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Preparation method of medicine for treating chronic hyperuricemia

A technology for hyperuricemia and medicine, applied in the medical field, can solve the problems of unsuitability for industrial production, high operational risk, and high chloride content, and achieve the effects of solving the problem of excessive chloride, high energy consumption, and high yield.

Inactive Publication Date: 2021-04-13
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are five steps in this process. The starting material is isonicotinic acid, and there is no special reaction. However, the process route is long and the total yield is not high. The first two steps use highly toxic and expensive trimethylsilyl cyanide. High risk of operation, not suitable for industrial production
CN106632265 discloses a method for preparing high-purity topicastat, which improves the purity of topicastat by forming hydrochloride and desalting process, but this method needs to add concentrated Hydrochloric acid, which is more dangerous and has a higher residual chloride content after desalting

Method used

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  • Preparation method of medicine for treating chronic hyperuricemia
  • Preparation method of medicine for treating chronic hyperuricemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] The preparation of embodiment 1 topicastat

[0026] Add 20.0kg of methyl 2-cyanoisonicotinate and 200kg of absolute ethanol into a 500L reaction kettle, control the temperature to 25-30°C, add hydrazine hydrate ethanol solution dropwise under stirring, and continue to stir for 2 hours at a temperature of 30-35°C. Concentrate the reaction solution under reduced pressure, evaporate to dryness at a temperature of 45-55°C; add 60kg of dichloromethane, stir for 1 hour, filter with suction at room temperature, rinse the filter cake with 15kg of ethyl acetate, drain it, and place the filter cake in a blast oven for After drying at 65°C for 12 hours, 14.3 kg of intermediate I was obtained.

[0027] Add 8.233kg of 4-cyanopyridine and 65kg of methanol into a 200L reaction kettle, add 641g of sodium methoxide under stirring, control the temperature at 25-30°C for 2 hours, add 14.25kg of intermediate I in batches, control the temperature at 25-35°C, After stirring and reacting for...

Embodiment 2

[0031] The preparation of embodiment 2 topicastat

[0032] Add 20.0kg of methyl 2-cyanoisonicotinate and 200kg of absolute ethanol into a 500L reaction kettle, control the temperature to 25-30°C, add hydrazine hydrate ethanol solution dropwise under stirring, and continue to stir for 2 hours at a temperature of 30-35°C. Concentrate the reaction solution under reduced pressure, evaporate to dryness at a temperature of 45-55°C; add 60kg of dichloromethane, stir for 1 hour, filter with suction at room temperature, rinse the filter cake with 15kg of ethyl acetate, drain it, and place the filter cake in a blast oven for After drying at 65°C for 12 hours, 14.3 kg of intermediate I was obtained.

[0033] Add 8.233kg of 4-cyanopyridine and 65kg of methanol into a 200L reaction kettle, add 641g of sodium methoxide under stirring, control the temperature at 25-30°C for 2 hours, add 14.25kg of intermediate I in batches, control the temperature at 25-35°C, After stirring and reacting for...

Embodiment 3

[0037] The preparation of embodiment 3 topicastat

[0038] Add 20.0kg of methyl 2-cyanoisonicotinate and 200kg of absolute ethanol into a 500L reaction kettle, control the temperature to 25-30°C, add hydrazine hydrate ethanol solution dropwise under stirring, and continue to stir for 2 hours at a temperature of 30-35°C. Concentrate the reaction solution under reduced pressure, evaporate to dryness at a temperature of 45-55°C; add 60kg of dichloromethane, stir for 1 hour, filter with suction at room temperature, rinse the filter cake with 15kg of ethyl acetate, drain it, and place the filter cake in a blast oven for After drying at 65°C for 12 hours, 14.3 kg of intermediate I was obtained.

[0039] Add 8.233kg of 4-cyanopyridine and 65kg of methanol into a 200L reaction kettle, add 641g of sodium methoxide under stirring, control the temperature at 25-30°C for 2 hours, add 14.25kg of intermediate I in batches, control the temperature at 25-35°C, After stirring and reacting for...

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Abstract

The invention discloses a preparation method of a medicine for treating chronic hyperuricemia. The method comprises the following steps: using methyl 2-cyanoisonicotinate and 4-cyanopyridine as initial raw materials, and carrying out hydrazinolysis reaction, condensation reaction, cyclization reaction and purification to obtain topiroxostat. On one hand, by using a hydrochloric acid alcohol solution, the energy consumption of the process is reduced, and the problem of poor safety is improved; and on the other hand, topiroxostat hydrochloride is refined and concentrated in alcohol water and then subjected to a salt dissolving process, so that the solubility of the topiroxostat in an alkaline solution is increased, the problem that chloride exceeds the standard is preliminarily solved, the salt dissolving process is more thorough, and the reaction proceeding degree is increased. Finally, in the purification process, the amount of chlorides in the product is further reduced by a method of hot melting the crude product in alcohol water, and the product quality is ensured; and the purity of the product is improved by selecting a purification solvent.

Description

technical field [0001] The invention belongs to the field of medical technology, in particular to a preparation method of a medicine for treating chronic hyperuricemia. Background technique [0002] Topiroxostat (topiroxostat), the chemical name is 4-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile, produced by Japan Fuji Pharmaceutical Co., Ltd. Developed by the company and launched in Japan in June 2013, the product name is For the treatment of gout and hyperuricemia. Topinastat is a selective xanthine oxidoreductase (XOR) inhibitor that forms a covalent bond (IV valence) to the molybdenum atom in the XOR reaction center by interacting with multiple amino acid residues of XOR (multiple Hydrogen bonding, hydrophobic interactions and aromatic ring interactions) play its inhibitory role. At present, there is no topinastat listed in my country. [0003] There is one main synthesis route of topilastat in the literature: using isonicotinic acid as the startin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61P19/06
CPCC07D401/14A61P19/06
Inventor 刘庆利单良魏淑红朱玉青王彦智刘磊
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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