FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of erythromycin A 9-oxime of formula I,
(Figure Remove)a key intermediate in the preparation of macrolide antibiotics such clarithromycin, roxithromycin and azithromycin and similar compounds.
BACKGROUND OF THE INVENTION
Erythromycin A 9-oxime of formula I,
(Figure Remove)
is used as a key intermediate for the preparation of clarithromycin, roxithromycin and azithromycin and similar compounds.
Clarithromycin, roxithromycin and azithromycin of following formulas
ROXITHROMYCIN
are semi-synthetic macrolide antibiotics related to erythromycin A. These antibiotics exhibit excellent antibacterial activity against gram-positive bacteria, some gram-negative bacteria, anaerobic bacteria etc. Erythromycin A 9-oxime has been first disclosed in US Patent 3,478, 014. Thereafter
several other approaches for preparing erythromycin A 9-oxime have been published starting from erythromycin A.
Japanese patent publication JP 6208399 A2 discloses the preparation of erythromycin oxime by oximation of erythromycin with hydroxyl amine salt in the presence of imidazole by stirring for four days.
In US 6,515,116, in reference example erythromycin A 9-oxime is prepared from erythromycin A using hydroxylamine hydrochloride and triethylamine in methanol.
Recently in WO 2006/064299 Al, erythromycin A 9-oxime is prepared by process which comprises, treating hydroxylamine hydrochloride with caustic flakes in aqueous isopropyl alcohol at 10 to 20°C to generate the hydroxylamine base in solution followed by addition of erythromycin A, adjusting the pH of the reaction mixture between 6.5 to 7.0 by glacial acetic acid, stirring for further 28 hours at 55°C, neutralizing by adding aqueous ammonia and water, adding additional volume of water to get the precipitate of erythromycin- A-9-Oxime.
Alternatively erythromycin A 9-oxime of formula I is prepared from erythromycin A thiocyanic acid salt of formula II
through erythromycin A of formula III

Specifically the erythromycin A thiocyanic acid salt of formula II is hydrolyzed to erythromycin A of formula III using ammonia in methylene chloride, thereafter resulting erythromycin A of formula III is converted to erythromycin A 9-oxime of formula I using hydroxylamine hydrochloride, triethyl amine in methanol. The above process suffers several drawbacks as it is time consuming process and work up for the preparation of erythromycin A is very tedious and further methylene chloride has to be distilled out completely before proceeding for oxime preparation as its presence results in reduction of yield.
The common and major drawbacks of most of the processes described above are multi step and mostly processes starting from erythromycin A, wherein an additional step is required to prepare erythromycin A.
Accordingly, a simple, cost-effective and environmentally friendly process for the preparation of erythromycin A 9-oxime of formula I is provided which is easy to operate on industrial scale.

SUMMARY OF THE INVENTION
The present invention relates to a simple, cost effective and industrially advantageous process for the preparation of erythromycin A 9-oxime of formula I

which comprises treating erythromycin thiocyanic acid salt of formula II

SCN-
. + .CHj NH
with hydroxylamine hydrochloride in the presence of organic base in alcoholic solvent at reflux temperature and
converting the resultining oxime hydrochloride to oxime by hydrolysis with ammonia.
More particularly, the above erythromycin A 9-oxime is used in the preparation of clarithromycin, roxithromycin and azithromycin.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to preparation of erythromycin A 9-oxime directly from erythromycin thiocyanic acid salt. Generally erythromycin thiocyanic acid salt is treated with hydroxylamine hydrochloride in the presence of base in alcoholic solvent. It is advantageous to use anhydrous solvent.
The alcoholic solvent includes, but not limited to methanol, ethanol, isopropanol etc and preferably methanol is used.
The organic base usually used is trialkylamine such as triethylamine, tributylamine and the like and preferably triethylamine is used.
Specifically erythromycin thiocyanic acid salt is taken in methanol along with hydroxylamine hydrochloride and triethylamine and reaction mixture is refluxed. The progress of reaction is monitored by thin layer chromatography (TLC) as well as by high performance liquid chromatography (HPLC). The reaction can advantageously be completed in 24-30 hours. After completion of reaction, reaction mixture is cooled to below 0°C to precipitate hydrochloride salt of erythromycin A 9-oxime. The product is filtered to remove unwanted salts in solution. Thereafter wet product is taken in alcoholic solvent and hydrolysed using base such as ammonia to prepare erythromycin A 9-oxime, which is isolated by filtration.
Erythromycin A 9-oxime prepared as above is used as such in the preparation of clarithromycin, roxithromycin and azithromycin without further purification, by using conventional methods.
The major advantages realized in the present invention are that hydrolysis and oximation reactions are carried out simultaneously in place of two steps i.e. hydrolysis followed by oximation, thus reducing number of steps, total time cycle, burden on equipment, avoiding use of methylene chloride and tedious reaction work up and hence results in high yield and process is easy to operate on commercial scale.
The following example is provided to enable one skilled in the art to practice the invention and is merely illustrative of the invention. The example should not be read as limiting the scope of the invention.
Preparation of erythromycin A 9-oxime
Erythromycin thiocyanic acid salt of formula II (50 gm., 0.063 mol.) was refluxed with hydroxylamine hydrochloride, (20.77gm., 0.299 mol.) and triethylamine (21.5gm., 0.213 mol.) in methanol (50ml.) for 30 hrs. After completion of reaction, the reaction mass was cooled to -5 to -10°C and stirred for about one hour at same temperature. Erythromycin A 9-oxime hydrochloride, thus crystallized out, was filtered. The wet cake was taken in isopropyl alcohol (45ml.) and to this aqueous ammonia solution was added to adjust the pH 10.0-10.5. The product, thus obtained was filtered, washed with water and dried at 90-95°C to obtain 37.0 gm of erythromycin A 9-oxime

We Claim:
1. A process for the preparation of erythromycin A 9-oxime of formula I

(Figure Remove)
which comprises treating erythromycin thiocyanic acid salt of formula II

OH
(Figure Remove)with hydroxylamine hydrochloride in the presence of organic base in alcoholic
solvent at reflux temperature and
converting the resulting oxime hydrochloride to oxime by hydrolysis with ammonia.

2. The process according to claim 1, wherein organic base is selected from
trialkylamine such as triethylamine, tributylamine.
3. The process according to claim 1, wherein organic base is triethylamine.
4. The process according to claim 1, wherein the alcoholic solvent is methanol,
ethanol, isopropanol etc.
5. The process according to claim 1, wherein the alcoholic solvent is methanol.
6. The process according to claim 1, wherein erythromycin A 9-oxime of formula I
prepared as above is converted to clarithromycin.
7. The process according to claim 1, wherein erythromycin A 9-oxime of formula I
prepared as above is converted to roxithromycin.
8. The process according to claim 1, wherein erythromycin A 9-oxime of formula I
prepared as above is converted to azithromycin.