FIELD OF THE INVENTION
The present invention relates to an improved and industrially advantageous process for preparation of moxifloxacin hydrochloride of formula I.
(Formula Removed)The present invention also provides moxifloxacin hydrochloride dihydrate and its
crystalline form.
BACKGROUND OF THE INVENTION
Moxifloxacin hydrochloride, of formula I, a fluoroquinolone, is a synthetic broad-spectrum anti-bacterial agent and is chemically known as l-cyclopropyl-6-fluoro-l,4-dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4-oxo-3-quinoline carboxylic acid hydrochloride.
(Formula Removed)US patent 4,990,517 discloses moxifloxacin, or pharmaceutically acceptable salts and its derivatives for the first time. The process disclosed for the preparation of moxifloxacin hydrochloride involves the condensation of l-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-l ,4-dihydro-3-quinoline carboxylic acid or its esters with (S,S) 2,8-diazabicyclo [4.3.0] nonane in presence of a base in an organic solvent and conversion of resulting moxifloxacin to hydrochloride at higher temperatures. The above process suffers from major drawback that it leads to the formation of desired moxifloxacin along with its potential isomer namely (4aS-Cis)-l-cyclopropyl-6-(2,8-diazabicyclo[4.3.0]non-8-yl)-7-fluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinoline
carboxylic acid as a major impurity. As the impurity and moxifloxacin are positional isomers, they are difficult to separate. Purification of moxifloxacin by tedious purifications to remove this isomeric impurity, results in lower yields thereby increasing the product cost. Further process is time consuming and not amenable from commercial point of view.
US patent 5,849,752 discloses monohydrate of moxifloxacin hydrochloride (CDCH) and its preparation by treating the anhydrous crystalline form of moxifloxacin hydrochloride with ethanol-water mixtures to get the monohydrate moxifloxacin hydrochloride, which crystallizes as prisms.
US 2006/0264635 discloses the process for the preparation of moxifloxacin
hydrochloride by the condensation of (l-cyclopropyl-6,7-difiuoro-8-methoxy-4-oxo-
l,4-dihydro-3-quinoline carboxylic acid- 03,04)bis(acyloxy-0)borate with [S,S]-2,8-
diazabicyclo-[4,3,0]nonane in the presence of bases like triethylamine or
diisopropylethyl amine or DBU in polar organic solvents like acetonitrile or
dimethylsulfoxide or dimethylformamide to give (4aS-Cis)-(l-cyclopropyl-7-(2,8-
diazabicyclo [4,3,0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinoline
carboxylic acid - 03,04) bis(acycloxy-0)borate. The above formed intermediate is then
treated with hydrochloric acid in short chain alcohol to form moxifloxacin
hydrochloride pseudohydrate. The moxifloxacin hydrochloride pseudohydrate upon
mixing with hydrochloric acid in presence of ethanol gives moxifloxacin hydrochloride
monohydrate. The process involves the synthesis of moxifloxacin hydrochloride
pseudohydrate and then its conversion to its monohydrate thereby incorporating an
additional step in the manufacturing process and may leads to lowering of yields.
PCT publication WO 2008/059223 discloses the process for the preparation of
moxifloxacin hydrochloride by reacting propionic anhydride and boric acid with ethyl-
1 -cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolone carboxylate to
obtain l-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinoline
carboxylic acid-O3, O4 bis(propyloxy-0)borate, then condensation of the above borate complex with (S,S)-2,8-diazabicyclo [4.3.0] nonane in an organic solvent such as
acetonitrile or n-butanol to obtain the intermediate (4aS-Cis)-(l-cyclopropyl-7-(2,8-
diazabicyclo [4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinoline
carboxylic acid - 03,04) bis(propyloxy-0)borate which is hydrolyzed using hydrochloric acid in methanol and distilled off to give moxifloxacin hydrochloride. Moxifloxacin hydrochloride is then purified using base acid treatment, the purification process involves the treatment of moxifloxacin hydrochloride with a base (ammonia) to form moxifloxacin free base which is then converted to moxifloxacin hydrochloride by acidifying the reaction mixture. Isolation of moxifloxacin hydrochloride by distillation of the reaction mixture may lead to product decomposition and moxifloxacin hydrochloride thus prepared requires further purification with base acid treatment which adds extra steps to the process.
The other disadvantage of the process is that it involves the conversion of moxifloxacin hydrochloride to its form C by again treatment with base (triethyl amine) in methanol to form moxifloxacin freebase and then with hydrochloric acid to yield form C. The process disclosed has number of steps, which makes it unsuitable to employ at industrial scale.
PCT publication WO2006/134491 discloses the process for the preparation of moxifloxacin hydrochloride form A by reacting (l-cyclopropyl-6,7-difluoro-l,4-dihydro-8-methoxy-4-(oxo-K))-3-quinolinecarboxylato-k03) difluoroboron with (4aS,7aS)octahydro-lH-pyrrolo [3,4-b]pyridine in presence of a base (s) in an organic solvent such as acetonitrile, methanol, ethanol, butanol to produce (l-cyclopropyl-6-fluoro-l,4-dihydro-8-methoxy-7-[(4aS,7a8)-octahydro-6H-pyrrolo[3,4-bjpyridin-6-yl]-4-(oxo-kO)-3-quinolinecarboxylato-kO3)difluoroboron (moxifloxacin boron difluoride chelate). Above chelate complex is cleaved by using organic base followed by distillation of reaction mixture to give moxifloxacin free base, which is then converted to moxifloxacin hydrochloride by reacting with hydrochloric acid in solvent mixtures. The process involves the isolation of the product by the distillation which may lead to decomposition. Process involves first cleavage of the borate complex using base and
then treatment with hydrochloric acid, which adds an extra step to the process and
involve use of more number of reagent and solvents i.e. first base then acid.
In most of the prior art processes as discussed, the isolation of compound is carried out
by the distillation of the reaction mixture which may lead to decomposition, and
formation of extra impurities due to degradation and also involves more number of
steps. Further, number of solvents have been used such as solvents for the reaction
media and anti solvents to isolate the intermediate, which is time consuming and
expensive.
Therefore there is a need to develop an improved process to overcome disadvantages of
the prior art, which involve easy isolation, avoid the need of base acid treatment and is
commercially viable. In order to achieve a high efficiency of the reaction for industrial
synthesis of moxifloxacin hydrochloride, the present invention provides an improved
process for the preparation of moxifloxacin hydrochloride, which is economically
viable, industrially advantageous as well as reproducible on industrial scale.
In addition, it is the nature of the pharmaceutical compounds to exist in various forms,
which may prove beneficial in the field of pharmaceutical sciences. Therefore, the
developing a new crystal modification of moxifloxacin hydrochloride is highly
appreciable.
OBJECT OF THE INVENTION
It is object of present invention is to provide an improved and industrially
advantageous process for the preparation of moxifloxacin hydrochloride of formula I.
Another object of the present invention is to provide a process for the preparation of
moxifloxacin hydrochloride through borate complex, which is prepared in the
presence of base and water as a solvent for the reaction.
Yet another object of the present invention is to provide a process for the preparation
of moxifloxacin hydrochloride through borate complex, which is prepared in the
presence of base and water immiscible organic solvent for the reaction.
Still another object of the present invention is to provide moxifloxacin hydrochloride
dihydrate and its crystalline form.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved and industrially
advantageous process for the preparation moxifloxacin hydrochloride of formula I,
(Formula Removed)hich comprises the steps of:
a), reacting a compound of formula II, (Formula Removed)
with boric acid and suitable reagent to form compound of formula III;
(Formula Removed)wherein both R can be same or different and can be selected from -OCOR1, halo group; and R1 can be alkyl selected from methyl, ethyl, propyl, butyl and the like
b). optionally, isolating compound of formula III;
c). condensing compound of formula III with [S,S]-2,8-diazabicyclo-[4,3,0]nonane of formula IV,
(Formula Removed)in presence of base in water to form borate complex of formula V;

Formula V

wherein R is as defined above d). optionally, isolating borate complex of formula V; e). treating the same with suitable source of hydrogen chloride for time sufficient to
precipitate moxifloxacin hydrochloride; f). filtrating moxifloxacin hydrochloride of formula I from the reaction mixture; and g). optionally, purifying moxifloxacin hydrochloride of formula I with a suitable
solvent. According to another aspect, the present invention provides a process for the preparation of borate complex of formula V,

(Formula Removed)
Formula V

wherein R is as defined above
by condensing compound of formula III,
(Formula Removed)
Formula III
wherein R is as defined above
with [S,S]-2,8-diazabicyclo-[4,3,0]nonane of formula IV,
(Formula Removed)in presence of base in water.
According to another aspect, present invention provides a process for the preparation
moxifloxacin hydrochloride of formula I,
(Formula Removed)which comprises the steps of:
a), treating compound of formula II, (Formula Removed)with boric acid and a suitable reagent to form compound of formula III; (Formula Removed)
wherein R is as defined above b). optionally, isolating compound of formula III;
(Formula Removed)c). condensing compound of formula III with [S,S]-2,8-diazabicyclo-[4,3,0]nonane of formula IV,
(Formula Removed)in presence of base in water immiscible organic solvent to form borate complex of formula V,
(Formula Removed)wherein R is as defined above d). optionally, isolating borate complex of formula V; e). treating the same with a suitable source of hydrogen chloride for time sufficient
to precipitate moxifloxacin hydrochloride; f). filtrating moxifloxacin hydrochloride of formula I; and g). optionally, purifying moxifloxacin hydrochloride of formula I with a suitable
solvent. According to another aspect, the present invention provides a process for the preparation of borate complex of formula V,
(Formula Removed)wherein R is as defined above
by condensing compound of formula III,
Formula III
wherein R as defined above
with [S,S]-2,8-diazabicyclo-[4,3,0]nonane of formula IV, H
(Formula Removed)in presence of base in water immiscible organic solvent.
Yet another object of the present invention is to provide moxifloxacin hydrochloride
dihydrate and its crystalline form.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates the powder X-ray diffraction pattern for moxifloxacin
hydrochloride monohydrate.
Figure 2 illustrates the powder X-ray diffraction pattern for moxifloxacin
hydrochloride dihydrate.
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention provides an improved and industrially
advantageous process for the preparation moxifloxacin hydrochloride of formula I.
According to one embodiment, the present invention provides a process for the
preparation of the moxifloxacin hydrochloride of formula I starting from compound of
formula II. The process involves the reaction of compound of formula II with boric acid
and suitable reagent to form compound of formula III which is then converted to
moxifloxacin hydrochloride through borate complex of formula V.
Specifically, the process involves the preparation of the compound of formula III by
reacting the compound of formula II with boric acid and a suitable reagent for few
minutes to several hours, preferably till the completion of the reaction. Suitable reagent includes but not limited to anhydride source such as acetic anhydride, propionic anhydride and the like; halide source such as fluoride source and the like. It is advantageous to add a suitable catalyst in the reaction mixture to enhance the reaction. Catalyst includes Lewis acid such as zinc chloride, aluminum chloride, ferrous chloride and the like; preferably, zinc chloride can be employed. Preferably, the reaction can be carried out at a temperature of 60 to 130 °C to give compound of formula III. The compound of formula III can be in situ proceeded for the further reaction or can be isolated from the reaction mixture. The compound of formula III can be isolated from the reaction mixture using suitable methods known in the art, preferably desired compound can be isolated by the addition of water to the reaction mixture followed by filtration.
The compound of formula III is then condensed with [S,S]-2,8-diazabicyclo-[4,3,0]nonane in the presence of base and water is employed as a solvent for the reaction to give borate complex of formula V, which forms the inventive feature of the invention.
Generally, the synthesis of borate complex of formula V involves the reaction of the compound of formula III with [S,S]-2,8-diazabicyclo-[4,3,0]nonane of formula IV in the presence of base in water as solvent. Base employed for the reaction can be inorganic or organic base. Inorganic base can be selected from alkali or alkaline metal hydroxides, carbonates, bicarbonates thereof such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate sodium hydroxide, potassium hydroxide and the like. Organic base can be selected from substituted amines such as triethyl amine, diisopropylethyl amine, diazabicyclo[5.4.0]undec-7-ene (DBU) and the like or combination thereof. Preferably, the base employed is triethyl amine. The reaction can be carried out at a temperature of about 20-80°C for 1-8 hours, preferably a temperature of about 45-55°C for 1-3 hours, more preferably till the completion of the reaction. The reaction completion can be monitored by suitable chromatographic techniques such as high pressure liquid chromatography (HPLC), thin
layer chromatography (TLC) and the like. Usually the reaction undergoes completion in 1-3 hours to give the borate complex of formula V. The borate complex of formula V can be optionally isolated from the reaction mixture by using suitable techniques known in the art. It is advantageous to proceed the reaction mixture as such for the further formation of moxifloxacin hydrochloride without isolation of borate complex of formula V.
It is highly advantageous to use water as solvent for the synthesis of borate complex of formula V as it avoid the use of organic solvent and makes the process economic from the commercial point of view as well as environmental friendly. The process described above avoids the need to control of the residual solvent content at the final API stage like moxifloxacin hydrochloride, as process employs water as a solvent for the reaction. The borate complex of formula V or reaction mixture containing borate complex of formula V is then converted directly to moxifloxacin hydrochloride by treatment with suitable source of hydrogen chloride.
According to one way, the borate complex of formula V or reaction mixture containing borate complex of formula V is extracted with a solvent and then treated with a suitable source of hydrogen chloride to break the borate complex and gives directly moxifloxacin hydrochloride
Specifically, the reaction mixture containing borate complex of formula V can be extracted with a suitable solvent followed by treatment with suitable source of hydrogen chloride at a temperature of 20°C to ambient temperature for 4-6 hours, preferably till the completion of the reaction. Suitable source of hydrogen chloride employed for the reaction includes aqueous hydrochloric acid, concentrated hydrochloric acid, gaseous hydrogen chloride, alcoholic hydrochloric acid, dimethylformamide hydrochloric acid and the like or combination thereof. Suitable solvent for the extraction includes but not limited to halogenated solvent as dichloromethane, dichloroethane, carbon tetrachloride; nitriles such as acetonitrile; ethers such as methyl tertiary butyl ether, tetrahydrofuran; ketones such as methyl isobutyl ketone, acetone; hydrocarbon such as toluene; esters such as ethyl acetate,
isoamyl acetate, isopropyl acetate and the like or mixture thereof. Thereafter, the reaction mixture is made acidic by the addition of suitable source of hydrogen chloride, as described above, preferably, till the pH of the reaction mixture reaches to 1 to 3, more preferably till pH 1.0 to 1.5 to precipitate the desired compound. The reaction mixture can be optionally stirred for 4-6 hours to ensure complete precipitation. The product thus precipitated can be isolated from the reaction mixture using conventional techniques known in the art such as filtration, decantation, centrifugation and the like. In another alternate way, borate complex of formula V or the reaction mixture containing the borate complex of formula V can be directly treated with suitable source of hydrogen chloride without extraction with a solvent.
Specifically, the process involves the treatment of borate complex of formula V or reaction mixture containing the borate complex of formula V 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 1.5. Suitable source of hydrogen chloride employed for the reaction includes aqueous hydrochloric acid, concentrated hydrochloric acid, gaseous hydrochloric acid, alcoholic hydrochloric acid, dimethylformamide hydrochloric acid and the like or combination thereof. The reaction can be carried out at a temperature of about 20-80°C for few minutes to few hours, preferably a temperature of 45-50°C optionally with stirring about 1 hour or till completion of the reaction. Thereafter, reaction mixture can be optionally stirred for few minutes to few hours, preferably 20-30 minutes. It is advantageous to dilute the resulting mixture with water. After dilution of the reaction mixture, reaction mixture can be stirred and then cooled. The product thus formed can be isolated from the reaction mixture using conventional techniques known in the art such as filtration, decantation, centrifugation and the like.
According to another embodiment, the present invention provides a process for the preparation of the moxifloxacin hydrochloride, by condensation of compound of formula III, with [S,S]-2,8-diazabicyclo-[4,3,0]nonane of formula IV in the presence of base in water immiscible organic solvent to give borate complex of formula V
which is finally converted to moxifloxacin hydrochloride and forms the inventive feature of the invention.
Specifically, the process involves the reaction of the compound of formula III with [S,S]-2,8-diazabicyclo-[4,3,0]nonane of formula IV in the presence of base in water immiscible organic solvent at a temperature of 20 °C to 80 °C for few minutes to few hours. Base employed for the reaction can be inorganic or organic base. Inorganic base can be selected from alkali or alkaline metal hydroxides, carbonates, bicarbonates thereof such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate sodium hydroxide, potassium hydroxide and the like. Organic base can be selected from substituted amine such as triethyl amine, diisopropylethyl amine, diazabicyclo[5.4.0]undec-7-ene (DBU) and the like or combination thereof. Preferably, the triethyl amine can be used for the reaction. The water immiscible organic solvent can be selected from solvent includes halogenated solvent such as dichloromethane, dichloroethane; esters such as ethyl acetate; hydrocarbon such as toluene; ether such as methyl-tert-butyl ether and the like or mixture thereof. The reaction can be carried out at a temperature of about 35-65 °C for 1-8 hours, preferably a temperature of about 40-55°C for 1-3 hours, more preferably till the completion of the reaction. The reaction completion can be monitored by suitable chromatographic techniques such as high-pressure liquid chromatography (HPLC), thin layer chromatography (TLC) and the like. Usually the reaction undergoes completion in 1-3 hours to give the borate complex. After completion of the reaction, the reaction mass is cooled to 25-30°C. Borate complex of formula V can be isolated from the reaction by using conventional techniques or can be proceeded as such for the synthesis of moxifloxacin hydrochloride. It is advantageous to proceed further without isolating borate complex of formula V from the reaction mixture.
The reaction mixture containing borate complex of formula V is then treated with a source of hydrogen chloride to break the borate complex and yielding moxifloxacin hydrochloride.
Specifically, the reaction mixture containing borate complex of formula V is treated with a suitable source of hydrogen chloride at a temperature of 20°C to ambient temperature for 4-6 hours, till the reaction mixture become acidic, preferably till the pH of the reaction mixture reaches to 1 to 3, more preferably till pH 1.0 to 1.5 to precipitate the desired compound. Source of hydrogen chloride employed for the reaction includes aqueous hydrochloric acid, concentrated hydrochloric acid, gaseous hydrochloric acid, alcoholic hydrochloric acid, dimethylformamide-hydrochloric acid and the like or combination thereof. The reaction mixture can be optionally stirred for 4-6 hours to complete the precipitation. The product thus precipitated can be isolated from the reaction mixture using conventional techniques known in the art such as filtration, decantation, centrifugation and the like.
Moxifloxacin hydrochloride thus prepared by any of the above process, can be optionally purified by employing a suitable purification method such as crystallization or washing with a suitable solvent to minimize the presence of impurity in the final product and/or to enhance the purity of the product. Specifically, moxifloxacin hydrochloride in a suitable solvent is crystallized at a temperature of 10 to 60°C to get desired polymorph of moxifloxacin hydrochloride. Suitable solvent includes water; alcohol such as methanol, ethanol, isopropyl alcohol and the like or mixture thereof. Preferably, the mixture of methanol and water can be employed for the crystallization. The crystallization process can be optionally repeated till the product of desired purity is obtained.
Moxifloxacin hydrochloride, thus prepared, may have purity more than 99%, preferably more than 99.5% by HPLC, more preferably more than 99.8% by HPLC. The identification of anhydrous and hydrated forms of pharmaceutical substances is of great importance in pharmaceutical science and industry. Similarly, polymorphism is very common among pharmaceutical substances. Different hydrated forms of the pharmaceutical compounds may differ in their physical properties such as melting point, solubility, chemical reactivity, etc. These can appreciably influence pharmaceutical properties such as dissolution rate and bioavailability.
It is found by the inventors of the present invention that moxifloxacin hydrochloride also exist in dihydrate form. The dihydrate of moxifloxacin hydrochloride can be confirmed by determining moisture content. The determination of the water content can be carried out by at least of Karl Fischer instrument or by thermal gravimetric analysis. The moxifloxacin hydrochloride shows moisture content 7.5-10% w/w as determined by Karl Fischer analysis, which confirms dihydrate of moxifloxacin hydrochloride. Thus present invention provides a new water containing crystalline modification i.e. moxifloxacin hydrochloride dihydrate which forms another novel feature of the invention. The moxifloxacin hydrochloride dihydrate contain stoichiometric amount of water which is bound by crystal lattice. It is confirmed by drying the moxifloxacin hydrochloride dihydrate sample for several hours to several days and found that moisture content remains same.
Moxifloxacin hydrochloride dihydrate can exist in amorphous or crystalline form. The polymorphic nature of moxifloxacin hydrochloride dihydrate can be characterized by X-Ray diffraction (PXRD), Infrared spectroscopy (IR) or differential scanning calorimetry (DSC). Crystalline nature of moxifloxacin hydrochloride dihydrate is characterized by X-ray diffractogram, which shows the unique characteristic peaks of moxifloxacin hydrochloride dihydrate as shown in figure 2. The X-ray diffractogram of moxifloxacin hydrochloride dihydrate shows two characteristic peak at 12.18 and 25.09 ° ± 0.2° 20 which are absent in X-ray diffractogram of moxifloxacin hydrochloride monohydrate. The X-ray diffraction patterns of moxifloxacin hydrochloride monohydrate and dihydrate samples are measured on a PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacings and relative intensities. One ordinarily skilled in the art understands that experimental differences may arise due to differences in instrumentation, sample preparation or other factors, which can alter the two-theta values, d-spacings and relative intensities slightly. Moxifloxacin hydrochloride dihydrate can be easily converted into the moxifloxacin hydrochloride monohydrate.
The major advantage of the present invention is to provide the use of the water as solvent for the condensation reaction. The use of water as a solvent has several added advantages for the commercial synthesis of any pharmaceutically active compound such as moxifloxacin hydrochloride. The use of water as a solvent for organic reaction offers several "green chemistry" benefits. Use of water immiscible solvent for the condensation reaction also provides an alternative process for the synthesis of moxifloxacin hydrochloride. The present invention also provides a process for the direct conversion of borate complex to moxifloxacin hydrochloride, which reduces the number of steps and employs only one reagent i.e hydrochloric acid to serve the purpose of breaking borate complex as well as formation of hydrochloride salt. The process described above avoids the need of distillation in the process and provides easy isolation of moxifloxacin hydrochloride. Another advantage of the present invention is to provide a new crystal modification of moxifloxacin hydrochloride in the form of moxifloxacin hydrochloride dihydrate.
Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. EXAMPLES:
Example 1: Preparation of l-cvclopropvl-6,7-difluoro-1.4-dihydro-8-methoxv-4-oxo-3-quinoline carboxylic acid-Q3,Q4) bis(acetate-Q)-borate l-Cyclopropyl-6,7-difluoro-l,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid (100 g) was added into the mixture of acetic acid (205ml) and zinc chloride (O.lg) and heated to about 65-70 °C. Boric acid (22 g) was added to the reaction mixture, heated to 115-120 ° C, and maintained for 6-7 hours. After the completion of reaction (monitored by TLC), reaction mixture was cooled to 0-5°C. Thereafter, chilled demineralized water (500ml) was added to the reaction mixture and stirred for 15-20 minutes at about 0-5°C. The resulting product was filtered, washed with chilled demineralized water (2x100ml) and suck dried to give 130 g of title compound.
Example 2: Preparation of moxifloxacin hydrochloride
A mixture of (l-cyclopropyl-6,7-difiuoro-l,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid-03,04) bis(acetate-0)-borate (25g), dernineralized water (50 ml), triethylamine (12.5g) and [S,Sj-2,8-diazabicyclo-[4,3,0]nonane (8.4g) was heated to 45-50 °C and maintained for about 1.0-1.5 hours. After the completion of reaction (monitored by TLC), reaction mass was cooled to 25-30°C. Dichloromethane (100 ml) was added to the reaction mixture and stirred for 20 minutes followed by the separation of the layers. The aqueous layer was further extracted by the dichloromethane (2 x 25 ml) and combined all the organic layers. The pH of reaction mixture was adjusted to 1.0-1.5 with concentrated hydrochloric acid solution at temperature of about 20-25°C and stirred for about 2 hours. The reaction mixture was then filtered and washed with chilled dichloromethane (25ml) and dried at 60-70 °C to give 21 g of title compound having purity 99.5% by HPLC.
The resulting product was crystallized from a mixture of methanol and water (8:2) to give moxifloxacin hydrochloride monohydrate having purity 99.8% by HPLC, moisture content: 4.0% w/w.
Example 3: Preparation of moxifloxacin hydrochloride
A mixture of (l-cyclopropyl-6,7-difluoro-l,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid-O3, O4) bis(acetate-0)-borate (25 g), dernineralized water (50ml), triethylamine (12.5g) and [S,S]-2,8-diazabicyclo-[4,3,0]nonane (8.4g) was heated to 45-50°C and maintained for about 1.0-1.5 hours. After the completion of reaction (monitored by TLC), reaction mass was cooled to 25-30 °C. The pH of reaction mixture was adjusted to 1.0-1.5 with concentrated hydrochloric acid and stirred for about 20 minutes. Further the dernineralized water (150 ml) was added to the reaction mixture and stirred for 1.0 hours at 45-50°C. The reaction mixture was cooled to about 25-30°C and stirred for 2 hours at same temperature. The resulting product was filtered, washed with dernineralized water (25ml) and dried at 60-70°C to give 22 g of the title compound having purity 99.0 % by HPLC, moisture content: 4.0% w/w.
Example 4: Preparation of moxifloxacin hydrochloride
A mixture of (l-cyclopropyl-6,7-difluoro-l,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid-O3, O4) bis(acetate-0)-borate (25g), dichloromethane (100ml), triethylamine (12.5g) and [S,S]-2,8-diazabicyclo-[4,3,0]nonane (8.4g) was heated to reflux and maintained for about 2.0 hours. After completion of the reaction (monitored by TLC), reaction mass was cooled to 25-30°C. The pH of reaction mixture was adjusted to 1.0-1.5 with concentrated hydrochloric acid at temperature of about 20-25°C and stirred for about 4-6 hours. The resulting product was then filtered, washed with dichloromethane (25ml) and dried at 60-70°C to give 22.5g of title compound which was washed with prechilled methanol (25ml) and dried at 60-70°C under vacuum to give 22.5g of title compound having purity 99.5% by HPLC. The resulting product was crystallized from a mixture of methanol and water (8:2) to give moxifloxacin hydrochloride monohydrate having purity 99.9% by HPLC. Example 5; Preparation of moxifloxacin hydrochloride dihydrate A mixture of (l-cyclopropyl-6,7-difluoro-l,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid-O3, O4) bis(acetate-0)-borate (25 g), dichloromethane (100ml), triethylamine (12.5g) and [S,S]-2,8-diazabicyclo-[4,3,0]nonane (8.4g) was heated to reflux and maintained for about 2.0 hours. After completion of the reaction (monitored by TLC), reaction mass was cooled to 25-30°C. The pH of reaction mixture was adjusted to 1.0-1.5 with concentrated hydrochloric acid at temperature of about 20-25°C and stirred for about 4-6 hours. The resulting product was then filtered, washed with dichloromethane (25ml) and dried at 60-70°C to give 22.5g of title compound having moisture content: 8.5 % w/w.

WE CLAIM
1). A process for preparation of moxifloxacin hydrochloride of formula I,
(Formula Removed)
comprising the step of:
a), treating compound of formula II, (Formula Removed)
Formula II
with boric acid and a suitable reagent to form compound of formula III;
(Formula Removed)
wherein both R can be same or different and can be selected from -OCORi,
halo group; and R1 can be alkyl selected from methyl, ethyl, propyl, butyl and
the like, b). optionally, isolating compound of formula III; c). condensing compound of formula III with [S,S]-2,8-diazabicyclo-
[4,3,0]nonane of formula IV,
(Formula Removed)
in presence of base in water to form borate complex of formula V,
(Formula Removed)
wherein R is as defined above d). optionally, isolating borate complex of formula V; e). treating with the same with a source of hydrogen chloride for a time
sufficient to precipitate moxifloxacin hydrochloride; f). filtrating moxifloxacin hydrochloride of formula I from the reaction mixture;
and g). optionally, purifying moxifloxacin hydrochloride of formula I with a suitable solvent. 2). The process according to claim 1, wherein
in step a), suitable reagent includes anhydride source such as acetic anhydride, propionic anhydride or halide source such as fluoride source and the like; and/or in step a) reaction can be carried out adding lewis acid which includes zinc
chloride, aluminum chloride, ferrous chloride and the like; and/or in step c), the base is inorganic base which includes alkali or alkaline metal hydroxides, carbonates, bicarbonates thereof such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate sodium hydroxide, potassium hydroxide and the like; or organic base which includes substituted amines such as triethyl amine, diisopropylethyl amine,
diazabicyclo[5.4.0]undec-7-ene (DBU) and the like or combination thereof;
and/or in step e) source of hydrogen chloride includes aqueous hydrochloric acid,
concentrated hydrochloric acid, gaseous hydrogen chloride, alcoholic
hydrochloric acid, dimethylformamide hydrochloric acid and the like or
combination thereof; and/or in step g), suitable solvent is selected from water, alcohol such as methanol,
ethanol, isopropyl alcohol and the like or mixtures thereof. 3). A process for preparation of borate complex of formula V,
(Formula Removed)
wherein both R can be same or different and can be selected from -OCORi, halo group; andRi can be alkyl selected from methyl, ethyl, propyl, butyl and the like, by condensing compound of formula III,
(Formula Removed)
wherein R is as defined above
with [S,S]-2,8-diazabicyclo-[4,3,0]nonane of formula IV, (Formula Removed)
in the presence of base in water.
4). The process according to claim 3, wherein base is inorganic base which includes
alkali or alkaline metal hydroxides, carbonates, bicarbonates thereof such as
sodium carbonate, potassium carbonate, sodium bicarbonate, potassium
bicarbonate sodium hydroxide, potassium hydroxide and the like; or organic base
which includes substituted amines such as triethyl amine, diisopropylethyl amine,
diazabicyclo[5.4.0]undec-7-ene (DBU) and the like or combination thereof.
5). A process for the preparation of moxifloxacin hydrochloride of formula I,
(Formula Removed)
comprising the steps of
a) treating compound of formula II, (Formula Removed)
with boric acid and a suitable reagent to form compound of formula III;
(Formula Removed)
wherein both R can be same or different and can be selected from -OCORi, halo group; and R1 can be alkyl selected from methyl, ethyl, propyl, butyl and the like, b) optionally, isolating compound of formula III;
c) condensing compound of formula III with [S,S]-2,8-diazabicyclo-[4,3,0]nonane of formula IV, H
(Formula Removed)
in presence of base in water immiscible organic solvent to form borate complex of formula V;
(Formula Removed)
wherein R is as defined above
d) optionally, isolating borate complex of formula V;
e) treating the same a suitable a source of hydrogen chloride for a time sufficient to precipitate moxifloxacin hydrochloride;
f) filtrating moxifloxacin hydrochloride of formula I; and
g) optionally, purifying moxifloxacin hydrochloride of formula 1 with a suitable
solvent.
6). The process according to claim 5, wherein
in step a), suitable reagent includes anhydride source such as acetic anhydride,
propionic anhydride or halide source such as fluoride source and the like; and/or in step a) reaction can be carried out adding lewis acid which includes zinc
chloride, aluminum chloride, ferrous chloride and the like; and/or in step c), the base is inorganic base which includes alkali or alkaline metal
hydroxides, carbonates, bicarbonates thereof such as sodium carbonate,
potassium carbonate, sodium bicarbonate, potassium bicarbonate sodium
hydroxide, potassium hydroxide and the like; or organic base which includes substituted amines such as triethyl amine, diisopropylethyl amine, diazabicyclo[5.4.0]undec-7-ene (DBU) and the like or combination thereof; and/or
in step c) water immiscible organic solvent includes halogenated solvent such as dichloromethane, dichloroethane; esters such as ethyl acetate, hydrocarbon such as toluene; ether such as methyl-tert-butyl ether; and the like or mixture thereof..
in step e) source of hydrogen chloride includes aqueous hydrochloric acid, concentrated hydrochloric acid, gaseous hydrogen chloride, alcoholic hydrochloric acid, dimethylformamide hydrochloric acid and the like or combination thereof; and/or
in step f), suitable solvent includes water, alcohol such as methanol, ethanol, isopropyl alcohol and the like or mixtures thereof. 7). A process for the preparation of borate complex of formula V,
(Formula Removed)
wherein both R can be same or different and can be selected from -OCORi, halo group; and R/ can be alkyl selected from methyl, ethyl, propyl, butyl and the like, by condensing compound of formula III,
(Formula Removed)
wherein R is as defined above
with [S,S]-2,8-diazabicyclo-[4,3,0]nonane of formula IV,
(Formula Removed)
in presence of base in water immiscible organic solvent.
8). The process according to claim 7, wherein in step a), the base can inorganic base which includes alkali or alkaline metal hydroxides, carbonates, bicarbonates thereof such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate sodium hydroxide, potassium hydroxide and the like; or organic base which includes substituted amines such as triethyl amine, diisopropylethyl amine, diazabicyclo[5.4.0]undec-7-ene (DBU) and the like or combination thereof; and water immiscible organic solvent includes halogenated solvent such as dichloromethane, dichloroethane; esters such as ethyl acetate, hydrocarbon such as toluene; ether such as methyl-tert-butyl ether; and the like or mixture thereof
9). Moxifloxacin hydrochloride dihydrate.
10). The moxifloxacin hydrochloride dihydrate according to claim 9, shows a powder X-ray diffraction pattern exhibiting peaks at diffraction angles 29 of about 12.18 and 25.09 ±0.2° 29.