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Preparation method of high-purity levamlodipine besylate

A technology of levamlodipine besylate and levamlodipine besylate is applied in the field of preparation of high-purity levamlodipine besylate, and can solve the problems of difficulty in filtration, poor quality of levamlodipine besylate, and refining effect Not ideal and other problems, to achieve the effect of good quality of finished products

Active Publication Date: 2012-09-12
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When the inventor tried to repeat the process, he also found that the problem of the process was the same as that of the process described in patent WO2005049571: after the reaction, the system was mud, which was difficult to filter
The quality of the obtained levamlodipine besylate is also relatively poor. Although this patent provides the method for refining levamlodipine besylate, the inventor finds that the refining effect is not ideal

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] Under nitrogen protection, dissolve 10g of levamlodipine in 160ml of water at 50°C, then add 40ml of an aqueous solution containing 4.5g of benzenesulfonic acid, continue to heat until fully dissolved, and then slowly drop to room temperature, a large amount of white will be precipitated during the cooling process. The solid was filtered with suction after 4 hours to obtain 13.7 g of a crude product of levamlodipine besylate with a yield of 99.4%.

[0014] Under nitrogen protection, the above crude levamlodipine besylate was dissolved in 15 ml of ethanol. After the crude product of levamlodipine besylate was completely dissolved, 120 ml of water was added dropwise with stirring. After 6 hours of crystallization, filtration was performed to obtain 12.7 g of levamlodipine besylate refined product with a yield of 92.7% and a content of 100%.

Embodiment 2

[0016] Under nitrogen protection, 10 g of levamlodipine was dissolved in 180 ml of water at 70°C. Then add 40 ml of an aqueous solution containing 4.5 g of benzenesulfonic acid, continue to heat to complete dissolution, then slowly reduce to room temperature, a large amount of white solids will be precipitated during the cooling process, and suction filtration after 4 hours to obtain the crude product of levamlodipine besylate 13.6 g, the yield is 98.7%.

[0017] Under nitrogen protection, the above crude levamlodipine besylate was dissolved in 13 ml of ethanol. After the crude product of levamlodipine besylate was completely dissolved, 120 ml of water was added dropwise with stirring. After 6 hours of crystallization, filtration was performed to obtain 12.8 g of refined L-amlodipine besylate with a yield of 94.1% and a content of 100%.

Embodiment 3

[0019] Under nitrogen protection, 10 g of levamlodipine was dissolved in 160 ml of water at 40°C. Then, 40 ml of an aqueous solution containing 4.5 g of benzenesulfonic acid was added, and heating was continued until it was completely dissolved. Then slowly cooled to room temperature, a large amount of white solids would be precipitated during the cooling process. After 4 hours, suction filtration to obtain 13.7 g of a crude product of levamlodipine besylate with a yield of 99.4%.

[0020] Under nitrogen protection, the above crude levamlodipine besylate was dissolved in 15 ml of ethanol. After the crude product of levamlodipine besylate was completely dissolved, 120 ml of water was added dropwise with stirring. After 6 hours of crystallization, filtration was performed to obtain 12.7 g of levamlodipine besylate refined product with a yield of 92.7% and a content of 100%.

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Abstract

The invention belongs to the field of chemical pharmacy, and particularly relates to a preparation method of high-purity levamlodipine besylate, which comprises the following steps: (1) under the protection of nitrogen, dissolving levamlodipine in proportional hot water, adding a water solution of benzenesulfonic acid until the solid is completely dissolved, slowly cooling to precipitate a laminar solid, and filtering to obtain a crude levamlodipine besylate product; and (2) under the protection of nitrogen, dissolving the crude levamlodipine besylate product in proportional ethanol until the crude levamlodipine besylate product is completely dissolved, dropwisely adding proportional water to precipitate a solid, and filtering to obtain the refined levamlodipine besylate product. The invention successfully solves the problem of great filtration difficulty in the past patent technique; and thus, the quality of the end levamlodipine besylate product is excellent, and the HPLC content (area normalization) is almost 100%.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, in particular to a preparation method of high-purity levamlodipine besylate. Background technique [0002] Amlodipine besylate is a calcium antagonist. It has two optical isomers, the levorotatory isomer has the effect of reducing blood pressure, and the dextrorotatory isomer not only has no antihypertensive effect, but also causes side effects such as headache, dizziness, and extremity edema. According to J.Med.Chem1986, 29, 1696, the antagonistic activity of levamlodipine besylate, calcium ion is about 1000 times that of dexamlodipine besylate, and 2 times that of the racemate. In view of the safety of medication, levamlodipine besylate is superior to amlodipine besylate. However, the solubility of levamlodipine besylate in many solvents (eg, ethanol, isopropanol, etc.) is very good, and it is difficult to obtain levamlodipine besylate with good properties and quality. Therefore, how to prep...

Claims

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Application Information

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IPC IPC(8): C07D211/90
Inventor 商艳梅郑忠辉于小萍张滨
Owner SHANDONG XINHUA PHARMA CO LTD
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