The way to get azithromycin dihydrochloride

 

(57) Abstract:

The invention relates to a new process for the preparation of the dihydrochloride of azithromycin, which is a pharmaceutically acceptable salt of the antibiotic azithromycin, suitable as an antibacterial agent with a broad spectrum of action. Describes how to obtain azithromycin dihydrochloride, wherein interact monohydrate azithromycin or dihydrate azithromycin dissolved in low (C1- C4) alcohol or low (C3- C6) ketone, 1.6 to 2 equivalents of hydrochloric gas dissolved in dry low (C1- C4) alcohol at a concentration of 12 - 20% (wt/V) and at a temperature of from 10 to 15oC, the resulting product is then precipitated by the precipitator at a temperature of from 10 to 25oC, when the ratio of solvent to the precipitator from 1 : 1.8 to 1 : 8 (V/V) and then allocate filtering. The technical result - the creation of a more acceptable from an economic and technical perspective a new way. 1 C.p. f-crystals.

The invention relates to a new process for the preparation of the dihydrochloride of azithromycin, which is a pharmaceutically acceptable salt of the antibiotic azithromycin, suitable cachesettings, semi-synthetic antibiotic, the representative of the class of azalides /Kobrehel G. et al, BE 892357, 7/1982; Bright, G. M., US 4474768, 10/1984 /has a broad spectrum of activity against bacteria, including gram-negative bacteria and intracellular microorganisms. Its hydrated form /SumamedR/ use in medicinal preparations suitable for oral administration, for the treatment of infectious bacterial diseases.

The same biological properties known for its salt accession, dichloropurine of azithromycin, which, thanks to its good solubility in water, can be used for oral administration in pharmaceutically acceptable forms /injection, infusion/.

So far in the literature have described two ways to get azithromycin dihydrochloride. According to Bright /the aforementioned patent /USA/ response interaction between azithromycin and pyridinecarboxamide carried out in methylene chloride, and after evaporation of the solvent from the aqueous solution by lyophilization allocate azithromycin dihydrochloride, while its output is 54%.

According Djokic et al., J: chem. Resarch (M), (M), 1988, 1239 - 1,261 azithromycin dihydrochloride is obtained by lyophilization cleaners containing hydrochloride aqueous solution of azithromycin that azithromycin dihydrochloride can be obtained in a new deposition method, which is more acceptable from an economic and technical point of view, than the ways deducted in the literature so far.

It was found that the azithromycin dihydrochloride can be obtained by a reaction between a mono - or dihydrate azithromycin dissolved in lowest /C1-C4/ alcohols or lower /C3-C6/ ketones with 2 equivalents of hydrochloric gas dissolved in dry low /C1-C4/ alcohol at a concentration of 12 - 20% /wt/rpm and a temperature of 10-15oC, whereupon the product precipitated by adding to the reaction mixture precipitator or by pouring the reaction mixture into the precipitator at a temperature of 10 - 25oC.

The term "lower alcohols" here refers to alcohols such as methanol, ethanol, n-propanol, i-propanol, n-butanol, and their isomeric forms.

The term "lower ketones indicated ketones such as diethylketone, methyl ethyl ketone, isobutylmethylxanthine or similar compounds, in which the soluble mono - and dihydrate azithromycin, and which are also mixed with the precipitating product, for example, ethers, preferably diisopropyl ether.

The ratio of solvent to the precipitator can izm added dropwise reactant of the reaction the suspension is stirred for one hour at the same temperature interval, then the received azithromycin dihydrochloride is filtered, washed precipitator and dried in vacuum.

The way to get azithromycin dihydrochloride of the present invention is illustrated but in no way limited to the following examples.

Example 1

To a solution dihydrate azithromycin /5 g, 0,0064 mol/ isopropanol /20 ml/ added dropwise under stirring for 5 minutes at a temperature of 10 - 15oC 2.5 ml of 18% hydrochloric gas in dry isopropanol /0,0124 mole of hydrochloric gas. The reaction mixture is added dropwise with stirring during 30 minutes to a diisopropyl ether /130 ml/. Stirring of the reaction mixture is continued for a further one hour at room temperature, then the precipitate was filtered, washed with cold isopropanol /5 ml and were dried for 5 hours in a vacuum dryer at 40oC. Received 5,15 g /98,4%/ azithromycin dihydrochloride, melting point : 186 - 192oC.

1H NMR /CD3OD/ ppm /ppm/

2,84 /S, 9H N/ CH3/2and NCH3/

3,36 /S3H, OCH3/.

Analysis of C38H72O12N22HCl

Calculated: 8,63 Cl

Found: 8,40% Cl

Example 2
within 5 minutes at a temperature of 10-15oC 2.5 ml of 18% hydrochloric gas in dry isopropanol /0,0124 mole of hydrochloric gas. Then, while maintaining the same temperature in the reaction mixture for 1 hour was added dropwise diisopropyl ether /60 ml/. After stirring for 1 hour at the same temperature, the precipitated salt was filtered. Received 5.2 g /98,9%/ azithromycin dihydrochloride.

Example 3

In accordance with the method described in example 2 of the dihydrate azithromycin /2 g 0,0025 moles/ dissolved in acetone /4 ml/ by reaction of interaction of 1.15 ml of 12.9% hydrochloric gas in dry methanol /0,0041 mole of hydrochloric gas/ got to 2.06 g /98,5%/ azithromycin dihydrochloride.

Example 4

In accordance with the method described in example 1 of the monohydrate azithromycin /2G, 0,0026 moles/ dissolved in methanol /8 ml/, of 1.16 ml of 12.9% hydrochloric gas in dry methanol /0,0041 mole of hydrochloric gas/ and diisopropyl ether /16 ml/ received 2,10 g /98,5%/ azithromycin dihydrochloride.

1. The way to get azithromycin dihydrochloride, wherein interact monohydrate azithromycin or dihydrate azithromycin, rastvorennogo gas, dissolved in dry low (C1-C4) alcohol at a concentration of 12 - 20% (wt./about.) and at a temperature of from 10 to 15oC, the resulting product is then precipitated by the precipitator at a temperature of from 10 to 25oC, when the ratio of solvent to the precipitator from 1 : 1.8 to 1 : 8 (vol./about.) and then allocate filtering.

2. The method according to p. 1, wherein the precipitant is a simple ether, particularly diethyl ether or diisopropyl ether.

 

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