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Preparation method and application of chiral pimobendan

A pimobendan and chiral technology, which is applied in the field of preparation of chiral pimobendan, can solve the problems of lengthy steps and poor economy, and achieve the effect of simple process and good safety

Inactive Publication Date: 2017-11-14
蒿莱医药技术(上海)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
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Problems solved by technology

However, we searched the literature and found that there is almost no synthesis literature of chiral pimobendan
Domestic only one dissertation (Li Zitong, Guangxi University dissertation, 2003) has carried out the synthetic report of levopimobendan as follows, but its steps are tedious, and will carry out chiral resolution to key intermediate, economical is not good Well, the following formula is its synthetic route,

Method used

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  • Preparation method and application of chiral pimobendan
  • Preparation method and application of chiral pimobendan

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preparation example Construction

[0035] The invention provides a preparation method of chiral pimobendan, comprising the following steps:

[0036] Step S1: prepare chiral intermediate 1 with chiral reagent, diammonium phthalate and aluminum trichloride, including step S1a: add the chiral reagent dropwise to the mixture of diammonium phthalate and aluminum trichloride In the solution, the obtained mixture was refluxed for one hour, and then cooled to 30 degrees to obtain the first mixture; step S1b: adding alcohol and water dropwise to the first mixture, then adding dichloromethane for extraction, washing with water, drying over anhydrous sodium sulfate, and filtering , spin dry, add petroleum ether, filter to obtain chiral intermediate 1, in this step, prepare chiral intermediate 1 with 2-chloropropionyl chloride, diammonium phthalate under the action of Lewis acid and aluminum trichloride , which is not limited to the use of aluminum trichloride, but also aluminum trichloride, ferric chloride, zinc chloride,...

Embodiment 1

[0047] Step S1: add dropwise in the mixed solution of starting material (26.7 grams) and aluminum trichloride (22 grams) with chiral reagent S-2-chloropropionyl chloride (20g), the resulting mixture is refluxed for one hour, then Cool to 30 degrees, slowly add methanol and water to the mixture, then add dichloromethane to extract, wash with water, dry with anhydrous sodium sulfate, filter, spin dry, add petroleum ether, and filter to obtain 15.6 grams of the key chiral Intermediate R-1.

[0048] Step S2: In a three-necked flask, add 400 mg of NaH and N,N-dimethylformamide (5 mL), slowly add 19 g of methylbenzyl malonate dropwise under ice cooling (half an hour), After the dropwise addition, the mixture was stirred at room temperature for 12 hours, and the N,N-dimethylformamide solution of intermediate 1 (15.6 g dissolved in 30 ml) was added to the above reaction mixture at one time, and the obtained suspension continued to Stir overnight at room temperature, quench with water...

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Abstract

The present invention relates to the preparation method and application of chiral pimobendan, comprising the following steps: preparing chiral intermediate 1 with chiral reagent, diammonium phthalate and aluminum trichloride; using chiral intermediate 1, Prepare intermediate 2 with base, N,N-dimethylformamide and malonic acid substituted ester; prepare intermediate 3 with intermediate 2 and a catalytic hydrogenation catalyst; prepare intermediate 4 with intermediate 3, alcohol and hydrazine hydrate; Intermediate 4, N,N-dimethylformamide and 4-methoxybenzaldehyde are prepared to obtain chiral pimobendan, and the method of the present invention only needs 5 steps to obtain chiral pimobendan, and the current The steps are shortened by more than half, and the starting materials are simple and easy to obtain; and the chiral pimobendan can be used to treat mild, moderate or severe congestive heart failure in dogs caused by atrioventricular valve insufficiency or myocardial hypertrophy , hypertrophic cardiomyopathy in pets, etc.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method and application of chiral pimobendan. Background technique [0002] Cardiotonic drug Pimobendna (Pimobendna) was developed by German Boeehringerlngelhem company and was first listed in Japan in 1994. The mechanism of action of this drug is different from that of traditional cardiotonic drugs. Its positive inotropic effect is mainly attributed to the enhancement of the sensitivity of cardiac contractile proteins to calcium ions and the inhibition of phosphodiesterase. Sensitizer drugs. It is clinically used to treat chronic and acute heart failure. In Europe and the United States, the drug is currently mainly used for the treatment of heart failure in pets. The chemical name of this product is: 4,5-dihydro-6-[2-(4-methoxyphenyl-1H-benzoimidazo-5-yl]-5-methyl-3(2H)da Azinonone, its structure is as follows. [0003] The 5-methyl group of pimobendan has a chir...

Claims

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Application Information

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IPC IPC(8): C07D403/04A61P9/04A61P9/00
CPCC07D403/04C07B2200/07
Inventor 李胜斌
Owner 蒿莱医药技术(上海)有限公司
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