FIELD OF THE INVENTION:
The present invention relates to the process for the preparation of 2',4"-di-o-benzoyl-6-o-
methyl erythromycin.
BACKGROUND OF THE INVENTION:
Ketolides represent a newer class of macrolide antibiotics which are 14 membered ring macrolide derivatives. These derivatives are used to prepare drugs which are used to treat respiratory tract infections.
6-o-methylerythromycin-A derivative (formula-1) is useful as intermediate for preparation of 6-0-methyl erythromycin A which is useful as an antibacterial agent.

Formula-1
Clarithromycin, also known as methyl-erythromycin, is a macrolide antibiotic obtained from methylation of 6-position hydroxyl group of erythromycin. It exhibits excellent anti-bacterial activity against Gram-positive bacteria, some Gram-negative bacteria, anaerobic bacteria, mycoplasma and chlamydia.
Clarithromycin prepared by various processes in which 6-hydroxy group of erythromycin A converted into 6-methoxy group.
US 4331803 discloses a method of making clarithromycin by protecting the hydroxyl group at 2'-position and the dimethylamine group at 3'-position of erythromycin A, conducting methylation of 6-position hydroxyl group of erythromycin A, and removing the protective groups from erythromycin. Because the hydroxyl group at the 11, 12, and 4' positions of erythromycin A can be easily methylated in a methylation reaction, many by-products are produced. It makes purification of the product difficult and affects the quality and the yield of the product.
EP0272110 discloses a method of preparing clarithromycin. First, erythromycin A 9-oxime is etherified with an acid catalysis to protect the hydroxyl group at the 9-position. Next, the hydroxyl groups at the 2'-position and 4"-position are silylanized to be protected. Then, the hydroxymethylation reaction is conducted at the 6-positions. Finally, hydrolyzation is conducted to remove the protecting groups at the 2'-position, the 4"-position and the 9-
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Morever, because macrolide antibiotic is not stable to acid, when an acid catalysis is used to
protect the hydroxyl group at the 9-position, erythromycin A 9-oxime is easily destroyed,
thereby the yield is reduced. The total yield is about 50% (according to erythromycin A 9-
oxime).
US 9051346 discloses the process for preparing 2',4"-di-o-benzoyl-6-o-methyl erythromycin
comprises reaction of erythromycin A 9-oximewith 2-mehtoxypropene in presence of
anhydrous dichloromethane and pyridine hydrochloride at RT and isolate protected oxime
which further reacted with benzoyl anhydride and triethyl amine and DMAP in presence of
ethyl acetate and isolate benzoylated protected oxime which further purified with column
choromatography. Benzoylated protected oxime further reacted with methyl idodide in
presence of anhydrous THF and DMSO, K.OH and isolate methylated protected oxime which
further which further purified with column choromatography to get pure methylated protected
oxime which further reacted with formic acid and sodium metabisulfite in presence of ethanol
and water to obtain 2\4"-di-o-benzoyI-6-o-methyl erythromycin and purified with column
chromatography.
The prior art processes for preparing 2%4"-di-o-benzoyI-6-o-methyl erythromycin involves
multistep purification and complexity. Isolation and purification of each step make the
process more tiresome and uneconomical. Hence it is required to develop an economical and
industrially feasible process to avoid multistep isolations and purifications of intermediate
products.
The present invention provides a robust, commercially viable insitu process for preparing
2',4"-di-o-benzoyl-6-o-methyl erythromycin.
SUMMARY OF THE INVENTION:
The present invention relates to the process for preparation of 2')4"-di-o-benzoyl-6-o-methyl
erythromycin of formula-I
In one aspect, the present invention relates to the process for preparation of erythromycin oxime comprising the steps of;

(a) reacting erythromycin thiocyanate with organic base in presence of suitable solvent at ambient temperature
(b) isolating crude erythromycin base
(c) reacting erythromycin base with hydroxy lam ine hydrochloride and organic base in presence of solvent
(d) basifying with organic base in presence of solvent
(e) isolating erythromycin oxime
In one another embodiment the present invention relates to the insitu process for preparing 2',4"-di-o-benzoyl-6-o-methyl erythromycin comprises;
(a) reacting erythromycin oxime with alkoxy alkane and pyridinium salt in presence of suitable solvent
(b) benzoylating with benzoic anhydride and suitable base in presence of suitable solvent
(c) methylating protected oxime with methylating agent in presence of base and solvent or mixture of two or more solvents
(d) deprotecting methylated protected oxime with Sodium metabisulfite, formic acid and suitable solvent
(e) isolating 2',4"-di-o-benzoyl-6-o-methyl erythromycin
(f) purifying with suitable solvent to get pure 2'34"-di-o-benzoyl-6-o-methyl erythromycin

DETAIL DESCRIPTION OF THE INVENTION:
The present invention relates to safe, economical and commercially feasible process for the preparation of 2',4"-di-o-benzoyl-6-o-methyI erythromycin of formula-1

In one embodiment, the present invention relates to the process for preparation of erythromycin oxime of formula-4 comprising the steps of;
(a) reacting erythromycin thiocyanate with organic base in presence of suitable solvent at ambient temperature
(b) isolating crude erythromycin base
(c) reacting erythromycin base with hydroxylamine hydrochloride and organic base in presence of solvent
(d) basifying with organic base in presence of solvent
(e) isolating erythromycin oxime
The process for preparation of erythromycin oxime of formula-4 depicted in the following reaction scheme-!

Scheme-I
The organic base is selected from the group consisting of liq. Ammonia, triethylamine, pyridine, pipertdine, N-methyl morpholine. diisopropylether amine, diisopropyl amine, isopropylethylamine.

The suitable solvent for step (a) is selected from non-polar solvents, halogenated solvents or
mixture of thereof. The non-polar solvent is selected from the group consisting of toluene,
xylene, hexane, 1,4-dioxane or mixture of two or more solvents. The halogenated solvent is
selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, 1,2-
dichJoroethane. The solvent used in step (c) & (d) is selected from alcoholic solvents. The
alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-
propanol, butanol or mixture of thereof.
The reaction temperature for step (c) is 70-80°C.
In one another embodiment the present invention relates to the insitu process for preparing
2',4"-di-o-benzoyl-6-o-methyl erythromycin comprises;
(a) reacting erythromycin oxime with alkoxy alkane and pyridinium salt in presence of suitable solvent
(b) benzoylating with benzoic anhydride and suitable base in presence of suitable solvent

(c) methylating protected oxime with methylating agent in presence of base and solvent or mixture of two or more solvents
(d) deprotecting methylated protected oxime with Sodium metabisulfite, formic acid and suitable solvent

(e) isolating 2',4"-di-o-benzoyl-6-o-methyl erythromycin
(f) purifying with suitable solvent to get pure 2',4"-di-o-benzoyl-6-o-methyl erythromycin
The process for preparation of erythromycin oxime of formula-4 depicted in the following reaction scheme-11

Scheme-II
The alkoxy alkane used in step (a) is selected from the group consisting of 2-methoxy propane, I-methoxy propane. 1-ethoxy propane, ethoxyethane. The pyridinium salt is

selected from the group consisting of pyridinium hydrobromide, pyridinium hydrochloride, pyridinium p-toluene sulfonate.
The suitable solvent used is selected from halogenated solvents. The halogenated solvents are selected from dichJoromethane, 1,2-dichloroethane, carbontetrachloride, chloroform or mixture of thereof.
The suitable base is organic base or mixture of two or more. The organic base is selected from the group consisting of triethylamine, dimethylaminopyridine, liq. Ammonia, pyridine, piperidine, N-methyl morpholine, diisopropylether amine, diisopropyl amine, isopropylethylamine.
The methylating agent is selected from the group consisting of methyl iodide, methyl bromide, Diazomethane, Dimethyl carbonate, Dimethyl dicarbonate, Dimethyl sulphate. The base used in step (c) is inorganic base selected from the group consisting of hydroxides like sodium hydroxide, potassium hydroxide, lithium hydroxide, carbonate salts of alkali and alkaline earth metals like potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate.
The solvent used in step (c) is non-polar solvent or mixture of two or more non-polar solvent. The non-polar solvent is selected from toluene, xylene or mixture of two or more solvents. The suitable solvent used in step (d) & (f) is selected from the group consisting of isopropyl alcohol, ethanol or mixture of two or more solvents.
The present invention discloses the insitu process for preparing 2',4"-di-o-benzoyl-6-o-methyl erythromycin which results in higher yield (46-57%) and higer purity (95-97%). The insitu process reduces the atom economy, load of solvents, reagents & effluent which protect ■ the environment. The insitu process can be economical and industrially beneficial as it excludes tedious multistep workup, isolation of intermediates and long reaction time. The following examples explain various other embodiments without limiting the scope of the present invention.
Example-1: Preparation of Erythromycin oxime from Erythromycin thiocyanate
To the solution of erythromycin thiocyanate in DCM added 25% ammonia solution and stirred at RT for 30 min. The organic layer was separated and washed with water. The organic layer was concentrated to get erythromycin base which further treated with methanol. The erythromycin base was charged to a flask containing methanol foliowed by the addition „ of hydroxvlamine hydrochloride and triethylamine. Heated the mixture at 75°C for I6hr. The

mixture was cooled at 5-10°C and stirred for 2hr. The slurry was filtered and washed with chilled MeOH. IPA was charged and mixture stirred for 15 min. Heated the mixture at 50-55°C. Liquid ammonia was added and stirred for lhr. The mixture was cooled to 15-20°C and stirred for 2hr. The solid residue collected, washed with water and dried under vaccum at 80-85°C to get 76-90% yield. Purity: 95-98.5%
Example-2: Preparation of 2\4"-di-o-benzoyl-6-o-methyl erythromycin To the flask e-oxime and DCM was charged and stirred for 15min at 0-5°C. Added 2-methoxy propane, pyridine HBr and temperature was gradually raised to 25°C. The reaction mixture was stirred for 3hr. Added benzoic anhydride, dimethylaminopyridine, triethylamine and dichloromethane and heated at 30-35°C for 16hr. Slowly added sodium bicarbonate and stirred at RT. Evaporated organic layer under vaccum. Charged toluene and stirred for 10 min. Added methyliodide, potassium hydroxide powder and stirred for lhr at 8-10°C. Added 40% DMA and stirred for 15min at 10-15°C. Organic layer was collected by the addition of DM water. Washed with toluene to the aqeous layer and stirred it for 30mih. Organic layer was collected and again washed with DM water. Organic layer was collected and concentrated under the vaccum. The residue obtained was treated with IPA and evaporated it. Added Sodium metabisulfite, isopropyl alcohol, DM water and stirred. Clear solution was observed by the addition of formic acid and observed pH was 3.2-4.9. Heated the reaction mixture at 75-80°C for 6h. Added dichloromethane, DM water and sodium hydroxide solution and stirred reaction mixture at RT for 30 min. Separated layer and collected both organic layer by washed with DM water. Organic layer was evaporated under the vaccum. Residue was collected and crystallized from IPA to get pure product.