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:
EFFICIENT 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 efficient process for (0-R>)-Diacetoxy-(8,9-
difluoro-6,7-dihydro-1-oxo-1 H,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 efficient process for (0-ll)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1-oxo-1 H,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-piperidinyl)-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
II

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-6W-pyrrol [3,2,1-/y] 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-1 H,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-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 44 (1996), page nos. 642-5 discloses the synthesis of (S)(0-ft)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1 -oxo-1 H,5H-benzo[ij] 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-li)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1 -oxo-1 H,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-li)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1 -oxo-1 H,5H-benzo[i,j] quinolizine-2-carboxy) borane. The present inventors have embarked upon a workup involving butyl alcohol, which improves the stability and handling problem.
In one aspect of the present invention there is provided a process for preparation of (0-li)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1-oxo-1 H,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

b) treating the reaction mass of step a) with butyl alcohol,
The non-limiting examples of butyl alcohol include n-butanol, sec-butanol, iso-butanol & tert-butanol and mixtures thereof.
The reaction when carried out in presence of butyl alcohol is more efficient on industrial scale, as the acetic anhydride is converted to butyl acetate, which can be easily removed.
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In another aspect there is provided a process for (0-fi)-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-ft)-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-fi)-Diacetoxy-(8,9-difluoro-6.7-dihydro-1-oxo-1 H,5H-benzon[I,j] quinolizine-2-carboxy) borane
To a four-necked flask was charged acetic anhydride (284 gm) and acetic acid (177 gm). To this was added boric oxide (76 gm). The mixture was heated under stirring for four hours at 120 °C to obtain a clear solution. The solution was cooled to 80 °C and 8,9-difluoro-5-methyl-6,7-dihydro-1-oxo-1h,5h-benzo[ij]-quinolizine-2-carboxylic acid was added. Heating was restarted and the reaction
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mixture stirred at 120 °C for four hours. The reaction was cooled to ambient temperature and to it was added n-Butanol (520 mL). After stirring for one hour the mixture was cooled to 15 °C and the solid was filtered. The wet cake was washed with n-Butanol & dried. 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-f£)-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,
a) heating the mixture of acetic anhydride, acetic acid and boric oxide with 8,9-difluoro-5-methyl-6,7-dihydro-1 -oxo-1 h, 5h-benzo[ij]-quinolizine -2-carboxylic acid of formula II,

Fo
Formula II
to obtain a compound of formula

Formula III
b) treating the reaction mass of step a) with butyl alcohol.
2. The process according to claim 1, wherein the butyl alcohol comprises one or more of n-butanol, sec-butanol, iso-butanol & tert-butanol and mixtures thereof.
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3. The process according to claim 2, wherein the butyl alcohol I is n-butanol.
4. A process for (0-fi)-Diacetoxy-(8,9-difluoro-6,7-dihydro-1-oxo-1H,5H-benzo[ij] quinolizine-2-carboxy) borane compound of Formula III, according to claim 1, having purity of 98 % or more.
5. A process for preparation of (0-li)-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.
Dated this 26TH day of May, 2007 For Wockhardt Limited

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