FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION.
(See section 10]
1. Title of the invention: "PREPARATION OF GEMIFLOXACIN PIVALATE"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India.
3. The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

Technical Field of the invention
The present invention describes the synthesis of gemifloxacin pivalate and process for its preparation.
Prior Art
Gemifloxacin is chemically known as 7-[(4Z)-3-(Aminomethyl)-4-(methoxyimino)-l-pyrrolidinyl]-1 -cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, is a fluoroquinolone derivative having potent antibacterial activity (Formula I).

Several processes for the preparation of gemifloxacin have been described in the literature, such as in U.S. 5,633,262, WO 01/18002, U.S. 6307059, Journal of Medicinal Chemistry (1997), 40 (22), 3584, which are herein incorporated by reference. U.S. 6,723,734 discloses methane sulphonic acid salt of gemifloxacin along with its process of preparation. WO 00/17199 and WO 01/18002 disclose improved processes for the preparation of methane sulphonate salt of gemifloxacin and its hydrates.
WO 03/ 087100 discloses a process for the preparation of acid salts of gemifloxacin which specifically describes the methane sulfonic acid salt. WO 06/134431 discloses a process for the preparation of formate salt of gemifloxacin, where as WO 06/134608 describes gemifloxacin polymorphs and lactate salt.
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Summary of the Invention
A novel salt of gemifloxacin or its hydrate with pivalic acid of Formula II and its process for preparation has been described.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
Detailed Description of the Invention:
Gemifloxacin pivalate is a crystalline solid. Crystalline gemifloxacin pivalate may be characterized by a powder X- ray diffraction pattern comprising strong peaks at about 25.65, 18.38, 7.62, 7.26 ± 0.2 degrees 20 and weak peaks at about 30.85, 29.96, 19.68, 17.68, 15.81, 14.56, 13.33, 12.46, 9.49 ± 0.2 degrees 29. Crystalline gemifloxacin pivalate may also be characterized by its DSC analysis. The DSC analysis shows an endotherm at about 155.16°C and an exotherm at about 199.35°C.
The pivalate salt of gemifloxacin or its hydrate has been prepared in suitable inert solvents that do not change under the reaction conditions. The suitable solvents for carrying out the process were selected from a set of solvents such as water, water- miscible solvents and mixtures thereof. Examples of water- miscible solvents include methanol, ethanol, isopropanol and mixtures thereof, preferably a mixture of methanol and water may be used. Pivalic acid may be in the range of about 0.9 to 1.5 mole equivalents, preferably 1.0 mole equivalent for salt preparation.
A mixture of gemifloxacin free base, pivalic acid and solvents may be heated from room temperature to 55°C to obtain a clear solution for a time period sufficient to complete the
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reaction, preferably about 15 to 90 minutes. The gemifloxacin pivalate or its hydrates may be isolated out of the solution by distillation and further treatment of the residue with isopropanol. Isolation of the salts may be accomplished by filtration or centrifugation or a combination there of followed by drying. The precipitated salts of gemifloxacin or its hydrate may be isolated in a solid state by filtration, followed by washing and drying.
Solvates and isomers of salts of gemifloxacin are also included within the scope of this invention.
The gemifloxacin pivalate or its hydrate has a broad antibacterial activity in comparison with the early stage antibacterial compounds, and therefore, has been widely and practically used for treatment of diseases in clinical fields such as acute bacterial exacerbation of chronic bronchitis and community acquired pneumonia. The salt is usually administered as part of a pharmaceutical composition which comprises the pivalate salt of gemifloxacin or its hydrate, and one or more pharmaceutically acceptable carriers, diluents or excipients and optionally other therapeutic ingredients.
The salt may be conventionally formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed, for example, per oral or parental.
In the foregoing section embodiments are described by way of examples to illustrate the process of invention. However, these are not intended by way of examples to illustrate the process of invention. However, these are not intended in any way to limit the scope of the present invention and several variants of these examples would be evident to persons ordinarily skilled in the art.
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Example
Preparation of gemifloxacin pivalate
To a suspension of (R, S)-7-(3-aminomethyl-4-synmethoxyiminopyrrolidin-l-yl)-l-cyclopropyl-6-fluoro-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3-carboxylic acid (10 gm) in a mixture of methanol (80 ml) and water (10 ml) was added pivalic acid (2.62 gm) at 50 -55°C and stirred for one hour at 50 - 55°C. The reaction mass was cooled to 25 - 30 and stirred for 8 hours. The reaction mass was distilled under vacuum at 50 - 55°C and the residue was treated with isopropanol (20 ml) at 50 - 55 °C. The slurry was cooled to 0-5°C and filtered. The solid was washed with isopropanol (10 ml). The wet material was dried at 50 - 55°C to give the pivalate salt of gemifloxacin. Yield: 68.7 %;
HPLC purity: 98.69; lH NMR (DMSO) (5 ppm): 8.60 (1H, s), 8.04 (1H, d), 4.56 (2H, br.s), 4.18 (1H, m), 3.94 (1H, m), 3.85 (3H, s), 3.74 (1H, m), 3.02 (1H, m), 2.72 (2H, m), 1.2 (2H, m), 1.18 (11H, m); MS (m/z): 490 [M-l]; IR (KBr) (D max cm-1): 2908, 1724, 1631, 1604, 1562, 1500, 1438, 1353, 1330, 1207, 1053, 902, 883, 806, 759, 698. PXRD: 30.85, 29.96, 25.65, 19.68, 18.38, 17.68, 15.81, 14.56, 13.33, 12.46, 9.49, 7.62, 7.26 degrees 20; DSC: 155.16°C(endotherm), 199.35°C (exotherm).
Figure 1 is IR spectra of gemifloxacin pivalate.
Figure 2 is a powder X-ray diffraction pattern of gemifloxacin pivalate.
Figure 3 is the DSC of gemifloxacin pivalate.
While several particular forms of the inventions have been described, it will be apparent that various modifications and combinations of the inventions detailed in the text can be made without departing from the spirit and scope of the inventions. For example, the pivalate salt of gemifloxacin can be included in a pharmaceutical composition and administered to treat a bacterial infection. Accordingly, it is not intended that the inventions be limited, except as by the appended claims.
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We claim:
1. A pivalate salt of gemifloxacin of Formula II or its hydrate.

2. The pivalate salt according to claim 1 having X-ray powder diffraction pattern as shown in Figure - 2.
3. The pivalate salt according to claim 1 having a DSC thermogram as shown in Figure - 3.

4. A process for preparing the pivalate salt of gemifloxacin or its hydrate, the process comprising contacting gemifloxacin free base with pivalic acid in one or more suitable solvents and isolating the pivalate salt or its hydrate.
5. The process according to claim 6, wherein pivalic acid is added in the range of about 0.8 to about 2.5 equivalents.
6. The process according to claim 6, wherein the solvent used for the reaction is a mixture of methanol and water in the ratio of 1:8.
7. The process according to claim 6, wherein the solids are isolated after distillation of the reaction mass and treating the residue with a suitable solvent preferably isopropanol.
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8. A method of treating bacterial infections comprising administering a pivalate salt of gemifloxacin or its hydrate.
9. An antibacterial composition comprising pivalate salt of gemifloxacin or its hydrate and one or more pharmaceutically acceptable carriers, diluents or excipients.
10. A process for the preparation of pivalate salt of gemifloxacin of formula II or its hydrate
as herein described and illustrated by the examples herein.

Abstract
The present invention describes the synthesis of gemifloxacin pivalate and process for its preparation.
Dated this 22nd day of June 2007

Name: Rajendra Agarwal
To
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The Controller of Patents The patent Office, At Mumbai