COMPLETE AFTER PROVISIONAL LEFT ON
10 NOV 2006
FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - IMPROVED PROCESS FOR THE
PREPARATION OF CEFEPIME

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 invention:
The present invention relates to an improved process for the preparation of
Cefepime of formula (I) or its pharmaceutical^ acceptable salt.

Background of the invention and prior art:
Cephalosporin antibiotics are used widely for the treatment of bacterial infections. Cefepime of formula (I) belongs to fourth generation of Cephalosporin due to its intrinsic antimicrobial properties. It possesses extended spectrum of activity for gram negative and gram positive organisms in comparison to other generations of Cephalosporins. Also it has minimal beta-lactamase activity due to rapid periplasmic penetration and high penicillin-binding protein (PBP) access.
Cefepime of formula (I) was first disclosed in US Patent No. 4,406,899. US Patent No. 4,754,031 discloses a process for its preparation.
US patent Nos. 4,767,852 and 5,003,073 discloses a process for the production of cephalosporin derivatives by acylating 7-amino-3-cephem-4- carboxylic acid with 2-mercaptobenzothiazolyl- (Z)-2- (2-aminothiazol-4-yl)-2- methoxyimino acetate of the formula (II) (MAEM), using solvents such as chlorinated hydrocarbon, or ethers such as ethyl acetate or in a mixture of such solvent with water. US patent No. 5,003,073 discloses and claims the compound of formula (II) and its use in the preparation of different cephalosporin derivatives.

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US patent No. 5,574,154 discloses a process for the preparation of the different cephalosporin derivatives by the condensation of MAEM with different cephem moieties in the presence of a solvent and a base. The solvent used for the condensation is selected from acetone, acetonitrile, carbon tetrachloride, methylene chloride, toluene, methanol, ethanol, iso- propanol, dioxane, iso-propyl ether, N-methyl pyrrolidone and dimethyl formamide and the base used is triethylamine.
In Tetrahedron Letters 31, 6481 (1990), Walker, D. G., reports the use of certain
thioesters, including 2-mercapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2)-
tritylaminothiazol-4-yl)- 2-methoxyiminoacetate and 2-mercapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate, as acylating agents in the synthesis of cefepime sulfate.
However there is a need to develop a process for the preparation of Cefepime or its pharmaceutically acceptable salt, which is simple and easy to handle on commercial scale.
Object of the invention:
It is an object of the present invention to provide an improved process for the preparation of Cefepime of formula (I) or its pharmaceutically acceptable salt, which is simple, high yielding and cost-effective.
Yet another object of the present invention is to provide an improved process for preparation of Cefepime of formula (I) or its pharmaceutically acceptable salt
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comprising a step of, reacting 2-mercaptobenzothiazolyl- (Z)-2- (2-aminothiazol-4-yl)-2- methoxyimino acetate of the formula (II) (MAEM)

with compound of formula (III),

wherein X is HI, HCI or H2S04
Summary of the invention:
Accordingly, the present invention provides a process for the preparation of Cefepime of formula (I) or its pharmaceutical^ acceptable salt comprising a step of, reacting compound of formula (II) with compound of formula (III) in presence of a base and dimethylformamide, optionally in presence of water.
Detailed description of the invention:
The inventors of the present invention has surprisingly found that the reaction of 2-mercaptobenzothiazolyl- (Z)-2- (2-aminothiazol-4-yl)-2- methoxyimino acetate of formula (II) with compound of formula (III), wherein X is HI, HCI or H2S04 is conveniently carried out in presence of a base and dimethylformamide, optionally in presence of water to give Cefepime or its pharmaceutically acceptable salt.

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The base is selected from organic or inorganic base selected from group comprising of triethylamine, diethylamine, tributylamine, pyridine, N-alkylaniline, N-methylmorpholine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or mixtures thereof.
The reaction is carried out at temperature of about 0°C to about reflux temperature of the reaction mixture. After the reaction is complete Cefepime can be converted to the desired salt and can be isolated by regular work-up procedures.
According to preferred embodiment, hydrochloride salt of compound of formula (II) is reacted with MAEM of formula (II) in presence of mixture of dimethylformamide-water and triethylamine as a base. The reaction is carried out at temperature in range of 0°C to 20°C. After the completion of the reaction hydrochloric acid is added to the reaction mixture to obtain Cefepime hydrochloride salt. The impurities are extracted in dichloromethane and the product is crystallized by adding acetone to the aqueous layer.
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: Preparation of Cefepime hydrochloride salt
To 25 g of (6R,7R)-7-amino-3-[(1-methyl-1-pyrrolidino)methyl] ceph-3-em-4-carboxylate hydrochloride salt is added chilled mixture of DMF-water (166 ml + 83.5 ml) and stirred at about 0-5°C. Slowly mixture of triethylamine and DMF (10 ml + 25
5

ml) is added to the reaction mixture in about 30-45 min. at about 0-5°C. Further 26. 5 g of MAEM is added and the reaction mixture is warmed to about 159C. After completion of the reaction, the reaction mass is cooled to about 10°C and 25 ml (1:1) HCI is added to it. Then the reaction mass is extracted twice with dichloromethane and aqueous layer is separated, charcoalized and filtered. The product is precipitated out by addition of Acetone. The reaction mass is cooled, filtered and dried to obtain title compound.
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 Cefepime of formula (I)

H,N

Formula (I)

COO

or its pharmaceutically acceptable salt comprising a step of, reacting compound of formula (II)

with compound of formula (III)
X. H2 N s

coo Formula (III)
wherein X represents HI, HCI or H2S04
in the presence of a base and dimethylformamide, optionally in presence of
water.
2. A process as claimed in claim 1, wherein said base is selected from the group comprising organic or inorganic base.
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3. A process as claimed in claim 2, wherein said organic base is selected from group comprising triethylamine, diethylamine, tributylamine, pyridine, N-alkylaniline, N-methylmorpholine or mixture thereof.
4. A process as claimed in claim 2, wherein said inorganic base is selected from group comprising sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or mixtures thereof.
Dated this 8th day of November 2006
DR. SANCHITA GANGULI
Of S. Majumdar & Co.
Applicants' Agent
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ABSTRACT

IMPROVED PROCESS FOR THE PREPARATION OF CEFEPIME
The present invention relates to provide a process for the preparation of Cefepime of formula (I)

or its pharmaceutically acceptable salt comprising a step of, reacting compound of formula (II)

with compound of formula (III)

in the presence of a base and dimethylformamide, optionally in presence of water.
1 0 NOV 2006