Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF CEFUROXIME SODIUM

Abstract

The present invention more particularly relates to an improved pross for the preparation of cefuroxime acid of formula (II). which comprising the steps of: (i) condensing 3-hydroxymethyl- 7-amino cephalosporinc acid of the formula (IV) with activated (fur-2-yl)-2-methoxyimino acetic acid of the formula (V) in the presence of an inorganic base in a solvent at a temperature in the range of -40°C to 10°C and isolating the product by adjusting the pH to 1.5 to 2.5 using an acid to produce (6R, 7R)- 7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3- hydroxymethyl ceph-3-em-4-carboxylic acid of the formula (VI), (ii) carbamoylating the compound of formula (VI) with isocyanate of formula (VII) wherein R is a labile group at a temperature in the range of -60°C to O°C to get compound of the formula (II).

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 cefuroxime sodium of formula (I). Description of the prior art Cefuroxime is a valuable broad spectrum antibiotic and having activity against wide range of gram-positive and gram-negative microorganisms. Cefuroxime sodium is physiologically acceptable non-toxic salt of cefuroxime and may be administered to human or used as a veterinary medicine. The preparation involves the condensation of 3-hydroxymethyl-7-amino cephalosporinc acid with (fur-2-yl)-2-methoxyimino acetic acid to produce (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid. Carbamoylation of resulting acid with isocyanate of formula RNCO wherein R is a labile substituent to get (6R,7R)-3-carbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-ceph-3-em-4-carboxylic acid (cefuroxime), followed by converting the cefuroxime into its sodium salt using mixture of water soluble sodium salt. In US patent 4,775,750 discloses the process for the preparation of the compound of formula (I), which involves carbamoylation of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid, and in situ preparation of cefuroxime sodium using sodium-2-ethylhexanote. The product obtained from this patent suffers in non-acceptable color and low purity. Reprocessing is needed to get sterile cefuroxime sodium. US patent 4,277,601 describes the process for the preparation of sodium cefuroxime as its THF solvate in situ manner. The process described in this patent involves the usage of multiple organic solvent system and thereby making the process complicated. Moreover, recrystallisation is needed to get the sterile cefuroxime sodium. Objectives of the invention The main objective of the present invention is to provide a process for the preparation of compound of general 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 cefuroxime sodium from cefuroxime acid. Still another objective of the present invention is to provide a process for the preparation of compound of formula (I) in good yield, high purity and with desirable particle size. Yet another objective of the present invention is to provide a simple method for the preparation of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid in pure form. Summary of the invention: Accordingly, the present invention provides an improved process for the preparation of compounds of formula (I), which comprises the steps of: (i) dissolving the compound of formula (II) in a water miscible solvent /water at a temperature in the range of 10°C to 50°C, (ii) subjecting the solution for carbon treatment followed by micron filtration, (iii) treating the solution with mixture of water soluble sodium salts of two weak acids in suitable alcoholic solvent at a temperature in the range of 10°Cto50°C, (iv) isolating the precipitated compound of formula (I) in pure form. Another embodiment of the present invention is to provide the process for the preparation of the compound of formula (II), which comprises the steps of: (i) condensing 3-hydroxymethyl-7-amino cephalosporine acid of formula (IV) with activated (fur-2-yl)-2-methoxyimino acetic acid ammonium salt of formula (V) in the presence of an inorganic base in a solvent at a temperature in the range of -40°C to 10° and isolating the product by adjusting the pH to 1.5 to 2.5 using an acid to produce (6R?7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid of formula (VI), (ii) carbamoylating the compound of formula (VI) with isocyanate of formula (VII) wherein R is a labile group in the presence of a solvent at a temperature in the range of -60°C to 0°C to get (6R,7R)-3-carbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-ceph-3-em-4-carboxylic acid of the formula (II). Detailed description of the invention In an embodiment of the present invention (6R,7R)-3-carbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-ceph-3-em-4-carboxylic acid the compound of formula (II) was dissolved in water miscible solvent /water such as acetone, THF, acetonitrile at a temperature in the range of 10°Cto50°C. In still another embodiment of the present invention the mixture of water soluble sodium salt of weak acid is selected from sodium lactate/sodium acetate, sodium 2-ethyl hexonate/sodium acetate and the like. The reaction may be carried out in an alcoholic solvent selected from methanol, ethanol, isopropyl alcohol or mixtures thereof, at a temperature in the range of 10°C to 50°C. In still another embodiment of present invention the compound of formula (I) was isolated from reaction mass by adding suitable water miscible solvent such as acetone, methanol or mixtures thereof. In yet another embodiment of the present invention 7-amino cephalosporinic acid of formula (III) was taken in solvents such as methanol, acetone, dichloromethane, THF, water or mixtures thereof, to that sodium hydroxide solution was added at a temperature in the range of -90°C to 0°C particularly at -60°C to -40°C. In yet another embodiment of the present invention fur-2-yl methoxyimino acetic acid of formula (V) was dissolved in polar solvents selected from dimethyl acetamide, dichloromethane, dimethylformamide and the like or mixtures thereof at a temperature in the range of -40°C to -10°C, more particularly to produce the active derivative of fur-2-yl-methoxyimino acetic acid using suitable reagent such as POCI3, PCI5, PCI3, SOCl2 and the like. In still another embodiment of present invention the compound of formula (IV) was reacted with the active derivative of fur-2-yl methoxyimino acetic acid ammonium salt of formula (V) at a temperature in the range of -40°C to -10°C, in the presence of inorganic base such as sodium bicarbonate, sodium hydroxide, potassium carbonate and sodium carbonate in the presence of solvents such as methanol, acetone, dichloromethane, THF, water or mixtures thereof to produce the compound of formula (VI). In yet another embodiment of the present invention, the acid used for adjusting pH in step (i) is selected from hydrochloric acid, sulphuric acid or ortho phosphoric acic. In yet another embodiment of the present invention, the labile group represented by R is selected from chlorosulphonyl, mono, di or trichloroacetyl, bromosulphonyl, trichloroethoxycarbonyl, trimethylsilyl or chlorobenzenesulphonyl group. In still another embodiment of the present invention the compound of formula (VI) was reacted with the compound of formula (VII) to produce the compound of formula (II), in the presence of a solvent selected from THF, methanol dichloromethane, acetone, water or mixtures thereof. 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): Step (i): Preparation of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethyIceph-3-em-4-carboxylic acid. (i) To the mixture of dimethyl acetamide (145 ml), dichloromethane (22 ml) and dimethylformamide (28 ml) in a dry flask, (fur-2-yl)-2-methoxyimino acetic acid ammonium salt (73 gm) was added and cooled the reaction mass to -40°C. To the reaction mass POCl3 (60 gm) was added at -40°C and stirred the reaction mass at -20±2°C for 45 minutes. The mass was cooled to -30°C and kept at that temperature till condensation. (ii) To the mixture of water (400 ml), methanol (400 ml) in another flask, 7-amino cephalosporinic acid (100 gm) was added and cooled the slurry to -50°C. To the reaction mass sodium hydroxide solution (29 gm NaOH in 200 ml water) was added at -50°C and stirred for 60 minutes at 40±2°C. After completion of reaction the pH of reaction was adjusted to 7 to 8 using dilute HCl. Temperature of this reaction mass was raised to 0°C by the addition of saturated sodium bicarbonate solution (800 ml) followed by (fur-2-yl)-2-methoxyimino acetic acid mass from step (i) at 0-2°C. After completion of reaction pH was adjusted to 2.0 using dilute HCl (80 ml). The product formed was filtered, washed with water followed by dichloromethane and dried the product under vacuum at 45°C to get the compound of formula (V) (116-118 gm) in pure form. Step (ii): Preparation of (6R,7R)-3-carbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-ceph-3-em-4-carboxylic acid (cefuroxime acid): (6R,7R)-7-[Z-2-(Fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethyl ceph-3-em-4-carboxylic acid (100 gm) was dissolved in THF (480 ml) at 0°C and cooled to -50°C. To the cooled solution chlorosulphonyl isocyanate(59 gm in 100 ml THF) solution was added at -50°C and stirred at the same temperature for 60 minutes. The reaction mass was poured into precooled water at 10°C. Stirred the mass at 10°C till completion of reaction. Reaction mass was washed with ethyl acetate and then aqueous layer was subjected to charcoal treatment. The pH of aqueous solution was adjusted to 2.0 using dilute HCl. The product formed was filtered and washed with water followed by isopropyl alcohol to produce the compound of formula (II)(105 gm). Step (iii) Preparation of (6R,7R)-3-carbamoyloxymethyl-7-[Z-2-(fur-2-yl)- 2-methoxyiminoacetamido]-ceph-3-em-4-carboxylic acid sodium (cefuroxime sodium): (6R,7R)-3-carbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyimino acetamido] -ceph-3-em-4-carboxylic acid ( 100 gm ) was dissolved in a mixture of acetone(650 ml)/water(800 ml) at 25°C. Activated carbon was added and stirred for 15 minutes at 25°C. The carbon was filtered and washed the bed with acetone /water. The solution was then passed through series of micron filters in a sterile area. The solution was warmed to 35°C. Mixture of sodium lactate solution (23 gm) (60% solution in water ) and sodium acetate(16.5 gm) in ethanol(25 ml) was added to the reaction mixture slowly at 35°C and stirred for 30 minutes. To the thick slurry acetone (900 ml) was charged at 35°C. The product obtained was filtered and washed with ethanol followed by acetone. The product was dried under vacuum to get dried material (98 gm) in pure form. Example (2): Preparation of (6R,7R)-3-carbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxy iminoacetamido]-ceph-3-em-4-carboxylic acid sodium (cefuroxime sodium): (6R,7R)-3-carbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyimino acetamido]-ceph-3-em-4-carboxylic acid (100 gm ) was dissolved in a mixture of acetone(650 ml)/water(800 ml) at 25°C . Activated carbon was added and stirred for 15 minutes at 25°C. The carbon was filtered and washed the bed with acetone /water. The solution was then passed through series of micron filters in a sterile area. The solution was warmed to 35°C. Mixture of sodium lactate solution (23 gm) (60% solution in water ) and sodium acetate(16.5 gm) in methanol(450 ml) was added to the reaction mixture slowly at 35°C and stirred for 30 minutes. The product obtained was filtered and washed with methanol (200 ml) followed by acetone. The product was dried under vacuum to get dried material (98 gm) in pure form. We Claim which comprising the steps of: (i) condensing 3-hydroxymethyl-7-amino cephalosporin acid of the formula (IV) with activated (fur-2-yl)-2-methoxyimino acetic acid of the formula (V) in the presence of an inorganic base in a solvent at a temperature in the range of -40°C to 10°C and isolating the product by adjusting the pH to 1.5 to 2.5 using an acid to produce (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethyl ceph-3-em-4-carboxylic acid of the formula (VI), ii) carbamoylating the compound of formula (VI) with isocyanate of formula (VII) RNCO (VII) wherein R is a labile group at a temperature in the range of -60°C to 0°C to get compound of the formula (II). 2) The process as claimed in claim 1, wherein the base used in step (i) is selected from sodium hydroxide, sodium bicarbonate, potassium carbonate or sodium carbonate. 3) The process as claimed in claim 1, wherein the solvent used in step (i) is selected from methanol, acetone, dichloromethane, THF, water or mixtures thereof. 4) The process as claimed in claim 1, wherein the acid used in step (i) is selected from hydrochloric acid, sulphuric acid or ortho phosphoric acid. 5) The process as claimed in claim 1, wherein the solvent used in step (ii) is selected from methanol, acetone, dichloromethane, THF, water or mixtures thereof. 6) The process as claimed in claim 1, wherein the labile group represented by R is selected from chlorosulphonyl, mono, di or trichloroacetyl, bromosulphonyl, trichloroethoxycarbonyl, trimethylsilyl or chlorobenzenesulphonyl group.

Documents:

819-mas-2002- abstract.pdf

819-mas-2002- claims duplicate.pdf

819-mas-2002- claims original.pdf

819-mas-2002- correspondence others.pdf

819-mas-2002- correspondence po.pdf

819-mas-2002- description complete duplicate.pdf

819-mas-2002- description complete original.pdf

819-mas-2002- form 1.pdf

819-mas-2002- form 13.pdf

819-mas-2002- form 3.pdf

819-mas-2002- form 5.pdf

819-mas-2002- pct.pdf