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Preparation method and intermediate of lepimectin

A time and compound technology, applied in the field of pesticides, can solve the problems of low milbemycin fermentation unit, unsuitable for industrialized large-scale production, and low total process yield, and achieve the effects of simplifying operations, reducing production costs, and shortening reaction routes.

Active Publication Date: 2020-06-02
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Above-mentioned technological shortcoming is: 1, technological route is long, and milbemycin fermentation unit is relatively low, and cost is relatively high, no matter be for the industrialization of levampycin or popularization and application on the pesticide market, all have very big restriction; 2 , The 13-position carbon in the obtained final product 13-(α-methoxyiminophenylacetoxy)milbemycin A4 core exists in a mixed form of α-configuration and β-configuration, which needs to be resolved by resolution technology Obtaining the 13-position is the Lepingmycin A4 of β configuration, is not suitable for industrialized large-scale production; Base) the process total yield of milbemycin A4 is lower, about 26%, wherein, raw material 15-hydroxyl-5-ketone milbemycin A4 also needs to be the starting material through 5 steps by milbemycin A4 The reaction is prepared, so the total yield of 13-(alpha-methoxyiminophenylacetoxy) milbemycin A4 is far lower than 26% from milbemycin

Method used

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  • Preparation method and intermediate of lepimectin
  • Preparation method and intermediate of lepimectin
  • Preparation method and intermediate of lepimectin

Examples

Experimental program
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Effect test

Embodiment 1

[0074] The synthesis of embodiment 1 2-methoxyiminophenylacetic acid

[0075] Dissolve 50g (0.030mol) of ethyl benzoylformate in 350mL of methanol solution containing 33g of methoxyamino hydrochloride, reflux at 80°C for 8h, TLC detects that the reaction is complete, extract with ethyl acetate (3×100mL), and concentrate Separation by silica gel column chromatography (elution system: methanol: chloroform = 1:9 (v / v) to obtain 53.6 g of ethyl 2-methoxyiminophenylacetate with a yield of 91%.

[0076] Dissolve 53.6g of ethyl 2-methoxyiminophenylacetate in 500mL of tetrahydrofuran and water mixture (v:v=1:1), slowly add 15mL of lithium hydroxide monohydrate, stir at 25°C for 5h, add 10M Hydrochloric acid was neutralized to neutral, extracted with ethyl acetate (3×300mL), the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, distilled to dryness under reduced pressure, and separated by silica gel column chromatography (elution system was e...

Embodiment 7

[0097] The preparation of embodiment 7 formula V-2 compound (lepinmycin A4)

[0098]

[0099] 3.2g (0.0167mol) of 2-methoxyiminophenylacetic acid, 5.90g (0.0087mol) of the compound of formula III-2 and 12g (0.0457mol) of triphenylphosphine were dissolved in 200mL toluene and tetrahydrofuran (5:1, v / v) into the mixed solution, add 10g (0.0574mol) diethyl azodicarboxylate dropwise at 0°C, after the dropwise addition, return to 10°C and stir for 3h, dilute with diethyl ether or n-hexane, filter to remove three Phenylphosphine oxide, the filtrate was concentrated under reduced pressure, the crude product was subjected to silica gel column chromatography, and the elution system was ethyl acetate:n-hexane=10:90 (v / v), to obtain 43.58 g of the compound of formula IV-2, ESI-MS : m / z 834.4[M+H] + , yield 49%.

[0100] 2g (0.0024mol) of the compound of formula IV-2 was added to 120mL of 1% (w / v) methanol solution of p-toluenesulfonic acid (1.2g, 0.007mol) in an ice-water bath, and...

Embodiment 8

[0105] The preparation of embodiment 8 Lepingmycin

[0106] 5g of asvermectin was added to 75mL of methanol and 95% sulfuric acid (90:10, v / v) mixed solution, under nitrogen protection, stirred at 25°C for 10h, then added 40mL of ice water for dilution, dichloromethane extraction ( 3 × 80mL), the organic layer was washed with saturated sodium bicarbonate solution and clear water, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure at 45°C, separated by silica gel column chromatography, and the elution system was ethyl acetate:petroleum Ether = 1:3 (v / v), to obtain 3.23 g of a mixture of the compound of formula II-1 and the compound of formula II-2, with a yield of 98%.

[0107] Dissolve 2g of the mixture of the compound of formula II-1 and the compound of formula II-2 in 25mL of dry dichloromethane, add 1.1g of imidazole, stir at 25°C until all the raw materials are dissolved, then add 1.65g (0.011mol) of tert-butyl...

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Abstract

The invention discloses a preparation method and an intermediate of lepimectin represented by a formula V. The preparation method comprises the following steps: by taking tenvermectin as an initial raw material, carrying out an acid hydrolysis reaction, adding a protecting group to a 5-hydroxyl group, then carrying out an SN2 reaction with 2-methoxyiminobenzeneacetic acid, and finally removing the5-hydroxyl protecting group to obtain the compound represented by the formula V. The preparation method has the advantages of low cost, high purity, high yield and suitability for industrial production.

Description

technical field [0001] The invention relates to the field of pesticides, in particular to a preparation method of levampycin and an intermediate thereof. Background technique [0002] Lepimectin, whose structural formula is shown in formula V, is another successful 16-membered macrolide antibiotic developed by Japan Sankyo Company, and was registered for use in Japan in 2006. The product contains two effective components of lepimycin A3 and lepimycin A4, wherein the content of lepimycin A3 is not more than 20%, and the content of lepimycin A4 is more than or equal to 80%. Lepingmycin is mainly used in the control of agricultural pests. The targets are Lepidoptera and Homoptera pests, such as Spodoptera litura, diamondback moth, cotton bollworm and mealybug, etc. The main mode of action is stomach poisoning and contact killing. Compared with other avermectins, Lepingmycin has the advantage of being unaffected by temperature, more stable, and quick-acting. For example, after...

Claims

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Application Information

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IPC IPC(8): C07D493/22
CPCC07D493/22Y02P20/55
Inventor 张绍勇王继栋张辉李建宋齐欢滕云白骅
Owner ZHEJIANG HISUN PHARMA CO LTD
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