Chemical synthesis method of Pimobendan

A technology for chemical synthesis and pimobendan, applied in the direction of organic chemistry and the like, can solve the problems of unsuitable large-scale preparation of pimobendan, long reaction route, potential safety hazards, etc., and achieves low cost, short reaction period, corrosiveness and the like. strong effect

Inactive Publication Date: 2017-03-22
QINGDAO AGRI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] The reaction route is long, and highly toxic and corrosive liquid bromine and expensive, flammable and explosive sodium hydride are used, which has high cost and potential safety hazards, and is not suitable for large-scale preparation of pimobendan

Method used

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  • Chemical synthesis method of Pimobendan
  • Chemical synthesis method of Pimobendan
  • Chemical synthesis method of Pimobendan

Examples

Experimental program
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Effect test

Embodiment 1

[0035]

[0036]Step ①: Dissolve acetanilide (0.2 mol, 27g) in a mixed solvent of 45mL carbon disulfide and 45mL dichloromethane, stir at room temperature to obtain a colorless transparent solution, and add anhydrous aluminum trichloride (0.4 mol, 52.4g ) and potassium iodide (0.01moL, 1.65g), heated to reflux for 1h, cooled to room temperature, added 2-methyl-3-methoxycarbonylpropionyl chloride (0.21moL, 34.4g), reacted at 70°C for 8h, concentrated under reduced pressure and recovered Solvent, the residue was poured into 800mL ice water containing 13ml of concentrated hydrochloric acid, left at room temperature for 2h, a light yellow precipitate was precipitated, filtered, and the precipitate was collected to obtain the crude product of 3-acetamidobenzoyl butyric acid methyl ester, which was weighed with 95% ethanol Crystallization gave 43.1 g of methyl 3-p-acetamidobenzoyl butyrate, yield 82%, melting point 212-213°C; 1HNMR (500MHz, DMSO-d6) δ1.23 (d, J=6.8Hz, 3H, CH3 ), 2...

Embodiment 2

[0048] Step ①: Dissolve acetanilide (0.2 mol, 27g) in a mixed solvent of 45ml carbon disulfide and 45ml N,N-dimethylformamide, stir at room temperature to obtain a colorless transparent solution, and add anhydrous trichloro Aluminum chloride (0.4 mol, 52.4g) and potassium iodide (0.015 mol, 2.48g), heated to reflux for 1h, cooled to room temperature, added 2-methyl-3-methoxycarbonyl propionyl chloride (0.21 mol, 34.4g), at 70 React at ℃ for 8 hours, concentrate under reduced pressure to recover the solvent, pour the residue into 800mL ice water containing 13ml of concentrated hydrochloric acid, leave it at room temperature for 2h, a light yellow precipitate precipitates, filter, collect the precipitate to obtain 3-acetamidobenzoyl butyric acid methyl ester The crude product was recrystallized from 95% ethanol to obtain 46.3 g of methyl 3-p-acetamidobenzoyl butyrate, with a yield of 88% and a melting point of 212-213°C.

[0049] Step ②: Mix the 3-p-acetamidobenzoyl butyric acid...

Embodiment 3

[0055] Step ①: Dissolve acetanilide (0.2 mol, 27g) in a mixed solvent of 45ml carbon disulfide and 45ml N,N-dimethylformamide, stir at room temperature to obtain a colorless transparent solution, and add anhydrous trichloro Aluminum chloride (0.4 mol, 52.4g) and potassium iodide (0.02 mol, 3.3g), heated to reflux for 1h, cooled to room temperature, added 2-methyl-3-methoxycarbonyl propionyl chloride (0.21 mol, 34.4g), at 70 React at ℃ for 8 hours, concentrate under reduced pressure to recover the solvent, pour the residue into 800mL ice water containing 13ml of concentrated hydrochloric acid, leave it at room temperature for 2h, a light yellow precipitate precipitates, filter, collect the precipitate to obtain 3-acetamidobenzoyl butyric acid methyl ester The crude product was recrystallized from 95% ethanol to obtain 46.3 g of methyl 3-p-acetamidobenzoyl butyrate, with a yield of 88% and a melting point of 212-213°C.

[0056] Step ②: Mix the 3-p-acetamidobenzoyl butyric acid m...

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Abstract

The invention discloses a chemical synthesis method of Pimobendan. The method comprises steps as follows: acetanilide and 2-methyl-3-(chloroformyl)propionate react to produce 3-p-acetylaminobenzoyl methyl butyrate in a mixed organic solvent under the action of a composite catalyst, 3-p-acetylaminobenzoyl methyl butyrate reacts with a nitration reagent, 3-(4-acetamido-3-nitrobenzoyl)-methyl butyrate is produced and subjected to a reflux reaction with alkali in an alcohol solvent to produce 3-(4-amino-3-nitrobenzoyl) butyrate, 3-(4-amino-3-nitrobenzoyl) butyrate and hydrazine hydrate are subjected to a reflux reaction, 4,5-dihydro-5-methyl-6-(4-amino-3-nitrophenyl)-3(2H)-pyridazinone is produced and reduced with zinc powder in absolute methanol, 4,5-dihydro-5-methyl-6-(3,4-diaminophenyl)-3(2H)-pyridazinone is produced and subjected to a reflux reaction with p-anisaldehyde, and Pimobendan is obtained. The method comprises a few reaction steps, operation is safe and convenient, and the cost is low.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical chemistry, in particular to a chemical synthesis method of 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 protein to Ca2+ and inhibiting the activity of phosphodiesterase III (PDE-3), and at the same time it has the effect of dilating blood vessels, so it is an ideal positive inotrope As a cardiotonic drug, it is clinically used to treat acute and chronic heart failure. Further studies have shown that pimobendan is also used for the treatment of heart failure in pet dogs. With the deepening of research, its application field ha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04
CPCC07D403/04
Inventor 郝智慧李玉文王苹苹张瑞丽
Owner QINGDAO AGRI UNIV
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