Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF LEVOFLOXACIN HAVING SINGLE INDIVIDUAL IMPURITY NOT MORE THAN 0.1% IN THE FORM OF LEVOFLOXACIN HEMIHYDRATES
Abstract	A method for the preparation of Levofloxacin having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form) which comprising. a) converting the Levofloxacin Q-Acid by condensing with N-methyl piperazine by using solvent or without using solvent by any known methods to (S)-9( -)- fluoro-3 -methyl-l 0-( 4-methyl-l-piperizinyl)- 7 -oxo- 2.3 -dihydro- 7 H -pyrido- "'I' [1,2,3-de}-1,4-benzoxazine-6-carboxylic acid (namely Levofloxacin technical). b )dissolving levofloxacin technical in acqueous alkaline solution; c )treating the resulting solution with activated carbon at room temperature; d) removing the undissolved particulate matter by filtration; e) bringing the pH of the aqueous alkaline levofloxacin solution to neutral using C" dilute mineral acid; .-'; f)removing the precipitated particulate matter by filtration; g)acidifying the resulting solution; h)treating the acidified solution with activated carbon at room temperature; i) filtering the undissolved particulate matter by filtration; j)neutralizing the acidic solution; k)filtering again to remove any particulate matter present and, 1) extracting the resulting product with chlorinated solvent and concentrating under vacuum using aqueous tetrahydreofuran or in admixture with other organic solvents to get highly pure levofloxacin having single individual impurity not more than 0.1 % and free from particulate matter & from the other enantiometer (R-formj as Ie ..uZoxacin hemihydrate of Formula I.

Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF LEVOFLOXACIN HAVING SINGLE INDIVIDUAL IMPURITY NOT MORE THAN 0.1% IN THE FORM OF LEVOFLOXACIN HEMIHYDRATES

Abstract

A method for the preparation of Levofloxacin having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form) which comprising. a) converting the Levofloxacin Q-Acid by condensing with N-methyl piperazine by using solvent or without using solvent by any known methods to (S)-9( -)- fluoro-3 -methyl-l 0-( 4-methyl-l-piperizinyl)- 7 -oxo- 2.3 -dihydro- 7 H -pyrido- "'I' [1,2,3-de}-1,4-benzoxazine-6-carboxylic acid (namely Levofloxacin technical). b )dissolving levofloxacin technical in acqueous alkaline solution; c )treating the resulting solution with activated carbon at room temperature; d) removing the undissolved particulate matter by filtration; e) bringing the pH of the aqueous alkaline levofloxacin solution to neutral using C" dilute mineral acid; .-'; f)removing the precipitated particulate matter by filtration; g)acidifying the resulting solution; h)treating the acidified solution with activated carbon at room temperature; i) filtering the undissolved particulate matter by filtration; j)neutralizing the acidic solution; k)filtering again to remove any particulate matter present and, 1) extracting the resulting product with chlorinated solvent and concentrating under vacuum using aqueous tetrahydreofuran or in admixture with other organic solvents to get highly pure levofloxacin having single individual impurity not more than 0.1 % and free from particulate matter & from the other enantiometer (R-formj as Ie ..uZoxacin hemihydrate of Formula I.

Full Text	FIELD OF THE INVENTION: This invention relates to an improved process for the preparation of Levofloxacin having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form) in the form of Levofloxacin Hemihydrate. More specially, the invention provides an improved process for the preparation of high purity form of Levofloxacin hemihydrate from Levofloxacin Q acid and Levofloxacin technical. The Levofloxacin in the form of Levofloxacin Hemihydrate prepared has a single individual impurity less than 0.1% free from particulate matter and other enantiomer (R-form). Levofloxacin form prepared by the process of the present invention is useful as an antibacterial. The invention also relates to an improved process for the preparation of the above pure form of Levofloxacin starting from 2,3,4,5 -tetrafluoro benzoic acid through the intermediates Levofloxacin Q acid and Levofloxacin technical. BACKGROUND OF THE INVENTION: Levofloxacin is the S - (-) isomer of the fluoroquinoline antibacterial Ofloxacin. It has a broad spectrum of activity, which included Gram - positive bacteria. [ Davis R, Bryson HM, Drugs, 4, 677 (1994)]. Levofloxacin is given by mouth or intravenously for the treatment of susceptible infections in a usual dose of 250 or 500mg. Once or twice daily, it is also administered topically as 0.5% eye drops for the treatment of bacteria conjunctivitis [Martindale, The Complete Drug Reference, 33rd edition, pp.219 (2002) and references cited therein]. The Levofloxacin hemihydrate is (S)-9-Fluoro-2,3-dihydro-3-methyl-10-(4- methyl-l-piperazinyl)-7-oxo-7H-pyrido[l,2,35-de]-l,4-benzoxazine -6- carboxylic acid hemihydrate. The chemical structure of Levofloxacin hemihydrate (CAS Registry No. [138199-71-0]) is shown as formula 1. US patent No. 5, 545,737 and EP patent No. 0444678 disclose a process for the preparation of levofloxacin hemihydrate or monohydrate selectively by controlling the water content of an aqueous solvent selected from the group consisting of methanol, ethanol, propanol and acetone in which levofloxacin is dissolved during crystallization. Niddamkil Desheim, Valeric et. al disclose in WO03/045329, and in WO 03/028665, methods for the purification of Levofloxacin using polar solvent such as DMSO, methyl ethyl ketone, acetonitrile, butanol and mixtures thereof and aqueous mixture thereof and / or using an antioxidant. Levofloxacin was first disclosed in US patent 5,053,407 and in Antimicrob, Agents chemother, 29, 163 (1986) by Hayakawa I, et.al. In this process 9,10-Difluro-3 -(hydroxymethyl)-7-oxo-2,3 -dihydro-7H-pyrido [1,2,3 -de]-l ,4-benzoxazine-6-carboxylic acid ethyl ester, a racemic intermediate in the synthesis of Ofloxacin was resolved and esterified with 3,5-dinitro benzoyl chloride, separated by HPLC column SUMIPAXOA-4200, using hexane, 1,2 dichloro ethane, ethanol as carrier solvent. The (-) optical isomer is partially hydrolyzed with ethanolic aqueous sodium bicarbonate to afford the (-) alcohol, which is treated with triphenyl phosphite methiodide in DMF giving the corresponding (-)-iodomethyl derivative. The reduction and simultaneous hydrolysis with tributyltin hydride in ethanol yield (-)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyriodo[l,2,3- is finally treated with N-methyl piperazine at 120°C in DMSO to give (-) Ofloxacin i.e. Levofloxacin. In US patent no. 5,053,407 racemic-3-acetoxy methyl-7,8-difluoro-2,3-dihydro-4H-[1,4] benzoxazine was resolved through its dinitrobenzoyl derivatives (or condensed with a cyclic amino acid or a reactive derivative through amide linkage) followed by debenzoylation, deacylation and dehydroxylation to obtain optically active 7,8-difluoro-2,3-dihydro-3-methyl-4H-[l-4]-benzoxazine which on condensation with diethyl ethoxy acrylomalonate followed by cyclization, hydrolysis and condensation with N-methyl piperazine to obtain Levofloxacin. Scientists of Daiichi prepared the intermediate (-)9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[ 1,2,3-de]-l,4-benzoxazine-6-carboxylic acid by either resolution or cinral specific synthesis. While condensation with N-methyl piperazine major reports disclosed in the presence of DMSO at above 100°C or chilation with BF3-OEt2 in ether and then condensation with N-methyl piperazine in the presence of DMSO, triethylamine has reported. The preparation of Levofloxacin has also been reported in US patent no. 4,777,253 and J.Med.Chem. 30,2283 (1987) by Mitcher et. al. Levofloxacin synthesized from 2,3,4,5-tetrafluoro benzoic acid which is treated with thionyl chloride to produce the corresponding acid chloride. Displacement of the acid chloride with inaionic acid half ester in the presence of n-Butyl lithium yield the p-ketoester.The p-ketoester is then treated with a trialkyl orthoformate in the presence of an acid anhydride yielding Ethyl-2-(2,3,4,5,-tetrafluoro benzoyl)-3-alkoxy acylate, which on reaction with (S)-2-amino-l-propanol to obtain enamino ketoester. The enamino ketoster is then cyclized such as by treatment with two moles equivalents of an alkali metal hydride, alkoxide at an elevated temperature to obtain alkyl-(-)-9-10-difluoro-3-methyl-7-oxo-2,3-dihydro-7//-pyrido-[ 1,2,3-de]-l,4-benzoxazine-6-carboxylate. The condensation reaction between N-methyl piperazine and alkyl (-)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de] 1,4-benzoxazine-6-carboxylate at temperature from 20°C to 200°C and preferably from 40°C to 90°C in the presence of a suitable organic solvent such as pyridine, chloroform, dimethylsulphoxide, sulfolane, dimethyl formamide, dimethylacetamide, I-methyl-2-Pyrrolidone. It is desirable to carry out the reaction in the presence of an acid-acceptor such as triethyl amine, potassium carbonate and the like a molar ratio of 1.0 to 1.2 mole of the acid-acceptor per mole of the ester. N-methyl piperazine can also be used an acid-acceptor in which two or more molar excess in used. Antons, Stefan et. al. Bayer. A.G. have reported in German patent no DE 4428020A, a process for the preparation of (-)-9,10-difluoro-2,3-dihydro-(S)-3-methyl-7-oxo-7H-pyrido-[ 1,2,3-de]-1,4-benzoxazine-6-carboxylic acid starting from 2.3,4,5-tetraflurobenzoyl chloride.The process comprises condensing 2,3,4,5-tetrafluro benzoyl chloride with either 3-(N-methyl piperazinyl)-acetylic acrylic acid ethyl ester or 3-(N,N-dimethylamiono) acetylic acrylic acid ethyl-ester followed by transamination with (S)-2-Amino propoanol, cyclization and hydrolysis. Schriewer et al Bayer A.G. has disclosed in US patent no. 5,237,060 a process of preparing enantiomerically pure l,8-bridged-4-quinolone-3-carboxylic acids, starting from 3~ethoxy-2-(2,3,4,5-tetrafluoro benzoyl) acrylic acid ethyl ester. 3-ethoxy-2-(2,3,4.5-tetrafluoro benzoyl)acrylic acid ethyl ester on condensation with (S)-2-amino propanol, cyclization using potassium carbonate, hydrolysis and condensation with N-methyl piperazine provides Lavofloxacin. Kim et. al of Korea Institute of Science and Technology reported in US patent no5,539,110 a method for the preparation of (-) piperazine derivative. The (-) 9,10-Difluoro-2,3-dihydro-3-methyll-7-oxo-H/-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylic acid is prepared starting from (S) (+)-2-Amino-l-propanol in four steps by condensing with alkyl silylated piperazine in the presence of organic polar solvent such as pyridine, dimethylsulfoxide, acetonitrile, dimethylformamide, N-methyl, pyrrolidine and sulfolane. Juan C, Carretoro et. al in Heterocycles vol 51, No. 7, 1999; have also published an efficient synthesis of Ofloxacine and Levofloxacin from 3,4-difluoroaniline. Key steps in the synthetic sequence are the regioselective functionalization at either C-2 or C-3 of the N-(tert-butoxy carbonyl)-3,4,-difluroaniline and the construction of the benzoxazine skeleton by O-alkylation of the corresponding phenol with propoylene oxide, which was transformed into Ofloxacin or Levofloxacin by condensing with N-methyl piperazine. Shohgo Atarashi et. al in Chem. Pharm. Bull 35(5) 1896-1902(1987), discloses, two optically active isomers of Ofloxacin and their fluoromethyl derivatives were prepared via their optically active intermediates resolved by use of high performance liquid chromatography (HPLC). The isomers were also obtained efficiently by an alternative route via separation of the diastereo isomers prepared in the reaction of benzoxazine with L-proline chloride, then condensation of N-methyl piperazine with (-)-9,10-difluoro-2,3-dihydro-(S)-3-methyl-7-oxo-7H-pyrido-[l,2,3-de]-l,4-benzoxazine-6-carboxylic acid in the presence of dimethyl sulphoxide. Carretero Gonzalver et al. of in US patent no 5, 521, 310 disclose a process for the preparation of benzoxazines which is to be used for the synthesis of Levofloxacin, Ofloxacin and derivatives starting from 3, 4- difluoroaniline. Nakamura, Hiroshi et al. in JP patent no. 2001 31,654, according to the process disclosed in this patent Ethyl 6,7,85-trifluoro-l,4-dihydro-l-(l~acetoxy methyl) ethyl-4-oxo quinoline-3-corboxylate is prepared and condensed with 1-methyl piperazine in toluene at 100°C for 2 hrs and then cyclized in the presence of sodium hydroxide in 2-propanol at 100°C for 2 hrs. Levofloxacin disclosed recently in Zhonggno Yaowu Huaxue Zazhi 2000, 10(4), 276-278 (Ch) by Li, Jiaming et al. from 2,3,4,5-tetrafluoro benzoic acid by chlorination, condensation with di-Et malonate, partial hydrolysis, decarboxylation, condensation with triethyl orthoformate, substitution with (S)-(+)-2-amino propanol, cyclization, hydrolysis and substitution with N-methyl piperazine. It is thus the basic object of the present invention to obtain a pure form of Levofloxacin having single individual impurity not more than 0.1% and free from particular matter for pharmaceutical applications from Levofloxacin Q-Acid with or even without the use of solvents. Also, the further objective of the present invention is to provide an improved process for the preparation of a Levofloxacin form having single individual impurity not more than 0.1% and free from particular matter for pharmaceutical applications such as Levofloxacin hemihydrate having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form). Yet another objective of the present invention is to provide an improved process for the preparation of a Levofloxacin form having single individual impurity not more than 0.1% and free from particular matter for pharmaceutical applications such as Levofloxacin hemihydrate - by dissolving Levofloxacin in water at different pH followed by filtration and using aqueous tetrahydrofuran for making the Levofloxacin hemihydrate. Still another objective of the present invention is to provide an improved process for the preparation of a Levofloxacin form having single individual impurity not more than 0.1% and free from particular matter for pharmaceutical applications such as Levofloxacin hemihydrate starting from 2, 3, 4, 5, tetrafluoro benzoic acid through the intermediates Levofloxacin Q-acid and Levofloxacin technical. SUMMARY OF THE INVENTION Thus according to the basic aspect of the present invention there is a method for the preparation of Levofloxacin having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form) which comprising: a) converting the Levofloxacin Q-Acid by condensing with N-methyl piperazine by using solvent or without using solvent by any known methods to (S)-9(-)-fluoro-3-methyl-10-(4-methyl-l-piperizinyl)-7-oxo-2.3-dihydro-7/f-pyrido-[l,2,3-de]-l,4-benzoxazine-6-carboxylic acid (namely Levofloxacin technical). b)dissolving levofloxacin technical in acqueous alkaline solution ; c)treating the resulting solution with activated carbon at room temperature; d) removing the undissolved particulate matter by filtration; e) bringing the pH of the aqueous alkaline levofloxacin solution to neutral using dilute mineral acid; f)removing the precipitated particulate matter by filtration; g)acidifying the resulting solution; h)treating the acidified solution with activated carbon at room temperature; i) filtering the undissolved particulate matter by filtration; j)neutralizing the acidic solution; k)filtering again to remove any particulate matter present and, 1) extracting the resulting product with chlorinated solvent and concentrating under vacuum using aqueous tetrahydreofuran or in admixture with other organic solvents to get highly pure levofloxacin having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiometer (R-form) as levofloxacin hemihydrate of Formula I. In the above disclosed method the said Levofloxacin Q-Acid used is obtained from 2,3,4,5 -tetrafluoro benzoic acid following the steps comprising: converting 2,3,4,5-tetrafluoro benzoic acid to its acid chloride by conventional method to give the diethyl - 2,3,4,5-tetrafluro benzyol malonate; partially hydrolyzing and decarboxylating the resulting diethyl - 2,3 4,5-tetrafluoro benzoyl malonate by conventional methods to give ethyl-2,3,4,5-tetrafluoro benzoyl acetate; converting the ethyl - 2,3,4,5 -tetrafluoro benzoyl acetate by known method to ethyl -2-(2,3,4,5-tetrafluro benzoyl) -3-ethoxy acrylate; condensing the ethyl-2-(2,3,4,5-tetrafluoro benzoyl)-3-ethoxy acrylate obtained in step (iii) with (S)-2-amino-l-propanol in a solvent, to give ethyl-2-(2,3,4,5-tetrafluoro benzoyl)-3-[(l-hydroxy prop-2(S)-yl) amino] acrylate; cyclismg the resulting ethyl -2-(2,3,455-tetrafluoro benzoyl)-3-[(l-hydroxy prop-2(S)-yll amino] acrylate by conventional methods to give (S)-ethyl- 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido-[ 1,2,3-de] -1,4-benzoxazine-6-carboxylate and, vi) further hydrolyzing (S)-ethyl-9-10—difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[l,2,3-de]-l,4-benzoxazine-6- carboxylate obtained in step (v) by known methods to give (S)-9,10-difluro-2-3 -dihydro-3 -methyl-7-oxo-7H-pyrido-[l,2,3-de]-l,4-benzoxine -6carboxylic acid (namely Levofloxacin Q-acid) carboxylic acid (namely Levofloxacin Q-acid). In the above process the in step (i), Diethyl malonate is acylated using 2,3,4,5-tetrafluoro benzoyl chloride in the presence of magnesium ethanol by making diethyl ethoxymagnesiomalonate.Also,in step (ii) the conversion is effected using an aqueous medium employing catalytic amount of para toluene sulfonic acid The reagents used for the condensation in step (iii) is triethyl orthoformate and acetic anhydride.The solvent used in step (iv) is methylene chloride.Also, the cyclisation in step (v) is done the presence of suitable base such as potassium carbonate and an aprotic solvent such as N, N-dimethyl formamide. The hydrolysis in step (vi) is carried out using acetic acid and dilute hydrochloric acid. The filtration in steps (i) & (j) may be effected using a 0.2 micron filter. The alkaline Levofloxacin solution is stirred at a pH in the range of 8.0 to 12.0, preferably 10.0-12.0, more preferably 11.0-11.5. In the above process of the invention, the condensation in step(a) is carried out either using aprotic solvent or without using solvent.The aprotic solvent which is used for condensation is pyridine. Moreover, the alkali used in step (h) is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide and the concentration of the solution is 5 to 20% preferably 8-10%.The pH is brought to 7.0-7.5 using dilute hydrochloric acid preferably 0.5N to 5N hydrochloric acid, more preferably IN hydrochloric acid. The precipitated particulate matter is filtered and the pH is adjusted to 3.0-6.0 preferably 4.0-5.5 more preferably 4.5-5.0 using glacial acetic acid. The aqueous acidic levofloxacin solution is treated with activated carbon at room temperature and the clear solution is filtered the pH to neutral preferably 7.0-7.5 using dilute aqueous ammonia solution. The neutral aqueous solution is again filtered and extracted with chlorinated solvent preferably methylene chloride.Importantly,the extract is concentrated under vacuum (600-650 mm of Hg) below 40°C and the resulting residue is concentrated after stirring with tetrahydrofuran or its mixture with any other organic solvent. The residue is slurred with 1-5% aqueous tetrahydrofuran preferably with 2-2.5% aqueous tetrahydrofuran.Preferably, the slurring with tetrahydrofuran is effected at 40-70°C preferably at 50-60°C more preferably at 58-60°C. The slurring with tetrahydrofuran is effected for a period in the range of 30 minutes to 2 hours preferably 30 minutes to 1 hour and then cooled to -5 to 15 C preferably 0-5°C and stirred for 30 minutes to 2 hours preferably 1 hour to 1 hour 30 minutes. The product is filtered and suck dried for 15 minutes to 1 hour preferably 30 minutes to 45 minutes and the product was dried at 50-80°C preferably at 70-75°C for 2 to 7 hours preferably 4-6 hours more preferably 5 to 5 hours 30 minutes. In accordance with another aspect of the present invention there is provided a process for preparation of Levofloxacin having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form) which comprises: dissolving levofloxacin technical grade in aqueous alkaline solution,. treating the resulting solution with activated carbon at room temperature, removing the undissolved particulate matter filtration, bringing the pH of the aqueous alkaline levofloxacin solution is neutral using dilute mineral acid, removing the precipitated particulate matter by filtration acidifying the resulting solution treating the acidified solution with activated carbon at room temperature, filtering the undissolved particulate matter by filtration, neutralizing the acidic solution, filtering again to remove any particulate matter present and, extracting the resulting product with chlorinated solvent and concentrating under vacuum using aqueous tetrahydrofuran or in admixture with other organic solvents to get highly pure levofloxacin hemihydrate having single individual impurity less than 0.1% and free from particulate matter & from the other enantiomer (R-form) as Levofloxacin hemihydrate of Formula I. In the above process of the invention the filtration in steps (viii) & (x) may be effected using a 0.2 micron filter.The alkaline Levofloxacin solution is stirred at a pH in the range of 8.0 to 12.0 preferably 10.0-12.0 more preferably 11.0-11.5.The alkali used is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide and the concentration of the solution is 5 to 20% preferably 8-10%.The pH is brought to 7.0-7.5 using dilute hydrochloric acid, preferably 0.5N to 5N hydrochloric acid, more preferably IN hydrochloric acid.The precipitated particulate matter is filtered and the pH is adjusted to 3.0-6.0 preferably 4.0 to 5.5 more preferably 4.5-5.0 using glacial acetic acid.The aqueous acidic levofloxacin solution is treated with activated carbon at room temperature and the clear solution is filtered the pH to neutral preferably 7.0-7.5 using dilute aqueous ammonia solution. The neutral aqueous solution is again filtered and extracted with chlorinated solvent preferably methylene chloride. The extract is concentrated under vacuum (600-650 mm to Hg) below 40°C and the resulting residue is concentrated after stirring with tetrahydrofuran or its mixture with any other organic solvent.The residue is slurred with 1-5% aqueous tetrahydrofuran preferably with 2-2.5% aqueous tetrahydrofuran.The slurring with tetrahydrofuran is effected at 40-70°C preferably at 50-60°C more preferably at 58-60°C. Moreover, the slurring with tetrahydrofuran is effected for a period in the range of 30 minutes to 2 hours preferably 30 minutes to 1 hour and then cooled to -5 to 15°C preferably 0-5°C and stirred for 30 minutes to 2 hours preferably 1 hour to 1 hour 30 minutes. The product is filtered and suck dried for 15 minutes to 1 hour preferably 30 minutes to 45 minutes and the product was dried at 50-80T preferably at 70-75 °C for 2 to 7 hours preferably 4-6 hours more preferably 5 to 5 hours 30 minutes. Importantly according to an aspect of the above process of the invention Levofloxacin technical is obtained by converting Levofloxacin Q-Acid by condensing with excess amount of N-methyl piperazine .In such process of preparation of Levofloxacin technical used in the process use of pyridine as a solvent is optional and it is possible to carry out the above preparation of Levofloxacin even without the solvent. Levofloxacin technical may be stirred in water and pH is adjusted to 8.0 to 12.0, preferably 10.0-12.0, more preferably 11.0-11.5 with dilute alkali metal hydroxide solution, preferably 5 to 20% alkali solution, more preferably 8-10%. The alkali metal hydroxide which may be used may be either sodium hydroxide or potassium hydroxide, preferably sodium hydroxide. The aqueous alkaline levofloxacin solution is treated with activated carbon, and the clear solution is filtered. Then the pH is brought to 7.0-7.5 using dilute hydrochloric acid, preferably 0.5N to 5N hydrochloric acid, more preferably IN hydrochloric acid. The precipitated particulate matter is filtered. Again the aqueous solution pH may be adjusted to 3.0-6.0 preferably 4.0 to 5.5 more preferably 4.5-5.0 using glacial acetic acid. The aqueous acidic levofloxacin solution was treated with activated carbon at room temperature and the clear solution may be filtered preferably through micron filter. Finally, the pH of the aqueous solution may be adjusted to neutral preferably 7.0-7.5 using dilute aqueous ammonia solution. The neutral aqueous solution may be again filtered preferably through micron filter and extracted with chlorinated solvent preferably methylene chloride. The extract may be concentrated under vacuum (600-650 mm of Hg) below 40°C. The resulting residue was concentrated after stirring with tetrahydrofuran or its mixture any other organic solvent. Finally the residue was slurred with 1-5% aqueous tetrahydrofuran preferably with 2-2.5% aqueous tetrahydrofuran at 40-70°C preferably at 50-60°C more preferably at 58-60°C for 30 minutes to 2 hours preferably 30 minutes to 1 hour then cooled to -5 to 15°C preferably 0-5°C and stirred for 30 minutes to 2 hours preferably 1 hour to 1 hour 30 minutes. The product was filtered and suck dried for 15 minutes to 1 hour preferably 30 minutes to 45 minutes and the product was dried at 50-80°C preferably at 70-75°C for 2 to 7 hours preferably 4-6 hours more preferably 5 to 5 hours 30 minutes to give highly pure Levofloxacin hemihydrate with single individual impurity less than 0.1%. Elemental analysis calculated for Ci8H2oFN304, VafeO is C 58.37%, H 5.71%, Nll.35%, and found is C58.38%, H5.67%, N 11.38%. The X-ray diffraction pattern of the Levofloxacin form with single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form) ,Levofloxacin hemihydrate, prepared by the process of the present invention is found to be identical to that of the Levofloxacin hemihydrate prepared by the process reported in US patent 5,545,737, EP patent 0444678 and Chem. Pharm. Bull, 43(4) 649-653) (1995). The typical X-ray diffraction pattern of the prepared Levofloxacin hemihydrate is given below. Accordingly to another preferred embodiment of the present invention there is provided an improved process for the preparation of Levofloxacin hemihydrate which comprises : Converting 2,3,4,5 - tetrafluoro benzoic acid to its acid chloride by conventional method to give the diethyl -2,3,4,5-tetrafluoro benzoyl malonate Partially hydrolyzing and decarboxylating the resulting diethyl-2,3,4,5,-tetrafluoro benzoyl malonate by conventional method to give ethyl-2,3,4,5-tetrafluoro benzoyl acetate. Converting the ethyl-2,34,5-tetrafluoro benzoyl acetate by known methods to ethyl-2-(2,3,4,5-tetrafluoro benzoyl)-3-ethoxy acrylate. Condensing the ethyl-2-(2,3,4,5-tetrafluoro benzoyl)-3-ethoxy acrylate obtained in step (iii) with (S)-2-amino-l-propanol in a solvent, to give ethyl-2-(2,3,4,5-tetrafluoro benzoyl)-3-[(1-hydroxy prop-2(S)-yl)amino] acrylate. Cyclizing the resulting ethyl-2(2,3,4,5-tgetrafluro benzoyl)-3-[(l-hydroxy prop-2(S)-yl)amino] acrylate by conventional methods to give (S)-ethyl-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido-[l,2,3-de]-l54-benzoxazine-6-carboxylate and, Further hydrolyzing (S)-ethyul-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7//-pyrido-[l,2,3,-de)-l,4-benzoxazine-6-carboxylate, obtained in step (v) by known methods to give (S)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido-[l,2,3-de]-l,4-benezoxazine-6-carboxylic acid (namely Levofloxacin Q-acid), Converting the Levofloxacin Q-acid by condensing with N-methyl piperazine by using solvent or without using solvent by any known method to (S)-9-fluro-3- methyl-10-(4-methyl-1 -piperazinyl)7-oxo-2,3-dihydro-7H-pyrido[ 1,2,3-de]-1,4-benezoxazine-6-carboxylic acid (namely Levofloxacin technical). Dissolving levofloxacin technical in aqueous alkaline solution Treating the resulting solution with activated carbon at room temperature Removing the undissolved particulate matter by filtration bringing the pH of the aqueous alkaline levofloxacin solution to neutral using dilute mineral acid, removing the precipitated particulate matter by filtration acidifying the resulting solutions treating the acidified solution with activated carbon at room temperature filtering the undissolved particulate matter by filtration neutralizing the acidic solution, filtering again to remove any particulate matter present and, extracting the resulting product with chlorinated solvent and concentrating under vacuum using aqueous tetrahydrofuran or in admixture with other organic solvents to get highly pure levofloxacin hemihydrate having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form). Reaction sequence in the scheme given below. SET OUT REACTION SCHEME In a preferred embodiment of the invention in step (i), Diethyl malonate may be acylated using 2,3,4,5-tetrafluoro benzoyl chloride in the presence of magnesium, ethanol by making diethyl ethoxymagnesiomalonate. The reagents used for the condensation in step (iii) may be triethyl orthoformate and acetic anhydride. In step (ii) the conversion may be effected using an aqueous medium employing catalytic amount of para toluene sulfonic acid. An example of the solvent used in step (iv) may be methylene chloride The cyclisation in step(v) may be done in the presence of suitable base such as potassium carbonate and an aprotic solvent such as N,N-dimethyl formamide. The hydrolysis in step (vi) may be done in the presence of suitable base such as potassium carbonate and an aprotic solvent sush as N,N-dimethyl formamide. The hydrolysis in step (vi) may be carried out using acetic acid and dilute hydrochloric acid. The details of the present invention are described in the following examples which are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention. SET OUT THE EXAMPLES Advantages of the present invention: It is possible to provide Levofloxacin having single individual impurity less than 0.1% and free from particulate matter as Levofloxacin hemihydrate. Levofloxacin having single individual impurity less than 0.1% and free from particulate matter as Levofloxacin hemihydrate prepared is free from the other enantiomer (R-form) The process of the present invention provides industrially feasible process The process is simple and safe and environmentally friendly It should be noted that the invention also envisages other embodiments falling within the scope of the present invention which will be obvious and apparent to one skilled in the art from the foregoing disclosure. WE CLAIM: . 1. A method for the preparation of Levofloxacin having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form) which comprising: a) converting the Levofloxacin Q-Acid by condensing with N-methyl piperazine by using solvent or without using solvent by any known methods to (S)-9(-)-fluoro-3 -methyl-10-(4-methyl-1 -piperizinyl)-7-oxo-2.3 -dihydro-7//-pyrido-[l,2,3-de]-l,4-benzoxazine-6-carboxylic acid (namely Levofloxacin technical). b)dissolving levofloxacin technical in acqueous alkaline solution ; c)treating the resulting solution with activated carbon at room temperature; d) removing the undissolved particulate matter by filtration; e) bringing the pH of the aqueous alkaline levofloxacin solution to neutral using dilute mineral acid; f)removing the precipitated particulate matter by filtration; g)acidifying the resulting solution; h)treating the acidified solution with activated carbon at room temperature; i) filtering the undissolved particulate matter by filtration; j)neutralizing the acidic solution; k)filtering again to remove any particulate matter present and, 1) extracting the resulting product with chlorinated solvent and concentrating under vacuum using aqueous tetrahydreofuran or in admixture with other organic solvents to get highly pure levofloxacin having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiometer (R-form) as le ofloxacin hemihydrate of Formula I. 2. A process as claimed in claim 1 wherein said Levofloxacin Q-Acid used is obtained from 2,3,4,5 -tetrafluoro benzoic acid following the steps comprising: converting 2,3,4,5-tetrafluoro benzoic acid to its acid chloride by conventional method to give the diethyl - 2,3,4,5-tetrafluro benzyol malonate; tetrafluoro benzoyl acetate; converting the ethyl - 2,3,4,5 -tetrafluoro benzoyl acetate by known method to ethyl -2-(2,3,4,5-tetrafluro benzoyl) -3-ethoxy acrylate; condensing the ethyl-2-(2,3,4,5-tetrafluoro benzoyl)-3-ethoxy acrylate obtained in step (iii) with (S)-2-amino-l-propanol in a solvent, to give ethyl-2-(2,3,4,5-tetrafluoro benzoyl)-3-[(l-hydroxy prop-2(S)-yl) amino] acrylate; cyclising the resulting ethyl -2-(2,3,4,5-tetrafluoro benzoyl)-3-[(l-hydroxy prop-2(S)-yll amino] acrylate by conventional methods to give (S)-ethyl- 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido-[l,2?3-de] -l,4-benzoxazine-6-carboxylate and, vi) further hydrolyzing (S)-ethyl-9-10"difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de]-l,4-benzoxazine-6- carboxylate obtained in step (v) by known methods to give (S)-9,10-difluro-2-3-dihydro-3-methyl-7-oxo-7H-pyrido-[l,2,3-de]-l,4-benzoxine -6carboxylic acid (namely Levofloxacin Q-acid) carboxylic acid (namely Levofloxacin Q-acid). 3. A process as claimed in claim 2 wherein in step (i), Diethyl malonate is acylated using 2,3,4,5-tetrafluoro benzoyl chloride in the presence of magnesium ethanol by making diethyl ethoxymagnesiomalonate 4. A process as claimed in anyone of claims 2 or 3 wherein in step (ii) the conversion is effected using an aqueous medium employing catalytic amount of para toluene sulfonic acid 6. A process as claimed in anyone of claims 2 to 5 wherein the solvent used in step (iv) is methylene chloride 7. A process as claimed in anyone of claims 2 to 6 wherein the cyclisation in step (v) is done the presence of suitable base such as potassium carbonate and an aprotic solven such as N, N-dimethyl formamide. 8. A process as claimed in anyone of claims 2 to 7 wherein the hydrolysis in step (vi) is carried out using acetic acid and dilute hydrochloric acid. 9. A process as claimed in anyone of claims 1 to 7 wherein, the condensation in step(a) is carried out either using aprotic solvent or without using solvent. 10. A process as claimed in claim 8 wherein, the aprotic solvent which is used for condensation is pyridine. 11. A process as claimed in anyone of claims 1 to 9 wherein the filtration in steps (i) & (j) may be effected using a 0.2 micron filter. 12. A process as claimed in anyone of claims 1 to 10 wherein the alkaline Levofloxacin solution is stirred at a pH in the range of 8.0 to 12.0, preferably 10.0-12.0, more preferably 11.0-11.5. 13. A process as claimed in anyone of claims 1 to 11 wherein the alkali used in step (h) is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide and the concentration of the solution is 5 to 20% preferably 8-10%. 14. A process as claimed in anyone of claims 1 to 12 wherein the pH is brought to 7.0-7.5 using dilute hydrochloric acid preferably 0.5N to 5N hydrochloric acid, more preferably IN hydrochloric acid. 15. A process as claimed in anyone of claims 1 to 13 wherein the precipitated particulate matter is filtered and the pH is adjusted to 3.0-6.0 preferably 4.0-5.5 more preferably 4.5-5.0 using glacial acetic acid. 16. A process as claimed in anyone of claims 1 to 14 wherein the aqueous acidic levofloxacin solution is treated with activated carbon at room temperature and the clear solution is filtered the pH to neutral preferably 7.0-7.5 using dilute aqueous ammonia solution. 17. A process as claimed in anyone of claims 1 to 15 wherein the neutral aqueous solution is again filtered and extracted with chlorinated solvent preferably methylene chloride 18. A process as claimed in anyone of claims 1 to 16 wherein the extract is concentrated under vacuum (600-650 mm of Hg) below 40°C and the resulting residue is concentrated after stirring with tetrahydrofuran or its mixture with any other organic solvent. 19. A process as claimed in anyone of claims 1 to 17 wherein the residue is slurred with 1-5% aqueous tetrahydrofuran preferably with 2-2.5% aqueous tetrahydrofuran. 20. A process as claimed in anyone of claims 1 to 18 wherein the slurring with tetrahydrofuran is effected at 40-70°C preferably at 50-60°C more preferably at 58-60°C. 21 A process as claimed in anyone of claims 1 to 19 wherein the slurring with tetrahydrofuran is effected for a period in the range of 30 minutes to 2 hours preferably 30 minutes to 1 hour and then cooled to -5 to 15 C preferably 0-5 C and stirred for 30 minutes to 2 hours preferably 1 hour to 1 hour 30 minutes. 22. A process as claimed in anyone of claims 1 to 21 wherein the product is filtered and suck dried for 15 minutes to 1 hour preferably 30 minutes to 45 minutes and the product was dried at 50-80°C preferably at 70-75°C for 2 to 7 hours preferably 4-6 hours more preferably 5 to 5 hours 30 minutes. 23. A process for preparation of Levofloxacin having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form) which comprises dissolving levofloxacin technical grade in aqueous alkaline solution,. treating the resulting solution with activated carbon at room temperature, removing the undissolved particulate matter filtration, bringing the pH of the aqueous alkaline levofloxacin solution is neutral using dilute mineral acid, removing the precipitated particulate matter by filtration acidifying the resulting solution treating the acidified solution with activated carbon at room temperature, filtering the undissolved particulate matter by filtration, neutralizing the acidic solution, filtering again to remove any particulate matter present and, extracting the resulting product with chlorinated solvent and concentrating under vacuum using aqueous tetrahydrofuran or in admixture with other organic solvents to get highly pure levofloxacin hemihydrate having single individual impurity less than 0.1% and free from particulate matter & from the other enantiomer (R-form) as Levofloxacin hemihydrate of Formula I. 24. A process process as claimed in claim 23 wherein the filtration in steps (viii) & (x) may be ?ffscted using a 0.2 micron filter. 25. A process as claimed in anyone of claims 23 or 24 wherein the alkaline Levofloxacin solution is stirred at a pH in the range of 8.0 to 12.0 preferably 10.0-12.0 more preferably 11.0-11.5. 26. A process as claimed in anyone of claims 23 to 25 wherein the alkali used is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide and the concentration of the solution is 5 to 20% preferably 8-10%. 27. A process as claimed in anyone of claims 23 to 26 wherein the pH is brought to 7.0-7.5 using dilute hydrochloric acid, preferably 0.5N to 5N hydrochloric acid, more preferably IN hydrochloric acid. 28. A process as claimed in anyone of claims 23 to 26 wherein the precipitated particulate matter is filtered and the pH is adjusted to 3.0-6.0 preferably 4.0 to 5.5 more preferably 4.5-5.0 using glacial acetic acid. 29. A process as claimed in anyone of claims 23 to 28 wherein the aqueous acidic levofloxacin solution is treated with activated carbon at room temperature and the clear solution is filtered the pH to neutral preferably 7.0-7.5 using dilute aqueous ammonia solution. 30. A process as claimed in anyone of claims 23 to 29 wherein the neutral aqueous solution is again filtered and extracted with chlorinated solvent preferably methylene chloride. 31. A process as claimed in anyone of claims 23 to 30 wherein the extract is concentrated under vacuum (600-650 mm to Hg) below 40°C and the resulting residue is concentrated after stirring with tetrahydrofuran or its mixture with any other organic boivent 32. A process as claimed in anyone of claims 23 to 31 wherein the residue is slurred with 1-5% aqueous tetrahydrofuran preferably with 2-2.5% aqueous tetrahydrofuran. 33. A process as claimed in anyone of claims 23 to 32 wherein the slurring with tetrahydrofuran is effected at 40-70°C preferably at 50-60°C more preferably at 58-60°C. 34. A process as claimed in anyone of claims 23 to 33 wherein the slurring with tetrahydrofuran is effected for a period in the range of 30 minutes to 2 hours preferably 30 minutes to 1 hour and then cooled to -5 to 15 C preferably 0-5 C and stirred for 30 minutes to 2 hours preferably 1 hour to 1 hour 30 minutes. 35. A process as claimed in anyone of claims 23 to 34 wherein the product is filtered and suck dried for 15 minutes to 1 hour preferably 30 minutes to 45 minutes and the product was dried at 50-80°C preferably at 70-75°C for 2 to 7 hours preferably 4-6 hours more preferably 5 to 5 hours 30 minutes. 36. A process for the preparation of Levofloxacin having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form) from Levofloxacin technical substantially as herein described with reference to the Example 1 & 2., 37. A process for the preparation of Levofloxacin having single individual not more than 0.1% and free from particulate matter & from the other enantiomer (R-form) from 2,3,4,5,-tetrafluoro benzoic acid substantially as herein described with reference to the Example 3.

Full Text

FIELD OF THE INVENTION:
This invention relates to an improved process for the preparation of Levofloxacin having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form) in the form of Levofloxacin Hemihydrate. More specially, the invention provides an improved process for the preparation of high purity form of Levofloxacin hemihydrate from Levofloxacin Q acid and Levofloxacin technical. The Levofloxacin in the form of Levofloxacin Hemihydrate prepared has a single individual impurity less than 0.1% free from particulate matter and other enantiomer (R-form). Levofloxacin form prepared by the process of the present invention is useful as an antibacterial. The invention also relates to an improved process for the preparation of the above pure form of Levofloxacin starting from 2,3,4,5 -tetrafluoro benzoic acid through the intermediates Levofloxacin Q acid and Levofloxacin technical.
BACKGROUND OF THE INVENTION:
Levofloxacin is the S - (-) isomer of the fluoroquinoline antibacterial Ofloxacin. It has a broad spectrum of activity, which included Gram - positive bacteria. [ Davis R, Bryson HM, Drugs, 4, 677 (1994)]. Levofloxacin is given by mouth or intravenously for the treatment of susceptible infections in a usual dose of 250 or 500mg. Once or twice daily, it is also administered topically as 0.5% eye drops for the treatment of bacteria conjunctivitis [Martindale, The Complete Drug Reference, 33rd edition, pp.219 (2002) and references cited therein].

The Levofloxacin hemihydrate is (S)-9-Fluoro-2,3-dihydro-3-methyl-10-(4-
methyl-l-piperazinyl)-7-oxo-7H-pyrido[l,2,35-de]-l,4-benzoxazine -6-
carboxylic acid hemihydrate. The chemical structure of Levofloxacin hemihydrate (CAS Registry No. [138199-71-0]) is shown as formula 1.
US patent No. 5, 545,737 and EP patent No. 0444678 disclose a process for the preparation of levofloxacin hemihydrate or monohydrate selectively by controlling the water content of an aqueous solvent selected from the group consisting of methanol, ethanol, propanol and acetone in which levofloxacin is dissolved during crystallization.
Niddamkil Desheim, Valeric et. al disclose in WO03/045329, and in WO 03/028665, methods for the purification of Levofloxacin using polar solvent such as DMSO, methyl ethyl ketone, acetonitrile, butanol and mixtures thereof and aqueous mixture thereof and / or using an antioxidant.
Levofloxacin was first disclosed in US patent 5,053,407 and in Antimicrob, Agents chemother, 29, 163 (1986) by Hayakawa I, et.al. In this process 9,10-Difluro-3 -(hydroxymethyl)-7-oxo-2,3 -dihydro-7H-pyrido [1,2,3 -de]-l ,4-benzoxazine-6-carboxylic acid ethyl ester, a racemic intermediate in the synthesis of Ofloxacin was resolved and esterified with 3,5-dinitro benzoyl chloride, separated by HPLC column SUMIPAXOA-4200, using hexane, 1,2 dichloro ethane, ethanol as carrier solvent. The (-) optical isomer is partially hydrolyzed with ethanolic aqueous sodium bicarbonate to afford the (-) alcohol, which is treated with triphenyl phosphite methiodide in DMF giving the corresponding (-)-iodomethyl derivative. The reduction and simultaneous hydrolysis with tributyltin hydride in ethanol yield (-)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyriodo[l,2,3-
is finally treated with N-methyl piperazine at 120°C in DMSO to give (-) Ofloxacin i.e. Levofloxacin.
In US patent no. 5,053,407 racemic-3-acetoxy methyl-7,8-difluoro-2,3-dihydro-4H-[1,4] benzoxazine was resolved through its dinitrobenzoyl derivatives (or condensed with a cyclic amino acid or a reactive derivative through amide linkage) followed by debenzoylation, deacylation and dehydroxylation to obtain optically active 7,8-difluoro-2,3-dihydro-3-methyl-4H-[l-4]-benzoxazine which on condensation with diethyl ethoxy acrylomalonate followed by cyclization, hydrolysis and condensation with N-methyl piperazine to obtain Levofloxacin.
Scientists of Daiichi prepared the intermediate (-)9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[ 1,2,3-de]-l,4-benzoxazine-6-carboxylic acid by either resolution or cinral specific synthesis. While condensation with N-methyl piperazine major reports disclosed in the presence of DMSO at above 100°C or chilation with BF3-OEt2 in ether and then condensation with N-methyl piperazine in the presence of DMSO, triethylamine has reported.
The preparation of Levofloxacin has also been reported in US patent no. 4,777,253 and J.Med.Chem. 30,2283 (1987) by Mitcher et. al. Levofloxacin synthesized from 2,3,4,5-tetrafluoro benzoic acid which is treated with thionyl chloride to produce the corresponding acid chloride. Displacement of the acid chloride with inaionic acid half ester in the presence of n-Butyl lithium yield the p-ketoester.The p-ketoester is then treated with a trialkyl orthoformate in the presence of an acid anhydride yielding Ethyl-2-(2,3,4,5,-tetrafluoro benzoyl)-3-alkoxy acylate, which on reaction with (S)-2-amino-l-propanol to obtain enamino ketoester. The enamino ketoster is then cyclized such as by treatment

with two moles equivalents of an alkali metal hydride, alkoxide at an elevated temperature to obtain alkyl-(-)-9-10-difluoro-3-methyl-7-oxo-2,3-dihydro-7//-pyrido-[ 1,2,3-de]-l,4-benzoxazine-6-carboxylate. The condensation reaction between N-methyl piperazine and alkyl (-)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de] 1,4-benzoxazine-6-carboxylate at temperature from 20°C to 200°C and preferably from 40°C to 90°C in the presence of a suitable organic solvent such as pyridine, chloroform, dimethylsulphoxide, sulfolane, dimethyl formamide, dimethylacetamide, I-methyl-2-Pyrrolidone. It is desirable to carry out the reaction in the presence of an acid-acceptor such as triethyl amine, potassium carbonate and the like a molar ratio of 1.0 to 1.2 mole of the acid-acceptor per mole of the ester. N-methyl piperazine can also be used an acid-acceptor in which two or more molar excess in used.
Antons, Stefan et. al. Bayer. A.G. have reported in German patent no DE 4428020A, a process for the preparation of (-)-9,10-difluoro-2,3-dihydro-(S)-3-methyl-7-oxo-7H-pyrido-[ 1,2,3-de]-1,4-benzoxazine-6-carboxylic acid starting from 2.3,4,5-tetraflurobenzoyl chloride.The process comprises condensing 2,3,4,5-tetrafluro benzoyl chloride with either 3-(N-methyl piperazinyl)-acetylic acrylic acid ethyl ester or 3-(N,N-dimethylamiono) acetylic acrylic acid ethyl-ester followed by transamination with (S)-2-Amino propoanol, cyclization and hydrolysis.
Schriewer et al Bayer A.G. has disclosed in US patent no. 5,237,060 a process of preparing enantiomerically pure l,8-bridged-4-quinolone-3-carboxylic acids, starting from 3~ethoxy-2-(2,3,4,5-tetrafluoro benzoyl) acrylic acid ethyl ester. 3-ethoxy-2-(2,3,4.5-tetrafluoro benzoyl)acrylic acid ethyl ester on condensation with (S)-2-amino propanol, cyclization using potassium carbonate, hydrolysis and condensation with N-methyl piperazine provides Lavofloxacin.

Kim et. al of Korea Institute of Science and Technology reported in US patent no5,539,110 a method for the preparation of (-) piperazine derivative. The (-) 9,10-Difluoro-2,3-dihydro-3-methyll-7-oxo-H/-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylic acid is prepared starting from (S) (+)-2-Amino-l-propanol in four steps by condensing with alkyl silylated piperazine in the presence of organic polar solvent such as pyridine, dimethylsulfoxide, acetonitrile, dimethylformamide, N-methyl, pyrrolidine and sulfolane.
Juan C, Carretoro et. al in Heterocycles vol 51, No. 7, 1999; have also published an efficient synthesis of Ofloxacine and Levofloxacin from 3,4-difluoroaniline. Key steps in the synthetic sequence are the regioselective functionalization at either C-2 or C-3 of the N-(tert-butoxy carbonyl)-3,4,-difluroaniline and the construction of the benzoxazine skeleton by O-alkylation of the corresponding phenol with propoylene oxide, which was transformed into Ofloxacin or Levofloxacin by condensing with N-methyl piperazine.
Shohgo Atarashi et. al in Chem. Pharm. Bull 35(5) 1896-1902(1987), discloses, two optically active isomers of Ofloxacin and their fluoromethyl derivatives were prepared via their optically active intermediates resolved by use of high performance liquid chromatography (HPLC). The isomers were also obtained efficiently by an alternative route via separation of the diastereo isomers prepared in the reaction of benzoxazine with L-proline chloride, then condensation of N-methyl piperazine with (-)-9,10-difluoro-2,3-dihydro-(S)-3-methyl-7-oxo-7H-pyrido-[l,2,3-de]-l,4-benzoxazine-6-carboxylic acid in the presence of dimethyl sulphoxide.

Carretero Gonzalver et al. of in US patent no 5, 521, 310 disclose a process for the preparation of benzoxazines which is to be used for the synthesis of Levofloxacin, Ofloxacin and derivatives starting from 3, 4- difluoroaniline.
Nakamura, Hiroshi et al. in JP patent no. 2001 31,654, according to the process disclosed in this patent Ethyl 6,7,85-trifluoro-l,4-dihydro-l-(l~acetoxy methyl) ethyl-4-oxo quinoline-3-corboxylate is prepared and condensed with 1-methyl piperazine in toluene at 100°C for 2 hrs and then cyclized in the presence of sodium hydroxide in 2-propanol at 100°C for 2 hrs.
Levofloxacin disclosed recently in Zhonggno Yaowu Huaxue Zazhi 2000, 10(4), 276-278 (Ch) by Li, Jiaming et al. from 2,3,4,5-tetrafluoro benzoic acid by chlorination, condensation with di-Et malonate, partial hydrolysis, decarboxylation, condensation with triethyl orthoformate, substitution with (S)-(+)-2-amino propanol, cyclization, hydrolysis and substitution with N-methyl piperazine.
It is thus the basic object of the present invention to obtain a pure form of Levofloxacin having single individual impurity not more than 0.1% and free from particular matter for pharmaceutical applications from Levofloxacin Q-Acid with or even without the use of solvents.

Also, the further objective of the present invention is to provide an improved process for the preparation of a Levofloxacin form having single individual impurity not more than 0.1% and free from particular matter for pharmaceutical applications such as Levofloxacin hemihydrate having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form).
Yet another objective of the present invention is to provide an improved process for the preparation of a Levofloxacin form having single individual impurity not more than 0.1% and free from particular matter for pharmaceutical applications such as Levofloxacin hemihydrate - by dissolving Levofloxacin in water at different pH followed by filtration and using aqueous tetrahydrofuran for making the Levofloxacin hemihydrate.
Still another objective of the present invention is to provide an improved process for the preparation of a Levofloxacin form having single individual impurity not more than 0.1% and free from particular matter for pharmaceutical applications such as Levofloxacin hemihydrate starting from 2, 3, 4, 5, tetrafluoro benzoic acid through the intermediates Levofloxacin Q-acid and Levofloxacin technical.
SUMMARY OF THE INVENTION
Thus according to the basic aspect of the present invention there is a method for the preparation of Levofloxacin having single individual impurity not more than

0.1% and free from particulate matter & from the other enantiomer (R-form) which comprising:
a) converting the Levofloxacin Q-Acid by condensing with N-methyl piperazine by using solvent or without using solvent by any known methods to (S)-9(-)-fluoro-3-methyl-10-(4-methyl-l-piperizinyl)-7-oxo-2.3-dihydro-7/f-pyrido-[l,2,3-de]-l,4-benzoxazine-6-carboxylic acid (namely Levofloxacin technical).
b)dissolving levofloxacin technical in acqueous alkaline solution ;
c)treating the resulting solution with activated carbon at room temperature;
d) removing the undissolved particulate matter by filtration;
e) bringing the pH of the aqueous alkaline levofloxacin solution to neutral using dilute mineral acid;
f)removing the precipitated particulate matter by filtration;
g)acidifying the resulting solution;
h)treating the acidified solution with activated carbon at room temperature;
i) filtering the undissolved particulate matter by filtration;
j)neutralizing the acidic solution;
k)filtering again to remove any particulate matter present and,
1) extracting the resulting product with chlorinated solvent and concentrating under vacuum using aqueous tetrahydreofuran or in admixture with other organic solvents to get highly pure levofloxacin having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiometer (R-form) as levofloxacin hemihydrate of Formula I.
In the above disclosed method the said Levofloxacin Q-Acid used is obtained from 2,3,4,5 -tetrafluoro benzoic acid following the steps comprising:

converting 2,3,4,5-tetrafluoro benzoic acid to its acid chloride by conventional method to give the diethyl - 2,3,4,5-tetrafluro benzyol malonate;
partially hydrolyzing and decarboxylating the resulting diethyl - 2,3 4,5-tetrafluoro benzoyl malonate by conventional methods to give ethyl-2,3,4,5-tetrafluoro benzoyl acetate;
converting the ethyl - 2,3,4,5 -tetrafluoro benzoyl acetate by known method to ethyl -2-(2,3,4,5-tetrafluro benzoyl) -3-ethoxy acrylate;
condensing the ethyl-2-(2,3,4,5-tetrafluoro benzoyl)-3-ethoxy acrylate obtained in step (iii) with (S)-2-amino-l-propanol in a solvent, to give ethyl-2-(2,3,4,5-tetrafluoro benzoyl)-3-[(l-hydroxy prop-2(S)-yl) amino] acrylate;
cyclismg the resulting ethyl -2-(2,3,455-tetrafluoro benzoyl)-3-[(l-hydroxy prop-2(S)-yll amino] acrylate by conventional methods to give (S)-ethyl- 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido-[ 1,2,3-de] -1,4-benzoxazine-6-carboxylate and,
vi) further hydrolyzing (S)-ethyl-9-10—difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[l,2,3-de]-l,4-benzoxazine-6- carboxylate obtained in step (v) by known methods to give (S)-9,10-difluro-2-3 -dihydro-3 -methyl-7-oxo-7H-pyrido-[l,2,3-de]-l,4-benzoxine -6carboxylic acid (namely Levofloxacin Q-acid) carboxylic acid (namely Levofloxacin Q-acid).
In the above process the in step (i), Diethyl malonate is acylated using 2,3,4,5-tetrafluoro benzoyl chloride in the presence of magnesium ethanol by making diethyl ethoxymagnesiomalonate.Also,in step (ii) the conversion is effected using an aqueous medium employing catalytic amount of para toluene sulfonic acid
The reagents used for the condensation in step (iii) is triethyl orthoformate and acetic anhydride.The solvent used in step (iv) is methylene chloride.Also, the

cyclisation in step (v) is done the presence of suitable base such as potassium carbonate and an aprotic solvent such as N, N-dimethyl formamide. The hydrolysis in step (vi) is carried out using acetic acid and dilute hydrochloric acid. The filtration in steps (i) & (j) may be effected using a 0.2 micron filter. The alkaline Levofloxacin solution is stirred at a pH in the range of 8.0 to 12.0, preferably 10.0-12.0, more preferably 11.0-11.5.
In the above process of the invention, the condensation in step(a) is carried out either using aprotic solvent or without using solvent.The aprotic solvent which is used for condensation is pyridine. Moreover, the alkali used in step (h) is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide and the concentration of the solution is 5 to 20% preferably 8-10%.The pH is brought to 7.0-7.5 using dilute hydrochloric acid preferably 0.5N to 5N hydrochloric acid, more preferably IN hydrochloric acid.
The precipitated particulate matter is filtered and the pH is adjusted to 3.0-6.0 preferably 4.0-5.5 more preferably 4.5-5.0 using glacial acetic acid.
The aqueous acidic levofloxacin solution is treated with activated carbon at room temperature and the clear solution is filtered the pH to neutral preferably 7.0-7.5 using dilute aqueous ammonia solution. The neutral aqueous solution is again filtered and extracted with chlorinated solvent preferably methylene chloride.Importantly,the extract is concentrated under vacuum (600-650 mm of Hg) below 40°C and the resulting residue is concentrated after stirring with tetrahydrofuran or its mixture with any other organic solvent. The residue is slurred with 1-5% aqueous tetrahydrofuran preferably with 2-2.5% aqueous tetrahydrofuran.Preferably, the slurring with tetrahydrofuran is effected at 40-70°C preferably at 50-60°C more preferably at 58-60°C.
The slurring with tetrahydrofuran is effected for a period in the range of 30 minutes to 2 hours preferably 30 minutes to 1 hour and then cooled to -5 to 15 C

preferably 0-5°C and stirred for 30 minutes to 2 hours preferably 1 hour to 1 hour 30 minutes.
The product is filtered and suck dried for 15 minutes to 1 hour preferably 30 minutes to 45 minutes and the product was dried at 50-80°C preferably at 70-75°C for 2 to 7 hours preferably 4-6 hours more preferably 5 to 5 hours 30 minutes.
In accordance with another aspect of the present invention there is provided a process for preparation of Levofloxacin having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form) which comprises:
dissolving levofloxacin technical grade in aqueous alkaline solution,.
treating the resulting solution with activated carbon at room temperature,
removing the undissolved particulate matter filtration,
bringing the pH of the aqueous alkaline levofloxacin solution is neutral using dilute mineral acid,
removing the precipitated particulate matter by filtration
acidifying the resulting solution
treating the acidified solution with activated carbon at room temperature,
filtering the undissolved particulate matter by filtration,
neutralizing the acidic solution,
filtering again to remove any particulate matter present and,
extracting the resulting product with chlorinated solvent and concentrating under vacuum using aqueous tetrahydrofuran or in admixture with other organic solvents to get highly pure levofloxacin hemihydrate having single individual

impurity less than 0.1% and free from particulate matter & from the other enantiomer (R-form) as Levofloxacin hemihydrate of Formula I.
In the above process of the invention the filtration in steps (viii) & (x) may be effected using a 0.2 micron filter.The alkaline Levofloxacin solution is stirred at a pH in the range of 8.0 to 12.0 preferably 10.0-12.0 more preferably 11.0-11.5.The alkali used is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide and the concentration of the solution is 5 to 20% preferably 8-10%.The pH is brought to 7.0-7.5 using dilute hydrochloric acid, preferably 0.5N to 5N hydrochloric acid, more preferably IN hydrochloric acid.The precipitated particulate matter is filtered and the pH is adjusted to 3.0-6.0 preferably 4.0 to 5.5 more preferably 4.5-5.0 using glacial acetic acid.The aqueous acidic levofloxacin solution is treated with activated carbon at room temperature and the clear solution is filtered the pH to neutral preferably 7.0-7.5 using dilute aqueous ammonia solution. The neutral aqueous solution is again filtered and extracted with chlorinated solvent preferably methylene chloride. The extract is concentrated under vacuum (600-650 mm to Hg) below 40°C and the resulting residue is concentrated after stirring with tetrahydrofuran or its mixture with any other organic solvent.The residue is slurred with 1-5% aqueous tetrahydrofuran preferably with 2-2.5% aqueous tetrahydrofuran.The slurring with tetrahydrofuran is effected at 40-70°C preferably at 50-60°C more preferably at 58-60°C. Moreover, the slurring with tetrahydrofuran is effected for a period in the range of 30 minutes to 2 hours preferably 30 minutes to 1 hour and then cooled to -5 to 15°C preferably 0-5°C and stirred for 30 minutes to 2 hours preferably 1 hour to 1 hour 30 minutes.
The product is filtered and suck dried for 15 minutes to 1 hour preferably 30 minutes to 45 minutes and the product was dried at 50-80T preferably at 70-75 °C for 2 to 7 hours preferably 4-6 hours more preferably 5 to 5 hours 30 minutes.

Importantly according to an aspect of the above process of the invention Levofloxacin technical is obtained by converting Levofloxacin Q-Acid by condensing with excess amount of N-methyl piperazine .In such process of preparation of Levofloxacin technical used in the process use of pyridine as a solvent is optional and it is possible to carry out the above preparation of Levofloxacin even without the solvent. Levofloxacin technical may be stirred in water and pH is adjusted to 8.0 to 12.0, preferably 10.0-12.0, more preferably 11.0-11.5 with dilute alkali metal hydroxide solution, preferably 5 to 20% alkali solution, more preferably 8-10%. The alkali metal hydroxide which may be used may be either sodium hydroxide or potassium hydroxide, preferably sodium hydroxide. The aqueous alkaline levofloxacin solution is treated with activated carbon, and the clear solution is filtered. Then the pH is brought to 7.0-7.5 using dilute hydrochloric acid, preferably 0.5N to 5N hydrochloric acid, more preferably IN hydrochloric acid. The precipitated particulate matter is filtered. Again the aqueous solution pH may be adjusted to 3.0-6.0 preferably 4.0 to 5.5 more preferably 4.5-5.0 using glacial acetic acid. The aqueous acidic levofloxacin solution was treated with activated carbon at room temperature and the clear solution may be filtered preferably through micron filter. Finally, the pH of the aqueous solution may be adjusted to neutral preferably 7.0-7.5 using dilute aqueous ammonia solution. The neutral aqueous solution may be again filtered preferably through micron filter and extracted with chlorinated solvent preferably methylene chloride. The extract may be concentrated under vacuum (600-650 mm of Hg) below 40°C. The resulting residue was concentrated after stirring with tetrahydrofuran or its mixture any other organic solvent. Finally the residue was slurred with 1-5% aqueous tetrahydrofuran preferably with 2-2.5% aqueous tetrahydrofuran at 40-70°C preferably at 50-60°C more preferably at 58-60°C for 30 minutes to 2 hours preferably 30 minutes to 1 hour then cooled to -5 to 15°C preferably 0-5°C and stirred for 30 minutes to 2 hours preferably 1 hour to 1 hour 30 minutes. The product was filtered and suck dried for 15 minutes to 1 hour preferably 30 minutes to 45 minutes and the product was dried at 50-80°C preferably at 70-75°C for 2 to 7 hours preferably 4-6 hours more preferably 5 to 5 hours 30 minutes to give highly pure Levofloxacin hemihydrate with single individual impurity less than 0.1%. Elemental analysis calculated for Ci8H2oFN304, VafeO is C 58.37%, H 5.71%, Nll.35%, and found is C58.38%, H5.67%, N 11.38%.
The X-ray diffraction pattern of the Levofloxacin form with single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form) ,Levofloxacin hemihydrate, prepared by the process of the present invention is found to be identical to that of the Levofloxacin hemihydrate prepared by the process reported in US patent 5,545,737, EP patent 0444678 and Chem. Pharm. Bull, 43(4) 649-653) (1995). The typical X-ray diffraction pattern of the prepared Levofloxacin hemihydrate is given below.
Accordingly to another preferred embodiment of the present invention there is provided an improved process for the preparation of Levofloxacin hemihydrate which comprises :
Converting 2,3,4,5 - tetrafluoro benzoic acid to its acid chloride by conventional method to give the diethyl -2,3,4,5-tetrafluoro benzoyl malonate
Partially hydrolyzing and decarboxylating the resulting diethyl-2,3,4,5,-tetrafluoro benzoyl malonate by conventional method to give ethyl-2,3,4,5-tetrafluoro benzoyl acetate.
Converting the ethyl-2,34,5-tetrafluoro benzoyl acetate by known methods to ethyl-2-(2,3,4,5-tetrafluoro benzoyl)-3-ethoxy acrylate.
Condensing the ethyl-2-(2,3,4,5-tetrafluoro benzoyl)-3-ethoxy acrylate obtained in step (iii) with (S)-2-amino-l-propanol in a solvent, to give ethyl-2-(2,3,4,5-tetrafluoro benzoyl)-3-[(1-hydroxy prop-2(S)-yl)amino] acrylate.
Cyclizing the resulting ethyl-2(2,3,4,5-tgetrafluro benzoyl)-3-[(l-hydroxy prop-2(S)-yl)amino] acrylate by conventional methods to give (S)-ethyl-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido-[l,2,3-de]-l54-benzoxazine-6-carboxylate and,
Further hydrolyzing (S)-ethyul-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7//-pyrido-[l,2,3,-de)-l,4-benzoxazine-6-carboxylate, obtained in step (v) by known methods to give (S)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido-[l,2,3-de]-l,4-benezoxazine-6-carboxylic acid (namely Levofloxacin Q-acid),
Converting the Levofloxacin Q-acid by condensing with N-methyl piperazine by using solvent or without using solvent by any known method to (S)-9-fluro-3-
methyl-10-(4-methyl-1 -piperazinyl)7-oxo-2,3-dihydro-7H-pyrido[ 1,2,3-de]-1,4-benezoxazine-6-carboxylic acid (namely Levofloxacin technical).
Dissolving levofloxacin technical in aqueous alkaline solution
Treating the resulting solution with activated carbon at room temperature
Removing the undissolved particulate matter by filtration
bringing the pH of the aqueous alkaline levofloxacin solution to neutral using dilute mineral acid,
removing the precipitated particulate matter by filtration
acidifying the resulting solutions
treating the acidified solution with activated carbon at room temperature
filtering the undissolved particulate matter by filtration
neutralizing the acidic solution,
filtering again to remove any particulate matter present and,
extracting the resulting product with chlorinated solvent and concentrating under vacuum using aqueous tetrahydrofuran or in admixture with other organic solvents to get highly pure levofloxacin hemihydrate having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form).
Reaction sequence in the scheme given below.
SET OUT REACTION SCHEME
In a preferred embodiment of the invention in step (i), Diethyl malonate may be acylated using 2,3,4,5-tetrafluoro benzoyl chloride in the presence of magnesium, ethanol by making diethyl ethoxymagnesiomalonate.
The reagents used for the condensation in step (iii) may be triethyl orthoformate and acetic anhydride.
In step (ii) the conversion may be effected using an aqueous medium employing catalytic amount of para toluene sulfonic acid.
An example of the solvent used in step (iv) may be methylene chloride
The cyclisation in step(v) may be done in the presence of suitable base such as potassium carbonate and an aprotic solvent such as N,N-dimethyl formamide.
The hydrolysis in step (vi) may be done in the presence of suitable base such as potassium carbonate and an aprotic solvent sush as N,N-dimethyl formamide.
The hydrolysis in step (vi) may be carried out using acetic acid and dilute hydrochloric acid.
The details of the present invention are described in the following examples which are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention.
SET OUT THE EXAMPLES
Advantages of the present invention:
It is possible to provide Levofloxacin having single individual impurity less than 0.1% and free from particulate matter as Levofloxacin hemihydrate.
Levofloxacin having single individual impurity less than 0.1% and free from particulate matter as Levofloxacin hemihydrate prepared is free from the other enantiomer (R-form)
The process of the present invention provides industrially feasible process
The process is simple and safe and environmentally friendly
It should be noted that the invention also envisages other embodiments falling within the scope of the present invention which will be obvious and apparent to one skilled in the art from the foregoing disclosure.
WE CLAIM: .
1. A method for the preparation of Levofloxacin having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form) which comprising:
a) converting the Levofloxacin Q-Acid by condensing with N-methyl piperazine by using solvent or without using solvent by any known methods to (S)-9(-)-fluoro-3 -methyl-10-(4-methyl-1 -piperizinyl)-7-oxo-2.3 -dihydro-7//-pyrido-[l,2,3-de]-l,4-benzoxazine-6-carboxylic acid (namely Levofloxacin technical).
b)dissolving levofloxacin technical in acqueous alkaline solution ;
c)treating the resulting solution with activated carbon at room temperature;
d) removing the undissolved particulate matter by filtration;
e) bringing the pH of the aqueous alkaline levofloxacin solution to neutral using dilute mineral acid;
f)removing the precipitated particulate matter by filtration;
g)acidifying the resulting solution;
h)treating the acidified solution with activated carbon at room temperature;
i) filtering the undissolved particulate matter by filtration;
j)neutralizing the acidic solution;
k)filtering again to remove any particulate matter present and,
1) extracting the resulting product with chlorinated solvent and concentrating under vacuum using aqueous tetrahydreofuran or in admixture with other organic solvents to get highly pure levofloxacin having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiometer (R-form) as le ofloxacin hemihydrate of Formula I.
2. A process as claimed in claim 1 wherein said Levofloxacin Q-Acid used is obtained from 2,3,4,5 -tetrafluoro benzoic acid following the steps comprising:
converting 2,3,4,5-tetrafluoro benzoic acid to its acid chloride by conventional method to give the diethyl - 2,3,4,5-tetrafluro benzyol malonate;
tetrafluoro benzoyl acetate;
converting the ethyl - 2,3,4,5 -tetrafluoro benzoyl acetate by known method to ethyl -2-(2,3,4,5-tetrafluro benzoyl) -3-ethoxy acrylate;
condensing the ethyl-2-(2,3,4,5-tetrafluoro benzoyl)-3-ethoxy acrylate obtained in step (iii) with (S)-2-amino-l-propanol in a solvent, to give ethyl-2-(2,3,4,5-tetrafluoro benzoyl)-3-[(l-hydroxy prop-2(S)-yl) amino] acrylate;
cyclising the resulting ethyl -2-(2,3,4,5-tetrafluoro benzoyl)-3-[(l-hydroxy prop-2(S)-yll amino] acrylate by conventional methods to give (S)-ethyl- 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido-[l,2?3-de] -l,4-benzoxazine-6-carboxylate and,
vi) further hydrolyzing (S)-ethyl-9-10"difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de]-l,4-benzoxazine-6- carboxylate obtained in step (v) by known methods to give (S)-9,10-difluro-2-3-dihydro-3-methyl-7-oxo-7H-pyrido-[l,2,3-de]-l,4-benzoxine -6carboxylic acid (namely Levofloxacin Q-acid) carboxylic acid (namely Levofloxacin Q-acid).
3. A process as claimed in claim 2 wherein in step (i), Diethyl malonate is
acylated using 2,3,4,5-tetrafluoro benzoyl chloride in the presence of magnesium
ethanol by making diethyl ethoxymagnesiomalonate
4. A process as claimed in anyone of claims 2 or 3 wherein in step (ii) the
conversion is effected using an aqueous medium employing catalytic amount of
para toluene sulfonic acid
6. A process as claimed in anyone of claims 2 to 5 wherein the solvent used in
step (iv) is methylene chloride
7. A process as claimed in anyone of claims 2 to 6 wherein the cyclisation in step (v) is done the presence of suitable base such as potassium carbonate and an aprotic solven such as N, N-dimethyl formamide.
8. A process as claimed in anyone of claims 2 to 7 wherein the hydrolysis in step (vi) is carried out using acetic acid and dilute hydrochloric acid.
9. A process as claimed in anyone of claims 1 to 7 wherein, the condensation in
step(a) is carried out either using aprotic solvent or without using solvent.
10. A process as claimed in claim 8 wherein, the aprotic solvent which is used for condensation is pyridine.
11. A process as claimed in anyone of claims 1 to 9 wherein the filtration in steps (i) & (j) may be effected using a 0.2 micron filter.
12. A process as claimed in anyone of claims 1 to 10 wherein the alkaline Levofloxacin solution is stirred at a pH in the range of 8.0 to 12.0, preferably 10.0-12.0, more preferably 11.0-11.5.
13. A process as claimed in anyone of claims 1 to 11 wherein the alkali used in step (h) is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide and the concentration of the solution is 5 to 20% preferably 8-10%.
14. A process as claimed in anyone of claims 1 to 12 wherein the pH is brought to 7.0-7.5 using dilute hydrochloric acid preferably 0.5N to 5N hydrochloric acid, more preferably IN hydrochloric acid.
15. A process as claimed in anyone of claims 1 to 13 wherein the precipitated particulate matter is filtered and the pH is adjusted to 3.0-6.0 preferably 4.0-5.5 more preferably 4.5-5.0 using glacial acetic acid.
16. A process as claimed in anyone of claims 1 to 14 wherein the aqueous acidic levofloxacin solution is treated with activated carbon at room temperature and the clear solution is filtered the pH to neutral preferably 7.0-7.5 using dilute aqueous ammonia solution.
17. A process as claimed in anyone of claims 1 to 15 wherein the neutral aqueous solution is again filtered and extracted with chlorinated solvent preferably methylene chloride
18. A process as claimed in anyone of claims 1 to 16 wherein the extract is concentrated under vacuum (600-650 mm of Hg) below 40°C and the resulting residue is concentrated after stirring with tetrahydrofuran or its mixture with any other organic solvent.
19. A process as claimed in anyone of claims 1 to 17 wherein the residue is slurred with 1-5% aqueous tetrahydrofuran preferably with 2-2.5% aqueous tetrahydrofuran.
20. A process as claimed in anyone of claims 1 to 18 wherein the slurring with tetrahydrofuran is effected at 40-70°C preferably at 50-60°C more preferably at 58-60°C.
21 A process as claimed in anyone of claims 1 to 19 wherein the slurring with tetrahydrofuran is effected for a period in the range of 30 minutes to 2 hours preferably 30 minutes to 1 hour and then cooled to -5 to 15 C preferably 0-5 C and stirred for 30 minutes to 2 hours preferably 1 hour to 1 hour 30 minutes.
22. A process as claimed in anyone of claims 1 to 21 wherein the product is filtered and suck dried for 15 minutes to 1 hour preferably 30 minutes to 45 minutes and the product was dried at 50-80°C preferably at 70-75°C for 2 to 7 hours preferably 4-6 hours more preferably 5 to 5 hours 30 minutes.
23. A process for preparation of Levofloxacin having single individual impurity not more than 0.1% and free from particulate matter & from the other enantiomer (R-form) which comprises
dissolving levofloxacin technical grade in aqueous alkaline solution,.
treating the resulting solution with activated carbon at room temperature,
removing the undissolved particulate matter filtration,
bringing the pH of the aqueous alkaline levofloxacin solution is neutral using dilute mineral acid,
removing the precipitated particulate matter by filtration
acidifying the resulting solution
treating the acidified solution with activated carbon at room temperature,
filtering the undissolved particulate matter by filtration,
neutralizing the acidic solution,
filtering again to remove any particulate matter present and,
extracting the resulting product with chlorinated solvent and concentrating under vacuum using aqueous tetrahydrofuran or in admixture with other organic solvents to get highly pure levofloxacin hemihydrate having single individual impurity less than 0.1% and free from particulate matter & from the other enantiomer (R-form) as Levofloxacin hemihydrate of Formula I.
24. A process process as claimed in claim 23 wherein the filtration in steps (viii) & (x) may be ?ffscted using a 0.2 micron filter.
25. A process as claimed in anyone of claims 23 or 24 wherein the alkaline Levofloxacin solution is stirred at a pH in the range of 8.0 to 12.0 preferably 10.0-12.0 more preferably 11.0-11.5.
26. A process as claimed in anyone of claims 23 to 25 wherein the alkali used is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide and the concentration of the solution is 5 to 20% preferably 8-10%.
27. A process as claimed in anyone of claims 23 to 26 wherein the pH is brought to 7.0-7.5 using dilute hydrochloric acid, preferably 0.5N to 5N hydrochloric acid, more preferably IN hydrochloric acid.
28. A process as claimed in anyone of claims 23 to 26 wherein the precipitated particulate matter is filtered and the pH is adjusted to 3.0-6.0 preferably 4.0 to 5.5 more preferably 4.5-5.0 using glacial acetic acid.
29. A process as claimed in anyone of claims 23 to 28 wherein the aqueous acidic levofloxacin solution is treated with activated carbon at room temperature and the clear solution is filtered the pH to neutral preferably 7.0-7.5 using dilute aqueous ammonia solution.
30. A process as claimed in anyone of claims 23 to 29 wherein the neutral aqueous solution is again filtered and extracted with chlorinated solvent preferably methylene chloride.
31. A process as claimed in anyone of claims 23 to 30 wherein the extract is concentrated under vacuum (600-650 mm to Hg) below 40°C and the resulting residue is concentrated after stirring with tetrahydrofuran or its mixture with any other organic boivent
32. A process as claimed in anyone of claims 23 to 31 wherein the residue is slurred with 1-5% aqueous tetrahydrofuran preferably with 2-2.5% aqueous tetrahydrofuran.
33. A process as claimed in anyone of claims 23 to 32 wherein the slurring with tetrahydrofuran is effected at 40-70°C preferably at 50-60°C more preferably at 58-60°C.
34. A process as claimed in anyone of claims 23 to 33 wherein the slurring with tetrahydrofuran is effected for a period in the range of 30 minutes to 2 hours preferably 30 minutes to 1 hour and then cooled to -5 to 15 C preferably 0-5 C and stirred for 30 minutes to 2 hours preferably 1 hour to 1 hour 30 minutes.
35. A process as claimed in anyone of claims 23 to 34 wherein the product is filtered and suck dried for 15 minutes to 1 hour preferably 30 minutes to 45 minutes and the product was dried at 50-80°C preferably at 70-75°C for 2 to 7 hours preferably 4-6 hours more preferably 5 to 5 hours 30 minutes.
36. A process for the preparation of Levofloxacin having single individual
impurity not more than 0.1% and free from particulate matter & from the other
enantiomer (R-form) from Levofloxacin technical substantially as herein
described with reference to the Example 1 & 2.,
37. A process for the preparation of Levofloxacin having single individual not
more than 0.1% and free from particulate matter & from the other enantiomer
(R-form) from 2,3,4,5,-tetrafluoro benzoic acid substantially as herein described
with reference to the Example 3.

Documents:

417-che-2003-abstract.pdf

417-che-2003-claims.pdf

417-che-2003-correspondnece-others.pdf

417-che-2003-correspondnece-po.pdf

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

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

417-che-2003-form 1.pdf

417-che-2003-form 26.pdf

417-che-2003-form 3.pdf

417-che-2003-form 4.pdf

417-che-2003-form 5.pdf

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Patent Number

229127

Indian Patent Application Number

417/CHE/2003

PG Journal Number

12/2009

Publication Date

20-Mar-2009

Grant Date

13-Feb-2009

Date of Filing

19-May-2003

Name of Patentee

NEULAND LABORATORIES LTD

Applicant Address

204, MERIDIAN PLAZA, 6-3-853/1, AMEERPEET, HYDERABAD 500 016,

Inventors:

#	Inventor's Name	Inventor's Address
1	A. SAHU	NEULAND LABORATORIES LTD, 204, MERIDIAN PLAZA, 6-3-853/1, AMEERPEET, HYDERABAD 500 016,
2	G.N. TRINADHACHARI	NEULAND LABORATORIES LTD, 204, MERIDIAN PLAZA, 6-3-853/1, AMEERPEET, HYDERABAD 500 016,
3	P. SRINEEVASULU	NEULAND LABORATORIES LTD, 204, MERIDIAN PLAZA, 6-3-853/1, AMEERPEET, HYDERABAD 500 016,
4	DR. D.R. RAO	NEULAND LABORATORIES LTD, 204, MERIDIAN PLAZA, 6-3-853/1, AMEERPEET, HYDERABAD 500 016,
5	DR. S.P.D. DWIVEDI	NEULAND LABORATORIES LTD, 204, MERIDIAN PLAZA, 6-3-853/1, AMEERPEET, HYDERABAD 500 016,

PCT International Classification Number

A61K9/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA