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:
AN IMPROVED 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 an improved process for the preparation of
azithromycin.
The following specification particularly describes the invention and the manner
in which it is to be performed.
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4. DESCRIPTION
The present invention provides an improved process for the preparation of azithromycin.
A/-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.

Formula-I
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.
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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 have surprisingly found that the boron complex of compound of Formula III obtained after reducing the compound of Formula II with boron containing reducing agent is effectively broken with the use of malic acid. This reduces the time and easily scalable at commercial scale.

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 the compound of formula II with suitable boron reducing agent,
b) extracting the boron complex of compound of Formula III from the reaction mass with suitable organic solvent,
c) treating the organic layer of step b) with a malic acid,
d) N-methylating product of step c) with formic acid and formaldehyde,
e) isolating azithromycin or salt thereof from the reaction mass thereof.
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, diborane,
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borane, trialkylboranes, dialkylalkoxyboranes, Vitride®, Lithium aluminium hydride and the like.
The boron complex of Formula-Ill, extracted in suitable organic solvent under basic condition are concentrated and treated with a malic acid in presence of water. Further pH is brought down to around 2.5 with hydrochloric acid and compound of formula III is extracted in organic solvent. Then resultant mixture is treated with formic acid and formaldehyde mixture. The azithromycin obtained is then isolated 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, aromatic solvents and other such as acetonitrile. 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.
EXAMPLES:
Preparation of cyclic amine (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. After completion the
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product is extracted with chloroform at pH 9.5. Chloroform layer was concentrated under vacuum and the residue was treated with water (1.0 lit) and malic acid (75 g). The pH of resultant mixture further adjusted to 2.5 with hydrochloric acid. The product was extracted in chloroform (500 ml x 2) after adjusting the pH 9.5 to 10.0 with sodium hydroxide solution.
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. The pH of reaction mixture was adjusted to 8.0 using Sodium hydroxide solution and aqueous layer was extracted with chloroform. The chloroform extract were concentrated to dryness. The residue was dissolved in methylene chloride (750.0 ml), filtered and concentrated and bone dried under reduced pressure. The solid obtained was dissolved in acetonitrile (750.0 ml). The acetonitrile was partially distilled out (600.0 ml) under vaccum. The slurry was cooled to 0-5°C and filtered to get anhydrous azithromycin.
Yield :45.0g.
Purity: 99.0 %.
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WE CLAIM:
1. A process for the preparation of azithromycin, wherein the process comprises
of
a) reducing the compound of formula II with suitable boron reducing agent,
b) extracting the boron complex of compound of Formula III from the reaction mass with suitable organic solvent,
c) treating the organic layer of step b) with a malic acid,
d) N-methylating product of step c) with formic acid and formaldehyde,
e) isolating azithromycin or salt thereof from the reaction mass thereof.

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 the organic solvent used for extraction is halogenated organic solvent.
4. A process of claim 1 wherein the acidic pH maintained is between 2.0 to 3.0.
Dated this 31st day of August, 2006 For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory
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