The present invention relates to a process for the preparation of Prulifloxacin. The present invention further relates to prulifloxacin having purity of about 99% or more.
Prulifloxacin is chemically 6-fluoro-1-methyl-7-{4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid of Formula I having the structure as depicted below:
(Figure Removed)
Prulifloxacin has an excellent antibacterial activity and has been placed in the market as a synthetic antibacterial agent. US Patent No 5,086,049 provides a process for the preparation of prulifloxacin by reacting 6-fluoro-1-methyl-4-oxo-7-piperazin-1-yl-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylicacid of Formula II,

(Figure Removed)
and 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one of Formula III,

(Figure Removed)
using N,N-dimethylformamide as a solvent. The process provided in the '049 patent further involves concentrating the reaction mixture, pouring the residue into water and isolating prulifloxacin by filtration. The resulting prulifloxacin is recrystallized from chloroform-methanol.

The present inventors have observed that it is difficult to obtain pure prulifloxacin by following the process provided in the prior art and the prulifloxacin obtained by the prior art is contaminated by substantial amount of impurities. Further, the prior art process does not provide any method to remove the excess of 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one used as a starting material.
The present inventors have developed a novel process for the preparation of substantially pure prulifloxacin, which is efficient in removing the organic and inorganic impurities related to the process. The present process includes the extraction of prulifloxacin in aqueous layer in the form of its acid addition salt, and thereby facilitates the removal of organic soluble impurities and excess of 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one. By following the present invention prulifloxacin can be obtained with a purity of about 99% or more.
A first aspect of the present invention provides prulifloxacin having purity of about 99% or above.
A second aspect of the present invention provides a process for the preparation of
prulifloxacin, wherein the process comprises,
a) reacting a compound of Formula II with a compound of Formula III to obtain
prulifloxacin,
(Figure Removed)

b) contacting the prulifloxacin obtained in step a) with an acid in a biphasic solvent
system, wherein the biphasic solvent system comprises water and a water immiscible
organic solvent,
c) separating the aqueous layer from the reaction mixture obtained in step b)
d) treating the aqueous layer with a base, and
e) isolating prulifloxacin from the reaction mixture thereof.
The compounds of Formula II and Formula III are prepared according to the methods provided in US Patent No 5,086,049. The compounds of Formula II and Formula III are reacted in the presence of an organic solvent and a base. The amount of compound of Formula III is equimolar or an excess to one mole of the compound of Formula II. The organic solvent is preferably selected from a group consisting of N,N-dimethyl formamide, dimethylsulfoxide and diglyme. The base is preferably an alkali metal carbonate. The reaction is effected by stirring the reaction mixture at 0° to 50°C. After the completion of the reaction, prulifloxacin is separated from the reaction mixture. The separation is carried out preferably by pouring reaction mixture into water and filtering out the prulifloxacin as a solid. The prulifloxacin so obtained is dissolved in a water immiscible organic solvent. The water immiscible organic solvent is selected from a group consisting of chloroform, cyclohexane, dichloromethane, 1,2-dichloroethane, diethyl ether, hexane, pentane, methyl-t-butyl ether, ethyl acetate and carbon tetrachloride. The water immiscible organic solvent can also be a mixture with a 61.3 alkanol. The water immiscible organic solvent containing prulifloxacin is treated with water. The biphasic reaction mixture so obtained is treated with an inorganic or an organic acid. Alternatively, the water immiscible organic solvent containing prulifloxacin is treated with aqueous solution of an inorganic or an organic acid. Preferably an inorganic acid selected from a group consisting of hydrochloric acid and hydrobromic acid is used. Subsequently the aqueous layer is separated from the reaction mixture and treated with an inorganic or an organic base so as to effect the precipitation of prulifloxacin as a free base. Preferably an inorganic base selected from a group consisting of alkali metal carbonates or hydroxides, and alkaline earth metal carbonates or hydroxides is used.
The precipitated solid prulifloxacin can be isolated from the aqueous layer by further layer separation. The aqueous layer containing precipitated prulifloxacin is treated with a water immiscible organic solvent. The water immiscible organic solvent is selected from a group consisting of chloroform, cyclohexane, dichloromethane, 1,2-dichloroethane, diethyl ether, hexane, pentane, methyl-t-butyl ether, ethyl acetate and carbon tetrachloride. The water immiscible organic solvent can also be a mixture with a Ci-3 alkanol. The organic layer is separated from the reaction mixture and the solvent is removed by concentration to obtain prulifloxacin as a solid. Alternatively, the

precipitated solid prulifloxacin can be directly isolated from the aqueous layer by filtration.
The prulifloxacin so obtained is further recrystallized to obtain prulifloxacin having purity of about 99% or above. Recrystallization is carried out from a mixture of a water immiscible organic solvent and a C1-3 alkanol. Preferably prulifloxacin is recrystallized from a mixture of chloroform and ethanol.
While the present invention has been described in terms of its specific embodiments, 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 invention.
EXAMPLE 1
PROCESS FOR THE PREPARATION OF PRULIFLOXACIN:
A solution of 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (35.5 g, 0.184 moles) in N,N-dimethylformamide (200 ml) was added drop wise at 0° to 5°C to a stirred solution of 6-fluoro-1 -methyl-4-oxo-7-piperazin-1 -yl-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (50 g, 0.143 moles and potassium bicarbonate (15.8 g,0.1578 moles) ) in N,N-dimethylformamide (200 ml). The resulting mixture was stirred at 25° to 28°C for 3-4 hrs. After the completion of the reaction, the reaction mixture was poured into water (1250 ml). The solid obtained was filtered, washed with water (100 ml), and subsequently dissolved in a mixture of chloroform: methanol (7:3 ratio, 1250 ml). The lower organic layer was separated and water (500 ml) was added to the organic layer. A dilute aqueous solution of Hydrochloric acid was added to the biphasic reaction mixture to adjust pH to 0.8 to 1.0. The reaction mixture was stirred for 15 minutes, allowed to settle and the upper aqueous layer was separated. This said process was repeated twice and the aqueous layers were combined. Activated charcoal (10%) was added to the combined aqueous layer and stirred for 30 minutes, filtered and cooled to 20° to 25°C. The pH of the reaction mixture was adjusted to 6.5 to 7.0 by adding an aqueous solution of sodium bicarbonate. The resulting solid was extracted with chloroform (375 ml), stirred for 15 minutes and the organic layer was separated. The aqueous layer was further extracted with a mixture of chloroform: methanol (7:3 ratio; 50 ml). The combined organic layer was distilled under vacumm at 35° to 40°C to recover the solvent up to 125 ml. The reaction mass so obtained was stirred for 3 to 4

hours at 28° to 30°C, filtered and washed with chilled chloroform (50 ml). The wet cake obtained was dried at 45°C for 12 hours to obtain the title compound.
Yield: 30 g HPLC Purity: 97 %
PROCESS FOR THE PREPARATION OF PURE PRULIFLOXACIN:
The prulifloxacin (30 gm) obtained in step a) was suspended in a mixture of chloroform: ethanol (10:1, v/v, 585 ml: 58.5 ml) and heated to reflux temperature. Activated carbon (3.9 gm) was added to the partially cleared solution and refluxed for 30 minutes, followed by filtration through Celite bed. The bed was further washed with chloroform: ethanol (10:1, v/v, 585 ml: 58.5 ml). The filtrate so obtained was distilled at atmospheric pressure till to partially remove the solvent. The concentrate so obtained was stirred at about 25+C for 1 hour, and filtered. The solid obtained was washed with chloroform: ethanol (39 ml X 2), dried under vacuum at 45 °C for 12 hours to obtain the title compound.
Yield: 22.0 g HPLC Purity: 99%

WE CLAIM:
1. Prulifloxacin having purity of about 99% or above.
2. A process for the preparation of prulifloxacin, wherein said process comprises,
a) reacting the compound of Formula II with a compound of Formula III to obtain prulifloxacin,
(Figure Removed)

b) contacting the prulifloxacin obtained in step a) with an acid in a biphasic solvent
system, wherein the biphasic solvent system comprises water and a water immiscible
organic solvent,
c) separating the aqueous layer from the reaction mixture obtained in step b)
d) treating the aqueous layer with a base, and
e) isolating prulifloxacin from the reaction mixture thereof.

3. A process according to claim 2, wherein step a) is carried out in the presence of an organic solvent and a base.

4 A process according to claim 3, wherein the organic solvent is selected from a group consisting of N,N-dimethyl formamide, dimethylsulfoxide and diglyme.

5, A process according to claim 2, wherein the water immiscible organic solvent of step
b) is selected from a group consisting of chloroform, cyclohexane, dichloromethane,
1,2-dichloroethane, diethyl ether, hexane, pentane, methyl-t-butyl ether, ethyl acetate
and carbon tetrachloride.

6. A process according to claim 2, wherein the acid is selected from a group consisting
of hydrochloric acid and hydrobromic acid.

7. A process according to claim 2, wherein the base is selected from a group consisting
of alkali metal carbonates or hydroxides, and alkaline earth metal carbonates or
hydroxides.
8. A process according to claim 2, wherein prulifloxacin obtained in step e) is further
recrystallized from a mixture of a water immiscible organic solvent and a C1-3 alkanol.
9. A process according to claim 8, wherein the water immiscible organic solvent is
chloroform.
10. A process according to claim 8, wherein the C1-3 alkanol is ethanol.