Preparation method of high-purity selamectin

A technology of selamectin and doramectin, which is applied in the field of preparation of high-purity selamectin, can solve the problem of low total yield of the process, low purity of selamectin crude product, and insufficient purity of selamectin Advanced problems, to achieve the effect of high total yield

Active Publication Date: 2019-07-12
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This process is the basic patented process route of selamectin. Many domestic manufacturers use this route, but the total yield of this process is not high, and each intermediate needs to be separated by silica gel chromatography. The crude selamectin obtained at last is also It needs to be purified by silica gel column chromatography and high pressure liquid chromatography, and the whole process is very unfavorable for industrial production
[0006] Chinese patent 98808106.7 is an improved selamectin preparation method patent applied by Pfizer Co., Ltd. of the United States. The whole route has undergone hydrogenation, oxidation, desugaring, and oximation, and desugaring and oximation are completed in one step. Although the route Relatively short, but toluene or methanol is used for the purification of the final product selamectin. These two solvents have no effect on the removal of some impurities, and the purity of the resulting refined selamectin is still not high enough.
[0011] However, the purity of the crude product of selamectin obtained by this process is relatively low, ranging from 65.2% to 81.2%, and the last step still needs reversed-phase C18 silica gel to prepare selamectin with higher purity, which does not utilize industrial production

Method used

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  • Preparation method of high-purity selamectin
  • Preparation method of high-purity selamectin
  • Preparation method of high-purity selamectin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] The preparation of embodiment 1 SL1 crude product

[0048]

[0049] Add 40kg DL and 184kg acetone to the 300L hydrogenation kettle, vacuum N 2 Replace 3 times, stop stirring, add Wilkinson catalyst, N 2 Replaced 3 times, H 2 Replace 3 times. Start stirring, 35-40°C, hydrogen pressure 0.3-0.4Mpa, react for 3-4 hours, monitor by HPLC, DL raw material peak area 2 replacement. Concentrate under reduced pressure and evaporate to dryness in an external bath at 40-50°C with a water pump to obtain 40.5 kg of crude product with a purity of 88.8%.

Embodiment 2

[0050] The refining of embodiment 2 SL1

[0051] Add 81kg of methanol to 40.5kg of crude product, dissolve quickly, and stir for about 5 minutes to precipitate solids. Naturally cool down to room temperature, then cool down to 15-17°C and stir for 10-12 hours, centrifuge 39kg of wet product, and dry in a vacuum oven at 40°C in a water bath After 4 hours, 36 kg of SL1 crystalline solid was obtained with a purity of 96.6%.

Embodiment 3

[0052] Example 3 Preparation of SL2

[0053]

[0054] Add 36kg SL1 and 250kg isopropanol obtained in Example 2 to a 1000L stainless steel reactor, and stir in a turbid state at a temperature of 20.2°C. Slowly add 13.1kg of concentrated sulfuric acid dropwise for about 20 minutes. After the nitrogen breaks the vacuum, under nitrogen protection Keep warm at 22-24°C and stir for about 0.5h. The system is dissolved and stirred for 2 hours. HPLC monitoring, SL1<6%, stop the reaction, pour the reaction solution into 1000kg of ice water, add 500kg of dichloromethane for extraction, and then use 250kg of dichloromethane to extract the water layer Extract with methane, combine the organic layers, wash once with 5% sodium bicarbonate, and wash three times with 5% saline each time. Add 35 kg of anhydrous sodium sulfate to the organic phase and dry for 1 h, filter the solid with suction and rinse with 60 kg of dichloromethane, and concentrate the dry product to 36 kg with a purity of 8...

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Abstract

The invention provides an improved selamectin preparation process. The process comprises the following steps: (1) performing hydrogen reduction on doramectin DL in the presence of a Wilson catalyst to obtain an intermediate SL1; (2) recrystallizing and purifying the intermediate SL1 obtained in the step (1) by use of methyl alcohol; (3) desugarizing the intermediate SL1 obtained in the step (2) by use of sulfuric acid to obtain an intermediate SL2; (4) oxidizing the intermediate SL2 obtained in the step (3) by use of manganese dioxide to obtain an intermediate SL3; (5) performing oximation on the intermediate SL3 obtained in the step (4) by use of hydroxylamine hydrochloride to obtain selamectin SL; (6) recrystallizing the crude product SL obtained in the step (5) for three times by use of methylbenzene, acetone and methyl alcohol to obtain purified SL.

Description

technical field [0001] The invention belongs to the field of pharmaceutical production, and relates to a preparation method of selamectin, in particular to a preparation method of high-purity selamectin. Background technique [0002] Abamectins are a group of macrolides fermented by Streptomyces, which can effectively control agricultural pests and a variety of harmful mites, especially those resistant to commonly used pesticides. Control effect. It is relatively safe for crops and will not kill natural enemies, which is conducive to ecological balance. At the same time, abamectins have a strong killing effect on human and animal parasitic nematodes and arthropod parasites, and have the advantages of broad spectrum, high efficiency and low toxicity. very broad. In the past two decades, good progress has been made in structural modification and transformation using natural avermectin components as parent compounds, such as ivermectin, doramectin, and moxidectin, Eprinomec...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H17/08C07H1/00C07H1/06
CPCC07H1/00C07H1/06C07H17/08
Inventor 袁建栋符新亮邢小佩丛启雷惠京城
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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