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Preparation method of multi-target anti-tumor drug

An anti-tumor drug, multi-target technology, used in anti-tumor drugs, drug combinations, organic chemistry and other directions, can solve the problems of non-compliance with drug quality, product impurities, low yield, etc., to reduce the risk of heavy metal pollution, The effect of lowering reaction temperature and increasing product yield and purity

Active Publication Date: 2021-01-01
GUANGZHOU NUCIEN PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This reaction requires a metal composite catalyst, the cost is high, and the generated product has more impurities, the yield is not high, and it does not meet the requirements of drug quality

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 Preparation of 2-carbamoyl-4-((3-fluoro-4-amino)phenoxy)pyridine (compound 4)

[0029] Add 19.36 kg of dimethyl sulfoxide and 7.2 kg of tetrahydrofuran into a 100L reactor, pass through nitrogen for protection, then add 4.88 kg of potassium tert-butoxide, and after it is completely dissolved, control the temperature at 10-20°C. Continue to add 4.54 kg of 4-amino-3-fluorophenol (compound 3), stir at room temperature for 10 minutes, add 5.57 kg of 4-chloro-2-pyridinecarboxamide (compound 2), continue to stir for 10 minutes, and react within 30 minutes The liquid temperature rises above 80°C. Start timing when the internal temperature rises to 80°C, and keep the reaction at 85±2°C for 2.0 hours. After the reaction, cool down to below 20°C, add 70 kg of 1M sodium hydroxide aqueous solution dropwise, and then slowly lower the inner temperature of the reactor to 0-2°C after the dripping is completed. The slurry was filtered while it was cold, and the filter cake w...

Embodiment 2

[0030] Example 2 Preparation of 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2-carboxamide (Compound 1)

[0031] Add 37.3 kg of dioxane into a 100 L reactor, protect it under nitrogen, then add 2.5 kg of intermediate 4, stir, and raise the temperature to 55°C. After intermediate 4 was completely dissolved, 2.2 kg of 4-chloro-3-(trifluoromethyl)phenylisocyanate (compound 5) was dissolved in 6.7 kg of dioxane and pre-cooled to 10°C, and added dropwise to 100 In the L reactor, continue to react with intermediate 4 for 1 hour after the dropwise completion. After cooling, the reaction solution was crystallized at 24°C for 15 hours to obtain compound 1. After centrifugal filtration, the filter cake was rinsed twice with 6.0 kg of ethyl acetate, and the weight of the filter cake after drying under reduced pressure was 3.8 kg. Pour 40.0 kg of methanol into a 100 L reactor, add the above-mentioned compound 1, raise the temperature to reflux, keep the tempe...

Embodiment 3

[0032] Example 3 Preparation of 2-carbamoyl-4-((3-fluoro-4-amino)phenoxy)pyridine (compound 4)

[0033] Add 23.23 kg of dimethyl sulfoxide and 6.0 kg of tetrahydrofuran into a 100L reactor, pass through nitrogen for protection, then add 5.37 kg of potassium tert-butoxide, and after it is completely dissolved, control the temperature at 10-20°C. Continue to add 4.99 kg of 4-amino-3-fluorophenol (compound 3), stir at room temperature for 10 minutes, add 6.13 kg of 4-chloro-2-pyridinecarboxamide (compound 2), continue to stir for 10 minutes, and react within 30 minutes The liquid temperature rises above 80°C. Start timing when the internal temperature rises to 80°C, and keep the reaction at 85±2°C for 2.0 hours. After the reaction, cool down to below 20°C, add 80 kg of 1M sodium hydroxide aqueous solution dropwise, and then slowly lower the inner temperature of the reactor to 0-2°C after the dripping is completed. The slurry was filtered while it was cold, and the filter cake w...

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Abstract

The invention relates to a preparation method of a multi-target anti-tumor drug. The method comprises the following steps: 1, nitrogen protection: by using a williamson ether synthesis method, using 4-amino-3-fluorophenol and 4-chlorine-2-pyridine carboxamide as raw materials and dimethyl sulfoxide and tetrahydrofuran as a mixed solvent under the effect of potassium tert-butoxide to generate 2-carbamoyl-4-((3-fluorine-4-amino) phenoxy) pyridine by reaction; and 2, reacting the 2-carbamoyl-4-((3-fluorine-4-amino) phenoxy) pyridine with 4-chlorine-3-(trifluoromethyl) benzene isocyanate in a dioxane solvent to obtain a crude product, and refining the crude product to obtain a final product 4-{4-[3-(4-chlorine-3-trifluoromethyl-phenyl)urea]-3-fluorine phenoxy} pyridine-2-formamide.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a multi-target antitumor drug 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine -The preparation method of 2-carboxamide. Background technique [0002] Vascular endothelial growth factor (VEGF) is one of the most important cell growth factors in the process of tumor angiogenesis. Tumor blood vessels are highly sensitive to VEGF, and the VEGF mRNA concentration in many tumor cells is significantly higher than that in normal cells, including lung cancer. In addition, the Raf / MEK / ERK transduction pathway exists in all eukaryotic cells, and it is transmitted from the extracellular to the nucleus through the specific cascade phosphorylation signals of Ras, Raf, MEK and ERK. Many tumor cells have the upregulation of this pathway. Once the pathway is overactivated, the acceleration of cell proliferation and the prolongation of cell survival will lead to the formatio...

Claims

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Application Information

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IPC IPC(8): C07D213/81A61P35/00
CPCC07D213/81A61P35/00
Inventor 胡双华张世喜郑琴香林寨伟
Owner GUANGZHOU NUCIEN PHARM CO LTD
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