WO2009093268A1

WO2009093268A1 - Process for the preparation of highly pure prulifloxacin

Info

Publication number: WO2009093268A1
Application number: PCT/IN2009/000060
Authority: WO
Inventors: Rahul Saxena; Naresh Kumar Verma; Kumar Jain Anshul; Venkateswaran Srinivasan Chidambaram; Lalit Wadhwa
Original assignee: IND-SWIFT LABORATORIES Ltd; Ind Swift Laboratories Ltd
Current assignee: IND-SWIFT LABORATORIES Ltd; Ind Swift Laboratories Ltd
Priority date: 2008-01-23
Filing date: 2009-01-22
Publication date: 2009-07-30
Anticipated expiration: 2010-07-23

Abstract

The present invention provides an industrially advantageous process for the preparation of highly pure prulifloxacin of formula I and its pharmaceutically acceptable salts. The present i innvention a also provides a novel process for the purification of prulifloxacin acid addition salt.

Description

PROCESS FOR THE PREPARATION OF HIGHLY PURE PRULIFLOXACIN FIELD OF THE INVENTION

The present invention provides an improved process for the preparation of highly pure prulifloxacin of formula I, an oral fluoroquinolone antibacterial agent or pharmaceutically acceptable salt thereof.

Formula I

The present invention provides a novel process for the purification of prulifloxacin acid addition salt.

BACKGROUND OF THE INVENTION Prulifloxacin, 6-fluoro- 1 -methyl-7-([4-(5-methyl-2-oxo- 1 ,3-dioxolen-4-yl)methyl- 1 -piperazinyl] -4-oxo-4H-[l,3]thiazeto[3,2-a]quinoline-3-carboxylic acid, of formula I,

Formula I is useful for treating bacterial infection in humans and animals. Prulifloxacin is a novel oral fluoroquinolone antibacterial agent and is effective against gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa. The compound has shown good efficacy against respiratory tract and urinary tract infections in clinical studies. Prulifloxacin, marketed as 'QUINSON' is a lipophilic prodrug of ulifloxacin of formula II, chemically known as 6-fluoro- l-methyl-4-oxo-7-(l-piperazinyl)-4H-[l,3]thiazeto[3,2-a]quinoline-3-carboxylic acid.

Formula II Prulifloxacin is first disclosed in U.S. patent No. 5,086,049. The patent discloses a process for the preparation of prulifloxacin by the condensation of ulifloxacin with a 4-halomethyl-5- methyl-l,3-dioxolen-2-one of formula III,

O_VCH₃ o=< T _γ

O^ ^x Formula III wherein X is halo selected from chloro, bromo or iodo in the presence or absence of aprotic solvent and a base to obtain prulifloxacin free base which is recrystallized with chloroform-methanol. In an exemplified process, 3,4-difluoroaniline is treated with carbon disulfide in the presence of triethylamine to obtain a salt of (3,4- difluoropheny^dithiocarbamic acid, which on further reaction with ethylchloroformate in the presence of dichloromethane gives 3,4-difluorophenyl isothiocyanate, which is purified by column chromatography. The resulting product is then treated with ethyl malonate in the presence of potassium hydroxide in 1 ,4-dioxane, followed by treatment with methoxymethyl chloride to give diethyl l-(3,4-difluorophenylamino)-l-(methoxymethylthio)-methylenemalonate which is further purified with column chromatography and then cyclised to give ethyl 6,7- difluoro-4-hydroxy-2-methoxymethylthio- quinoline-3-carboxylate. The resulting product is treated with concentrated hydrochloric acid to hydrolyse the mercapto protecting group followed by reaction with ethylidene bromide in the presence of potassium carbonate, potassium iodide and dimethylformamide to give ethyl 6,7-difluoro-l-methyl-4-oxo-4H-(l,3)thiazeto(3,2- a)quinoline-3-carboxylate. The ester so formed is condensed with piperazine in the presence of dimethylformamide and purified by column chromatography followed by basic hydrolysis to give ulifloxacin, which is then converted to prulifloxacin. The above process involves the use of harmful reagents like methoxymethyl chloride, expensive and toxic solvent like 1,4-dioxane and expensive and commercially unavailable reagent like ethylidene bromide. A general shortcomings of the prior art method resides in that process proposed involve, apart from applying column chromatography at several steps, isolation steps at every intermediate stage, which are acknowledged to decrease yield and rendering any process cumbersome. Prulifloxacin is prepared with low purity of 80-85% and having some impurities in unacceptable limits. Removal of these impurities by usual purification procedures, such as recrystallization, distillation, washing, is difficult and requires extensive and expensive multiple purification processes.

An article, namely, Chinese Chemical Letter 2006, 17 (6), 714-716 discloses the preparation of prulifloxacin starting from 3-chloro-4-fluoroaniline through a reaction sequence to obtain novel intermediate 7-chloro-6-fluoro-l-methyl-4-oxo-4H-(l,3)thiazeto(3,2-a)quinoline-3-carboxylate which can further be used for synthesizing prulifloxacin. Yield of the above intermediate is only 20.6% as reported therein. The process of conversion of said intermediate to prulifloxacin is not disclosed. In our hands it was found that no product was obtained when the said intermediate was made to react with piperazine. Hence, the process seems to be unattractive from commercial point of view.

In view of the above, it is clear that the prior art processes are not-amenable for easy scale up, teaches the use of expensive and harmful reagents and results in low overall yield and purity. Therefore, there is an urgent need to develop an improved, efficient, cost effective, operationally facile, and amenable process for the preparation of prulifloxacin at industrial scale. The process of the present invention is easily and conveniently feasible for industrial scale production without using column chromatography and involves one pot process at intermediate stages; hence the use of number of organic solvents is minimized.

OBJECT OF THE INVENTION

The main object of the present invention is to provide an industrially advantageous, cost- effective and environmentally friendly process for preparing highly pure prulifloxacin in high yields.

Another object of the present invention is to provide a process for the purification of the prulifloxacin acid addition salts.

Yet another object of the invention is to provide a process for the preparation of prulifloxacin in fewer steps, without the isolation of most of the intermediates and by employing the use of minimal number of solvents.

SUMMARY OF THE INVENTION

The present invention provides an improved process for the preparation of prulifloxacin of formula I and pharmaceutically acceptable salts thereof, which comprises the step of: (a) reacting 3,4-difluoroaniline with carbon disulfide in the presence of a suitable base followed by reaction with ethylchloro formate to obtain 3,4-difiuorophenyl isothiocyanate;

(b) optionally purifying 3,4-difluorophenyl isothiocyanate by distillation under reduced pressure;

(c) treating 3,4-difluorophenyl isothiocyanate with diethyl malonate in the presence of a base in a solvent to form [[(3,4-difluorophenyl)amino]-mercapto methylene] -malonic acid diethyl ester S-potassium salt of formula IV;

Formula IV

(d) alkylating compound of formula IV with diethyl sulfate in an organic solvent to form [(3,4- difluorophenyl)amino](ethylthio)methylenemalonate of formula V;

Formula V

(e) cyclizing compound of formula V in situ by refluxing the reaction mixture to form ethyl 4- hydroxy-6,7-difluoro-2-(ethylthio)quinoline-3-carboxylate of formula VI;

Formula VI

(f) acylating compound of formula VI in the presence of a suitable reagent like acetyl halide, or acetic anhydride and a base in a solvent to obtain ethyl 4-acetoxy-6,7-difluoro-2-

(ethylthio)quinoline-3-carboxylate of formula VII;

Formula VII

(g) treating compound of formula VII in situ with a chlorinating agent in a suitable solvent to form a compound of formula VIII;

Formula VIII

(h) treating compound of formula VIII in situ with an alkali metal acetate in a solvent to form ethyl 6,7-difluoro- 1 -methyl-4-oxo-4H-( 1 ,3)thiazeto(3 ,2-a)quinoline-3 -carboxylate of formula IX ;

Formula IX

(i) condensing compound of formula IX with piperazine in a suitable solvent to obtain ulifloxacin ethyl ester of formula X;

Formula X

(j) hydrolysing ulifloxacin ethyl ester of formula X using an acid or a base in a suitable solvent to obtain ulifloxacin of formula II;

Formula II (k) optionally purifying ulifloxacin of formula II;

(1) condensing ulifloxacin of formula II with 4-halomethyl-5-methyl-l,3-dioxolen-2-one of formula III

O_VCH₃ o=< Jl _v

O^ ^x Formula III wherein X is halo selected from chloro, bromo or iodo in the presence of a suitable base;

(m) treating the resulting reaction mass with a suitable acid to obtain prulifloxacin acid addition salt; (n) optionally purifying prulifloxacin acid addition salt with an organic solvent; (o) hydrolysing prulifloxacin acid addition salt in the presence of a base in a suitable solvent; and

(p) isolating prulifloxacin from the reaction mixture.

According to another embodiment, the present invention provides a process for the preparation of prulifloxacin of formula I, which comprises the step of:

(a) condensing ulifloxacin of formula II with 4-halomethyl-5-methyl-l,3-dioxolen-2-one of formula III in the presence of a suitable base;

(b) treating the resulting reaction mass with an acid to obtain prulifloxacin acid addition salt;

(c) optionally purifying prulifloxacin acid addition salt with an organic solvent; (d) hydrolysing prulifloxacin acid addition salt in the presence of a base in a suitable solvent; and

(e) isolating prulifloxacin from the reaction mixture.

According to yet another embodiment, the present invention provides a process for the purification of prulifloxacin acid addition salts. DETAILED DESCRIPTION OF THE INVENTION

The process of the present invention is an improved and efficient process for the preparation of highly pure prulifloxacin of formula I.

One embodiment of the present invention provides a process for the preparation of prulifloxacin and its pharmaceutically acceptable salts. Specifically, prulifloxacin of formula I can be prepared starting from 3,4-difluoroaniline and reacting the same with carbon disulfide in the presence of a suitable base to obtain triethylammonium-(3,4-difluorophenyl)dithiocarbamate at a temperature of 0 to 30 ⁰C, preferably till the completion of the reaction. Base employed in the reaction includes organic amines such as trialkylamine; or inorganic base such as alkali or alkaline metal hydroxides, carbonates, bicarbonates, hydrides or alkoxide thereof and the like. Preferably the base used is selected from triethylamine, sodium hydroxide, potassium hydroxide, calcium hydroxide and the like. Solvent includes aliphatic or aromatic hydrocarbon such as hexane, toluene, xylene; ethers such as isopropyl ether; halogenated solvents such as dichloromethane, chloroform; and the like or mixtures thereof. The reaction can also be performed in the absence of solvent. Triethylammonium-(3,4-difluorophenyl)dithiocarbamate in a suitable solvent (as described above) or the reaction mixture is then treated with ethylchloroformate at a temperature of below 5 °C to obtain 3,4-difluorophenyl isothiocyanate in the presence or absence of a suitable base in a solvent. Suitable solvents includes halogenated solvents such as dichloromethane; aliphatic or aromatic hydrocarbon such as toluene, xylene; and the like or mixture thereof. Suitable base are same as described above. After the completion of the reaction, the desired product is isolated by suitable methods such as layer separation followed by evaporation or distillation of the solvent. According to one another embodiment, of the present invention, 3,4-difluoroaniline can directly be converted to 3,4-difluorophenyl isothiocyanate in one step using an inorganic base in the absence of any organic solvent. Typically, inorganic bases includes alkali or alkaline metal hydroxides, carbonates, bicarbonates, hydrides or alkoxide thereof which are selected from sodium hydroxide, potassium hydroxide, calcium hydroxide and the like. In particular, the base used is sodium hydroxide. Base employed in the reaction can be used as such or their aqueous solution is used. The process is advantageous as the use of organic solvents is minimized and process can be easily, conveniently and inexpensively scaled-up for industrial production.

Typically, 3,4-difluoroaniline is treated with aqueous solution of inorganic base along with carbon disulfide at a temperature of 0-10⁰C. The reaction mass is then stirred at a temperature of 35-55 ⁰C for 10-30 hours. The reaction mixture is then cooled to a temperature of 20-35 ⁰C and filtered to remove salts. Ethylchloroformate is added slowly to the filtrate at a temperature of 10- 20 ⁰C and stirred at 35-55°C for few hours and extracted with aliphatic or aromatic hydrocarbon such as hexane. The organic layer is washed with water to isolate 3,4-difluorophenyl isothiocyanate. Preferably, the product is isolated by concentration under reduced pressure. The resulting product i.e. 3,4-difluorophenyl isothiocyanate obtained by any methods can optionally be purified by the methods well known in the art like extraction with a solvent, recrystallization, distillation and the like or can be used as such for the next step. Preferably, 3,4- difluorophenyl isothiocyanate is purified by distillation under reduced pressure. 3,4- Difluorophenyl isothiocyanate so obtained is having purity of more than 95% by HPLC. 3,4-Difluorophenyl isothiocyanate, so formed, is then reacted with diethyl malonate in the presence of a base in a solvent to obtain [[(3,4-difluorophenyl) amino] -mercaptomethylene]- malonic acid diethyl ester S-potassium salt of formula IV. Base can be organic or inorganic base. Organic base includes trialkylamine. Inorganic base includes alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxide and hydride thereof. Preferably base used is potassium hydroxide. Organic solvent includes aliphatic or aromatic hydrocarbon such as toluene; amide solvents such as dimethylformamide, N-methylpyrrolidone; sulfoxide solvents such as dimethylsulfoxide; nitrile solvent such as acetonitrile or mixture thereof. Preferably toluene is used. It is advantageous to use toluene as solvent in place of 1,4-dioxane as described in prior art, as toluene represent a cheap, easily recoverable and environment friendly solvent. In a preferred embodiment, present invention provides a process for the preparation of [[(3,4- difluorophenyl)amino]-mercaptomethylene]-malonic acid diethyl ester S-potassium salt of formula IV from 3,4-difluoroaniline by using same solvent for all the three steps. Suitable solvents that can be used in first three steps includes aliphatic or aromatic hydrocarbon such as toluene, xylene; cyclohexane, hexane and the like or mixture thereof. Preferably the solvent employed is toluene. It is advantageous to perform the reactions in the presence of a solvent which is same for the three steps of the reaction. Use of minimal number of solvents makes the process cost effective and commercially attractive.

According to another embodiment, the present invention provides a one pot process for the preparation of compound of formula VI directly from compound of formula IV by using the single solvent for the reaction. The intermediate compound of formula V is in situ processed to compound of formula VI in same pot. It is advantageous to perform the reaction in the presence of a solvent which is common for the both steps of the reaction. One pot process avoids the lengthy separation process and the purification of the intermediates. This, in turn, saves the time and resources and is highly efficient to increase the yield of the desired compounds. Generally, the process involves the reaction of compound of formula IV with diethyl sulfate to form [(3,4-difluorophenyl)amino] (ethyl thio)methylenemalonate of formula V in an organic solvent. The organic solvents includes aliphatic or aromatic hydrocarbon such as toluene, xylene, paraffin oil; esters such as ethyl acetate; ethers such as diphenyl ether and the like or mixture thereof. Compound of formula V is insitu further cyclized to ethyl 4-hydroxy-6,7-difluoro-2- (ethylthio)quinoline-3-carboxylate of formula VI. It is optional to isolate the intermediate of formula V by the suitable techniques. Preferably the reaction is carried out in the ethylacetate or xylene. Use of water immiscible solvent like ethylacetate and xylene in the above reaction makes the work up very easy and increases the yield and purity of the resulting product by removing the water soluble impurities from the reaction mixture. Both the solvents are easily recoverable as compared to water miscible ethanol which is described in prior art. Particularly, the reaction mixture is refluxed for 2-10 hours, preferably till the completion of the reaction. After completion of the reaction, solvent is distilled out. The traces of solvent, if present in the reaction mass can be removed by distillation using suitable solvent selected from alcoholic solvents such as methanol; aliphatic or aromatic hydrocarbon such as hexane or mixture thereof. During the reaction ethanol is formed as by product. It is necessary to eliminate ethanol from the reaction mixture for the completion of the reaction, which is achieved by distillation. This makes the process efficient for the large scale production and results in high yield of the product.

According to yet another embodiment, the present invention provide a one pot process for the preparation of ethyl 6,7-difluoro-l-methyl-4-oxo-4H-(l,3)thiazeto(3,2-a)quinoline-3-carboxylate of formula IX directly from 4-hydroxy compound of formula VI. The reaction steps acetylation of 4-hydroxy compound followed by chlorination and then condensation with the piperazine moiety are carried out without isolation of the intermediates in same pot. This makes the process commercially attractive by reducing the time and requirement of workup of the intermediates for the isolation.

4-Hydroxy compound of formula VI is acylated in the presence of a suitable reagent that includes acetyl halide, acetic anhydride and the like in the presence of a base in a solvent to obtain ethyl 4-acetoxy compound of formula VII. Base can be organic or inorganic. Organic base includes trialkylamine such as triethylamine and the like; inorganic base includes alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxide or hydrides thereof. Solvent includes halogenated solvent such as dichloromethane, chloroform; aliphatic or aromatic hydrocarbon such as hexane and the like or mixture thereof. The reaction is conducted at a temperature of about -5 to 10 °C and progress of the reaction is monitored by TLC. After the completion of the reaction, water and water immiscible solvents is added to the reaction mixture followed by distillation of the some part or whole of solvent. The resulting residue can be used as such for the further reaction or product can be isolated using suitable techniques like isolation of the compound of formula VII by the addition of a suitable solvent which includes alcoholic solvent to the resulting residue.

The isolated intermediate of formula VII can be used as such for the further reaction or optionally be purified in aliphatic or aromatic hydrocarbon such as hexane; alcoholic solvent such as isopropyl alcohol or mixture thereof. 4-Acetoxy compound of formula VII is further treated with a chlorinating agent in the presence of a suitable solvent at a temperature of 0 ⁰C to the reflux temperature of the solvent to form a compound of formula VIII. Chlorinating agent includes N- chlorosuccinimide, sulfuryl chloride and the like. Suitable solvent includes halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride; aliphatic or aromatic hydrocarbon such as n-hexane or mixture thereof. The compound of formula VIII can optionally be isolated. It is advantageous to proceed to next stage as such without isolation of the intermediate compound, as it lowers the processing time and the resulting product is achieved in high yield.

The compound of formula VIII is further treated with an alkali metal acetate preferably sodium acetate in the presence of a solvent at a temperature of room temperature to reflux temperature of the solvent to form ethyl 6,7-difluoro-l-methyl-4-oxo-4H-(l,3)thiazeto(3,2-a)quinoline-3- carboxylate of formula IX. The reaction takes about 1-10 hours for completion of reaction. Solvent includes ketone such as acetone; nitrile such as acetonitrile; aliphatic or aromatic solvent such as hexane; ether such as isopropyl ether, tetrahydrofuran; ester such as ethylacetate; halogenated solvent such as chloroform or mixture thereof. Thereafter, the reaction mixture is diluted with water to precipitate (1 ,3)thiazeto compound of formula IX. (l,3)Thiazeto compound of formula IX can further be optionally purified to remove unwanted impurities using an alcoholic solvent like methanol, ethanol, isopropanol or mixture thereof or used as such in the next step. Specifically, compound of formula IX is refluxed in an alcoholic solvent for few minutes to few hours, preferably for 1 hour. Thereafter the mixture is cooled to ambient temperature and purified compound of formula IX is isolated from the solution by suitable techniques such as filtration.

(l,3)Thiazeto compound of formula IX is then condensed with piperazine to obtain ulifloxacin ethyl ester of formula X. The process involves the reaction of compound of formula IX with piperazine in a suitable solvent at ambient temperature to reflux temperature of the solvent. Suitable solvent includes amide solvents such as dimethylformamide, dimethylacetamide; nitrile solvent such as acetonitrile; ketone such as acetone; sulfoxide solvent such as dimethylsulfoxide; sulfolane; aprotic solvents and the like or mixture thereof. Reaction is conducted for a period of about 10-40 hours, preferably for 24 hours, more preferably till reaction completion. The ulifloxacin ethyl ester is precipitated either by cooling of the reaction mixture or by addition of water; the precipitates are isolated by solvent removal using suitable techniques like filtration. Ulifloxacin ethyl ester of formula X is further hydrolysed to give ulifloxacin of formula II. The hydrolysis of ester functionality present in the ulifloxacin ethyl ester of formula X can be performed with any method known in art for the hydrolysis of the ester. Specifically, the hydrolysis involves the treatment of ulifloxacin ethyl ester of formula X in the presence a suitable base or an acid in a suitable solvent. Hydrolysis reaction is preferably conducted at a temperature of about ambient temperature to 100°C and it takes about 1-10 hours for complete hydrolysis. Suitable base includes alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxide, hydride thereof. Acid for the hydrolysis includes organic and inorganic acid selected from sulfuric acid, phosphoric acid or mixture thereof. Solvent includes Ci_-4 alcohols, water and mixture thereof, preferably selected from water, methanol, ethanol, propanol, butanol or mixture thereof. Ulifloxacin isolated from the reaction mixture can further optionally be purified by slurry wash with an organic solvent. Solvent includes water, alcohols like methanol, ethanol, isopropanol; ketones such as acetone or mixtures thereof. The conversion of ulifloxacin to pure prulifloxacin represents the inventive part of the present invention.

Generally, ulifloxacin of formula II is condensed with 4-halomethyl-5-methyl-l,3-dioxolen-2- one of formula III, in the presence of a suitable base followed by treatment with a suitable acid to obtain prulifloxacin acid addition salt, which is then hydrolyzed in the presence of a base to yield pure prulifloxacin. Specifically, the process involves the condensation of ulifloxacin of formula II with 4- halomethyl-5-methyl-l,3-dioxolen-2-one of formula III in presence of a suitable base at a temperature of -1O⁰C to ambient temperature, preferably at a temperature of 0 to -5 ⁰C. The reaction can be carried out in presence of absence of the solvent. Suitable base during condensation include inorganic base such as alkali metal or alkaline metal hydroxides, hydrides, carbonates, bicarbonate or alkoxide thereof or organic base such as trialkylamine and the like. Preferably base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N,N-diisopropylethylamine, sodium acetate and the like. Polar aprotic solvent can be selected from amide solvents such as N,N-dimethylformamide, N- methylpyrrolidone; sulfoxide solvents such as dimethylsulfoxide, ethers such as diglyme, monoglyme, nitrile solvents such as acetonitrile and the like or mixture thereof. The reaction time may vary depending upon the amount of starting material, type of solvent and base used and reaction temperature. After the completion of the reaction, water and water immiscible solvents are added to the reaction mixture followed by distillation of the some part or whole of solvent. Thereafter, a suitable acid is added to the resulting residue for the formation of acid addition salt of prulifloxacin. Suitable acid addition salts which may be formed includes those formed with pharmaceutically acceptable organic or inorganic acids and are well known to those of skill in the art. Acids commonly employed to form such salts includes inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and the like; salts with organic acids such as formic acid, acetic acid, tartaric acid, lactic acid, oxalic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, and the like. Preferred pharmaceutically acceptable acid addition salts includes those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as formic acid, fumaric acid, maleic acid, oxalic acid and succinic acid. A particularly preferred acid addition salt is the hydrochloride. Hydrochloric acid employed for the preparation of acid addition salts can be anhydrous, hydrochloric acid with suitable solvent that includes ethers, esters, amide solvents, alcohol, aliphatic or aromatic hydrocarbon or mixture thereof. Preferably the nature of hydrochloric acid employed is selected from alcoholic hydrochloride such as methanolic hydrochloride; amide solvent with hydrogen chloride such as N, N- dimethylformamide hydrochloride; ethereal hydrochloride such as isopropylether hydrochloride; ester hydrochloride such as ethyl acetate hydrochloride; and the like, it is advantageous to carry out the generation of the prulifloxacin acid addition salt in anhydrous conditions. Similarly other acid employed in the reaction can be used as such or with solvent as described above. Specifically, 4-halomethyl-5-methyl-l,3-dioxolen-2-one of formula III, preferably wherein X is bromo, is reacted with ulifloxacin in the presence of a suitable base in a solvent at a temperature of about -10 to 10⁰C. The progress of reaction is monitored by TLC or HPLC. After completion of reaction, the reaction mixture is diluted with halogenated solvent like dichloromethane and water. The layers are separated and aqueous layer is extracted with dichloromethane. All organic layers are combined and dried over sodium sulfate. Optionally the organic layer can be concentrated or the organic layer as such is treated with suitable acid to prepare corresponding acid addition salt. Thereafter, desired acid is added to the organic layer at a temperature of about -10 to 10⁰C, preferably till the pH of the reaction mass is about 0.5-1.5 to prepare prulifloxacin acid addition salt. The product can be isolated by any standard method known in the art such as by filtration, centrifugation or decantation. Typically, this product is isolated by filtration. Preferably, prulifloxacin hydrochloride is prepared by using an alcoholic hydrochloride or amide solvents with hydrogen chloride. More preferably methanolic hydrochloride or N,N- dimethylformamide hydrochloride for the generation of prulifloxacin hydrochloride. Prulifloxacin acid addition salts prepared according to the present invention as described above can optionally be purified by the methods well known in the art like extraction with a solvent, recrystallization, slurry wash in a suitable solvent and base acid treatment. One another embodiment of the present invention provides a process for the purification of prulifloxacin acid addition salt by suspending it in a suitable solvent at a temperature of about 40°C to reflux temperature of the solvent, preferably at a temperature of 100-140°C. Suitable solvents includes amide solvents such as dimethylformamide, N-methylpyrrolidone; sulfoxide solvents such as dimethylsulfoxide, nitrile solvent such as acetonitrile; halogenated solvents such as chloroform; alcoholic solvents such as methanol, the like and/or mixtures thereof. Afterwards, the reaction mass is preferably cooled to a temperature of about 10-35°C and maintained for about 10 minutes to about 24 hours to afford highly pure prulifloxacin acid addition salt having purity of more than 99.0% by high performance liquid chromatography (HPLC), preferably more than 99.3 % by HPLC. The above process may be repeated in order to increase purity even further either with same or different solvent used for the first purification. The purification of the prulifloxacin hydrochloride is optional to enhance the purity of the product. Prulifloxacin acid addition salt with or without purification is treated with a base in the presence of a suitable solvent to convert to highly pure prulifloxacin which is suitable for application in pharmaceutical compositions. Base can be selected from, but not limited to organic and inorganic base such as triethylamine, ammonia, alkali or alkaline metal hydroxide, carbonates, bicarbonate, hydride or alkoxide thereof such as sodium bicarbonate, potassium bicarbonate and the like. Solvent employed can be selected from water; alcohols such as methanol, ethanol, isopropanol, butanol, tert.-butanol; halogenated solvent such as dichloromethane, chloroform; ketones such as acetone; amide solvents such as N,7V-dimethylformamide, dimethylacetamide; sulfoxide solvents such as dimethylsulfoxide; nitrile solvents such as acetonitrile, ethers such as isopropyl ether; and the like or mixtures thereof. The reaction is usually performed at a temperature of about less than 10°C preferably till reaction completion. The prulifloxacin obtained by the process of the present invention is having purity greater than 99.0%, preferably greater than 99.3% by HPLC. If required, the product can further be purified using methods well known in the art like recrystallization from suitable solvent. Suitable solvents employed for the purification includes halogenated solvents such as chloroform; alcoholic solvents such as methanol; amide solvents such as methylformamide, dimethylformamide, dimethylacetamide; sulfoxide solvents such as dimethylsulfoxide; nitrile solvents such as acetonitrile; dimethylimidazolidinone and the like or mixtures thereof.

It has been observed that by the inventors of the present invention that when the process proceeds through the acid addition salt without the isolation of prulifloxacin base, high purity of the product is obtained which is suitable for application in pharmaceutical compositions.

Compound of formula III can be procured from the commercial source or prepared by the methods known in prior art like US patent no. 3,020,290; 4,843,070 etc. Typically, compound of formula III can be prepared by the halogenation of 4,5-dimethyl-[l,3]dioxol-2-one with a suitable halogenating agent. The order and manner of combining the reactants at any stage of the process are not important and may be varied. The reactants may be added to the reaction mixture as solids, or may be dissolved individually and combined as solutions. Further any of the reactants may be dissolved together as sub-groups, and those solutions may be combined in any order. Major advantages realized in the present invention are that process may be easily and conveniently scaled-up for industrial large-scale production and the process is simple, economical, high throughput and environment friendly and provides prulifloxacin in high purity. Another advantage of the invention is that it involves one pot processes for the formation of intermediate at various stages which avoid the lengthy separation process and the purification of the intermediates, and in turn save the time, resources and highly efficient to increase the yield of the desired compounds.

The purity of the prulifloxacin is more than 99%, preferably more than 99.2%, more preferably more than 99.45%.

Although, the following examples illustrate the present invention in more detail, but should not be construed as limiting the scope of the invention. EXAMPLES

Example- 1 Preparation of 3,4-difluorophenyl isothiocyanate

Method A: To a stirred solution of sodium hydroxide (0.62 kg) in water (3.1It) was added carbon disulfide (1.76 kg) at 5-10⁰C. The reaction mass was cooled to 2-5°C and 3,4- difluoroaniline (2.0 kg) was added slowly, stirred at 40-45⁰C for 24 hours. Reaction mixture was further cooled to 30-35⁰C and filtered to remove salts. To the filtrate was added slowly ethylchloroformate (1.84 kg) at 15-20⁰C. The reaction mass was stirred at 35°C for 1.5 hours and extracted with hexane. The organic layer was washed with water and concentrated under reduced pressure to obtain 2.3 kg (87 %) of title compound as oil. Method B: To a solution of 3,4-difluoroaniline (25g, 0.19mol) and triethylamine (58.75g, 0.58mol) in toluene (75ml), carbondisulfide (58.7g, 0.77 mol) was added under ice cooling. The reaction mass was stirred at 25-30⁰C for 12 hours. The resulting precipitates were filtered, washed with toluene to give 56.8 g of triethylammonium(3,4-difluorophenyl)dithiocarbamate. The resulting product was added to toluene (250ml) and trietylamine (20.98g, 0.21mol) followed by addition of ethylchloroformate (22.3g, 0.21 mol) and stirred at 0-5⁰C for 3.0 hours. Then water (180 ml) was added and organic layer was separated. The organic layer was washed with water and concentrated to dryness under reduced pressure to give 29 g (88%) of title compound having purity 89% by HPLC. Example 2: Purification of 3,4-difluorophenyl isothiocyanate 3,4-Difluorophenyl isothiocyanate (571 g ) was distilled under reduced pressure of 5 mbar at 80⁰C to afford 296 g of pure title compound having purity 98.95 % by HPLC. Example 3: Preparation of [[(3,4-Difluorophenyl)amino]-mercaptomethylene]-malonic acid diethyl ester S-potassium salt To a stirred suspension of potassium hydroxide (94.15 g) in toluene (2130 ml) was added slowly diethyl malonate (272.64 g). After stirring at room temperature for 30 minutes, 3,4- difluorophenyl isothiocyanate (213 g) was added gradually to this mixture at room temperature. The reaction mass was stirred at 25-30⁰C for one hour. After completion of the reaction, the product was filtered at 15-20⁰C, washed with hexane and dried to obtain 412 g (89.9 %) of title compound having purity 97.37 % by HPLC. Example 4: Preparation of ethyl 4-hydroxy-6,7-difluoro-2(ethylthio)quinoline -3- carboxylate

Method A: Diethyl sulfate (161.88 g) was added slowly to a stirred suspension of [(3,4- difluorophenyl)amino]mercaptomethylene]malonic acid diethyl ester S-potassium salt (434 g) in ethyl acetate (2.17 It.) at 0-5⁰C. The reaction mass was stirred for 3.5 hours at room temperature. After completion of reaction (monitored by TLC), water was added to the reaction mass and the layers were separated. The organic layer was washed with 10% solution of sodium chloride and dried over sodium sulfate and concentrated under reduced pressure to obtain 414 g (98%) of [(3,4-difluorophenyl)amino](ethylthio) methylene malonate having purity 96.85 % by HPLC. The resulting product (385g) was taken in o-xylene (2310 ml). The reaction mixture was refluxed azetropically for 3 hours. After the completion of the reaction, o-xylene was distilled off under reduced pressure. The residue was taken in hexane (1732 ml), stirred at 0-5⁰C for one hour and filtered to obtain 231g (68.8%) of the title compound having purity 97.44 % by HPLC. Method B: Diethyl sulfate (10.96g, 0.07mol) was added to a suspension of [(3,4- difluorophenyl)amino]mercaptomethylene]malonic acid diethyl ester S-potassium salt (25g, 0.068mol) in o-xylene with ice cooling and stirred for 10 hours at 35 ⁰C. Water was added to the reaction mixture and the organic layer was separated. Organic layer was refluxed for three hours. After the completion of the reaction (checked by thin layer chromatography), xylene was distilled off under reduced pressure. The residue was refluxed in methanol and cooled to 20-25⁰C and filtered to give 9.6g (46%) of title compound having purity 97.80% by HPLC. Example 5: Preparation of ethyl 4-hydroxy-6,7-difluoro-2(ethylthio)quinoline -3- carboxylate

[(3,4-Difluorophenyl)amino](ethylthio)methylene malonate (1.0 kg) was taken in o-xylene (6.0 It.). The reaction mixture was refluxed azeotropically for 4 hours. Reaction completion was checked by TLC. After the completion of the reaction, o-xylene was distilled off under reduced pressure and the residue was taken in methanol (1.5 It). The methanol was distilled off under reduced pressure to remove the traces of o-xylene. The reaction mass was cooled to 5-10⁰C, stirred for 2 hours, filtered and dried to obtain 630 g (63 %) of the title compound having purity 97.86% by HPLC. Example 6: Preparation of ethyl 6,7-difluoro-l-methyl-4-oxo-4H-(l,3)thiazeto (3,2- a)quinoline-3-carboxylate

Method A: To a stirred solution of ethyl 4-hydroxy-6,7-difluoro-2-(ethylthio)quinoline-3- carboxylate (50 gm, 0.159mol), triethylamine (19.36g, 0.192mol) in hexane (400 ml), was added acetyl chloride (38.5 g, 0.541mol) at 0-5° C. After completion of reaction, water (200ml) and dichloromethane (150 ml) was added. The layers were separated and washed with 5% solution of sodium bicarbonate and then with water. Organic layer was distilled off under reduced pressure to recover 450 ml of solvent. To the remaining solution of n-hexane, a solution of sulfuryl chloride (54.8g, 0.406mol)in n-hexane was added at reflux. Hexane was distilled off under vacuum. Tetrahydrofuran (350ml) and sodiumacetate (75.Og, 0.915mol) were added to the reaction mass and refluxed for 5 hours. Water (1.0 It) was added to the mixture to precipitate the product. The precipitates were filtered, washed with water and sucked dried. Methanol (1.0 It) was added to the resulting precipitates and refluxed for 1 hour. The mixture was cooled to rooπr temperature, filtered and dried to give 22.4g of title compound having purity 99.11% by HPLC. Method B: To a stirred solution of ethyl 4-hydroxy-6,7-difluoro-2-(ethylthio)quinoline-3- carboxylate (50 gm, 0.159mol), triethylamine (19.36g, 0.192mol) in dichloromethane (200 ml), was added acetyl chloride (15.0 g, 0.191 mol) at 0-5⁰C. After completion of reaction, water (75ml) was added followed by layer separation. The organic layer was washed with 5% solution of sodium bicarbonate and then with water. Organic layer was distilled off under reduced pressure. To the resulting residue, n-hexane and triethylamine were added and refluxed; thereafter a solution of sulfuryl chloride (54.8g, 0.406mol) in hexane was added to the reaction mixture. Hexane was distilled off under vacuum. Tetrahydrofuran (392ml) and sodiumacetate (84g, 1.02mol) were added to the reaction mass and refluxed for 5 hours. Water (1.12 It) was added to the reaction mixture to precipitate the product. The precipitates were filtered, washed with water and sucked dried. Methanol (1.12It) was added to the resulting precipitates and refluxed for 1 hour. The mixture was cooled to room temperature, filtered and dried to give 22.5g of title compound having purity 98.8% by HPLC. Example 7: Preparation of Ulifloxacin ethyl ester

Method A: Dimethylformamide (13.94 It), ethyl 6,7-difluoro-l-methyl-4-oxo-4H- (l,3)thiazeto(3,2-a)quinoline-3-carboxylate (1.39kg) and piperazine (1.39kg) were stirred at 20- 25°C for 20-22 hours. Reaction completion was checked by TLC. Water (69.5 It) was added and the reaction mixture was filtered, washed with water and dried to obtain 1.11kg of ulifloxacin ethyl ester having purity 97.47 % by HPLC.

Method B: Ethyl-6,7-difluoro- 1 -methyl -4-oxo-4H-( 1 ,3)thiazeto(3 ,2-a)quinolne-3 -carboxylate (5g) taken in acetonitrile (50 ml), piperazine (5g) was added and reaction mass was refluxed at 90-95⁰C for 1 hour. Reaction completion was checked by TLC. Reaction mass was cooled to 10⁰C, stirred for further 40-45 minutes. Thereafter the reaction mass was filtered, washed and dried to obtain 6.06 g of ulifloxacin ethyl ester having purity 96.01% by HPLC. Example 8: Preparation of Ulifloxacin

Tertiary butanol (5.55It), 6-fluoro-l-methyl-4-oxo-7-(l-piperazinyl)-4H-[l,3]thiazeto [3,2- a]quinoline-3-carboxylic acid ethyl ester (1.1 lkg), potassium hydroxide (0.37kg) and water (2.75 It) were added at room temperature. The reaction mixture was heated to 60⁰C and maintained for 1.5 hours. Reaction completion was checked by TLC. This was followed by the addition of water (22.2 It) and acetic acid (0.39 It). The reaction mixture was filtered, washed with water followed by slurry wash with acetone (2.22 It) twice and dried to obtain 0.95 kg of ulifloxacin having purity 97.56% by HPLC. Example 9: Preparation of 4-bromomethyl-5-methyl-l,3-dioxolen-2-one:

Dimethylformamide (0.3It), 4-chloromethyl-5-methyl-l,3-dioxolen-2-one (0.14 kg) and sodium bromide (0.19kg) were stirred for one hour at room temperature. Acetone (1.5It) was added to the mixture and stirred for another one hour at room temperature. The reaction mixture was filtered and washed with acetone. Filtrate was concentrated under reduced pressure to obtain the title compound as oil.

Example 10: Preparation of prulifloxacin hydrochloride

Method A: To the mixture of dimethylformamide (1.5 It) and 6-fluoro-l-methyl-4-oxo-7-(l- piperazinyl)-lH,4H-[l,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (0.3kg), 4-bromomethyl-5- methyl- 1, 3 -dioxolen-2-one, obtained above was added and cooled to 0-5⁰C. Triethylamine (0.87kg) in dimethylformamide (0.3 It) was added slowly in 1-2 hours. After completion of the reaction (monitored by TLC), dichloromethane (3.0 It) and water (1.5 It) were added to the reaction mixture. The layers were separated and aqueous layer was extracted twice with dichloromethane (1.5 It). All organic layers were combined, dried over sodium sulfate followed by distillation. Methanolic hydrochloride (20-25 % w/w, 0.24 It) was added to organic layer at 0- 5°C and stirred. The solid, thus precipitated out was filtered, washed with dichloromethane and dried to obtain 0.36kg of the title compound having purity 92.73 % by HPLC. Method B: To the mixture of dimethylformamide (125 ml), 6-fluoro-l-methyl-4-oxo-7-(l- piperazinyl)-lH,4H-[l,3-]thiazeto[3,2-a]quinoline-3-carboxylic acid (25g), 4-bromomethyl-5- methyl-l,3-dioxolen-2-one, obtained above was cooled to 0-5⁰C. Triethylamine (8g, 0.08mol) in dimethylformamide (25.0ml) was added to the reaction mixture. Thereafter dichloromethane (250ml) followed by water was added. The layers were separated and aqueous layer was extracted twice with dichloromethane (125 ml). The combined organic layer was dried over sodium sulfate followed by distillation. 20-25 % w/w DMF. HCl (25ml) was added to the resulting residue at 0-5⁰C, filtered, washed with dimethylformamide (12.5ml) followed by methanol (50 ml) and dried to give 33.0g of the title compound having purity 90.3% by HPLC. Example 11: Purification of prulifloxacin hydrochloride

Dimethylformamide (1.34 It) was added to prulifloxacin hydrochloride (67g) and reaction mass was heated to 110-112°C for 1 hour. The reaction mixture was cooled to 25-30⁰C and stirred for 2 hours, filtered, washed with N,iV-dimethylforamide. The product was slurry washed with isopropanol (0.670 It) and dried to obtain 48.8g of title compound having purity 99.30 % by HPLC.

Example 12: Preparation of prulifloxacin Method A: Dichloromethane (1.4It) was added to prulifloxacin hydrochloride (14Og) and the mixture was cooled to 0-5⁰C. Triethylamine (284g) was added to the reaction mixture at 0-5⁰C with slow stirring for 1.5 hours. The reaction mixture was filtered, washed with demineralized water and isopropyl alcohol, and then dried to obtain 99g of title compound having purity 99.35

% by HPLC.

Method B: Demineralized water (10ml) was added to prulifloxacin hydrochloride (1 g) and the reaction mass was cooled to 0-5 ⁰C, 10% liquid ammonia solution was added to achieve the pH-

7. Reaction mass was stirred for 1 hour, filtered, washed with demineralized water and dried to obtain 0.98 g of the title compound having purity 98.05% by HPLC.

Method C: Dichloromethane and methanol (10:1,100ml) were added to prulifloxacin hydrochloride (1Og) and the reaction mixture was cooled to 0-5⁰C. Triethylamine (2.03g) was added to the reaction mixture at 0-5⁰C and slowly stirred for 1.5 hours. The reaction mixture was filtered, washed with water and isopropyl alcohol, and then dried to obtain 6g of the title compound having purity 99.48 % by HPLC.

Method D; Dimethylformamide (100ml) was added to prulifloxacin hydrochloride (1Og) and the mixture was cooled to 0-5⁰C. Triethylamine (2.03g) was added to the reaction mixture at 0-5⁰C and slowly stirred for 1.5 hours. The reaction mixture was filtered, washed with water and isopropyl alcohol, and then dried to obtain 6.3g of the title compound having purity 99.24% by

HPLC.

Method E: Chloroform and methanol [10:1,100ml) were added to prulifloxacin hydrochloride

(1Og) and cooled to 0-5⁰C. Triethylamine (2.03 g) was added to the reaction mixture at 0-5⁰C and slowly stirred for 1.5 hours. The reaction mixture was filtered, washed with water and isopropyl alcohol, and then dried to obtain 5.8g of title compound having purity 99.37% by HPLC.

Method F: Acetone (150ml) was added to prulifloxacin hydrochloride (30 g) and the reaction mixture was cooled to 0-5⁰C. Solution of sodium bicarbonate (2% solution) was added to the reaction mixture. The precipitated product was filtered, washed with water. The precipitates were refluxed with acetone and cooled to 20-25 ⁰C. The mixture was filtered to give 25 g of title compound having purity 93.73% by HPLC.

Example 13: Purification of Prulifloxacin

Prulifloxacin (15g, 93.73% purity by HPLC) in dimethylformamide (13.5 ml) was heated to 110 to 115 ⁰C for 1 hour and cooled to 20- 25 ⁰C. The mixture was stirred for 2 hours, filtered and washed with dimethylformamide and isopropyl alcohol to give 12.27 g of the title compound having purity 98.46% by HPLC. Above compound was further purified in dimethylformamide

(9.0 ml) in the same way to obtain give 8.5 g of the title compound having purity 99.55% by

HPLC.

Claims

WE CLAIM:

1). A process for the preparation of prulifloxacin of formula I, which comprises:

Formula I

(a) reacting 3,4-difluoroaniline with carbon disulfide in the presence of a suitable base followed by reaction with ethyl chloroformate to obtain 3,4-difluorophenyl isothiocyanate;

(c) treating 3,4-difluorophenyl isothiocyanate with diethyl malonate in the presence of a base in a solvent to form [[(3,4-difluorophenyl)amino]-mercaptomethylene]-malonic acid diethyl ester S-potassium salt of formula IV;

Formula IV

(d) alkylating compound of formula IV with diethyl sulfate in an organic solvent to form

[(3,4-difluorophenyl)amino] (ethylthio)methylenemalonate of formula V;

Formula V

(e) cyclizing compound of formula V in situ by refluxing the reaction mixture to form ethyl 4-hydroxy-6,7-difluoro-2-(ethylthio)quinoline-3-carboxylate of formula VI ;

Formula VI

(f) acylating compound of formula VI in the presence of a suitable reagent like acetyl halide or acetic anhydride and a base in a solvent to obtain ethyl 4-acetoxy-6,7-difluoro-2-

(ethylthio)quinoline-3-carboxylate of formula VII;

Formula VII

(g) treating compound of formula VII in situ with chlorinating agent like chlorosuccinimide, sulfuryl chloride in the presence of a suitable solvent to form a compound of formula VIII;

Formula VIII

(h) treating compound of formula VIII in situ with alkali metal acetate in the presence of a solvent to form ethyl 6,7-difluoro-l-methyl-4-oxo-4H-(l,3)thiazeto(3,2-a)quinoline-3- carboxylate of formula IX;

Formula IX

Formula X

(j) hydrolysing ulifloxacin ethyl ester of formula X using an acid or a base in the presence of a suitable solvent like Cj_-4 alcohols, water and mixture thereof to obtain ulifloxacin of formula II; (k) optionally purifying ulifloxacin of formula II by slurry washing with a suitable solvent;

(1) condensing ulifloxacin of formula II,

Formula II with 4-halomethyl-5-methyl- 1 ,3-dioxolen-2-one of formula III

O_VCH₃ o=< T _γ

O"^~^x Formula HI wherein X is halo selected from chloro, bromo or iodo in the presence of a suitable base;

(m) treating the resulting reaction mass with an acid to obtain prulifloxacin acid addition salt;

(n) optionally purifying prulifloxacin acid addition salt with an organic solvent;

(o) hydrolysing prulifloxacin acid addition salt in the presence of a base in a suitable solvent; and (p) isolating prulifloxacin from the reaction mixture. 2). The process according to claim 1 , wherein in step a) suitable base includes organic base such as trialkylamine or inorganic base such as alkali or alkaline metal hydroxides, carbonates, bicarbonates, hydrides or alkoxide thereof.

3). The process according to claim 1, wherein in step c) base is organic or inorganic base selected from trialkylamine, alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxides and hydrides thereof.

4). The process according to claim 1, wherein in step c) solvent includes aliphatic or aromatic hydrocarbon such as toluene; amide solvents such as dimethylformamide, N- methylpyrrolidone; sulfoxide solvents such as dimethylsulfoxide; nitrile solvent such as acetonitrile or mixture thereof.

5). The process, according to claim 1, wherein in step d) organic solvent includes aliphatic or aromatic hydrocarbon such as toluene, xylene, paraffin oil; esters such as ethyl acetate; ether such as diphenyl ether and the like or mixture thereof.

6). The process according to claim 1 , wherein in step f) base includes organic or inorganic base selected from trialkylamine, alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxides and hydrides thereof.

7). The process according to claim 1, wherein in step f) solvent includes halogenated solvent such as dichloromethane, chloroform; aliphatic or aromatic hydrocarbon such as hexane or mixture thereof. 8). The process according to claim 1, wherein in step g) suitable solvent includes halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride; aliphatic or aromatic hydrocarbon such as n-hexane or mixture thereof.

9). The process according to claim 1, wherein in step h) solvent includes ketone such as acetone; nitrile such as acetonitrile; aliphatic or aromatic solvent such as hexane; ether such as isopropyl ether, tetrahydrofuran; ester such as ethylacetate; halogenated solvent such as chloroform and the like or mixture thereof.

10). The process according to claim 1, wherein in step i) suitable solvent includes amide solvents such as dimethylformamide, dimethylacetamide; nitrile solvent such as acetonitrile; ketone such as acetone; sulfoxide solvent such as dimethylsulfoxide; sulfolane; aprotic solvents or mixture thereof.

11). The process according to claim 1, wherein in step k) a suitable solvent includes water, alcohols like methanol, ethanol, isopropanol; ketones such as acetone or mixtures thereof. 12). The process according to claim 1, wherein in step 1) base is inorganic base that includes alkali metal or alkaline metal hydroxides, hydrides, carbonates, bicarbonate or alkoxide thereof such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, JV,7V-diisopropyl ethylamine, sodium acetate or organic base such as trialkylamine. 13). The process according to claim 1, wherein in step m), an acid includes inorganic acid such hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid; organic acid such as formic acid, acetic acid, tartaric acid, lactic acid, oxalic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, and the like. 14). The process according to claim 1, wherein in step n) an organic solvent includes amide solvents such as dimethylformamide, 7V-methylpyrrolidone; sulfoxide solvents such as dimethylsulfoxide, nitrile solvent such as acetonitrile; halogenated solvents such as chloroform; alcoholic solvents such as methanol, the like and/or mixtures thereof; 15). The process according to claim 1, wherein in step o) base includes organic or inorganic base such as trialkylamine, ammonia, alkali or alkaline metal hydroxide, carbonates, bicarbonate, hydride or alkoxide thereof. 16). The process according to claim 1, wherein in step o) solvent includes water; alcohols such as methanol, ethanol, isopropanol, butanol, tert.-butanol; halogenated solvent such as dichloromethane, chloroform; ketones such as acetone; amide solvents such as N,N- dimethylformamide, dimethylacetamide; sulfoxide solvents such as dimethylsulfoxide; nitrile solvents such as acetonitrile, ethers such as isopropyl ether; or mixtures thereof. 17). A process for the preparation of prulifloxacin of formula I,

(b) treating the resulting reaction mass with an acid to obtain prulifloxacin acid addition salt; (c) optionally purifying prulifloxacin acid addition salt with an organic solvent;

(d) hydrolysing prulifloxacin acid addition salt in presence of base in a suitable solvent; and

(e) isolating prulifloxacin from the reaction mixture.

18).The process according to claim 17, wherein in step a), base is inorganic base that includes alkali metal or alkaline metal hydroxides, hydrides, carbonates, bicarbonate or alkoxide thereof such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate; or organic base such as trialkylamine, N.iV-diisopropyl ethylamine.

19). The process according to claim 17, wherein in step b), an acid includes inorganic acid such hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid; organic acid such as formic acid, acetic acid, tartaric acid, lactic acid, oxalic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid; and the like. 20).The process according to claim 17, wherein in step c) an organic solvent includes amide solvents such as dimethylformamide, N-methylpyrrolidone; sulfoxide solvents such as dimethylsulfoxide, nitrile solvent such as acetonitrile; halogenated solvents such as chloroform; alcoholic solvents such as methanol, the like and/or mixtures thereof; 21). The process according to claim 17, wherein in step d) base includes organic or inorganic base such as trialkylamine, ammonia, alkali or alkaline metal hydroxide, carbonates, bicarbonate, hydride or alkoxide thereof. 22). The process according to claim 17, wherein in step d) solvent includes water; alcohols such as methanol, ethanol, isopropanol, butanol, tert.-butanol; halogenated solvent such as dichloromethane, chloroform; ketones such as acetone; amide solvents such as N, N- dimethylformamide, dimethylacetamide; sulfoxide solvents such as dimethylsulfoxide; nitrile solvents such as acetonitrile, ethers such as isopropyl ether; or mixtures thereof. 23). A process for the purification of prulifloxacin acid addition salt comprises: a) suspending prulifloxacin acid addition salt in a suitable solvent; b) cooling the reaction mixture; and c) isolating highly pure prulifloxacin acid addition salt.

24).The process according to claim 23, wherein in step a) a suitable solvent includes amide solvents, sulfoxide solvents, nitrile solvent, halogenated solvents, alcoholic solvents or mixtures thereof.

25). The process according to claim 23, wherein in step a) a suitable solvent is dimethylformamide, 7V-methylpyrrolidone, dimethylsulfoxide, acetonitrile, chloroform, methanol or mixtures thereof. 26). A process for the preparation of highly pure prulifloxacin which comprises: a) hydrolyzing prulifloxacin acid addition salt with a base in the presence of a solvent; and b) isolating prulifloxacin there from.

27).The process according to claim 26, wherein base includes organic or inorganic base such as trialkylamine, ammonia, alkali or alkaline metal hydroxide, carbonates, bicarbonate, hydride or alkoxide thereof.

28). The process according to claim 26, wherein solvent includes water, alcohols, halogenated solvent, ketones, amide solvents, sulfoxide solvents, nitrile , ethers; or mixtures thereof. 29).The process according to claim 26, wherein solvent is water, methanol, ethanol, isopropanol, butanol, tert.-butanol, dichloromethane, chloroform, acetone, JV.TV-dimethylformamide, dimethylacetamide, acetonitrile, isopropyl ether, dimethylsulfoxide or mixture thereof.