FORM 2THE PATENT ACT 1970(39 of 1970)&The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10 and rule13)
1. TITLE OF THE INVENTIONEFFICIENT PROCESS FOR THE PREPARATION OF CLARITHROMYCIN
2. APPLICANT (S)(a) NAME: WOCKHARDT LTD.(b) NATIONALITY: INDIAN(c) ADDRESS: Wockhardt Towers, Bandra-Kuria Complex, Bandra(East), Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTIONThe present invention relates to efficient process for the preparation of clarithromycin.
The following specification particularly describes the invention and the manner In which it is to be performed.

4. DESCRIPTION
The present invention relates to efficient process for the preparation of clarithromycin.
Clarithromycin is chemically known as 6-0-Methylerythromycin-A having structure depicted in Formula I. Clarithromycin is a second generation semi synthetic erythromycin A derivative belonging to class of macrolide antibiotic and having a strong activity against Gram-positive bacteria, some negative-bacteria, anaerobic bacteria, mycoplasma and Chlamydia. Clarithromycin is well known useful antibacterial agents and shows excellent effect for the treatment of infections by oral administration.

US Patent No. 4,331,803 discloses a process for the synthesis of Clarithromycin. Several other processes are known in the art for preparation of Clarithromycin viz. US Patent Nos. 4,670,549; 4,672,109; 5,274,085; 5,719,272; 5,837,829; 5,852.180; 5,864,023; 5,892,008; 5,929,219; 6,900,296 and PCT application WO 2005/90377 A1; WO 2006/100691 A2.
The present inventors have developed an efficient methylation process of protected oxime of formula-ll, a useful intermediate for the synthesis of Clarithromycin. The process is simple and easily viable on Industrial scale.
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Further the present inventors have developed the purification process for clarithromycin using alcohol.
The details of one or more embodiments of the inventions are set forth in the description below.
In one of the aspect of the present invention there is provided a process for preparation of clarithromycin wherein said process includes the steps of,
a) adding methylating agent to protected oxime of formula-ll in tertiary solvent to get compound of Formula III,

b) converting compound of formula III to clarithromycin
c) Isolating the clarithromycin from the reaction mixture thereof.
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In second aspect of the present invention there is provided a process of purification clarithromycin by using the primary alcohols.
In a third aspect the of the present invention clarithromycin is converted to form-ll in secondary alcohols.
A process for preparation of clarithromycin involves treating protected oxime with the methylating agent in tertiary solvent i.e. a mixture of tetrahydrofuran, toluene
and dimethylsulphoxide in the presence of base. The product methylated protected oxime is then converted to clarithromycin by the method known in the art.
Clarithromycin obtained thereof is then purified by the process, which involves adding clarithromycin to the primary alcohol and isolating the crystallized clarithromycin from the reaction mixture thereof. Further crystallized clarithromycin is dissolved in secondary alcohol and convert to form -II of Clarithromycin as depicted in Fig. I.
The methylating agent includes such as methyl iodide, dimethylsulfate and the like. The base includes potassium hydroxide, sodium hydroxide, potassium carbonate and the like. The alcohol includes primary and secondary alcohols such as methanol, ethanol, n-propanol, isopropanol, isobutanol or mixtures thereof.
The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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.

EXAMPUE-I Preparation of Clarithromycin
To the protected oxime of formula-ll (128 g) toluene (2.6 Litre) was added. Then
about 700 ml of toluene was removed and mixture was cooled to room
temperature. Then to reaction mixture tetrahydrofuran (128 ml), dimethylsulfoxide
(1.9 litre) were added and the reaction mass was further cooled to 8-10 °C. To
the resultant mixture methyl iodide (18.84 gm) and potassium hydroxide (9.5 gm)
were added. The reaction mass was then stirred at &-10 "C for two hours. After
completion of reaction 40% dimethylamine solution (32.6 ml) and water was
added. The toluene layer was separated concentrated.
To the residue obtained thereof ethanol (0.76 Litre) was added under stirring and
then ethanol was partially distilled out (128 ml). Reaction mass was then cooled
to room temperature and to it water (0.640 Litre), sodium bisulphite (236 gm) and
fomnic acid (36.6 gm) were added. Reaction mixture was then refluxed for 5-6
hours. To this reaction mixture water (1.9 Litre) was added and pH was adjusted
to 11.5-12.0 with aqueous sodium hydroxide solution. The reaction mixture was
then cooled to 0-5°C and filtered; wet cake was washed with water and dried
under vacuum to get the title compound.
Yield = 80.10 gm
Purification of Claritiiromycin
Stage-I
Clarithromycin (80 gm) was dissolved in ethanol (960 ml) at reflux temperature to
obtain clear solution. Partially ethanol 250 ml was removed. Then the reaction
mass was cooled to about 40-45° C, filtered and dried.
Stage-ll
Clarithromycin of step-l was again dissolved in isopropyl alcohol (373 ml) at
reflux temperature and partially concentrated under reduced pressure to volume
275 ml. The reaction mixture was then cooled to room temperature and pure
clarithromycin form -II was isolated.
Yield = 39.0 gm.
HPLC Purity =99.6%

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WE CLAIM:
1. A process for preparation of clarithromycin wherein said process includes the steps of,
a) adding methylating agent to protected oxime of formula-ll in tertiary solvent to get compound of Formula III,

b) converting compound of formula III to clarithromycin.
c) isolating the clarithromycin the reaction mixture thereof.

2. A process of claim 1 wherein tertiary solvent is a mixture of tetrahydrofuran, toluene and dimethylsulphoxide.
3. A process of claim 2 wherein the ratio of tertiary solvent is 1:26:15 respectively.
4. A process of claim 1 wherein methylating agent and protected oxime compound of formula II is used in mole ratio of 1:1.
5. A process of claim 1 wherein the base includes potassium hydroxide, sodium hydroxide, potassium carbonate and the like.
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6. A process of purification of Clarithromycin by using the primary alcohols.
7. A process of claim 6 wherein primary alcohol includes ethanol, methanol and n-propanol alcohol.
8. A process of claim 6 wherein the clarithromycin is converted to form 11 in secondary alcohols.
9. A process of Claim 8 wherein secondary alcohols includes isopropanol, isobutanol and the like.
10. A process of claim 5 wherein the Clarithromycin is having purity 99.0% or more by HPLC

Dated this 19th day of Jan, 2007