Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF CEFOTAXIME SODIUM

Abstract

An improved process for the preparation of the sterile cefotaxime sodium of formula (I), comprising the steps of: i). dissolving the compound of formula (II) in a mixture of polar solvent/less polar solvent at a temperature in the range of - 20 °C to 50 °C in the presence of base, ii). charco Ii sing the solution followed by micron filtration, iii). treating the solution with sodium salt of aliphatic carboxylic acid in ethyl acetate at a temperature in the range of 10°C to 50 °C, iv). precipitating the product by adding organic solvent and v). isolating the precipitated cefotaxime sodium of formula (I), in pure form.

Full Text

Field of the invention The present invention relates to a process for the preparation of active cephalosporin antibiotic derivative. The present invention more particularly relates to an improved process for the preparation of sterile cefotaxime sodium of formula (I). Description of the prior art Cefotaxime is a broad spectrum third generation cephalosporin antibiotic and having activity against wide range of gram-positive and gram-negative microorganisms. Cefotaxime sodium is physiologically acceptable non-toxic salt of cefotaxime and may be administered to human. The preparation involves the condensation of 7-ACA with MAEM to yield cefotaxime, followed by converting the cefotaxime into its sodium salt. In US patent 4,152,432 discloses the process for the preparation of cefotaxime sodium of formula (I), which involves treating the cefotaxime acid in aqueous solvent such as methanol, ethanol or acetone in the presence of base and sodium ions to give cefotaxime sodium. US patent 5,831,086 describes the process for the preparation of sodium cefotaxime. The process described in this patent involves the usage acetone/water. Both processes described in the above patents give cefotaxime sodium with poor color and quality. Objectives of the invention The main objective of the present invention is to provide a process for the preparation of sterile cefotaxime sodium of formula (I), which has better quality such as color and solubility. Another objective of the present invention is to provide direct manufacturing process for the preparation of crystalline sterile cefotaxime sodium of formula (I), from cefotaxime acid. Still another objective of the present invention is to provide a process for the preparation of cefotaxime sodium of formula (I), in good yield, high purity and with desirable particle size. The advantage of using the less polar solvent such as ethyl acetate in this process is to get stable cefotaxime sodium of formula (I), higher production yield and lesser amount of unwanted by-products. Summary of the invention: Accordingly, the present invention provides an improved process for the preparation of sterile cefotaxime sodium of formula (I), which comprises the steps of: i). dissolving the compound of formula (II) in a mixture of polar solvent/less polar solvent at a temperature in the range of - 20 °C to 50 °C in the presence of base, ii). charcolising the solution followed by micron filtration, iii). treating the solution with sodium salt of aliphatic carboxylic acid in ethyl acetate at a temperature in the range of 10 °C to 50 °C, iv). precipitating the product by adding organic solvent and v). isolating the precipitated cefotaxime sodium of formula (I), in pure form. Detailed description of the invention In another embodiment of the present invention the polar solvent used in step (i) is selected from methanol, ethanol, or acetone. In another embodiment of the present invention the less polar solvent used in step (i) is selected from ethyl acetate, methyl acetate or n-butyl acetate. In another embodiment of the present invention the sodium salt of carboxylic acid used in step (iii) is selected from sodium lactate, sodium acetate, sodium 2-ethyl hexonate, sodium diethylacetate and the like or mixtures thereof In still another embodiment of the present invention the base employed in step (i) is selected from triethyl amine, diethyl amine, n-butyl amine and preferably triethyl amine. In yet embodiment of present invention the compound of formula (I) was isolated from reaction mass by adding suitable organic solvent such as ethyl acetate, methyl acetate, n-butyl acetate and preferably ethyl acetate. In still another embodiment of the present invention the compound of formula (II) was prepared in good yield and with high purity by the procedure described in the co-pending application No. 784/MAS/2002 filed on October 24, 2002. 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 1 Preparation of sodium [6R-[6a,7P(Z)]-3-I(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-cephem-4-carboxylicacid (cefotaxime sodium) [6R-[6a,7p(Z)]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl) (methoxyimino)acetyl]amino]-3-cephem-4-carboxylic acid (100 g) was dissolved in a mixture of methanol (190ml) / ethyl acetate (95ml) by addition of triethylamine (19.2g) at -15 °C. Activated carbon was added and stirred for 15 minutes at 0 °C. The carbon was filtered off and washed the bed with methanol (95 ml) / ethyl acetate (95ml). The solution was then passed through series of micron filters in a sterile area. Sodium 2-ethyl hexanoate (67.7 g) in ethyl acetate (285 ml) was added slowly at 6 °C and stirred for 30 minutes. To the product slurry, ethyl acetate (1230 ml) was charged at 6 °C. The product obtained was filtered and washed with ethyl acetate. The product was dried under vacuum to get dried material (93- 95 g) in pure form. We claim: 1) An improved process for the preparation of the sterile cefotaxime sodium of formula (I), comprising the steps of: i). dissolving the compound of formula (II) in a mixture of polar solvent/less polar solvent at a temperature in the range of- 20 °C to 50 °C in the presence of base, ii). charcolising the solution followed by micron filtration, iii). treating the solution with sodium salt of aliphatic carboxylic acid in ethyl acetate at a temperature in the range of 10 °C to 50 °C, iv). precipitating the product by adding organic solvent and v). isolating the precipitated cefotaxime sodium of formula (I), in pure form. 2. The process as claimed in claim 1, wherein the polar solvent used in step (i) is selected from methanol, ethanol or acetone. 3. The process as claimed in claim 1, wherein the less polar solvent used in step (i) is selected from ethyl acetate, methyl acetate or n-butyl acetate. 4. The process as claimed in claim 1, wherein the base used in step (i) is selected from triethyl amine, diethyl amine or n-butyl amine. 5. The process as claimed in claim 1, wherein the sodium salt of carboxylic acid used in step (iii) is selected from sodium lactate, sodium acetate, sodium 2-ethyl hexanoate, sodium diethylacetate or mixtures thereof. 6. The process as claimed in claim 1, wherein the organic solvent used in step (iv) is ethyl acetate, methyl acetate or n-butyl acetate. 7. The process as claimed in claim 1, wherein the cefotaxime sodium of formula (I), is a crystalline sterile product. 8. The process as claimed in claim 1, wherein the cefotaxime sodium of formula (I), is a syn isomer.

Documents:

0023-mas-2003 abstract duplicate.pdf

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0023-mas-2003 abstract.pdf

0023-mas-2003 claims duplicate.pdf

0023-mas-2003 claims.pdf

0023-mas-2003 correspondence others.pdf

0023-mas-2003 correspondence po.pdf

0023-mas-2003 description (complete) duplicate.pdf

0023-mas-2003 description (complete).pdf

0023-mas-2003 form-1.pdf

0023-mas-2003 form-13.pdf

0023-mas-2003 form-19.pdf

0023-mas-2003 form-3.pdf

0023-mas-2003 form-5.pdf

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