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Preparation method of roxadustat intermediate

A technology for roxadustat and intermediates, which is applied in the field of preparation of roxadustat intermediates, and can solve the difficulties of obtaining dimethyl ketomalonate, unpurified multi-step reaction intermediates, and difficulty in industrialization Advanced problems, to achieve the effect of enhancing labor protection, improving atomic economic efficiency, high yield and product purity

Active Publication Date: 2021-04-16
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the use of a type of solvent, carbon tetrachloride, will also generate the genotoxic impurity benzene sulfonate; the multi-step reaction intermediates are not purified and directly fed, which is not conducive to quality control; the route of isoquinoline ring formation is basically completely based on the original research route prepared by
[0009] Shanghai Xunhe Pharmaceutical Technology Co., Ltd. disclosed the synthesis method of roxadustat intermediate in Chinese patent application CN106478503A. The patent method has relatively short reaction steps, but the dimethyl ketomalonate used is not easy to obtain, and the cyclization The reaction needs to reach a high temperature of nearly 200 ° C, and the industrialization is difficult.

Method used

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  • Preparation method of roxadustat intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0057] Add 5g of 4-phenoxyphthalic anhydride and 50g of acetone into a 100ML three-necked flask, stir and dissolve, then add 5.8g of anhydrous potassium carbonate and 5.4g of N-benzylglycine methyl ester hydrochloride. Slowly raise the temperature to reflux, control the temperature at 55-60°C, and react for 4 hours. After the reaction, cool down to room temperature and filter. The filter cake is washed with acetone (10g×2), and drained until no liquid drips down to obtain 10.6g of compound 1 potassium salt wet product .

[0058] Add 106g of purified water and 10.6g of compound 1 potassium salt wet product into a 250ML three-necked flask, and stir to dissolve. Control the temperature at 0-10°C, and adjust the pH value to 2-3 with 2M hydrochloric acid. The crystallization was carried out under heat preservation and stirring for 2 hours. The filter cake was washed with purified water (10 g x 2), sucked dry and air-dried at 50-60° C. for 8 hours to obtain 8.3 g of white solid com...

Embodiment 2

[0068] Add 50g of 4-phenoxyphthalic anhydride and 500g of acetone into a 1L three-necked flask, stir and dissolve, then add 58g of anhydrous potassium carbonate and 54g of N-benzylglycine methyl ester hydrochloride. Slowly raise the temperature to reflux, control the temperature at 55-60°C, and react for 4 hours. After the reaction, cool down to room temperature and filter. The filter cake is washed with acetone (100g×2), and drained until no liquid drips down to obtain 119g of compound 1 potassium salt wet product.

[0069] Add 1.2kg of purified water and 119g of compound 1 potassium salt wet product into a 2L three-necked flask, and stir to dissolve. Control the temperature at 0-10°C, and adjust the pH value to 2-3 with 2M hydrochloric acid. The crystallization was carried out under heat preservation and stirring for 2 hours. The filter cake was washed with purified water (100 g x 2), drained and air-dried at 50-60° C. for 8 hours to obtain 85 g of white solid compound 1 wit...

Embodiment 3

[0079] Add 500g of 4-phenoxyphthalic anhydride and 5kg of acetone into a 10L double-layer glass reactor, stir and dissolve, then add 580g of anhydrous potassium carbonate and 540g of N-benzylglycine methyl ester hydrochloride. Slowly raise the temperature to reflux, control the temperature at 55-60°C, and react for 4 hours. After the reaction, cool down to room temperature and filter. The filter cake is washed with acetone (1kg×2), and dried until there is no droplet to obtain 1.3kg of compound 1 potassium salt wet product. .

[0080] Add 13kg of purified water and 1.3kg of compound 1 potassium salt wet product into a 30L double-layer glass reactor, and stir to dissolve. Control the temperature at 0-10°C, and adjust the pH value to 2-3 with 2M hydrochloric acid. Insulated and stirred for 2 hours to crystallize, the filter cake was washed with purified water (1kg×2), sucked dry, and air-dried at 50-60°C for 8 hours to obtain 837g of white solid compound 1 with a yield of 95%. ...

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Abstract

The invention discloses a preparation method of a roxadustat intermediate. The method comprises the following steps: anhydride ring opening, esterification, ring closing, aromatization, deprotection, chlorination and methylation to obtain the roxadustat intermediate. According to the invention, the preparation method provided by the invention makes full use of the atom economy theory, is easy to operate, low in cost and low in pollution, and is suitable for large-scale industrial production; and only one-time refining is carried out, the chromatographic purity can reach 99.5% or above, and the total yield of the six-step reaction is 30% or above.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of a roxadustat intermediate. Background technique [0002] Roxadustat is the first oral small molecule HIF-PHI developed by Fibrogen, mainly for the treatment of renal anemia, which can inhibit HIF-prolyl hydroxylation under normal oxygen partial pressure Enzymes, stabilize HIF-α, promote endogenous erythropoietin Erythropoietin, EPO production and improve iron absorption and utilization, and comprehensively regulate erythropoiesis. The results of two Phase III clinical trials in China for the treatment of anemia in dialysis-dependent (DD-CKD) and non-dialysis-dependent (NDD-CKD) chronic kidney disease patients met the primary efficacy endpoints. On December 18, 2017, roxadustat was included in the priority review by CDE as "having obvious therapeutic advantages compared with existing treatment methods", and China became the first market country for the wo...

Claims

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Application Information

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IPC IPC(8): C07D217/26
Inventor 邹贻泉徐浩宇顾国庆宣景安董达文李博吉烨徐晓剑李浩冬薛莲
Owner YANGTZE RIVER PHARM GRP CO LTD
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