PROCESS FOR THE PREPARATION OF CEPHALOSPORIN ANTIBIOTICS Field of the Invention The present invention relates a process for the preparation of beta-lactam antibiotics, which have wide range of anti-bacterial activity. More particularly, the present invention relates to a process for the preparation of cephalosporin antibiotics of the formula (I) wherein R, represents hydrogen, trityl, CH3, CRaRbCOORC where Ra and Rb independently represent hydrogen or methyl and R represents hydrogen or (C1- C6) alkyl; R2 is carboxylate ion or COORd, where Rd represents hydrogen, ester or a counter ion which forms a salt; R3 represents hydrogen, CH3, CH2OCOCH3, CH=CH2,

Background of the Invention 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 5,003, 073 discloses and claims the compound of formula (II) and its use in the preparation of different cephalosporin derivatives.

US patent 5,026, 843 discloses a process for preparing ceftriaxone disodium comprising reacting 7-amino-3-{[(2, 5-dihydro-6-hydroxy-2-methyl-5- oxo-1, 2,4-triazin-3-yl) thio] methyl}-3-cephem-4-carboxylic acid with 2- mercaptobenzothiazole 2- (2-aminothiazol-4-yl)-2-syn-methoxyiminoacetate in an aqueous solution in suitable solvents, in the presence of an amine and the obtained aqueous solution is treated with a base selected from the group consisting of dicyclohexylamine, diphenylamine, diisopropylamine, N-tert- butylcyclohexylamine and N, N-dibenzylethylendiamine.

US patent number 5,574, 154 discloses and claims 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.

US patent number 5,583, 216 describes a process for the manufacture of cephalosporin derivatives, which includes a number of cephalosporins of our interest such as cefotaxime, ceftriaxone, ceftazidime, as well as for ceftiofur. The process comprises the introduction of aminothiazole acetic acid derivative into the amine group of 7-ACA derivative. However, the patent does not specifically envisage the usage of MAEM for the condensation, since MAEM has not been reported before the filing of this patent.

WO 00/68234 discloses a process for the preparation of cefpodoxime acid, comprising condensing 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid with MAEM in the presence of an organic solvent and an organic base and optionally in the presence of water.

Thus MAEM has become the standard acylating agent for the preparation of cephalosporins having an oximino group and a 2-aminothiazolyl group in 7- position of cephem compounds.

US patent 5,026, 843 use of THF/water for the condensation in the presence of an amine and then treating the compound formed with a base selected from the group consisting of dicyclohexylamine, diphenylamine, diisopropylamine, N-tert-butylcyclohexylamine and N, N- dibenzylethylenediamine.

We have during the course of our research efforts to develop an easily scalable and commercially viable process for the preparation of cephalosporins observed that the use of THF gives high yields and the process is easy to handle in the large scale operations without use of additional base such as dicyclohexylamine, diphenylamine, diisopropylamine, N-tert- butylcyclohexylamine and N, N-dibenzylethylendiamine thereby reducing the reaction time and cost.

Objectives of the Invention The primary objective of the invention is to provide a process for the preparation of cephalosporin antibiotics of the general formula (I), which is simple, high yielding and cost effective.

Still another objective of the present invention is to produce cephalosporin antibiotics that are highly pure and free from toxic byproducts.

Summary of the Invention Accordingly, the present invention provides a process for the preparation of cephalosporin antibiotics of the formula (I) wherein R, represents hydrogen, trityl, CH3, CRRBCOOR, where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (Cl- C6) alkyl; R2 is carboxylate ion or COORd, where Rd represents hydrogen, ester or a counter ion which forms a salt; R3 represents hydrogen, CH3, CH20COCH3, CH=CH2,

which comprises the steps of (i) condensing the compound of the formula (II) wherein Ri is as defined above with 7-amino cephem derivative of the formula (III) wherein R4 is hydrogen or trimethylsilyl, R2 and R3 are as defined above using a base in the presence of THF/water and optionally an other solvent at a temperature in the range of-50 °C to 20 °C to produce a compound of formula (I) where all symbols are as defined above, (ii) adding a solvent to the reaction mixture after completion of the reaction, (iii) isolating the compound of formula (I) and if desired (iv) converting the compound of formula (I) to its pharmaceutically acceptable esters, salts or solvates.

The process is shown in Scheme-1

Scheme-1 Detailed Description of the Invention In another embodiment of the present invention the organic base is selected from triethylamine, diethylamine, tributylamine, pyridine, N- alkylanilines, N-methylmorpholine or mixtures thereof.

In another embodiment of the present invention the organic solvent used in step (i) is selected from dimethyl acetamide, DMF, N-methyl pyrrolidine, ethyl acetate, methylene dichloride, ethylene dichloride, acetone, toluene, xylene and the like or mixtures thereof.

In another embodiment of the present invention the solvent added in step (ii) is selected from ethyl acetate, methylene dichloride, ethylene dichloride, acetone, benzene, toluene, xylene and the like or mixtures thereof.

In yet another embodiment of the present invention the counter ion represented by Rd is alkali metal, preferably sodium.

In yet another embodiment of the present invention the ester represented by Rd is selected from lower alkyl, p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group or prodrug esters such as proxetil, axetil, hexetil, pivoxil and the like.

In still another embodiment of the present invention the compound of formula (I) obtained is a syn-isomer.

The following examples are provided by way of illustration only and should not be limited to construe the scope of the invention.

Example-1 Preparation of 7- [ [ (Z)-2- (2-Aminothiazol-4-yl)-2-methoxy iminolacetamido]- 3-[[(2, 5-dihydro-6-hydroxy-2-methyl-5-oxo-1, 2, 4-triazin-3-yl) thio] methyl]-3- cephem-4-carboxylic acid Disodium salt (Ceftriaxone Sodium): 7-Amino-3-[[(2, 5-dihydro-6-hydroxy-2-methyl-5-oxo-1, 2,4-triazin- 3yl) thio] methyl] 3-cephem-4-carboxylic acid (60 gm) and 2-mercapto- benzothiazolyl- (Z)-2- (2-aminothiazol-4-yl)-2-methoxyimino acetate (73 gm) (MAEM) were taken in water/THF mixture and cooled to 0 °C. Triethylamine was added to the mixture and stirred at 0 to 5 °C. After completion of the reaction, ethyl acetate was added to the reaction mixture. The aqueous and organic layers were separated and sodium 2-ethyl hexanoate was added to the aqueous layer. The product was precipitated by the addition of acetone. The product formed was filtered, washed and dried to give the crude product. The crude product was dissolved in acetone/water mixture at low temperature (-15 °C) and the product was precipitated back by raising the temperature the temperature to room temperature. The product was precipitated by the addition of acetone. The resultant product was filtered, washed and dried to yield the pure product (88 g).

Example-2 Preparation of 7- [ [ (Z)-2- (Aminothiazol-4-yl)-2-methoxyimino] acetamido]-3- (furanylcarbonyl) thiomethy]-3-cephem-4-carboxylic acid hydrochloride (Ceftiofur HCl) : 7-Amino-3- [ (2-furanylcarbonyl) thiomethy] -3-cephem-4-carboxylic acid (120 gm) and 2-mercapto-benzothiazolyl- (Z)-2- (2-aminothiazol-4-yl)-2-methoxyimino acetate (140 gm) (MAEM) were taken in water/THF mixture and cooled to 5 to 10 °C. Triethylamine was added to the mixture and stirred at 0 to 5 °C till the completion of the reaction. After completion of the reaction, ethyl acetate was added to the reaction mixture. The aqueous layer was saturated with sodium chloride and THF was added to it. The aqueous and organic layers were separated and to the THF layer concentrated HC1 was added to form ceftiofur hydrochloride, which was precipitated by addition of isopropyl ether. The product formed was filtered, washed and dried to give the product (170 g).

Example-3 Preparation of 3-Acetyloxymethyl-7- [ (Z)- (2-aminothiazolyl-4-yl) =2- (methoxyimino) acetamido]-3-cephem-4-carboxylic acid (Cefotaxime acid) : 7-Amino cephalosporanic acid (100 gm) and 2-mercapto-benzothiazolyl- (Z)-2- (2- aminothiazol-4-yl) -2-methoxyimino acetate (138 gm) (MAEM) were taken in a mixture of water/THF. Triethylamine (52 ml) was added to the mixture and stirred at 6 to 8 °C for 12 hrs. Ethyl acetate was added to the reaction mass to extract out THF. The aqueous and organic layers were separated and the aqueous layer having the product was treated with activated carbon. Carbon was filtered off and to the filtrate, ethyl acetate was added followed by dilute hydrochloric acid to adjust the pH to 2.5 at 10 to 15 °C. The product formed was filtered and washed with water followed by isopropyl alcohol to give the product (165 g).

Example-4 Preparation of (6R,7R)-7-[2-(2-Aminothiazol-4-yl)-2(Z)- (methoxyimino)acetamido]-3-(1-methylpyrrolidinomethyl)-3-cep hem-4- carboxylate (Cefepime sulfate) 7-Amino-3- [ ( 1-methyl-1-pyrrolidinio) methyl] ceph-3-em-4-carboxylate hydroiodic salt (90 gm) was treated with 2-mercaptobenzothiazolyl- (Z)-2- (2- aminothiazol-4-yl) -2-methoxyimino acetate (MAEM) (82 gm) and triethylamine (22.3 gm) in a mixture of THF (630 ml), water (630 ml) and dimethyl acetamide (DMAc) (108 ml). After completion of the reaction, THF was removed form the reaction mass by ethyl acetate extraction. The aqueous layer was acidified to pH 1.2 with sulfuric acid. Acetone was added to salt out the product completely. The product was filtered, washed with acetone and dried under vacuum to get the cefepime suflate (yield: 110 gm, purity > 98%).