Title of Invention

IMPROVED PROCESS FOR THE PREPARATION OF CEPHALOSPORIN ANTIBIOTICS

Abstract

The present invention more particularly relates to a process for the preparation of cephalosporin antibiotics of the formula (I) wherein R1 represents hydrogen, trityl, CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Re represents hydrogen or (C1-C6)alkyl; R2 is carboxylate ion or COORd, where Rd represents hydrogen or a counter ion which forms a salt; R3 represents hydrogen, CH3, CH2OCOCH3, CH=CH2,

Full Text

Field of the Invention The present invention relates to an improved process for the preparation of beta-lactam antibiotics, which have wide range of antibacterial activity. More particularly, the present invention relates to a process for the preparation of cephalosporin antibiotics of the formula (I) wherein R1 represents hydrogen, trityl, CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6) alkyl; R2 is sodium salt of carboxylate ion or hydrogen and R3 represents hydrogen, CH3, CH2OCOCH3, CH=CH2, OMe Background of the Invention Most of the prior art processes widely suggest the following scheme for the preparation of cephalosporin antibiotics of the formula (I), which comprises reacting a compound of the formula (II) with a compound of the formula (III). US patent Nos. 4,767,852 and 5,003,073 disclose a process for the production of cephalosporin derivatives by acylating 7-amino-3-cephem-4-carboxylic acid derivative 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 5,026,843 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 obtained is treated with a base selected from the group consisting of dicyclohexylamine, diphenylamine, diisopropylamine, N-tert-butylcyclohexylamine and N,N-dibenzylethylendiamine. This patent discloses the use of THF/water for the condensation. Moreover, the complexity in workups with THF/water condensation is solved i.e., adding another solvent like ethyl acetate, methylene chloride etc., for extraction and isolation of either the acid or its salts. 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 (DMF) and the base used is triethylamine. WO 00/68234 discloses a process for the preparation of cefpodoxime acid, comprising condensation of 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. US 5,527,906 describes a process for the preparation of Ceftriaxone disodium hemiheptahydrate involving condensation of 7-amino-3-{[(2,5-dihydro-2-methyl-6-hydroxy-5-oxo-as-triazin-3-yl )thio]methyl}-cephem-4-carboxylic acid derivative with MAEM using NaHC03 in aqueous acetone. Even though this patent motivates the direct isolation of sodium salt of cephalosporin after acylation or condensation reaction, this patent yields a product in which the sodium content in final product is not consistent, as it utilizes the inorganic base for condensation. US 5,574,155 describes a process for the preparation of Ceftriaxone disodium hemiheptahydrate by condensing 7-amino-3-{[(2,5-dihydro-6- hydroxy-2-methyl-5-oxo-l,2,4-triazin-3-yl)thio] methyl}-3-cephem-4- carboxylic acid (7-ACT) with MAEM using aqueous acetone in the presence of an organic base that does not contain sodium ions, according to this process workup is required before adding sodium ion source. Even though many prior art processes report methods for the preparation of compound of formula (I), each process has some limitation with respect to color, quality, yield or residual solvent content in the final API. Hence in view of the commercial importance of compound of formula (I) there remains a need for a better process. During the course of our research efforts to develop an easily scalable and commercially viable process for the preparation of cephalosporins, we have observed that the use of aqueous acetone gives high yields and the process is easy to handle in the large scale operations without use of organic base such as triethylamine, dicyclohexylamine, diphenylamine, diisopropylamine, N-tert-butylcyclohexylamine and N, N-dibenzylethylendiamine thereby reducing the reaction time and cost. Unexpectedly it was observed that, this condensation i.e acylation of 7-cephem moiety and salification could be achieved using single base in single solvent. This invention is ecofriendly, cost effective, high yielding and easy to scale up with very less unit operations. None of the prior art suggests the use of sodium 2-ethyl hexonate as a base during the course of acylation. 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 provide a process for the preparation of sodium salt cephalosporin antibiotics using single solvent and single base. Summary of the Invention Accordingly, the present invention provides a process for the preparation of cephalosporin antibiotics of the formula (I) wherein R1 represents hydrogen, trityl, CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6)alkyl; R2 is sodium salt of carboxylate ion R3 represents hydrogen, CH3, CH2OCOCH3, CH=CH2, OMe which comprises the steps of: (i) condensing the compound of the formula (II) wherein R1 is as defined above with 7-amino cephem derivative of the formula (III) wherein R2 and R3 are as defined above; using conjugate base of an organic acid in the presence of aqueous acetone at a temperature in the range of-50 °C to 60 °C to produce a compound of formula (I) where all symbols are as defined above, wherein the improvement consists of usage of conjugate base of an organic acid, and (ii) isolating the compound of formula (I) The process is shown in Scheme-1 Detailed Description of the Invention In an embodiment of the present invention the conjugate base of an organic acid is selected from sodium 2-ethylhexanoate, sodium lactate, sodium acetate, sodium citrate, sodium propionate or mixtures thereof. In another embodiment of the present invention condensation reaction is carried out in aqueous acetone. In still another embodiment of the present invention the compound of formula (I) is isolated from the reaction mass as sodium salt if required by the addition of excess acetone. Alternatively the pH of the reaction mass adjusted to lower side to isolate the compound of formula (I) as acid. In yet another embodiment of the present invention, the use of conjugate base of an organic acid like sodium 2-ethyl hexonate obviates the use of organic amine during condensation step and hence provides a process to isolate the sodium salt directly. One of the problems associated with acylation or condensation stage is degradation of final API and the degradation is directly associated with the basicity of the base used. The use of inorganic base like sodium carbonate or strong organic bases like sodium methoxide is not advisable, as they tend to degrade the final API. Because of the less basic nature of sodium 2-ethyl hexonate the degradation of the final API is minimized and it also provides direct isolation of sodium salt. Hence the process of the present invention is commercially more viable over the existing prior art processes. In yet another embodiment of the present invention the compound of formula (I) obtained is a syn-isomer. In still another embodiment of the present invention the staring material 7-amino cephem derivative of formula (III) is prepared by utilizing the technique known in the prior art. In one more embodiment of the present invention, the commercially valuable cephalosporin compounds of formula (I) that can be manufactured by the process of this invention includes Ceftriaxone, Cefotaxime, Cefditoren, Ceftizoxime and the like or its sodium salt or its hydrated form of sodium salt. If required the compound of formula (I) is converted into its pharmaceutically acceptable salt by utilizing the process known in prior art. The following examples are provided by way of illustration only and should not be limited to construe the scope of the invention. Example 1 Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[ (Z)-2-(4-methylthiazol-5-yl)ethenyl]- 8-oxo-5-thia-l-azabicyclo[4.2.0] oct-2-ene-2-carboxylate (Cefditoren sodium) To a mixture of water (250mL) and acetone (500 mL) 7-amino-3-[(Z)-2-(4- methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid (50 g) and 2- mercaptobenzothiazolyl (Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate (70.4 g) (MAEM) were added at 5-10°C. It was followed by addition of sodium 2-ethylhexanoate (77.0 g) in three lots and stirred till completion of reaction. After completion of reaction, further acetone was added (2.5L) and the precipitated solid was filtered and washed with acetone (500ml) and dried to give 60 g of Cefditoren sodium of 97-99 % purity. Advantages: 1. Using the process according to the invention, the desired sodium salt of Cephalosporin antibiotic is prepared directly, that is without having to isolate the free acid. 2. The product is isolated from the reaction mixture directly in highly pure form and high yield. 3. The present invention is eco-friendly and economical as product isolation is very simple. 4. Unit operation is less and hence advantageous from operational point of view in plant. 5. Degradation of final API is minimized. The cefditoren sodium thus obtained is converted to Cefditoren pivoxil as follows; Prepartion of Cefditoren Pivoxil To DMF (600 mL), Cefditoren Sodium (l00g) was added at toom temperature and stirred to get clear solution. To the clear solution, solid sodium bicarbonate (1.6g) was added. The reaction mass was cooled to -35 to -40°C and iodomethyl pivalate (45.83g) was added in one lot and stirred for 2 h. The reaction was quenched by pouring the reaction mixture into a mixture of ethyl acetate and water (1.2 L). Sodium thiosulphate and EDTA were added into this and mixture and the mixture was stirred followed by pH adjustement the with dilute HC1. The layers were seperated and the organic layer was washed with brine solution. The organic layer was charcolised and the carbon bed was washed with ethyl acetate. The ethyl acetate layer was poured into isopropyl ether. The solid obtained was stirred at 5°C, filtered, washed with IPE and finally dried to get the title compound. Purity (HPLC): 97-99% Yield 70-80 g. We claim; 1. A process for the preparation of cephalosporin antibiotics of the formula (I) wherein R1 represents hydrogen, trityl, CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (CrC6)alkyl; R2 is carboxylate ion or COOR^, where Rd represents a counter ion which forms a salt; R3 represents hydrogen, CH3, CH2OCOCH3, CH=CH2, 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 R2 and R3 are as defined above using a conjugate base of an organic acid in aqueous acetone to produce a compound of formula (I) where all symbols are as defined above, and (ii) isolating the precipitated compound of formula (I). 2. The process according to claim 1, wherein the conjugate base of an organic acid used is selected from sodium 2-ethylhexanoate, sodium lactate, sodium acetate, sodium citrate, sodium propionate or mixtures thereof. 3. A process for the preparation of Cefditoren sodium of formula which comprises the steps of: (i) condensing the compound of the formula (II) with 7-amino cephem derivative of the formula (IV) using sodium 2-ethyl hexanoate in aqueous acetone, and ii) isolating Cefditoren sodium in pure form. Dated this sixth (6th) day May 2006 for Orchid Chemicals & Pharmaceuticals Ltd.,

Documents:

0560-che-2005-abstract.pdf

0560-che-2005-claims.pdf

0560-che-2005-correspondnece-others.pdf

0560-che-2005-description(complete).pdf

0560-che-2005-description(provisional).pdf

0560-che-2005-form 1.pdf

0560-che-2005-form 5.pdf

560-CHE-2005 AMENDED CLAIMS 14-11-2011.pdf

560-CHE-2005 CORRESPONDENCE OTHERS 14-11-2011.pdf

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