Title of Invention

PROCESS FOR THE PREPARATION OF A CHPEALOSPORIN ANTIBIOTIC

Abstract

A process for the preparation of 7-[2-amino-2-phenylacetamido]-3-cephem-4- carboxylic acid derivatives of the formula (I). wherein R represents hydrogen, ester which form a prodrug or a counter ion which forms a salt. The said process comprising the steps of: i) silylating the APCA in the presence of an ether solvent to produce silylated APCA and ii) condensing the silylated APCA of the with the mixed anhydride in the presence of an ether solvent, cosolvent and a base to produce DMF solvate followed by de solvating to yield the title compound.

Full Text

Field of the Invention The present invention relates to a process for the preparation of 7-a-aminoacyl-cephalosporin derivatives having the general formula (I). More particularly, the present invention relates to a process for the preparation of cefprozil of the formula (I), its esters, pharmaceutically acceptable salts or wherein R represents hydrogen, ester which form a prodrug or a counter ion, which forms a salt. 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. US patent No. 4,694,079 discloses a process for the preparation of DMF solvate of cefprozil as shown in scheme 1 below: US patent No. 5,608,055 discloses a process for the production of 7-a-aminoacyl-cephalosporin by acylating 7-amino-ceph-3-em-4-carboxylic acid or a derivative thereof in a halogen-free and water-immisble or sparingly soluble solvent in water selected from ketones, esters, aromatic hydrocarbon, alkanols. US patent Nos. 6,136,967 and 5,869,648 discloses a process for the preparation of cefprozil comprising : i) preparing a (Z)-isomer enriched 7-amino-3-(l-propen-l-yl)-3-cephem-4-carboxylic acid in free acid or salt form by depleting 7-amino-3-{(E)-l-propen-l-yl}-3-cephem-4-carboxylic acid in a mixture of 7-amino-3-{(Z)-l-propen-l-yl}-3-cephem-4-carboxylic acid and 7-amino-3-{(E)-l-propen-l-yl}-3-cephem-4-carboxylic acid by subjecting a solution of a mixture of (Z)- and (E)-isomers to adsorption chromatography, and, if desired, isolating a (Z)-isomer enriched 7-amino-3-(l-propen-l-yl)-3-cephem-4-carboxylic acid in free acid or salt form; and ii) acylating the (Z)-isomer enriched 7-amino-3-(l-propen-l-yl)-3-cephem-4-carboxylic acid in free acid or salt form obtained in step (i) at the amine group in position 7 of the ring system to obtain cefprozil. None of the prior art processes teaches the usage of ether solvents for the silylation of APCA and condensation steps. Hence we focused our research with these solvents and found a simple process for the preparation of cefprozil. Objective of the Invention The main objective of the present invention is to provide a process for the preparation of 7-oc-aminoacyl-cephalosporin derivatives of the general formula (I). Another objective of the present invention is to provide a stable process for the preparation of 7-a-aminoacyl-cephalosporin derivatives of the general formula (I) using an ether solvent in high purity and yield. Summary of the Invention Accordingly, the present invention provides a process for the preparation of 7-[2-amino-2-(4-hydroxyphenyl)acetamido]-3-cephem-4-carboxylic acid derivatives of the formula (I) wherein R represents hydrogen, ester which form a prodrug or a counter ion which forms a salt, comprising the steps of: i) silylating the APCA of formula (II) using a mixture of trimethyl chlorosilane (TMCS) and hexamethyl disilazane (HMDS) in the presence of solvent to produce silylated APCA of formula (III) and ii) condensing the silylated APCA of the formula (III) with the mixed anhydride of the formula (IV) in the presence of an ether solvent, a co-solvent and a base at a temperature in the range of -50 °C to 10 °C to produce DMF solvate of compound of formula (V), and iii) desolvating the compound of formula (V) in the presence of solvent to yield the compound of formula (I). Detailed description of the invention In an embodiment of the present invention the silylation in step (i) is carried out in the presence of an ether solvent selected from ethers such as THF, isopropyl ether, diethyl ether, dioxane, and the like or mixtures thereof. In another embodiment of the present invention the condensation in step (ii) is carried out in the presence of an ether solvent selected from ethers such as THF, isopropyl ether, diethyl ether, dioxane, and the like or mixtures thereof and base such as triethylamine, pyridine, N-methyl morpholine, diethyl amine, diisopropyl amine, 2,6-Lutidine and the like. The reaction is carried out at a temperature in the range of -50 °C to 10 °C. In still another embodiment of the present invention the co-solvent in step (ii) is selected from DMF, DMAc5 monomethyl formamide, N-methyl-2-pyrrolidine and the like or mixtures thereof. In still 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. In yet another embodiment of the present invention the starting material APCA can be prepared by known methods available in prior art or from the procedure disclosed in our co-pending application No. 800/MAS/2002. In an embodiment of the present invention the APCA used in step (i) is either Z isomer enriched or mixture of Z & E isomers. In yet another embodiment of the present invention, the counter ion which forms salt is selected from sodium, potassium, lithium, ammonium tertiary butyl amine, benzyl amine, dibenzyl amine, diethyl amine, triethyl amine, dicyclohexyl amine, octyl amine and the like. In still another embodiment of the present invention the prodrug ester represented is -(CH2)-0-C(=0)-C(CH3)3, - CH(CH3)-0-C(=0)-CH3 or -CH(CH3)-0-C(=0)-0-CH(CH3)2 and the like. In yet another embodiment of the present invention the compound of formula (I) is a monohydrate. In yet another embodiment of the present invention the compound of formula (I) obtained is a (Z)-isomer. The present invention is provided by the examples given 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) Preparation of (6R,7R)-7-[2-amino-2-(4-hydroxyphenyl)acetamido]-3- [(Z)-propenyl]-3-cephem-4-carboxylic acid DMF solvate (V) 7-Amino-3-((Z/E)-propen-l-yl)ceph-3-em-4-carboxylic acid (APCA) (II) (5g, 0.0208mole) was stirred in THF (25ml) at 34°C. TMCS (1.73g, 0.0159mole) and HMDS (2.6g, 0.0159mole) were added and stirred for 2hrs at 36 to 39°C to form yield silylated APCA (III) which has used in next step as such without purification. Then cooled to -5°C. Simultaneously, Dane salt (6.94, 0.0229mole) in THF (35ml) was stirred and cooled to 0°C. DMF (17.5ml) was added and further cooled to -45°C. N-methylmorpholine (0.5ml) and methyl chloroformate (2.16g, 0.0229mole) were added and stirred for 1.5hrs at -35°C to -40°C to form compound (IV). The cold mixture of compound (III) was added into compound (IV) and the resulting slurry was stirred at -35°C to -40°C for 2.0hrs. 1:1 HC1 (7.5ml) and water (10ml) were added at -40°C. The temperature was gradually allowed to raise to 5°C and stirred for lOmin. The THF in reaction mixture was distilled off under vacuum and the mass was cooled to 0°C. DMF (60ml) and IPA (30ml) were added and stirred at 0 to 5°C for lOmin. and filtered. The filtrate was warmed to 30°C, triethylamine was added rapidly to adjust the pH to 6 at 30 to 35°C. The slurry was stirred at 0 to 5°C for Ihr. The precipitate was filtered and washed with acetone (25ml). The wet material was air dried to yield the title compound. Step (ii) Preparation of (6R,7R)-7-[2-amino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)-propenyl]-3-cephem-4-carboxylic acid (I) (6R,7R)-7-[2-Amino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)-propenyl]-3-cephem-4-carboxylic acid DMF solvate (V) (6.3 gm) obtained from step (i) was stirred in water (10ml) at 33°C for 60min. The compound was collected by filtration and washed with water (2ml) followed by acetone (5ml) and dried in vacuum at room temperature to give the title compound (yield 4.5g, 97.8%pure, moisture content 5.5%). Example 2 Step (i) Preparation of (6R,7R)-7-[2-amino-2-(4-hydroxyphenyl)acetamido]-3- [(Z)-propenyl]-3-cephem-4-carboxyIic acid DMF solvate (V) 7-Amino-3-((Z/E)-propen-l-yl)ceph-3-em-4-carboxylic acid (APCA) (II) (5g, 0.0208mole) was stirred in isopropyl ether (25ml) at 34°C. TMCS (1.73g, 0.0159mole) and HMDS (2.6g, 0.0159mole) were added and stirred for 2hrs at 36 to 39°C to form yield silylated APCA (III) which has used in next step as such without purification. Then cooled to -10°C. Simultaneously, Dane salt (6.94, 0.0229mole) in isopropyl ether (35ml) was stirred and cooled to 0°C. DMF (12ml) was added and further cooled to -45°C. N-methylmorpholine (0.5ml) and methyl chloroformate (2.16g, 0.0229mole) were added and stirred for 1.5hrs at -35°C to -40°C to form compound (IV). The cold mixture of compound (III) was added into compound (IV) and the resulting slurry was stirred at -35°C to -40°C for 2.0hrs. 1:1 HC1 (7.5ml) and water (10ml) were added at -40°C. The layers were separated and aq.layer cooled to 0°C. DMF (60ml) and IPA (30ml) were added and stirred at 0 to 5°C for lOmin. and filtered. The filtrate was warmed to 30°C, triethylamine was added rapidly to adjust the pH to 6 at 30 to 35°C. The slurry was stirred at 0 to 5°C for Ihr. The precipitate was filtered and washed with acetone (30ml). The wet material was air dried to yield the title compound. Step (m Preparation of (6R,7R)-7-[2-amino-2-(4-hydroxyphenyl)acetamido]-3- [(Z)-propenyl]-3-cephem-4-carboxylic acid (I) (6R,7R)-7-[2-Amino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)-propenyl]-3-cephem-4-carboxylic acid DMF solvate (V) obtained from step (i) was stirred in water (10ml) at 33°C for 60min. The compound was collected by filtration and washed with water (2ml) followed by acetone (5ml) and dried in vacuum at room temperature to give the title compound. We claim: 1. A process for the preparation of 7-[2-amino-2-phenylacetamido]-3- cephem-4-carboxylic acid derivatives of the formula (I) wherein R represents hydrogen, ester which form a prodrug selected from a group -(CH2)-0-C(=0)-C(CH3)35 - CH(CH3)-0-C(=0)-CH3 or -CH(CH3)-0-C(=0)-0-CH(CH3)2 or a counter ion, which forms a salt, comprising the steps of: i) silylating the APCA of formula (II) using a mixture of trimethyl chlorosilane and hexamethyl disilazane in the presence of an ether solvent to produce silylated APCA of formula ii) condensing the silylated APCA of the formula (III) with the mixed anhydride of the formula (VI) in the presence of an ether solvent, cosolvent and a base at a temperature in the range of-50 °C to 10 °C to produce DMF solvate of compound of formula (V), and iii) desolvating the compound of formula (V) in the presence of solvent to yield the title compound. 2. The process as claimed in claim 1, wherein an ether solvent used step (i) is selected from THF, isopropyl ether, diethyl ether, dioxane or mixtures thereof. 3. The process as claimed in claim 1, wherein an ether solvent used step (ii) is selected from THF, isopropyl ether, diethyl ether, dioxane, or mixtures there. 4. The process as claimed in claim 1, wherein the co-solvent used step (ii) is selected from DMF, DMAc or mixtures thereof. 5. The process as claimed in claim 1, wherein the base used in step (ii) is selected from triethylamine, Pyridine, diisopropyl amine, N-methyl morpholine, diethylamine, 2,6-Lutidine and the like. 6. The process as claimed in claim 1, wherein the desolvation in step (iii) is carried out using solvent such as water, or water-alcohol mixture. 7. The process as claimed in claim 5, wherein the alcohol is selected from methanol, ethanol, n-propanol, iso-propanol. 8. The process as claimed in claim 1, wherein the compound of formula (I) obtained is a monohydrate. 9. The process as claimed in claim 1, wherein the compound of formula (I) obtained is a (Z) isomer.

Documents:

502-che-2003-abstract.pdf

502-che-2003-claims.pdf

502-che-2003-correspondnece-others.pdf

502-che-2003-correspondnece-po.pdf

502-che-2003-description(complete).pdf

502-che-2003-form 1.pdf

502-che-2003-form 19.pdf

502-che-2003-form 5.pdf

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