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The preparation method of fluxotinib

A technology of fluorophenol and fluorophenyl, which is applied in the field of preparation of the compound fludrotinib, can solve the problems of low yield, long reaction time, and poor product purity, and achieve high yield, simple preparation process and good purity Effect

Active Publication Date: 2021-02-12
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Although the reaction steps of this route are relatively short, in step one reaction, the reaction time is too long, the yield is extremely low (50%), and a preparative column is required for purification, which cannot be scaled up industrially
In step 2, because palladium catalyst consumption is very large (40%), yield is low (60%), product purity is poor (85.3%) and can't carry out industrial scale-up

Method used

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  • The preparation method of fluxotinib
  • The preparation method of fluxotinib
  • The preparation method of fluxotinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0062] (1) Preparation of Compound III

[0063]

[0064] 4-Bromo-3-fluorophenol (4.82g, 25.24mmol), bis-pinacol borate (8.25g, 32.47mmol), potassium acetate (6.16g, 62.84mmol), tetrakis(triphenylphosphine ) Palladium (1.46g, 1.28mmol) was put into the reaction flask, 1,4-dioxane (56ml) was added, heated and stirred under reflux for 4 hours, T=95°C, TLC detected 4-bromo-3-fluorophenol The basic response is complete. After the reaction solution was cooled, it was filtered with diatomaceous earth and washed with ethyl acetate (10ml×2). Combine the filtrates, add water (25ml), and extract with ethyl acetate (40ml×3). The organic layers were combined, washed successively with water (40ml) and sodium chloride solution (40ml×2), and dried over anhydrous sodium sulfate. Concentrate by filtration, and the residue is slurried with n-hexane (30ml) for 20 hours. After filtering, the filter cake was washed with n-hexane and air-dried at 45°C to obtain 4.70 g of a brown powder solid,...

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Abstract

The invention relates to a method for preparing fluzotinib. The compound can be used for treating non-small cell lung cancer. The method comprises the following steps: by taking (R)-5-bromine-3-[1-(2,6-dichloro-3-fluorophenyl) ethyoxyl]-2-nitropyridine as an initial raw material, firstly, in the presence of a proper catalyst and alkali, performing coupling reaction with a hydroxyphenylboronic acid pinacol ester compound III so as to obtain a compound VII, then in the presence of alkali, performing esterification so as to obtain a compound VI, next in the presence of the proper catalyst and alkali, performing coupling reaction with a dimethylphosphinic oxide compound IV so as to obtain a compound V, and finally performing nitroreduction to obtain a compound I. The method is reasonable in process design, high in reaction yield, simple and convenient to operate and free of harsh reaction condition, and industrial production can be effectively achieved with high quality.

Description

technical field [0001] The present invention relates to the technical field of pharmaceutical manufacturing, specifically, a method for preparing the compound fluzotinib for the treatment of non-small cell lung cancer, that is, (R)-3-[1-(2,6-dichloro-3- A preparation method of fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphonooxy-4-yl]pyridin-2-amine. Background technique [0002] Fluzotinib, chemical name: (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethyl Phosphonooxy-4-yl]pyridin-2-amine, structure: [0003] [0004] Fluxotinib is a drug useful in the treatment of non-small cell lung cancer, the leading cause of cancer death worldwide, by modulating the activity of anaplastic lymphoma kinase (ALK) and cMet kinase. Approximately 85% of lung cancers are non-small cell lung cancer (NSCLC). ALK gene rearrangements involving a small inversion within chromosome 2p to form a fusion gene containing part of echinoderm microtubule-binding prote...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/53C07D213/63
CPCC07D213/63C07F9/5054C07F9/5325
Inventor 余俊于海洲
Owner JIANGSU HANSOH PHARMA CO LTD