FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

1. Title of the invention.

AN IMPROVED PROCESS FOR THE PREPARATION OF ERYTHRONCYIN A (I) AND ERYTHROMYCIN A OXIME (II)

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 an improved process for the preparation of Erythroncyin A (I) and Erythromycin A oxime (II). Erythromycin A (I) belongs to Macrolide class of compound and is well known for its antibiotic activity. Erythromycin A oxime (II) is a key intermediate for the preparation of other semi synthetic Macrolides such as Clarithromycin, Azithromycina and Roxithromycin.
Background and Prior Art
Erythromycin A was first discovered in 1950s. Erythromycin A and its salts are widely used in the treatment of various infections, caused by both Gram-positive and Gram-negative organisms.
Generally, Erythromycin A is prepared by fermentation process. The fungus Saccharopolyspora erythaeas is the source of a number of structurally related macrolide antibiotics known collectively as erythromycins. Among these, Erythromycin A (I) has proven to be of great importance, occupying a prominent position in medicine by virtue of its useful antibacterial activity (Ref: Current Pharmaceutical Design, 2000, 6, 181-223).
Erythromycin A is the desired product which is produced by fermentation process. However, another form of Erythromycin, which is known as Erythromycin B (III) is also being generated inter se as an impurity during fermentation process. Also, other related impurities is being generated during fermentation process. Considering the structural similarity between Erythromycin A (I) and Erythromycin B (III), it is very difficult to obtain pure Erythromycin A (I) substantially free of Erythromycin B (III) and requires column chromatography.

So, there is a need for a simple process for the preparation of Erythromycin A (I) substantially free of Erythromycin B (III).
Erythromycin A Oxime (II) was first desclosed in US patent No. 3,478,014. Erythromycin A Oxime (II) is a key intermediate of the various semi synthetic Macrolide antibiotics such as Clarithormycin, Azithromycin, Roxithromycin. The process for the preparation of Erythromycin A oxime (II) is described EP0503932. Erythormhycin A is treated with hydroxyl amine hydrochloride in presence of pyridine and treated with Ethanol to obtain sCrude Erythromycin A oxime (II).

However, the Erythromycin A used in the process is 95% pure. So, Erythromycin A oxime prepared according to above process is required additional purification. Therefore, it is important to use Erythromycin A (I) substantially free form Erythromycin B (III) to obtain Erythromycin A Oxime (II) substantially free from Erythromycin B oxime (IV).
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OBJECTS OF THE INVENTION
One object of the invention is to provide a process for the preparation of Erythronmycin A (I) substantially free of Erythromycin B (II).
Other object of the invention of the invention is to provide a process for the preparation of highly pure Erythromycin A (I)
Another object of this invention is to provide a process for the preparation of Erythromycin Aoxime(ll).
Yet another object of the present invention is to provide a process for the preparation of Erythromycin A oxime (II) substantially free of Erythromycin B oxime (III).
SUMMARY OF INVENTION
Acoording to a broad aspect of the invention there is provided a process for the preparation of Erythromycin A (I); which comprises
(i) treating Erythromycin thiocyanate with ammonia in halogenated solvent
(ii) isolating Erythromycin A
According to another aspect of the invention, there is provided a process for the preparation of Erythromycin A oxime (II), which comprises
(a) treating erythromycin thiocyanate with ammonia in halogenated solvent
(b) isolating Erythromycin A (I) substantially free of Erythromycin B
(c) treating Erythromycin A (I) with hydroxyl amine hydrochloride in presence of triethyl
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amine in lower alcohol to obtain Erythromycin A oxime hydrochloride
(d) treating Erythromycin A oxime hydrochloride with ammonia in lower alcohol
(e) isolating Erythromycin A oxime (II)
DETAILED DESCRIPTION OF THE INVENTION
Halogenated solvent can be selected from methylene dichloride, ethylene dichloride, chloroform and carbon tetrachloride. The preferred solvent is methylene dichloride.
Ammonia used in step (i) can be in the form of aq. Ammonia or ammonia gas. The preferred form of ammonia is aq. Ammonia.
Accordingly, Erythromycin thiocyanate is dissolved in halogenated solvent and further treated with ammonia to obtain clear solution. Erythromycin A (I) is isolated from the solution by conventional method such as extraction, distillation, crystallization.
Erythromycin A (I) prepared in accordance with the present invention is substantially free of Erythromycin B (III) and other impurities and avoids further purification.
Halogenated solvent used in step (a) of the preferred aspect can be selected from methylene dichloride, ethylene dichloride, chloroform and carbon tetrachloride. The preferred solvent is methylene dichloride.
Ammonia used in step (a) of the preferred aspect can be in the form of aq. Ammonia or ammonia gas. The preferred form of ammonia is aq. Ammonia.
Accordingly, Erythromycin thiocyanate is suspended in halogenated solvent and further treated with ammonia to obtain clear solution. Erythromycin A (I) is isolated from the solution by conventional method such as extraction, distillation, crystallization, which is substantially free of Erythromycin B (III).
Erythromycin A (I) is further treated with hydroxyl amine hydrochloride in presence of triethyl amine in lower alcohol to obtain Erythromycin A oxime hydrochloride. Lower alcohol can be selected from methanol, ethanol, isopropanol, n-praopanol, n-butanol, isobutanol, tert-butanol. The preferred lower alcohol is methanol, isopropanol.
Erythromycin A oxime hydrochloride obtained in step (d) is treated with ammonia in lower
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alcohol to obtain Erthromycin A oxime (II), which is isolated by conventional manner such as extraction, distillation and crystallization.
Lower alcohol can be selected from methanol, ethanol, isopropanol, n-praopanol, n-butanol, isobutanol, tert-butanol.
The process of the present invention produces Erythromycin A oxime (II) substantially free of Erythromycin B oxime (IV), which is simple, environment friendly and does not require additional purification. In short, the process provided by the present invention is commercially viable process..
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.
EXAMPLES: EXAMPLE-1: Preparation of Erythromycin A (I)
375 Kg. of Erythromycin thiocynate (Erythromycin B thiocyanate content: -1.5 to 3.5%) is added to 2100 L of MDC and stirred. 500 L of Liquid ammonia is added to reaction mixture to obtain clear solution. The layers are allowed to settle and organic layer is separated out.
It is further cooled to obtain crystallized Erythromycin A (Erythromycin B content -0.2 to 0.7%) Purity: -93 to 96%
EXAMPLE-2:
Preparation of Erythromycin A oxime (II):
375 Kg. of Erythromycin thiocynate (Erythromycin B thiocyanate content: -1.5 to 3.5%) is added to 2100 L of MDC and stirred. 500 L of Liquid ammonia is added to reaction mixture to obtain clear solution. The layers are allowed to settle and organic layer is separated out.
It is further cooled to obtain crystallized Erythromycin A. Erythromycin A is added to 400 L of methanol under stirring. 145 Kg. of Triethyl amine (TEA), 200 Kg. of Hydroxyl amine hydrochloride is added to reaction mass and stirred. The reaction mass is refluxed for about 20-24. After completion of reaction, the reaction mass is cooled, stirred and filtered
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to give Erythromycin A oxime hydrochloride, which is further treated with 450 of aq. ammonia in isopropanol The reaction mass is cooled, filtered and dried to give Erythromycin A oxime (II). (Erythromycin oxime B content -0.2 to 0.5%) Purity: -97 to 99%
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.
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We claim:
1. A process for the preparation of Erythromycin A, which comprises
(i) treating Erythromycin thiocyanate with ammonia in halogenated solvent (ii) isolating Erthromycin base
2. A process as claimed in claim 1, wherein halogenated solvent is selected form
methylene dichloride, ethylene dichloride, chloroform, carbon tetra chloride
3. A process as claimed in claim 2, where in solvent is methylene dichloride
4. A process as claimed in claim 1, wherein ammonia used in step (i) can be aqueous ammonia or ammonia gas.
5. A process as claimed in claim 4, wherein ammonia used in step (i) is aqueous ammonia.
6. A process for the preparation of Erythromycin A oxime (II),

which comprises
(a) treating erythromycin thiocyanate with ammonia in halogenated solvent
(b) isolating Erythromycin A (I) substantially free of Erythromycin B
(c) treating Erythromycin A (I) with hydroxyl amine hydrochloride in presence of triethyl amine in lower alcohol to obtain Erythromycin A oxime hydrochloride
(d) treating Erythromycin A oxime hydrochloride with ammonia in lower alcohol
(e) isolating Erythromycin A oxime (II)
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7. A process as claimed in claim 6, wherein halogenated solvent is selected form methylene dichloride, ethylene dichloride, chloroform, carbon tetra chloride.
8. A process as claimed in claim 7, wherein halogenated solvent is methylene dichloride
9. A process as claimed in claim 6, wherein ammonia used in step (a) can be aqueous ammonia or ammonia gas.
10.A process as claimed in claim 9, wherein ammonia used in step (i) is aqueous ammonia
11. A process as claimed in claim 10, lower alcohol is selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol and tert-butanol.
12.A process as claimed in claim 11, wherein lower alcohol is methanol or isopropanol
13. Erthromycin A (I) substantially free of Erythromycin B (II) prepared by the process as claimed in claim 1.
H.Eryhromycin A oxime (II) substaintally free of Erythromycin B oxime (iV) prepared by the process as claimed in claim 6.
15.A process for the preparation of Erythromycin A (I) such as herein described in accompanying text, description and examples.
16.A process for the preparation of Erythromycin A oxime (II) such as herein described in accompanying text, description and examples.

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ABSTRACT
Title: An improved process for the preparation of Erythroncyin A (I) and Erythromycin A oxime (II)
The present invention relates to the process for the preparation of Erythromycin A (I) substantially free of Erythromycin B (III) by treating Erythromycin thiocyanate with ammonia in halogenated solvent. Also, Erythromycin A oxime (II) is prepared.
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