FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
Title of the invention. -A PROCESS FOR THE PREPARATION OF
ERYTHROMYCIN ESTOLATE

2. Applicant(s)
(a) NAME :
(b) NATIONALITY:
(c) ADDRESS :

ALEMBIC LIMITED
An Indian Company.
Alembic Campus, Alembic Road, Vadodara - 390 003, Gujarat, India.

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of the Invention
The present invention relates to process for the preparation of Erythromycin Estolate (I).

(I)
Background of the invention
Erythromycin Estolate (I) is widely used in the treatment of various bacterial infections, caused by both Gram-positive and Gram-negative organisms. Erythromycin Estolate is chemically known as Erythromycin 2'- propanoate dodecyl sulfate or erythromycin propionate lauryl sulfate or lauryl sulfate salt of the propionic acid ester of erythromycin or propionyl erythromycin lauryl sulfate. Erythromycin Estolate is having molecular formula C52H97NO18S and molecular weight 1056.39.
Erythromycin Estolate (I) was first disclosed and claimed in US 3000874 which is filed on Apr. 08, 1959 and granted on Sep. 19, 1961 and assigned to Elli Lilly and


company. This patent also discloses a process for preparation Erythromycin Estolate without mentioning a yield and purity.
Various patent/ applications describes/claims process for the preparation of Erythromycin Estolate particularly DE 1114499, PL 52448 and PL 146603. But these processes remain silent either about the yield or purity or both of the final products. It is also observe that most of the prior art process as mentioned herein above does not results a highly pure Erythromycin Estolate with good yield and purity.
Therefore, there is a need to develop a process for the preparation Erythromycin Estolate which is cost effective and which gives good result with respect to good yield and purity.
Surprisingly, present inventors develop a process for the preparation of Erythromycin Estolate which is not only cost effective but also gives excellent result with respect to high purity and yield of final product. This process involves the production of Erythromycin Estolate which comprises i) treating erythromycin thiocyanate with a base in suitable solvent to obtain erythromycin, ii) esterifying said erythromycin with propionic anhydride in suitable solvent to obtain Erythromycin 2'-propionate and iii) treating said Erythromycin 2'-propionate with alkali or alkaline-earth metal lauryl sulfate in suitable solvent.
Objects of the invention
The primary object of this invention is to provide a process for the preparation of Erythromycin Estolate (I).
Other object of the invention is to provide a process for the preparation of highly pure Erythromycin Estolate (I).
Another object of the invention is to provide a process for the preparation of Erythromycin Estolate (I) which gives excellent result with regards to high yield and purity.


Another object of the invention is to provide a process for the preparation of Erythromycin Estolate (I) which is cost effective and feasible at industrial level.
A further object of the invention is to provide a process for the preparation of Erythromycin Estolate (I) comprising steps of:
i) treating erythromycin thiocyanate with a base in suitable solvent to obtain
erythromycin,
ii) esterifying erythromycin obtained in step (i) with propionic anhydride in
suitable solvent to obtain Erythromycin 2'-propionate, iii) treating Erythromycin 2'-propionate obtained in step
(ii) with alkali or alkaline-earth metal lauryl sulfate in suitable solvent.
Brief description of the accompanying figures
Fig. 1 depicts the powder X-ray diffraction (XRD) pattern of crystalline Erythromycin Estolate (I) as prepared in accordance with the present invention.
Detailed description of the invention
The present invention provides a process for the preparation of Erythromycin Estolate (I) comprising steps of:
i) treating erythromycin thiocyanate with a base in suitable solvent to obtain
erythromycin,
ii) esterifying said erythromycin obtained in step (i) with propionic anhydride in
suitable solvent to obtain Erythromycin 2'-propionate and iii) treating Erythromycin 2'-propionate obtained in step
(ii) with alkali or alkaline-earth metal lauryl sulfate in suitable solvent.
The term "treating" as used hereinabove includes suspending, dissolving, adding, mixing, combining, accumulating and melting or totaling in any of the suitable solvent as described herein below.


The term "suitable solvent" as used hereinabove includes but not limited to substituted or unsubstituted; a) alcoholic solvent, b) halogenated hydrocarbon solvent, c) aliphatic or aromatic hydrocarbon solvent, d) ester solvent, e) ether solvent, f) cyclic ether solvent, g) nitrile solvent, h) aqueous solvent, i) ketonic solvent j) polar or nonpolar protic solvent, xi) polar or nonpolar aprotic solvent and the like or mixture thereof.
The preferred suitable solvent for step (i) is mixture of aqueous solvent and halogenated hydrocarbon solvent. The aqueous solvent is water. The halogenated hydrocarbon solvent that includes but not limited to methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride, and the like or mixture thereof and the preferred one is methylene dichloride.
The preferred suitable solvent for step (ii) is halogenated hydrocarbon solvent or ketonic solvent. The halogenated hydrocarbon solvent that includes but not limited to methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride, and the like or mixture thereof. The preferred one is methylene dichloride. The ketonic solvent that includes but not limited to acetone, ethyl methyl ketone, methyl isobutyl ketone and the like or mixture thereof. The preferred one is acetone. The preferred suitable solvent for step (iii) is mixture of aqueous solvent and halogenated hydrocarbon solvent or ketonic solvent. The aqueous solvent is water. The halogenated hydrocarbon solvent that includes but not limited to methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride, and the like or mixture thereof and the preferred one is methylene dichloride. The ketonic solvent that includes but not limited to acetone, ethyl methyl ketone, methyl isobutyl ketone and the like or mixture thereof and the preferred one is acetone.
The "base" as used herein that includes but not limited to organic bases or inorganic bases such as imidazole, triethyl amine, diethyl amine, methylamine, t-butylamine, pyrrolidine, pyridine, morpholine, di-N-propylamine, n-butylamine, isopropylamine, piperidine, picoline, ammonia, alkali or alkaline earth metal hydroxide, alkali or alkaline earth metal carbonate or bicarbonate, alkali or alkaline earth metal hydrides


and the like or mixture thereof. The preferred base is ammonia in the form of aq. ammonia or ammonia gas. The preferred one is aq. Ammonia.
The term "alkali or alkaline-earth metal" as used hereinabove includes but not limited to sodium, potassium, lithium, magnesium, calcium, barium and the like or mixture thereof. The preferred one is sodium.
The term "esterifying" as used hereinabove esterification reaction in which two reactants typically an alcohol and acid to form an ester as the reaction product.
In step (i) as mentioned hereinabove, Erythromycin thiocyanate is dissolved in halogenated solvent and treated with base to get Erythromycin base which may be used as isolated or not isolated for further step.
In step (ii) as mentioned hereinabove, Erythromycin base obtained in step (i) is treated with propionic anhydride in suitable solvent to get Erythromycin 2'-propionate which may be used as isolated or not isolated for further step.
In step (iii) as mentioned hereinabove, Erythromycin 2'-propionate obtained in step (ii) is treated with sodium lauryl sulfate in suitable solvent to get Erythromycin Estolate which may be purified with suitable solvent as defined herein above.
Step (i) and (iii) as mentioned hereinabove may involve pH adjustment for isolation of the product.
Erythromycin Estolate (I) prepared in accordance with the present invention is free of other forms and other impurities.
Erythromycin Estolate (I) as prepared in accordance with the present invention is crystalline in nature and characterized by powder X-ray diffraction peaks at about 3.2, 4.3, 4.9, 5.8, 6.4, 8.6, 9.7, 12.8, 13.4, 17.2 and 19.0 ±0.2 degree two-theta as shown in Fig. 1.


A crystalline form of Erythromycin Estolate (I) as prepared in accordance with present invention is isolated from reaction mass by conventional isolation procedure such as filtration, centrifugation, washing the wet cake and drying or by evaporation of solvent.
While the present invention has been described in terms of its specific embodiments, 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.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Example 1
Ammonia solution (100 ml) was added to Erythromycin Thiocyanate (100 g) in methylene dichloride (800 ml) at room temperature. After completion of reaction, reaction mixture was settled down and layer was separated to obtain erythromycin base in organic layer. This organic layer was evaporated completely and to get residue. To this residue, acetone (200 ml) was added and then Propionic anhydride (15 g) was added to obtain Erythromycin 2'-propionate. To this solution of Erythromycin 2'-propionate with acetone, a solution of sodium lauryl sulfate (40g) in DM Water (500 ml) was added to obtain solid which was filtered and dried to obtain solid Erythromycin Estolate. Yield: -115 - 125gm w/w HPLC Purity: -95 to 98 %
Example 2
Ammonia solution (100ml) was added to Erythromycin Thiocyanate (100g) in methylene dichloride (800 ml) to obtain erythromycin base in organic layer. To said organic layer with erythromycin base, Propionic anhydride (25 g) was added to form Erythromycin 2'-propionate. To this solution of Erythromycin 2'-propionate in methylene dichloride, a solution of sodium lauryl sulfate (40 g) in DM Water (500 ml)


was added at room temperature. After completion of reaction, the reaction mixture
was evaporated to obtain solid which was filtered and dried to obtain Erythromycin
Estolate.
Yield: -80- 100gm w/w
HPLC Purity: -95 to 98 %
Example 3
Ammonia solution (100ml) was added to Erythromycin Thiocyanate (100g) in methylene dichloride (800 ml) at room temperature. After completion of reaction, reaction mixture was settle down and layer was separated to obtain erythromycin base in organic layer. To this organic layer, propionic anhydride (25g) was added. After completion of reaction, methylene chloride was completely evaporated to obtain residue of Erythromycin 2'-propionate. To this residue, acetone (200 ml) was added and then a solution of sodium lauryl sulfate (40g) in DM Water (500ml) was added to obtain solid which was filtered and dried to obtain solid Erythromycin Estolate.
Yield: -80- 100gm w/w HPLC Purity: -95 to 98 %


We claim:
1. A process for preparation of Erythromycin Estolate comprising steps of:
i) treating erythromycin thiocyanate with a base in suitable solvent to
obtain erythromycin,
ii) esterifying erythromycin obtained in step (i) with propionic
anhydride in suitable solvent to obtain Erythromycin 2'-propionate
and iii) treating Erythromycin 2'-propionate obtained in step
(ii) with alkali
or alkaline-earth metal lauryl sulfate in suitable solvent
2. The process according to claim 1, wherein suitable solvent used is selected from substituted or unsubstituted; a) alcoholic solvent, b) halogenated hydrocarbon solvent, c) aliphatic or aromatic hydrocarbon solvent, d) ester solvent, e) ether solvent, f) cyclic ether solvent, g) nitrile solvent, h) aqueous solvent, i) ketonic solvent j) polar or nonpolar protic solvent, xi) polar or nonpolar aprotic solvent or mixture thereof.
3. The process according to claim 2, wherein suitable solvent used is selected from halogenated hydrocarbon solvent, aqueous solvent and ketonic solvent or mixture thereof.
4. The process according to claim 3, wherein suitable solvent used is methylene chloride, water and acetone or mixture thereof.
5. The process according to claim 1, wherein base used is selected from organic bases or inorganic bases such as imidazole, triethyl amine, diethyl amine, methylamine, t-butylamine, pyrrolidine, pyridine, morpholine, di-N-propylamine, n-butylamine, isopropylamine, piperidine, picoline, ammonia,


alkali or alkaline earth metal hydroxide, alkali or alkaline earth metal carbonate or bicarbonate, alkali or alkaline earth metal hydrides or mixture thereof.
6. The process according to claim 5, wherein base used is ammonia.
7. The process according to claim 1, wherein alkali or alkaline-earth metal used is selected from sodium, potassium, lithium, magnesium, calcium, barium or mixture thereof.
8. Crystalline form of Erythromycin Estolate, characterized by powder X-ray diffraction peaks at about 3.2, 4.3, 4.9, 5.8, 6.4, 8.6, 9.7, 12.8, 13.4, 17.2 and 19.0 ±0.2 degree two-theta.





A B S T R A C T
The present invention relates to an improved process for the preparation of Erythromycin Estolate (I) which comprises i) treating erythromycin thiocyanate with a base in suitable solvent to obtain erythromycin base, ii) esterifying said erythromycin base with propionic anhydride in suitable solvent to obtain Erythromycin 2'-propionate and iii) treating said Erythromycin 2'-propionate with alkali or alkaline-earth metal lauryl sulfate in suitable solvent.