Synthetic method of 20,23-dipiperidine-5-O-carbomycin amine glycosyl-tildipirosin

A mycaminoglycosyl and tylonolide technology, applied in chemical instruments and methods, sugar derivatives, sugar derivatives, etc., can solve the problems of cumbersome post-processing, complicated steps, and high three wastes, and save raw materials. cost, simplify the synthesis process, and reduce the effect of the three wastes

Inactive Publication Date: 2018-07-10
湖北回盛生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] As mentioned above, the existing chemical synthesis process of tylosin basically uses tylosin as the starting material, and undergoes hydrolysis, amination, iodination, and secondary amination to obtain the new tylosin raw material drug. Complicated, low yield, cumbersome post-treatment, high amount of three wastes

Method used

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  • Synthetic method of 20,23-dipiperidine-5-O-carbomycin amine glycosyl-tildipirosin
  • Synthetic method of 20,23-dipiperidine-5-O-carbomycin amine glycosyl-tildipirosin
  • Synthetic method of 20,23-dipiperidine-5-O-carbomycin amine glycosyl-tildipirosin

Examples

Experimental program
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Effect test

Embodiment 1

[0044] A kind of synthetic method of 20,23-diiodo-5-O-mycaminosyl-tylonolide, the steps are as follows:

[0045] 1. In a 1000 ml three-necked flask, dissolve 300 g of tylosin phosphate in 700 ml of methanol, place the three-necked flask in an ice bath to cool, and at the same time feed nitrogen into the three-necked flask to make it in a nitrogen atmosphere, stir Slowly add 50 g of solid sodium borohydride, and stir for 3 hours to react. After the reaction is complete, stop feeding nitrogen, and cool the three-necked flask to 30° C. to obtain a mixed product.

[0046] 2. Add 0.5 mol / L sulfuric acid solution to the three-necked flask containing the mixed product, adjust the pH value of the system to 2, raise the temperature to 50°C, and keep it warm for 3 hours to obtain the crude intermediate. Dissolve the crude intermediate in 1000 ml of water Dilute with 1400 ml of dichloromethane, add 5mol / L sodium hydroxide solution under stirring to adjust the pH to 6.5, let stand to sepa...

Embodiment 2

[0052] A kind of synthetic method of 20,23-diiodo-5-O-mycaminosyl-tylonolide, the steps are as follows:

[0053] 1. In a 1000 ml three-necked flask, dissolve 300 grams of tylosin phosphate in 700 ml of ethanol, place the three-necked flask in an ice bath to cool, and at the same time, feed nitrogen into the three-necked flask to make it in a nitrogen atmosphere, and stir Slowly add 80g of zinc amalgam under low temperature, stir and react for 8 hours, stop feeding nitrogen after the reaction is completed, and cool the three-necked flask to 30°C to obtain a mixed product.

[0054] 2. Add 40wt% hydrobromic acid solution to the three-necked flask containing the mixed product, adjust the pH value of the system to 2, heat up to 50°C, and heat-preserve and hydrolyze for 8 hours to obtain the crude intermediate, which is mixed with 1000 ml of water Dilute with 1400 ml of dichloromethane, add 5mol / L sodium hydroxide solution under stirring to adjust the pH to 6.5, let stand to separat...

Embodiment 3

[0057] A kind of synthetic method of 20,23-diiodo-5-O-mycaminosyl-tylonolide, the steps are as follows:

[0058] 1. In a 1000 ml three-necked flask, dissolve 300 grams of tylosin phosphate in 700 ml of butanone, place the three-necked flask in an ice bath to cool, and simultaneously feed nitrogen into the three-necked flask to make it in a nitrogen atmosphere, Slowly add 50 g of aluminum isopropoxide under stirring, and react with stirring for 10 hours. After the reaction is completed, stop feeding nitrogen, and cool the three-necked flask to 30° C. to obtain a mixed product.

[0059] 2. Add 85wt% formic acid solution to the three-necked flask containing the mixed product, adjust the pH value of the system to 2, heat up to 50°C, and heat-preserve and hydrolyze for 24 hours to obtain the crude intermediate. The crude intermediate is mixed with 1000 ml of water and 1400 Dilute with milliliter of dichloromethane, add 5mol / L sodium hydroxide solution under stirring to adjust the p...

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Abstract

The invention discloses a synthetic method of 20,23-dipiperidine-5-O-carbomycin amine glycosyl-tildipirosin. The synthetic method comprises the following steps: (1) adding 20,23- dihalo-5-O-carbomycinamine glycosyl-tildipirosin, piperidine and potassium carbonate in a reaction container, carrying out heating refluxing for 4-5 h while stirring, after fluxing is finished, filtering an obtained mixing system, adding purified water in filtrate, fully stirring and then standing for layering, and separating to obtain an organic layer; (2) adding pure water in the organic layer again, adjusting pH value to be 2-3, standing for layering, separating to obtain a water layer, cooling the water layer to the temperature of 0 DEG C, adjusting pH value to be 8.0-8.5, standing for layering, separating toobtain a water phase, extracting the water phase by using an organic solvent to obtain an organic phase, removing the organic solvent, filtering, and concentrating till the product is dry to obtain acrude product; and (3) refining the crude product to obtain the 20,23-dipiperidyl-5-O-carbomycin amine glycosyl-tildipirosin. By the method, the 20,23- dihalo-5-O-carbomycin amine glycosyl-tildipirosin is directly used as a starting material, the route for synthesizing tildipirosin is greatly simplified, and the synthesizing cost is reduced.

Description

technical field [0001] The invention relates to the technical field of macrolides, in particular to a method for synthesizing 20,23-dipiperidine-5-O-mycaminosyl-tylonolide. Background technique [0002] 20,23-dipiperidinyl-5-O-mycaminosyl-tylosin (Tildipirosin), alias: Tildirosin, is a semi-synthetic macrolide antibiotic, which is the derivative of tylosin derivative. The structural formula is as follows: [0003] [0004] 20,23-Dipiperidinyl-5-O-mycaminosyl-tylonolide is the latest macrolide semi-synthetic antibiotic for animals developed by Merck, which is a derivative of tylosin , has a very obvious therapeutic effect on the respiratory diseases of cattle and pigs, and the drug effect is stronger than that of tylosin and tilmicosin, and it is specially used for animals, less dosage, full treatment with one administration, super long elimination half-life, High bioavailability, low residue and other advantages. [0005] Regarding the chemical synthesis method of 20,...

Claims

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Application Information

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IPC IPC(8): C07H17/08C07H1/00
CPCC07H17/08C07H1/00
Inventor 张卫元沈华葛健郑春红邱壮李钰
Owner 湖北回盛生物科技有限公司
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