Intermediate for topipitastat, preparation method thereof, and method for preparing topipitastat from intermediate

A technology of topicastat and intermediates, applied in the field of pharmaceutical synthesis, can solve the problems of residual by-products, high cost, complicated procedures, etc., and achieve the effects of reducing the generation of three wastes, reducing working hours, and reducing costs

Inactive Publication Date: 2018-07-06
BEIJING CHENG JI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] This route can prepare the target product in small batches, but it has obvious defects: in the reaction of condensing 2-cyanoisonicotinic acid methyl ester and hydrazine hydrate to prepare 2-cyanoisonicotinic acid carbohydrazide, the cyanide on the pyridine ring The base can also react with hydrazine hydrate, and its reactivity is strong, and the generated by-products will remain in the subsequent reaction, resulting in relatively large impurities in the final product, which requires repeated refining to obtain high-purity topicastat
[0021] After the ring-closing reaction, this route needs to add an amino protecting group first, and then carry out cyanation. After cyaniding, the protecting group needs to be removed. The process is more complicated, and due to the poor solubility of the intermediate, a large amount of solvent needs to be used for extraction. and washing, so the operation is cumbersome, the cost is high, and it is not suitable for industrial production

Method used

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  • Intermediate for topipitastat, preparation method thereof, and method for preparing topipitastat from intermediate
  • Intermediate for topipitastat, preparation method thereof, and method for preparing topipitastat from intermediate
  • Intermediate for topipitastat, preparation method thereof, and method for preparing topipitastat from intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0047] 1) Preparation of isonicotinic acid formyl hydrazide nitrogen oxide

[0048] Put 153g of methyl isonicotinate nitrogen oxide, 100g of hydrazine hydrate (85%), and 1.5L of methanol into a 3L single-necked flask, heat up to 50°C while stirring, react for 8h, cool down to below 20°C, filter, and use the filter cake After washing with 300ml of cold methanol, it was dried at 55°C for 8h to obtain 120g of off-white solid with a yield of 78.4%.

[0049] 2) Preparation of 3-(4-pyridyl)-5-(1-oxo-4-pyridyl)-1,2,4-triazole

[0050] Take 115g of 4-cyanopyridine, dissolve it in 1150ml of methanol, add 30g of sodium methoxide, stir at room temperature for 1 hour, add 150g of isonicotinic acid formohydrazide, raise the temperature to 90°C, all the solids are dissolved, and continue to reflux to gradually precipitate a light yellow solid. After 20 hours of reaction, the temperature was lowered to below 20°C, 1150ml of acetonitrile was added, stirred for 1h, the solid was filtered out,...

Embodiment 2

[0058] 1) Preparation of isonicotinic acid formyl hydrazide nitrogen oxide

[0059] Put 3000g of methyl isonicotinate nitrogen oxide, 2000g of hydrazine hydrate (85%), and 30L of methanol into a 50L glass jacketed reaction kettle, heat up to 50°C under stirring, react for 8h, cool down to below 20°C, filter, filter After the cake was washed with 6000ml of cold methanol, it was vacuum-dried at 55°C for 12h to obtain 2870g of off-white solid with a yield of 95.6%.

[0060] 2) Preparation of 3-(4-pyridyl)-5-(1-oxo-4-pyridyl)-1,2,4-triazole

[0061] Take 2850g of 4-cyanopyridine, 30L of methanol, and 450g of sodium methoxide, put them into a 100L glass jacketed reaction kettle, stir at room temperature for 1 hour, add 3370g of isonicotinic acid formohydrazide, raise the temperature to 90°C, all the solids are dissolved, and continue to reflux A light yellow solid gradually precipitated, and after 20 hours of reaction, the temperature was lowered to below 20°C, 30L of acetonitrile...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to an intermediate for topipitastat, a preparation method thereof, and a method for preparing topipitastat from theintermediate. The intermediate for the topipitastat is 3-(4-pyridyl)-5-(1-oxo-4-pyridyl)-1,2,4-triazole p-toluenesulfonate, and the structural formula of the intermediate is represented by formula (I). The preparation methods are characterized in that methyl isonicotinate oxynitride and hydrazine hydrate undergo a condensation reaction, a ring closing reaction and a salt formation reaction to obtain the intermediate, and the intermediate and N,N-dimethylformyl chloride undergo a cyanation reaction and a refining reaction to obtain the topipitastat. The methods effectively solve the technical problems of complex preparation process and low purity of topiroxostat, and have the advantages of simple process, good reproducibility, low cost, environmental protection and energy saving, so the methods have high industrial values and remarkable social and economic benefits. The preparation methods are used for preparing the key intermediate for the topiroxostat and the topiroxostat.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a topicastat intermediate and a preparation method thereof, and a new method for preparing a bulk drug topicastat by using the intermediate. Background technique [0002] Topiroxostat, developed by Fuji Pharmaceutical of Japan, is a new type of highly selective and reversible xanthine oxidase inhibitor. Topicastat was approved for marketing in Japan on June 28, 2013 for gout and hyperuricemia, trade name: Topicastat has a significant inhibitory effect on both oxidized and reduced XOR, so its effect of lowering blood uric acid is more powerful and durable, and has no adverse effects on the cardiovascular system, with better safety and clinical efficacy performance Significantly, it can greatly reduce the blood uric acid level, has good tolerance and few adverse reactions, and has great application prospects in the treatment of hyperuricemia and gout. [0003] The chemical name of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 张凯童丰何立涛陈永建
Owner BEIJING CHENG JI PHARMA
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