Synthesis method of topiroxostat

A technology of topicastat and its synthetic method, which is applied in the direction of organic chemistry, can solve the problems of unfavorable industrial production, cost reduction, high cost, etc., and achieve the effect of convenient operation, good purity and simple steps

Active Publication Date: 2017-10-20
KAIFENG PHARMA GRP +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] And patents CN104151297A, CN105348264A etc. all use isonicotinic acid-N-oxide as the starting material when preparing topicastat, resulting in high cost, which is not conducive to enterprises to reduce costs in industrial production
[0016] The starting materials

Method used

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  • Synthesis method of topiroxostat
  • Synthesis method of topiroxostat
  • Synthesis method of topiroxostat

Examples

Experimental program
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Effect test

Embodiment 1

[0029] In a 250ml three-necked flask, add 1g of tungsten powder to 10ml of 30% hydrogen peroxide by mass, and react for 20 minutes at 40-50°C, then add 100ml of methanol, 20g of 4-cyanopyridine, and 20ml of 30% hydrogen peroxide by mass, and raise the temperature to 60-65°C, react for 6h, after the reaction is completed, cool and crystallize naturally, wait for the temperature to cool to 25°C, continue to stir for 1h, filter with suction, and dry to obtain 20.5g of white crystals, namely intermediate 1, with a yield of 89.1%. HPLC purity (normalized method): 99.8%. NMR data related to Intermediate 1: H 1 NMR (400M Hz DMSO), 7.92(d, J=7.2,2H), 8.39(d, J=7.2,2H)

[0030] In a 250ml three-necked flask, add 0.4g sodium methoxide, 200ml methanol, 20g 4-cyanopyridine nitrogen oxide (intermediate 1), heat up to 40°C, react for 2h, add 17.8g ammonium chloride, react for 1h and then cool naturally Continue to stir for 0.5 h at 25°C, filter with suction, and dry to obtain 35.8 g of wh...

Embodiment 2

[0033] Embodiment 2: the preparation method of intermediate 1

[0034] In a 250ml three-necked flask, add 1g of tungsten powder to 10ml of 30% hydrogen peroxide by mass, and react for 20 minutes at 40-50°C, then add 100ml of water, 20g of 4-cyanopyridine, and 20ml of 30% hydrogen peroxide by mass, and heat up To 60-65°C, react for 6h, after the reaction is completed, cool and crystallize naturally, wait for the temperature to cool to 25°C, continue to stir for 1h, filter with suction, and dry to obtain 18.9g of white crystals, crude product, HPLC purity (normalization method) : 80.5%.

Embodiment 3

[0035] Embodiment 3: the preparation method of intermediate 1

[0036] In a 250ml three-necked flask, add 2.8g of tungsten powder to 20ml of 30% hydrogen peroxide by mass, and react for 0.5h at 40-50°C, then add 100ml of methanol, 20g of 4-cyanopyridine, and 20ml of 30% hydrogen peroxide in sequence , heated up to 60-65°C, reacted for 5h, after the reaction was completed, cooled and crystallized naturally, after the temperature was cooled to 25°C, continued to stir for 1h, filtered with suction, and dried to obtain 19.5g of white crystals, namely intermediate 1, with a yield of 84.4 %, HPLC purity (normalized method): 99.5%.

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Abstract

The invention belongs to the field of medicine and chemical industry and discloses a synthesis method of topiroxostat. The method comprises that 4-cyanopyridine as a starting raw material is oxidized by hydrogen peroxide to form an intermediate 1, the intermediate 1, sodium methoxide and ammonium chloride undergo a reaction to produce an intermediate 2, the intermediate 2 and 4-cyanopyridine undergo an annulation reaction under action of cuprous bromide and sodium carbonate to produce an intermediate 3, and the intermediate 3 and trimethylsilyl cyanide undergo a cyanation reaction to produce topiroxostat. The method utilizes low-price 4-cyanopyridine as a starting raw material, and in the first reaction step, methanol is used as a solvent and 4-cyanopyridine nitrogen oxide as the intermediate 1 is prepared. The method has a high yield and produces a high-purity product. The whole route is easy to operate and is conducive to industrial mass production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a synthesis method of topinostat. Background technique [0002] Gout is a disease caused by purine metabolic disorders. It has been listed by the United Nations as one of the 20 major chronic diseases in the 21st century, and it is the second largest metabolic disease after diabetes. Its clinical features are hyperuricemia and the resulting acute gout, chronic arthritis, and tophi deposition. In severe cases, it can cause joint deformities, renal insufficiency, and other important organ damage. In Western developed countries such as Europe and the United States, an average of 1% to 2% of men are affected by gout, and the prevalence rates of hyperuricemia and gout among American adults reach 21% and 3.9%, respectively. In my country, the prevalence of hyperuricemia and gout is also on the rise. After entering the 1990s, the prevalence of hyperuricemia in ...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 乔永辉王文远季明志孟庆乐崔浩刘博朱慧峰
Owner KAIFENG PHARMA GRP
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