A kind of synthetic method of warnemulin hydrochloride

A technology of vonimulin hydrochloride and synthesis method, which is applied in chemical instruments and methods, preparation of sulfonate esters, preparation of organic compounds, etc. volatilization and other problems, to achieve the effect of promoting the complete reaction, high reaction yield and product purity, and reducing the amount of use

Active Publication Date: 2018-08-14
河北远征禾木药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in this synthetic method, tert-butyl methyl ether with low boiling point is used as the reaction solvent many times, especially in the post-treatment process of step 3 (compound 21), the reactant after the solvent is evaporated must be poured into tert-butyl methyl ether with low boiling point while hot. In ether, this will cause serious volatilization of tert-butyl methyl ether, which will affect the health of workers and increase the content of volatile ether in the working environment. Tert-butyl methyl ether is not easy to recycle, which is not environmentally friendly and unsafe
And step four reaction is heterogeneous suspension reaction, and reaction time is long, and reaction is not thorough enough, thereby causes the reaction yield of this step not high

Method used

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  • A kind of synthetic method of warnemulin hydrochloride
  • A kind of synthetic method of warnemulin hydrochloride
  • A kind of synthetic method of warnemulin hydrochloride

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] A kind of synthetic method of warnemulin hydrochloride, specifically comprises the following steps:

[0059] (1) Synthesis of pleuromutilin with dimethylsemiphotoamine

[0060] In a 500mL four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser, add compound 11 (75.7g, 0.2mol), 200mL tetrahydrofuran, and 40mL water, and add dropwise a tetrahydrofuran solution of p-toluenesulfonyl chloride ( Dissolve 42g, 0.22mol of p-toluenesulfonyl chloride in 100mL of tetrahydrofuran), add 50mL of 10N NaOH solution after dripping; heat the reaction mixture to reflux, reflux for 1 hour, the reaction solution is yellow and turbid, stop the reaction; filter, filter The cake was dried at 75°C to obtain 96 g of white solid (Compound 12), with a yield of 90.1%.

[0061] In a 500mL three-necked flask equipped with a stirrer, add compound 12 (96g, 0.18mol), a tetrahydrofuran solution of dimethylsemicarcinamide hydrochloride (dissolve 25.5g, 0.18mol dimethyl...

Embodiment 2

[0071] A kind of synthetic method of warnemulin hydrochloride, specifically comprises the following steps:

[0072] (1) Synthesis of pleuromutilin with dimethylsemiphotoamine

[0073] In a 500mL four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser, add pleuromutilin (133.5g, 0.3mol), 300mL tetrahydrofuran, 60mL water, and add dropwise the tetrahydrofuran of p-toluenesulfonyl chloride under stirring. solution (dissolve 63g, 0.33mol p-toluenesulfonyl chloride in 150mL tetrahydrofuran), then add 75mL 10N NaOH solution; heat the reaction mixture to reflux for one hour, the reaction solution is yellow and turbid, stop the reaction, filter, and filter the cake at 75°C After drying, 145.0 g of white solid (compound 12) was obtained, with a yield of 90.7%.

[0074] In a 500mL three-neck flask equipped with a stirrer, add compound 12 (145.0g, 0.27mol), dimethylsemiphotoamine hydrochloride (38.3g, 0.27mol) and 300mL tetrahydrofuran, and stir at 35°C...

Embodiment 3

[0084] A kind of synthetic method of warnemulin hydrochloride, specifically comprises the following steps:

[0085] (1) Synthesis of pleuromutilin with dimethylsemiphotoamine

[0086] In a 500mL four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser, add pleuromutilin (75.7g, 0.2mol), 200mL tetrahydrofuran, 40mL water, and add dropwise the tetrahydrofuran of p-toluenesulfonyl chloride under stirring. solution (dissolve 42g, 0.22mol of p-toluenesulfonyl chloride in 100mL of tetrahydrofuran), and then add 50mL of 10N NaOH solution; heat the reaction mixture to reflux for one hour, the reaction solution is yellow and turbid, stop the reaction, filter, and filter the cake at 75°C After drying, 96 g of white solid (compound 12) was obtained, with a yield of 90.1%.

[0087] In a 500mL three-neck flask equipped with a stirrer, add compound 12 (96g, 0.18mol), dimethylsemicarpine hydrochloride (25.5g, 0.18mol) and 200mL tetrahydrofuran, and add ben...

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Abstract

The invention discloses a synthesis method of valnemulin hydrochloride. The synthesis method comprises the following three steps: synthesis of dimethylcysteamine pleuromulin from pleuromulin, synthesis of D-valine dane salt from D-valine and synthesis of valnemulin hydrochloride from dimethylcysteamine pleuromulin and D-valine dane salt. The synthesis method has the advantages that lots of homogeneous reactions are adopted, the post-treatment method is simple, organic solvents can be recycled, the reaction yield and the product purity are high, safety and environment-friendliness are realized, the reaction is moderate, and thus, the method is very suitable for industrialized enlarged production; with the adoption of the method, the repeated washing step during D-valine hydrolysis and salt formation is omitted, the production operation is simplified, the labor intensity is reduced, the consumption of low-boiling-point ether solvents is greatly reduced, volatilization of the solvents is reduced, low pollution is caused, and the method is conducive to the health of workers and the safety of the environment.

Description

technical field [0001] The invention relates to a synthesis method of diterpene antibiotics, in particular to a synthesis method of warnemulin hydrochloride, which belongs to the technical field of drug synthesis. Background technique [0002] Valnemulin hydrochloride is a semi-synthetic antibiotic of pleuromutilin (Valnemulin Hydrochloride). It has a wide antibacterial spectrum and strong antibacterial activity. Mycoplasma septicemia, Mycoplasma pneumoniae, Streptococcus, Actinobacillus, Pasteurella, Treponema hyodysenteriae and Treponema coliformis have good antibacterial activity, and have the characteristics of short drug withdrawal period and low toxicity. It is used in the treatment of mycoplasma pneumonia, swine dysentery, porcine colitis and porcine ileitis. In 1999, the European Union approved the use of warnemulin hydrochloride for the prevention and treatment of swine dysentery caused by Brachyspira hyodysenteriae infection and swine enzootic pneumonia caused by ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C319/20C07C323/52C07C303/26C07C309/73C07C319/14C07C227/26C07C229/30
CPCC07C227/26C07C303/26C07C319/14C07C319/20C07C323/52C07C229/30C07C309/73
Inventor 黄凯李金明张玉贾国宾苑七星郭建立魏永辉孔瑞岗杜永军
Owner 河北远征禾木药业有限公司
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