CLIAMS:We Claim:

1. A process for the preparation of Nadifloxacin boron complex of Formula II:

Formula II

or its pharmaceutically acceptable salt, which comprises:
a) reaction of 8,9-Difluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2- carboxylic acid of Formula III

Formula III

with boric acid in presence of acetic anhydride and acetic acid to provide of formula IV; and

Formula IV
b) reaction of the compound of formula IV with 4-hydroxy piperidine in presence of dimethyl sulfoxide and triethyl amine to provide Nadifloxacin boron complex of Formula II or a pharmaceutically acceptable salt thereof.

2. The process of claim 1, wherein the step a) is conducted at a temperature of 120-130 °C.

3. The process of claim 1, wherein the compound of Formula IV has purity greater than 85%.

4. The process of claim 1, wherein the step b) is conducted at a temperature of about 50 to 55 °C.

5. The process of claim 1, wherein the step b) is reduces formation of hydroxy impurity of formula A:

Formula A.

6. The process of claim 1, wherein the compound of formula II is converted to Nadifloxacin or a pharmaceutically acceptable salt thereof.

7. A process for the purification of Nadifloxacin, which comprises:

a) crystallization of crude Nadifloxacin or its salt from a mixture of nitrile and alcohol; and
b) treatment of the compound of step a) with base and acid to provide pure Nadifloxacin.

8. The process of claim 7, wherein the mixture is acetonitrile and methanol.

9. The process of claim 7, wherein the base is sodium hydroxide and acid is hydrochloric acid.

10. The process of claim 7, wherein the pure Nadifloxacin contains purity greater than or equal to 99% by HPLC.
,TagSPECI:Field of Invention

The present invention relates to a process for the preparation of intermediate of Nadifloxacin or a pharmaceutically acceptable salt thereof and its conversion to Nadifloxacin or its pharmaceutically acceptable salt.

Background of the invention

Nadifloxacin, chemically known as (±)-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidino)-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, represent as Formula I:

Formula I

Nadifloxacin is indicated for the treatment bacterial Gram-positive, Gram-negative and anaerobic infections; especially infections caused by resistant Gram-positive organism and Gram-negative organism, mycobacterial infections and emerging nosocomial pathogen infections

U.S. Patent No. 4,399,134 discloses Nadifloxacin and Chem. Pharm. Bull 44 (1996), page nos. 642-5 discloses optically active S-(-)-Nadifloxacin. The process involves use of 3,4-difluoro-6-bromo acetanilide as a starting material, by cyclization reduction of 8-bromo-5,6-difluoro-2-methyl-quinoline, and then by reduction, cyclization, boric anhydride, condensation and hydrolysis to provide Nadifloxacin

Indian patent application Nos. 1015/MUM/2007 and 1010/MUM/2007, Chinese application No. 101298452 discloses a process for the preparation boron complex, intermediate of Nadifloxacin, which involves reaction of 8,9-difluoro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylic acid with boric oxide in presence of acetic anhydride and acetic acid.

None of the prior art processes provides appreciated yield and purity for the Nadifloxacin boron complex as well as Nadifloxacin or a pharmaceutically acceptable salt thereof, therefore, there is a need to develop simple, industrially feasible and cost effective process for Nadifloxacin or a pharmaceutically acceptable salt thereof.

Summary of the Invention

The present invention provides an improved process for the preparation of Nadifloxacin boron complex and its conversion to Nadifloxacin or a pharmaceutically acceptable salt thereof.

In an aspect, the present invention provides a process for the preparation of Nadifloxacin boron complex of Formula II:

Formula II

or its pharmaceutically acceptable salt, which comprises:

a) reaction of 8,9-Difluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2- carboxylic acid of Formula III

Formula III

with boric acid in presence of acetic anhydride and acetic acid to provide of formula IV; and

Formula IV

b) reaction of the compound of formula IV with 4-hydroxy piperidine in presence of dimethyl sulfoxide and triethyl amine to provide Nadifloxacin boron complex of Formula II or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process for the purification of Nadifloxacin, which comprises:
a) crystallization of crude Nadifloxacin or its salt from a mixture of nitrile and alcohol; and
b) treatment of the compound of step a) with base and acid to provide pure Nadifloxacin.

Description of the Invention

The term “pure” as used herein, unless otherwise defined, refers to Nadifloxacin or a pharmaceutically acceptable salt thereof that has purity of about 99 % or above.

The intermediates of the Nadifloxacin, compound of Formula III and Formula IV, as used herein may be free base or its salt.

The salt as used herein, unless otherwise defined, refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide and the like; organic slat may include acetate, mesylate, tosylate and the like.

In an aspect, the present invention provides a process for the preparation of Nadifloxacin boron complex of Formula II:

Formula II

or its pharmaceutically acceptable salt, which comprises:

a) reaction of 8,9-Difluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2- carboxylic acid of Formula III:

Formula III

with boric acid in presence of acetic anhydride and acetic acid to provide of formula IV; and

Formula IV

b) reaction of the compound of formula IV with 4-hydroxy piperidine in presence of dimethyl sulfoxide and triethyl amine to provide Nadifloxacin boron complex of Formula II or a pharmaceutically acceptable salt thereof.

The inventors of the present invention found that the prior art processes give incompletion of the reaction, lower yield and purity due to the use of boric oxide, and further concluded that an unusual, specific reaction conditions and reagents of the present invention improves the yield as well as purity of the intermediate of Nadifloxacin, which improves directly the yield and purity of Nadifloxacin or a pharmaceutically acceptable salt thereof.

The step a) involves reaction of 8,9-Difluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid of Formula III with boric acid in presence of acetic anhydride and acetic acid to provide of formula IV; and.

The reaction is conducted at a temperature of about room temperature to reflux temperature or at 120 to 130 °C. The reaction may be performed for a period of 30 minutes to 4 hours.
After completion of the reaction, the reaction mixture is cooled and combined with water to obtain the precipitation of solid of Formula IV with purity greater than 85%.

The inventors of the present invention surprisingly found that the use of boric acid completes the consumption of starting material to below 2% and improves the yield and purity of the compound of formula IV.

The compound of formula III can be prepared as per the prior art, for example, Chem. Pharm. Bull 44 (1996), page nos. 642-5 or can be prepared according to the following scheme:

The step b) involves reaction of the compound of formula IV with 4-hydroxy piperidine in presence of dimethyl sulfoxide and triethyl amine to provide Nadifloxacin boron complex of Formula II or a pharmaceutically acceptable salt thereof.

The use of dimethyl sulfoxide and triethyl amine of the present invention improves the purity and yield of the Nadifloxacin boron complex of Formula II and reduces/removes the formation of impurities, for example, hydroxy impurity of Formula A:

Formula A.

The step b) is conducted at a temperature of about 20 to about 60 °C or 50 to 55 °C. The reaction may be stirred for 30 minutes to 2 hours or more at the same temperature.

After completion of the reaction, the reaction mixture is cooled and treated with sodium chloride and filtered to provide solid of Formula II.

The resultant solid of Formula II is subjected for deprotection using base such as sodium hydroxide and potassium hydroxide at a temperature of 20-50 °C or at room temperature for a period of 30 minutes to 2 hours in presence of solvent. The solvent is used for deprotection includes but is not limited to alcohol such as methanol, ethanol, isopropyl alcohol and the like or a combination of water thereof.

The resultant reaction mixture may be treated with aqueous acid to attain pH of about 4 to 5 to provide crude Nadifloxacin or a pharmaceutically acceptable slat thereof having purity about 96% by HPLC.

The resultant crude may be subjected for further purification to obtain pure Nadifloxacin or a salt thereof.

In another aspect, the present invention provides a process for the purification of Nadifloxacin, which comprises:

a) crystallization of crude Nadifloxacin or its salt from a mixture of nitrile and alcohol; and
b) treatment of the compound of step a) with base and acid to provide pure Nadifloxacin.

The step a) involves crystallization of crude Nadifloxacin or its salt from the mixture of nitrile and alcohol.

The nitrile solvent used for crystallization includes but is not limited to acetonitrile, propionitrile and the like; and alcohol such as methanol, ethanol, isopropyl alcohol, n-butanol and the like.

The crystallization involves steps of providing solution of crude Nadifloxacin, distill off solvent till to observe precipitation of solid and then cooling the suspension to enhance the precipitation.

The solution is provided by the dissolution of crude Nadifloxacin or its salt in a solvent mixture at a temperature of about 20 to about 100 °C or 60 to 80 °C. Then the solution is subjected for distillation at a reflux temperature to initiate the precipitation of solid and then cooled to below 35 °C. The reaction suspension may be further stirred for 30 minutes to 1 hour to increase the yield of the compound.

The obtained solid is filtered by using known filtration techniques such as filtration by vacuum and subjected for further step.

The step b) involves treatment of the compound of step a) with base and acid to provide pure Nadifloxacin.

The compound is treated first with base, for example, sodium hydroxide and potassium hydroxide followed by acid, for example, hydrochloric acid, in presence of water to provide pure Nadifloxacin or a salt thereof.

The basification and acidification of step b) may be conducted at a temperature of about 20 to about 40 °C or 25 to 35 °C .

The resultant compound, Nadifloxacin or a pharmaceutically acceptable salt thereof have the yield greater than or equal to 85%.

The resultant compound, Nadifloxacin or a pharmaceutically acceptable salt thereof, contain the purity greater than or equal to 98%.

The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.

EXAMPLES

Example 1:

Preparation of Nadifloxacin boron complex (Formula IV)

Acetic acid (70g) and acetic anhydride (180 g) were charged to boric acid (25 g) in the RBF. The Mixture was heated to 120-130 °C for 2 hr, and charged 8,9-difluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2- carboxylic acid (100 g) and maintained for at 120-130 ° for 2-3 hours. After completion of the reaction, cooled to 15-20°C and water (1000 mL) was added slowly. The solid obtained was filtered and dried at 65-70 °C for 8 hr to get 132.1 g of Nadifloxacin boron complex.

HPLC purity: 88.60%

Example 2:

Preparation of Nadifloxacin crude

To a mixture dimethyl sulfoxide (200 mL) and Nadifloxacin boron complex (100 gm), triethyl amine (50 gm) and 4-hydroxy piperidine (30 g) were added. The reaction mixture was heated to 50-55 °C for 2 hours. After completion of the reaction, cooled to 40-45 °C and sodium chloride (150 g) and water (1500 mL) were added. The reaction mass was further cooled to 20-25 °C and maintained for 1 hour. The material was filtered and washed with water (500 mL) to get the yellow coloured solid. This was suspended in water (700 mL) and methanol (300 mL) and then caustic lye (100 g) was added slowly. The reaction mixture was stirred for 1-2 hr. After completion of the reaction, cooled the reaction mass to 20-25°C the charged conc. HCl, (100 mL) slowly to get the pH 4 to 5. The material was filtered and washed with water (400 mL) and dried at 60-65 °C for 6 hours to get (57.2 g) of Nadifloxacin crude.

HPLC purity: 96.7%

Example 3:

Purification of Nadifloxacin.

Nadifloxacin crude (50 g) was dissolved in acetonitrile (875 mL) and methanol (875 mL) at 60-80 0C. The solvent was distilled to half to get precipitation. This was further cooled to 20-30 0C and maintained for 1 hour. The material was filtered to get wet cake. The wet cake was dissolved in water (750 mL) and Lye (20 g) and acidified with Conc. HCl (27 mL) The precipitated material was filtered, washed with water (250 mL), dried to get (42.3 g) of Nadifloxacin.

HPLC purity: 99.25%