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Preparation method of topiroxostat

A technology of topinostat and compounds, applied in the field of drug preparation, can solve the problems of low yield, low purity, unsuitable for industrial production, etc.

Active Publication Date: 2022-04-12
安徽美致诚药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In summary, the current method for synthesizing topicastat in the art has the disadvantages of low yield and low purity, and is not suitable for industrialized production

Method used

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preparation example Construction

[0055] The invention provides a kind of preparation method of topicastat, comprises the following steps:

[0056] (1) 2-cyanopyridine and hydrazine hydrate are mixed for nucleophilic reaction to obtain a compound having a structure shown in formula II;

[0057]

[0058] (2) Mixing the compound having the structure shown in formula I and the compound having the structure shown in formula II for amidation reaction to obtain the compound having the structure shown in formula III;

[0059]

[0060] The compound having the structure shown in formula I is an acid chloride compound, an ester compound, a mixed anhydride compound or an acyl imidazole compound;

[0061] (3) subjecting the compound having the structure shown in formula III to a ring closure reaction to obtain topicastat.

[0062] The present invention provides and the synthetic route of topicastat such as figure 1 As shown, the following combination figure 1 To elaborate:

[0063] In the present invention, 2-cyan...

Embodiment 1

[0105] The preparation of embodiment 1 2-cyanoisonicotinic acid chloride

[0106] Add 300mL of dichloromethane and 30g of 2-cyano-4-pyridinecarboxylic acid into a 500mL four-neck flask, cool down to 0-5°C in an ice-water bath, add 64.3g of oxalyl chloride, drop 3 drops of DMF, and Insulated and stirred for 3 hours, then slowly raised to room temperature and reacted for 24 hours. After the reaction was completed, concentrated to dryness under reduced pressure to obtain 33.4 g of oily 2-cyanoisonicotinic acid chloride, with a yield of 99.4%.

Embodiment 2

[0107] Example 2 Preparation of methyl 2-cyanoisonicotinate

[0108] Add 20 g of 2-cyano-4-pyridinecarboxylic acid and 19.3 g of thionyl chloride into the three-necked flask, stir at room temperature for 30 minutes, add 40 g of methanol dropwise, stir at room temperature for 3 hours, then raise the temperature to 45°C for 2 hours, after the reaction is completed, Concentrate to dryness under reduced pressure, add 200mL dichloromethane, cool down to -5°C, adjust the pH to 7-8 with sodium carbonate, separate the organic layer, dry the organic layer with anhydrous sodium sulfate and filter, and concentrate the filtrate to dryness under reduced pressure 20.3 g of methyl 2-cyanoisonicotinate was obtained as a white solid, with a yield of 92.7%.

[0109] The NMR spectrum of the product is as figure 1 Therefore, the NMR data are as follows: 1 H-NMR (500MHz, DMSO-d6) δ: 8.96(1H,d), 8.38(1H,d), 8.14(1H,d), 3.93(3H,s).

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Abstract

The invention relates to the technical field of medicine preparation, and provides a preparation method of topiroxostat. The preparation method comprises the following steps: mixing 2-cyanopyridine and hydrazine hydrate for nucleophilic reaction to obtain a compound with a structure as shown in a formula II, and then taking the compound with the structure as shown in the formula I and the compound with the structure as shown in the formula II as raw materials to obtain topiroxostat through amidation reaction and cyclization reaction. The preparation method provided by the invention has the advantages of easily available raw materials, simple operation, high yield of each step, high product purity and less generated three wastes, and is suitable for industrial production; in addition, the compound with the structure shown in the formula III can be obtained only through one-step nucleophilic reaction, the synthesis route is short, and the cost is low. Furthermore, the preparation method provided by the invention is mild in reaction condition, and the amidation reaction is carried out at low temperature, so that the risk of cyano hydrolysis can be reduced, and the safety is better.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a preparation method of topinostat. Background technique [0002] Topinastat, the chemical name is 5-(2-cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole. Topilastat is a selective xanthine oxidoreductase (XOR) inhibitor with apurine structure, which has a competitive inhibitory effect on xanthine oxidoreductase, thereby inhibiting uric acid production, and has no inhibitory effect on other pyrimidine purine metabolic enzymes. Topicastat has a significant inhibitory effect on both oxidized and reduced XOR, so its effect of lowering uric acid is more powerful and durable, and it can be used for the treatment of gout and hyperuricemia. [0003] At present, the method for synthesizing topicastat mainly includes the following: [0004] CN1561340 is a Chinese patent applied by Fuji Pharmaceutical Co., Ltd. of Japan, in which isonicotinic acid-N-oxide is used as the starting...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
Inventor 史卫明史惠忠
Owner 安徽美致诚药业有限公司
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