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Preparation method of benidipine hydrochloride

A technology of benidipine hydrochloride and carboxylic acid, applied in the field of pharmaceutical synthesis, can solve problems such as difficult industrial scale-up production, difficult purification, long reaction time, etc., and achieves a technology that is beneficial to industrial production, has no potential safety hazard and stable reaction yield. Effect

Active Publication Date: 2014-03-19
广东暨大基因药物工程研究中心有限公司
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Problems solved by technology

[0009] The above-mentioned method has the following disadvantages: (1) the reaction time is long and the yield is low; (2) when synthesizing the intermediate N-benzyl-3-piperidinyl acetoacetate, it is necessary to use a compound that explodes at room temperature. Dangerous diketene is used as a raw material, which poses a great safety hazard; (3) The raw material N-benzyl-3-piperidinyl acetoacetate used is a high-boiling oily substance, which is not conducive to purification, let alone industry Production
[0012] Though this method can effectively improve productive rate, there is following deficiency: (1) methyl 3-nitrobenzyl acetoacetate is unstable, easily decomposes into 3-nitrobenzaldehyde and methyl acetoacetate under high temperature, thereby causes There are many by-products in the reaction, and post-processing is troublesome; (2) the synthesis of N-benzyl-3-piperidinyl 3-aminocrotonate also needs to use diketene, which has a danger of polymerization explosion, as a raw material, which increases a great potential safety hazard ; (3) N-benzyl-3-piperidinyl 3-aminocrotonate is a high-boiling oil, difficult to purify
[0015] This method has the following defects: the synthesis of acid chlorides with thionyl chloride needs to be carried out at low temperature (-20 ° C), and the reaction is violent, the temperature changes greatly, and improper operation can easily decompose the raw materials, resulting in increased side reactions, difficult product purification, and difficult Industrial scale-up production

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  • Preparation method of benidipine hydrochloride
  • Preparation method of benidipine hydrochloride
  • Preparation method of benidipine hydrochloride

Examples

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Embodiment 1

[0052] In the present invention, the N-benzyl-3-hydroxypiperidine used in step 2) can be synthesized by the following method: 27.4 grams (0.198mol, 2.0eq) of potassium carbonate are suspended and dissolved in 50ml DMF, and in the solution Add 10.0 g (0.0988 mol, 1.0 eq) of 3-hydroxypiperidine and 18.6 g (0.108 mol, 1.09 eq) of benzyl bromide, stir at 60°C for 3 days, monitor the disappearance of 3-hydroxy piperidine by TLC, and then cool down to room temperature. Add 300 ml of water to the reaction solution and stir for 30 minutes, extract with ethyl acetate, add about 150 ml of water for extraction three times, combine the organic layers, wash with about 50 ml of water, and wash the organic layer with anhydrous sodium sulfate Dry, filter and spin dry to obtain 15.1 g of product, the yield is 79.7%, and the product is light yellow oil. The N-benzyl-3-hydroxypiperidine that obtains is carried out the identification of proton magnetic spectrum: 1 H NMR(500MHz,CDCl3),δ1.48-1.55(...

Embodiment 2

[0054] Add 50 grams (0.15mol, 1.0eq) of 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid to 500 Add 18.2 grams (0.18mol, 1.2eq) of triethylamine to milliliter of dichloromethane solution, add 28.54 grams (0.165mol, 1.1eq) of diethyl chlorophosphate, react at 20°C for 1 hour, TLC tracking, raw material reaction After completion, a reaction liquid containing mixed acid anhydride is formed. 25.80 g (0.135 mol, 0.9 eq) of N-benzyl-3-hydroxypiperidine was added to the reaction solution, stirred at 20°C for 5 minutes and then refluxed for 4 hours, during which time TLC was followed. After the reaction was completed, the reaction solution was lowered to 40°C and decolorized by adding activated carbon, filtered, and the filtrate was spin-dried to obtain the crude product of benidipine (since dichloromethane was used as the solvent, the spin-drying was not required, and the next step was directly carried out). After the crude benidipi...

Embodiment 3

[0056] 25 grams (0.075mol, 1.0eq) of 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid was added in 250 Add 15.15 g (0.15 mol, 2.0 eq) of triethylamine to 1 ml of tetrahydrofuran solution, add 18.2 g (0.105 mol, 1.4 eq) of diisopropyl chlorophosphate, react at 30°C for 2 hours, follow TLC, and the reaction of raw materials is complete Finally, a reaction liquid containing mixed acid anhydride is formed. 15.77 g (0.0825 mol, 1.1 eq) of N-benzyl-3-hydroxypiperidine was added to the reaction solution, stirred at 30°C for 15 minutes and then refluxed for 6 hours, during which TLC was followed. After the reaction was completed, the reaction solution was lowered to 50° C., decolorized by adding activated carbon, filtered, and the filtrate was spin-dried to obtain crude benidipine. After the benidipine crude product is dissolved in dichloromethane, it is washed with 6% NaOH solution, water, 2.5mol / L hydrochloric acid and water succes...

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Abstract

The invention relates to a preparation method of benidipine hydrochloride. The preparation method comprises the synthesis steps of: the synthesis of mixed anhydrides: adding one equivalent of 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-5-methyl carboxylate-3-carboxylic acid to an organic solvent, adding 1.1-1.4 equivalents of chlorophosphite under an alkaline condition, and reacting at a temperature ranging from 20 to 30 DEG C for 1-2 hours to form a reaction liquid containing the mixed anhydrides; the synthesis of benidipine: adding 0.9-1.1 equivalents of N-benzyl-3-hydroxypiperidine to the reaction liquid of the mixed anhydrides, stirring at a temperature ranging from 20 to 30 DEG C for 5-15 minutes and refluxing for 4-6 hours to obtain the a reaction liquid containing the benidipine. The preparation method of the benidipine hydrochloride provided by the invention is simple to operate, high and stable in reaction yield, mild in reaction conditions, free of potential safety hazards, easy to purify and high in purity, and also advantageous for industrial production.

Description

technical field [0001] The invention relates to a preparation method of benidipine hydrochloride, belonging to the field of drug synthesis. Background technique [0002] Benidipine hydrochloride is a dihydropyridine calcium antagonist. The benidipine hydrochloride obtained through the synthesis reaction is usually a mixture of α and β diastereomers. Generally, the α and β diastereomers can be separated by recrystallization. Isomer separation. [0003] Benidipine hydrochloride is an α-isomer, which is a mixture of (R,R) and (S,S) isomers (the ratio of the two is 1:1). Its chemical name is: 3-[3(RS)-1-benzylpiperidin-3-yl]5-methyl(4RS)-2,6-dimethyl-4-(3-nitrophenyl) -1,4-dihydro-3,5-dicarboxylate hydrochloride. Its structural formula is as follows: [0004] [0005] Pharmacological studies have shown that benidipine and Ca 2+ The binding to the specific site of the channel has a higher affinity than other dihydropyridine calcium ion antagonists, and the dissociation of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90A61K31/4545A61P9/12A61P9/08
CPCC07D211/90
Inventor 张庆华陈波徐广宇邓华峰
Owner 广东暨大基因药物工程研究中心有限公司
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