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Purification method of clevidipine butyrate

A technology of clevidipine butyrate and a purification method, which is applied in the field of purification of clevidipine butyrate, can solve the problems that the inorganic impurities of clevidipine butyrate exceed the standard, etc., and achieve the effect of easy industrialization

Active Publication Date: 2013-12-04
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, no effective method has been proposed for purification before in the literature, and only relying on the recrystallization of common solvents does not solve the problem of excessive inorganic impurities of clevidipine butyrate

Method used

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  • Purification method of clevidipine butyrate
  • Purification method of clevidipine butyrate
  • Purification method of clevidipine butyrate

Examples

Experimental program
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Effect test

experiment example 1

[0032] The crude product of clevidipine butyrate obtained by conventional method reaction is a filler with octadecylsilane bonded silica gel; acetonitrile-methanol-water (25:48:27) is mobile phase; the detection wavelength is 238nm, and the measured purity is 98.24%; the largest single impurity is 0.18%; the arsenic salt is measured by the arsenic spot colorimetric method, and the arsenic salt is 10ppm; the lead salt is measured by the heavy metal colorimetric method, and the lead salt is 20ppm; the standard solution colorimetric method is used to measure Chloride 20ppm. The experimental results are shown in Table 1:

[0033] Table 1

[0034]

[0035] Experimental results show: the clevidipine butyrate crude product used in the present invention has a purity of 98.24% after testing, and a total impurity of 1.76%, a purity lower than 99.5%; the largest single impurity is 0.18%, exceeding the required 0.1%; arsenic Salt is 10ppm, greater than 2ppm required for injection; le...

experiment example 2

[0037] The clevidipine butyrate crude product and the product purity, the largest single impurity, arsenic salt, lead salt, and chloride determination results are shown in Table 2 after the method of embodiment 1 is refined:

[0038] Table 2

[0039]

[0040] The experimental results show that: through the above experiments, it can be seen that after refining with ethanol and acetonitrile, a product with a purity greater than 99.5% is obtained; after refining with 85% ethanol, arsenic salts, lead salts, chlorides, etc. are significantly reduced. The purity of the obtained clevidipine butyrate product is 99.92%, and the largest single impurity is 0.02%; the arsenic salt is 0.2ppm measured by atomic absorption, the lead salt is less than 2ppm, and the chloride is less than 5ppm.

experiment example 3

[0042] The clevidipine butyrate crude product and the product purity, maximum single impurity, arsenic salt, lead salt, and chloride determination results are shown in Table 3 through the method for embodiment 2 refining:

[0043] table 3

[0044]

[0045] The experimental results show that: through the above experiments, it can be seen that after refining with ethanol and acetonitrile, a product with a purity greater than 99.5% is obtained; after refining with 85% ethanol, arsenic salts, lead salts, chlorides, etc. are significantly reduced. The purity of the obtained clevidipine butyrate product is 99.95%, and the largest single impurity is 0.02%; the arsenic salt is 0.2ppm measured by atomic absorption, the lead salt is less than 2ppm, and the chloride is less than 5ppm.

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Abstract

The invention discloses a purification method of clevidipine butyrate The purification method comprises following steps: step A, an ethanol solution of clevidipine butyrate is prepared, and organic impurities are removed by crystallization purification; step B, crystals purified by ethanol are dissolved in acetonitrile, and then are precipitated by adding water so as to remove a large amount of inorganic impurities; and step C, the crystals purified by acetonitrile are dissolved in an ethanol solution with a concentration of 50 to 90% so as to remove a small amount of inorganic impurities. The products are dissolved completely by mixing the poor solvent with the good solvent so as to realize complete purification; the purity of clevidipine butyrate reaches 99.5%; and arsenic, lead and chloride indexes are all much lower than that of standards.

Description

technical field [0001] The invention relates to a chemical separation and purification method, in particular to a purification method of clevidipine butyrate. Background technique [0002] Clevidipine butyrate, the chemical name is 4-(2,3-dichlorobenzyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl (1- Butyryloxy) methyl ester is an ultra-short-acting dihydropyridine calcium channel blocker, used to reduce blood pressure in patients who are not suitable for oral administration or oral therapy is ineffective. In the acute hypertensive period, clevidipine can quickly and safely lower blood pressure and maintain the target range of blood pressure control. [0003] There are many disclosed synthesis methods of clevidipine butyrate, such as a preparation method of clevidipine butyrate (Chinese patent CN200910214376.1), Manufacturing process (US patent US6,350,877), Short-actiong dihydropyridines (US patent 5,856,346), 1,4-Dihydropyridine derivatives (EP0106275A...

Claims

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Application Information

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IPC IPC(8): C07D211/90
Inventor 李丽川蒋亮史少辉阳海张翔张韬梁隆程志鹏
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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