Preparation method of Roxadustat

A technology of methyl and formate esters, which is applied in the field of preparation of the drug Nordrestat, can solve problems such as difficult acquisition of enlightening raw materials, difficulty in industrial production, and cumbersome preparation process, and achieve the goal of promoting development, easy access to raw materials, and simple process Effect

Active Publication Date: 2015-09-09
南通华宇化工科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Moreover, the enlightening raw materials of the above reaction routes are not easy to obtain, and protection and deprotection reactions need to be carried out many ...

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

[0039] Add tyrosine (18.1 g, 0.1 mmol) and 250 mL of methanol into the dry reaction flask, cool down to 0-5° C. in an ice bath, and add 10 g of concentrated sulfuric acid with a weight percentage of 98% dropwise within 1 hour. After dropping, the temperature was raised to reflux. Stir the reaction for 16-20 hours, and TLC detects that the reaction is complete. Concentrate under normal pressure, add 100mL of pure water to the residue, adjust the pH to 6.5-7.0 with 10% by weight sodium hydroxide, a solid precipitates, filter, wash the chlorine cake with methanol and water (1:1), and vacuum dry to obtain white Solid tyrosine methyl ester (II) 15.3g, yield 78.5%; EI-MS m / z: 196[M+H] + .

Embodiment 2

[0041] In nitrogen atmosphere and ice bath, add tyrosine methyl ester (II) (9.8g, 50mmol), potassium methoxide (3.5g, 50mmol) and methanol 50mL in the reaction flask, after no gas is generated, heat to reflux, stir React for 2 hours. Concentrate under normal pressure to remove the solvent, add 25 mL of dimethyl sulfoxide and freshly prepared copper powder (0.2 g, 3.1 mmol) to the residue, and slowly heat up to 150-155 °C under stirring. After about half an hour, add bromobenzene (7.9 g , 50mmol), continue to heat up to 170-175°C, stir and react for 3 hours, and TLC detects that the reaction is complete. Cool to 60°C, add methanol and keep boiling slightly, filter while hot, wash the filter cake three times with hot ethanol, combine the organic phases, cool to 0°C, filter, and dry in vacuo to obtain a white solid 2-amino-3-(4- Methyl phenoxyphenyl)propionate (III) 11.5g, yield 84.9%; EI-MS m / z: 272[M+H] + .

Embodiment 3

[0043] Add 2-amino-3-(4-phenoxyphenyl) methyl propionate (III) (10.8g, 40mmol), 40% by weight acetaldehyde (20g, 0.2mol) and weight percent in reaction flask 50 mL of 35% concentrated hydrochloric acid was refluxed for 1 hour. Continue to add 40% by weight acetaldehyde (10 g, 0.1 mol) and 25 mL of concentrated hydrochloric acid with 35% by weight, and then reflux for 3-5 hours. Cool to 4-7 ° C, add ethyl acetate, extract and separate layers. The aqueous layer was adjusted to pH 11-12 with sodium hydroxide solution, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid 1-methyl-3-methyl-3-formate-7- Phenoxy-1,2,3,4-tetrahydroisoquinoline (IV) 8.4g, yield 70.7%; mass spectrum (EI): EI-MS m / z: 298[M+H] + .

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Abstract

The invention discloses a preparation method of Roxadustat. The preparation steps are as follows: the Roxadustat is prepared from tyrosine through esterification, etherification, cyclization, dehydrogenation, oxidative rearrangement and acylation reaction. The preparation method has the advantages that the raw materials are easily obtained; the process is simple; and the preparation method is economic and environmental-friendly, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of Nordrestat, which may be used to treat chronic anemia. Background technique [0002] Nordrestat (Roxadustat) is a small molecule of hypoxia-inducible factor (HIF) prolyl hydroxylase developed by FibroGen in the United States and licensed by Astellas and AstraZeneca Inhibitor, code-named FG-4592. As a first-in-class new oral drug, FG-4592 is currently in phase III clinical testing for the treatment of anemia associated with chronic kidney disease and end-stage renal disease. Because the medicine does not yet have a standard Chinese translation, the applicant here transliterates it as "Nordrestat". [0003] The chemical name of Nordrestat (Roxadustat, I) is: N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline) carbonyl] glycine, and its structural formula is: [0004] [...

Claims

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Application Information

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IPC IPC(8): C07D217/26
CPCC07D217/26
Inventor 许学农
Owner 南通华宇化工科技有限公司
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