DESC:Field of the Invention:
The present invention relates to a crystalline form of 1-cyclopropyl-8-methyl-7-(5-
methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
compound of formula-1, which is represented by the following structural formula:
5
Formula-1
The present invention also relates to process for the preparation crystalline form of the
compound of formula-1 and processes for the preparation of compound of formula-1.
Background of the Invention:
1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-10 4-oxo-1,4-dihydro
quinoline-3-carboxylic acid is known as Ozenoxacin. It is a novel fluorine-free quinolone
antibacterial agent, developed by Ferrer Internation SA under the brand name of XEPITM as
1 % topical cream for the treatment of impetigo due to Staphylococcus aureus or Strepto
coccus pyogenes. The drug is approved in USA in December 2017 and September 2015 in
15 Japan.
The patent US6335447B1 first described 1-cyclopropyl-8-methyl-7-(5-methyl-6-
(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid as compound and
disclosed various processes for the preparation of ozenoxacin. The said patent herein after
referred to as US’447. The US’447 reported ozenoxacin melting point equal to or higher than
20 250°C.
The patent US8507684B2 discloses various acid addition salts of 1-cyclopropyl-8-
methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic
acid, such as citrate salt, hemifumarate salt, maleate salt, L-tartarate salt, mesylate salt,
hydrochloride salt, potassium salt and sodium salt and their processes.
25 There are various processes reported for the preparation of ozenoxacin, but not
disclosed any polymorphs or crystalline forms of ozenoxacin in the prior art.
3
Polymorphism, the occurrence of different crystal forms, is a property of some
molecules and molecular complexes. A single molecule may give rise to a variety of
polymorphs having distinct crystal structures and physical properties like melting point,
thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential
scanning calorimetry - "DSC"), X-ray diffraction pattern, infrared absorption 5 fingerprint, and
solid state NMR spectrum. One or more of these techniques may be used to distinguish
different polymorphic forms of a compound.
Discovering new salts and new polymorphic forms and solvates of a pharmaceutical
product can provide materials having desirable processing properties, such as ease of handling,
10 ease of processing, storage stability, ease of purification or as desirable intermediate crystal
forms that facilitate conversion to other polymorphic forms. New polymorphic forms and
solvates of a pharmaceutically useful compound or salts thereof can also provide an
opportunity to improve the performance characteristics of a pharmaceutical product. It
enlarges the repertoire of materials that a formulation scientist has available for formulation
15 optimization, for example by providing a product with different properties, e.g., better
processing or handling characteristics, improved dissolution profile, or improved shelf-life.
For at least these reasons, there is a need for additional salts and solid state forms of
ozenoxacin.
The present invention provides a crystalline form of 1-cyclopropyl-8-methyl-7-(5-
20 methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid of
formula-1 and processes for their preparation.
Brief Description:
The first aspect of the present invention is to provide a crystalline form of 1-
cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline
25 -3-carboxylic acid of formula-1, herein after designated as crystalline form-M.
The second aspect of the present invention is to provide a process for the preparation
of crystalline form-M of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-
4-oxo-1,4-dihydro quinoline-3-carboxylic acid.
The third aspect of the present invention is to provide process for the preparation of 1-
30 cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline
-3-carboxylic acid compound of formula-1.
4
Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of Crystalline Form-M of 1-cyclopropyl-8-methyl-7-
(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid of
formula-1 obtained according to example-16
Figure 2: Illustrates the PXRD pattern of Crystalline Form-M of 1-cyclopropyl-5 8-methyl-7-
(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid of
formula-1obtained according to example-12.
Figure 3: Illustrates IR spectrum of Crystalline Form-M of 1-cyclopropyl-8-methyl-7-(5-
methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid of
10 formula-1obtained according to example-12.
Figure 4: Illustrates the DSC thermogram of Crystalline Form-M of 1-cyclopropyl-8-methyl-
7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid of
formula-1obtained according to example-12.
Detailed Description:
15 As used herein the term “suitable solvent” used in the present invention refers to
“hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane,
cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as
dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene
glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,
20 diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether,
1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate,
isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as
dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), Nmethylpyrrolidone
(NMP) and the like; “chloro solvents” such as dichloromethane,
25 dichloroethane, chloroform, carbontetrachloride and the like; “ketone solvents” such as
acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as
acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol,
ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-
fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol,
30 diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol
5
monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar
solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or organic
base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium
carbonate, lithium carbonate and the like; “alkali metal bicarbonates” 5 such as sodium
bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium
hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such
as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium
tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides
10 such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides
such as sodium amide, potassium amide, lithium amide and the like; and organic bases like
dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine,
triethylamine, pyridine, 4-dimethylamino pyridine (DMAP), N-methyl morpholine (NMM),
2,6-lutidine, lithium diisopropylamide; organo silicon bases such as lithium
15 hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium
hexamethyldisilazide (KHMDS) or mixtures thereof.
The term “acid” used in the present invention refers to inorganic acids selected from
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc; organic
acids such as acetic acid, maleic acid, malic acid, tartaric acid, oxalic acid, trifluoroacetic acid,
20 methane sulfonic acid, p-toluene sulfonic acid etc.; Lewis acids and like.
The first aspect of the present invention provides Crystalline Form-M of 1-cyclo
propyl-8-methyl-7-(5-methyl- 6-(methylamino) pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-
carboxylic acid of formula-1. The crystalline form-M of the present invention is characterized
25 by its powder X-Ray diffraction pattern having peaks at about 7.28, 9.33, 11.27, 13.97, 15.52,
16.8, 19.19, 22.59, 23.84, 24.94, 26 and 28.29 ± 0.2° 2?.
The Crystalline Form-M of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)
pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid of formula-1 is further
characterized by its powder X-Ray diffraction pattern substantially in accordance with figure-1.
30 The Crystalline Form-M of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)
pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid of formula-1 is further
6
characterized by its IR spectrum substantially in accordance with figure-3.
The Crystalline Form-M of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)
pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid of formula-1 is further
characterized by its DSC thermogram substantially in accordance with figure-4.
The second aspect of the present invention is to provide a process 5 for the preparation
of the Crystalline Form-M of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-
yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid of formula-1, comprising of:
a) Stirring the compound of formula-1 in a suitable solvent,
b) adding a suitable acid to the solution of step-a) and stirring at suitable temperature,
10 isolating the compound,
c) adjusting the pH of the solution obtained in step-b) with a suitable base,
d) filtering the solid obtained in step-c) provides the crystalline form-M of 1-cyclopropyl-8-
methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxy
licacid compound of formula-1.
15 Wherein in step-a) the suitable solvent is selected from polar protic, polar aprotic, alcohol,
ether, ketone, chloro, water and mixture thereof. Step-b) suitable acid is citricacid, tataricacid,
methane sulphonic acid, para toluenesulfonicacid, maleicacid, fumaricacid, camphorsulfonic
acid, hydrobromicacid, aceticacid, trifluoroaceticacid; suitable temperature is 0°C to 100°C,
preferably 20-85°C; in step c) the suitable base is potassium hydroxide, sodium hydroxide,
20 lithium hydroxide, bariumhydroxide, aq.ammonia, triethylamine, diisopropylamine, diiso
propylethylamine ; in Step-c) suitable pH range is 5.0 to 7.0;
The other preferred embodiment of the present invention is to provide a process for
the preparation of the Crystalline Form-M of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl
amino)pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid of formula-1, comprising
25 of:
a) stirring the compound of formula-1 in isopropanol and water,
b) adding methane sulphonic acid to the solution of step-a)and stirring at 40-45°C,
c) adjusting the pH of the solution obtained in step-b) with aq. sodium hydroxide solution,
d) filtering the solid obtained in step-c) provides the crystalline form-M of 1-cyclopropyl-8-
30 methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic
acid compound of formula-1.
7
The other embodiment of the present invention is to provide a process for the
preparation of the Crystalline Form-M of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl
amino) pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid of formula-1, comprising
of:
a) suspending the compound of formula-5 1 in an organic solvent,
b) stirring the compound obtained in step-a) in base solution at suitable temperature,
c) isolating the compound obtained in step-b), purifying in suitable solvent,
d) suspending the compound obtained in step-c) in suitable solvent,
e) adjusting the pH of the solution obtained in step-d) with suitable base, acid at suitable
10 temperature isolating the compound,
f) optionally purifying the compound obtained in step-e) in suitable solvent to provide the
crystalline form-M of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-
oxo-1,4-dihydro quinoline-3-carboxylic acid compound of formula-1.
Wherein in step-a) the suitable solvent is selected from polar aprotic, alcohol, ether, ketone,
15 chloro, water and mixture thereof. Step-b) suitable base, solvent is selected from sodium
hydroxide, potassium hydroxide, lithium hydroxide in alcoholic solution, sodium methoxide,
sodium ethoxide, potassium methoxide, potassium ethoxide; preferably: alcoholic base,
potassium hydroxide in ethanol; suitable temperature is 0°C to 100°C, preferably 20-85°C; in
step c) the suitable solvent is alcohol, ketone, chloro, ester; step-d) suitable solvent is water,
20 alcohol, ketone, chloro and mixture thereof; step-e) suitable base is selected from potassium
hydroxide, sodium hydroxide; suitable acid is selected from hydrochloric acid; citric acid,
acetic acid; preferably hydrochloric acid; pH range is 11-12 & 4-6; step-f) suitable solvent is
selected from alcohol, chloro, ester, ketone, DMF, acetonitrile, polar aprotic solvents, water
and mixture thereof;
25 The other embodiment of the present invention is to provide a process for the
preparation of the Crystalline Form-M of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl
amino) pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid of formula-1, comprising
of:
a) suspending the compound of formula-1 in tetrahydrofuran,
30 b) stirring the compound obtained in step-a) in ethanolic KOH, stirring at 25-35°C,
c) isolating the compound obtained in step-b) and purifying in ethanol,
8
d) suspending the compound obtained in step-c) in water,
e) adjusting the pH of the solution obtained in step-d) with potassium hydroxide and
hydrochloric acid at suitable temperature and isolating the compound,
f)purifying the compound obtained in step-e) in water to provide the crystalline form-M of 1-
cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-5 1,4-dihydro quinoline
-3 -carboxylic acid compound of formula-1.
The third aspect of the present invention is to provide processes for the preparation of
1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydro
quinoline -3- carboxylic acid compound of formula-1, comprising of ;
10
Formula-1
a) reacting the compound of formula-7
15 Formula-7
with compound of formula-8
Formula-8
in presence of a palladium catalyst, base in a suitable solvent to produce compound of
20 formula-9
9
Formula-9
b) reacting the compound obtained in step-a) using a suitable reagent to get the compound of
formula-1,
c) suspending the compound obtained in step-b) 5 in an organic solvent,
d) stirring the compound obtained in step-c) in base solution at suitable temperature,
e) isolating the compound obtained in step-d) purifying in suitable solvent and isolating,
f) suspending the compound obtained in step-e) in suitable solvent,
g) adjusting the pH of the solution obtained in step-f) with suitable base, acid at suitable
10 temperature and isolating the compound of formula-1,
h) optionally purifying the compound obtained in step-g or b) in suitable solvent to provide
the crystalline form-M of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-
4-oxo-1,4-dihydro quinoline-3-carboxylic acid compound of formula-1.
Wherein the step-a) catalyst is selected from tetrakis(triphenylphosphine)palladium(0),
15 palladium (II) acetate, tris(dibenzylideneacetone)dipalladium(0), Pd(dppf)Cl2, Dichlorobis(tri
cyclohexylphosphine)palladium(II); preferably Dichlorobis (tricyclohexyl phosphine)
palladium (II); ligand is selected from xantphos, X-phos, BINAP, bis(diphenyl phosphino)
ferrocene, triphenylphosphine; Sphos, bis(diphenylphosphino)methane; base is selected from
inorganic base, organic base; solvent is selected form toluene, benzene, dioxane, acetonitrile,
20 tetrahydrofuran, dimethylformamide, ester, water, alcohol and mixture thereof; step-b) suitable
reagent is selected from Con.Hydrochloric acid, methane sulphonic acid, sulphuric acid,
hydrobromic acid; preferably Con.Hydrochloric acid, methane sulphonic acid; suitable solvent
is alcohol, ketone, ester, acetonitrile, ether, chloro, water and mixture thereof; step-c) the
suitable solvent is selected from polar aprotic, alcohol, ether, ketone, chloro, water and
25 mixture thereof; in step-d) suitable base, solvent is selected from sodium hydroxide,
potassium hydroxide, lithium hydroxide in an alcoholic solution, sodium methoxide, sodium
ethoxide, potassium methoxide, potassium ethoxide; preferebly: potassium hydroxide in
ethanol; suitable temperature is 0°C to 100°C, preferably 20-85°C; in step e) the suitable
10
solvent is alcohol, ketone, ester; in step-f) suitable solvent is water, alcohol, chloro, acetone
and mixture thereof; in step-g) suitable base is selected from potassium hydroxide, sodium
hydroxide; suitable acid is selected hydrochloric acid; citric acid, acetic acid; preferably
hydrochloric acid; pH range is 11-12 & 4-6; step-h) suitable solvent is selected from alcohol,
ester, ketone, ester, polar aprotic, nitrile, polar protic, chloro, water 5 and mixture thereof;
Other aspect of the present invention is to provide process for the preparation of 1-
cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline
-3- carboxylic acid compound of formula-1,comprising of ;
a)reacting the compound of formula-7a
10
Formula-7a
with compound of formula-8a
Formula-8a
15 in presence of bis(tricyclohexylphosphine palladium dichloride), sodium bicarbonate in
toluene, water to produce compound of formula-9a
Formula-9a
b)reacting the compound obtained in step-a) with hydrochloric acid to get the compound of
20 formula-1,
c)suspending the compound obtained in step-b) in tetrahydrofuran,
d)stirring the compound obtained in step-c) in ethanolic KOH, at 25-35°C,
e)isolating the compound obtained in step-d) and purifying in ethanol, isolating,
11
f) suspending the compound obtained in step-e) in water,
g)adjusting the pH of the solution obtained in step-f) with potassium hydroxide, hydrochloric
acid at suitable temperature and isolating the compound of ofrmula-1,
h) purifying the compound obtained in step-g) in water to provide the crystalline form-M of
1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-5 4-oxo-1,4-di hydro
quinoline-3-carboxylic acid compound of formula-1.
The process for preparation of 5-methyl-6(N-methylbenzamido)pyridin-3-ylboronic
acid compound of formula-8a is known in the art. 2-amino-5-bromo-3-methylpyridine is
10 reacted with formaline solution in presence of sodium hydroxide in methanol to get N-(5-
bromo-3-methyl-2-pyridyl)-N-(methoxymethyl)amine. The obtained compound is reduced
with sodium borohydride in tetrahydrofuran to get N-(5-bromo-3-methyl-2-pyridinyl)-Nmethylamine,
in situ the obtained compound reacting with benzoyl chloride in presence of tri
ethylamine to get N-(5-bromo-3-methylpyridin-2-yl)-N-methylbenzamide. The obtained
15 compound is reacted with triisopropyl borate in presence n-butyl lithium in tetrahydrofuran to
get the 5-methyl-6(N-methylbenzamido)pyridin-3-ylboronic acid.
The process for preparation of ethyl-7-chloro-1-cyclopropyl-8-methyl-4-oxo-1,4-
dihydroquinoline-3-carboxylate compound of formula-7a is known in the art. Reacting 2,4-
dichloro-3-methylbenzoic acid with ethyl-3-(N,N-dimethylamino)acrylate in presence thionyl
20 chloride in toluene, in situ the obtained compound reacting with cyclopropyl amine in toluene
to get ethyl-3-(cyclopropyl) -2-(2,4-dichloro-3-methylbenzoyl) acrylate. The obtained
compound is reacted with potassium carbonate in DMSO to get the ethyl-7-chloro-1-cyclo
propyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate.
The other process for preparation of ethyl-7-chloro-1-cyclopropyl-8-methyl-4-oxo-1,4-
25 dihydroquinoline-3-carboxylate compound of formula-7a is by reacting 2,4-dichloro-3-methyl
benzonitrile with potassium ethylmalonate in presence of zinc chloride in 1,2 dichloroethane
to obtain ethyl 3-(2,4-dichloro-3-methylphenyl)-3-oxopropanoate. The obtained compound is
reacted with dimethylformamide dimethylacetal (DMF-DMA) to obtain ethyl-2-(2,4-dichloro
-3-methylbenzoyl)-3-(dimethylamino)acrylate. The obtained compound is reacted with cyclo
30 propylamine in toluene to get ethyl-3-(cyclopropyl)-2-(2,4-dichloro-3-methyl benzoyl)
acrylate. The obtained compound is cyclized with potassium carbonate in DMSO to get ethyl12
7-chloro-1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate.
Schematic representation of the process for the preparation of oxenoxacin :
Scheme-1
5
Wherein X is Cl, Br; Protecting group (PG): Boc, Acetyl, trifluoroacetyl, F-moc, benzoyl,
benzyl, t-butyloxycarbonyl;
10
13
Scheme-2:
The particle size of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-
yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid compound of formula-5 1 produced by the
present invention can be reduced by micronization or milling to get the desired particle size to
achieve desired solubility profile. Techniques that may be used for particle size reduction
include, but not limited to ball, roller and hammer mills, and jet mills. Milling or
micronization may be performed before drying, or after the completion of drying of the
10 product. Particle size of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-
4-oxo-1,4-dihydroquinoline-3-carboxylicacid produced according to the present process is
14
D90 <100 microns, Preferably D90 <50 microns, more preferably D90 <20 microns.
PXRD analysis of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-
4-oxo-1,4-dihydroquinoline-3-carboxylicacid was carried out using BRUKER D8
ADVANCED/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 5 1.5406 A° and
continuous scan speed of 0.03°/min. IR spectra were recorded on a Perkin-Elmer FT-IR
spectrometer.
The process described in the present invention was demonstrated in examples
illustrated below. These examples are provided as illustration only and therefore should not be
10 construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of N-(5-bromo-3-methyl-2-pyridyl)-N-(methoxymethyl)amine
A round bottom flask was charged with 40 % formaldehyde solution (60 ml), methanol (300
ml) and sodium hydroxide (21.4 gr) and stirred for 30-45 min at 25-35°C. 2-amino-5-bromo-
15 3-methylpyridine (100 gr) was charged to the above solution and stirred for 4-5 hr. The
reaction mixture was quenched with water (600 ml) stirred for 2 hr. The obtained solid was
filtered, again suspended in water (600 ml) and stirred for 30 min. The obtained solid was
filtered and washed with water (100 ml) and dried to get the title compound.
Yield: 115.5 gr
20 Example-2: Preparation of N-(5-bromo-3-methylpyridin-2-yl)-N-methylbenzamide
A round bottom flask was charged with N-(5-bromo-3-methyl-2-pyridyl)-N-(methoxy methyl)
amine (100 gr), tetrahydrofuran (250 ml) and stirred for 10 min. The reaction mixture cooled
25-35°C, charged sodium borohydride (4.9 gr) and stirred for 1 hr. After completion of the
reaction, the reaction mixture was charged with triethylamine (87 gr) and benzoyl chloride (91.
25 gr) was added slowly and refluxed for 5 hr. The reaction mixture was cooled to 25-30°C,
quenched with water (750 ml) and further cooled to 0-10°C and stirred for 2 hr. The
precipitated compound was filtered, washed with water (100 ml). The wet compound was
charged in RBF with n-heptane (400 ml), heated to 60-70°C and for 1 hr. The reaction mixture
was cooled to 0-10°C and stirred for 1 hr, the obtained solid was filtered and washed with n30
heptane (100 ml) to get the title compound.
Yield: 132 gr
15
Example-3: Preparation of compound of formula-8a
A round bottom flask was charged with N-(5-bromo-3-methylpyridin-2-yl)-N-methyl
benzamide (150 gr), tetrahydrofuran (1500 ml) and triisopropyl borate (111 gr) stirred for 10
min under nitrogen atmosphere. The reaction mixture was cooled to -70°C to -75°C, charged
n-Butyl lithium solution (255 ml, 2.5 M) cautiously for 2hr, and stirred 5 at same temperature
for 2 hr. The reaction mixture was quenched with water (1.5 lit) slowly at below -20°C,
gradually raised the temperature to 25-35°C and stirred for 1 hr. The both layers were
separated, the aqueous layer was washed with ethyl acetate (3x300 ml). The aqueous layer pH
was adjusted to 4.25 with hydrochloric acid (90 ml), the precipitated compound was filtered
10 and washed with water (150 ml) and dried to get the title compound.
Yield: 95 gr
Example-4: Preparation of compound of formula-6a
A round bottom flask was charged with thionylchloride (348 gr), 2,4-dichloro-3-methyl
benzoic acid (100 gr) and N, N-dimethyl formamide (2 ml) and heated to relux and stirred for
15 4 hr. The reaction mixture was distilled off, co-distilled with toluene (100 ml). The reaction
mixture was charged with toluene (500 ml), triethylamine (98.5 gr) and ethyl-3-(N,N-dimethyl
amino)acrylate (95.05 gr) heated to 100-115°C stirred for 3 hr. The reaction mixture was
cooled to 25-35°C, charged with cyclo propylamine (30.6gm) stirred for 4 hr. The precipitated
compound was filtered, washed with toluene (100 ml). The obtained compound was charged
20 with water (500 ml), stirred for 2 hr. The obtained solid was filtered and washed with water
(100 ml), dried to get the title compound.
Yield: 116.90 gr
Example-5: Preparation of compound of formula-7a
A round bottom flask was charged with compound of formula-6a (100 gr), DMSO (300 ml)
25 and potassium carbonate (80 gr), heated to 95-105°C and stirred for 4 hr. The reaction mixture
was cooled to 25-30°C, diluted with hydrochloric acid (100 ml) and water (800 ml) stirred for
1.5 hr. The precipitated solid was filtered and washed with water (100 ml). The wet compound
was stirred in isopropanol (200 ml) for 1 hr, filtered the obtained solid and washed with
isopropanol (100 ml) dried to get the title compound.
30 Yield: 88 gr.
16
Example-6: Preparation of compound of formula-7a
A round bottom flask was charged with compound of formula-6a (100 gr), DMSO (300 ml)
and potassium carbonate (120.9 gr), heated to 80-90°C and stirred for 4 hr. The reaction
mixture was cooled to 25-30°C, diluted with water (800 ml) stirred for 1.5 hr. The precipitated
solid was filtered and washed with water (100 ml), dried to 5 get the title compound.
Yield: 88 gr
Example-7: Preparation of compound of formula-9a
A round bottom flask was charged with compound of formula-7a (50 gr), toluene (150 ml),
compound of formula-8a (66 gr), sodium bicarbonate (33 gr) and water (100 ml) stirred for 1
10 hr under nitrogen atmosphere. Bis(triphenylphosphine)palladium dichloride (0.6 gr) was
added to the above reaction mixture at 25-35°C, stirred for 12 hr at 80-90°C. The reaction
mixture was cooled to 25-35°C charged with water (250 ml), further cooled to 0-10°C and
stirred for 4 hr. The obtained compound was filtered and washed with water (100 ml) to get
the wet compound. The obtained compound was charged in RBF with ethyl acetate (250 ml),
15 heated to 75-85°C stirred for 2 hr and cooled the solution to 25-35° stirred for 2 hr. The
obtained solid was filtered and washed with ethyl acetate (50 ml). The same purification
process was repeated to get pure title compound.
Yield: 55 gr.
Example-8: Preparation of compound of formula-1
20 A round bottom flask was charged with compound of formula-9a (50 gr), hydrochloric acid
(500 ml) and heated to 90-100°C stirred for 6 hr. The reaction mixture was cooled to 25-35°C,
washed with dichloromethane (5x100 ml) and separated both layers. The aqueous layer was
diluted with ethanol (250 ml) and the solution pH was adjusted to 11.2 with sodium hydroxide
solution (180 gr in 350 ml), stirred for 4 hr at 25-35°C. The obtained solution pH was adjusted
25 to 5.25 with dil.HCl and stirred for 45 min. The obtained solid was filtered and washed with
water (50 ml). The obtained compound was suspended with water (500 ml) and stirred for 45
min, filtered the obtained solid and dried to get the title compound.
Yield: 35.9 gr.
Purity by HPLC:NLT 96 %
30
17
Example-9: Preparation of compound of formula-1
A round bottom flask was charged with compound of formula-9a (50 gr), methane sulfonic
acid (77.5 gr) and heated to 90-100°C stirred for 6 hr. The reaction mixture was cooled to 25-
35°C, washed with dichloromethane (5x100 ml) and separated both layers. The aqueous layer
was diluted with ethanol (250 ml) and the solution pH was adjusted 5 to 11.5 with sodium
hydroxide solution (180 gr in 350 ml), stirred for 4 hr at 25-35°C. The obtained solution
reaction mass pH was adjusted to 5.25 with dil.hydrochloric acid and stirred for 45 min. The
obtained solid was filtered and washed with water (50 ml). The obtained compound was
charged with water (500 ml) and stirred for 45 min, filtered the obtained solid and dried to get
10 the title compound.
Yield: 35 gr.
Example-10: Preparation of compound of formula-1
A round bottom flask was charged with compound of formula-7a (50 gr), toluene (150 ml),
compound of formula-8a (66 gr), sodium bicarbonate (33 gr) and water (100 ml) stirred for 1
15 hr under nitrogen atmosphere. Bis(triphenylphosphine)palladiumdichloride (0.3 gr) was added
to the above reaction mixture at 25-35°C, stirred for 12 hr at 80-90°C. The reaction mixture
was cooled to 25-35°C quenched with water (250 ml), further cooled to 0-10°C and stirred for
4 hr. The obtained compound was filtered and washed with water (100 ml) to get the wet
compound of formula-9a. The obtained compound was charged in RBF with dil.hydrochloric
20 acid (750 ml), washed with dichloromethane (3x150 ml) and separated both layers. The
aqueous layer was taken, heated to 90-100°C stirred for 6 hr. The reaction mixture was cooled
to 25-35°C, washed with dichloromethane (5x150 ml) and separated the both layers. The
aqueous layer was diluted with ethanol (375 ml) and the solution pH was adjusted to 11.3 with
sodium hydroxide solution (300 gr in 600 ml), stirred for 6 hr at 25-35°C. The reaction mass
25 pH was adjusted to 5.2 with dil.HCl and stirred for 45 min. The obtained solid was filtered and
washed with water (100 ml). The obtained wet compound was again slurred in water (750 ml)
and stirred for 45 min, filtered the obtained solid and dried to get the title compound.
Yield: 37 gr.
Example-11: Preparation of compound of formula-1
30 A round bottom flask was charged with compound of formula-7a (50 gr), toluene (150 ml),
compound of formula-8a (66 gr), sodium bicarbonate (33 gr) and water (100 ml) stirred for 1
18
hr under nitrogen atmosphere. Bis(triphenylphosphine)palladium dichloride (0.3 gr) was
added to the above reaction mixture at 25-35°C, stirred for 12 hr at 80-90°C. The reaction
mixture was cooled to 25-35°C charged with water (250 ml), further cooled to 0-10°C and
stirred for 4 hr. The obtained compound was filtered and washed with water (100 ml) to get
the wet compound. The obtained compound was charged in 5 RBF with water (550 ml),
methanesufonicacid (116.3 gr) and washed with dichloromethane (3x150 ml), separated the
both layers. The aqueous layer was heated to 90-100°C stirred for 6 hr. The reaction mixture
was cooled to 25-35°C, washed with dichloromethane (5x150 ml) and separated the both
layers. The aqueous layer was diluted with ethanol (375 ml) and the solution pH was adjusted
10 to 11.8 with sodium hydroxide solution (300 gr in 600 ml), stirred for 6 hr at 25-35°C. The
reaction mass pH was adjusted to 5.3 with dil.hydrochloric acid and stirred for 45 min. The
obtained solid was filtered and washed with water (100 ml). The obtained compound was
charged with water (750 ml) and stirred for 45 min, filtered the obtained solid and dried to get
the title compound.
15 Yield: 55 gr.
Example-12: Preparation of crystalline form-M of compound of formula-1
A round bottom flask was charged with compound of formula-1 (50 gr), tetrahydrofuran (250
ml), solution of KOH in ethanol (7.7 gr in 250 ml) and stirred for 2 hr at 25-35°C. Filtered the
obtained compound and washed with ethanol (50 ml). The obtained potassium salt of
20 compound of formula was charged in RBF with ethanol (375 ml), heated to 40-50°C and
stirred for 30 min. The reaction mixture was cooled to 25-35°C stirred for 2 hr and filtered the
obtained solid, washed with ethanol (50 ml). The same purification process was repeated twice
in ethanol and filtered. The obtained compound was charged in RBF with water (900 ml)
adjusted the pH to 11.6 with potassium hydroxide solution (10 ml) and stirred for 2 hr. The
25 reaction mass was filtered through hyflow bed to remove solid particles and washed with
water (900 ml). The filtrate layer pH was adjusted to 5.2 with hydrochloric acid (15 ml) stirred
for 1 hr. Filtered the obtained compound and washed with water (100 ml) to get wet
compound. The obtained wet compound was charged in RBF with water (1 lit), heated to 70-
80°C and stirred for 1 hr. The reaction mixture was cooled to 50-60°C stirred for 45 min and
30 filtered the obtained compound and washed with water (100 ml). The same purification
process was repeated with water and dried the obtained compound to get the tilted compound.
19
Yield: 32 gr. The PXRD of the obtained compound is depicted in figure-2
Purity by HPLC: 99.78%
PSD: D(90) =14 microns; D(50) = 6 microns; D(10)= 2 microns;
Example-13: Purification of compound of formula-1
A round bottom flask was charged with compound of formula-1 (10 gr), 5 dimethyl formamide
(100 ml) and stirred for 4 hr at 110-120°C. The reaction mixture was cooled to 25-35°C and
stirred for 30 min. The precipitated solid was filtered and washed with DMF (25 ml) to get the
title compound-1.
Yield: 6.0 gm.
10 Example-14: Purification of compound of formula-1
A round bottom flask was charged with compound of formula-1 (10 gr), N-methylpyrrolidone
(100 ml) and stirred for 4 hr at 70-80°C. The reaction mixture was cooled to 25-35°C stirred
for 30 min. The precipitated solid was filtered and washed with NMP (50 ml) to get the title
compound.
15 Yield: 5.4 gm.
Example-15: Purification of compound of formula-1
A round bottom flask was charged with compound of formula-1 (10 gr), DMSO (100 ml) and
stirred for 4 hr at 70-80°C. The reaction mixture was cooled to 25-35°C stirred for 30 min.
The precipitated solid was filtered and washed with DMSO (50 ml) to get the title compound.
20 Yield: 6. 4 gm.
Example-16: Preparation of crystalline form-M of compound of formula-1
A round bottom flask was charged with the compound of formula-1 (12 gm), water (12 ml)
and isopropanol (60 ml). The obtained suspension was stirred at 40-45°C for 30 min.
methanesulphonicacid (6.5 gm) was added to the above suspension and stirred at same
25 temperature for 30 min. The obtained solution was filtered through hyflow bed and washed
with isopropanol (12 ml). The obtained solution was cooled to 25-30°C and stirred for 2 hrs,
filtered the resulting solid. The obtained solid was charged in water (12 ml) and pH of the
solution was adjusted to 5.7 with 10 % sodium hydroxide solution (6 ml) and stirred for 30
min. The obtained solid was filtered and washed with water (25 ml) dried to get the title
30 compound. The PXRD of the obtained compound is depicted in figure-1.
Yield: 5.5 gm;
20
Example-17: Preparation of crystalline form-M of compound of formula-1
A round bottom flask was charged with the compound of formula-1 (12 gm), water (10 gm)
and isopropanol (50 ml). The obtained suspension was stirred at 40-45°C for 30 min.
Hydrobromic acid (6.5 ml) was added to the above solution and stirred at same temperature
for 30 min. The obtained solution was filtered through hyflow 5 bed and washed with
isopropanol (12 ml). The obtained filtrate was cooled to 25-30°C and stirred for 2 hrs, filtered
the resulting solid. The obtained solid was charged in water (12 ml) and pH of the solution was
adjusted to 5.6 with 10 % sodium hydroxide solution (6 ml) and stirred for 30 min. The
obtained solid was filtered and washed with water (20 ml) dried to get the title compound.
10 Yield: 6.2 gm;
Example-18: Preparation of crystalline form-M of compound of formula-1.
A round bottom flask was charged with compound of formula-1 (25 gr), tetrahydrofuran (125
ml), solution of KOH in ethanol (4.2 gr in 125 ml) and stirred for 2 hr at 25-35°C. Filtered the
obtained compound and washed with ethanol (25 ml). The obtained potassium salt compound
15 was charged in RBF with ethanol (190 ml), heated to 40-50°C and stirred for 30 min. The
reaction mixture was cooled to 25-35°C stirred for 2 hr and filtered the obtained solid, washed
with ethanol (25 ml). The same purification process was repeated twice in ethanol and filtered.
The obtained compound was charged in RBF with water (450 ml) adjusted the pH to 11.4 with
potassium hydroxide solution (5 ml) and stirred for 2 hr. The reaction mass was filtered
20 through hyflow bed to remove solid particles and washed with water (450 ml). The filtrate
layer pH was adjusted to 5.3 with hydrochloric acid (8 ml) stirred for 1 hr. Filtered the obtained
compound and washed with water (50 ml) to get wet compound. The obtained compound was
suspended in DMF (250 ml) stirred for 4-5 hr. The reaction mixture was cooled to 25-35°C
stirred for 30 min. The obtained solid was filtered and washed with DMF to get the title
25 compound.
Yield: 17.5 gr; The PXRD is matching with figure-2. ,CLAIMS:1. Crystalline Form-M of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-
4-oxo-1,4-dihydro quinoline -3-carboxylic acid of formula-1.
is characterized by its powder X-Ray diffraction pattern having peaks 5 at about 7.28, 9.33,
11.27, 13.97, 15.52, 16.8, 19.19, 22.59, 23.84, 24.94, 26 and 28.29 ± 0.2° 2?; Further
characterized by its PXRD pattern as depicted in figure-1.
2. A process for the preparation of the Crystalline Form-M of 1-cyclopropyl-8-methyl-7-(5-
methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid of
10 formula-1, comprising of:
a) Stirring the compound of formula-1 in a suitable solvent,
b) adding a suitable acid to the solution obtained in step-a) and stirring at suitable
temperature,
c) adjusting the pH of the solution obtained in step-b) with a suitable base, isolating the
15 compound,
d) filtering the obtained solid in step-c) provides the crystalline form-M of 1-cyclopropyl-8-
methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid compound of formula-1.
wherein in step-a) the suitable solvent is selected from polar protic, polar aprotic, alcohol,
20 ether, ketone, chloro, water and mixture thereof. Step-b) suitable acid is selected form organic
acid, inorganic acid; suitable temperature is 0°C to 100°C, preferably 20-85°C; in step c) the
suitable base is organic base, inorganic base; in Step-c) suitable pH range is between 5.0 to 7.0;
3. A process for the preparation of the Crystalline Form-M of 1-cyclopropyl-8-methyl-7-(5-
methyl-6-(methyl amino)pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid of
25 formula-1, comprising of:
a) stirring the compound of formula-1 in isopropanol and water,
b) adding methane sulphonic acid to the solution obtained in step-a) stirring at 40-45°C,
isolating the compound,
22
c) adjusting the pH of the solution obtained in step-b) with aq. sodium hydroxide solution,
d) filtering the obtained solid in step-c) provides the crystalline form-M of 1-cyclopropyl-8-
methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic
acid compound of formula-1.
4. A process for the preparation of the Crystalline Form-M of 1-cyclopropyl-5 8-methyl-7-(5-
methyl-6-(methyl amino)pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid of
formula-1, comprising of:
a) suspending the compound of formula-1 in an organic solvent,
b) stirring the compound obtained in step-a) in base solution at suitable temperature,
10 c) isolating the compound obtained in step-b) purifying in a suitable solvent,
d) suspending the compound obtained in step-c) in a suitable solvent,
e) adjusting the pH of the solution obtained in step-d) with a suitable base and acid at a
suitable temperature isolating the compound,
f) optionally purifying the compound obtained in step-e) in suitable solvent to provide the
15 crystalline form-M of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-
oxo-1,4-dihydro quinoline-3-carboxylic acid compound of formula-1.
wherein the suitable solvent is selected from polar protic, polar aprotic, alcohol, ether, ketone,
ester, nitrile, chloro, water and mixture thereof; step-b) suitable base is alcoholic base;
preferably: potassium hydroxide in ethanol; suitable temperature is 0°C to 100°C, preferably
20 20-85°C; step-e) suitable base is selected from inorganic base; suitable acid is selected
hydrochloric acid; pH range is 11-12 and 4-6;
5. A preparation of the Crystalline Form-M of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl
amino)pyridin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid of formula-1, comprising
of:
25 a) suspending the compound of formula-1 in tetrahydrofuran,
b) stirring the compound obtained in step-a) in ethanolic KOH, stirring at 25-35°C,
c) isolating the compound obtained in step-b) and purifying in ethanol,
d) suspending the compound obtained in step-c) in water,
e) adjusting the pH of the solution obtained in step-d) with potassium hydroxide, hydro
30 chloric acid at suitable temperature and isolating the compound,
f) purifying the compound obtained in step-e) in water to provides the crystalline Form-M
23
of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl amino)pyridin-3-yl)-4-oxo-1,4-di hydro
quinoline-3-carboxylic acid compound of formula-1.
6. A process for the preparation of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl amino)
pyridin-3-yl)-4-oxo-1,4-dihydroquinoline -3- carboxylic acid compound of formula-1,
5 comprising of ;
Formula-1
a)reacting the compound of formula-7
10
Formula-7
with compound of formula-8
Formula-8
15 in presence of palladium catalyst, base in suitable solvent to produce compound of formula-9
Formula-9
b)reacting the compound obtained in step-a) using suitable reagent to get the compound of
formula-1,
20 c)suspending the compound of formula-1 in an organic solvent,
24
d)stirring the compound obtained in step-c) in base solution at suitable temperature,
e)isolating the compound obtained in step-d) purifying in a suitable solvent,
f)suspending the compound obtained in step-e) in a suitable solvent,
g)adjusting the pH of the solution obtained in step-f) with a suitable base, acid at a suitable
temperature and isolating the 5 compound of formula-1,
h)optionally purifying the compound obtained in step-g or b) in suitable solvent to provide the
crystalline form-M of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-
oxo-1,4-dihydro quinoline-3-carboxylic acid compound of formula-1.
7. A process for the preparation compound of formula-1 according to claim 6 wherein the
10 suitable solvent is selected form toluene, benzene, polar aprotic solvent, polar protic, ether,
nitrile, ester, chloro, water, alcohol and mixture thereof; palladium catalyst; base is selected
from inorganic base, organic base; step-b) suitable reagent is organic acid, inorganic acid;
preferably Con.HCl, methane sulphonic acid; step-d) suitable base is alcoholic base;
preferably: potassium hydroxide in ethanol; suitable temperature is 0°C to 100°C, preferably
15 20-85°C; step-g) suitable base is selected from inorganic base; suitable acid is selected
hydrochloric acid; pH range is 11-12 and 4-6;
8.A process for the preparation of 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)
pyridin-3-yl)-4-oxo-1,4-dihydroquino line -3- carboxylic acid compound of formula-1,
comprising of;
20 a)reacting the compound of formula-7a
Formula-7a
with compound of formula-8a
25 Formula-8a
in presence of bis(tricyclohexylphosphine palladiumdichloride), sodium bicarbonate in toluene,
25
water to produce compound of formula-9a
Formula-9a
b)reacting the compound obtained in step-a) with hydrochloric acid, to get the compound of
5 formula-1,
c)suspending the compound obtained in step-b) in tetrahydrofuran,
d)stirring the compound obtained in step-c) in ethanolic KOH, stirring at 25-35°C,
e)isolating the compound obtained in step-d) and purifying in ethanol,
f) suspending the compound obtained in step-e) in water,
10 g)adjusting the pH of the solution obtained in step-f) with potassium hydroxide, hydrochloric
acid at suitable temperature and isolated,
h) purifying the compound obtained in step-g) in water to provides the crystalline form-M of
1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-di hydro
quinoline-3-carboxylic acid compound of formula-1.
15 9. The 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydro
quinoline-3-carboxylic acid compound of formula-1, obtained according to any of preceding
claims having purity by HPLC> 95%, preferably > 99% ; more preferably>99.5 %
10. A pharmaceutical composition comprising 1-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl
amino) pyridin-3-yl)-4-oxo-1,4-di hydroquinoline-3-carboxylic acid of formula-1 obtained
20 according to any of preceding claims and a pharmaceutically acceptable carrier.