Title of Invention	"AN IMOROVED PROCESS TO PREPARE CEFPROZIL"
Abstract	The present invention provides an industrially advantageous, improved acylation process for the preparation of Cephalosporin, Cefprozil which comprises the N-acylation of a silylated derivative of 7-amino-3 -(1 -propen-1 -yl)-3 -cephem-4-carboxylic acid with D-(-)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride.

Full Text

FIELD OF THE INVENTION The present invention provides an industrially advantageous, improved acylation process for the preparation of Cefprozil which comprises the N-acylation of a silylated derivative of 7-amino-3-(1 -propen-1 -yl)-3-cephem-4-carboxylic acid with D-(-)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride. BACKGROUND OF THE INVENTION Cefprozil of Formula I is a broad spectrum antibacterial compound possessing activity against both Gram positive and Gram negative microorganisms and chemically known as (6R,7r)-7-[(R)-2-amino-2-(p-hydroxyphenyl)acetamido]-8-oxo-3-propenyl-5-thia-l-azabicyclo[4,2.0]oct-2-ene-2-carboxylic acid monohydrate. Cefprozil and its preparation has been first disclosed in US Patent 4,520,022 which comprises the step of protecting the amino group of 4-hydroxyphenylglycine, reacting with 3-chloromethyl cephem ester in the presence of dicyclohexylcarbodiimide, a condensing agent and conversion of 3-chloromethyl group of resulting compound to 3-propenyl group, via Wittig reaction, followed by the removal of protecting groups to obtain Cefprozil. Another US Patent 4,699,979 discloses the preparation of Cefprozil which comprises the reaction of amino protected 4-hydroxyphenylglycine with 3-propenylcephem ester in the presence of dicyclohexylcarbodiimide and removing the protecting groups to obtain Cefprozil. Both of the above methods involve the use of expensive reagents in protecting and deprotecting steps and have the problems that the use of moisture-sensitive dicyclohexylcarbodiimide requires rigorous anhydrous conditions and the product obtained is of low purity due to difficulty of removing residual side product dicyclohexylurea. US Patent 4,694,079 describes preparation of Cefprozil in the form of N,N-dimethylformamide solvate wherein the acylation of 7-amino-3-(l-propen-l-yl)-3-cephem-4-carboxylic acid is carried out with acid chloride hydrochloride of D-(-)-2-(p-hydroxyphenyl)glycine in the presence of a weak base, such as iVjiV-dimethylaniline. Although this process is an improvement over above processes and has the advantage that the amino protecting group (the hydrochloride) can be easily removed by adjusting the pH of the reaction mixture, even though this process has some disadvantages like use of suspected carcinogenic compound N,N-dimethylaniline during acylation reaction and the final product is always contaminated with this compound. To prepare the final product of required purity, extensive purifications are required as health regulations of many countries prohibit the administration of such contaminated products. The exemplified process in US 4,694,079 make use of chromatographic and lyophilization techniques to obtain the pure product. The use of chromatography and lyophilization is cumbersome, tedious and not practical on an industrial scale. However, in our hands, we observed that E-isomer formation is more, possibly due to the presence of N,N-dimethylaniline hydrochloride. Further, the yields are also low. In view of the above, it is an object of the present invention to prepare pure Cefprozil in good yields by simple and efficient process, which is convenient to operate on an industrial scale. DETAILED DESCRIPTION OF THE INVENTION The instant invention relates to an industrially advantageous process for the preparation of pure Cefprozil, (6i?,7i?)-7-[(R)-2-amino-2-(p-hydroxyphenyl)acetamido]-8-oxo-3-propenyl-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohydrate. Preferably, the present invention provides an improved acylation process for preparing Cefprozil, which results in better yields, high purity and low production cost. Usually, the acylation process is carried out by first reacting 3-propenylcephem compound of Formula II with silylating agent and then condensing the resulting silylated product with acid chloride hydrochloride of D-(-)-2-(p-hydroxyphenyl)glycine of Formula III As hydrogen chloride is formed during acylation reaction, a weak base, which act as a proton acceptor, must always be present. The weak base used in this step should be strong enough to capture all of the hydrogen chloride generated during the reaction, if all of the acid is not neutralized it will react with unreacted silylated 3-propenylcephem compound of Formula II and produce a species which is unreactive towards acylation. On the other hand, weak base should be less basic than the amino group of the D-(-)-2-(p-hydroxyphenyl)glycine, since this group will otherwise be deprotected and imdesired side product will be formed. We have now surprisingly found that by using N-trimethylsilylacetamide as a silylating agent the use of toxic weak base like N,N'-dimethylaniline during acylation reaction can be avoided, and also formation of E-isomer can be controlled. Further, N-Trimethylsilylacetamide serves both the purposes as a silylating agent as well as a weak base. The acetamide formed by the reaction of trimethylsilyl radical with acid, acts as a hydrogen chloride acceptor during acylation reaction. Specifically, according to present invention Cefprozil of Formula I - cleavage of silyl groups by hydrolysis or alcoholysis - isolation of Cefprozil as N,N-dimethylformamide solvate and - conversion of Cefprozil-N,N-dimethylfonnamide solvate to Cefprozil. The 7-amino-3-(l-propen-l-yl)-3-cephem-4-carboxylic acid of Formula II, which is predominantly Z-isomer and D-(-)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride of Formula III can be prepared by following any of the methods known in the prior art. The 3-propenylcephem compound of Formula II may advantageously be silylated in an inert organic solvent to form in-situ solution of silylated derivative. It is important to add sufficient N-trimethylsilylacetamide to solubilize the compound of Formula II before treating with acid chloride hydrochloride of Formula III. Suitable solvents which may be used in acylation process are all inert organic solvents in which silylated derivative is soluble for example tetrahydrofuran, methylene chloride or the like and most preferably anhydrous methylene chloride is used. Soluble silylated derivative is then treated with acid chloride hydrochloride of Formula III, preferably with one molar equivalent and most preferably with a slight excess of the acid chloride hydrochloride. Acetamide may optionally be added to ensure complete neutralization of hydrochloric acid generated during acylation. The silylation of compound of Formula II is completed at about 20-40°C while the N-acylation is advantageously carried out at -15 to 20°C more preferably at -10 to -5 °C. After iV-acylation is complete, as determined by the high performance liquid chromatography, water or a mixture of water and suitable alcohol is added to cleave the silyl protecting group. Suitable alcohol can be selected from C1-C4 lower alcohols such as methanol, ethanol, n-propanol or the like and mixture thereof. Thereafter, the layers are separated, the aqueous layer is diluted with N,N-dimethylformamide and pH of the aqueous layer is adjusted between 4.5 to 7.0 with suitable base to precipitate (6i?,77?)-7-[(R)-2-amino-2-(p-hydroxyphenyl)acetamido]-8-oxo-3-propenyl-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in the form of N^N-dimethylformamide solvate, which is filtered and dried. The suitable base can be selected from triethylamine, aqueous ammonia or the like and preferably aqueous ammonia is used. The conversion of Cefprozil N,N-dimethylformamide solvate to Cefprozil, in accordance with the present invention is preferably carried out in a solvent such as water, lower alcohols and mixture thereof. The reaction is generally carried out at a temperature range of 30-60°C and preferably at 40-45°C. The lower alcohol can be selected from methanol, ethanol, isopropanol or like and a mixture thereof. The resulting reaction mass is then stirred for 1-2 hours to ensure the crystallization of the desired Cefprozil in the form of its monohydrate, which is isolated by filtration. The Cefprozil, thus obtained is pure and having better yields than reported in US Patent 4,694,079. The present process also provides control of the stereochemical configuration of E-isomer. Another advantage of the present invention is the improved acylation process which avoids the uses of suspected carcinogen N,N-dimethylaniline and the troublesome purification like chromatography. Moreover, N-trimethylsilylacetamide serves as a silylating agent and as well as a weak base, thus a cost effective and industrially viable process is in place. The examples below illustrate our invention without limiting the scope of the invention. Example-1 (A) PREPARA TION OF CEFPROZIL N,N-DIMETHYLFORMAMIDE SOL VA TE To a suspension of 7-amino-3-(l-propen-l-yl)-3-cephem-4-carboxylic acid (25 g, 0.104 mol) in methylene chloride (500 ml) was added N-trimethylsilylacetamide solution (containing 50.8 g, N-trimemethylsilylacetamide, 0.387 mol) at 20-25°C and the reaction mass was stirred at 30-35°C for about 30-45 minutes to obtain a clear solution. The solution was then cooled to -10°C and acetamide (12.5 g, 0.211 mol) was added. Thereafter, D-(-)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride (38.7 g) was added portionwise over a period of 25-30 minutes and stirred for 1-2 hours at -10°C. After completion of reaction, methanol (12.5 ml) and water (110 ml) were added and stirred at 0-5°C for 30 minutes. The layers were separated, aqueous layer was filtered and diluted with N,N-dimethylformamide (625 ml). The pH of the aqueous layer was adjusted to 6.5-6.8 with aqueous ammonia at 25-30°C and stirred for 1 hour at same temperature. The reaction mass was then cooled to 0-5°C and stirring was continued for further 1-2 hours. The product, thus obtained was filtered, washed with chilled acetone and dried under reduced pressure to obtain Cefprozil as a N,N-dimethylformamide solvate (45 g) having purity 97.55% by HPLC. (B) PREPARATION OF CEFPROZIL The Cefprozil N,N-dimethylformamide solvate (42 g) was added portionwise to water (42 ml) at 40"45°C. After completion of addition, the reaction mass was stirred for further 1-2 hours at the same temperature. Thereafter, the reaction mass was cooled to 0-5°C and stirred for 1-2 hours. The product was filtered, washed with chilled acetone (2x30 ml) and dried under reduced pressure to obtain 28.5 g of the title compound as monohydrate having purity 99.01% by HPLC. 1HNMR (D20 + Na2C03) : S(ppm); 1.51 (d, 3HX 10/11, J=6.6 Hz, Z-CH3), 1.708 (d, 3H X 0.8/11, J=6.0 Hz, E-CH3), 3.09-3.39 (m, 2H, 2-H), 4.673 (s, IH, CHCO), 5.01-5.02 (d, IH, J=4.8 Hz, 6-H), 5.52-5.66 (m, 2H, 7-H & vinyl H), 5.79- 5.82 (d, IH, J=ll.lHz, vinyl H), 6.84 (d, 2H, Ar-H), 7.25 (d, 2H, Ar-H) Example-2 (A) PREPARA TION OF CEFPROZIL N,N-DIMETHYLFORMAMIDE SOL VA TE To a suspension of 7-amino-3-(l-propen-l-yl)-3-cephems-4-carboxylic acid (lOg, 0.042 mol) in methylene chloride (200 ml) was added N-trimethylsilylacetamide solution (containing 20.3 g of N-trimethylsilylacetamide 0.16 mol) at 20-25°C and reaction mass stirred at 25-30°C for 45 minutes to obtain a clear solution. The solution was then cooled to -10°C and D-(-)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride (14.4 g) was added in portions over a period of 30-35 minutes and stirred for 30 minutes at -10°C. After completion of reaction, methanol (5 ml) and water (45 ml) were added and stirred for 15 minutes at 0-5°C. The layers were separated, aqueous layer was filtered and diluted with 150 ml of N,N-dimethylformamide, The pH of reaction mass was adjusted to 6.5-6.8 with aqueous ammonia at 25-30°C and the suspension was stirred for 30 minutes at ambient temperature. The reaction mass was then cooled to 0-5°C and stirring was continued for further 1-2 hours. The product, thus obtained was filtered, washed with chilled acetone and dried under reduced pressure to obtain Cefprozil as A/;A^-dimethylformamide solvate (17.5 gm) having purity 97.73% by HPLC. (B) PREPARA TION OF CEFPROZIL The Cefprozil N.N-dimethylformamide solvate (15 g) was added portionwise to a mixture of water (30 ml) and methanol (30 ml) at 40-45°C and the reaction mass was stirred for further 1-2 hour at same temperature. Thereafter, reaction mass was cooled to 20°C, filtered, washed with chilled water and dried under reduced pressure to obtain 9.0 g of the title compound as monohydrate having purity 99.24% by HPLC. 'H NMR (D2O + Na2CO3i): S(ppm); 1.51 (d, 3HX 9.93/11, J=6.9Hz, Z-CH3), 1.70 (d, 3H X 1.07/11, J=6.3Hz, E- CH3), 3.09-3.39 (m, 2H, 2-H), 4.628 (s, IH, CHCO), 4.98-5.00 (d, IH, J=4.5Hz, 6-H), 5.51-5.66 (m, 2H, 7-H & vinyl H), 5.78-5.82 (d, IH, 1 l.lHz,vinyl H), 6.82 (d, 2H, Ar-H), 7.23 (d, 2H, Ar-H). WE CLAIM: 1. An improved process for the preparation of Cefprozil, (6R,57R)-7-[(7?)-2-amino-2-(p-hydroxyphenyl)acetamido]-8-oxo-3-propenyl-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohydrate having the Formula I comprising the steps of; (a) reacting a compoimd, 7-amino-3-(l-propen-l-yl)-3-cephem-4-carboxylic acid of Formula II with a silylating agent, iV-trimethylsilylacetamide, (b) condensing the resulting silylated derivative with D-(-)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride of Formula III in methylene chloride, (c) hydrolysis of silyl groups by conventional methods, (d) treating the resulting reaction mass with N,N-dimethylformamide to isolate Cefprozil in the form of iV,A^"dimethylformamide solvate and (e) converting Cefjprozil A/iTV-dimethylformamide solvate to Cefprozil by treating with water or mixture of water and lower alcohols. 2. The process according to claim 1 wherein in step(e) lower alcohol can be selected from methanol, ethanol, isopropanol or like and a mixture thereof.

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