FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
PROVISIONAL SPECIFICATION
(SECTION 10, rule 13)


AN IMPROVED PROCESS OF PREPARING MOXIFLOXACIN OR ACID ADDITION SALTS THEREOF
Enaltec Labs Private Limited
an Indian Company,
registered under the Indian company's Act 1957
and having its registered office at
B/520, Nand Dham, Sector 11, CBD Belapur,
Navi Mumbai-400 614, INDIA
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION



FIELD OF THE INVENTION
The present invention relates to an improved process of preparing Moxifloxacin or acid addition salts thereof.
BACKGROUND OF THE INVENTION
The Moxifloxacin hydrochloride, l-cyclopropyl-7-[S,S]-2,8-diazabicyclo [4.3.0]non-8-yl)-6-fluoro,l,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid hydrochloride , has the following structure:

Moxifloxacin hydrochloride is a broad- spectrum antibacterial fluoroquinolone. It is particularly effective against gram-positive bacteria and is significantly better than sparfloxacin and ciprofloxacin as disclosed in European Patent 350,733 and European Patent 550,903. Moxifloxacin has activity against gram- negative and gram-positive organisms, including streptococcus pneumonia, staphylococcus aureus, pseudomonas aerugnosa, particularly against respiratory disease-causing pathogens like mycoplasma pneumonia, mycobacterium tuberculosis and chlamydia pneumonias, and the activity shown to be unaffected by [beta]-lactamases.
U.S. Patent 5,157,117 discloses (l-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo- 1,4-dihydro-3-quinoline carboxylic acid-03,04)bis-(acyloxy-0) borate and a process for its preparation by reacting ethyl-l-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinoline carboxylate with boric acid and acetic anhydride in the presence of zinc
3 1 MAR 2009


chloride, followed by its conversion to gatifloxacin hydrochloride.
Hydrates of moxifloxacin hydrochloride known are the anhydrous and monohydrate. U.S. Patent 5,849,752 discloses the monohydrate of moxifloxacin hydrochloride and its preparation by treating the anhydrous crystalline form with ethanol/ water mixtures. Further, U.S. Patent 5,849,752 discloses chromatographic purification of crude moxifloxacin followed by the preparation of anhydrous moxifloxacin hydrochloride and its further conversion to monohydrate. The process of monohydrate formation is not simple and involves heating the anhydrous moxifloxacin hydrochloride in an ethanol/water mixture at 70°C, followed by evaporation of the solvent.
European Patents 350733, 550903 and 657,448 disclose the preparation of moxifloxacin hydrochloride involving 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-diaza bicyclo[4.3.0]nonane in the presence of a base and its conversion to hydrochloride salt at higher temperatures, affording moxifloxacin and its positional isomer, (4as-cis)-I-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 moxifloxacin and the impurity mentioned above are positional isomers, they are difficult to separate. Purification of moxifloxacin to remove this isomer results in lower yields, thereby increasing the product cost. Similarly, methods described in the prior art involves the preparation of moxifloxacin, followed by its conversion to the hydrochloride salt, thus incorporating an additional step in the manufacturing process and leading to low yields.
Accordingly, there is a need for a process that overcomes the problems encountered in the prior art process while still affording the desired product in high yield in a cost-effective manner.


SUMMARY OF THE INVENTION
In one embodiment,
The present invention provides an improved process for the preparation of pure
Moxifloxacin or acid addition salts thereof comprising the step of:
Condensing borate complex or ester of l-cyclopropyl-6,7-difluoro- 1 ,4-dihydro-8-
methoxy-4-oxo-3-quinoline carboxylic acid with [S,S]-2,8-diazabicycIo-[4.3.0]-nonane
or its derivative in presence of a base in a chlorinated solvent(s) or mixture thereof.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment,
The present invention provides an improved process for the preparation of pure Moxifloxacin or acid addition salts thereof comprising the step of: Condensing borate complex or ester of l-cyclopropyl-6,7-difluoro- 1 ,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid with [S,S]-2,8-diazabicyclo-[4.3.0]-nonane or its derivative in presence of a base in a chlorinated solvent(s) or mixture thereof. Isolating the pure Moxifloxacin hydrochloride in usual manner as reported in literature. In other embodiment,
The present invention also provides the efficiency of condensation reaction by using chlorinated solvent. The conversion of borate complex or ester of 1-cyclopropyl-6,7-difluoro- 1 ,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid to Moxifloxacin hydrochloride was more than 95 %, also the achieved yield was around 85 to 90 % of the theory.
The borate complex like but not limited to 0,0-bis(acyloxy-0)borate or 0,0-bis(propyloxy-0)borate or 0,0-difluoroboron,etc.,but mote preferably 0,0-bis(acyloxy-0)borate.
The esters like methyl, ethyl, prpoyl, isobutyl, t-butyl, etc, more preferably ethyl.
The starting materials, of l-cyclopropyl-6,7-difluoro- 1 ,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid ot its borate complexes, esters, , [S,S]-2,8-diazabicyclo-[4.3.0]-nonane or its derivatives , were prepared by literature reported methods.
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Definitions
Pharmaceutically acceptable salts forming part of this invention include salts derived from acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutic ally acceptable solvates may be hydrates or comprise other solvents of crystallization such as alcohols.
Salts can be obtained by dissolving the free compound in a suitable solvent, e.g., in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (e.g., ethanol and isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The salts are obtained by filtering, re-precipitating, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by basification or by acidifying into the free compounds which, in turn can be converted into salts.
The substances according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuum and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material.
In general, chlorinated solvents include, but are not limited to, dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride.
In general, the compounds prepared in the above described processes are obtained in pure form by using well known techniques such as crystallization using solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, water or their combinations, or column chromatography using alumina or silica gel and eluting the column with solvents such as hexane, petroleum ether (pet.ether), chloroform, ethyl acetate, acetone, methanol or their combinations.
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reaction on HPLC, the product formation is 83.2 %.Evaporate the solvent and hydrolyze and isolate the product in usual manner as reported in literature to get Moxifloxacin hydrochloride (24.5 gm ) having HPLC purity 99.12 %.
Example-3
Preparation of Moxifloxacin Hydrochloride:-
l-cyclopropyl--6,7-difluoro- 1 ,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid O,O-bis(acyloxy-0)borate (35.6 gm) was dissolved in Toluene (100 ml) at 0-5°C and [S,S]-2,8-diazabicyclo-[4.3.0]-nonane (10 gm) followed by triethylamine(10 gm) was added at 0-5°C,stir the reaction mass for additional 01 hr at the same temperature. Raise the temperature to 25-35°C and maintains for 10 hr at same temperature. Monitor the reaction on HPLC, the product formation is 81.2 %.Evaporate the solvent and hydrolyze and isolate the product in usual manner as reported in literature to get Moxifloxacin hydrochloride (26.3 gm ) having HPLC purity 99.12 %.



Features and advantages:-
1) Improved process for the preparation of pure Moxifloxacin or acid addition salts
thereof comprising the step of:
a) Condensing borate complex or ester of l-cyclopropyl-6,7-difluoro- 1 ,4-dihydro-8-methoxy-4-oxo-3-quinoIine carboxylic acid with [S,S]-2,8-diazabicyclo-[4.3.0]-nonane or its derivative in presence of a base in a chlorinated solvent(s) or mixture thereof.
2) According to claim l,the borate complex like 0,0-bis(acyloxy-0)borate or 0,0-bis(propyloxy-0)borate or 0,0-difluoroboron,etc.,but mote preferably 0,0-bis(acyloxy-0)borate.
3) According to claim 1, the esters like methyl, ethyl, prpoyl, isobutyl, etc, more preferably ethyl.
4) According to claim 1, the chlorinated solvents like but not limited to
dichloromethane. ethylene dichloride, chloroform,etc.
All patent and non-patent publications cited in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.