Process for producing azelnidipine

Abstract

The invention relates to a process for producing azelnidipine. A yield improving and refining and purifying method is provided for synthesizing a dihydropyridine calcium antagonist. The process comprises the following steps of: performing N-alkylation cyclization, esterification and Pinner synthesis on epoxy chloropropane and aminodiphenylmethane serving as initial raw materials to obtain 3,3-diaminoacrylic acid-1-diphenylmethyl-3-azetidinyl ester acetate; and performing Hantzsch synthesis with 2-(3-nitrobenzylidene)isopropyl acetoacetate to prepare the azelnidipine, wherein the 2-(3-nitrobenzylidene)isopropyl acetoacetate is obtained by performing Knoevenagel reaction on nitrobenzaldehyde and isopropyl acetoacetate, and alpha-crystal form azelnidipine is prepared by crystal transition. By the process, the defects of a large number of side reactions, high production cost and the like of the foreign process are overcome, the process has the advantages of mild reaction condition, high yield, high product quality, no use of a class 1 solvent benzene, and the like, and the product is further purified.

Description

technical field [0001] The invention provides a yield-enhancing and refining method for synthesizing dihydropyridine calcium antagonists. Background technique [0002] Azhedipine was first developed by Sankyo Corporation of Japan, and its preparation Azhedipine Tablets was approved to go on the market in Japan in late May 2003. [0003] Using epichlorohydrin and benzhydrylamine as starting materials, 3,3-diaminoacrylic acid-1-benzhydryl-3-azheterocycle is obtained through N-alkylation cyclization, esterification, and Pinner synthesis Butyl acetate, and then synthesized with 2-(3-nitrobenzylidene) isopropyl acetoacetate by Hantzsch to obtain azelnidipine crude product, the crude product was dissolved in ethyl acetate, dried with anhydrous sodium sulfate, added methanol Heat up to reflux, cool, stir, filter, add cyclohexane, stir at 50°C for 30 minutes, and evaporate the solvent to dryness at 60°C under reduced pressure to obtain the product. The total yield of the process (i...

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Problems solved by technology

[0005] The synthesis and crystal formation process have been improved: in the addition reaction, after the reflux reaction, suction filtration, the filtrate continues to react, so that the raw materials that are not fully reacted can be further transformed; in the esterification reaction, the by-product 1,3-di Cyclohexyl urea (DCU), reduce cost and reduce pollution; in Pinner synthesis, optimize feed ratio and reaction temperature, reduce transesterification side reactions; in Hantzsch synthesis, replace sodium methoxide with sodium hydroxide, the yield is increased by 74% to 82%; completed the new process of dioxane-n-hexane crystallization to obtain α-crystal form, the total yield of this process (in terms of diphenylmethylamine) is 35.0%, with mild reaction conditions and better yield , good product quality and other advantages, suitable for large-scale production, the inventive method improves the product yield, overcomes the defects of many side reactions and high production costs that exist in foreign processes, and further purifies the product

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