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Preparation method of milbemycin oxime

A technology of milbemycin and milbemycin, applied in the direction of organic chemistry, can solve the problems of high cost, large investment in equipment, and difficulty in realizing industrialized production, and achieve the effect of increasing production capacity and reducing costs

Active Publication Date: 2016-01-20
HUBEI HONCH PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main problem of the above-mentioned preparation method of milbexime is that silica gel chromatography or preparative chromatography not only requires a large investment in equipment, consumes a large amount of solvent, and has high cost, but also is difficult to scale up and realize industrial production.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] The preparation method of the milbemycin provided by the present embodiment, its steps are as follows: 1, take by weighing 130Kg dried milbemycelium, milbemycin A 3 and A 4 The calibrated contents are 0.55% and 2.57%, respectively, which are added to a 1500L stirring extraction tank, and 750L of n-heptane and acetone mixed solvent with a volume ratio of 6:1 are added, stirred and extracted at 30rpm for 2h, filtered, and the filter cake is subjected to the above conditions Extract 2 times and combine the filtrates. Pump the filtrate into the concentrator, concentrate under reduced pressure at 55°C to about 300L, and obtain concentrate A.

[0019] 2. Transfer the concentrated solution A from the previous step to a 1000L extraction kettle, add 300L of 85% ethanol aqueous solution, stir at 25rpm for 15min, let it stand for 30min, and separate the liquids. The upper n-heptane phase is extracted once again with 300L of 85% ethanol solution, and the extracts are combined , c...

Embodiment 2

[0025] The preparation method of the milbemycin provided by the present embodiment, its steps are as follows: 1, take by weighing 130Kg dried milbemycelium, milbemycin A 3 and A 4 The calibrated contents are 0.56% and 2.59%, respectively, which are added to a 1500L stirring extraction tank, and 950L of n-heptane and acetone mixed solvent with a volume ratio of 4:1 are added, stirred and extracted at 30rpm for 2h, filtered, and the filter cake is subjected to the above conditions Extracted 4 times and combined the filtrates. Pump the filtrate into the concentrator, concentrate under reduced pressure at 50°C to about 300L, and obtain concentrate A.

[0026] 2. Transfer the concentrated solution A from the previous step to a 1000L extraction kettle, add 290L of 76% ethanol aqueous solution, stir at 25rpm for 15min, let stand for 30min, separate the liquids, extract the upper n-heptane phase with 300L85% ethanol solution once again, and combine the extracts , concentrated under ...

Embodiment 3

[0032] The preparation method of the milbemycin provided by the present embodiment, its steps are as follows: 1, take by weighing 130Kg dried milbemycelium, milbemycin A 3 and A 4 The calibrated contents are 0.58% and 2.55%, respectively, which are added to a 1500L stirring extraction tank, and 1200L of n-heptane and acetone mixed solvent with a volume ratio of 8:1 are added, stirred and extracted at 30rpm for 2h, filtered, and the filter cake is subjected to the above conditions Extracted 3 times and combined the filtrates. Pump the filtrate into the concentrator, concentrate under reduced pressure at 60°C to about 300L, and obtain concentrate A.

[0033] 2. Transfer the concentrated solution A from the previous step to a 1000L extraction kettle, add 250L of 88% ethanol aqueous solution, stir at 25rpm for 15min, let it stand for 30min, and separate the liquids. The upper n-heptane phase is extracted once again with 300L of 85% ethanol solution, and the extracts are combined ...

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Abstract

The invention provides a preparation method of milbemycin oxime. The preparation method of milbemycin oxime comprises the following steps: extracting milbemycins, namely taking milbe mycelia obtained through fermentation as a raw material, extracting, concentrating, extracting, concentrating, extracting again and concentrating again, so as to obtain milbemycin; preparing milbemycin ketone, namely taking the milbemycin as a raw material, establishing an oxidation reaction system, after reaction is finished, filtering, concentrating, extracting and concentrating the reaction system, so as to obtain an intermediate product milbemycin ketone; synthesizing milbemycin oxime, namely dissolving milbemycin ketone with methanol and dioxane, dropwise adding hydroxylamine hydrochloride solution and reacting, concentrating the reaction system, extracting, drying and concentrating, so as to obtain a milbemycin oxime crude product; and purifying milbemycin oxime, namely crystallizing the milbemycin oxime crude product with a mixed solvent of trichloromethane and normal heptane, dissolving a crystalline product with ethanol, dropwise adding into water while stirring for carrying out crystallization, filtering, and drying, so that the milbemycin oxime finished product is obtained. The preparation method of the milbemycin oxime has the advantages that productivity is greatly improved, and cost is obviously reduced, so that the preparation method provided by the invention is obviously better than an existing preparation method.

Description

technical field [0001] The invention belongs to the field of synthesis and purification of chemicals, and in particular relates to a synthesis and purification method of a semi-synthetic macrolide anthelmintic. Background technique [0002] Milbemycin Oxime (MilbemycinOxime) is a macrolide anti-endoparasite drug, and it is an oxime derivative of Milbemycin A3 and A4. 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 site on the target worm cells, which affects the permeability of the cell membrane to Cl-, and then causes the inhibit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/22
CPCC07D493/22
Inventor 付光明何福彪张文凯余翔
Owner HUBEI HONCH PHARMA
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