Title of Invention	IMPROVED PROCESS FOR THE PURIFICATION OF PIPERACILLIN
Abstract	The present invention relates to an improved process for the purification of Piperacillin or its hydrate. The Piperacillin purified according to this process has higher aqueous solubility and very low-level residual solvent. This invention also relates to a process for the preparation of Piperacillin of formula (I).

Full Text

Field of the Invention The present invention relates to an improved process for the purification of Piperacillin. This invention also relates to a process for the preparation of Piperacillin of formula (I). Background of the Invention Piperacillin is a beta-lactam antibiotic and is mainly bactericidal. It inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. Piperacillin sodium is widely admixered in combinations with tazobactam sodium. Tazobactam protects piperacillin against Richmond and Sykes types II, III, IV, and V beta-lactamases; staphylococcal penicillinase; and extended-spectrum beta-lactamases. Tazobactam enhances and extends the antibiotic spectrum of piperacillin to include beta-lactamase producing bacteria normally resistant to piperacillin. The chemical name of piperacillin sodium is sodium (2S, 5R, 6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-l- piperazinecarboxamido)-2- phenylacetamido]-3,-3-dimethyl- 7-oxo-4-thia~l-azabicyclo [3.2.0]heptane-2-carboxylate. US patent 4,112,090 claims Piperacillin and its pharmaceutical^ acceptable salts. This patent also disclose various processes for the preparation Piperacillin. US patent 4,477,452 claims a process for freeze-drying an aqueous solution of sodium piperacillin, by evaporating a frozen aqueous solution of sodium piperacillin under vacuum from the frozen state to dryness. US patent 6,828,438 a process for the preparation of sodium salt of 6[D-(-)a-4-(ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido]penicillanic acid (Piperacillin). The process involves reaction of the Piperacillin with a reagent selected from the group consisting of sodium hydroxide, sodium carboxylates and sodium alcoholates, followed by a separation of the so obtained sodium salt by precipitation. Most of the literature reported process for the preparation of Piperacillin sodium involves either crystallization using organic solvent or lyohilisation. One of the major problems associated in crystallization method is the product obtained has higher residual solvent. The lyohilisation technique involves initial dissolution of Piperacillin or Piperacillin monohydrate in aqueous medium, followed by freeze-drying. The drawback associated with in this process is Piperacillin monohydrate obtained by prior art process has poor solubility in aqueous medium and has higher residual solvent, hence makes the process difficult; Because of these drawbacks there is a need to develop a purification process required for Piperacillin or Piperacillin monohydrate. In view of importance of Piperacillin sodium, we have found a process for the preparation of Piperacillin monohydrate that has higher solubility in aqueous medium and meets residual solvent content as per ICH guidelines and meets the requirements of USP. Objectives of the Invention The main objective of the present invention provides an improved process for the purification Piperacillin monohydrate of formula (I), which has better solubility in aqueous medium. Another objective of the present invention also provides a process for the preparation of Piperacillin monohydrate of formula (I). Summary of the Invention Accordingly, the present invention provides an improved process for the preparation of Piperacillin of formula (I), which comprising the steps of: (i) condensing the 6-APA of formula (II) or its salt with R- (-)-a-[[(4-Ethyl-2, 3-dioxo- 1-piperazinyl) carbonyl] amino] benzene acid chloride of formula (III) in the presence of a solvent to yield Piperacillin of formula (I), (i) disoloving Piperacillin of formula (I) using a solvent consisting of methanol, water and ethyl acetate in the presence or absence of base, and (i) precipitating Piperacillin (I) or its hydrates. The scheme disclosing the process is given below scheme: The present invention also relates to an improved process for the purification of Piperacillin of formula (I) or its hydrate, the said process comprising the steps of: a) dissolving Piperacillin of formula (I) using a solvent consisting of methanol, water and ethyl acetate, in the presence or absence of base, b) subjecting the step (a) solution to carbon treatment, and c) precipitating Piperacillin or its hydrate. Description of the Invention In an embodiment of the present invention the salt of 6-APA is prepared by treating 6-APA with corresponding base which includes trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine, N, N Dimethyl acetamide, dicyclohexylamine, diethylamine, TMG (tetramethylguanidine). In another embodiment of the present invention the solvent used in step (i) is selected from water, acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, methanol, ethanol, methoxyethanol, diethyl ether, isopropyl ether, benzene, toluene, methylene chloride, chloroform, ethyl acetate, methyl isobutyl ketone and the like or mixtures thereof In still another embodiment of the present invention the with R- (-)-a-[[(4-Ethyl-2, 3-dioxo-l-piperazinyl) carbonyl] amino] benzene acid chloride is prepared by reacting R- (-)-a-[[(4-Ethyl-2, 3-dioxo-l-piperazinyl) carbonyl] amino] benzene acid with phosphoryl chloride, sulfuryl chloride PC13, PC15, POCI3 and the like. In another embodiment of the present invention the base used in the present invention is selected from sodium carbonate, sodium bicarbonate, TEA, DEA, TMG and the like. In yet another embodiment of present invention the Piperacillin monohydrate obtained according to this invention has higher solubility in aqueous medium, which makes the Piperacillin sodium process convenient. Also the present invention yield the product having low level residual solvent, which gives commercial advantages to this invention. In another embodiment of the present invention the Piperacillin obtained according to this process is in monohydrate. The foregoing technique has been found to be attractive from commercial, technological and ecological perspective. Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention within the scope of disclosure. The present invention is illustrated with the following examples, which should not be construed for limiting the scope of the invention. Example 1 Preparation of Piperacillin (I): R- (-)-a-[[(4-Ethyl-2, 3-dioxo-l-piperazinyl) carbonyl] amino] benzene acetic acid (156.3 gm) was dissolved in Dichloromethane (500 ml) and N, N Dimethyl acetamide (250 mL). To the resultant solution phosphoryl chloride (79gm) was added at -20°C and stirred for one hour. The reaction mixture was cooled to -45°C. To this mixture, previously prepared solution of 6APA Diethylamine salt soltion (Prepared by treating Diethyl amine (37.2 gm) with 6-APA (100 gm) at 20-30 °C in 500 mL Dichloromethane) was added at -43 to -45°C in 30 min. The resultant solution was stirred till completion of reaction. After completion of reaction water was added to the reaction mixture and stirred at 0°C. The layers obtained was separated and pH of organic layer (MDC) was adjusted pH 6.2 - 6.5 using 5.7 % aqueous solution of sodium bicarbonate (1500 mL) at 10-15°C. Layers again were separated and to aqueous layer Ethyl acetate was added. The pH of resultant solution adjusted to pH 2.0- 2.2 at 10 - 15°C using 18 % HC1. The precipitate obtained filtered and dried to yield Piperacillin Acid (240 gm) Process for the purification of Piperacillin 100 gm crude Piperacillin was dissolved in Methanol (140 ml) at 28 -31°C. To this solution Ethyl acetate (140 ml) was added. The solution was treated with activated carbon 2.0 g at 28-32 C for 15 min and then carbon is filtered off. To the filtrate of water (310 mL) was added slowly at 32 - 34°C. The resultant solid was cooled to 5 - 10°C and filtered washed with water dried under vacuum at 45°C to yieldpure Piperacillin (91.3 gm (M/C 3.41%), HPLCpurity: 99.21%) Example 2: purification of Piperacillin To Piperacillin (50 gm) in water (109 ml) 9% Aq. Solution of sodium bicarbonate was charged to get clear solution at 30°C. To the clear solution was subjected to carbon treatment. To the filtrate, Methanol (82-mL) and Ethyl acetate (50 ml) were added. The reaction mixture pH was adjusted to 2.2 - 2.2 at 20 - 25°C with 18 % HC1 solution. The solid obtained was filtered and dried to get 42.6gm titled product. (M/C 3.1%, Purity 99.0 %). We claim: 1. A process for the preparation of Piperacillin of formula (I), which comprising the steps of: (i) condensing the 6- APA of formula (II) or its salt (i) with R- (-)-a-[[(4-Ethyl-2, 3-dioxo-1 -piperazinyl) carbonyl] amino] benzene acid chloride of formula (III) in the presence of a solvent to yield Piperacillin of formula (I), (i) disoloving Piperacillin of formula (I) using a solvent consisting of methanol, water and ethyl acetate in the presence or absence of base, and (i) precipitating Piperacillin (I) or its hydrates. 2. The process as claimed in claim 1, wherein solvent used in step (i) is selected from water, acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, methanol, ethanol, methoxyethanol, diethyl ether, isopropyl ether, benzene, toluene, methylene chloride, chloroform, ethyl acetate, methyl isobutyl ketone or mixtures thereof. 3. The process as claimed in claim 1, wherein salt of 6-APA is prepared using a base is selected base which includes trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine, dicyclohexylamine, diethylamine, TMG (tetramethylguanidine). 4. A process for purification of Piperacillin of formula (I), the said process comprising the steps of: a) dissolving Piperacillin of formula (I) using a solvent consisting of methanol, water and ethyl acetate, in the presence or absence of base, b) subjecting the step (a) solution to carbon treatment, and c) precipitating Piperacillin or its hydrate. 5. A process according to claim 1 or 4, wherein the base used is selected form sodium carbonate, sodium bicarbonate, TEA, DEA, TMG.

Documents:

0596-che-2005-abstract.pdf

0596-che-2005-claims.pdf

0596-che-2005-correspondnece-others.pdf

0596-che-2005-description(complete).pdf

0596-che-2005-form 1.pdf

596-CHE-2005 AMENDED CLAIMS 26-02-2013.pdf

596-CHE-2005 AMENDED PAGES OF SPECIFICATION 26-02-2013.pdf

596-CHE-2005 CORRESPONDENCE OTHERS 26-02-2013.pdf

596-CHE-2005 AMENDED CLAIMS 09-04-2012.pdf

596-CHE-2005 CORRESPONDENCE OTHERS 09-04-2012.pdf