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Preparation method of Roxadustat

A technology for biopharmaceuticals and compounds, which is applied in the field of preparation of biopharmaceuticals, can solve the problems of unfavorable industrial production and high requirements for reaction temperature equipment, and achieve the effects of good industrialization prospects, reduction of by-products, and simplified process routes.

Active Publication Date: 2018-05-11
XUZHOU WANBANG JINQIAO PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The route in Kebomei’s original research patent WO2014014834A1 requires a step of intermediate state conversion when synthesizing compound 3, and the last step of urethane exchange reaction requires the use of an autoclave, the reaction temperature and equipment requirements are relatively high, which is not conducive to large-scale 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

[0028] Preparation of compound 2:

[0029]

[0030] Compound 1 (100g, 0.338mol) was dissolved in 215mL acetic acid / trifluoroacetic acid (volume ratio: 7 / 1) mixed solvent, and tetramethylaminomethane (43.25g, 0.423mol) was slowly added dropwise. After the addition was complete, the temperature was raised to React at 45°C for 15 hours, the TLC plate detects that the reaction is complete, the reaction solution is cooled to room temperature, and directly put into the next step without any treatment.

[0031] Preparation of compound 3:

[0032]

[0033] At room temperature, acetic anhydride (43.13 g, 0.423 mol) was added dropwise to the reaction solution for the preparation of Compound 2 above. After the addition was complete, the reaction solution was heated to 90° C. for 12 hours. The TLC plate detected that the reaction was complete, and the reaction solution was cooled to room temperature and added dropwise to 1L of water, the solid product slowly precipitated, filtered ...

Embodiment 2

[0041] Preparation of compound 2:

[0042]

[0043] Compound 1 (150g, 0.507mol) was dissolved in 300mL acetic acid / trifluoroacetic acid (volume ratio: 10 / 1) mixed solvent, and tetramethylaminomethane (64.88g, 0.634mol) was slowly added dropwise. After the addition was complete, the temperature was raised to React at 50°C for 12 hours, the TLC plate detects that the reaction is complete, the reaction solution is cooled to room temperature, and directly put into the next step without any treatment.

[0044] Compound 3 was prepared according to the method described in Example 1 to obtain 155 g of Compound 3 with a total yield of 83.07% and an HPLC purity of 99.05%.

[0045] Preparation of compound 4:

[0046]

[0047]Add compound 3 (150g, 0.41mol), 750ml ethyl acetate, sodium carbonate (24.2g, 0.22mol), Pd / C (22.5g) in sequence to the hydrogenation reactor, and pressurize the hydrogen to 0.8MPa after nitrogen replacement , the reaction solution was heated to 50°C for 12 h...

Embodiment 3

[0052] Compound 2, Compound 3 and Compound 4 were prepared as described in Example 2.

[0053] Preparation of Compound 5:

[0054]

[0055] Compound 4 (30g, 0.097mol) and glycine (36.4g, 0.485mol) were dissolved in ethylene glycol methyl ether (150mL), then triethylamine (TEA) (29.45g, 0.291mol) was added, and the mixture was heated to React at 95°C for 1.5h, TLC plate detects that the reaction is complete, the reaction solution is lowered to room temperature to concentrate the solvent, add 300mL of water to dissolve, extract with ethyl acetate three times, collect the aqueous phase and adjust the pH with dilute hydrochloric acid, the solid slowly precipitates, filter, filter cake After washing with water and then with acetone, the filter cake was collected and dried to obtain 31.8 g of compound 5, with a total yield of 92.98% and an HPLC purity of 99.79%.

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Abstract

The invention discloses a preparation method of Roxadustat, compound 1 and bis(dimethylamino)methane are heated in a mixed solvent of acetic acid and trifluoroacetic acid for reaction to form compound2; acetic anhydride is added to the obtained reaction solution of the compound 2 for completing reaction by heating to form compound 3; the compound 3 is dissolved in ethyl acetate and heated, then is catalyzed by Pd / C, and reduced by hydrogen to obtain compound 4; the compound 4 and glycine are dissolved in a solvent, and heated under the action of an organic base for reaction to obtain compound5; wherein the solvent is one or more of dioxane, ethylene glycol monomethyl ether, toluene, acetonitrile and n-propanol, the organic base is one or more of triethylamine, 1,8-diazabicyclo undecane-7-ene, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, and ethylenediamine; the preparation method has the advantages of shorter reaction time, low reaction temperature, low equipment condition requirements and high crude product purity, is suitable for large-scale industrial production, and has a good industrialization prospect.

Description

technical field [0001] The invention belongs to the technical fields of organic synthesis route design and medicine and chemical industry, and specifically relates to a synthesis method of a small molecule inhibitor used to regulate the level or activity of HIF in the body, and more specifically relates to a preparation 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 t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/26
CPCC07D217/26
Inventor 韩瑞燕李春雷乔德水
Owner XUZHOU WANBANG JINQIAO PHARMA
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