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Method for preparing tulathromycin

A telamycin and synthesis method technology, applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., can solve the problems of many impurities in the reaction, poor selectivity, difficult to purify, etc.

Active Publication Date: 2018-05-08
WISDOM PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this route, when Cbz protects the hydroxyl group at the 2″ position, and when Swern oxidizes the hydroxyl group at the 4′ position, there are other active groups in the compound to participate in competing reactions, resulting in poor selectivity, many reaction impurities, and difficult purification.

Method used

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  • Method for preparing tulathromycin
  • Method for preparing tulathromycin
  • Method for preparing tulathromycin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0034] 1, preparation formula III (R=Me) compound

[0035] Add compound formula I (500g, 645.16mmol) and CH 2 Cl 2 (3.5L), the system was fully stirred to maintain the system temperature at about 20 degrees. Slowly add p-methylbenzyl chloroformate (formula II, R=Me, 180 g, 975 mmol) dropwise to the reaction system through the dropping funnel, and maintain the temperature of the system at about 20 degrees during the dropping process. After the dropwise addition, the system was incubated for 3 hours. The system was slowly added with 4 L of saturated aqueous sodium bicarbonate solution to quench the reaction, and after the addition was complete, the system was stirred at room temperature for 2 hours. The system was left to stand for 2 hours, separated, the organic phase was washed with 1 L of water, and then 250 g of anhydrous sodium sulfate was added to the organic phase, stirred and dried. After filtration, the organic phase was concentrated under reduced pressure until the...

Embodiment 7

[0049] Compound IV (R=NO) prepared in embodiment 7 2 , 25g, 26.3mmol) was added to a 500mL reaction flask, and CH was added to the system 2 Cl 2 (180mL), after stirring and dissolving, the temperature of the reaction system was cooled to about 0°C in an ice-salt bath, and then trimethylsilylcyanide (3.3g, 33.3mmol) was slowly added through a syringe. After the addition, the system was naturally warmed up to room temperature and reacted overnight, then slowly added TBAF (1M in THF, 35mL) dropwise to the system, and the reaction was incubated for 3 hours after the dropwise addition was completed. Slowly add H to the reaction system 2 O (100 mL) quenched the reaction, the system was left to stand and separated, the organic phase was separated, the organic phase was washed twice with saturated brine (2×80 mL), and the organic phase was dried over anhydrous sodium sulfate. Filter, concentrate the organic phase under reduced pressure until there is no obvious fraction, add ethyl ...

Embodiment 8

[0051] Compound V (R=NO) prepared in embodiment 8 2 , 16g, 16.3mmol) was added to a 500mL small autoclave, then isopropanol (120mL) and HOAc (45mL) were added, and after stirring to dissolve, Pd / C (2.5g, 10%) was added under nitrogen protection. The system was replaced with nitrogen three times, and the hydrogenation reaction was carried out at 35° C. and 5 atm for 24 hours. After the reaction was complete, the reaction solution was taken out, filtered twice through a Buchner funnel, the filter cake was washed with isopropanol (20 mL), the filtrate was combined, the filtrate was concentrated under high vacuum and reduced pressure until no obvious fraction was present, and ethyl acetate (10 mL) was added to the residue. , stirred to dissolve, slowly added heptane (50mL) dropwise, stirred overnight, a large amount of white solids precipitated out of the system, filtered, and the filter cake was washed with a little cooled n-heptane and dried to obtain the compound of formula VI ...

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Abstract

The invention relates to a novel method for preparing tulathromycin. The method includes the steps that 3,4-acetonylidene protected demethylazithromycin is used as a starting material, a 2-hydroxyl group is firstly protected, then a 4-hydroxyl group is oxidized to a carbonyl group under Swern conditions, TMSCN is used for performing a cyano group addition reaction on the carbonyl group under the action of TBAF, a resulting intermediate compound is subjected to a hydrogenation reaction in the presence of HOAc with Pd / C as a catalyst, the cyano group in the compound is converted into an amine methyl group while a 2-hydroxy group protecting group and 3,4-acetonylidene protection are removed, and finally under the action of base, an amine methyl compound is reacted with 1-halogenated propane to achieve the preparation of tulathromycin.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a new method for preparing telamycin. Background technique [0002] As a third-generation macrolide antibiotic, Tulathromycin has low concentration, long action time, low minimum inhibitory concentration, low dosage, good water solubility for injection, low overall treatment cost and convenient use during use. And other advantages, have been widely concerned by the field of veterinary medicine. [0003] Tyramycin, also known as tulamycin and tolamycin, has a trade name of "Draxxin" (the Chinese name is "Rui Ke Xin" or "Rui Ke Xin"). The drug is a new type of erythromycin semi-synthetic veterinary drug researched and developed by Pfizer Animal Health in the late 1990s. It is mainly used to treat and prevent animals from Actinobacillus pleuropneumoniae, Mycoplasma, Pasteurella, Respiratory diseases caused by Haemophilus parabacterium, Bordetella bronchiseptica, etc. The drug wa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/00C07H1/00
CPCC07H1/00C07H17/00C07H19/24Y02P20/55
Inventor 邹平储玲玲邱小龙胡林张程亮曾祥军苟少华吴忠平沈伟符剑许明王平张新刚时光好王军强陈俊曹雷
Owner WISDOM PHARM CO LTD
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