FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION (See section 10; rule 13)
1. TITLE OF THE INVENTION -
PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE ERYTHROMYCIN
2. APPLICANT(S)
(a) NAME: MEHTA API PVT. LTD.
(b) NATIONALITY: An Indian Company
(c) ADDRESS: 203, Centre Point, J B Nagar, Andheri (East),
Mumbai 400059
3. PREAMBLE TO THE DESCRITION
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 preparation of substantially
pure Erythromycin of formula (I).
More particularly, the present invention is directed to an improved process for
preparing substantially pure erythromycin wherein crude erythromycin is converted
into acid addition salt followed by breaking of said acid addition salt to give
substantially pure erythromycin,
More specifically the present invention relates to an improved process for
preparation of substantially pure erythromycin having single maximum unknown
impurity not more than 0.2%.
The present invention also relates to process for preparation of pharmaceutical
derivatives of erythromycin by using substantially pure erythromycin obtained by
present invention.
BACKGROUND OF THE 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 penicillin.
As erythromycin derivatives, clarithomycin and azithromycin have exhibited remarkable improvement on stability in acid solutions and metabolism dynamics, lot of researches have been done on new derivatives with features of combating drug resistance. Therefore availability of high-purity erythromycin, as the raw material, is fundamental to produce its pharmaceutical derivatives.
Conventionally known techniques for purifying erythromycin from culture solutions include an extraction technique based on the nature of erythromycin A which is more . soluble in an organic solvent at an alkaline pH and in water at an acidic pH, an ion-exchange technique, a technique using reverse phase adsorbents, and a technique using liquid-liquid extraction between a potassium sulfate-containing buffer and an organic solvent (Soviet Patent No. 306,669). Other purification techniques are also known, for example, a technique using recrystallization from an appropriate organic solvent and a technique in which erythromycin is dissolved in an appropriate organic solvent and then precipitated by addition of water ("Antibiotics" edited by Yusuke Sumiki, University of Tokyo Press, pages 366, 593, 926, 1056 and elsewhere, 1961). US6767998 discloses process for purifying erythromycin employing liquid-liquid

extraction. US8436154 discloses process for purifying erythromycin by crystallizing erythromycin from dichloromethane under alkaline conditions. WO2014140699 discloses process for preparing erythromycin from erythromycin thiocynate using water as solvent in presence of base. Purity
However, no technique reported in prior-art is known to be capable of purifying erythromycin so as to obtain substantially pure erythromycin with single maximum unknown impurity below 0.2%
All the referenced patents and applications are incorporated herein by reference in their entirety. Furthermore, where a definition or use of a term in a reference, which is incorporated by reference herein, is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
SUMMARY OF THE INVENTION
The present invention is directed towards improved processes for the preparation of substantially pure erythromycin of formula - (I), which overcomes the disadvantages of the formerly known methods.
According to one aspect of the invention, there is provided a process for preparation of substantially pure erythromycin characterized in converting crude erythromycin into acid addition salt and further breaking the said acid addition salt followed by isolating substantially pure erythromycin from suitable solvent or mixture of solvents thereof.
According to another aspect of the invention, there is provided a process for preparation of pharmaceutical derivatives of erythromycin by using substantially pure erythromycin as prepared according to present invention.
The present invention provides an efficient process for preparation of erythromycin in significantly higher purity as compared to prior-art making the process cost-effective.
DETAILED DESCRIPTION OF THE INVENTION:
In accordance with the present invention to provide a process for the preparation of substantially pure erythromycin of formula - (I) the synthetic steps comprises:
a) converting crude erythromycin into acid addition salt by reacting with suitable acid in suitable solvent.
b) breaking the said acid addition salt in presence of suitable base
c) after breaking said acid addition salt isolating substantially pure erythromycin from a solvent or a mixture of solvents thereof
None of the Prior-art methods employing preparation of erythromycin have reported purity having single maximum impurity below 0.20%.

The present invention is further elaborated below:
In accordance with one aspect of the present invention there is provided a process
for the preparation of substantially pure erythromycin which comprises of:
a) converting crude erythromycin into acid addition salt by reacting with suitable acid in suitable solvent.
Suitable acid used for salt formation is selected from a group of acids comprising of stearic acid, phosphoric acid, hydrochloric acid, sulfuric acid, acetic acid, propionic acid/lauric acid, oleic acid, tartaric acid, citric acid, benzoic acid, phthalic acid, salicylic acid, lactic acid, and the like. The suitable acid is preferably stearic acid or phosphoric acid.
The reaction may be carried out at temperatures ranging from about but not limiting to -10°C to 50°C, preferably at 20°C to40°C and more preferably at 50 to 60°C.
Suitable solvent used for salt formation is selected from a group of solvents comprising of Ketonic solvents Hke acetone, methylethyl ketone, methyl isobutyl ketone, hydrocarbons like toluene, cyclohexane, xylene; halogenated solvents such as dichloromethane, dichloroethane, chloroform ; alcohols; esters such as ethyl acetate, isobutyl acetate; ethers such as Tetrahydrofuran, Diethylether, tert-butyl methyl ether and/ or mixtures thereof in various proportions. The suitable solvent is preferably Acetone.
The reaction time and the temperature should be suitable to bring the salt formation to completion, without the production of unwanted side products.
After the completion of salt formation, the said acid addition salt is isolated using conventional techniques like precipitation by anti-solvent, crystallization or distillation.
Preferably isolation is carried out by precipitation of salt employing use of an anti-solvent, more preferably isolation is carried out by employing use of water as an anti-solvent.
b) breaking the said acid addition salt using a suitable base in suitable solvent
Suitable base is selected from a group comprising of organic bases like ammonia, triethylamine, triisopropylamine, tripropylamine, tributylamine, triisobutylamine, 2-dimethylaminononane, ethyldiinethylamine, benzyldiethylamine, ethylpiperidine, butylpiperidine, l-ethyl-methylpiperidine, butyl-2-methylpiperidine, methylpyrrolidine, l-propylpyrrolidine, 4-ethylmorpholine, 4-isobutylmorpholine, l,4-dimethylpiperazine, 1,4-diethylpiperazine and the like or inorganic bases like Sodium hydroxide, Potassium hydroxide, Lithium Hydroxide, Sodium carbonate, potassium carbonate, sodium bicarbonate and the like. The suitable base is preferably ammonia.
Suitable solvent used for salt formation is selected from a group of solvents comprising of Ketonic solvents like acetone, methylethyl ketone, methyl isobutyl ketone, halogenated solvents such as dichloromethane, dichloroethane, chloroform; hydrocarbons like toluene, cyclohexane, xylene; alcohols like methanol, ethanol,

propanol, isopropanol; esters such as ethyl acetate, isobutyl acetate; ethers such as Tetrahydrofuran, Diethylether, tert-butyl methyl ether, apotic solvents like dimethyl sulfoxide, dimethylfromamide and/ or mixtures thereof in various proportions. The suitable solvent is preferably dichloromethane.
The reaction may be carried out at temperatures ranging from about but not limiting to -10°C to 50°C, preferably at 20°C to 40°C and more preferably at 30°C to 35°C.
After the salt breaking is complete the reaction mass may be optionally filtered to separate the precipitated solids followed by water washing of the reaction mass which is proceeded further as such for isolation of pure erythromycin.
c) after breaking the said acid addition salt isolating substantially pure erythromycin from suitable solvent or mixture of solvents thereof by crystallization, precipitation or distillation.
Suitable solvent used for salt formation is selected from a group of solvents comprising of Ketonic solvents like acetone, methylethyl ketone, methyl isobutyl ketone, halogenated solvents Such as dichloromethane, dichloroethane, chloroform; hydrocarbons like toluene, cyQiohexane, xylene; alcohols like methanol, ethanol, propanol, isopropanol; esters such as ethyl acetate, isobutyl acetate; ethers such as Tetrahydrofuran, Diethylether, tert-butyl methyl ether, apotic solvents like dimethyl sulfoxide, dimethylfromamide and/ or mixtures thereof in various proportions. The suitable solvent is preferably dichloromethane.
The isolation is preferably carried out by crystallization.
The crystallization may be carried out at temperatures ranging from about but not
limiting to -10°C to 50°C, preferably at -10°C to 10°C and more preferably at 0°C to
5°C.
The isolated erythromycin is further washed with suitable solvent to give substantially
pure erythromycin.
Solvent used for washing is preferably dichloromethane.
In accordance with another aspect of the invention, there is. provided a process for preparation of pharmaceutical cierivatives of erythromycin by using substantially pure erythromycin as prepared according to present invention by employing processes known to a person skilled in the art.
EXAMPLES
The following examples are used to illustrate the invention, but are not intended to limit the invention in any way.
I). Preparation of crude erythromycin using thiocynate salt.
To (500 ml) ethyl acetate in a 4Neck Round Bottom flask, charge (100gms) erythromycin thiocynate. Charge 20% aqueous solution of NaOH to the reaction mass iffl aJkaXme pH foitewed by )ayer separation. Water-wash the organic fayer and distill under vacuum below 65°Q to give crude erythromycin.

II). Preparation of erythromycin stearate using crude erythromycin.
Charge (200 ml) acetone to the concentrate as obtained in example I) followed by addition of (40 gms) stearic acid at 50-55°C to get a clear solution followed by gradual addition of (400 ml) water to the reaction mass. Cool the reaction mass at 0-5°C and stirr for 60 mins. Filter the reaction mass to give erythromycin stearate
III). Preparation of erythromycin phosphate using crude erythromycin.
Charge (200 ml) Dichloromethane to the concentrate as obtained in example I) followed by addition of phosphoric acid at 10-15°C till pH of reaction-mass is acidic. Cool the reaction mass at 0-5°C and stirr for 60 mins. Filter the reaction mass to give crude erythromycin phosphate
IV). Preparation of pure erythromycin from erythromycin stearate
To (500 ml) dichloromethane in a 4Neck Round Bottom flask, charge (100gms) erythromycin stearate to get a clear solution at 30-35°C. Charge aqueous Ammonia to the reaction mass till pH ~10-12. Filter-off the precipitated solids. Treat the filtrate with aqueos ammonia till the pH ~10-12. Filter-off the precipitated inorganics. Water-wash the filtrate thrice and cool the reaction mass at 0-5°C. Stirr for 1 hr and filter to give pure erythromycin.
V). Preparation of pure erythromycin from erythromycin phophate.
To (500 ml) water in a 4Neck Round Bottom flask, charge (100gms) erythromycin phosphate to get a clear solution at 30-35°C. Charge aqueous Ammonia to the reaction mass till pH ~10-12. Charge (500 ml) dichloromethane to the reaction mass and stirr for 5 min. Separate the layer and water wash organic layer thrice. Cool the organic layer at 0-5°C. Stirr for 1 hr and filter to give pure erythromycin.

CLAIMS:
We Claim,
1) A process for preparation of substantially pure erythromycin of formula (I)
comprising:
a) converting crude erythromycin into acid addition salt by reacting with suitable acid in suitable solvent
b) breaking the said acid addition salt using a suitable base in suitable solvent
c) after breaking the said acid addition salt isolating substantially pure erythromycin from suitable solvent or mixture of solvents thereof by crystallization, precipitation or distillation.

2) The process as claimed in claim 1), wherein suitable acid is stearic acid or phosphoric acid.
3) The process as claimed in claim 1), wherein suitable base is Sodium hydroxide or ammonia.
4) The process as claimed in claim 1), wherein suitable solvent is acetone or dichloromethane
5) The process as claimed in claim 1), wherein step a) is carried out at a temperature comprised between 50°C to 60°C.
6) The process as claimed in claim 1), wherein step b) is carried out at a temperature comprised between 30°C to 35°C.
7) The process as claimed in claim 1), wherein isolation according to step c) is carried out by crystallization.
8) The process as claimed in claim 9), wherein crystallization is carried out at a temperature comprised between 0°C to 5°C.
9) A process for preparing pharmaceutical derivatives of erythromycin by using substantially pure erythromycin as prepared according to claim 1.
10)The process as claimed in claim 11), wherein pharmaceutical derivatives of erythromycin comprises of clarithromycin, azithromycin or acid addition salts thereof.