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Method for synthesizing milbemycin oxime compound

A technology of milbe oxime and compounds, which is applied in the field of preparation of milbe oxime compounds, can solve problems such as research and development limitations, and achieve the effects of mild reaction conditions, high yield, and easy industrialization

Inactive Publication Date: 2017-04-19
RINGPU TIANJIN BIOLOGICAL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the protection of intellectual property rights and fermentation strains, the research and development of this type of product has been restricted. There are few research products on milbexime compounds in China, and only Zhejiang Hisun has milbexime APIs and tablets on the market.

Method used

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  • Method for synthesizing milbemycin oxime compound
  • Method for synthesizing milbemycin oxime compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] A: hydroxyl protection reaction: take 50g abamectin raw material and dissolve in 500ml dichloromethane. Turn on the reactor to stir, set the reactor to be kept at 10°C, and stir. First add 13.2g of triethylamine, then add 8.8g of acetic anhydride, after 3 hours of reaction, add 200ml of water to wash after the reaction, adjust the pH of the water phase to 9.5, stir and wash, then stand to separate the phases, and use dichloromethane for the water phase Extract twice, combine the organic phase, wash the organic phase with saturated NaCl, separate the phases, dehydrate the organic phase with anhydrous sodium sulfate, filter, concentrate, crystallize, filter and dry to obtain 52.8 g of compound 1.

[0039] B: Hydrolysis reaction: Add compound 1 in step A to the reactor, add 5u glycoside hydrolase, stir and hydrolyze at 40°C for 5 hours, extract and dry to obtain 33.8 g of compound 2.

[0040] C: Hydroxyl removal reaction: Dissolve the compound 2 in step B in 200ml tetrahydr...

Embodiment 2

[0045] A: hydroxyl protection reaction: take 50g abamectin raw material and dissolve in 200ml chloroform. Turn on the reactor to stir, set the reactor to be kept at 30°C, and stir. First add 7.1g of diethylamine, then add 29.2g of benzyloxycarbonyl chloride, react for 6 hours, add 200ml of water to wash after the reaction, adjust the pH of the water phase to 9.5, stir and wash, let stand to separate the phases, and wash the water with three Methyl chloride was extracted twice, and the organic phase was combined. The organic phase was washed with saturated NaCl. After phase separation, the organic phase was dehydrated with anhydrous sodium sulfate, filtered, concentrated, crystallized, and filtered to dry to obtain 51.4 g of compound 1.

[0046] B: Hydrolysis reaction: Add compound 1 in step A to the reactor, add 20u glycoside hydrolase, stir and hydrolyze at 50°C for 3 hours, extract and dry to obtain 34.1 g of compound 2.

[0047] C: Hydroxyl removal reaction: Dissolve compo...

Embodiment 3

[0052] A: hydroxyl protection reaction: take 50g abamectin raw material and dissolve in 100ml ethyl acetate. Turn on the reactor to stir, set the reactor to be kept at 50°C, and stir. First add 14.2g of pyridine, then add 22g of di-tert-butyl dicarbonate, react for 8 hours, add 200ml of water to wash after the reaction, adjust the pH of the water phase to 9.5, stir and wash, let stand to separate the phases, and wash the water with ethyl acetate The ester was extracted twice, the organic phase was combined, and the organic phase was washed with saturated NaCl. After phase separation, the organic phase was dehydrated with anhydrous sodium sulfate, filtered, concentrated, crystallized, filtered and dried to obtain 50.5 g of compound 1.

[0053] B: Hydrolysis reaction: Add compound 1 in step A to the reactor, add 50 u of glycoside hydrolase, stir and hydrolyze at 30°C for 6 hours, extract and dry to obtain 32.1 g of compound 2.

[0054] C: Hydroxyl removal reaction: Dissolve the...

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Abstract

The object of the invention is to provide a method for synthesizing a milbemycin oxime drug. The implementation method provided by the invention comprises the steps: subjecting one or the mixture of avermectin B1a and avermectin B1b, which serves as a raw material, to a hydroxyl protecting reaction so as to protect a hydroxyl group at the C5 position; then, carrying out hydrolysis so as to remove a glycosyl group at the C13 position; then, carrying out a reaction so as to remove a hydroxyl group at the C13 position; and then, removing a hydroxyl protection group at the C5 position, carrying out hydroxyl oxidation so as to produce keto-carbonyl, and carrying out an oximation reaction, thereby finally obtaining a milbemycin oxime compound. According to the method, the milbemycin oxime compound product is synthesized from avermectins, which serve as the raw material, by a chemical synthesis method; and the chemical synthesis method has mature route and has no need of taking milbemycin, which is required to be obtained through fermentation, as the raw material, so that the cost and scarcity of the raw material are reduced, the large-scale industrial production is better facilitated, milbemycin oxime products are enriched, and thus, the shortage of domestic pet parasite treatment drugs is made up.

Description

technical field [0001] The invention belongs to the field of chemical synthesis of veterinary raw materials, and in particular relates to a preparation method of milbexime compounds. Background technique [0002] Milbemycin (Milbemycin) is a sixteen-membered ring macrolide compound extracted and separated from Streptomyces by Japanese chemist Aoki in 1967. Milbemycin has a good effect on mites, agricultural pests and garden pests. At the same time, it also has a good performance in pet medicine, such as cat and dog deadly parasite dirofilariasis has a good effect. [0003] With the deepening of the research, milbemycin derivatives appear continuously, among which milbemycin is the representative. Milbemycin A 3 and A 4 Oxime derivatives, English name: Milbemycinoxime, molecular formula: C 63 h 88 N 2 o 14 (if attached figure 1 shown), milbexime is figure 1 Mixture of compounds I and II shown, molecular weight: 1097.4. CAS number: 129496-10-2, white solid. Soluble ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/22
CPCC07D493/22Y02P20/55
Inventor 井丁丁李旭东刘爱玲魏微郑超
Owner RINGPU TIANJIN BIOLOGICAL PHARMA
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