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Synthesis method of Vadadustat

A synthesis method and condensing agent technology, applied in the direction of organic chemistry, etc., can solve the problems of short process flow, long synthesis steps, cumbersome operation, etc., and achieve the effect of reasonable technical scheme, simplified operation, and easy access to reagents

Inactive Publication Date: 2016-08-10
湖南欧亚药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The synthesis steps are relatively long, and the intermediate products and final products contain many impurities and by-products. Therefore, a large amount of solvents are required for purification, the operation is cumbersome, and the yield is low. At the same time, there is a safety risk in production due to the hydrogenation reaction, which is not conducive to industrialization. Production promotion, so it is necessary to explore the synthetic method of Vadadustat which is suitable for industrialized production because of its short process flow, simple operation and low cost

Method used

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  • Synthesis method of Vadadustat
  • Synthesis method of Vadadustat
  • Synthesis method of Vadadustat

Examples

Experimental program
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Effect test

Embodiment 1

[0028] A) Preparation of N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester:

[0029] 3,5-dichloro-2-pyridinecarboxylic acid (19.2g, 0.10mol) and N,N'-carbonyldiimidazole (24.3g, 0.15mol) were dissolved in N,N-dimethylformamide (100mL), added Glycine methyl ester hydrochloride (15.1g, 0.12mol) was added dropwise with N,N-diisopropylethylamine (51.7g, 0.40mol), the reaction mixture was stirred at 35°C for 8 hours, and TLC was spotted to confirm that the reaction was complete. The reaction solution was concentrated to dryness by rotary evaporation, adjusted to neutrality by adding dilute hydrochloric acid, extracted by adding ethyl acetate, dried over magnesium sulfate, concentrated by rotary evaporation to dryness, and recrystallized from methanol to obtain N-(3,5-dichloropyridine-2- Carbonyl) glycine methyl ester, off-white solid (21.6g), yield 82.0%, the reaction formula of this step is as follows:

[0030]

[0031] B) Preparation of N-[5-(3-chlorophenyl)-3-chloropy...

Embodiment 2

[0041] A) Preparation of N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester:

[0042] 3,5-dichloro-2-pyridinecarboxylic acid (20.5g, 0.107mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (26.5g, 0.17mol) were dissolved in N , N-dimethylacetamide (130mL), added glycine methyl ester hydrochloride (17.4g, 0.139mol), added dropwise triethylamine (54.0g, 0.53mol), the reaction mixture was stirred at 25°C for 10 hours, TLC Spot the plate to confirm the completion of the reaction, the reaction solution was concentrated to dryness by rotary evaporation, adjusted to neutrality by adding dilute hydrochloric acid, extracted by adding ethyl acetate, dried over magnesium sulfate, concentrated by rotary evaporation to dryness, and recrystallized from methanol to obtain N-(3,5- Dichloropyridine-2-carbonyl) glycine methyl ester, off-white solid (24.0g), yield 85.4%, the reaction formula of this step is the same as Example 1;

[0043] B) Preparation of N-[5-(3-chlorophenyl)-3-chlo...

Embodiment 3

[0050] A) Preparation of N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester:

[0051] 3,5-Dichloro-2-pyridinecarboxylic acid (30.0g, 0.16mol) and 1-hydroxybenzotriazole (35.9g, 0.27mol) were dissolved in N,N-dimethylformamide (220mL), added Glycine methyl ester hydrochloride (26.6g, 0.21mol), 4-dimethylaminopyridine (105.0g, 0.86mol) was added dropwise, and the reaction mixture was stirred and reacted at 30°C for 12 hours. TLC spotting confirmed that the reaction was complete, and the reaction solution was rotary evaporated Concentrate to dryness, add dilute hydrochloric acid to adjust to neutrality, add ethyl acetate to extract, dry over magnesium sulfate, concentrate to dryness by rotary evaporation, and recrystallize from methanol to obtain N-(3,5-dichloropyridine-2-carbonyl)glycine methyl Ester, off-white solid (33.6g), yield 81.7%, the reaction formula of this step is the same as Example 1;

[0052] B) Preparation of N-[5-(3-chlorophenyl)-3-chloropyridine-2-carbony...

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Abstract

The invention discloses a synthesis method of Vadadustat. The method 3,5-dichloro-2-picolinic acid and glycine methyl ester hydrochloride carry out condensation reaction; the obtained N-(3,5-dichloropyridine-2-carbonyl) glycine methyl ester and 3-chlorobenzene Boronic acid is carried out catalytic coupling reaction; The N-[5-(3-chlorophenyl)-3-chloropyridine-2-carbonyl] glycine methyl ester obtained and sodium methylate are carried out methoxy substitution reaction; The obtained N- [5-(3-chlorophenyl)-3-methoxypyridine-2-carbonyl]glycine is hydrolyzed to obtain finished product Vadadustat. The synthesis method has short route steps, simplified operation and low cost, is a green and environment-friendly method, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of Vadadustat. Background technique [0002] The chemical name of the HIF inhibitor Vadadustat (code name AKB-6548) is N-[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]glycine, and its chemical structure is: [0003] [0004] Vadadustat is an oral HIF inhibitor for the treatment of anemia and chronic kidney disease. It is a new drug under research invented by Akebia Therapeutics, an American biopharmaceutical company. At present, it has completed the key clinical phase II research and treatment trial, and successfully reached the in vivo target set by the researchers. Targets such as hemoglobin level and good safety, the curative effect is remarkable, and will be carried out in phase III clinical trials. [0005] A synthetic route for preparing Vadadustat disclosed in US Patent US20120309977: starting with 3-chlorophe...

Claims

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Application Information

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IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 李兴民陈健
Owner 湖南欧亚药业有限公司
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