Title of Invention	A PROCESS FOR PREPARING CEFTIOFUR SODIUM FROM ITS HYDROHALIDE SALTS
Abstract	(57) Abstract: The present invention relates to a process for preparing sodium salt of cephalosporins from their corresponding hydrohalide sah, which is neutralixed with irimethylsiiylating agent for the first time. PRICE: THIRTY RUPEES

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FIELD OF THE INVENTION The present invention relates to a novel method for preparing ceftiofur sodium from its hydrohalide salts. The invention discloses a new and economical process for preparation of ceftiofur acid starting from ceftiofur hydrohalide salt and treating it with a trimethylsilylating agent. The ceftiofur acid thus prepared was converted into its sodium salt by using some highly efficient sodium exchange reagent. BACKGROUND OF INVENTION Ceftiofur is the generic name given to compound of formula (I) Ceftiofur acid, its salts with alkali metal, alkaline earth metal and amines are reported for the first time in US patent no. 4464367. All these derivatives of ceftiofur are known to have stability problems and are difficult to purify due to amorphous nature of the compounds. An attempt to overcome these problems was made in US patent No. 4877782 by preparing zinc complexes of ceftiofur which have better dispersibility in water and can be used in pharmacological preparations. US patent No. 4902683 explains the isolation of ceftiofur in the form of crystalline hydrohalide salts which has better solubility and other physical properties compared to parent compounds. The hydrohalide salts as such cannot be used for parenteral administration, therefore it is necessary to convert a hydrohalide salt to sodium salt in order to use the drug as injectable. Several methods are reported in patents for converting cephalosporanic acid to their corresponding alkali metal salt. This step is of special importance in case of injectable antibiotics. Surprisingly, very few methods are disclosed for preparing ceftiofur sodium starting from hydrohalide salt of ceftiofur. US patent No. 4937330 describes the use of polyvinylpyridine for neutralization of hydrohalide salt to get free acid and then treating the free acid with sodium-2-ethylhexanoate. The use of sodium-2-ethyl hexanoate for this purpose is subject of several patents in field of cephalosporin antibiotics. The neutralization of hydrohalide salt using polyvinyl pyridine resin involves an extra filtration step in the process and the resin loses activity after certain batches and needs replacement which adds cost to the process. In general, the process for liberation of ceftiofur free acid from hydrohalide salt using either resinous bases or non-resinous bases is associated with several problem. Keeping all these problems in mind, the Applicant discloses a simple, economical and commercially viable process for preparing ceftiofur sodium starting from ceftiofur hydrohalide salt which obviates the above mentioned limitations and does not use known neutralizing agents for this purpose. The process comprises of two steps: (a) treatment of hydrohalide salt of ceftiofur with a trimethylsilylating agent which will neutralize the ceftiofur hydrohalide salt to give free ceftiofur acid; and (b) the reaction of free ceftiofur acid with sodium exchanging agents'for making sodium salt of ceftiofur acid OBJECTS OF THE INVENTION The primary object of the invention is a new process for preparing a ceftiofur sodium. Another object of this invention is to neutralize the hydrohalide salt of ceftiofur to get free ceftiofur acid. This has been achieved by using N,0-bistrimethylsilyl acetamide, bis-trimethylsilylurea and Hexamethyl disilazane (HMDS).The applicant reports for the first time the use of these trimethylating agents for the purpose of neutralizing the hydrohalide salt of any cephem acid. Yet another object of the invention relates to use of trimethylsilylating agent for the first time for the purpose of neutralizing the hydrohalide salt of any cephem acid. Still another object of this invention is to make sodium salt thus prepared from ceftiofur acid using sodium lactate, sodium ethylacetoacetate, sodium-2-ethyl hexanoate and sodium acetate as sodium exchange reagent. SUMMARY OF THE INVENTION The present invention relates to a process for preparing sodium salt of cephalosporins from their corresponding hydrohalide salt, which is neutralized with trimethylsilylating agent for the first time. DETAILED DESCRIPTION OF THE INVENTION According to this invention treatment of hydrohalide salt of ceftiofur with a silylating agent in an aprotic solvent at a temperature ranging from 25 to 60°C for 8-12 hrs gives free acid. The hydrohalide salt of ceftiofur employed in the present invention is well-known and commercially available. Hence, the present invention relates to a process for preparing ceftiofur sodium of formula (II) said process comprising the steps of: a) dissolving a ceftiofur hydrohalide salt in an aprotic organic solvent such as hereindescribed and neutralizing it with a silylating agent such as hereindescribed at a temperature in the range of 25 to 65 °C, b) precipitating the ceftiofur acid by quenching with water, c) dissolving the ceftiofur acid from step (b) in a solvent and reacting with a sodium exchanging reagent such as hereindescribed, d) precipitating ceftiofur sodium with a solvent as hereindescribed, and e) isolating the ceftiofur sodium by conventional methods. Since the solubility of hydrohalide salt of ceftiofur is very poor in organic solvent and in aqueous phase, it is required to be neutralized. Silylating agents such as N,0-bistrimethylsilyl acetamide, bissilyl-urea (BSU) and hexamethyl disilazane (HMDS) used herein plays a dual role in this reaction. First, it solublizes the hydrohalide salt of ceftiofur in an aprotic organic solvent and thereby production of ceftiofur acid by neutralization of the hydrohalide salt, thus avoiding use of any other _ base. The silylating agent was used in mole ratio of 1.0 to 5.0 w.r.t hydrohalide salt but the most preferred ratio is about 3.0 moles w.r.t. hydrohalide salt of ceftiofur. The solvents used in the process are selected from any of tetrahydrofuran, dioxane, Dichloromethane, dimethylacetamide (DMAc), acetone, acetonitrile and mixtures thereof. Most suitable solvents were acetonitrile and DMAc. The reaction was carried out at temperature range of 25-60°C but best results were obtained at 35-40°C. The reaction duration was about 8-12 hours. The wet cake of ceftiofur acid thus obtained was converted to sodium salt using sodium exchanging agents like sodium lactate, sodium ethyl acetoacetate, sodium acetate and sodium 2-ethyl hexanoate. Ceftiofur acid was dissolved in suitable solvent and reacted with suitable sodium-exchanging reagent, whereby the ceftiofur sodium product was precipitated by the addition of ethyl acetate or acetone. The preferred process of this invention is to prepare sodium salt of ceftiofur starting from hydrohalide salt of ceftiofur acid. 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-1 7-[2-(2-amino-l,3-thiazol-4-yl)2-methoxyimino)acetaimdo]-3-[(fur-2-ylcarbonyI)thiomethyl]-3-cephem-4-carboxylicacid A sample of ceftiofur hydrochloride salt (25.0 g) was suspended in acetonitrile (125 ml) around 28-30°C. N,0 bis trimethylsilyl acetamide (27.5 gm) was added slowly. The temperature rose upto 45°C. The resultant solution was stirred for 8-9 hours at 28-30°C. The solution was added to water (1000 ml) and stirred at 28-30°C for 45-50 minutes. The solid material obtained was filtered and washed with water (2 x 50 ml). Product was dried under vacuum at 40-42°C for 6-8 hours to give 20g title compound. £xample-2 7-[2-(2-amino-l,3-thlazol-4-yl)2-methoxyimino)acetamido]-3-[(fur-2-ylcarbonyl)thiomethyl]-3-cephem-4-carboxylicacid A sample of ceftiofur hydrochloride salt (25.0 g) was suspended in dimethylacetamide (105 ml) around 28-30°C. N,0 bis trimethylsilyl acetamide (27.5 gm) was added. The temperature rose upto 45 °C. The resultant solution was stirred for 8-9 hours at 28-30°C. The solution was added to water (1000 ml) and stirred at 28-30°C for 45-50 minutes. The solid material obtained was filtered and washed with water (2 x 50 ml). Product was dried under vacuum at 40-42°C for 6-8 hours to give (19g) title compound. £xample-3 7-[2-(2-amino-l,3-thiazol-4-yl)2-methoxyimino)acetamido]-3-[(tur-2-ylcarbonyl)thiomethyl]-3-cephem-4-carboxylicacid A sample of ceftiofur hydrochloride salt (25.0 g) was suspended in acetonitrile (125 ml) around 28-30°C. Bissilylurea (BSU) (35 gm) was added slowly to it. The temperature rose upto 45°C. The resultant solution was stirred for 8-9 hours at 28-30°C. The solution was added to water (1000 ml) and stirred at 28-30°C for 45-50 minutes. The solid material obtained was filtered and washed with water (2 x 50 ml). Product was dried under vacuum at 40-42°C for 6-8 hours to give (20g) title compound. £xample-4 7-[2-(2-amino-l,3-thiazol-4-yl)2-methoxyimino)acetamido]-3-[(fur-2-ylcarbonyl)thiomethyl]-3-cephem-4-carboxylicacid A sample of ceftiofur hydrochloride salt (25.0 g) was suspended in acetonitrile (125 ml) around 28-30°C. Hexamethyl disilazane (40 gm) was added slowly. The temperature rose upto 45°C. The resultant solution was stirred for 8-9 hours at 28- 30°C. The solution was added to water (1000 ml) and stirred at 28-30°C for 45-50 minutes. The solid material obtained was filtered and washed with water (2 x 50 ml). Product was dried under vacuum at 40-42°C for 6-8 hours to give (20g) title compound. Example -5 Sodium 7-[2-(2-amino-l,3-thiazol-4-yl)2-methoxyiinino)acetamido]-3-[(fur-2-ylcarbonyl)thiomethyl]-3-cephem-4-carboxylate A sample of ceftiofur acid (5.0 gm, anhydrous basis) was suspended in methanol (25 ml) around 20-22°C. Triethylamine (1 g) was added dropwise in 20 minutes. The solution was treated with carbon and filtered off at 20-25°C. A solution of sodium lactate 60% w/w (1.7 g) in methanol (10 ml) at 28°C, was added drop wise and stirred. Acetone (165 ml) was added further for complete crystallization at 20-25°C. The crystalline product formed was filtered and washed with ethyl acetate (3x10 ml), product was dried under vacuum at 40-42°C for 3-4 hours to get 3.8 gm of ceftiofur sodium (purity by HPLC 97.0%). Example 6 Sodium 7-[2-(2-amino-l,3-thiazol-4-yl)2-methoxyimino)acetamido]-3-[(fur-2-ylcarbonyl)thiomethyl]-3-cephem-4-carboxylate A sample of ceftiofur acid (5.0 g, anhydrous basis) was suspended in methanol (25 ml) around 20-22°C. Triethylamine (1.0 gm) was added dropwise in 20 minutes. The resultant solution was treated with carbon and filtered off at 20-25°C. A solution of ethyl acetoacetate sodium salt (1.5 g) in 10 ml of methanol was added dropwise to ceftiofur acid solution around 20-25°C and stirred. Ethyl acetate (40 ml) was added further for complete crystallization at 20-28°C. The crystals were filtered and washed with ethyl acetate (3 x 10 ml). Product was dried under vacuum at 40-42°C for 3-4 hours to get 3.73 gm of ceftiofur sodium (purity by HPLC 98.0%) Example 7 Wet ceftiofur acid (2.5 gm on anhydrous basis, 4.7 mmol) was dissolved in tetrahydrofuran (45 ml) and the resultant cleai- solution was treated with sodium-2-ethyl hexanoate (1.2 gm, 7.2 nmiol) at room temperature for 10 minutes. Acetone was added to precipitate out the ceftiofur sodium in crystalline form, which was separated by filtration. Solid was washed with acetone and dried at 40-42°C to get 1.8 gm of ceftiofur sodium (purity by HPLC>97%). Example 8 Wet ceftiofur acid (2.5 gm on anhydrous basis, 4.7 mmol) was dissolved in tetrahydrofuran (45 ml) and the resultant clear solution was treated with sodiumethylacetoacetate (1.1 gm, 7.3 mmol) at room temperature for 10 minutes. Acetone was added to precipitate out the sodium ceftiofur in crystalline form, which was separated by filtration. Solid was washed with acetone and dried at 40-42°C to get 1.9 gm of ceftiofur sodium (purity by HPLC>98%). Example 9 A sample of ceftiofur acid (5,0 g, anhydrous basis) was suspended in methanol (25 ml) around 20-22°C. Triethylamine (1.0 gm) was added dropwise in 20 minutes. The resultant solution was treated with carbon and filtered off at 20-25°C. A solution of anhydrous sodium acetate (1.5 g) in 20 ml of methanol was added dropwise to ceftiofur acid solution around 20-25°C. Ethylacetate (40 ml) was added further for complete crystallization around 20-28°C. The crystals were filtered and washed with ethyl acetate (3 x 10 ml). Product was dried under vacuum at 40-42°C for 3-4 hours to get 3.73 gm of ceftiofur sodium (purity by HPLC 97.0%). We claim: l.A process for preparing ceftiofur sodium of formula said process comprising the steps of: a) dissolving a ceftiofur hydrohalide salt in an aprotic organic solvent such as hereindescribed and neutralizing it with a silylating agent such as hereindescribed at a temperature in the range of 25 to 65 °C, b) precipitating the ceftiofur acid by quenching with water, c) dissolving the ceftiofur acid from step (b) in a solvent and reacting with a sodium exchanging reagent such as hereindescribed, d) precipitating ceftiofur sodium with a solvent as hereindescribed, and e) isolating the ceftiofur sodium by conventional methods. 2. A process as claimed in claim 1 wherein the silylating agent is selected from N,0-bis trimethylsilyl acetamide, hexamethyldisilazane (HMDS) and bissilylurea (BSU) and mixtures thereof. 3. A process as claimed in claim 1 wherein the aprotic organic solvent is selected from acetone, tetrahydrofuran, acetonitrile, dioxane, dimethylacetamide and mixtures thereof. 4. A process as claimed in claim 1 wherein the sodium ^ exchanging reagent is selected from sodium lactate, sodium ethyl acetoacetate, anhydrous sodium acetate and sodium-2-ethyl hexanoate. 5. A process as claimed in claim 1 wherein the ratio of silylating agent to hydrohalide salt of ceftiofur is 1 mole to 5 moles. 6. A process as claimed in claim 1 wherein the hyrdrohalide salt of ceftiofur is selected from hydrochloride or hydrobromide. 7. A process as claimed in claim 1 wherein the solvent in step (c) is selected from tetrahydrofuran, dioxane, dichloromethane, dimethylacetamide, acetone and acetonitrile. 8. A process as claimed in claim 1 wherein the solvent in step (d) is selected from ethyl acetate or acetone. 9. A process for preparing a ceftiofur sodium compound substantially as hereindescribed and illustrated.

Documents:

0810-mas-2001 abstract.pdf

0810-mas-2001 claims.pdf

0810-mas-2001 correspondence-others.pdf

0810-mas-2001 correspondence-po.pdf

0810-mas-2001 description (complete).pdf

0810-mas-2001 form-1.pdf

0810-mas-2001 form-26.pdf

0810-mas-2001 form-3.pdf

0810-mas-2001 petition.pdf