CAS number：577778-58-6
molecular formula：C13H8N6
molecular weight：248.24
EINECS number：1592732-453-0

English synonyms

FYX 051;Topiroxostat;Topiroxostat,FYX-051;5-(2-Cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole;Topiroxostat 5-(2-Cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole;4-[5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile;2-Pyridinecarbonitrile, 4-[5-(4-pyridinyl)-1H-1,2,4-triazol-3-yl]-;Topiroxostat impurty

Related categories

API API; API; Reference Substance-Impurity Reference Substance; API, Intermediate; Pharmaceutical Intermediate; Intermediate; Inhibitor; Small Molecule Inhibitor; Inhibitors; Small Molecule Inhibitor, Natural Product; Pharmaceutical API; Medicine raw materials; flavors and fragrances; organic raw materials; pharmaceutical inhibitors; pharmaceutical inhibitors; API; medical raw materials; chemicals; chemical reagents; biochemical industry; organic chemistry

Introduction

Topiroxostat (topiroxostat, FYX-051), the chemical name is 5-(2-cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole, produced by Japan A non-purine selective xanthine oxidoreductase inhibitor developed by Fuji Pharmaceutical Co., Ltd. that selectively and reversibly inhibits xanthine oxidoreductase and lowers serum uric acid levels.

Chemical properties

Use

●  Topicastat has a competitive inhibitory effect on xanthine oxidoreductase, thereby inhibiting uric acid production. It has no inhibitory effect on other pyrimidine purine metabolizing enzymes, but has selective inhibitory effect on xanthine oxidoreductase. Topicastat has a significant inhibitory effect on both oxidized and reduced XOR, so its effect of lowering uric acid is more powerful and durable, so this product can be used for the treatment of chronic hyperuricemia in gout.

Production method

Using N2-Boc-isonicotinic acid hydrazine-1 oxygen (compound 1) and 4-cyanopyridine (compound 2) as starting materials, compound 1 was cyanated, deprotected, and salted to obtain compound 4; compound 4 reacts with compound 2 in a ring-closing reaction to form a salt to obtain compound 5, which is purified by salt formation, impurity removal by activated carbon, alkali adjustment, and drying to obtain a high-purity product.
●  Add compound 1 and dimethylcarbamoyl chloride to acetonitrile at room temperature, and add trimethylsilyl cyanide under nitrogen protection; heat up to 60°C for 3 hours; after the reaction is complete, cool the reaction solution to room temperature and pour it into water Stir and crystallize, and adjust the pH value to 6-8; after the crystallization is complete, filter, wash the filter cake with water, and dry the solid to obtain an off-white powder, which is compound 3.
●  Compound 3 and p-toluenesulfonic acid were added to ethyl acetate to react for 24 hours; TLC detection showed that the solution was a white suspension after the reaction, and the solid was filtered, the filter cake was washed with ethyl acetate, and dried to obtain a white solid, which was Compound 4.
●  Dissolve compound 2 in ethanol, then add sodium methoxide, react at room temperature for 2 hours; then add compound 4 and heat up to reflux temperature for 20 hours; cool down to room temperature, pour the solution into water, stir and crystallize, filter, The filter cake was washed with water and dried to obtain a pale yellow wet product; the wet product was added together with p-toluenesulfonic acid into a mixed solvent of methanol: water: ethyl acetate (5:1:1), stirred at room temperature, and the final reaction solution was White suspension, filtered to obtain a light yellow solid; dry under reduced pressure at 80°C; add the light yellow solid to a mixed solvent of methanol:water (6:1), protect with nitrogen, heat up and reflux for reaction, after the solid dissolves, add Activated carbon was refluxed, filtered hot, cooled to room temperature for crystallization, and dried to obtain a white solid, compound 5.
●  Add compound 5 and sodium carbonate to a mixed solvent of acetone/water (volume ratio 1:1), stir at room temperature, filter, and wash the obtained solid with water and dry to obtain an off-white solid, which is topicastat API. 2. Using isonicotinic acid nitrogen oxide as raw material, using 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline as oxidant to synthesize isonicotinic acid methyl nitrogen oxide, and then using trimethyl Silane cyanide (TMSCN) is used as a cyanide reagent to synthesize 2-cyanoisonicotinic acid methyl ester; After the reaction of sodium methoxide, it is docked with 2-cyanoisonicotinic acid hydrazide to carry out the ring-closing reaction of triazole to obtain the final product of topicastat.
 3. First carry out condensation reaction with isonicotinic acid nitrogen oxide and mono-Boc-protected hydrazine to prepare Boc-protected isonicotinic acid hydrazide nitrogen oxide; then react with TMSCN to add cyano group; then remove the Boc protecting group, and 4-cyanopyridine docking was carried out to carry out the ring closure reaction of triazole to obtain the final product of topicastat.

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