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Preparation method of Ataluren

An intermediate and mixed 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: 2021-06-29
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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  • Preparation method of Ataluren
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  • Preparation method of Ataluren

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-4

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

[0048]

Embodiment 1

[0049] Example 1: At 25°C, hydroxylamine hydrochloride (139.0g, 2mol) and water (2L) were added to the reaction flask, and then sodium bicarbonate was used to adjust the pH of the solution to 8, and the compound of formula II (161.2g, 1mol) Dissolve in 6L of methanol, drop into the above reaction solution, keep the internal temperature at 20-25°C, after the dropwise addition, continue to stir and react for 6 hours, TLC shows that the raw materials are completely reacted, concentrate the reaction solution under reduced pressure, and then add water Dilute and extract with ethyl acetate. The organic phase was dried with an appropriate amount of anhydrous sodium sulfate, concentrated under reduced pressure, and dried in vacuo 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, hydroxylamine hydrochloride (139.0g, 2mol) and water (2L) were added to the reaction flask, and then potassium bicarbonate was used to adjust the pH of the solution to 8, and the compound of formula II (161.2g, 1mol) Dissolve in 6L of methanol, drop into the above reaction solution, keep the internal temperature at 40-45°C, continue to stir and react for 4 hours after the dropwise addition, TLC shows that the raw materials are completely reacted, concentrate the reaction solution under reduced pressure, and then add water Dilute and extract with ethyl acetate. The organic phase was dried with an appropriate amount of anhydrous sodium sulfate, concentrated under reduced pressure, and dried in vacuo 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 Ataluren. The preparation method comprises an addition step in which under an alkaline condition, 3-cyanobenzoate reacts with hydroxylamine hydrochloride by using a first mixed solvent to obtain an intermediate as shown in a formula III, a condensation step in which in a first organic solvent, a condensation reaction is conducted on the intermediate shown in the formula III and o-fluorobenzoic acid to obtain an intermediate shown in a formula IV, a cyclization step in which in a second organic solvent, catalyzing is conducted by using Lewis acid, and intramolecular dehydration is conducted on the intermediate in the formula IV to obtain an intermediate in a formula V, and an ester hydrolysis step in which under an alkaline condition, ester hydrolysis is conducted on the intermediate in the formula V by using a second mixed solvent to obtain the product. Cheap raw materials are subjected to addition, condensation, cyclization and ester hydrolysis, the reaction conditions are mild, the process is simple, the cost is low, and industrial production is facilitated. Meanwhile, the solvent in the reaction process can be basically recycled, the synthesis cost is low, and the reaction environment is good; in addition, the purification operation is simple, and the total yield and the product purity of the target compound Ataluren are high.

Description

technical field [0001] The invention relates to the technical field of chemistry and medicine, in particular to a preparation method of a small molecule drug atalurin. Background technique [0002] Duchenne muscular dystrophy (DMD) is an X-chromosomal recessive genetic disorder that occurs mainly in boys. According to statistics, on average, one out of every 3,500 newborn boys in the world suffers from this disease. Patients will experience muscle weakness or atrophy due to the continuous degeneration of skeletal muscles before school age, resulting in difficulty in walking. Cystic fibrosis (CF) is a fatal autosomal recessive disease, the main clinical symptom is chronic obstructive pulmonary disease, and it is one of the most common genetic diseases in whites. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Patients with both types of diseases have a short life expectancy and seriously affect the quality of life. [0003...

Claims

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Application Information

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Patent Type & Authority Applications(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