US 20070244318A1

(19) United States

(12) Patent Application Publication (10) Pub. No.: US 2007/0244318 A1
Rao et al. (43) Pub. Date: Oct. 18, 2007

(54) PROCESS FOR THE PREPARATION OF (52) US. Cl. ............................................................ .. 544/101
LEVOFLOXACIN HEMIHYDRATE

(76) Inventors: Davuluri Rammohan Rao, Hyderabad (57) ABSTRACT

(IN); Shiprakash Dhar DWivedi,
Hyderabad (IN); Pamujula
Sreenivasulu, Hyderab (IN); Arabinda The present invention relates to an improved process for
Sahu, Hyderabad (IN); Ganala Naga preparation of Levo?oxacin hemihydrate having single indi
Trinadhachari, Hyderabad (IN); vidual impurity not more than 0.1% and free from particu
Surapaneni Sasi Kiran, Hyderabad late matter & from the other enantiomer (R-form) Which
(1N) comprises dissolving levo?oxacin technical grade in aque
ous alkaline solution, treating the resulting solution With
Correspondence Address: activated carbon at room temperature, removing the undis
MOORE & VAN ALLEN PLLC
P.O. BOX 13706 solved particulate matter ?ltration, bringing the pH of the
Research Triangle Park, NC 27709 (US) aqueous alkaline levo?oxacin solution to neutral using
dilute mineral acid, removing the precipitated particulate
(21) Appl. No.: 10/578,078 matter by ?ltration, acidifying the resulting solution, treating
the acidi?ed solution With activated carbon at room tem
(22) PCT Filed: Aug. 11,2004 perature, ?ltering the undissolved particulate matter by
(86) PCT No.: PCT/IN04/00343
?ltration, neutralizing the acidic solution, ?ltering again to
remove any particulate matter present and, extracting the
§ 371(c)(1), resulting product With chlorinated solvent and concentrating
(2), (4) Date: Mar. 7, 2007 under vacuum using aqueous tetrahydrofuran or in admix
ture With other organic solvents to get highly pure levof
Publication Classi?cation loxacin hemihydrate having single individual impurity is
(51) Int. Cl. less than 0.1% and free from particulate matter & from the
C07D 491/14 (2006.01) other enantiomer (R-form).
US 2007/0244318 A1 Oct. 18, 2007

PROCESS FOR THE PREPARATION OF (1986) by HayakaWa I, et al. In this process 9,10-Di?uoro
LEVOFLOXACIN HEMIHYDRATE 3 -(hydroxymethyl) -7 -oxo-2,3 -dihydro-7H-pyrido[1,2,3 -
??e]-1,4-benZoxaZine-6-carboxylic acid ethyl ester, a race
FIELD OF INVENTION mic intermediate in the synthesis of O?oxacin Was resolved
[0001] This invention provides an improved process for and esteri?ed With 3,5-dinitro benZoyl chloride, separated by
the preparation of Levo?oxacin hemihydrate. More spe HPLC column SUMIPAX-OA-4200, using hexane, 1,2
cially, the invention provides an improved process for the dichloro ethane, ethanol as carrier solvent. The (—) optical
preparation of high purity Levo?oxacin hemihydrate from isomer is partially hydrolyZed With ethanolic aqueous
Levo?oxacin technical. The Levo?oxacin hemihydrate pre sodium bicarbonate to afford the (—) alcohol, Which is
pared has a single individual impurity less than 0.1% free treated With triphenyl phosphite methiodide in DMF giving
from particulate matter and other enantiomer (R-form). the corresponding (—)-iodomethyl derivative. The reduction
Levo?oxacin hemihydrate prepared by the process of the and simultaneous hydrolysis With tributyltin hydride in
present invention is useful as an antibacterial. The invention ethanol yield (—)-9,10-di?uoro-3-methyl-7-oxo-2,3-dihy
also relates to an improved process for the preparation of dro-7H-pyrido[1,2,3-1e]1,4-benZoxaZine-6-carboxylic acid
Levo?oxacin hemihydrate starting from 2,3,4,5,tetra?uoro Which is ?nally treated With N-methyl piperaZine at 120° C.
benZoic acid through the intermediates Levo?oxacin Q acid in DMSO to give (—) O?oxacin i.e. Levo?oxacin.
and Levo?oxacin technical.
[0007] In Us. Pat. No. 5,053,407 racemic-3-acetoxy
BACKGROUND OF THE INVENTION methyl-7,8-di?uoro-2,3-dihydro-4H-[1,4]-benZoxaZine Was
[0002] Levo?oxacin is the S-(—) isomer of the ?uoro resolved through its dinitrobenZoyl derivatives (or con
quinoline antibacterial O?oxacin. Levo?oxacin is generally densed With a cyclic amino acid or a reactive derivative
considered to be about tWice as active as O?oxacin. It has a through amide linkage) folloWed by debenZoylation, deacy
broad spectrum of activity, Which included Gram-positive lation and dehydroxylation to obtained optically active 7,8
bacteria. [Davis R, Bryson H M, Drugs, 4, 677(l994)]. di?uoro-2,3-dihydro-3-methyl-4H-[1,4]-benZoxaZine Which
Levo?oxacin is given by mouth or intravenously for the on condensation With diethyl ethoxy acrylomalonate fol
treatment of susceptible infections in a usual dose of 250 or loWed by cycliZation, hydrolysis and condensation With
500 mg. once or tWice daily. It is also administered topically N-methyl piperaZine to obtain Levo?oxacin.
as 0.5% eye drops for the treatment of bacteria conjunctivitis [0008] Scientists of Daiichi prepared the intermediate
[Martindale, The Complete Drug Reference, 33rd edition, (—)9,10-di?uoro-3 -methyl-7-oxo-253 -dihydro-7H-pyrido[1,
pp. 219 (2002) and references cited therein]. 2,3-de]-1,4-benZoxaZine-6-carboxylic acid by either resolu
[0003] The Levo?oxacin hemihydrate is (S)-9-Fluoro-2, tion or chiral speci?c synthesis. While condensation With
3 -dihydro -3 -methyl-10-(4-methyl-1piperaZinyl)-7-oxo-7H N-methyl piperaZine major reports disclosed in the presence
pyrido[1,2,3-de]-1,4-benZoxaZine-6-carboxylic acid hemi of DMSO at above 1000 C. or chilation With BF34OEt2 in
hydrate. The chemical structure of Levo?oxacin ether and then condensation With N-methyl piperaZine in the
hemihydrate (CAS Registry No. [138199-71-0]) is shoWn as presence of DMSO, triethylamine has reported.
formula I.
[0009] The preparation of Levo?oxacin has also been
reported in Us. Pat. No. 4,777,253 and J. Med. Chem. 30,
2283 (1987) by Mitcher et al. Levo?oxacin synthesiZed
from 2,3,4,5-tetra?uoro benZoic acid Which is treated With
thionyl chloride to produce the corresponding acid chloride.
Displacement of the acid chloride With malonic acid half
ester in the presence of n-Butyl lithium yield the [3-ketoester.
The [3-ketoester is then treated With a trialkyl orthoforrnate
in the presence of an acid anhydride yielding Ethyl-2-(2,3,
4,5-tetra?uoro benZoyl)-3-alkoxy acylate, Which on reaction
With (S)-2-amino-1-propanol to obtain enamino ketoester.
The enamino ketoester is then cycliZed such as by treatment
With tWo moles equivalents of an alkali metal hydride,
[0004] Us. Pat. No. 5,545,737 and EP patent No. alkoxide at an elevated temperature to obtain alkyl-(—)-9,
0444678 disclose a process for the preparation of levo?oxa 10-di?uoro~3 -methyl-7-oxo -2,3 -dihydro-7H-pyrido-[1,2,3 -
cin hemihydrate or monohydrate selectively by controlling afe]-1,4-benZoxaZine-6-carboxylate. The condensation reac
the Water content of an aqueous solvent selected from the tion betWeen N-methyl piperaZine and alkyl (—)-9,10
group consisting of methanol, ethanol, propanol and acetone di?uoro-3 -methyl-7-oxo -2,3 -dihydro-7H-pyrido[1,2,3 -fe]1,
in Which levo?oxacin is dissolved during crystallization. 4-benZoxaZine-6-carboxylate at temperature from 20° C. to
200° C. and preferably from 40° C. to 90° C. in the presence
[0005] Niddamhil Desheim, Valeric et al. disclose in WO
of a suitable organic solvent such as pyridine, chloroform,
03/045329, and in WO 03/028665, methods for the puri? dimethylsulphoxide, sulfolane, dimethylforrnamide, dim
cation of Levo?oxacin using polar solvent such as DMSO,
ethylacetamide, 1-methyl-2-Pyrrolidone. It is desirable to
methyl ethyl ketone, acetonitrile, butanol and mixtures carry out the reaction in the presence of an acid-acceptor
thereof and aqueous mixture thereof and/or using an anti
such as triethyl amine, potassium carbonate and the like a
oxidant.
molar ratio of 1.0 to 1.2 mole of the acid-acceptor per mole
[0006] Levo?oxacin Was ?rst disclosed in Us. Pat. No. of the ester. N-methyl piperaZine can also be used as an
5,053,407 and in Antimicrob. Agents chemother. 29, 163 acid-acceptor in Which tWo or more molar excess is used.
US 2007/0244318 A1 Oct. 18, 2007

[0010] Antons, Stefan et al. Bayer. AG. have reported in Jiaming et al. from 2,3,4,5-tetra?uoro benZoic acid by
German patent no DE 4428020A, a process for the prepa chlorination, condensation With di-Et malonate, partial
ration of (—)-9,10-di?uoro-2,3-dihydro-(S)-3 -methyl-7-oxo hydrolysis, decarboxylation, condensation With triethyl
7H-pyrido-[1,2,3 -de]-1,4-benZoxaZine-6-carboxylic acid orthoformate, substitution With (S)-(+)-2-aminopropanol,
starting from 2,3,4,5-tetra?uoro benZoyl chloride. The pro cycliZation, hydrolysis and substitution With N-methyl pip
cess comprises condensing 2,3,4,5-tetra?uoro benZoyl chlo eraZine.
ride With either 3-(N-methyl piperaZinyl)-acetylic acrylic
[0017] In vieW of the need for the Levo?oxacin hemihy
acid ethyl ester or 3-(N,N-dimethylamino)acetylic acrylic drate having single individual impurity not more than 0.1%
acid ethyl ester folloWed by transamination With (S)-2
and free from particulate matter for pharmaceutical appli
Amino propanol, cycliZation and hydrolysis. cations, We under took R&D Work toWards this direction.
[0011] SchrieWer et al. Bayer AG. has disclosed in US. [0018] Accordingly, the main objective of the present
Pat. No. 5,237,060 a process of preparing enantiomerically invention is to provide an improved process for the prepa
pure 1,8-bridged-4-quinolone-3-carboxylic acids, starting ration of Levo?oxacin hemihydrate having single individual
from 3-ethoxy-2-(2,3,4,5-tetra?uoro benZoyl) acrylic acid impurity not more than 0.1% and free from particulate
ethyl ester. 3-ethoxy-2-(2,3,4,5-tetra?uoro benZoyl) acrylic matter & from the other enantiomer (R-form).
acid ethyl ester on condensation With (S)-2-amino propanol,
cycliZation using potassium carbonate, hydrolysis and con [0019] Yet another objective of the present invention is to
densation With N-methylpiperaZine provides Levo?oxacin. provide an improved process for the preparation of Levof
loxacin hemihydrate by dissolving Levo?oxacin in Water at
[0012] Kim et al. of Korea Institute of Science and Tech different pH folloWed by ?ltration and using aqueous tet
nology reported in US. Pat. No. 5,539,110 a method for the rahydrofuran for making the Levo?oxacin hemihydrate.
preparation of (—) piperaZine derivative. The (—) 9,10
Di?uoro-253-dihydro-3-methyl-7-oxo-7/?pyrido[1,2,3 [0020] Still another objective of the present invention is to
A ]-1,4-benZoxaZine-6-carboxylic acid is prepared starting provide an improved process for the preparation of Levof
from (S) (+)-2-Amino-1-propanol in four steps by condens loxacin hemihydrate starting from 2,3,4,5/tetra?uoro ben
ing With alkyl silylated piperaZine in the presence of organic Zoic acid through the intermediates Levo?oxacin Q-acid and
polar solvent such as pyridine, dimethylsulfoxide, acetoni Levo?oxacin technical.
trile, dimethylformamide, N-methyl pyrrolidine and sul
folane. SUMMARY OF THE INVENTION
[0013] Juan. C. Carretero et al. in Heterocycles vol 51, No [0021] Accordingly, the present invention provides an
7, 1999; have also published an ef?cient synthesis of O?oxa improved process for preparation of Levo?oxacin hemihy
cin and Levo?oxacin from 3,4-di?uoroaniline. Key steps in drate having single individual impurity not more than 0.1%
the synthetic sequence are the regioselective functionaliZa and free from particulate matter & from the other enanti
tion at either C-2 or C-3 of the N-(tert-butoxy carbonyl)-3, omer (R-form) Which comprises
4,-di?uoroaniline and the construction of the benZoxaZine
skeleton by O-alkylation of the corresponding phenol With [0022] (i) dissolving levo?oxacin technical grade in
propylene oxide, Which Was transformed into O?oxacin or aqueous alkaline solution,
Levo?oxacin by condensing With N-methyl piperaZine. Sho
hgo Atarashi et al. in Chem. Pharm. Bull 35 (5) 1896-1902
[0023] (ii) treating the resulting solution With activated
carbon at room temperature,
(1987). discloses, tWo optically active isomers of O?oxacin
and their ?uoromethyl derivatives Were prepared via their [0024] (iii) removing the undissolved particulate matter
optically active intermediates resolved by used of high through ?ltration,
performance liquid chromatography (HPLC). The isomers
Were also obtained ef?ciently by an alternative route via [0025] (iv) bringing the pH of the aqueous alkaline levo
separation of the diastereo isomers prepared in the reaction ?oxacin solution to neutral using dilute mineral acid,
of benZoxaZine With L-proline chloride, then condensation
of N-methyl piperaZine With (—)-9,10-di?uoro-2,3-dihydro [0026] (v) removing the precipitated particulate matter
(S) -3 -methyl-7-oxo-7i/-pyrido-[1,2,3 -de]-1,4-benZoxaZine by ?ltration,
6-carboxylic acid in the presence of dimethyl sulphoxide. [0027] (vi) acidifying the resulting solution,
[0014] Carretero GonZalver et al. of in US. Pat. No. [0028] (vii) treating the acidi?ed solution With activated
5,521,310 disclose a process for the preparation of benZox carbon at room temperature,
aZines Which is to be used for the synthesis of Levo?oxacin
O?oxacin and derivatives starting from 3,4-di?uoroaniline. [0029] (viii) ?ltering the undissolved particulate matter
[0015] Nakamura, Hiroshi et al. in JP patent no 2001
by ?ltration,
31,654. according to the process disclosed in this patent [0030] (ix) neutraliZing the acidic solution,
Ethyl 6,7,8-tri?uoro-1,4-dihydro-1-(1-acetoxymethyl)ethyl
4-oxoquinoline-3-carboxylate is prepared and condensed [0031] (x) ?ltering again to remove any particulate
With 1-methyl piperaZine in toluene at 1000 C. for 2 hrs and matter present and
then cycliZed in the presence of sodium hydroxide in 2-pro
panol at 1000 C. for 2 hrs. [0032] (xi) extracting the resulting product With chlo
rinated solvent and concentrating under vacuum using
[0016] Levo?oxacin disclosed recently in Zhonggno aqueous tetrahydrofuran or in admixture With other
YaoWu Huaxue ZaZhi 2000, 10 (4), 276-278 (Ch) by Li, organic solvents to get highly pure levo?oxacin hemi
US 2007/0244318 A1 Oct. 18, 2007

hydrate having single individual impurity less than

0.1% and free from particulate matter & from the other -continued
enantiomer (R-for'm).
Angle d value Intensity
[0033] In a preferred embodiment of the present invention Z-ThetaO angstrom %
the ?ltration in steps (viii) & (x) may be effected using a 0.2 13.092 6.75695 38.5
micron ?lter. 13.360 6.62202 4.1
13.761 6.42997 2.2
[0034] Levo?oxacin technical is prepared either by using 14.744 6.00343 1.0
pyridine as a solvent or Without using solvent by any knoWn 15.833 5.59291 7.9
methods. Levo?oxacin technical may be stirred in Water and 18.382 4.82260 1.3
19.918 4.68723 4.8
pH is adjusted to 8.0 to 12.0, preferably 10.0-12.0, more 19.435 4.56359 13.0
preferably 11.0-11.5 With dilute alkali metal hydroxide 20.037 4.42795 9.4
solution, preferably 5 to 20% alkali solution, more prefer 23.442 3.79187 1.6
ably 8-10%. The alkali metal hydroxide Which may be used 24.222 3.67147 1.3
24.459 3.63 649 1.3
may be either sodium hydroxide or potassium hydroxide, 25.028 3.55510 2.4
preferably sodium hydroxide. The aqueous alkaline levof 25.819 3.44792 2.3
loxacin solution is treated With activated carbon, and the 26.415 3.37141 6.5
clear solution is ?ltered. Then the pH is brought to 7.0-7.5 26.743 3.33087 6.3
27.708 3.21699 1.0
using dilute hydrochloric acid, preferably 0.5N to 5N hydro 28.979 3.07872 2.1
chloric acid, more preferably 1N hydrochloric acid. The 30.466 2.93177 1.0
precipitated particulate matter is ?ltered. Again the aqueous 30.661 2.91353 1.3
solution pH may be adjusted to 3.0-6.0 preferably 4.0 to 5.5 31.456 2.84173 1.8
32.994 2.71263 1.1
more preferably 4.5-5.0 using glacial acetic acid. The aque 34.468 2.59993 1.8
ous acidic levo?oxacin solution Was treated With activated 37.740 2.38172 1.0
carbon at room temperature and the clear solution may be 40.480 2.22663 2.7
?ltered preferably through micron ?lter. Finally the pH of 42.486 2.12601 2.0
44.042 2.05443 1.0
the aqueous solution may be adjusted to neutral preferably 45.337 1.99873 1.9
7.0-7.5 using dilute aqueous ammonia solution. The neutral
aqueous solution may be again ?ltered preferably through
micron ?lter and extracted With chlorinated solvent prefer [0036] According to another embodiment of the present
ably methylene chloride. The extract may be concentrated invention there is provided an improved process for the
under vacuum (600-650 mm of Hg) below 400 C. The preparation of Levo?oxacin hemihydrate Which comprises
resulting residue Was concentrated after stirring With tet
rahydrofuran or its mixture any other organic solvent. [0037] (i) Converting 2,3,4,5-tetra?uoro benZoic acid to
Finally the residue Was slurred With 1-5% aqueous tetrahy its acid chloride by conventional method to give the
drofuran preferably With 2-2.5% aqueous tetrahydrofuran at diethyl-2,3,4,5-tetra?uoro benZoyl malonate.
40-700 C. preferably at 50-600 C. more preferably at 58-600 [0038] (ii) Partially hydrolyZing and decarboxylating
C. for 30 minutes to 2 hours preferably 30 minutes to 1 hour the resulting diethyl-2,3,4,5-tetra?uoro benZoyl mal
then cooled to —5 to 150 C. preferably 0-5o C. and stirred for onate by conventional methods to give ethyl-2,3,4,5
30 minutes to 2 hours preferably 1 hour to 1 hour 30 tetra?uoro benZoyl acetate.
minutes. The product Was ?ltered and suck dried for 15
minutes to 1 hour preferably 30 minutes to 45 minutes and [0039] (iii) Converting the ethyl-2,3,4,5-tetra?uoro
the product Was dried at 50-800 C. preferably at 70-750 C. benZoyl acetate by knoWn methods to ethyl-2-(2,3,4,
for 2 to 7 hours preferably 4-6 hours more preferably 5 to 5 5-tetra?uoro benZoyl)-3-ethoxy acrylate.
hours 30 minutes to give highly pure Levo?oxacin hemi
hydrate With single individual impurity less than 0.1%. [0040] (iv) Condensing the ethyl-2-(2,3,4,5-tetra?uoro
Elemental analysis calculated for C18H2OFN3O4.1/2H2O is C
benZoyl)-3-ethoxy acrylate obtained in step (iii) With
(S)-2-amino-1-propanol in a solvent, to give ethyl-2
58.37%, H 5.71%, N 11.35%, and found is C 58.38%, H
5.67%, N 11.38%. (2,3,4,5-tetra?uoro benZoyl)-3-[(1-hydroxyprop-2(S)
yl)amino]acrylate,
[0035] The X-ray diffraction pattern of the Levo?oxacin
hemihydrate prepared by the process of the present inven [0041] (v) Cyclising the resulting ethyl-2-(2,3,4,5-tet
tion is found to be identical to that of the Levo?oxacin ra?uoro benZoyl)-3-[(1-hydroxy prop-2(S)-yl)amino]
hemihydrate prepared by the process reported in Us. Pat. acrylate by conventional methods to give (S)-ethyl-9,
No. 5, 545,737, EP patent 0444678 and Chem. Pharm. Bull, 10-di?uoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido
43 (4) 649-653 (1995). The typical X-ray diffraction pattern [1 ,2,3-Je]-1,4-benZoxaZine-6-carboxylate and,
of the prepared Levo?oxacin hemihydrate is given beloW. [0042] (vi) further hydrolyZing (S)-ethyl-9,10-di?uoro
2,3-dihydro-3-methyl-7-oxo-7H-pyrido-[1,2,3-de]-1,4
benZoxaZine-6-carboxylate, obtained in step (v) by
Angle d value Intensity
knoWn methods to give (S)-9,10-di?uoro-2,3-dihydro
Z-ThetaO angstrom % 3-methyl-7-oxo-7H-pyrido-[1,2,3 -?fe]-1,4-benZox
aZine-6-carboxylic acid (namely Levo?oxacin Q-acid),
6.654 13.27346 100.0
9.704 9.10667 60.2 [0043] (vii) converting the Levo?oxacin Q-Acid by
condensing With N-methyl piperaZine by using solvent
US 2007/0244318 A1 Oct. 18, 2007

or Without using solvent by any known methods to [0050] (xiv) treating the acidi?ed solution With acti
(S)-9-?uoro -3 -methyl-10-(4-methyl-1-piperaZinyl)-7 vated carbon at room temperature,
oxo-2,3-dihydro-7H-pyrido[1,2,3-cfe]-1,4-benZox
aZine-6-carboxylic acid (namely Levo?oxacin techni [0051] (xv) ?ltering the undissolved particulate matter
cal), by ?ltration,
[0044] (viii) dissolving levo?oxacin technical in aque [0052] (xvi) neutraliZing the acidic solution,
ous alkaline solution,
[0053] (xvii) ?ltering again to remove any particulate
[0045] (ix) treating the resulting solution With activated matter present and,
carbon at room temperature,
[0046] (x) removing the undissolved particulate matter [0054] (xviii) extracting the resulting product With chlo
by ?ltration, rinated solvent and concentrating under vacuum using
aqueous tetrahydrofuran or in admixture With other
[0047] (xi) bringing the pH of the aqueous alkaline organic solvents to get highly pure levo?oxacin hemi
levo?oxacin solution to neutral using dilute mineral hydrate having single individual impurity not more
acid, than 0.1% and free from particulate matter & from the
[0048] (xii) removing the precipitated particulate matter other enantiomer (R-form).
by ?ltration, [0055] Reaction sequence is shoWn in the scheme given
[0049] (xiii) acidifying the resulting solution, beloW.

F COOH F COCl
l) D]. gthyl tnalonate COOCZH

Thionylchloride
4>
2) Megnesiurn
—>

3) Ethanol COOCZH
F F F 4) Toluene 1:

l) Paratoluene
sulphonic acid
2) Water
3) Toluene

F cooczn5 cooczn5
l) Triethyl ortho formate
<—
2) Acetic anhydride
F F OC2H5

l) (S)-arnino propanol
2) Methylene chloride

F COOCZHS F cooczn5 F cooczn5

I 1) Potassium carbonate
—
l l) Hydrochloric acid l
F F NH 2) N, N-dirnethyl fonnarnide F N 2) Acetic acid F N

F HO\)\ Me 0% Me 0% Me

l) N-methyl piperazine
2) Pyridine
3) Methanol
US 2007/0244318 A1 Oct. 18, 2007

-continued
1) Sodium hyroxide
2) Hydrochloric acid
F COOH 3) Acetic acid
4) Aq. Ammonia
<—
l
5) Methylene chloride
6) Activated carbon
7) Tetrahydrofuran
(\N N -1/2 H2O
MeN\) O\/k Me
Levo?oxacin hemihydrate Levo?oxacin (Tech)

[0056] In a preferred embodiment of the invention in step into the ?ask and heated to gentle re?ux temperature (58-60°
(i) , Diethyl malonate may be acylated using 2,3,4,5-tet C.). Maintained the reaction mixture under the conditions
ra?uoro benZoyl chloride in the presence of magnesium, for 30 minutes, cooled the contents of the ?ask to 00 C., kept
ethanol by making diethyl ethoxymagnesiomalonate. for 1 hour at 0-5° C. Filtered the product and Washed the
product With chilled 2-2.5% aqueous tetrahydrofuran (50
[0057] The reagents used for the condensation in step (iii) ml), suck dried for 15 minutes. Dried the product at 70-75°
may be triethyl orthoformate and acetic anhydride.
C., to constant Weight. The yield Was 34.0 g. HPLC purity
[0058] In step (ii) the conversion may be effected using an 99.82% and single individual impurity less than 0.1%.
aqueous medium employing catalytic amount of para tolu Moisture content: Calculated for Levo?oxacin hemihydrate
ene sulfonic acid. Was 2.43% and found is 2.45%. Elemental analysis: calcu
[0059] An example of the solvent used in step (iv) may be lated for Cl8H2OFN3O4. VZ H2O is C 58.37%, H 5.71%, N
11.35% and found is C 58.38%, H 5.67% and N 11.38%.
methylene chloride.
[0060] The cyclisation in step (v) may be done in the EXAMPLE-2
presence of suitable base such as potassium carbonate and
an aprotic solvent such as N,N-dimethyl forrnamide. Preparation of (—)-9-f uoro-3-methyI-10(4-methyl
1-piperaZinyl)-7-oxo-2,3-dihyd ro-7?-pyrido [1,2,3,
[0061] The hydrolysis in step (vi) may be carried out using <fel-1,4-benZoxaZine-6carboxylic acid Hemihydrate
acetic acid and dilute hydrochloric acid. (Levo?oxa-cin Hemihydrate of the Formula 1)
[0062] The details of the present invention are described in [0064] In a 500 ml four neck ?ask ?tted With a stirrer, Was
the folloWing examples Which are provided only to illustrate placed 244 ml of DM Water and 2.2 g of Levo?oxacin
the invention and therefore should not be construed to limit technical, stirred for 15 minutes. The pH Was adjusted to
the scope of the invention. 110-115 With 10% dilute sodium hydroxide at 25-30° C.,
1.1 g of activated carbon Was added into the ?ask and stirred
EXAMPLE-1 for 15 minutes. Filtered the solution over 0.2 micron milli
pore ?lter paper, Washed the carbon bed With 10 ml of DM
Preparation of (—)-9-?uoro-3-methyl-10(4-methyl-1 Water. To the clear ?ltrate, 1N
piperaZinyl)-7-oxo-2,3-dihydro-7fI-PVrJdO [1 ,2,,3,
<fel-1.,4-benZoxaZiiie-6-carboxylic acid Hemihy [0065] Hydrochloric acid (54 ml) Was added till the pH
drate (Levo?oxacin Hemihydrate of the Formula 1) reached 7.0-7.5 at 25-30° C. Filtered the solution and
Washed the bed With 10 ml of DM Water. To the clear ?ltrate,
[0063] In a 1000 ml four neck ?ask ?tted With a stirrer, added acetic acid (5.3 ml) till pH Was reached 45-50.
Was placed 550 ml of DM Water and 50 g of Levo?oxacin Added 1.1 g of activated carbon and stirred for 15 minutes.
technical, stir for 15 minutes. Adjusted the pH to 11.0-11.5 Filtered the solution and again ?ltered the solution over 0.2
With 10% dilute sodium hydroxide at 25-30° C., 2.5 g of micron Millipore ?lter paper. To the clear ?ltrate, aqueous
activated carbon Was added into the ?ask and stirred for 15 ammonia solution (8.5 ml) Was added till the pH Was
minutes. Filtered the solution, Washed the carbon bed With reached 7.0-7.5. Filtered the solution over 0.2 micron Mil
25 ml of DM Water. The pH of the clear ?ltrate Was adjusted lipore ?lter paper. The product Was extracted With methylene
to 7.0-7.5 With, 1N Hydrochloric acid at 25-30° C. Filtered chloride (3><242 ml). Distilled olf combined methylene
the solution and Washed the bed With 25 ml of DM Water. To chloride layer under reduced pressure beloW 40° C. mass
the clear ?ltrate acetic acid Was added till the pH reached temperature. Charged 22 ml ethyl acetate and co-distill the
4.5-5.0. 2.5 g of activated carbon Was added and stirred for methylene chloride. 2-2.5% aqueous tetrahydrofuran (22
15 minutes. Filtered the solution and again ?ltered the ml) and ethyl acetate (44 ml) Were charged into the ?ask and
solution over 0.2 micron Millipore ?lter paper. To the clear heated to gentle re?ux (58-60° C.). Maintained for 30
?ltrate, aqueous ammonia solution Was added to get pH minutes cooled the contents of the ?ask to 00 C., kept for 1
7.0-7.5. Filtered the solution over 0.2 micron Millipore ?lter hour at 0-5° C. Filtered the product and Washed the product
paper. The product Was extracted With methylene chloride With chilled ethyl acetate (22 ml), suck dry for 15 minutes.
(3x550 ml). Distilled olf combined methylene chloride layer Dried the product at 70-75° C., to constant Weight. The yield
under reduced pressure beloW 40° C. temperature. Charged of (—)-9-?uoro-3-methyl-10(4-methyl-1-piperaZinyl)-7
50 ml tetrahydrofuran and co-distilled the methylene chlo oxo-2,3-dihydro-7H-pyrido[1,2,3,-cfe]-1,4-benZoxaZine-6
ride. 2-2.5% aqueous tetrahydrofuran (150 ml) Was charged carboxylic acid (Levo?oxacin hemihydrate of the formula 1)
US 2007/0244318 Al Oct. 18, 2007

was 18.2 g. HPLC purity 99.87% and single individual sulfuric acid (sulfuric acid content 11.5-12.5% W/v) Was
impurity less than 0.1%. Moisture content : Calculated for added to the contents of the ?ask beloW 35° C. The contents
Levo?oxacin hemihydrate is 2.43% and found is 2.48%. of the ?ask Were stirred for 15 min. at 25-30° C. and
Elemental analysis: calculated for Cl8H2OFN3O4. V2 H21 is separated both layers. The aqueous layer Was extracted With
C 58.37%, H 5.71%, M 11.35% and found is C 58.36%, H toluene (2><500 ml) tWice. Organic layers Were mixed and
5.70% and N 11.37%. Washed With vacuum salt solution (200 g vacuum salt With
1 L Water). The organic layer Was ?ltered over high ?oW bed
EXAMPLE -3 and again Washed With vacuum salt solution (200 g of
vacuum salt With 1 L DM Water) folloWed by DM Water (500
Preparation of (—)-9-?uoro-3-methyl-10f4-methyl ml) Washing. The aqueous layer of DM Water Washing Was
checked for sulfate test (sulfates should be absent). If
3<<-<fel-1,4-benZoxaZme-6-carboxy iic acid Hemi sulfates Were present, again the organic layer Was Washed
hydrate (Levo?oxaein Hemihydrate of the Formula With DM Water (500 ml) till sulfates Were absent. Organic
1) from 2,3,4,5-tetra?uoro benZoic acid layer Was concentrated under vacuum (550-650 mm/ Hg) up
to mass temperature 80° C. to give quantitative yield of
Step (i) Preparation of 2,3,4,5-Tetra?uoro benZoyl chloride; diethyl-2,3,4,5-tetra?uoro benZoyl malonate. HPLC purity:
98.35%.
[0066] Into a three necked 2 L round bottom ?ask
equipped With a mechanical stirrer, thermometer socket and Step (iii) Preparation of (—)-Ethyl-9q 0-di?uoro-23 -dihydro
a condenser, thionyl chloride 560 ml, (7.713 mol) 2,3,4,5 3-methyl-7-oxo-7.?“-pyrido-?,,2,3-<fel-1.,4-benZoxaZine-6
Tetra?uoro benZoic acid 200 g (2.577 mol) and N,N-dim carboxylate:
ethyl forrnamide 10 ml Were charged. The contents of the [0068] Into a 3 lit 3 neck round bottom ?ask is provided
?ask Were heated gradually and very cautiously to 85-90° C. With a mechanical stirrer, thermometer socket and a con
during 6 to 8 hrs under re?ux. After attaining the mass denser, DM Water (1265 ml) diethyl-253,4,5-tetra?uoro ben
temperature 85-90° C., a sample Was taken out and checked Zoyl malonate 790.58 g (2.35 mol) and para toluene sul
for the content of 2,3,4,5-tetra?uoro benZoic acid by TLC. phonic acid (3.4 g) Were charged. The contents of the ?ask
The contents of the ?ask Were cooled to 45-50° C. Vacuum Were re?uxed (80-90° C.) under stirring and maintained at
(600-670 mm/Hg) Was applied and thionyl chloride Was the same temperature for 3 hrs. After completion of 3 hrs.
distilled off up to reaction mass temperature 900 C. The maintenance, TLC Was checked for ketodiester content. If
contents of the ?ask Was cooled to room temperature and ketodiester content is more than 1.0%, then para toluene
break the vacuum With nitrogen. High vacuum (690-720 sulphonic acid (3.4 g) Was charged into the reaction mixture
mm/ Hg) Was applied to the contents of ?ask and collected ISt and maintained 3 hrs. at re?ux temperature. TLC Was
fraction beloW 70° C. vapour temperature. Pure fraction Was checked for ketodiester content present in the reaction
collected separately vapour temperature above 70° C. Yield mixture. If ketodiester content Was more than 1.0% then
530 g (96.8%). HPLC purity 98.50% again para toluene sulphonic acid (3.4 g) Was charged and
Step (ii) Preparation of Diethyl-2,3,4,5-Tetra?uoro benZoyl re?uxed for 3 hrs. same thing Was repeated till TLC shoWs
malonate the content of ketodiester Was beloW 1.0%. The reaction
mixture Was cooled to 30-35° C. and separated both layers.
[0067] Into a four neck 10 Lit round bottom ?ask equipped Aqueous layer Was extracted With toluene (2><500 ml) tWice.
With a mechanical stirrer, thermometer socket and a con Organic layers Were mixed and Washed With 5% sodium
denser, 3.4 L toluene, 565 g (3.53 mol) of diethyl malonate bicarbonate solution (500 ml) folloWing by DM Water
and 365 ml of ethanol Were charged. The contents of the (2><500 ml) tWice. The aqueous layer of second Washing Was
?ask Were stirred at room temperature for 20 min. The checked for sulfate test. If sulfates present the organic layer
moisture content of the contents of ?ask Was checked. It Was again Washed With DM Water (500 ml) till sulfates
should be not more than 0.1% W/v. The contents of the ?ask absent. Organic layer Was concentrated under vacuum (650
Were transferred into another single neck ?ask. Into the four 750 mm/Hg) at 60-65° C. to give 608 g of ethyl-2,3,4,5
necked ?ask, 150 ml of ethanol, 86 g (3.54 mol) magnesium tetra?uorobenZoyl acetate (ketoester). To ketoester Without
turnings and catalytic amount of chloroform (10 ml) Were further puri?cation, 544 ml (5.76 mol) Acetic anhydride and
charged and Waited for 30 min. for initiation of the reaction. 511 g (3.45 mol) triethyl orthoforrnate Were charged into
The above prepared diethyl malonate, ethanol and toluene above reaction mixture. The contents of the RB ?ask Were
mixture Was gradually and uniformly added to reaction heated to 120-125° C. and maintained for 4 hrs. at 120-125°
mixture While stirring at 70-90° C. (exothermic reaction) C., loW boilers Were collected at receiver end While main
over a period of 3 to 4 hrs. The contents of the ?ask Were taining the reaction at 120-125° C. After 4 hrs maintenance,
stirred for additional 2 hrs. at 70-90° C. and cooled to 50-55° the contents of the RJB ?ask Was cooled to 90-100° C.,
C. and distilled off solvent under vacuum (600-650 mm of vacuum (650-700 mm/Hg) Was applied to the reaction
Hg). The residual ethanol Was removed by aZeotropic dis mixture and solvent Was distilled off up to mass temperature
tillation With toluene, then residue is redissolved in 2 L of 125° C. The reaction mixture Was cooled to 80-85° C. and
dry toluene and 200 ml of tetrahydrofuran and cooled to 250 ml toluene Was charged. Again vacuum (650-700
30-35° C. The contents of the ?ask are further cooled to 0-5° mm/Hg) Was applied and solvent Was distilled off up to 125°
C. and 500 g (2.35 mol) 2,3,4,5-Tetra?uoro benZoyl chloride C. The distillation Was continued at 125° C. till distillation
With 500 ml toluene mixture solution is added sloWly drop ceases. The reaction mixture Was cooled to 30-35° C. 800 ml
Wise over a period of 1-2 hrs. at 0-5° C. The contents of the methylene chloride Was charged and further cooled to 0-5°
?ask are stirred for 30 min. at 0-5° C. and alloWed to 20-25° C. While stirring. 133 g (1.77 mol) (S)-(+)-2-amino-1
C. and maintained for 30 min at 20-25 ° C. TLC is checked propanol With 270 ml methylene chloride Was charged into
for the content of 2,3,4,5-Tetra?uoro benZoic acid. Dilute reaction mixture at 0-5° C. over a period of 1-2 hrs. After
US 2007/0244318 A1 Oct. 18, 2007

addition, reaction mixture Was allowed to 30-35° C. gradu 4-benZoxaZine-6-carboxylic acid hemihycMrate (Levof
ally and maintained at 30-35° C. for 2 hrs. Reaction mixture loxacin Hemihydrate of the Formula 1);
Was Washed With Water tWice and dried With anhydrous
[0071] In a 4 neck ?ask ?tted With a stirrer, Was placed 2.2
sodium sulfate. Meanwhile 850 ml N-dimethyl forrnamide,
L of DM Water and 200 g of Levo?oxacin technical, stir for
444 g potassium carbonate Were charged into another ?ask
15 minutes. Adjusted the pH to 11.0-11.5 With 10% dilute
provided With mechanical stirrer and distillation set-up. The
sodium hydroxide at 25-30° C., 10 g of activated carbon Was
contents Were stirred and heated to 120° C. The methylene
added into the ?ask and stirred for 15 minutes. Filtered the
chloride layer Was added during 2 hrs. at 120° C. and
solution, Washed the carbon bed With 100 ml of DM Water.
methylene chloride Was collected at receiver end. Stirring
The pH of the clear ?ltrate Was adjusted to 7.0-7.5 With, 1N
Was continued for another 30 minutes the reaction mixture
Hydrochloric acid at 25-30° C. Filtered the solution and
Was cooled to 65-70° C. Vacuum (650-700 mm of Hg) Was
Washed the bed With 100 ml of DM Water. To the clear
applied to the reaction mixture and distilled off the solvent
?ltrate acetic acid Was added till the pH reached 4.5-5.0. 10
till half quantity of charged N,N-dimethyl formamide Was
g of activated carbon Was added and stirred for 15 minutes.
collected. The reaction mixture Was cooled to 20-25° C. DM
Filtered the solution and again ?ltered the solution over 0.2
Water (4 L) Was charged into the reaction mixture While
micron Millipore ?lter paper. To the clear ?ltrate, aqueous
stirring. Stirring Was continued for 1 hr. at 25-30° C. and
ammonia solution Was added to get pH 7.0-7.5. Filtered the
?ltered. Material Was Washed With DM Water (500 ml) and
solution over 0.2 micron Millipore ?lter paper. The product
suck dried. 650 ml acetone and Wet material Were charged
into the ?ask. The contents of the ?ask Were cooled to 0-5°
Was extracted With methylene chloride (3><2.2 L). Distilled
oif combined methylene chloride layer under reduced pres
C. and maintained 30 minutes at 0-5° C. Material Was
sure beloW 40° C. temperature. Charged 200 ml tetrahydro
?ltered and Washed With 650 ml acetone. The material Was
furan and co-distilled the methylene chloride. 2-2.5% aque
dried at 70-75° C. to give 315 g (—)-ethyl-9,10-di?uoro-2,
ous tetrahydrofuran (600 ml) Was charged into the ?ask and
3 -dihydro -3 -methyl-7-oxo-7H-pyrido-[1,2,3 -de]-1,4-ben heated to gentle re?ux temperature (58-60° C.). Maintained
ZoxaZine-6-carboxylate. HPLC purity: 99.23°/o. the reaction mixture under the conditions for 30 minutes,
Step (iv) Preparation of MAJO-Di?uoroAJ-dihydro cooled the contents of the ?ask to 00 C., kept for 1 hour at
A -mett.Lyl A -oxo-T?“-pyrido-?.2,3-de 1-1,4-benZoxaZine-6 0-5° C. Filtered the product and Washed the product With
carboxylic acid: chilled 2-2.5% aqueous tetrahydrofuran (200>ml), suck
dried for 15 minutes. Dried the product at 70-75° C., to
[0069] Into a 1 L 3 neck round bottom ?ask equipped With constant Weight. The yield Was 142 g. HPLC purity 99.90%
mechanical stirrer, thermometer socket and condenser, 125 and single individual impurity less than 0.1%. Moisture
ml Water, 125 ml concentrated hydrochloric acid, 250 ml content: Calculated for Levo?oxacin hemihydrate Was
acetic acid and 100 g (0.32 mol) (—)-ethyl-9,10-di?uoro-2, 2.43% and found is 2.50%. Elemental analysis: calculated
3-dihydro-3-methyl-7-oxo-7H pyrido [1,2,3-cfe]-1,4-ben for Cl8H2OFN3O4.V2H2O is C 58.37%, H 5.71%, N 11.35%
ZoxaZine-6-carboxylate Were charged. The contents Were and found is C 58.35%, H 5.72% and N 11.38%.
heated to 75-80° C. and maintained for 6 hrs at 75-80° C.
Advantages of the Present Invention
After 6 hrs the conversion of reaction Was monitored by
TLC. The reaction mixture Was cooled to 15-20° C. and [0072] (i) Levo?oxacin hemihydrate prepared having
maintained for 1 hr. at 15-20° C. Material Was ?ltered and single individual impurity less than 0.1% and free from
Washed With Water. Wet material Was slurred With Water at particulate matter.
45-50° C. and ?ltered. Dried at 70-80° C. to give 80 g of
(—)9, 10-di?uoro -2,3-dihydro-3-methyl-7 -oxo-7H-pyrido[1, [0073] (ii) Levo?oxacin hemihydrate prepared is free
2,3-de]-1,4-benZoxaZine-6-carboxylic acid. HPLC purity: from the other enantiomer (R-form).
99.33%. [0074] (iii) The process of the present invention pro
Step (v) Preparation of (—V9-?uoro-3 -methyl-10(4-methyl vides industrially feasible process.
1-piperaZinvlV7-oxo-2,3-dihydro-7//-pyrido ri,2,3,-de1-1, [0075] (iv) The process is simple and safe and environ
4-benZoxaZine-6-carboxylic acid (Levo?oxacin Technical): mentally friendly
[0070] Into a 3 necked round bottom ?ask equipped With [0076] It should be noted that the invention also envisages
a mechanical stirrer, thermometer socket and a condenser, other embodiments falling Within the scope of the present
228 g (2.28 mol) N-methyl piperaZine, 1.2 L pyridine and invention Which Will be obvious and apparent to one skilled
200 g (0.712 mol) (—)-9,10-di?uoro-2,3-dihydro-3-methyl in the art from the foregoing disclosure.
7-oxo-7H-pyrido[1,2,3 -de]-1,4-benZoxaZine-6-carboxylic
acid are charged the contents are heated to re?ux at 120° C.
for 10 hrs. and conversion is monitored by TLC. The 1. An improved process for preparation of Levo?oxacin
reaction mixture is concentrated under vacuum (600-650 hemihydrate having single individual impurity not more
mm of Hg) to leave residue, 200 ml methanol is charged and than 0.1% and free from particulate matter and from the
further concentrated. 800 ml Methanol is charged to residue other enantiomer (R-form) Which comprises
and heated to re?ux for 30 min. reaction mass is cooled to
10-15° C. and maintained for 1 hour, material is ?ltered and
i. dissolving levo?oxacin technical grade in aqueous
Washed With 100 ml chilled methanol to give 210 g of alkaline solution,
Levo?oxacin (technical) HPLC purity: 98.58%. ii. treating the resulting solution With activated carbon at
room temperature,
Step (vi) Preparation of (—)-9-?uoro -3 -methyl-10(4-methyl
1-piperaZinyl)-7-oxo -2,3 -dihydro -7lr-pyrido ?,2,3 ,-<fel-1 - iii. removing the undissolved particulate matter ?ltration,
US 2007/0244318 A1 Oct. 18, 2007

iv. bringing the pH of the aqueous alkaline levo?oxacin 1 hour and then cooled to —5 to 150 C. preferably 0-5o C. and
solution to neutral using dilute mineral acid, stirred for 30 minutes to 2 hours preferably 1 hour to 1 hour
30 minutes.
V. removing the precipitated particulate matter by ?ltra
13. An improved process as claimed in claim 1 Wherein
tion, the product is ?ltered and suck dried for 15 minutes to 1 hour
vi. acidifying the resulting solution, preferably 30 minutes to 45 minutes and the product Was
dried at 50-800 C. preferably at 70-750 C. for 2 to 7 hours
vii. treating the acidi?ed solution With activated carbon at
preferably 4-6 hours more preferably 5 to 5 hours 30
room temperature, minutes.
viii. ?ltering the undissolved particulate matter by ?ltra 14. An improved process for the preparation of Levof
tion, loxacin hemihydrate Which comprises,
iv. neutraliZing the acidic solution, i. Converting 2,3,4,5-tetra?uoro benZoic acid to its acid
chloride by conventional method to give the diethyl-2,
x. ?ltering again to remove any particulate matter present
and, 3,4,5-tetra?uoro benZoyl malonate,
xi. extracting the resulting product With chlorinated sol ii. Partially hydrolyZing and decarboxylating the resulting
vent and concentrating under vacuum using aqueous
diethyl-2,3,4,5-tetra?uoro benZoyl malonate by con
tetrahydrofuran or in admixture With other organic ventional methods to give ethyl-2,3,4,5-tetra?uoro ben
solvents to get highly pure levo?oxacin hemihydrate Zoyl acetate,
having single individual impurity less than 0.1% and iii. Converting the ethyl-2,3,4,5-tetra?uoro benZoyl
free from particulate matter and from the other enan acetate by knoWn methods to ethyl-2-(2,3,4,5-tet
tiomer (R-form). ra?uoro benZoyl)-3-ethoxy acrylate,
2. An improved process as claimed in claim 1 Wherein the
?ltration in steps (viii) and (x) may be effected using a 0.2 iv. Condensing the ethyl-2-(2,3,4,5-tetra?uoro benZoyl)
micron ?lter. 3-ethoxy acrylate obtained in step (iii) With (S)-2
3. An improved process as claimed in claim 1 Wherein the amino-1-propanol in a solvent, to give ethyl-2-(2,3,4,
alkaline Levo?oxacin solution is stirred at a pH in the range 5-tetra?uorobenZoyl) -3 -[(1 -hydroxyprop -2 (S)
of 8.0 to 12.0, preferably 10.0-12.0, more preferably 11.0 yl)amino]acrylate,
1 1 .5. v. Cyclising the resulting ethyl-2-(2,3,4,5-tetra?uoroben
4. An improved process as claimed in claim 1 Wherein the Zoyl) -3 -[(1-hydroxyprop-2(S)-yl)amino]acrylate by
alkali used is selected from sodium hydroxide or potassium conventional methods to give (S)-ethyl-9,10-di?uoro
hydroxide, preferably sodium hydroxide and the concentra 2,3-dihydro-3-methyl-7-oxo-7H-pyrido-[12,3-de]-1,4
tion of the solution is 5 to 20% preferably 8-10%. benZoxaZine-6-carboxylate and,
5. An improved process as claimed in claim 1 Wherein the
pH is brought to 7.0-7.5 using dilute hydrochloric acid, vi. further hydrolyZing (S)-ethyl-9,10-di?uoro-2,3-dihy
preferably 0.5N to 5N hydrochloric acid, more preferably dro-3-methyl-7-oxo-7H-pyrido-[1,2,3-de]-1,4-benZox
1N hydrochloric acid. aZine-6-carboxylate, obtained in step (v) by knoWn
6. An improved process as claimed in claim 1 Wherein the methods to give (S)-9,10-di?uoro-2,3-dihydro-3-me
precipitated particulate matter is ?ltered and the pH is thyl-7-oxo-7H-pyrido-[1,2,3-de]-1,4-benZoxaZine-6
adjusted to 3.0-6.0 preferably 4.0 to 5.5 more preferably carboxylic acid (namely Levo?oxacin Q-acid),
4.5-5.0 using glacial acetic acid. vii. converting the Levo?oxacin Q-Acid by condensing
7. An improved process as claimed in claim 1 Wherein the With N-methyl piperaZine by using solvent or Without
aqueous acidic levo?oxacin solution is treated With activated using solvent by any knoWn methods to (S)-9-?uoro
carbon at room temperature and the clear solution is ?ltered 3-methyl-10-(4-methyl-1-piperaZinyl)-7-oxo-2,3-dihy
the pH to neutral preferably 7.0-7.5 using dilute aqueous dro-7H-pyrido[1,2,3-de]-1,4-benZoxaZine-6-carboxy
ammonia solution. lic acid (namely Levo?oxacin technical),
8. An improved process as claimed in claim 1 Wherein the
neutral aqueous solution is again ?ltered and extracted With viii. dissolving levo?oxacin technical in aqueous alkaline
chlorinated solvent preferably methylene chloride. solution,
9. An improved process as claimed in claim 1 Wherein the ix. treating the resulting solution With activated carbon at
extract is concentrated under vacuum (600-650 mm of Hg) room temperature,
below 400 C. and the resulting residue is concentrated after
stirring With tetrahydrofuran or its mixture With any other x. removing the undissolved particulate matter by ?ltra
another organic solvent. tion,
10. An improved process as claimed in claim 1 Wherein xi. bringing the pH of the aqueous alkaline levo?oxacin
the residue is slurred With 1-5% aqueous tetrahydrofuran solution to neutral using dilute mineral acid,
preferably With 2-2.5% aqueous tetrahydrofuran.
11. An improved process as claimed in claim 1 Wherein xii. removing the precipitated particulate matter by ?ltra
the slurring With tetrahydrofuran is effected at 40-700 C. tion,
preferably at 50-600 C. more preferably at 58-600 C.
xiii. acidifying the resulting solution,
12. An improved process as claimed in claim 1 Wherein
the slurring With tetrahydrofuran is effected for a period in xiv. treating the acidi?ed solution With activated carbon at
the range of 30 minutes to 2 hours preferably 30 minutes to room temperature,
US 2007/0244318 A1 Oct. 18, 2007

xv. ?ltering the undissolved particulate matter by ?ltra 26. An improved process as claimed in claim 14 Wherein
tion, the pH is brought to 7.0-7.5 using dilute hydrochloric acid,
preferably 0.5N to 5N hydrochloric acid, more preferably
xvi. neutralizing the acidic solution, 1N hydrochloric acid.
xvii. ?ltering again to remove any particulate matter 27. An improved process as claimed in claim 14 Wherein
present and, the precipitated particulate matter is ?ltered and the pH is
xviii. extracting the resulting product With chlorinated adjusted to 3.0-6.0 preferably 4.0 to 5.5 more preferably
solvent and concentrating under vacuum using aqueous 4.5-5.0 using glacial acetic acid.
tetrahydrofuran or in admixture With other organic 28. An improved process as claimed in claim 14 Wherein
solvents to get highly pure levo?oxacin hemihydrate the aqueous acidic levo?oxacin solution is treated With
having single individual impurity not more than 0.1% activated carbon at room temperature and the clear solution
and free from particulate matter and from the other is ?ltered the pH to neutral preferably 7.0-7.5 using dilute
enantiomer (R-form). aqueous ammonia solution.
15. An improved process as claimed in claim 14 Wherein 29. An improved process as claimed in claim 14 Wherein
in step (i), Diethyl malonate is acylated using 2,3,4,5 the neutral aqueous solution is again ?ltered and extracted
tetra?uoro benZoyl chloride in the presence of magnesium, With chlorinated solvent preferably methylene chloride.
ethanol by making diethyl ethoxymagnesiomalonate. 30. An improved process as claimed in claim 14 Wherein
16. An improved process as claimed in claim 14 Wherein the extract is concentrated under vacuum (600-650 mm of
in step (ii) the conversion is effected using an aqueous Hg) below 400 C. and the resulting residue is concentrated
medium employing catalytic amount of para toluene sul after stirring With tetrahydrofuran or its mixture With another
fonic acid. organic solvent.
17. An improved process as claimed in claim 14 Wherein 31. An improved process as claimed in claim 14 Wherein
in the reagents used for the condensation in step (iii) is the residue is slurred With 1-5% aqueous tetrahydrofuran
triethyl orthoformate and acetic anhydride. preferably With 2-2.5% aqueous tetrahydrofuran.
18. An improved process as claimed in claim 14 Wherein 32. An improved process as claimed in claim 14 Wherein
the solvent used in step (iv) is methylene chloride. the slurring With tetrahydrofuran is effected at 40-700 C.
19. An improved process as claimed in claim 14 Wherein preferably at 50-600 C. more preferably at 58-600 C.
the cyclisation in step (v) is done in the presence of suitable 33. An improved process as claimed in claim 14 Wherein
base such as potassium carbonate and an aprotic solvent the slurring With tetrahydrofuran is effected for a period in
such as N,N-dimethyl formamide. the range of 30 minutes to 2 hours preferably 30 minutes to
20. An improved process as claimed in claim 14 Wherein 1 hour and then cooled to —5 to 150 C. preferably 0-5o C. and
the hydrolysis in step (vi) is carried out using acetic acid and stirred for 30 minutes to 2 hours preferably 1 hour to 1 hour
dilute hydrochloric acid. 30 minutes.
21. An improved process as claimed in claim 14 Wherein,
34. An improved process as claimed in claim 14 Wherein
the condensation in step (vii) is carried out either using
aprotic solvent or Without using solvent. the product is ?ltered and suck dried for 15 minutes to 1 hour
preferably 30 minutes to 45 minutes and the product Was
22. An improved process as claimed in claim 21 Wherein,
dried at 50-800 C. preferably at 70-750 C. for 2 to 7 hours
the aprotic solvent Which is used for condensation is pyri
dine. preferably 4-6 hours more preferably 5 to 5 hours 30
minutes.
23. An improved process as claimed in claim 14 Wherein
the ?ltration in steps (xv) and (xvii) may be effected using 35. An improved process for the preparation of Levof
a 0.2 micron ?lter. loxacin hemihydrate having single individual impurity not
24. An improved process as claimed in claim 14 Wherein more than 0.1% and free from particulate matter and from
the alkaline Levo?oxacin solution is stirred at a pH in the the other enantiomer (R-form) from Levo?oxacin technical.
range of 8.0 to 12.0, preferably 10.0-12.0, more preferably 36. An improved process for the preparation of Levof
11.0-11.5. loxacin hemihydrate having single individual impurity not
25. An improved process as claimed in claim 14 Wherein more than 0.1% and free from particulate matter and from
the alkali used in step (viii) is selected from sodium hydrox the other enantiomer (R-form) from 2,3,4,5-tetra?uoro ben
ide or potassium hydroxide, preferably sodium hydroxide Zoic acid.
and the concentration of the solution is 5 to 20% preferably
8-10%.