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A kind of preparation method of ataluron

An intermediate and organic solvent technology, applied in the field of preparation of small molecule drug Ataluron, can solve the problems of expensive raw materials and precious metal catalysts, unsuitable for industrial production, unable to realize industrialization, etc., and achieves low synthesis cost and mild reaction conditions. , the effect of high product purity

Active Publication Date: 2022-05-27
北京大学生命科学华东产业研究院 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] 1. The reaction route is long and the total yield is low;
[0010] 2. Expensive raw materials and precious metal catalysts are used in the synthesis process, or high temperature, stuffy tank, and oxidation processes are used, which is not suitable for industrial production;
[0011] 3. During the synthesis process, gases such as sulfur dioxide and hydrogen chloride will be produced, causing serious environmental pollution;
[0012] 4. In the reaction process, it is necessary to use organic solvents such as carbon tetrachloride, which is highly carcinogenic and toxic;
[0013] 5. The final purification adopts column chromatography operation, which cannot realize industrialization

Method used

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  • A kind of preparation method of ataluron
  • A kind of preparation method of ataluron
  • A kind of preparation method of ataluron

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-4

[0047] The preparation of the compound of formula III, the reaction formula is as follows:

[0048]

Embodiment 1

[0049] Example 1: at 25°C, add hydroxylamine hydrochloride (139.0 g, 2 mol) and water (2 L) to the reaction flask, then use sodium bicarbonate to adjust the pH of the solution = 8, and compound the compound of formula II (161.2 g, 1 mol) Dissolve in 6L of methanol, drop into the above-mentioned reaction solution, keep the internal temperature at 20-25 ° C, after the dropwise addition, continue to stir the reaction for 6 hours, TLC shows that the raw materials are completely reacted, the reaction solution is concentrated under reduced pressure, and then water is added Diluted and extracted with ethyl acetate. The organic phase was dried with an appropriate amount of anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum to obtain 186.4 g of a white solid compound (compound of formula III) with a yield of 96%.

Embodiment 2

[0050] Example 2: at 25° C., add hydroxylamine hydrochloride (139.0 g, 2 mol) and water (2 L) to the reaction flask, then use potassium bicarbonate to adjust the pH of the solution = 8, the compound of formula II (161.2 g, 1 mol) Dissolve in 6L of methanol, drop into the above-mentioned reaction solution, keep the internal temperature at 40-45 ° C, after the dropwise addition, continue to stir the reaction for 4 hours, TLC shows that the raw materials are completely reacted, the reaction solution is concentrated under reduced pressure, and then water is added Diluted and extracted with ethyl acetate. The organic phase was dried with an appropriate amount of anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum to obtain 174.6 g of a white solid compound (compound of formula III) with a yield of 90%.

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Abstract

The invention discloses a preparation method of Ataluron, comprising: an addition step, in which 3-cyanobenzoate is reacted with a first mixed solvent and hydroxylamine hydrochloride under alkaline conditions to obtain an intermediate of formula III; condensation In the first organic solvent, the intermediate of formula III is subjected to condensation reaction with o-fluorobenzoic acid to obtain the intermediate of formula IV; The intermediate of formula V is obtained by intramolecular dehydration; in the ester hydrolysis step, under alkaline conditions, the intermediate of formula V is subjected to ester hydrolysis using the second mixed solvent to obtain it. The invention uses cheap raw materials through four steps of addition, condensation, cyclization and ester hydrolysis, the reaction conditions are mild, the process is simple, the cost is low, and it is favorable for industrialized production. At the same time, the solvent in the reaction process can be basically recovered, the synthesis cost is low, and the reaction environment is good; in addition, the purification operation is simple, and the total yield and product purity of the target compound Ataluron are high.

Description

technical field [0001] The invention relates to the technical field of chemical medicine, in particular to a preparation method of a small molecule drug Ataluron. Background technique [0002] Duchenne muscular dystrophy (DMD) is an X-chromosome recessive disorder that occurs mainly in boys. According to statistics, one out of every 3,500 newborn boys in the world suffers from the disease. Before school age, patients experience muscle weakness or atrophy due to the continuous degeneration of skeletal muscles, making it difficult to walk. Cystic fibrosis (CF) is a fatal autosomal recessive disease characterized by chronic obstructive pulmonary disease and is one of the most common inherited diseases in whites. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The life expectancy of patients with these two types of diseases is very short, which seriously affects the quality of life. [0003] Although drugs to cure Duchenne mu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D271/06
CPCC07D271/06
Inventor 皮红军周威吴江吴晓发沈南星朱文涛
Owner 北京大学生命科学华东产业研究院