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A kind of preparation method of tiamulin fumarate with high yield

A technology of tiamulin fumarate and high yield is applied in the field of preparation of tiamulin fumarate with high yield, and can solve the problems of complicated post-processing, low product yield, many synthesis steps, etc., and achieve stable product quality , The effect of improving the reaction yield and improving the reaction yield

Active Publication Date: 2014-10-15
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] The pleurutilin extract was taken, filtered through a 0.2 μm membrane, and the temperature of the solution was slowly cooled to 15° C. at a rate of 5° C. / h under stirring. Add 1.1 times the molar mass of p-toluenesulfonyl chloride to the solution, and at the same time add 40% NaOH 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] Add quaternary ammonium salt and diethylaminoethanethiol successively in the ketone phase, the molar mass of adding quaternary ammonium salt is 1 times of the molar mass of sulfonated product, and the molar mass of adding diethylaminoethanethiol is sulfonation 1.3 times that of the product. Add 40% NaOH solution twice 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, add 4 times t...

Embodiment 2

[0030] 1. Sulfonation reaction

[0031] The pleurutilin extract was taken, filtered through a 0.2 μm membrane, and the temperature of the solution was slowly cooled to 17° C. at a rate of 5° C. / h under stirring. Add 1.2 times the molar mass of p-toluenesulfonyl chloride to the solution, and at the same time add 40% NaOH solution to control the pH at 9.5. After fully stirring and reacting for 35 minutes, the solution was washed twice with 5 times the volume of pure water.

[0032] 2. Amination reaction

[0033] Add quaternary ammonium salt and diethylaminoethanethiol successively in the ketone phase, the molar mass of adding quaternary ammonium salt is 1.5 times of the molar mass of sulfonated product, and the molar mass of adding diethylaminoethanethiol is sulfonation 1.35 times of the product. Add a 40% NaOH solution 2.5 times the volume of the solution, control the pH to 9.5, and the reaction temperature is 55°C, and fully react for 1 hour. After the reaction is complete...

Embodiment 3

[0038] 1. Sulfonation reaction

[0039] The pleurutilin extract was taken, filtered through a 0.2 μm membrane, and the solution was slowly cooled to 20° C. at a rate of 5° C. / h under stirring. Add 1.3 times the molar mass of p-toluenesulfonyl chloride to the solution, and at the same time add 40% NaOH 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] Add quaternary ammonium salt and diethylaminoethanethiol successively in the ketone phase, the molar mass of adding quaternary ammonium salt is 2 times of the molar mass of sulfonated product, and the molar mass of adding diethylaminoethanethiol is sulfonation 1.5 times the product. Add a 40% NaOH solution three times the volume of the solution, control the pH to 10.0, and the reaction temperature at 60°C, and fully react for 1 hour. After the reaction is complete, add 5 times the volume of water ...

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Abstract

The invention relates to a method for preparing tiamulin fumarate with high yield. The method firstly adds p-toluenesulfonyl chloride 1.1-1.3 times its molar mass to the extract of pleurutilin, and stirs it at pH 9-10. Carry out sulfonation reaction under the state, after washing with pure water, add the quaternary ammonium salt of 1-2 times its molar mass and the diethylaminoethanethiol of 1.3-1.4 times its molar mass successively to this sulfonated product, in Carry out amination reaction at pH 9-10, 50-60°C, add water for extraction, discard the water phase, filter the ketone phase through membrane, concentrate in vacuum to 60-70% of the original volume, add methanol and fumaric acid for synthesis After salt reaction, tiamulin fumarate is obtained. On the premise of ensuring the product quality, this process improves the product yield and makes the final product quality yield reach 115%-120%. The use of diethylaminoethanethiol is reduced in the production process, which reduces the production cost and has certain development prospects.

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 Patents(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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