-methanol in the reaction liquid Stop the reaction after the concentration of oxy-7-fluoro-quinoline-3-carbonitrile no longer drops, cool down to room temperature, filter and remove the acidic ionic liquid loaded on silica gel to obtain the filtrate; add the filtrate dropwise to 300ml saturated aqueous sodium bicarbonate solution at room temperature Crystallize, stir for 20-30min, filter and dry to constant weight to obtain 4-(2,4-dichloro-5-methoxyphenylamine)-7-fluoro-6-methoxyquinoline-3-carbonitrile Solid; 4-(2,4-dichloro-5-m...

Embodiment 3

[0045] After determining the acidic ionic liquid IL / TFA@SiO supported on silica gel 2 After being used as a catalyst, the molar ratio of the solvent and its 4-chloro-6-methoxyl 7-fluoro-quinoline-3-carbonitrile to 2,4-dichloro-5-methoxyaniline in the present invention, the amount of catalyst Optimized, the method is as follows:

[0046] Add 4-chloro-6-methoxy 7-fluoro-quinoline-3-carbonitrile (4.72g, 20mmol), 2,4-dichloro-5-methoxyaniline (20-30mmol) into the reaction flask , stir and dissolve in 80ml of solvent, then add catalyst (50mg-1.41g, 1.0wt%~30wt%), stir and disperse evenly, heat up to 90-100°C (solvent reflux reaction with boiling point lower than 90°C) for reaction, HPLC detection, Stop the reaction after the concentration of 4-chloro-6-methoxy 7-fluoro-quinoline-3-carbonitrile in the reaction solution no longer drops, cool down to room temperature, filter and remove the acidic ionic liquid loaded on silica gel to obtain the filtrate; Add dropwise to 300ml saturat...

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Abstract

The invention belongs to the technical field of chemical medicines, and specifically relates to a preparation method of an intermediate for leukemia treatment medicines. The method comprises the stepsof supporting N-[3-(triethoxysilyl)propyl]-4,5-dihydroimidazole onto silica, and then reacting with 1,4-butyl sultone and trifluoroacetic acid to generate a silica gel supported acidic ionic liquid;and catalyzing the reaction of 4-chloro-6-methoxy 7-fluoro-quinoline-3-carbonitrile and 2,4-dichloro-5-methoxyaniline by using the acidic ionic liquid as an acidic catalyst to generate an intermediate 4-(2,4-dichloro-5-methoxyphenylamine)-7-fluoro-6-methoxyquinoline-3-nitrile for leukemia treatment medicines. The yield is up to 90.2%, and the process is environment-friendly; and the silica gel supported acidic ionic liquid can be removed from the reaction system by simple filtration, and can catalyze the aromatic nucleophilic substitution reaction of various substrates.

Description

technical field [0001] The invention belongs to the technical field of chemical medicines, and in particular relates to a preparation method of intermediates for medicines for treating leukemia. Background technique [0002] Bosutinib was developed by Wyeth Pharmaceuticals of the United States and was approved by the European Union as an "orphan drug" for the treatment of chronic myelogenous leukemia (CML) in September 2010. On September 4, 2012, the drug was approved by the U.S. Food and Drug Administration (FDA) under the trade name Bosulif. On March 27, 2013, the European Food and Drug Administration (EMA) approved the listing, and on September 26, 2014, the Japanese PMDA approved the listing. [0003] The skeleton structure of bosutinib is an aromatic ether, which consists of two structural fragments, a quinoline amine ring and a piperazine ring. The retrosynthetic analysis is shown in Scheme 1: [0004] [0005] 4-(2,4-dichloro-5-methoxyaniline)-7-fluoro-6-methoxyq...

Claims

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Application Information

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IPC IPC(8): C07D215/54B01J31/02
CPCC07D215/54B01J31/0295
Inventor 邹永旗商立华
Owner 邹永旗
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