This application claims priority to Indian patent application numbered 1576/CHE/2011 filed on May 06, 2011, the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Levofloxacin hemihydrate.

BACKGROUND OF THE INVENTION:

Levofloxacin, (S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1 -piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid of the formula-l is given below
Levofloxacin is the S-enantiomer of Ofloxacin, a fluoroquinolone antibacterial agent. The mechanism of action of Levofloxacin and other fluoroquinolone antibacterials involves the inhibition of DNA gyrase (bacterial topolsomerase II), an enzyme required for DNA replication, transcription repair and recombination.

U.S Pat. No. 5,051,505 discloses the process for preparation of piperazinyl quinolone derivatives by reaction of dihaloquinolones with piperazine derivatives and tetra alkyl ammonium halides in presence of a polar solvent such as acetonitrile, Dimethyl formamide (DMF), pyridine, sulfolane and Dimethylsulfoxide (DMSO).

U.S. Pat No. US 7629458 discloses the process for preparation of Levofloxacin by reaction of (S)-(-) 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4] benzoxazine-6-carboxylic acid with N-methyl piperazine in a polar solvent or as a neat mixture at an elevated temperature of 70°C to 120° C and recovering Levofloxacin by using the techniques well known in the art. The Application further discloses the polymorphic or pseudomorphic forms (form-A, form-B, form-C, form-F, form-G, and form-H) of Levofloxacin and the processes for their preparation.

U.S. Pat No. 5,545,737 is particularly disclosed the processes for preparation of hemihydrate free of monohydrate by crystallizing crude Levofloxacin in aqueous ethanol containing 2-10% moisture content and process for monohydrate free of hemihydrate by crystallizing crude Levofloxacin in aqueous ethanol containing 10% or more than 10% moisture content.

While isolation of Levofloxacin from the reaction mixture obtained by the condensation of (S)-(-) 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4] benzoxazine-6-carboxylic acid with N-methyl piperazine, several byproducts and salts are formed and it is difficult to separate Levofloxacin from byproducts and salts.

Thus the present invention provides an improved process for the isolation of Levofloxacin without carry forward the byproducts and salts in the final Active Pharmaceutical Ingredient.

OBJECT AND SUMMARY OF THE INVENTION:

The main object of the present invention is to provide an improved process for the preparation of Levofloxacin.

The process for the preparation of Levofloxacin is shown in the following scheme.

Accordingly, the present invention provides an improved process for the preparation of pure Levofloxacin comprising, reacting (S)-(-)9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][1,4] benzoxazine-6-carboxylic acid with N-methyl piperazine, characterized in that after completion of the reaction, reaction mixture containing Levofloxacin in water immiscible solvent is washed with aqueous sodium chloride solution to isolate Levofloxacin free of byproducts and salts.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of Levofloxacin by reacting (S)-(-)9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][1,4] benzoxazine-6-carboxylic acid with N-methyl piperazine, wherein the improvement comprises, after completion of the reaction, reaction mixture containing Levofloxacin in water immiscible solvent is washed with aqueous sodium chloride solution to isolate Levofloxacin free of byproducts and salts.

During the preparation of Levofloxacin, (S)-(-)9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][1,4] benzoxazine-6-carboxylic acid is condensed with N-methyl piperazine. The formed byproducts and salts are not removed easily by simple filtration or by the addition of water. If water is added to the Levofloxacin containing water immiscible solvent, the byproducts and salts are not separated and thick emulsion is formed, which is not separable. Present inventors surprisingly found that by addition of aqueous sodium chloride solution to the Levofloxacin containing water immiscible solvent solution the formed byproducts and salts are separated from the product.

Accordingly, one aspect of the present invention provides, an improved process for the preparation of Levofloxacin comprising, reacting (S)-(-)9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][1,4] benzoxazine-6-carboxylic acid with N-methyl piperazine, characterized in that after completion of the reaction, reaction mixture containing Levofloxacin in water immiscible solvent is washed with aqueous sodium chloride solution to isolate Levofloxacin free of byproducts and salts.

The present invention provides, an improved process for the preparation of Levofloxacin comprising, reacting (S)-(-)9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][1,4] benzoxazine-6-carboxylic acid with N-methyl piperazine, characterized in that after completion of the reaction, reaction mixture is concentrated; crude reaction mixture containing Levofloxacin is dissolved in water immiscible solvent and washed with aqueous sodium chloride solution to isolate Levofloxacin free of byproducts and salts.

In one embodiment of the present invention, 1 to 20% aqueous sodium chloride solution is used for the washing of reaction mixture containing Levofloxacin in water immiscible solvent. Preferably 5 to 15% aqueous sodium chloride solution is used. More preferably 5 to 10% aqueous sodium chloride solution is used.

In one more embodiment, water immiscible solvent is selected from toluene, dichloromethane, chloroform, carbon tetrachloride or mixtures thereof, preferably chloroform.

The Levofloxacin formed by this process is further converted into Levofloxacin hemihydrate by the conventional methods.

According to the present invention, (S)-(-) 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]-1,4-benzoxazine-6-carboxylic acid is condensed with N-methyl Piperazine and after completion of the reaction the reaction mixture is concentrated and crude reaction mixture containing Levofloxacin is dissolved in water immiscible solvent like toluene, dichloromethane, chloroform or carbon tetrachloride, preferably chloroform and washed with aqueous sodium chloride solution.

The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limiting the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art.

Examples:

Comparative Example: Process for the preparation of Levofloxacin without using aqueous sodium chloride solution (S)-(-) 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]-1,4-benzoxazine 6-carboxylic acid (250 gm) was suspended in n-Butanol (160 gm). To this N-Methyl Piperazine (200 gm) was added and the temperature was raised to 120 °C to 125 °C. Reaction mass was maintained at the same temperature for 6 hours and cooled 100 °C. n-Butanol was distilled of completely under vacuum at a temperature below 100 °C. To this a mixture of chloroform and toluene was added and stirred. The mixture of chloroform and toluene distilled off completely under vacuum at a temperature below 100 °C. The reaction mass was cooled and chloroform was added. To this water was added and stirred. Total material was emitted, there was no layer separation was observed. Reaction mass was filtered and washed with IPA. The isolated material contains unwanted salts with low purity.

Exampie-1: Process for the preparation of Levofloxacin (S)-(-) 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (250 gm) was suspended in n-Butanol(160 gm). To this N-Methyl Piperazine (200 gm) was added and the temperature was raised to 120 °C to 125 °C. Reaction mass was maintained at the same temperature for 6 hours and cooled 100 °C. n-Butanol was distilled of completely under vacuum at a temperature below 100 °C. To this a mixture of chloroform and toluene was added and stirred. The mixture of chloroform and toluene distilled off completely under vacuum at a temperature below 100 °C. The reaction mass was cooled and chloroform (1750 ml) was added. To this 5% sodium chloride solution was added and stirred. The layers were separated and chloroform was added to the aqueous layer. Again layers are separated and both the organic layers were combined. To this DM water was added and to the organic layer EDTA was added. To this carbon was added and filtered. The filtrate was washed with chloroform. The chloroform was completely distilled under vacuum. To this isopropyl alcohol was added, filtered to yield Levofloxacin.

Example-2: Process for the preparation of Levofloxacin hemihydrate Levofloxacin obtained from the Example-1 was taken and isopropyl alcohol (850 ml) was added. The temperature was raised to 65 °C to 90 °C. The reaction mass was cooled to room temperature and filtered. The filtrate was washed with chilled ethanol and dried under vacuum to yield Levofloxacin hemihydrate.

We claim:

1. An improved process for the preparation of Levofloxacin comprising, reacting (S)-(-)9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][1,4] benzoxazine-6-carboxylic acid with N-methyl piperazine, characterized in that after completion of the reaction, reaction mixture containing Levofloxacin in water immiscible solvent is washed with aqueous sodium chloride solution.

2. The process according to claim 1, wherein 1 to 20% aqueous sodium chloride solution is used for the washing of reaction mixture containing Levofloxacin in water immiscible solvent.

3. The process according to claim 2, wherein 5 to 15% aqueous sodium chloride solution is used for the washing of reaction mixture containing Levofloxacin in water immiscible solvent.

4. The process according to claim 2, wherein 5 to 10% aqueous sodium chloride solution is used for the washing of reaction mixture containing Levofloxacin in water immiscible solvent.

5. The process according to any of the claims 1 to 4, wherein water immiscible solvent is selected from toluene, dichloromethane, chloroform, carbon tetrachloride or mixtures thereof.

6. The process according to any of the claims 1 to 5, wherein the Levofloxacin is further converted into Levofloxacin hemihydrate.

7. An improved process for the preparation of Levofloxacin comprising, reacting (S)-(-)9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][1,4] benzoxazine-6-carboxylic acid with N-methyl piperazine, characterized in that after completion of the reaction, reaction mixture is concentrated; crude reaction mixture containing Levofloxacin is dissolved in water immiscible solvent and washed with aqueous sodium chloride solution.

8. The process according to claim 7, wherein 1 to 20% aqueous sodium chloride solution is used, preferably 5 to 15%, most preferably 5 to 10%.

9. The process according to claim 7, wherein water immiscible solvent is selected from toluene, dichloromethane, chloroform, carbon tetrachloride or mixtures thereof.

10. The process according to any of the claims 7 to 9, wherein the Levofloxacin is further converted into Levofloxacin hemihydrate.