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Preparation method of Roxadustat

A technology of roxadustat and compounds, which is applied in the field of preparation of roxadustat, can solve the problems of unsuitability for industrial production, difficulty in obtaining starting materials, and high reaction temperature, and achieve no safety hazard, short reaction time, and simple operation Effect

Active Publication Date: 2020-07-10
SHANDONG BESTCOMM PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The starting materials of this process are not easy to obtain, and the price is relatively expensive; the chloroacetic acid used is moderately toxic, the carcinogenicity of methyl chloride has genotoxicity, the oxidation of potassium permanganate is strong, and hydrochloric acid, sulfuric acid, liquid bromine and chloroacetic acid are all controlled products. Reagents have certain safety hazards; the reaction temperature in the first step is as high as 150°C, and the reaction temperature in the ninth step is as high as 220°C; the storage of methyl chloride and ammonia gas cylinders has relatively large safety hazards and is not suitable for industrial production

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

[0074] Example 1: Methyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate

[0075]

[0076] Methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (50.00g, 169.45mmol) was added to 500ml of tetrahydrofuran, then NBS (31.67g, 177.93mmol) and AIBN (1.39g, 8.47mmol) ). After the addition, react at 25°C for 1h. TLC analysis (petroleum ether-ethyl acetate=3:2) showed that the reaction was complete. Post-treatment: Concentrate under reduced pressure to remove most of the solvent, then add 500ml of methanol and heat to reflux for 0.5h, cool down, filter, wash the filter cake with about 50ml of methanol, and dry to obtain 60.60g of off-white solid, yield 95.64%, LC- MS spectrum see figure 1 , The spectrum shows no obvious impurity peaks.

[0077] 1 H-NMR(600MHz, DMSO-d 6 ): δ3.00 (3H, s), 7.27 (2H, dd, J=7.2, 1.2Hz), 7.34 (1H, t, J=7.2Hz), 7.41 (1H, d, J=2.4Hz), 7.54 (2H, td, J=7.2, 1.2 Hz), 7.69 (1H, dd, J=9.0, 2.4 Hz), 8.37 (1H, d, J=9.0 Hz), 11.54 (1H, s).

Embodiment 2

[0078] Example 2: 1-Bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid

[0079]

[0080] Methyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (71.00g, 189.74mmol) was added to 300ml of ethanol, then sodium hydroxide (22.71g, 569.22mmol) and 300ml were added A mixture of water. After the addition, the temperature is raised to reflux for about 1 hour. TLC analysis (petroleum ether-ethyl acetate=5:1) showed that the reaction was complete. Post-treatment: cool down, concentrate under reduced pressure to remove part of the solvent, then add 500ml of water, 2M hydrochloric acid to adjust the pH to 2-3, stir and crystallize for 0.5h, filter, and dry to obtain 67.70g of light red solid, related substances 99.31%, yield 99.06%.

[0081] 1 H-NMR(600MHz, DMSO-d 6 ): δ 7.27 (2H, dd, J=7.2, 1.2 Hz), 7.34 (1H, t, J=7.2 Hz), 7.42 (1H, d, J=2.4 Hz), 7.54 (2H, td, J= 7.2, 1.2 Hz), 7.68 (1H, dd, J=9.0, 2.4 Hz), 8.36 (1H, d, J=9.0 Hz), 13.08 (about 2H, brs).

Embodiment 3

[0082] Example 3: (1-Bromo-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine methyl ester

[0083]

[0084] Add 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid (20.00g, 55.53mmol) to 250ml of dichloromethane, and then add glycine methyl ester hydrochloride (10.46g, 83.30mmol) ) And PyBOP (43.35g, 83.30mmol), and finally triethylamine (22.48g, 222.12mmol) was added. After the addition, the temperature is controlled at 25°C to react for about 2h. TLC analysis (DCM-MeOH (10:1)+3dHAc) showed that the reaction was almost complete. Post-treatment: add 120ml of water to the reaction system, separate the liquids, extract twice with dichloromethane (200ml×2), combine the organic phases, dry with anhydrous magnesium sulfate, decolorize with activated carbon, filter, and concentrate under reduced pressure to obtain 75.02g of a white solid.

[0085] Refining: add 400ml of isopropanol to the above crude product, heat and reflux for 0.5h, cool down, filter, wash the filter cake wit...

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Abstract

The invention provides a preparation method of Roxadustat. The preparation process provided by the invention has the advantages of cheap and easily available initial raw materials, short synthetic route, short reaction period, no environmental pollution, simple operation, avoidance of harsh reaction conditions, simple operation and post-treatment, high yield and product purity, easy purifying of intermediates in each step, low production cost, suitability for industrial large-scale production, and accordance with the principle of green chemistry.

Description

[0001] 1. Technical field [0002] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a preparation method of rosastat. [0003] 2. Background technology [0004] Roxadustat (Roxadustat, FG-4592) was originally developed by FibroGen in the United States. In April 2006, Astellas reached a license agreement with FibroGen, and obtained the development rights of Roxastat in Europe, CIS, Middle East and South Africa. On July 31, 2013, AstraZeneca (AstraZeneca) and FibroGen reached a strategic cooperation agreement for development rights in the United States, China, and major markets outside of the aforementioned Astellas license areas. [0005] On December 18, 2018, Roxastat, which was jointly developed by Fabojin China and AstraZeneca China, was first approved for marketing in China for the treatment of anemia caused by chronic kidney disease (CKD) in patients undergoing dialysis treatment. The marketed preparations are capsules, the specific...

Claims

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Application Information

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IPC IPC(8): C07D217/26
CPCC07D217/26
Inventor 姜坤甄宜战高冈严孝红陈晓荔张蕙
Owner SHANDONG BESTCOMM PHARMA CO LTD
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