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Topiroxostat preparation technology

A preparation process and topicastat technology, applied in the field of medicine and chemical industry, can solve the problems of harsh reaction conditions, high price and high reaction cost, and achieve the effects of improving reaction speed, short synthesis steps and improving solubility

Active Publication Date: 2016-05-11
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The common feature of the above three methods is that the cyano group is introduced through the ReissertHenze reaction, but the reactant trimethylsilyl cyanide used in this reaction is a highly toxic compound, and the price is expensive, the operation is dangerous, and the environment is polluted.
[0013] 2. Patent CN104151297A discloses that methyl isonicotinate-N-oxide is used as a starting material to generate 2-cyanoisonicotinic acid methyl in the presence of copper catalyst (CuX), metal cyanide and dimethylcarbamoyl chloride. ester, obtained 2-cyanoisoniazid through hydrazinolysis, and finally condensed with 4-cyanopyridine to obtain the crude product of topinostat. In this method, sodium cyanide, potassium cyanide, zinc cyanide, and copper cyanide are also used as Highly toxic reaction reagent, high risk of operation, and great environmental pollution
[0015] 3. In order to avoid the application of the above-mentioned highly toxic trimethylsilyl cyanide compound and highly toxic metal cyanide, CN201310713972.0 reported the use of methyl isonicotinate and formamide or formamide mixture in the environment of sulfuric acid, ferrous sulfate and hydrogen peroxide 2-formamide isonicotinic acid methyl ester is obtained by middle reaction, and 2-cyanoisonicotinic acid methyl ester is obtained by dehydration reaction. This route adopts amide method to add cyano group, which has high safety, but the amidation reaction process is cumbersome and the experimental process A large amount of formamide and concentrated sulfuric acid will be used in the process, which requires higher production equipment, and the post-treatment process is more cumbersome; in addition, the yield is low, and the final yield of the target compound 2-cyanoisonicotinic acid methyl ester is only 30%. , which increases the production cost
[0019] 5. Chen Yun et al. reported in the literature "Synthetic Process Improvement of Tobicistat" that 2-cyanoisonicotinic acid methyl ester was used as raw material, and the key intermediate Boc-protected 2-nitrile group was prepared by hydrolysis and acylation reaction. Isoniazid; deprotected by TsOH to obtain 2-cyanoisonicotinic acid hydrazide 3 / 2 p-toluenesulfonate; then synthesize tobicistat through condensation reaction with 4-cyanopyridine, the total yield is 32%; the The route uses expensive 2-cyanoisonicotinic acid methyl ester as the starting material, and alkali hydrolysis to obtain 2-cyanoisonicotinic acid is condensed into hydrazide by expensive DCC and HOBt. The reaction requires anhydrous conditions and many side reactions , which also uses amino protection and deprotection operations, the steps are cumbersome, the yield is low, the reaction cost is high, and it is not suitable for industrial production
[0026] In summary, some of the traditional synthetic methods require the use of highly toxic cyanide reagents, and heavy metal pollution is serious after the reaction; some reactions need to be carried out under high temperature and high pressure conditions, requiring high production equipment, difficult catalyst synthesis, and expensive ligands. Large investment; some of the three wastes are seriously discharged, the reaction conditions are harsh, and they do not meet the production requirements of industrialization and environmental protection

Method used

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Experimental program
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Effect test

Embodiment 1

[0048] Embodiment 1: the synthesis of 2-cyanoisonicotinic acid

[0049] Add 31.5g (0.2mol) of 2-chloroisonicotinic acid, potassium ferrocyanide trihydrate (16.9g, 40mmol), silver iodide (1.4g, 6mmol), polyethylene glycol 400 (3.2g, 8mmol) into the reaction flask ), potassium iodide (1.0g, 6mmol) were dissolved in N, N-dimethylformamide 500mL, reflux and stirred for 2 hours, the reaction solution was filtered, the filtrate was distilled under reduced pressure, the residue was added to ethyl acetate 150mL, and the insoluble matter was removed by filtration. Add dilute hydrochloric acid to the filtrate to adjust the pH to 6.5; wash twice with 50 mL of water, dry the organic phase with anhydrous magnesium sulfate, filter, and evaporate the solvent from the filtrate to obtain crude 2-cyanoisonicotinic acid, add ethanol to the residue and heat After dissolving, cool to 20-25°C for crystallization for 2 hours, filter and dry to obtain 2-cyanoisonicotinic acid (25.2 g) in the form of ...

Embodiment 2

[0050] Embodiment 2: the synthesis of 2-cyanoisonicotinic acid

[0051] Add 2-chloroisonicotinic acid (78.8g, 0.5mol), anhydrous potassium ferrocyanide (36.8g, 100mmol), silver iodide (5.9g, 25mmol), polyethylene glycol 1000 (30.0g, 30mmol), potassium iodide (4.2g, 25mmol) were dissolved in 1000mL of tetrahydrofuran, reflux and stirred for 12 hours, the reaction solution was filtered, the filtrate was distilled under reduced pressure, the residue was added to ethyl acetate 250mL, the insoluble matter was removed by filtration, and the pH of the filtrate was adjusted to 6.2; Wash twice with 50 mL of water, dry the organic phase with anhydrous magnesium sulfate, filter, and evaporate the solvent from the filtrate to obtain crude 2-cyanoisonicotinic acid, add ethanol to the residue, heat to dissolve, and cool to 20 Crystallize at -25°C for 2 hours, filter, and dry to obtain white needle-like crystals of 2-cyanoisonicotinic acid (66.0 g). The HPLC purity is 98.6%, and the yield is...

Embodiment 3

[0052] Example 3: Synthesis of 2-cyanoisonicotinic acid

[0053] Add 2-chloroisonicotinic acid (78.8g, 0.5mol), potassium ferrocyanide trihydrate (63.4g, 150mmol), silver iodide (8.2g, 35mmol), polyethylene glycol 1000 (50g, 50mmol) into the reaction flask ), potassium iodide (8.3g, 50mmol) were dissolved in N-methylpyrrolidone 1000mL, 100 ° C stirring reaction for 5 hours, the reaction solution was filtered, the filtrate was distilled under reduced pressure, the residue was added to ethyl acetate 300mL, the insoluble matter was removed by filtration, and the filtrate was added to Adjust the pH to 6.6 with dilute hydrochloric acid; wash twice with 100 mL of water, dry the organic phase with anhydrous magnesium sulfate, filter, and evaporate the filtrate to obtain crude 2-cyanoisonicotinic acid, add ethanol to the residue and heat to dissolve Afterwards, cool to 20-25° C. for crystallization for 2 hours, filter, and dry to obtain 2-cyanoisonicotinic acid (63.0 g) in the form of...

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Abstract

The invention discloses a topiroxostat preparation method. According to the method, 2-chloroisonicotinic acid which is cheap and easy to obtain serves as an initial material, potassium ferrocyanide serves as a green cyanogens source, AgI-KI-PEG generates 2-cyanoisonicotinate through cyanation of a mixed catalysis system and then directly acts with hydrazine hydrate to obtain 2-cyanoisonicotinate hydrazide under the action of an amide condensing agent phenyl dichlorophosphate (PDCP), and the product and 4-cyanopyridine are condensed to obtain topiroxostat. Through technological improvement of the reaction, reaction steps are shortened, the reaction yield is obviously increased by 90% or above, and the technological cost is obviously reduced. Meanwhile, a 2-chloroisonicotinic acid raw material which is cheaper and easy to obtain is used, use of corrosive thionyl chloride and other chlorinating agents is avoided, and the technology is suitable for industrial production. The method is short in synthesis step, easy to operate, mild in reaction condition, economical, environmentally friendly and suitable for industrial production, and the yield is obviously increased.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical engineering, in particular to a preparation of 5-(2-cyano4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole (topinostat) craft. Background technique [0002] Topiroxostat (Topiroxostat, CAS: 577778-58-6), chemical name: 5-(2-cyano4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole, English name: 4-[5-(Pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile, its chemical structure is as follows: [0003] [0004] The drug was developed by Fuji Pharmaceutical Industry Co., Ltd. of Japan. It selectively and reversibly inhibits xanthine oxidoreductase. It is a selective inhibitor of non-purine xanthine oxidase and can reduce serum uric acid levels; the drug started in 2004 Clinical trials were carried out. Phase I and Phase II clinical trials were conducted by Japan Fuji Pharmaceutical Co., Ltd., and Phase III clinical trials were jointly conducted by Japan Sanwa Chemical Industry Co., Ltd. and Fuji P...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 孙松李呈龙张庆东
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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