New crystal form of topirastat and preparation method thereof
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A technology of topirax and crystal form, applied in the chemical and pharmaceutical field, to achieve the effect of high product purity, single crystal form, and short operation time
Active Publication Date: 2017-05-17
SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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[0005] Japan Fuji Pharmaceutical Co., Ltd. first disclosed this compound and its synthesis route in patent CN1561340, and disclosed two crystal forms of topirastat and a hydrate in patent WO2014014515. The patent introduces that crystal form I is in The solubility in water is 6.2 μg / ml, the solubility of crystal form II is 4.2 μg / ml, and the solubility of hydrate is 1.9 μg / ml. It can be seen that topirastat is a drug that is difficult to dissolve in water. Compared with crystal form II and hydrate, crystal form I of sestat has a higher solubility and is the preferred crystal form in preparations. However, it is reported in the patent CN104042577 that in the process of tablet compression, there is mutual interaction between form I and form II. The phenomenon of crystal transformation, the transformation of crystal form has a potential impact on the dissolution rate and stability of pharmaceutical preparations, the above-mentioned properties of topirastat make it have a huge potential in the preparation of solid preparations with good dissolution and / or stability challenge
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Embodiment 1
[0027] Add 500ml of dichloromethane, 100ml of methanol, 30.0g of topirastat to a clean and dry 1000ml reaction flask, add 18.4g of triethylamine, stir until the solid dissolves, add 0.6g of activated carbon, decolorize for 1 hour, filter out the activated carbon, Transfer the filtrate to another 1000ml reaction bottle, add 6N hydrochloric acid dropwise, adjust the pH to 6~7, after the dropwise addition, stir for 30min, filter with suction, rinse the filter cake with 30ml of a mixture of dichloromethane and methanol, and drain it , and the solid was air-dried at 30° C. for 6 hours to obtain a white solid, 28.5 g, which was topirastat crystal form III, with a yield of 95.0% and a purity of 99.8% by HPLC. The X-powder diffraction pattern of the topirastat crystal form III prepared in Example 1 is shown in figure 1 , whose DSC spectrum is shown in figure 2 , whose infrared spectrum is shown in image 3 .
Embodiment 2
[0029] Add 250ml of dichloromethane, 50ml of methanol, 30.0g of topirastat to a clean and dry 500ml reaction flask, add 36.8g of triethylamine, stir until the solid dissolves, add 0.6g of activated carbon, decolorize for 1 hour, filter out the activated carbon, Transfer the filtrate to another 500ml reaction bottle, add 6N hydrochloric acid dropwise, adjust the pH to 6~7, after the dropwise addition, stir for 30min, filter with suction, rinse the filter cake with 30ml of a mixture of dichloromethane and methanol, and drain it , and the solid was air-dried at 30° C. for 6 hours to obtain a white solid, 29.1 g, with a yield of 97.0% and a purity of 99.7% by HPLC.
Embodiment 3
[0031] Add 750ml of dichloromethane, 150ml of methanol, 30.0g of topirastat to a clean and dry 2000ml reaction flask, add 12.3g of triethylamine, stir until the solid dissolves, add 0.6g of activated carbon, decolorize for 1 hour, filter out the activated carbon, Transfer the filtrate to another 2000ml reaction bottle, add 6N hydrochloric acid dropwise, adjust the pH to 6~7, after the dropwise addition, stir for 30min, filter with suction, rinse the filter cake with 30ml of a mixture of dichloromethane and methanol, and drain it , and the solid was air-dried at 30° C. for 6 hours to obtain a white solid, 27.9 g, with a yield of 93.0% and a purity of 99.9% by HPLC.
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Abstract
The invention belongs to the field of chemical pharmaceutical technologies, and particularly relates to a novel topiroxostat crystal form. 2-theta characteristic peaks in X-ray powder diffraction patterns of the novel topiroxostat crystal form are positioned at 5.38+ / -0.2, 8.29+ / -0.2, 10.78+ / -0.2, 15.46+ / -0.2, 21.59+ / -0.2 and 26.88+ / -0.2 degrees. The invention further provides a method for preparing the novel topiroxostat crystal form. The method includes adding topiroxostat into organic solvents; adding alkali into the organic solvents; stirring the topiroxostat and the alkali in the organic solvents until that solid clearly dissolves; adding activated carbon for color removal; filtering the organic solvents to obtain filter liquid; dripping acid in the filter liquid to adjust pH (potential of hydrogen) of the filter liquid until the pH of the filter liquid reaches 6-7; dissolving solid out of the filter liquid; performing extraction filtration on the filter liquid to obtain filter cakes; leaching the filter cakes; drying the filter cakes to obtain the novel topiroxostat crystal form. The novel topiroxostat crystal form and the method have the advantages that the novel topiroxostat crystal form is good in thermal stability and high in wet stability and solubility; products are high in purity, are quite suitable for long-term storage and are suitable for preparing solid preparations with good dissolution and / or stability; the products prepared by the aid of the method have the single and stable crystal form and are quite suitable for industrial production.
Description
technical field [0001] The invention belongs to the technical field of chemical industry and pharmacy, and in particular relates to a new crystal form of topirastat and a preparation method thereof. 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] Japan Fuji Pharmaceutical Co., Ltd. first disclosed this compound and its synthesis route in ...
Claims
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Application Information
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Patent Type & Authority Patents(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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