Preparation method of topiroxostat

A technology of topicastat and compounds, applied in the direction of organic chemistry and the like, can solve problems such as serious environmental pollution and large dosage, and achieve the effects of high product purity, reduced dosage, and mild reaction conditions

Inactive Publication Date: 2014-12-24
于宗光
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] This route step is simple, although the cyanide agent zinc cyanide used is cheaper, but co

Method used

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  • Preparation method of topiroxostat
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  • Preparation method of topiroxostat

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Experimental program
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Embodiment 1

[0036] Embodiment 1: the preparation of formula (4) compound 4-(5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl)pyridine-N-oxide

[0037] Dissolve 1.20 g (0.01 mol) of 4-cyanopyridine-N-oxide (compound of formula 5) in 50 ml of methanol, then add 50 mg of sodium methoxide, and stir until dissolved. Then 1.37 g (0.01 mol) of isoniazid (compound of formula 6) was added, and heated to reflux for 10 hours. After the reaction, the precipitated solid was filtered out, washed with methanol, and then dried with a vacuum pump to obtain 1.87 g of a yellow powder product, the compound of formula (4), with a yield of 78%.

Embodiment 2

[0038] Embodiment 2: the preparation of formula (4) compound 4-(5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl)pyridine-N-oxide

[0039] Dissolve 12.0 g (0.10 mol) of 4-cyanopyridine-N-oxide (compound of formula 5) in 500 ml of methanol, then add 1.0 g of sodium methoxide, and stir until dissolved. Then, 13.7 g (0.10 mol) of isoniazid (compound of formula 6) was added, and heated to reflux for 15 hours. After the reaction, the precipitated solid was filtered out, washed with methanol and dried with a vacuum pump to obtain 18.2 g of the compound of formula (4) as a yellow powder product with a yield of 77%.

Embodiment 3

[0040] Embodiment 3: Formula (3) compound 3-(2-cyanopyridin-4-yl)-N, N-dimethyl-5-(pyridin-4-yl)-1H-1,2,4-three Preparation of azole-1-carboxamides.

[0041]With formula (4) compound 2.39g (10mmol), dimethylcarbamoyl chloride (0.22ml, 22mmol), zinc cyanide (1.40g, 12mmol), cuprous iodide 0.19g (1mmol) is dissolved in 100ml acetonitrile, the mixture React at 80°C for 5 hours, TLC detects the reaction (n-hexane / ethyl acetate=1:1), after the reaction is complete, cool to room temperature, add 100ml of water and stir for 5-30 minutes, discard the organic layer, and use the water layer Ethyl acetate was extracted three times, 100ml each time, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product, which was subjected to column chromatography with n-hexane / ethyl acetate=4:1 to obtain a pale yellow solid 2.97 g, yield 93%, HPLC purity (normalization method): 97.7%; melting point: 112...

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Abstract

The invention relates to a preparation method of topiroxostat, which comprises the following steps: reacting an initial raw material compound isoniazide disclosed as Formula (6) with a compound 4-cyano-pyridyl-N-oxide disclosed as Formula (5) to generate a triazole compound disclosed as Formula (4), reacting the triazole compound disclosed as Formula (4) in the presence of a copper catalyst (CuX), zinc cyanide (Zn(CN)2) and dimethylamino formyl chloride to generate a cyanotriazole compound disclosed as Formula (3), reacting the compound disclosed as Formula (3) in the presence of p-toluenesulfonic acid to generate a compound disclosed as Formula (2), and finally, alkalifying with inorganic alkali to obtain the target compound disclosed as Formula (1) (topiroxostat). The method is simple in operation and after-treatment, and greatly lowers the consumption of the zinc cyanide due to the use of the copper catalyst, so that the reaction conditions are milder, and the purity of the prepared product is high; and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of topicastat, which belongs to the field of medicine and chemical industry. Background technique [0002] Gout is a common disease caused by abnormal production of uric acid due to purine metabolism disorder. It has been listed by the United Nations as one of the 20 most stubborn diseases in the 21st century, and it is the second most metabolic disease after diabetes. "Hyperuricemia and Gout Treatment Chinese Expert Consensus" pointed out that the prevalence of hyperuricemia (HUA) showed an overall trend of increasing year by year, with males higher than females, and there were certain regional differences. The southern and coastal areas were economically developed. The prevalence rate in this region is higher than that in other regions in China during the same period. More importantly, the patients with HUA are showing a trend of getting younger and younger. According to statistics, the prevalence of HUA...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 不公告发明人
Owner 于宗光
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