FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
A PROCESS FOR PREPARATION OF PURE AZITHROMYCIN

2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: D-4, M.I.D.C. Area, Chikalthana, Aurangabad -431210
(M.S.) India
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a process for preparation of azithromycin in wherein the impurity level is below 0.3%.
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 a process for preparation of pure azithromycin, wherein the impurity level is below 0.3%.
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.

Formula-I
The processes for preparation of Azithromycin are disclosed \n the U.S. patent 4,517,359 and U.S. patent 4,474,768. The ring expansion of erythromycin-A and subsequent conversion to azithromycin is described in the '768 Patent.
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.
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. Patent No. 6,268,489 discloses azithromycin dihydrate as a crystalline form of'azithromycin, which is stable and non-hygrosc6pic. The *489 Patent also discloses azithromycin monohydrate as a crystalline form of azithromycin which is unstable and hygroscopic.
Several other processes for the preparation of azithromycin, intermediates useful in the preparation of azithromycin and different polymorphic forms of azithromycin are known in the art such as U.S. patent Nos. 4526889, 4963528, 4886792, 5686587, 5869629, 6013778, 6504017, 6420537, 6365574, 6703372, 6451990, 6586576, 6528492, 6936591, 6949519, 6268489, 5250518, 6977243, 7053192, 7081525, U.S. patent application Nos. 2003139583, 2004043944, 2004043945, 2004138149, 2004014951, 2005090459, 2005119468, 20050222052, 2006063725, 20050222052, 2006019908, 2006183890, PCT application Nos. WO 2002009640, WO 2005003144, WO 2007015265, WO 2007017898 and WO 2007029266.
The process of making azithromycin involves conversion of erythromycin base to imino ether via Beckmann's rearrangement followed by reduction and subsequent methylation to yields azithromycin. The isolation of Azithromycin is carried out at basic pH followed by removal of solvent yields the product. The product obtained by removal of solvent under heating leads the formation of impurities in finish product. The increased level of impurities decreases the purity as well assay of the finish product. To remove these impurities there are more then one crystallization is required.
While developing the process for making azithromycin having individual impurities less than 0.2% inventors come across the process wherein the Azithromycin is isolated by pH adjustment without exposing finish product to heat. The azithromycin is finally crystallized in a single solvent to get purity more than 99%.
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The azithromycin obtained by the process of the invention having purity more ' than 99% and individual impurity level below 0.2% when measured by HPLC.
In one of the aspect of the invention the process for the preparation of azithromycin, the process includes steps of
a) treating the 9-Dexo-9a-aza-9a-hornoeythrornycin-A with
formic acid and formaldehyde in
suitable solvent,
b) extracting azithromycin in water at acidic pH,
c) isolating azithromycin from the reaction mixture of step b)
with water miscible solvent in presence of base.
The 9-Dexo-9a-aza-9a-homoeythromycJn-A is prepared by the method known in the art e.g US patent application No. 2003139583. The 9-Dexo-9a-aza-9a-homoeythromycin-A is treated with formaldehyde and formic acid in suitable solvent. After completion of reaction water was added to reaction mixture and pH is adjusted to 2-6 with acids. If suitable organic solvent is haloalkane, ester or ethers or in case of polar aprotic solvent it may be removed either by distillation or by extraction of reaction mixture at basic pH with haloalkane, esters or ether solvent after addition of water in the reaction mixture. Finally azithromycin present in haloalkane, ester or ether solvent is extracted in water at acidic pH. Azithromycin is isolated from the acidic water solution by adding water miscible solvent and adjusting the pH of reaction mixture with base between 8.5 to12.
The process of the invention avoids exposure of azithromycin to heat after the formation of azithromycin. Exposure of azithromycin to higher temperature leads the formation of impurities in higher concentration more than 0.5% e.g 3-Deoxy azithromycin, 3'-N-Demethyl-3'-N-formyl azithromycin and 2-Desethyl-2-propyl azithromycin.
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The term suitable solvent includes the haloalkane, ester, ethers such as chloroform, methylene chloride, carbon tetra chloride, ethyl acetate and diethyl ether and polar aprotic solvents such as acetone, dimethyl sulphoxide, dimethyl formamide, dimethyl acetamide, dimethyl acetamide and pyridine.
Bases include inorganic and organic basses such as hydroxides and carbonates of alkaline earth metal, amines such as triethylamine, diethyl amine, diclohexyl amine, tertiary butyl amine and the like.
The term acid includes the mineral acids such as hydrochloric acid, sulphuric acid and Organic acids such as acetic acid formic acid, phosphoric acid and the like.
The water miscible solvents include the acetone, acetonitrile and mixture thereof.
In an another aspect of the preparation of pure azithromycin the process includes steps of;
a) dissolving azithromycin in acetonitrile solvent,
b) isolating pure azithromycin from the reaction mixture thereof.
The Azithromycin starting material can be prepared by the method known in the art. The term azithromycin includes polymorph of azithromycin such as dihydtrate, monohydrate, solvate, anhydrous crystalline or amorphous having HPLC purity 90-96% and impurities 0.5% or more. In general azithromycin is dissolved in acetonitrile solvent by heating and then isolating pure azithromycin from the reaction mixture thereof. The pure azithromycin is having purity 99.0% or more. The impurities 3-Deoxy azithromycin, 3'-N-Demethyl-3'-N-formyl azithromycin and 2-Desethyl-2-propyl azithromycin are also reduced to level of less than 0.2% when measured by HPLC.
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The term isolation involves the removal of solvent by distillation, decantation, filtration and centrifugation of reaction mixture.
Embodiments of the invention include one or more of the following features. For example, the process is carried out where acetonitrile is removed under reduced pressure. The azithromycin is obtained shows amorphous nature.
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.
EXAMPLE 1: Process for Azithromycin
To the solution of 9-Dexo-9a-aza-9a-homoeythromycin-A solution in chloroform Formic acid (33.4 g) and formaldehyde solution (44.6 g) was added The reaction mixture was reflux for 12 hours. After completion of the reaction, water (1.7LI) was added and the pH was brought to 4.0 with hydrochloric acid. The chloroform layer was separated and to the aqueous layer Acetonitrile (650 ml) was added and the pH of the reaction mixture was adjusted between 10 and 10.5 using triethylamine. The resulting slurry was stirred for 2 hrs at room temperature and filtered. The solid obtained was washed with water and dried under vacuum to get crude Azithromycin. Yield: 180 g HPLC purity: 95.31 %
EXAMPLE 2: Process for the purification of Azithromycin
Azithromycin crude (175 g) was dissolved in Acetonitrile (525 ml) by heating at 50 to 55° C to get a clear solution. The acetonitrile (250 ml) was partially removed from the reaction mixture and solution was cooled between 0 and 5°C.
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The resulting slurry was stirred at the same temperature for 2 hours and filtered.
The obtained solid was washed with chilled Acetonitrile and dried under vacuum
to yield title product.
Yield: 135g
HPLC purity: 99.56 %
3-Deoxy azithromycin: 0.18%
3'-N-Demethyl-3'-N-formyl azithromycin: 0.10%
2-Desethyl-2-propyl azithromycin : 0.15%
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WE CLAIM:
1. A process for the preparation of azithromycin, the process comprising:
a) treating the 9-Dexo-9a-aza-9a-homoeythromycin-A with
formic acid and formaldehyde in
suitable solvent,
b) extracting azithromycin in water at acidic pH,
c) isolating azithromycin from the reaction mixture of step b)
with water miscible solvent in presence of base.
2. The process of claim 1, wherein acidic pH is 2- 6.
3. The process of claim 1, wherein the suitable solvent is selected from the group of haloalkanes and polar a protic solvent or mixtures thereof.
4. The process of claim 2, wherein haloalkanes comprises of chloroform, dichloromethane, carbon tetrachloride and mixtures thereof.
5. The process of claim 2, wherein polar a protic solvent is acetone, Dimethyl formide, Dimethyl sulphoxide, dimethyl acetamide and pyridine.
6. The process of claim 1, wherein the water miscible solvent in is selected from the group of acetonitrile and acetone.
7. The process of claim 1, wherein the bases are hydroxides and carbonates of alkaline earth metal, amines such as triethylamine, diethyl amine, diclohexyl amine and tertiary butyl amine.
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8. A process of the preparation of pure azithromycin, the process comprises
of;
a) dissolving azithromycin in acetonitrile solvent,
b) isolating pure azithromycin from the reaction mixture thereof.
9. The process of claim 8, wherein azithromycin is amorphous in nature.
] 0. The process of claim 8, wherein the HPLC purity of of azithromycin 99%
or more and the content of 3-Deoxy azithromycin, 3'-N-Demethyl-3'-N-
formyl azithromycin and 2-Desethyl-2- propyl azithromycin
is less than 0.2 % when measured by HPLC.

Dated this _th day of July, 2008

For Wockhardt Limited


(Mandar Kodgule) Authorized Signatory
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