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Preparation method of tildipirosin

A new and independent technology of Taidiluo, applied in the field of medicine, can solve the problems of many by-products and unsuitable for industrial production

Inactive Publication Date: 2018-05-15
SHANDONG LUKANG SHELILE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Prior art WO2008012343 is a synthesis method reported by the original research company, using tylosin as a raw material, undergoing amination reduction, high-concentration strong acid hydrolysis, and iodide activation at the 23rd position, and then performing amination reaction again to obtain tylosin, a by-product More, the total product yield is only 12.2%, not suitable for industrialized production

Method used

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  • Preparation method of tildipirosin

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preparation example Construction

[0026] The present invention provides a new preparation method of tedrol, comprising the following steps:

[0027] (1) Mixing tylosin, piperidine, a reducing agent and an organic solvent, and performing the first amination reaction to obtain compound I;

[0028] (2) Mix the compound I, acid and water, and carry out a neutralization reaction to obtain a salt solution;

[0029] (3) After stepwise acid hydrolysis of the salt solution, alkalization treatment is carried out to obtain compound II;

[0030] (4) Mixing the compound II, oxidant, and organic solvent, and performing an oxidation reaction to obtain compound III;

[0031] (5) mixing the compound III, piperidine, a reducing agent and an organic solvent, and performing a second amination reaction to obtain tedirosin;

[0032] The structures of Compound I, Compound II and Compound III are as follows:

[0033] Compound I;

[0034] Compound II; Compound III.

[0035] In the present invention, compound I is obtained b...

Embodiment 1

[0095] (1) Mix 1000g (1.1mol) of tylosin, 468g of piperidine and 5L of butyl acetate, heat up to 50°C, add 25g of formic acid dropwise, and carry out the amination reaction; 3L of deionized water was added to quench the reaction, and the phases were separated to obtain an organic phase containing compound I;

[0096] (2) Mix the organic phase containing compound I with 5L of deionized water, adjust the pH value of the system to 2 using dilute sulfuric acid with a mass concentration of 30%, and separate the phases to obtain a salt solution;

[0097] (3) in described salt solution, adding mass concentration is 50% dilute sulfuric acid 250ml, and the mol ratio of described sulfuric acid and tylosin is 1.2:1, stirs at room temperature and carries out preliminary hydrolysis, and the time of described preliminary hydrolysis is 1h; after the completion of the preliminary hydrolysis, add 160ml of concentrated sulfuric acid with a mass concentration of 80%, the molar ratio of the sulfu...

Embodiment 2

[0103] (1) Mix 1000g (1.1mol) tylosin, 468g piperidine and 5L isopropyl acetate, heat up to 53°C, keep the system temperature constant, add 60g sodium cyanoborohydride in batches, and carry out amination reaction ; After reacting for 1 hour, cool down to room temperature, add 3L deionized water to the system to quench the reaction, and separate phases to obtain an organic phase containing compound I;

[0104] (2) Mix the organic phase containing compound I with 5L of deionized water, adjust the pH value of the system to 3 by using dilute sulfuric acid with a mass concentration of 30%, and separate the phases to obtain a salt solution;

[0105] (3) in described salt solution, adding mass concentration is 50% dilute sulfuric acid 250ml, adds 2g hydrobromic acid simultaneously, and the mol ratio of described sulfuric acid and tylosin is 1.2:1, stirs at room temperature and carries out preliminary hydrolysis, The time for the preliminary hydrolysis is 1.5h; after the completion of...

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Abstract

The invention provides a preparation method of tildipirosin. The preparation method of the tildipirosin comprises the following steps: mixing tylosin, piperidine, a reducing agent and an organic solvent and performing first amination reaction to obtain a compound I; mixing a compound I, acid and water and performing neutralizing reaction to obtain a salt solution; adding acid into the salt solution step by step to perform hydrolysis, and performing alkaline treatment to obtain a compound III; mixing the compound III, piperidine, a reducing agent and an organic solvent and performing second amination reaction to obtain the tildipirosin. The tylosin serves as the raw material, the 20th aldehyde group of the tylosin is transformed into piperidyl through the amination reaction, so that byproducts caused by hydrolysis of the aldehyde group in the subsequent hydrolysis reaction is avoided; the 4th glycosyl and 15th glycosyl are removed through the hydrolysis, the 23rd hydroxyl is transformedinto piperidyl through oxidation reaction and amination reaction sequentially, and the tildipirosin is obtained, so that the byproducts are effectively reduced and the total yield is increased.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of tedirosin. Background technique [0002] Tildipirosin is the latest animal-specific macrolide semisynthetic antibiotic developed by Pfizer, and it is a derivative of tylosin. At present, the high morbidity and mortality of respiratory diseases are the primary problems faced by the global pig and cattle farming industry. In the process of cattle farming, the annual global economic loss due to respiratory diseases is as high as more than 300 million US dollars. Tedirosin is used to prevent and treat respiratory infectious diseases caused by sensitive bacteria in pigs and cattle. A single administration can provide a full course of treatment. Its drug effect is stronger than that of tylosin and tilmicosin. The effect is very obvious, and the dosage is small, the half-life is long, the bioavailability is high, and the residue is low. [0003] Prior art WO2008012343 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/08C07H1/00
CPCC07H1/00C07H17/08
Inventor 武茂成郭强桑艳丽吴敬营郭晓梅赵琪
Owner SHANDONG LUKANG SHELILE PHARMA
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