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Preparation method of high-yield tiamulinfumarate

A high-yield technology for tiamulin fumarate, which is applied in the field of preparation of high-yield tiamulin fumarate, can solve the problems of cumbersome post-processing, many synthesis steps, and low product yield, and achieve stable product quality , Improve the reaction yield, the effect of increasing the reaction yield

Active Publication Date: 2013-01-16
宁夏泰瑞制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most pharmaceutical companies use this process to prepare tiamulin fumarate, but this process has many synthesis steps and cumbersome post-processing procedures, resulting in low product yields

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] 1. Sulfonation reaction

[0023] Take the pleuromone extract, filter it through a 0.2μm membrane, and slowly cool the solution to 15°C at a rate of 5°C / h while stirring. To the solution, 1.1 times the molar mass of p-toluenesulfonyl chloride was added, and 40% NaOH solution was added to the solution to control the pH at 9.0. After fully stirring for 30 minutes, the solution was washed twice with 5-6 times the volume of pure water.

[0024] 2. Amination reaction

[0025] The quaternary ammonium salt and diethylaminoethanethiol are sequentially added to the ketone phase. The molar mass of the quaternary ammonium salt is 1 times the molar mass of the sulfonated product, and the molar mass of the diethylaminoethanethiol added is sulfonated. 1.3 times the product. Add a 40% NaOH solution of 2 times the volume of the solution, control the pH to 9.0 and the reaction temperature to 50°C, and fully react for 1 hour. After the reaction is complete, 4 times the volume of water is add...

Embodiment 2

[0030] 1. Sulfonation reaction

[0031] Take the pleuromone extract, filter it through a 0.2μm membrane, and slowly cool the solution to 17°C at a rate of 5°C / h while stirring. To the solution, 1.2 times the molar mass of p-toluenesulfonyl chloride was added, and 40% NaOH solution was added to the solution to control the pH at 9.5. After fully stirring the reaction for 35 minutes, the solution was washed twice with 5 times the volume of pure water.

[0032] 2. Amination reaction

[0033] The quaternary ammonium salt and diethylaminoethanethiol are sequentially added to the ketone phase. The molar mass of the quaternary ammonium salt is 1.5 times the molar mass of the sulfonated product, and the molar mass of the diethylaminoethanethiol added is sulfonated. 1.35 times the product. Add a 40% NaOH solution 2.5 times the volume of the solution, control the pH at 9.5 and the reaction temperature at 55°C, and fully react for 1 hour. After the reaction is complete, add 4.5 times the vol...

Embodiment 3

[0038] 1. Sulfonation reaction

[0039] Take the pleuromone extract, filter it through a 0.2μm membrane, and slowly cool the solution to 20°C at a rate of 5°C / h while stirring. To the solution was added 1.3 times the molar mass of p-toluenesulfonyl chloride, while adding 40% NaOH solution to the solution to control the pH at 10.0. After fully stirring for 40 minutes, the solution was washed twice with 6 times the volume of pure water.

[0040] 2. Amination reaction

[0041] The quaternary ammonium salt and diethylaminoethanethiol are sequentially added to the ketone phase. The molar mass of the added quaternary ammonium salt is twice the molar mass of the sulfonated product, and the molar mass of the diethylaminoethanethiol added is sulfonated. 1.5 times the product. Add a 40% NaOH solution of 3 times the volume of the solution, control the pH at 10.0 and the reaction temperature at 60°C, and fully react for 1 hour. After the reaction is completed, 5 times the volume of water is ...

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Abstract

The invention relates to a preparation method of high-yield tiamulinfumarate. The method comprises the following steps of: adding paratoluensulfonyl chloride which is 1.1-1.3 times the molar mass of truncated pleurotin ketone extract into the truncated pleurotin ketone extract; performing sulfonation reaction under a stirring state at the pH (Potential of Hydrogen) of 9-10; washing with pure water; adding quaternary ammonium salt in an amount which is 1-2 times of the molar mass of a sulfonation product and diethylaminoethylmercaptide in an amount which is 1.3-1.4 times the molar mass of the sulfonation product into the sulfonation product in sequence; performing amination reaction under the conditions of pH of 9-10 and temperature of 50-60 DEG C; adding water to extract; removing water phase; performing membrane filtration on ketone phase; performing vacuum concentration until the volume is 60-70 percent of the original volume; and adding methanol and fumaric acid to perform salt forming reaction to obtain the tiamulinfumarate. According to the process, the product yield is increased on the premise of guaranteeing product quality, so that the final product quality yield reaches 115-120 percent. The use of the diethylaminoethylmercaptide is reduced in a production process, the production cost is reduced, and preparation method has certain development prospect.

Description

technical field [0001] The invention belongs to the technical field of biopharmaceutical synthesis, in particular to a method for preparing tiamulin fumarate with high yield. Background technique [0002] Tiamulin fumarate is a kind of diterpenoid (pluromulin) antibiotic that is produced by fermentation to produce pleuromutilin, and then semi-synthesized to salt. It acts as a bacteriostasis by inhibiting the synthesis of microbial ribosomal receptor proteins. The product has a bactericidal effect at high concentrations, and the bactericidal effect is strongest in an environment of pH 8.5~9.0. Tiamulin is the first pleuromutilin antibiotic for animals, and it has a very broad application prospect in the veterinary medicine industry and the prevention and control of livestock and poultry diseases. [0003] The production process of tiamulin fumarate is to firstly ferment Pleurotus mutilus or Pleurotus pasterii to obtain pleuromutilin fermentation broth, extract pleuromutilin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/52C07C319/20C07C319/14
Inventor 王义任勇王彬周丽娜
Owner 宁夏泰瑞制药股份有限公司
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