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A technology of topinostat and synthetic method, applied in the field of chemical pharmacy, to achieve the effect of cheap raw materials, simple operation and easy availability of raw materials
Inactive Publication Date: 2016-10-12
JIANGSU YUEXING PHARMA
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[0006] After searching, there is no bibliographical report about the synthesis of this impurity, therefore, it has important practical significance to provide a kind of synthetic method of topirestat for the preparation of impurity standard substance
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Embodiment 1
[0020] Example 1: Preparation of methyl 2-cyano-4-pyridinecarboxylate
[0021]
[0022] Add methylisonicotinic acid-N-oxide (2) (15.31g, 0.1mol) and 200ml of acetonitrile into a 250ml three-necked flask and stir to completely dissolve, then add triethylamine (15g, 0.15mol), trimethylsilyl cyanide (29.76g, 0.3mmol) after nitrogen protection reflux reaction for 20 hours, TLC detection reaction ended. The solvent was distilled to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography, eluting with dichloromethane-methanol (50:1), to obtain a white crystal with a yield of 13.48 g, 83.14%.
[0024] Embodiment two: the preparation of 2-cyanoisoniazid
[0025]
[0026] Add methyl 2-cyano-4-pyridinecarboxylate (3) (13.48g, 0.083mmol) and 130ml methanol into a 250ml three-necked flask, stir, cool to -5°C in an ice-salt bath, and dropwise add hydrazine hydrate (80%) 13.48 g, react at -5°C for 6 h, and TLC detects that the reaction is complete. Recrystallized with ethanol to obtain 11.12 g of white crystals, with a yield of 82.46%.
[0028] Example 3: Preparation of 2-(3-(2-aminopyridin-4-yl)-1H-1,2,4-triazol-5-yl)isoniazid
[0029]
[0030] Add 2-cyanoisoniazid (4) (5.56g, 0.034mmol) and 50ml of methanol into a 100ml three-necked flask and stir, then add sodium methoxide (0.37g, 0.0068mmol), stir at room temperature for 1 hour, then add another part of 2-cyano Isoniazid (4) (5.56g, 0.034mmol) was heated to reflux for 26 hours, and the reaction was detected by TLC. After cooling to room temperature, it was filtered and dried to obtain 9.21 g of a light yellow solid with a yield of 88.42%.
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Abstract
The invention discloses a topiroxostat impurity synthesis method, and belongs to the chemical pharmaceutical technical field. The method comprises the steps: with methyl isonicotinic acid-N-oxide (2) as a starting material, generating 2-cyano-4-pyridine carboxylic acid methyl ester from methyl isonicotinic acid-N-oxide (2) and trimethylsilyl cyanide; carrying out hydrazinolysis of the compound (3) to generate 2-cyano-isoniazid (4); and carrying out ring self-formation of the compound (4) to generate a target 2-(3-(2-amino pyridine-4-yl)-1H-1,2,4-triazole-5-yl)isoniazide (1). The synthesized high-purity topiroxostat impurity can be used as an impurity standard in topiroxostat finished product detection analysis, so as to enhance accurate positioning and qualitation on the impurity in the topiroxostat finished product detection analysis, be conducive to strengthening of the control of the impurity, and improve the quality of the topiroxostat finished product; the method provided by the invention has the advantages of cheap and easily obtained raw materials, and simple operation; the yield of the obtained product is 85%+ / -5%, and the HPLC purity is not less than 98%.
Description
technical field [0001] The invention belongs to the technical field of chemical pharmacy, and in particular relates to a topinastat impurity 2-(3-(2-aminopyridin-4-yl)-1H-1,2,4-triazol-5-yl)isoniacin Synthesis of hydrazine. Background technique [0002] With the development of society and the change of diet structure, the incidence of gout presents an increasing trend. Topirostat (Topiroxostat) was developed by Japan Fuji Pharmaceutical Co., Ltd., and was approved for marketing in Japan in June 2013. Topirostat has a significant inhibitory effect on both oxidized and reduced XOR, so it reduces the activity of uric acid. The effect is more powerful and long-lasting, so this product can be used to treat chronic hyperuricemia of gout. There are two advantages over allopurinol. 1: Allopurinol only has an inhibitory effect on reduced XOR, while topicastat has a significant inhibitory effect on both oxidized and reduced XOR, so its effect of lowering uric acid is more powerful ...
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