FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"AN IMPROVED PROCESS FOR THE PREPARATION OF
BESIFLOXACIN"
2. APPLICANT:
(a) NAME: INDOCO REMEDIES LIMITED
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(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 formed.

FIELD OF INVENTION:
The present invention relates to an improved process for the preparation of 7-[(3R)-3-aminohexahydro-lH-azepin-l-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoIine-3-carboxylic acid of formula -1 and its pharmaceutically acceptable salt.

BACKGROUND AND PRIOR ART:
The compound 7-[(5R)-3-aminohexahydro-lH-azepin-l-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula - I and its hydrochloride salt having international non proprietary 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-[(5R)-3-aminohexahydro-lH-azepin-l-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula - I (Besifloxacin), wherein 1-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxoquinoline-3-carboxyIic acid of formula - II and (R)-3-aminohexahydro-lH-azepin of formula - III were refluxed in acetonitrile, then the precipitate is washed with chloroform, methanol and ether to obtain 7-[(3R)-3-aminohexahydro-1H-azepin-1 -yl]-1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3 -carboxylic acid of formula - IV. The compound of formula - IV in chloroform was treated with sulfuryl chloride and the crude product was purified by silica gel column chromatography, then recrystallized in ethanol-chloroform to obtain 7-[(5R)-3-aminohexahydro-lH-azepin-l-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula -1. The reaction sequence is as represented in scheme -1 below.


Scheme -1
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 the compound of formula - I, wherein compound 8-chloro-l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula - V is reacted with (R)-3-[N-(3-nitroberizylidene)amino]hexahydro-lH-azepin of formula - VI to obtain 3-nitrobenzylidene protected compound of formula - VII, which is deprotected with hydrochloric acid to obtain 7-[(3R)-3-aminohexahydro-1H-azepin-1 -y1]-8-chloro-1 -cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula - I. The reaction sequence is as represented in scheme - 2 below.


The drawback of the above process involves in use of nitro protected intermediate requiring deprotection of the compound to isolate Besifloxacin and the increase number of steps.
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 of formula - II is reacted with (R)-3 - [N-(3-nitrobenzylidene)amino]hexahydro-lH-azepin of formula - VI in the presence of triethylamine in N,N-dimethylformamide to get 3-nitrobenzylidene protected compound of formula - VIII. Deprotection of the compound of formula - VIII with hydrochloric acid in solvent acetonitrile to get 7-[(3R)-3-aminohexahydro-lH-azepin-l-yl]-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula - IV. The compound of formula - IV in acetic acid was treated with sulfuryl chloride and the product obtained is purified with N,Ndimethylformamide and acetonitrile followed by water to obtain 7-[(3R)-3 -aminohexahydro-1H-azepin-1 -yl] -8-chloro-1 -cyclopropyl-6-fluoro-1,4-dihydro-

4-oxoquinoline-3-carboxylic acid of formula - I. The compound of formula - I is converted into its hydrochloride by treating with aqueous hydrochloric acid, and the hydrochloride salt is purified with mixture of acetonitrile and water. The reaction sequence is as represented in scheme - 3 below.

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.
The compound (R)-3-aminohexahydro-lH-azepin of formula - III used for the preparation of Besifloxacin, the preparation of which is described in Journal of Medicinal Chemistry, 40(7), 1090-1098 (1997), wherein the compound (R)-3-aminohexahydro-lH-azepin-2-one of formula - IX is reduced using lithium aluminium hydride in solvent tetrahydrofuran to get the compound (R)-3-aminohexahydro-lH-azepin of formula - III. The reducing agent lithium aluminium hydride used for the reaction is highly flammable, metastable at room temperature, during prolonged storage it slowly decomposes to Li3AlH6 and LiH,

pyrophoric under ambient conditions and needs storage in ethereal solvents such as ether or tetrahydrofuran to protect from decomposition.
Therefore, there remains a need for an improved process for preparing the compound 7-[(3R)-3-aminohexahydro-lH-azepin-l-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula -1 that eliminates protection/deprotection of intermediate compounds, employs safe and economical reagents for the reaction and reduces the time cycle of the reaction.
The present Inventors have come out with an improved process which ameliorates the problems in the prior art to improve the yield, safety and economy for the preparation of the compound 7-[(5R)-3-aminohexahydro-lH-azepin-l-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula - I starting with an improved method for preparation of (R)-3-aminohexahydro-lH-azepin of formula - III using safe and plant friendly reagent sodium bis(2-methoxyethoxy)aluminium hydride as reducing agent, which has good solubility in aromatic solvents, its solutions are more stable to moisture and air, it is easier to handle and safer to use; requires no special handling or equipment modification.
OBJECTIVE OF THE INVENTION:
The main objective of the present invention is to prepare 7-[(3R)-3-armnohexahydro-lH-azepin-1 -yl]-8-chloro-l -cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula -1 and its pharmaceutically acceptable salt by robust, rigid and industrial friendly process.
Another objective of the present invention is to prepare (R)-3-aminohexahydro-lH-azepin of formula - III using safe and industrial friendly reagent.
SUMMARY OF THE INVENTION:
The present invention provides an improved process for the preparation of 7-[(3i2)-3-aminOhexahydro-lH-azepin-l-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula - I and its pharmaceutically acceptable salt


comprising the steps of: i. reacting the compound (R)-3-ammohexahydro-lH-azepin-2-one of formula - DC

with sodium bis(2-methoxyethoxy)aluminium hydride to get the compound (R)-3-aminohexahydro-lH-azepin of formula - III or its acid addition salt of formula -IIIA;

ii. reacting the compound of formula - III or its acid addition salt of Formula - IIIA with l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula - II

in presence of a polar aprotic solvent at reflux to get the compound l-[(3R)-3-aminohexahydro-1H-azepin-1 -yl] -1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula - IV;


iii. chlorinating the compound of formula - IV with sulruryl chloride in combination with formic acid yields the compound 7-[(3R)-3-aminohexahydro-lH-azepin-l-yl]-8-chloro-l-cyclopropyl-6~fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula -I; and
iv. converting the compound of formula - I into its pharmaceutically acceptable acid addition salt.
DETAILED DESCRIPTION OF THE INVENTION:
The present inventions provides an improved process for the preparation of compound 7-[(3R)-3-aminohexahydro-lH-azepin-l-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula -1 and its pharmaceutically acceptable salt.

In one aspect of the present invention the compound (i?)-3-aminohexahydro-l-f/-azepin-2-one of formula - IX is reacted with the reagent sodium bis(2-methoxyethoxy)aluminium hydride in presence of solvent to get the compound (/?)-3-aminohexahydro-l#-azepin of formula - III or its acid addition salt of formula - IIIA. The reaction is carried out at temperature of 0°C to 70°C. The solvent used for the reaction are selected from tetrahydrofuran, toluene, xylene and cyclohexane either single or mixture thereof, wherein the preferred solvent used is tetrahydrofuran and toluene either single or mixture

thereof. The most preferred solvent used for the reaction is tetrahydrofuran. The reaction. is carried out at temperature range of 0°C to 70°C, wherein the preferred temperature for the reaction is 25°C to 70°C. The most preferred temperature for the reaction is 60°C to 70°C. After completion of the reaction the compound (R)-3-aminohexahydro-lH-azepin of formula - III is isolated as free base or as its acid addition salt of formula - IIIA. The acid addition salt prepared is selected from hydrochloride, hydrobromide, sulphate or phosphate salts, wherein the preferred salt is hydrochloride salt prepared by using dry hydrochloric acid gas or its solution in organic solvent or water. The acid addition salt of Formula - III A can be monovalent or divalent salt of the respective acid used. The reaction sequence can be represented as given below in scheme - 4.

In another aspect of the present invention the compound (R)-3-aminohexahydro-lH-
azepin of formula - III or its acid addition salt of formula - IIIA is reacted with the
compound 1 -cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid of
formula - II in presence of polar aprotic solvent at reflux temperature to get the
compound 7-[(3R)-3-aminohexahydro-1H-azepin-1-yl]-1-cyclopropyl-6-fluoro-1,4-
dihydro-4-oxoquinoline-3-carboxylic acid of formula - IV. The polar aprotic solvent used for the reaction is selected from N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide and acetonitrile, wherein the preferred solvent for the reaction is N,N-dimethylformamide and acetonitrile either single or mixture thereof, the most preferred solvent used for the reaction is acetonitrile.
In another aspect of the invention when acid addition salt of the compound (R)-3-aminohexahydro-l.tf-azepin of formula - IIIA is used for the reaction, then the reaction is carried out in presence of a base selected from sodium hydroxide, potassium hydroxide,

potassium carbonate, sodium bicarbonate, triethylamine and pyridine. The most preferred base used for the reaction is triethylamine. The compound used for the present invention is acid addition salt of the compound (R)-3-aminohexahydro-lH-azepin of formula - IIIA.
In yet another aspect of the present invention the compound 7-[(5R)-3-aminohexahydro-1H-azepin-1 -yl] -1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3 -carboxylic acid of formula - IV is chlorinated using reagent sulfuryl chloride in combination with formic acid to get the compound 7-[(3R)-3-aminohexahydro-1H-azepin-1 -yl]-8-chloro-1 -cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula -1.
Earlier the chlorination of the compound of formula - IV 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-lH-azepin-l-yl]-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula - IV 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-[(5R)-3-aminohexahydro-lH-azepin-l-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula -1.
The inventors ameliorated the disadvantages associated with the prior art by using sulfuryl chloride in combination with formic acid. In the present invention the reaction was carried out using reduced molar quantity of sulfuryl chloride for 1.0 mole of the compound of formula - IV. 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 - IV, 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-IH-azepin-l-yl]-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of

formula - IV. The compound 7-[(3R)-3-aminohexahydro-lH-azepin-l-yl]-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula - IV is freely soluble in 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 the compound 7-[(3R)- 3.aminohexahydro-1H-azepin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula -1 [Besifloxacin Base]. The above observation is further illustrated in the following table 1.

Sr.
No. 1-Cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid Sulfuryl chloride Solvent In process HPLC %
Theoretical
Yield %Purity
by HPLC
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% 65.0% to 75.0 % 99.59%
* Checked by TLC; ** SI - Single Impurity
Table 1 In another aspect of the present invention the compound 7-[(3R)-3-aminohexahydro-lH-azepin-1 -yl]-8-chloro-1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula -1 is further converted to its pharmaceutically acceptable salt in presence of solvent.
In accordance with the above embodiment the compound of formula -1 is taken in solvent at the temperature of 20 - 30°C and under stirring hydrochloric acid is added either in gaseous form or its solution in organic solvent or water to isolate the compound Besifloxacin hydrochloride. The solvent used is selected from methanol, ethanol, isopropanol and water either single or mixture thereof. The hydrochloride salt formed precipitates out is stirred for one hour and filtered to get the solid product of the compound 7-[(3R)-3-aminohexahydro-lH-azepin-l-yl]-8-chloro-l-cyclopropyl-6-fluoro-

l,4-dihydro-4-oxoquinoline-3-c:arboxylic acid [Besifloxacin hydrochloride] of formula -I. The compound Besifloxacin hydrochloride obtained if required is optionally purified in suitable solvent to isolate pure compound.
The reaction sequence of the present invention is as given in Scheme 5 below.

Scheme 5 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 (R)-3-aminohexahydro-lH-azepin.
In a dry flask, charged tetrahydrofuran (200 ml) and sodium bis(2-methoxyethoxy)aluminium hydride (280 ml) at 0°C. Charged (R)-3-aminohexahydro-lH-azepin-2-one hydrochloride (40 gm) in 15 minutes maintaining the temperature of the reaction mass between 0 to 5°C. Raised the temperature of the reaction mixture to attain 25 - 30°C and then to reflux. Monitored the reaction for completion on TLC, after

completion of the reaction, cooled the reaction mixture to 0°C and slowly charged water
(170 ml) and maintained under stirring for 15 min. Added potassium carbonate (50 gm) to
the reaction mixture and stirred for 1 hour. Filtered off solid and washed with
tetrahydrofuran (200 ml) and distilled off organic layer under vacuum. Residue was
striped off with cyclohexane at 40°C to isolate the compound (R)-3-aminohexahydro-lH-
azepin.
Dry Wt: 22 gm
Example 2: Preparation of (R)-3-aminohexahydro-lH-azepin dihydrochloride.
In a dry flask charged tetrahydrofuran (200 ml) and sodium bis(2-methoxyethoxy)aluminium hydride (280 ml) at 0°C. Charged (R)-3-aminohexahydro-lH-azepin-2-one hydrochloride (40 gm) in 15 min maintaining the temperature of the reaction mass between 0 to 5°C. Raised the temperature of the reaction mixture to attain 25 - 30°C and then to reflux. Monitored the reaction for completion on TLC, after completion of the reaction, cooled the reaction mixture to 0°C and slowly charged water (170 ml) and maintained under stirring for 15 min. Added potassium carbonate (50 gm) to the reaction mixture and stirred for 1 hour. Filtered off solid and washed with tetrahydrofuran (200 ml) and distilled off organic layer under vacuum up-to half the volume. This organic layer with (R)-3-aminohexahydro-lH-azepin passed hydrochloric acid gas to achieve pH=2. Passing of hydrochloric acid gas was stopped and the reaction was allowed to stir for 30 min. Filtered off solid and washed with toluene (10 ml) to get the compound (R)-3-aminohexahydro-lH-azepin dihydrochloride. Dried the compound till constant weight. Dry wt: 26 gm.
Example 3: Preparation of 7-[(3R)-3-aminohexahydro-lH-azepin-l-yl]-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid.
In a flask charged acetonitrile (3.0 lit), l-cyclopropyl-l,4-dihydro-6,7-diflouro-4-oxoquinoline-3-carboxylic acid (40 gm, 1 eq.) and (R)-3-aminohexahydro-lH-azepin (20.66 gm, 1.2eq.) and stirred. Raised the temperature of the reaction mass to 80 - 85°C and maintained for 24 - 48 hours. After completion of reaction cooled the reaction mass to 25 - 30°C and maintained for 3 hours. Filtered the solid mass and washed with acetonitrile (80 ml). Wet cake was leached in acetonitrile (200 ml) at 50 - 55°C for 1

hour. Cooled the reaction mass to 25 - 30°C and filtered, washed with acetonitrile (80 ml) to get the compound 7-[(5R)-3-aminohexahydro-lH-azepin-l-yl]-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid. Dried the product at 55 - 60°C till constant weight. Dry wt = 36 gm.
Example 4: Preparation of 7-[(5R)-3-aminohexahydro-lH-azepin-l-yl]-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylicacid.
In a flask containing acetonitrile (200 ml) charged (R)-3-aminohexahydro-lif-azepin dihydrochloride (16.9 gm) followed by triethylamine (31.5 gm) and stirred. Raised the temperature of the reaction mass to 60°C and stirred for 30 minutes. Charged to the reaction mass l-cyclopropyl-l,4-dihydro-6,7-diflouro-4-oxoquinoline-3-carboxylic acid (20gm, leq.) and acetonitrile(1300 ml). Raised the temperature of the reaction mass to 80°C and maintained the reaction mass at 80 - 85°C for 24 - 48 hours. After completion of the reaction cooled the reaction mass to 25 - 30°C and maintained for 3 hours. Filtered the solid mass and washed with acetonitrile (100 ml). Wet cake was leached in acetonitrile (100 ml) at 50 - 55°C for 1 hour. Cooled the reaction mass to 25 - 30°C and filtered, washed with acetonitrile (100 ml) to get the compound 7-[(5R)-3-aminohexahydro-lH-azepin-l-yl]-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid. Dried the product at 55 - 60°C till constant weight. Drywt = 20gm.
Example 5: Preparation of 7-[(5R)-3-aminohexahydro-lH-azepin-l-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinou*ne-3-carboxyIicacid [Besifloxacin].
In a flask containing formic acid (140 ml) charged 7-[(5R)-3-aminohexahydro-lH-azepin-l-yl]-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (40 gm leq.) and cooled under stirring to 15 - 20°C. Charged sulfuryl chloride (22.52 gm 1.5 eq.) to the reaction mass maintaining temperature of the reaction mass at 15 - 20°C and stirred for one hour at 20 - 25°C. After completion of reaction charged N,N-dimethylformamide (320 ml) and maintained the slurry for 6 hours at 20 - 25°C. Raised the temperature of the reaction mass to 50 - 55°C and maintained for one hour at the same temperature. Cooled the reaction mass to 25 - 30°C, filtered the solid and washed with acetonitrile (120 ml). Wet solid mass was taken in N,N-dimethylformamide (320 ml) and stirred at 55 - 60°C

for one hour. Cooled and filtered the solid at 30 - 35°C, washed with chilled water (40 ml) followed by acetonitrile (120 ml) to get the compound 7-[(5R)-3-aminohexahydro-IH-azcpin-1 -yl]-8-chloro-1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Dried the product at 55 - 60°C till constant weight. Dry wt = 28 gm.
Example 6: Preparation of 7-[(3R)-3-aminohexahydro-lH-azepin-l-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride [Besifloxacin hydrochloride].
In a flask charged methanol (600 ml) and 7-[(3R)-3-aminohexahydro-lH-azepin-l-yl]-8-
chloro-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (40 gm)
and stirred at 25 - 30°C. To the reaction mass dropwise charged concentrated
hydrochloric acid (25.6 ml) maintaining temperature at 20 - 25°C. After complete
addition, maintained the slurry for one hour at 20 - 25°C. Filtered and washed with
methanol (80 ml) to get the compound 7-[(5R)-3-aminohexahydro-lH-azepin-l-yl]-8-
chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid
hydrochloride [Besifloxacin hydrochloride] Dried the product at 60 - 65°C under vacuum till constant weight. Dry wt = 32 gm.

We Claim,
1. A process for the preparation of 7-[(3R)-3-aminohexahydro-lH-azepin-l-yl]-8-chloro-1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula -1 and its pharmaceutically acceptable salt

comprising the steps of; i. reacting the compound (R)-3-aminohexahydro-lH-azepin-2-one of formula - IX

with sodium bis(2-methoxyethoxy)aluminium hydride in presence of solvent to get the compound (R)-3-aminohexahydro-lH-azepin of formula - III or its acid addition salt of formula - IIIA;

(wherein HX is hydrochloride, hydrobromide, sulphate or phosphate)
ii. reacting the acid addition salt compound of formula - IIIA with 1-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid formula - II


in presence of a polar aprotic solvent and a base at reflux temperature to get the compound 7-[(3R)-3-aminohexahydro-lH-azepin-1 -yl]-1 -cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula - IV;

iii. chlorinating the compound of formula - IV with sulfuryl chloride in combination with formic acid yields the compound 7-[(3R)-3-aminohexahydro-lH-azepin-l-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula -1;
iv. reacting the compound of formula - I with an acid in presence of solvent to. isolate the acid addition salt of the compound of formula -1; and
v. optionally purifying the acid addition salt of the compound of formula - I to get pure acid addition salt compound of formula -1.
2. The process as claimed in claim 1, wherein the solvent used in step (i) is selected from the group consisting of tetrahydrofuran, toluene, xylene and cyclohexane either single or mixture thereof.
3. The process as claimed in claim 2, wherein the solvent used is selected from tetrahydrofuran and toluene either single or mixture thereof.
4. The process as claimed in claim 1, wherein the reaction in step (i) is carried out at temperature in the range of 0°C to 70°C.

5. The process as claimed in claim 4, wherein the reaction is carried out at temperature in the range of 60°C to 70°C.
6. The process as claimed in claim 1, wherein the acid addition salt of formula - IIIA in step (ii) are selected from the group consisting of hydrochloride, hydrobromide, sulphate or phosphate salt.
7. The process as claimed in claim 6, wherein the acid addition salt of formula - IIIA is hydrochloride salt.
8. The process as claimed in claim 1, wherein the polar aprotic solvent used in step (ii) for the reaction is selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide and acetonitrile.
9. The process as claimed in claim 1, wherein the base used in step (ii) for the reaction is selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, triethylamine and pyridine.
10. The process as claimed in claim 9, wherein the base used for the reaction is triethylamine.
11. The process as claimed in 1, wherein the molar ratio of the compound 7-[(3R)-3-aminohexahydro-lH-azepin-l-yl]-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula - IV to sulfuryl chloride in the range of 1: 1.2 moles to 1: 1.7 moles.
12. The process as claimed in claim 1, wherein the solvent used in step (iv) is selected from the group consisting of methanol, ethanol, isopropanol and water either single or mixture thereof.

13. The process as claimed in claim 1, wherein the acid addition salt of formula -1 compound in step (iv) is hydrochloride salt prepared by adding either hydrochloric acid gas, or solution of hydrochloric acid in organic solvent or water to the compound of Formula I.