Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF OFLOXACIN

Abstract

Present invention discloses an improved process for the preparation of Ofloxacin of formula (I) which comprises reacting 2,4-dichloro-5-fluoro-3-nitrobenzoic acid with thionyl chloride followed by methyl 3-dimethylaminoacrylate to get the acrylate derivative of formula (XXV). Reacting the compound of formula (XXV) with dl- alaninol gave the alanine derivative of formula (XXVI), treating the alanine derivative with a base gave the quinolone derivative of formula (XXVII) which on reaction with N- methylpiperazine gives the corresponding piperazine derivative of formula (XXVIII). Cyclization of the piperazine derivative of formula (XXVIII) with a base gave the methyl ester of Ofloxacin (XXIX) which upon hydrolysis gave Ofloxacin.

Full Text

FIELD OF INVENTION The present invention relates to an improved process for the preparation of Ofloxacin. Ofloxacin is ((±)-9-fluoro-2,3 -dihydro-3 -methyl- 10-(4-methyl-l-piperizinyl)-7-oxo-7H-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylic acid) having the formula-I given below. Ofloxacin is a broad-spectrum fluorinated quinolone antibacterial Ofloxacin has been in the market for quite some time as racemate as well as chiral isomer (levofloxacin, S-(-)-isomer). BACKGROUND OF INVENTION Ofloxacin was disclosed by I. Hayakawa and Y. Tanaka, Daiichi Seiyanku Co, ltd., in US Patent No. 4,382,892, 1983. Ofloxacin is one of the leading antibacterial fluoroquinolones in the market today; e.g. see: Chem. Pharm. Bull. 1984, 32, 4907-4913, 4923; Daiichi Seiyanku Drugs Future 1983, 8, 395; Collect. Czech. Chem. Commun, 1991,56, 1937. The S-(-)-isomer of Ofloxacin known as levofloxacin is 8 to 128 times more active than Ofloxacin depending upon the bacteria tested, J. Med. Chem. 1987, 30, 2283-2286, Drugs of the Future 1992, 17(7), 559-563, Antimicrob. Agents Chemother. 1989, 32, 1336-1340. Hayakawa's method of preparing Ofloxacin is described in EP no 0047005A1 (equivalent US Pat. No. 4,382,892). The process starts with 2,3,4-trifluoronitrobenzene shown in Scheme-I. 2,3,4-Trifluoronitrobenzene of the formula (II) is converted to 2,3-difluoro-6-nitrophenol of the formula (III) in dimethyl sulfoxide in the presence of potassium hydroxide. The yield of the compound of the formula (III) as per this reaction is only 29%. 2,3-Difluoro-6-nitrophenol of the formula (III) is converted to 2-acetonyloxy-3,4-difluoronitrobenzene of the formula (IV) which is reductively ring closed to give an isomeric mixture of 7,8-difluoro-2,3-dihydro-3-methyl-4H-l,4-bezoxazine of formula (V). The compound of the formula (V) is converted to diethyl (7,8-difluoro2,3-dihydro-3-methyl-4H-1,4-benzoxazinyl)-methylenemalonate of the formula (Va) by reaction with diethyl ethoxymethylene-malonate. Cyclization of this malonate ester with ethyl polyphosphate gives (±)-ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]benzoxazine-6-carboxylate of the formula (VI) The benzoxazine carboxylate ester of the formula (VI) is hydrolyzed to the corresponding acid and reacted with N-methylpiperazine in dimethyl sulfoxide to get Ofloxacin of the formula (I). The low yield of 2,3-difluoro-6-nitrophenol limits the overall yield of Ofloxacin in this process. A large quantity (nearly 50g for 7g of nitro compound of formula (IV)) of Raney nickel is required to effect the reductive amination for preparing the compound of formula (V) which makes the process uneconomical for its commercial application. Another route for the preparation of Ofloxacin is described in US Pat. No. 4,672,831; 4,859,773; 4,958,045; and DE 3522406A1 which is shown in Scheme-II. Basic raw material used in this process is 2,3,4,5-tetraflurobenzoic acid of the formula (VII) which is much more expensive than the Hayakawa's starting compound, 2,3,4-trifluoro-nitrobenzene. The reaction is shown in the Scheme II. In this process, 2,3,4,5-tetraflurobenzoic acid is reacted with thionyl chloride followed by ethyl magnesium malonate to get the keto ester of formula (VIII). Reaction of keto ester of formula (VIII) with triethyl orthoformate and acetic anhydride gave the enol ether of formula (IX) which upon reaction with alaninol gave the enamino derivative of formula (X). Cyclization of the enamino compound of formula (X) in the presence of base gave the compound of formula (VI) which upon hydrolysis gave the compound of formula (XI). Condensation of compound of formula (XI) with N-methylpiperazine gave Ofloxacin of formula (I). Another route for the preparation of Ofloxacin is described in Chem. Pharm. Bull, 1986, 34(10), 4098-4102 starting from keto-ester of the formula (VIII) which is shown in Scheme-Ill. According to the process disclosed involves reacting keto-ester of the formula (VIII) with N-methylpiperizine to get the compound of the formula (XII). Condensation of the compound of the formula-XII with N,N-dimethylformamide dimethylacetal gave the enamino derivative of the formula (XIII). Replacement of dimethylamino group present in compound of the formula (XIII) with dl-alaninol gave the enamino derivative of the formula (XIV). Cyclization under basic conditions gave the quinolone derivative of the formula (XV). Hydrolysis of the compound of the formula (XV) gave Ofloxacin of the formula (I). Main disadvantage in this process is the formation of ortho-piperazinyl impurity during coupling of keto-ester of the formula (VIII) with N-methylpiperazine. Removal of this impurity requires column chromatography which is not only difficult but also expensive which makes the process not suitable for commercial viability. Yet another process for the preparation of Ofloxacin is described in Collect. Czech. Chem. Commun. 1991, 56, 1937 shown in scheme-IV. In this process 4,8-dihydroxy-quinoline derivative of the formula (XVI) is reacted with propargyl bromide to get the benzoxazine derivative of the formula (XVII). Coupling of compound of the formula (XVII) with N-methylpiperazine gave the compound of the formula (XVIII) which upon hydrogenation gave Ofloxacin. Main disadvantage in this process is the preparation of the starting dihydroxy compound of formula (XVI). Preparation of this intermediate involves the chemistry given in the basic patent for the preparation of Ofloxacin as shown in SchemeII Yield of the required product (50%) is also not attractive for commercial production of Ofloxacin. A process for the preparation of levofloxacin analogous to is described in Heterocycles, 1997, 45, 137 is shown in Scheme-V. According to the process given in this reference, S-alaninol of the formula (XIX) is reacted with ethyl propiolate of the formula (XX) to get the enamino derivative of the formula (XXI). Protection of the hydroxy group as acetate followed by coupling with the benzoyl chloride of the formula (XXII) gave the a-benzoyl-p-enaminoacrylate ester of the formula (XXIII) . Treatment of the compound of the formula (XXIII) with a strong base followed by hydrolysis gave the quinolonic acid intermediate of Ofloxacin. Condensation of this acid with N-methylpiperizine gave Ofloxacin of the formula (I). XXIV I Scheme-V Main drawback in this process is non-availability of ethyl propiolate on commercial scale. Also, this compound is not stable under normal conditions of storage. Another compound, 2,3,4,5-tetrafluorobenzoic acid used in the process is very expensive. Therefore the process is not economically viable. Keeping in view of the difficulties in commercialization of the above mentioned known processes and cost constraints, we initiated R & D for developing a simple and cheap and at the same time economically and commercially viable process for the preparation of Ofloxacin of the formula (I). One of the major drawbacks in all the above-mentioned prior art processes is the requirement of the use of poly-fluorinated benzene derivatives. In general, fluorinated benzene compounds are very expensive and not readily and easily available. Accordingly, the main objective of the present invention is to provide an improved process for the preparation of Ofloxacin of the formula (I) which is commercially viable, simple, and also economical. Another objective of the present invention is to provide an improved process for the preparation of Ofloxacin of the formula (I) which will not require rare, non-commercial or expensive raw materials. Still another objective of the present invention is to provide an improved process for the preparation of Ofloxacin of the formula (I) which does not require the use of poly-fluorinated benzene derivatives. During our sustained research work for the development of processes for the preparation of various quinolone derivatives, we observed that the presence of a nitro group adjacent to a chloro group in the benzene ring will make the chloro group much more reactive than a fluoro group in the displacement reactions while building the quinolone moiety. While developing a process for the preparation of Ofloxacin of the formula (I) with the above mentioned objectives we carried out experiments starting from a nitrobenzene derivative with two adjacent chloro groups so that the two chloro groups can be easily displaced in building the structure of Ofloxacin ring system and finally displacing the nitro group with an alkoxy group by intramolecular cyclization reaction to complete the ring system of Ofloxacin. Accordingly, we utilized 2,4-dichloro-5-fluoro-3-nitrobenzoic acid as the starting material, as it is a cheap and readily available compound to carry out the above reaction. The above mentioned approach was successful to achieve the objectives mentioned above. This observation helped to develop a cost-effective and simple process for the preparation of Ofloxacin of the formula (I) which can be easily and conveniently adapted for its application on a commercial scale. The process for the preparation of Ofloxacin if the formula (I) according to the present invention is shown in Scheme-VI.. Accordingly, the present invention provides an improved process for the preparation of Ofloxacin of formula (I), which comprises: (i) Reacting 2,4-dichloro-5 -fluoro-3 -nitrobenzoyl chloride with methyl 3-dimethylaminoacrylate in the presence of a base in a solvent system at a temperature in the range of 20-120 °C to get the compound of the formula (XXV), (ii) Reacting the compound of the formula (XXV) with dl-alaninol in a solvent system at a temperature in the range of 0-40 °C to get the compound of the formula (XXVI) (iii) Reacting the resulting compound of the formula (XXVI) with a base in a solvent at a temperature in the range of-10 to 60 °C to get the cyclized compound of the formula (XXVII), (iv) Reacting the resulting compound of the formula (XXVII) with N-methylpiperazine in the presence or absence of a base and in a solvent medium at a temperature in the range of 10-100 °C to get the compound of the formula (XXVIII), (v) Reacting the resulting compound of the formula (XXVIII) with a base in a non-polar solvent system at a temperature in the range of 20-100 °C to get the cyclized compound of the formula (XXIX), (vi) Hydrolyzing the ester derivative of the formula (XXIX) so formed using acid or base to get Ofloxacin of the formula (I) In the reaction of 2,4-dichloro5-fluoro-3-nitrobenzoyl chloride with methyl 3-dimethylaminoacrylate in step (i) to get the compound of formula (XXV) the base employed may be selected from pyridine, alkyl pyridine, trialkyl amine, preferably trialkylamine. The solvent employed may be selected from hydrocarbon solvents such as hexane, heptane, toluene, xylene, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, acetonitrile, preferably toluene, acetonitrile. The preferred temperature of the reaction is 50-100 °C. The reaction of compound of the formula (XXV) with dl-alaninol, in step (ii), to get the compound of the formula (XXVI), as a crystalline solid, in high yield (more than 90%) may be carried out in a solvent such as methanol, ethanol, isopropanol, heptane, cyclohexane, toluene, methylene chloride, acetonitrile, THF, dioxane, ether, DMF. Preferred temperature of reaction is 20-30 °C. The base employed in step (iii) may be selected from the group consisting of lithium diisopropylamide, alkyl lithium, metal hydrides, metal carbonates, metal bicarbonates, metal alkoxides, DBU (l,8-diazabicyclo-undec-7-ene, DABCO (1,4-diazabicycloocatne, DBN (l,5-diazabicyclonon-5-ene, pyridine, dimethylaminopyridine, and triethylamine. The solvent, which may be employed in step (iii), may be selected from THF, toluene, heptane, DMF. Preferred temperature of the reaction is 10-40 °C. In step (iv), the base employed may be selected from metal carbonates, metal bicarbonates, and metal alkoxides, DBU (l,8-diazabicyclo-undec-7-ene, DABCO (1,4-diazabicycloocatne, DBN (l,5-diazabicyclonon-5-ene, pyridine The cyclized product of the formula (XXVII) has been isolated and characterized. Alternately the compound of the formula (XXVII) is used in situ for the next reaction (N-methylpiperazine condensation, The N-methylpiperazine condensation reaction in step (iv) may preferably be carried out in the same solvent as used in step (iii). The temperature used for the reaction may be in the range of 20-60°C, preferably 20-30°C. The base employed in step (v) may be selected from a group consisting of metal carbonates, metal bicarbonates, metal alkoxides, DBU (l,8-diazabicyclo-undec-7-ene, DABCO (1,4-diazabicycloocatne, DBN (l,5-diazabicyclonon-5-ene. The solvent employed in step (v) may be selected from acetonitrile, toluene, cyclohexane, THF, DMF, DMAc and the like. Preferred temperature of the reaction is 40-80 °C. The base such as metal hydroxides, metal carbonates, metal bicarbonates may be used for the hydrolysis of the ester group present in compound of the formula (XXIX) to get the compound of the formula (I) in step (vi). In the acid hydrolysis of compound of formula (XXIX) in step (vi) aqueous acids such as sulfuric acid, acetic acid, phosphoric acid, hydrobromic acid, hydrochloric acid may be used. The temperature used for the reaction may be in the range of 15-60°C. Overall yield of Ofloxacin made by the present process is more than 70% and the purity is more than 99.8%. The details of the process of the invention are provided in the Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Example 1 Preparation of Ofloxacin (i) Preparation of methyl 2-(2,4-dichloro-5-fluoro-3-nitrobenzovlV3-dimethylamino acrylate Into a 2L, three-necked RB flask was charged 800ml of toluene and 108g of methyl 3-dimethylaminoacrylate. Triethylamine (94 g) was added to the reaction mass. A solution of methyl 2,4-dichloro-5-fluoro-3-nitrobenzoyl chloride (prepared from 200g of 2,4-dichloro-5-fluoro-3-nitrobenzoic acid using thionyl chloride) in toluene (400ml) was added to the reaction mass at 25-30 °C. The reaction mass was heated to 100-105°C and maintained for 4hr. Reaction mass was cooled to RT and filtered the solid. To the filtrate water was added and extracted product into toluene. Toluene layer was treated with carbon and distilled off solvent under vaccum to get 320g of crude compound. To the crude 300ml of IPA was added and heated to 60-65°C. The resultant solution was cooled under stirring to 0-5 °C and filtered the solid. The wet cake was washed with 100ml of chilled IPA and dried at 50-60°C to get 250 g of methyl 2-(2,4-dichloro-5-fluoro-3-nitrobenzoyl)-3-dimethylamino acrylate of the formula (XXV)), as light yellow colored solid. Melting point is 125-126°C. IR (KBr): 3444, 3068, 2946, 1690, 1627, 1569, 1549, 1453, 1427, 1395, 1378, 1359, 1312, 1199, 1130, 1107, 1058, 1037, 968, 833, 802, 787, 760, and 745 cm. (ii) Preparation of methyl (±)-2-(2,4-dichloro-5-fluoro-3-nitrobenzoyl)-3-(3-hydroxy-2-propylamino)-acrylate Into a 1L, three-necked RB flask was charged 200g of methyl 2-(2,4-dichloro-5-fluoro-3-nitrobenzoyl)-3-dimethylamino acrylate and 1L methylene chloride. A solution of (±)-2-amino-1-propanol (60 g) in methylene chloride (100ml) was slowly added to the reaction mass at RT. The reaction mass was stirred for 6hr and added water. Methylene chloride layer was separated, dried and distilled off solvent under vaccum. The residue was dissolved in isopropanol and cooled to 0-5 °C. Solid compound was filtered and washed with chilled isopropanol to get 220g of methyl (±)-2-(2,4-dichloro-5-fluoro-3-nitrobenzoyl)-3-(3-hydroxy-2-propylamino)-acrylate of the formula (XXVI) as light yellow colored solid after drying at 40-50 °C. Melting point is 123-124 °C. IR (KBr): 3511, 3079, 2953, 1694, 1636, 1550, 1458, 1443, 1424, 1399, 1365, 1340, 1313, 1266, 1226, 1199, 1111, 1057,1011, 976, 885, 832, 807, 781, 757, 732, 653, 604, 551cm"1. 1H- NMR (300MHz, CDC13): 8 10.90 (dd, J = 6.96Hz, 14.28Hz, 1H, exch. with D20, NH); 8.38 (d, J = 14.65Hz, 1H, Ar. H); 7.80 (d, J = 8.80Hz, 1H, =CHNH-); 5.12 (t, J = 5.13Hz, 1H, exch. with D20, -CH2OH); 3.70-3.78 (m, 1H, -NHCHCH3); 3.49 (s, 3H, -C02Me); 3.40-3.60 (m, 2H, -CH2OH); 1.23 (d, J = 6.59Hz, 3H, -CHCH3). (iii) Preparation of methyl (±)-l-(3-hydroxy-2-propyl)-6-fluoro-7-chloro-8-nitro-4-oxo-quinoline-3-carboxylate Into 1L, three-necked, RB flask was added 300ml of dry THF and 8g of sodium hydride (55% in paraffin oil). The suspension was cooled to -5 °C and added 40 g of solid methyl (±)-2-(2,4-dichloro-5-fluoro-3-nitrobenzoyl)-3-(3-hydroxy-2-propylamino)-acrylate, prepared by the process described in step (ii) in lots keeping the temperature below 0 °C. The reaction mass was slowly allowed to reach 10-15 °C and maintained for 3hr. TLC of the reaction mass showed the absence starting material. The reaction mass was cooled to 0-5 °C and quenched with acetic acid. Water (200ml) was added to the reaction mass and extracted product into methylene chloride. Methylene chloride layer was dried and distilled to get the crude compound. To the crude compound formed methanol (20ml) was added and stirred for 15-20min. Filtration gave 11.5g of methyl (±)-l-(3-hydroxy-2-propyl)-6-fluoro-7-chloro-8-nitro-4-oxo-quinoline-3-carboxylate of the formula XXVII as off-white solid. Melting point is 219-220 °C. IR (KBr): 3396, 3077, 2952, 1706,1643, 1596, 1539, 1476, 1452, 1437, 1388, 1351, 1320, 1201, 1175, 1086, 1045, 857, 802, and 773cm'1. 'H-NMR (300MHz, CDC13): 88.68 (s, 1H, -NHCH=); 8.32 (d, J - 8.80Hz, 1H, Ar. H); 5.20 (d, J = 5.10Hz, 1H, exch. with D20, -CH2OH); 4.01-4.10 (m, 1H, -CHCH3); 3.71 (s, 3H, -C02Me); 3.54-3.67 (m, 2H, -CH2OH); 1.44 (d, J = 6.60Hz, 3H, -CHCH3). (iv) Preparation of methyl (±)-l-(3-hydroxy-2-propyl)-6-fluoro-7-(4-methyl-piperazinyl)-8-nitro-4-oxo-quinoline-3-carboxylate Into a 2L, three-necked RB flask was added 46 g of methyl (±)-l-(3-hydroxy-2--propyl)-6-fluoro-7-chloro-8-nitro-4-oxo-quinoline-3-carboxylate of the formula XXVII prepared by the process described in step (iii) above, acetonitrile (900 ml), and N-methylpiperazine (46 g). The reaction mixture was stirred at RT for 15hr and removed the solvent using rotavopor under vaccum. The residue was suspended in water and stirred for lhr. The reaction mass was filtered and the cake washed with water. The wet cake was dissolved in 10% acetic acid (250 ml) and treated with carbon. The acetic acid layer was neutralized with ammonia get the pH 8.0-9.0 and filtered the solid. The wet cake was washed with water and dried to get 50g of methyl (±)-l-(3-hydroxy-2-propyl)-6-fluoro-7-(4-methylpiperazinyl)-8-nitro-4-oxo-quinoline-3-carboxylate of the formula (XXVIII) as yellow colored solid. Melting point is 215-218 °C. IR (KBr): 3392, 2948, 2850, 2795, 1731, 1702, 1638, 1606, 1547, 1478, 1455, 1363, 1322, 1288, 1263, 1220, 1198, 1175, 1148, 1105, 1068, 1007, 950, 905, 834, 804, 775, 761, 701, and 670 cm'1. 'H-NMR (300MHz, CDC13): 8 8.45 (s, 1H, -NCH=); 8.14 (d, J = 11.72Hz, 1H, Ar. H); 5.21 (t, J = 5.13Hz, exch. with D20, 1H, -CH2OH); 4.11-4.19 (m, 1H, -CHCH2OH); 3.76 (s, 3H5 -C02Me); 3.58-3.64 (m, 2H, -CH2OH); 2.97-3.16 (m, 4H, 2 x -NCH2-); 2.32-2.42 (m, 4H, 2x-NCH2-);2.19(s,3H,-NCH3); 1.41 (d, J = 6.60Hz, 3H, -CHCH3). (v) Preparation of methyl (±)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-l-piperizinyl)-7-oxo-7H-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylate Into a 1L, three-necked RB flask was charged 585ml of dry DMF, 70 g of methyl (±)-l-(3-hydroxy-2-propyl)-6-fluoro-7-(4-methylpiperazinyl)-8-nitro-4-oxo-quinoline-3-carboxylate of the formula (XXVIII) prepared by the process described in step (iv), and 81g of potassium carbonate. The reaction mass was heated to 100-110 °C and maintained for 4hr. The reaction mass cooled to 0 °C and maintained for 2hr. The reaction mass was filtered and the cake washed with 50ml of DMF and 300ml of water. The wet cake was dried at 60-70 °C to get 55g of methyl (±)-9-fluoro-253-dihydro-3-methyl-10-(4-methyl-l-piperizinyl)-7-oxo-7H-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylate of the formula (XXIX) as white solid. Melting point is 223-224 °C. IR (KBr): 2934, 2840, 2792, 1716, 1623,1579,1551,1479,1442,1346,1322,1296,1243,1155, 1093,1070,1006, 870, and 800 cm"1. !H-NMR (300MHz, CDC13): 8 8.60 (s, 1H, -NCH=); 7.41 (d, J = 12.82Hz, 1H, Ar. H); 4.68-4.72 (m, 1H); 4.49 (d, J = 11.72Hz, 1H); 4.30 (d, J = 11.72Hz, 1H); 3.73 (s, 3H, -C02Me); 3.22-3.42 (m, 4H, 2 x -NCH2-); 2.40-2.44 (m, 4H, 2 x -NCH2-); 2.21 (s, 3H, -NCH3); 1.39 (d, J = 6.60Hz, -CHCH3). (vi) Preparation of (±)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyH-piperizinyl)-7-oxo-7H-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylicacid (Ofloxacin) Into a 1L, three-necked RB flask was added 450ml of 1.4% aqueous sodium hydroxide and 45g of methyl (±)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-l-piperizinyl)-7-oxo-7H-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylate prepared by the process described in step (v). The reaction mass was heated to 70-80 °C and maintained for 30min. Carbon (5g) was added to the reaction mass and filtered. The pH of the filtrate was adjusted to 7.0-7.5 with acetic acid and cooled to 5-10 °C and maintained for lhr. The reaction mass was filtered and the cake washed with chilled water. A small sample was purified by extraction into methylene chloride and distilled of methylene chloride to get white crystalline Ofloxacin. Melting pointy is 274 °C. Purity by HPLC is 99.92%. Example 2 Preparation of Ofloxacin (i) Preparation of methyl (±)-2-(2,4-dichloro-5-fluoro-3-nitrobenzoyl)-3-(3-hydroxy- 2-propylamino)-acrylate Into a 2L, three-necked RB flask was charged 800ml of toluene and 108g of methyl 3-dimethylaminoacrylate. Triethylamine (94g) was added to the reaction mass. A solution of methyl 2,4-dichloro-5-fluoro-3-nitrobenzoyl chloride (prepared from 200g of 2,4-dichloro-3-nitro-5-fluorobenzoic acid using thionyl chloride) in toluene (400ml) was added to the reaction mass at 25-30 °C. The reaction mass was heated to 100-105°C and maintained for 4hr. Reaction mass was cooled to RT and filtered the solid. To the filtrate water was added and extracted the compound of the formula (XXV) into toluene. Toluene layer was dried and used directly in next step. The above toluene layer was taken into a 2L, three-necked RB flask and added (±)-2-amino-1-propanol (60 g) slowly at RT. The reaction mass was stirred for 6hr and added water. Toluene layer was separated, dried and distilled off solvent under vaccum. The residue was dissolved in isopropanol and cooled to 0-5 °C. Solid compound was filtered and washed with chilled isopropanol to get 270g of methyl (±)-2-(2,4-dichloro-5-fluoro-3-nitrobenzoyl)-3-(3-hydroxy-2-propylamino)-acrylate of the formula (XXVI) as light yellow colored solid after drying at 40-50 °C. Melting point is 210-212 °C. (ii) Preparation of methyl (±)-l-(3-hydroxy-2-propyl)-6-fluoro-7-(4-methyI-piperazinyl)-8-nitro-4-oxo-auinoline-3-carboxvlate Into 1L, three-necked, RB flask was added 300ml of dry THF and 8g of sodium hydride (55% in paraffin oil). The suspension was cooled to -5 °C and added 40 g of solid methyl (±)-2-(2?4-dichlor0-5-fluoro-3-nitrobenzoyl)-3-(3-hydroxy-2-propylamino)-acrylate prepared as described above in lots keeping the temperature below 0 °C. The reaction mass was slowly allowed to reach 10-15 °C and maintained for 3hr. TLC of the reaction mass showed the absence of starting material. The reaction mass was cooled to 0-5 °C and added N-methylpiperzinde. Slowly the reaction mass was allowed to reach 25°C and maintained for 8-10hr. The reaction mass was poured into water and stirred for lhr. Solid compound was filtered and washed with water. The wet solid was suspended in methanol and filtered to get 35g of yellow colored solid compound of formula (XXVIII). Melting point is 206-208 °C. (iii) Preparation of Ofloxacin of formula (I) Thirtyfive grams of the compound obtained as described above was taken into a 500ml three-necked RB flask and added DMF (300ml) and potassium carbonate (40g). The reaction mass was heated to 100-120°C and maintained for 4hr. TLC of the reaction mass indicated the absence of starting material The reaction mass was cooled to 5-10°C and maintained for lhr. The reaction mass was filtered and washed with water to get 40g of a wet compound. The wet cake obtained above was suspended in water and added sodium hydroxide. The reaction mass was heated to 60-70°C and maintained for 4hr. Carbon was added to the reaction mass and filtered. The filtrate was cooled to RT and neutralized with acetic acid to get white precipitate. After stirring for 1hr at 5-10°C the reaction mass was filtered and the cake washed with 10ml of chilled water. The wet solid was dried at 50-60°C to get 28g of white to off-white colored Ofloxacin of the formula (I) solid. Melting point is 272 °C. Purity by HPLC is 99.1%. Advantages of present invention 1. The yield of Ofloxacin of formula (I) prepared by the process of the invention is more than 60% and purity (>99.8%). 2. Process does not require the use of costly poly-fluorinated benzene derivatives thereby making the process simple and economical. 3. Process can be used for commercial production of Ofloxacin of the formula (I). 4. Process, if required, can be carried out continuously without isolating some of the intermediates. 5. The process is environmentally safe. We Claim: 1. An improved process for the preparation of Ofloxacin of formula (I), I which comprises: (i) Reacting 2,4-dichloro-5-fluoro-3-nitrobenzoyl chloride with methyl 3- dimethylaminoacrylate in the presence of a base in a solvent system at a temperature in the ranee of 20-120 °C to set the compound of the formula (XXV), /v\v (ii) Reacting the compound of the formula (XXV) with dl-alaninol in a solvent system at a temperature in the range of 0-40 °C to get the compound of the formula (XXVI) (iii) Reacting the resulting compound of the formula (XXVI) with a base in a solvent at a temperature in the range of-10 to 60 °C to get the cyclized compound of the formula (XXVII), (iv) Reacting the resulting compound of the formula (XXVII) with N-methylpiperazine in the presence or absence of a base and in a solvent medium at a temperature in the range of 10-100 °C to get the compound of the formula (XXVIII), (v) Reacting the resulting compound of the formula (XXVIII) with a base in a non-polar solvent system at a temperature in the range of 20-100 °C to get the cyclized compound of the formula (XXIX), (vi) Hydrolyzing the ester derivative of the formula (XXIX) so formed using acid or base to get Ofloxacin of the formula (I) 2. A process as claimed in claim 1 wherein the base employed in step (i) is selected from pyridine, alkyl pyridine, trialkyl amine, preferably trialkylamine. 3. A process as claimed in claims 1 and 2 wherein the trialkylamine used is triethylamine. 4. A process as claimed in claims 1 to 3 wherein the solvent employed in step (i) is selected from hydrocarbon solvents like hexane, heptane, toluene, xylene, ether solvents like diethyl ether, diisopropyl ether, tetrahydrofuran, acetonitrile, preferably toluene, acetonitrile. 5. A process as claimed in claims 1 to 4 wherein the preferred temperature of the reaction is 50-100 °C. 6. A process as claimed in claims 1 to 5 wherein the solvent such as methanol, ethanol, isopropanol, heptane, cyclohexane, toluene, methylene chloride, acetonitrile, THF (tetrahydrofuran), dioxane, ether, DMF (N,N-dimethylformamide), preferably methanol, THF or toluene is used in step (ii). 7. A process as claimed in claims 1 to 6 wherein the temperature used in the reaction in step (ii) is in the range of 15-30 °C, more preferably in the range of 20-30 °C. 8. A process as claimed in claims 1 to 7 wherein a base such as lithium diisopropylamide, alkyl lithium, metal hydrides, metal carbonates, metal bicarbonates, metal alkoxides, DBU (1,8-diazabicyclo-undec-7-ene, DABCO (1,4-diazabicycloocatne, DBN (1,5-diazabicyclonon-5-ene, pyridine, dimethylaminopyridine, and triethylamine, preferably potassium t-butoxide or sodium hydride is used in step (iii). 9. A process as claimed in claims 1 to 8 wherein the solvent such as toluene, cyclohexane, heptane, THF (tetrahydrofuran), dioxane, DMF (N,N-dimethylformamide), preferably THF or DMF is used in step (iii). 10. A process as claimed in claims 1 to 9 wherein the temperature used in the reaction in step (iii) is in the range of 20-40 °C. 11. A process as claimed in claims 1 to 10 wherein the base such as metal carbonates, metal bicarbonates, metal alkoxides, DBU (l,8-diazabicyclo-undec-7-ene, DABCO (1/4-diazabicycloocatne, DBN (l,5-diazabicyclonon-5-ene, preferably metal carbonates or bicarbonates is used in step (iv). 12. A process as claimed in claims 1 to 11 wherein the solvent such as methanol, ethanol, isopropanol, heptane, cyclohexane, toluene, methylene chloride, acetonitrile, THF (tetrahydrofuran), dioxane, ether, DMF (N,N-dimethylformamide), preferably methanol, THF or toluene is used in step (iv). 13. A process as claimed in claims 1 to 12 wherein the temperature used in the reaction step (iv) is in the range of 20-70 °C, more preferably 50-70 °C. 14. A process as claimed in claims 1 to 13 wherein a base such as lithium diisopropylamide, alkyl lithium, metal hydrides, metal carbonates, metal bicarbonates, metal alkoxides, DBU (l,8-diazabicyclo-undec-7-ene, DABCO (1,4-diazabicycloocatne, DBN (l,5-diazabicyclonon-5-ene, pyridine, 4-dimethylaminopyridine, and triethylamine, preferably, metal carbonates, metal bicarbonates, or triethylamine is used in step (v). 15. A process as claimed in claims 1 to 14 wherein a solvent such as methanol, ethanol, isopropanol, acetonitrile, THF (tetrahydrofuran), dioxane, ether, DMF (N,N-dimethylformamide), DMAc (N,N-dimethylacetamide), pyridine, DMSO (dimethyl sulfoxide), preferably methanol, THF, DMF or toluene is used in step (v). 16. A process as claimed in claims 1 to 15 wherein the temperature used in the reaction step (v) is in the range of 40-80 °C. 17. A process as claimed in claims 1 to 16 wherein the acid such as aqueous sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, preferably sulfuric acid is used in step (vi). 18. A process as claimed in claims 1 to 17 wherein a base such as sodium or potassium hydroxide, carbonate, bicarbonate, preferably sodium or potassium hydroxide. 19. An improved process for the preparation of Ofloxacin of the formula (I) substantially as herein described with reference to the Examples 1 & 2. Dated this 28th day of December 2004

Documents:

1081-CHE-2003 CORRESPONDENCE-OTHERS 03-11-2009.pdf

1081-che-2003-abstract.pdf

1081-che-2003-claims.pdf

1081-che-2003-correspondnece-po.pdf

1081-che-2003-description(complete).pdf

1081-che-2003-description(provisional).pdf

1081-che-2003-form 1.pdf

1081-che-2003-form 18.pdf

1081-che-2003-form 5.pdf

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