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Method for preparing tylosin macrolide and derivatives thereof

A technology of tylosin and macrolide, which is applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problems of product purity and yield decline, lactone bond hydrolysis, etc., and reduce the synthesis cost, increase yield, and the effect of process operation stability

Active Publication Date: 2014-06-25
烟台万润药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0034] When the L-group replaces the hydroxyl group, it is necessary to use a compound that can provide an L-group such as: iodine, methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, etc. These compounds may bind to the carbon-carbon double bond in the substrate molecule Or secondary hydroxyl groups with less steric hindrance have side reactions, which may lead to hydrolysis of lactone bonds, resulting in more by-products and decreased product purity and yield

Method used

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  • Method for preparing tylosin macrolide and derivatives thereof
  • Method for preparing tylosin macrolide and derivatives thereof
  • Method for preparing tylosin macrolide and derivatives thereof

Examples

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Embodiment 1

[0150] Preparation of 20,23-dipiperidinyl-5-O-mycaminosyl-tylonolide from tylosin A.

[0151]

[0152] Part A. Reductive amination and acid hydrolysis of mycaminosoxy substituents. 23-O-(6-deoxy-2,3-di-O-methyl-D-allosyl)-20-piperidinyl-5-O-mycaminosyl-tylonolide compound ( 2) Preparation.

[0153]

[0154] Toluene (1431g), tylosin A (1) (229g; tylosin A ≥ 80%, and tylosin A, B, C and D ≥ 95%), piperidine (25.5g) and Formic acid (67.5 g) was charged to the reactor. The mixture was heated to 65-75°C with stirring and kept at this temperature for 4-5 hours. Take a small sample and evaporate the solvent to dryness, and monitor 23-O-(6-deoxy-2,3-di-O-methyl-D-allosyl)-20-piperidinyl-5-O-carbamycin by HPLC Formation of the glycosyl-tylonolide compound (2). After the reaction was complete (tylosin A (1) HPLC content ≤ 2%), the product mixture was cooled to ambient temperature.

[0155] Part B. Acid hydrolysis of 6-deoxy-2,3-di-O-methyl-D-allosyl substituent and 23-hydrox...

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Abstract

The invention relates to a method for preparing tylosin macrolide and derivatives thereof. The method for preparing the tylosin macrolide and derivatives thereof comprises the following steps: in the presence of a fatty hydrocarbon polar solvent or aromatic hydrocarbon solvent, mixing tylosin A or salt of tylosin A and a piperidyl compound I with formic acid or aqueous solution of formic acid, so as to generate a 20-piperidyl-tylosin compound; then mixing and stirring with HCOOH or aqueous solution of HCOOH, so as to generate a 23-O-(6-deoxidation-2,3-bis-O-methyl-D-allose)-20-piperidyl-5-O-mycaminose-tylosin lactone compound; then reacting with an inorganic acid for 3-8 hours to form a 23-hydroxyl-20-piperidyl-5-O-mycaminose-tylosin lactone compound; then oxidizing to obtain an active compound by adopting a selective combined oxidizer system; reacting the active compound with a piperidyl compound II and formic acid or aqueous solution of formic acid, thus obtaining a tylosin macrolide and derivative of the tylosin macrolide. In the preparation process of the compounds, application amount of inorganic acid is reduced to 25-36 mol equivalent weight, less byproducts and high-concentration waste water are produced, and yield is increased.

Description

technical field [0001] The invention relates to a preparation method of tylosin macrolides and derivatives thereof, belonging to the field of pharmacy. Background technique [0002] It has been known for a long time that tylosin macrolides are useful in the treatment of infectious diseases in humans, livestock, poultry and other animals. Early tylosin macrolides included 16-membered tylosin macrolides, eg, tylosin A: [0003] [0004] Patents US4920103, US4820695 and EP0103465B1 all have reports on 16-membered tylosin macrolide compounds. In recent years, various tylosin derivatives have been developed to improve the antibacterial activity and selectivity of these compounds. [0005] Tylosin derivatives include, for example: tylosin B (alias desmycocin), tylosin C (alias macrocin) and tylosin D (alias relomycin), with the following structural formula: [0006] [0007] From the structural formulas of Tylosin B, C, and D, it can be seen that they are all obtained fro...

Claims

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Application Information

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IPC IPC(8): C07H17/08C07H1/00
Inventor 杜体健谷长虹孙宝佳吕作亮高健陈阳郝飞跃孙蕊
Owner 烟台万润药业有限公司
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