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Preparation method of high-purity benidipine hydrochloride

A benidipine hydrochloride, high-purity technology, applied in the field of biomedicine, can solve the problems of adverse environmental protection, time-consuming and labor-intensive consumption, and large consumption of organic solvents

Inactive Publication Date: 2021-05-18
山东华素制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The above separation method is a multi-step operation, and even column chromatography is required to effectively separate the isomers. Negative Effects

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] (1) Take 50g of 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid and add 500ml of dichloromethane solution , add 18.2g triethylamine, add 28.54g diethyl chlorophosphate, react at 20°C for 1 hour, get 2,6-dimethyl-4-(m-nitrophenyl)-1,4-di Hydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid reacts with chlorophosphate to produce mixed acid anhydride;

[0025] (2) Add 25.80g of N-benzyl-3-hydroxypiperidine to the mixed acid anhydride solution to react with N-benzyl-3-hydroxypiperidine, stir at 20°C for 5 minutes and then reflux for 4 hours to obtain Benny horizon;

[0026] (3) Activated carbon decolorization: decolorize with activated carbon after cooling the reaction liquid containing benidipine to 40°C;

[0027] (4) Dissolving and washing: Dissolve the decolorized crude benidipine hydrochloride in dichloromethane, wash with 4% NaOH solution, water, 1.5mol / L hydrochloric acid and water in sequence, and dry to...

Embodiment 2

[0030] (1) Take 25g of 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid and add 250ml of dichloromethane solution , add 15.15g triethylamine, add 18.2g diethyl chlorophosphate, react at 30°C for 2 hours, get 2,6-dimethyl-4-(m-nitrophenyl)-1,4-di Hydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid reacts with chlorophosphate to produce mixed acid anhydride;

[0031] (2) Add 15.77g N-benzyl-3-hydroxypiperidine to the mixed acid anhydride solution to react with N-benzyl-3-hydroxypiperidine, stir at 30°C for 15 minutes and then reflux for 6 hours to obtain Beni horizon;

[0032] (3) Activated carbon decolorization: decolorize with activated carbon after cooling the reaction solution containing benidipine to 50°C;

[0033] (4) Dissolving and washing: dissolve the decolorized crude benidipine hydrochloride in dichloromethane, wash with 6% NaOH solution, water, 2.5mol / L hydrochloric acid and water in sequence, and dry to...

Embodiment 3

[0036] (1) Take 50g of 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid and add 500ml of dichloromethane solution , add 20.2g triethylamine, add 32g diethyl chlorophosphate, react at 30°C for 2 hours, get 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydro Pyridine-5-carboxylic acid methyl ester-3-carboxylic acid reacts with chlorophosphate to produce mixed acid anhydride;

[0037] (2) Add 28.67g N-benzyl-3-hydroxypiperidine to the mixed acid anhydride solution to react with N-benzyl-3-hydroxypiperidine, stir at 25°C for 20 minutes and then reflux for 6 hours to obtain Beni horizon;

[0038] (3) Activated carbon decolorization: decolorize with activated carbon after cooling the reaction solution containing benidipine to 45°C;

[0039] (4) Dissolving and washing: dissolve the decolorized crude benidipine hydrochloride in dichloromethane, wash with 8% NaOH solution, water, 2mol / L hydrochloric acid and water in sequence, and dry to obta...

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Abstract

The invention relates to a preparation method of high-purity benidipine hydrochloride, and solves the technical problems. The preparation method comprises the following steps: reacting 2, 6-dimethyl-4-(m-nitrophenyl)-1, 4-dihydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid with chlorophosphate under an alkaline condition to generate mixed anhydride; enabling the mixed acid anhydride to react with the N-benzyl-3-hydroxypiperidine to generate benidipine; cooling the reaction liquid containing benidipine to 40-50 DEG C, and decolorizing with activated carbon; dissolving the decolored benidipine crude product with dichloromethane, washing with a NaOH solution, water, hydrochloric acid and water in sequence, then drying, and spin-drying the solvent to obtain a benidipine hydrochloride crude product; and dissolving a benidipine hydrochloride crude product in a mixed solution of ethanol and acetone, refluxing, stirring, and separating out a benidipine hydrochloride pure product. The method can be widely applied to the field of medicine preparation.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a preparation method of high-purity benidipine hydrochloride. Background technique [0002] The chemical name of benidipine hydrochloride is (±)-(R*)-1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinecarboxylate The hydrochloride salt of ester [(R*)-1-benzyl-3-piperidinol ester] belongs to dihydropyridine calcium ion antagonists, which can efficiently and specifically bind to the binding site of dihydropyridine receptors , for Ca 2+ The channel has a highly efficient and specific inhibitory effect. Benidipine not only acts on muscle-type (L-type) Ca 2+ The channel is inhibitory and also acts on voltage-dependent N-type and T-type Ca 2+ The channel also has an inhibitory effect, and is currently the only calcium antagonist that has effects on the above three channels. In addition, benidipine still has high affinity to cell membrane, vascular selectivity and renal protection, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90
CPCC07D211/90
Inventor 王熙红滕世涛薛春啟王文材
Owner 山东华素制药有限公司
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