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Method for synthesizing roxadustat intermediate

A technology of roxadustat and intermediates, applied in the field of chemical preparation, can solve the problems of high cost, shortage of 5-bromophthalide supply, large pollution, etc., and achieve the effect of low cost and easy control of reaction

Inactive Publication Date: 2019-11-26
成都蓝蜻蜓生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since Roxadustat was approved for marketing in China in December 2018, the demand has been huge, resulting in a tight supply of its key intermediate 5-bromophthalide, which is in short supply, and the price of 5-bromophthalide is relatively expensive, resulting in the final roxadustat. Salastat has a higher production cost
[0003] In the current production of chemical products, 5-bromophthalide is mostly prepared from phthalimide as the starting material through digestion, nitro reduction, carbonyl reduction, diazotization-bromination and other reactions. High, low total yield, many by-products and heavy pollution

Method used

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  • Method for synthesizing roxadustat intermediate
  • Method for synthesizing roxadustat intermediate
  • Method for synthesizing roxadustat intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0024] The purpose of this embodiment is to provide a kind of method of synthesizing roxadustat intermediate, and concrete steps are as follows:

[0025] Add 75.0g (0.35mol) of 4-bromo-2-methylbenzoic acid and 600g of ethylene dichloride to the three-necked reaction flask, mix to obtain mixture one, then add N-bromosuccinimide to mixture one 68.3 g (0.38 mol), 3.3 g (0.02 mol) of azobisisobutyronitrile, mix well to obtain mixture 2, heat mixture 2 to 60°C, and react for 3 h; after the reaction is completed, a reaction solution is obtained, and the reaction solution is used Wash once with 5% aqueous potassium carbonate solution and once with saturated sodium chloride solution, then dry with anhydrous sodium sulfate, and concentrate to dryness to obtain 71.8 g of 5-bromophthalide with a yield of 96.6%. The purity is 98.5 g by liquid chromatography. %.

Embodiment 2

[0027] The purpose of this embodiment is to provide a kind of method of synthesizing roxadustat intermediate, and concrete steps are as follows:

[0028] In the three-necked reaction flask, add 500g (2.3mol) of 4-bromo-2-methylbenzoic acid, 2500g of dichloroethane, and mix to obtain mixture one, and then add 414g of N-bromosuccinimide to mixture one (2.3mol), 19g (0.12mol) of azobisisobutyronitrile, mix well to obtain mixture 2, heat mixture 2 to 60°C for reaction, and react for 5h; Wash once with potassium carbonate aqueous solution and once with saturated sodium chloride solution, then dry with anhydrous sodium sulfate, and concentrate to dryness to obtain 478 g of 5-bromophthalide in a yield of 96.5%. The purity is 98.8% detected by liquid chromatography.

Embodiment 3

[0030] The purpose of this embodiment is to provide a kind of method of synthesizing roxadustat intermediate, and concrete steps are as follows:

[0031] In the three-necked reaction flask, add 400g (1.86mol) of 4-bromo-2-methylbenzoic acid and 4000g of ethylene dichloride, mix to obtain mixture one, then add 398g of N-bromosuccinimide to mixture one (2.24mol), 60g (0.37mol) of azobisisobutyronitrile, mixed evenly to obtain mixture two, the mixture two was heated to 70 ° C for reaction, and the reaction was carried out for 4h; Wash once with potassium carbonate aqueous solution and once with saturated sodium chloride solution, then dry with anhydrous sodium sulfate, and concentrate to dryness to obtain 380 g of 5-bromophthalide in a yield of 95.9%. The purity is 98.3% detected by liquid chromatography.

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Abstract

The invention belongs to the technical field of chemical preparation, and discloses a method for synthesizing a roxadustat intermediate. The method comprises the following steps: mixing 4-bromo-2-methylbenzoic acid and a solvent to obtain a mixture 1, adding N-bromosuccinimide and an initiator into the mixture 1, performing uniform mixing to obtain a mixture 2, and performing a reaction to obtainthe roxadustat intermediate 5-bromophthalide. The method provided by the invention has the following advantages: the method for synthesizing the roxadustat intermediate provided by the invention adopts the 4-bromo-2-methylbenzoic acid as the reaction raw material, the raw material is simple and easy to obtain, the costs are low, the reaction is easy to control, and the final product 5-bromophthalide has a yield of 96.5% or more and purity of 98.5% or more.

Description

technical field [0001] The invention belongs to the technical field of chemical preparation, in particular to a method for synthesizing a roxadustat intermediate. Background technique [0002] The oral drug Roxadustat (Codename FG-4592) capsules is the world's first small molecule hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) drug for the treatment of renal anemia. Hypoxia-inducible factor (HIF) not only increases the expression of erythropoietin, but also increases the expression of erythropoietin receptors and proteins that promote iron absorption and circulation. Roxadustat inhibits PH enzyme by mimicking ketoglutarate, one of the substrates of prolyl hydroxylase (PH), and affects the role of PH enzyme in maintaining the balance of HIF production and degradation rates, so as to correct anemia. , provides a new treatment for patients with anemia caused by chronic kidney disease. Since roxadustat was approved for listing in China in December 2018, the de...

Claims

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Application Information

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IPC IPC(8): C07D307/88
CPCC07D307/88
Inventor 王俊凯刘斯佳
Owner 成都蓝蜻蜓生物技术有限公司
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