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One-pot method for synthesizing Topiroxostat

A technology of topinostat and hydrazine hydrate, which is applied in the field of one-pot synthesis of topinostat, and can solve the cumbersome purification method of 2-cyanoisonicotinic acid methyl ester, cumbersome operation of topinostat, and limited industrial application, etc. problems, to achieve good production and practical value, high utilization rate of raw materials, and low production cost

Inactive Publication Date: 2016-10-26
NANJING UNIV OF TECH
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Problems solved by technology

[0004] WO2003064410 describes the preparation method of topilastat, using 2-cyanoisonicotinic acid methyl ester as raw material to react with hydrazine hydrate to generate 2-cyanoisonicotinic acid hydrazide, and the obtained intermediate is condensed with 4-cyanopyridine to synthesize Topicastat is obtained in the ring, and the above-mentioned method is carried out in two steps to synthesize topinotinate, and the operation is cumbersome, and the intermediate 2-cyanoisonicotinic acid methyl ester is easily hydrolyzed by the reaction with hydrazine hydrate, so that the 2-cyanoisonicotinic acid methyl ester The purification method is cumbersome, which limits its industrial application
[0005] In 2014, Zhuang Yan et al. used methyl isonicotinate N-oxide as a raw material to obtain topicastat through cyanidation, hydrazinolysis, and condensation into a ring. Not clear, cumbersome to operate

Method used

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  • One-pot method for synthesizing Topiroxostat

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Experimental program
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Embodiment 1

[0020] Add methyl 2-cyanoisonicotinate (487.1g, 3mol) and dissolve it in 1L ethanol in the reactor, stir at room temperature, add hydrazine hydrate (187.9g, 3mol) dropwise, then raise the temperature to 40°C and stir for 4h, TLC The reaction was detected (ethyl acetate:petroleum ether=1:2), and the reaction was completed. Then add sodium methoxide (28g, 0.5mol), stir for 20min until dissolved, then add compound 4-cyanopyridine (312.33g, 3mol), react at 80°C for 10h, and detect by TLC (ethyl acetate:petroleum ether=1:4) , after the reaction was finished, cooled to normal temperature for crystallization, the precipitated solid was filtered, washed with 500ml of ethanol, and vacuum-dried to obtain 405.5g of a light yellow powder product, topicastat, with a yield of 63%. mp: 323.5-325.7°C. ESI-MS(m / z):249[M+H] + . 1 H NMR (400MHz, DMSO) δ15.41(s, 1H), 8.92(d, J=5.1Hz, 1H), 8.79(d, J=5.9Hz, 2H), 8.53(s, 1H), 8.31(dd , J=5.1, 1.6Hz, 1H), 8.01(dd, J=4.5, 1.5Hz, 2H). The H-NMR spe...

Embodiment 2

[0022] Add methyl 2-cyanoisonicotinate (487.1g, 3mol) and dissolve it in 1L of methanol in a reactor, stir at 0°C, add hydrazine hydrate (187.9g, 3mol) dropwise, then raise the temperature to 10°C and stir for 1h, TLC The reaction was detected (ethyl acetate:petroleum ether=1:2), and the reaction was completed. Potassium carbonate (207g, 1.5mol) was added, stirred for 20min until dissolved, then compound 4-cyanopyridine (312.33g, 3mol) was added, reacted at 80°C for 2h, detected by TLC (ethyl acetate:petroleum ether=1:4) , after the reaction was finished, cooled to normal temperature and crystallized, the precipitated solid was filtered, washed with 500ml of methanol, and vacuum-dried to obtain 399.8g of light yellow powdery product topicastat, with a yield of 62.1%. mp: 323.8-326.7°C. ESI-MS(m / z):249[M+H] + . 1 H NMR (400MHz, DMSO) δ15.41(s, 1H), 8.92(d, J=5.1Hz, 1H), 8.79(d, J=5.9Hz, 2H), 8.53(s, 1H), 8.31(dd , J=5.1, 1.6Hz, 1H), 8.01 (dd, J=4.5, 1.5Hz, 2H).

Embodiment 3

[0024] Add methyl 2-cyanoisonicotinate (487.1g, 3mol) and dissolve it in 1L of ethyl acetate in a reactor, stir at room temperature, add hydrazine hydrate (187.9g, 3mol) dropwise, then raise the temperature to 30°C and stir for 2h , TLC detected the reaction (ethyl acetate:petroleum ether=1:2), and the reaction was complete. Then add sodium methoxide (28g, 0.5mol), stir for 20min until dissolved, then add compound 4-cyanopyridine (468g, 4.5mol), react at 60°C for 2h, TLC detection (ethyl acetate:petroleum ether=1:4) , after the reaction was finished, cooled to normal temperature for crystallization, the precipitated solid was filtered, washed with 500ml of ethyl acetate, and then vacuum-dried to obtain 385.5g of a light yellow powdery product, topicastat, with a yield of 59.8%. mp: 323.2-325.8°C. ESI-MS(m / z):249[M+H] + . 1 H NMR (400MHz, DMSO) δ15.41(s, 1H), 8.92(d, J=5.1Hz, 1H), 8.79(d, J=5.9Hz, 2H), 8.53(s, 1H), 8.31(dd , J=5.1, 1.6Hz, 1H), 8.01 (dd, J=4.5, 1.5Hz, 2H). ...

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Abstract

The invention discloses a one-pot method for synthesizing Topiroxostat. The one-pot method comprises the following steps: dissolving 2-cyano methyl isonicotinate into a solvent, reacting with hydrazine hydrate to generate an intermediate 2-cyanoisoniazide, then adding alkali for reaction in the same reactor, then adding 4-cyanopyridine to form a ring, and finally purifying to obtain the Topiroxostat. The one-pot method is short in technological process, simple in operation, high in raw material utilization rate and low in production cost, and has higher production and practical value.

Description

technical field [0001] The invention relates to a method for synthesizing topicastat; in particular, to a method for synthesizing topistat in one pot. Background technique [0002] Topicastat is a new generation anti-hyperuric acid and gout drug jointly developed by Fuji Pharmaceutical Co., Ltd. and Sanwa Chemical. Topilastat is a non-purine xanthine oxidase inhibitor, which can inhibit both oxidized and reduced xanthine oxidase, and inhibit the production of uric acid. It was launched in Japan in August 2013. Compared with the currently clinically used anti-gout drugs such as colchicine and non-steroidal anti-inflammatory drugs, topinastat has the advantages of strong uric acid-lowering effect, less adverse reactions, and good safety. [0003] Topiroxostat, the chemical name is 5-(2-cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole, its structure is as follows: [0004] WO2003064410 describes the preparation method of topilastat, using 2-cyanoisonicotinic acid methyl ester as...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 王德才高瑞黄民华范兴风王鑫刘宗文
Owner NANJING UNIV OF TECH
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