FORM 2
THE PATENT ACT, 1970
(39 OF 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
PROCESS FOR THE PREPARATION OF BESIFLOXACIN
2. APPLICANT:
a. NAME: INDOCO REMEDIES LIMITED
b. NATIONALITY: INDIAN
c. ADDRESS: Indoco House, 166 C.S.T. Road, Santacruz East,
Mumbai - 400 098, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE: Process for the preparation of besifloxacin.
FIELD OF INVENTION:
The present invention relates to a novel process for the preparation of besifloxacin and its pharmaceutically acceptable salt.
The present invention further relates to novel intermediate and process for the preparation of the novel intermediate of besifloxacin.
BACKGROUND AND PRIOR ART:
The compound 7-[(3R)-3-aminohexahydro-1H-azepin-1 -yl]-8-chloro-1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride represented below as the compound of formula - I having international nonproprietary name as "besifloxacin hydrochloride acting as an antibacterial agent.

US patent No. 5,447.926 describes a class of quinolone carboxylic acid derivatives including 7-[(3R)-3-aminohexahydro-1H-azepin-l-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid (besifloxacin), wherein l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid and (R)-3-aminohexahydro-1H-azepin were refluxed in acetonitrile, then the precipitate is washed with chloroform, methanol and ether to obtain 1- [(Ji?)-3 -aminohexahydro-1H-azepin-1 -yl] -1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. The compound 7-[(3R)-3-aminohexahydro-1H-azepin-l-yl]-1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in chloroform was treated with sulfuryl chloride and the crude product was purified by silica gel column chromatography and recrystallized in mixture of solvent ethanol-chloroform to obtain 7-[(3R)-3 -aminohexahydro-1H-azepin-1 -yl]-8-chloro-1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

The drawbacks of the above process are the use of toxic solvent chloroform for the reaction, purification of intermediate using column chromatography, use of large molar quantity of sulfuryl chloride, prolonged time cycle of reaction and use of chlorinated solvent for final product purification.
PCT application WO 2008/045673 describes another method for preparing 7-[(3R)-3-aminohexahydro-1H-azepin-1-yl]-8-chloro-1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, wherein compound 8-chloro-l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid is reacted with (R)-3-[N-(3-nitrobenzylidene)amino]hexahydro-1H-azepin to obtain 3-nitrobenzylidene protected compound, which is deprotected with hydrochloric acid to obtain 7-[(3R)-3-aminohexahydro-1H-azepin-1 -yl] -8-chloro-1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
The above process involves use of nitro protected intermediate requiring deprotection of the compound to isolate besifloxacin, which results in increase number of steps and effects the economy of the process.
US patent No. 8,252,783 describes another method for the preparation of the compound of formula - I, wherein l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid is reacted with (R)-3-[N-(3-nitrobenzylidene)amino]hexahydro-1H-azepin in the presence of triethylamine in N,N-dimethylformamide to get 3-nitrobenzylidene protected compound. Deprotection of the compound with hydrochloric acid in solvent acetonitrile to get 7- [(3R)-3 -aminohexahydro-1H-azepin-1 -y 1] -1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid which is treated with sulfuryl chloride in acetic acid to get crude besifloxacin. The crude product obtained is purified with N,N-dimethylformamide and acetonitrile followed by water to obtain pure 7-[(3R)-3-aminohexahydro-1H-azepin-l-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, which is converted into its hydrochloride by treating with aqueous hydrochloric acid, and the hydrochloride salt is purified with mixture of acetonitrile and water.
The drawback of the above prior art lies in the use of excess moles of sulfuryl chloride and the protection and deprotection of the intermediate increases the number of steps affecting the economy of the process.

Therefore, there remains a need for preparing the compound 7-[(3R)-3-aminohexahydro-1H-azepin-1 -yl]-8-chloro-1 -cyclopropyl-6-fluoro-1.4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride of formula - I which employs safe and economical reagents for the reaction, makes the process industrially viable and reduces the time cycle of the reaction.
The present inventors have come out with a novel process for the preparation of 7-[(3R)-3-aminohexahydro-1 H-azepin-1 -yl]-8-chloro-1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride of formula -I which ameliorates the problems in the prior art to improve the yield, safety and economy of the process by employing novel intermediate, borate complex compound, which has good reactivity and facilitates the reaction of (R)-3-aminohexahydro-1H-azepin with compound of formula - II at lower temperature, requiring no special handling or equipment modification.
OBJECTIVE OF THE INVENTION:
The main objective of the present invention is to prepare besifloxacin hydrochloride of formula -I by robust, rigid and industrial friendly process.
Another objective of the present invention is to prepare the novel intermediate compound 7-[(3R)-3 -aminohexahydro-1H-azepin-1 -yl]-1-cyclopropyl-6-fluoro-4-oxo-l ,4-dihydroquinoline-3-carboxylic acid borate complex of formula - III;

wherein R1 and R2 are an aliphatic acyl group containing 2 to 6 carbon atoms. Yet another objective of the present invention is to provide process for the preparation of the novel intermediate compound 7-[(3R)-3-aminohexahydro-1H-azepin-l-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid borate complex of formula - III.

Yet another objective of the present invention is to prepare (R)-1-cyclopropyl-6-fluoro-7-halo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid borate complex of formula -II;

wherein R1 and R2 are an aliphatic acyl group containing 2 to 6 carbon atoms; and X is selected from chlorine, bromine or fluorine.
SUMMARY OF THE INVENTION:
The present invention provides a novel process for preparation of besifloxacin hydrochloride of formula-1.

According to primary object of the present invention, there is provided a simple, cost effective and industrially safe process for the preparation of besifloxacin hydrochloride, the compound of formula -1 which comprises the steps of:
a. reacting the compound of formula - IV or its acid addition salt of formula - IVA

wherein R is H or amine protecting group,

with l-cyclopropyl-6-fluoro-7-halo-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid borate complex of formula - II

wherein R1 and R2 are an aliphatic acyl group containing 2 to 6 carbon atoms; and X is selected from chlorine, bromine or fluorine;
in presence or absence of a base and a solvent at a temperature in the range of 40°C to the reflux temperature of the solvent used to get the compound 7-[(3R)-3-aminohexahydro-1H-azepin-1 -yl]-1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid borate complex of formula - III

wherein R1 and R2 are an aliphatic acyl group containing 2 to 6 carbon atoms; which on in situ hydrolysis with an acid yields 7-[(3R)-3-aminohexahydro-1H-azepin-1 -yl] -1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid the compound of formula - V or its salt;


b. reacting the compound of formula - V with sulfuryl chloride in presence of solvent to
obtain the compound besifloxacin hydrochloride of formula -I; and
c. optionally purifying the compound of formula -I as obtained in step (b) by reacting
with a base in presence of solvent followed by reaction with hydrochloric acid to obtain pure besifloxacin hydrochloride.
According to another aspect, the present invention provides the process for the preparation
of 7- [(3R)-3 -aminohexahydro-1H-azepin-1 -yl] -1 -cyclopropyl-6-fluoro-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid borate complex of formula - III

wherein R1 and R2 are an aliphatic acyl group containing 2 to 6 carbon atoms which comprises the steps of reacting the compound of formula - IV or its acid addition salt of formula - IVA

wherein R is H or amine protecting group,
with l-cyclopropyl-6-fluoro-7-halo-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
borate complex of formula - II


wherein R1 and R2 are an aliphatic acyl group containing 2 to 6 carbon atoms; and X is selected from chlorine, bromine or fluorine;
in presence of a base and a solvent at a temperature in the range of 40°C to the reflux temperature of the solvent used to get the compound 7-[(37?)-3-aminohexahydro-1H-azepin-1 -yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid borate complex of formula - III.
In yet another aspect, the present invention provides the compound of formula - III.

wherein Ri and R2 are an aliphatic acyl group containing 2 to 6 carbon atoms.
In yet another aspect, the present invention provides the compound 7-[(3R)-3-aminohexahydro-1H-azepin-1 -yl] -1 -cy clopropyl-6-fluoro-4-oxo-1,4-dihydro-3 -quinolinecarboxylic acid-O3,O4-bis(acetoxy-0)borate of formula - III A.

In yet another aspect the present invention provides the compound 7-[(3R)-3-aminohexahydro-lH-azepin-l-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(propionyloxy-0)borate of formula - III B.


In yet another aspect, the present invention provides the compound 7-[(3i?)-3-aminohexahydro-1H-azepin-1 -yl] -1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3 -quinolinecarboxylic acid-O3,O4-bis(butyroxy-0)borate of formula - III C.

DETAILED DESCRIPTION OF THE INVENTION:
The present inventions provides a novel process for the preparation of compound besifloxacin hydrochloride of formula -I.


In an embodiment of the present invention the preparation of bcsifloxacin hydrochloride of formula -I comprises:
a. reacting the compound of formula - IV or its acid addition salt of formula - IVA

wherein R is H or amine protecting group,
with l-cyclopropyl-6-fluoro-7-halo-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-
borate complex of formula - II

wherein R1 and R2 are an aliphatic acyl group containing 2 to 6 carbon atoms; and X is selected from chlorine, bromine or fluorine;
in presence or absence of a base and a solvent at a temperature in the range of 40°C to the reflux temperature of the solvent used to obtain the compound 7-[(3i?)-3-aminohexahydro-1H-azepin-1 -yl]-1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid borate complex of formula - III;

wherein R1 and R2 are an aliphatic acyl group containing 2 to 6 carbon atoms,

which on in situ hydrolysis with an acid yields 7-[(3R)-3-aminohexahydro-1H-azepin-l-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid the compound of formula - V or its salt;

b. reacting the compound of formula - V with sulfuryl chloride in presence of a solvent
to obtain the compound besifloxacin hydrochloride of formula -I;; and
c. optionally purifying the compound of formula -1 as obtained in step (b) by reacting
with a base in presence of a solvent followed by reaction with hydrochloric acid to
obtain pure besifloxacin hydrochloride,
The term "in situ" is used herein to mean that within the reaction mixture and without isolation of the intermediate compound.
In an embodiment of the present invention, the base used in step (a) of the process is selected
from the group consisting of organic and inorganic base. The organic base used for the
reaction was selected from the group consisting of N,N-dimethylaniline, pyridine,
morpholine, terf-butylamine, diisopropylamine, diisopropylethylamine,
diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine, sodium methoxide and potassium tert-butoxide. The inorganic base used for the reaction was selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride or mixture thereof. The preferred base used for the reaction was selected from triethylamine, diisopropylamine, potassium bicarbonate or mixture thereof.
In an embodiment of the present invention, the reaction of l-cyclopropyl-6-fluoro-7-halo-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid borate complex of formula - II with the compound of formula - IV is carried out in presence of solvent selected from the group

consisting of acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, toluene, xylene, dichloromethane, dichloroethane, chloroform or a mixture thereof.
In an embodiment of the present invention, the reaction of step (a) is carried out at a suitable temperature, preferably at a temperature ranging from 40°C to the reflux temperature of the solvent used for the reaction. The most preferred temperature of the reaction is in the range of 45°C to 60°C.
The completion of the reaction was monitored on HPLC. After completion of the reaction of step (a), the borate complex of formula - III can be optionally isolated from the reaction mixture by using suitable techniques known in the art or taken in situ for hydrolysis to isolate the carboxylic acid compound of formula - V. It is advantageous to proceed the reaction mixture as such without isolation of borate complex of formula - III.
In an embodiment of the present invention, the borate complex compound of formula - III was hydrolysed in situ using suitable acid. The process involves the treatment of reaction mixture containing the borate complex of formula - III with suitable source of hydrogen chloride, preferably till the pH of the reaction mixture reaches to 1 to 3, more preferably till pH 1.0 to 2.0. Suitable source of hydrogen chloride employed for the reaction includes aqueous hydrochloric acid, concentrated hydrochloric acid, gaseous hydrochloric acid, alcoholic hydrochloric acid and the like or combination thereof. The reaction can be carried out at a temperature of about 20°C to 50°C, preferably a temperature of 25°C to 35°C optionally with stirring for about one hour or till completion of the hydrolysis. The precipitated solid mass was filtered and washed with the solvent and dried to obtain 7-[(3R)-3 -aminohexahydro-1H-azepin-1 -yl]-1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid the compound of formula - V. or its salt.
In an embodiment of the present invention, after completion of the reaction of step (a), the reaction mass was concentrated under vacuum to get a residual mass. The obtained residual mass was diluted with cyclohexane and stirred for one hour. The precipitated solid mass was filtered and washed with cyclohexane and dried under vacuum at 40°C to 45°C to obtain the compound 7-[(3R)-3-aminohexahydro-1H-azepin-l-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid borate complex of formula - III.

In an embodiment of the present invention, the isolated compound of formula - III was further treated with suitable source of hydrogen chloride, in suitable solvent preferably acetonitrile, till the pH of the reaction mixture reaches 1 to 3, and more preferably till pH 1.0 to 2.0. Suitable source of hydrogen chloride employed for the reaction includes aqueous hydrochloric acid, concentrated hydrochloric acid, gaseous hydrochloric acid, alcoholic" hydrochloric acid and the like or combination thereof. The reaction can be carried out at a temperature of about 20°C to 50°C, preferably at a temperature of 25°C to 35°C optionally with stirring about one hour or till completion of the hydrolysis. The precipitated solid mass was filtered and washed with the solvent and dried to obtain 7-[(3R)-3-aminohexahydro-1H-azepin-1 -yl] -1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3 -quinoline- carboxylic acid the compound of formula - V or its salt.
In an embodiment of the present invention, R group recited in the definition are H or amine protecting group selected from tert-butoxycarbonyl (Boc), benzylidene or nitrobenzylidene; and R1 and R2 recited in the definition are an aliphatic acyl group containing 2 to 6 carbon atom selected from acetyl, propionyl, butyryl, pentanoyl (valeryl) and hexanoyl, wherein the preferred aliphatic acyl group is butyryl.
In an embodiment of the present invention, the compound of l-cyclopropyl-6-fluoro-7-halo-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid-borate complex of formula - II used in step (a) can be prepared by process known in the prior art. The compound 1 -cyclopropyl-6-fluoro-7-halo-4-oxo-l,4-dihydro-3-quinoline carboxylic acid was reacted in presence of boric acid with an acid anhydride selected from the group consisting of acetic anhydride, propionic anhydride, butyric anhydride, pentanoic anhydride and hexanoic anhydride. The halo substituent at 7-position is selected from chloro, bromo or fluoro compound. The preferable halo substituted compound used is chloro compound. The reaction is carried out at temperature in the range of 80°C to 120°C. The preferred temperature of the reaction is at 100°C to 110°C. The reaction is worked up by cooling the reaction mass to 40°C to 45°C and charging cyclohexane to the reaction mas. Maintained the reaction mass at 20°C to 30°C for an hour and filtered, washed the solid with cyclohexane and followed with water to obtain the compound of formula - II.
In an embodiment of the present invention, the compound 7-[(3R)-3-aminohexahydro-1H-azepin-1 -yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid the

compound of formula - V or its salt is reacted as in step (b) with sulfuryl chloride in presence of solvent to obtain besifloxacin hydrochloride of formula -1.
Earlier the chlorination of the compound of formula - V as per the prior art is carried out in presence of solvent chloroform or acetic acid. Both the solvents has got disadvantages associated with them, the solvent chloroform has a proven health hazard and causes cancer on prolonged exposure, whereas the use of acetic acid for the chlorination reaction forms an unstirrable heterogeneous sticky mass after the addition of sulfuryl chloride, which requires large volume of solvent to make it stirrable and homogeneous. Also the large molar ratio of reagent sulfuryl chloride is required varying from 2.5 mole to 5.0 mole for 1,0 mole of the compound 7-[(3R)-3-aminohexahydro-1H-azepin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid compound of formula - V for completion of the reaction. The large excess use of solvent and molar ratio of the chlorinating reagent implies longer time for completion of the reaction and increase in the formation of impurity which affects and lowers the final yield of the product 7-[(3R)-3-aminohexahydro-1H-azepin-1-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid.
In an embodiment of the present invention, the solvent used for the reaction with sulfuryl chloride as in step (b) is mixture of acetic acid and formic acid. The compound 7-[(3R)-3-aminohexahydro-1H-azepin-1 -yl] -1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3 -quinoline carboxylic acid compound of formula - V or it's salt is freely soluble in the mixture of solvent acetic acid and formic acid and forms clear solution which facilitates the smooth addition of sulfuryl chloride and forms homogeneous reaction mixture restricting the impurity formation during chlorination reaction which results in an improved yield of besifloxacin hydrochloride of formula -1,
In an embodiment of the present invention, the reaction was carried out using reduced molar quantity of sulfuryl chloride for 1.0 mole of the compound of formula - V. The molar ratio of sulfuryl chloride used is in the range of 1.2 mole to 1.7 mole for 1.0 mole of the compound of formula - V, wherein the preferred ratio used is 1.4 mole to 1.6 mole of sulfuryl chloride, the most preferred ratio of sulfuryl chloride used is 1.5 mole for 1.0 mole of compound 7-[(3R)-3 -aminohexahydro-1H-azepin-1 -yl]-1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid compound of formula - V or its salt. The above observation is further illustrated in the following table 1.

Table 1:

Sr.
No. Compound of formula - V Sulfuryl chloride Solvent In process HPLC Theoretical Yield HPLC Purity
1 1 mole 2 to 5 mole MDC or
chloroform 50%* Unreacted - -
2 1 mole 2 to 3 mole Acetic acid 76.63 SI** 17% 41 to 52% 99.32%
3 1 mole 1.5 mole Formic acid 91.11% SI-3.14% 65 to 75 % 99.59%
4 1 mole 1.5 mole Acetic acid
& Formic acid 92.49 % SI - 0.98 % 72 to 78 % 99.60 %
* Checked by TLC; ** SI - Single Impurity
In an embodiment of the present invention, besifloxacin hydrochloride is optionally purified by reacting with a base in presence of a solvent and followed by reaction with hydrochloric acid to obtain pure besifloxacin hydrochloride.
In an embodiment of the present invention, the solvent used for purification in step (c) is selected from the group consisting of methanol, ethanol, isopropanol, water or a mixture thereof.
In accordance with the above embodiment the besifloxacin hydrochloride obtained in step (b) is suspended in methanol and treated with a base selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide at the temperature of 20°C - 30°C. Charged activated carbon, stirred at 25°C to 35°C for one hour. Filtered through Hyflow bed and then the filtrate is treated with hydrochloric acid, wherein the hydrochloric acid is added either in gaseous form or its solution in organic solvent or water to isolate the compound besifloxacin hydrochloride. The precipitated solid is stirred for one hour and filtered to isolate pure besifloxacin hydrochloride.

In an embodiment of the present invention provides the process for the preparation of 7-[(3R)-3 -aminohexahydro-1 H-azepin-1 -yl]-1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid borate complex of formula - III

wherein R1 and R2 are an aliphatic acyl group containing 2 to 6 carbon atoms
which comprises the steps of:
reacting the compound of formula - IV or its acid addition salt of formula - IVA

wherein R is H or amine protecting group,
with l-cyclopropyl-6-fluoro-7-halo-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
borate complex of formula - II

wherein Ri and R2 are an aliphatic acyl group containing 2 to 6 carbon atoms; and X is selected from chlorine, bromine or fluorine;
in presence of a base and a solvent at a temperature in the range of 40°C to the reflux temperature of the solvent to get the compound 7- [(3R)-3 -aminohexahydro- 1H-azepin-1 -yl]-1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid borate complex of formula - III.

In an embodiment of the present invention, the base used in the reaction of 1-cyclopropyl-6-fluoro-7-halo-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid borate complex of formula -II with the compound of formula - IV is selected from the group consisting of organic and inorganic base. The organic base used for the reaction was selected from the group consisting of N,N-dimethyIaniline, pyridine, morpholine, tert-butylamine, diisopropylamine, diisopropylethylamine, diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine, sodium methoxide and potassium tert-butoxide. The inorganic base used for the reaction was selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride or mixture thereof. The preferred base used for the reaction was selected from triethylamine, diisopropylamine, potassium bicarbonate or mixture thereof.
In an embodiment of the present invention, the reaction of 1 -cyclopropyl-6-fluoro-7-halo-4-oxo-l,4-dihydro-3-quinolinecarboxyIic acid borate complex of formula - II with the compound of formula - IV is carried out in presence of solvent selected from the group consisting of acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, toluene, xylene, dichloromethane, dichloroethane, chloroform or a mixture thereof.
In an embodiment of the present invention, the reaction of l-cyclopropyl-6-fluoro-7-halo-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid borate complex of formula - II with the compound of formula - IV is carried out at a suitable temperature, preferably at a temperature ranging from 40°C to the reflux temperature of the solvent used for the reaction. The most preferred temperature of the reaction is in the range of 45°C to 60°C.
The completion of the reaction was monitored on HPLC. After completion of the reaction of step (a), the borate complex of formula - III can be optionally Isolated from the reaction mixture by using suitable techniques known in the art or taken in situ for hydrolysis to isolate the carboxylic acid compound of formula - V or its salt.
In an embodiment of the present invention, after completion of the reaction of 1 -cyclopropyl-6-fluoro-7-halo-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid borate complex of formula -II with the compound of formula - IV, the reaction mixture was concentrated under vacuum to get a residual mass. The obtained residual mass was diluted with cyclohexane and stirred for one hour. The precipitated solid mass was filtered and washed with cyclohexane and

dried under vacuum at 40°C to 45°C to obtain the compound 7-[(3R)-3-aminohexahydro-1H-azepin-l-yl]-l-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid borate complex of formula - III.
In an embodiment of the present invention, the R1 and R2 recited in the definition are an aliphatic acyl group containing 2 to 6 carbon atom selected from acetyl, propionyl, butyryl, pentanoyl (valeryl) and hexanoyl, wherein the preferred aliphatic acyl group is butyryl.
In an embodiment the present invention provides the compound of formula - III,

wherein R1 and R2 are an aliphatic acyl group containing 2 to 6 carbon atoms.
In yet another aspect, the present invention provides the compound 7-[(3R)-3-aminohexahydro-1 H-azepin-1 -yl] -1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3 -quinolinecarboxylic acid-O3,O4-bis(acetoxy-0)borate of formula - III A.

In yet another aspect, the present invention provides the compound 7-[(3R)-3-aminohexahydro-1 H-azepin-1 -yl] -1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3 -quinolinecarboxylic acid-O3,O4-bis(propionyloxy-0)borate of formula - III B.


In yet another aspect, the present invention provides the compound 7-[(3R)-3-aminohexahydro-1H-azepin-1 -y 1] -1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3 -quinolinecarboxylic acid-O3O4-bis(butyroxy-0)borate of formula - III C;

The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention.
Examples:
Example 1: Preparation of 7-[(3R)-3-aminohexahydro-1H-azepin-l-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(acetoxy-O)borate.


In a dry flask, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(acetoxy-0)borate (10.00 g) was suspended in acetonitrile (50 ml) and (R)-3-aminohexahydro-1H-azepin (4.10 g) was added at 25°C to 30°C. To the above reaction mass was added triethylamine (2.43 g) at 25°C to 30°C, the temperature of the reaction mass was raised to 45°C to 50°C and maintained for 6 - 8 hours. After completion of the reaction, the reaction mass was concentrated under vacuum to get residual mass. Charged cyclohexane (40 ml) to the residual mass and maintained under stirring for one hour. The resulting product was filtered, washed with cyclohexane (2x5 ml) and dried under vacuum at 40°C to 45 °C to obtain 7.70 g of 7-[(3R)-3-aminohexahydro-1H-azepin-l-yl]-1-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-3-quinoline carboxylic acid-O3,O4-bis(acetoxy-0)borate. Yield: 64.71%. HPLC Purity: 75.12%.
Example 2: Preparation of 7-[(3R)-3-aminohexahydro-1H-azepin-1-yl]-l-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride.

In a dry flask, 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(acetoxy-0)borate (10.00 g) was suspended in acetonitrile (50 ml) and (R)-3-aminohexahydro-1H-azepin (2.97 g) was added at 25°C to 30°C. To the above reaction mass was added triethylamine (2.43 g) at 25°C to 30°C, the temperature of the reaction mass was raised to 45°C to 50°C and maintained for 6 - 8 hours. After completion of the reaction, the reaction mass was cooled to 25°C to 30°C and adjusted the pH to 1.0 - 2.0 with cone. hydrochloric acid. The reaction mass was stirred for one hour maintaining the temperature at 25°C to 30°C. The product was filtered, washed with acetonitrile (2x5 ml) and dried at 55°C to 60°C to obtain 4.40 g of 7-[(3R)-3-aminohexahydro-1H-azepin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride. Yield: 45.50%. HPLC Purity; 91.00%.

Example 3: Preparation of 7-[(3R)-3-aminohexahydro-1H-azepin-l-yl] -1-cyclopropyl-
6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxyIic acid-O3,O4-bis(propionyloxy-
O)borate.

In a dry flask, 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-l?4-dihydro-3-quinolinecavboxylic acid-O3,O4-bis(propyloxy-0)borate (5.00 g) was suspended in acetonitrile (25 ml) and (R)-3-aminohexahydro-1H-azepin (1.95 g) was added at 25°C to 30°C. To the above reaction mass was added triethylamine (1.39 g) at 25°C to 30°C, the temperature of the reaction mass was raised to 45°C to 50°C and maintained for 6 - 8 hours. After completion of the reaction, the reaction mass was concentrated under vacuum to get residual mass. Charged cyclohexane (20 ml) and maintained under stirring for one hour. The resulting product was filtered, washed with cyclohexane (2x5 ml) and dried under vacuum at 40°C to 45°C to obtain 4.00 g of 7-[(3R)-3 -aminohexahydro-1H-azepin -1 -yl] -1 -cyclopropyl-6-fluoro-4-oxo-1 ,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(propionyloxy-0)borate. Yield: 68.00%. HPLC Purity: 68.98%.
Example 4: Preparation of 7-[(3R)-3-aminohexahydro-1H-azepin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride.

In a dry flask, 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(propionyloxy-0)borate (12.00 g) was suspended in acetonitrile (60 ml) and (R)-3-aminohexahydro-lif-azepin (4.91 g) was added at 25°C to 30°C. To the above reaction

mass was added triethylamine (4.15 g) at 25°C to 30°C, the temperature of the reaction mass was raised to 45°C to 50°C and maintained for 6 - 8 hours. After completion of the reaction, the reaction mass was cooled to 25°C to 30°C and adjusted the pH to 1.0 - 2.0 with cone. hydrochloric acid. Stirred the reaction mass for one hour maintaining temperature at 25°C to 30°C. The product was filtered, washed with acetonitrile (2x12 ml) and dried at 55°C to 60°C to get 7.00 g of 7-[(3R)-3-aminohexahydro-1H-azepin-l-yl]-l-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride. Yield: 64.46%. HPLC Purity: 96.57%.
Example 5: Preparation of 7-[(3R)-3-aminohexahydro-1H-azepin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(butyroxy-0)borate.

7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(butyroxy-0)borate (10.00 g) was suspended in acetonitrile (50 ml) and (R)-3-aminohexahydro-1H-azepin (3.88 g) was added at 25°C to 30°C. To the above reaction mass was added triethylamine (3.24 g) at 25°C to 30°C, the temperature of the reaction mass was raised to 45°C to 50°C and maintained for 6 - 8 hours. After completion of the reaction, the reaction mass was concentrated under vacuum to get residual mass. Charged dichloromethane (50 ml), stirred and washed the dichloromethane layer with purified water (2x10 ml). Concentrated the dichloromethane layer under vacuum to obtain residual mass. Charged fresh dichloromethane (15 ml), stirred and charged diisopropyl ether (30 ml) to the reaction mass and maintained at 25°C to 30°C for one hour. The resulting product was filtered, washed with diisopropyl ether (2x10 ml) and dried under vacuum at 40°C to 45°C to get 7.58 g 7-[(3i?)-3-aminohexahydro-l//-azepin-l-yl]-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(butyroxy-0)borate. Yield: 65.00%. HPLC Purity: 97.36%.

1H NMR Spectrum (CDC13): δ = 0.8 (6H, t), 1.5 (4H, m), 2.3(4H, t), 4.0 (1H, m), 1.2 (411, d), 1.5 (2H, d), 2.0 (10H, m), 6.3 (1H, s), 7.9 (1H, s), 8.8 (1H, s). IR (cm-1): 3197, 2964, 2875,2771, 1633, 1273, 1136,970. [M+H]: 544
Example 6: Preparation of 7-[(3R)-3-aminohexahydro-1H-azepin-l-yl]-1-cycIopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride.

In a flask, 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(butyroxy-0)borate (25.00 g) was suspended in acetonitrile (125 ml) and (R)-3-aminohexahydro-1H-azepin (9.80 g) was added at 25°C to 30°C. To the above reaction mass was added triethylamine (8.20 g) at 25°C to 30°C, the contents were heated to 45°C to 50°C and maintained for 6 - 8 hours. After completion of the reaction, the reaction mas was cooled to 25°C to 30°C, adjusted the pH to 1.0 - 2.0 with cone, hydrochloric acid (12.5 ml) and maintained the reaction mass at 25°C to 30°C for 1 hour. The product was filtered, washed with acetonitrile (2 x 12.5 ml) and dried at 55°C to 60°C to give 10.00 g of 7-[(3R)-3-aminohexahydro-1H-azepin-1 -yl] -1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride. Yield: 47.00%. HPLC Purity: 99.22%.
Example 7: Preparation of 7-[(3R)-3-aininohexahydro-1H-azepin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride (besifloxacin hydrochloride)


In a flask, 7-[(3R)-3-aminohexahydro-lH-azepin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride (9.00 g) was suspended in mixture of acetic acid and formic acid (36 ml). The contents were cooled to 15°C to 20°C followed by addition of sulphuryl chloride (4.62 g) and maintained the reaction mass at 15°C to 20°C for 2 hours. After completion of the reaction, dimethylfomamide (90 ml) was added at 20°C to 25°C and maintained the reaction mass at 25°C to 30°C for 8-10 hours. The product was filtered and dried at 60°C to 65°C to get 5.20 g of besifloxacin hydrochloride. Yield: 53.17%. HPLC Purity: 99.26%.
Example 8: Purification of Besifloxacin hydrochloride.

In a flask, besifloxacin hydrochloride (5.00 g) was suspended in methanol (75 ml) and sodium hydroxide solution (25 ml) was charged maintaining at 25°C to 30°C. The reaction mass was stirred and maintained at 25°C to 30°C for 30 minutes to get a clear solution. To the reaction mass cone, hydrochloric acid (3 ml) was added and maintained at 25°C to 30°C for two hours. The product was filtered, washed with methanol (2x5 ml) and dried at 60°C to 65°C to get 3.50 g of pure besifloxacin hydrochloride. Yield: 70.00%. HPLC Purity: 99.93%.
Example 9: Preparation of 7-[(3R)-3-aminohexahydro-1H-azepin-1-yl]4-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride.


In a flask was charged 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(butyroxy-0)borate (10.00 g) in acetonitrile (60 ml) and (R)-3-aminohexaliydro-1H-azepin (4.58 g) was added at 25°C to 30°C. The temperature of the reaction mass was raised to 45°C to 50°C and maintained for 6 - 8 hours. After completion of the reaction, the reaction mass was cooled to 25°C to 30°C. Charged methanol (10 ml) to the reaction mass and adjusted the pH between 1.0 to 2.0 with cone, hydrochloric acid (4 ml). The reaction mass was maintained at 25°C to 30°C for one hour. The precipitated solid mass was filtered, washed with acetonitrile (2x10 ml) followed with methanol (2x10 ml) and dried at 55°C to 60°C to get 5.00 g of besifloxacin hydrochloride. Yield: 58.80%. HPLC Purity: 98.70%.
Example 10: Preparation of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(acetoxy-0)borate.

In a dry flask acetic anhydride (52.00 g) was charged and heated under stirring to 80°C to 90°C. boric acid (5.26 g) was added maintaining the temperature at 80°C to 90°C. The temperature was raised further to 105°C to 110°C and maintained for three hours. The reaction mass was cooled to 70°C to 75°C and 7-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid (20.00 g) was added under stirring. The temperature of the reaction mass was raised to 100°C to 105°C and maintained at 100°C to 105°C for 3 - 4 hours. After completion of the reaction, the reaction mass was cooled to 40°C to 45°C, charged cyclohexane (140 ml) and maintained at 25°C to 30°C for one hour. The product was filtered, washed with cyclohexane (2x30 ml) and dried at 40°C to 45°C under vacuum to get 26.00 g of 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-ls4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(acetoxy-O)borate. Yield: 89.41%. HPLC Purity: 99.27%.

1H NMR (DMSO-d6): δ=1.44 (S, 4H), 1.90 (S, 6H), 4.19 (T, 1H), 8.37-8.39 (S, 1B), 8.86-8.87 (S, 1H), 9.23 (S, 1H). IR (cm-1): 1710-1720, 1730-1750. [M+H]: 409.60.
Example 11: Preparation of 7-chIoro-l-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(acetoxy-0)borate.

In a dry flask acetic anhydride (52.00 g) was charged and heated under stirring to 80°C to 90°C, boric acid (5.26 g) was added maintaining the temperature at 80°C to 90°C. The temperature was raised further to 105°C to 110°C and maintained for three hours. The reaction mass was cooled to 70°C to 75°C and 7-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (20.00 g) was added under stirring. The temperature of the reaction mass was raised to 100°C to 105°C and maintained at for 3 - 4 hours. After completion of the reaction, the reaction mass was cooled to 0°C to 5°C, charged purified water (100 ml) and maintained at 0°C to 5°C for one hour. The product was filtered, washed with purified water and dried at 40°C to 45°C under vacuum to get 24.00 g of 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(acetoxy-O)borate. Yield: 82.53%. HPLC Purity: 98.00%.
Example 12: Preparation of 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid-O3,O4-bis(propionyloxy-0)borate.


In a dry flask propionic anhydride (48.72 g) was charged and heated under stirring to 80°C
to 90°C, boric acid (5.26 g) was added maintaining the temperature at 80°C to 90°C. The
temperature was raised further to 105°C to 110°C and maintained for three hours. The
reaction mass was cooled to 70°C to 75°C and 7-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid (20.00 g) was added under stirring. The temperature of the
reaction mass was raised to 145°C to 150°C and maintained for 3 - 4 hours. After completion
of the reaction, the reaction mass was cooled to 40°C to 45°C, charged cyclohexane (140
ml) and maintained at 25°C to 30°C for one hour. The product was filtered, washed with
cyclohexane (2 x 30 ml) and dried at 40°C to 45°C under vacuum to get 29.50 g of 7-chloro-
l-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3,O4-
bis(propionyloxy-O)borate. Yield: 94.95%. HPLC Purity: 98.99%.
Example 13: Preparation of 7-chloro-1-cyclopropyI-6-iluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(butyroxy-0)borate.

In a dry flask butyric anhydride (46.00 g) was charged and heated under stirring to 80°C to 90°C, boric acid (5.26 g) was added maintaining temperature at 80°C to 90°C. The temperature was raised further to 105°C to 110°C and maintained for three hours. The reaction mass was cooled to 70°C to 75°C and 7-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid (20.00 g) was added under stirring. The temperature of the reaction mass was raised to 100°C to 105°C and maintained at for 3 - 4 hours. After completion of the reaction, the reaction mass was cooled to 40°C to 45°C, charged cyclohexane (140 ml) and maintained at 25°C - 30°C for one hour. The product was filtered, washed with cyclohexane (2 x 30 ml) and dried at 40°C - 45°C under vacuum to get 32.50 g of 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(butyroxy-O)borate. Yield: 98.31%. HPLC Purity: 97.91%.

Example 14: Preparation of 7-chloro-1-cyclopropyI-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid-O3O4-bis(butyroxy-0)borate.

In a dry flask butyric anhydride (43.87 g) was charged and heated under stirring to 80°C to 90°C, boric acid (5.00 g) was added maintaining the temperature at 80°C to 90°C. The temperature was raised further to 105°C to 110°C and maintained for three hours. The reaction mass was cooled to 70°C to 75 °C and methyl 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (20.00 g) was added under stirring. The temperature of the reaction mass was raised to 100°C to 105°C and maintained at for 3 - 4 hours. After completion of the reaction, the reaction mass was cooled to 40°C to 45°C, charged cyclohexane (140 ml) and maintained at 25°C to 30°C for one hour. The product was filtered, washed with cyclohexane (2 x 30 ml) and dried at 40°C to 45°C under vacuum to get 28.00 g of 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(butyroxy-0)borate. Yield: 88.89%. HPLC Purity: 99.70%.
Example 15: Preparation of l-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(acetoxy-0)borate.

In a dry flask acetic anhydride (26.00 g) was charged and heated under stirring to 80°C to 90°C, boric acid (2.84 g) was added maintaining temperature at 80°C to 90°C. The temperature was raised further to 105°C to 110°C and maintained for three hours. The

reaction mass was cooled to 70°C to 75°C and under stirring charged 1-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid (10.00 g) was added. The temperature of the reaction mass was raised to 100°C to 105°C and maintained at for 3-4 hours. After completion of the reaction, the reaction mass was cooled to 40°C to 45°C charged cyclohexane (70 ml) and maintained at 25°C to 30°C for one hour. The product was filtered, washed with cyclohexane (2x15 ml) and dried at 40°C to 45°C under vacuum to get 11.88 g of 1-cyclopropyl-6,7-difluoro-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(acetoxy-0)borate. Yield: 80.16%. HPLC Purity: 93.87%.
Example 16: Preparation of 7-[(3R)-3-aminohexahydro-1H-azepin-l-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride,

In a dry flask, 7-[(3i?)-3-aminohcxahydro-1H-azepin-1-yl]-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-3-quinoline carboxylic acid-O3,O4-bis(butyroxy-O)borate (25.00 g) was suspended in acetonitrile (125 ml). Adjusted the pH of the reaction mass with cone. hydrochloric acid (10 ml) between 1.0 - 2.0 maintaining temperature at 25°C to 30°C, the temperature was raised to 35°C to 40°C and maintained the reaction mass for one hour. The reaction mass was cooled gradually to 25°C to 30°C and maintained for one hour. The product was filtered, washed with acetonitrile (2 x 12.5 ml) and dried at 55°C to 60°C to get 8.20 g of 7-[(3R)-3-aminohexahydro-lH-azepin-l-yl]-8-chloro-l-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride. Yield: 45.00%. HPLC Purity: 98.70%.

Example 17: Preparation of 7-[(3R)-3-aminohexahydro-1H-azepin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride,

In a dry flask, l-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-O3,O4.bis(acetoxy-0)borate (5.00 g) was suspended in acetonitrile (25 ml) and (R)-3-aminohexahydro-1H-azepin (2.28 g) was added at 25°C to 30°C. To the above reaction mass was added triethylamine (1.62 g) at 25°C to 30°C, the contents were heated to 45°C to 50°C and maintained for 6 - 8 hours. After completion of the reaction, the reaction mas was cooled to 25°C to 30°C, charged purified water (5 ml) & adjusted the pH to 1.0 - 2.0 with cone. hydrochloric acid (3 ml). Maintained the reaction mass at 25°C to 30°C for 1 hour. The product was filtered, washed with acetonitrile (3x5 ml) and dried at 55°C to 60°C to give 4.7 g of 7-[(3R)-3-aminohexahydro-1H-azepin-l-yl]-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid hydrochloride. Yield: 93.40%. HPLC Purity: 98.21%.

We Claim:
1. A process for the preparation of besifloxacin hydrochloride of formula -1

which comprises the steps of: a. reacting the compound of formula - IV or its acid addition salt of formula - IVA

wherein R is H or amine protecting group, with 7-halo-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-3-quinoline carboxylic acid-borate complex of formula - II

wherein R1 and R2 are an aliphatic acyl group containing 2 to 6 carbon atoms; and X is selected from chlorine, bromine or fluorine.
in presence or absence of a base and a solvent at a temperature in the range of 40°C to the reflux temperature of the solvent used, to obtain the compound 7-[(3R)-3-

aminohexahydro-1H-azepin-1 -yl]-1 -cyclopropyl-6-fluoro-4-oxo-1 ,4-dihydroquinoline-3-carboxylic acid borate complex of formula - III;

wherein R1 and R2 are an aliphatic acyl group containing 2 to 6 carbon atoms, which on in situ hydrolysis with an acid yields 7-[(3R)-3-aminohexahydro-lH-azepin-1 -yl]-1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid the compound of formula - V or its salt;

. b. reacting the compound of formula - V with sulfuryl chloride in presence of a solvent to obtain besifloxacin hydrochloride of formula -1; and c. optionally purifying the compound of formula -1 as obtained in step (b) by reacting with a base in presence of solvent followed by reaction with hydrochloric acid to obtain pure besifloxacin hydrochloride.
2. The process according to claim 1, wherein the base used in step (a) of the process is an organic base selected from the group consisting of N,N-dimethylaniline, pyridine, morpholine, tertiary-butylamine, diisopropylamine, diisopropylethylamine, diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine, sodium methoxide and potassium tert-butoxide.

3. The process according to claim 1, wherein the base used in step (a) of the process is
an inorganic base selected from the group consisting of sodium hydroxide, potassium
hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium
bicarbonate, potassium bicarbonate or sodium hydride.
4. The process according to claim 1, wherein the solvent used in step (a) of the process
is selected from the group consisting of acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, toluene, xylene, dichloromethane, dichloroethane, chloroform or a mixture thereof
5. The process according to claim 1, wherein the halo substituent used in the compound
of Formula II in step (a) of the process is selected from chlorine, bromine or fluorine.
6. The process according to claim 1, wherein the acid used for hydrolysis in step (a) of
the process is hydrochloric acid.
7. The process according to claim 1, wherein the step (a) reaction is carried out at
temperature in the range of 45°C to 60°C.
8. The process according to claim 1, wherein the solvent used in step (b) of the process
is mixture of acetic acid and formic acid.
9. The process according to claim 1, wherein the base used in step (c) is selected from
the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide and the solvent is selected from the group consisting of methanol, ethanol, isopropanol, water or a mixture thereof.

10. The compound of formula - III;

wherein R1 and R2 are an aliphatic acyl group containing 2 to 6 carbon atoms. selected from the group consisting of;
a. The compound 7-[(3R)-3-aminohexahydro-1H-azepin-l-yl]-l-cyclopropyl-6-
fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(acetoxy-
0)borate of formula - III A;

b. The compound (7- [(3R)-3 -aminohexahydro-1H-azepin-1 -yl] -1 -cyclopropyl-6-
fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3,O4-bis(propionyloxy-
0)borate of formula - III B; and


c. The compound 7-[(3R)-3-aminohexahydro-lH-azepin-l-yl]-l-cyclopropyl-6-
fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid- O3,O4-bis(butyroxy-
0)borate of formula - III C.