Title of Invention

A PROCESS FOR THE PREPARATION OF CEPHALOSPORIN ANTIBIOTIC

Abstract

A process for the preparation of cephalosporin antibiotic of the formula (I) Which comprises: (i) activating the compound of formula (III) as acid haide in an organic solvent (ii)treating the reaction mass obtained from step (i) with water (iii)separating the organic layer containing the derivative of formula(III) and condensing it 7-amino cephaloporin derivative by maintaining the pH in the range 5.0-10.0 using an inorganic base of the formula(XV),and (iv) cyclizing the compound of formula (XVI) with thiourea in the presence of solvent and salt of organic or inorganic acid at a temprerature in the range of-50 to +50 oC to produce compound of formula(I).

Full Text

Field of the Invention The present invention relates to a process for the preparation of cephalosporin antibiotic of the formula (I) wherein R represents hydrogen atom or a readily hydrolysable ester group and X represents one of the groups WO 00/63214 discloses a process for the preparation of cephalosporins by condensation of carboxy ester intermediate with silylated thiourea. wherein R is hydrogen or silyl group and R' is silyl group or COOR' is a carboxylic acid salt; X is halogen. The process comprises reacting the compound of formula (IX) with compound of formula (III) and desilylating the compound of formula (X) and cyclizing the desilylated compound with thiourea to produce cefpodoxime acid of formula (XII). The above processes uses the silylating agent in a solvent for condensation of halo acid of formula (III) with cephem derivative and then desilylating the silylated cephem derivative to react with thiourea to produce desired cephalosporin antibiotic. The present process avoids the use of silylation step and thereby reduces the cost of production and also makes the process simple and easy to implement in commercial scale. GB 2012276 describes 7-(4-halogeno-3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative of the formula (XIII) wherein the symbols have the same meanings as defined above, which comprises reacting the above compound (I) with thiourea. This patent also describes a process for the preparation of compounds of formula (XIII), which comprises reacting the compound of formula (III) or its reactive derivative with compound of formula (IX) using organic amine. Objectives of the Invention The primary objective of the invention is to provide a new method for the preparation of cephalosporin antibiotic of the formula (I), which would be easy to implement in commercial scales. Another objective of the present invention is to provide an improved process for the preparation of cephalosporin antibiotic of the formula (I) in high purity and yield. Another objective of the present invention is to provide a simple process for producing cephalosporin antibiotic of the formula (I), which avoids the use of silyation and desilylation, thereby reducing the cost of production and increasing the productivity. Summary of the Invention where all symbols are as defined above, ii) maintaining the pH in the range 5.0-10.0 using an inorganic base, iii) cyclizing the compound of formula (XVI) with thiourea in the presence of solvent and salt of organic or inorganic acid at a temperature in the range of-50 to +50 °C to produce compound of formula (I), defined above and iv) converting the compound of formula (I) to its pharmaceutically acceptable salts, esters or hydrates by conventional methods. Detailed Description of the Invention In yet another embodiment of the present invention, the condensation of compound of formula (III) with (XV) is performed by using the activated derivative of formula (III) in the presence of a solvent selected from dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, isobutyl alcohol, n-butanol, tert-butanol, tetrahydrofuran, aromatic hydrocarbons, acetone, ethyl methyl ketone, diethyl ketone, pentan-3-one, cyclohexanone, methyl isobutyl ketone, dioxane, acetonitrile, DMAc, A^A^-dimethylformamide, dialkylethers, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, water and the like or mixtures thereof. In yet another embodiment of the present invention, the inorganic base used for maintaining the pH is selected from ammonia, sodium carbonate, sodium bicarbonate, ammonium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like. The compound of formula (III) is activated as acid halides, mixed anhydrides, active esters, active amides. The acid halides are acid chlorides or acid bromides. The mixed anhydrides are anhydrides of the compounds of formula (III) with pivaloyl chloride, ethyl chloroformate, benzyl chloroformate. In yet another embodiment of the present invention the cyclization of compound of (XVI) is carried out using solvents selected from water, tetrahydrofuran, acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone, pentan-3-one, cyclohexanone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C1-C5)alcohol, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, and the like or mixtures thereof. In another embodiment of the present invention, salts of organic or inorganic acid is selected from sodium acetate, sodium carbonate, sodium bicarbonate, potassium acetate, ammonium acetate, ammonium carbonate, barium carbonate, calcium carbonate, potassium carbonate, potassium bicarbonate, sodium ethoxide and the like. In yet another embodiment of the present invention the reaction is carried out in a single pot. The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention. Example 1 Cefepime hydrochloride Step (i) Preparation of Cefepime sulfate To dichloromethane (300 mL), 4-chloro-2-methoxyimino-3-oxobutyric acid (50 g) was added under stirring to get a clear solution at 23-28 °C and cooled to -5 to 0 °C under nitrogen. To the cold solution, phosphorous pentachloride (64 g) was added under nitrogen and stirred for 30-40 min. The reaction mixture was cooled to -25 to -20 °C and cold water (500 mL) added to it. The organic layer was separated and charged into 7-amino-3-((N-methylpyrrolidino)methyl)-3-cephem-4-carboxylic acid (100 g) in aqueous acetone (700 mL) at -5 to 0 °C over a period of 30-40 min while maintaining the pH in the range 6.0-7.0 using dil. ammonia solution (15%). Thiourea (28 g), and sodium acetate trihydrate (56 g) were added to the reaction mixture at -5 to 0 °C. The temperature of the reaction mixture was allowed to rise to 18-20 °C over a period of 20 min and stirred well. The aqueous layer was separated and dil. sulphuric acid added to adjust the pH to 1.1-1.2 at 15-20 °C, followed by excess acetone (4000 mL). The resulting slurry was cooled to 0-2 °C, filtered, and washed with water and acetone. The wet material of cefepime sulfate was used as such for the preparation of cefepime hydrochloride. Step (ii) Preparation of cefepime hydrochloride To a stirred mixture of water (210 mL) and ethyl acetate (70 mL), cefepime sulfate (104 g, wet) was added at 18-20 °C. A solution of amberlite LA-2 resin (110 mL) in ethyl acetate (440 mL) was added over a period of 45-60 min while maintaining the pH 3.8-3.9. The aqueous layer was separated and the organic layer extracted with water (70 mL). The aqueous layers were combined and charcoalized. The filtrate was warmed to 35-40 °C and the pH adjusted to 0.7-0.8 with hydrochloric acid. Acetone (2800 mL) was added over 75 min at 35-38 °C under stirring. The product obtained was filtered, and washed with aqueous acetone and acetone. Drying under vacuum afforded pure cefepime hydrochloride. Example 2 Preparation of Ceftriaxone 4-Chloro-2-methoxyimino-3-oxobutyric acid (14.5 g) was added to dichloromethane (90 mL) at 25-30 °C. The clear solution obtained was cooled to -5 to 0 °C under nitrogen. To the cold solution, phosphorous pentachloride (18.5 g) at -5 to 0 °C under nitrogen. After stirring for a period of 1 h at this temperature, the reaction mixture was cooled to -35 to -30 °C under nitrogen. To the reaction mixture, cold water (200 mL) was added at -5 to 0 °C and the organic layer separated. The organic layer was added to 7-ACT (20 g) in aqueous acetone (200 mL) at -5 to 0 °C in 30-40 min while maintaining the pH 9.8-7.0 using dil. ammonia. The pH of the reaction mixture was maintained until completion of the reaction. The aqueous layer was separated at -5 to 0 °C. To the aqueous layer, thiourea (6.5 g) and sodium acetate trihydrate (13 g) were added and the temperature raised to 18-20 °C. The reaction mixture was stirred for 1 h. Sodium acetate (5 g) was added and the stirring continued for another 1 h. The reaction mixture was charcoalized & dil HC1 added to the filtrate to set the pH ~ 2.0 over a period of 60-70 min. The product, ceftriaxone acid, obtained was separated by filtration and washed with water. The ceftriaxone acid was dissolved in water using triethylamine. To the clear solution obtained, sodium 2-ethylhexanoate (25 g) was added followed by acetone (340 mL) and then stirred for 15 min at 18-20 °C. Insoluble impurity was removed and to the clear solution, acetone (560 mL) added. The precipitated product of ceftriaxone sodium was obtained by filtration followed by washing with acetone & drying under vacuum. Example 3 Preparation of Ceftriaxone 4-Chloro-2-methoxyimino-3-oxobutyric acid (14.5 g) was added to dichloromethane (90 mL) at 25-30 °C. The clear solution obtained was cooled to -5 to 0 °C under nitrogen. To the cold solution, phosphorous pentachloride (18.5 g) at -5 to 0 °C under nitrogen. After stirring for a period of 1 h at this temperature, the reaction mixture was cooled to -35 to -30 °C under nitrogen. To the reaction mixture, cold water (200 mL) was added at -5 to 0 °C and the organic layer was separated. The organic layer was added to 7-ACT (20 g) in water (100 mL) containing polyethyleneglycol (10 g) at -5 to 0 °C in 30-40 min while maintaining the pH 9.8-7.0 using dil. ammonia. The pH of the reaction mixture was maintained until completion of the reaction. The aqueous layer was separated at -5 to 0 °C. To the aqueous layer, thiourea (6.5 g) and sodium acetate trihydrate (13 g) were added and the temperature raised to 18-20 °C. The reaction mixture was stirred for 1 h. Sodium acetate (5 g) was added and the stirring continued for another 1 h. The reaction mixture was charcoalized & dil HC1 added to the filtrate to set the pH - 2.0 over a period of 60-70 min. The product, ceftriaxone acid, obtained was separated by filtration and washed with water. The ceftriaxone acid was dissolved in water using triethylamine. To the clear solution obtained, sodium 2-ethylhexanoate (25 g) was added followed by acetone (340 mL) and then stirred for 15 min at 18-20 °C, Insoluble impurity was removed and to the clear solution, acetone (560 mL) added. The precipitated product of ceftriaxone sodium was obtained by filtration followed by washing with acetone & drying under vacuum. Example 4 Preparation of Cefotaxime 4-Chloro-2-methoxyimino-3-oxobutyric acid (20 g) was added to dichloromethane (120 mL) at 25-30 °C. The clear solution obtained was cooled to -5 to 0 °C under nitrogen. To the cold solution, phosphorous pentachloride (25 g) at -5 to 0 °C under nitrogen. After stirring for a period of 1 h at this temperature, the reaction mixture was cooled to -30 to -25 °C under nitrogen. To the reaction mixture, cold water (250 mL) was added at -5 to 0 °C and the organic layer separated. The organic layer was added to 7-aminocephalosporanic acid (25 g) in aqueous acetone (175 mL) at -5 to 0 °C in 30-40 min while maintaining the pH at 6.5-7.0 using dil. ammonia (15%). The pH of the reaction mixture was maintained until completion of the reaction. To the reaction mixture, thiourea (11 g) and sodium acetate trihydrate (22 g) were added and the temperature raised to 18-20 °C The reaction mixture was stirred for 1 h. To the reaction mixture, dil HC1 was added to set the pH - 3.0 over a period of 30-40 min to crystallize the product. Cold water was added and the product was obtained by filtration and washing with water and acetone. We claim : 1. A process for the preparation of cephalosporin antibiotic 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; R3 is carboxylate ion or COORd, where Rd represents hydrogen, ester or a counter ion which forms a salt; R4 represents H, OCH3, OCOCH3, ==CH2, where all symbols are as defined above, ii) maintaining the pH in the range 5.0-10.0 using an inorganic base, iii) cyclizing the compound of formula (XVI) with thiourea in the presence of solvent and salt of organic or inorganic acid at a temperature in the range of-50 to +50 °C to produce compound of formula (I), defined above and iv) converting the compound of formula (I) to its pharmaceutically acceptable salts, esters or hydrates by conventional methods. 2. The process as claimed in claim 1, wherein the solvent used for condensation is selected from dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, isobutyl alcohol, n-butanol, tert-butanol, tetrahydrofuran, aromatic hydrocarbons, acetone, ethyl methyl ketone, diethyl ketone, pentan-3-one, cyclohexanone, methyl isobutyl ketone, dioxane, acetonitrile, DMAc, A^,7V-dimethylformamide, dialkylethers, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, water or mixtures thereof 3. The process as claimed in claim 1, wherein the inorganic base used in step (ii) is selected from ammonia, sodium carbonate, sodium bicarbonate, ammonium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide. 4. The process as claimed in claim 1, wherein the solvent used for cyclization is selected from water, tetrahydrofuran, acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone, pentan-3-one, cyclohexanone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (CrC5)alcohol, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol or mixtures thereof 5. The process as claimed in claim 1, wherein the salts of organic or inorganic acid is selected from sodium acetate, sodium carbonate, sodium bicarbonate, potassium acetate, ammonium acetate, ammonium carbonate, barium carbonate, calcium carbonate, potassium carbonate, potassium bicarbonate or sodium ethoxide. 6. The process as claimed in claim 1, wherein the the reaction is carried out in a single pot.

Documents:

673-che-2003-abstract.pdf

673-che-2003-assignement.pdf

673-che-2003-claims.pdf

673-che-2003-correspondnece-others.pdf

673-che-2003-correspondnece-po.pdf

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

673-che-2003-form 1.pdf

673-che-2003-form 3.pdf