Field of the invention:

The present invention relates to a novel polymorphic form of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound represented by the following structural formula-1 and process for its preparation.

Background of the invention:

l-[(2,6-Difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide is a triazole drug with antiepileptic activity which is particularly useful to treat Lennox-Gastaut syndrome and it is known from US4789680A.

W098/56772 herein designated as '772' patent reports various crystalline forms of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide, in particular crystal modifications designated as A, A', B and C.

The above said '772' patent disclosed a process for the preparation of crystal modification-B of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide, comprising of dissolving the l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide in formic acid at 58-63°C followed by adding the obtained solution to methanol at 0-20°C. The obtained reaction mixture is washed with formic acid and isolated immediately by filtering followed by washing with cold methanol. Drying the compound at about 60°C provides the crystal modification-B.

US2011034523A1 disclosed two more novel crystalline forms of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide designated as form-a and form-p.

Crystalline forms often show different physical and/or biological characteristics which may assist in the manufacture or formulation of the active compound, with the purity levels and uniformity required for regulatory approval. Crystalline forms of such active compounds may also possess improved pharmacological characteristics, for example, improved bioavailability.

Crystal modification-A of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide is more stable than the other known crystalline forms and is the one present on the market, has a low apparent density, poor flowability and a strong tendency to form agglomerates.

Therefore there exists a need for crystal forms other than those prior reported forms of 1-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide which have the desired and the required biological qualities which would be helpful in optimizing, manufacturing and formulating an effective pharmaceutical composition.

Brief Description of the Invention:

The first aspect of the present invention is to provide a novel crystalline polymorph (designated as form-M) of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1.

The second aspect of the present invention is to provide a process for the preparation of crystalline form-M of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide, comprising of;

a) Dissolving the l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide in formic acid at a suitable temperature,

b) adding the solution obtained in step-a) to a suitable solvent at a suitable temperature,

c) stirring the reaction mixture at a suitable temperature,

d) filtering the precipitated solid to provide crystalline form-M of l-[(2,6-difluorophenyl)methyl]-1H-1, 2, 3-triazole-4-carboxamide.

The third aspect of the present invention is to provide a one pot process for the preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, comprising of;

a) Reacting the 2,6-difluorobenzyl bromide compound of formula-2 with sodium azide in a suitable solvent to provide 2,6-difluorobenzyl azide compound of formula-3,

b) reacting the compound of formula-3 in-situ with propiolic acid in a suitable solvent to provide l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxylic acid compound of formula-4,

c) treating the compound of formula-4 in-situ with thionyl chloride to provide l-[(2,6- difluorophenyl)methyl]-lH-l,2,3-triazole-4-carbonyl chloride compound of formula-5,

d) treating the compound of formula-5 in-situ with aqueous ammonia solution in a suitable solvent to provide l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1,

e) optionally purifying the compound of formula-1 from a suitable solvent.

The fourth aspect of the present invention is to provide a process for the preparation of 1-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, comprising of;

a) Reacting the 2,6-difluorobenzyl bromide compound of formula-2 with sodium azide in a suitable solvent to provide 2,6-difluorobenzyl azide compound of formula-3,

b) reacting the compound of formula-3 with propiolic acid in a suitable solvent to provide l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxylic acid compound of formula-4,

c) optionally purifying the compound of formula-4 from a suitable solvent,

d) treating the compound of formula-4 with thionyl chloride to provide l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carbonyl chloride compound of formula-5,

e) treating the compound of formula-5 with aqueous ammonia solution in a suitable solvent to provide l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1,

f) optionally purifying the compound of formula-1 from a suitable solvent.
The fifth aspect of the present invention is to provide an improved process for the preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, comprising of;

A) Reacting the 2,6-difluorobenzyl azide compound of formula-3 with 2-chloroacrylonitrile compound of formula-6 in a suitable solvent to provide l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carbonitrile compound of formula-7,

b) hydrolyzing the compound of formula-7 in-situ in presence of a suitable aqueous base to provide l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1.

The sixth aspect of the present invention is to provide a process for the preparation of 1-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, comprising of reacting the 2,6-difiuorobenzyl azide compound of formula-3 with 2-chloroacrylamide compound of formula-8 in a suitable solvent to provide l-[(2,6-difluorophenyl)methyl]-lH-1,2,3-triazole-4-carboxamide compound of formula-1 and the obtained compound is optionally purifying from a suitable solvent to provide pure compound of formula-1.

The seventh aspect of the present invention is to provide a process for the preparation of 1-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, comprising of;

a) Reacting the 2,6-difiuorobenzyl azide compound of formula-3 with 3-butyn-2-one in a suitable solvent to provide 1-(1 -(2,6-difiuorobenzyl)- 1H-1,2,3 -triazol-4-yl)ethanone compound of formula-9,

b) converting the compound of formula-9 into l-[(2,6-difluorophenyl)methyi]-lH-l,2,3-triazole-4-carboxylic acid compound of formula-4 by treating with a halogen in presence of a suitable base in a suitable solvent followed by treating with a suitable acid,

c) amidation of compound of formula-4 by treating with a suitable amine source in a suitable solvent to provide l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1.

The eighth aspect of the present invention is to provide a process for the preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, comprising of;

a) Reacting the 2,6-difiuorobenzyl azide compound of formula-3 with 3-butyn-2-one in a suitable solvent to provide 1-(1-(2,6-difiuorobenzyl)-1H-1,2,3-triazol-4-yl)ethanone compound of formula-9,

b) converting the compound of formula-9 into l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxylic acid compound of formula-4 by treating with conc.sulfuric acid in a suitable solvent,

c) amidation of compound of formula-4 by treating with a suitable amine source in a suitable solvent to provide l-[(2,6-difiuorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1.

Brief description of the drawings:

Figure-1: Illustrates the PXRD pattern of crystalline form-M of l-[(2,6-difluorophenyl)methyl]- lH-l,2,3-triazole-4-carboxamide compound of formula-1.

Detailed description of the invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethylether, diethylether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulphoxide, acetonitrile and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol and the like; "polar solvents" such as water or mixtures thereof.

As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as sodium carbonate, potassium carbonate and the like; "alkali metal bicarbonates" 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 tert.butoxide and the like; and organic bases like diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine or mixtures thereof.

The first aspect of the present invention provides a novel crystalline polymorph of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, which is characterized by its powder X-ray powder diffraction pattern showing characteristic peaks at 11.0, 18.4, 21.6, 24.1, 26.2 and 33.1±0.2 degrees of 29. This crystalline form of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide is hereinafter designated as crystalline form-M. The crystalline form-M of the present invention is further characterized by its PXRD pattern showing peaks at 8.0, 15.2, 20.2, 30.8 and 32.2 ±0.2 degrees of 29. The PXRD of crystalline form-M is substantially in accordance with the PXRD pattern depicted in figure-1.

The second aspect of the present invention provides a process for the preparation of crystalline form-M of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide, comprising of;

a) Dissolving the l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide in formic acid at a suitable temperature,

b) adding the solution obtained in step-a) to a suitable solvent at a suitable temperature,

c) stirring the reaction mixture at a suitable temperature,

d) filtering the precipitated solid to provide crystalline form-M of l-[(2,6-difiuorophenyl)methyl]-1H-1,2,3 -triazole-4-carboxamide.

Wherein, in step-a) the suitable temperature is 25-30°C; in step-b) the suitable solvent is selected from alcoholic solvents, preferably methanol; in step-b) and step-c) the suitable temperature is ranging between -70°C to 40°C, preferably between -55°C to 30°C.

A preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide, comprising of;

a) Dissolving the l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide in formic acid at 25-30°C,

b) adding the solution obtained in step-a) to methanol at -50°C to -55°C,

c) stirring the reaction mixture at -50°C to -55°C,

d) filtering the precipitated solid to provide crystalline form-M of l-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide.

Another preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide, comprising of; a) Dissolving the l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide in formic acid at 25-30°C,

b) adding the solution obtained in step-a) to methanol at -10°C to -15°C,

c) stirring the reaction mixture at -10°C to -15°C,

d) filtering the precipitated solid to provide crystalline form-M of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide.

Another preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide, comprising of;

a) Dissolving the l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide in formic acid at 25-30°C,

b) adding the solution obtained in step-a) to methanol at 25-30°C,

c) stirring the reaction mixture at 25-3 0°C,

d) filtering the precipitated solid to provide crystalline form-M of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide.

The l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound utilized in the second aspect can be synthesized by any of the below mentioned processes.

The third aspect of the present invention provides a one pot process for the preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, comprising of; a) Reacting the 2,6-difluorobenzyl bromide compound of formula-2 with sodium azide in a suitable solvent provides 2,6-difluorobenzyl azide compound of formula-3,

b) reacting the compound of formula-3 in-situ with propiolic acid in a suitable solvent provides l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxylic acid compound of formula-4,

c) treating the compound of formula-4 in-situ with thionyl chloride provides l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carbonyl chloride compound of formula-5,

d) treating the compound of formula-5 in-situ with aqueous ammonia solution in a suitable solvent provides l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1,

e) optionally purifying the compound of formula-1 from a suitable solvent. Wherein, in step-a) the suitable solvent is selected from polar-aprotic solvents, chloro solvents, polar solvents or mixtures thereof;

in step-b) to step-d) the suitable solvent is selected from hydrocarbon solvents, preferably toluene; and in step-e) the suitable solvent is selected from alcoholic solvents, ketone solvents, polar solvents or mixtures thereof.

A preferred embodiment of the present invention provides one-pot process for the preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, comprising of;

a) Reacting the 2,6-difluorobenzyl bromide compound of formula-2 with sodium azide in a mixture of dichloromethane, dimethylsulfoxide and water to provide 2,6-difluorobenzyl azide compound of formula-3,

b) reacting the compound of formula-3 in-situ with propiolic acid in toluene to provide l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxylic acid compound of formula-4,

c) treating the compound of formula-4 in-situ with thionyl chloride to provide l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carbonyl chloride compound of formula-5,

d) treating the compound of formula-5 in-situ with aqueous ammonia solution in toluene to provide l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1.

The fourth aspect of the present invention provides a process for the preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, comprising of;

a) Reacting the 2,6-difluorobenzyl bromide compound of formula-2 with sodium azide in a suitable solvent provides 2,6-difluorobenzyl azide compound of formula-3,

b) reacting the compound of formula-3 with propiolic acid in a suitable solvent provides l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxylic acid compound of formula-4,

c) optionally purifying the compound of formula-4 from a suitable solvent,

d) treating the compound of formula-4 with thionyl chloride provides l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carbonyl chloride compound of formula-5,

e) treating the compound of formula-5 with aqueous ammonia solution in a suitable solvent provides l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1,

f) optionally purifying the compound of formula-1 from a suitable solvent.

Wherein, in step-a) the suitable solvent is selected from polar-aprotic solvents, chloro solvents, polar solvents or mixtures thereof;

in step-b) the suitable solvent is selected from hydrocarbon solvents, preferably toluene;

in step c) the suitable solvent is selected from hydrocarbon solvents, polar aprotic solvents, ester solvents, alcoholic solvents, ketone solvents, ether solvents or mixtures thereof;

in step e) the suitable solvent is selected from alcoholic solvents, hydrocarbon solvents,

polar solvents, ketone solvents or mixtures thereof;
in step-f) the suitable solvent is selected from ketone solvents, alcoholic solvents or mixtures thereof;

The fifth aspect of the present invention provides an improved process for the preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, comprising of;

a) Reacting the 2,6-difluorobenzyl bromide compound of formula-2 with sodium azide in a suitable solvent provides 2,6-difluorobenzyl azide compound of formula-3,

b) reacting the compound of formula-3 in-situ with 2-chloroacrylonitrile compound of formula-6

c) hydrolyzing the compound of formula-7 in-situ in presence of a suitable aqueous base provides l-[(2,6- difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1.

Wherein, in step-a) the suitable solvent is selected from polar solvents, chloro solvents, polar aprotic solvents or mixtures thereof; in step-b) the suitable solvent is selected from hydrocarbon solvents, ketone solvents, polar solvents or mixtures thereof; in step-c) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides; preferably sodium hydroxide.

A preferred embodiment of the present invention provides a process for the preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, comprising of;

a) Reacting the 2,6-difluorobenzyl bromide compound of formula-2 with sodium azide in a mixture of dichloromethane, dimethylsulfoxide and water provides 2,6-difluorobenzyl azide compound of formula-3,

b) reacting the compound of formula-3 in-situ with 2-chloroacrylonitrile compound of formula-6 in water provides l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carbonitrile compound of formula-7,

c) hydrolyzing the compound of formula-7 in-situ in presence of aqueous sodium hydroxide in acetone provides l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1.

The sixth aspect of the present invention provides a process for the preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, comprising of reacting the 2,6-difluorobenzyl azide compound of formula-3 with 2-chloroacrylamide compound of formula-8 in a suitable solvent selected from hydrocarbon solvents, ether solvents, ester solvents, polar aprotic solvents, alcohol solvents, polar solvents or mixtures thereof; provides l-[(2,6-difluoro phenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1 and the obtained compound is purified from a suitable solvent.

The seventh aspect of the present invention provides a process for the preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, comprising of; a) Reacting the 2,6-difluorobenzyl azide compound of formula-3 with 3-butyn-2-one in a suitable solvent provides l-(l-(2,6-difluorobenzyl)-lH-l,2,3-triazol-4-yl)ethanone compound of formula-9,

b) converting the compound of formula-9 into l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxylic acid compound of formula-4 by treating with a halogen selected from chlorine, bromine or iodine in presence of a suitable base in a suitable solvent, followed by treating with a suitable acid,

c) amidation of compound of formula-4 by treating with a suitable amine source in a suitable solvent provides l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1.

Wherein in step-a) the suitable solvent is selected from hydrocarbon solvents, polar solvents, polar aprotic solvents, ester solvents, ether solvents, alcohol solvents or mixtures thereof.

In step-b) the suitable base is selected from inorganic bases, preferably alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents, polar-solvents such as water and the suitable acid is selected from hydrochloric acid, hydro bromic acid, sulfuric acid, acetic acid, oxalic acid, trifiuoro acetic acid, para toluene sulfonic acid and methane sulfonic acid.

In step-c) the suitable amine source is selected from ammonia, ammonia gas, ammonium hydroxide, ammonium chloride, ammonium formate, ammonium acetate, and the suitable solvent is selected from ether solvents, ester solvents ketone solvents, polar solvents and chloro solvents.

The eighth aspect of the present invention provides a process for the preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, comprising of;

a) Reacting the 2,6-difluorobenzyl azide compound of formula-3 with 3-butyn-2-one in a suitable solvent provides l-(l-(2,6-difluorobenzyl)-lH-l,2,3-triazol-4-yl)ethanone compound of formula-9,

b) converting the compound of formula-9 into 1 -[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4-carboxylic acid compound of formula-4 by treating with conc.sulfuric acid in a suitable solvent,

c) amidation of compound of formula-4 by treating with a suitable amine source in a suitable solvent provides l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1.

Wherein in step-a) & step-c) the suitable solvents and the suitable amine source are same as defined in the seventh aspect of the present invention and the suitable solvent in step-b) is selected from chloro solvents.

The PXRD analysis of the crystalline l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min. l-[(2,6-Difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of the present invention was analyzed by HPLC under the following conditions;

Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector and integrator; Column: Cosmicsil Aster C18XD, 150 X 4.6mm 3um (or) equivalent; Flow rate: 1.0 rnL/min; Wavelength: 215 nm; Column temperature: 25°C; Injection volume: 20 uL; Run time: 60 min; Diluent: 0.1% orthophosphoric acid in water:acetonitrile (50:50) v/v; Mobile phase-A: Buffer; Mobile phase-B: Tetrahydrofuran:Methanol:Acetonitrile:Water (20:30:30:20) v/v/v/v; Buffer: Weigh accurately about 6.8 gm of potassium dihydrogen phosphate and transfer it into 1000 ml of milli-Q-water. Adjust the pH to 4.0 with dil.ortho phosphoric acid and filtered the solution through 0.22 um Nylon membrane filter paper; Elution: Gradient.

The particle size distribution of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of the present invention was measured using Malvern Mastersizer 2000 instrument. l-[(2,6-Difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball mills, roller and hammer mills and jet mills. Milling or micronization may be performed before drying or after the completion of drying of the product.

The present invention is schematically represented as follows. Scheme-1:

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 construed as limitation to the scope of the invention.

Examples:

Example-1: Preparation of 2,6-difluorobenzyl azide (FormuIa-3)

A solution of 2,6-difluorobenzyl bromide compound of formula-2 (150 gm) in dichloromethane (450 ml) was slowly added to a mixture of dimethylsulfoxide (405 ml), water (45 ml) and sodium azide (51.3 gm) at 25-30°C and stirred for 3 hrs at the same temperature. After completion of the reaction, water was added to the reaction mixture and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water and distilled off the solvent completely under atmospheric pressure to get the title compound as a residue. Yield: 120.0 gm.

Example-2: Preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazoIe-4-carbonitrile (Formula-7)

A mixture of 2,6-difluorobenzyl azide compound of formula-3 (120 gm), 2-chloroacrylonitrile compound of formula-6 (120 gm) and water (480 ml) was heated to 80-85°C and stirred for 24 hrs at the same temperature. After completion of the reaction, distilled off 180 ml of water from the reaction mixture under reduced pressure at below 85°C. Cooled the reaction mixture to 25-30°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 180.0 gm.

Example-3: Purification of l-[(2,6-difiuorophenyl)methyl]-lH-l,2,3-triazole-4-carbonitrile (Formula-7)

A mixture of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carbonitrile compound of formula-7 (180 gm) and methanol (1200 ml) was heated to 60-65°C and stirred for 30 min at the same temperature. Carbon (12 gm) was added to the reaction mixture at 60-65°C and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Cooled the filtrate to 0-5°C, water (360 ml) was added and stirred for 90 min at the same temperature. Filtered the precipitated solid, washed with a mixture of methanol and water and dried to get the title compound. Yield: 135.0 gm.

Example-4: Preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide
(Formula-1)

A mixture of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carbonitrile compound of formula-7 (60 gm) and acetone (240 ml) was stirred for 15 min at 25-30°C. Filtered the reaction mixture through hyflow bed and washed with acetone. Water (300 ml) followed by sodium hydroxide solution (1.1 gm of sodium hydroxide in 18 ml of water) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 5 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Filtered the solid and washed with a mixture of water and acetone. Yield: 63.0 gm.

Example-5: Preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide (Formula-1)

A solution of 2,6-difluorobenzyl bromide compound of formula-2 (150 gm) in dichloromethane (450 ml) was slowly added to a mixture of dimethylsulfoxide (405 ml), water (45 ml) and sodium azide (51.3 gm) at 25-30°C and stirred for 3 hrs at the same temperature. After completion of the reaction, water was added to the reaction mixture and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water and distilled off the solvent completely under atmospheric pressure. 2-Chloroacrylonitrile compound of formula-6 (120 gm) and water (480 ml) were added to the obtained compound and heated the reaction mixture to 80-85°C and stirred for 24 hrs at the same temperature. After completion of the reaction, distilled off the excess 2-chloroacrylonitrile under reduced pressure. Cooled the reaction mixture to 25-30°C. Acetone (720 ml) was added to the obtained reaction mixture and carbon (24 gm) was added to it. Heated the reaction mixture to 40-45°C and stirred for 1 hr at the same temperature.

Filtered the reaction mixture through hyflow bed and water (500 ml) was added to the filtrate at 25-30°C and stirred for 15 min at the same temperature. Aq.sodium hydroxide solution (3.3 gm of sodium hydroxide in 54 ml of water) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 5 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Filtered the solid and washed with a mixture of water and acetone. Acetone (600 ml) was added to the obtained solid, heated the reaction mixture to 50-55°C and stirred for 60 min at the same temperature. Cooled the reaction mixture to 25-30°C, filtered the precipitated solid and washed with acetone to get the title compound. Yield: 60.0 gm.

Example-6: Preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide (Formula-1)

A mixture of 2,6-difluorobenzyl azide compound of formula-3 (10 gm), 2-chloroacrylonitrile compound of formula-6 (10 gm) and water (40 ml) was heated to 80-85°C and stirred for 24 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C and the pH of the reaction mixture was adjusted to 7.3 using aq.sodium hydroxide solution at 25-30°C. Water (10 ml) and sodium hydroxide (0.4 gm) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 5 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 4.0 gm.

Example-7: Preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide (Formula-1)

A mixture of 2,6-difluorobenzyl azide compound of formula-3 (10 gm), 2-chloroacrylonitrile compound of formula-6 (10 gm) and water (40 ml) was heated to 80-85°C and stirred for 24 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C. Carbon (1 gm) was added to the reaction mixture at 25-30°C, heated the reaction mixture to 40-45°C and stirred for 60 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with water. Adjusted the pH of the filtrate to 7.3 using aq.sodium hydroxide solution. Water (10 ml), acetone (50 ml) and sodium hydroxide (0.4 gm) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 5 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 5.0 gm.

Example-8: Purification of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide (Formula-1)

A mixture of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1 (63 gm) and acetone (600 ml) was heated to 50-55°C and stirred for 60 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 15 min at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get pure title compound.

Yield: 59.0 gm; Purity by HPLC: 99.99%.

Particle size distribution (before micronization): D(0.1) is 1.69 um; D(0.5) is 8.05 um; D(0.9) is 39.12 um; Particle size distribution (after micronization): D(0.1) is 1.22 um; D(0.5) is 3.30 um; D(0.9) is 9.06 jim; Specific surface area: 1.47 m2/g (before micronization), 2.55 m /g (after micronization).

Example-9: Preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide (Formula-1)

A mixture of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carbonitrile compound of formula-7 (60 gm) and acetone (240 ml) was stirred for 15 min at 25-30°C. Filtered the reaction mixture through hyflow bed and washed with acetone. Water (300 ml) followed by sodium hydroxide solution (1.1 gm of sodium hydroxide in 18 ml of water) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 5 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Filtered the solid and washed with a mixture of water and acetone. 600 ml of acetone was added to the obtained wet compound, heated the reaction mixture to 50-55°C and stirred for 60 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 15 min at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get pure title compound. Yield: 59.0 gm; Purity by HPLC: 99.99%.

Example-10: Preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxylic acid (Formula-4)

A mixture of 2,6-difluorobenzyl azide compound of formula-3 (50 gm), propiolic acid (20 gm) and toluene (400 ml) was heated to 70-75 °C and stirred for 24 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Filtered the solid, washed with toluene and dried to get the title compound. Yield: 53.0 gm;

Example-11: Preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide (Formula-1)

A mixture of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxylic acid compound of formula-4 (25 gm) and thionyl chloride (125 ml) was heated to 65-70°C and stirred for 2 hrs at the same temperature. Distilled off thionyl chloride from the reaction mixture under reduced pressure and co-distilled with toluene. 200 ml of toluene was added to the reaction mixture. The reaction mixture was added to pre-cooled aqueous ammonia solution (200 ml) at 5-10°C and stirred for 90 min at the same temperature. Filtered the solid, washed with toluene and dried to get the title compound. Yield: 22.0 gm.

Example-12: Preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide (Formula-1)

A solution of 2,6-difluorobenzyl bromide compound of formula-2 (30 gm) in dichloromethane (90 ml) was slowly added to a mixture of dimethylsulfoxide (90 ml) and sodium azide (10.2 gm) at 25-3 0°C and stirred for 3 hrs at the same temperature. After completion of the reaction, water was added to the reaction mixture. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. The total organic layer was washed with water and distilled off the solvent completely from the organic layer under reduced pressure. Cooled the residue to 25-30°C. Toluene (213 ml) followed by propiolic acid (8.4 gm) were added to the obtained residue at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 24 hrs at the same temperature. Cooled the reaction mixture to 25-3 0°C and thionyl chloride (180 ml) was added. Heated the reaction mixture to 65-70°C and stirred for 3 hrs at the same temperature. Distilled off thionyl chloride from the reaction mixture under reduced pressure and co-distilled with toluene. 240 ml of toluene was added to the reaction mixture. The reaction mixture was added to pre-cooled aqueous ammonia solution (240 ml) at 5-10°C and stirred for 90 min at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 17.5 gm;

Particle size distribution (before micronization): D(0.1) is 1.87 um; D(0.5) is 9.15 um; D(0.9) is 42.65 um; Particle size distribution (after micronization): D(0.1) is 1.30 um; D(0.5) is 4.12 urn; D(0.9) is 13.18 um; Specific surface area: 1.32 m2/g (before micronization), 2.19 m2/g (after micronization).

Example-13: Preparation of crystalline form-M of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide (Formula-1)

Methanol (100 ml) was charged into a clean and dry RBF at 25-30°C and cooled to -50°C to -55°C. A solution of l-[(2,6-difiuorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide (10 gm) in formic acid (100 ml) was slowly added to the above pre-cooled methanol at -50°C to -55°C and stirred for 90 min at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. The PXRD of the obtained compound is shown in figure-1. Yield: 9.0 gm.

The crystalline form-M of the obtained compound is characterized by its characteristic lines at interplanar spacings (d-values) of 10.93, 8.03, 5.80, 4.79, 4.38, 4.09, 3.68, 3.39, 2.89, 2.77 and 2.69A° determined by means of an X-ray powder diffraction pattern.

Example-14: Preparation of crystalline form-M of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide (Formula-1)

Methanol (50 ml) was charged into a clean and dry RBF at 25-30°C and cooled to -10°C to -15°C. A solution of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide (5 gm) in formic acid (50 ml) was slowly added to the above pre-cooled methanol at -10°C to -15°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. The PXRD of the obtained compound is shown in figure-1. Yield: 3.0 gm.

Example-15: Preparation of crystalline form-M of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4- carboxamide (Formula-1)

A solution of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide (5 gm) in formic acid (50 ml) was slowly added to methanol (50 ml) at 25-3 0°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. The PXRD of the obtained compound is shown in figure-1. Yield: 2.9 gm.

We Claim:

1. Crystalline form-M of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide, characterized by;

a) its PXRD pattern having peaks at about 11.0, 18.4, 21.6, 24.1, 26.2 and 33.1±0.2 degrees of 29, and

b) its powder X-ray diffraction pattern substantially in accordance with figure-1.

2. A process for the preparation of crystalline form-M of 1 -[(2,6-difluorophenyl)methyl]-1H-1,2,3- triazole-4-carboxamide, comprising of;

a) Dissolving the l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide in formic acid at a suitable temperature,

b) adding the solution obtained in step-a) to a suitable solvent at a suitable temperature,

c) stirring the reaction mixture at a suitable temperature,

d) filtering the precipitated solid to provide crystalline form-M of l-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide.

3. A process according to claim 2, wherein, in step-a) the suitable temperature is 25-30°C; in step-b) the suitable solvent is selected from alcoholic solvents; in step-b) and step-c) the suitable temperature is ranging between -70°C to 35°C, preferably between -55°C to 30°C.

4. A process for the preparation of crystalline form-M of 1 -[(2,6-difluorophenyl)methyl]-1H-1,2,3- triazole-4-carboxamide, comprising of;

a) Dissolving the l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide in formic acid at 25-3 0°C,

b) adding the solution obtained in step-a) to methanol at -50°C to -55°C,

c) stirring the reaction mixture at -50°C to -55°C,

d) filtering the precipitated solid to provide crystalline form-M of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide.

5. A process for the preparation of crystalline form-M of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide, comprising of;

a) Dissolving the l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide in formic acid at 25-30°C,

b) adding the solution obtained in step-a) to methanol at -10°C to -15°C,

c) stirring the reaction mixture at -10°C to -15°C,

d) filtering the precipitated solid to provide crystalline form-M of l-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide.

6. A process for the preparation of crystalline form-M of 1 -[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide, comprising of;

a) Dissolving the l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide in formic acid at 25-30°C,

b) adding the solution obtained in step-a) to methanol at 25-3 0°C,

c) stirring the reaction mixture at 25-30°C,

d) filtering the precipitated solid to provide crystalline form-M of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide.

7. The crystalline compound obtained according to the processes described in claims 2, 4, 5 & 6 is characterized by its characteristic lines at interplanar spacings (d-values) of 10.93, 8.03, 5.80, 4.79, 4.38, 4.09, 3.68, 3.39, 2.89, 2.77 and 2.69 A° determined by means of an X-ray powder diffraction pattern.

8. One-pot process for the preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, comprising of;

a) Reacting the 2,6-difluorobenzyl bromide compound of formula-2 with sodium azide in a mixture of dichloromethane, dimethylsulfoxide and water to provide 2,6-difiuorobenzyl azide compound of formula-3,

b) reacting the compound of formula-3 in-situ with propiolic acid in toluene to provide l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxylic acid compound of formula-4,

c) treating the compound of formula-4 in-situ with thionyl chloride to provide l-[(2,6-difiuorophenyl)methyl]-lH-l,2,3-triazole-4-carbonyl chloride compound of formula-5,

d) treating the compound of formula-5 in-situ with aqueous ammonia solution in toluene to provide l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1.

9. One-pot process for the preparation of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, comprising of;

a) Reacting the 2,6-difluorobenzyl bromide compound of formula-2 with sodium azide in a mixture of dichloromethane, dimethylsulfoxide and water to provide 2,6-difluorobenzyl azide compound of formula-3,

b) reacting the compound of formula-3 in-situ with 2-chloroacrylonitrile compound of formula-6 in water followed by in-situ hydrolyzing the obtained compound in presence of a suitable aqueous alkali metal hydroxide such as sodium hydroxide optionally using acetone as a solvent to provide l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide compound of formula-1, c) purifying the compound of formula-1 from acetone to provide pure l-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide compound of formula-1.

10. The process according to claims 2, 4, 5 and 6, wherein the crystalline form-M of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide is characterized by its PXRD pattern substantially in accordance with figure-1.