Title of Invention	AN IMPROVED PROCESS FPR THE PREPERATION OF CEFPROZIL
Abstract	The present invention relates to a process for the preparation of cefprozil of the formula (I), its esters, pharmaceutically acceptable salts or hydrates. wherein R represents hydrogen, ester which form a prodrug or a counter ion which forms a salt.

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 Background of the Invention CeQjrozil 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 cefyrozil as shown in scheme I below : us patent No. 5,608,055 discloses a new 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 solvent. 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-carboxyHc acid in a mixture of 7-amino-3-{(Z)-l-propen-l-yl}-3-cephem-4-ca^boxylic 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-carboxyHc 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. Objective of the Invention The main objective of the present invention is to provide a process for the preparation of 7-a-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 halogenated solvents in high purity and yield. Summary of the Invention Accordingly, the present invention provides a process for the preparation of 7-[2-amino-2-phenylacetamido]-3-cephem-4-carboxylic acid which forms a salt, comprising the steps of: i) converting the compound of formula (VII) wherein Ri represents carboxy protecting group to a compound of the formula (VIII) using Wittig reagent in the presence of solvent and alkali iodide, ii) reacting the compound of formula (VIII) with acetaldehyde using lithium chloride in the presence of solvent at a temperature in the range of -10 °C to 30 °C to produce a compound of formula (IX) wherein Ri is as defined above. iii) deesterifying the carboxy protecting group of compound of the formula (IX) using an acid in the presence of solvent at a temperature in the range of 10 °C to 50 °C to yield compound of formula (X), iv) converting the compound of formula (X) to compound of formula (XI) wherein X represents a counter ion which forms a salt in the presence of a base and solvent, v) neutralizing the compound of formula (XI) followed by enzymatic hydrolysis to produce APCA of formula (V), vi) silylating the APCA of formula (V) using a mixture of trimethyl silylchloride and hexamethyl disilazane in the presence of a halogenated solvent to produce silylated APCA of formula (XII) and vii) condensing the silylated derivative of APCA of the formula (XII) with the mixed anhydride of the formula (XIII) in the presence of a solvent and a base at a temperature in the range of -50 °C to 10 °C to produce DMF solvate of compound of formula (XIV), viii) hydrolyzing the DMF solvate of compound of formula (XIV) in the presence of solvent to yield the title compound. The process is shown in Scheme-2 Detailed description of tlie invention In an embodiment of the present invention the group represented by R* is selected from (Ci-C3)alkyl group such as methyl, ethyl, propyl or isopropyl. In yet another embodiment of the present invention the solvent used in step (i) may be selected from methylenechloride, acetone, water and the like or mixtures thereof. In an embodiment of the present invention the reaction with acetaldehyde is carried out using solvents such as DMF, isopropyl alcohol methylene chloride, acetonitrile and the like or mixture thereof In an embodiment of the present invention the reaction with acetaldehyde is carried out preferably at a temperature in the range of 0-5°C. In yet another embodiment of the present invention the deesterification is carried out using phenol/trifluoroacetic acid, anisole /trifluoroacetic acid, formic acid using solvent such as methylenechloride, ethyl acetate, water and the like or mixture thereof In yet another embodiment of the present invention the deesterification is carried out preferably at a temperature in the range of 30-35°C. In yet another embodiment of the present invention the conversion in step (iv) is carried out in the presence of solvent selected from water, acetone, DMF, THF, DMAc, DMSO, halogenated alkenes and the like using base such as sodium hydroxide, lithium hydroxide, potassium hydroxide or organic base such as tertiary butyl amine, benzyl amine, dibenzyl amine, diethyl amine, dicyclohexyl amine, benzothiazole and the like. In yet another embodiment of the present invention the silylation in step (vi) is carried out in the presence of solvents such as halogenated hydrocarbons, ethyl acetate, cyclohexane and the like. In yet another embodiment of the present invention the condensation in step (vii) is carried out in the presence of halogenated solvents such as methylenechloride, CCI4, CHCI3 and the like and base such as triethylamine, N-methyl morpholine, diethylamine and the like. The reaction is carried out at a temperature in the range of -50 °C to 10 °C. In yet another embodiment of the present invention, the desolvation in step (viii) 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 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, benzothiazole and the like. In yet another embodiment of the present invention, there is Example 1 Step (i) Preparation of 4-methoxybenzyl 7-phenylacetamido-3- [(triphenylphosporanylidene) methyl] -3-cephem-4-carboxylate (VIII) To a suspension of 4-methoxybenzyl 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate (VII) (lOOg, 0.2053mole) in methylenechloride (600ml), Nal (32.3g, 0.2155mole), triphenylphosphine (56.6g, 0.2155mole) and water (600ml) were added. The mixture was stirred at 32 to 35°C under nitrogen atmosphere for 90 min. The organic layer was separated and IN NaOH (217ml) was added. The resulting reddish brown mixture was stirred at 30 to 32°C for 20 min. The organic layer was separated and washed with water (500ml) followed by 20%w/w aq. NaCl solution (500ml). The organic layer was diluted upto 1000ml using fresh methylene chloride. The title compound (VIII) in methylene chloride was taken in solution for the next reaction. Step (in Preparation of 4-methoxybenzyl 7-phenyIacetamido-3-((Z/E-propen-l-yl)-3-cephem-4-carboxylate (IX) To a cold suspension of lithium chloride (26.2g, 0.6179mole) in dry DMF (100ml), the solution of 4-methoxybenzyl 7-phenylacetamido-3- [(triphenylphosporanylidene)methyl] -3-cephem-4-carboxylate (VIII) obtained in step (i) in methylene chloride (1000ml) was added. The resulting solution was cooled to 0 to 5°C. Acetaldehyde (139ml, 2.48mole) was added to the above mixture at 0 to 5°C. The reaction mixture was stirred for 18 hrs at 0 to 5°C and water (400ml) was added and stirred at 10 to 15°C for lOmin. The organic layer was separated, concentrated under vacuum and washed. To this concentrate, IPA (800ml) was added at 30°C and stirred to get the precipitate of (IX). Water (900ml) was added and filtered to yield the title compound (yield 86g, purity 95%). Step (iii) Preparation of 7-phenylacetamido-3-[(Z/E)-propen-l-yl]-ceph-3-em-4- carboxylic acid (X) 4-Methoxybenzyl 7-phenylacetamido-3 -((Z/E)-propen-1 -yl)-3-cephem-4-carboxylate obtained in step (ii) (50g) was dissolved in phenol (50ml) and TFA (14.5g). The reaction mixture was stirred at 30 to 35°C for 4 to 5 hrs and transferred to a mixture of water (250ml) and ethyiacetate (250ml) at 20°C. The pH was adjusted to 8.0 using 2N NaOH solution. The organic layer was separated and aq.layer was extracted with ethyiacetate (50ml). The combined aq.layer was charcoalised and filtered. pH of the filtrate was adjusted to 2.0 to 2.5 with 15% sulfuric acid and stirred for 30min. Filtered and washed with water (2x50ml) to yield the title compound (yield (wet) 74g, purity 94.8%). Step (iv) Preparation of 7-phenylacetamido-3-[(Z/E-propen-l-yI]-ceph-3-em-4- carboxylic acid dicyclohexylamine salt (XI) 7-Phenylacetamido-3-[(Z/E)-propen-1 -yl]-ceph-3-em-4-carboxylic acid obtained in step (iii) above (5g, Z/E ratio of 82/18) dissolved in acetone (80ml) and water (40ml). To this solution dicyclohexylamine (2.5g) was added, stirred and filtered through suction and washed with ethyiacetate (10ml) to yield the title compound (yield 2.5g, purity : 99.7%). Step (v) Preparation of 7-amino-3-((Z/E)-propen-l -yl)ceph-3-em-4-carboxylie acid (V) 7-Phenylacetamido-3-[(Z/E-propen-1 -yl]-ceph-3-em-4-carboxylic acid dicyclohexylamine salt (lOOg) was taken in ethyiacetate (1.61t) and water (l.Olt). pH of resulted slurry was adjusted to 2.0 using 15% sulfuric acid. The layers were separated. To the ethyiacetate layer, water (l.Olt) was added and pH was adjusted to 8.0 using 10% ammonia solution. The layers were separated. The aqueous layer was washed with butyl acetate (250ml). To the aqueous layer, PenG-amidase (48g, dry basis) was added. pH was maintained between 7.8 and 8.0 using 5% ammonia for 4 to 5 hrs. PenG-amidase was separated by filtration and the filtrate was treated with activated carbon. Carbon was filtered off and pH of the filtrate was adjusted to 3.5 using 1:1 HCl solution at 30°C. The precipitate was stirred, filtered and washed with water (2x60ml) and dried to yield the title compound (yield 39g). Step (vi) Preparation of (6R,7R)-7-[2-amino-2-(4-hydroxyphenyl)acetamido]-3- [(Z)-propenyI]-3-cephem-4-carboxyIic acid DMF solvate (XIV) 7-Amino-3-((Z/E)-propen-l-yl)ceph-3-em-4-carboxylic acid (V) (50g, 0.208Imole) was stirred in methylenechloride (250ml) at 30°C. Tetramethylchlorosilane (17.3g, 0.1594mole) and hexamethyldisilazane (25.75g, 0.1594mole) were added and stirred for 2hrs at 30 to 35°C to form yield compound (Xll) in situ. Ihen cooled to -10°C. Simultaneously, Dane salt (67.4g, 0.2223mole) in methylenechloride (350ml) was stirred and cooled to -10°C. DMF (120ml) was added and further cooled to -45 °C. N-methylmorpholine (0.5ml) and ethylchloroformate (24.8g, 0.2285mole) were added and stirred for 1.5hrs at ^0°C to -45°C to form compound (XIII). The cold mixture of compound (XII) was added into compound (XIII) at -60°C. The resulting slurry was stirred at -45°C to -50°C for 1.5hrs. 1:1 HCl (55ml) and water (100ml) were added at -45°C. The temperature was gradually allowed to raise to 5°C and stirred for lOmin. The aq. layer was separated, the organic layer was extracted with 1:1 HCl solution (10ml) and the combined aq. layers were cooled to 0 to 5°C. DMF (600ml) and IPA (300ml) 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 IPA (80ml) followed by acetone (300ml). The wet material was air dried to yield the title compound (yield 110.4, moisture content 3.4%). Step (vin Preparation of (6R,7R)-7-[2-ainino-2-(4-hydroxyphenyl)acetamido]-3- [(Z)-propenyl]-3-cephem-4-carboxylic acid monohydrate (I) (6R,7R)-7-[2-Amino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)-propenyl]-3-cephem-4-carboxylic acid DMF solvate (XIV) (llOg) was stirred in water (160ml) 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 65g, 99.1%pure, moisture content 5.5%). Example 2 Step (i) Preparation of 4-metlioxybenzyl 7-phenyIacetamido-3- [(triphenylphosporanylidene) metliyl]-3-cepliem-4-carboxylate(VIII) To a stirred suspension of 4-methoxybenzyl 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate (VII) (lOg, 0.0205mole) in acetone (50ml), sodium iodide (3.1g, 0.0207mole) and triphenylphosphine (5.9g, 0.0226mole) were added. The mixture was stirred at 30 to 32°C for 1.5hrs. The resulting mixture was concentrated in vacuo to get the residual oil. To this concentrate methylene chloride (50ML) was added and to the resultant solution, 2N NaOH solution (20ml) was added and stirred at 30 to 32°C for 20min. The organic layer was separated and washed with water (25ml) and dried over anhydrous sodium sulfate to give the title compound (VIII) in methylene chloride. Step (in Preparation of 4-methoxybenzyl 7-phenylacetamido-3-((Z/E-propen-l- yl)-3-cephem-4-carboxylate (IX) To a cold suspension of lithium chloride (26.2g, 0.6179mole) in dry DMF (100ml), the . solution of 4-methoxybenzyl 7-phenylacetamido-3-[(triphenylphosporanylidene) methyl]-3-cephem-4-carboxylate (VIII) obtained in step (i) in methylene chloride (1000ml) was added. The resulting solution was cooled to 0 to 5°C. Acetaldehyde (139ml, 2.48mole) was added to the above mixture at 0 to 5°C. The reaction mixture was stirred for 18 hrs at 0 to 5°C and water (400ml) was added and stirred at 10 to 15°C for lOmin. The organic layer was separated, concentrated under vacuum and washed. To this concentrate, IPA (800ml) was added at 30°C and stirred to get the precipitate of (IX). Water (900ml) was added and filtered to yield the title compound (yield 86g, purity 95%). Step (iii) Preparation of 7-phenylacetamido-3-[(Z/E-propen-l-yl]-cepli-3-em-4- carboxylic acid dicyclohexylamine salt (XI) 7-Phenylacetamido-3-[(Z/E)-propen-l-yl]-ceph-3-em-4-carboxylic acid obtained in step (iii) above (50g) was dissolved in phenol (50ml) and TFA (14.25g) and it was stirred at 30 to35°C for 3 to 4hrs. The mixture was added to cold mixture of water (250ml) and ethylacetate (250ml), pH was adjusted to 8.0 using 2N NaOH solution at 20-22°C. The aq. layer was separated and ethylacetate (400ml) was added and the pH was adjusted to 2.0 to 2.3 using 15%w/v sulfuric acid. The upper ethyl acetate layer was separated and to this water (300ml) and acetone (50ml) were added. Dicyclohexylamine was added in drops and pH adjusted to 5.0. Subsequently the resultant precipitate was stirred, filtered, washed with ethylacetate (50ml) and dried to give the title compound (yield (dry) 35g). Step (iv) Preparation of 7-ainmo-3-((Z/E)-propen-l-yI)ceph-3-em-4-carboxylic acid (V) 7-Phenylacetamido-3-[(Z/E-propen-1 -yl]-ceph-3-em-4-carboxylic acid dicyclohexylamine salt (lOOg) was taken in ethylacetate (1.61t) and water (l.Olt). pH of resulted slurry was adjusted to 2.0 using 15% sulfuric acid. The layers were separated. To the ethylacetate layer water (l.Olt) was added and pH was adjusted to 8.0 using 10% ammonia solution. The layers were separated. The aqueous layer was washed with butyl acetate (250ml). To the aqueous layer, PenG-amidase (48g, dry basis) was added. pH was maintained between 7.8 and 8.0 using 5% ammonia for 4 to 5 hrs. PenG-amidase was separated by filtration and filtrate was treated with activated carbon. Carbon was filtered off and pH of the filtrate was adjusted to 3.5 using 1:1 HCl solution at 30°C. The precipitate was stirred, filtered and washed with water (2x60ml) and dried to yield the title compound (yield 39g). Step (v) Preparation of (6R,7R)-7-[2-amino-2-(4-hydroxypIienyl)acetamido]-3-[(Z)-propenyl]-3-cepliem-4-carboxylic acid DMF solvate (XIV) 7-Amino-3-((Z/E)-propen-l-yl)ceph-3-em-4-carboxylic acid (V) (50g, 0.2081mole) was stirred in methylenechloride (250ml) at 30°C. Tetramethylchlorosilane (17.3g, 0.1594mole) and hexamethyldisilazane (25.75g, 0.1594mole) were added and stirred for 2hrs at 30 to 35°C to form yield compound (XII) in situ. Then cooled to -10°C. Simultaneously, Dane salt (67.4g, 0.2223mole) in methylenechloride (350ml) was stirred and cooled to -10°C. DMF (120ml) was added and further cooled to ~A5°C. N-methylmorpholine (0.5ml) and ethylchloroformate (24.8g, 0.2285mole) were added and stirred for l.Shrs at -40°C to ^5°C to form compound (XIII). The cold mixture of compound (XII) was added into compound (XIII) at -60°C. The resulting slurry was stirred at -45°C to -50°C for l.Shrs. 1:1 HCl (55ml) and water (100ml) were added at -45°C. The temperature was gradually allowed to raise to 5°C and stirred for lOmin. The aq. layer was separated, the organic layer was extracted with 1; 1 HCl solution (10ml) and the combined aq. layers were cooled to 0 to 5 °C. DMF (600ml) and IPA (300ml) 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 IPA (80ml) followed by acetone (300ml). The wet material was air dried to yield the title compound (yield 110.4, moisture content 3.4%). Step (vn Preparation of (6R,7R)-7-[2-amino-2-(4-hydroxyphenyl)aeetainido]-3- [(Z)-propenyl]-3-cephem-4-carboxylic acid monohydrate (I) (6R,7R)-7-[2-Amino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)-propenyl]-3-cephem-4-carboxylic acid DMF solvate (XIV) (llOg) was stirred in water (160ml) 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 65g, 99.1%pure, moisture content 5.5%), 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 Ri is as defined above, iii) deesterifying the carboxy protecting group of compound of the formula (IX) using an acid in the presence of solvent at a temperature in the range of 10 °C to 50 °C to yield compound of formula (X), viii) hydrolyzing the DMF solvate of compound of formula (XIV) in the presence of solvent to the compound of formula (I). 2. The process as claimed in claim 1, wherein the group represented by R^ is selected from (Ci-Csjalkyl group such as methyl, ethyl, propyl or isopropyl. 3. The process as claimed in claim 1, wherein the solvent used in step (i) may be selected from methylenechloride, acetone, water and the like or mixtures thereof. 4. The process as claimed in claim 1, wherein the solvent used for the reaction with acetaldehyde is selected from DMF, isopropyl alcohol methylene chloride, acetonitrile and the like or mixture thereof. 5. The process as claimed in claim 1, wherein the reaction with acetaldehyde is carried out preferably at a temperature in the range of 0-5°C. 6. The process as claimed in claim 1, wherein the deesterification is carried out using phenol/trifluoroacetic acid, anisole /trifluoroacetic acid, formic acid using solvent such as methylenechloride, ethyl acetate, water and the like or mixture thereof 7. The process as claimed in claim 1, wherein the deesterification is carried out preferably at a temperature in the range of 30-35°C. 8. The process as claimed in claim 1, wherein the conversion in step (iv) is carried out in the presence of solvent selected from water, acetone, DMF, THF, DMAc, DMSO or halogenated alkenes. 9. The process as claimed in claim 1, wherein the conversion in step (iv) is carried out using base such as sodium hydroxide, lithium hydroxide, potassium hydroxide or organic base such as tertiary butyl amine, benzyl amine, dibenzyl amine, diethyl amine, dicyclohexyl amine, benzothiazole. 10. The process as claimed in claim 1, wherein the silylation in step (vi) is carried out in the presence of solvents such as halogenated hydrocarbons, ethyl acetate or cyclohexane. 11. The process as claimed in claim 1, wherein the condensation in step (vii) is carried out in the presence of halogenated solvents such as methylenechloride, CCI4 or CHCI3. 12. The process as claimed in claim 1, wherein the condensation in step (vii) is carried out using a base such as triethylamine, N-methyl morpholine, diethylamine and the like. 13. The process as claimed in claim 1, wherein the desolvation in step (viii) is carried out using solvent such as water, or water-alcohol mixture. 14. The process as claimed in claim 13, wherein the alcohol is selected from methanol, ethanol, n-propanol, iso-propanol. 15. The process as claimed in claim 1, wherein 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 or benzothiazole.

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