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Preparation method of high-purity milbemycins

A mirbemycin and high-purity technology, applied in the field of chemistry, can solve the problems of no milbemycin preparation method, expensive mirbemycin use, low production technology, etc., and achieves high product purity, difficult by-products, The effect of improving the purity of the preparation

Inactive Publication Date: 2015-04-08
CHONGQING DAXIN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because milbemycin is protected by foreign patents, the milbemycin used in my country mainly comes from foreign imports, and the high price has greatly restricted the use of milbemycin
In terms of production technology and application, our country is far below the level of foreign countries, and there is no preparation method of milbemycin in the current literature

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Take 1L of HP20 resin and pack it into a column (diameter-to-height ratio = 1:6), take 12 g of crude milbemycin (56%), dissolve it with 60% ethanol to 3000 mL and put it on the column. Use 50% ethanol to desorb the resin column for detection. Combine the separated milbemycin A3 and A4, concentrate the water layer to 500mL, add 500mL ethyl acetate for extraction, take the ethyl acetate layer, concentrate, and the dry matter weighs 8.09g (content: 82%).

[0018] Take 2 g of the enriched milbemycins A3 and A4 and dissolve them in 30 mL of methanol. The solution was put into a semi-preparative liquid chromatograph. The semi-preparative liquid chromatograph used was Agilent 1200, and the semi-preparative column was LP-C8 (Shanghai Yuexu Technology Co., Ltd.), 25.01*250mm, with a particle size of 5-8 μm. Inject 4mL per needle, mobile phase is acetonitrile: water: methanol = 70:28:2 (volume ratio), flow rate 15mL / min~20mL / min, UV detection wavelength is 244nm, collect A3 and ...

Embodiment 2

[0021] Take 1.8L of HP100 resin (Shanghai Huazhen Resin Co., Ltd.) and pack it into a column (diameter-to-height ratio = 1:8), take 26.39 g of crude milbemycin (51.20%), dissolve it in 60% ethanol to 3000 mL, and put it on the column. Use 60% dichloromethane to desorb the resin column, and gradient extraction detection. Combine the separated milbemycin A3 and A4, concentrate the water layer to 810mL, add 810mL ethyl acetate for extraction, take the ethyl acetate layer, concentrate, and the dry matter weighs 14.5g (the content is 93.21%).

[0022] Take 2 g of the enriched Milbemycin A3 and A4 and dissolve them in 30 mL of acetonitrile. The solution was put into a semi-preparative liquid chromatograph. The semi-preparative liquid chromatograph used was Agilent 1200, and the semi-preparative column was LP-C8 (Shanghai Yuexu Technology Co., Ltd.), 25.01*250mm, with a particle size of 5-8 μm. Inject 4mL per needle, mobile phase is acetonitrile: water: methanol = 70:28:2 (volume ra...

Embodiment 3

[0025] Take 2L of HP300 macroporous adsorption resin and pack it into a column (diameter-to-height ratio=1:7), take 14.94g of crude milbemycin (53.21%), dissolve it with 60% ethanol until 3000mL is put on the column. Use 55% ethanol to desorb the resin column, and gradient extraction detection. Combine the separated milbemycin A3 and A4, concentrate the water layer to 450mL, add 450mL ethyl acetate for extraction, take the ethyl acetate layer, concentrate, and the dry matter weighs 8.91g (content: 89.23%).

[0026] Take 2 g of the enriched Milbemycin A3 and A4 and dissolve them in 30 mL of acetonitrile. The solution was put into a semi-preparative liquid chromatograph. The semi-preparative liquid chromatograph used was Agilent 1200, and the semi-preparative column was LP-C8 (Shanghai Yuexu Technology Co., Ltd.), 25.01*250mm, with a particle size of 5-8 μm. Inject 4mL per needle, the mobile phase is acetonitrile: water: methanol = 70:28:2, the flow rate is 15mL / min~20mL / min, t...

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Abstract

The invention discloses a preparation method of high-purity milbemycins. A milbemycin crude product is enriched by a macroporous adsorption resin, and milbemycins A3 and A4 are separated out, concentrated and dried; and then the dried powder of the milbemycins A3 and A4 is dissolved with methanol or acetonitrile, and the high-purity milbemycins A3 and A4 are prepared by semi-preparative liquid chromatography. The preparation method is simple, no side products and impurity residues exist, the product separation and purification is stable, and the purity of the finished products is high and can reach up to 99.99%.

Description

technical field [0001] The invention belongs to the field of chemistry, and in particular relates to a method for preparing a macrolide antibiotic milbemycin standard product. Background technique [0002] Milbemycin (milbemycin) is a macrolide anti-endoparasite drug, mainly including A3 and A4 homologues, and is commonly used as an anthelmintic for dogs. Milbemycin is effective in controlling and preventing most common parasitic diseases. It is usually used to prevent heartworm disease, control dog and cat diseases caused by nematodes and hookworms, and whipworm disease in dogs. Because milbemycin is protected by foreign patents, the milbemycin used in my country mainly comes from foreign imports, and the high price has greatly restricted the use of milbemycin. In terms of production technology and application, our country is far below the level of foreign countries, and there is no preparation method of milbemycin in the current literature. The self-developed preparatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/22
CPCC07D493/22
Inventor 周筠翔赵燕谢云张洪兰詹付凤叶静
Owner CHONGQING DAXIN PHARMA