Novel method for preparing pimobendan from by-product for synthesizing pimobendan

A technology of pimobendan and by-products, applied in the field of pharmaceutical chemical industry, can solve the problems of many reaction steps, unsuitable for industrialized production and the like, and achieve the effect of reducing production cost

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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Since the synthesis process using chlorinated benzene as the starting material involves many reaction steps (13-step reaction) and uses unit reaction operations such as liquid bromine and high-pressure ammoniation, it is not suitable for industrial production

Method used

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  • Novel method for preparing pimobendan from by-product for synthesizing pimobendan
  • Novel method for preparing pimobendan from by-product for synthesizing pimobendan
  • Novel method for preparing pimobendan from by-product for synthesizing pimobendan

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Experimental program
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Effect test

Embodiment 1

[0020]

[0021] By-product (chemical name is (5RS)-6-[1-(4-methoxybenzyl)-2-(4-methoxybenzyl)-1 H -Benzimidazol-6-yl]-5-methyl-4,5-dihydro-3(2 H )-pyridazinone) (4.54 g, 10 mmol) was dissolved in a mixed solvent of 50 ml of acetone and 25 ml of water, cerium ammonium nitrate (10.96 g, 20 mmol) was added, and the reaction was stirred at 25°C for 2 hours, and a precipitate was precipitated, filtered , the precipitate was collected, and the obtained solid was washed successively with 100 ml of water and 20 ml of acetone, and dried to obtain 3.03 g of a white solid. Add 45 ml of ethyl acetate to the resulting white solid, stir, heat to reflux for 30 minutes, cool, and filter the resulting white precipitate to obtain 2.94 g of pimobendan, with a yield of 88.1%. m.p: 241.1~242.5℃. 1 H-NMR (500MHz, DMSO-d6) δ: 12.86 (br s, 0.5H), 12.83 (br s, 0.5H), 10.91 (br s, 0.5H), 10.88 (br s, 0.5H), 8.12 ( d, J = 9.0, 2H), 8.02 (br s, 0.5H), 7.85 (br s, 0.5H), 7.73 (d, J = 8.5Hz, 0.5H), 7...

Embodiment 2

[0023] By-product (chemical name is (5RS)-6-[1-(4-methoxybenzyl)-2-(4-methoxybenzyl)-1 H -Benzimidazol-6-yl]-5-methyl-4,5-dihydro-3(2 H )-pyridazinone) (9.08 g, 20 mmol) was dissolved in a mixed solvent of 100 ml of acetone and 50 ml of water, added cerium ammonium nitrate (32.9 g, 60 mmol), stirred at 22°C for 2.5 hours, precipitated, filtered , the precipitate was collected, and the obtained solid was washed successively with 200 milliliters of water and 40 milliliters of acetone, and dried to obtain 6.23 grams of a white solid. Add 90 ml of ethyl acetate to the resulting white solid, stir, heat to reflux for 30 minutes, cool, and filter the resulting white precipitate to obtain 6.01 g of pimobendan, with a yield of 90%.

Embodiment 3

[0025] By-product (chemical name is (5RS)-6-[1-(4-methoxybenzyl)-2-(4-methoxybenzyl)-1 H -Benzimidazol-6-yl]-5-methyl-4,5-dihydro-3(2 H )-pyridazinone) (4.54 g, 10 mmol) was dissolved in a mixed solvent of 50 ml of acetone and 25 ml of water, cerium ammonium nitrate (13.7 g, 25 mmol) was added, and the reaction was stirred at 20°C for 3 hours, a precipitate was precipitated, filtered , the precipitate was collected, and the obtained solid was washed successively with 100 ml of water and 20 ml of acetone, and dried to obtain 3.23 g of a white solid. Add 45 ml of ethyl acetate to the resulting white solid, stir, heat to reflux for 30 minutes, cool, and filter the resulting white precipitate to obtain 3.05 g of pimobendan, with a yield of 91%.

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Abstract

The invention discloses a novel method for preparing pimobendan from a by-product for synthesizing the pimobendan. The method comprises the following steps that the by-product (the chemical name is (5RS)-6-[1-(4-methoxybenzyl)-2-(4-methoxyphenyl)-1H-benzimidazole-6-yl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone) obtained in the pimobendan synthesizing process is dissolved into a mixed solvent and reacts with ceric ammonium nitrate (CAN) at 20-25 DEG C for 2-3 hours so as to obtain a pimobendan crude product; and the obtained pimobendan crude product is heated and refluxed in an organic solvent, and cooling, filtering and drying are carried out so as to obtain the pimobendan. According to the method, the unwanted by-product is converted into a required pimobendan product, waste is turned intowealth, and therefore the production cost is greatly lowered.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical chemistry, in particular to a novel method for preparing pimobendan from by-products of synthesizing pimobendan. Background technique [0002] Pimobendan, also known as Pimobendan (Pimobendan), trade name Acardi®, its chemical name is 4, 5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazole- 5-yl]-5-methyl-3(2H)-pyridazinone was developed by Boechringer Ingelhem in Germany and first listed in Japan in 1994. The pharmacological action of pimobendan is characterized by enhancing the sensitivity of cardiac contractile proteins to calcium ions and inhibiting the activity of phosphodiesterase III (PDE-3), while also having the effect of dilating blood vessels, so it is an ideal positive muscle As a cardiotonic drug, it is clinically used to treat acute and chronic heart failure. Further studies have shown that pimobendan is also used in the treatment of heart failure in pet dogs. With the deepening...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04
CPCC07D403/04Y02P20/55
Inventor 不公告发明人
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