Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF CEPHALOSPORIN PRODRUG
Abstract	The present invention relates to an process for the preparation of cefditoren pivioxil of the formula

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Field of the Invention The present invention relates to an improved process for the preparation of cephalosporin prodrug. The present invention particularly relates to an improved process for the preparation of Cefditoren pivoxil of the formula (I). Background of the Invention Cefditoren has a low toxicity to mammals but exhibits a very much broad antibacterial spectrum against positive-bacteria and gram-negative bacteria. A pivaloyloxy methyl ester of Cefditoren, in which the 4-carboxyl group has been esterified with the pivaloyloxymethyl group for the purpose of enhancing the absorbability of the cephem compound via the digestive tubes upon the oral administration thereof, is such a pro-drug which is known by a generic name Cefditoren pivoxil. Cefditoren and Cefditoren pivoxil are known to be a highly excellent therapeutic agent, which have extensively been utilized for the therapeutic treatments and preventive treatments of bacterial infections caused, by a variety of gram-positive bacteria and gram-negative bacteria. Cefditoren pivoxil is, by itself, antibacterially inactive but is useful as a pro-drug, which is administrable orally and can be converted into the antibacterially active Cefditoren in the digestive tubes of mammals, by cleaving the ester-forming pivaloyloxymethyl group there from. US patent number 4,839,350 discloses a process for the preparation of Cefditoren pivoxil in which the last step involves deprotection of trityl group using TFA/Anisole (Example 2). Because of that the TFA content in final product is high and needs further purification. The patent also discloses a process for the preparation of pivoxil ester from sodium salt. US patent number 4,918,068 discloses a process for the preparation of Cefditoren pivoxil. The process comprises reacting the compound of formula (II) wherein M represents sodium salt, potassium salt, calcium salt, TEA salt, DCHA salt with compound of formula (III) R2—X (III) wherein R2 denotes ester forming group and X denotes a leaving group such as halogen, arylsulfonyloxy, lower alkanesulfonyloxy group. This patent discloses a process wherein Cefditoren sodium in DMF was reacted with iodomethyl pivalate in the presence of sodium carbonate and isolating product using ethyl acetate and IPE. The conventional processes reported has some disadvantages such as impurity/residual solvent content is high in final product and requires purification to get final product. Considering the foregoing limitations, we undertook an investigation in our lab to identify a process, which yields a product with high quality and with less number of impurities. This would permit commercializing the production of highly pure Cefditoren pivoxil without any further purifications, which in turn reduces the consumption of the solvents for purification, which directly has effect on the total cost of the process and is environmental friendly. Objectives of the Invention The main objective of the present invention is to provide an improved commercially viable process for the preparation of Cefditoren pivoxil of the formula (I), which would be easy to implement in manufacturing scale. Another objective of the present invention is to provide an improved commercially viable process for the preparation of Cefditoren pivoxil of the formula (I), which has reduced percentages of impurities and residual solvent in the final product. Another objective of the present invention is to provide an improved commercially viable process for the preparation of Cefditoren pivoxil of the formula (I), without any purification steps, thereby reducing the solvent usage. Another objective is to provide an improved commercially viable process for the preparation of Cefditoren pivoxil of the formula (I), which avoids the use of chromatography for purification. Summary of the Invention Accordingly, the present invention provides an improved process for the preparation of Cefditoren pivoxil of the formula (I) the said process comprising the steps of: i) reacting Cefditoren acid or its sodium salt of the formula (IV) with 1-halomethyl pivalate of the formula (V) where X represents halogen atom such as chlorine, bromine or iodine using a base such as linear or cyclic guanidine, amidine, bicyclic nitrogen containing heterocyclic bases, aromatic heterocyclic bases, aniline bases in the presence of a solvent at a temperature in the range of-40 °C to 50 °C to produce Cefditoren pivoxil of the formula (I) and ii) isolating the pure Cefditoren pivoxil of the formula (I). The reaction is shown in scheme-I below : Detailed description of the invention In another embodiment of the present invention, the solvent used in step (i) is selected from THF, dichloromethane, acetone, toluene, butan-2-one, acetonitrile, DMAc, DMF, N-methyl pyrolidine, DMSO or a mixture thereof. In still another embodiment of the present invention, the base used in step (i) such as tetramethylguanidine, tetraethyl guanidine, 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), l,8-diazabicyclo(5,4,0)undec-7-ene (DBU), di-isopropylethyl amine, I,4-diazabicyclo[2.2.2]octane (DABCO), l,5,7-triazabicyclo-(4,4,0)-dec-5-ene, N,N-dimethyl aniline, pyridine. In yet another embodiment of the present invention, the compound of formula (I) obtained is a syn isomer. In yet another embodiment of the present invention, the compound of formula (I) obtained is a cis isomer. The foregoing technique has been found to be markedly attractive, both from commercial point of view, as well as from manufacturing viewpoint, and affords good quality of cefditoren pivoxil of the formula (I) for the following reasons: The use of the bases mentioned above for the reaction yields a product with reduced percentage of A^ isomer. Less number of solvents is used for the purification of the crude product. Impurity content/Residual solvent minimized. Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure. The present invention is illustrated with the following examples, which should not be construed as limiting to the scope of the invention. Example 1 Preparation of (6R,7R)-7-[2-ammo-4-thiazoIyI[(methoxyimino)acetyl]amino]-3-[2-(4-methyI-5-thiazolyl)vinyl-3-cephem-4-carboxylic acid (2,2-dimethyM-oxopropoxy) methyl ester. (Cefditoren pivoxil) Di-isopropyl ethylamine (2.3 g) was added to a mixture of (6R,7R)-7-[2-amino-4-thiazolyl[(methoxyimino)acetyl]amino]-3-[2-(4-methyl-5-thiazolyl)vinyl-3-cephem-4-carboxylic acid (Cefditoren acid, 10 g) and tetrabutyl ammonium hydrogen sulfate (1 g) in DMF (50 ml) at - 20 °C. To the reaction mixture 1 - iodomethyl pivalate (4.4 g, 100 % purity basis) was added. After completion of reaction, the reaction mixture was added into a mixture of 0.5 % sodium thio sulphate solution and ethyl acetate. The pH adjusted to 7.0 by using dil HCl. Layers were separated and organic layer pH adjusted to 7.0 by using dil HCl. Layers were separated and organic layer concentrated. To residue IPE was added stirred, the solid obtained was filtered dried under vacuum to give titled compound (yield 7 g) Example 2 Preparation of (6R,7R)-7-[2-amino-4-thiazoIyl[(methoxyimino)acetyl]amino]-3-[2-(4-methy^5-thiazolyI)viny^3-cephem-4-carboxylic acid (2,2-dimethyl-l-oxopropoxy) methyl ester. (Cefditoren pivoxil) DBU (2.7 g) was added to a mixture of (6R,7R)-7-[2-amino-4-thiazolyl[(methoxyimino)acetyl]amino]-3-[2-(4-methyl-5-thiazolyl)vinyl-3-cephem-4-carboxylic acid (Cefditoren acid, 10 g) and tetrabutyl ammonium hydrogen sulfate (1 g) in DMF (50 ml) at - 20 °C. To the reaction mixture 1 - iodomethyl pivalate (4.4 g, 100 % purity basis) was added. After completion of reaction, the reaction mixture was added into a mixture of 0.5 % sodium thio sulphate solution and ethyl acetate. The pH adjusted to 7.0 by using dil HCl. Layers were separated and organic layer concentrated. To residue IPE was added stirred, the solid obtained was filtered dried under vacuum to give titled compound (yield 8.8 g) Example 3 Preparation of (6R,7R)-7-[2-amino-4-thiazolyl[(methoxyimino)acetyl] amino]-3-[2-(4-methyI-5-thiazoIyl)vinyl-3-cephem-4-carboxylic acid (2,2-dimethyH-oxopropoxy) methyl ester. (Cefditoren pivoxil) DCHA (3.2 g) was added to a mixture of (6R,7R)-7-[2-amino-4-thiazolyl[(methoxyimino)acetyl]amino]-3"[2-(4-methyl-5-thiazolyl)vinyl-3-cephem-4-carboxylic acid (Cefditoren acid, 10 g) and tetrabutyl ammonium hydrogen sulfate (1 g) in DMF (50 ml) at - 20 °C. To the reaction mixture 1 - iodomethyl pivalate (4.4 g, 100 % purity basis) was added. After completion of reaction, the reaction mixture was added into a mixture of 0.5 % sodium thio sulphate solution and ethyl acetate. The pH adjusted to 7.0 by using dil HCl. Layers were separated and organic layer concentrated. To residue IPE was added stirred, the solid obtained was filtered dried under vacuum to give titled compound (yield 9,0 g) We Claim: 1) A process for the preparation of Cefditoren Pivoxil, which comprising the steps of i) reacting Cefditoren acid or its sodium salt of the formula (IV) where X represents halogen atom such as chlorine, bromine or iodine using a base such as linear or cyclic guanidine, amidine, bicyclic nitrogen containing heterocyclic bases, aromatic heterocyclic bases, aniline bases in the presence of a solvent at a temperature in the range of-40 °C to 50 °C to produce Cefditoren pivoxil of the formula (I) and ii) isolating the pure Cefditoren pivoxil of the formula (I). 2) The process as claimed in claim 1, wherein solvent used in step (i) is selected from THF, dichloromethane, acetone, toluene, butan-2-one, acetonitrile, DMAc, DMF, N-methyl pyrolidine, DMSO or a mixture thereof 3) The process as claimed in claim 1, the base used in step (i) selected from tetramethylguanidine, tetraethyl guanidine, l,5-diazabicyclo(4.3.0)non-5-ene (DBN), l,8-diazabicyclo(5,4,0)undec-7-ene (DBU), di-isopropylethyl amine, l,4-diazabicyclo[2.2.2]octane (DABCO), l,5,7-triazabicyclo-(4,4,0)-dec-5-ene, N,N-dimethyl aniline, or pyridine.

Documents:

514-che-2003-abstract.pdf

514-che-2003-claims.pdf

514-che-2003-correspondnece-others.pdf

514-che-2003-correspondnece-po.pdf

514-che-2003-description(complete).pdf

514-che-2003-description(provisional).pdf

514-che-2003-form 1.pdf

514-che-2003-form 13.pdf

514-che-2003-form 5.pdf

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