FIELD OF THE INVENTION:
The present invention relates to the process for the preparation of Erythromycin, 9-[0-(l-methoxy-t-methylethyl)oxime], 2',4"-dibenzoate
BACKGROUND OF THE INVENTION:
Polyketides are complex organic compounds that are often highly active biologically. Many
pharmaceuticals are derived from or inspired by polyketides. Macrolides belong to the
polyketide class of natural products that consist of a large macrocyclic lactone ring. Some
macrolides, erythromycin and semi synthetic derivatives such as Azithromycin,
Clarithromycin, Telithromycin, Cethromycin have antibiotic or antifungal activity. These
macrolides are used and marketed as pharmaceutical drugs.
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.
Erythromycin, 9-[0-(l-methoxy-l-methylethyl)oxime], 2\4"-dibenzoate (formula-1) is
useful as intermediate for preparation of macrolides.
WO 2004080391 and US 7601695 discloses a family of macrolide and ketolide antibiotics, their salts and preparation thereof.
US 9051346 (herein after US'346) discloses the process for preparing Erythromycin, 9-[0-(l-methoxy-l-methylethyl)oxime|, 2\4"-dibenzoate comprises reaction of erythromycin A 9-oxime with 2-mehtoxypropene in presence of anhydrous dichloromethane and pyridine hydrochloride at RT and isolate protected oxime which further reacted with benzoic anhydride and triethvl amine and DMAP in _p.re§ence„ of ethyl .aqpuite and isolate

Erythromycin, 9-[0-(l-methoxy-l-methylethyl)oxime], 2',4"-dibenzoate with 80% yield
which further purified with column choromatography.
US'346 also discloses the insitu process for preparing Erythromycin, 9-[0-(l-methoxy-l-
methylethyl)oxime], 2',4"-dibenzoate without isolation of protected oxime comprises
reaction of erythromycin A 9-oxime with 2-mehtoxypropene in presence of anhydrous
dichloromethane and pyridine hydrobromide which further reacted with benzoic anhydride,
triethyl amine and DMAP in presence of ethyl acetate and isolate Erythromycin, 9-[0-(l-
methoxy-l-methylethyl)oxime], 2',4"-dibenzoate with purity of 48-51%. The unpurified
product dissolved in ethyl acetate and washed with saturated sodium bicarbonate, water and
brine. The isolated product was crystallized from IPE/n-hexane to get 84% yield.
The prior art process requires silica gel column chromatography for purification which results
in loss of product that makes the process uneconomical and unworthy. Moreover the said
process involves use of strong acid catalyst which is hazardous and result in lower yield and
purity due to decomposition of product.
Thus it is necessary to develop safe, a cost-effective and industrially feasible process.
The present invention provides a robust, commercially viable insitu process for preparing
Erythromycin, 9-[0-(l-methoxy-l-methylethyl)oxime], 2\4"-dibenzoate.
SUMMARY OF THE INVENTION:
The present invention relates to the insitu process for preparation of Erythromycin, 9-[0-(l-
methoxy-l-methylethyl)oxime], 2',4"-dibenzoate of formula-!
In one embodiment, the present invention relates to the insitu process for preparation of Erythromycin, 9-[0-(l-methoxy-l-methylethyl)oxime]. 2".4;:-dibenzoate comprising the steps of;

(a) reacting 9-N-Oxime erythromycin A HCI with alkoxy alkane and weak acidic catalyst
in presence of suitable solvent at ambient temperature
(b) acylating with acylating agent in presence of acylating catalyst
(c)'-basifying with organic base
(d) isolating Erythromycin, 9-[0-(l-methoxy-l-methylethyl)oxime], 2',4"-dibenzoate
DETAIL DESCRIPTION OF THE INVENTION:
The present invention relates to safe, inexpensive and industrially viable insitu process for the preparation of Erythromycin, 9-[0-(l-methoxy-l-methylethyl)oxime], 2',4"-dibenzoate of formula-I
In one aspect, the present invention relates to the insitu process for preparation of Erythromycin, 9-[0-(l-methoxy-l-methylethyl)oxime], 2\4"-dibenzoate comprising the steps of;
(a) reacting 9-N-Oxime erythromycin A HCI with alkoxy alkane and weak acidic catalyst in presence of suitable solvent at ambient temperature
(b) acylating with acylating agent in presence of acylating catalyst
(c) basifying with organic base
(d) crystallizing with alcoholic solvent
(e) isolating Erythromycin, 9-[0-(l-methoxy-l-methylethyl)oxime], 2\4"-dibenzoate
The process for preparation of Erythromycin, 9-[0-(l-methoxy-l-methyIethyl)oxime|,
2\4"-dibenzoate of formula-1 depicted in the following reaction scheme-l

The alkoxy alkane used in step (a) is selected from the group consisting of 2-methoxy
propene, 2-ethoxy propene.'
The weakly acid catalyst in step (a) is pyridinium salt of weak acid and is selected from the
group consisting of pyridinium p-toluene sulfonate(PPTS),Pyridinium
trifluoroacetate(PTFA).
The suitable solvent for step (a) is selected from non-polar solvents, polar aprotic 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 polar aprotic solvent is
selected from the group consisting of dichloromethane, ethylacetate, dimethylsulfoxide,
dimethyl formamide or mixture of two or more solvents.
The acylating agent and acylating catalyst for acylation in step (b) is benzoic anhydride and
dimethylaminopyridine.respectively.
The organic base for basification in step (c) is selected from the group consisting of
triethylamine, pyridine, piperidine, N-methyl morpholine, liq. Ammonia, diisopropylether
amine, diisopropyl amine, isopropylethylamine.
The alcoholic solvent used in step (d) is selected from the group consisting of isopropanol.
methanol, ethanol, n-propanol. butanol or mixture of thereof.
The reaction temperature for step (c) is.35-40°C.
The main advantage of present invention is use of efficient, inexpensive, not moisture
sensitive, safe weak acid catalyst such as pyridinium p-toluene sulfonate(PPTS),Pyridinium
trinuoroacetate(PTFA) for preparing protected oxime and acylation reaction.
It is noteworthy that weaker acid salt PPTS/PTFA is mild enough to be used on complex systems containing sensitive polyfunctional groups and encountered no serious difficulty to prepare protected oxime. Weak acid catalysts decreases ratio of decomposition which results

in higher yield (88%) with higher purity (92%) as compare to strong acid catalyst. More over weak acidic character, unlike strong acid catalyst, does not corrupt the equipments.
The main drawback of prior art US' 346 process is use of strong acid catalyst such as pyridine hydrochloride, pyridine hydrobromide. The strong acid catalyst increases decomposition rate which results in lower yield (84%) and lower purity (48-51%). Furthermore said prior art describes purification of unpurifled products remained after successive batches and use of silica gel column chromatography which results in yield loss that makes prior art process uneconomical, tedious and cumbersome. While the present invention does not involve use of silica gel column chromatography. In addition the present invention process obtains pure Erythromycin, 9-[0-(l-methoxy-l-methylethyl)oxime], 2\4"-dibenzoate with simple crystallization process that results in higher yield (88%) and higher purity (92%>). The insitu process like present invention reduces the atom economy, load of solvents, reagents & effluent which protect the environment.
The following examples explain various other embodiments without limiting the scope of the present invention.
Example-1: Preparation of Erythromycin, 9-[0-(l-methoxy-l-methylethyl)oxime|, 2\4"-dibenzoate
To the solution of E-oxime in dichloromethane added 2-methoxypropene and pyridinium-p-toluene sulphonate and stirred for 3h at RT. Added benzoic anhydride, dimethylaminopyridine and triethyl amine and stirred at 35-40 °C for 12 h. The reaction mixture was washed with sodium bicarbonate solution and followed by water. Organic layer distilled off u/v and crystallized from isopropyl alcohol to get 88% titled compound. Purity: 91-93%
ExampIe-2: Preparation of Erythromycin, 9-|0-(l-methoxy-l-methylethyl)oxime|, 2',4"-dibenzoate
To the solution of E-oxime in dichloromethane added 2-methoxypropene and pyridinium trifluoroacetate and stirred for 3h at RT. Added benzoic anhydride, dimethylaminopyridine and triethyl amine and stirred at 35-40 °C for 12 h. The reaction mixture was washed with sodium bicarbonate solution and followed by water. Organic layer distilled off u/v and crystallized from isopropyl alcohol to get 81-85%> titled compound. Purity: 91-94%