Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF CEFIXIME

Abstract

The present invention provides an improved process for the preparation of cefixime of formula (I). The said process comprising the steps of: (i) dissolving the methyl ester compound of formula (II) in water/ethyl acetate using sodium bicarbonate at a temperature in the range of 10°C to 35°C, (Ii) hydrolysing this solution with sodium hydroxide at a temperature in the range of O°C to 25°C and (iii) acidifying the resultant mass to pH 2.3 to 3.0 with dil acid in the presence or absence of solvent at a temperature in the range of 10°C to 45°C, to isolate the cefixime of formula (I).

Full Text

Field of the invention The present invention relates to a process for the preparation of an orally active cephalosporin antibiotic. The present invention more particularly relates to an improved process for the preparation of cefixime of the formula (I). Description of the prior art Cefixime is an orally active third-generation cephalosporin antibiotic and is more potent against gram-negative bacteria. Preparation of the compound of formula (I) involves condensation of 7-amino-3-vinyl-3-cephem-4-carboxylic acid with the derivative of (Z)-2-amino-a-( 1 -methoxycarbonylmethoxyimino)-4-thiazole acetic acid to produce methyl ester compound of formula (II), followed by hydrolysis produce the title compound. GB 2 330 140 discloses a process for the preparation of the compound of formula (I) which comprises treating the compound of formula (II) with Na2C03 in DMF and water, which has the following problems: (i) color of product was poor, (ii) fails in residual solvent i.e. DMF, (iii) poor quality of product. GB 2 330 141 discloses a process for the preparation of the compound of formula (I) which comprises treating the compound of formula (II) in an organic solvent with aqueous solution of Na2CO3 and phase transfer catalyst, the bi-phasic reaction has the following problems: (i) color of product was poor, (ii) poor quality and yield of product. In US patent 4,409,214 and WO 95/33753 discloses the process for the preparation of cefixime in which the hydrolysis step involves the use of hazardous trifluoroacetic acid and anisole. In WO 99/52913 the hydrolysis step along with deblocking the amino protective group and carboxylate protective group involves the use of phenol and protonic acid. The steps described in the above patents are more complicated and also suffer from low yield and poor quality. J.Antibiotics (1985), 38, 1738 discloses various processes for the preparation of cefixime of formula (I). The processes involve the use of column for purification thereby suffers in poor yield. Column purification cannot be used in large-scale operations, there by making the process non-commercial. We have now found an improved process for the preparation of the compound of formula (I), which process has advantages over the processes described in the above-mentioned prior art documents. Objectives of the invention The main objective of the present invention is to provide a process for the preparation of cefixime formula (I), which have better quality such as color and solubility. Another objective of the present invention is to provide a process for the preparation of compounds of formula (I), which avoid use of hazardous chemicals like TFA and also easy to implement on commercial scales. Still another objective of the present invention is to provide a process for the preparation of compounds of formula (I) in good yield and high purity. Summary of the invention: Accordingly, the present invention provides an improved process for the preparation of Cefixime of formula (I), which comprises the steps of: (i) dissolving the methyl ester compound of formula (II) in water/ethyl acetate using sodium bicarbonate at a temperature in the range of 0°C to 35°C, (ii) hydrolysing this solution with sodium hydroxide at a temperature in the range ofO°C to 25°C and (iii) acidifying the resultant mass to pH 2.3 to 3.0 with dil acid in the presence or absence of solvent at a temperature in the range of 10°C to 45 °C, to isolate the cefixime of formula (I). Detailed description of the invention In an embodiment of the present invention the compound of formula (II) may be dissolved in water/ethyl acetate using sodium bicarbonate solution at a temperature in the range 0°C to 35°C, more particularly from 24°C to 26°C, In yet another embodiment of the present invention the above said reaction mass may be treated with sodium hydroxide solution at a temperature in the range of 0°C to 25°C, more particularly from 0°C to 1°C in aqueous medium, In still another embodiment of the present invention the product may be isolated by adjusting pH to 2.3 to 3.0? by using dil HO, H2S04 and orthophosphoric acid, more particularly to pH 2.5±0.05 in the presence or absence of solvent such as acetone, and the like, at a temperature in the range of 10°C to 45°C more particularly from 36°C to 38°C to produce cefixime of formula (I) in pure form. In another embodiment of the present invention, the compound of formula (I) obtained is in trihydrate form. In yet another embodiment of the present invention, the compound of formula (I) obtained is syn isomer. The present invention is exemplified by the following example, which is provided for illustration only and should not be construed to limit the scope of the invention. Example: Preparation of [6R-[6a,7P(Z)]-7-[2-amino-4-thiazolyl[(carboxymethoxy) imino] acetyl] amino] -3-vinyl-3-cephem-4-carboxyIic acid. To, [6R-[6a,7P(Z)]]-7-[[(2-amino-4-thiazolyl)[(methoxycarbonylmethoxy) imino]acetyl]amino]-3-vinyl-3-cephem-4-carboxylic acid compound of formula (II) (100 gm) in distilled water (1000 ml) and ethyl acetate (500 ml), sodiumbicarbonate (19 gm) was slowly added at 24 - 26 °C till clear solution formation. The solution was cooled to 0 - 1°C and 15 % Sodium hydroxide solution (180 ml) was added. The resultant solution was stirred at 6 - 8°C till the completion of reaction. pH of reaction mass was adjusted to 4.8 - 5.0 with 19% aqueous HC1 acid solution. The Aqueous layer was separated and subjected to carbon treatment. To the clean filtrate, mixture of water (580 ml) and acetone (670 ml) was added. The pH of solution was adjusted to 2.45 to 2.55 with 8-10% dil. HC1 acid at 34 - 36°C. The reaction mass was slowly cooled to 1 - 3°C and stirred for 120 minutes. The product obtained was filtered and washed the wet product with water (1000 ml) and dried under vacuum to get the title compound in pure form (97.5 gm). We Claim 1. An improved process for the preparation of Cefixime of formula (I) the said process comprising the steps of: (i) dissolving the compound of formula (II) in water/ethyl acetate using sodium bicarbonate at a temperature in the range ofO°C to the35°C, (ii) treating this solution with sodium hydroxide at a temperature in the range of 0°C to25°C, (iii) acidifying the resultant mass to pH 2.3 to 3.0 with dil HC1 in the presence of solvent at a temperature in the range of 10°C to 45 °C, to isolate the compound of formula (I). 2. The process as claimed in claim 1, wherein the reaction temperature for step (i) is 24°C to the 26°C 3. The process as claimed in claim 15 wherein the reaction temperature for step(ii)isO°C to l°C. 4. The process as claimed in claim 1, wherein the pH for isolation is 2.5±0.05. 5. The process as claimed in claim 1, wherein the solvent used for isolation is acetone. 6. The process as claimed in claim 1, wherein cefixime of formula (I) is in trihydrate form. 7. The process as claimed in claim 1, wherein cefixime of formula (I) obtained is a syn isomer.

Documents:

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785-mas-2002 - claims.pdf

785-mas-2002 - correspondence others.pdf

785-mas-2002 - correspondence po.pdf

785-mas-2002 - description complete.pdf

785-mas-2002 - form 1.pdf

785-mas-2002 - form 13.pdf

785-mas-2002 - form 3.pdf

785-mas-2002 - form 5.pdf

785-mas-2002 - pct.pdf