Tulathromycin intermediate and preparation method thereof, as well as preparation method of tulathromycin

A technology of teramycin and intermediates, which is applied in the field of teramycin drug synthesis, can solve the problems of easy ring opening, many by-products, low yield and the like, and achieves low production cost, convenient operation and improved product yield. Effect

Active Publication Date: 2012-11-21
TIANJIN ZHONGSHENG TIAOZHAN BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In this synthetic route, the acetyl group is used to double protect the hydroxyl group and the amino group, and the acetyl group is removed under the condition of alkaline alcohol solution. Since the prepared compound is a thirteen-membered macrolide compound, there is an ester in its structure The thirteen-membered macrocycle is easy to ring-open under the condition of alkaline alcohol solution, there are many by-products, and the yield is not high

Method used

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  • Tulathromycin intermediate and preparation method thereof, as well as preparation method of tulathromycin
  • Tulathromycin intermediate and preparation method thereof, as well as preparation method of tulathromycin
  • Tulathromycin intermediate and preparation method thereof, as well as preparation method of tulathromycin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Such as Figure 1-3 Shown, a kind of synthetic method of telamycin, its steps are as follows:

[0054] 1. Double protected azithromycin A (Ⅱ), namely (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl- 3-O-methyl-α-L-hexapyranosyl)oxy]-2-ethyl-3,4,10-trihydro-3,5,8,10,12,14-hexamethyl Base-11-[[3,4,6-tridehydro-3-(dimethylamino)-2-O-(tert-butoxycarbonyl)-β-D-hexylopyranosyl]oxy] - Preparation of 1-oxa-6-(tert-butoxycarbonyl)azacyclopentadecan-15-one (Ⅱ)

[0055] Add 15g (20.4mml) (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl) into a 250ml three-neck flask -3-O-methyl-α-L-hexapyranosyl)oxy]-2-ethyl-3,4,10-trihydro-3,5,8,10,12,14-hexa Methyl-11-[[3,4,6-tridehydro-3-(dimethylamino)-β-D-hexylopyranosyl]oxy]-1-oxa-6-aza Cyclopentadecan-15-one (I), 90ml tetrahydrofuran, 1.2g 4-dimethylaminopyridine, temperature control -5-5 degrees, slowly drop 11.1g (51.0mml) di-tert-butyl dicarbonate into it , After dropping, after s...

Embodiment 2

[0066] Such as figure 1 Shown, a kind of synthetic method of telamycin, its steps are as follows:

[0067] 1. (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L -hexapyranosyl)oxy]-2-ethyl-3,4,10-trihydro-3,5,8,10,12,14-hexamethyl-11-[[3,4, 6-Tridehydro-3-(dimethylamino)-2-O-(tert-butoxycarbonyl)-β-D-hexylopyranosyl]oxy]-1-oxa-6-(tert Preparation of butoxycarbonyl)azacyclopentadecan-15-one (Ⅱ)

[0068] Add 15g (20.4mml) (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl) into a 250ml three-neck flask -3-O-methyl-α-L-hexapyranosyl)oxy]-2-ethyl-3,4,10-trihydro-3,5,8,10,12,14-hexa Methyl-11-[[3,4,6-tridehydro-3-(dimethylamino)-β-D-hexylopyranosyl]oxy]-1-oxa-6-aza Cyclopentadecan-15-one (I), 90ml tetrahydrofuran, 8.4g potassium carbonate, temperature control -5-5 degrees, slowly drop 11.1g (51.0mml) di-tert-butyl dicarbonate into it, dropwise, stir Half an hour later, the temperature was raised to reflux, and afte...

Embodiment 3

[0079] Such as figure 1 Shown, a kind of synthetic method of telamycin, its steps are as follows:

[0080] 1. (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L -hexapyranosyl)oxy]-2-ethyl-3,4,10-trihydro-3,5,8,10,12,14-hexamethyl-11-[[3,4, 6-Tridehydro-3-(dimethylamino)-2-O-(tert-butoxycarbonyl)-β-D-hexylopyranosyl]oxy]-1-oxa-6-(tert Preparation of butoxycarbonyl)azacyclopentadecan-15-one (Ⅱ)

[0081] Add 15g (20.4mml) (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl) into a 250ml three-neck flask -3-O-methyl-α-L-hexapyranosyl)oxy]-2-ethyl-3,4,10-trihydro-3,5,8,10,12,14-hexa Methyl-11-[[3,4,6-tridehydro-3-(dimethylamino)-β-D-hexylopyranosyl]oxy]-1-oxa-6-aza Cyclopentadecan-15-one (I), 90ml dichloromethane, 1.2g 4-dimethylaminopyridine, temperature control -5-5 degrees, slowly dropwise add 22.2g (102.0mml) di-tert-dicarbonate Butyl ester, after dripping, stirred for half an hour, raised the temperature to re...

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Abstract

The invention provides a tulathromycin intermediate, a preparation method of the tulathromycin intermediate, and a preparation method of the tulathromycin. The preparation method of the tulathromycin has the advantages of mild condition, convenience for operation, and low cost. The preparation method of the tulathromycin comprises the following steps of: using azithromycin A as a raw material; protecting 2'-hydroxy and 6'-amino in the azithromycin A through di-tert-butyl dicarbonate so as to obtain double-protective azithromycin A; carrying out Swern oxidation to 4''-hydroxy to the double-protective azithromycin A; salifying along with trifluoroacetic acid; and synchronously removing boc t-butyloxycarbonyl to obtain the azithromycin A bitrifluoroacetic acid salt of 4''-carbonyl; and then reacting with trimethylsulfonium bromide to obtain 4''-epoxy compound; and finally carrying out nucleophilic addition on the 4''-epoxy compound by n-propylamine so as to obtain the phosphate of tulathromycin; and further neutralizing via alkaline to obtain the target compound tulathromycin; and synchronously obtaining the tulathromycin intermediate of azithromycin A bitrifluoroacetic acid salt of 4''-carbonyl.

Description

technical field [0001] The invention relates to the field of telamycin drug synthesis, in particular to a telamycin intermediate, a preparation method thereof and a telamycin preparation method. Background technique [0002] Tulathromycin (Tulathromycin) is a macrolide semi-synthetic antibiotic developed by Pfizer Animal Health Products Company in the United States. The prevention and treatment of respiratory system diseases of pigs and cattle caused by bacilli, etc., especially for the infectious diseases of cattle and pigs, has a very obvious therapeutic effect. Because there are 3 amine groups in the structure of telamycin, it has fast absorption and low dosage. , long-lasting drug effect, and a single administration can provide a whole course of treatment and many other advantages. [0003] The preparation method of telamycin at present stage comprises following technical scheme: [0004] 1. Pfizer Products Company reported that using azithromycin A (I) as a raw materi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/00C07H1/00
Inventor 余贵菊王建董泽新王勇程雪娇焦小军
Owner TIANJIN ZHONGSHENG TIAOZHAN BIOTECH
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