CZ288601B6 - Process for preparing azithromycin dihydrochloride - Google Patents

Abstract

The invented preparation process is characterized in that azithromycin monohydrate or dihydrate being dissolved in lower alcohol containing 1 to 4 carbon atoms or in lower ketone having 3 to 6 carbon atoms is brought into reaction with 1.6 to 2 equivalents of gaseous hydrogen chloride being dissolved in a dry lower alcohol containing 1 to 4 carbon atoms in concentration of 12 to 20 percent by weight/volume and at a temperature ranging from 10 to 15 degC. The obtained product is then precipitated by addition of insoluble agent at a temperature ranging from 10 to 25 degC at ratio of the solvent/insoluble agent in the range of 1 : 1.8 to 1 : 8 (volume/volume) and subsequently it is isolated by filtration.

Description

A process for the preparation of azithromycin dihydrochloride

Technical field

The present invention relates to a novel process for the preparation of azithromycin dihydrochloride, which is a pharmaceutically acceptable salt of the antibiotic azithromycin, useful as an antibacterial agent with a broad spectrum of activity.

BACKGROUND OF THE INVENTION

Azithromycin, a semi-synthetic macrolide antibiotic, is representative of the azalide class (Kobrehel G. et al., BE 892357, 7/1982; Bright GM, US 4474768, 10/1984), showing a broad spectrum of activity against microbes including gram-negative bacteria and intracellular bacteria. microorganisms. Its dihydrate form (Sumamed ™) is used in pharmaceutical formulations suitable for oral administration for the treatment of infectious bacterial diseases.

The same biological properties are known for its addition salt, which, for its good solubility in aqueous media, can be used for parenteral administration in pharmaceutically acceptable forms (injection, infusion).

So far, two methods for the preparation of azithromycin dihydrochloride have been described in the literature. According to Bright (US cited above), the reaction of azithromycin and pyridine hydrochloride is carried out in methylene chloride and, after evaporation of the solvent, azithromycin dihydrochloride is isolated from the aqueous solution by lyophilization in 54.4% yield.

According to Djokich et al., J.Chem.Research (M), 1988, 1239-1261, azithromycin dihydrochloride is obtained by lyophilizing an aqueous solution of azithromycin hydrochloride (pH 6.4-6.5) in 91.6% yield.

It has now been found - and this constitutes an object of the invention - that azithromycin dihydrochloride can be prepared by a novel precipitation process that is more economically and technically more acceptable than those previously described in the literature.

SUMMARY OF THE INVENTION

It was ensured that azithromycin dihydrochloride can be obtained by reacting azithromycin mono- or dihydrate dissolved in lower C 1 -C 4 alcohols or lower C 3 -C 6 ketones with 2 eq. hydrogen chloride gas dissolved in dry C 1 -C ₄ alcohol at a concentration of 12 to 20% (w / v) at a temperature of 10 to 15 ° C, and the product precipitates by adding a non-solvent to the reaction mixture or pouring the reaction mixture into the non-solvent at at a temperature of 10 to 25 ° C.

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

By "lower ketones" is meant ketones such as dimethyl ketone, methyl ethyl ketone, isobutyl methyl ketone and the like in which the azithromycin mono- and dihydrate is readily soluble and which are also miscible with product non-solvents such as ethers, preferably diisopropyl ether.

The ratio of solvent to non-solvent may vary from 1: 1.8 to 1: 8, and a ratio of 1: 5.8 (w / v) is most preferred.

After completion of the dropwise addition of the reactants, the reaction mixture is stirred for an additional hour at the stated temperature interval, then the azithromycin dihydrochloride obtained is filtered off, washed with cold non-solvent and dried in vacuo.

The process for preparing azithromycin dihydrochloride of the present invention is illustrated by the following non-limiting examples.

-1GB 288601 B6 s

and

DETAILED DESCRIPTION OF THE INVENTION

Example 1

To a solution of azithromycin dihydrate (5 g, 0.0064 mol) in isopropanol (20 ml) was added dropwise 2.5 ml of a 18% solution of hydrogen chloride gas in dry isopropanol (0.0124 mol of hydrogen chloride gas) with stirring for 5 minutes at temperature 10-15 ° C. The resulting reaction mixture was added dropwise to diisopropyl ether (130 mL) with stirring over 30 minutes. Stirring of the reaction mixture was continued for another hour at room temperature, then the precipitate was filtered off, washed with cold isopropanol (5 ml) and dried in a vacuum oven at 40 ° C for 5 hours. 5.15 g (98.4%) of azithromycin dihydrochloride are obtained, m.p. Mp 186-192 ° C.

1 H NMR (CDCl ₃ ) δ ppm 2.84 (s, 9H N (CH ₃ ) ₂ and NCH ₃ )

3.36 (s, 3H, _OCH3).

Elemental analysis for C ₃₈ H ₇₂ O ₁₂ N ₂ · ₂ · HCl calculated 8.63% Cl found 8.40% Cl.

Example 2

To a solution of azithromycin dihydrate (5 g, 0.0064 mol) in acetone (10 ml) was added dropwise over 5 minutes 2.5 ml of a 18% solution of hydrogen chloride gas in dry isopropanol (0.0124 mol hydrogen chloride gas) at 10 ° C. to 15 ° C. Diisopropyl ether (60 ml) was then added dropwise to the reaction mixture while maintaining the same temperature, and the precipitated salt was filtered off. 20 5.20 g (98.9%) of azithromycin dihydrochloride are obtained.

Example 3

Following the procedure of Example 2, from azithromycin dihydrate (2 g, 0.0025 mol) dissolved in acetone (4 ml) by reaction with 1.15 ml of a 12.9% solution of hydrogen chloride gas in dry methanol (0.0041 mol hydrogen chloride gas), 2.06 g (98.5%) of azithromycin dihydrochloride.

Example 4

According to the method of Example 1, from azithromycin monohydrate (2 g, 0.0026 mol) dissolved in methanol (8 ml), 1.16 ml of a 12.9% solution of hydrogen chloride gas in dry methanol (0.0041 mol hydrogen chloride gas) and diisopropyl ether ( 16 ml), yielding 2.10 g (98.5%) of azithromycin dihydrochloride.

Claims (2)

30 PATENT CLAIMS A process for the preparation of azithromycin dihydrochloride, characterized in that azithromycin monohydrate or azithromycin dihydrate dissolved in a lower C ₄ -C ₄ alcohol or lower C ₃ -C ₆ ketone is reacted with 1.6 to 2 equivalents of hydrogen chloride gas dissolved in a dry lower C 1 -C ₄ alcohol at a concentration of 12 to 20% w / v and at a temperature 10 to 15 ° C, the product obtained is precipitated by the addition of a non-solvent at a temperature of 10 to 25 ° C, at a solvent: non-solvent ratio of 1: 1.8 to 1: 8 v / v. and then isolated by filtration. Method according to claim 1, characterized in that the non-solvent is an ether, preferably diethyl ether or diisopropyl ether.