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Preparation method of roxadustat

A technology of roxadustat and hydroxyl, applied in the field of medicine, can solve the problems such as inability to effectively meet the production requirements of enterprises, low conversion rate, long reaction time, etc., and achieve the effects of enhanced reducibility, improved synthesis efficiency, and high utilization rate of raw materials

Pending Publication Date: 2020-08-14
CHONGQING SANSHENG IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In this route, the reaction time for preparing A2 from A1 is long, which takes about 30 hours, and the conversion rate is low, about 60% to 70%, which cannot effectively meet the production needs of enterprises.
A3 is prepared by palladium-carbon hydrogenation reduction, which also has certain operational difficulties and risks

Method used

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  • Preparation method of roxadustat
  • Preparation method of roxadustat
  • Preparation method of roxadustat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The preparation of 1-((dimethylamino)methyl)-4-hydroxyl-7-phenoxyisoquinolinyl-3-carboxylic acid methyl ester (formula 2) is as follows:

[0033]

[0034] In a 250ml three-neck round bottom flask, 20g of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (Formula 1), 8.3g of tetramethyldiamine, and 30g of glacial acetic acid were added. After the feeding is completed, the temperature is raised to 55-60° C., and the reaction is carried out for 12 hours until the reaction of the raw materials in the liquid phase is basically completed. Cool down to obtain a glacial acetic acid solution containing methyl 1-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinolinyl-3-carboxylate, with a liquid phase purity of 97.0-98.5%.

Embodiment 2

[0036] The preparation of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester, the reaction formula is as follows:

[0037]

[0038] Add 25g of glacial acetic acid solution containing 1-((dimethylamino)methyl)-4-hydroxyl-7-phenoxyisoquinolinyl-3-carboxylic acid methyl ester (formula 2) in a 1L four-necked flask, 13g Zinc powder, stir, then add 7.5g of 5% dilute hydrochloric acid, heat up to 50-60°C, until the raw materials in the liquid phase basically react, cool down, filter, and the filtrate is rotary evaporated to obtain 4-hydroxy-1-methyl-7- Methyl phenoxyisoquinoline-3-carboxylate (Formula 3) has a purity of 96.9% and a yield of 87.7%.

Embodiment 3

[0040] Preparation of 4-Hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester

[0041] Add 25g of glacial acetic acid solution containing 1-((dimethylamino)methyl)-4-hydroxyl-7-phenoxyisoquinolinyl-3-carboxylic acid methyl ester (formula 2) in a 1L four-necked flask, 13g Flake zinc, stir, add 7.5g of 5% dilute hydrochloric acid, and heat up to 50-60°C. After the reaction of the raw materials in the liquid phase is basically completed, the temperature is lowered, filtered, and the filtrate is rotary evaporated to obtain methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (Formula 3).

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Abstract

The invention relates to a preparation method of roxadustat. In the method, methyl 4-hydroxy-7-phenoxyisoquinoline-3-formate and N,N,N',N'-tetramethyldiaminomethane as raw materials are reacted in glacial acetic acid and methyl 1-((dimethylamino) methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate is obtained after the reaction is finished; the obtained methyl 1-((dimethylamino) methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate is dissolved into glacial acetic acid, zinc is added, diluted hydrochloric acid is added, and after the reaction is finished, methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate is obtained; the obtained methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate is mixed with glycine, and dissolved into methanol, sodium methoxide is added, and after the reaction is finished, the target product roxadustat is obtained. The method is mild in reaction condition, simple and controllable in operation, low in preparation cost and suitable for large-scale industrial production, the obtained target product is high in purity, and the production requirements of enterprises are met.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of roxadustat. Background technique [0002] Roxadustat is a new type of hypoxia-inducible factor (HIF)-prolyl hydroxylase (PH) enzyme inhibitor. By stabilizing HIF, inhibiting its degradation, activating the transcription of related genes, and producing corresponding physiological responses, moderate Increase the concentration of erythropoietin, improve the sensitivity of erythropoietin (EPO) receptor, coordinate the production of red blood cells, reduce the level of hepcidin, increase the content and activity of transferrin receptor, promote the absorption and utilization of iron, and resist feel good. The chemical structural formula of roxadustat is as follows: [0003] [0004] The invention patent WO2014 / 14834 discloses the synthesis method of this compound, and the reaction process is shown in the following route: [0005] [0006] In this route, the re...

Claims

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Application Information

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IPC IPC(8): C07D217/26
CPCC07D217/26
Inventor 杨志坤彭磊何伟王珑霖张燕
Owner CHONGQING SANSHENG IND CO LTD
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