Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF CEFPROZIL
Abstract	The present invention relates to DMSO solvate of Cefprozil (I), which is precursor in the preparation of Cefprozil. The present invention also provides a process for the preparation ofDMSO solvate ofCefprozil.

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Field of the Invention The present invention relates to DMSO solvate of CefProzil (I). The present invention also provides a process for the preparation of DMSO solvate of Ce^rozil. The novel solvates are important precursor in the preparation of Cefprozil. Background of the Invention Cefprozil is chemically known as (6R,7R)-7"[2-amino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)-propenyl]-3-cephem"4-carboxylic acid. It is an orally effective cephalosporin antibiotic having a broad spectrum of antibacterial activity against both gram positive and gram-negative organisms and is disclosed in US Patent No. 4,520,022. Many pharmacologically active organic compounds can also crystallize such that second, foreign molecules, especially solvent molecules, are regularly incorporated into the crystal structure of the principal pharmacologically active compound. This phenomenon is referred to as pseudopolymorphism and the resulting structures as pseudopolymorphs. When the second molecule is a solvent molecule, the pseudopolymorphs can be referred to as solvates. However, it is generally not possible to predict whether a particular organic compound will form solvates or not, the discovery of a solvates of a pharmaceutically useful compound provides an opportunity to improve the performance characteristics of a pharmaceutical product. Identification of new solvates also acts as useful intermediates/precursor in the isolation, purification of cephalosporin antibiotics. The isolation of cephalosporin from the aqueous medium always yield final product in poor quality, whereas if isolation of cephalosporin was carried out via solvates and followed by desolvation yields the product in good quality. DMF is widely used solvent for the purification of Cefprozil of formula (II). US patent No. 4,694,079 claims crystalline dimethylformamide solvate of 7-[(D)-2-amino-2-(4-hydroxyphenyl)acetamido]-3"((Z)-l-propen-l-yl)-3-cephe m-4-carboxylic acid and also discloses a process for the preparation of DMF solvate of Cefprozil as shown in scheme I below : During our continued search to find alternative solvent for DMF, we found that DMSO act as solvent which form solvates with Cefprozil, and after desolvating it yields cephalosporin with good yield and purity when compared to DMF. Objective of the Invention The main objective of the present invention is to provide a novel DMSO solvate Cefprozil of formula (I). Another objective of the present invention is to provide a process for the preparation of DMSO solvate Cefprozil of formula (I). Still another objective of the present invention is to provide a process for the preparation of Cefprozil of formula (II), by desolvating the compound of formula (I). Summary of the Invention Accordingly, the present invention provides a novel DMSO solvate Cefprozil of formula (I) i) acylating APCA of formula (IV) or its active derivative with 4-hydroxyphenylglycine or its derivative in the presence of a solvent, ii) isolating the DMSO solvate of formula (I), and iii) desolvating the DMSO solvate of formula (I) in the presence of solvent to yield the Cefprozil of formula (II). The process is shown in Scheme-2 Detailed description of the invention In an embodiment of the present invention acylation of compound of formula (IV) using compound of formula (III) may be effected with any convenient acylation agent such as for example, an acid halide (e.g. chloride or bromide), an anhydride or mixed anhydride, e.g. with pivalic acid or formed with a haloformate, e.g. a lower alkylhaloformate such as ethyl chloroformate, methyl chloroformate or reacting the compound of formula (IV) with phenyl glycine chloride hydrochloride or alternatively, the acid itself can be used, together with an esterifying agent, e.g. carbonyldiimidazole or a carbodiimide such as N,N*-dicyclohexylcarbodiimide. In another embodiment of the present invention acylation with an acid halide may be effected in the presence of an acid binding agent, e.g. a tertiary amine such as triethylamine, dimethylformamide, dimethylaniline, N-methyl morpholine; an inorganic base such as calcium carbonate or sodium bicarbonate; or an oxirane. In yet another embodiment of the present invention the salts of APCA of formula (IV) is activated using silylating agents such as hexamethyldisilazane (HMDS), trimethylchlorosilane(TMCS), trimethylsilyl iodide (TMSI), N,0-bis-(trimethylsilyl)-acetamide (BSA), methyltrimethylsilyltrifluoroacetamide (MSTFA), N,0-bistrimethylsilyltrifluoroacetamide (BSTFA) or by converting APCA into salts using secondary or tertiary amine such as l,8-diazabicyclo[5,4,0]undec-7-ene (DBU), DBN, or 1,1,3,3-tetramethylguanidine (TMG). In still another embodiment of the present invention the solvent used for acylation is selected from tetrahydrofuran, chloroform, dichloromethane (MDC), dichloroethane, ethylacetate, DMSO, acetone and the like or mixtures thereof. In yet another embodiment of the present invention, the desolvation in step (iii) is carried out using solvent such as water, or water-alcohol mixture wherein the alcohol is selected from methanol, ethanol, n-propanol, iso-propanol and the like. 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 Step (i & ii) Preparation of (6R,7R)-7-[2-ainino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)- propenyl]-3-cephem-4-carboxylic acid DMSO solvate (XIV) To 7-Amino-3-((Z/E)-propen-l-yl)ceph-3-em-4-carboxylic acid (APCA) (V) (25 g) in methylene chloride (150ml) at 28-30°C, TMCS (8.6 g) and HMDS (12.9 gm) were added and stirred for 2 hrs and cooled to -5 °C. Simultaneously, Dane salt (Potassium D-N-(l-methoxycarbonylpropen-2-yl) oc-amino-p-hydroxyphenylacetate) (34 g) in methylenechloride (240ml) was stirred and cooled to -40°C. N-methylmorpholine (0.5g) and methylchloro formate (10.8 g) DMSO (60 ml) were added and further cooled to -70°C. To this silylated APCA was added at -70°C. The resulting slurry was stirred at -40°C to ^5*^0 till completion of reaction. HCl (25ml) and water (75ml) were added and temperature was raised to 8 -10°C. The aq, layer was separated, the organic layer was extracted with HCl solution and the combined aq. layers were cooled to 0 to 5°C. inorganic residue obtained was filtered, The filtrate was warmed to 30°C, ammonia was added to adjust the pH to 6 followed by acetone (600 ml) was added. The slurry was stirred for Ihr. The precipitate was filtered and washed with acetone (200ml). The wet material was air dried to yield the title compound (yield 48 g). Step (iii) Preparation of (6R,7R)-7-I2-amino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)- propenyl]-3-cephem-4-carboxy!ic acid monohydrate (I) (6R,7R)-7-[2-Amino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)-propenyl]-3-cephem-4-carboxylic acid DMSO solvate (48 g) prepared according to the procedure given in step (i) was stirred in water at 30°C for 40min. The Crude compound was collected by filtration and washed with water (30ml) followed by acetone (30ml). The wet crude was dried in vacuum at room temp to give dried material which was then stirred in water (140ml) at 15°C, pH was adjusted to 1.0 using 1:1 HCl to get clear solution. Then pH was readjusted to 5.0 using 10% ammonia solution at 15 to 20°C. The precipitate was cooled to 2 to 5°C, stirred for 1.5hr, filtered and washed with water (30ml) followed by acetone (30ml) and dried in vacuum at room temperature to give the title compound (yield 35g, 99.5 %pure, moisture content 5.5%). We claim: 1. A DMSO solvate of Cefprozil (I) 2. A process for the preparation of DMSO solvate of Cefprozil, which comprising the steps of: a) acylating APCA of formula (IV) or its active derivative with 4-hydroxyphenylglycine of formula (III) or its derivative in the presence of a solvent and DMSO, and b) isolating the DMSO solvate of formula (I). 3. A process according to step (a) of Claim 2, wherein the solvent used in acylation is selected from tetrahydrofuran, chloroform, dichloromethane (MDC), dichloroethane, ethylacetate, DMSO, acetone or mixtures thereof 4. A process according to Claim 2, further comprising converting DMSO solvate of Cefprozil into Cefprozil of formula (II), which comprises the desolvation of DMSO solvate of Cefprozil by treating with water.

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1447-CHE-2004 AMENDED PAGES OF SPECIFICATION 26-07-2011.pdf

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