Synthetic method of anti-tumor medicament lonidamine

A synthesis method and anti-tumor technology, applied in the direction of organic chemistry, etc., can solve the problems of high production cost of lonidamine, achieve the effects of shortening the synthesis time, increasing the reaction yield, and cheap price

Inactive Publication Date: 2013-06-19
盐城格瑞茵化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem to be solved in the present invention is to overcome the higher problem of production cost of lonidamine

Method used

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  • Synthetic method of anti-tumor medicament lonidamine
  • Synthetic method of anti-tumor medicament lonidamine
  • Synthetic method of anti-tumor medicament lonidamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045]Synthesis of 2,4-dichlorobenzyl bromide:

[0046] (1) 10.0g (0.06mol) 2,4-dichlorotoluene, 9.95g (0.072mol) NBS, 1.0g

[0047] Azodiisobutyronitrile and 100g dichloroethane were put into a 250ml four-neck bottle, and the temperature was raised to 80°C under stirring, and the reaction was stopped after 8 hours of heat preservation, and filtered; the mother liquor was washed with water, dilute sodium hydroxide solution, and saturated sodium sulfite solution respectively. The organic phase was separated several times, and the solvent dichloroethane was distilled off to obtain 14.2 g of light yellow 2,4-dichlorobenzyl bromide liquid. Yield: 80.1%.

[0048] (2) 10.0g (0.06mol) 2,4-dichlorotoluene, 13.26g (0.072mol) NBS, 1.0g

[0049] Azobisisobutyronitrile and 100g of dichloroethane were thrown into a 250ml four-necked bottle, and the temperature was raised to 80°C under stirring, and the reaction was stopped after 6 hours of heat preservation, and filtered; the mother liqu...

Embodiment 2

[0051] Synthesis of N-acetylphenylhydrazine:

[0052] (1) Add 98.0g (1.55mol) of glacial acetic acid and 100.0g of water into a 250ml three-necked flask, and add benzene under stirring

[0053] Hydrazine 40.0g (0.37mol), heated to reflux, kept warm for 4h, cooled to room temperature, a large amount of yellow solid precipitated, filtered, washed with water, dried to obtain 80.0g N-acetylphenylhydrazine, yield: 82.0%, melting point: 127℃~ 129°C.

[0054] (2) Add 58.5g (0.92mol) of glacial acetic acid and 100.0g of water into a 250ml three-neck flask, add benzene under stirring

[0055] Hydrazine 40.0g (0.37mol), heated to reflux, kept warm for 4h, cooled to room temperature, a large amount of yellow solid precipitated, filtered, washed with water, dried to obtain 58.5g of N-acetylphenylhydrazine, yield: 60.0%, melting point: 127℃~129 ℃.

Embodiment 3

[0057] Synthesis of N-acetylaminoxime acetanilide:

[0058] (1) Add 5.0g (0.033mol) acetylphenylhydrazine, 40g (0.282mol) anhydrous sodium sulfate, 7.5g (0.108mol) hydroxylamine hydrochloride, 6g (0.100mol) glacial acetic acid and 125.0g Add water, stir and raise the temperature to 90°C; then add 7.2g (0.044mol) chloral hydrate dissolved in 14.4g water dropwise into the reaction solution, the drop is completed in about 5 minutes, start timing with the drop, and stop after 15 minutes of reaction For reaction, immediately pour the reaction solution into a certain amount of water, cool to room temperature, filter, wash with water, and dry to obtain 6.40 g of light yellow solid, yield: 86.9%, melting point: 133°C-135°C.

[0059] (2) Add 5.0g (0.033mol) acetylphenylhydrazine, 35g (0.282mol) anhydrous sodium sulfate, 7.5g (0.108mol) hydroxylamine hydrochloride, 6g (0.100mol) glacial acetic acid and 125.0g Add water, stir and raise the temperature to 90°C; then add 7.2g (0.044mol) c...

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Abstract

The invention discloses a synthetic method of anti-tumor medicament lonidamine. The synthetic method comprises the following steps: taking 2,4-dichloromethylbenzene and phenylhydrazine as a starting raw material, performing acetylation on the phenylhydrazine, then reacting with hydroxylamine hydrochloride and chloral hydrate to generate N- acetylamino oximino acetylaniline, further performing rearrangement, cyclocondensation and hydrolysis under the catalysis of concentrated sulfuric acid to generate 1H-indazole-3-carboxylic acid; and enabling the 2,4-dichloromethylbenzene and N-bromosuccinimide (NBS) to react to generate 2,4-dichlorobenzyl bromide, and then reacting with the 1H-indazole-3-carboxylic acid to generate the lonidamine. The synthetic method disclosed by the invention has the characteristics of simple instruments and equipment required for the synthetic method, easiness in getting the raw materials, low cost, high yield and the like. During the reaction process, the industrial three wastes are simple to process, and the synthetic method is green and environment-friendly; and the obtained product has the advantages of stable quality, low content of single impurity and higher quality in comparison with the similar products in the industry, and is more suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to the synthesis of the antineoplastic drug lonidamine, more specifically the antineoplastic drug lonidamine, namely 1-(2,4-dichlorobenzyl)-1H-indazole- The synthetic method of 3-carboxylic acid namely lonidamine. Background technique [0002] In 2010, the International Union Against Cancer pointed out that cancer has become the "number one killer" that seriously threatens people's health. [0003] According to the data released recently by the health department of our country, whether in urban or rural areas, malignant tumors have surpassed cardiovascular diseases and become the number one cause of death among Chinese residents. Therefore, finding effective anticancer drugs and methods suitable for industrial production is one of the most important fields of current drug research. [0004] Lonidamine is an indazole derivative, and indazole, as the bioisostere of indole, has ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/56
Inventor 殷剑夏明珠董海龙丁峰徐松
Owner 盐城格瑞茵化工有限公司
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