PROCESS FOR THE PREPARATION OF BALOFLOXACIN DIHYDRATE
INTRODUCTION
Aspects of the present application relates to process for the preparation of balofloxacin dihydrate.
The drug compound having the adopted name "balofloxacin" is a third generation fluoroquinolone antibacterial drug, and has a chemical name 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-yl]-4-oxoquinoline-3-carboxylic acid, and is represented by structural Formula I.
(Structure Removed)
Balofloxacin dihydrate, represented by Formula II, is chemically known as 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-yl]-4-oxoquinoline-3-carboxylic acid dihydrate, and is represented by Formula II.
(Formula Removed)
Balofloxacin monohydrate, represented by Formula III, is chemically known as 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-yl]-4-oxoquinoline-3-carboxylic acid monohydrate, and is represented by Formula III.
(Formula Removed)
US 5,051,509 claims 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-yl]-4-oxoquinoline-3-carboxylic acid (i.e. balofloxacin of Formula I). This patent also discloses the process for the preparation of balofloxacin with 30% yield, by reacting 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (i.e. DFQ of Formula IV) with 3-methylaminopiperidine dihydrochloride (i.e. 3-MAP dihydrochloride of Formula V) employing acetonitrile as solvent and triethylamine as base (Scheme-1).The process of US 5,051,509 employs costly solvent acetonitrile and triethylamine as base which is considered to be toxic and harmful. Furthermore, the process involves the use of column chromatography which is not preferred commercially for large scale production.
(Scheme Removed)
US 5,597,923 claims 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-
methylaminopiperidin-1-yl]-4-oxoquinoline-3-carboxylic acid dihydrate (i.e.
balofloxacin dihydrate of Formula II). US 5,597,923 also discloses 1-cyclopropyl-6-
fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-yl]-4-oxoquinoline-3-
carboxylic acid monohydrate (i.e. balofloxacin monohydrate of formula III). US
5,597,923 further discloses the process for the preparation of balofloxacin
dihydrate (scheme-2) by reacting DFQ-BF2 Ester with 3-methylaminopiperidine
dihydrochloride (i.e. 3-MAP dihydrochloride of Formula V) employing methylene
dichloride as solvent and triethylamine as base to give balofloxacin boron
difluoride complex (Q-35-BF2), which is further hydrolyzed with aqueous sodium hydroxide to afford crude balofloxacin of Formula I. Crude balofloxacin thus obtained is converted to balofloxacin dihydrate (Type-I crystal) of Formula II.
Scheme-2
(Scheme Removed)
The process of US 5,597,923 employs boron fluoride chelate which is considered to be hazardous on industrial scale.
US 5,597,923 also claims that 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-yl)-4-oxoquinoline-3-carboxylic acid dihydrate (i.e. balofloxacin dihydrate of Formula II) has been obtained by recrystallizing 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-y l)-4-oxoquinoline-3-carboxylic acid (i.e. balofloxacin of Formula I) from a 50:50 mixture of water and ethanol. US Patent Number 5,597,923 further discloses that 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopipehdin-1-yl)-4-oxoquinoline-3-carboxylic acid monohydrate (i.e. balofloxacin monohydrate of Formula III) has been obtained by recrystallizing 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-y l)-4-oxoquinoline-3-carboxylic acid (i.e. balofloxacin of Formula I) from methanol.
US 5,869,661 claims a method of producing balofloxacin, which is characterized by adding an alkylboric acid ester to a 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (i.e. DFQ of Formula IV),
and 3-methylaminopiperidine; and condensing the reaction mixture with heating in the absence of a solvent or in the presence of a solvent.
US 7,875,722 claims a method for producing balofloxacin, a salt thereof, or a hydrate, wherein the method comprises reacting a mixture comprising 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid {i.e. DFQ of Formula IV), a salt of a 3-methylamino piperidine and a trifluoroboron compound (trifluoroboron-diethyl ether complex or a trifluoroboron-tetrahydrofuran complex) in a solvent and in the presence of a base, to form a boron chelate compound, and further removing a boron chelate moiety from the boron chelate compound.
US 5,157,117 claims 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3- quinolinecarboxylic acid-O3,O4) bis (acetate-O)-borate {i.e. DFQ-B(OAc)2 of Formula VI) and 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-y l)-4-oxoquinoline-3-carboxylic acid borate complex {i.e balofloxacin borate complex of Formula VII).
(Formula Removed)
There still remains a need to provide process for the preparation of balofloxacin dihydrate, which is simple, cost effective, commercially viable, sustainable, eco-friendly, and free from impurities.
The main object of the present application is to provide cost effective process for the preparation of balofloxacin dihydrate of Formula II.
Yet another objective of the present application is to provide a process for the preparation of balofloxacin dihydrate of Formula II, free from impurities like DFQ of Formula IV and O-desmethyl balofloxacin of Formula VIII.
(Formula Removed)
BRIEF DESCRIPTION OF DRAWINGS
Fig. 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of balofloxacin dihydrate obtained according to Example 1;
Figure 2 is an illustration of a PXRD pattern of balofloxacin hydrochloride obtained according to Example 4, Step 2;
Figure 3 is an illustration of a PXRD pattern of balofloxacin monohydrate obtained according to Example 5;
Figure 4 is an illustration of an Infrared absorption spectra for balofloxacin hydrochloride obtained according to Example 4, Step 2;
Figure 5 is an illustration of an Infrared absorption spectra for balofloxacin dihydrate obtained according to Example 1;

Figure 6 is an illustration of an Infrared absorption spectra for balofloxacin monohydrate obtained according to Example 5.
SUMMARY
In an aspect, the present application includes a one pot process for the preparation of balofloxacin dihydrate of Formula II,
(Formula Removed)
the embodiments comprising one or more of the following steps, individually or in the sequence recited:
i) reacting 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester of Formula IX
(Formula Removed)
with acetoxyborate complex;
ii) condensing 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid-O3,O4) bis (acetate-O)-borate of Formula VI
(Formula Removed)
as obtained from step i) involving the use of acetoxyborate complex, with 3-methylaminopiperidine dihydrochloride of Formula V
(Formula Removed)
in the presence of a base in a suitable solvent at a suitable temperature for a suitable time;
iii) adjusting the pH in the range of 9.0 to12.0 of solution of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-yl)-4-oxoquinoline-3-carboxylic acid borate complex of Formula VII
(Formula Removed)
as obtained from step ii) with a base;
iv) adjusting the pH in the range of 8.0 to 9.0 of the solution of step iii) with an
acid;
v) optionally, isolating balofloxacin hydrochloride of Formula X

(Formula Removed)
from step iii) by adjusting the pH with hydrochloric acid;
vi) isolating crude balofloxacin from solution of step iv);
vii) adding water to the crude balofloxacin of step vi);
viii) adjusting the pH in the range of 1.0 to 3.0 of the solution of step vii) with an
acid; ix) extracting the solution of step viii) with a non aqueous solvent; x) adjusting the pH in the range of 8.0 to 9.0 of aqueous layer as obtained
from step ix) with a base;
xi) isolating balofloxacin dihydrate of Formula II in pure form; and xii) optionally, converting balofloxacin hydrochloride of Formula X of step v) to
balofloxacin dihydrate of Formula II
(Formula Removed)
or balofloxacin monohydrate of Formula III.
(Formula Removed)
DETAILED DESCRIPTION
All temperatures are in degrees Celsius unless specified otherwise. All measurements made are at about 25°C and about atmospheric pressure, and all percentages and ratios used herein are by weight of the total composition, unless otherwise designated.
As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements that are not recited. The terms "having" and "including" are also to be construed in the same manner. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute term or value. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those having skill in the art. This includes the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
In an aspect, the present application includes a process for the preparation of balofloxacin dihydrate of formula II.
(Formula Removed)
1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester of Formula IX may be prepared using any processes known in the art.
In another aspect of the present application actetoxyborate complex, is generated in-situ using acetic acid, zinc chloride, acetic anhydride and boric acid.
In an embodiment of the present application, the said base in step ii) and iii) is an inorganic base.
Inorganic base in steps (ii) and (iii) includes, but are not limited to: carbonates, bicarbonates and hydroxides of alkali metals and alkaline earth metals, such as, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, and the like, and any mixtures thereof.
In another embodiment of the present application, the said base in step x) is aqueous ammonia.
Suitable solvent in step ii) and ix) include, but are not limited to: non aqueous solvent.
Non aqueous solvent in steps ii) and ix) includes, but are not limited to: halogenated solvents such as methylene dichloride; esters such as ethyl acetate; ketones such as methyl isobutyl ketone; hydrocarbon such as cyclohexane, toluene; ethers such as methyl tertiary butyl ether and the like, and any mixtures thereof.
Suitable temperatures that may be employed for condensing 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3- quinolinecarboxylic acid-O3,O4) bis (acetate-O)-borate of Formula VI with 3-methylaminopiperidine dihydrochloride of Formula V in step ii) are between 20°C. to 50°C.
Suitable times for condensing 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3- quinolinecarboxylic acid-O3,O4) bis (acetate-O)-borate of Formula VI with 3-methylaminopiperidine dihydrochloride of Formula V in step ii) depend on the temperature and other conditions, and may be generally less than about 10 hours, or less than about 7 hours, or less than about 5 hours, or any other suitable times. Longer times are also suitable.
In an embodiment of the present application, the pH of the solution of step iii) is adjusted in the range of 9.0 to12.0, preferably in the range of 10.0 to 11.0.

In an embodiment of the present application, the pH of the solution of steps iv) and x) is adjusted in the range of 8.0 to 9.0, preferably in the range of 8.4 to 8.6.
Suitable acid in step iv) and step viii) include, but are not limited to: hydrochloric acid, sulphuric acid, acetic acid and the like, and any mixtures thereof.
In an embodiment of the present application, the pH of the solution of step viii) is adjusted in the range of 1.0 to 3.0.
In the present process for the preparation of balofloxacin dihydrate of formula II, optionally, balofloxacin hydrochloride of Formula X can be isolated in step v).
Further, balofloxacin hydrochloride of Formula X of step v) may be converted into balofloxacin dihydrate of Formula II or balofloxacin monohydrate of Formula III.
The present process for the preparation of balofloxacin dihydrate, and acid-base workup affords high purity and greater yield of balofloxacin dihydrate.
The excess use of boric acid and zinc chloride may lead to formation of impure complex. Therefore, the excess use of boric acid and zinc chloride is avoided in present process.
Acetic acid and acetic anhydride should be completely distilled to avoid the preparation of impure borate complex in present process.
The present process for the preparation of balofloxacin of formula I avoids excess usages of costly reagent(s) such as 3-methylaminopiperidine dihydrochloride of Formula V. In the present process, 0.16 to 0.19 mole of 3-methylaminopiperidine dihydrochloride is employed for 0.155 mole of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester formula IX which makes the present process cost effective.

Further, the present process for the preparation of balofloxacin dihydrate of formula II avoids use of harmful, costly and toxic solvent(s)/reagent(s) such as acetonitrile which makes the present process cost effective and sustainable.
All aspects of the present application such as base, temperature, reaction conditions should be strictly followed to avoid the preparation of impurities such as DFQ of Formula IV and O-desmethyl balofloxacin of Formula VIII. The use of methylene dichloride for extractions in step ix) of present process plays a vital role in keeping the impurities viz.DFQ of Formula IV in balofloxacin dihydrate under limit.
The aqueous layer of step x) should be fully degassed to remove dissolved solvents to maintain residual solvent under limit in balofloxacin dihydrate of Formula II.
Certain aspects and embodiments of the present application are described in further details by the examples below, which are provided only for the purpose of illustration and are not intended to limit the scope of the application in any manner.
EXAMPLE 1: Preparation of balofloxacin dihydrate
To a stirred solution of acetic acid (100 mL), zinc chloride (0.05 g, 0.4 mmol) and acetic anhydride (75 g, 0.7353 mol), boric acid is added in three lots (3x 3.66 g, 0.18 mol) into reaction mixture at 35C. to 40°C. The reaction mixture is stirred for 30 minutes at 35C. to 40°C. 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester (50 g,0.155 mol) is added at 35C. to 40°C. The temperature of the reaction mass is increased to 115C. to 120C. and allowed to stir at the same temperature for 120 minutes. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to get 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid-O3,O4) bis (acetate-O)-borate as a residue which is poured in methylene dichloride (150 mL). The reaction mixture is stirred at 20C. to 25 C. for 15 minutes followed by addition of 3-methylaminopiperidine dihydrochloride (39 g,0.208 mol) and a dilute solution of triethyl amine [100 mL

(0.713 mol) in 100 mL of methylene dichloride] at 20°C. to 25°C. The reaction mixture is stirred for 5 hours to 7 hours at 35 C. to 40°C. After completion of the reaction, the reaction mixture is concentrated under reduced pressure and concentrated mass is diluted with water (450 mL). The reaction mass is stirred for 15 minutes followed by addition of aqueous sodium hydroxide solution [60 g (1.5 mol) in 250 mL of water] and the reaction mixture is stirred for 2 hours to 3 hours. After completion of the reaction, the pH of the reaction mass is adjusted to 8.4-8.5 with dilute hydrochloric acid to give crude product which is filtered and washed with water. The wet product is suspended in 750 mL of water and pH is adjusted to 2.0-3.0 with dilute hydrochloric acid and the aqueous layer is extracted with 50 mL of methylene dichloride to remove impurities. The pH of the degassed aqueous layer is adjusted to 8.4-8.5 with aqueous ammonia and allowed to stir for 2 hours at 20C. to 25C. for complete crystallization. The precipitated solid is filtered, washed with water and dried to afford 59 g of the title compound. (HPLC Purity: 98.48 %, Water content: 9.15%).
EXAMPLE 2: Preparation of balofloxacin dihydrate
To a stirred solution of acetic acid (50 mL), zinc chloride (0.05 g, 0.4 mmol) and acetic anhydride (75 g, 0.7353 mol), boric acid is added in three lots (3x 3.66 g, 0.18 mol) into reaction mixture at 35C. to 40°C. The reaction mixture is stirred for 15 minutes at 35C. to 40°C 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester (50 g,0.155 mol) is added at 35C. to 40°C. The temperature of the reaction mass is increased to 115C. to 120C. and allowed to stir at the same temperature for 120 minutes. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to get 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3- quinolinecarboxylic acid-O3,O4) bis (acetate-O)-borate as a residue which is poured in methylene dichloride (150 mL). The reaction mixture is stirred at 20C. to 25C. for 15 minutes followed by addition of 3-methylaminopiperidine dihydrochloride (40 g,0.214 mol) and sodium carbonate (110 g, 1.04 mol) at 20C. to 25°C. The reaction mixture is stirred for 5 hours to 7 hours at 35C. to 40°C After completion of the reaction, the reaction mixture is concentrated under reduced pressure and concentrated mass is diluted with water (750 mL). The reaction mass is stirred for 15 minutes followed

by addition of aqueous sodium carbonate solution [90 g (0.85 mol) in 300 mL of water] to adjust the pH to 10.5 at 20°C. to 25°C. The reaction mixture is stirred for 2 hours to 3 hours at 75C. to 85oC. After completion of the reaction, the pH of the reaction mass is adjusted to 8.4-8.5 with dilute hydrochloric acid to give crude product which is filtered, washed with water and dried to afford 52 g of the title compound. (HPLC Purity: 99.57 %, Water content: 8.8%).
EXAMPLE 3: Preparation of balofloxacin dihydrate
To a stirred solution of acetic acid (50 mL), zinc chloride (0.05 g, 0.4 mmol) and acetic anhydride (75 g, 0.7353 mol), boric acid is added in three lots (3x 3.66 g, 0.18 mol) into reaction mixture at 35°C. to 40°C. The reaction mixture is stirred for 15 minutes at 35C. to 40°C. 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester (50 g,0.155 mol) is added at 35C. to 40°C. The temperature of the reaction mass is increased to 115C. to 120C. and allowed to stir at the same temperature for 120 minutes. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to get 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3- quinolinecarboxylic acid-O3,O4) bis (acetate-O)-borate as a residue which is poured in methylene dichloride (300 mL). The reaction mixture is stirred at 20C. to 25°C. for 15 minutes followed by addition of 3-methylaminopiperidine dihydrochloride (35 g,0.187 mol) and sodium carbonate (75 g, 0.70 mol) at 20C. to 25°C. The reaction mixture is stirred for 5 hours to 7 hours at 35C. to 40°C. After completion of the reaction, the reaction mixture is concentrated under reduced pressure and concentrated mass is diluted with water (750 mL). The reaction mass is stirred for 15 minutes followed by addition of aqueous sodium carbonate solution [50 g (0.47 mol) in 750 mL of water] to adjust the pH to about 10.5 at 20°C. to 25°C. The reaction mixture is stirred for 2 hours to 3 hours at 80°C. to 90°C. After completion of the reaction, the pH of the reaction mass is adjusted to 8.4-8.5 with dilute hydrochloric acid to give crude product which is filtered, washed with water. The wet product is suspended in 1500 mL of water and pH is adjusted to 1.5-2.0 with dilute hydrochloric acid and the aqueous layer is extracted with methylene dichloride (3 x 50 mL) to remove impurities. The pH of the degassed aqueous layer is adjusted to 8.4-8.5 with aqueous ammonia solution at 20C. to 25°C. The temperature of the reaction

mass is increase to 80C. to 95°C. and allowed to stir for 2 hours, cooled to 50°C. The precipitated solid is filtered, washed with water and dried to afford 52g of the title compound. (HPLC Purity: 99.99 %, Water content: 8.83%).
EXAMPLE 4: Preparation of balofloxacin hydrochloride
STEP 1: Preparation of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3- quinolinecarboxylic acid-O3,O4) bis (acetate-O)-borate [DFQ-B(OAc)2]
To a stirred solution of acetic acid (20 ml_), zinc chloride (0.02 g, 0.15 mmol) and acetic anhydride (29.6 ml_, 0.290 mol), boric acid is added (3.9 g, 0.0625 mol) into reaction mixture at 38C. to 40°C. The reaction mixture is stirred for 15 minutes at 35°C. to 40°C. 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester (20 g,0.0619 mol) is added at 38C. to 40 C The temperature of the reaction mass is increased to 110C. to 120C. and allowed to stir at the same temperature for 120 minutes. After completion of the reaction, the reaction mixture is concentrated under reduced pressure and again co-distilled with cyclohexane (20 mL) in vacuum. Cyclohexane (80 mL) is added to the reaction mixture at 60C. to 70°C, stirred for 1 hour, cooled to 20°C. to 25C. and stirred for 2 hours. The precipitated solid is filtered, washed with cyclohexane and dried to afford 26 g of the title compound. (HPLC Purity: 98.77 %).
STEP 2: Preparation of balofloxacin hydrochloride
A mixture of 3-methylaminopiperidine dihydrochloride (40 g, 0.213 mol), triethyl amine (26.1 g, 0.258 mol) and methylene dichloride (50 mL) is stirred for 15 minutes at 20°C. to 25°C. A solution of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3- quinolinecarboxylic acid-O3,O4) bis (acetate-O)-borate [DFQ-B(OAc)2] [25 g (0.059 mol) in 50 mL of methylene dichloride] is added into the reaction mixture and stirred for 2 hours at 20C. to 25°C. After completion of the reaction, the reaction mixture is concentrated under reduced pressure and methanol (200 mL) is added into the reaction mixture. An aqueous solution of sodium hydroxide [8 g (0.23mol) in 20 ml of purified water] is added into the

reaction mixture at 20C. to 25°C. The reaction mixture is stirred at 75C. to 80°C.for 2hours. After completion of reaction, the pH of the reaction mass is adjusted to about 1.0-1.5 with dilute hydrochloric acid at 20C. to 25°C. The precipitated solid is filtered, washed with mixture of methanol and water and dried to afford 19.2 g of the title compound. (HPLC Purity: 97.53 %; water content: 6%).
EXAMPLE 5: Preparation of balofloxacin monohydrate
Balofloxacin hydrochloride of example 4 (5 g, 0.013 mol) is suspended in a mixture of methanol (40 mL) and water (10 mL) at 20C. to 25C. and the pH of the reaction mixture is adjusted to about 8.5 with 25% aqueous sodium hydroxide solution. The reaction mixture is stirred at 20C. to 25C. for 2 hours.. The precipitated solid is filtered, washed with aqueous methanol and dried to afford 3.0 g of the title compound (HPLC Purity: 99.43 %; water content: 3.5%).
EXAMPLE 6: Preparation of balofloxacin dihydrate
Balofloxacin hydrochloride of example 4 (5 g, 0.013 mol) is suspended in a mixture of methanol (10mL) and water (40 mL) at 20°C. to 25°C The pH of the reaction mixture is adjusted to about 8.5 with 25% aqueous sodium hydroxide solution. The reaction mixture is stirred at 20C. to 25°C. for 2 hours. The precipitated solid is filtered, washed with aqueous methanol and dried to afford 4.2 g of the title compound (HPLC Purity: 96.6 %; water content: 9.0%).

We Claim:
1. A one pot process for the preparation of balofoxacin dihydrate of Formula II,
(Formula Removed)
comprising one or more of the following steps, individually or in the sequence recited:
(i) reacting 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester of Formula IX,
(Formula Removed)
with acetoxyborate complex;
(ii) condensing 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3- quinolinecarboxylic acid-O3,O4) bis (acetate-O)-borate of Formula VI,
(Formula Removed)
as obtained from step i) involving the use of acetoxyborate complex, with 3-methylaminopiperidine dihydrochloride of Formula V,
(Formula Removed)
in the presence of a base in a suitable solvent at a suitable temperature for a suitable time;
(iii) adjusting the pH in the range of 9.0 to12.0 of solution of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1 -yl)-4-oxoquinoline-3-carboxylic acid borate complex of Formula VII
(Formula Removed)
as obtained from step ii) with a base;
(iv) adjusting the pH in the range of 8.0 to 9.0 of the solution of
step iii) with an acid;
(v) optionally, isolating balofloxacin hydrochloride of Formula X
(Formula Removed)
from step iii) by adjusting the pH with hydrochloric acid;
(vi) isolating crude balofloxacin from solution of step iv);
(vii) adding water to the crude balofloxacin of step vi);
(viii) adjusting the pH in the range of 1.0 to 3.0 of the solution of
step vii) with an acid;
(ix) extracting the solution of step viii) with a non aqueous solvent; (x) adjusting the pH in the range of 8.0 to 9.0 of aqueous layer as
obtained from step ix) with a base;
(xi) isolating balofloxacin dihydrate of Formula II in pure form; and (xii) optionally, converting balofloxacin hydrochloride of Formula X
of step v) to balofloxacin dihydrate of Formula II
(Formula Removed)
or balofloxacin monohydrate of Formula III.
(Formula Removed)
2. The process according to claim 1, wherein acetoxyborate complex is generated in-situ.
3. The process according to claim 1, wherein base in step ii) and iii) is an inorganic base.
4. The process according to claim 1, wherein base in step ii) and iii) is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, and any mixtures thereof.
5. The process according to claim 1, wherein suitable solvent in step ii) and ix) is selected from the group consisting of methylene dichloride, ethyl acetate, methyl isobutyl ketone, cyclohexane, toluene, methyl tertiary butyl ether, and any mixtures thereof.
6. The process according to claim 1, wherein temperature for condensing 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid-O3,O4) bis (acetate-O)-borate of Formula VI with 3-methylaminopiperidine dihydrochloride of Formula V in step ii) is between 20°C. to 50°C.
7. The process according to claim 1, wherein acid in step iv) and step viii) is selected from the group consisting of hydrochloric acid, sulphuric acid, acetic acid, and any mixtures thereof.
8. The process according to claim 1, wherein the pH of the solution of step iii) is adjusted in the range of 9.0 to12.0,
9. The process according to claim 1, wherein the pH of the solution of steps iv) and x) is adjusted in the range of 8.0 to 9.0.
10. A one pot process for the preparation of balofoxacin hydrochloride of Formula X,
(Formula Removed)
comprising one or more of the following steps, individually or in the sequence recited:
(i) reacting 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester of Formula IX,
(Formula Removed)
with acetoxyborate complex;
(ii) condensing 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3- quinolinecarboxylic acid-O3,O4) bis (acetate-O)-borate of Formula VI,
(Formula Removed)
as obtained from step i) involving the use of acetoxyborate complex, with 3-methylaminopiperidine dihydrochloride of Formula V,
(Formula Removed)
in the presence of a base in a suitable solvent at a suitable temperature for a suitable time;
(iii) adjusting the pH in the range of 9.0 to12.0 of solution of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1 -yl)-4-oxoquinoline-3-carboxylic acid borate complex of Formula VII
(Formula Removed)
as obtained from step ii) with a base;
(iv) adjusting the pH in the range of 8.0 to 9.0 of the solution of
step iii) with an acid;
(v) isolating balofloxacin hydrochloride of Formula X
(Formula Removed)