Title of Invention	A PROCESS FOR THE PREPARATION 1-(2-(ARYLMETHOXY)ETHYL)-1H-TETRAZOLE-5-THIOLS
Abstract	The present invention provides process for the preparation of 1-(2 (arylmethoxy)ethyl)-1H-tetrazole-5-thiols of the formula (I), wherein R1, R2, R3 are same or different and independently represent hydrogen, (CI-C4)alkoxy, aryl(CI-C4)alkoxy or substituted aryl(CI-C4)alkoxy group; aryl group represents five or six membered aromatic group.

Full Text

Field of the Invention The present invention relates to l-(2-(aiylmethoxy)ethyl)-lH-tetrazole-5-; thiols of the formula (I), wherein R1 R2, R3 are same or different and independently represent hydrogen, (C1-C4)alkoxy, aryl(C1-C4)alkoxy or substituted aryl(C1-C4)alkoxy group; aryl group represents five or six membered aromatic group. The present invention also provide a process for the preparation of the compound of the formula (I) and it use. The 1 -(2-(arylmethoxy)ethyl)-1 H-tetrazole-5-thiols of formula (I) are useful as intermediates in the preparation of 1-oxacephalosporins of the formula en), wherein R is difluoromethyl or monofluoromethyl; R4 is hydrogen or a counter ion, or a carboxy-protecting group or an ester which forms a prodrug. The 1-oxacephalosporins of the formula (II) are useful as bacterial growth inhibitors on human, animal, plant, perishable objects. They are useful for treating or preventing human, veternary, or poultry infections caused by sensitive Gram-positive bacteria or Gram-negative bacteria. They are stable and effective against bacteria resistant to other p-lactam antibiotics. Background of the Invention In view of the vital pharmacological activities of 1-oxacephalosporins of the formula (II), various methods of preparation were reported (Tsuji, T.; Marisada, 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-1-oxacephem of the general formula (III) was treated with l-(2-(Hydroxyethyl)-lH-tetrazole-5-thiol of formula (IV) to get condensation product of the formula (V). The compound of the formula (V) was treated with 4-methylbenzyloxycarbonyl chloride of formula (VI) under dry condition to get the compound of the formula (VII), in which the hydroxy group was protected as a "carbonate". The protected intermediate of the formula (VII) was further modified in several steps and finally deprotected to get the 7a-methoxy-l- 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 not eco-friendly. In addition, transportation of the same is not possible without the danger of explosion. The compound has very low stability even at low temperature, which prohibits the use of the same compound on commercial scale. The use of benzyloxycarbonyl chloride as a 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-l-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 trifluoroacetic acid only works and affords a jelly mixture wherein the isolation of the oxacephem was always difficult leading to low yield & quality. We have further observed that all of the above hazardous reagents do not work if we use alone & the combination is inevitable. Thus we were in search of various protected l-(2-hydroxyethyl)-lH-tetrazole-5-thiols to employ in the cephalosporin synthesis. We examined a wide variety of protecting groups, attached with l-(2-(hydroxyethyl)-lH-tetrazole-5-thiols of the formula (IV), condensed with 3-chloromethyl-l-oxacephems of the formula (III), modified in several steps like 7a-methoxylation (high pH reaction), deacylation (low pH reaction), acylation (low pH reaction) and finally deprotected all the protecting groups. All of the protecting groups failed to produce satisfactory results at either one or more of the steps mentioned above. With our continued search and intense investigation, we finally ended with the title compound of the invention of the formula (I). The compound of formula (I) was found to perform well in all of the steps of the synthetic scheme. The deprotection was smooth at the final step & gave good yield of 7a-methoxy-l-oxacephalosporins as compared with the known protecting group. We also examined various methods of producing the said title compounds of the formula (I). Some of the approaches involve the protection of the thiol of 1-(2-hydroxyethyl)-lH-tetrazole-5-thiol of the formula (IV) with various protecting groups followed by attachment of substituted arylmethyl halide, and releasing protected thiol to get the title compound of the formula (I). In another attempt, we have protected the thiol of l-(2-hydroxyethyl)-lH-tetrazole-5-thiol of the formula (IV) in the form of disulphide by dimerization. The attachment of the substituted arylmethyl halide to the above mentioned dimer led to the cleavage of the dimer to get back the starting thiol, namely l-(2-hydroxyethyl)-lH-tetrazole-5~ thiol of the formula (IV). Objectives of the Invention The objective of the present invention is to provide novel l-(2-(arylmethoxy) ethyl)-lH-tetrazole-5-thiols of the formula (I). Another objective of the present invention is to provide l-(2-arylmethoxyethyl)-lH-tetrazole-5-thiols of the formula (I) which are useful in the preparation of oxacephalosporins of the formula (II). Another objective of the present invention is to provide 1 -(2-arylmethoxyethyl)-lH-tetrazole-5-thiols of the formula (I) which permit easy, complete and clean deprotection of the protecting groups under mild conditions to afford oxacephalosporins of the formula (II) in good quality & yield. Another objective of the invention is to provide a process for producing the compounds of the formula (I), which can be implemented on manufacturing scale. Another objective of the present invention is to provide a process for preparing the l-(2-(arylmethoxy)ethyl)-lH-tetrazole-5-thiols of the formula (I) employing commercially available raw materials which are non- hazardous and eco-friendly. Yet another objective of the present invention is to provide a commercially viable and high-yielding process for producing l-(2-(arylmethoxy)ethyl)-lH-tetrazole-5-thiols of the formula (I). wherein Ru R2, R3 are same or different and independently represent hydrogen, (C1-C4)alkoxy, aryl(C1-C4)alkoxy or substituted aryl(C1-C4)alkoxy group; aryl gjroup represents five or six membered aromatic group. Another embodiment of the present invention provides the process for the preparation of novel l-(2-(arylmethoxy)ethyl)-lH-tetrazole-5-thiols of the formula (I) the said process comprising the steps of: (i) treating alkali/alkaline earth metal salt of ethanolamine, prepared from ethanolamine and a base, with a substituted arylmethyl halide of formula (VIII), wherein R1 R2, R3 are as defined above and L is a leaving group such as halogen like fluoro, chloro, bromo, iodo; tosylate, mesylate or triflate in an organic solvent at a temperature in the range of -10 to 120 °C, for a period of 15 min to 2 hrs to produce 2-(substituted arylmethoxy)ethylamine of the general formula (IX), (ii) treating the 2-(substituted arylmethoxy)ethylamine of the general formula (IX) with carbon disulphide in the presence of a tertiary amine in an aqueous organic solvent at a temperature in the range of 0°C to 40°C, and treating the product with methylating agent to produce the dithiocarbamate of the general formula (X), (iii) cyclizing the dithiocarbamate of the formula (X) with an azide in a solvent system to produce l-(2-(arylmethoxy)ethyl)-lH-tetrazole-5-thiols of the formula (I). Yet another embodiment of the present invention provides novel methyl 2-(substituted arylmethoxybenzyloxyethyl)-dithiocarbamate of the formula (X) wherein R1 R2, R3 and aryl are as defined above. Detailed description of the invention In another embodiment of the present invention, the five or six membered aromatic group is selected from phenyl, pyridyl, furyl, thiophenyl, pyrrolyl and the like. In yet another embodiment of the present invention, the solvent used in step (i) is selected from DMSO, DMF, DMAC, acetonitrile, acetone, diethylene glycol dimethylether (diglyme), THF, or a mixture thereof. In still another embodiment of the present invention, the substituted ;arylmethyl halide employed in step (i) is selected from 4-methoxybenzyl chloride, 2-methoxybenzyl chloride, 2,4-dimethoxybenzyl chloride, 3,4,5-trimethoxybenzyl chloride, 4-methoxybenzyl bromide, or 2-chlorobenzyl chloride. In another embodiment of the present invention, the condensation in step (i) is carried out at a temperature in the range of -10 °C to +120 °C. In still another embodiment of the present invention, the base employed in step (i) is selected from alkali/alkaline earth metal hydroxides or the corresponding hydrides or the corresponding alkoxides such as sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, or potassium t-butoxide. In still another embodiment of the present invention, the tertiary amine used in step (ii) is selected from triethylamine, trimethylamine, tri-n-butylamine, pyridine, ethyldiisopropylamine, N-methylpyrrolidine, N-methylpiperidine and the like. In still another embodiment of the present invention, the organic solvent used in step (ii) is selected from methanol, ethanol, isopropanol, acetone, THF, I dioxane, acetonitrile, or mixtures thereof. In another embodiment of the present invention, the methylating agent used in step (ii) is selected from iodomethane, dimethyl sulfate, TMSI, trimethyl oxonium tetrafluroborate, methyl triflate, diazomethane and the like. In another embodiment of the present invention, the azide used in step (iii) is selected from inorganic azide or organic azide. In another embodiment of the present invention, the inorganic azide used for cyclizing in step (iii) is selected from sodium azide, potassium azide, or calcium azide. In yet another embodiment of the present invention, the organic azide used for cyclizing in step (iii) is selected from quaternary ammonium or phosphonium azide such as tetra-n-butylammonium azide, tri-n-butylbenzylammonium azide, tetraethylammonium azide, or tetra-n-butylphosphonium azide. In another embodiment of the present invention, the solvent system used for cyclizing with inorganic azide in step (iii) is an aqueous organic solvent. In another embodiment of the present invention, the aqueous organic solvent used is methanol, ethanol, isopropanol, acetone, acetonitrile, THF, diethylene glygol dimethyl ether or mixtures thereof. In another embodiment of the present invention, the solvent system used for cyclizing with organic azide in step (iii) is a biphasic medium. In yet another embodiment of the present invention, the organic solvent used for the biphasic medium is selected from dichloromethane, chloroform, dichloro ethane, or toluene. The starting materials of the present invention, substituted arylmethyl halides and ethanolamine are commercially available and are cheap. 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 yield of pure 2-(substituted arylmethoxy)ethylamine of the general formula (IX). The present invention is exemplified by the following examples, which is provided for illustration only and should not be construed to limit the scope of the invention. Example 1: Step (i): Preparation of 2-(4-methoxybenzyloxy)ethylamine: Ethanolamine (7.8 gm) was added drop-wise to the suspension of sodium hydride (4.4gm, 60 %) in dimethyl sulfoxide (60 ml) at 20-25°C. To the resultant slurry, 4-methoxybenzyl chloride (10 gm) was added drop-wise in 1-2 hrs and stirred vigorously for 2 hrs. After completion of reaction, the reaction mixture was quenched into water. The aqueous layer was extracted with dichloromethane. The solvent was removed under vacuum and the product, 2-(4-methoxybenzyloxy)ethylamine, distilled out under high vacuum (9.5-11.0 gms). !H NMR (CDC13, Bruker 400 MHz Avance): 5 2.78 (t, 2H), 3.49 (t, 2H), 3.79 (s, 3H), 4.46 (s, 2H), 6.87-7.28 (4H); Mass m/e (M+l): 182.0. Step (ii): Preparation of methyl 4-methoxybenzyloxyethyl dithiocarbamate: 2-(4-methoxybenzyloxy)ethyl amine (9.0 gm) obtained in step (i) was ; added to methanol (45 ml) and water (9 ml) at 30-32°C and cooled to 10-15°C. Triethylamine (7.0 gm) and carbon disulfide (5.5 gm) were added and stirred for 1-1.5 hrs. Iodomethane (9.0 gm) was added and stirred well until completion of reaction. After the reaction was over, methanol was distilled out under vacuum. The residue obtained was diluted with water and the product extracted .irito dichloromethane. The solvent was removed under vacuum and the product distilled under high vacuum to get methyl 4-methoxybenzyloxyethyl dithiocarbamate, which was taken to next step without further purification. Step (iii): Preparation of l-(2-(4»methoxybenzyIoxy)ethyl)-lH-tetrazole-5-thiol: Methyl 4-methoxybenzyloxyethyl dithiocarbamate obtained from the Step (if) was added to methanol (100 ml) and water (14.8 ml). To the clear reaction mass, sodium azide (5.1 gm) was added. The reaction mixture was stirred at 60-65°C and maintained at this temperature till completion of reaction. After completion of reaction, methanol was distilled out under vacuum and the product was isolated in conventional manner to get 10.0-12.5 g of 1 -(2-(4-methoxybenzyloxy)ethyl)-lH-tetrazole-5-thiol (X). *H NMR (CDC13, Bruker 400 MHz Avance): 5 3.76 (s, 3H), 3.92 (dd, 2H), 4.83 (s, 2H), 4.84 (dd, 2H), 6.82-7.27 (4H); Mass m/e (M+l): 267.2 10.0-12.5. Example 2: Slfep i: Preparation of 2-(4-methoxybenzyloxy)ethylamine: To a slurry of potassium t-butoxide (53.75 gm) in dimethyl sulphoxide (200 ml), ethanolamine (31.20 gm) was added at 20 T 24°C. A solution of 4-methoxybenzyl chloride (50 gm) in dimethyl sulphoxide was added dropwise at 23 - 27°C. This reaction mixture was stirred further 30 minutes and monitored by HPLC After completion of reaction, reaction mass was added to water at 25 ± 2°C, stirred for 15 minutes and the 2-(4-methoxybenzyloxy)ethylamine was extracted by dichloromethane (500 ml). The solvent was removed under vacuum and the product, 2-(4-methoxybenzyloxy)ethylamine, distilled out under high vacuum (S3±2 gm). This crude materials was used without further purification for the next st0p. Step (ii): Preparation of methyl 4-methoxybenzyloxyethyl dithiocarbamate: The 2-(4-methoxybenzyloxy)ethyl amine (53±2 gm ) obtained from step i was dissolved in a mixture of water (25 ml) and methanol (150 ml), triethyl amine (31.41 gm ) was added and cooled to 10-15 °C . Carbon disulphide (23.63 gm) was added to the reaction mixture at 10-15°C and stirred at 10-15°C. Dimethyl sulphate (37.28 gm) was added at 10-15°C, stirred further 30 minutes and monitored by HPLC. After completion of reaction, the reaction mass was added to cold water and the product was extracted with dichloromethane 125 ml. The dichloromethane layer was distilled at 23 ± 2°C under reduced pressure to produce (75-79 gm) of methyl 4-methoxybenzyloxyethyldithiocarbamate. This crude materials was used without further purification to the next step. Step (iii): Preparation of l-(2-(4-methoxybenzyloxy)ethyl)-lH-tetrazole-5-thiol: To a clear solution of Methyl 4-methoxybenzyloxyethyl dithiocarbamate (15-79 gm), in a mixture of methanol (700 ml) and water (70 ml), sodium azide (26 gm ) was added at 30°C. The reaction mixture was heated to 65°C and maintained at this temperature till completion of reaction. After completion of reaction, methanol was distilled at 30-40 °C under reduced pressure. The slurry thus obtained was added with water (700 ml), cooled to 25 ± 2°C, and washed With dichloromethane (500 ml). The aqueous layer was treated with charcoal (7, gin) Carbon was filtered and washed with water (100 ml). Dichloromethane (300 nil) was added to the aqueous layer, cooled to 25 ± 2°C and the pH of the solution was adjusted to 2.6 ± 0. The dichloromethane layer was separated. Dichloromethane layer was distilled at 42-45°C, to produce 50-55 gm of l-(2-(4-methoxybenzyloxy)ethyl)-lH-tetrazole-5-thiol (X) and refrigerated to get solid material. The methyl mercaptan generated during the course of reaction was trapped using sodium hypochlorite solution (excess) by nitrogen gas. We Claim: 1. A process for the preparation of l-(2-(arylmethoxy)ethyl)-lH-tetrazole-5-thiols of the formula (I) the said process comprising the steps : (i) treating alkali/alkaline earth metal salt of ethanolamine, prepared from ethanolamine and a base, with a substituted arylmethyl halide of formula (VIII), wherein Ri, R2, R3 are same or different and independently represent hydrogen, (Ci-C4)alkoxy, aryl(CrC4)alkoxy or substituted aryl(Ci-C4)alkoxy group; aryl group represents five or six membered aromatic group selected from phenyl, pyridyl, furyl, thiophenyl, pyrrolyl and the like; and L is a leaving group such as halogen like fluoro, chloro, bromo, iodo; tosylate, mesylate or triflate in an organic solvent at a temperature in the range of -10 to 120 °C, for a period of 15 min to 2 hrs to produce 2-(substituted arylmethoxy)ethylamine of the general formula (IX), (ii) treating the 2-(substituted arylmethoxy)ethylamine of the general formula (IX) with carbon disulphide in the presence of a tertiary amine in an aqueous organic solvent at a temperature in the range of 0°C to 40°C, and treating the product with iodomethane to produce the dithiocarbamate of the general formula (X). (iii) cyclizing the dithiocarbamate of the formula (X) with an azide in a solvent system to produce l-(2-(arylmethoxy)ethyl)-lH-tetrazole-5-thiols of the formula (I) wherein Rl5 R2, R3 and aryl groups are defined above. 2. The process claimed in claim 1, wherein the reaction temperature for step (i) is preferably in the range of 20°C to 30°C 3. The process as claimed in claim 1, wherein the organic solvent used in step (i) is is selected from DMSO, DMF, DMAC, acetonitrile, acetone, diethylene glycolmonomethylether, THF, or a mixture thereof. 4. The process as claimed in claim 1, wherein the base used in step (i) is selected from sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, or potassium t-butoxide. 5. The process as claimed in claim 1, wherein the solvent used in step (ii) is selected from methanol, ethanol, isopropanol, acetone, THF, dioxane, acetonitrile, or mixtures thereof. 6. The process as claimed in claim 1, wherein the tertiary amine used in step (ii) is selected from triethylamine, trimethylamine, tri-n-butylamine, pyridine, ethyl diisopropylamine, N-methyl pyrrolidine or N-methylpiperidine. 7. A process as claimed in claim 1, wherein the azide used in step (iii) is inorganic azide or organic azide. 8. A process as claimed in claim 7, wherein the inorganic azide used is selected from sodium azide, potassium azide, or calcium azide. 9. A process as claimed in claim 7, wherein the organic azide used is selected from quaternary ammonium or phosphonium azide such as tetra-n-butylammonium azide, tri-n-butylbenzylammonium azide, tetraethylammonium azide, or tetra-n- butylphosphonium azide. 10. The process as claimed in claim 1, wherein the solvent system used for cyclizing with inorganic azide is an aqueous organic solvent. 11. The process as claimed in claim 10, wherein the aqueous organic solvent used is methanol, ethanol, isopropanol, acetone or mixtures thereof 12. The process as claimed in claim 1, wherein the solvent system used for cyclizing with organic azide is a biphasic medium. 13. The process as claimed in claim 12, wherein the solvent used for biphasic medium in step (iv) is selected from dichloromethane, chloroform, dichloroethane, or toluene.

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