Title of Invention	A NEW METHOD FOR PREPARATION OF CEFTIOFUR SODIUM
Abstract	THE PRESENT INVENTION DESCRIBED PROCESS FOR PREPARATION OF CEFTIOFUR SODIUM REPRESENTED BY FORMULA BY THE CONDENSATION OF 3-{-2-{FURYLACR} THIOMETHY}-3-CEPHEM-4-CARBOXYLIE ACID RWEPRESENTED BY FORMULA {11}WITH 5-PHENY-1,3,4-OXADIAZOLE-2-THI-2-{2-AMINOTHIAZOL-4-YL}-2-METHOXYIMINO}ACETATE REPRESENT BY FORMULA(III)

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FIELD OF THE INVENTION The present invention discloses a process for preparation of ceftiofur sodium. The invention provides a process wherein ceftiofur sodium is prepared by condensation of 3-[2-(fury carbonyl) thiornethyl]-3-cephem-4-carboxylic acid represented by formula (II) with 5-phenyl-l,3.4-oxadiazole-2-thio-2-{2-aminothiazo!-4-yl)2- methoxyimino)acetate represent by formula (III) and the ceftiofur amine salt, which is prepared during the condensation, is converted into its sodium salt. BACKGROUND OF INVENTION Ppftinfiir 11: thp opiiprii- Ceftiofur acid, its alkali m, alkaline earth metal and amines salts were reported for the first time in US patent no. 4464367. Later on it was discovered that all these derivatives of ceftiofur are known to have stability problems. They are difficult to purify due to amorphous nature of the compounds. From the beginning, preparation of ceftiofor sodium has posed challenges for organic chemists regarding purity, .stability and crystalline. Several attempts have been made to prepare ceftiofur sodium for obviating above mentioned problems. One of the solution was provided in US patent No. 4877782 by preparing zinc complexes of ceftiofur which have better dispensability in water and can be used in pharmacological preparations. US patent No. 490268.1 also explains die isolation of more stable ceftiofur in the form of crystalline hydro halide salts which has has better solubility and other physical properties compared to parent compounds. During the isolation of ceftiofur hydrochloride salt most of the impurities present in compound are removed during filtration. The hydrohalide salts as such cannot be used for potential administration, therefore it is necessary to convert a hydrohalide salt to sodium salt in order to use the drug as inject able. Several methods are reported in chemical literature for converting cephalosporin acids to their corresponding alkali metal salts. This step is of special importance in case of inject able antibiotics. Surprisingly, very few methods are disclosed for preparing ceftiofur sodium starting from either certifier hydrohalide salt or ceftiofur acid . Using conventional method it is difficult to get pure ceftiofur sodium from ceftiofur hydrochloride without isolating ceftiofur acid as intermediate. Since during the neutralization of ceftiofur hydrochloride with any sodium base one molecule hydrochloric acid attached to ceftiofur also get neutralized resulting formation of sodium chloride which is very difficult to remove from the required compound. Till date there is no chemical method reported to separate the sodium chloride from ceftiofur sodium since both are very similar in properties especially in solubility’s. Alternatively one can isolate ceftiofur acid first and then treat it with sodium base but it is also problematic due to Its amorphous nature of ceftiofur acid and severe problems during filtration of ceftiofur acid are observed. US patent No. 4937330 describes the use of polyvinyl pyridine for neutralization of hydrohalide salt to get free acid and then insitu treating the free acid with sodium-2-ethylhexanoate. The use of sodium-2-ethyl hexameter for this purpose is subject of several patents in field of cephalosporin antibiotics. The polyvinyl pyridine resin loses activity after certain batches and needs replacement, which makes the process expensive. In general, the process for liberation of ceftiofur free acid from hydrohalide salt using either resin bases or non-resinous bases is associated with above problems. Keeping all these problems in mind, the applicant disclose a simple, economical and commercially viable process for preparing ceftiofur sodium which obviates all the above mentioned limitations. In this regard, a reference to applicants co-pending US application 09/754,302 is made herewith. OBJECTS OF THE INVENTION Therefore, the primary object of the invention is to provide a process for preparing ceftiofur sodium without the preparation of ceftiofur hydrochloride as intermediate. Another object of the invention is to concentrate the aqueous solution of ceftiofur amine salt as well as ceftiofur sodium salt by employing evaporation under reduced pressure using effective heat transfer methods e.g. agitated thin film evaporator, falling film evaporator, rising film evaporator, forced circulation evaporator etc. Yet another objective of this invention is to prevent the deterioration of product during evaporation process and this has been achieved by using agitated thin film evaporator, falling film evaporator, rising fihn evaporator, forced circulation evaporator etc. Still another object of the invention is to prepare Ceftiofur Sodium from Ceftiofur amine by treating with Sodium-2-ethylhexanote, sodium acetate, sodium-bicarbonate or sodium lactate. One more objective of the invention is to precipitate Ceftiofur sodium using an organic solvent. Still yet another objective of the present invention is to prepare Ceftiofur sodium from ceftiofur amine salt. Still another objective of the invention is to provide ceftiofur sodium from from ceftiofur amine salt solution by concentrating and neutralizing with stoichiometric equivalent of mineral acid in presence sodium chloride and organic solvent, followed by treating the organic layer with sodium base. SUMMARY OF THE INVENTION To meet the above objectives, the present invention provides a process for preparation of ceftiofur sodium by the condensation of 3-[2-(furylcarbonyl) thioniethyl]-3-cephem-4-carboxy!ic acid with 5-phenyl -l,3,4-oxadiazole-2-thio-2-(2- aminothiaxol-4-yl)2-methox:yimino) acetate . The ceftiofur amine sail prepared during the condensation is initial converted in situ into its sodium sail. The solution thus obtained is concentrated without subjecting to high temperature by using effective techniques of which have never been used for this class of compounds. The ceftiofur amine salt is converted into its sodium salt by using sodium-2-ethylhexanoate, sodium acetate or sodium bicarbonate. Finally ceftiofur sodium can be isolated either by crystallizing out by the addition of an organic solvent. DETAILED DESCRIPTION OF THE INVENTION The present invention provides the process for preparation of ceftiofur sodium (I) from ceftiofur amine salt by treating with sodium base, shown here below. The said process comprises steps of; (a) condensing 3-[2-(furylcarbonyl) thiomethyl]-3-cephem-4-carboxy!ic acid represented by formula (II) with 5-phenyM,3,4"Oxadiazole-2-thio-2-(2-arninothiazol-4-yl)2-methoxyimino)acetate represent by formula (III) in a mixture of water and a organic solvent in the presence of an amine base at a pH range of 7.0 to 8.5 and at a temperature between -25°C to 30°C and and at a temperature in the range of-25 ° and 30°C and subsequent extraction with a solvent selected from dichloromethane or ethyl acetate. to obtain Ceftiofur amine salt in aqueous phase, b) treating the aqueous solution of Ceftiofur amine salt of step (a) with charcoal, filtering and evaporating the aqueous solution at a temperature in the range of 10 - 35 °C and at a reduced pressure in the range of 10 to 20 mm of mercury to remove water to yield a slurry of Ceftiofur amine salt, c) treating the slurry of step (b) containing Ceftiofur amine salt with sodium base, precipitating and isolating Ceftiofur sodium by adding organic solvent, followed by filtering the precipitated solid and drying the filtered solid, and d) treating Ceftiofur sodium of step (c) with a potassium dehydrogenate phosphate buffer at pH 7.5, followed by sterile filtration using micron filter and lyophilizing to get sterile buffered Ceftiofur sodium. In this process of the invention, ceftiofur sodium may be obtained also by adding ceftiofur amine salt solution to an organic solvent and sodium chloride, neutralizing with stoichiometric amount of mineral acid, separating organic layer and treating with charcoal, filtering and treating with sodium base to precipitate ceftiofur sodium which is filtered, dried and treating it with buffer at pH 7.5, followed by sterile filtration using micron filter and lypholisation to get sterile buffer ceftiofur sodium. In the above process the condensation reaction of step (a) is quenched by adding dichloromethane or ethyl acetate into the reaction mixture. Addition of dichloromethane or ethyl acetate removes all the impurities, which are soluble in organic phase. Organic phase is separated from aqueous phase that contains ceftiofur amine salt. The concentration of ceftiofur amine salt in aqueous solution is about 10-15%. It is difficult to isolate ceftiofur sodium by adding any amount of organic solvent at this concentration. The aqueous solution containing ceftiofur as amine salt is treated with two different pathways of operations to achieve maximum yield of the product. The aqueous layer isolated from the reaction is treated by two different routes described here below. The aqueous solution separated from reaction has about 10-15 "At concentration of ceftiofur amine salt in water. In order to reduce the amount of water from this solution, it is subjected to the distillation of water. Since the satieties of cephalosporin’s are not very good in solution at high temperature. Only a technique, which could remove water at very fast rate and without heating the product at higher temperature, can be useful for the purpose. After studying several evaporating and drying processes we feel that thin film evaporators and drier are best for our work. Attempts to concentrate this solution from initial low concentration by batch distillation under reduced pressure causes very high degree of decomposition as product is exposed to heat due to large residence time. Using low temperature distillation technique known as film evaporation can carry out the removal of such a large amount of water. Agitated thin film evaporator, falling film evaporator, rising film evaporator, forced circulation evaporator etc are few devices, which work on this principle. Thin film evaporation is a continuous distillation process and has never been reported for isolation of ceftiofur salts by anybody. The total residence time of compound in evaporator is few seconds. This avoids exposure of product for long time to high temperature. Hence reducing the decomposition of product. The dilute solution is fed to agitated thin film evaporator having a high-speed rotor. Feed is spread as a thin film. Water is evaporated immediately as there is a large differential temperature across the unit. The entire unit is kept at reduced pressure of the order of 10 to 20 mm of Hg. Use of this technique avoiding healing the compound for longer duration, which results decomposition of products during evaporation. Highly concentrated thick slunk of ceftiofur amine salt is isolated and treated with sodium-2-ethylhexanoate or sodium acetate or sodium bicarbonate. The thick slurry containing ceftiofur sodium is slowly poured into a pool of an organic solvent which precipitates out white to ceramic solid .The solid thus obtained is filtered under nitrogen atmosphere. The success of this process lie in the ability of evaporators to concentrate the ceftiofur salt solution at temperatures in minimum time and at temperature at which decomposition is negligible . Alternatively the same set of operation are also done by first converting ceftiofur amine salt to sodium salt and then evaporation of water using above mentioned technique. Alternatively, an organic solvent is added to the aqueous layer separated from the reaction. A stoichioinetric amount of acid is added to neutralize the amine salt to make the carboxyl ate group free. As soon as the certifier amine salt is neutralized the partition coefficient shifted in favor of organic phase and ceftiofur lie comes soluble in the organic solvent .The two phases are separated, the organic phase is treated with sodium-2-ethylhexanoate or sodium acetate at a temperature l)-20°C. .-Addition of more organic solvent into this results in thick precipitation of ceftiofur sodium. Both these routes provides methods by which ceftiofur sodium can be obtained in high purity (95-99%) and excellent yield (85-95%) without the necessity for preparing ceftiofur hydrochloride. In an embodiment the organic solvent used for carrying out the condensation of cephalosporin derivative of formula (II ) and 2-amino thiazolyl methoxyimino acetic acid derivative of (III ) is selected from a the group comprising of tetrahydrofuran, 1,4-dioxane, acetone ,N,N,-dimethylfonTiamide .acetonitrile and a mixture thereof. In another embodiment, the amine base is selected from a group comprising triethylamine, diethyl amine, tributylamiune, diisopropylethylamine N-menthylaniline or amines of similar basis ties but the preened base is triethylamine. In an embodiment the organic solvent added for precipitating out ceftiofur sodium from a aqueous solution is selected from group of solvents comprising of acetone, isopropyl alcohol, tetrahydrofuran, ethyl acetate and a mixture thereof. In an another embodiment the concentration of aqueous solutions at" ceftiofur amine salt or ceftiofur sodium salt is achieved by evaporating water with film evaporator at low temperatures about ]0-35°C and reduced pressure at 10-20mm of Hg. The residence time of a few seconds with a narrow spread, this is an important fennier for heat sensitive compound .The evaporation is achieved in a single pass avoiding product re-circulation and possible degradation The deposition of the product on the heat transfer surface is avoided due to the intense agitation in the liquid film. The evaporator is selected form agitated thin film evaporator, falling film evaporator, rising film evaporator or a combination thereof In yet another embodiment the sodium based is selected from group of sodium-2-ethlyhexonate, sodium-bi-carbonate, sodium lactate or sodium acetate. In still yet another embodiment the sterile buffered ceftiofur sodium is obtained by treating ceftiofur sodium with buffer at a pH 7.5, followed by lypholisation. In yet another embodiment, the buffer is selected from a group comprising of sodium bicarbonate, potassium bicarbonate, sodium hydrogen phosphate, sodium diliydrogen phosphate, potassium hydrogen phosphate, potassium dehydrogenate phosphate or mixture thereof. The invention is illustrated with following examples but it should be understood that the invention is not intended to be limited to the specific embodiments herein. Example -I Sodium-7-Il(Z)-2-(Aininothiazol-4-yl)-2-methoxyiininolacetamido]-3-(2-furanylcarbonyl) thioimethyl|-3-cephem-4-carboxylate (sterile buffered Ceftiofur sodium) 7-Amino-3-[(2-furanyIcarboxyl)thiomethy]-3-cephem-4-carboxylic acid (lO.Og) and 2-mercapto-5-phenyl-l,3,4-oxadiazolyl-(Z)-2-{2-aminothiazol-4-y])-2-methoxyimino acetate (15.9g) are added to a mixture of tetrahydrofuran (100ml) and water (100ml) at temperature0-5°C. The pH of reaction was maintained at 7.0 to 8.0 by addition of triethylamine during the reaction. After completion of reaction, the reaction mixture is extracted with methylene chloride (lOOml x 3). Tie aqueous layer is trailed with charcoal (0.500g) The filtrate is subjected to a agitated thin film evaporator working at 20°C -25°C with 15-20 mm of Hg, to get viscous slurry of ceftiofur triediylamine salt. Sodium-2-ethyIhexanoate C5.9g) is added to the mass and the mixture is stirred vigorously. The homogeneous mixture is added slowly in the pool of isopropyl alcohol at a temperature of 20-25°C, white to creamiest solid precipitated out in the solution, which is cooled to 0-5°C for 2.0h. Ceftiofur sodium thus prepared is filtered under inert atmosphere and dried under vacuum to get 13.0g of ceftiofur sodium . The ceftiofur sodium thus prepared is dissolved in 120 ml of water .The pH of the solution is adjusted to 7.5 by adding sodium bicarbonate .Potassium dehydrogenize phosphate(0.4-0.5g) is added ,the solution is filtered through a 0.2 mince filter under sterile condition and subjected to lyophilisation to obtained sterile buffered ceftiofur sodium ( 13.8g ) with 97-98 %HPLC purity. Example -II Sodium-7-|[(Z)-2-(Aminothiazol-4-yl)-2-methoxyimino) acetamido|-3-{2-furanylcarbonyl) thiomethyl]-3-cephem-4-carboxylate (sterile buffered Ceftiofur sodium) 7-Amino-3-[(2-furanylcarboxyl)thiomethy!]-3-cephem-4-carboxylic acid (5.0g) and 2-mercapto-5-phenyl-l,3,4-oxadiazo!yl-{Z)-2-(2-aminothiazol-4-yi)-2-metho\yimino acetate (7.59g) are added to a mix ire of acetone (50ml) and water (50ml) at temperature 0-5 C. The pH of reaction was maintained at 7.0 to 8.0 by addition of triethylamine during the reaction. After completion of reaction, the reaction mixture is extracted with methylene chloride (75ml x 3). The aqueous layer is treated with charcoal (0.250g) and diluted with water . The filtrate is subjected to a agitated thin film evaporator working at 20^0 -25 C with 15-20 mm of Hg, to get viscous slurry of ceftiofur triethylamine saw. Sodium-2-ethylhexanoale (5.9g) is added to the mass and the mixture is stirred vigorously. The homogeneous mixture is added slowly in the pool of acetone at a temperature of 20-25 C, white to ceramic solid precipitated out in the solution, which is cooled to 0-5"C for 2.0h. Ceftiofur sodium thus prepared is filtered under inert atmosphere and dried under vacuum . Product is converted into buffered sterile ceftiofur sodium as describe in example-I to gel 14.0g of ceftiofur sodium with HPLC (purity) of 98.0%, Example -III Sodium-7-[[(Z)-2-(Aminothiazol-4-yl)-2-methoxyimino| acetanilide]-3-(2-furanylcarbonyl) thiomethyl|-3-cephem-4-carboxylate (sterile buffered Ceftiofur sodium) 7-Aniino-3-[(2-furanylcarboxyl)thiomethyl]-3-cephem-4-caTboxylic acid (5.0g) and 2-mercapto-5-pheny!-!,3,4-oxadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-met])oxymoron acetate {7.59g) are added to a mixture of acetone (50ml) and water (50ml) at temperature 0-5 C, The pH of reaction was maintained at 7.0 to S.O by addition of triethylamine during the reaction. After complexion} of reactioji, the reaction mixture is extracted with methylene chloride {75ml x 3). The aqueous layer is treated with charcoal (0.250g). The filtrate is treated with sodium bi carbonate ( grams I and the resulting subjected to a agitated thin film evaporator working at 20"C -25"C with 15-20 mm of Hg, to get viscous slurry. This slurry is added slowly to the poor! of acetone at a temperature of 20-25"C, white to ceramic solid precipitated out in the solution, which is cooled to O-SV for 2.0h. Ceftiofur sodium thus prepared is filtered under inert atmosphere and dried under vacuum. Product is converted into buffered sterile ceftiofur sodium as describe in example-I to get 14.0g of ceftiofur sodium with HPLC (purity) of 98.0%. Example -IV Sodium-7-I[(Z)-2-(Aminothiazol-4-yl)-2-methoxyimiiiol acetamidol-3-(2-furanylcarbonyl) thiomethyll-3-cephem-4-carboxylate (sterile buffered Ceftiofur sodium) 7-Amino-3-[(2-furanylcarboxyl)thiomethyl]-3-cephem-4-carboxylic acid (30.0g. 88.2 mmol) and 2-mercapto-5-phenyl-l,3,4-oxadia2olyi-(Z)-2-(2-aminothia7-ol-4-yl)-2-methoxyimino acetate (47.7g, 132.0 mmol) are added to a mixture of dichloromethane (400ml) and methanol (15ml) at temperature 0-5"C. Triethylamine(25,0ml) is added to the reaction mixture in 50-60 min. After completion of reaction, the reaction mixture is extracted with water ( 400ml). The aqueous layer is separated and treated with charcoal (0,500g). Tetrabydrofuran (400m]) and lOOg of sodium chloride is added to this solution followed by addition of (9.2ml) of hydrochloric acid (35%) . the mixture is shirred for 10 min and layers are separated . Tetrabydrofuran layer is treated with charcoal and added to another 75mi solution tetrabydrofuran containing 13.5g of sodium-2-ethylhexanoate under stirring. This solution is added slowly in the pool of tetrahydrofuran(550ml) at a temperature of 20V, white to ceramist solid precipitated out in the solution, which is cooled to 0-5°C for 2,0oh. Ceftiofur sodium thus prepared is filtered under inert atmosphere, washed with acetone and dried under vacuum to get 36-38g of ceftiofur sodium with HPLC (purity) of 08,0%,The ceftiofur sodium thus prepared is dissolved in 350ml of water .The pH of the solution is adjusted to 7.5 by adding sodium bicarbonate .Potassium dehydrogenate phosphate(1.44-1.6g) is added ,the solution is filtered through a 0.2 micron filter under sterile condition and subjected to lyophilisation to obtained sterile buffered ceftiofur sodium ( 37-38 g ) EXAMPLE V Sodium-7-(|{Z)-2-(Aminothiazol-4-yl)-2-inethoxytininoI acetamido]-3-(2-furanylcarbonyl) thiometliyll-3-cepbeni-4-c3rboxyl3te (sterile buffered Ceftiofur sodium) 7-Amino-3-[(2-furanylcarboxyl)thiomethyl]-3-cephem-4-carboxylic acid (5.0g) and 2-mercapto-5-phenyl-l,3,4-oxadiazoly!-(Z)-2-{2-aminothiazol-4-yl)-2-methoxy!mino acetate (7.59g) are added to a mixture of acetone (50ml) and water (50nil) at temperature 0-5""C. The pH of reaction is maintained at 7.0 to 8.0 by addition of triethylamine during the reaction. After completion of reaction, the reaction mixture is extracted with methylene chloride (75ml x 3). The aqueous layer is treated with sodium-2-ethythexanoate (2.95g) and charcoal zed with activated charcoal (0,5g), Charcoal is filtered and the filtrate is subjected to agitated thin film evaporator working at 20""C-25""C with 15-20 mm of Hg, to get viscous slurry of Ceftiofur sodium salt which is added is add4ed slowly in 200 ml of acetone at a temperature of 20-25""C, white to ceramic solid precipitated out in the solution, which is cooled to 0.5"C for 2.0h. Ceftiofur sodium thus prepared is filtered under inert atmosphere and dried under vacuum. Product is converted into buffered sterile Ceftiofur sodium as describe in Example-1 to obtain 14.0g of Ceftiofur sodium with HPLC (purity) of 98.0%. in a mixture of water and an organic solvent, in the presence of an amine base such as hereindescribed at a pH range of 7.0 to 8.5 and at a temperature between -25°C and 30°C and subsequent extraction with a solvent selected from dichloromethane or ethylacetate to obtain a Ceftiofur amine salt in aqueous phase; (b) adding an organic solvent to the aqueous solution of Ceftioftir amine salt of step (a) and neutralizing the mixture with a stoichiometric amount of a mineral acid and (c) adding sodium chloride to separate the organic layer from step (b) which is treated with charcoal, filtered and treated with a sodium base to precipitate Ceftioftir sodium followed by filtering the precipitated solid and drying the filtered solid and dj treating Ceftiofur sodium of step (c) with a potassium dihydrogen phosphate buffer at pH 7.5, followed by sterile filtration using micron filter and lyophilisation to get sterile buffered Ceftiofur sodium. 2. A process as claimed in claim 1, wherein the sodium base is used selected from a group comprising sodium lactate, sodium-2-ethylhexaonate, sodium acetate or sodium bicarbonate. 3. A process as claimed in claim 1, wherein the neutralization of Ceftiofur amine salt is carried out by using one mole equivalent of hydrochloric acid. 4. A process as claimed in claim 1, wherein the organic solvent used in step (a) is selected from a group comprising tetrahydrofuran, acetone, isopropyl alcohol, acetonitrile or 1,4-dioxane. 5. A process as claimed in claim 1, wherein the solvent used in step (b) is selected from a group comprising tetrahydroftiran, acetone, ethylacetate, isopropyl alcohol, 1,4-dioxane, acetonitrile or mixtures thereof 6. A process as claimed in claim 1, wherein the amine base is selected from the group consisting of triethylamine, diethylamine, tributylamiune, diisopropylethylamine N-menthylaniline or amines of similar basisities, prefereably triethylamine. 7. The process for preparing sterile buffered Ceftiofiir sodium of formula (1) substantially herein described with reference to examples.

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