Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF OXACEPHALOSPORIN

Abstract

(57) Abstract: The present invention provides an improved process for the preparation of oxacephalosporin of formula (I). wherein R1a hydrogen or fluoro; R, is hydrogen or a counter-ion which forms a salt or csters which forms a prodrug, which cornprising the steps of; 1. condensing alkali/alkaline earth metal salt of 1-(2-(arylmethoxy)ethyl)-lH-tetrazole-5-thiol of the formula (X.) with 3-chlorotnethyl-l-oxa-cephems of the formula (IV) to produce 3-( I-(2-arylmethoxyethyl)-lH-5-tetrazolyl)-thiomethylcephems of the formula CXI), 2. converting the 3-(1-C2-arylmethoxyethyl)-lH-5-tetrazolyl) thiomethyl cephems of the formula (Xl) to a compound of formula (XII), 3. deacylating 7β-acylamino-7α-methoxy-3-(l-('2-arylrnethoxyethyl)~1H-5-tetrazolyl)thiomethylcephems of the formula (XII) to produce 7P-amino-7α-methoxy-3-(l-(2-arylmethoxyethyl)-1H-5-tetrazolyl)thiomethyl cephem of formula (XIII), and 4. acylating the compound Of formula (XIII) with thioaceticacid to produce 7β-acylamino-7α-mediox.y.3-( 1 -(2-(arylmcthoxy)othyl)-1 H-tetrazol-5~ ylthiomethyl)cephems of the formula (II) and deprotecting alcohol protective group, PRICE: THIRTY RUPEES

Full Text

Field of the Invention The present invention provides a simple and effieicnt process for the preparation 7P-(n uorinated metliyithioacctaiiiido)-7a-nietho.\y-3-( I -(2-hydro.\y ethyl)-] H-5-tetrazolyl)thiomethyl-l-dethia-l-oxa-3-cephem-4-carboxylic acid derivatives of the formula (I), wherein R|a hydrogen or fluoro; R) is hydrogen or a counter-ion which forms a salt or esters which forms a prodrug. Ihe present invention also provides 7P-(fluorinated methylthioaeetamido)-7a-methoxy-3-( 1 -(2-arylmethoxyethyl)-1 H-5-tetrazolyl)thiomethyl-1 -dethia-1 -oxa-3-cephem-4-carboxylic acid derivatives of the formula (II), 4 wherein Ru, hydrogen or fluoro; R5 is a carboxy-protecting group which can be removed under mild conditions; Rib is an alcohol-protecting group, which can be removed cleanly under mild conditions and represented by the formula (III), (C|-C4)alkoxy, aryl(CrC4)alkoxy or substituted aryl(C|-C4)alkoxy group; aryl group represents five or six membered aromatic group. The present invention also provides a simple and efficient process for the preparation of the compound of formula (II). The 7-methoxy-l-oxacephalosporins of the formula (I) are useful as bacterial growth inhibitors on human, animal, plant, perishable objects. They are useful for treating or preventing human, veterinary, or poultry infections caused by sensitive Gram-positive bacteria or Gram-negative bacteria. They arc stable and effective against bacteria resistant to other P-lactam antibiotics. Background of the iFnention In view of the vital pharmacological activities of 7-methoxy-l-oxacephalosporins of the formula (I), various methods of preparation were reported (Tsuji, T.; Narisada, M.; Hamashima, Y.; Yoshida, T. J. Antibiot. 1985, 38(4), 466; US Patent 4,532,233, 4,529,722 & GB 2 144 119). In most of the cases, the 3-chloromethyl-I-oxaccphem of the general formula (IV) was treated with l-(2-(hydroxyethyl)-lll-letrazole-5-thiol of formula (V) to get condensation product of the formula (VI), which was treated with 4-mcthylbcnzyloxycarbonyl chloride of the formula (VII) under inert conditions to get the compound of the formula (VI11) in which the hydroxy group was protected as a "carbonate". The protected intermediate of the formula (Vlll) was further modified in several steps and finally dcprotcctcd to get the 7a-methoxy-l-oxaccphalosporin of formula (1). The process as described is shown in scheme- 1 Alternatively, 3-chloromcthyl-l-oxacephcm of the general formula (IV) was condensed with l-(2-(4-methylbcnzyloxycarbonyloxy)ethyl)-lH-tetrazolc-5-thiol of formula (IX) under inert condition to get the compound of the fonnula (VIII) and subsequently carried on several steps leading to the 7a-mcthoxy-l-oxacephalosporin of the formula (I). The process shown in scheme- II The limitation of the above method is that 4-methylbenzyloxycarbonyl chloride is neither commercially available nor can be produced in a conventional manufacturing facility as the production of it involves the use of "phosgene" on large scale, which is hazardous and non cco-fricndly. in addition, transportation of the same is not possible without the danger of explosion. Fhe compound has very low stability even at low temperature, which prohibits the use of the same on commercial scale. Logically the use of benzyloxycarbonyl chloride as an alternative reagent in place of 4-methylbenzyloxycarbonyl chloride was reported in the literature to protect the hydroxy group. We have observed that the deprotection to get the 7a-methoxy-1-oxacephalosporin, requires hazardous reagents which are again cumbersome to use on larger scale. The reagents like stannic chloride/aluminum chloride/titanium tetrachloride in combination with excess Iriflir loacclic-acid only works and afforcis a jelly mixture wherein the isolalion of the oxaeephcm was always difficult leading to low yield & quality. We have further observed that all the above hazardous reagents do not work if we use alone & the combination is inevitable. Thus we investigated variously protected l-(2-(hydroxy)cthyl)-lH-tetrazole-5-thiols to employ in the oxacephalosporin synthesis. With most of the alcohol-protecting groups, satisfactory conversions could not be achieved in one or more of the following steps: attachment of the alcohol-protected l-(2-(hydroxy)cthyl)-llI-tctrazole-5-thiols to the 3-chloromethyl-1-oxaeephcm of the general Ibrmula (IV); methoxylation employing sodium melhoxide (or lithium methoxide) under high basic pll to get 7a-mcthoxy derivative; deacylation with tertiary amines and phosphorous pentachloride at high temperature; acylation under acidic pH; final deprotcction to remove both the carboxy-protecting group and alcohol-protecting group. With our continued search and intense investigation, we finally achieved identifying a clean process for producing the title compound of the invention of the formula (fl), which employs l-(2-arylmethoxyethyl)-llI-tctrazole-5-thiols of the formula (IX). This has been found to perform well in all of the steps of the synthetic scheme and also effect smooth deprotcction at the last step to yield the final 7a-mcthoxy-l-oxaeephalosporins of the general formula (1) in good purity and yield. Objectives of the Invention The main objective of the present invention is to provide a process for the preparation of 7p-(fiuorinated methylthioacetamido)-7a-methoxy-3-( 1 -(2-liydroxy ethyl)-lH-5-tetrazolyl)thiomethyl-l-dethia-l-oxa-3-cephem-4-carboxylic acid of the formula (I). Another objective of the present invention is to provide a commercial process for the preparation of 7(3-(nuorinated mcthylthioacctamido)-7a-mcthoxy- 3-( I -(2-liydroxyclhyI)-111-5-tclra/olyl)thiomcthyl-1 -dcthia-1 -o.\a-3-ccplicm-4-carboxylic acid of the formula (I) which would be easy to implement on mainifacluring scales. Another objective of the present invention is to provide simple method of dcprotection of the compounds of the formula (II) to afford 7p-(fluorinated methylthioacetamido)-7a-methoxy-3-( 1 -hydroxyalkyl-5-tetrazolyl)thiomethyl-1 -dcthia-l-oxa-3-ccphcm-4-carboxylic acid of the formula (1), employing a single reagent such as triduoroacctic acid alone or stannic chloride alone without any additional hazardous inorganic reagents as well as high boiling nitromelhane. Another objective of the present invention is to provide novel intermediates of formulae (XI), (Xll), (XllI) and (II) their use in the preparation of oxacephalosporin of the formula (III). The intermediates being reported are stable through all the steps of oxacephem manufacturing and further permit an easy, complete and clean dcprotection under mild conditions at the last step. Summary of the Invention Accordingly, the present invention provides a simple and efficient process for the preparation 7p-(fluorinated methylthioacctamido)-7a-mcthoxy-3-(l-(2-hydroxyethyl)-1 i l-5-tctra/olyl)lhiomelhyl-1 -dcthia-1 -oxa-3-cephcm-4-carboxylic acid derivatives of the formula (1), wlicicin R|,| hydrogen, or (fluoro; K| is hydrogen or a eounler-ion whicli Ibrnis a sail or cslcrs which ronns a prodrug, the said process comprising the steps of: (i) condensing alkaU/alkalinc earth metal salt of I-(2-(arylmethoxy)ethyl)-lH-lctrazole-5-thiol of the formula (X) with 3-chloromethyl-l-oxa-cephems of the foiTHula (IV) in an organic solvent at a temperature in the range of-50 °C to 80 °C, over a period of 30 min to 4 hrs; to produce 3-(l-(2-arylmethoxyethyl)-lH-5-tetrazolyl)-thiomethyIcephems of the fomiula (Xi), (ii) converting the 3-(l-(2-arylmcthoxyethyl)-l H-5-tetrazolyl) thiomethyl cephems of the formula (XI) to a compound of formula (Xll) using a halogcnating agent in an organic solvent, followed by treatment with alkali/alkaline earth metal methoxides at a temperature in the range of 0 °C to-100°C, (iii) deacylating 7P-acylamino-7a-methoxy-3-( 1 -(2-arylmethoxyethyl)-1H-5-tetra/,olyl)thiomcthylccphcms of the'formula,(XI I) with an organic base and a chlorinating agent like phosphorous pentachloride in an organic solvent at a Icmpcralure in the range of -50 °C to 40 °C; quenching with liydroxylic solvents at a temperature in the range of-50 °C lo 40 °C, to produce 7^-amino-7a-melhoxy-3-(l-(2-ary!mcthoxyethyl)-lH-5-tctrazolyl)thiomelhyl cephem of formula (XIII), (iv) acylating 7|i-amino-7a-mcthoxy-3-(l-(2-(arylmelhoxy)ethyl)-lli-tclrazol- 5-ylthiomethyl)cephems of the formula (XIII) with thioaccticacid of the formula (XIV) in an organic solvent, in the presence of an organic base and an activating agent at a temperature in the range of -50 °C to 40 °C, to produce 7P-acylamino-7a-mcthoxy-3-( 1 -(2-(arylmclhoxy)cthyl)-1H- tetrazol-5-ylthiomcthyl)ccphems of the formula (II) and (v) dcprotccting bolli the protecting groups in 7P-acyl;iniino-7a-incthoxy-3-( 1-(2-(ary!metlioxy)ethyl)-lH-tctrazol-5-ylthioincthyl)ccplicnis of the fonmila (II) with a halogenated acid in the presence of a trapping agent in an organic solvent, at a temperature in the range of -40 °C to 20 °C over a period of 30 inin to 3 hrs; precipitating the product by adding an organic solvent and filtering the product; isolating 7p-acylamino-7a-methoxy-3-(l-(2-(arylmethoxy)cthyI)-l ll-tefra/,oI-5-ylthiomethyl)ccphcms of the formula (i). The scheme as described in above is as shown in Scheme 111. Another embodiment of the present invention is to provide 7[3-(nuoiinalcd mcthyltluoucctamido)-7a-mcthoxy-3-( 1-(2-arylnietIioxycthyl)-11 l-5-lelra/_olyl) thiomethyl-I-dcthia-l-oxa-3-ccphem-4-carboxyIic acid derivatives of the formula (11), wherein R|a hydrogen or fluoro; R5 is a carboxy-protecting group which can be removed under mild conditions; Rn, is an alcohol-protecting group, which can be removed cleanly under mild conditions and represented by the formula (III), wherein R2, R3, R4 are same or different and independently represent hydrogen, (CrC4)alkoxy, aryI(C|-C4)alk.oxy or substituted aryI(C|-C4)alkoxy group; aryl group represents live or six membcred aromatic group. In another embodiment of the present invention there is provided a novel intermediate of formula (XI) wherein R5 is a carboxy-protccling group which can be removed under mild conditions and Ru, is an alcohol-protecting group. In another embodiment of the present invention there is provided a novel intermediate of formula (XII) wherein R5 is a earboxy-protceting group which can be removed under mild conditions and Rn, is an alcohol-protecting group. in another embodiment of the present invention there is provided a novel intermediate of formula (XI If) wherein R5 is a carboxy-protecting group which can be removed under mild conditions and R][-, is an alcohol-protecting group. Description of the Invention in an embodiment of the present invention the counter ion represented by R) is alkali metal ions, preferably sodium. In still another embodiment of the present invention the prodrug ester represented by R| is suitable in vivo hydrolysable ester groups include, for example, acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymcthyl, oc- acetoxycthyl, oc-pivaloyloxyethyl; alkoxycarbonyloxyalkyl groups ethoxyearbonyloxymethyl and cc- ethoxycarbonyloxyethyl; dialkylaminoalkyl groups such as dimethylamiiiomethyl, diethylaminomethyl, dimethylaminoelhyl; 2-alkoxycarbonyl)-2-alkcnylgroups such as 2-(ethoxycarbonyl)but-2-enyl. 41 In another cmbodimcnl of the present invention, the carboxy-proteeting group represented by R5 is is diphenylmelhyl, 4-methoxybenzyl, 2-mcthoxybcnzyl or 2-chlorobenzyl 4-nitroben/,yi, 4-mcthylbcn/,yl, 3,4-dinielhoxyben/.yl, 2,4-dimcthoxybenzyl, 2,4,6-trimcthoxybcnzyl, 2,4,6-trimcthylbenzyl, pcnta methyl benzyl, 3,4-methylcnedioxybcnzyl, t-butyl, t-amyl, trityl, methoxy substituted trityl, benzhydrl, trimethylsilyl, t-butyldimethylsilyl, allyl, cinammyl. Further examples of these groups arc found in Theodora W.Greene, Wuts, "protective Groups in Organic Synthesis", John Wiley and Sons, New York, 1981, Chapter 5. The species of carboxy-prolecting group employed is not critical so long as Ihc dcrivatized carboxylic acid is stable to the condition of subsequent reaction(s) on other positions of the ring system and can be removed at the appropriate point without disrupting the remainder of the molecule. In another embodiment of the present invention, the five or six membcrcd aromatic group is selected from phenyl, pyridyl, furyl, thiophcnyl, pyrrolyl and the like. In yet another embodiment of the present invention, the alcohol-protecting group represented by R2, R3, R4 are same or different and independently represent hydrogen, (Ci-C4)alkoxy, aryl(Ci-C4)alkoxy, substituted aryl(C!-C4)alkoxy group or substituted amino group. In yet another embodiment of the present invention, organic solvent used in step (i) is selected from DMSO, DMF, DMAc, acetonitrile, acetone, diethylene glycol tlimclhyl ether, Tl II', or mixture thereof In another embodiment of the present invention, the condensation in step (i) is carried out preferably at temperature in the range of -20 to -30 °C. Jn another embodiment of the present invention, the halogenting agent used in step (ii) is selected form t-butoxy chloride, N-ehlorosuceinimide, N-bromosuccinimide, bromine or chlorine. In still another embodiment of (he present invention, the organie solvent used in step (ii) is selected from dichioromethane, chloroform, or ethylene chloride. In still another embodiment of the present invention, the alkali/alkaline earth metal methoxides employed in step (ii) is selected from sodium methoxide, lithium methoxide, magnesium methoxide or potassium methoxide. Jn still another embodiment of the present invention, the step (ii) is carried out at a temperature range of 0 °C to -100 °C, and preferably at -50 °C to -90 °C. In yet another embodiment of the present invention, the organic base used in step (iii) is selected from pyridine, quinoline, isoquinoline, triethylamine, DBU, DI3N or diisopropylethylamine. In yet another embodiment of the present invention, the hydroxylic solvent used in step (iii) is selected from methanol, isoprpanol, ethanol, 1,3-butanediol and ethylene glycol or mixtures thereof. In yet another embodiment of the present invention, the organic solvent used in step (iii) is selected from dichioromethane, dichloroethanc, DMF, acelonilrilc, lill', DM Ac and tiie like. In yet another embodiment of the present invention, the organic base used in step (iv) is selected from pyridine, quinoline, isoquinoline, triethylamine, or diisopropylethylamine. In yet another embodiment of the present invention, the solvent used in step (iv) is selected from dichioromethane, chloroform, carbon tetrachloride, THF, DMF, dioxane, acetonitrile, diethylene glycoldimethyl ether, water, toluene, acetone or mixtures thereof In another embodiment of the present invention, the thioaceticacid used in step (iv) is selected from difluorothioacetic acid, fluorothioacetic acid. In another embodiment of the present invention the activating agent used in step (iv) is selected from POCl^, SOCI2, PCI5. oxalyl chloride, diphcnyl t cliorophosphoridatc, dialkyl chorophosphoridate, mcrcapto bcnzothiazolc or bis-(2-oxo-oxazolidinyl) phosphonic chloride. In yet another embodiment of the present invention, the trapping agent used in step (v) is selected from anisole, thioanisole, N,N-dimethylaniline, or ethanedithioi and the organic solvent is selected from dichloromethane, chloroform, toluene, TUF, acetonitrile or formic acid. In another embodiment of the present invention halogenated acid used in step (v) is selected from Iriiluoroacelic acid, dilluoroacclic acid, stannic ciiloridc or chlorodifluoroacelic acid. In yet another embodiment of the present invention, the solvent used in step (v) for precipitation is j;elected from diisopropyl ether, diethyl ether, dichloromethane, 'fllF, chloroform, dichloroclhane or toluene. The foregoing technique has been found to be markedly attractive, both from commercial point of view, as well as from manufacturing view point, and affords good quality of 7P-acylamino-7a-methoxy-3-(l-(2-(arylmethoxy)ethyl)-lH-tctrazol-5-ylthiomethyl)cephems of the formula (11 ). The starting materials of the present invention, the 3-chloromethyl-l-oxa ccphem of the general formula (IV) can be prepared by the procedures well known in the art. Yet another starling material of the present invention, l-(2-arylmethoxy ethyl)-lH-tctrazole-5-thiols of the formula (IX) can be prepared in good yield and with high purity by the procedure described in the co-pending application No. Many other beneficial results can be obtained by applying disclosed invention in a different manner or bv modifvinp \hr. invrnHnn with thn ^mnn nV disclosure. The present invention is exemplified by the following example, which is provided for illustration only and should not be construed to limit the scope of the invention. To a cold solution o(" diphenylmethyl 7oc-bcn/,amitio-3-chloromelhyl-l-oxa-3-cephem-4-carboxylate (5 gni) in dry DMf was added solution of sodium l-(2-(4-mcthoxybenzyloxy)clhyl)-lH-tctra/ole-5-thiolate (prepared from 4 gm of l-(2-(4-methoxybenzyloxy)ethyl)-l H-tetrazole-5-thiol) in DMF and the reaction mixture was stirred well at -25 °C to -27 °C. After completion of the reaction, the reaction mixture was quenched into cold water, extracted with ethyl acetate and distilled off ethylacetate to produce diphenylmethyl 7cc-benzamido-3-(l-(2-( 4-methoxybenzyloxy)ethyl)-1 H-tctrazol-5-ylthiomethyl)-1 -oxa-3-cephem-4-carboxylate (7.2 gm). Diphenylmethyl 7a-ben/aniido-3-( I -(2-(4-methoxybenzyloxy)ethyl)-11 l-letrazol-5-ylthiomethyl)-l-oxa-3-cephem-4-carboxylate (5gm) obtained in step (i) above was dissolved in dichloromethane (50 rnl) under dry condition and the solution was cooled to After completion of the reaction, the reaction mixture was treated with ghicial acetic acid followed by cold water under vigorous stirring. The product was extracted with dichloromethane and washed with sodium thiosulphate solution. The organic layer was dried and concentrated to get diphenylmethyl 7p-benzamido-7a-methoxy-3-( 1 -(2-(4-methoxybenzyloxy)ethyl)- i H-tetrazol-5-yIthiomethyl)-I-oxa-3-cephem-4-carboxylate, which was used in next step without further purification. Diphenylmethyl 7p-benzamido-7a-methoxy-3-( 1 -(2-(4-methoxybcnzyloxy)ethyl) -lH-tetrazol-5-ylthiomethyl)-l-oxa-3-cephem-4-carboxylate (15 gm) obtained according to the procedure described in (ii) was dissolved in dichloro methane at 28 °C under dry condition and the reaction mixture was cooled to 0-5 °C. To the cold solution, pyridine (3.8 ml) and phosphorous pcntachloride (9.0 gm) were added and the temperature was raised to 30 °C. After stirring well for 1 hr, the reaction mixture was cooled to -30 °C and treated with methanol. After the reaction mixture was over, the reaction mixture was quenched in to a solution of sodium bicarbonate, and the product extracted in to dichloromethane. The organic layer was washed with dil. MCI, followed by sodium bicarbonate solution, dried and evaporated to get diphenylmethyl 7p-amino-7a-mcthoxy-3-(l-(2-(4-mcthoxybenzyloxy)ethyl)-111-tetrazol-5-ylthiomcthyl)-1-oxa-3-cephem-4-carboxylate, which was used in next step without further purification. « Diphcnylmcthyl 7p-aniino-7a-mclhoxy-3-(l-(2-(4-methoxybcnzyIoxy)ethyl)-lH-tetrazol-5-ylthiomethyl)-l-oxa-3-cephcm-4-carboxylate, obtained in step (iii) above was dissolved in dichloiomethane (150 ml) under dry condition and the solution was cooled to -40 °C. To the clear solution, under stirring, pyridine (7.0 ml), diniioromethylthioacetic acid (3.64 gm) and phosphorous oxychloride (2.2 ml) were added at this temperature and the resultant reaction mixture was stirred at this temperature for 1 hr. After tlie reaction was over, the reaction mixture was washed with water and the solvent removed under vacuum to get diphcnylmcthyl 7P-difliioromethylthioacetylamino-7a-methoxy-3-(l-(2-(4-mcthoxyben/,yloxy) ethyl)-lH-tetrazol-5-ylthiomethyl)-l-oxa-3-cephem-4-carboxylate, which can be used in next step without the need of any further purification. Diphenylmetiiyl 7p-difluoromcthyithioacctylamino-7a-mcthoxy-3-(l-(2-(4- methoxybenzyloxy)ethyl)-llI-tetrazol-5-ylthiomethyl)cephem-4-carboxylatc (4 gm) was dissolved in dichloromethane (20 ml) at 28 °C under dry condition and the clear solution was cooled to -20 °C. To the cold stirred solution, anisole (3.2 ml), trifluoroacctic acid (8 ml) were added at this'tempcrature and stirred well for 3 hrs. After the completion of, the reaction mixture was poured into diisopropyl ether and the precipitated product was filtered. The filtered solid was dissolved in * a mixlure of cold ctliyl acclalc, 2-lnitanone and dil. 1IC1. The organic layer was separated and extiaeted with cold aqueous sodium biearbonate solition. The aqueous layer was acidified and extracted into a mixture ethyl acetate and 2-butanone. The organic layer was concentrated and the lesidue was dissolved in aqueous sodium bicarbonate solution, washed with dichloromethane and lyophilized to get pure sodium 7P-difluoromethylthioacetylamino-7a-methoxy-3-(l-(2-(4-methoxybenzyi oxy)ethyl)-1 H-tetrazol-5-ylmethyl)cephem-4-carboxylate. Wc Claim 1. A process for the preparation of the compound of fomiula (1), wherein R1a is hydrogen or fluoro; R1 is hydrogen or a counter-ion which forms a salt or esters which forms a prodrug; the said process comprising the steps of: i. condensing alkali/alkahne earth metal salt of l-(2-(arylmethoxy)ethyl)-lH- tctrazolc-5-thiol of the formula (X) with 3-chloromcthyl-l-oxa-ccpiiems of the formula (IV) in an organic solvent at a temperature in the range of-50 °C to 80 °C; preferably -40° to 40°C, over a period of 30 min to 4 hrs; to produce 3-( l-(2-arylmethoxyethyl)-1 H-5-tetrazolyl)-thiomethylcephems of the formula (XI), ii. converting the 3-(l-(2-arylmethoxyethy])-lH-5-tetrazolyl) thiomethyl ccphcms of the formula (XI) to a compound of formula (XII) using a halogenating agent in an organic solvent, followed by treatment with alkali/alkaline earth metal methoxides at a temperature in the range of -100 °C to 0°C; preferably -100° to -20°C, iii. deacylating 7P-acylamino-7a-methoxy-3-( 1 -(2-arylmcthoxycthyl)-1H-5- tetrazolyI)thiomethylcephems of the formula (XII) with an organic base and a chlorinating agent like phosphorous pentachloride in an organic solvent at a temperature in the range of -50 °C to 40 °C; quenching with hydroxylic solvents at a temperature in the range of -50 °C to 40 °C, to produce 7P-amino-7a-methoxy-3-( 1 -(2-arylmethoxyethyl)-1 H-5-tetrazolyl)thiomethyl ccphcm of formula (XI11), i V. acylating 7P-aiTiino-7a-mcthoxy-3-( 1 -(2-(aryImethoxy)etliyl)-1 M-tctrazo!-5-ylmethyl)cephems of the formula (XIII) with tiiioaceticacid of the formula (XIV) in an organic solvent, in the presence of an organic base and an activating agent at a temperature in the range of -50 °C to 40 °C, to produce 7P-acylamino-7a-methoxy-3-( I -(2-(ai-ylmethoxy)ethyl)-1 H-tetrazol-5-ylthiomethyl)cephems of the formula (II) and V. (Icprotcctiiij^ holli Ihc prolccling groups in 7p-acylmmino-7(x-inelhoxy-3-( l-(2-(arylmethoxy)ethyI)-IH-tetrazoI-5-ylthiomethyl)cephems of the formula (II) with a halogenatcd acid in the presence of a trapping agent in an organic solvent, at a temperature in the range of-40 °C to 20 °C over a period of 30 min to 3 hrs; precipitating the product by adding an organic solvent and filtering the product; isolating 7P-acylamino-7a-methoxy-3-(I-(2-(arylmethoxy)ethyl)-lH-tctrazol-5-ylthiomethyl)cephems of the formula (I). 2. The process as claimed in claim 1, wherein the counter ion represented by Ri is preferably sodium ion. 3. The process as claimed in claim 1, wherein the prodrug ester represented by R1 arc acyloxyalkyl groups such as aceloxymethyl, pivaloyloxynicthyl, oc- acctoxycthyl, oc-pivaloyloxycthyl; alkoxycarbonyloxyalkyl groups cthoxycarbonyloxymcthyl and oc- cthoxycarbonyloxycthyl; dialkylaminoalkyl groups such as dimcthylaminomethyl, dicthylaminomcthyl, dimcthylaminocthyl; 2-alkoxycarbony])-2-alkenylgroups such as 2-(ethoxycarbonyl)but-2-cnyl. 4. The process as claimed in claim 1, wherein the alkali/alkaline earth metal methoxide employed in step (ii) is selected from like sodium mcthoxide, lithium methoxide, or potassium mcthoxide. 5. The process as claimed in claim 1, wherein the solvent used in step (i) is selected from DMSO, DMF, DMAc, acetonitrile, acetone, diethylcnc glycoldimethyl ether, THF, or mixture thereof. 6. The process as claimed in claim I, wherein the organic solvent used in step (ii) is selected from dichloromethane, chloroform, THF, ethylene chloride, acctonilrilo. 7. The process as claimed in claim 1, wherein the halogenating agent used in step (ii) is selected from t-butoxychloride, N-chlorosuccinimide, N-bromo succinimide, bromine or chlorine. 8. The process claimed in claim 1, wherein the preferable reaction temperature for step (ii) is in the range of-50°C to -90°C. 9. The process as claimed in claim 1, wherein the organic base used in step (iii) is selected from pyridine, quinoline, isoquinoline, triethylamine, DBU, DBN or diisopropylethylamine and solvent used is selected from dichloromethane, dichlorocthane, DMF, acclonitrilc, THF, DMAc and the like. 10. The process as claimed in claim 1, wherein the hydroxylic solvent used in step (iii) is selected from methanol, isoprpanol, cthanol, 1,3-butancdiol and ethylene glycol or mixtures thereof. 11. The process as claimed in claim 1, wherein the solvent used in step (iv) is selected from dichloromethane, chloroform, THF, dioxane, acetonitrile, diethylene glycol dimethylcthcr, or toluene. 12. The process as claimed in claim 1, wherein the organic base used in step (iv) is selected irom pyridine, quinoline, isoquinoline, triethylamine, or diisopropylethylamine. 13. The process as claimed in claim 1, wherein the organic solvent used in step (v) is selected from dichloromethane, chlorofomi, toluene, THF, acetonitrile, acetone, carbon tetrachloride or fomiic acid. 14. The process as claimed in claim 1, wherein the halogenating acid used in step (v) is selected from trifluoroacetic acid, difluoroacetic acid, stannic chloride or chlorodifluoroacetic acid. 15. The process as claimed in claim 1, wherein the solvent used in step (v) for precipitation is selected from diisopropyl ether, diethyl ether, dichloromethane, THF, chloroform, dichloroethane or toluene.

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0847-mas-2002 form-3.pdf

0847-mas-2002 form-5.pdf

abs-847