Synthesis method of roxadustat

A technology that can be used to generate compounds and compounds, applied in the field of medicine and chemical industry, can solve the problems of difficult industrial production, expensive starting materials, harsh reaction conditions, etc., and achieve the effects of short production cycle, low cost and easy operation.

Active Publication Date: 2019-03-01
SHENZHEN KEXING PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] Patent CN108017583A is a preparation method of Kebomei, which is an improvement on the original patent WO2014014834A1, but the starting materials selected are relatively expensive
[0021] In summary, the existing synthetic method of Kebomei has ...

Method used

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  • Synthesis method of roxadustat
  • Synthesis method of roxadustat
  • Synthesis method of roxadustat

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Embodiment 1

[0100] The preparation of embodiment 1 compound B

[0101] Add 136.5ml of acetic acid and compound A (27.3g, 0.1mol) to the reaction flask, slowly add acetic anhydride (61.2g, 0.6mol) under stirring, and then heat up to 65--70°C for 2-3 hours. The solvent was distilled off under reduced pressure, 300 ml of 80% ethanol aqueous solution was added, stirred, filtered, and dried to obtain 35.3 g of solid compound B with a yield of 99.0% and a purity of 95.6%.

Embodiment 2

[0102] The preparation of embodiment 2 compound C

[0103] Add 357.0ml of anhydrous ethyl alcohol and compound B (35.7g) to the reaction flask, add concentrated sulfuric acid (1ml), raise the temperature to 70-78°C for 2-3 hours, after completion, evaporate the solvent under reduced pressure, add 500ml of water / 200ml of ethyl acetate After ester extraction and liquid separation, the organic layer was concentrated to dryness under reduced pressure to obtain 37.0 g of compound C with a yield of 96.2% and a purity of 92.9%.

[0104] MS:[M+1]=386.1

[0105] 1 H NMR(400MHz,DMSO)δ8.50(s,1H)7.03-7.55(m,10H),5.15(d,1H),4.15(q,2H),2.23(s,3H),1.92(s,3H ), 1.25(t,3H).

Embodiment 3

[0106] The preparation of embodiment 3 compound D

[0107] Add 154.0ml of acetonitrile and compound C (38.5g) to the reaction flask, add phosphorus oxychloride (76.5g), raise the temperature to 78-80°C for 2-3 hours, after completion, evaporate the solvent under reduced pressure, add 500ml of water / 200ml of acetic acid Ethyl ester extraction, liquid separation, and the organic phase was concentrated to dryness under reduced pressure to obtain 31.2 g of compound D with a yield of 85.0% and a purity of 97.7%.

[0108] MS:[M+1]=368.1

[0109] 1 H NMR(400MHz,DMSO)δ7.02-7.58(m,8H),6.55(d,1H),4.11(q,2H),2.34(s,3H),2.20(s,3H),1.22(t, 3H).

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Abstract

The invention provides a synthesis method of roxadustat. The roxadustat is prepared from 2-amino-3-hydroxyl-3-(4-phenoxyphenyl)propionic acid through the steps of acetic anhydride protection, esterification, cyclization, aromatic ring oxidation, hydrolysis and glycine condensation. The material used in the synthesis method is simple and easy to obtain, reaction operation is simple, the reaction conditions are mild, the product purity is high, the generation cycle is short, cost is low, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The present invention relates to the field of medicine and chemical industry, in particular to the synthesis method of Kebomei. Background technique [0002] Roxadustat is a small molecule inhibitor developed by FibroGen in the United States for regulating the stability or activity of hypoxia-inducible factor HIF. HIF (Hypoxia Inducible Factor) is a specific transcription factor that is very sensitive to cellular hypoxia and plays a key role in the homeostasis of oxygen in organisms. [0003] Kebomei, as a new type of oral hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), has a good effect in the treatment of anemia patients with kidney disease. These drugs can stimulate the body to produce an effect similar to that in the plateau area, prompting the body to produce more red blood cells to transport the oxygen needed by the body, thereby improving the red blood cells in the blood associated with anemia in patients with end-stage renal...

Claims

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Application Information

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IPC IPC(8): C07D217/26
CPCC07D217/26
Inventor 柏江涛马鸿杰赵彦轻
Owner SHENZHEN KEXING PHARM CO LTD
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