Title of Invention

PROCESS FOR THE PREPARATION OF CEPHALOSPORIN ANTIBIOTIC

Abstract

Abstract The present invention more particularly relates to a process for the preparation of cephalosporin antibiotics of the formula (I) wherein R<sub>1</sub> represents hydrogen, trityl, CH3, CR<sub>a</sub> R<sub>b</sub> COOR<sub>c</sub> where R<sub>a</sub> and R<sub>b</sub> independently represent hydrogen or methyl and R<sub>c</sub> represents hydrogen or (Cp C<sub>6</sub> )alkyl; R<sub>3</sub> is carboxylate ion or COOR<sub>C</sub> , where R<sup>d</sup> represents hydrogen, which form a prodrug or a counter ion which forms a salt; R<sub>4</sub> represents hydrogen, CH3, CH2OCH3, CH2OCOCH3, CH=CH2,

Full Text

Field of the Invention The present invention relates a process for the preparation of beta-lactam antibiotics, which have wide range anti-bacterial activity. The present invention more particularly relates to a process for the preparation of cephalosporin antibiotics of the formula (I) wherein Ri represents hydrogen, trityl, CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Re represents hydrogen or (Cp C6)alkyl; R3 is carboxylate ion or COORd, where R represents hydrogen, which form a prodrug or a counter ion which forms a salt; R4 represents hydrogen, CH3, us patent 4,767,852 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 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 hemiheptahydrate by acylation of ACT by using MAEM as acylating agent in good yield and quality. 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, di-isopropyl 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. 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. However, none of the prior-art patents teach the use of THE as a solvent with triethylamine as base for condensation. 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 jdelds and the process is easy to handle in the large scale operations. 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 will be 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 Ri represents hydrogen, trityl, CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and R represents hydrogen or (Cp C6)alkyl; R3 is carboxylate ion or COOR'*, where R* represents hydrogen, which form a prodrug or a counter ion which forms a salt; R4 represents hydrogen, CH3, which comprises the steps of (i) condensing the compound of the formula (II) wherein R1 is as defined above with 7-amino cephem derivatives of the formula (III) wherein R5 is hydrogen or trimethylsilyl, R3 and R4 are as defined above using a base in the presence of THF/ water 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) separating the organic layer and aqueous layer, (iv) precipitating the product formed by the addition of a solvent, (v) filtering, washing, drying the precipitated product, (vi) isolating the compound of formula (I) and if desired (vii) converting the compound of formula (I) to its pharmaceutically acceptable esters, salts or solvates. 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 solvent added in step (ii) is selected from ethyl acetate, methylene dichloride, ethylene dichloride, toluene, xylene and the like or mixtures thereof. In another embodiment of the present invention the solvent used to precipitate the product in step (iv) is selected from di-isopropyl ether, iso-propyl alcohol, acetone, acetonitrile, ethyl acetate, dimethyl carbonate and the like or mixtures thereof In yet another embodiment of the present invention the counter ion represented by R1 is alkali metal, preferably sodium. 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-Aniinothiazol-4-yl)-2-methoxy imino]acetamido]-3- [[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-l,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-l,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 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-cephein-4-carboxylie 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 HCL was added to form ceftiofur hydrochloride, which was precipitated by addition of di-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). We claim: 1. A process for the preparation of cephalosporin antibiotics of the formula (I) wherein Ri represents hydrogen, trityl, CH3, CRaRbCOORc where Rg and Rb independently represent hydrogen or methyl and Re represents hydrogen or (Cr C6)alkyl; R3 is carboxylate ion or COORd, where Rd represents hydrogen, which form a prodrug or a counter ion which forms a salt; R4 represents hydrogen, CH3, CH2OCOCH3, CH=CH2, base in the presence of tetrahydrofuran (THF) and water 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) separating the organic layer and aqueous layer, (iv) precipitating the product formed by the addition of a solvent, (v) filtering, washing, drying the precipitated product, (vi) isolating the compound of formula (I) and if desired (vii) converting the compound of formula (I) to its pharmaceutically acceptable esters, salts or solvates. 2. The process according to claim 1, wherein the organic base used is selected from triethylamine, diethylamine, tributylamine, pyridine, N-alkylanilines, N-methylmorpholine or mixtures thereof. 3. The process according to claim 1, wherein the solvent added in step (ii) is selected from ethyl acetate, methylene dichloride, ethylene dichloride, toluene, xylene or mixtures thereof. 4. The process according to claim 1, wherein the solvent used to precipitate the product in step (iv) is selected from di-isopropyl ether, iso-propyl alcohol, acetone, acetonitrile, ethyl acetate, dimethyl carbonate or mixtures thereof. 5. The process according to claim 1, wherein the counter ion represented by R4 is alkali metal, preferably sodium. 6. The process according to claim 1, wherein the compound of formula (I) is a syn-isomer.

Documents:

0784-mas-2002 abstract duplicate.pdf

0784-mas-2002 abstract.pdf

0784-mas-2002 abstrcate duplicate.pdf

0784-mas-2002 claims duplicate.pdf

0784-mas-2002 claims.pdf

0784-mas-2002 correspondece-others.pdf

0784-mas-2002 correspondece-po.pdf

0784-mas-2002 correspondence-others.pdf

0784-mas-2002 correspondence-po.pdf

0784-mas-2002 description (complete) duplicate.pdf

0784-mas-2002 description (complete).pdf

0784-mas-2002 form-1.pdf

0784-mas-2002 form-13.pdf

0784-mas-2002 form-19.pdf

0784-mas-2002 form-5.pdf