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Process for preparing 20,23-bi-piperidyl-5-O-carbon mould amine glycosyl-tylosin lactone

A mycaminoglycosyl and tylonolide technology, which is applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., can solve the problems of many by-products, cumbersome reaction steps and high cost, and achieve simplified production. Process, high purity, easy industrial application effect

Active Publication Date: 2013-01-09
QILU ANIMAL HEALTH PROD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This synthetic method, reaction step is loaded down with trivial details, and its acidic hydrolysis adopts hydrobromic acid, and by-product is more, and the water requirement of iodo step is less than 100ppm, and the condition is too harsh, and final product is purified through multiple recrystallizations, and product loss is serious, and yield is only 12.2% %,higher cost

Method used

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  • Process for preparing 20,23-bi-piperidyl-5-O-carbon mould amine glycosyl-tylosin lactone
  • Process for preparing 20,23-bi-piperidyl-5-O-carbon mould amine glycosyl-tylosin lactone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] A preparation method of 20,23-dipiperidinyl-5-O-mycaminosyl-tylonolide, the steps are as follows:

[0047] (1) Dissolve 300kg of tylosin tartrate in 4500kg of purified water, then add 741.6kg of sulfuric acid with a mass percentage of 20% while keeping the temperature at 50°C, and hydrolyze for 8 hours. The peak of tylosin detected by HPLC completely disappears. Detected by HPLC, 150kg of 23-hydroxyl-5-O-mycaminosyl-tylonolide was obtained, with a molar yield of 82.8%;

[0048] (2) Add 755 kg of dichloromethane to the 150 kg reaction liquid containing 23-hydroxy-5-O-mycaminosyl-tylonolactone prepared in step (1), and adjust the pH with 5 mol / L sodium hydroxide solution When the value reaches 8, separate layers, take the organic layer, add 21.5kg of piperidine, 11.5kg of anhydrous formic acid, heat to 40°C, reflux for 5h, and detect 23-hydroxy-5-O-mycaminosyl-Taylor by HPLC The lactone content is less than 2g / L, and 149kg of 20-piperidinyl-23-hydroxy-5-O-mycaminosyl-tyl...

Embodiment 2

[0053] A preparation method of 20,23-dipiperidinyl-5-O-mycaminosyl-tylonolide, the steps are as follows:

[0054] (1) Dissolve 300kg of tylosin tartrate in 5400kg of purified water, then add 370.8kg of sulfuric acid with a mass percentage of 40% at a temperature of 80°C, and hydrolyze for 6 hours. The peak of tylosin detected by HPLC completely disappears. Detected by HPLC, 151 kg of 23-hydroxyl-5-O-mycaminosyl-tylonolide was obtained, with a molar yield of 83.4%;

[0055] (2) Add 755kg of dichloromethane to the 151kg reaction liquid containing 23-hydroxy-5-O-mycaminosyl-tylonolactone prepared in step (1), and adjust the pH with 5mol / L sodium hydroxide solution When the value reaches 10, separate layers, take the organic layer, add 25.8kg of piperidine, 13.8kg of anhydrous formic acid, heat to 40°C, reflux for 5.5h, and detect 23-hydroxy-5-O-mycaminosyl-Thai by HPLC The content of tylonolide is less than 2g / L, and 155kg of 20-piperidinyl-23-hydroxyl-5-O-mycaminosyl-tylonolide...

Embodiment 3

[0060] A preparation method of 20,23-dipiperidinyl-5-O-mycaminosyl-tylonolide, the steps are as follows:

[0061] (1) Dissolve 300kg of tylosin tartrate in 6000kg of purified water, then add 302kg of sulfuric acid with a mass percentage of 98% while keeping the temperature at 90°C, and hydrolyze for 6 hours. The peak of tylosin detected by HPLC disappears completely. Detected and obtained 130 kg of 23-hydroxy-5-O-mycaminosyl-tylonolide, with a molar yield of 71.8%;

[0062] (2) Add 755 kg of dichloromethane to the 130 kg reaction liquid containing 23-hydroxy-5-O-mycaminosyl-tylonolactone prepared in step (1), and adjust the pH with 5 mol / L sodium hydroxide solution When the value reaches 12, separate layers, take the organic layer, add 43kg of piperidine, 26kg of anhydrous formic acid, heat to 40°C, reflux for 6h, and detect the content of 23-hydroxy-5-O-mycaminosyl-tylonolide by HPLC Less than 2g / L, 138kg of 20-piperidinyl-23-hydroxyl-5-O-mycaminosyl-tylonolide was obtained;...

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Abstract

The invention relates to a process for preparing 20,23-bi-piperidyl-5-O-carbon mould amine glycosyl-tylosin lactone. Tylosin tartrate serves as a raw material, an intermediate product of 23-oxhydryl-5-O-carbon mould amine glycosyl-tylosin lactone is obtained through hydrolyzation, an organic phase is extracted through phase inversion, and an intermediate product of 20-piperidyl-23-oxhydryl-5-O-carbon mould amine glycosyl-tylosin lactone is produced through combination with piperidine under the effect of methanoic acid. A final product of the 20,23-bi-piperidyl-5-O-carbon mould amine glycosyl-tylosin lactone is formed by ammonization with the piperidine through iodination. By the aid of the process, the production technology is simplified, the dosage of auxiliary raw materials such as the piperidine, iodine and an organic solvent is greatly reduced, the purity of the obtained product is higher than 98%, the yield of the final product of the 20,23-bi-piperidyl-5-O-carbon mould amine glycosyl-tylosin lactone reaches 58.7%, and the process has good industrial application prospects.

Description

technical field [0001] The invention relates to a preparation method of 20,23-dipiperidinyl-5-O-mycaminosyl-tylonolide, belonging to the technical field of veterinary antibiotic synthesis. Background technique [0002] 20,23-dipiperidinyl-5-O-mycaminosyl-tylonolide, also known as Tediroxin, molecular formula: C 41 h 71 N 3 o 8 Molecular weight: 734.02, is a broad-spectrum macrolide antibiotic, mainly used to treat livestock respiratory diseases. The synthetic method of this compound, foreign patent document report has two kinds of synthetic methods. [0003] A patent US 6514946 published by the Japanese Microbial Chemistry Research Foundation, using 20,23-diiodo-5-O-mycaminosyl-tylonolide as raw material, acetonitrile as solvent, and piperidine at reflux temperature After reacting for 1 h, the product was obtained by column chromatography with a mass yield of 86.4%. The raw material 20,23-diiodo-5-O-mycaminosyl-tylonolide is not suitable for obtaining, and the product ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/00C07H1/00
Inventor 方明锋李永东刘全才孔梅吴连勇
Owner QILU ANIMAL HEALTH PROD
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