FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
AN IMPROVED PROCESS FOR THE PREPARATION OF 7-SUBSTITUTED 3,3-DIMETHYL-4-AMINO-PIPERIDINO-QUINOLONE CARBOXYLIC ACID
DERIVATIVES
2. APPLICANT (S)
(a) NAME : Wockhardt Limited
(b) NATIONALITY : Indian
(c) ADDRESS : Wockhardt Towers
Bandra-Kurla Complex, Bandra (E) Mumbai-400 051, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in
which it is to be performed. __
-1-

AN IMPROVED PROCESS FOR THE PREPARATION OF 7-SUBSTITUTED 3,3-
DIMETHYL-4-AMINO-PIPERIDINO-QUINOLONE CARBOXYLIC ACID
DERIVATIVES
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-4-oxo-l,4-dihydro-quinolin-3-carboxylic acid hydrochloride salt and optically pure enantiomers thereof, of formula I.

BACKGROUND OF THE INVENTION
The fluoroquinolone class of compounds form an important armamentarium as antibacterial
agents due to their broad spectrum and excellent pharmacokinetics. Several compounds from
this class of antibacterials are in clinical use, for example nalidixic acid, norfloxacin,
ofloxacin, ciprofloxacin, and moxifloxacin.
WO 02/085886 and WO 03/050107 disclose (RS)-(±)- and (R)-(+)- and (S>(-)-isomers of 1-
cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-4-oxo-l,4-dihydro-
quinolin-3-carboxylic acid hydrochloride salt having preferred antibacterial properties.

According to the process disclosed in the WO 02/085886, the compound of formula I is prepared by treating the 4-amino-3,3-dimethyl-piperidine with the intermediate 1-
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cyclopropyl-6,7-difluoro-8-methyl-l,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04difluoro boron chelate to give the free base, l-cyclopropyl-6-fluoro-8-methyI-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid. The hydrochloride salt is prepared by treating the free base with the ethanolic hydrochloric acid. The process disclosed in the '886 patent application suffers from poor yield due to formation of impurities during the condensation reactions. The present invention provides an improved process for the preparation of l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-4-oxo-l,4-dihydro-quinolin-3-carboxylic acid free base and hydrochloride salt of formula I.
In another embodiment the present invention is related to a process to prepare the intermediates that are necessary to obtain the compounds of Formula I. The present invention is also related to the polymorphs of the compound of formula I.
SUMMARY OF THE INVENTION
The present invention describes an improved process for the preparation of compounds of formula I i.e. (^-(±)-l-cyclopropyl-6-fluoro-8~methyl-7-(4-amino-33-dimethyl-piperidin-l-yl)-4-oxo-l,4-dihydro-quinolin-3-carboxylic acid hydrochloride salt (1), (S)-(-)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-4-oxo-l,4-dihydro-quinolin-3-carboxylic acid hydrochloride salt (2) and (R)-(+)-1 -cyclopropyl-6-fiuoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-4-oxo-l,4-dihydro-quinolin-3-carboxylic acid hydrochloride salt (3).


1 CRS)-(1(RS)-(±)-isomer
2 (S)-(-)-isomer
3 (R)-(+)-\somer
A further aspect of the invention relates to an improved process for the purification of (RS)-(±)-4-amino-3,3-dimethyl-piperidine. The (JR5)-(±)-4-amino-3,3-dimethyl-piperidine is obtained from (R5)-(±)-4-amino-l-benzyl-3,3-dimethyl-piperidine by hydrogenation in the presence of a catalytic amount of reducing agent. The crude product is treated with aqueous sodium hydroxide and then purified by vacuum distillation to give pure (RS)-(±)-4-amino-
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3,3-dimethyI-piperidine. The step of treatment with aqueous sodium hydroxide helps in removal of impurities and the improvement of yield in subsequent condensation reaction.
Another embodiment of the present invention is related to an improved process for the purification of (S)-(-)-4-amino-3,3-dimethyl-piperidine and (R)-(+)-4-amino-3,3-dimethyl-piperidine. The enantiomers of 4-amino-3,3-dimethyl-piperidine is obtained from chirally pure 4-amino-l-benzyloxycarbonyl-3,3-dimethyl-piperidine by catalytic amount of reducing agent. The crude product is treated with aqueous sodium hydroxide and then purified by vacuum distillation to give pure 4-amino-3,3-dimethyl-piperidine. The step of treatment with aqueous sodium hydroxide helps in removal of impurities and the improvement of yield in subsequent condensation reaction.
The amine, racemic or chirally pure enantiomer of 4-amino-3,3-dimethyl-piperidine is reacted with 1 -cyclopropyl-6,7-difiuoro-8-methyl-l,4-dihydro-4-oxo-quinoline-3-carboxylate O3, O4 difluoroboron chelate in the presence of triethylamine in acetonitrile to give 1-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-pipendin-1 -yl)-4-oxo-1,4-dihydro-quinolin-3-carboxylic acid as a free base.
A further aspect of the invention describes isolation of substantially chemically pure (RS)-(±)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-4-oxo-l,4-dihydro-quinolin-3-carboxylic acid free base, and substantially chemically and chirally pure enantiomers of 1 -cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l -yI)-4-oxo-l,4-dihydro-quinolin-3-carboxylic acid as their respective free bases, free from impurities without using column chromatography, which is of a significant advantage thus amenable for scale up to large-scale production.
A further aspect of the invention is related to the recovery of starting materials that can be recycled after proper treatment or derivatization. The unreacted starting material (RS)-(±)-4-amino-3,3-dimethyl-piperidine or its isomers and the l-cyclopropyl-6,7-difluoro-8-methyl-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid can be recovered from the reaction mixture by changing the pH during the work up of the reaction mixture. Thus, resulting in a process with efficient recycling of the starting materials.
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A further aspect of the invention is related to a process for the preparation of hydrochloride salt of the compounds of formula I.
A further aspect of the invention describes the characterization of the polymorphs of (RS)-(±)-l-cyclopropyl-6-fluoro-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-8-methyl-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride (1), (S)-(-)-l-cyclopropyl-6-fluoro-7-(4-amino-3,3-dimethyl-piperidin-l -yl)-8-methyl-l ,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride (2), (R)-(+)-l-cyclopropyl-6-fluoro-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-8-methyl-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride (3).
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is Powder X-Ray Diffraction pattern of Compound 1.
FIG. 2 is Differential Scanning Calorimetric thermogram of Compound 1.
FIG. 3 is Infra-Red spectrum of Compound 1.
FIG. 4 is PowrJer X-Ray Diffraction pattern of Compound 2.
FIG. 5 is Differential Scanning Calorimetric thermogram of Compound 2.
FIG. 6 is Infra-Red spectrum of Compound 2.
FIG. 7 is Powder X-Ray Diffraction pattern of Compound 3.
FIG. 8 is Differential Scanning Calorimetric thermogram of Compound 3.
FIG. 9 is Infra-Red spectrum of Compound 3.
DETAILED DESCRIPTION OF INVENTION
The present invention relates to an improved process for the preparation of (RS)-(±)-l-cyclopropyl-6-fIuoro-8-methyl-7-(4-amino-6,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid free base and it's hydrochloride salt, (S)-(-)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid free base and it's hydrochloride salt and (R)-(+)-1 -cyclopropyl-6-fluoro-8-methy]-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid free base and it's hydrochloride salt, as depicted in Scheme 1.
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(RS)-(±)- and (S)-(-)- and (R)-(+")- enantiomers of 4-amino-3,3-dimethvl-piperidine
The present invention relates to an improved process for the preparation of for (RS)-(±)-4-
amino-3,3-dimethyl-piperidine, comprising the following steps;
a) Reacting (RS)-(±)-4-amino-l-benzyl-3,3-dimethyl-piperidine prepared according to the procedure described in US Patent No. 6,878,713, with hydrogenation catalyst selected from 20% palladium hydroxide on carbon (slurry made in water), 10% palladium on carbon, 5% palladium on carbon in a suitable solvent selected from aliphatic alcohol or aqueous alcohol under 200 - 400 psi hydrogen pressure in a Parr pressure reactor, and stirring at 30 °C to 65 °C for l0 hrs to l2 hrs;
b) filtering the reaction mixture over a celite bed, and recovering the catalyst that can be reused for the next batch of the same reaction after addition of additional 2% w/w fresh catalyst;
c) washing the celite bed with fresh alcohol and evaporating the filtrate to dryness to provide crude 4-amino-3,3-dirnethyl-piperdine as viscous oil;
d) purifying the viscous oil by treating it with 15% aqueous sodium hydroxide solution at 35 °C to 40 °C temperature for 30 minutes and allowing layers to separate;
e) drying the oily layer over sodium sulphate and distilling under vacuum at 10 mm vacuum to obtain chemically pure (RS)-(±)-4-amino-3,3-dimethyl-piperidine.
In another embodiment the invention relates to the preparation of enantiomers of (RS)-(±)-4-amino-3,3-dimethylpiperidine i.e. (S)-(-)-4-amino-3,3-dimethylpiperidine or (R)-(+)-4-amino-3,3-dimethylpiperidine, comprising the following steps;
a) reacting (S)-(-)-4-amino-l-benzyloxycarbonyl-3,3-dimethylpiperidine or (.R)-(+)-4-amino-l-benzyloxycarbonyl-3,3-dimethylpiperidine (prepared as per procedure described in US Patent No. 6,878,713) with a hydrogenation catalyst selected from 20% palladium hydroxide on carbon (slurry made in water), 10% palladium on carbon, 5% palladium on carbon in a suitable solvent selected from aliphatic alcohol or aqueous alcohol under 200-400 psi hydrogen pressure in a Parr pressure reactor and stirring at 30 °C to 65 °C for 10 hrs to 12 hrs;
b) filtering the reaction mixture over a celite bed and recovering the catalyst, which can be reused for next batch of the same reaction after addition of the additional 2% w/w fresh catalyst;
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c) washing the celite bed with fresh alcohol and evaporating the filtrate to dryness to provide crude (S)-(-)-4-amino-3,3-dimethylpiperidine or (R)-(+)-4-amino-3,3-dimethylpiperidine respectively as a semisolid residue;
d) purifying the semisolid residue by treating with 15% aqueous sodium hydroxide solution at 35 °C to 35 °C temperature for 30 minutes and allowing oily layers to separate;
e) drying the oily layer over sodium sulphate and distilling under vacuum at 10 mm to obtain substantially chemically and chirally pure (S)-(-)-4-amino-3,3-dimethylpiperidine or (R)-(+)-4-amino-3,3-dimethylpiperidine respectively.
Racemic. (S)-(-)- and (R)-(+)- enantiomers of l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-
3,3-dimethvl-piperidin-l-yl)-l,4-dihvdro-4-oxo-quinoline-3-carboxylic acid hydrochloride
salt
The distilled 4-amino-3,3-dimethyl-piperidine is further reacted with the borate ester of the 1-
cyclopropyl-6,7-difluoro-8-methyl-1 ,4-dihydro-4-oxo-quinoline-3-carboxylate O3, O4
difluoroboron chelate to provide the l-cycIopropyl-6-fhioro-8-methyl-7-(4-amino-3,3-
dimethyl-piperidin-l-yl)-1,4-dihydro-4-oxo-quinoline-3-carbdxylic acid as a free base.
The 4-amino-3,3-dimethyl-piperidine can be racemic or chirally pure enantiomer either (S)-(-
) or (R)-(+)-isomer, to provide respective (RS)-(±)- or (S)-(-) or (R)-(+)- 1-cyclopropy 1-6-
fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-
carboxylic acid free base.
The process comprises following steps;
a) treating l-cyclopropyl-6,7-difluoro-8-methyI-l,4-dihydro-4-oxo-quinoline-3-carboxylate
O3, O4 difluoroboron chelate with (RS)-(±)- or (S)-(-) or (R)-(+)-4-amino-3,3-dimethyl-
piperidine in presence of a base such as triethylamine in a solvent such as acetonitrile at a
temperature between 20 °C to 65 °C, and stirring for a period of 4 days;
b) evaporating the reaction mixture to dryness to provide a residue;
c) adding methanol and triethylamine to a residue and stirring at 65 °C to 70 °C for 3 hours;
c) further evaporating the reaction mixture to dryness to afford a residue and adding water
and concentrated hydrochloric acid to the residue to provide a suspension;
d) filtering the precipitated solid under suction to recover unreacted l-cyclopropyl-6,7-
difluoro-8-methyl-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid, which could be recycled
after appropriate derivatization;
e) treating the aqueous filtrate with a solvent such as chloroform, methylene chloride, ether,
ethylacetate to remove impurities and adjusting the pH of aqueous layer to 13 by addition of
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45 % w/v aqueous sodium hydroxide, further adjusting the pH of aqueous layer to pH 8 by addition of concentrated hydrochloric acid under stirring to provide a solid and stirring the suspension at 20 °C to 45 °C for 12 hours to 18 hours to effect complete precipitation;
f) isolating the precipitated solid by conventional filtration techniques followed by drying the
solid at a temperature 70 °C to 90 °C under vacuum to afford l-cyclopropyl-6-fluoro-8-
methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic
acid as a free base;
g) treating the aqueous filtrate with solid sodium hydroxide and extracting with
dichloromethane, evaporating the dichloromethane layer to dryness to provide unreacted 4-
amino-3,3-dimethyl-piperidine, which can be recycled after vacuum distillation.
The present invention further provides a process for preparing (RS)-(±)- or (S)-(-) or (R)-(+)-1 -cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l -yl)-l ,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride salt, comprising following steps;
a) heating a mixture of free base (RS)-(±)- or (S)-(-) or (R)-(+)- 1-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-'4"-oxo-quinoline-3-carboxylic acid and concentrated hydrochloric acid at 55 °C to 60 °C for 1 hour to provide a clear solution;
b) filtering the clear solution through celite and followed by adding acetone to the clear solution and stirring the mixture for two hours at 30 °C to 35 °C to effect precipitation;
c) isolating the precipitated solid by conventional filtration techniques followed by drying the solid at a temperature of 80 °C under vacuum to afford (RS)-(±)- or (S)-(-) or (R)-(+)-1-cyclopropyl-6-fluoro-8-methyI-7-(4-amino-3,3-dimethyl-piperidin-1 -yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride salt.
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Another embodiment of the present invention is identification and characterization of the
polymorphs of (RS)-(±)-1 -cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyI-piperidin-
l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride salt and (S)-(-)-l-
cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3 -dimethyl-piperidin-1 -yl)-1,4-dihydro-4-oxo-
quinoline-3-carboxylic acid hydrochloride salt and (R)-(+)-l-cyclopropyl-6-fluoro-8-methyl-
7-(4-amino-3,3-dimethyl-piperidin-l -yl)-l ,4-dihydro-4-oxo-quinoline-3-carboxylic acid
hydrochloride salt by X-Ray Powder Diffractogram (XRPD), Differential Scanning Colorimetry thermogram (DSC) and Infra-red spectrum (IR).
The crystalline polymorph of (RS)-(±)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride salt is characterized by X-ray powder diffraction pattern with peaks at about (2θ values) 7.02± 0.2, 7.58± 0.2, 7.90± 0.2, 13.46± 0.2, 14.04± 0.2, 14.52± 0.2, 15.26± 0.2, 16.48± 0.2, 18.40± 0.2,
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19.62± 0.2, 20.66± 0.2, 21.16± 0.2,21.54± 0.2, 22.14± 0.2, 22.52± 0.2, 24.08± 0.2, 24.52± 0.2, 25.74± 0.2, 26.64+ 0.2, 27.32± 0.2, 28.32± 0.2, 29.42± 0.2, 30.24± 0.2, 31.66± 0.2, 32.66± 0.2, 34.20± 0.2, 36.18±.0.2, 36.52± 0.2, 37.92± 0.2, 38.08± 0.2 as shown in FIG. 1. The DSC exhibits a significant endotherm peak around 298.50 °C as depicted in FIG. 2. The characteristic IR values at (KBr, cm-1) 3448, 2951, 1722, 1618, 1533, 1458, 1378, 1317, 1265, 1235, 1172, 1111, 1047, 805 as shown FIG. 3.
The crystalline polymorph of (S)-(-)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride salt is characterized by X-ray powder diffraction pattern with peaks at about (29 values) 7.04± 0.2, 7.50± 0.2, 9.68± 0.2, 13.34± 0.2, 14.22± 0.2, 14.66± 0.2, 15.14± 0.2, 15.74± 0.2, 15.94± 0.2, 17.14± 0.2, 17.84± 0.2, 18.76± 0.2, 19.06± 0.2, 2252± 0.2, 24.12± 0.2, 25.64± 0.2, 26.02± 0.2, 26.28± 0.2, 29.94± 0.2, 30.82± 0.2, 32.34± 0.2, 35.00± 0.2, 37.18± 0.2, 37.68± 0.2, 39.50± 0.2 as shown FIG. 4. The DSC exhibits a significant endotherm peak around 297.66 °C as depicted in FIG. 5. The characteristic IR values at (KBr, cm-1) 3433, 2951, 1708, 1618, 1517, M58, 1427, 1377, 1317, 1265, 1237, 1108, 1049, 978, 807 as shown FIG. 6.
The crystalline polymorph of (R)-(+)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride salt is characterized by X-ray powder diffraction pattern with peaks at about (29 values) 7.06± 0.2, 7.54± 0.2, 9.72± 0.2, 13.38± 0.2, 14.70± 0.2, 15.16± 0.2, 17.16± 0.2, 17.86± 0.2, 18.80± 0.2, 19.08± 0.2, 22.54± 0.2, 24.16± 0.2, 25.68+ 0.2, 26.04± 0.2, 26.32± 0.2, 29.98± 0.2, 30.88+ 0.2, 32.38± 0.2, 35.10+ 0.2, 37.22± 0.2, 37.78± 0.2, 39.54± 0.2 as shown FIG. 7. The DSC exhibits a significant endotherm peak around 307 °C as depicted in FIG. 8. The characteristic IR values at (KBr, cm-1) 3427, 2870, 1708,1619, 1535, 1457, 1315, 1265, 1237, 1107, 1050, 807 as shown FIG. 9.
EXAMPLES
The starting material l-cyclopropyl-6,7-difluoro-8-methyl-l,4-dihydro-4-oxo-quinoline-3-carboxy-late O3, O4 difluoroboron chelate was prepared as per procedure described in JP 63316757 (1989), JP 0372476 (1991). The amines (&S)-(±)-4-amino-l-benzyl-3,3-dimethyl-piperidine, (S)-(-)-4-amino-l-benzyloxycarbonyl-3,3-dimethyl-piperidine, (K)-(+)-4-amino-l --benzyloxycarbonyl -3,3-dimethyl-piperidine, are prepared according to the procedure
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described in US Patent No. 6,878,713. Mass spectra were recorded on Waters Micromass Quatro- II instrument and Optical rotation recorded on Rudolph (Model DPIA31) instrument.
EXAMPLE 1 Preparation of (J?5^-f±)-4-amino-3,3-dimethyl-piperidine: A solution of (RS)-(±)-4-amino-l-benzyl-3,3-dimethyl-piperidine (425 gm, prepared as per procedure described in US Patent No. 6,878,713), methanol (2.3 lit) was charged in Pan-pressure reactor to provide a clear solution. To the clear solution, 20 % palladium hydroxide on carbon (74 gm, slurry made in 50 ml water) was charged. The suspension was stirred at hydrogen pressure 250 psi at 65 °C for overnight. After TLC showed completion of reaction, the reaction mixture was filtered over a celite bed. The catalyst was recovered (the recovered catalyst can be re-used for the next batch of same reaction after the addition of additional 2 % w/w fresh catalyst). The celite bed was washed with fresh methanol (200 ml). The filtrate was evaporated to dryness to provide crude (RS)-(±)-4-amino-3,3-dimethyl-piperidine as viscous oil in 250 gm quantity. The crude oil was stirred with 15% aqueous sodium hydroxide solution (500 ml, prepared from 75 gm sodium hydroxide pallets dissolved in 500 ml water) at 35 °C to 40 °C temperature for 30 minutes. Layers were separated. The oily layer was dried over sodium sulphate and distilled under vacuum at 10 mm vacuum and constant boiling fraction was collected as an thick viscous colorless oil in 154 gm (61 %) quantity, m/z = 129 (M+l), PMR: (CDC13, 5 ppm) 0.9 (s, 6H), 1.5 (m, 2H), 1.58 (bs, 2H, D2O exchangeable), 2.26 - 2.68 (m, 4H), 3.06 (m, 1H), 3.52 (bs, 1H, D2O exchangeable).
EXAMPLE 2
Preparation of (.SVM-4-amino-3.3-dimethyl-piperidine:
A suspension of 10% palladium on carbon (53 g) and chirally more than 98.5% pure, (S}-(-)-4-amino-l-benzyloxycarbonyl-3,3-dimethylpiperidine (530 g, prepared as per procedure described in US Patent No. 6,878,713), in methanol (3000 ml) was stirred at 300 psi hydrogen pressure at 30 °C to 35 °C for 23 hr. The catalyst was filtered over a celite bed (recovered catalyst can be re-used for the same reaction in the next batch after the addition of 2% w/w fresh catalyst). The bed was washed with methanol and filtrate was evaporated to dryness to afford crude (S)-(-)-4-amino-3,3-dimethylpiperidine as a white semisolid residue in 257 gm quantity. The semi solid residue was stirred with 15% w/v aqueous sodium hydroxide solution (500 ml) for 30 minutes at 30 °C to 35 °C. The layers were allowed to
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separate and the oily layer-was dried over sodium sulfate and distilled under vacuum (10 mm of Hg) to afford (S)-(-)-4-amino-3, 3-dimethylpiperidine as a colourless thick viscous oil at a constant boiling temperature. Yield 190 gm (75 %),
m/z 129 (M+l), [α]D25 = -34.44° (c 1, methanol).
EXAMPLE 3
Preparation of (R)-(+)-4-amino-3.3-dimethyl-piperidine:
By following the procedure described in Example 2, and using more than 98.5% chirally pure, (R)-(+)-4-arnino-l-benzyloxycarbonyl-3,3-dimethylpiperidine (42 gm, prepared as per procedure described in US Patent No. 6,878,713), the compound (R)-(+)-4-amino-3,3-dimethyl-piperidine was prepared in 12.8 gm (59%) quantity, m/z 129 (M+l), [α]D25 = +34.17° (c 1, methanol):
EXAMPLE 4
Preparation of (RS)-(±)- 1 -cyclopropyl-6-fluoro-8-methvl-7-(4ramino-3,3-dimethvl-piperidin-
l-yl)-1.4-dihydro-4-oxo-quinoline-3-carboxylic acid (free base):
To a solution of l-cyclopropyl-6,7-difluoro-8-methyl-l,4-dihydro-4-oxo-quinoline-3-carboxylate O3, O4 difluoroboron chelate (110 gm) in a acetonitrile (440 ml) was added freshly vacuum distilled (RS)-(±)-4-amino-3,3-dimethyl-piperidine (150 gm) and triethylamine (94 ml) sequentially at 35 °C. The resulting mixture was stirred at 55 °C to 65 °C for 4 days. The reaction mixture was evaporated to dryness and the residue was stirred at 65 °C to 70 °C after addition of methanol (220 ml) and triethylamine (55 ml) for 3 hours. The reaction mixture was evaporated to dryness to provide a residue and the residue was stirred with water (660 ml) and concentrated hydrochloric acid (330 ml) mixture to provide a suspension. Solid, thus separated, l-cyclopropyl-6,7-difluoro-8-methyl-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid was filtered at suction. This solid can be recycled after appropriate derivatization. The aqueous filtrate was washed with chloroform (500 ml) to remove impurities. Aqueous layer was adjusted to pH 13 by addition of 45% w/v aqueous sodium hydroxide (450 ml). The pH of aqueous layer was adjusted to pH 8 by addition of concentrated hydrochloric acid (220 ml) under stirring to provide a solid and the suspension was stirred at 30 °C to 35 °C for 18 hours to effect complete precipitation. Precipitated solid was filtered under suction and was washed with water (100 ml). It was dried under vacuum at 80 °C to provide l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-
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l,4-dihydro-4-oxo-quinolioe-3-carboxylic acid as an off white solid in 46 gm quantity. (64.8% based on recovery of l-cyclopropyI-6,7-difluoro-8-methyl-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid). The aqueous filtrate was saturated with solid sodium hydroxide and was extracted with dichloromethane (250 ml X 3). Evaporation of dichloromethane layer provided un-reacted (RS)-(±)-4-amino-3,3-dimethyl-piperidine, which can be recycled after vacuum distillation.
m/z = 388, PMR (200 MHz, CDC13, δ ppm): 0.80-0.95 (m, 2H), 1.01 (s, 6H), 1.10-1.20 (m, 2H), 1.85-1.95 (m, 2H), 2.60-2.70 (m, 2H), 2.80 (s, 3H), 2.90-3.00 (m, 1H), 3.10-3.35 (m, 4H), 4.00-4.20 (m, 1H), 7.90 (d, 1H), 8.95 (s, 1H).
EXAMPLE 5 Preparation of (S)-(-)-1 -Cvclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-1 -
yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid (free base):
To a solution of l-cycloprbpyl-6,7-difluoro-8-methyl-l,4-dihydro-4-oxo-quinoline-3-carboxylate O3, O4 difluoroboron chelate (212 gm) in a acetortitrile (1 lit) was added, freshly vacuum distilled (S)-(-)-4-amino-3,3-dimethyl-piperidine (250 gm) and triethylamine (216 ml) sequentially at 35 °C. The resulting mixture was stirred at 55 °C to 60 °C for 4 days. The reaction mixture was evaporated to dryness and the residue was stirred in methanol (424 ml) and triethylamine (106 ml) mixture at 65 °C to 70 °C for 3 hours. The reaction mixture was evaporated to dryness to provide a residue and the residue was stirred with water (840 ml) and concentrated hydrochloric acid (424 ml) mixture to provide precipitation. Precipitated solid was filtered under suction to recover unreacted l-cyclopropyl-6,7-difluoro-8-methyl-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid. This solid can be recycled after appropriate derivatization. The aqueous filtrate was washed with chloroform (800 ml) to remove impurities and the layers were separated. Aqueous layer was adjusted to pH 13 by addition of 45% w/v aqueous sodium hydroxide (400 ml). The pH of aqueous layer was adjusted to 8 with concentrated hydrochloric acid (320 ml). The reaction mixture was stirred for 18 hours at 30 °C to 35 °C to effect complete precipitation. Precipitated solid was filtered under suction and the wet cake was washed with water (100 ml). The solid was dried under vacuum at 80 °C to provide free base (S)-(-)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid as an off white solid. Yield: 78 gm (56%, based on recovery of l-cyclopropyl-6,7-difluoro-8-methyl-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid). The aqueous filtrate was saturated with solid sodium
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hydroxide and then was -extracted, with dichloromethane (250 ml X 3). Evaporation of dichloromethane layer provided un-reacted (S)-(-)-4-amino-3,3-dimethyl-piperidine, which can be recycled after vacuum distillation. m/z388, [α]D25 = -263.85° (c 0.5,DMSO).
EXAMPLE 6 Preparation of (R)-(+)- 1 -cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-
l-yl)-l,4-dihvdro-4-oxo-quinoline-3-carboxvlic acid (free base):
By following the procedure described in Example 5 and using (R)-(+)-4-amino-3,3-dimethylpiperidine (11.8 gm), and l-cyclopropyl-6,7-difluoro-8-methyl-l,4-dihydro-4-oxo-quinoline-3-carboxylate O3, O4 difluoroboron chelate (8.58 gm) the compound (R)-(+)- 1-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3 -dimethyl-piperidin-1 -yr)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (free base) was prepared in 2.9 gm quantity.
m/z388(M+l), [α]D25 =+261.04°(c0.5, DMSO).
EXAMPLE 7 Preparation of (RS)-(±)-l-cvclopropvl-6-fluoro-8-methvl-7-(4-amino-3,3-dimethvl-piperidin-
l-yiyi.4-dihvdro-4-oxo-quinoline-3-carboxvlic acid hydrochloride salt (1):
A mixture of free base l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid (137 gm) and concentrated hydrochloric acid (137 ml) was heated at 55 °C to 60 °C for 1 hour to provide a clear solution. The clear solution was filtered through celite and acetone (1.6 lit) was added to the clear solution. The clear solution was stirred for two hours at 30 °C to 35 °C to effect precipitation. Precipitated solid was filtered at suction and the solid cake was washed with acetone (100 ml). The solid was dried at 80 °C under vacuum to provide 93 gm (8,4%) of title compound,
m/z 388 (M+l), PMR (400 MHz, DMSO-D6, δ ppm): 0.70-0.80 (m, 1H), 0.9-0.95 (m, 1H), 1.01 (s, 6H), 1.10-1.25 (m, 2H), 1.80-1.95 (m, 2H), 2.44-2.49 (m, 4H), 2.52-2.54 (m, 1H), 2.66-2.70 (m, 1H), 3.13-3.16 (m, 3H), 4.30 (m, 1H), 7.78 (d, 1H), 8.80 (s, 1H). The polymorph was characterized by the following analytical data. Differential Scanning Colorimetry (DSC): 298.50 °C XRPD analysis:
(29 values): 7.02+ 0.2, 7.58± 0.2, 7.90± 0.2, 13.46+ 0.2, 14.04± 0.2, 14.52+ 0.2, 15.26± 0.2, 16.48± 0.2, 18.40± 0.2, 19.62+ 0.2, 20.66+ 0.2, 21.16+ 0.2, 21.54± 0.2, 22.14+ 0.2, 22.52+
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0.2, 24.08± 0.2, 24.52± 0.2, 25.74* 0.2, 26.64± 0.2, 27.32± 0.2, 28.32± 0.2, 29.42± 0.2,
30.24± 0.2, 31.66± 0.2, 32.66± 0.2, 34.20± 0.2, 36.18± 0.2, 36.52+ 0.2, 37.92± 0.2, 38.08±
0.2.
IR values (KBr, cm-'): 3448, 2951, 1722, 1618, 1533, 1458, 1378, 1317, 1265, 1235, 1172,
1111,1047,805.
EXAMPLE 8 Preparation of (£)-(-)-1 -cyclopropvl-6-fluoro-8-methvl-7-(4-amino-3,3-dimethyl-piperidin-1 -
yl)-K4-dihvdro-4-oxo-quinoline-3-carboxvlic acid hydrochloride salt (2):
A mixture of (S)-(-)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid (78 gm) and concentrated hydrochloric acid (78 ml) was heated at 55 °C to 60 °C for 1 hour to provide a clear solution. The clear solution was filtered through celite and the clear filtrate was stirred with of acetone (412 ml) for two hours at 30 °C to 35 °C to effect precipitation. The solid was filtered under suction; the wet cake was washed with acetone (100 ml) and was dried at 80 °C under vacuum to provide the title compound as an off white solid. Yield 93 gm (84%). m/z 3§8(M+1), [α]D25 = -275.9° (c 0.5, methanol), Chiral purity by HPLC: 99.57%. The polymorph was characterized by the following analytical data. Differential Scanning Colorimetry (DSC): 297.66 °C XRPD analysis:
(28 values): 7.04± 0.2, 7.50± 0.2, 9.68± 0.2, J3.34± 0.2, 14.22± 0.2, 14.66± 0.2, 15.14± 0.2, 15.74+ 0.2, 15.94± 0.2, 17.14± 0.2, 17.84± 0.2, 18.76± 0.2, 19.06± 0.2, 22.52± 0.2, 24.12± 0.2, 25.64± 0.2, 26.02± 0.2, 26.28± 0.2, 29.94± 0.2, 30.82+ 0.2, 32.34± 0.2, 35.00+ 0.2, 37.18± 0.2, 37.68± 0.2, 39.50±0.2.
IR values (KBr, cm-1): 3433, 2951, 1708, 1618, 1517, 1458, 1427, 1377, 1317, 1265, 1237, 1108,1049,978,807.
EXAMPLE 9 Preparation of (R)-(+)-1 -cvclopropvl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-
l-yl)-L4-dihydro-4-oxo-quinoline-3-carboxvlic acid hydrochloride salt (3):
By following the procedure described in Example 8 and using (R)-(+)-1-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid ( 2.0 gm), the title compound was prepared in 1.3 gm quantity.
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m/z 388 (M+l), [α]D25 = +278.23°.( c 0.5, methanol), Chiral purity by HPLC: 99.62%. The
polymorph was characterized by the following analytical data.
Differential Scanning Colorimetry (DSC): 307 °C
XRPD analysis:
(20 values): 7.06± 0.2, 7.54+ 0.2, 9.72± 0.2, 13.38+ 0.2, 14.70+ 0.2, 15.16+ 0.2, 17.16+ 0.2,
17.86± 0.2, 18.80± 0.2, 19.08± 0.2, 22.54± 0.2, 24.16± 0.2, 25.68± 0.2, 26.04± 0.2, 26.32±
0.2, 29.98± 0.2, 30.88+ 0.2, 32.38± 0.2, 35.10± 0.2, 37.22+ 0.2, 37.78± 0.2, 39.54± 0.2.
IR values (KBr, cm-1): 3427, 2870, 1708, 1619, 1535, 1457, 1315, 1265, 1237, 1107, 1050,
807.
TEST EXAMPLE-1
X-ray Powder Diffraction Analysis: 300 mg each of the teat sample prepared as above were thinly spread on a sample holder. X-ray powder diffraction analyses (40kv x 40 mA Rigaku D/max 2200) were performed under the conditions listed below:
Scan speed 5/ min
Sampling time 7 min Scan mode: continuous
29/8 reflection
Cu target (Ni filter)
Results of the X-ray diffraction analysis of test compounds are depicted in FIG. 1, FIG. 4 and FIG 7.
TEST EXAMPLE-2
Thermal Analysis: For the Differential Scanning Calorimetry, PERKIN-ELMER system was used. 2.5 mg of the sample was weighed into the aluminum pan, which was then press sealed with an aluminum lid. After three tiny needle holes were made on the lid the sample was tested by heating from 30 °C to 300 °C at a rate of 10 °C/min.
Results of the differential scanning calorimetry of the test compounds are depicted in FIG. 2, FIG. 5 and FIG 8.
TEST EXAMPLE-3
Infra-red spectrum analysis: Infra-red spectrum was obtained on BRUCKER VECTOR 22 system and by using KBr pellet.
Results of the Infra-red spectrum analysis of the test compounds are depicted in FIG. 3, FIG. 6 and FIG 9.
16

Claims:
1. A process for the preparation of racemic or S-(-)- or R-(+)- enantiomers of a compound
of formula I,

comprising:


a) reacting compound of formula III with hydrogenation catalyst in a suitable solvent
under hydrogen pressure;
wherein R is CH2Ph or OCOCH2Ph;
b) filtering the reaction mixture and recovering the catalyst;
c) isolating the crude compound of formula IV by concentrating the filtrate obtained in step (b);
d) purifying the product obtained in above step by treating with 15% aqueous sodium hydroxide solution;
e) isolating the pure product i.e. racemic or (S)-(-)- or (R)-(+)- enantiomer of pure compound of formula IV;
f) the pure product obtained in the step (e) is treated with l-cyclopropyl-6,7-diflouro-8-methyl-l,4-dihydro-4-oxo-quinoline-3-carboxylate O3, O4 difluoroboron chelate (V), in presence of a base in suitable solvent;
17


g) evaporating the reaction mixture to dryness to provide a residue;
h) adding methanol and triethylamine to a residue and stirring at 65 °C to 70 °C for 3
hours;
i) recovering unreacted l-cyclopropyl-6,7-diflouro-8-methyl-l,4-dihydro-4-oxo-
quinoline-3-carboxylic acid from the reaction mixture;.
j) ;the aqueous filtrate of the step (i) is washed with an organic solvent to remove
impurities;
k) the aqueous layer of step (j) is basified to pH 13 by sodium hydroxide;
1) then the pH is adjusted to 8 by concentrated hydrochloric acid and stirred to allow
precipitation of the product;
m) filtering the solid obtained in step (1), washing the solid with water and dried under
vacuum to obtain product of formula II;
n) treating compound of formula II with concentrated hydrochloric acid to provide
compound of formula I.
o) treating the aqueous filtrate obtained in step (m) with solid sodium hydroxide and
extracting with dichloromethane, evaporating dichloromethane layer to dryness to
provide unreacted (RS)-(±)- or (£)-(-)- or (R)-(+) isomer of 4-amino-3,3-dimethyl-
piperidine, which can be recycled after vacuum distillation.
2. The process as claimed in claim 1, for the preparation of
(R5)-(±)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinolin-3-carboxylic acid hydrochloride salt;
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(R)-(+)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinolin-3-carboxylic acid hydrochloride salt;
(S)-(-)-l -cyclopropyl-6-fluofo-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l -yl)-l ,4-dihydro-4-oxo-quinolin-3-carboxylic acid hydrochloride salt.
3. The process as claimed in claim 1, wherein in step (a) the hydrogenation catalyst is selected from 5% palladium on carbon, 10% palladium on carbon or 20% palladium hydroxide on carbon.
4. The process as claimed in claim 1, wherein in step (a) the suitable solvent is aliphatic alcohol or aqueous alcohol.
5. The process as claimed in claim 1, wherein in step (a) the suitable solvent is methanol.
6. The process as claimed in claim 1, wherein in step (a) hydrogen pressure is in the range of 200 to 400 psi.

7. The process as claimed in claim 1, wherein in step (a) the reaction is stirred at a temperature in the range of 30 °C to 65 °C.
8. The process as claimed in claim 1, wherein in step (b) the recovered catalyst is reused by the addition of 2% w/w fresh catalyst.
9. The process as claimed in claim 1, wherein the base in step (f) is triethylamine.

10. The process as claimed in claim 1, wherein in step (f) the suitable solvent is acetonitrile.
11. The process as claimed in claim 1, wherein in step (f) the reaction is stirred at a temperature in the range of 20 °C to 65 °C.
12. The process as claimed in claim 1, wherein in step (f) the reaction mixture is stirred for 4 days.
13. The process as claimed in claim 1, wherein step (g) comprises,
i. the solvent of the reaction mixture of step (f) is evaporated to provide a residue;
ii. to the above residue water was added and acidified with cone, hydrochloric acid;
iii. isolating the precipitated solid, i.e. l-cyclopropyl-6,7-diflouro-8-methyl-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid, by filtration.
19

14. The process as claimed in claim, 1, wherein in the step (h) the organic solvent comprises chloroform, methylene chloride, ether, ethylacetate.
15. A crystalline form of (RS)-(±)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid monohydrochloride having X-ray powder diffraction pattern with peaks about 7.02+0.2, 7.58+0.2, 7.90±0.2, 13.46+0.2, 14.04±0.2, 14.52±0.2, 15.26±0.2, 16.48±0.2, 18.40±0.2, 19.62±0.2, 20.66±0.2, 21.16±0.2, 21.54±0.2, 22.14±0.2, 22.52±0.2, 24.08±0.2, 24.52±0.2, 25.74±0.2, 26.64±0.2, 27.32±0.2, 28.32±0.2, 29.42±0.2, 30.24±0.2, 31.66±0.2, 32.66±0.2, 34.20±0.2, 36.18±0.2, 36.52±0.2, 37.92±0.2, and 38.08±0.2 two-theta degrees.
16. A crystalline form of (RS)-(±)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carbdxylic acid monohydrochloride of claim 15 which has a Differential Scanning Calorimetry thermogram, which exhibits a significant endo peak about 298.50 °C.
17. A crystalline form of (RS)-(±)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidjn-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid monohydrochloride of claim 15 having identified characteristic bands about 3448, 2951, 1722, 1618, 1533, 1458, 1378, 1317, 1265, 1235, 1172, 1111, 1047, 805 cm-1 in Infra red spectrum.
18. A crystalline form of (S)-(-)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid monohydrochloride having X-ray powder diffraction pattern with peaks about 7.04+ 0.2, 7.50+ 0.2, 9.68± 0.2, 13.34+ 0.2, 14.22± 0.2, 14.66± 0.2, 15.14± 0.2, 15.74± 0.2, 15.94± 0.2, 17.14± 0.2, 17.84± 0.2, 18.76± 0.2, 19.06± 0.2, 22.52± 0.2, 24.12± 0.2, 25.64± 0.2, 26.02± 0.2, 26.28± 0.2, 29.94± 0.2, 30.82±0.2, 32.34+ 0.2, 35.00+ 0.2, 37.18±0.2, 37.68±0.2, and 39.50± 0.2 two-theta degrees.
19. A crystalline form of (S)-(-)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid monohydrochloride of claim 18 which has a Differential Scanning Calorimetry thermogram, which exhibits a significant endo peak about 297.66 °C.
20. A crystalline form of (S)-(-)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid monohydrochloride of claim 18 having identified characteristic bands about 3433, 2951, 1708, 1618, 1517, 1458, 1427, 1377, 1317, 1265, 1237, 1108, 1049, 978, 807 cm-1 in Infra red spectrum.
20

21. A crystalline form of (R)-(+)-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyI-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid monohydrochloride having X-ray powder diffraction pattern with peaks about 7.06+ 0.2, 7.54± 0.2, 9.72± 0.2, 13.38± 0.2, 14.70± 0.2, 15.16± 0.2, 17.16± 0.2, 17.86± 0.2, 18.80± 0.2, 19.08± 0.2, 22.54± 0.2, 24.16± 0.2, 25.68± 0.2, 26.04± 0.2, 26.32± 0.2, 29.98± 0.2, 30.88± 0.2, 32.38± 0.2, 35.10± 0.2, 37.22± 0.2, 37.78± 0.2, and 39.54± 0.2 two-theta degrees.
22. A crystalline form of (R)-(+)-1 -cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid monohydrochloride of claim 21 which has a Differential Scanning Calorimetry thermogram, which exhibits a significant endo peak about 307 °C.
23. A crystalline form of (R)-(+)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid monohydrochloride of claim 21 having identified characteristic* bands about 3427, 2870, 1708, 1619, 1535, 1457, 1315, 1265,1237,1107, 1050, 807 cm'1 in Infra red spectrum.


Dated this 29th day of September 2006

21

ABSTRACT
The present invention relates to an improved process for the preparation of l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-4-oxo-l,4-dihydro-quinolin-3-carboxylic acid hydrochloride salt and optically pure enantiomers thereof.
22