Synthetic method of roxadustat and intermediate thereof, and intermediate of roxadustat

A synthetic method and compound technology, applied in the direction of organic chemistry, can solve the problems of unfavorable industrial production, cumbersome operation, long steps, etc., and achieve the effect of less three wastes, simple post-processing, and short steps

Active Publication Date: 2021-12-21
JUMPCAN (SHANGHAI) MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] The technical problem to be solved by the present invention is to provide

Method used

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  • Synthetic method of roxadustat and intermediate thereof, and intermediate of roxadustat
  • Synthetic method of roxadustat and intermediate thereof, and intermediate of roxadustat
  • Synthetic method of roxadustat and intermediate thereof, and intermediate of roxadustat

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preparation example Construction

[0209] The specific embodiment of the preparation method of roxadustat of the present invention and the synthesis method of its intermediate are described in the following examples:

[0210] In the following examples, where the temperature is not specified for reactions or operations, etc., it generally means that the temperature is carried out at room temperature.

[0211] In the following examples, unless otherwise stated, the purity refers to HPLC purity or GC purity.

Embodiment 1

[0214] The synthesis of embodiment 1 roxadustat

[0215] The synthetic route is as follows:

[0216]

[0217] 1.1 Synthesis of Intermediate M1-1

[0218] Heat 2.95g (0.01mol) of compound 5 in 29.5g (about 0.4mol) of N,N-dimethylformamide (DMF) to 60°C-70°C to dissolve completely, and use 4.76g (0.02mol) of sodium persulfate 9.6 g (about 0.53 mol) of water was dissolved and added to the above solution, and stirred for 6 hours. TLC monitors that the reaction is complete, the reaction solution is cooled to room temperature, ethyl acetate (80mL) is added, washed with water (40mL×4), the organic phase is concentrated to a volume of 8-10mL, suction filtered, washed with a small amount of ethyl acetate, and the filter cake is vacuum-dried , 2.7 g of white solid was obtained, the yield was 73.5%, and the purity was 97.22%.

[0219] MS(ESI) m / z: 367.1[M+1] + , 1 H-NMR (400MHz, DMSO-d 6)δ11.62(s,1H),8.38(t,J=8.1Hz,1H),8.11(d,J=58.9Hz,1H),7.72(d,J=22.0Hz,1H),7.44-7.58( m,3H),7....

Embodiment 2

[0235] The synthesis of embodiment 2 intermediate 9

[0236] The synthetic route is as follows:

[0237]

[0238] 2.1 Synthesis of Intermediate M1-2

[0239] Heat 2.95g (0.01mol) of compound 5 in 29.5g (about 0.4mol) of N-methylacetamide to 60°C-70°C to completely dissolve, and 4.76g (0.02mol) of sodium persulfate with 9.6g (about 0.53mol) ) was dissolved in water and added to the above solution, and stirred for 8 hours. TLC monitors that the reaction is complete, the reaction solution is cooled to room temperature, ethyl acetate (80mL) is added, washed with water (30mL×4), the organic phase is concentrated to a volume of about 8-10mL, suction filtered, washed with a small amount of ethyl acetate, and dried. 2.4 g of white solid was obtained, the yield was 65.0%, and the purity was 98.76%.

[0240] MS(ESI) m / z: 367.2[M+1] + , 1 H-NMR (400MHz, DMSO-d 6 )δ11.59(s,1H),8.36(t,J=7.3Hz,2H),7.71(s,1H),7.56(d,J=9.0Hz,1H),7.46(t,J=7.4Hz, 2H), 7.25(t, J=7.3Hz, 1H), 7.14(d, J=7...

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Abstract

The invention discloses a synthesis method of roxadustat and an intermediate thereof and the intermediate of roxadustat. Specifically, the invention discloses a synthesis method of a compound M1, which comprises the following step: under the action of an oxidizing agent, a compound SM and a compound SM-A are subjected to a reaction as shown in the specification. The method provided by the invention has the advantages of cheap and easily available raw materials, short reaction steps, high yield and simple post-treatment process, and is suitable for industrial production.

Description

[0001] This application claims the priority of Chinese patent application CN2020105660802 with a filing date of June 19, 2020 and CN2020111483928 with a filing date of October 23, 2020. This application cites the full text of the above-mentioned Chinese patent application. technical field [0002] The present invention relates to a method for synthesizing roxadustat and its intermediates and the intermediates thereof. Background technique [0003] Roxadustat (Roxadustat) is a hypoxia-inducible factor proline hydroxylase inhibitor (HIF-PHI), developed by Fibrogen Company of the United States, licensed by Astellas and AstraZeneca, has been It is marketed in China for the treatment of anemia associated with chronic kidney disease and end-stage renal disease. [0004] The chemical name of roxadustat is: N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline)carbonyl]glycine, and its structural formula is as follows: [0005] [0006] The known synthetic routes of roxadustat mainly...

Claims

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Application Information

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IPC IPC(8): C07D217/26
CPCC07D217/26
Inventor 张勇王果杨飞刘凤伟周春东张梓桐
Owner JUMPCAN (SHANGHAI) MEDICAL TECH CO LTD
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