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Preparation process of 5-(2-cyano4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole

A preparation process, pyridyl-based technology, applied in the field of medicine and chemical industry, can solve the problems of high post-processing requirements, cumbersome post-processing process, and only 30% yield, achieve toxicity and less pressure on the environment, and shorten process time consumption , The effect of simplifying production operations

Inactive Publication Date: 2017-10-31
JINAN KANGHE MEDICAL TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] In summary, there are two main methods for introducing cyano groups in topilastat compounds at this stage: one is to use pyridine nitrogen oxide as the reaction substrate and use cyanide reagents to introduce cyano groups. This method is relatively simple but requires The use of highly toxic cyanide has high requirements for production operations and waste liquid post-treatment, and there are relatively large safety hazards; second, the use of amide method to add cyano groups has high safety, but this method is cumbersome to operate, and it needs to be used during the experiment. A large amount of formamide and concentrated sulfuric acid have high requirements on equipment, and the post-treatment process is relatively cumbersome; in addition, the yield is low, and the yield of the target compound 2-cyanoisonicotinic acid methyl ester is only 30%.

Method used

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  • Preparation process of 5-(2-cyano4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole
  • Preparation process of 5-(2-cyano4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole
  • Preparation process of 5-(2-cyano4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: the preparation method of compound III

[0038] Method 1: Add compound II (137.0g, 1.0mol) to a mixture of phosphorus oxychloride (137g, 1.0mol) and N,N-dimethylformamide (292g, 4.0mol) cooled at 0-5°C In the solution, keep stirring at 0-5°C for 6 hours. After the reaction, the I 2 (279.4g, 1.1mol) and 28% ammonia water (674ml, 10mol) were added to the reaction liquid, and the stirring reaction was continued for 3 hours at 20-25°C. Pour the reaction solution into a saturated aqueous solution of sodium sulfite, extract with dichloromethane, separate the organic phase and dry it with anhydrous sodium sulfate, filter and evaporate to dryness, add ethanol to the residue and heat to dissolve, then cool to 20-25°C to crystallize for 2 hours , filtered and dried to obtain white needle crystals, 66.7g, yield: 41.2%

[0039] Method 2: Compound II (137.0g, 1.0mol) was added to phosphorus oxychloride (150.7g, 1.1mol) and N,N-dimethylformamide (292.0g, 4.0mol) cool...

Embodiment 2

[0041] Embodiment 2: the preparation method of compound IV

[0042] Method 1: add compound III (64.8g, 0.4mol) and methanol (650ml) respectively, after stirring evenly, then add 80% hydrazine hydrate (37.5g, 0.6mol), after adding, the reaction system shows yellow suspension, 20 The reaction was stirred at -25°C for 2 hours, followed by TLC. After the reaction was completed, it was filtered, washed with 30ml of ice methanol, and dried to obtain 31.2g of a light yellow solid. Yield: 48.1%

[0043] Method 2: add compound III (64.8g, 0.4mol) and methanol (650ml) respectively, after stirring evenly, then add 80% hydrazine hydrate (37.5g, 0.6mol), after the addition, the reaction system shows a yellow suspension, 0 Stir the reaction at ℃ for 4 hours, follow the reaction process by TLC, after the reaction is completed, filter, wash with 20ml ice methanol, and dry to obtain 26.2g, light yellow solid, yield: 40.5%

[0044] Method 3: add compound III (64.8g, 0.4mol) and ethanol (650ml)...

Embodiment 3

[0047] Embodiment 3: the preparation method of crude product

[0048] Method 1: Add the raw material 4-cyanopyridine (20.8g, 0.2mol), dissolve it in 350ml of methanol, add 27% methanol solution of sodium methoxide (40g, 0.2mol) at 20-25°C, and react the solution at 20-25 °C and stirred for 2 hours, during which the reaction solution was a clear and transparent solution. Compound IV (32.4g, 0.2mol) was added to the reaction solution, followed by heating to reflux, 2-cyanoisonicotinic acid hydrazide gradually dissolved, heating to reflux for 14 hours, a large amount of solids were precipitated, the reaction was completed, and cooled to 20-25 °C, the solid was filtered, the filter cake was washed twice with 150 ml of methanol, and dried to obtain 30.0 g of a yellow solid, with a yield of 60.5%.

[0049] Method 2: Add the raw material 4-cyanopyridine (20.8g, 0.2mol), dissolve it in 350ml of ethanol, add 27% methanol solution of sodium methoxide (40g, 0.4mol) at 20-25°C, and the r...

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Abstract

The invention belongs to the field of medicine and chemical industry, and specifically discloses a preparation of 5-(2-cyano4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole (topinostat) The process is characterized in that the compound III 2-cyano group is synthesized by a one-pot method using compound II methyl isonicotinate as a starting material and phosphorus oxychloride, N,N-dimethylformamide, iodine simple substance, and 28% ammonia water Methyl isonicotinate, then compound IV 2-cyanoisonicotinic acid hydrazide is synthesized, and then compound IV2-cyanoisonicotinic acid hydrazide is condensed with 4-cyanopyridine to prepare topinostat crude product Ia, and crude product Ia is passed through with p-toluene After the sulfonic acid is salified, topinastat p-toluenesulfonate Ib is formed, and finally desalted and refined to obtain the finished product I of topinostat. The invention reduces the reaction steps, improves the yield of finished products, has low toxicity in the reaction process, has little impact on the environment, has a short reaction route, and greatly reduces the cost.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, in particular to a preparation process of 5-(2-cyano4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole (topinostat) . technical background [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 Pharmaceuti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 张颖宋柱文朱玉正高国锐王瑞林
Owner JINAN KANGHE MEDICAL TECH
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