FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
IMPROVED PROCESS FOR INTERMEDIATE OF
NADIFLOXACIN
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to improved process for 2-bromo-4,5-
difluoroaniline, and to their application in the synthesis of Nadifloxacin and its enantiomers, salt and prodrug thereof.
The following specification particularly describes the invention and the manner
in which it is to be performed.
1

4. DESCRIPTION
The present invention relates to improved process for 2-bromo-4,5-difluoroaniline, and to their application in the synthesis of Nadifloxacin and its enantiomers, salt and prodrug thereof.
Nadifloxacin of Formula I, is chemically 9-Fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-1 H,5H-benzo[ij]quinolizine-2-carboxylic acid and 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.

Formula I
U.S. Patent No. 4,399,134 and JP Patent No. 58,90,511 discloses Nadifloxacin. Nadifloxacin is racemic [(±)-9-fluoro-8-{4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1 H -5H-benzo[i,j]quinolizine-2-carboxylic acid.
Chem. Pharm. Bull 44 (1996), page nos. 642-5 and JP Kokai Tokyo Koho 63,192,753 discloses optically active S-(-)-Nadifloxacin, further discloses Racemic RS-(±)-Nadifloxacin derives its biological activity primarily from the S-(-)-enantiomer.
U.S. Patent No. 6,514,986 discloses the substantially amorphous and substantially crystalline form of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1 -oxo-1 H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt.
2

U.S. Patent No. 6,664,267, discloses a crystalline monohydrate form of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1 H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt.
Several Japanese patent / application, for eg. JP0141127 B4, JP63192753 A2 and JP 2731853 B2 discloses Nadifloxacin in its optical form.
Chem. Pharm. Bull. 38(9), 2459-62,1990 discloses the synthesis of 2-bromo-4,5-difluoroaniline at reduced temperature.
While working on the process for intermediates of Nadifloxacin, It was found by the present inventors that 2-bromo-4,5-difluoroaniline synthesis involves the following impurities 2,6-dibromo-4,5-difluoroaniline and 2-Bromo-3,4-difluoroaniline an isomeric product, which require the additional step of distillation and purification. The present inventors have embarked upon a simple selective bromination technique at lower temperature of - 40°C to - 50°C for preparation of 2-bromo-4,5-difluoroaniline in high purity and better yield. Hence distillation and purification steps are avoided. Further there is no need to isolate the 2-bromo-4,5-difluoroaniline, the reaction mass can be directly subjected to subsequent step.
Omitting the isolation work-up between two steps means that the second step will be performed in the crude reaction solution resulting from the previous step. Potential major advantages includes: higher yield (through avoidance of loss of the intermediate in the work-up); elimination of isolation, purification, drying and analysis of the intermediate; significant reduction in equipment demand (eg. reactors, filters, driers, etc.); and significant reduction of the process time.
3

In one aspect of the present invention there is provided a process for preparation of 2-bromo-4,5-difluoroaniline compound of Formula III. The process includes step of,

Formula II
to obtain a compound of formula III

a) brominating 3,4 Difluroaniline of formula II in presence of potassium carbonate and methylene chloride, at a temperature of -40 °C to - 50 °C,
Formula III
The bromination reaction when carried out at temperature of - 40 °C to - 50 °C is selective and thus the compound of formula III is subjected to subsequent step without isolation.
Optionally the product can also be isolated and subjected to subsequent step.
In another aspect there is provided a process for 2-bromo-4,5-difluoroaniline compound of Formula III, having purity of 96 % or more.
In another aspect there is provided a process for 2-bromo-4,5-difluoroaniline compound of Formula III, as an intermediate in synthesis of Nadifloxacin and its enantiomers, salt and prodrug thereof.
4

The compound of formula III is converted to Nadifloxacin and its enantiomers, salt and prodrug thereof by any process known to the skilled artisan. For eg. The compound of formula III is condensed with crotonaldehyde, treated with a series of catalyst like palladium on carbon and platinum on carbon for debromination and hydrogenation respectively, optionally resolved, treated with diethyl ethoxymethylenemalonate, phosphoric acid and subsequently treated with boron triacetate to get Nadifloxacin or optionally its enantiomers.
Similarly the salt and prodrug of Nadifloxacin can be made by any process known to the skilled artisan.
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: Preparation of 2-bromo-4,5-difluoroaniline
To a four-necked flask was charged methylene chloride (1000 mL), anhydrous potassium carbonate (100 gm) and 3,4-difluoroaniline (100 gm). The reaction mixture was cooled to -10 °C in an ice salt bath. Bromine (133 gm) was added drop wise maintaining the temperature between -10 and -15°C. The reaction mixture was stirred for another two hours at -10 to -15 °C. TLC showed that the starting material was almost consumed. The reaction was quenched by the slow addition of water (500 mL). The layers were separated and the aqueous layer was washed with methylene chloride (100 mL). The organic layer was separated and combined with the earlier organic extract. The combined organic extract was washed with water (500 mL) and then concentrated by distillation under atmospheric pressure.
Purity: 87.0% (By HPLC)
5

Example 2: Preparation of 2-bromo-4,5-difluoroaniline
To a four-necked flask was charged methylene chloride (300 mL), potassium carbonate (18.5 gm) and 3,4-difluoroaniline (25 gm). The flask was immersed in a dry ice - acetone cooling bath. When the temperature of the reaction mixture reached - 50 °C, a solution of bromine (44 gm) was added dropwise maintaining temperature of the reaction mixture below - 40°C. The reaction mixture was stirred for one more hour at the same temperature. The reaction was monitored by TLC. Water (200 mL) was added carefully and the layers separated. The aqueous extract was washed with methylene chloride (50 mL) and the layers separated. The combined organic extracts were washed with water and the organic layer separated and concentrated under atmospheric pressure to yield the product. The residue was used as such without further purification for the next stage reaction.
Purity: 96.0%(By HPLC)
6

WE CLAIM:
1. A process for preparation of 2-bromo-4,5-difluoroaniline compound of Formula III. The process comprising, '
a) brominating 3,4 Difluroaniline of formula II in presence of potassium carbonate and methylene chloride, at a temperature of - 40 °C to - 50 °C,

to obtain a compound of formula
F

Formula III
2. A process for preparation of 2-bromo-4,5-difluoroaniline compound of Formula III, according to claim 1, having purity of 96 % or more.
3. A process for preparation of 2-bromo-4,5-difluoroaniline compound of Formula III, according to claim 1, as an intermediate in synthesis of Nadifloxacin and its enantiomers, salt and prodrug thereof.