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New route for synthesizing tulathromycin

A telamectin and synthetic route technology, which is applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problems of high cost and safety, harsh reaction conditions, and difficult separation and purification of products, and achieve Easy to obtain, simple reaction process, easy to achieve effect

Active Publication Date: 2015-09-02
RINGPU TIANJIN BIOLOGICAL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the process of hydroxyl oxidation and epoxidation, the methods currently used generally use a reaction temperature of -70 to -30°C, the reaction conditions are harsh, or a highly toxic oxidant is used for the reaction, and the product is not easy to separate and purify. Apps have significant cost and security concerns

Method used

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  • New route for synthesizing tulathromycin
  • New route for synthesizing tulathromycin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] 2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[[2,6-dideoxy-3-C-methyl-3-O-methyl-4-oxo -α-L-nucleo-hexapyranosyl]-oxy]-2-ethyl-3,4,10-trihydroxy acid-3,5,8,10,12,14-hexamethyl-11- [[3,4,6-trideoxy-3-(dimethylamino)-2-O-acetyl-β-D-xyl-hexapyranosyl]oxy]-1-oxo-6-aza Cyclopentadecane (15-membered macrocycle) (with figure 2 Compound I) Preparation:

[0047] Add 140 g of hydroxyl-protected demethylazithromycin to a 2000 mL three-neck reaction flask, add 1400 ml of dichloromethane and stir to dissolve, heat up to 30°C, then add 71.7 g of pyridinium dichromate, keep stirring for 2 hours to obtain a reaction solution. After the reaction, add 400mL saturated NaCl solution to the above reaction solution, wash, and separate the phases, take the organic phase, add an appropriate amount of anhydrous sodium sulfate solid, filter, concentrate and dry to obtain compound I, white solid powder 114.4g, molar yield The rate is 82.2%, and the content is 92.3%.

Embodiment 2

[0049] 2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[[2,6-dideoxy-3-C-methyl-3-O-methyl-4-oxo -α-L-nucleo-hexapyranosyl]-oxy]-2-ethyl-3,4,10-trihydroxy acid-3,5,8,10,12,14-hexamethyl-11- [[3,4,6-trideoxy-3-(dimethylamino)-2-O-acetyl-β-D-xyl-hexapyranosyl]oxy]-1-oxo-6-aza Cyclopentadecane (15-membered macrocycle) (with figure 2 Compound I) Preparation:

[0050] Add 70g of hydroxyl-protected demethylazithromycin to a 1000mL three-necked reaction flask, add 700ml of dichloromethane and stir to dissolve, heat up to 30°C, then add 38.6g of chlorpyridinium chromate, and stir for 5 hours to obtain a reaction solution. After the reaction, add 200mL saturated NaCl solution to the above reaction solution, wash, and separate the phases, take the organic phase, add an appropriate amount of anhydrous sodium sulfate solid, filter, concentrate and dry to obtain compound I, white solid powder 56.3g, molar yield The rate is 80.1%, and the content is 91.3%.

[0051] Chromatographic conditions of...

Embodiment 3

[0053] (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[[2,6-dideoxy-3-C-methyl-3-O-methyl-4-C -[(cyclopropyl)amido]-4-O-carboethoxy-α-L-nucleo-hexapyranosyl]-oxy]2-ethyl-3,4,10-trihydroxy-3, 5,8,10,12,14-Hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-2-O-acetyl-β-D-wood-hexypyr Preparation of pyranosyl]oxy]-1-oxa-6-azacyclopentadecane (15-membered macrocycle) (compound II):

[0054] Add 500ml of ethyl acetate into a 1000mL three-necked reaction flask, raise the temperature to 20°C, then add 5.1g of cyclopropylnitrile and 4.6g of acetic acid, and stir evenly. The temperature was raised to 10° C., then 50 g of the product (Compound I) in Example 1 was added, and stirred for 2 hours to obtain a reaction solution. After the reaction, add 200mL saturated NaCl solution to the above reaction solution, wash and separate the phases, take the organic phase, add an appropriate amount of anhydrous sodium sulfate solid, filter, concentrate and dry to obtain compound II, 49.8g of white solid p...

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Abstract

The invention discloses a new route for synthesizing tulathromycin. The new route for synthesizing the tulathromycin is different from the previous epoxidation reaction, ring-opening reaction and the like reaction process. The new route for synthesizing the tulathromycin uses Passerini reaction, all the groups are led in by one time, and then the tulathromycin is obtained through Clemmensen reaction and hydrogenation reduction reaction. The new route for synthesizing the tulathromycin includes steps that taking hydroxyl protecting demethylation azithromycin, generating hydroxyl protecting ketone (compound I) through oxidation reaction, leading amido bond and cyclopropyl to a ketone-hydroxyl group position, generating (compound II), reducing the hydroxyl into methylene through Clemmensen reaction, generating (compound III), carrying out hydrogenation and ring opening on cyclopropyl to generate n-propyl through ring-opening reaction, and obtaining the tulathromycin (compound IV). The new route for synthesizing the tulathromycin is simple in process, easy to implement, easy to obtain reaction reagent, moderate in reaction condition, high in selectivity, less in by-product, easy to purify and low in facility request.

Description

technical field [0001] The invention belongs to the field of chemical synthesis of veterinary raw materials, and in particular relates to a preparation method of telamectin. Background technique [0002] Tyramectin, also known as turamectin, dragamectin. It is the latest animal-specific macrolide semi-synthetic antibiotic developed by Pfizer Animal Health. It was launched in the European Union and the United States in 2004. It is used for the prevention and treatment of respiratory infectious diseases caused by sensitive bacteria in cattle and pigs and bovine infectious keratoconjunctivitis caused by Moraxella bovis. A single dose of telamectin provides a full course of therapy. Pigs are generally administered intramuscularly, and cattle are administered subcutaneously in the neck. Molecular formula is C 41 h 79 N 3 o 12 , molecular weight 806.23, CAS number: 280755-12-6. The density is 1.17. See attached figure 1 , Tyramectin molecular structure. [0003] Tyrame...

Claims

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Application Information

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IPC IPC(8): C07H17/00C07H1/00
Inventor 井丁丁李旭东刘爱玲夏雪林刘拓聂丽娜
Owner RINGPU TIANJIN BIOLOGICAL PHARMA
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