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Preparation method of azelnidipine

A technology for azeldipine and a compound, which is applied in the field of preparation of azeldipine, can solve the problems of increased space barriers, cumbersome operations, large changes in chemical properties, etc., and achieves the advantages of reducing impurities, improving product quality, and meeting the requirements of medicinal standards. Effect

Inactive Publication Date: 2017-01-04
WEIHAI DISU PHARMA CO LTD +1
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Problems solved by technology

[0012] Chinese patent 200510104895.4 (page 7) prepared Azhedipine according to the preparation method provided in the literature according to Reaction Formula 1. It was found that the operation was cumbersome, and the yield and quality were not ideal. The actual yield was only about 15%. The yield of 85.6% is far from
[0015] Although this method has certain advantages in the preparation of nifedipine, it is difficult to obtain azedipine by this method after replacing β-aminocrotonate with compound c
The reason may be: the chemical group of compound c is relatively large, and its chemical properties are greatly changed compared with β-aminocrotonate. Cyclobutylamine and diphenyl make the steric barrier increase, which weakens the activity of Hantzsch reaction

Method used

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  • Preparation method of azelnidipine
  • Preparation method of azelnidipine
  • Preparation method of azelnidipine

Examples

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Embodiment 1

[0035] The first step Pinner reaction

[0036] Add 750 g of dichloromethane, 65.65 g (1.43 mol) of absolute ethanol and 120 g (1.42 mol) of nitrile acetic acid (compound 1) into the reaction flask in sequence, mix and stir, and cool down to -10°C~0°C. Pass dry hydrogen chloride gas until saturated, and keep the reaction for 8~12h to the end. The solvent was recovered under reduced pressure at room temperature, 600 g of dichloromethane was added to the residue, mixed and stirred, and the temperature was lowered to -5°C~0°C, dry ammonia gas was introduced until saturation, and the reaction was kept for 3~5h to the end. The solvent was recovered under reduced pressure at room temperature to obtain 137.4 g of amidine acetic acid (compound 2). The yield in this step is 94.8%, and the HPLC purity is 99.6%.

[0037] Second step Hantzsch reaction

[0038] Add 520g of isopropanol, 106g (1.04mol) of amidine acetic acid (compound 2) and 288.6g (1.06mol) of compound 3 to the reaction f...

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Abstract

The invention relates to a preparation method of azelnidipine, belongs to the field of medicines and opens up a new way for synthesizing dihydropyridine calcium antagonists. With cyanoacetic acid as a raw material, the method comprises the following sequential steps: synthesizing isopropyl 2-amino-3-carboxyl-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-5-formate through a Pinner reaction and a Hantzsch reaction; and performing DCC dehydration esterification with 1-diphenylmethyl-3-hydroxyl azetidine hydrochloride to obtain a crude product of azelnidipine; and performing further crystal transformation to obtain alpha-crystal type azelnidipine.

Description

technical field [0001] The invention relates to a preparation method of azhedipine, which belongs to the technical field of medicine. Background technique [0002] Azelnidipine is a dihydropyridine calcium channel blocker jointly developed by Japan Sankyo Co., Ltd. and Ube Industries Co., Ltd. It has good antihypertensive effect and was first listed in Japan in May 2003: [0003] [0004] At present, there are many references about the preparation method of azedipine at home and abroad, such as European patent EP0266922; Chinese patent ZL87107150; Chem. Pharm. Bull. 43(5), 1995, P788-796; JP Tokai Sho 63-253082; JP Tokaihei 11-116570; Drug of Future Vol.15, NO.7, 1990, P671-673, etc. The preparation methods provided by these routes are to combine compound 3 or its two synthetic raw materials (m-nitrobenzaldehyde a, isopropyl acetoacetate b) and compound c under strong basic conditions, using isopropanol as a solvent, High-temperature reflux reaction (as shown in reactio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 刘超苗华明葛执信肖阳
Owner WEIHAI DISU PHARMA CO LTD
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