Title of Invention	"AN IMPROVED PROCESS FOR THE PREPARATION OF PHARMACEUTICAL GRADE CEFPODOXIME PROXETIL"
Abstract	The present invention discloses an improved and cost effective process for purification and isolation of pharmaceutical grade cefpodoxime proxetil.

Full Text

The present invention discloses an improved and cost effective process for industrial manufacture of cefpodoxime proxetil, and the said process of the present invention consistently gives high yield and purity. Chemically, cefpodoxime proxetil is 1-isopropoxycarbonyloxyethyl(6R, 7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-(methoxymethyl)-3-cephem-4-carboxylate of Formula I, as shown in the accompanied drawings and is known from US Patent No. 4,486,425 assigned to Sankyo of Japan. Cefpodoxime proxetil is one of the limited class of third generation cephalosporin derivatives which can be administered orally as it is readily adsorbed through the digestive tract and then readily hydrolized and converted in vivo to the corresponding carboxylic acid which in turn has potent broad spectrum antibacterial activity as well as remarkable stability against ß-lactamases. Pharmaceutical compounds are required in highly pure form because of the fear of unknown and potentially harmful effects of impurities. For purposes of patients' safety, it is highly desirable to limit the amount of impurities present in any medicament administered to a patient. This is achieved by either devising a process for or by additional purification steps like chromatography or recrystallization etc. The purity of intermediates and raw materials is essential for obtaining the target pharmaceutical compounds in high yield and purity. A number of methods have been outlined in US 4,486,425 for the synthesis of the cefpodoxime esters. However, in each of these methods, esterification of the carboxylic acids of the cephem ring results in impurities which have to be removed using silica gel column chromatography, as illustrated in the examples. US patents 4,482,710 and 5,461,043 also illustrate the synthesis of cefpodoxime proxetil using methods outlined in US 4,486,425 which employ chromatography after the esterification step to remove impurities and to get pure cefpodoxime proxetil. PCT application WO 99/35149 filed by Biochemie describes the preparation of cefpodoxime proxetil with a focus on the adjustment of diastereoisomeric ratio of the two diastereoisomers of cefpodoxime proxetil in the product mixture. Although, the process illustrated in this PCT application does not use chromatographic techniques for isolation of products, the process involves additional steps of protection and deprotection at the amino position of the thiazolyl moiety. Thus none of the prior art processes are satisfactory for the reasons described above. An object of the present invention, therefore, is to provide a cost effective and industrially advantageous process for purification and isolation by which the desired syn isomer of pharmaceutical grade cefpodoxime proxetil of Formula I, may be obtained in high purity and yield thus, obviating the need for chromatography or additional steps of protection and deprotection. Accordingly, the present invention provides a novel and industrially advantageous process for isolating the pharmaceutical grade cefpodoxime proxetil of Formula I, as shown in the accompanied drawings, which removes the common impurities (the 2-isomer of Formula II and anti-isomer of Formula III, as shown in the accompanied drawings) formed during the esterification reaction. Further, the process of the present invention also has the capabilities to eliminate the other side products formed during the esterification step i.e. the reaction of 1-iodoethylisopropyl carbonate of Formula IV with the unprotected amino group of the thiazolyl moiety of cefpodoxime proxetil of Formula I, Thus, the product obtained by following the present process is highly pure without the use of chromatography or without carrying out additional steps of protection and deprotection. More specifically, the present invention relates to a process for purification and isolation of pharmaceutical grade cefpodoxime proxetil of Formula I, as shown in the accompanied drawings or a pharmaceutically acceptable salt thereof comprising the steps: (a) dissolving cefpodoxime proxetil or adding a solution containing cefpodoxime proxetil into a polar organic solvent as described herein or mixture (s) thereof followed by its addition after optional concentration into a non-polar organic solvent as described herein or mixture(s) thereof to precipitate the solid; (b) dissolving the product obtained from the above step into water miscible polar organic solvent followed by its addition after optional concentration into water to obtain pharmaceutical grade cefpodoxime proxetil. The scope of the present invention also covers the process for obtaining pharmaceutical grade cefpodoxime proxetil wherein the order of purification and isolation I.e. steps (a) and (b) is reversed. In turn cefpodoxime proxetil of Formula I may be obtained in situ by reacting 7-(2-(2-aminothiazol-4-yl)-2-methoxy-3-cephem carboxylic acid i.e. cefpodoxime acid (prepared as per the general process described in EP 29557) of Formula V or salt thereof, as shown in the accompanied drawings, with 1-iodoethyl isopropylcarbonate of Formula IV, as shown in the accompanied drawings, in the presence of a base which is followed by purification and isolation of pharmaceutical grade cefpodoxime proxetil as per the steps (a) and (b). In the meaning of the present invention, the term "water-miscible" shall refer to organic solvents which show essentially unlimited, preferably 100% miscibility with water. The polar organic solvents may have limited water miscibiity and the term "limited miscibility" shall also include water-immiscible organic solvents. Example for essentially water-miscible or water soluble organic solvents include lower alcohols such as methanol, ethanol and isopropanol; lower alkyl ketones such as acetone, lower alkyl glycol ethers such as methyl glycol; dipolar aprotic solvents such as N, N-dimethyl formamide (DMF), N, N-dimethylacetamide (DMA) and dimethyl sulfoxide (DMSO) and cyclic ethers such as tetrahydrofuran, dioxane or mixture(s) thereof. Particularly preferred are methanol, ethanol, isopropanol and acetone. Examples of polar organic solvents having limited miscibility in water include carboxylic acid esters such as ethyl acetate, higher alkyl ketones such as methylisobutyl ketone; chlorinated hydrocarbons, such as dichloromethane or mixture(s) thereof. Particularly preferred are ethyl acetate and dicholoromethane. Suitable non-polar organic solvents include hydrocarbons such as hexane, xylene; higher alkyl ethers such as diisopropyl ether, cyclic hydrocarbons such as cyclohexane or mixture(s) thereof. Particularly preferred are diisopropyl ether and cyclohexane. Slow preferably dropwise addition of the solution into a well stirred non-polar solvent or water (in first and second precipitation respectively) gives the desirable purity of product while dumping of the solution may result in lumps or gummy product. Cefpodoxime acid of Formula V used in the esterification reaction may be in the form of a salt, for example, an alkali metal salt, such as sodium or potassium salt, an ammonium salt or salt with nitrogen containing bases, such as triethylamine and dicyclohexylamine. The base may be inorganic, such as potassium carbonate, sodium carbonate and sodium bicarbonate or organic, such as triethylamine, dicyclohexylamine, 1,8-diazabicyclo [5,4.0] undec-7-ene (DBU) and N, N-dimethylaniline or a mixture thereof. If the starting compound of Formula V is in the form of a carboxylic acid salt such as sodium or potassium, it may be used in the reaction as such, without any base. The reaction is performed in the presence of a solvent. Suitable solvents include dimethylformamide, dimethylacetamide, dimethylsulphoxide, tetrahydrofuran, dichloromethane, ethylacetate, acetonitrile or mixture(s) thereof. The reaction is conducted at ambient temperature or with cooling, preferably at -10 to 0°C. The reaction mixture containing cefpodoxime proxetil in situ is then poured in to a polar organic solvent having limited miscibility or solubility in water and washed successively with aqueous solutions of hydrochloric acid, sodium bicarbonate, sodium thiosulphate and sodium chloride in sequence. The washed organic layer is concentrated and is then added into a non-polar organic solvent to accomplish the first precipitation. The product is further purified by dissolving the product in a water miscible and optionally subjecting it to carbon treatment followed by partial concentration and addition of the concentrated layer into water to effect second precipitation and obtain highly pure cefpodoxime proxetil. The separated solid is filtered and dried. The compounds of Formula I may be obtained in the form of acid addition salts with pharmaceutically acceptable acids, for example inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid or organic acids such as malonic acid, oxalic acid and tartaric acid. In the following section one preferred embodiment is described by way of example to illustrate the process of this invention. However, it is not intended in any way to limit the scope of the present invention. EXAMPLE Preparation of cefpodoxime proxetil in situ 10g of (6R.7R) 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3- (methoxymethyl)3-cephem-4-carboxylic acid was added to 60ml of N, N-dimethylacetamide and the mixture was cooled to -8°C. DBU (3.33g) was added followed by addition of 1-iodoethyl isopropyl carbonate (5.85g) at -8 to -5°C. The reaction mixture was stirred for 45 min at the same temperature. The reaction mixture thus obtained was poured into ethylacetate (300ml) followed by addition of water (300ml) at 20-22°C. The mixture was agitated for 10 min and the organic layer was separated. The organic layer was then washed successively with aqueous hydrochloric acid, aqueous sodium thiosulphate and finally with aqueous sodium chloride. Purification and isolation of pharmaceutical grade cefpodoxime proxetil Step - (a) The ethyl acetate layer as obtained above was concentrated to about 40 ml at 30-35°C under reduced pressure and added to cyclohexane (300ml) under stirring at 25°C during about 30 minutes. The precipitated solid was then filtered and washed with cyclohexane. Step (b) The wet product from Step (a) was added to methanol (40ml) at room temperature to obtain a solution and was concentrated at 30-35°C under reduced pressure to about 30ml. It was then added to water (180ml) in 15 minutes at 20-25°C to obtain a solid which was filtered and washed with a cold mixture of methanol and water (1:6 v/v, 20ml). The filtered solid was dried to obtain 9g of pharmaceutical grade cefpodoxime proxetil. (Diastereoisomeric mixture ratio B/A+B = 0.52 where B is the more polar isomer, Assay : 98%). WE CLAIM: 1. A process for purification and isolation of pharmaceutical grade cefpodoxime proxetil of Formula I, as shown in the accompanied drawings or a pharmaceutically acceptable salt thereof comprising the steps: a) dissolving cefpodoxime proxetil or adding a solution containing cefpodoxime proxetil into a polar organic solvent as described herein or mixture (s) thereof followed by its addition after optional concentration into a non-polar organic solvent as described herein or mixture(s) thereof to precipitate the solid; b) dissolving the product obtained from the above step into water miscible polar organic solvent followed by its addition after optional concentration into water to obtain pharmaceutical grade cefpodoxime proxetil. 2. The process according to claim 1, wherein pharmaceutical grade cefpodoxime proxetil is obtained by reacting cefpodoxime acid of Formula V, as shown in the accompanied drawings or a salt thereof with 1-iodoethyl isopropyl carbonate of Formula IV, as shown in the accompanied drawings, optionally in the presence of a base followed by purification and isolation of pharmaceutical grade cefpodoxime proxetil as per the steps (a) and (b) of Claim 1. 3. The process according to claim 1 or claim 2, wherein the solution obtained after dissolving cefpodoxime proxetil or by adding a solution containing cefpodoxime proxetil into a polar organic solvent is washed with water aqueous acidic and / or basic solution. 4. The process according to claim 1 or claim 2, wherein the order of purification and isolation is reversed. 5. The process according to claim 1 or claim 2, wherein a polar organic solvent has limited miscibility in water 6. The process according to claim 5 wherein a polar organic solvent having limited miscibility in water is ethylacetate or dichloromethane. 7. The process according to claim 1 or claim 2 wherein non-polar organic solvent is higher alkyl ether or cyclic hydrocarbon. 8. The process according to claim 7 wherein higher alkyl ether and cyclic hydrocarbon are diisopropyl ether and cyclohexane. 9. The process according to claim 1 or claim 2 wherein the water miscible organic solvent is methanol, ethanol, isopropanol or acetone. 10. The process according to claim 9 wherein the water miscible organic solvent is methanol. 11. The process according to claim 2 wherein the sodium salt of cefpodoxime acid is used. 12. The process according to claim 2 wherein the base used is potassium carbonate, sodium carbonate, dicyclohexylamine, 1,8-diazabicylco [5.4.0] undec-7-ene (DBU) or mixture(s) thereof. 13. The process according to claim 2, wherein the reaction is performed at -10 to 0°C. 14. The process for the preparation of pharmaceutical grade cefpodoxime proxetil or a salt thereof, as herein described and illustrated by the examples herein.

Documents:

191-del-2001-abstract.pdf

191-del-2001-claims.pdf

191-del-2001-correspondence-others.pdf

191-del-2001-correspondence-po.pdf

191-del-2001-description (complete).pdf

191-del-2001-drawings.pdf

191-del-2001-form-1.pdf

191-del-2001-form-19.pdf

191-del-2001-form-2.pdf

191-del-2001-form-3.pdf