HELD 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,.
(FormulaRemoved)


The present invention also 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-dioxolcn-4-yl)mcthyl-l-piperazinyl]-4-oxo-4H-[l,3]thiazeto[3,2-a]quinoline-3-carboxylic acid, of formula I,

(FormulaRemoved)



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-pipcrazinyI)-4H-[l,3]thia/.eto[3,2-a]quinoline-3-carboxylic acid.
(FormulaRemoved)

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-bromomethyl-5-methyl-l,3-dioxolen-2-one in the presence or absence of aprotic solvent and a base to obtain prulifloxacin free base which is recrystallized with chloroform-methanol. Ulifloxacin is prepared by starting from 3,4-difluoroaniline. In an exemplified process, 3,4-difluoroaniline is treated with carbon disulfide in the presence of triethylamine to obtain a salt of (3.4-difluorophenyl)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-difiuorophenylamino)-l-(methoxymethylthio)-methylenemalonatc which is further purified with column chromatography and then cyclised to give ethyl 6,7-dinuoro-4-hydroxy-2-methoxymelhylthioquinoline-3-carboxylale. The resulting product is treated with concentrated hydrochloric acid to hydrolysc the mercaptyl protecting group followed by reaction with ethylidene bromide in the presence of potassium carbonate, potassium iodide and dimethylformamidc 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 ulifioxacin.

The above process involves the use of harmful reagents like methoxymethyl chloride and 1,4-dioxane. 1,4-Dioxane combines with atmospheric oxygen on standing to form explosive peroxides. Also. 1,4-dioxane is an expensive and toxic solvent as it forms contamination plumes in groundwater when released to the environment. Prior art processes also teach the use of expensive and commercially unavailable reagent like ethylidene bromide and technically arduous purification technique like column chromatography at several stages that makes the process unattractive on industrial point of view. Also the prior art process results in the formation of prulifloxacin 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-mcthyl-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 pipcrazine. 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, environmentally benign and amenable process for the preparation of prulifloxacin at industrial scale.
Accordingly, the 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. The process may be easily and

conveniently feasible for industrial scale production without using column chromatography, hence the use of organic solvents is minimized.
SUMMARY OF THE INVENTION
The present invention provides an improved process of the preparation of prulifioxacin of formula I, or its pharmaceutically acceptable salts, (FormulaRemoved)

which comprises, condensing ulifloxacin of formula II
(FormulaRemoved)
with 4-halomethyl-5-methyl-l,3-dioxolen-2-one of formula III
(FormulaRemoved)
where in X is halo selected from chloro, bromo or iodo in the presence of suitable base and polar aprotic solvent;
treating the resulting reaction mass with suitable acid to obtain prulifloxacin acid addition salt;

optionally purifying prulifloxacin acid addition salt with a suitable organic solvent;
hydrolysing prulifloxacin acid addition salt with a base in the presence of a suitable solvent and
isolating prulifloxacin.
According to another embodiment, the present invention provides a process for the purification of prulifloxacin acid addition salt.
DETAILED DESCRIPTION OF THE INVENTION
The process of this invention is an improved and efficient process for the preparation of highly pure prulifloxacin of formula I
(FormulaRemoved)


One embodiment of the present invention provides a process for the preparation of prulifloxacin by reacting ulifloxacin of formula II,
(FormulaRemoved)


with 4-halomethyl-5-methyl-l,3-dioxolen-2-one of formula III.
(FormulaRemoved)

wherein X is halo selected from chloro, bromo or iodo
Ulifloxacin of formula II can be prepared by conventional procedures reported in prior art such as U.S. patent nos. 4,426,381; 4,843,070; 5,086,049; Journal of Medicinal Chemistry 1992, 35, 4727-4738; Journal of Heterocyclic Chemistry 34, 1773 (1997). However some improvements are made in the prior processes to make it industrially applicable and environment friendly which are described herein for reference. However, specific illustrations of processes are described in the Examples section that follows.
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 halogcnating agent.
Specifically, ulifloxacin of formula II can be prepared starting from 3,4-difluoroaniline and reacting the same with carbon disulfide in the presence of suitable base in suitable solvent to obtain triethylammonium-(3,4-difluorophenyl)dithiocarbamate. Base may be selected from triethylamine, and the like. Solvent may be selected from hexane, isopropyl ether, dichloromcthane, chloroform, the like or mixtures thereof. The reaction can also be performed in the absence of solvent.
Trielhylammonium-(3.4-difluorophenyl)dithiocarbamate is then treated with ethylchloroformate at a temperature of below 5°C to obtain 3,4-difluorophenyl isothiocyanatc. The resulting product can be 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 98% by HPLC.
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 inorganic base in the absence of any organic solvent. Typically, inorganic bases include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like. In particular, the base used is sodium hydroxide. 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 added slowly to an aqueous solution of inorganic base along with carbon disulfide at a temperature of 0-10°C. The reaction mass is then stirred at a temperature of 35-55°C for 10-30 hours. The reaction mixture is then cooled to a temperature of 20-35°C and filtered to remove salts. Ethylchloroformate is added slowly to the filtrate at a temperature of 10-20°C and stirred at 35°C for few hours and extracted with hexane. The organic layer is washed with water to isolate 3,4-difluorophenyl isothiocyanate. Preferably, the product is isolated by concentration under reduced pressure.
3,4-Difluorophenyl isothiocyanate so formed is then reacted with diethyl malonate in the presence of base preferably potassium hydroxide in an organic solvent to obtain [[(3,4-difluorophenyl)amino]-mercaptomethylene]-malonic acid diethyl ester S-potassium salt of formula IV.
(FormulaRemoved)
Organic solvent can be selected from toluene, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile and the like. 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.

Compound of formula IV is treated with diethyl sulfate to form [(3,4-difluorophenyl)amino[(ethylthio)methylenemalonate of formula V.
(FormulaRemoved)
Specifically, compound of formula IV is treated with diethyl sulfate in an organic solvent preferably ethyl acetate, at a temperature of about 0 to 5°C. The reaction mass is further stirred for 2-5 hours, preferably till reaction completion at ambient temperature. After completion of reaction, the reaction mass is diluted with water and layers are separated. The organic layer is washed with brine and dried over sodium sulfate and concentrated under reduced pressure to afford compound of formula V in high yield and purity greater than 95% by HPLC.
Use of ethyl acetate as solvent in the above reaction makes the work up very easy and increases the yield and purity of the resulting product. Ft is easily recoverable as compared to water miscible ethanol described in prior art.
Compound of formula V is further cyclized to ethyl 4-hydroxy-6,7-difluoro-2-(ethylthio)quinoline-3-carboxylate of formula VI in a solvent like xylene, diphenyl ether, paraffin oil and the like.
(FormulaRemoved)
Preferably o-xylene is used and the reaction mixture is refluxed azeotropically for 2-10 hours. After completion of the reaction, xylene is distilled out. The traces of xylene, if present in the reaction mass can be removed by distillation using suitable solvent like methanol. hexane and the like. During the reaction ethanol is formed as by product. It is necessary to eliminate ethanol from the reaction mixture to accomplish completion of the reaction, which is achieved by a/eotropic

distillation. This makes the process efficient for the large scale production and results in high yield of the product.
4-Hydroxy compound of formula VI is further acylated in the presence of suitable reagent like acetyl chloride in the presence of base like triethylamine in a halogenated solvent like dichloromethane, chloroform and the like to obtain ethyl 4-acetoxy-6,7-difluoro-2-(ethylthio)quinoline-3-carboxylate of formula VII.
(FormulaRemoved)

The reaction is conducted at a temperature of about -5 to 10 °C and progress of the reaction is monitored by TLC. The product can optionally be purified in hexane or alcoholic solvent like isopropyl alcohol or used as such in the next step.
4-Acetoxy compound of formula VII is further treated with sulfuryl chloride in the presence of suitable solvent like n-hexane, carbon tetrachloridc and the like preferably at reflux temperature of the solvent. A part or whole of solvent is distilled off to form a compound of formula VIII.
(FormulaRemoved)
The compound of formula VIII can optionally be isolated. But it is advantageous not to isolate the intermediate compounds, as it lowers the processing time and the resulting product is achieved in high yield.
The compound of formula VIII is further treated with alkali metal acetate preferably sodium acetate in the presence of solvent like tetrahydrofuran at reflux temperature of the solvent and it takes about 1-10 hours for completion of reaction. Thereafter, the reaction mixture is diluted with water to precipitate ethyl

6,7-difluoro-l-methyl-4-oxo-4H-(l,3)thiazeto(3,2-a)quinoline-3-carboxylate of formula IX

(FormulaRemoved)

(l,3)Thiazeto compound of formula IX can further be purified to remove unwanted impurities using alcoholic solvent like methanol, ethanol, isopropanol and the like or used as such in the next step.
(l,3)Thiazeto compound of formula IX is condensed with piperazine in suitable solvent at ambient temperature to obtain ulifloxacin ethyl ester of formula X

(FormulaRemoved)

Suitable solvent can be selected from dimethylformamide, acetonitrile, acetone and the like. Reaction is preferably conducted for a period of about 10-20 hours, preferably till reaction completion. This is followed by the dilution of reaction mixture by addition of water that results in the precipitation of ulifloxacin ethyl ester which is isolated by filtration.
Ulifloxacin ethyl ester of formula X is further hydrolysed with suitable base like alkali metal hydroxide in the presence of suitable solvent to obtain ulifloxacin of formula II. Solvent can be selected from C|.4 alcohols, water and mixture thereof. Reaction is preferably conducted at a temperature of about ambient temperature to 100°C and it takes about 1-10 hours for complete hydrolysis. After completion of reaction, the reaction mixture is neutralized using dilute acid such as acetic acid and thereafter ulifloxacin is isolated. Ulifloxacin can further be purified by slurry

wash with an organic solvent. Solvent can he selected from alcohols like methanol, ethanol, isopropanol; ketones such as acetone or mixtures thereof with water.
The order and manner of combining the reactants at any stage of the process arc 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.
The conversion of ulifloxacin to pure prulifloxacin represents the inventive part of the present invention. Generally, ulifloxacin of formula II is condensed with 4-halomcthyl-5-methyl-l,3-dioxolen-2-onc of formula III,
(FormulaRemoved)
wherein X is halo selected from chloro, bromo or iodo
in the presence of suitable base and polar aprotic solvent followed by treatment with suitable acid to obtain prulifloxacin acid addition salt, which is then hydrolysed in the presence of base to yield pure prulifloxacin.
Suitable base during condensation can be selected from metal carbonates and bicarbonatcs like sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and organic bases like triethylamine, N,N-diisopropylethylamine, sodium acetate and the like. Polar aprotic solvent can be selected from /V.jV-dimethylformamide, jV-methylpyrrolidone, dimcthylsulfoxidc, ethers such as diglyme, monoglyme and the like. Alternatively, the reaction can be performed in the absence of solvent also. The reaction time may vary depending upon the amount of starting material, type of solvent and base used and reaction temperature.

Suitable acid addition salts which may be formed include 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 include inorganic acids such 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, bcnzencsulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, and the like. Preferred pharmaceutically acceptable acid addition salts include 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.
Typically, 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 triethylaminc in dimethylformamide at a temperature of about -10 to 10°C. 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 twice with dichloromethane. All organic layers are combined and dried over sodium sulfatc. Optionally the organic layer can be concentrated or the organic layer as such is treated with suitable acid to prepare corresponding acid addition salt. Specifically to the organic layer desired acid is added at a temperature of about -10 to 10°C, preferably till the pH of the reaction mass is about 0.5-1.5 to prepare prulifioxacin acid addition salt. Generally, 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.
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 selected from dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile, chloroform, methanol, the like and/or mixtures thereof, at a temperature of about 40°C to reflux temperature of the solvent, more preferably at a temperature of 100-140°C. 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 99.3% by high performance liquid chromatography (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.
After purification, highly pure prulifloxacin acid addition salt 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, metal bicarbonate 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 and the like; halogenated solvent such as dichloromethane, chloroform, the like and mixtures thereof. 'I'hc 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%. 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 like chloroform, methanol, dimethylformamide, dimethylsulfoxide, dimethylacetamide, acetonitrile. the like and 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.
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.
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-l Preparation of 3,4-difluorophenyl isothiocyanate
Method A
(i) Preparation of triethylammoiiium(3,4-difluorophenyl)dithiocarbamate
To a stirred solution of 3,4-difluoroaniline (1.0 kg) and triethylamine (0.94 kg) in hexane (3 It), was added carbon disulfide (0.71 kg) under cooling. The reaction mass was stirred at 25-30°C for 12 hours. After completion of reaction (monitored by TLC), the resulting product was filtered, washed with hexane to obtain 2.35 kg of the title compound as a yellow colored powder.
(ii) Preparation of 3,4-difluorophenyl isothiocyanatc
Triethylaimmonium-(3,4-difluorophenyl)dithiocarbamate (2.35 kg) was taken in dichloromethane (10 It) and triethylamine (0.94 kg). To the resulting suspension was added ethylchloroformate (1 kg) with stirring at 0-5°C for 3 hours. After completion of reaction (monitored by TLC), water (6 It) was added and layers were separated. The organic layer was washed with water and concentrated under reduced pressure to obtain 1.2 kg of the title compound as oil.

Method B
To a stirred solution of sodium hydroxide (0.62 kg) in water (3.lit) was added carbon disulfide (1.76 kg) at 5-10°C. The reaction mass was cooled to 2-5°C and 3,4-difluoroaniline (2.0 kg) was added slowly, stirred at 40-45°C for 24 hours. Reaction mixture was further cooled to 30-35°C and filtered to remove salts. To the filtrate was added slowly ethylchloroformate (1.84 kg) at I5-20"C. 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.
Example 2: Purification of 3,4-difluorophenyl isothiocyanatc
3,4-Difluorophenyl isothiocyanate (571 g ) was distilled under reduced pressure of 5 mbar at 80"C to afford 296 g of pure title compound having purity 98.95 % by HPLC.
Example 3: Preparation of [[(3,4-Difluorophenyl)amino|-
mercaptomcthylcncj-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 25-30°C for one hour. After completion of the reaction, the product was filtered at 15-20T, washed with hexane and dried to obtain 412 g (89.9 %) of title compound having purity 97.37% by 11PLC.
Example 4: Preparation of[(3,4-difluorophenyl)amino](cthylthio)methylcnc malonate.
Diethyl sulfatc (161.88 g) was added slowly to a stirred suspension of [(3,4-difluorophenyl)ainino]mercaptomethylene]malonic acid diethyl ester S-potassium salt (434 g) in ethyl acetate (2.17 It.) at 0-5°C. 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 the title compound having purity 96.85 % by HPLC.
Example 5: Preparation of ethyl 4-hydroxy-6,7-difluoro-2(ethylthio)quinoline -3-carboxylatc
Method A
[(3,4-Difluorophenyl)aminol(ethylthio)methylenc malonate (385g) was taken in o-xylene (2310 ml). The reaction mixture was refluxed azeotropically 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 0-5°C for one hour and filtered to obtain 23 Ig (68.8%) of the title compound having purity 97.44 % by HPLC.
Method B
f(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 5-10°C, 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 4-acetoxy-6,7-difluoro-2-(ethylthio)quinoline -3-carboxylate
To a solution of ethyl 4-hydroxy-6,7-difluoro-2-(ethylthio)quinoIine-3-carboxylate (230g), triethylamine (329.26g) in dichloromethane (1840 ml) was added acetyl chloride (177.1 g ) slowly at 0-5°C and stirred. After completion of reaction, water (345ml) was added and the layers were separated. Organic layer was washed with 5% solution of sodium bicarbonate and then with water. Dichloromethane was distilled off under reduced pressure. The residue was taken

in isopropyl alcohol (920 ml), filtered, washed with isopropyl alcohol and dried to obtain 203.9g (80%) of ethyl 4-acetoxy-6,7-difluoro-2-(ethylthio)qiiinolinc -3-carboxylate having purity 98.59 % by HPLC.
Example 7: Preparation of ethyl 4-acetoxy-6,7-difluoro-2-(ethylthio)quinoline -3-carboxylate
To a solution of ethyl 4-hydroxy-6,7-difluoro-2-(ethylthio)quinoline-3-carboxylate (1.0kg), triethylamine (1.43 kg) in dichloromethane (8.0 It.) was added acetyl chloride (0.77 kg,) slowly at 0-5°C. Reaction completion was checked by TLC. After completion of reaction, water (l.5lt.) was added and organic layer was separated. Organic layer was washed with 5% solution of sodium bicarbonate and then with water. Dichloromethane was distilled off under reduced pressure. The residue was taken in isopropyl alcohol (4.01t.), filtered, washed with isopropyl alcohol and dried to obtain 1.05 kg (93%) of ethyl 4-acetoxy-6,7-difluoro-2-(ethylthio)quinoline -3-carboxylate having purity 99.07 % by HPLC.
Example 8: Preparation of ethyl 6,7-difluoro-l-methyl-4-oxo-4H-(l,3)thia/eto (3,2-a)quinoline-3-carboxylate
n-Hexane (10 It) and ethyl 4-acetoxy-6,7-difluoro-2-(ethylthio)-quinoline-3-carboxylate (1.0kg) were refluxed. A solution of sulfuryl chloride (0.84kg) in n-hexane (2 It) was added slowly to the reaction mass while refluxing. Reaction completion was checked by TLC. The solvent was distilled off under vacuum followed by the addition of tctrahydrofuran (7 It) and sodium acetate (1.5kg) to the above residue. The reaction mass was refluxed for 5 hours. Reaction completion was checked by TLC. To the above reaction mixture water (20 It) was added. The precipitated product was filtered, washed with water and suck dried. Wet product was refluxed with methanol (20 It) for one hour, cooled to room temperature, filtered and dried to obtain 0.47kg of ethyl 6,7-difluoro-l-methyl-4-oxo-4H-(l,3)thiazeto (3,2-a)quinoline-3-carboxylate having purity 98.26% by HPLC.

Example 9: Preparation of 6-fluoro-l-methyl-4-oxo-7-(l-piperazinyl)-4H-[1,3] thiazeto[3,2-alquinoline-3-carboxylic acid ethyl ester (Ulifloxacin ethyl ester)
Method A
Dimethyl formamide (13.94 It), ethyl 6,7-difluorol-methyl-4-oxo-4ll-(L3)thiazeto(3,2-a)quinoline-3-carboxylate (1.39kg) and pipera/ine (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 l.llkg 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-earboxylate (5g) taken in acetonitrile (50 ml), piperazine (5g) was added and reaction mass was re fluxed at 90-95"C for 1 hour. Reaction completion was checked by TLC. Reaction mass was cooled to 10°C, stirred for futher 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 10: Preparation of 6-fluoro-l-methyl-4-oxo-7-(l-piperazinyl)-4II-[l,3]thiazeto[3,2a|quinoline-3-carboxylic acid (Ulifloxacin)
Tertiary butanol (5.55lt), 6-fluoro-l-methyl-4-oxo-7-(l-piperazinyl)-4H-[l,3]thiazeto [3,2-a]quinoline-3-carboxylic acid ethyl ester (l.llkg), potassium hydroxide (0.37kg) and water (2.75 It) were added at room temperature. The reaction mixture was heated to 60°C 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 6-fluoro-l-methyl-4-oxo-7-(l-piperazinyl)-4H-[l,3]thia/eto[3,2a] quinoline-3-carboxylic acid (ulifloxacin) having purity 97.56% by HPLC.

Example 11: Preparation of crude prulifloxacin hydrochloride. (i) Preparation ot'4-bromomethyl-5-methyl-l,3-dioxolen-2-one:
Dimethylformarnide (0.31t), 4-chloromethyl-5-methyl-l,3-dioxolcn-2-onc (0.14kg) and sodium bromide (0.19 kg) were stirred for one hour at room temperature. Acetone (1.5 It) was added to the above 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.
(ii) Preparation of prulifloxacin hydrochloride
To the mixture of dimelhylforamide (1.5 It) and 6-fluoro-l-mcthyl-4-oxo-7-(l-piperazinyl)-lH,4H-[l,3]|thiazetof3,2-a|quinoline-3-carboxylic acid (0.3kg), 4-bromomethyl-5-methyl-l,3-dioxolen-2-one, obtained above was added and cooled to 0-5°C. 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. 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 crude title compound having purity 92.73 % by HPLC.
Example 12: Purification of prulifloxacin hydrochloride
Dimethylformamide (1.34 It) was added to prulifloxacin hydrochloride (67g) and the reaction mass was heated to 110-112°C for 1 hour. The reaction mixture was cooled to 25-30°C and stirred for 2 hours, filtered, washed with N,N-dimethylforamide. The product was slurry washed with isopropyl alcohol (0.670 It) and dried to obtain 48.8g of prulifloxacin hydrochloride having purity 99.30 % by HPLC.

Example 13: Preparation of prulifloxacin Method A
Dichloromethane (1.4 It) was added to prulifloxacin hydrochloride (14()g) and the reaction mixture was cooled to 0-5°C. Triethylamine (284g) was added to the reaction mixture at 0-5°C 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 (10 ml) was added to prulifloxacin hydrochloride (I g) and the reaction mass was cooled to 0-5 °C, 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 (10g) and the reaction mixture was cooled to 0-5°C. Triethylamine (2.03g) was added to the reaction mixture at 0-5°C 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 1)
Dimethylformamidc (100ml) was added to prulifloxacin hydrochloride (lOg) and reaction mixture was cooled to 0-5°C. Triethylamine (2.03g) was added to the reaction mixture at 0-5°C 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 hydrochloridc (l0g) and the reaction mixture was cooled to 0-5°C. Triethylamine (2.03g) was added to the reaction mixture at 0-5°C 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.
Example 14: Purification of Prulifloxacin
Chloroform and methanol (10:1, 10 ml) were added to prulifloxacin (0.9 g, 98.05% purity by HPLC), refluxed for 30 minutes at 75-80°C. The reaction mass was cooled to 25-30°C, stirred for 10-15 minutes, filtered and washed with chloroform: methanol (10:1, 10 ml), to obtain 0.9 g (wet) of the title compound having purity 99.05% by HPLC. Above compound was further purified in chloroform: methanol (10:1, 10 ml) in the same way to obtain 0.7 g of the title compound having purity 99.27% by HPLC.

WE CLAIM:
1. A process for the preparation of prulifloxacin of formula I,
(Formula Removed)

which comprises:
a) condensing ulifloxacin of formula II,
(Formula Removed)

with 4-halomethyl-5methyl-l,3-dioxolcn-2-one of formula III,
(Formula Removed)

wherein X is halo selected from chloro, bromo or iodo in the presence of suitable base and polar aprotic solvent,
b) treating the resulting reaction mass with suitable acid to obtain prulifloxacin
acid addition salt,
c) optionally purifying prulifloxacin acid addition salt with a suitable organic
solvent;
d) hydrolysing prulifloxacin acid addition salt with a base in the presence of a
suitable solvent, and
c) isolating prulifloxacin.

2. The process according to claim 1, wherein in step a) base is selected from
sodium carbonate, potassium carbonate, sodium bicarbonate, potassium
bicarbonate and triethylamine, N,Ndiisopropylethylamine, sodium acetate and
solvent is selected from N,N-dimethylformamide, N-mcthylpyrrolidone,
dimethylsulfoxide, ethers such as diglyme, monoglyme.
3. The process according to claim 1, wherein in step b), acid is selected from
inorganic acids such 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, ethancsulfonic acid,
ben/enesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid,
camphorsulfonic acid, and the like; preferably hydrochloric acid.
4. The process according to claim 1, wherein in step d) organic solvent is
selected from dimethylformamide, dimethylsulfoxide, ,N-methylpyrrolidonc,
acetonitrile, chloroform, methanol, the like and/or mixtures thereof.
5. The process according to claim 1, wherein in step e) base is selected from
triethylamine, ammonia, metal bicarbonate such as sodium bicarbonate,
potassium bicarbonate and the like and solvent is selected from water,
alcohols such as methanol, ethanol, butanol, ter-butanol and the like;
halogenatcd solvent such as dichloromethane, chloroform, the like and
mixtures thereof.
6. A process for the purification of prulifloxacin acid addition salt comprises:

a) suspending prulifloxacin acid addition salt in a suitable solvent such as
N,N-dimethylformamide, N,N-dimethylsulfoxide, N-methylpyrrolidonc,
acetonitrile, chloroform, methanol, the like and/or mixtures thereof at a
temperature of about 40°C to reflux temperature of the solvent;
b) cooling the reaction mixture to a temperature of about 10-35°C;
c) isolating highly pure prulifloxacin acid addition salt.

7. A process for the preparation of highly pure prulifloxacin of formula 1
(Formula Removed)
comprises:
a) reacting 3,4-difluoroaniline with carbon disulfide in the presence of
suitable base like aqueous alkali metal hydroxide, followed by reaction
with ethylchloroformate to obtain 3,4-difluorophenyl 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 base like potassium hydroxide in an organic solvent like
toluene, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone,
acetonitrile and the like to obtain [[(3,4-difluorophenyl)amino|-
mercaptomethylene]-malonic acid diethyl ester S-potassium salt of
formula IV;
(Formula Removed)

d) alkylating compound of formula IV with diethyl sulfate in an organic
solvent like ethyl acetate to form [(3,4-difluorophenyl)amino|(ethylthio)
methylenemalonate of formula V;
(Formula Removed)
c) cyclizing compound of formula V to ethyl 4-hydroxy-6,7-difluoro-2-(ethylthio)quinoline-3-carboxylate of formula VI by refluxing azeotropically in suitable solvent like o-xylene, diphenyl ether, paraffin oil and the like;

(Formula Removed)


f) acylating compound of formula VI in the presence of suitable reagent like acetyl chloride and base like triethylamine in a halogenated solvent like dichloromethane, chloroform and the like to obtain ethyl 4-acetoxy-6,7-difluoro-2-(ethylthio)quinoline-3-carboxylate of formula VII;

(Formula Removed)

g) optionally purifying compound of formula VII with an alcoholic solvent like isopropyl alcohol;
h) treating compound of formula VII with sulfuryl chloride in the presence of suitable solvent like n-hexane or carbon tetrachloride, preferably at reflux temperature of the solvent to form a compound of formula VIII;
(Formula Removed)

i) treating compound of formula VIII with alkali metal acetate like sodium acetate in the presence of solvent like tetrahydrofuran at reflux temperature of the solvent followed by the addition of water to form ethyl

6,7-difluoro-l-rneihyl-4-oxo-4H-(l,3)thiazeto(3,2-a)quinolinc-3-carboxylate of formula IX;

(Formula Removed)


j) optionally purifying compound of formula IX using alcoholic solvent like methanol, ethanol, isopropanol;
k) condensing compound of formula IX with pipcrazine in suitable solvent like dimcthylformamide, acetonitrilc, acetone and the like to obtain ulifloxacin ethyl ester of formula X;

(Formula Removed)


1) hydrolysing compound of formula X with suitable base like alkali metal hydroxide in the presence of suitable solvent like C1-4 alcohols, water and mixture thereof to obtain ulifloxacin of formula II;

(Formula Removed)



m) optionally purifying ulifloxacin of formula II by slurry washing with an organic solvent selected from alcohols such as methanol, ethanol, isopropanol or ketones such as acetone or mixture thereof with water;
n) converting ulifloxacin of formula II to form prulifloxacin.

8. 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 suitable solvent at a temperature of-5 to!0°C and
b) isolating prulifloxacin therefrom.

9. The process according to claim 8, wherein base is selected from tricthylaininc.
ammonia, metal bicarbonate such as sodium bicarbonate, potassium
bicarbonate and the like and solvent is selected from water; alcohols such as
methanol, ethanol, butanol, tert. butanol and the like; halogenated solvent such
as dichloromethane, chloroform, the like and mixtures thereof.
10. The process according to claim 8, wherein acid addition salt is the one formed
with acid selected from inorganic acids such hydrochloric acid, sulfuric acid,
nitric acid, phosphoric acid, hydrobromic acid, and the like; salts with organic
acids such as formic acid, acetic acid, lartaric 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; preferably
hydrochloric acid.