DESCRIPTION

The present invention relates to a process for the preparation of Levofloxacin hemihydrate. Further  the present invention relates to a process for the purification of Levofloxacin hemihydrate to afford more than or equal to 99.5% pure Levofloxacin hemihydrate.

Levofloxacin Hemihydrate of Formula I is chemically known as (-)-(S)-9-fluoro2 3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1 2 3-de]-1 4-benzoxazine-6-carboxylic acid hemihydrate  which is used for treating bacterial infections.

Formula I
Levofloxacin is known as antimamicrobial agent  and is active against a broad spectrum of gram-positive and gram negative bacteria. Levofloxacin particularly more effective against streptococcus and staphylococcus strains of bacteria.

U.S. Patent No. 4 382 892 is directed toward pyrido[1 2 3-de][1 4]benzoxazine derivatives and methods of preparing them.

U.S. Patent No. 5 053 407 is directed toward optically active pyridobenzoxazine derivatives  including Levofloxacin  its processes  and intermediates useful for preparing such derivatives.

U.S. Patent No. 5 051 505 is directed toward processes for preparing piperazinyl quinolone derivatives. The process comprises reacting dihaloquinolones with piperazine derivatives and tetraalkyl ammonium halides in the presence of a polar solvent.

U.S. Patent No. 5 155 223 is directed toward the preparation of quinolinecarboxylic acids.

U.S. Patent No. 5 545 737  U.S. 7 425 628 B2  U.S. 2006/276463 A1 and an article titled "Effect of dehydration on the formation of Levofloxacine Pseudopolymorphs " Chem. Pharm. Bull. 43(4) 649-653 (1995)  disclose levofloxacin hemihydrate by controlling the water content of an aqueous solvent in which levofloxacin is dissolved during a crystallization.

There is a requirement to develop a simple and commercially available process to provide pure levofloxacin hemihydrate. Therefore  the present inventors developed an improved process for preparing crude levofloxacin and purification process for pure levofloxacin hemihydrate.

In one aspect of the present invention relates to a process for the preparation of pure Levofloxacin hemihydrate  which includes steps of:

a) 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 in dimethylsulfoxide at a temperature of about 80 °C to about 110°C 

b) precipitation of solid of step (a) by using antisolvent  methanol 

c) purification of crude levofloxacin hemihydrate of step b) using solvent mixture comprising first solvent selected from alcohol; second solvent selected from chlorinated solvent; and third solvent selected from water  wherein the said chlorinated solvent volume is not more than 10 times per gram of crude Levofloxacin.

As used herein  the term "precipitated" includes the formation and/or increase of a solid in a reaction mixture.

As used herein  the term “crude” includes the purity of levofloxacin is less than or equal to 99% determined by HPLC.

As used herein  the term “pure” includes the purity of levofloxacin is more than or equal to 99.5% determined by HPLC.

The Levofloxacin Q-acid term here after used for (S)-(-)-9 10-difluoro-3-methyl-7-oxo-2 3-dihydro-7H-pyrido [1 2 3-de][1 4]benzoxazine-6-carboxylic acid.

The volume of DMSO used for conducting the reaction may range from 0.5 to about 2 ml per gram of levofloxacin Q-acid.

The N-methyl piperazine used for the reaction may range from 1 to 4 molar equivalents per molar equivalent of levofloxacin Q-acid.

The duration of the reaction of levofloxacin Q-acid with N-methyl piperazine usually depends on solvent  temperature and reaction conditions. The suitable temperature for conducting the reaction to prepare Levofloxacin is about 85 to about 110 °C. The time period for completion of the reaction may range from 1 to 4 hours.

The solvent used for the reaction is dimethyl sulfoxide (DMSO)  which is effecting the reaction to complete the conversion of starting material (Levofloxacin-Q-acid) to less than 0.1% or below level of detection with in the time period of less than 3 hour.

After completion of the reaction  the reaction mixture is subjected to precipitation of solid by using suitable techniques  especially with the anti-solvent technique. The anti-solvent used for the precipitation is methanol with a quantity of 5-10 times per gram of levofloxacin-Q-acid at a temperature of about 35-60°C. The obtained suspension may be stirred for certain time period to increase the precipitation of the crude levofloxacin.

The obtained suspension further subjected for recovery by using suitable techniques like filtration by vacuum  centrifugation or decanting and the like.

The resulted crude levofloxacin is subjected to purification  which involves dissolution of crude in a solvent mixture alcohol  dichloromethane and water at a temperature of about 40-60°C  treatment of solution with charcoal  concentration of clear solution till to get 3-4 times of solute to effect the precipitation followed by filtration to provide pure levofloxacin hemihydrate.

In another aspect of the present invention relates to a process for the purification of crude levofloxacin  which include steps of:
i) suspending crude levofloxacin in a solvent mixture of alcohol  chlorinated solvent and water  wherein said chlorinated solvent volume is not more than 10 times per gram of crude levofloxacin;
ii) providing the solution of step i) by increasing the temperature;
iii) precipitating solid from the solution of step ii) by using suitable techniques;
iv) recovering the solid of step iii) to afford pure Levofloxacin hemihydrate.

The crude levofloxacin contacted with a mixture of solvents to form suspension at room temperature. First solvent from the mixture of solvent is alcohol such as methanol  ethanol  isopropyl alcohol and the like. Second solvent from the mixture is selected from chlorinated solvent  for example  dichloromethane  dichloroethane  chlorobenzene and the like. Third solvent from the mixture of solvents is water.

In an embodiment  the present invention comprises purification of crude levofloxacin using solvent mixture comprising methanol  dichloromethane and water. The volume of dichloromethane is less than about 10 ml per gram of crude levofloxacin. The volume of methanol is 1 to 18 or 10-15 ml per gram of crude levofloxacin. The preferred ration of dichloromethane and methanol may be 1:15.

The purification process is simple and commercially viable for preparing pure levofloxacin hemihydrate  which avoids formation of unknown impurity by the degradation of levofloxacin. The removal of unknown impurity having mass 410 is very difficult from the product by using available purification techniques and affects the overall yield.

The degradation impurity may be formed due to the use of excess amount of chlorinated solvent or use of different reaction conditions known from the prior art. The present inventors used chlorinated solvent less than or equal to 10 times per gram of crude levofloxacin  which affected the purity of levofloxacin.

The suspension of crude levofloxacin is subjected to heating to about 35 to about 60°C  or 50-55°C to get clear solution and then treated with charcoal. The obtained reaction mixture is filtered to remove charcoal and to make the clear and particle free solution.

The present purification process avoids the formation of suspension during charcoal treatment and particle free filtration. The use of chlorinated solvent  for example  dichloromethane  provides improved solubility and avoids the formation of crystals during charcoal treatment and particle free filtration.

The resultant clear solution may be subjected to precipitation using distillation till to get 2-5 volumes of solute and then cooled to form the suspension. The cooling temperature is below 20 °C. The obtained suspension may be stirred for certain time usually 10 to 30 minutes to increase the formation of solid.

Finally  the solid is recovered from the obtained suspension by using filtration  centrifugation or decanting and the like.

The present invention is further illustrated by the following example  which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLES
Example -1: A process for the preparation of Levofloxacin

Levofloxacin-Q-acid (100 gm) and N-Methyl piperazine (75 gm) were suspended in dimethylsulfoxide(150 ml) simultaneously into reaction flask. The reaction mixture was heated to 95-100°C and maintained for 2 hrs. After completion of the reaction  the reaction mixture was cooled to 50-55°C  charged methanol (700ml)  stirred at 5-100C  filtered to get crude Levofloxacin.
HPLC purity>99.0% with > 85% yield.

Crude Levofloxacin (100 gm) was suspended in mixture of methanol (1500 ml)  dichloromethane (100 ml) and water (25ml)  and then heated to 50-55°C to get clear solution followed by treated with charcoal. The clear solution was concentrated till to get 3-4 times solvent remained in the reaction mixture  cooled to 5-10 0C and then filtered to get pure Levofloxacin hemihydrate.
HPLC purity>99.6%  Any unknown impurity below 0.1%.
Yield: 90% yield.

We Claim:

1. A process for the preparation of pure Levofloxacin hemihydrate  which comprises:
a) 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 dimethylsulfoxide at a temperature of about 80 °C to about 110°C to form Levofloxacin;
b) precipitation of solid of step (a) by using antisolvent  methanol to provide crude levofloxacin;
c) purification of crude levofloxacin hemihydrate of step b) using solvent mixture comprising first solvent selected from alcohol; second solvent selected from chlorinated solvent; and third solvent selected from water  wherein the chlorinated solvent volume is 1-10 times per gram of crude levofloxacin.
2. The process of claim 1  wherein said DMSO used for reaction is 0.5 to about 2 ml per gram of levofloxacin-Q-acid.

3. The process of claim 1  wherein said N-methyl piperazine used for the reaction is 1 to 4 molar equivalents per molar equivalent of levofloxacin Q-acid.

4. The process of claim 1  wherein said alcohol is methanol and chlorinated solvent is dichloromethane.

5. A process for the purification of crude levofloxacin  which comprises:
i) suspending crude levofloxacin in a solvent mixture of alcohol  chlorinated solvent and water  wherein said chlorinated solvent volume is not more than 10 times per gram of crude levofloxacin;
ii) providing the solution of step i) by increasing the temperature;
iii) precipitating solid from the solution of step ii) by using suitable techniques;
iv) recovering the solid of step iii) to afford pure Levofloxacin hemihydrate.
6. The process of claim 5  wherein said chlorinated solvent is dichloromethane.

7. The process of claim 5  wherein said chlorinated solvent and alcohol is present in the ratio of 1:15.

8. The process of claim 5  wherein said temperature in step ii) is about 35 to about 60°C.

9. The process of claim 5  wherein said precipitation of solid is obtained by distillation followed by cooling.

10. The process of 5  wherein said pure levofloxacin hemihydrate is having purity more than or equal to 99.5% determined by HPLC

Dated this 21st day of September  2012 For Wockhardt Limited

(Dr Mandar Kodgule)
Authorized Signatory