FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTION - "A PROCESS FOR THE PREPARATION OF
BESIFLOXACIN"
2. APPLICANT(S)
(a) NAME: AJANTA PHARMA LTD.
(b) NATIONALITY: Indian
(c) ADDRESS: Ajanta House, Charkop, Kandivali (W),
Mumbai - 400067. Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION
The present invention relates to a process for the preparation Besifloxacin
BACKGROUND OF THE INVENTION
The chemical species, of the formula (I) is generically known as besifloxacin, a synthetic antibacterial agent, known to have activity against Gram-positive and Gram-negative bacteria.

The chemical species, of the formula (I) is disclosed in patent No. EP0493608B1. Preparative processes described in this patent are carried out by: (a) reacting a compound having formula (II) with a compound having formula (III) to produce a compound having formula (IV); and (b) halogenating the compound having Formula (IV) with a halogenating agent to produce the fluoroquinolone having Formula (I).
Patent No. US7632944B2 describes process for the preparation of fluoroquinolones carboxylic acids and its salt. The process comprises: (a) reacting a compound having formula (II) with a compound having formula (III) to produce a compound having formula (IV); and (b) halogenating the compound having Formula (IV) with a halogenating agent to produce fluoroquinolones having Formula (I).

Prior art processes disclosed in EP0493608B1 and US7632944B2 for the preparation of fluoroquinolones carboxylic acids provides less yield of final product, require high amount of solvent, high reaction time, unable to perform complete conversion of starting material into product and resulting final product is associated with undesirable impurities. Therefore, there is a need for an improved process for preparing Besifloxacin giving high purity and yield.
The present inventors have developed a process for preparing Besifloxacin, which is advantageous in terms of better removal of undesirable impurities, complete conversion of reactants into product, less solvent requirement, better yield profile and less reaction time requirement.
OBJECT OF INVENTION
The object of the present invention is to provide a process for the preparation of. Besifloxacin and its acceptable salt
Another object of the invention is to provide a process for the compound of formula (I) which results in complete removal of undesirable impurities, giving highly pure product, better yield profile and requires less reaction time.
SUMMARY OF INVENTION
According to one aspect of the present invention there is provided a process for the preparation of Besifloxacin Hydrochloride of formula-I

comprising:



i. Refluxing a compound having formula (II)
with compound having Formula (III)
(in)
in an organic solvent to obtain precipitate of crude compound having Formula (IV)

ii. Filtering the precipitate & washing the filtrate to obtain compound
of Formula (IV); iii. Halogenating the compound of Formula (IV) with halogenating
agent in the organic solvent to produce crude compound having
Formula (I); iv. Purifying the crude compound to obtain pure compound having
Formula (I).

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for preparing Besifloxacin that have Formula (I)

The compound having formula (I) is prepared by reacting first compound having formula (II) with second compound having formula (III) to produce compound having Formula (IV) and followed by halogenation of compound having Formula (IV) with halogenating agent. The reaction is represented as shown in Scheme 1

The process for the preparation of Besifloxacin Hydrochloride of formula-l comprising:

i. Refluxing a compound having formula (II) with compound having
Formula (III) in an organic solvent to obtain precipitate of crude
compound having Formula (IV). ii. Filtering the precipitate & washing the filtrate to obtain compound
of Formula (IV) iii. Halogenating the compound of Formula (TV) with halogenating
agent in the organic solvent to produce crude compound having
Formula (I). iv. Purifying the crude compound to obtain pure compound having
Formula (I).
The process according to present invention wherein organic solvents used in step (i) are acetone, chloroform, dichloromethane and acetonitrile, more preferably acetone, acetonitrile & most preferably acetonitrile.
The process according to present invention wherein halogenating agents used in step (ii) is sulfuryl chloride.
The process according to present invention wherein organic solvents used in step (ii) are acetic acid, formic acid, preferably acetic acid.
The process according to present invention wherein about 1 to 3 mole preferably about 1 mole of compound having Formula (II) is reacted with about 1 to 10 moles preferably about 1 to 5 moles of compound having Formula (III) in the solvent and refluxed to obtain precipitate.
The process according to present invention wherein precipitate is filtered & washed with acetonitrile to obtain compound of Formula (IV).
The process according to present invention wherein about 1 to 20 moles preferably 1 to 15 moles & more preferably about 1 to 10 moles of compound of

Formula (IV) is halogenated using halogenating agent in acetic acid at room temperature.
The process according to present invention, wherein purification step involves steps of;
i. Reacting crude compound having formula (I) with the aqueous solution of alkali, at temperature in the range of 0-100°C, preferably 0-40°C & more preferably 10-30°C. ii. Filtering the filtrate obtain in step (i) and concentrating with dilute
hydrochloric acid to obtain of crude besifloxacin hydrochloride. iii. Filtering the crude Besifloxacin hydrochloride & washing with water to obtain pure besifloxacin hydrochloride (Formula I).
The process according to present invention 1 to 20 moles preferably 1 to 15 moles & more preferably about 1 to 10 moles of compound of Formula (IV) halogenating agent sulfuryl chloride in the solvent acetic acid (5 times) with stirring at room temperature at least for 4 hour. Use of acetic acid as a solvent leads to complete reaction and reduces undesired impurities. After completion of the reaction precipitate is collected, washed with water and dried in oven to obtain yellow crystals of compound having Formula (I).
The process according to present invention preferred quantity of acetic acid solvent is in the 10-20 times weight by volume to the quantity of reactants.
The compound having Formula (I) is purified by reacting crude compound having formula (I) with the aqueous solution of alkali, mixture is stirred at temperature in the range of 0-100°C, preferably 0-40°C & more preferably 10-30°C followed by hyflo filtration. Filtrate is contacted with dilute acid and precipitate is collected by filtration, washed with water to obtain compound having Formula (I).

The yield of the compound having Formula (I) by the process of the present invention is in the range of 90-95 %
The compound having Formula (I) as prepared by the process of the present invention is highly pure with HPLC purify of about 99-99.5 %.
Compound having Formula (I) as provided by the present invention has a therapeutic utility as an antibacterial.
EXAMPLES
Example 1
l-Cyclopropyl-6-fluoro-7-(3-(R)-Amino-Hexahvdro-lH-azepin-1-yl)-4-oxoquinoline-3-carboxylic acid
100 g of l-Cyciopropyl-6,7-difluoro-4-oxoquinoline-3-carboxylic acid and 75.2 g (R)-3-Amino hexahydro-1H-azepin dissolved into 2000 ml of acetonitrile and refluxed for 4 hour. After cooling, the precipitate was collected by filtration, washed with acetonitrile to obtain 129 g of colourless crystals of the target compound (yield: 95.0%)
Example 2
7-[3('R1-Aminoperhvdroazepin-l-vl]-8-chloro-l-cvclopropvl-6-fluoro-4-oxo-l, 4-dihvdroquinoIine-3-carboxylic acid hydrochloride (Crude Besifloxacin hydrochloride)
43.8 ml of Sulfuryl chloride was added dropwise to a solution of 129 g of 1-Cyclopropyl-6-fluoro-7-(3-(R)-Amino-Hexahydro-1H-azepin-l-yl)-4-oxoquinoline-3-carboxylic acid in 1290 ml glacial acetic acid, and the mixture was stirred for 4 hour at room temperature. After an addition of water, the precipitate was collected by filtration, washed with water, dried in oven to obtain 84 g of pale yellow crystals of the target compound (yield: 54.0%)

Example 3
Purification of crude Besifloxacin hydrochloride
49.0 ml of 40% aqueous Sodium hydroxide solution was added dropwise to a suspension of 84 g crude Besifloxacin hydrochloride and 840 ml water, and mixture was stirred till clear solution at room temperature. After hyflo filtration, 89 ml 50% (v/v) dilute hydrochloric acid added dropwise in 1 to 2 hour in filtrate, stirred for 1 to 2 hour, the precipitate was collected by filtration, washed with water, dried in oven to obtain 70 g of off white crystals of the target compound (yield:83.0%)

WE CLAIM
1. A process for the preparation of Besifloxacin Hydrochloride of formula-I

comprising: v. Refluxing a compound having formula (II)

with compound having Formula (III)

in an organic solvent to obtain precipitate of crude compound having Formula (IV)

vi. Filtering the precipitate & washing the filtrate to obtain compound
of Formula (IV); vii. Halogenating the compound of Formula (IV) with halogenating agent in the organic solvent to produce crude compound having Formula (I); viii. Purifying the crude compound to obtain pure compound having Formula (I).
2. The process as claimed in claim 1 wherein organic solvents used in step (i) are acetone, chloroform, dichloromethane and acetonitrile, more preferably acetone, acetonitrile & most preferably acetonitrile.
3. The process as claimed in claim 1 wherein halogenating agents used in step (ii) is sulfuryl chloride.
4. The process as claimed in claim 1 wherein organic solvents used in step (ii) are acetic acid, formic acid, preferably acetic acid.
5. The process as claimed in claim I wherein about 1 to 3 mole preferably about 1 mole of compound having Formula (II) is reacted with about 1 to 10 moles preferably about 1 to 5 moles of compound having Formula (III) in the solvent and refluxed to obtain precipitate.
6. The process as claimed in claim 5 wherein precipitate is filtered & washed with acetonitrile to obtain compound of Formula (IV).
7. The process as claimed in claim 1 wherein about 1 to 20 moles preferably 1 to 15 moles & more preferably about 1 to 10 moles of compound of Formula (IV) is halogenated using halogenating agent in acetic acid at room temperature.
8. The process as claimed in claim 7, wherein halogenating agents used in step (ii) is sulfuryl chloride.

9. The process as claimed in claim 7 wherein acetic acid is used in range of 10-20 times weight by volume to the quantity of reactants.
10. The process as claimed in claim 1, wherein purification step involves steps of:
i. Reacting crude compound having formula (I) with the aqueous
solution of alkali, at temperature in the range of 0-100°C,
preferably 0-40°C & more preferably 10-30°C; ii. Filtering the filtrate obtain in step (i) and concentrating with dilute
hydrochloric acid to obtain of crude besifloxacin hydrochloride; iii. Filtering the crude Besifloxacin hydrochloride & washing with
water to obtain pure besifloxacin hydrochloride (Formula I).
11. A process for preparation of compound of Formula (I) substantially as
herein described and illustrated with reference to the accompanying
examples.