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Preparation method of valnemulin hydrochloride intermediate as veterinary drug bulk drug

A technology of warnemulin hydrochloride and raw materials, which is applied in the field of preparation of warnemulin hydrochloride intermediates of veterinary drug raw materials, can solve the problems of reduced yield, complicated preparation process, long reaction time, etc., and achieve mild reaction conditions, Simple purification process and low solvent toxicity

Active Publication Date: 2020-09-01
山东亚华生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Invention patent CN106496085B discloses an intermediate compound for synthesizing warnemulin hydrochloride and a preparation method for warnemulin hydrochloride, which includes reacting pleuromutilin with p-toluenesulfonyl chloride to generate pleuromutilin p-toluenesulfonate; The pleuromutilin p-toluenesulfonate reacts with a special intermediate compound, and finally deprotected by hydrochloric acid to generate warnemulin hydrochloride. The preparation process of warnemulin hydrochloride does not require dimethyl cysteamine hydrochloride , p-toluenesulfonyl chloride plays the role of activating the hydroxyl group, but produces an equimolar amount of p-toluenesulfonic acid as a by-product, and its removal from the product will result in lower yields and increased operating steps
[0010] Pleuromutilin reacts with dimethylcysteamine after p-toluene sulfonation. There are many reports on this step reaction at home and abroad (US7612103). However, these methods all face the same problem, that is, the reaction needs to use The amount of toluenesulfonyl chloride is large, which needs to exceed the equimolar amount, resulting in a large amount of by-product toluenesulfonic acid entering the wastewater system, which requires additional special retreatment, and the reaction time is longer, and the preparation process is more complicated.

Method used

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  • Preparation method of valnemulin hydrochloride intermediate as veterinary drug bulk drug
  • Preparation method of valnemulin hydrochloride intermediate as veterinary drug bulk drug
  • Preparation method of valnemulin hydrochloride intermediate as veterinary drug bulk drug

Examples

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Effect test

Embodiment 1

[0038] Example 1 Preparation method of a veterinary raw material drug Vonimulin hydrochloride intermediate

[0039] The veterinary raw material drug intermediate is a pleuromutilin dimethylcysteamine substitute, and its preparation method includes the following steps:

[0040] Take 11.36 g (0.03 mol) of pleuromutilin and dissolve it in 200 mL of toluene. After it is dissolved, add 4.25 g (0.03 mol) of dimethylcysteamine hydrochloride, and then add 2.4 g (0.06 mol) of sodium hydroxide. ) And solid catalyst Al 2 O 3 on silica(0.6%)(4g, 0.18mmol), keep the temperature at 80-85°C and stir the reaction for 10 h; after the reaction is complete, add 10 g of boric acid, stir and react for 30 minutes, then filter and discard the filter residue; the filtrate is concentrated to dryness , Recrystallized with methyl tert-butyl ether to obtain 11.9 g of pleuromutilin dimethylcysteamine substitute, which is the same as the high-pressure liquid phase retention time of the intermediate synthesized...

Embodiment 2

[0042] Example 2 Preparation method of a veterinary raw material drug Vonimulin hydrochloride intermediate

[0043] The veterinary raw material drug intermediate is a pleuromutilin dimethylcysteamine substitute, and its preparation method includes the following steps:

[0044] Take 11.36 g (0.03 mol) of pleuromutilin and add it to 200 mL of methyl tert-butyl ether, then add 4.25 g (0.03 mol) of dimethylcysteamine hydrochloride, and then add 1.2 g (0.03 mol) of sodium hydroxide mol) and aluminum tungstophosphate AlPW 12 O 40 (6 g, 0.021 mol), the reaction was stirred at room temperature for 2 h; after the reaction was completed, 10 g of boric acid was added and reacted for 30 minutes; filtered, the filter residue was washed with methyl tert-butyl ether and discarded, the filtrate was concentrated in vacuo to precipitate a solid, filtered , Dried to obtain 10.5 g of pleuromutilin dimethylcysteamine substitute, with a yield of 75% and a purity of 97.10%.

Embodiment 3

[0045] Example 3 Preparation method of a veterinary raw material drug Vonimulin hydrochloride intermediate

[0046] Under the protection of nitrogen, add 100 mL of methyl tert-butyl ether, 23.5 g (0.062 mol) of pleuromutilin, 9.83 g (0.0694 mol) of dimethylcysteamine hydrochloride, and hexachloro ring into a 2L three-necked flask. Triphosphazene (TAPC) (2.1g, 0.0062mol), 1.5 g of benzyltributylammonium chloride, heated to 50°C and stirred for 1 hour, after removing the solvent in vacuum, add 100 mL H2O and 70 mL 1mol / L NaOH solution Into the reaction mixture, cool to 10°C, stir for 15min and filter, wash the filter cake with water and cold methyl tert-butyl ether (30ml each), and dry at 55°C to obtain pleuromutilin dimethylcysteamine substitution The product is 27.4g, the yield is 95%, and the purity is 97.0%.

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Abstract

The invention provides a preparation method of a valnemulin hydrochloride intermediate as a veterinary drug bulk drug. The intermediate is a pleuromutilin dimethyl cysteamine substituent. According tothe preparation method of the intermediate, pleuromutilin and dimethyl cysteamine hydrochloride are used as raw materials, and a solvent, alkali and a catalyst are added for reaction to obtain the intermediate, wherein the catalyst is phosphonitrilic chloride trimer, aluminum dodecatungstate phosphate, silicon dioxide loaded aluminum oxide, silicon dioxide loaded zirconium oxide or silicon dioxide loaded titanium oxide. By adopting the preparation method disclosed by the invention, the traditional two-step reaction is replaced by the one-step reaction, the purification process in the reactionprocess is simple, the catalyst can be repeatedly used, p-toluenesulfonyl chloride is not required to be used, the wastewater amount is reduced, and the preparation method is environment-friendly andsuitable for industrial large-scale production.

Description

Technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of a veterinary raw material medicine vonimoline hydrochloride intermediate. Background technique [0002] Valnemulin Hydrochloride (the structural formula is as follows) is a new generation of pleuromutilin (pleuromutilin) ​​semi-synthetic antibiotics. It belongs to diterpenes and has the characteristics of strong antibacterial activity and broad antibacterial spectrum. It can be made into feed premix It is used for the prevention and treatment of pig bacterial diseases [Chinese Journal of Pharmaceuticals, 2010, 41(4), 244-246]. [0003] [0004] Molecular structure of vonimoline hydrochloride [0005] In 2010, the raw materials and premixes of Vonimulin hydrochloride developed by my country were approved by the Ministry of Agriculture as the national second-class veterinary drug. The raw materials and premixes of Vonimulin hydrochloride have b...

Claims

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Application Information

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IPC IPC(8): C07C323/52C07C319/14
CPCC07C319/14C07C2603/82C07C323/52
Inventor 崔心江杨尚金贾涛
Owner 山东亚华生物科技有限公司
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