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A technology of topiramate and pyridine, applied in the field of preparation of topirastat, can solve the problems of high difficulty in industrialization, low yield and the like, and achieve the effects of reducing operation difficulty, high yield, and reducing post-reaction processing burden
Active Publication Date: 2015-09-30
SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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Both routes have obvious disadvantages. The first route uses a highly toxic cyanation reagent, which has great potential safety hazards. The second route uses formamide to carry out carbamylation on the pyridine ring. The rate is low, the patent report is less than 40%, and the industrialization is difficult
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preparation example Construction
[0035] The preparation method of the compound of formula 5 used in embodiment 1-4 is:
[0036] In a 1000ml reaction flask, add 120g of 4-cyanopyridine-N-oxide, 360ml of 1,2-dichloroethane, 183.6g of phosphorus oxychloride, cool the reaction system to -2±2°C, add three Ethylamine 151.5g, dropwise time is 2h, after the dropwise addition is completed, keep warm for 2h, after the reaction is completed, the reaction solution is concentrated until no more fractions flow out, add 240ml of water, stir, a large amount of solids are precipitated, suction filtration, filter cake Rinse with water and dry to obtain 117.5 g of off-white solid, namely 2-chloro-4-cyanopyridine.
[0037] In a 1000ml reaction flask, add 110g of 2-chloro-4-cyanopyridine, add 660ml of methanol, 0.86g of sodium methoxide, stir at 25°C for 2h, then add 120g of isoniazid, continue to stir at 25°C for 2h, then Raise the temperature to methanol reflux, keep it warm for 12 hours, cool the reaction solution to room tem...
Embodiment 1
[0039] In a 2500ml reaction flask, add 180g of compound of formula 5, 13.3g of catalyst CuI, 18.5g of ligand DMEDA, KI 60g of K 4 [Fe(CN) 6 ]128.65g, Na 2 CO 3 74g, N,N-dimethylformamide 1080ml, under the protection of nitrogen, heat up to 120°C, keep warm for 10h, cool to room temperature, filter with suction, rinse the filter cake with water, and dry to obtain a white to light yellow solid, namely the product Topirastat, the yield is 80%.
Embodiment 2
[0041] In a 2500ml reaction flask, add 180g of compound of formula 5, 33.0g of catalyst CuI, 92.5g of ligand DMEDA, KI 116g of K 4 [Fe(CN) 6 ]77.2g, Na 2 CO 3 59.2g, N-methylpyrrolidone 1080ml, under the protection of nitrogen, heat up to 150°C, keep warm for 24h, cool to room temperature, filter with suction, rinse the filter cake with water, and dry to obtain a white to light yellow solid, namely the product topiramate He, the yield was 75.5%.
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Abstract
The invention belongs to the field of medicine and chemical engineering, and particularly relates to a preparation method for topiroxostat. 2-chloro-4-[(5-pyridine-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine is subjected to a cyanation reaction under the action of a cyanation reagent in the presence of a catalyst, base and a ligand to obtain topiroxostat. The preparation method comprises the following steps: 4-cyanopyridine-N-oxide is taken as a starting material, 1,2-dichloroethane is taken as a solvent, triethylamine is taken as base, phosphorus oxychloride is used as a chlorinated reagent, and chlorination is conducted to obtain 2-chloro-4-cyanopyridine; 2-chloro-4-cyanopyridine and isoniazide are in a methanol solvent, sodium methoxide is taken as a catalyst, and close-loop condensation is performed to obtain 2-chloro-4-[(5-pyridine-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine. The preparation method has the advantages that a safe and cheap cyanogroup source is selected, a hypertoxic cyanation reagent is avoided, the environmental harm is reduced, the product yield is high, the purity is high, and the suitability for industrial mass production is high.
Description
technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of topirastat. Background technique [0002] 4-[5-(Pyridin-4-yl)-1H-[1,2,4]triazol-3-yl]pyridine-2-carbonitrile, Chinese name: Topirostat, English name: Topiroxostat, commodity Name: TOPILORIC, is a non-purine xanthine oxidoreductase selective inhibitor for the treatment of gout, hyperuricemia. It was jointly developed by Japan Fuji Pharmaceutical Co., Ltd. and Sanwa Chemical Research Institute. In June 2012, it submitted a marketing application to the Ministry of Health, Labor and Welfare of Japan. On June 28, 2013, Topirastat tablets were approved. [0003] The chemical structure of 4-[5-(pyridin-4-yl)-1H-[1,2,4]triazol-3-yl]pyridine-2-carbonitrile (Topiroxostat) is as follows: [0004] [0005] The publicly reported synthetic routes of topirastat mainly contain the following: [0006] The patent CN1561340 applied by Fuji Phar...
Claims
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Application Information
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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 孙滨伊茂聪张宁马庆双王晓光
Owner SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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