Title of Invention	A PROCESS FOR THE PREPARATION OF TAZOBACTAM
Abstract	The present invention relates to a process for the preparation of pencillin derivative. More particularly, the present invention relates to a process for the preparation of tazobactam of the formula (I) its esters, pharmaceutically acceptable salts or hydrates.

Full Text

Field of the Invention The present invention relates to a process for the preparation of penciling deR1vative. More particularly, the present invention relates to a process for the preparation of tazobactam of the formula (I) its esters, pharmaceutically acceptable salts or hydrates. Background of the Invention Tazobactam is chemically known as 2a-methyl-2p-(l,2,3-tR1azol-l-yl)-methylpenam-3a-carboxylate-1,1-dioxide. It is an orally effective penicillin antibiotic having a broad spectrum of antibacteR1al activity against both gram positive and gram-negative organisms and is disclosed in US Patent No. .,_ _ N 4,562,073. US patent No. 4,562,073 discloses tazobactam of formula (I) and its deR1vatives. This patent also descR1bes process for their preparation as shown in scheme - 1 below: wherein R1 is hydrogen or tR1alkylsilyl; R2 is hydrogen, tR1alkylsilyl or COOR1" wherein R2" is hydrogen, C1-18 alkyl, C2-7 alkoxymethyl, etc., R3 has the same meaning as above R2" and R4 represents carboxyl protecting group. US patent No. 4925934 discloses a process for the preparation of tazobactam of formula (I) compR1sing reacting a beta-lactic deR1vative of the following formula (V) wherein R represents a benzyl group having an electron-donating group as a subsistent on the phenyl R1ng, a diphenylmethyl group which may have an electron-donating group as a subsistent on the phenyl R1ng or a tert-butyl group with a cresol. US patent No. 4,891,369 discloses compounds of formula (VI) wherein n is 0, 1 or 2; and N-Y is monocyclic or bicycles heterocyclic R1ng which has 2 to 4 nitrogen atoms as hetero atom in its R1ng structure and which may be optionally substituted with the proviso that said heterocyclic R1ng is not 1,2,3-tR1azol-1-yl; or salts or esters thereof and a process for its preparation as shown in scheme 2 below : wherein R is hydrogen or a carboxyl protecting group, R1 is hydrogen or halogen, R2 is hydrogen, lower alkyl, lower alkoxy, halogen, azido, lower alkylthio, pthalimide or a group -NHR3, wherein R3 is hydrogen or acryl, and -N-Y is an optionally substituted monocyclic or bicyclical heterocyclic group having 1 to 4 nitrogen atoms as hereto atom in the R1ng structure, the process compR1sing reacting a compound represented by the formula (VII) wherein X is chloR1ne or bromine, and R, R1 and R2 are as defined above with heterocyclic compound represented by the formula ~N Y wherein N, Y are as defined above, wherein the reaction is carR1ed out in a solvent at a temperature of about 0 °C to 80 °C. us patent No. 4,496,484 discloses compounds of formula (VII) (VII) wherein X represents chloR1ne atom or bromine atom and R represents hydrogen atom or penicillin carboxyl-protecting radical, and a process for its preparation comprising reacting a compound of the formula (XII) o^^^ S (XII) COOR wherein R is as defined above with a chloR1nating reagent or brominating reagent. US patent No. 4,898,939 discloses process for prepaR1ng a 2p-substituted-methylpenicillin compound of the formula (XI) "CH3 (XI) COOR wherein ~N Y is an optionally substituted heterocyclic group containing 2 to 4 nitrogen atoms as the heteroatom in the R1ng structure, and R1 is a penicillin carboxyl protecting group, the process compR1sing reacting an azetidinonedisulfide compound of the formula H^ ^S-S-R (XII) COOR, wherein R1 is as defined above and R is a substituted or unsubstantiated heterocyclic group with a nitrogen-containing heterocyclic compound of the formula wherein —N Y is is as defined above in the presence of a metal compound. Objective of the Invention The objective of the present invention is to develop a simple and commercially viable process for the preparation of tazobactam of the formula (I). Summary of the Invention Accordingly, the present invention provides a process for the preparation of tazobactam of the formula (I) COOH which compR1ses the steps of: i) esteR1fying the compound of formula (XIII) using an esteR1fying agent in the presence of a solvent to produce a compound of formula (XIV) wherein R represents substituted methyl groups such as p-methoxybenzyl, p-nitrobenzyl, o- chlorobenzyl, benzyl, t-butyl or diphenylmethyl, ii) oxidizing the compound of formula (XIV) using an oxidizing agent in the presence of a solvent at a temperature in the range of -20 °C to 20 °C to a compound of formula (XV), iii) opening the penman R1ng of the formula (XV) 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 (XII) where R1 represents a heteroaryl R1ng system and all other symbols are as defined above, iv) stylizing the compound of formula (XII) using organic or inorganic nitR1tes in the presence of an acid and a solvent at a temperature in the range of- 20 °C to 30 °C to obtain compound of formula (VII), v) reacting the compound of formula (VII) with tR1azole using a reagent in the presence of solvent to obtain compound of formula (XI), vi) oxidizing the compound of formula (XI) using an oxidizing agent in the presence of a solvent under acidic conditions at a temperature in the range of -30 °C to 50 °C to a compound of formula (V) and vii) desteR1fying the compound of formula (V) using a catalyst in the presence of solvent to yield tazobactam of the formula (I). The process is shown in scheme -3 below : COOH COOH (XIH) O (XIV) COOR (XV) COOR Detailed DescR1ption of the Invention In yet another embodiment of the present invention the esteR1fication in step (i) is carR1ed out using esteR1fying agents such as p-methoxybenzyl bromide, p-methoxybenzyl chloR1de, p-nitrobenzyl bromide, p-nitrobenzyl chloR1de, o-chlorobenzyl chloR1de, benzyl bromide and the like in the presence of a solvent selected from methylene dichloR1de, N,N-dimethylformamide, acetonitR1le, dioxane, tetrahydrofuran, ethyl acetate, N,N-dimethylacetamide, water and the like or mixtures thereof The reaction may be carR1ed out at a temperature in the range of 10to50°C. In yet another embodiment of the present invention the oxidation in step (ii) is carR1ed out using peracetic acid, m-chloroperbenzoic acid, H2O2, tR1fluoroperacetic acid, magnesium monoperoxyphthalate and the like in the presence of solvent selected from methylene dichloR1de, chloroform, toluene, N,N-dimethylformamide, ethyl acetate, acetic acid, N,N-dimethylacetamide, acetone. The reaction may be carR1ed out at a temperature in the range of -20 to 20 °C. In yet another embodiment of the present invention the R1ng opening in step (iii) is carR1ed out using a mercaptan selected from 2-mercaptobenzothiazole, 2-mercaptobenzooxazole, 2-mercaptobenzimidazole, 2-mercapto-5-methylterazole in the presence of a solvent selected from 1,4-dioxane, toluene, xylene and the like. The reaction is carR1ed out at a temperature in the range of 80 °C to 150 °C. In yet another embodiment of the present invention the cyclization in step (iv) is carR1ed out using cyclizing agent selected from metal nitR1tes such as sodium nitR1te, potassium nitR1te, or organic nitR1tes such as amyl nitR1te, isoamyl nitR1te, nitrosonium tetrafluoroborate, and the like in the presence of an acid selected from HCl, sulfuR1c acid, phosphoR1c acid, acetic acid, and the like and solvent selected from DMF, acetonitR1le, N,N-dimethylacetamide, ethyl acetate, dioxane, THF, methylene dichloR1de, ethylene dichloR1de, toluene and the like. The reaction is carR1ed out at a temperature in the range of-20 °C to 40 °C. In yet another embodiment of the present invention, the reaction of compound of the formula (XI) and with tR1azole is carR1ed out using reagent such as phase transfer catalyst selected from tetrabutylammonium bromide, benzyltR1butylammonium bromide, benzyltR1octylammonium bromide, benzyltR1phenylphosphonium bromide: and the like, or metal carbonates such as sodium carbonate, potassium carbonate and the like, or metal oxide such as sodium methodize, potassium t-butoxide, sodium ethnocide and the like in the presence of solvent selected from water, THF, dioxane, dialyze, monoglyme, DMF, DMAC, DMSO, acetone, ethyl acetate, sulpholane, acetonitR1le, n-butane, isopropanol, methanol, ethanol, cyclohexanol, toluene, anisole, dichloromethane, dichloromethane, carbon tetrachloR1de, chlorobenzene and the like or mixtures thereof The reaction is carR1ed out at a temperature in the range of lO°C to 50°C. In yet another embodiment of the present invention, the oxidation in step (vi) is carR1ed out using oxidizing agents selected from potassium permanganate, peracetic acid, tR1fluoroperacetic acid, m-chloroperacetic acid, magnesium monoperoxyphthalate, oxone and the like in the presence of solvent selected from acetone, water, acetic acid, methylene chloR1de, ethylene chloR1de, and the like. The oxidation may be conducted in the presence of an acid such as aliphatic carboxylic acid, aliphatic sulphonic acid and the like. The reaction temperature can vary from -30 to +50 °C, and preferably from -10 to +30 °C. In yet another embodiment of the present invention, the deesteR1fication may be carR1ed out using metal catalyst such as 5-10% Pd/C, 5% Pt, Adam"s catalyst and the like in the presence or absence of a base selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like and solvent such as toluene, ethyl acetate, methyl acetate, THF, methanol, water and the like or mixtures thereof. In an embodiment of the present invention the heteroaryl group represented by R1 is selected from 2-mercaptobenzothiazole, 2-mercaptobenzooxazole, 2-mercaptobenzimidazole or 2-mercapto-5-methyltetrazole. In an embodiment of the present invention there is provided a process for the preparation of compound of formula (XIII) which compR1ses the steps of a) halogenations the clear solution of compound of formula (XVII) using halogen/hydrogen halide as a halogen ting agent such as Br2/HBr, I2/HI, Cl2/HClin the presence of metal nitrites such as sodium nitrite or potassium nitrite to obtain compound of formula (XVIII) and b) dehalogenating the compound of formula (XVIII) to obtain compound of formula (XIII). The reaction is shown in scheme - 4 below : In an embodiment of the present invention there is provided an alternate process for the preparation of compound of formula (XIII) which comprises halogenation of the compound of formula (XVII) using halogenating agent in the presence of solvent, extracting the dihalo compound from organic phase into aqueous phase by adjusting the pH and dehalogenating with metals like magnesium, iron, and the like while adjusting the pH of the resultant solution to obtain of compound of formula (XIII). In an additional embodiment, the dehalogenation is carried out either in a biphasic medium comprising water and a water-immiscible organic solvent while adjusting the pH or in a homogeneous medium like methanol, ethanol and the like. In yet another embodiment of the present invention, the solvent used may be selected from methylene dichloride, ethylene dichloride and the like. In yet another embodiment of the present invention, the dihalo compound is extracted in to the aqueous phase by adjusting the pH using alkali/alkaline earth metal hydroxides, carbonates, or oxides such as sodium hydroxide, sodium carbonate, calcium oxide and the like. The following examples are provided by way of illustration only and should not be limited to construe the scope of the invention. Example Step (i) Preparation of 2,2-dimethylpenam-3a-carboxylic acid p-nitrobenzyl ester To a solution of 2,2-dimethylpenam-3a-carboxylic acid (65 g) in DMAc (270 ml), p-nitrobenzyl bromide (67.5 g) was added and stirred at for 36 hrs. The progress of the reaction was monitored by HPLC. Isopropyl ether (370 ml) was added ate RT in 30-40 min and cooled to 0-5 °C. DM water (300 ml) was added at 2-5 °C and temperature raised to RT and stirred for 30 min filtered, washed with water followed by isopropyl ether and dried to yield the title compound (100 g). Purity 99% by HPLC. Step (ii) Preparation of 2,2-dimetliylpenam-3a-carboxylic acid 1-oxide p-nitrobenzyl ester A solution of 2,2-dimethylpenam-3a-carboxylic acid p-nitrobenzyl ester (100) in methylene dichloride (360 ml) was cooled to -10 °C. To this solution, peracetic acid (80 ml) was added at -10 °C in 60-70 min. After the reaction was over, DM water (125 ml) was added and the organic layer separated. The aqueous layer was extracted with MDC (400 ml) at 0-5 °C, and washed with 5% sodium chloride solution (210 ml). The pH of the organic layer was adjusted to 6.0-6.5 using sodium bicarbonate and stirred for 15 min. The aqueous layer was separated and extracted with MDC (100 ml) at 0-5 °C. The organic layers were combined and washed with 5% sodium chloride solution. The organic layer was charcoalized, concentrated under vacuum to remove methylene chloride and treated with isopropyl ether. The product obtained was filtered and dried under vacuum to yield the title (100 g, purity: 98% by HPLC). Step gin Preparation of p-nitrobenzyl 2-oxo-4-(benzothiazol-2-yl)ditliio-a-isopropenyI-1-azetidine acetate A solution of 2,2-dimethylpenam-3a-carboxylic acid 1-oxide p-nitrobenzyl ester (100 g) in toluene (1.4 L) was refluxed in a Dean-Stark apparatus with 2-mercaptobenzothiazole (100 g). After completion of the reaction, the solvent distilled off under vacuum, treated with isopropyl ether, filtered, washed with isopropyl ether and dried under vacuum to yield the tile compound (125 g, purity 92% by HPLC). Step (iv) Preparation of p-Nitrobenzyl 2P-chIorometliyI-2a-metliyIpenam-3a- carboxylate To a solution of p-nitrobenzyl 2-oxo-4-(benzothiazol-2-yl)dithio-a-isopropenyl-1-azetidine acetate (120 g) in MDC (1130 ml) at 0-5 °C, dil. HCl (1050 ml) was added. To this an aqueous sodium nitrite solution (qty to be specified 225 ml) at 0-5 °C was added in 30-40 min and maintained at this temperature for 30 min. The reaction mixture filtered and washed with chilled MDC (150 ml). The organic layer was separated and the aqueous layer extracted with MDC (150 ml) at 0-5 °C. The combined organic layer was washed with DM water (250 ml). The pH was adjusted to 4.0-4.5 with 10% sodium hydroxide at 0-5 °C and stirred for 15 min. The organic layer was separated and washed with DM water. The organic layer was concentrated under vacuum. Acetone (60 ml) was added and cooled to 3-6 °C. The clear solution was charcolized. Filtered the reaction mixture washed with chilled acetone. Isopropyl ether (360 ml) was added and temperature was raised to 22-25 °C and stirred for 30 min, washed with IPE and dried to yield the title compound (75 g, purity 95% by HPLC). Step (v) Preparation of p-nitrobenzyl 2α -methyI-2P-(l,2,3-triazol-l- yI)methylpenam-3a-carboxyIate To a solution of 1,2,3-lH-triazole (140 g) in DM water (420 ml), calcium carbonate (6.7 g) was added, warmed to 42 °C and stirred for 40 min. To this p-nitrobenzyl 2P-chloromethyl-2α -methylpenam-3a-carboxylate (100 g) in acetone (780 ml) was added and stirred at 35-37 °C for 4 hrs. After completion of the reaction, the reaction mass was cooled to 25-30 °C, MDC (9900 ml) was added and pH set to 7.0-7.5 with 10% sodium carbonate solution. After stirring for another 15 mint he organic layer were separated. The aqueous layer was extracted with MDC (300 ml). The organic layers were combined , washed with DM water (300ml x 3), filtered, and dried under vacuum to yield the title compound, which is used for fitter reaction without purification . Step (vi) Preparation of p-Nitrobenzyl 2a-methyl-2P-(l,2,3-trlazoI-l-yl)- methylpenam-3a-carboxyIate-l,l-dioxide To a solution of p-nitrobenzyl 2a-methyl-2p-(l,2,3-triazol-l-yl)methylpenam-3a-carboxylate obtained in the previous step in acetone (500 ml), DM water was added and cooled to 0-4 C. To this acetic acid (270 ml) and KMn04 (86 g) were added and the temperature was allowed to raise to 15-20 °C. After the reaction was over, an aqueous solution of H2O2 was added in water until complete depolarization at 0 C, and raise the temperature to 12-15 °C. To this MDC (900 ml) and water (500 ml) was added and stirred for 20 min. at 10-15 °C. The aqueous layer was separated and washed with MDC (300 ml). The combined organic layers was washed with DM water (500 ml), the pH set 7.0-7.5 with aqueous sodium carbonate solution and stirred for 15 min. The organic layer was washed with water and distill off the MDC under vacuum. Ethyl acetate was added, stirred, filtered and dried to to yield the title compound (70 g). Step (vii) Preparation of 2a-methyl-2P-(l,2,3-triazoI-l-yl)-methylpenain-3a- carboxylate-l,l-dioxide To ethyl acetate (450 ml) in an autoclave at 25-30 °C, p-nitrobenzyl 2a-methyl-2(5-(l,2,3-triazol-l-yl)-methylpenam-3a-carboxylate-1,1-dioxide (70 g) was added. To this 10% Pd-C (10 g) in DM water was added. The reaction mass was cooled to 16-19 °C, pressurized with hydrogen and maintained for 60 min. After the reaction was over, the reaction mixture was filtered, washed with DM water and cooled to 10-15 °C. The pH was adjusted using cone. HCl to 6.0-6.5 and stirred for 15 min. The aqueous layer was separated and washed with ethyl acetate (150 ml x 3) The pH of the aqueous layer was adjusted to 5.5-5.8 with cone. HCl and charcoalized. The pH of the aqueous filtrate was adjusted with cone. HCl to ~2.5 at 12-15 °C. The product obtained was filtered, washed with cold DM water, and dried to yield the title compound (20 g). Example 2 Preparation of 2,2-dimetliyI-penam-3-carboxylic acid Step (i) Preparation of 6,6-dibromopenicillanic acid Into a 2L round-bottomed flask containing DM water (100 ml) at 0-3 °C, hydrogen bromide (30 ml, 47-49% solution), and bromine (48 ml) were added followed by a solution of sodium nitrite 0-3 °C. To this reaction mass, a clear solution of 6-APA (100 g) and sodium nitrite solution were added at 0-2 C over a period of 90-120 min. and stirred for 45 min at 4-6 C. To this stirred reaction mixture, water (500ml) and aqueous solution of sodium metabisulfite (50 ml) were added and stirred for 20 min at 8 C. The crystallized material was filtered, washed with water and dried under vacuum to yield the title compound (145 g, purity 97.5%). Step (ii) Preparation of 2,2-dimethyl-penam-3-carboxylic acid To a cold mixture of 6,6-dibromopenicillanic acid (140 g) in water (250 ml) sodium carbonate solution was added at 0-5 °C to adjust the pH to 5.6-5.8 to get clear solution (if not clear adjusted the pH with HCl to 5-5.6). To this magnesium powder (20 g) was added while maintaining the pH at 3-8 °C in 60-90 min. The pH was adjusted to 4-4.5 and stirred for 90-120 min. The pH was adjusted to 4.0-4.5 with HCl solution at 3-8 °C and added magnesium powder (25 g) slowly while maintaining the pH at 4-4.5 with HCl at 3-8 °C and stirred for 60-90 min. . Filtered the reaction mass and washed with water and cooled to 0-5 C. Adjusted the pH to 2-2.5 with HCl and added sodium chloride and stirred for 15 min. To this ethyl acetate was added and separated the aqueous layer and extracted with ethyl acetate (250 ml x 2). Combined the ethyl acetate layers, activated carbon was added and stirred for 30 min. at 3-8 C. Filtered, washed with ethyl acetate and added matrix solution. The temperature was raised and filtered the reaction mass, washed with ethyl acetate and dried under vacuum at RT to yield the title compound (70 g, purity 99% by HPLC). We claim: 1. A process for the preparation of tazobactam of the formula (I) which compR1ses the steps of: i) esteR1fying the compound of formula (XIII) using an esteR1fying agent in the presence of a solvent at a temperature in the range of 10 to 50 °C to produce a compound of formula (XIV) wherein R represents substituted methyl groups such as p-methoxybenzyl, p-nitrobenzyl, o-chlorobenzyl, benzyl, or diphenylmethyl, ii) oxidizing the compound of formula (XIV) using an oxidizing agent in the presence of a solvent at a temperature in the range of -20 °C to 20 °C to a compound of formula (XV), iii) opening the p« 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 (XII) where R1 represents a heteroaryl R1ng system and all other symbols are as defined above, iv) cyclizing the compound of formula (XII) using organic or inorganic nitR1tes in the presence of an acid and a solvent at a temperature in the range of- 20 °C to 40 °C to obtain compound of formula (VII), v) reacting the compound of formula (VII) with tR1azole using a reagent in the presence of solvent to obtain compound of formula (XI), vi) oxidizing the compound of formula (XI) using an oxidizing agent in the presence of a solvent under acidic conditions at a temperature in the range of-30 °C to 50 °C to a compound of formula (V) and vii) desteR1fying the compound of formula (V) using a catalyst in the presence of solvent to yield tazobactam of the formula (I). 2. The process as claimed in claim 1, wherein the esteR1fying agent used is selected from p-methoxybenzyl bromide, p-methoxybenzyl chloR1de, p- nitrobenzyl bromide, p-nitrobenzyl chloR1de, o-chlorobenzyl chloR1de or benzyl bromide. 3. The process as claimed in claim 1, wherein the solvent used in step (i) is selected from methylene dichloride, N,N-dimethylformamide, acetonitrile, dioxane, tetrahydrofuran, ethyl acetate, N,N-dimethylacetamide, water or mixtures thereof 4. The process as claimed in claim 1, wherein the oxidation in step (ii) is carried out using peracetic acid, m-chloroperbenzoic acid, H2O2, trifluoroperacetic acid or magnesium monoperoxyphthalate. 5. The process as claimed in claim 1, wherein the solvent used for oxidation in step (ii) is selected from methylene dichloride, chloroform, toluene, N,N-dimethylformamide, ethyl acetate, acetic acid, N,N-dimethylacetamide or acetone. 6. The process as claimed in claim 1, wherein the oxidation in step (ii) is carried out at a temperature in the range of-20 to 20 °C. 7. The process as claimed in claim 1, wherein the step (iii) is carried out using a mercaptan selected from 2-mercaptobenzothiazole, 2-mercaptobenzooxazole, 2-mercaptobenzimidazole or 2-mercapto-5-methylterazole. 8. The process as claimed in claim 1, wherein the solvent used in step (iii) is selected from 1,4-dioxane, toluene or xylene. 9. The process as claimed in claim 1, wherein the step (iii) is carried out at a temperature in the range of 80 °C to 150 °C. 10. The process as claimed in claim 1, wherein the cyclizing agent is selected from metal nitrites such as sodium nitrite, potassium nitrite, or organic nitrites. 11. The process as claimed in claim 1, wherein the acid used in step (iv) is selected from HCl, sulfuric acid, phosphoric acid or acetic acid. 12. The process as claimed in claim 1, wherein the solvent used in step (iv) is selected from DMF, acetonitrile, N,N-dimethylacetamide, ethyl acetate, dioxane, THE, methylene dichloride, ethylene dichloride or toluene. 13. The process as claimed in claim 1, wherein the reagent used in step (v) is phase transfer catalyst, metal carbonates or metal oxide. 14. The process as claimed in claim 1, wherein the solvent used in step (v) is selected from water, THF, dioxane, doglike, monoglyme, DMF, DMAC, DMSO, acetone, ethyl acetate, sulpholane, acetonitrile, n-butane, isopropanol, methanol, ethanol, cyclohexanol, toluene, anisole, dichloromethane, dichloromethane, carbon tetrachloride , chlorobenzene or mixtures thereof. 15. The process as claimed in claim 1, wherein the reaction in step (v) is carried out at a temperature in the range of 10°C to 50 °C. 16. The process as claimed in claim 1, wherein the oxidizing used in step (vi) is selected from potassium permanganate, peracetic acid, trifluoroperacetic acid, m-chloroperacetic acid, magnesium monoperoxyphthalate or oxone. 17. The process as claimed in claim 1, wherein the solvent used in step (vi) is selected from acetone, water, acetic acid, methylene chloride or ethylene chloride. 18. The process as claimed in claim 1, wherein the step (vi) is carried out at a temperature in the range of-30 to +50 °C. 19. The process as claimed in claim 1, wherein the catalyst used in step (vii) is selected from 5-10% Pd/C, 5% Pt or Adam"s catalyst. 20. The process as claimed in claim 1, wherein the base used in step (vii) is selected from sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate. 21. The process as claimed in claim 1, wherein the solvent used in step (vii) is selected from toluene, ethyl acetate, methyl acetate, THF, methanol, water or mixtures thereof 22. The process as claimed in claim 1, wherein the heteroaryl group represented by R1 is selected from 2-mercaptobenzothiazole, 2- mercaptobenzooxazole, 2-mercaptobenzimidazole or 2-mercapto-5- methyltetrazole.

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