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High-purity, small-particle-diameter and low-solvent-residue azilsartan bulk drug and preparation method thereof

A technology for raw materials and solvents, applied in the field of drug synthesis, can solve the problems of large particle size, high solvent residue, low purity and the like

Inactive Publication Date: 2018-11-30
珠海润都制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] In view of the deficiencies of the existing azilsartan raw materials, such as low purity, large particle size or high solvent residue, it is necessary to develop a high-quality azilsartan and its preparation method

Method used

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  • High-purity, small-particle-diameter and low-solvent-residue azilsartan bulk drug and preparation method thereof
  • High-purity, small-particle-diameter and low-solvent-residue azilsartan bulk drug and preparation method thereof
  • High-purity, small-particle-diameter and low-solvent-residue azilsartan bulk drug and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] The preparation of embodiment 1 compound III-1

[0106]

[0107] Add 60g of N,N-dimethylformamide into the reaction flask, add 19.5g of sodium carbonate under stirring, stir evenly, add 8.5g of hydroxylamine hydrochloride, raise the temperature to 35°C, stir for 30 minutes, add 25g of compound IV-1, Continue to raise the temperature to 60°C, and stir for 24 hours. After the reaction, cool down to crystallize, and filter to obtain the crude compound III-1. The obtained crude product and DMSO were added into a reaction flask, heated up for crystallization for 1 hour, cooled down for crystallization, filtered, and dried to obtain compound III-1 with a yield of 75%.

Embodiment 2

[0108] The preparation of embodiment 2 compound II-1

[0109]

[0110] Add 30g of ethyl acetate, 15g of compound III-1, and 3g of trimethylamine into the reaction flask, stir, cool down to 5°C, slowly add 5.1g of isopropyl chloroformate, and continue the reaction at this temperature. Water was added to quench, the aqueous layer was washed once with ethyl acetate, the ethyl acetate solution was combined, the ethyl acetate layer was washed once with water, and concentrated under reduced pressure to obtain solid V-1. Add the obtained solid V-1 and toluene into a reaction flask, stir and raise the temperature to 100°C for reaction. After the reaction, cool down to crystallize, and filter to obtain the crude compound II-1. The obtained crude product II-1 was added to toluene, stirred and crystallized at 50° C. for 1 h, cooled to 10° C., stirred and crystallized for 1 h, and filtered and dried to obtain compound II-1 with a yield of 77%.

Embodiment 3

[0111] Example 3 Preparation of Compound III-2

[0112]

[0113] Add 200g DMSO to the reaction bottle, add 18g sodium hydroxide under stirring, stir evenly, add 24g hydroxylamine hydrochloride, heat up to 70°C, stir for 2h, add 25g of compound IV-2, continue to heat up to 85°C, stir for 20h, After the reaction, the temperature was lowered for crystallization and filtered to obtain the crude compound III-2. The obtained crude product, DMF and acetone mixed solution were added into a reaction flask, heated up for crystallization for 3 hours, cooled down for crystallization, filtered, and dried to obtain compound III-2 with a yield of 80%.

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PUM

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Abstract

The present invention discloses a high-purity, small-particle-diameter and low-solvent-residue azilsartan bulk drug and a preparation method thereof. The purity of the azilsartan bulk drug is more than or equal to 99.9%; the particle size of D90 is less than or equal to 20 [mu]m; and the solvent residue is less than or equal to 500 ppm. The present invention also discloses a high-purity intermediate used for preparing the azilsartan bulk drug and a preparation method thereof, wherein the purity of the intermediate is more than or equal to 99.9%.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to azilsartan, in particular to azilsartan with high purity, small particle size and low solvent residue and a preparation method thereof. Background technique [0002] Azilsartan (AzIlsartan) chemical name: 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazole-3- Base) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid, molecular formula: C25H20N4O5, molecular weight: 456.45, structural formula I is: [0003] [0004] Azilsartan is an AT1 subtype angiotensin II receptor antagonist (ARB) developed by Japan's Takeda Corporation, which was approved for marketing in Japan on January 18, 2012. As a new generation of dual-function ARBs, it not only antagonizes the type 1 receptor of angiotensin II (AT1 receptor), but also may reduce the risk of cardiovascular disease and diabetes through multiple mechanisms. Clinical trials have proved that azilsartan has good curative effect, low inci...

Claims

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Application Information

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IPC IPC(8): C07D413/10
CPCC07B2200/13C07D413/10
Inventor 徐成张榕芳覃志俊蔡强焦慎超祁红林黄肖艳刘月花周爱新陈新民
Owner 珠海润都制药股份有限公司
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