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Preparation method of topiroxostat

A technology for topicastat and compounds, which is applied in the fields of drug synthesis and organic compound synthesis and preparation, can solve the problems of rare starting materials, low purity, and difficulty in obtaining starting materials, and achieves simple and feasible process route and reasonable method selection. , the effect of overcoming the problems of the prior art

Inactive Publication Date: 2016-03-16
CP PHARMA QINGDAO CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Patent EP1471056A1 mentions a synthetic method of topicastat, but the synthetic route is longer; the synthetic method involved in "Bioorganic & Medicinal Chemistry Letters 19 (2009) 6225-6229" has a shorter route, but the synthetic starting materials are difficult to obtain and difficult to obtain. Industrialized production; the synthesis method of topicastat in "TetrahedronLetters49(2008) 4369-4371" has harsh production conditions, requires high temperature and high pressure, and the starting materials are rare, so it is also difficult to industrialized production; patents CN104230891A and CN104151297A use copper catalysis
[0010] In summary, there are certain limitations in the existing methods, such as low yield, low purity, long cycle, etc.

Method used

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  • Preparation method of topiroxostat
  • Preparation method of topiroxostat
  • Preparation method of topiroxostat

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Embodiment

[0024] The main process involved in this embodiment is the same as in the summary of the invention, wherein the specific process of compound 3 and compound 5 is as follows:

[0025]

[0026] 1. Preparation of compound 3:

[0027] At room temperature, add 3.1Kg of compound 1 and 3.95Kg of dimethylcarbamoyl chloride into 20L of acetonitrile, and add 1.822Kg of trimethylsilyl cyanide under nitrogen protection; heat up to 60°C for 3 hours; after the reaction is complete, reduce the reaction solution to After room temperature, pour into 200L water and stir for crystallization for 3 hours, and adjust the pH value to 6-8; after the crystallization is complete, filter, wash the filter cake with 500mL water, and dry at 45°C to obtain 1.55Kg of off-white powder, which is compound 3. The rate is 48%.

[0028] 2. Preparation of compound 3:

[0029] At room temperature, add 4Kg of compound 1 and 5.1Kg of dimethylcarbamoyl chloride into 20L of acetonitrile, and add 2.35Kg of trimethyls...

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Abstract

The invention discloses a preparation method of topiroxostat, and belongs to the technical field of medicine synthesis and organic compound synthesis and preparation. N2-Boc-isonicotinic acid hydrazide-(compound 1)oxide and 4-cyanopyridine(compound 2) serve as the initial raw materials, and a compound 1 is subjected to cyanation, protect base removal and salifying to form a compound 4; the compound 4 and a compound 2 are subjected to a ring closing reaction and salifying to form a compound 5, and the compound 5 is subjected to salifying and refining, impurity removing achieved through activated carbon, alkali regulating and drying to form a high-purity product. By means of the method, the defects of the prior art are overcome, and the method has the advantages that raw materials are stable and easy to obtain, reaction conditions are mild, the technological process is simple, convenient and easy to control and the yield is high; the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of topicastat, which belongs to the technical field of medicine synthesis and organic compound synthesis and preparation. Background technique [0002] Topinostat, Chinese chemical name: 4-[5-(pyridin-4-yl)-1 H -1,2,4-triazol-3-yl]pyridine-2-carbonitrile, the structural formula is as follows: [0003] [0004] Molecular formula: C 13 h 8 N 6 [0005] Molecular weight: 248.24 [0006] Topinastat is an XOR inhibitor developed by Fuji Pharmaceutical Co., Ltd. of Japan. It is used for the treatment of gout and hyperuricemia. It was launched in Japan in June 2013. Currently, the product is not registered for sale in China. [0007] Gout is a crystal-associated arthropathy caused by the deposition of monosodium urate, which is directly related to hyperuricemia caused by purine metabolism disorders and / or decreased uric acid excretion, especially acute characteristic arthritis and chronic tophi Diseases ...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 王明刚陈阳生任莉孙桂玉刘晓霞臧云龙汪泓
Owner CP PHARMA QINGDAO CO LTD
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