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Preparation method of important intermediate of roxadustat

A technology for roxadustat and its intermediates, which is applied in the field of preparation of important intermediates of roxadustat, which can solve the problems of high requirements on site and safety, difficulty in popularizing and producing raw materials of roxadustat in large quantities, etc.

Pending Publication Date: 2021-03-05
NANJING HAIRUN PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Compound 3e is an important intermediate for the preparation of roxadustat, but the reaction described in the prior art uses palladium carbon and hydrogen high-pressure reaction, and sometimes heating is required. The high temperature and high pressure conditions are harsh, and there are high requirements for site and safety. Difficult to promote for the production of large quantities of raw materials for roxadustat

Method used

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  • Preparation method of important intermediate of roxadustat
  • Preparation method of important intermediate of roxadustat

Examples

Experimental program
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Embodiment 1

[0027] Take the raw material 3c (1g, 2.7mmol), add 20ml of tetrahydrofuran, add iron powder (0.89g, 15.9mmol), add acetic acid (3.0g, 50mmol) dropwise at room temperature, heat at 60°C for 12 hours after the addition, and detect the reaction of the raw material by TLC Complete, cool down to room temperature, filter with Celite pad, wash with 10ml THF, collect the filtrate, add 180ml water dropwise to the filtrate, solid precipitates, filter with suction, and dry to obtain 0.75g of the final product 3e, yield: 90%.

Embodiment 2

[0029] Take raw material 3c (1g, 2.7mmol), add 20ml of tetrahydrofuran, add zinc powder (0.89g, 13.6mmol), add acetic acid (1.7g, 28.3mmol) dropwise at room temperature, heat at 60°C for 4 hours after the addition, and detect the raw material by TLC After the reaction was complete, cool down to room temperature, filter with diatomaceous earth, wash with 10ml of THF, collect the filtrate, add 180ml of water dropwise to the filtrate, the solid precipitated, filtered with suction, and dried to obtain 0.77g of the final product 3e, yield: 93%.

Embodiment 3

[0031] Take raw material 3c (1g, 2.7mmol), add 10ml of N,N-dimethylformamide, add zinc powder (0.89g, 13.6mmol), add acetic acid (1.7g, 28.3mmol) dropwise at room temperature, and heat for 40 React at ℃ for 4 hours, TLC detects that the reaction of the raw materials is complete, cool down to room temperature, filter with diatomaceous earth, wash with 2ml of N,N-dimethylformamide, collect the filtrate, add 180ml of water dropwise to the filtrate, the solid precipitates, filter with suction, After drying, 0.76 g of the final product 3e was obtained, yield: 91%.

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Abstract

The invention belongs to the field of preparation of drug intermediates, and relates to a preparation method of an important intermediate 3e of roxadustat. According to the method, 3c is used as an initial raw material and reacts with acetic acid and metal powder in a solvent under the action of the acetic acid and the metal powder to prepare 3e. The method is mild in reaction condition; high temperature and high pressure are not needed; the reaction can be carried out under normal pressure; the method is suitable for industrial amplification; and the yield and purity of the method are equivalent to those of a contrast patent of which the number is CN103435546B.

Description

technical field [0001] The invention belongs to the field of preparation of pharmaceutical intermediates, and in particular relates to a preparation method of an important intermediate of roxadustat. Background technique [0002] Roxadustat, trade name: Arizhuo, is the world's first small molecule hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor developed by FibroGen (Chinese name: FibroGen). Red blood cell production, regulation of iron metabolism, and reduction of hepcidin in the treatment of renal anemia. On December 17, 2018, the drug passed the priority review and approval process in China for the first time in the world. It is a Class 1 innovative drug. The drug is currently available in the United States and Japan None of them are listed yet. Its chemical name is N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinolyl)carbonyl]glycine, and its chemical structure is as follows: [0003] [0004] Example 3 of paragraph [0633] of the CN103435546B specification d...

Claims

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Application Information

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IPC IPC(8): C07D217/26
CPCC07D217/26
Inventor 赵俊孙敏贾剑敏孙焕亮解杰蔡开明李靖
Owner NANJING HAIRUN PHARM CO LTD
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