Milbemycin oxime separation and purification method

A milbexime, separation and purification technology, applied in the direction of organic chemistry, etc., to reduce environmental pollution, increase production capacity, and reduce costs

Active Publication Date: 2015-02-04
HUBEI HONCH PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, the drug has been listed in Japan, the United States, the European Union and other cou

Method used

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  • Milbemycin oxime separation and purification method
  • Milbemycin oxime separation and purification method
  • Milbemycin oxime separation and purification method

Examples

Experimental program
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Embodiment 1

[0028] (1), take by weighing 120g milbexime crude product, the liquid chromatography detection spectrogram of crude product is as follows figure 1 Shown, where milbexime A 4 Calibration content is 8.4%, milbexime A 3 The calibration content of milbexime is 5.6%. Dissolve the crude product of milbexime with 110g of acetone, then add 120g of silica gel and mix well, place it in a vacuum oven and dry it under vacuum at 35-45°C for 4-10 hours; then weigh 240g of silica gel for column chromatography , soak the silica gel with 0.8 to 2.5 times the volume of chloroform and stir evenly, then pour it into a Ф6.8cm×100cm glass chromatography column, beat evenly, and elute with 1500mL n-heptane to balance; then the dried mixture is washed with 300mL n-heptane Mix the heptane thoroughly, load it on the column, and the loading volume is 5% to 20% of the column volume;

[0029] Adopt the mixed solvent of n-heptane / acetone to carry out elution as mobile phase, the volume ratio of n-heptane...

Embodiment 2

[0039] (1), weigh 3Kg crude product of milbe oxime, wherein milbe oxime A 4 Calibration content is 8.7%, milbexime A 3 The calibration content of milbexime is 6.5%. Dissolve the crude product of milbexime with 3.11Kg of acetone, then add 3Kg of silica gel and mix well, place it in a vacuum oven and dry it under vacuum at 40°C for 6h; then weigh 6Kg of silica gel for column chromatography, and Soak in 12L chloroform and stir evenly, then pour it into a Ф22.8cm×100cm glass chromatography column, beat evenly, and elute with 40L n-heptane to balance; then mix the dried mixture thoroughly with 7.5L n-heptane, and load it on the column On, the sample volume is 5% to 20% of the column volume;

[0040] Adopt the mixed solvent of n-heptane / acetone to carry out elution as mobile phase, the volume ratio of n-heptane / acetone is 97:3, HPLC monitors the elution situation of milbexime, collects milbexime A 3 and A 4 Components with a total purity greater than 40% were evaporated to drynes...

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Abstract

The invention provides a milbemycin oxime separation and purification method. The milbemycin oxime separation and purification method comprises the following steps: carrying out crude separation on a sample to be separated through silicagel column chromatography, wherein the silicagel column chromatography adopts wet-process column packing and dry-method sample loading; purifying the product after crude separation by high performance liquid chromatography; concentrating the purified sample by a nanofiltration membrane to obtain concentrated solution; performing reduced-pressure vaporization to the concentrated solution, filtering and drying to obtain a refined product; dissolving the refined product, heating up, dropwise adding isooctyl alcohol, normal heptane or petroleum ether, cooling to be crystallized, and filtering to obtain a crystallized product; dissolving the crystallized product, filtering, dropwise adding filtrate into purified water stirred constantly, after dropwise adding, carrying out suction filtration to obtain a crystal transformation product; drying the crystal transformation product, crushing, and drying again to obtain milbemycin oxime finished product. The method can realize industrial production of milbemycin oxime in China firstly, and the product has high purity and high yield which are higher than those of the similar products at home and abroad.

Description

technical field [0001] The invention belongs to the field of separation and purification of chemicals, and in particular relates to a method for separation and purification of a semi-synthetic macrolide anthelmintic drug milbexime. Background technique [0002] Milbemycin Oxime (Milbemycin Oxime) is a macrolide antibody endoparasite drug, and is an oxime derivative of Milbemycin A3 and A4, of which Milbemycin Oxime 4 Oxime must not be lower than 80%. A 3 Oxime must not exceed 20%. Milbexime has a broad-spectrum anti-parasitic effect, and has a good killing effect on internal and external parasites, especially nematodes and arthropods. Lee et al. studied the neuropharmacological mechanism of milbexime on the viability of Bloodstrongylus cantonensis and Dirofilaria imimaginum in vitro, and showed that the inhibitory and stimulatory effects of milbexime on the two worms were achieved through gabergic and cholinergic mechanisms . The drug binds to the specific high-affinity...

Claims

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Application Information

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IPC IPC(8): C07D493/22
CPCC07D493/22
Inventor 何福彪付光明张文凯
Owner HUBEI HONCH PHARMA
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