Barnidipine hydrochloride compound and preparation method thereof

Abstract

The invention discloses a barnidipine hydrochloride compound and a preparation method thereof. The preparation method comprises the following steps: (1) using 3-hydroxypropionitrile to react with diketene, to obtain an intermediate 1; (2) enabling the intermediate 1 to react with m-nitrobenzaldehyde and Beta-amino methyl crotonate, to obtain an intermediate 2; (3) enabling the intermediate 2 to behydrolyzed by strong base, to obtain an intermediate 3; (4) enabling the intermediate 3 to be resolved by chiral organic base, to obtain an intermediate 4; (5) enabling the intermediate 4 to react with thionyl chloride, (S)-1-benzyl-3-pyrrolidinol, and HCI ethanol solution, to obtain a crude product of barnidipine hydrochloride; and (6) performing ethyl alcohol pulping and refining, and ethyl alcohol recrystallization on the crude product of the barnidipine hydrochloride, to obtain the barnidipine hydrochloride.

Description

technical field [0001] The invention relates to a dihydropyridine calcium antagonist antihypertensive drug, in particular to a barnidipine hydrochloride compound and a preparation method thereof, belonging to the technical field of medicine. Background technique [0002] Barnidipine hydrochloride, its chemical name is: (S)-3-((S)-1-benzylpyrrolidinyl)-2,6-dimethyl-4-(3-nitrophenyl)-1 ,4-Dihydropyridine-3,5-dicarboxylate hydrochloride, molecular formula C 27 h 29 N 3 o 6 HCl, molecular weight 528, structural formula: [0003] [0004] Barnidipine Hydrochloride (Barnidipine Hydrochloride) is a powerful, long-acting, optically active third-generation dihydropyridine calcium antagonist antihypertensive drug developed by Japan Yamanouchi Company. It was first launched in Japan in 1992. Available in Korea, Philippines and Thailand. At present, this product has passed the mutual recognition procedure of the European Union, and has been approved for marketing in the Netherl...

AI Technical Summary

Problems solved by technology

[0009] The defect of this method is: the final synthesized product is a mixture of S-type and R-type, not the single enantiomer barnidipine hydrochloride we need, and its mixture product also needs column purification, Difficult to industrialized mass production

[0013] The disadvantage of this method is that the starting material 1,4-dihydropyridine-3,5-dicarboxylate dicarbamoylmethyl ester is not easy to obtain, and it needs to be catalyzed by biological protease. At present, this biosynthesis method is not available. suitable for mass production

[0017] The defect of this method is that: the intermediate and the final product generated from the first step reaction need to pass through the column with silica gel, which is only suitable for a small amount of preparation in the laboratory and is difficult to carry out industrialization; the synthesis of the main intermediate monocarboxylic acid The yield is not high and the quality is poor, which affects the purity of the final product. It must be purified through the column, which will lead to high product cost

[0021] The defect of this method is: the use efficiency of the key chiral intermediate (S)-1-benzyl-3-hydroxypyrrolidine adopted is relatively low; In this route, this intermediate will participate in the reaction every step, and its efficiency lower; because the cost of the intermediate is higher and the price is expensive, it will inevitably lead to the high cost of the synthesized target compound, and in the last step, it is necessary to split the chromatographic column or the resolution of the resolving agent, which also reduces the cost of other raw materials. Synthetic efficiency reduces the yield, increases the difficulty of purification of product synthesis, and is not easy for large-scale industrial production, resulting in higher costs

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