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Preparation method of key intermediate of Pimobendan

A technology for pimobendan and intermediates, applied in the field of preparation of 4,5-dihydro-5-methyl-6--3 pyridazinone, which can solve the problem of harsh production conditions, difficulty in realizing industrialized production, and many steps and other problems, to achieve the effects of less environmental pollution, easy industrial scale-up, and fewer reaction steps

Inactive Publication Date: 2017-12-29
天津长芦华信化工股份有限公司
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Problems solved by technology

However, there are many steps involving high-temperature reactions in this method, and the production conditions are relatively harsh, and the use of highly toxic KCN is unfavorable for suitability for industrialized production
[0014] In summary, most of the current research methods have long routes and low total yields; the production conditions are relatively harsh, and all reagents are highly toxic, making it difficult to achieve industrial production

Method used

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  • Preparation method of key intermediate of Pimobendan
  • Preparation method of key intermediate of Pimobendan
  • Preparation method of key intermediate of Pimobendan

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preparation example Construction

[0042] A preparation method of pimobendan key intermediate, comprising the following steps:

[0043] (i) Synthesis of compound Ⅰ

[0044] In an organic solvent, using acetanilide and 2-bromopropionyl bromide as raw materials, under the action of a Lewis acid catalyst, compound I, i.e. N-(4-(2-bromopropionyl)phenyl)acetamide, is generated;

[0045] (ii) Compound I undergoes a nucleophilic substitution reaction to generate Compound II

[0046] Compound I undergoes a nucleophilic substitution reaction with diethyl malonate in a reaction solvent under the action of a base to generate compound II, namely 2-ethoxycarbonyl-3-(4-acetamidobenzoyl)-butyric acid ethyl ester;

[0047] (Ⅲ) Compound II generates compound III through nitration reaction

[0048] Compound II and mixed acid generate compound III through nitration reaction, that is, ethyl 2-ethoxycarbonyl-3-(3-nitro-4-acetamidobenzoyl)-butyrate;

[0049] (iv) Compound Ⅲ is hydrolyzed to generate compound Ⅳ

[0050] Compound...

Embodiment 1

[0067] (i) Stir 100g of acetanilide and 150g of 2-bromopropionyl bromide into 3L of DMSO solvent, add 60g of ferric chloride catalyst, keep the reaction temperature at -15~-10℃, and stir for 2h~3h , slowly poured the reaction solution into crushed ice, stirred to precipitate a solid and then filtered it. The filter cake was washed with water and dried to obtain 190 g of compound I with a purity of 97% and a melting point of 122°.

[0068] (ii) 100g of compound I, 35g of potassium tert-butoxide, and 120g of diethyl malonate were added to the DMA solution under stirring, and the reaction temperature was kept at 70°C~75°C until TLC traced the disappearance of the raw materials. After the reaction was completed, the system was slowly poured into 1L of ice water to quench, stirred until solid precipitated, filtered and dried to obtain 121 g of Compound II with a purity of 95%.

[0069] (Ⅲ) Mix 600ml of concentrated sulfuric acid and 300ml of concentrated nitric acid and lower the t...

Embodiment 2

[0075] (i) Stir 100g of acetanilide and 200g of 2-bromopropionyl bromide into 2L of dichloromethane solvent, add 200g of zinc chloride catalyst, keep the reaction temperature at -20°C~-30°C, and stir for 1h After ~2h, the reaction solution was slowly poured into crushed ice, the solid was precipitated under stirring, and then filtered. The filter cake was washed with water and dried to obtain 195g of compound I with a purity of 96% and a melting point of 122°.

[0076] (ii) Add 100 g of compound I, 30 g of sodium ethoxide, and 100 g of diethyl malonate into the THF solution under stirring, and keep the reaction temperature at 50°C~55°C until TLC traces the disappearance of the raw materials. After the reaction was completed, the system was slowly poured into 1L of ice water to quench, stirred until solid precipitated, filtered and dried to obtain 120 g of Compound II with a purity of 95%.

[0077] (Ⅲ) Mix 300ml of concentrated sulfuric acid and 900ml of concentrated nitric aci...

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Abstract

The invention discloses a preparation method of a key intermediate of Pimobendan. The method comprises steps as follows: (i) a compound I is synthesized; (ii) the compound I is subjected to nucleophilic substitution, and a compound II is produced; (iii) the compound II is subjected to a nitration reaction, and a compound III is produced; (iv) the compound III is subjected to a hydrolysis reaction, and a compound IV is produced; (v) the compound IV is subjected to a decarboxylation reaction, and a compound V is produced; (vi) the compound V and a hydrazine hydrate solution react, and a compound VI is produced; (vii) the compound VI and a hydrazine hydrate solution react, and a compound VII is produced. The invention provides the preparation method of the key intermediate of Pimobendan, namely, 4,5-dihydro-5-methyl-6-(3,4-diaminophenyl)-3(2H)pyridazinone. A few reaction steps are used, highly toxic and high-corrosivity raw materials such as liquid bromine, potassium cyanide and the like are not required to be used, and the method has low environmental pollution and facilitates industrial amplification.

Description

technical field [0001] The invention belongs to a preparation method of a key intermediate of pimobendan, in particular to a 4,5-dihydro-5-methyl-6-(3,4-diaminophenyl)-3(2H) The preparation method of pyridazinone. Background technique [0002] The chemical name of pimobendan is 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)- Pyridazinone, molecular structure formula is as follows: [0003] [0004] Pimobendan is a cardiotonic drug with a calcium ion effect, and its main use is to treat heart failure in pet dogs. Pharmacological and clinical tests have shown that the drug has a strong positive inotropic effect, a strong vasodilator effect and platelet aggregation effect. It is not only an inhibitor of phosphodiesterase Ⅲ, but its cardiotonic effect is mainly caused by increasing the sensitivity of cardiac contractile protein to calcium ions and inhibiting the vasoconstriction of angiotensin Ⅱ. It does not increase the concentration of intracellu...

Claims

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Application Information

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IPC IPC(8): C07D237/04
Inventor 仝庆陈俭月崔学文龚振礼张彬彬
Owner 天津长芦华信化工股份有限公司
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