FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
ECONOMIC 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 economic process for (0-β)-Diacetoxy-(8,9-
difluoro-6,7-dihydro-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxy) borane, 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.
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4. DESCRIPTION
The present invention relates to economic process for (0-li)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxy) borane, 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-pipehdinyl)-5-methyl-1-oxo-1H,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.
o o
.F
OH

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. 38(9), 2459-62, 1990 discloses the synthesis of substituted 1,2-dihydro-6-oxo-6/-/-pyrrol [3,2,1-ij] quinoline -5-carboxylic acids.

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.
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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-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt. 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-1H,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 44 (1996), page nos. 642-5 discloses the synthesis of (S)(0-R>)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1 -oxo-1H,5H-benzo[i,j] quinolizine-2-carboxy) borane using toluene, involving multiple filtration steps.
While working on the process for intermediates of Nadifloxacin, It was found by the present inventors that (0-fi)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxy) borane synthesis involves the difficulty of complete removal of acetic anhydride, which if present in the reaction mass poses considerable problem in centrifugation step, also the (0-ft)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxy) borane complex is heat sensitive and having low stability in toluene. Acetic anhydride is hazardous and poses handling problem. Hence there was a need of an industrially efficient process for synthesis of (0-R>)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxy) borane. The present inventors have embarked upon workup involving water, which improves the stability and handling problem.
In one aspect of the present invention there is provided a process for preparation of (0-fi)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1 -oxo-1H,5H-benzo[i,j] quinolizine-2-carboxy) borane compound of Formula III. The process includes step of,
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a) heating the mixture of acetic anhydride, acetic acid and boric oxide with 8,9-difluoro-5-methyl-6,7-dihydro-1-oxo-1h,5h-benzo[ij]-quinolizine-2-carboxylic acid of formula II,

Formula II
to obtain a compound of formula

Formula III
b) treating the reaction mass of step a) with water,
The reaction when carried out in presence of water is more efficient on industrial scale, as the acetic anhydride is converted to acetic acid, which can be easily removed. Further the process becomes economic, as water is an inexpensive solvent.
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In another aspect there is provided a process for (0-fl)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxy) borane compound of Formula III, having purity of 98 % or more.
In another aspect there is provided a process for (0-R>)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxy) borane complex of Formula III, as an intermediate in synthesis of Nadifloxacin and its enantiomers, salt and prodrug thereof.
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 coupled with 4-hydroxypiperidine in acetonitrile, optionally resolved, 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: (0-β)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1-oxo-1H,5H-benzon[i,j] quinolizine-2-carboxy) borane
To a one liter four-necked flask was charged acetic anhydride (94.2 m), acetic acid (60.6 mL) and Boric oxide (24.3 gm). The reaction mixture was heated at 110-115 °C for four hours to obtain a clear solution. To the solution was added 8,9-Difluoro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]-quinolizine-2-carboxylic acid (93.5 gm) and the reaction mixture heated for another four hours at 110-115 °C. TLC of the reaction mixture after four hours showed completion of reaction.
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The reaction mixture was cooled to ambient temperature and then water (520 mL) was added. The product separated out as a crystalline solid. The reaction was further diluted with water (2.5 Lit) in another flask and the solid filtered and washed with water. The boron complex was isolated as a brown crystalline solid. Purity by HPLC = 98.0 %.
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WE CLAIM:
1. A process for preparation of (0-fl)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxy) borane compound of Formula III. The process comprising,

Formula II
to obtain a compound of formula

a) heating the refluxed mixture of acetic anhydride, acetic acid and boric oxide with 8,9-difluoro-5-methyl-6,7-dihydro-1-oxo-1h,5h-benzo[ij]-quinolizine-2-carboxylic acid of formula II,
Formula III
b) treating the reaction mass of step a) with water.
2. A process for (0-H)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxy) borane compound of Formula III, according to claim 1, having purity of 98 % or more.
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3. A process for preparation of (0-β)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxy) borane complex of formula III, according to claim 1, as an intermediate in synthesis of Nadifloxacin and its enantiomers, salt and prodrug thereof.

Abstract
The present invention relates to economic process for (0-β)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxy) borane, and to their application in the synthesis of Nadifloxacin and its enantiomers, salt and prodrug thereof.

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