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Synthesis and purification method of tildipirosin

A technology of tediloxine and purification method, applied in the field of medicine, can solve the problems of poor stability of tediloxine, low product yield and the like, and achieve the effects of short time consumption, simple and easy operation of purification process, and mild reaction conditions

Active Publication Date: 2021-04-20
武汉回盛生物科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In view of this, it is necessary to provide a kind of synthesis and purification method of tedirosin, in order to solve the poor stability of the production process of tedirosin in the prior art , The technical problem of low product yield

Method used

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  • Synthesis and purification method of tildipirosin
  • Synthesis and purification method of tildipirosin
  • Synthesis and purification method of tildipirosin

Examples

Experimental program
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Embodiment 1

[0043] A. Synthesis of 20-piperidinyl-5-O-mycaminosyl-tylonolide (Ⅱ): Weigh 120g of tylosin phosphate (0.118mol), add it to a three-necked reaction flask, and add 360ml Ethyl acetate is dissolved, then add 54ml of formic acid solution with a mass fraction of 85%, 18ml of piperidine, the temperature rises to 75°C, and starts to cool after 5 hours of reaction; after the temperature of the reaction solution drops to 25°C, add 300ml of water and 120ml of mass fraction to 40% hydrobromic acid solution was stirred for 30 minutes and then separated into layers to obtain the lower layer aqueous solution A.

[0044] B. Synthesis of 23-hydroxy-20-piperidinyl-5-O-mycaminosyl-tylonolide (III): Heat the aqueous solution A obtained in the above process to 68°C for hydrolysis reaction, and start after 5 hours of reaction Cool down; after the temperature of the reaction solution drops to 25°C, add 100ml of dichloromethane, stir for 30 minutes, let stand, extract and separate layers, and take ...

Embodiment 2

[0049] A. Synthesis of 20-piperidinyl-5-O-mycaminosyl-tylonolide (Ⅱ): Weigh 120g of tylosin phosphate (0.118mol), add it to a three-necked reaction flask, add 500ml Chloroform is dissolved, then add 72ml mass fraction and be 85% formic acid solution, 24ml piperidine, temperature rises to 62 ℃, begin to cool down after reacting 8h; 40% hydrobromic acid solution was stirred for 30 minutes and then separated into layers to obtain the lower layer aqueous solution A.

[0050] B. Synthesis of 23-hydroxy-20-piperidinyl-5-O-mycaminosyl-tylonolide (III): Heat the aqueous solution A obtained in the above process to 73°C for hydrolysis reaction, and start the reaction after 4 hours Cool down; after the temperature of the reaction solution drops to 25°C, add 150ml of chloroform, stir for 30min, then let it stand, extract and separate layers, and take the upper aqueous phase; add 300ml of potassium hydroxide solution with a concentration of 6mol / L to the aqueous phase to adjust the pH The...

Embodiment 3

[0055] A. Synthesis of 20-piperidinyl-5-O-mycaminosyl-tylonolide (Ⅱ): Weigh 120g of tylosin phosphate (0.118mol), add it to a three-necked reaction flask, add 1500ml Dissolve toluene, then add 24ml of formic acid solution with a mass fraction of 85%, and 36ml of piperidine, the temperature rises to 90°C, and starts to cool down after 3 hours of reaction; after the temperature of the reaction solution drops to 25°C, add 1200ml of water and 70ml with a mass fraction of 40% The hydrobromic acid solution was stirred for 30 minutes, and then the layers were left to stand to obtain the lower aqueous solution A.

[0056] B. Synthesis of 23-hydroxy-20-piperidinyl-5-O-mycaminosyl-tylonolide (III): Heat the aqueous solution A obtained in the above process to 55°C for hydrolysis reaction, and start the reaction after 8 hours Cool down; after the temperature of the reaction solution drops to 25°C, add 200ml of dichloromethane, stir for 30min, then let stand, extract and separate layers, a...

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Abstract

The invention discloses a synthesis and purification method of tildipirosin. The method comprises the following steps of dissolving tylosin phosphate in an organic solvent, adding formic acid and piperidine, and performing a heating reaction; performing cooling, adding water and hydrobromic acid, and performing standing for layering; hydrolyzing an aqueous solution A, performing cooling, adding the organic solvent, and performing standing for layering; adding alkali into a water phase to adjust the pH value to 6.5-7.0, adding the organic solvent and alkali to adjust the pH value to be greater than 13, performing standing for layering to obtain a filtrate, and controlling the water content to be less than 0.1% through atmospheric distillation; adding triphenylphosphine and pyridine, performing heating, dropwise adding an iodine solution, continuously reacting, performing cooling, adding alkali for quenching, and performing standing for layering; adding an alkali catalyst and piperidine into the filtrate C, performing a heating reaction, performing cooling, adding acid to adjust the pH value to 6.20-6.80, and performing standing for layering; adding the organic solvent into the water phase, and performing standing for layering; and continuously adding the organic solvent and the alkali into the water phase to adjust the pH value to be greater than 13, and performing standing for layering to obtain a filtrate D. The method is simple to operate, mild in reaction condition, low in cost and high in product yield, and the purity and content of the obtained tildipirosin are both greater than 99%; and the method is beneficial to industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for synthesizing and purifying tedirosin. Background technique [0002] Tildipirosin is a macrolide semi-synthetic antibiotic, a derivative of tylosin, and its structural formula is as follows: [0003] [0004] Tedirosin has a unique chemical structure, it is replaced by two piperidines at C20 and C23, and a carbamycin lactone ring is connected at C5. Since these three nitrogen atoms are easily protonated, tedirosin is a tribasic molecule. Tedirosin is used to treat and prevent respiratory diseases in cattle and pigs, and has many advantages such as drug resistance, less dosage, one-time administration, low residue, and animal-specific use. Tedirosin not only has the advantages of macrolide antibiotics, but also has high bioavailability (78.9%), which is superior to other macrolide antibiotics with a long half-life (9Day), and it can remain in the body for a long ...

Claims

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Application Information

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IPC IPC(8): C07H17/08C07H1/00C07H1/06
Inventor 张卫元孙凯付咏堂彭康洲张湛明姜园
Owner 武汉回盛生物科技股份有限公司
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