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Synthesis method of selamectin

A synthesis method and selamectin technology, which are applied in the field of drug synthesis, can solve the problems of complicated post-processing operations and separation steps, high cost, low yield and the like, and achieve shortened production cycle, high raw material utilization rate and high yield. Effect

Pending Publication Date: 2022-03-01
ZHEJIANG RONGYAO CHEM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] In summary, there are many shortcomings in the existing patented technology: such as low yield, high cost, cumbersome post-processing operations and separation steps, etc.

Method used

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  • Synthesis method of selamectin
  • Synthesis method of selamectin
  • Synthesis method of selamectin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1 oxidation reaction

[0039]

[0040] Add 500mL of dichloromethane into the three-necked bottle, weigh 100g of doramectin A, add it into the three-necked bottle at one time through the addition funnel, stir and dissolve, then add 200g of manganese dioxide, at room temperature (20-30°C ) reacted for 8 hours, LC-MS monitored the reaction, the reaction could be processed after the raw materials were reacted, and the LC-MS purity of the product was 97.65%. After the reaction, the manganese dioxide was removed by suction filtration, and the filtrate was decompressed to remove the solvent in a 45°C water bath to obtain a light yellow solid, which was dried in a 45°C oven to constant weight to obtain 98.96g of intermediate B, with a yield of 99%.

Embodiment 2

[0041] Embodiment 2 desugaring, oximation reaction

[0042]

[0043] Add 600mL of tert-butanol into the three-necked flask, add 100g of Intermediate B, and stir to dissolve at room temperature. Dissolve 19g of hydroxylamine hydrochloride in 30mL of water, slowly add the aqueous solution of hydroxylamine hydrochloride to the system dropwise after dissolving, react at 26-35°C for 35-48 hours, monitor the reaction by LC-MS, stop the reaction when the remaining 10-12% of raw material B , LC-MS purity of product C was 80%.

[0044] Dissolve 15g of sodium carbonate in 50mL of water, and slowly add it dropwise into the system after dissolving. Remove the solvent under reduced pressure in a water bath at 50°C to obtain a yellow solid, add 500mL of water, stir at room temperature for 2 hours, filter with suction, place the filter cake in an oven at 50°C, and weigh it to obtain 89.33g after drying, with a yield of 104%.

Embodiment 3

[0045] Embodiment 3 desugaring, oximation reaction

[0046]

[0047] Add 500mL of isopropanol into the three-necked flask, add 100g of intermediate B, and stir to dissolve at room temperature. Dissolve 19g of hydroxylamine hydrochloride in 30mL of water, slowly add the aqueous solution of hydroxylamine hydrochloride to the system dropwise after dissolving, react at 26-35°C for 35-48 hours, monitor the reaction by LC-MS, stop the reaction when the remaining 10-12% of raw material B , LC-MS purity of product C was 76%.

[0048]Dissolve 15g of sodium carbonate in 50mL of water, and slowly add it dropwise into the system after dissolving. Remove the solvent under reduced pressure in a water bath at 50°C to obtain a yellow solid, add 500mL of water, stir at room temperature for 2 hours, filter with suction, place the filter cake in an oven at 50°C, and weigh it to obtain 88.17g after drying, with a yield of 103%.

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Abstract

The invention provides a synthetic method of selamectin, which specifically comprises the following steps of: oxidizing doramectin by manganese dioxide, oximating and desugaring by a hydroxylamine hydrochloride aqueous solution through a one-step method, and finally selectively reducing under the action of a Wilkinson catalyst and hydrogen to obtain the selamectin. According to the method, C-5 hydroxyl of the raw material doramectin is oxidized into carbonyl, generation of impurities in the follow-up reaction process is reduced, tert-butyl alcohol with large steric hindrance is used as a solvent, transesterification impurities generated when methyl alcohol or isopropyl alcohol is used as the solvent are avoided, the hydrogenation reaction is carried out in the last step, a crude product is purified and then put into the hydrogenation reaction, and the yield of doramectin is increased. The catalyst consumption is reduced, and the cost is greatly reduced. The method disclosed by the invention is relatively high in yield, and the total yield reaches 57%. HPLC (High Performance Liquid Chromatography) quality analysis is carried out on a pure selamectin product, the purity is 97.11%, and known impurities and unknown impurities meet the requirements of pharmacopeia. The synthesis method provided by the invention is simpler, more economical and more efficient, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and relates to a synthesis method of avermectins, in particular to a synthesis method of selamectin. Background technique [0002] Abamectins are a group of macrolides fermented by Streptomyces, which are the most widely used broad-spectrum antiparasitic drugs, and commercialized drugs include avermectins ( AVM), ivermectin (IVM), doramectin (DRM), eprinomectin (EPR) and selamectin (SEI), etc. [0003] Selamectin (also known as selamectin) is an abamectin antibiotic fermented by a new strain of genetically recombined Streptomyce savermitilis. Lamectin is chemically synthesized and structurally modified. It was first launched in the UK in July 1999 under the trade name Revolution. Selamectin has a wide range of inhibitory and killing effects on many parasites, including fleas, scabies, ticks, hookworms, lice, nematodes and heartworms. Fleas and Ctenocephalus canis), mites, ticks, and...

Claims

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Application Information

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IPC IPC(8): C07H17/08C07H1/00
CPCC07H17/08C07H1/00
Inventor 钟秀文黄友纯张蕾陈文腾俞永平陈仁尔
Owner ZHEJIANG RONGYAO CHEM
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