FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule!3)
1. TITLE OF THE INVENTION: "SYNTHESIS OF GEMIFLOXACIN
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008,
Maharashtra, India 3.PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Technical field of the Invention
The present invention relates to processes for synthesis of Gemifloxacin and pharmaceutically acceptable salts, solvates, polymorphs or hydrates thereof using novel intermediates. The present invention further relates to a besylate salt of Gemifloxacin and pharmaceutical compositions thereof. The present invention also relates to a process for preparation of a key intermediate (V) or its salt thereof via novel intermediate.
Background and prior art
EP688772 and its equivalent US5633262 disclosed novel antibacterial naphthyridine carboxylic acid derivatives and salts thereof; Gemifloxacin (I) is one of them. It is a broad spectrum antibacterial agent and possessing a highly improved pharmacokinetic property.
H2N----V
Y
H,CO—N
\^N N N
F^AACOoH O
(I)
The processes of preparation of Gemifloxacin as disclosed in US5633262/ US5869670 comprise reaction of l-cyclopropyl-6-fluoro-7-chloro-l,4-dihydro-4-oxy-naphthyridine-3-carboxylic acid with 4-aminomethyl-3-methoxyiminopyrrolidine / 4- N-protected amino methyl-3-methoxyimino-pyrrolidine in a solvent in presence of an acid acceptor to obtain Gemifloxacin.
WO2006134608 describes a method for preparation of Gemifloxacin comprising reacting l-cyclopropyl-6-fluoro-7-chloro-l, 4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid with boric acid to give borane intermediate that reacts further with 4-aminomethyl-3-methoxyiminopyrrolidine followed by hydrolysis to obtain Gemifloxacin.
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There are few patents related to various salts of Gemifloxacin and processes thereof. One of them is US5776944, directed to Gemifloxacin methanesulphonate salt and its hydrate.
Mesylate salts of the drug compounds contain impurities of methyl ester, ethyl ester and isopropyl ester of methane sulfonic acid. Some of these esters are toxic and have noxious effects on human body. Hence alternate salts, other than mesylate salt, are preferred.
With the advancement of technology there have been continuous efforts to develop simple, safe, easy scale-up and cost effective processes for synthesis of Gemifloxacin and its intermediates with good yields and purity. The present invention is an attempt to provide such a process using novel intermediates.
Objectives of the invention
It is an object of the present invention to provide processes for synthesis of Gemifloxacin and pharmaceutically acceptable salts thereof through novel intermediates.
It is another object of the present invention to provide a besylate salt of Gemifloxacin and pharmaceutical compositions thereof.
One more object of the present invention is to provide a process for preparation of a compound of formula (V) or its salt, used as a key intermediate in the synthesis of Gemifloxacin , in high yields via novel intermediates.
Brief Description of the drawings
Figure 1 depicts an X-ray diffraction spectrum of Gemifloxacin besylate. Figure 2 depicts an Infra-red absorption spectrum of Gemifloxacin besylate.
Detailed description of the invention
In one aspect the present invention describes simple, economical and easy scale-up processes for synthesis of Gemifloxacin of formula (I) and its pharmaceutically acceptable salt with substantial yield and purity.
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The reaction scheme 1 can be collectively depicted as follows:



Ck„NL ^N
COOH
B(OCOCH2CH3;

(A)
(C)

o o

(B)
CH3H2Cvo'B^^CH2CH3
o o
CH3H2C >:° CH2CH3 (E)
o o

NH,OH
NHBoc

HON=C N-^NN^
CH,H2C_0:B:O^CH2CH3

CH30NH,
NH2
MeO. V-i 'Y'
N<^N N
(D)

F II .
CH3H2CrS'B:^CH2CH3 (F)
o o
CH3X, where X= CI, Br, I
NHBoc H3CON<^N^NYN.
0R'° ^0'B0~
0 O
(G)
CH3H2Cro:B:o^CH2CH3
Hydrolysis

.

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In a preferred embodiment of the present invention, the method for preparation of Gemifloxacin comprises following steps:
i) reaction of propionic anhydride and boric acid to get a boron propionate complex that reacts further with l-cyclopropyl-6-fluoro-7-chloro-l, 4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid (A) to obtain l-cyclopropyl-6-fluoro-7-chloro-l, 4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid-03,04 bis (propyloxy-O)borate, a novel intermediate of formula (B).
ii) condensation of compound (B) with a compound of formula (V) or a salt thereof by optionally using a base in an organic solvent to form novel intermediate (C).
iii) further, methoxylation of compound (C) is carried out by :
a. using a suitable methoxylating agent such as methoxyamine hydrochloride
to get another novel intermediate compound of formula (D) or;
b. protecting with Di-t-butoxycarbonyl carbonate to get a novel intermediate
compound of formula (E) which is further reacted with hydroxylamine to
get a novel oxime intermediate of formula (F). The compound of formula
(F) is then reacted with methyl halide to get another novel intermediate
compound of formula (G).
iv) compound (D) or (G) is hydrolysed using an acid to obtain Gemifloxacin or its acid addition salt.
v) The acid addition salt formed in step iv) is further released to get free Gemifloxacin base and can be converted to its pharmaceutically acceptable salts.
Compound (V) or its salt is an important intermediate used in synthesis of Gemifloxacin. Hence obtaining compound (V) in high amounts and high purity in turn results in high yield and purity of Gemifloxacin. In another preferred aspect, the present invention
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provides a process for preparation of compound (V) or its salt in high yields with high purity.
The reaction scheme 2 is represented as follows:

N H
(II)

HO.

OH

NC O^)
V-\-o
N H
(HI)

Reduction


H2N

N H
(V)

O

Hydrolysis

The process of the present invention comprises addition of ethane-1, 2-diol across the carbonyl group of compound of formula (II). The reaction results in formation of a novel spiro intermediate of formula (III). Compound of formula (II) can be prepared by prior art method using glycine ethyl ester and acrylonitrile as the precursors.
Compound of formula (III) is subjected to reduction using a suitable hydrogenating or a reducing agent in presence of a suitable solvent to obtain another novel compound of formula (IV). After completion of the reaction, intermediate (IV) is hydrolyzed using a suitable acid. The reaction is allowed to complete at a suitable temperature to get a compound of formula (V) and it is isolated.
Gemifloxacin can be prepared by another route as depicted in Scheme 3 as follows:
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T
NH,

o
i
F
cLx> N_/"•
CH3H2C 0;B;0^CH2CH3 ^-WN~° 6^6 CH_H
K o o
(B) (D)
Hydrolysis

MeO

T

F' ^ V "COOH
0

(I)
The alternative route of synthesis of Gemifloxacin comprises coupling of compound (B) in presence of a suitable solvent with compound (VI) or a salt thereof to form compound (D). The solvent can be acetone, acetonitrile, hexane, heptane, cyclohexane, dichlorobenzene or mixtures thereof. Intermediate (D) is further hydrolyzed using an acid to obtain Gemifloxacin or its acid addition salt. The acid addition salt is further released to get free Gemifloxacin base and can be converted to its pharmaceutically acceptable salts. This is another feature of the present invention.
One more preferred embodiment of the present invention a besylate salt of Gemifloxacin. The besylate salt is found to have good flow characteristics and dissolution. Hence it is suitable for preparing a pharmaceutical formulation.
A feature of the present invention is Gemifloxacin besylate which is non-toxic and characterized by X-ray powder diffraction (XRPD) pattern shown in fig. 1. The characteristic XRPD spectrum of Gemifloxacin besylate characterized by having the 2theta + 0.2 at least as tabulated in the Table 1 below;
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Table 1

Gemifloxacin Besylate
Diffraction angles (2q°) Relative intensity (%I/Io)
4.880 84
9.300 75
9.820 34
10.280 52
10.800 47
13.140 53
13.980 19
16.600 25
17.180 80
18.000 86
19.080 50
19.660 31
19.760 32
20.700 46
21.060 100
21.380 62
22.420 46
23.060 29
23.240 31
24.080 65

Gemifloxacin Besylate
Diffraction angles (2q°) Relative intensity (%I/Io)
24.160 62
24.600 82
25.660 88
25.920 89
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26.520 40
27.160 29
28.260 55
33.780 24
34.640 25
36.860 26
38.060 26
39.640 31
Gemifloxacin Besylate of the present invention is characterized by Infra-red (IR) absorption spectrophotometry having characteristic peaks at 3449, 3055, 2932,1717, 1635,1463,1392, 1361,1332,1218,1189, 1121,1034, 995, 964, 903,871, 845,808, 728, 693, 618,567,496 cm'1 in the IR spectrum.
Gemifloxacin Besylate of the present invention is further characterized by melting point of 206-208 °C with decomposition.
A method for preparation of Gemifloxacin besylate can be a single pot process that involves direct conversion of Gemifloxacin to its besylate salt without isolating or purifying Gemifloxacin base. Gemifloxacin is dissolved in a suitable solvent such as C1-C6 alcohols or water or mixtures thereof, most preferably methanol and heated at a temperature of 40-55°C, preferably at 45-50°C. A solution of benzene sulfonic acid in a suitable solvent such as C1-C6 alcohols or water or mixtures thereof, most preferably methanol is added thereto gradually. The reaction mass is cooled to 25-30°C, further chilled to temperatures less than 10°C, most preferably 0-5°C and the resulting solid is filtered. The solid is washed with a suitable solvent such as Q-C6 alcohols or water or mixtures thereof, most particularly chilled methanol and dried under vacuum at a suitable temperature, preferably at 40-45°C to get Gemifloxacin besylate salt.
In one more aspect the present invention includes, within the scope of the present invention, pharmaceutical compositions comprising Gemifloxacin besylate that can be admixed with one or more pharmaceutical carriers. The pharmaceutical composition may be, but are non-limiting to, oral dosage form such as liquids or suspensions, emulsions or
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in solid dosage forms such as tablets, capsules, powders, granules or inhalation formulations such as aerosols or injectables or parenteral dosage forms, transdermal administrations and the like.
Dated this 1st day of October 2007

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