WO2008038122A2

WO2008038122A2 - Processes for the preparation of 7-substituted 3,3-dimethyl-4-amino-piperidino-quinolone carboxylic acid derivatives

Info

Publication number: WO2008038122A2
Application number: PCT/IB2007/002846
Authority: WO
Inventors: Prasad Keshav Deshpande; Satish Baliram Bhavsar; Sanjeev Narhari Joshi; Rajesh Prabhakar Kale
Original assignee: Wockhardt Research Centre
Priority date: 2006-09-29
Filing date: 2007-09-28
Publication date: 2008-04-03
Also published as: WO2008038122A3

Abstract

The present invention relates to process for the preparation of racemic and optically pure enantiomers of 1-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-1-yl)-4- oxo-l,4-dihydro-quinolin-3-carboxylic acid and salts thereof. The present invention also provides novel crystalline forms of racemic and optically pure enantiomers of 1-cyclopropyl- 6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-1 -yl)-4-oxo-1,4-dihydro-quinolin-3- carboxylic acid hydrochloride and compositions containing polymorphs. The present invention further provides pure (RS)-(±)-4-amino-3,3-dimethyl-piperidine and pure (R) or (S)-enantiomers of 4-amino-3,3-dimethyl-piperidine compounds.

Description

PROCESSES 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 process for the preparation of racemic and optically pure enantiomers of 1 -cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin- 1 -yl)-4- oxo-l ,4-dihydro-quinoIin-3-carboxylic acid and salts thereof. The present invention also provides novel crystalline forms of racemic and optically pure enantiomers of 1 -cyclopropyl- 6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin- 1 -yl)-4-oxo- 1 ,4-dihydro-quinolin-3- carboxylic acid hydrochloride and compositions containing polymorphs. The present invention further provides pure (/?S)-(±)-4-amin_o-3,3-dimethyl-piperidine and pure (R) or (S)-enantiomers of 4-amino-3,3-dimethyl-piperidine compounds.

Background of the Invention

The fluoroquinolone class of compounds due to their broad spectrum and excellent pharmacokinetics form an important armamentarium as antibacterial agents. Several compounds from this class of antibacterial are in clinical use, for example nalidixic acid, norfloxacin, ofloxacin, ciprofloxacin, and moxifloxacin.

International PCT Publications, WO 02/085886 and WO 03/050107 disclose {RS)-(±)- and (/?)-(+)- and (5)-(-)-isomers 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 and salts thereof of Formula I having preferred antibacterial properties.

According to the process disclosed in the WO 02/085886 and Wp 03/050107, the compound of Formula I is prepared by treating the 4-amino-3,3-dimethyl-piperidine with the intermediate 1 -cyclopropyl-όj-difluoro-δ-methyl- 1 ,4-dihydro-4-oxo-quinoline-3-carboxylate -O³,O⁴-difluoroboron chelate to give a free base, l -cyclopropyl-6-fluoro-8-methyl-7-(4- amino-3,3-dimethyl-piperidin- 1 -yl)- 1 ,4-dihydro-4-oxo-quinoline-3-carboxylic acid. The hydrochloride salt is prepared by treating the free base with .ethaholic hydrochloric acid. The reported processes results in a low overall yield of the product due to formation of impurities during 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 the Foπnula I!

Summary of the Invention In one general aspect there is provided a process for the preparation of compounds of * Formula I which includes (7?5)-(±)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3- dimethyl-piperidin-l -yl)-4-oxo-l,4-dihydro-quinolin-3-carboxylic acid and salts thereof (Compound 1), (£)-(-)- l -cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin- l -yl)-4-oxo-l ,4-dihydro-quinolin-3-carboxylic acid and salts thereof (Compound 2) and (R)- (+)-l -cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l -yl)-4-oxo-l ,4- dihydro-quinolin-3-carboxylic acid and salts thereof (Compound 3).

Formula-I

In another aspect of the invention there is provided a process for the preparation of salts of the compounds of Formula I.

In yet another aspect of the invention there is provided novel crystalline foπns of (RS)-(±)-\- cyclopropyl-6-fluoro-7-(4-amino-3,3-dimethyl-piperidin- 1 -yl)-8-methyl- 1 ,4-dihydro-4-oxo- quinoline-3-carboxylic acid hydrochloride (Compound 1), (5)-(-)- l-cyclopropyl-6-fluoro-7- (4-amino-3,3-dimethyl-piperidin-l-yl)-8-methyl-l ,4-dihydiO-4-oxo-quinoline-3-carboxylic acid hydrochloride (Compound 2), (/?)-(+)- l -cyclopropyl-6-fluoro-7-(4-amino-3,3-dimethyl-₍ piperidin- 1 -yl)-8-methyl- 1 ,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride (Compound 3).

In yet another aspect of the invention provides a pharmaceutical composition comprising a crystalline foπns of (/?5)-(±)- 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 (Compound 1) or (5)-(-)-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' (Compound 2) or (R)-(+)-\ - cyclopropyl-ό-fluoro-V-C^amino-S^-dimethyl-piperidin-l -yO-δ-methyl-l ^-dihydro^-oxo- quinoline-3-carboxylic acid hydrochloride and one or more pharmaceutically acceptable carriers, excipients or diluents. Pharmaceutical composition of present invention includes but not limited to solid oral, liquid or injectable dosage form.

In yet another aspect of the invention there is provided pure (ΛS)-(±)-4-amino-3,3-dimethyl- piperidine and pure (R) or (S)-enantiomers of 4-amino-3,3-dimethyl-piperidine compounds.

. Description of the Drawings FIG. 1 is a Powder X-Ray Diffraction pattern of Compound 1.

FIG. 2 is a Differential Scanning Calorimetric thermogram of Compound 1.

FIG. 3, is an Infra-Red spectrum of Compound 1.

FIG. 4 is a Powder X-Ray Diffraction pattern of Compound 2.

FIG. 5 is a Differential Scanning Calorimetric thermogram of Compound 2. FIG. 6 is an Infra-Red spectrum of Compound 2.

FIG. 7 is a Powder X-Ray Diffraction pattern of Compound 3.

FIG. 8 is a Differential Scanning Calorimetric thermogram of Compound 3.

FIG. 9 is an Infra-Red spectrum of Compound 3.

Detailed Description of the Invention

In one general aspect there is provided a process for the preparation of compounds of Formula I which includes (Λ5^I)-(±)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3- dimethyl-piperidin-l -yl)-4-oxo- l,4-dihydro-quinolin-3-carboxylic acid and salts thereof (Compound 1), (5)-(-)- l -cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin- l-yl)-4-oxo-l,4-dihydro-quinolin-3-carboxylic acid and salts thereof (Compound 2) and (R)- (+)- 1 -cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin- 1 -yl)-4-oxo- 1 ,4- dihydro-quinolin-3-carboxylic acid and salts thereof (Compound 3).

Formula-I In general, the process for the preparation of a compound of Formula I and salts thereof, the process includes the steps of: a) converting a compound of Formula III to a compound of Formula IV in a suitable solvent,

III IV wherein R is CH₁Ph, OCOCH₁Ph wherein R is CH₂Ph or OCOCH₂Ph; b) reacting the compound of Formula IV with a compound of Formula V in the presence of a base to get the compound of Formula I;

c) optionally reacting the compound of Formula I with an acid to get a salt of the compound of Formula I; and d) isolating the compound of Foπnula I or salts from reaction mass thereof. -

The process for the preparation of compounds of Formula I i.e. (Λ5)-(±)-l-cyclopropyl-6- fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin- 1 -yl)- 1 ,4-dihydro-4-oxo-quinoline-3- carboxylic acid free base and its salt, (5)-(-)-l -cyclopropyl-6-fluoro-8-methyl-7-(4-amino- 3.3-dimethyl-piperidin-l-yl)-1 ^4-dihydro-4-oxo-quinoline-3-carboxylic acid free base and its salt and (^)-(+)-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 its salt.

In another general aspect, the process for preparation of compound of Foπnula I includes the steps of: a) treating compound of Foπnula-V with compound of Formula-IV in the presence of a base; b) concentrating the reaction mixture; c) treating the residue with triethylamine in a suitable solvent; d) recovering unreacted l-cyclopropyl-6,7-difluoro-8-methyl-l ,4-dihydiO-4-oxo- quinoline-3-carboxylic acid and compound of Formula IV; e) purifying arid isolating the product of Formula I.

In general, 1 -cyclopropyl-όj-difluoro-δ-methyl- 1 ,4-dihydro-4-oxo-quinoline-3-carboxylate O³, O⁴ difluoroboron chelate is treated with a amine of Formula IV wherein the amine comprises of (RS)-(±)- or (S)-(-) or (R)-{+) isomer. The reaction is performed in the presence of a base such as triethylamine, diethylamine, isoprpylamiηe and the like in a suitable solvent , such as acetonitrile, propionitrile, DMF, DMSO and mixtures thereof at _ja temperature between 20 ⁰C to 65 ⁰C, and stirring for a period of 4 days. The reaction mixture is further evaporated to dryness to provide a residue. The residue is diluted with methanol and triethylamine is added to the residue. The reaction mixture is stirred at 65 °C to 70 ⁰C for 3- 12 hours. The reaction mixture is further evaporated to dryness and diluted with water. The reaction mixture is, further acidified with .concentrated hydrochloric acid to provide a suspension. The precipitated solid is filtered to recover unreacted l-cyclopropyl-6,7-difluoro- 8-methyl-l ,4-dihydro-4-oxo-quinoline-3-carboxylic acid. The aqueous filtrate is extracted with an organic solvent such as chloroform, methylene chloride, ether, ethylacetate to remove impurities. The pH of the aqueous layer is adjusted to 13 by addition of 45 % w/v aqueous sodium hydroxide, followed by further adjusting the pH of aqueous layer to pH 8 by addition of concentrated hydrochloric acid. The reaction mixture is stirred for sufficient time to effect the complete precipitation. The precipitated solid is isolated by conventional filtration techniques followed by drying the solid at a temperature 70 ⁰C to 90 ⁰C under vacuum to afford compound of Formula I as a free base. The aqueous filtrate is treated with solid ' sodium hydroxide and extracted with a suitable solvent such as chloroform, dichloromethane, ether and the like. The organic layer upon evaporation to dryness provides unreacted amine of Formula IV.

A further aspect of the invention relates to isolation of substantially chemically pure (RS)-(±)- 1 -cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin- 1 -yl)-4-oxo- 1 ,4- dihydro-quinolin-3-carboxylic acid free base, and substantially chemically and chirally pure enantiomers 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 as their respective free bases, free from impurities without use of column chromatography, which is of a significant advantage thus amenable for scale up to large-scale production.

A further aspect of the invention relates to a process for the preparation of salts of the Formula II. The process for preparing compound of Formula II involves the steps of: :a) treating a compound of Formula I with an acid; b) adding an antisolvent to effect precipitation; and c) isolating the product of Formula II from the reaction mixture thereof.

I II wherein Z is hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate and salts of organic acids such as acetate, lactate, succinate, oxalate, maleate, fumarate, malate, tartrate, citrate, ascorbate, gluconate, benzoate, cinnamate, methane sulfonate and p-toluene sulfonate.

The compound of Formula II is treated with an acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid and organic acids such as acetic acid, lactic acid, succinic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartratic acid, citric acid, ascorbic acid, gluconic acid, benzoic acid, cinnamic acid, methane sulfonic acid and p-toluene sulfonic acid. The reaction is earned out at a temperature in the range of 20 to 100 ⁰C. The reaction mixture is cooled and an antisolvent such as acetone, acetonitrile, alcohol such as methanol, ethanol and the like. The term "antisolvent" refers to a solvent which on addition to the reaction mixture can cause precipitation of the product. The precipitated solid is isolated from the reaction mass thereof.

In an another aspect is provided the polymorphs of (/?5)-(±)- 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 (5)-(-)-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 and (/?>(+)- 1 -cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin- 1 -yl)- 1 A- dihydr^'o-4-oxo-quinoline-3-carboxylic acid hydrochloride salt. The polymorphs are characterized by X-Ray Powder Diffractogram (XRPD), Differential Scanning Colorimetry thermogram (DSC) and Infra-red spectrum (IR).

The crystalline polymorph of (ΛS)-(±)-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 has X-ray powder diffraction pattern as shown in FIG. 1 , with peaks at about (2Θ values) 7.02± 0.2, 7.58+ 0.2, 7.901 0.2, 13.46+ 0.2,_, 14.04± 0.2, 14.52± 0.2, 15.26± 0.2, 16.48± 0.2, 18.401 0.2, 19.62± 0.2, 20.661 0.2, 21.161 0.2, 21.541 0.2, 22.141 0.2, 22.521 0.2; 24.08+ 0.2, 24.521 0.2, 25.741 0.2, 26.641 0.2, 27.321 0.2, 28.321 0.2, 29.421 0.2, 30.24+ 0.2, 31.66+ 0.2, 32.66+ 0.2, 34.20+ 0.2, 36.181 0.2, 36.521 0.2, 37.921 0.2, 38.081 0.2. The DSC exhibits a significant endotherm peak around 298.50 ⁰C as depicted in FIG. 2. The characteristic IR values at (KBr, cm^"1) 3448, 2951, 1722, 1618, 1533, 1458, 1378, 1317, 1265, 1235, 1 172, 1 1 1 1 , 1047, 805-as shown FIG. 3/

The crystalline polymorph of (S)-(-)-l -cyclopropyl-6-tTuoro-8-methyl-7-(4-amino-3,3- dimethyl-piperidin- l -yl)- l ,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride salt has X-ray powder diffraction pattern as shown FIG. 4, with peaks at about (2θ values) 7.041

0.2, 7.501 0.2, 9.681 0.2, 13.341 0.2, 14.221 0.2, 14.66+ 0.2, 15.14+ 0.2, 15.741 0.2, 15.941

0.2, 17.141 0.2, 17.841 0.2, 18.76i^S0.2, 19.061 0.2, 22.52^vi 0.2, 24.121 0.2, 25.64+ 0.2,

26.021 0.2, 26.281 0.2, 29.941 0.2, 30.821 0.2, 32.341 0.2, 35.001 0.2, 37.181 0.2, 37.681 0.2, 39.501 0.2. The DSC exhibits a significant endotheπn peak around 297.66 ⁰C as depicted in FIG. 5. The characteristic IR values at (KBr, cm^'1) 3433,^' 2951 , 1708, 1618, 1517, 1458,

^" 1427, 1377, 1317, 1265, 1237, 1 108, 1049, 978, 807 as shown FIG. 6. The crystalline polymorph of (7?)-(+)-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 as shown FIG. 7, with peaks at about (2Θ 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, 35.1O± 0.2, 37.22± 0.2, 37.78± 0.2, 39.54± 0.2. The DSC exhibits a significant endotherm peak around 307 ⁰C as depicted in FIG. 8. The characteristic IR values at (KBr, cm^{" 1}) 3427, 2870, 1708, 1619, 1535, 1457, 1315, 1265, 1237, 1 107, 1050, 807 as shown FIG. 9.

Another aspect of the invention relates to an improved process for the preparation of compound of formula IV, which includes compounds - (Λ5)-(±)-4-amino-3,3-dimethyl- piperidine, (5)-(-)-4-amino-3,3-dimethyl-piperidine and (7?)-(+)-4-amino-3,3-dimethyl- piperidine in high purity. The process for preparation of compound of formula IV includes the steps of: a) reacting compound of Formula III with a hydrogenation catalyst in a suitable solvent; b) isolating the crude amine of Formula IV from the reaction mixture thereof; and c) purifying the amine of Formula IV from the reaction mixture thereof.

HI IV wherein R is CH₂Ph, OCOCH₂Ph

The process includes obtaining (/?S)-(±)-4-amino-3,3-dirnethyl-piperidine from {RS)-{±)-4- amino-l-benzyl-3,3-dimethyl-piperidine by hydrogenation in the presence of a catalytic amount of a hydrogenating agent. The (Λ5)-(±)-4-amino-3,3-dimethyl-piperidine so obtained may be treated with aqueous sodium hydroxide and then purified by vacuum distillation to give pure (/?S)-(±)-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. Similarly, for the enantiomers of 4-amino-3,3-dimethyl-piperidine are obtained from chirally pure 4-amino-l-benzyloxycarbonyl-3,3-dimethyl-piperidine by using a catalytic amount of a hydrogenating reagent. The (R) or (S)-enantiomers of 4-amino-3,3- dimethyl-piperidine so obtained may be treated with aqueous sodium hydroxide and then purified by vacuum distillation to give pure (R) or (S)-enantiomers of 4-amino-3,3-dimethyl- piperidine.

Examples of hydrogenation catalyst include 20% palladium hydroxide on carbon (slurry made in water), 10% palladium on carbon, and 5% palladium on carbon and the like in presence of a hydrogen source such as hydrogen gas, ammonium foπnate, cyclohexene and the like.

Examples of suitable solvent for the hydrogenation reaction includes alcohols such as methanol, ethanol, isopropanol, or mixtures thereof. The mixtures of alcohols with water are also contemplated.

The process may produce the pure (Λ5)-(±)-4-amino-3,3-dimethyl-pipeπdine and pure (R) or (S)-enantiomers of 4-amino-3,3-dimethyl-piperidine having purity of 99.8 % or more when measured by HPLC.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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.

Examples :

The starting material l-cyclopropyl-6,7-difluoro-8-methyl-l ,4-dihydro-4-oxo-quinoline-3- carboxy-late O , O⁴ difluoroboron chelate was prepared as per procedure described in JP 63316757 (1989), JP 0372476 (1991 ). The amines (Λ5)-(±)-4-amino-l-benzyl-3,3-dimethyl- piperidine, (5)-(-)-4-amino- 1 -benzyloxycarbonyl-3,3-dimethyl-piperidine, (/?)-(+)-4-amino- 1 - -benzyloxycarbonyl-S^-dimethyl-piperidine, were prepared according to the procedure described in U.S. Patent No. 6,878,713. Mass spectra were recorded on Waters Micromass Quatro- II instrument and Optical rotation was recorded on Rudolph (Model DPIA31 ) instrument. Example 1 : Preparation of (/?S)-(±)-4-amino-3,3-dimethyl-piperidine:

A solution of (ΛS)-(±)-4-amino-l-benzyl-3,3-dimethyl-piperidine (425 gm, prepared as per

-procedure described in U.S. Patent No. 6,878,713), methanol (2.3 lit) was charged in Parr pressure reactor to provide a clear solution. To a clear solution, 20 % palladium hydroxide on carbon catalyst (74 gm, slurry made in 50 ml water) was charged. The suspension was stirred at hydrogen pressure 250 psi at 65 ⁰C for overnight. After TLC showed completion of reaction, the reaction mixture was filtered over celite bed. The catalyst was recovered (the recovered catalyst was re-used in the next batch of the same reaction after 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 (ΛS)-(±)-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 pellets dissolved in 500 ml water) at 35 ⁰C to 40 ⁰C temperature for 30 minutes. The layers were separated. The oily layer was dried over sodium sulphate and distilled under vacuum at 10 mm and a constant boiling fraction was collected as a thick viscous colorless oil in 154 gm (61 %) quantity with a purity of 99.99 % when measured by HPLC. m/z = 129 (M+ 1 ), PMR: - (CDCl₃, δ ppm) 0.9 (s, 6H), 1.5 (m. 2H), 1.58 (bs, 2H, D₂O exchangeable), 2.26 - 2.68 (m, 4H), 3.06 (m, 1 H), 3.52 (bs, IH, D₂O exchangeable).

Example 2; Preparation of (5)-(-)-4-amino-3, 3-dimethyl-piperidine:

A suspension of 10% palladium on carbon (53 g) and chirally more than 98.5% pure, (£)-(-)-- 4-amino-l -benzyloxycarbonyl-3, 3-dimethylpiperidine (530 g, prepared as per procedure described in U.S. Patent No. 6,878,713), in methanol (3000 ml) was stiσed at 300 psi hydrogen pressure at 30 ⁰C to 35 ⁰C for 23 hr. The catalyst was filtered over a celite bed (the recovered catalyst was re-used for the same reaction in the next batch after addition of 2% w/w fresh catalyst). The bed was washed with methanol and the filtrate was evaporated to dryness to afford crude (5)-(-)-4-amino-3, 3-dimethylpiperidine as a white semi-solid 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 ⁰C to 35 ⁰C. The layers were allowed to 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-dimcthylpipcridinc as colorless thick viscous oil at a constant boiling temperature. Yield 190 gm (75 %) with purity 99.99 % when measured by HPLC, m/z 129 (M+l), [α]_D ²⁵ = -34.44° (c 1 , methanol). Example 3: Preparation of (β)-(+)-4-amino-3,3-dimethyl-piperidine:

By following the procedure described in Example 2, and using more than 98.5% chirally pure, (Λ)-(+)-4-amino-l -benzyloxycarbonyl-3, 3-dimethylpiperidine (42 gm, prepared as per procedure described in U.S. Patent No. 6,878,713), the compound (/?)-(+)-4-amino-3,3- dimethyl-piperidine was prepared in 12.8 gm (59%) quantity with a purity of 99.99 % when measured by HPLC, m/z 129 (M+l ), [α]_D ²⁵ ₌ +34.17° (c 1 , methanol).

Example 4: Preparation of (7?.y)-(±)-l-cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3- dimethyl-piperidin-l-yl)-K4-dihydiO-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 (1 10 gm) in acetonitrile (440 ml), a freshly vacuum distilled (/?S)-(±)-4-amino-3,3-dimethyl-piperidine (150 gm) and triethylamine (94 ml) were added sequentially at 35 ⁰C. The resulting mixture was stirred at 55 ⁰C to 65 ⁰C 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, 1 -cyclopropyl-όJ-difluoro-S-methyl- 1 ,4-dihydro-4-oxo-quinoline-3- carboxylic acid was filtered at suction. The aqueous filtrate was washed with chloroform (500 ml) to remove impurities. The 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. The precipitated solid was filtered under suction and was washed with water (100 ml). It was dried under vacuum at 80 ⁰C to provide l-cyclopropyl-6-fiuoro-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 in 46 gm quantity. (64.8% 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 hydroxide and was extracted with dichloromethane (250 ml X 3). Evaporation of the dichloromethane layer provided un-reacted (/?5)-(±)-4-amino-3,3-dimethyl-piperidine, which was recycled after vacuum distillation. m/z = 388, PMR (200 MHz, CDCl₃, 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, I H), 3.10-3.35 (m, 4H), 4.00-4.20 (m, IH), 7.90 (d, IH), 8.95 (s, IH).

Example 5: Preparation of (5D-(-)-l-Cvclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3- dimethyl-piperidin-l-yl)-l ,4-dihydro-4-oxo-quinoline-3-carboxylic acid (free base): To a solution of l -cyclopropyl-όJ-difluoro-S-methyl-l ^-dihydro^-oxo-quinoline-S- carboxylate O³, O⁴ difluoroboron chelate (212 gm) in acetonitrile ( 1 lit), freshly vacuum distilled (S)-(-)-4-amino-3,3-dimethyl-piperidine (250 gm) and triethylamine (216 ml) were added sequentially at 35 ⁰C. The resulting mixture was stirred at 55 ⁰C to 60 ⁰C 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 ⁰C to 70 ⁰C 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 1 -cyclopropyl-6,7-difiuoro- 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 ⁰C to effect complete precipitation. The 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 a free base (£)-(-)- 1 -cyclopropyl-6-fluoro-8-methyl-7-(4- amino-3,3-dirnethyl-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 hydroxide and then was extracted with dichloromethane (250 ml X 3). Evaporation of the dichloromethane layer provided un-reacted (S)-(-)-4-amino-3,3-dimethyl-piperidine, which was recycled after vacuum distillation. m/z 388, [α]_D ²⁵ = -263.85° (c 0.5, DMSO). Example 6: Preparation of (/?)-(+)- l-cvclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3- dimethyl-piperidin-l-yl)-l ,4-dihvdro-4-oxo-quinoline-3-carboxylic acid (free base): By following the procedure described in Example 5 and using (Λ)-(+)-4-amino-3,3- dimethylpiperidine ( 1 1.8 gm), and l-cyclopropyl-όJ-difluoro-S-methyl-l ^-dihydro-Φoxo- quinoline-3-carboxylate O³, O⁴ difluoroboron chelate (8.58 gm), the compound, (/?)-(+)- 1 - cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin- 1 -yl)- 1 ,4-dihydro-4-oxo- quinoline-3-carboxylic acid (free base) was prepared in 2.9 g quantity. m/z 388 (M+l), [α]_D ²⁵ ₌ +261.04° (c 0.5, DMSO).

Example 7: Preparation of (/?£)-(+)- l -cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3, 3- dimethyl-piperidin-l -yl)-l,4-dihvdro-4-oxo-qυinoline-3-carboxylic acid hydrochloride salt

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 ⁰C to 35 °C to effect precipitation. The 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 (84%) of title compound. m/z 388 (M+ 1 ), PMR (400 MHz, DMSO-D₆, δ ppm): 0.70-0.80 (m, I H), 0.9-0.95 (m, I H). 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, I H), 2.66-2.70 (m, I H), 3.13-3.16 (m, 3H), 4.30 (m, I H), 7.78 (d, I H), 8.80 (s, I H). The polymorph was characterized by the following analytical data. Differential Scanning Colorimetry (DSC): 298.50 °C. XRPD analysis: (2Θ values): 7.02±0.2, 7.58±0.2, 7.90±0.2, 13.46+0.2, 14.0410.2, 14.52±0.2, 15.26±0.2, 16.48±0.2, 18.40+0.2, 19.6210.2, 20.6610.2, 21.1610.2, 21.5410.2, 22.14+0.2, 22.5210.2, 24.0810.2, 24.52+0.2, 25.7410.2, 26.6410.2, 27.3210.2, 28.3210.2, 29.4210.2, 30.24+0.2, 31.66+0.2, 32.6610.2, 34.2010.2, 36.1810.2, 36.52+0.2, 37.9210.2, 38.0810.2. IR values (KBr, cm^{" 1}): 3448, 2951 , 1722, 1618. 1533. 1458, 1378, 1317, 1265, 1235, 1 172, 1 1 1 1, 1047, 805. Example 8: Preparation of (5^f)-(-)-l -cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3J-dimethyl- piperidin-l-yl)-l,4-dihvdro-4-oxo-quinoline-3-carboxylic 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 ⁰C to 60 ⁰C for 1 hour to provide a clear solution. The clear solution was filtered through celite and the clear filtrate was stirred with acetone (412 ml) for two hours at 30 ⁰C to 35 ⁰C to effect precipitation. The solid was filtered under suction; the wet cake was washed with acetone (100 ml) and was dried at 80.⁰C under vacuum to provide the title compound as an off white solid. Yield 93 gm (84%). m/z 388(M+1), [α]_D ²⁵ ₌ -275.9° (c θ.5, methanol), Chiral purity by HPLC: 99.57%. The polymoφh was characterized by the following analytical data. Differential Scanning Colorimetry (DSC): 297.66 °C. ^{' ~}

XRPD analysis: (2Θ 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, 22.52± 0.2, 24.121 0.2, 25.641 0.2, 26.021 0.2, 26.281 0.2, 29.941 0.2, 30.821 0.2, 32.341 0.2, 35.001 0.2, 37.181 0.2, 37.681 0.2, 39.50+ 0.2.

IR values (KBr, cm ¹): 3433, 2951, 1708, 1618, 1517, 1458, 1427, 1377, 1317, 1265, 1237, 1 108, 1049, 978, 807.

Example 9: Preparation of (/?)-(+)- 1 -cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3, 3- dimethyl-piperidin-l -yl)-l,4-dihvdro-4-oxo-quinoline-3-carboxylic acid hydrochloride salt

By following the procedure described in Example 8 and using (/?)-(+)- 1 -cyclopropyl-6- fluoiO-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l-yl)-l ,4-dihydro-4-oxo-quinoHne-3- carboxylic acid ( 2.0 gm), the title compound was prepared in 1.3 gm quantity. m/z 388 (M+ 1 ), [α]_D ²⁵ = +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 ⁰C. XRPD analysis: (2Θ values): ,7.061 0.2, 7.541 0.2, 9.72+ 0.2, 13.381 0.2, 14.701 0.2, 15.161 0.2. 17.161 0.2, 17.861 0.2, 18.801 0.2, 19.081 0.2, 22.541 0.2, 24.161 0.2, 25.681 0.2, 26.041 0.2, 26.321 0.2, 29.981 0.2, 30.881 0.2, 32.38+ 0.2, 35.101 0.2, 37.221 0.2, 37.781 0.2, 39.541 0.2. IR values (KBr, cm^{" 1}): 3427, 2870, 1708, 1619, 1535, 1457, 1315, 1265, 1237, 1 107, 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

2Θ/Θ reflection

Cu target (Ni filter) Results of the X-ray diffraction analysis of test compounds are depicte_^d 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 aluminium lid. After three tiny needle holes were made on the lid the sample was tested by heating from 30 ⁰C to 300 ⁰C 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 FlG 9.

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.

Claims

We Claim:

1. A process for the preparation of a compound of Formula I and salts thereof,

Formula I the process comprising the steps of: a) converting a compound of Formula III to a compound of Formula IV in a suitable solvent,

III IV wherein R is CH₂Ph or OCOCH₂Ph; b) reacting the compound of Formula IV with a compound of Formula V in the presence of a base to get the compound of Formula I;

I c) optionally reacting the compound of Formula I with an acid to get a salt of the compound of Foπnula I; and d) isolating the compound of Foπnula I or II from the reaction mass thereof

II wherein Z is hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate and salts of organic acids such as acetate, lactate, succinate, oxalate, maleate, fumarate, malate, tartrate, citrate, ascόrbate, gluconate, benzoate, cinnamate, methane sulfonate and p-toluene sulfonate.

2. The process of claim 1 , wherein the compound of Formula I comprises one or more of RS-(±)-l -cyclopropyl-6-fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin-l -yl)-l ,4- dihydro-4-oxo-quinolin-3-carboxylic acid salt thereof; 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 salt thereof; and

S-(-)- 1 -cyclopropyl-6"fluoro-8-methyl-7-(4-amino-3,3-dimethyl-piperidin- 1 -yl)- 1 ,4- dihydro-4-oxo-quinolin-3-carboxylic acid salt thereof.

3. The process of claim 1 , wherein the compound of Formula III is converted to the compound of Foπnula IV by using a hydrogenation catalyst.

4. The process of claim 3, wherein the hydrogenation catalyst comprises one or more of 5% palladium on carbon, 10% palladium on carbon or 20% palladium hydroxide on carbon.

5. The process of claim 1 , wherein the suitable^'solvent used in step a) comprises one or more of methanol, ethanol, isopropyl alcohol, or mixtures thereof.

6. The process of claim 1 , wherein the pure compound of Formula IV is obtained by treating the compound of Foπnula IV with aqueous sodium hydroxide solution.

7. The process of claim 6, wherein the pure compound of Formula IV has a purity of 99.8 % or more when measured by HPLC₁

8. The process of claim 1 , wherein in the step b) the base comprises one or more of methylamine, ethyl amine, triethylamine, or mixtures thereof.

9. The process of claim 1 , wherein the acid comprises one or more of hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate and salts of organic acids such as acetate, lactate, succinate, oxalate, maleate, fumarate, malate, tartarate, citrate, ascorbate, gluconate, benzoate, cinnamate, methane sulfonate, and/?-toluene sulfonate.

10. A crystalline form of (Λ5)-(±)-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 characteristic X-ray diffraction peaks at about 7.90±0.2, 13.46±0.2, 14.04±0.2, 14.52±0.2, 15.26±0.2, 18.40±0.2, two-theta degrees. -

,

1 1. The crystalline form of claim 10, having a Differential Scanning Calorimetry thermogram, which exhibits a significant endo peak at about 298.5 ⁰C.

12-. A crystalline form of (5)-(-)- 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 characteristic X-ray diffraction peaks at about 7.50± 0.2, 13.34± 0.2, 25.64± 0.20.2 two-theta degrees.

13. The crystalline form of claim 12, having a Differential Scanning Calorimetry thermogram, which exhibits a significant endo peak at about 297.6 ⁰C.

14. A crystalline form of (/?)-(+)-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 characteristic X-ray diffraction peaks at about 7.54± 0.2, 13.38± 0.2, 14.70± 0.2, 17.86+ 0.2, 25.68± 0.2, two-theta degrees.

15. The crystalline foπn of claim 14, having a Differential Scanning Calorimetry thermogram, which exhibits a significant endo peak at about 307.0 ⁰C.

16. A pharmaceutical composition comprising the compound according to claim 10 and one or more pharmaceutically acceptable carriers, excipients or diluents.

17. A pharmaceutical composition comprising the compound according to claim 12 and one or more pharmaceutically acceptable carriers, excipients or diluents.

18. A pharmaceutical composition comprising the compound according to claim 14 and one or more pharmaceutically acceptable earners, excipients or diluents.