FORM 2
THE PATENT ACT 1970
(39 of 1970)
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
A ONE-POT PROCESS FOR THE PREPARATION OF
AZITHROMYCIN.
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a one-pot process for the preparation of azithromycin the preparation of

The following specification particularly describes the invention and the mannerIn which it is to be performed


4. DESCRIPTION
The present invention provides a one-pot process for the preparation of azithromycin.
N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A, known by its generic name Azithromycin of Formula I, is a broad-spectrum semi-synthetic macrolide antibiotic compound belonging to the erythromycin A family.

The processes for preparation of Azithromycin are disclosed in the US Patent 4,517,359 and US Patent 4,474,768. The ring expansion of erythromycin-A and subsequent conversion to azithromycin is described in U.S. Patent No. 4,474,768.
U.S. Patent 4,963,531 provides a process for preparing azithromycin dihydrate. The '531 Patent further provides that on storage at low humidity the azithromycin dihydrate loses water. In addition, samples of azithromycin mono- and di-hydrate stored at higher humidity rapidly absorbed water. Therefore, the water percentage (percent hydration) in the crystals can vary depending on the relative humidity during storage.
European Patent EP 1313749 B1 provides a method for preparation of azithromycin which comprises removing an organic solvent from the solution comprising the hydrated compound in the organic solvent or a solution of the

hydrated compound in a mixture of the organic solvent and water so as to provide anhydrous compound.
U.S. Pat. No. 4,328,334 discloses a method of preparing the compound of formula (III) by reducing the compound of formula (II) in a methanol solution maintained at 4°C with sodium borohydride.
The present inventors found the novel process of breaking boron complex after methylating the boron complex of formula III.

In one of the aspect of the present invention there is provided a process for the preparation of azithromycin, wherein the process comprises of
a) reducing compound of Formula-ll with suitable boron reducing agent,
b) extracting the boron complex of compound of Formula III from the reaction mass,
c) N-methylating the boron complex of compound of Formula III with formic acid and formaldehyde to get azithromycin boron complex,
d) isolating azithromycin from reaction mass thereof by breaking the boron complex of azithromycin.
wherein the process is characterized by the fact that no intermediate is isolated from step a) to step c).

The conversion of Formula-II to azithromycin is carried out in one-pot without isolation of intermediates. The reduction of compound of Formula II is carried out in presence of water optionally containing an organic solvent. The boron containing reducing agents are known in the art and include but not limited to sodium borohydride, diorama, borane, trialkylboranes, dialkylalkoxyboranes, Vitride®, Lithium aluminium hydride and the like.
The boron complex of Formula III extracted in organic solvent is N-methylated with formic acid and formaldehyde mixture. After completion of reaction, water is added and organic layer is separated out. To the aqueous layer an alcohol solvent is added. The resultant solution was cooled to a temperature less than 0°C, followed by addition of dilute hydrochloric acid to adjust the pH to below 1.0. After stirring for 30 minutes, Azithromycin is extracted in organic halogenated which is crystallized in acetonitrile-water mixture/ isopropyl alcohol-water mixture which can then be converted to its suitable hydrated or anhydrous form. Person skilled in the art through EP 1313749 B1 knows this process.
The non-limiting examples of organic solvents include alcohols, haloalkanes, esters, ethers or aromatic solvents. Alcohol solvent includes (C1-C6) straight and branched chain alcohols, such as methanol, ethanol and isoprapanol. The halogenated solvent includes halo (C1-C6) alkanes such as methylene chloride, chloroform, carbon tetrachloride, 1,1,1-trichloroethylene, 1,1,2-trichloroethylene and the like.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
4

EXAMPLES:
Preparation of boron complex of cyclic amine of formula -III:
6,9-lmino ether (Formula-ll) (100 g) was suspended in water (1.0 lit). The reaction mixture was cooled to 0-5°C To the resulting reaction mixture, chilled aqueous solution of sodium borohydride (18.0 g in 200ml water) was added at temperature between 0-5°C and pH was maintained between 6.0 -8.0 with formic acid. After completion of borohydride addition, the reaction mixture was stirred at 0-5°C for 1 hr and then at room temperature for 10 hrs. The pH was adjusted to 9.5 with Sodium hydroxide solution and then aqueous layer was extracted with chloroform (300 ml x2). Combined chloroform extracts containing title compound was taken for next step.
Preparation of Azithromycin:
The pH of chloroform extract was adjusted to 5.0 to 5.5 with methylating mixture i.e. formic acid (17.0 g) and formaldehyde (17.0 g) and refluxed for 10 hr. After completion of reaction, water (500 ml) was added and pH brought to 4.0 with hydrochloric acid. Chloroform layer was separated and in aqueous layer methanol (500 ml) was added. The resulting reaction mixture was cooled to -10 to -20°C and pH was adjusted to 1.0 with hydrochloric acid. Then reaction mixture was basified with sodium hydroxide and extracted with chloroform (300 ml x 2). The combined chloroform extracts were concentrated to dryness and crystallized with isopropyl alcohol/ water or acetonitrile / water mixture to get the title compound.
Yield: 65 g.,
Purity: 98.0% (By HPLC)
5

WE CLAIM:
1. A process for the preparation of azithromycin, wherein the process comprises
of
a) reducing compound of Formula-ll with suitable boron reducing agent,
b) extracting the boron complex of compound of Formula III from the reaction mass,
c) N-methylating the boron complex of compound of Formula III with formic acid and formaldehyde to get azithromycin boron complex,
d) isolating azithromycin from reaction mass thereof by breaking the boron complex of azithromycin.
wherein the process is characterized by the fact that no intermediate is isolated from step a) to step c).
2. A process of claim 1 wherein the reducing agent comprises of sodium borohydride, diborane, borane, trialkylboranes, dialkylalkoxyboranes, Vitride® or Lithium aluminium hydride.
3. A process of claim 1 wherein extraction of the boron complex of the compound of Formula III from the reaction mass is carried out with halogenated organic solvent.
4. A process of claim 1 wherein boron complex of compound of Formula III is broken at acidic pH below 1.0 in presence of alcohol solvent at below 0°C.
5. A process of claim 4, wherein the alcohol solvent used is from the linear and branched chain C1-C6 alcohols.