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Preparation method of milbemycin oxime intermediate

A technology of milbexime and intermediates, which is applied in the field of preparation of milbexime intermediates, can solve problems such as difficult separation and extraction, low yield, and many by-products, achieve mild reaction conditions, reduce production costs, and yield and The effect of high purity

Inactive Publication Date: 2016-09-21
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is Dess-Martin oxidizing agent expensive in this method, the shortcoming of using a large amount (documentation report uses 2equiv)
In the document Bulletin of the Chemical Society of Japan, Vol.65, nb.12, pp.3300-3307, 1992, the selenium dioxide oxidation method of milbemycin has been reported, but the method has low yield and many by-products, Disadvantages such as difficulty in separation and extraction
[0006] Several milbemycin oxidation methods disclosed in the above-mentioned documents are not suitable for industrialized production

Method used

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  • Preparation method of milbemycin oxime intermediate
  • Preparation method of milbemycin oxime intermediate
  • Preparation method of milbemycin oxime intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0036] Weigh 5g of milbemycin A4 and put it into a 250mL four-necked bottle, add 25ml of acetonitrile, add 0.73g of 2,2,6,6-tetramethylpiperidine-nitrogen-oxide (tempo) and 222mg of potassium bromide, Stir while maintaining the temperature at 20-25°C. Next, 62 mL of sodium hypochlorite aqueous solution with a pH of 9.0 was added under stirring conditions, wherein the concentration of sodium hypochlorite in the solution was 0.3 mol / L, and the addition was completed within 45 minutes, and then incubated at 20-25°C for 30 minutes. Then add 30mL of 5% (w / v) sodium thiosulfate solution to quench the reaction, concentrate acetonitrile at 40°C until there is no dripping, add 100mL of dichloromethane to stir, separate layers, add 50mL of dichloromethane to the aqueous phase for extraction, and combine the obtained The organic phase was washed once with 75mL of 5% (w / v) NaCl solution, and the organic phase obtained after washing was directly concentrated to dryness to obtain 5.8g of so...

Embodiment 2

[0038] Weigh 5g of milbemycin A3 / A4 (mass content 90%, wherein A3:A4=1:4) into a 250mL four-necked bottle, add 25ml of ethyl acetate, add 2,2,6,6-tetramethyl Base piperidine-nitrogen-oxide (tempo) 0.14g and potassium bromide 222mg, keep stirring at -2-5°C. Next, add 41 mL of sodium hypochlorite aqueous solution with a pH of 11.5 under stirring conditions, wherein the concentration of sodium hypochlorite in the solution is 0.5 mol / L, the addition is completed within 15 minutes, and then the reaction is incubated at -2-5°C for 30 minutes. Then add 30mL 5% (w / v) sodium thiosulfate solution to quench the reaction, add 75mL ethyl acetate and stir, separate layers, add 50mL ethyl acetate to the aqueous phase for extraction, combine the organic phases obtained and use 75mL 5% (w / v) v) NaCl solution was washed once, and the organic phase obtained after washing was directly concentrated to dryness to obtain 5.6 g of solids with a yield of 82%, wherein the oxidation product Milbetone A3...

Embodiment 3

[0040] Weigh 5g of Milbemycin A3 / A4 (mass content 90%, wherein A3:A4=1:4) into a 250mL four-necked bottle, add 25ml of dichloromethane, add 2,2,6,6-tetramethyl Base piperidine-nitrogen-oxide (tempo) 0.014g and potassium bromide 2220mg, keep stirring at 0-5°C. Next, add 47mL of sodium hypochlorite aqueous solution with a pH of 10.5 under stirring conditions, wherein the concentration of sodium hypochlorite in the solution is 0.8mol / L, the addition is completed within 20min, and then the reaction is incubated at 0-5°C for 30min. Then add 30mL 5% (w / v) sodium thiosulfate solution to quench the reaction, add 75mL dichloromethane to stir, separate layers, add 50mL dichloromethane to the aqueous phase for extraction, combine the organic phases obtained and use 75mL 5% (w / v) v) NaCl solution was washed once, and the organic phase obtained after washing was directly concentrated to dryness to obtain 5.3 g of solids with a yield of 78%, wherein the oxidation product Milbetone A3 was 16...

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Abstract

The invention relates to a preparation method of a milbemycin oxime intermediate II. The preparation method comprises the step of reacting milbemycins (I) with pypocholoride as an oxidant in the presence of a catalyst and bromide to generate the milbemycin oxime intermediate II. The preparation method provided by the invention is simple in process operation, high in yield, low in cost, and is very suitable for industrial production. The formula I and the formula II are shown in the description, wherein R is equal to CH3 or C2H5.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of a milbexime intermediate. Background technique [0002] Milbexime is a new type of semi-synthetic macrolide anthelmintic, which can drive and kill both internal and external parasites. It is recognized as a broad-spectrum, efficient and safe anthelmintic. The synthesis of milbemycin A3 / A4 usually uses milbemycin A3 / A4 as raw material, and the milbeketone A3 / A4 (milbexime intermediate) is obtained through oxidation reaction, and then the milbemycin A3 / A4 is obtained through oximation reaction , the reaction flow is as follows: [0003] [0004] Various oxidation methods of milbemycin A3 / A4 are disclosed in the prior art, including manganese dioxide oxidation method, Swern oxidation method, Jones oxidation method, Dess-Martin oxidation method, selenium dioxide oxidation method and the like. People such as Tsukamoto have reported the mangane...

Claims

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Application Information

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IPC IPC(8): C07D493/22
CPCC07D493/22
Inventor 黄强杨勇温伟江杨志清孙利生
Owner ZHEJIANG HISUN PHARMA CO LTD
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