FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
and
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10 and rule 13]
1. Title: A process for the preparation of (Z)-(6R, 7R)-3-
(acetoxymethyl)-7-[2-(2-ainino-l-thiazol-4-yl)-2-niethoxyiminoacetamido]-8-oxo-5-
thia-l-azabicyclo [4,2,0]oct-2-en-2-carboxylie acid.
2. Applicant: Claris Lifesciences Limited,
Claris Corporate Headquarters, Nr. Parimal Crossing, Ellisbridge, Ahmedabad - 380 006, India.
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 process for the production of 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (Cefotaxime Acid). The synthesis of Cefotaxime Acid includes the reaction of 2-mercaptobenzothiazoIyl-(Z)-2-(2- aminothiazol-4-yl)-2-methoxyimino acetate with 7-amino-3-acetoxy methyl-3-cephem-4-carboxy\ic acid (7-ACA) in a mixture of organic base and water, and treatment of the reaction mass with the solvent to remove the impurities and byproducts from the product.
BACKGROUND OF THE INVENTION
Antibiotics of cephalosporin series are widely used in therapy for the treatment of diseases, which are caused by general pathogenic bacteria in human beings and animals. It is known that such antibiotics are useful for the treatment of diseases caused by bacteria-exhibiting resistance to other antibiotics, e.g., penicillin-resistant bacteria; and also for the treatment of penicilin-sensitive patients.
Cefotaxime is a third-generation cephalosporin antibiotics, it has broad-spectrum activity against both Gram-positive and Gram-negative organism. The bactericidal activity of Cefotaxime works by inhibiting bacterial cell wall biosynthesis. Cefotaxime shows high affinity for penicillin-binding proteins (PBP) in the cell wall including PBP lb and PBP III. A positive feature of Cefotaxime is that it displays a resistance to penicillinases (is it penicillinase or penicillinases??)and is useful to treat infections that are resistant to penicillin derivatives. Cefotaxime has in vitro activity against a wide range of Gram-positive and Gram-negative organisms. Cefotaxime should be administered by both Intravenous as well as Intramuscular route.
DESCRIPTION OF THE PRIOR ART
It is also well known that the activity of a cephalosporin compound may be varied by changing the substituents on the 3- and/or 7-position of the cephem ring. In this regard, there

have been many studies made in developing a variety of cephalosporin antibiotics with broad spectra of antibiotic activities by introducing a 7-p acylamido group and various substituents on the 3-position of the cephem ring.
Cephalosporin antibiotics inhibit bacteria by interfering with the synthesis of essential structural components of the bacterial cell wall. They are considered as highly effective antibiotics with low toxicity and can be used for treatment of a wide variety of bacterial infections. A number of cephalosporin derivatives have been discovered with increased potency and improved stability.
US 4,098,888 discloses cephem compounds and processes for their preparation. US 4,152,432 disclose cephalosporanic acid derivatives, in particular cefotaxime, and process for preparing the derivatives.
US 4,767,852 discloses a process for the preparation of known 2-oxyiminoacetamido-3-cephem-4-carboxylic acid derivatives, including cefotaxime, by acylating 7-amino-3-cephem-4-carboxylic acid derivatives already substituted at the 3-position with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-rnethoxyiminoacetate, the latter being often referred to as MAEM.
US 5,026,843 disclose a process for preparing ceftriaxone disodium salt hemi-heptahydrate. As the first step in the process disclosed in that patent, 7-amino-3- {(2,5- dihydro- 6-hydroxy-2-methyl-5-oxo-l,2,4-triazin-3- yl) thiomethyl}-3-cephem-4-carboxylic acid (7-ACT) already suitably substituted at the 3-position is acylated at the 7-position using 2-mercaptobenzothiazolyl-(Z)-2-(2- aminothiazol-4-yl)-2-methoxyimino acetate (MAEM) as the acylating agent. 2-mercaptobenzotbiazoIyI-(Z)-2-(2- aminothiazol-4-yl)-2-methoxyimino acetate (MAEM) has become the standard acylating agent for the preparation of cephalosporins having an oximino group and a 2-aminothiazoIyl group in the 7-acylamido side chain. Byproduct of this reaction is the toxic compound, viz., 2-mercaptobenzothiazole.

US 4,767,852 and US 5,003,073 disclose a process for the production of cephalosporin derivatives by acylating 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA) derivative with 2-mercaptobenzothiazolyl-(Z)-2-(2- aminothiazoI-4-yl)-2-methoxyimino acetate (MAEM), using solvents such as chlorinated hydrocarbons, ethers or esters such as ethyl acetate or in a mixture of such solvent with water.
US 5,574,154 discloses and claims a process for the preparation of the different cephalosporin derivatives by the condensation of 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate (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, isopropanol, dioxane, isopropyl ether, N-methyl pyrrol idone and dimethyl formamide (DMF) and the base used is triethylamine,
WO 200068234 discloses a process for the preparation of Cefotaxime acid, comprising condensation of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA) with 2-mercaptobenzothiazolyl-(Z)-2-(2- aminothiazol-4-yl)-2-methoxyimino acetate (MAEM) in the presence of an organic solvent and an organic base and optionally in the presence of water.
IN 784/MAS/2002, discloses a process in which condensation was carried out in tetrahydrofuran and water, followed by addition of ethyl acetate to the removal of byproducts. Though this process affords good quality product, it is associated with problems like solvent recovery.
US 5831086 discloses a process for preparing Cefotaxime acid by reacting with 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA) with 2-mercaptobenzothiazolyl-(Z)-2-
(2- aminothiazol-4-yl)-2-methoxyimino acetate (MAEM) in a solvent mixture of Acetone and Water in the presence of base.

US 5567813 describes a process for the production of cephalosporins, in particular Cefotaxime, in which diethylthiophosphoryl-(Z)-(2-aminothiazol-4-yl)rnethoyimino acetate is coupled with 7-aminocephalosporanic acid derivative in specific solvents lile Dichloromethane, Dichloro ethane, Chloroform, Carbon tetrachloride, Toluene, Xylene, Acetonitrile, Ethyl acetate, Dioxane, Tetrahydrofuran, Acetone, N,N-dimethyl formamide, N,N-dimethyl acetamide, alcohols in presence of Organic base, a tertiary amine such as Triethyl amine, tri-n-butyl amine, diisopropyl ethylamine, pyridine, N,N-dimetyl aniline, etc. can be used.
Many prior art report methods for the preparation of Cefotaxime acid, each process has some limitation with respect to color, quality, yield or residual solvent content in the final product. Hence in view of the commercial importance of Cefotaxime acid there remains a need for a better process.
OBJECTIVE OF THE INVENTION
Objective of the present invention is to provide a process for the preparation Cefotaxime acid, in which the by-products are minimized during the process, which yield highly pure product, through simple industrially viable technique.
Another objectives of the invention are to provide a process for the preparation of cephalosporin antibiotics Cefotaxime Acid, which is simple, high yielding and cost effective.
During the course of research efforts to develop an easily scalable and commercially viable process for the preparation of Cefotaxime acid, it has been observed that the use of aqueous solvents like tetrahydrofuran in the presence of organic base gives high yields and the process is easy to handle in the large scale operations. Unexpectedly it was observed that, this condensation i.e acylation of 7-cephem moiety and Isolation could be achieved using single base. This invention is ecofriendly, cost effective, high yielding and easy to scale up with very less unit operations. The uses of triethylamine as a base during the course of condensation and the technique of isolating the final Product by the addition of para-toluene sulphonic acid monohydrate gives high yield final Product. In this invention, 2-

mercaptobenzothiazole is by-product on condensation of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA) and 2-mercaptobenzotbiazolyI-(Z)-2-(2- aminothiazol-4-yl)-2-methoxyimino acetate (MAEM). This by-product is removed from the reaction mixture by the treatment of solvent. After the condensation is complete the solvent with the by-product (2-mercaptobenzothiazole) is extracted from the reaction mixture.
Summery of the invention :
The invention relates to a process of manufacturing a compound of (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-l,3-thiazol-4-yl)-2-metlioxyiminoacetamido]-8-oxo-5-thia -l-azabicyclo[4>2,0]oct-2-en-2-carboxylic acid the said method comprising:
a) Contacting of a compound of the 7-Amino-3-cephem-4-carboxylic acid (7-ACA), suspended in a mixture of organic solvent and water in presence of organic base, with a compound of the S- (2-benzothiazolyl-2-(2-aminothiazol-4-yl)-2-methoxyimino thioacetate (MAEM);
b) Extraction of the aqueous layer;
c) Charcoalisation of aqueous layer for the removal of colour and impurity;
d) Isolation of (Z)-(6R,7R)-3-Acetoxy-methyl)-7-(2-aminothiazole-4-yl)-2-methoxyimino)acetoamido)-8-oxo-5-thia-1-aza-bicyclo (4,2,0)oct-2-en-2-carboxylic acid in presence of suitable organic acids.
In step (a), of the process any polar or non polar solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, N,N-dimethyl foramide, N,N-dimethyI acetamide, alcohols such as methanol, ethanol, isopropyl alcohol, water or a mixture of two or more solvents selected thereof.
Preferably said organic solvent is tetrahydrofuran, acetone and water.
In step (a), of the process organic base are triethyl amine, 2,3-picoline, 2,4-picoline, 1,4-
dimethyl piperazine, N-ethylpiperidine, N-methyl morpholine, trimethyl aniline, pyridine,

dimethyl amino pyridine, N-methyJ piperidine, N-methyl pyridine, N-ethyl dimethyJ aniline, diethyl amine, N-ethyldimethyl amine, diisopropyl ethyl amine, N,N-dimethyl aniline and tributyl amine.
Preferably, the organic base is triethyl amine.
The contact time for step (a), is about 15 min. to about 60 min., with stirring and maintaining
temperature about 0°C to 30°C.
In step (a), of the process compound other than MAEM are 2-mercapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyirnino acetate or 2-mercapto-5-phenyl-l,3,4-oxadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate can be used.
In step (b), of the process extraction other than Dichloro methane is Ethylene dichloride or halogenated solvent cab be used.
In step (c), of the process ,charcolisation is carried out at 20°C to 35°C. In step (d), of the process suitable organic acids are para-toluene sulphonic acid monohydrate, methane sulfonic acid, benzene sulfonic acid and hydrochloric acid. In step (d), of the process the reaction mixture is stirred for over night at ambient temperature and than cooled at about 10°C to about 20°C and stirred for about 1 to 5 hours to get wet cake. In the process unreacted 7-Amino-3-cephetn-4-carboxylic acid is not more than 2% by HPLC.
Detail description of the invention :
A process for the preparation of (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-lJ3-thiazol-4-yl)-2-methoxyiminoacetamido]-8-oxo-5-thia-1 -azabicyclo [4,2,0]oct-2-cn-2-carboxylic acid carried out as follows.
Condensation of 7-amino-3-acetoxymethyI-3-cephem-4-carboxylic acid (7-ACA) with 2-mercaptobenzothiazoIyl-(Z)-2-(2- aminothiazol-4-yl)-2-methoxyimino acetate (MAEM) in presence of water and water miscible organic solvent. Wherein the improvement consists of the usage of acetone and tetrahydrofuran,

1) It was found during the course of the research that by-product 1-mercaprobenzothiazole is easily soluble in the solvent like acetone and tetrahydrofuran. Adding of the acetone and tetrahydrofuran to the step (1), by-product will dissolve in the solvents.
2) After completion of reaction, the solvent (acetone and tetrahydrofuran) with the by product is extracted with methylene dichloride. After the extraction fresh acetone is added to the reaction mass.
3) Cefotaxime acid is isolated from Aqueous laer with para-toluenesulphonic acid monohydrate.
4) After the complete crystallization, filter and wash the material with acetone and dry the material.
The present embodiment of the process comprises, Condensation of 7-Amino-3-
acetoxymethyI-3-cephem-4-carboxylic acid (7-ACA) with 2-mercaptobenzothiazolyl-(Z)-2-
(2- aminothiazol-4-yI)-2-methoxyimino acetate (MAEM) in presences of water,
tetrahydrofuran, acetone and organic base. 7-ACA (7-Amino-3-acetoxymethyl-3-cephem-4-
carboxylic acid) suspended in a mixture of water, acetone and tetrahydrofuran, and than
cooled the reaction mass at low temperature. Add organic base drop wise with constant
stirring and than stir the reaction mass for about 1 hour at ambient temperature. The organic
base are triethylamine, 2,3-picoline, 2,4 -picoline, 1,4-dimethyl piperazine, N-
ethylpiperidine, N-methyl morpholine, tri methyl aniline, pyridine, dimethyl amino pyridine,
N-methyl piperidine, N-methyl pyridine, N-ethyl dimethyl aniline, diethyl amine, N-
ethyldimethyl amine, diisopropyl ethyl amine, N,N-dimethyl aniline and tributyl amine. Add
2-mercaptobenzothiazolyl-(Z)-2-(2- aminothiazol-4-yl)-2-methoxyimirio acetate (MAEM)
portion wise with constant stirring within. Compound other than 2-mercaptobenzothiazolyl-
(Z)-2-(2- aminothiazol-4-yl)-2-methoxyimino acetate (MAEM) that can react with 7-ACA
(7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid) to manufacture Cefotaxime acid are
2-mercapto-5-methyl-l,3,4-thiadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate
or 2-mercapto-5-phenyl-1,3,4-oxadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino
acetate can be used. Monitor the reaction by high performance liquid chromatography

(HPLC) till 7-AC A is less than 2 %. After completion of the reaction the mixture of acetoae, tetrahydrofuran and by-product is extracted with methylene dichloride. Collect the aqueous layer and add acetone to the aqueous solution. Cefotaxime acid is isolated with suitable organic acids. Add organic acid portion wise to the reaction mass at ambient temperature with constant stirring. Stir the reaction mass over night at ambient temperature and than cool the reaction mass, stir for 3 hour to 5 hour at same temperature for complete isolation of product. Organic acids used for the isolation of Cefotaxime are para-toluene sulphonic acid monohydrate, methane sulfonic acid, benzene sulfonic acid and hydrochloric acid. After complete isolation, filter the product by vacuum filtration. Wash the cake with sufficient amount of acetone. After washing collect the wet cake and dry it at about 40 °C to 50°C under vacuum up to moisture content less than equal to 2 %.
In embodiment of the present invention the compound Cefotaxime acid is isolated from the reaction mass by the addition of para-toluene sulphonic acid monohydrate. During the process of acetone and tetrahydrofuran addition, the by-product 2-mercaptobenzothiazole (MBT) is dissolved in acetone and tetrahydrofuran. Accordingly the present invention provides a simple technique of recovering the 2-mercaptobenzothiazole (MBT). Recovering 2-mercaptobenzothiazole (MBT) from the reaction mass by extracting acetone and tetrahydrofuran from the reaction mass with methylene dichloride. Surprisingly the compound thus isolated does not contain any detectable limit of 2-mercaptobenzothiazole (MBT), whereas the literature processes yields the compound Cefotaxime acid that contains the said 2-mercaptobenzothiazole (MBT) as an impurity. Owing to the toxic nature of 2-mercaptobenzothiazole (MBT), the presence of 2-mercaptobenzothiazole (MBT) in the final product (Cefotaxime acid) is not advisable in terms of pharmacopoeial requirement. Since the present invention obviates the problem associated with prior art process, it is economically and industrially viable.
Advantages:
l.The product is isolated from the reaction mixture directly in highly pure form and high yield.

2.The present invention is eco-friendly and economical as product isolation is very
simple.
3.Unit operation is Jess and hence advantageous from operational point of view in
plant.
Example: 1
10 gm 7-AC A are suspended in 31.6 ml Acetone, 3.66 ml water and 10 ml THF. Chilled it up to 0°C to 5°C. Add 5.86 ml Triethylamine dropwise with constant stirring. Stirr for 30 min. at 0°C to 5°C. Add 13.0 gm MAEM portion wise with constant stirring within 5-10 min. Stirr for 5 hours at this temperature (Check online HPLC). Add 40 ml Dichloromethane and separate the layer. Take aq. Layer and add 20 ml acetone and shake well. Take aq. Layer in to RBF and add 0.1 gm sodium hydrosulphite, 0.1 gm EDTA and 1 gm charcoal. Stirr for 30 min and degassing. Filter the solution through filter paper and 0.45 micron filter paper. Collect filtrate in to RBF. Add 8.396 gm p-toluenesulphonic acid monohydrate portion wise with constant stirring. Stirrforl0 min. Add pitch qty. of Cefotaxime acid for seeding and stirr for 2 hours at 0°C-5°C. Stirr at RT for overnight. Stirr at 10°C to 15°C for 4 hours. Filter and wash the material with 90 ml Acetone. Suck dry and dry at 45°C under Vacuum for 10 hours.
Example: 2
25 gm 7-ACA are suspended in 112.5 ml Acetone, 12.5 ml water and 30 ml THF. Chilled it up to 0°C to 5°C. Add 12.67 ml N-Methyl morpholine dropwise with constant stirring. Stirr for 30 min. at 0°C to 5°C. Add 40.21 gm MAEM portion wise with constant stirring within 5-10 min. Stirr for 5 hours at this temperature (Check online HPLC). Add 100 ml Dichloromethane and separate the layer. Take aq. Layer and add 50 ml acetone and shake well. Take aq. Layer in to RBF and add 0.25 gm sodium hydrosulphite, 0.25 gm EDTA and 2.5 gm charcoal. Stirr for 3G min and degassing. Fitter the solution through niter paper and 0.45 micron filter paper. Collect filtrate in to RBF. Add 24.47 gm p-toluenesulphonic acid monohydrate portion wise with constant stirring. Stirrforl0 min. Add pitch qty. of Cefotaxime acid for seeding and stirr for 2 hours at 0°C-5°C. Stirr at RT for overnight. Stirr at I0°C to 15°C for 4 hours. Filter and wash the material with Acetone. Suck dry and dry at 45°C under Vacuum for 10 hours.

Example: 3
10 gm 7-AC A are suspended in 45 ml Acetone, 5 ml water and 12 ml THF. Chilled it up to 0°C to 5°C. Add 6.40 ml Triethylamine dropwise with constant stirring. Stirr for 30 min. at 0°C to 5°C. Add 16.08 gm MAEM portion wise with constant stirring within 5-10 min. Stirr for 5 hours at this temperature (Check online HPLC). Add 40 ml Dichloromethane and separate the layer. Take aq. Layer and add 20 ml acetone and shake well. Take aq. Layer in to RBF and add 0.1 gm sodium hydrosulphite, 0.1 gm EDTA and 1 gm charcoal. Stirr for 30 min and degassing. Filter the solution through filter paper and 0.45 micron filter paper. Collect filtrate in to RBF. Add 8.14 gm benzene sulphonic acid portion wise with constant stirring. Stirrforl0 min. Add pitch qty. of Cefotaxime acid for seeding and stirr for 2 hours at 0°C-5°C. Stirr at RT for overnight. Stirr at 10°C to 15°C for 4 hours. Filter and wash the material with 90 ml Acetone. Suck dry and dry at 45°C under Vacuum for 10 hours.
Example: 4
25 gm 7-ACA are suspended in 112.5 ml Acetone, 12.5 ml water and 30 ml THF. Chilled it up to 0°C to 5°C. Add 16 ml Triethylamine dropwise with constant stirring. Stirr for 30 min. at 0°C to 5°C. Add 40.21 gm MAEM portion wise with constant stirring within 5-10 min. Stirr for 5 hours at this temperature (Check online HPLC). Add 100 ml Dichloromethane and separate the layer. Take aq. Layer and add 50 ml acetone and shake well. Take aq. Layer in to RBF and add 0.25 gm sodium hydrosulphite, 0.25 gm EDTA and 2.5 gm charcoal. Stirr for 30 min and degassing. Filter the solution through filter paper and 0.45 micron filter paper. Collect filtrate in to RBF. Add 12.36 gm methanesulphonic acid portion wise with constant stirring. Stirrforl0 min. Add pitch qty. of Cefotaxime acid for seeding and stirr for 2 hours at 0°C-5°C. Stirr at RT for overnight. Stirr at 10°C to 15°C for 4 hours. Filter and wash the material with 225 ml Acetone. Suck dry and dry at 45°C under Vacuum for 10 hours
Example: 5
50 gm 7-ACA are suspended in 225 ml Acetone, 25 ml water and 60 ml THF. Chilled it up to 0°C to 5°C. Add 32 ml Triethylamine dropwise with constant stirring. Stirr for 30 min. at

0°C to 5°C. Add 80.42 gm MAEM portion wise with constant stirring within 5-10 min. Stirr for 5 hours at this temperature (Check online HPLC). Add 200 ml Dichloromethane and separate the layer. Take aq. Layer and add 100 ml acetone and shake well. Take aq. Layer in to RBF and add 0.5 gm sodium hydrosulphite, 0.5 gm EDTA and 5 gm charcoal. Stirr for 30 min and degassing. Filter the solution through filter paper and 0.45 micron filter paper. Collect filtrate in to RBF. Add 24.72 gm methanesulphonic acid portion wise with constant stirring. Stirrforl0 min. Add pitch qty. of Cefotaxime acid for seeding and stirr for 2 hours at 0°C-5°C. Stirr at RT for overnight. Stirr at 10°C to 15°C for 4 hours. Filter and wash the material with 450 ml Acetone. Suck dry and dry at 45°C under Vacuum for 10 hours

We claim,
1. A process of manufacturing a compound of (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetamido]-8-oxo-5-thia-1 -azabicyclo-[4,2,0]oct-2-en-2-carboxylic acid the said method comprising:
a) contacting of a compound of the 7-Amino-3-cephem-4-carboxyIic acid (7-
ACA), suspended in a mixture of organic solvent and water in presence of organic
base, with a compound of the S- (2-benzothiazolyl-2-(2- aminothiazol-4-yl)-2-
methoxyimino thioacetate (MAEM);
b) extraction of the aqueous layer;
c) charcoalisation of aqueous layer for the removal of colour and impurity; d)isolation of (Z)-(6R,7R)-3-Acetoxy-methyl)-7-(2-aminothiazoIe-4-yI)-2-methoxyimino)acetoamido}-8-oxo- 5-thia-l -aza-bicycto (4,2,0)oct-2-en-2-carboxylic acid in presence of suitable organic acids.
2. The process of claim 1 wherein step (a), wherein the organic solvents are selected
from any polar or non polar solvents such as dichloromethane, dichloroethane,
chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, dioxane,
tetrahydrofuran, N,N-dimethyl foramide, N,N-dimethyl acetamide, alcohols such as
methanol, ethanol, isopropyl alcohol, water or a mixture of two or more solvents
selected thereof.
3. The process of claim 1, wherein the said organic solvent is selected from
tetrahydrofuran, acetone and water.
4. The process of claim 1, wherein step (a), the said organic base are selected from
triethyl amine, 2,3-picoline, 2,4-picoline, l,4-dimethyl piperazine, N-ethylpiperidine,
N-methyl morpholine, trimethyl aniline, pyridine, dimethyl amino pyridine, N-methyl

piperidine, N-methyl pyridine, N-ethyl dimethyl aniline, 'diethyl amine, N-ethyldimethyl amine, diisopropyl ethyl amine, N,N-dimethyl aniline and tributyl amine.
5. The process of claim 1, wherein the organic base is triethyl amine.
6. The process of claim 1, wherein the contact time for step (a), is about 15 min. to about 60 min., with stirring and maintaining temperature about 0°C to 30°C.
7. The process of claim 1, wherein step (a), compound other than MAEM are 2-mercapto-5-methyl-l,3,4-thiadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate or 2-mercapto-5-phenyl-1,3,4-oxadiazolyl-(Z)-2-(2-aminothiazol-4-yl)- 2-methoxyimino acetate can be used.
8. The process of claim 1 wherein step (b), extraction other than Dichloro methane is Ethylene dichloride or halogenated solvent cab be used.
9. The process of claim 1 wherein step (c), charcolisation is carried out at 20°C to 35°C.
10. The process of claim 1, wherein step (d), suitable organic acids are para-toluene
sulphonic acid monohydrate, methane sulfonic acid, benzene sulfonic acid and
hydrochloric acid.
11. The process of claim 1, wherein step (d), the reaction mixture is stirred for over night at ambient temperature and than cooled at about 10°C to about 20°C and stirred for about 1 to 5 hours to get wet cake.

12. The process of claim 1, where in unreacted 7-Amino-3-cephem-4-carboxylic acid is not more than 2% by HPLC.