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Improved method of preparing azhediping

A technology for azeldipine and a compound, which is applied in the field of preparing azeldipine, can solve problems such as inability to find an acid-base environment, and achieve the effects of reducing production equipment and personnel allocation, reducing energy consumption and cost, and reducing one-step reaction.

Active Publication Date: 2007-12-05
SICHUAN KELUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This contradiction will make it impossible to find a suitable acid-base environment that can make the reaction go smoothly in the preparation of Azedipine.

Method used

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  • Improved method of preparing azhediping

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] In the 5000ml there-necked flask, add isopropanol 2800ml successively, compound (1) 94g (0.62mol), compound (2) 84ml (88.8g, 0.62mol) and compound (3) free base 188.6g (0.59mol), The reaction was stirred at room temperature for about 12 hours. Suction filtration, add the filtrate to 7000ml of 5% acetic acid water, stir evenly, extract with ethyl acetate, and use saturated NaHCO 3 Wash with water until the water layer becomes alkaline, wash once with saturated sodium chloride water, once with clear water, dry over anhydrous sodium sulfate, recover ethyl acetate by distillation under reduced pressure, add about 1000ml methanol to the raffinate, stir and heat (65°C) 1 hour, stirred and cooled to crystallize, suction filtered, washed with methanol, and dried under reduced pressure at 30° C. to obtain 286 g (light yellow crystals) of azedipine methanolate, yield 79.1%, HPLC (area normalization method) content 99.527%. Add 286 g of azedipine methanolate into 5720 ml of cyclo...

Embodiment 2

[0040] Add 2000ml of ethyl acetate, 94g (0.62mol) of compound (1), 84ml (88.8g, 0.62mol) of compound (2) and 224g (0.59mol) of compound (3-1) in a 5000ml three-necked flask, and stir the reaction at room temperature 16 hours or so. Suction filtration, the filtrate was added 5% NaHCO 3 In 3000ml of water, stir evenly, let stand to separate layers, wash the ethyl acetate solution once with saturated sodium chloride water, wash once with clear water, dry over anhydrous sodium sulfate, recover ethyl acetate by distillation under reduced pressure, add about 1000ml Methanol, stirred and heated (65° C.) for 1 hour, stirred and cooled to crystallize, suction filtered, washed with methanol, and dried under reduced pressure at 30° C. to obtain 264 g (light yellow crystals) of azedipine methanolate, yield 73%, HPLC (area normalized Chemical method) content 99.364%, add 264g of azedipine methanolate into 5280ml cyclohexane, stir and heat to 50°C internal temperature, remove methanol and ...

Embodiment 3

[0043] According to the preparation scheme provided in Example 1, stirring reactions were carried out below 0°C, 0-10°C, 10-20°C, 20-30°C, 40°C, 50°C, and 60°C to obtain azedipine 38.6%, Yields of 75.4%, 83.7%, 78.9%, 54.2%, 32.6%, 14.9%.

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Abstract

An improved process for preparing Azhediping includes such steps as reaction between three raw compounds in solvent while stirring, filtering, water washing of filtrate, extracting in organic solvent, washing with alkali solution, drying, vacuum concentrating, crystallizing in methol, and recrystallizing. Its advantages are high output rate and high purity.

Description

technical field [0001] The invention relates to a method for synthesizing dihydropyridine calcium antagonists, more specifically, the invention relates to a method for preparing azedipine. Background technique [0002] Azeldipine, the chemical name is 3,5-pyridinedicarboxylic acid, 1,4-dihydropyridine-2-amino-6-methyl-4-(3-nitrophenyl)-, 3-(1- (Benzhydryl)-3-azetidinyl) 5-(1-methylethyl) ester, (±). It is a new generation of calcium antagonist developed by Japan Sankyo (SANKYO) Co., Ltd. The company filed a patent application for the compound in Europe in 1986, and the authorized announcement was issued on September 8, 1993, with the patent number EP0266922. The product was approved for marketing in Japan in 2003. [0003] In 1987, Japan's Sankyo (SANKYO) Co., Ltd. filed a patent application for the preparation method of azhedipine in China, and it was approved and announced on August 19, 1992. The patent number is ZL87107150. [0004] At present, the references on the pr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07D211/90C07D205/04
Inventor 林奉儒周忠银黄耀宗赵同华张洪宇杨蕾梁隆程志鹏
Owner SICHUAN KELUN PHARMA CO LTD