Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF CEPHEM DERIVATIVES

Abstract

wherein Rl represents a carboxy-protecting group viz., substituted methyl group, which can be deprotected easily, such as t-bUtyl group, diphenylmethyl, 4- methoxybenzyl, 2-methoxybenzyl, 2-chlorobenzyl or benzyl group; R2 represents hydrogen, (C1-C4)alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted phenoxy group. 11 .The chloromethylcephem derivatives of the formula (I) prepared according to the process of the present invention are useful for the preparation of cephalosporin antibiotics of the formula (II). -

Full Text

Field of the Invention The present invention provides an improved process to produce the wherein R4 is carboxylate ion or COOR^, where Rj represents hydrogen, esters which form a prodrug or a counter ion which forms a salt; R^ represents H, CH3, The cephalosporin antibiotics of the formula (II) have wide range of biological activity. Specifically the cephalosporin antibiotics of the formula (II) have very good antibiotic activity. Background of the Invention In view of the importance of the 3-chloromethylcephems of the formula (I), as key intermediates for the synthesis of a wide variety of cephalosporin drugs, various methods of preparation were reported (US Patent 4,853,468; US Patent 4,789,740). In most of the cases, sulfonyl azetidinone derivatives of the formula (III) were subjected to allylic/ene-type chlorination with various chlorinating agents like chlorine, chlorine oxide, etc., to obtain the chloro azetidinone of the formula (IV). The chloro azetidinone compounds of the formula (IV) were iurther cyclized at low temperature in the presence of a base to get chloromethylcephems of the formula (I). where Ri and R2 are as defined above; R3 represents phenyl, (Ci-C4)alkyJphenyl, (Ci-C4)alkoxyphenyl or a heteroaryl group. Widi our continued search and intense investigation, we finally achieved identifying a clean process for producing the chloromethyl cephem derivatives of the formula (I). Objectives of the Invention The main objective of the present invention is to provide a simple and efficient process for producing chloromethylcephem derivatives of the formula (I) through 3-chloromethyl azetidinone compounds of the formula (IV). Another objective of the present invention is to provide a process for manufacturing chloromethyl azetidinone compounds of the formula (IV), without employing the reagents like chlorine, chlorine oxide, etc., which are hazardous and difficult-to-handle in manufacturing scales. Yet another objective of the present invention is to provide an electrochemical system, to ensure selective chlorination of sulfonyl azetidinone compounds of the formula (III), which is eco-friendly. Yet another objective of the present invention is to provide an electrochemical system which avoids the use of costly Platinum electrodes for electrolysis. Still another objective of the present invention is to provide an electrochemical system wherein the consumption of electricity is low. Another objective of the present invention is to provide an electrochemical system, in which the compounds of investigation are stable when they come in contact with the new electrode combination, thereby permitting easy scale up on industrial scale. wherein R, represents a carboxy-protecting group viz., substituted methyl group, which can be deprotected easily, such as t-butyl group, diphenylmethyl, 4-methoxybenzyl, 2-methoxyben2yl, 2-chlorobenzyl, or benzyl group; R2 represents hydrogen, (Ci-C4)alkyi, substituted or unsubstituted phenyl or substituted or unsubstituted phenoxy, the said process comprising the steps of (i) esterifying Pen G K of formula (V) using an esterifying agent in the presence of a solvent at a temperature in the range of 25 °C to 50 °C to produce a compound of formula (VI), (ii) oxidizing the compound of formula (VI) using an oxidizing agent at a temperature in the range of -10 °C to 10 °C to produce a compound of formula (VII) where R], R2 and R3 are as defined above, vm; upciiiug uic penam ring of the formula (VII) using a mercaptan in the presence of a solvent at a temperature in the range of 80 °C to 150 °C to produce a compound of formula (VIII) where R? represents a heteroaryl ring system and all other symbols are as defined above, (iv) converting a compound of formula (VIII) to a compound of formula (IX) where Rg represents (C]-C6)alkyl or aryl group using a metal salt of aryl sulfinic acid or (Ci-Cfi)alkyl sulfinic acid and a solvent at a temperature in therangeof25°Cto40°C, (v) chlorinating the compound of formula (IX) using chlorine gas at a temperature in the range of 15 °C to 40 °C to produce a compound of formula (X), where Rg represents (C|-C6)alkyl or aryl group and all other symbols are as defined above, (vi). cyclizing the compound of formula (X) using a base in a solvent at a temperature in the range of -60 °C to +50 °C to produce chloromethylcephem derivatives of the formula (I). The process of synthesizing chloromethyl cephem derivatives of the where R] and R2 are as defined above. Description of the Invention In an embodiment of the present invention the heteroaryl group represented by R7 is selected from 2-mercaptobenzothiazole, 2-mercaptobenzooxazole, 2-mercaptobenzimidazole or 2-mercapto-5-niethyltetrazole. In still another embodiment of the present invention the counter ion represented by R^ is alkali metal, preferably sodium. In still another embodiment of the present invention the prodrug ester represented by R^ is -(CH2)-0-C{-0)-C(CH3)3, - CH(CH3)-0-C(-0)-CH3 or -CH(CH3)-0-C(-0)-0-CH{CH3)2- In another embodiment of the present invention the compound of formula (I) obtained is a syn-isoraer. In yet another embodiment of the present invention the esterification in step (i) is carried out using esterifying agents such as p-methoxybenzyl bromide, p-methoxybenzyl chloride, p-nitrobenzyl bromide, p-nitrobenzyl chloride, o-chlorobenzyl chloride in the presence of a solvent selected from methylenedichloride, dimethyl formamide, acetonitrile, dioxane, tetrahydrofuran, ethyl acetate or dimethyl acetamide. The esterifjcation in step (ii) is also carried out using esteriiying agents such as diphenyl diazoraethane generated from benzophenone hydrazone in an acid medium and a solvent selected from methylene dichloride, chloroform, ethyl acetate, toluene, water, in the presence of catalytic quantities of iodine. The oxidation in step (ii) is carried out using peracetic acid, m-chloroperbenzoic acid, H2O2, trifluoroperacetic acid, magnesium monoperoxy phthalate and the solvent is selected from methylenedichloride, chloroform, toluene, dimethyl fonnamide, ethyl acetate, acetic acid, dimethyl acetamide, acetone or dioxane. In yet another embodiment of the present invention the ring opening in step (iii) is carried out using a mercaptan selected from 2-mercaptoben2othiazole, 2-mercaptobenzooxazole, 2-mercaptobenzimidazole, 2-mercapto-5-methyltetrazoie and the like, in the presence of a solvent selected from 1,4-dioxane, toluene or xylene. In yet another embodiment of the present invention the conversion in step (iv) is carried out using metal salt of aryl sulfinic acid selected from Copper (II) p-toluenesulfinate, Copper (II) benzenesulfmate, Silver (II) p-toluenesulfmate. Silver (II) benzenesulfinate and the like in the presence of a solvent selected from acetone, THF, dioxane, acetonitrile, alcohols such as methanol, ethanol or iso-propanol, with or without water. In yet another embodiment of the present invention the cyclisation in step (vi) is carried out using a base selected from ammonia, ammonium salts like ammonium carbonate, ammonium acetate; organic amines like di-isopropylamine, diethylamine, methylamine, triethylamine and the like in the presence of a solvent selected from DMF, acetonitrile, dimethyl acetamide, ethyl acetate, dioxane, THF, methylene dichloride and the like. The foregoing technique has been found to be attractive from commercial, technological and ecological views, and affords chloromethyl azetidinones cephem derivatives of the fomiula (IV). Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention within the scope of disclosure. The present invention is illustrated with the following examples, which should not be construed for limiting the scope of the invention. Example 1: Step -1 Preparation of p-Methoxvbenzyl 6-phenacetamidQpencillanate To N,N-dimethylacetamide (100 ml), 6-phenacetamidopenicillanic acid potassium (100 gm) was added at 27°C under dry condition. The reaction mixture was stirred for 15-20 minutes. Sodium bromide (27.6 gm), and p-methoxybenzyl chloride (42.0 gm) were added at 25-27°C and maintained under stirring until the reaction was complete. The reaction mixture was poured into a mixftire of cold water and dichloromethane, and filtered. The product was taken in cold dichloromethane (450 ml) and used in the next step as such without any isolation. Step -2 FreparatioD of p-Methoxybenzyl 6-pheDacetamidopeiicillanate-l-Qxide The product obtained in step-1 above in dichloromethane was oxidized with peracetic acid (72 ml). After the reaction was complete, the organic layer was separated and washed with water and saturated sodiimi bicarbonate solution. The dichloromethane layer was treated with cold water containing phosphoric acid, separated the organic layer. The organic layer was treated with charcoal, concentrated under vacuum and stirred with isopropyl ether (150 ml). The product obtained was filtered and dried under vacuum to get p-methoxybenzyl 6-phenacetamidopenicillanate-l-oxide. step -3 Preparation of p-MethoxvbenzvI 2-f2-benzothiazQlvldithio)-a-fl- methvlethenvn-4-oxo-3-phenacetamido-l-azetidineacetate To dry toluene (500 ml) contained in a RB flask fitted with a Dean-Stark water separator, p-methoxybenzyl 6-phenacetamidopencillanate-l-oxide (25 gm) obtained in step-2 above and 2-mercaptobenzothiazole (8.9 gin) were added at 27°C under nitrogen. The reaction mixture was heated under reflux over a period of 30 minutes and maintained at reflux temperature over 5 hours (The reaction may also be carried out in dioxane as a solvent). After the reaction was over, the solvent was removed under vacuum to afford p-methoxybenzyl 2-(2-benzothiazolyldithiQ)-a-( 1 -methylethenyl)-4-oxo-3-phenacetamido-1 -azetidineacetate, which was taken to next step. Step -4 Preparation of p-Methoxvbeaz;^"] 2-(p-tQlMeiiesiilfoiivlthio)-a-fl- metii vlethenvl)~4-oxo-3-phen acetamido-1 -azetidineacetate p-Methoxybenzyl 2-(2-benzothiazo]yIdithio)-a-(l-methylethenyI)-4-oxo-3- phenacetamido-1-azetidineacetate (25 gm) obtained in step-3 above was taken in aqueous acetone (220 mL) at 27-30 °C. Copper (II) p-toluene sulfmate (13.5 gm) was added to the mixture portion-wise. The contents of the reaction mixture were stirred and maintained for 1 hour. After the reaction was over, the reaction mixture w^ filtered, concentrated and taken in ethyl acetate. To the ethyl acetate layer saturated sodium chloride was added (50 ml x 2) and stirred. The organic layer was separated, concentrated, treated with methanol and dried under vaccum to yield p-methoxybenzyl 2-(p-toluenesulfonylthio)-a-(l-methylethenyl)-4-oxo-3- phenacetamido-]-azetidineacetate, which is used in the next with out any further purification. Step -5 Preparation of p-Methoxvbenzvl 2-fp-toluenesulfonvlthioVa-fl- chloromethvlethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate 1,4-Dioxane (150 ml) was added to p-methoxybenzyl 2-(p-toIuenesu]fonylthio)-a-(l-methylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate (5.0 gm) obtained in step-4 above followed by sodium bicarbonate (90 gm) at 26-28°C. Dry chlorine gas was passed slowly. After the completion of the reaction, reaction mixture was filtered and washed with dichloromethane (150 ml). To the filterate, cold water (450 ml) was added, organic layer separated, and washed with a solution of sodium thiosulphate followed by water. The organic layer was treated with charcoal, concentrated and worked up as usual to get p-methoxybenzyl 2-(p-toluenesulfonylthio)-a-(l-chloromethylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate, which was taken to next step without purification. Step -6 Preparation of p-Methoxvbenzvl 7-phenacetamido-3-chloroinethvl-3-cephem-4-carboxvlate p-Methoxybenzyl 2-(p-toluenesulfonylthio)-a-(l-chloromethyIethenyl)-4-oxo-3-phenacetamido-1-azetidineacetate (25 gm) obtained in step-5 above was added to DMF (125 ml) and cooled to ^0 °C. A solution of ammonia (11.5 ml) in DMF was added and maintained at the same temperature until the reaction was complete. The reaction mixture was acidified with dil. HCl, quenched in to water. and the product extracted into methylene dichloride. The organic layer was washed with water, and concentrated to remove the solvent. The residue was treated with methanol, filtered and dried under vacuum to get p-methoxybenzyl 7-phenacetamido-3-chloromethyl-3-cephem-4-carboxylate. Example 2: Step -1 Preparation of p-methoxvbenzvl 6-phenacetamido pencillanate To N,N-dimethyIacetamide (100 ml), 6-phenacetamido penicillanic acid potassium (100 gm) was added at 27°C under dry condition. The reaction mixture was stirred for 15-20 minutes. Sodium bromide (27.6 gm), and p-methoxybenzyl chloride (42.0 gm) were added at 25-27°C and maintained until the reaction was complete. The reaction mixture was poured into a mixture of cold water and dichloromethane, and filtered. The product was taken in cold dichloromethane (450 ml) and used in the next step as such without any isolation. Step -2 Preparation of p-methoxvbenzvl 6-pheDacetamido pencillanate-l-oxide The product obtained in step-1 above in dichloromethane was oxidized with peracetic acid (72 ml). After the reaction was complete, the organic layer was separated and washed with water, and saturated sodium bicarbonate solution. The dichloromethane layer was treated with cold water containing phosphoric acid, separated the organic layer. The organic layer was treated with charcoal, concentrated under vacuum and stirred with dichloroethane and isopropyl ether (150 ml). The product obtained was filtered and dried under vacuum to get p-methoxybenzyl 6-phenacetamido penicillanate-1-oxide. Step -3 Preparation of p-methoxybenzvl 2-(2-benzothiazolyldithioVa-(l- methylethenyn-4-oxo-3-phenacetamido-l-azetidineacetate To dry toluene (375 ml) contained in a RB flask, p-methoxybenzyl 6-phenacetamido pencillanate-1-oxide (25 gm) obtained in step-2 above and 2-mercaptobenzothiazole (4.4 gm) were added at 27°C under nitrogen. The reaction mixture was heated under reflux over a period of 30 minutes and maintained at reflux temperature over 5 hours with slow distillation of the solvent (The reaction may also be carried out in toluene as a solvent with a conventional Dean-Stark set up, with continuous removal of water). Afiter the reaction was over, the solvent was removed under vacuum, to afford p-methoxybenzyl 2-(2-benzothiazolyldithio)-a-(l-methylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate, which was taken to next step. Step -4 Preparation of p-methoxvbenzyl 2-f2-toittenevsulfonvlthio)-a-(l- methvlethen vl)-4-oxo-3-p henacetamido-1 -azetidineacetate p-Methoxybenzyl 2-(2-benzothiazolyldithio)-a-( 1 -methylethenyl)-4-oxo-3 - phenacetamido-1-azetidineacetate (25 gm) obtained in step-3 above was taken in aqueous acetone (220 mL) at 27-30 °C. Copper (11) p-toluene sulfmate (13.5 gm) was added to the mixture portion wise. The contents of the reaction mixture were stirred and maintained for 1 hour. After the reaction was over, the reaction mixture was filtered, washed with ethyl acetate. The organic layer was separated, concentrated, and dried under vaccum to yield p-methoxybenzyl 2-(2- toluenesulfonylthio)-a-(l-methylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate, which is used in the next with out any further purification. Step -5 Preparation of p-methoxybenzvl 2-t2-toluenesulfonvlthioVa-d- chloromethvlethenvn-4-oxo-3-phenacetamidO"l-azetidineacetate Ethyl acetate (150 ml) was added to p-methoxybenzyl 2-(2-toluenesulfonylthio)-a-(l-niethylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate (5.0 gm) obtained in step-4 above followed by sodium bicarbonate (90 gm) at 26-28°C. Dry chlorine gas was passed slowly. After the completion of the reaction, reaction mixture was filtered. To the filterate, cold water (450 ml) was added. The organic layer was separated, and washed with a solution of sodium thiosulphate followed by water. The organic layer was treated with charcoal, concentrated and worked up as usual to get p-methoxybenzyl 2-(2-toluenesulfonylthio)-a-(l-chloromethylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate, which was taken to next step without purification. Step -6 Preparation of p-methoxybenzyl 7-phenacetamido-3-chloromethvU3-cephein- 4-carboxvlate p-Methoxybenzyl 2-(2-toluenesulfonylthio)-a-(l-chloromethylethenyl)-4-oxo-3-phenacetamido-1-azetidineacetate (25 gm) obtained in step-5 above was added to DMF (125 ml) and cooled to ^0 "C. A solution of ammonia (11.5 ml) in DMF was added and maintained at the same temperature until the reaction was completed. The reaction mixture was acidified with dil. HCl, filtered. The solid obtained was extracted with DMF : methanol (2:9) with charcoal, concentrated and treated with cold methanol to get p-methoxybenzyl 7-phenacetamido-3-chlororaethyl- 3 -cephem-4-carboxylate. We Claim 1. An improved process to produce the chloromethylcephem derivatives of the formula (I) wherein R1 represents a carboxy-protecting group viz., substituted methyl group, which can be deprotected easily, such as t-butyl group, diphenylmethyl, 4-methoxybenzyl, 2-methoxybenzyl, 2-chlorobenzyl or benzyl group; R2 represents substituted or unsubstituted phenyl the said process comprising the steps of (iii). opening the penam ring of the formula (VII) using a mercaptan in the presence of a solvent at a temperature in the range of 80 °C to 150 °C to produce a compound of formula (VIII) (vi). cyclizing the compound of formula (X) using a base in a solvent at a temperature in the range of -60 °C to +50 °C to produce chloromethylcephem derivatives of the formula (I). 2. The process according to claim 1, wherein the esterification in step (i) is carried out using esterifying agents such as p-methoxybenzyl bromide, p-methoxybenzyl chloride, p-nitrobenzyl bromide, p-nitrobenzyl chloride, benzyl bromide or o-chlorobenzyl chloride. 3. The process according to claim 1, wherein the esterification in step (i) is carried out in the presence of a solvent selected from methylene dichloride, N^N-dimethyl formamide, acetonitrile, dioxane, tetrahydrofiiran, ethyl acetate or N,N-dimethyl acetamide. 4. The process according to claim I, wherein esterifying agents such as diphenyl diazomethane generated from benzophenone hydrazone in an acid medium 5. The process according to claim I, wherein the esterification in step (i) is carried out in the presence of a solvent selected from methylene dichloride, chloroform, ethyl acetate, toluene, water, in the presence of catalytic quantities of iodine or potassium iodide. 6. The process according to claim 1, wherein the oxidation in step (ii) is carried out using peracetic acid, m-chloroperbenzoic acid, H2O2, trifluoroperacetic acid or magnesium monoperoxy phthalate 7. The process according to claim 1, wherein the oxidation in step (ii) is carried out in the presence of a solvent from methylene dichloride, chloroform, toluene, N,N-dimethyl formamide, ethyl acetate, acetic acid, N,N-dimethyl acetamide, acetone or dioxane. 8. The process according to claim 1, wherein the ring opening in step (iii) is carried out using a mercaptan selected from 2-mercaptobenzothiazole, 2-mercaptobenzooxazole, 2-mercaptobenzimidazole or 2-mercapto-5-methyltetrazole. 9. The process according to claim 1, wherein the solvent used for ring opening in step (iii) selected from 1,4-dioxane, toluene or xylene. 10. The process according to claim 1, wherein the conversion in step (iv) is carried out using metal salt of aryi suifinic acid selected from Copper (11) p- toluenesulfinate. Copper (II) benzenesulfinate, sodium toluenesulfmate, Silver (11) p-toluenesulfinate or Silver (II) benzenesulfinate. 11. The process according to claim 1, wherein the conversion in step (iv) is carried out in the presence of a solvent selected from acetone, THF, dioxane, acetonitrile, alcohols such as methanol, etbanol or isopropanol, with or without water. 12. The process according to claim 1, wherein the cyclisation in step (vi) is carried out using a base selected from ammonia, ammonium salts like ammonium carbonate, ammonium acetate; organic amines like N,N-diisopropyIamine, N,N-diethylamine, methylamine or triethylamine. 13. The process according to claim 1, wherein the cyclisation in step (vi) is carried out in the presence of a solvent selected from DMF, acetonitrile, N,N-dimethylacetamide, ethyl acetate, dioxane, THF, methylene dichloride.

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