PROCESSES FOR PREPARING MARBOFLOXACIN

INTRODUCTION

The present invention relates to processes for the preparation of marbofloxacin and its intermediate compounds.

Marbofloxacin Is 9-fluoro-2,3-dlhydro-3-methyl-10-(4-methyl-1-plperazinyl)-7-oxo-7H-pyrido[3,2,1-ij][4.2,1]benzoxadiazine-6-carboxylic acid, and is structurally represented by Formula (I).

Marbofloxacin is a fluoroquinolone derivative with antibacterial activity useful as an effective antibacterial agent.

U.S. Patent No. 4,801,584 ("the '584 patent") discloses marbofloxacin, its pharmaceutically acceptable salts, and processes for its preparation, wherein one of the processes involves reacting B-hydroxy-6,7-difluoro-1-(methylamino)-4-oxo-4H-quinollne-3-carboxylic acid with para-formaldehyde in dioxane to obtain 9,10-difluoro-2.3-dihydro-3-methyl-7-oxo-7H-pyrido[3,2,1-ij][4,2,1]benzoxadiazine-6-carboxylic acid, which is condensed with N-methylpiperazine in the presence of dry pyridine to give marbofloxacin.

The '584 patent also discloses another process for the preparation of marbofloxacin in which one of the process steps involves the amination of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-quinolinQ-3-carboxylate using 0-(2,4-dinitrophenyl) hydroxylamine, which is subsequently converted into 8-hydroxy-6,7-difluoro-1-(methylamino)-4-oxo-4H-qulnoltne-3-carboxylicacid.

Research Disclosure No. 1988, 291, 548-551 discloses an alternative route starting from commercially available 2,3,4,5-tetrafluorob6nzolc acid. The process disclosed therein Involves reacting ethyl 6,8-difluoro-1-(methylamino)-7-(4-methylpipera2in-1-yl)-4-oxo-4H-quinoline-3-carboxylate with benzyl alcohol to obtain ethyl 8-benzyloxy-6-fluoro-1-(methylamino)-7-(4-methyi-1-piperazinyl)-4-oxo-4H-quinoline-3-carboxylate, which is deprotected to obtain ethyl 8-hydroxy-6-fluorO'1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-quinoline-3-carboxyiate, which is hydrolyzed to obtain 8-hydroxy'6-f!uoro-1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-quinoline-3-carboxylic acid, which is cyclized to produce marbofloxacin.

U.S. Patent No. 5,892,040 ("the '040 patent") discloses a process for the preparation of marbofloxacin that involves:

a) reacting alkyl 6,8"difluoro-1-(N-methylformamido)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-quinoline-3-carboxylate with an alkali metal hydroxide in an aqueous medium to form an alkali metal 8-hydroxy-6-fluoro-1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-quinoline-3-carboxylate;

b) cyclizing the reaction product of Step a) with formic acid and formaldehyde to obtain marbofloxacin dihydroformate salt; and

c) neutralizing the marbofloxacin dihydroformate salt with an aqueous base.
According to the process described in the '040 patent, Step a) involves the use of potassium hydroxide in an aqueous medium at temperature of about 80-120 C, preferably at a reflux temperature, from about 20-100 hours. The reaction goes to practical completion by utiiizing at least about 10 mole equivalents of alKaii metal hydroxide and increasing the reaction time to 70-100 hours. The alkali metal hydroxide is preferably

present in a concentration of about 10-20% by weight of the aqueous solution.
Italian Patent 1313683 discloses a process for the preparation of marbofloxacin. The process disclosed therein involves reacting ethyl 6,8-difluoro-1-(N-methylformamido)-7-(4-methyl-1-pipera2inyl)-4-oxo-4H-quinoline-3-carboxylate with benzyl alcohol and sodium methoxide to obtain sodium 8-benzyloxy-6-fiuoro-1-(methyiamino)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-quinoline-3-carboxylate, which on deprotection gives 8-hydroxy-6-fiuoro-1-(methyiamino)-7-(4-methyl-1-pipera2inyi)-4-oxo-4H-quinoline-3-carboxylic acid, which is further cyciized with formaldehyde and formic acid to obtain marbofloxacin dihydroformate salt that may be hydrolyzed to produce marbofloxacin.

Despite existence of various process disclosures as discussed above, there is still an ongoing need for industrially amenable and cost effective processes for the preparation of marbofloxacin and its intermediates.

SUMMARY OF THE INVENTION

The present invention includes processes for the preparation of marbofloxacin, which processes comprise one or more of the following steps, individually or in the sequence recited:

1) reacting 6,8-difluoro-1-(formylmethylamino)-1,4-dihydro-7-(4-methyl"1-
piperazinyl)-4-oxo-3-quinolinecarboxylic acid ester of Formula (II) wherein R is a straight or branched chain C1.4 alkyl; with an acid used in the range of 2-10 equivalents of compound of Formula (tl) at temperature ranging between 60° to 100 X to obtain 6,8-difluoro-1-(methylamino)-1,4-dihydro-7(4-methyl-1-piperazinyi)-4-oxo-3-quinolinecarboxylic acid addition salt of Formula (III) wherein HX is an acid selected from HCI, HNO3, H2S04, HBr and the like and n = 1 or 2; and

2) reacting the compound of Formula (III) with an alkali metal hydroxide in a
non-aqueous medium to obtain a compound of Formula (IV) wherein M is an alkali metal;

3) reacting the compound of Formula (IV) with and acid and aqueous
formaldehyde solution to obtain Marbofloxacin.

The present invention also includes a process for the preparation of marbofloxacin, which process comprises:

a) reacting the compound of Formula (III) with an alkali metal hydroxide in a
non-aqueous medium to obtain a compound of Formula (IV)

wherein M is an alkali metal;

b) reacting a compound of Formula (IV) with hydrochloric acid and
formaldehyde to obtain a compound of Fonnuia (la).

wherein n(HX) is an acid selected from HCI, HNO3, H2SO4, HBr and the like where n = 1 or 2.

c) converting the compound of Formula (la) to Marbofloxacin.

The present invention includes processes for the purification of marbofloxacin of
Formula (I), which processes comprises one or more of the following steps, individually or in the sequence recited:

a) dissolving crude marbofloxacin in a suitable solvent and a base; and

b) isolating pure marbofloxacin or its acid addition salt.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is X1 ray powder diffraction (XRPD) pattern of marbofloxacin obtained according to Example 7.

Fig. 2 Is a differential scanning calorimetry (DSC) curve of marbofloxacin obtained according to Example 7.

Fig. 3 is a thermogravimetric analysis (TGA) curve of marbofloxacin obtained according to Example 7.

Fig. 4 is an infrared absorption spectrum of marbofloxacin obtained according to Example 7.

DETAILED DESCRIPTION OF THE INVENTION All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25''C and about normal pressure unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range "between" two values. The terms "about," "generally," "substantially," and the like, are to be construed as modifying another term or value such that it is not an absolute, but does not read on the prior art, as defined by the circumstances and context as understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value. Whether so indicated or not, all values recited herein are approximate.

This document may refer to a material such as in this Instance, marbofloxacin and its salts, crystalline forms, solvates, or optical isomers by reference to patterns, spectra, or other graphical data "substantially" as shown In a Figure, or by one or more data points. By "substantially" used in such a context, it will be appreciated that patterns, spectra, and other graphical data can be shifted in their positions, relative intensities, and/or values due to a number of factors known to those of skill In the art. For example, in the crystailographic and powder X-ray diffraction arts, such shifts in peak positions or the relative intensities of one or more peaks can occur because of, without limitation; the equipment used, the sample preparation protocol, preferred packing and orientations, the radiation source, operator error, method and length of data collection, and the like. However, those of ordinary skill in the art should be able to compare the figures herein with a pattern generated of an unknown form of, in this case, marbofloxacin, and confirm its identity as one of the forms disclosed and claimed herein. The same holds true for other techniques that may be reported herein.

Crystalline forms may be characterized by such analytical methods as X-ray powder diffraction ("XRPD") pattern, differential scanning calorimetry ("DSC") curves, and thermogravimetric analysis ("TGA") curves. The XRPD data reported in this application were obtained on RIGAKU dmax 2200 Powder X-ray Diffractometer with Cu-Ka radiation having a wavelength of about 1.5405 A.

In addition, where a reference is made to a figure, it is permissible to, and this document includes and contemplates, the seiection of any number of data points illustrated in the figure that uniquely define that crystalline form. salt, solvate, and/or optical isomer, within any associated and recited margin of error, for purposes of identification.

The present invention includes processes for the preparation of marbofloxacin, which processes comprise one or more of the following steps, individually or in the sequence recited:

1) reacting 6,8-difiuoro-1-(formylmethyiamino)-1,4-dihydro-7-(4-methyl-1-
piperazinyi)-4-oxo-3-quinolinecarboxylic acid ester of Formula (It)

wherein R is a straight or branched chain C1 alkyl; with an acid used in the range of 2-10 equivalents of compound of Formula (II) at temperature ranging between 60° to 100 °C to obtain 6,8-difluoro-1-(methyiamino)-1,4-dihydro-7(4-methyi-1-piperazinyl)'4-oxo-3-quinolinecarboxyiic acid addition salt of Formula (III)

wherein HX Is an acid selected from HCI, HNO3, H2SO4, HBr and the like and n = 1 or 2; and

2) reacting the compound of Formula (III) with an alkali metal hydroxide in a non¬
aqueous medium to obtain a compound of Formula (IV) wherein M is an alkali metal;

3) reacting the compound of Formula (IV) with and acid and aqueous formaldehyde solution to obtain Marbofloxacin.

Step 1) involves reacting 6,8-difluoro-1-(formylmethylamino)-1,4-dihydro-7-(4-methyi-1-pipera2inyi)-4-oxo-3-qulnolinecarboxylic acid ester of Formula (II) with an acid to obtain 6,8-difluoro-1-(methylamino)-1,4-dihydro-7(4-methyl-1-piperazinyl)-4'-oxo-3-quinolinecarboxyllc acid addition salt of Formula (III).

Suitable acid which may used in step 1) include and are not limited to mineral acids, such as, for example, HCI, H2SO4, HNO3, and HBr. For example, the acid may be HCI.

The acid used in the reaction may have a concentration of about 5-20% or about 8-14%.

The amount of acid used may be about 2-10 equivalents or about 3-8 equivalents with respect to the compound of Formula (II). For example, the amount of acid used may be about 2-10 equivalents of a 5-20% acid or about 3-8 equivalents of an 8-14% acid.

The temperature for the reaction step 1) may be in the range of about OC to about 110*C. For example, the temperature of the reaction may range from about 60X to about lOCC. The reaction may be maintained at the desired temperature for a for a time period suitable for the completion of the reaction.

The obtained acid addition salt may be isolated or used in situ for the next step.

Step 2) involves reacting a compound of Formula (III) with an alkali metal hydroxide in a non-aqueous medium to obtain a compound of Formula (IV).

Suitable alkali metal hydroxides include and are not limited to lithium hydroxide, potassium hydroxide, sodium hydroxide, and cesium hydroxide.

The amount of alkali metal hydroxide used in step 2) may range between 2-20 equivalents with respect to the compound of Formula (III). For example 10 equivalents of the alkali metal hydroxide may be used.

The alkali metal hydroxide is used in a non-aqueous medium, which may be any glycol medium, such as, for example, ethyiene glycol. The present inventors have surprisingly found that canying out the reaction of Step 2) in a non-aqueous medium, would facilitate the completion of the reaction in less than about 15 hre.

The temperature of the reaction Step 2) may be In the range of about 90 *'C to about 160°C. For example the temperature of the reaction may be in the range of about, 115 °C to about 135 "C.

The reaction may be maintained at the desired temperature for a for a time period suitable for the completion of the reaction.

For example, a compound of Formula (III) may be reacted with potassium hydroxide in ethylene glycol to produce potassium 8-hydroxy-6-difluoro-1-(N-methyl amino)-7-(4-methyl-1-piperazinyi)-4-oxo-4H-quinoiine'3-carboxylate which may be isolated or used in situ for the next step.

Step 3) involves converting the compound of Formula (IV) to marbofloxacin.

For example, the compound of Formula (IV) may be cyclized by reacting with aqueous formaldehyde in the presence of an acid to obtain marbofloxacin.

Suitable acids for cyclization include and are not limited to organic acids, such as, for example, para-toluenesulphonic acid; inorganic acids, such as, for example, hydrochloric acid, sulfuric acid, and the like; and mixtures thereof.

The amount of acid used may be about 0.5-5 volumes or about 2-3 volumes with respect to the compound of Fonnula (IV).

The formaldehyde used in the cyclization reaction may have a concentration of about 37-41% or about 37%. The amount of formaldehyde used may be about 0.1-5 volumes or about 0.3-1.0 volumes with respect to the compound of Formula (V).
For example, the amount of acid used may be about 1-20 volumes of 37-41% formaldehyde or about 8-10 volumes of 37% formaldehyde.

The temperature for cyclization may range from about SCC to about 110'C, or 60*0 to 75°C, The time period to achieve the desired product yield and purity ranges from about 10 minutes to about 5 hours.

The product of Step 3) may be an acid salt, which may be neutralized to the corresponding free base by treating with ammonia, an alkali metal hydroxide, or an aikyi amine, optionally in combination with solvents, such as methanol, isopropyl alcohol, ethanoi, and acetone. Suitable alkali metal hydroxides include and are not limited to potassium hydroxide and sodium hydroxide. Suitable alkyl amines include and are not limited to C1_15 alkyl amines, such as. for example, triethylamine and tributylamine.

For example, the reaction mass containing a compound of Formula (IV) hydrochloric acid, and aqueous formaldehyde may be maintained at a temperature of about 70'*C for a suitable time period, and neutralized with aq. ammonia to obtain marbofloxacin of Formula (I).

The present invention also includes a process for the preparation of marbofloxacin, which process comprises:

a) reacting the compound of Formula (III) with an alkali metal hydroxide in a
non-aqueous medium to obtain a compound of Formula (IV)

wherein M is an alkali metal;

b) reacting a compound of Formula (IV) with hydrochloric acid and
formaldehyde to obtain a compound of Formula (la).

wherein HX is an acid selected from HCI, HNO3, HZSOA, HBr and the like where n = 1or2.

c) converting the compound of Formula (la) to marbofloxacin.
Steps a) and b) of the process may be carried out according to the process described above.

Step c) involves neutralizing the product of step b) to obtain marbofloxacin by treating with a base selected from ammonia, an alkali metal hydroxide, or an alkyl amine, in combination with solvents, such as methanol, isopropyl alcohol, ethanol, and acetone. Suitable alkali metal hydroxides include and are not limited to potassium hydroxide and sodium hydroxide. Suitable alkyl amines include and are not limited to C1-15 alkyl amines, such as, for example, triethylamine and tributylamine.

The present invention includes processes for the purification of marbofloxacin of Formula (I), which processes comprises one or more of the following steps, individually or in the sequence recited:

a) dissolving crude marbofloxacin in a suitable solvent and a base; and

b) isolating pure marbofloxacin or its acid addition salt.

Purification step a) involves dissolving crude marbofloxacin in a suitable solvent and a base.

Suitable solvents include and are not limited to water, methanol, ethanol, IPA, butanol, DMF, DMSO. and acetone.

Suitable bases include and are not limited to ammonia, alkali metal hydroxides, such as, for example, potassium hydroxide and sodium hydroxide; and C1-15 alkyl amines, such as, for example, triethylamine, tributylamine.

The reaction mass may be maintained at a temperature from about 15** C to about reflux temperature of the solvent used to obtain a clear solution.

Purification step b) involves isolating pure marbofloxacin or its acid addition salt.

Pure Marbofloxacin may be Isolated optionally, by subjecting the above clear solution to azeotropic distillation to remove at least half of the volume of the solvent-base mixture at a temperature up to the boiling point of the solvent used optionally under vacuum to precipitate the solid.

Further, Isolation of pure marbofloxacin may be earned out by any conventional process by the person having ordinary skill in the art.

For example, marbofloxacin may be isolated by cooling the reaction mass of step a) to a tower temperature of about 0°C to about 35°C

For example marbofloxacin may be isolated by cooling the reaction mass to a temperature of about 5-10'C, filtering, washing the wet cake with chilled solvent, and drying the product obtained.

The present invention Includes marbofloxacin or its acid addition salt having purity of at least about 99.5% or at least about 99.8%.

Development of purification techniques such as crystallization instead of column chromatography has the advantage of reducing the volume of solvent required and improving up-scalability. This process also provides enhanced purity and yield.

Marbofioxacin obtained by the processes of present invention may be characterized by X-ray powder diffraction (XRPD) patterns, differential scanning calorimetry (DSC) curves and thermogravtmetric analysis (TGA) curves.

Marbofioxacin obtained by the processes of present invention may be characterized by one or more XPRD characteristic peaks at diffraction angles 2-theta of about 5.72, 6.16, 6.60, 7.38. 7.74. 10.22, 10.80, 12.26, 13.30, 14.58, 14.72, 14.96, 15.08, 16.44, 17.56, 17.88, 19,36. 21,80, 21.96, 22.66. 23.76, 24.20, 26.10. 26.52. 28.04 and 40.20 ±0.2 degrees theta, and/or an XPRD pattern substantially as shown in Fig. 1.

PXRD data reported herein for marbofioxacin were obtained using a RIGAKU dmax 2200 Powder X-ray Diffractometer with Cu-Ka radiation having a wavelength ofabout 1.5405 A.

Marbofioxacin obtained by the processes of present invention may be characterized by a DSC exothermic peak at about 281.90°C, and/or a DSC thermogram substantially as shown in Fig. 2.

Differential scanning calorlmetric analyses reported herein for marbofioxacin were carried out on a SHIMAD2U, DSC-60A, Differential Scanning Calorimeter with a ramp of IOC/minute up to 350'C. The starting temperature was 40° °C and ending temperature was 350°C.

Marbofioxacin obtained by the processes of present invention may be characterized by a thermogravimetric weight loss of about 1.297%, and or a TGA curve substantially as shown In Fig. 3.

Thermal gravimetric analyses reported herein for marbofioxacin were carried out on a SWIWIADZU, DTG - 60. Thermogravimetric Analyzer with a ramp of IOC/minute up to 250''C.

Marbofioxacin obtained by the processes of present invention may be characterized by having an infrared absorption (IR) spectrum in a potassium bromide (KBr) pellet substantially as shown in Fig. 4.

The reaction conditions applied in the processes of the present invention are environmentally friendly, efficient, and mild on the product, leading to higher yields and purity and can be adapted to an industrial scale.

Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXAMPLES Example 1: Preparation of ethyl 6,8*difluoro-1-(N-methylfonTiamido)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-quinoline-3-carboxylate of Formula (Ha)
Ethyl 6.8-difluoro-1 -(N-methylformamido)-7-(4-methyl-1 -piperazinyl)-4-oxo-4H-quinoline-3-carboxylate of Fonmula (lla) may be prepared according to the following Scheme 1, wherein ethyl 2,3,4,5-tetrafluoro benzoyl acetate (A) is heated with ethyl 0-formate and acetic anhydride to produce ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxyacrylate (B). On treatment with (N-amino-N-methyl)formamide, (B) yields ethyl 3-(N'-formyl-N'-methyl-hydrazino)-2*(2,3,4,5*tetrafluorobenzoyl)acrylate (C). (C) may be cyclized using triethylamine in toluene to produce ethyl 6,7,8-trifluoro-1-(methylformamida)-4-oxo-4H-quinoline-3-carboxylate (D), which may be condensed with N-methyl piperazine to produce the compound of Formula (IIa).

The basic process is related to that disclosed by Grohe et ai, "Cycloaracylierung von Enamlne, II. Synthese von 1-Amino-4-Chinolon-3-

carbonsauren," Liebigs Annalen Der Chemie, Vol. 1987, No. 10, pages 871-879, 14 October 1987. However, final condensation with N-methyl piperazine is disclosed for forming a different compound.

Example 2: Preparation of ethyl 6,8-difluoro-1-(N"methylformamido)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-qulnoline-3-carboxylate hydrochloride of Formula (IIIa)

Water (400 ml) and the compound of Formula (I la) (200 g) are charged into a round bottom flask at 28°C and concentrated HCI (124 ml) is added slowly at a temperature below 40X, and the mass is heated to 95-1 OOC. 300 ml of water and ethanol are distilled under vacuum at 100°C. The mass is cooled to 25-30°C. Acetone (400 ml) is added and the mass is cooled to O-SC. The mass is maintained at O-SX for 30-60 minutes and the product is filtered. The product is washed with pre-chilled acetone (200 ml) and dried under vacuum at 70-75''C for 12-15 hours to obtain the title compound.
Yield: 181.0 g (95%).

Example 3: Preparation of marbofloxacin from the compound of Formula (IIIa)
Ethylene glycol (100 ml) and potassium hydroxide (17.3 g) are stirred for 10-15 minutes for dissolution. A compound of Formula (IIIa) (10 g) is added and the mass is heated to 120-130'C, and then maintained for 24 hours. The mass is cooled to 30°C and water (15 ml) is added. Hydrochloric acid (36%, 18 ml) is slowly added below 40°C.fwTnic acid (6 ml) is slowly added below 40''C and the mass is stirred for 20-30 minutes. Formaldehyde (5 ml) is added and the mass is then heated to 70-75 and maintained for 1-2 hours. The mass is slowly cooled to 15-20°C and stinBd for 30-60 minutes. The obtained solid dihydroformate salt is filtered and the wet cake is washed with pre-chilled demineralized water (5 ml). The material is suction dried for 2-3 hours. Methanol (50 ml), demineralized water (15 ml), and the wet cake are charged into a round-bottom flask and stirred for 10-15 minutes.

Ammonia solution (25%, 7.5 ml) is added and stirred for 30-60 minutes at 25-35X. The turbid solution is filtered and the wet cake is washed with methanol (5 ml) at 25-35''C. The water and methanol are distilled at 60-70°C under vacuum until 20 ml remain. The mass is cooled to 0-5°C and maintained for 30-60 minutes. The solid is filtered at 0-5°C and the wet cake is washed with methanol (10 ml). The material is suction dried for 30-60 minutes and the product is dried at eo-TO'C under vacuum for 18-20 hours.
Yield: 6.51 g (70%).

Example 4: preparation of marbofloxacin from a compound of Formula (IIIa)
Ethylene glycol (150 ml) and potassium hydroxide (72.2 g) are stirred for 10-15 minutes for dissolution. A compound of Formula (IIIa) (50 g) is added and the mass is heated to 115-125''C, and then is maintained for 10-12 hours at 115-125''C. The mass is cooled to 25-35''C and water (150 ml) is added. Formal acid (98%, 100 ml) is slowly added below 45X and the mass is stirred for 30-60 minutes. Formaldehyde (37-41%, 35 ml) is added to the mass, which is then heated to 70-75*C and maintained for 1-2 hours. The mass is slowly cooled to O-SC and stirred for 1-2 hours. The obtained solid dihydroformate salt is filtered and the wet cake is washed with pre-chilled water (50 ml). The material is suction dried for 1 hour and washed with pre-chilled acetone (50 ml) and suction dried for 1 hour. Methanol (250 ml), water (100 ml), and the wet cake are charged into a round-bottom flask and stirred for 10-15 minutes. Ammonia solution (25%, 40 ml) is added and stirred for 30-60 minutes at 25-35°C. The turbid solution is filtered and the wet cake is washed with methanol (50 ml) at 25-35**C. The filtrate is distilled at 60-70°C under vacuum until 75-100 ml remain. The mass is cooled to 10-15'C and maintained for 30-60 minutes. The solid free base Is filtered at 10-15C and the wet cake is washed with chilled methanol (50 ml). The material is suction dried for 30-60 minutes and the product is dried at 60-70*C under vacuum for 10-12 hours. Yield: 33.0 g (70.8%).

Example 5: Preparation of marbofloxacin from a compound of Formula (IIIa)
Water (360 ml) and potassium hydroxide (86.6 g) are stirred for 10 minutes. A compound of Formula (IIIa) (50 g) is added and the mass is heated to 100-104°C. The mass is maintained for 106-110 hours at 100-104 °C, then Is copied to 25-

SSC and water (65 ml) is added. Hydrochloric acid (36%, 125 ml) is slowly added below AOC and the mass is stirred for 30 minutes. Formaldehyde (37%, 19 ml) is added and the mass is heated to yO-ysC. The mass is maintained for 1-2 hours at 70-75 °C and then is slowly cooled to 0-5'C and maintained for 30-60 minutes. The obtained solid hydrochloride salt is filtered and the bed is washed with pre-chilled water (25 ml) at 0-5*'C. The material is suction dried. Ethanol (250 ml), water (75 ml), ammonia solution (25%, 38 ml) and the wet cake are charged Into a round-bottom flask and stirred for 1-2 hours at 25-35° C. The turbid solution is filtered and the bed is washed with ethanol (50 ml). The filtrate is distilled at 65-70°C under vacuum until 100 ml remain. The mass is cooled to O-S'C and maintained for 30-60 minutes. The solid free base is filtered and the wet cake is washed with pre-chilled ethanol (50 ml). The product is dried under vacuum at 60-70''C for 15-20 hours. Yield: 23,3 g (50%).

Example 6: Preparation of marbofloxacin from a compound of Formula (IIa) Ethylene glycol (60 ml) and potassium hydroxide (28.05 g) are stirred for 10-15 minutes for dissolution. A compound of Formula (IIa) (20 g) is added. The mass is heated to 120-135°C and maintained for 4-6 hours. The mass is cooled to 30°C and water (60 ml) is added. Formic acid (98-100%, 40 ml) is slowly added below 40°C and stirred for 20-30 minutes. Formaldehyde (37-41%, 12 ml) is added to the mass, which Is heated to 70-75°C and maintained for 1-2 hours. The mass is slowly cooled to 0-5*0 and stin-ed for 30-60 minutes. The obtained solid dihydrofonnate salt is filtered and the wet cake is washed with pre-chilled water (20 ml). The material is suction dried for 2-3 hours. Methanol (100 ml), water (30 ml), and the wet cake are charged into a round-bottom flask and stirred for 10-15 minutes. Ammonia solution (25%, 20 ml) is added and stirred for 30-60 minutes at 25-35X. The turbid solution is filtered and the wet cake is washed with methanol (10 ml) at 25-35''C. The water and methanol are distilled at 60-70°C under vacuum until 40 ml remain. The mass is cooled to 0-5''C and maintained for 30-60 minutes. The solid free base is filtered at O-SC and the wet cake is washed with methanol (20 ml). The material is suction dried for 30-60 minutes and the product is dried at 60-70''C under vacuum for 18-20 hours.

Yield: 12.6 9(71%).

Example 7: Purification of marbofloxacin

To crude marbofloxacin (25 g) is added methanol (125 ml) and ammonia (18.75 ml). Half of the volume of the methanol and ammonia solution is removed by azeotropic distillation. The mass is slowly cooled and maintained for 1 hour. The product is filtered and washed with chilled methanol (25 ml). The product is suction dried for 30 minutes and dried under vacuum for 12 hours, to yield pure marbofloxacin of a purity 99.80%. XRD pattern, DSC thermogram, TGA, and IR are substantially in accordance with Figs. 1. 2, 3, and 4, respectively. Yield: 22 g (88.0%),

We Claim:

1. A process for the preparation of marbofloxacin comprising the steps of:

1) reacting 6,8-difluoro-1-(formyimethylamino)-1,4-dihydro-7-(4-methyl-1-
piperazinyl)-4-oxo-3-quinoltnecarboxylic acid ester of Formula (II)

wherein R is a straight or branched chain C1-4 alkyl; with an acid used in the range of 2-10 equivalents of compound of Formula (II) at temperature ranging between 60° to 100 °C to obtain 6,8-difluoro-1-(methylamino)-1,4-dihydro-7(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid addition salt of Formula (III)

wherein HX is an acid selected from HCl, HNO3, H2SO4, HBr and the like and n = 1 or 2; and

2) reacting the compound of Formula (III) with an alkali metal hydroxide in a non-aqueous medium to obtain a compound of Formula (IV)

wherein M is an alkali metal;

3) reacting the compound of Formula (IV) with and acid and aqueous formaldehyde solution to obtain Marbofloxacin.

2. The process for the preparation of marbofloxacin, which process comprises:

a) reacting the compound of Formula (III) with an alkali metal hydroxide in a non-aqueous medium in a time duration ranging between 4-15 hours to obtain a compound of Formula (IV)


wherein M is an alkali metal;

b) reacting a compound of Formula (IV) with hydrochloric acid and
formaldehyde to obtain a compound of Formula (la).

wherein n(HX) is an acid selected from HCl, HNO3. H2SO4, HBr and the like where n = 1 or 2.

c) converting the compound of Formula (la) to Marbofloxacin.

3. A process for the preparation of Marbofloxacin comprising the steps:

1) reacting compound of Formula (IIa)

with an acid used in the range of 2-10 equivalents of compound of Formula (IIa) at temperature ranging between 60° to 100 °C to obtain compound of Formula (III)

wherein HX is an acid selected from HCl, HNO3, H2SO4, HBr and the like and n = 1 or2; and

2) reacting the compound of Formula (ill) with an alkali metal hydroxide in
ethylene glycol medium to obtain a compound of Formula (IV)


wherein M is an alkali metal;

3) reacting the compound of Formula (IV) with and acid and aqueous
formaldehyde solution to obtain Marbofloxacin.

4. A process for the preparation of Marbofloxacin comprising the steps:

1) reacting compound of Formula (IIa)

with hydrochloric acid used in the range of 3-8 equivalents of compound of Formula (IIa) at temperature ranging between 60*' to 100 "C to obtain compound of Formula (IIIa);

2) reacting the compound of Formula (IIIa) with potassium hydroxide in
ethylene glycol medium to obtain a compound of Formula (IV);

3) reacting the compound of Formula (IVa) with aqueous hydrochloric acid
and formaldehyde to obtain Marbofloxacin.

5. The process of claim 1 or 4, wherein alkali metal hydroxide used may be
selected from lithium hydroxide, potassium hydroxide, sodium hydroxide, and
cesium hydroxide.

6. A process for purification of marbofloxacin comprising the steps of:

a) dissolving crude marbofloxacin in a solvent and a base; and

b) isolating pure marbofloxacin.

7. The process of claim 7, wherein the solvent may be selected from water,
methanol, ethanol, IPA, butanol, DMF, DMSO, and acetone.

8. The process of claim 7, wherein the base may be selected from ammonia,
potassium hydroxide, sodium hydroxide, triethylamine and tributylamine.

9. The process of claim 7, wherein the marbofloxacin obtained has a purity
above 99%.