FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
A Novel Process For Liberation Of Erythromycin From Erythromycin salts
APPLICANT:
CALYX CHEMICALS AND PHARMACEUTICALS LTD. 2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India
Indian Company incorporated under the Companies Act 1956
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION
The present invention relates to a novel process for the liberation of Erythromycin from Erythromycin salts. More particularly, the present invention relates to a novel process for the liberation of Erythromycin from Erythromycin thiocyanate in presence of a base and using water as a solvent.
BACKGROUND OF INVENTION
Erythromycin of formula I is the most important member of the macrolide
antibiotics of microbial origin. It is effective against many Gram-positive and
Gram-negative bacteria and is often used for people who have an allergy to
penicillins.

Erythromycin was first disclosed in U.S. patent 2,653,899 in 1952. Various prior art discloses different processes for preparation of Erythromycin.
497/MUM/2005 discloses preparation of Erythromycin base from Erythromycin thiocyanate in presence of halogenated solvents and ammonia. The process involves use of 6 volumes of chlorinated solvent such as dichloromethane for liberating Erythromycin thiocyanate from Erythromycin.

627/MUM/2005 discloses preparation of 6,9 imino ether from Erythromycin thiocyanate. As stated in this patent application, the process comprises dissolving Erythromycin thiocyanate in methylene chloride and adding liquid ammonia as a base, separating organic layer, distilling solvent from organic layer to obtain residue of Erythromycin base which further converted to the title compound.
Other patent applications e.g. 626/MUM/2005, WO2007029266 and WO200902319K also describe preparation of Erythromycin from Erythromycin thiocyanate in dichloromethane using aqueous ammonia.
Polish patent PL83707 describes preparation of low melting Erythromycin base by treating Erythromycin thiocyanate with of 20% aqueous ethanol and 5% NaOH at 40-50°C followed by filtering and treating the precipitate with water and alkali till suspension shows no reaction of SCN ions and pH becomes constant to obtain erythromycin base.
Therefore, the processes reported in literature for the liberation of Erythromycin from Erythromycin thiocyanate employ organic solvents, primarily halogenated solvents which have bad impact on environment when one is dealing with industrial scale. During the recovery of chlorinated solvents, there is particular loss of solvent which can not be accounted, thus causing environment pollution and also considerable economical loss.
The inventors of the present invention have surprisingly found a novel process for the liberation of Erythromycin from Erythromycin thiocyanate using water as a solvent in presence of a base which has not been previously reported in any prior art as Erythromycin thiocyanate is insoluble in water. It is a common practice to obtain the product from its salt that use a solvent in which salt is soluble and product is insoluble. But process of the present invention uses water as a solvent in which Erythromycin thiocyanate is insoluble.

The process of the present invention is also cost effective, operationally simple, industrially feasible and environment friendly.
OBJECT OF INVENTION
i) An object of the present invention is to provide a novel process for the liberation of Erythromycin from Erythromycin salts. More particularly, the present invention provides a novel process for the liberation of Erythromycin from Erythromycin thiocyanate in water in presence of a base.
ii) Another object of the present invention is to provide a novel process for the preparation of Erythromycin with more than 95% purity and good yield.
iii) Another object of the present invention is to obtain Erythromycin substantially free of impurities by avoiding any purification process.
iv) Yet another object of the present invention is to provide simple, economic, environment friendly and industrially viable processes for liberation of Erythromycin from Erythromycin salts such as Erythromycin thiocyanate.
SUMMARY OF INVENTION
According to an aspect of the present invention, there is provided a novel process for the liberation of Erythromycin of Formula I from Erythromycin salts such as Erythromycin thiocyanate


Another aspect of the present invention is to provide Erythromycin with more than 95% purity simply by washing Erythromycin, obtained by the process of present invention with water. Thus, process of present invention avoids further purification process.

DETAILED DESCRIPTION OF INVENTION
The present invention provides a novel process for the liberation of Erythromycin of Formula 1 from Erythromycin salts.

In particular, the present invention relates to a novel process for the liberation of Erythromycin of Formula I from Erythromycin thiocyanate of Formula II

by treating Erythromycin thiocyanate of Formula II with a base in presence of water as a solvent.

In an aspect, the process of the present invention further comprises isolation of obtained Erythromycin by optional cooling, filtering and washing the product with water till it is free from ammonium thiocyanate and further drying it to get Erythromycin.
In an embodiment of the present invention, the base used is selected from organic or inorganic base, wherein organic base is selected from dimethylamine, diethylamine or triethylamine and inorganic base is selected from ammonia. sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide. Preferably, ammonia is used.
In another embodiment of the present invention, ammonia used can be in the form of aqueous ammonia or ammonia gas or combination thereof.
It has been observed by inventors of the present invention that ammonia as a base works most effectively in terms of completion of liberation of Erythromycin, yield and purity of the obtained Erythromycin than the other bases e.g. above-mentioned inorganic bases such as sodium hydroxide, sodium carbonate, sodium bicarbonate etc. Further, aqueous ammonia does not work efficiently at low temperature and same is the case with other bases.
Thus, inventors of the present invention provide a novel process for liberation of Erythromycin in presence of base and water as a solvent. None of the prior art teaches use of water as a solvent. For the person skilled in art it is common to get the product like Erythromycin base by liberating it from salt like Erythromycin thiocyanate in a solvent like chlorinated solvent in which the salt is soluble and the product is insoluble. However, in the process of the present invention solvent used is water in which both salt Erythromycin thiocyanate and product Erythromycin is insoluble.

In another embodiment of the present invention, the range of suitable stoichiometries of base with respect to Erythromycin thiocyanate is between 1-5 equivalents and range of suitable stoichiometries of water solvent with respect to Erythromycin thiocyanate is between 1-5 equivalents, preferably 1.
In another embodiment of the present invention, the process of liberation of Erythromycin is carried out at temperature ranging from 30 °C to 80 °C.
In yet another embodiment, process of the present invention provides Erythromycin base with more than 95% purity simply by washing it with water and avoiding further purification process. Thus, Erythromycin base obtained by the process of the present invention is substantially free of impurities.
The detail of the invention provided in the following example is given by the way of illustration only and should not be construed to limit the scope of the present invention.
EXAMPLES AND COMPARATIVE EXAMPLES
Comparative Example 1
For comparison purposes. Erythromycin base was prepared by process as known in the art
100 g active Erythromycin thiocyanate was suspended in MDC (560 ml).To it, a solution of NaOH (8.8 g in 154 ml water) was added and the mass was refluxed for 1 hour. Cooled to RT and separated the aqueous and organic phases. The organic phase was washed with water (5 x l00 ml).Then it was concentrated partially to dehydrate, chilled to 0 to 5°C, stirred for 1 hour and filtered. Washed the cake with chilled MDC (50 ml). Wet cake was then dried at 50 to 55°C. Dry weight: 92 to 94 g (Moisture: 5%).

HPLC purity:
Erythromycin thiocyanate HPLC analysis: Erythromycin A: 84.61%,
Erythromycin B: 1.37%, Erythromycin C: 1.46%
Erythromycin base HPLC analysis: Erythromycin A: 96.28%, Erythromycin B: 0.17%, Erythromycin C: 0.71%
Experimental Example 1
Preparation of Erythromycin base according to present invention.
Erythromycin thiocyanate (243 g) was suspended in water (200 ml). The slurry was heated up to 35°C and liquor Ammonia (200 ml) was added in half an hour. The mass was heated further up to 70°C and stirred for 1 hour. The suspension was cooled to ambient temperature and filtered. The residue was washed with water till free from ammonium thiocyanate (test with FeCb solution). The product was dried at 55 to 60°C. Yield: 212 g (moisture: 5%)
Erythromycin thiocyanate HPLC analysis: Erythromycin A: 84.61%, Erythromycin B: 1.37%, Erythromycin C: 1.46%
Erythromycin base HPLC analysis: Erythromycin A: 96.34%, Erythromycin B: 0.6S%, Erythromycin C. 1.15%
Experimental Example 2
Erythromycin thiocyanate (121.5 g) was suspended in water (100 ml). The slurry was heated up to 35°C and liquor Ammonia (100 ml) was added in.half an hour. The mass was heated further up to 70°C and stirred for 1 hour. The suspension was cooled to 50°C temperature and filtered. The residue was washed with water

till free from ammonium thiocyanate (test with FeCl3 solution). The product was dried at 55 to 60°C.
Yield: 106 gm.
Erythromycin thiocyanate HPLC analysis: Erythromycin A: 84.61%, Erythromycin B: 1.37%, Erythromycin C: 1.46%
Erythromycin base HPLC analysis: Erythromycin A: 96.58%, Erythromycin B: 0.69%, Erythromycin C: 1.03%
Experimental Example 3
To a suspended solution of Erythromcyin thiocyanate (32 g) in water (100 ml) was charged 19 ml Dimethyl amine (40%) and the mass was heated at 70°C for 3 hours. The suspension was cooled to 50°C , filtered and washed with water till free from dimethyl ammonium thiocyanate (test with FeC13 solution). The product was dried at 55 to 60°C.
Yield: 24.6 g (moisture :5.92%)
Erythromycin thiocyanate HPLC analysis: Erythromycin A: 76.63%), Erythromycin B :3.02%, Erythromycin C:0.77%
Erythromycin base HPLC analysis: Erythromycin A: 81.37%, Erythromycin B: 4.85%, Erythromycin C: 1.01%
Experimental Example 4
To a suspended solution of Erythromcyin thiocyanate (32 g) in water(80 ml) was charged Diethyl amine (9.2 g) and the mass was heated at 70°C for 2 hours. The suspension was cooled to 50°C ,filtered and washed with water till free from

diethyl ammonium thiocyanate (test with FeC13 solution).The product was dried
at 55 to 60°C.
Yield : 19.1 g (moisture :5.45%)
Erythromycin thiocyanate HPLC analysis: Erythromycin A: 84.61%, Erythromycin B :1.37%, Erythromycin C:1.46%
Erythromycin base HPLC analysis: Erythromycin A: 95.28%, Erythromycin B: 1.15%, Erythromycin C: 0,98%
Advantages of the novel process of the present invention for the liberation of Erythromycin from Erythromycin thiocyanate are
1. The process of the present invention is carried out in water as a solvent.
Thus, the process avoids use of any organic solvent especially chlorinated
solvents.
2. The process of the present invention is thus environmentally friendly.
3. The process of the present invention provides Erythromycin base with more than 95% purity by avoiding further purification process.
4. The process of the present invention avoids tedious steps of isolation of erythromycin base such as separation of organic solvent, concentration of solvent etc.
5. The process of the present invention is thus economic and industrially viable.

We claim
1. A novel process for the liberation of Erythromycin of Formula I

by treating Erythromycin thiocyanate of Formula II with a base in presence of water as a solvent 2. The process for liberation of Erythromycin as claimed in claim 1. further comprises isolation of obtained Erythromycin by optional cooling, filtering and washing the product with water

3. The process for liberation of Erythromycin as claimed in claim 1, wherein the base used is selected from organic or inorganic base, wherein organic base is selected from dimethylamine, diethylamine or triethylamine and inorganic base is selected from ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, preferably ammonia is used
4. The process for liberation of Erythromycin as claimed in claim 3, wherein
ammonia used can be in the form of aqueous ammonia or ammonia gas or combination thereof
5. The process for liberation of Erythromycin as claimed in claim 1 or 3, wherein the range of suitable stoichiometrics of the base with respect to the Erythromycin thiocyanate is between 1 to 5 equivalents
6. The process for liberation of Erythromycin as claimed in claim 1, wherein the said process is carried out at temperature ranging from 30 °C to 80 °C
7. The process for liberation of Erythromycin as claimed in claim 1, wherein the range of suitable stoichiometries of water solvent with respect to Erythromycin thiocyanate is between 1 to 5 equivalents, preferably 1.