DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF TRIAZOL-5-ONE DERIVATIVE”

SRF LIMITED, AN INDIAN COMPANY,
SECTOR 45, BLOCK-C, UNICREST BUILDING,
GURGAON – 122003,
HARYANA (INDIA)

The following specification particular describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention provides a process for preparation of a compound of formula I. The compounds of formula I are very useful and have wide applications as intermediate in agriculture industry,

Formula I
wherein R is hydrogen, NR1R2, NO2, NR1SO2CH3; R1 and R2 are independently hydrogen, alkyl, halogenated alkyl, halogenated aryl, aryl, substituted aryl; X’ is chloro and n is an integer from 1-3.

BACKGROUND OF THE INVENTION
The present invention provides a process for preparing compound of formula I, mainly N-[2,4-dichloro-5-[4-(difluoromethyl)-3-methyl-5-oxo-1,2,4-triazol-1-yl]phenyl] methane sulfonamide also known as sulfentrazone and intermediates thereof. These are an important herbicide.
Indian Patent No. 399439 discloses a preparation of sulfentrazone from phenyl hydrazine by converting it to 5-methyl-2-phenyl-2,4-dihydro-[1,2,4]-triazol-3-one followed by alkylation, chlorination, nitration, reduction and sulfonylation to obtain sulfentrazone. The chlorination step of given process involves two chlorination steps, and two solvent systems, which has the problems of serious equipment corrosion, complicated operation, high effluent load. Further, it provides low yield and recovery of solvents is difficult.
Chinese Patent No. 103951627B discloses a preparation of sulfentrazone from 1-phenyl-3-methyl-1H-1,2,4-triazole-5-ketone comprising the step of difluoromethylation, chlorination, nitration and reduction, and further performing methyl sulfone chloride sulfonylation to obtain N-(2,4-difluoro-5-(4-difluoro methyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole-1-yl) phenyl) sulfamide.
Chinese Patent No. 109796419B discloses a preparation of sulfentrazone comprising a step of reacting 2-(2,4-dichloro-5-halogeno benzene)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazole-3-ketone with borate under the reaction condition of n-butyllithium or a Grignard reagent to substitute 5-site halogen with boric acid or a borate group and coupling it with methanesulfonamide under the catalysis of a copper catalyst to generate sulfentrazone.
Chinese Patent No. 106478532B discloses a preparation of sulfentrazone starting from o-chlorophenylhydrazine hydrochloride comprising the step of converting it to 1-(o-chlorophenyl)-3-methyl-1H-1,2,4-triazol-5-one, which upon alkylation, chlorination, nitration, reduction and finally sulfonylation gives sulfentrazone.
Chinese Patent No. 113402472B discloses a preparation of sulfentrazone starting from a mixture of o-chloronitrobenzene and p-chloronitrobenzene comprising the step of reduction, cyclization, alkylation, chlorination, and finally sulfonylation gives sulfentrazone.
Chinese Patent Application No. 114315744A discloses a preparation of sulfentrazone starting from 2,4-dichloroaniline comprising the step of nitration, amino-group protection, diazotization, cyclization, alkylation, and finally sulfonylation gives sulfentrazone.
Chinese Patent Application No. 107629015A discloses a preparation of sulfentrazone intermediate, 1-(2,4-dichlorophenyl)-3-methyl-4-difluoromethyl-1,2,4-triazol-5-one, comprising the step of converting p-chloroaniline to p-chlorophenylhydrazine hydrochloride, converting it to 1-p-chlorophenyl-3-methyl-1H-1,2,4-triazol-5-one, followed by chlorination to obtain 1-(2,4-dichlorophenyl)-3-methyl-4-difluoromethyl-1,2,4-triazol-5-one (sulfentrazone intermediate).
U.S. Patent 4,980,480 provides a process for preparation of 1-(2,4-dichlorophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one by chlorination using sulfuryl chloride or elemental chlorine in presence of iron in acetic acid.
U.S. Patent 5,468,868 provides a process for preparation of 1-(2,4-dichlorophenyl)-3-methyl-4,5-dihydro-1H-1,2,4-triazol-5-one by two-step chlorination of 4,5-dihydro-1-phenyl-3-methyl-1H-1,2,4-triazol-5-one using chlorine in presence of N,N-dimethylformamide followed by chlorination of 1-(4-chlorophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one in acetic acid/water.
Chinese Patent 111689915 provides preparation of 1-(2,4-dichlorophenyl)-4-difluoromethyl-3-methyl-1H-1,2,4-triazol-5-one by two step chlorination of 1-phenyl-3-methyl-4-difluoromethyl-1H-1,2,4-triazole-5-ketone in presence of a mixture of antimony trichloride and aluminium trichloride.
The known processes involve two step chlorination, using different solvents, thereby requiring multiple operations for product isolation. Also, the known processes involve large amount of effluent of acetic acid and a water mixture.
Therefore, there is a need in the art to develop an economical process for preparation of compound of formula I.
The present invention provides a process for preparation of compound of formula I and intermediates thereof with higher selectivity for desired product and is a greener, more efficient, safer, and more reliable process at industrial scale.

OBJECT OF THE INVENTION
The main object of the present invention provides a simple, safe, and commercially viable process for preparation of compound of formula I, such as N-2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl] phenyl methanesulfonamide and intermediate thereof in good yield and selectivity.
SUMMARY OF THE INVENTION
The present invention provides a process for preparation of a compound of formula I,

Formula I
wherein R is hydrogen, NR1R2, NO2, NR1SO2CH3; R1 and R2 are independently hydrogen, alkyl, halogenated alkyl, halogenated aryl, aryl, substituted aryl; X’ is chloro and n is an integer from 1-3,
comprising chlorinating a compound of formula II,

Formula II
wherein R is hydrogen, NR1R2, NO2, NR1SO2CH3; R1 and R2 are independently hydrogen, alkyl, halogenated alkyl, halogenated aryl, aryl, substituted aryl; X is chloro, bromo or iodo, and d is an integer from 0-2, provided d=n.
using hydrochloric acid and an oxidising agent.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, “alkyl” includes unsubstituted and substituted C1-C4 alkyl chain selected from methyl, ethyl, propyl, isopropyl and butyl or the like; “halogenated alkyl” refers to C1-C4 alkyl chain containing halogen such as trifluoromethyl, difluoromethyl, fluoromethyl, dichloromethyl, difluoroethyl, trifluoroethyl, monofluoroethyl; “aryl” refers to a substituted or unsubstituted phenyl, pyridine, pyrimidine, pentyl and hexyl or the like. The subtitled groups may include halogen, aryl, amine, cyano, hydroxy, ester, ketone and aldehyde.
The oxidising agent is selected from a group consisting of hydrogen peroxide, potassium permanganate, sodium hypochlorite, sodium chlorite, sodium chlorate, sodium dichromate, perchlorate, chlorine dioxide, chlorine, sodium chloride with hydrogen peroxide or the like.
In an embodiment, the present invention provides a process for preparation of compound of formula I, comprising a step of chlorinating a compound of formula II using hydrochloric acid and an oxidising agent to obtain a compound of formula I.
The chlorination of a compound of formula II to obtain a compound of formula I is carried out at a temperature of 20-110ºC, more preferably at a temperature of 40-70°C.
The molar ratio of hydrochloric acid to the compound of formula II is in the range of 1-20, more preferably in the range of 4-10.
The molar ratio of hydrogen peroxide to the compound of formula II is in the range of 1- 3 equivalents with respect to the compound of formula II, more preferably 1.0-1.5 equivalents with respect to the compound of formula II.
In an embodiment, the present invention provides a process for preparation of compound of formula I, comprising chlorinating a compound of formula II using hydrochloric acid and an oxidising agent in a solvent.
The solvent is selected from a group consisting of water, acetic acid and organic solvent such as acetonitrile, acetone, pyridine, piperidine, methylpyridine, methyl ethyl pyridine, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide or the like.
In another embodiment, the present invention provides a process for preparation of compound of formula I, by reacting a compound of formula II and hydrochloric acid and an oxidising agent in absence of an organic solvent.
In an embodiment, the present invention provides a process for preparation of compound of formula I by chlorinating a compound of formula II using hydrochloric acid and 10-60% hydrogen peroxide, more preferably 30-50% of hydrogen peroxide.
In an embodiment, the present invention provides a process for preparation of compound of formula I by chlorinating a compound of formula II using 10-40% hydrochloric acid and hydrogen peroxide.
In another embodiment, the present invention provides a process for preparation of a compound of formula I, by reacting a compound of formula II and hydrochloric acid and an oxidising agent in the presence or absence of a catalyst. The preferred catalyst is selected from a group consisting of phase transfer catalyst like tetraethylammonium chloride, benzyl triethylammonium chloride, tetrabutylammonium bromide and transition metal catalyst like palladium acetate.
In another embodiment, the present invention provides a process for preparation of a compound of formula I, by reacting a compound of formula II and hydrochloric acid and an oxidising agent in the presence or absence of a catalyst. The preferred catalyst is selected from a group consisting of manganese sulphate, manganese chloride, manganese nitrate, manganese oxide, cuprous chloride, cuprous bromide, iron chloride, sodium chloride, magnesium chloride, iron sulphate and calcium chloride. The catalyst is used from 0.01-1 equivalent, more preferably 0.01-0.1 equivalent with respect to compound of formula II.
In an embodiment of the present invention, the compound of formula I is selected from a group consisting of 1-(2,4-dichlorophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one; 1-(4-chlorophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one; 1-(2,4-dichlorophenyl)-4,5-dihydro-3-ethyl-1H-1,2,4-triazol-5-one; 1-(2,4-dichlorophenyl)-4,5-dihydro-3-fluoromethyl-1H-1,2,4-triazol-5-one; 1-(2,4-dichlorophenyl)-4,5-dihydro-3-difluoromethyl-1H-1,2,4-triazol-5-one; 1-(2,4-dichlorophenyl)-4,5-dihydro-3-(2,2-difluoroethyl)-1H-1,2,4-triazol-5-one; 4,5-dihydro-3-methyl-1-phenyl-1H-1,2,4-triazol-5-one; 1-(2,4-dichlorophenyl)-4,5-dihydro-3-chloromethyl-1H-1,2,4-triazol-5-one; 1-(2,4-dichlorophenyl)-4,5-dihydro-1H-1,2,4-triazol-5-one; 1-(2,4-dichlorophenyl)-4,5-dihydro-3-fluoromethyl-1H-1,2,4-triazol-5-one; 1-(2,4-dichlorophenyl)-4-difluoromethyl-3-methyl-1H-1,2,4-triazol-5-one; 1-(4-chlorophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one; 1-(4-chlorophenyl)-4-trifluoromethyl-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one; 1-(2,4-dichlorophenyl)-4-trifluoromethyl-3-methyl-1H-1,2,4-triazol-5-one; 1-(2,4-dichloro-5-methylsulfonylaminophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one; 1-(4-chlorophenyl)- 4,5-dihydro-1H-1,2,4-triazol-5-one; 1-(2,4-dichlorophenyl)-4,5-dihydro-1H-1,2,4-triazol-5-one; 1-(2,4-dichloro-5-methylsulfonylaminophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one; 1-(2,4-dichloro-5-methylsulfonylaminophenyl)-4,5-dihydro-3-difluoromethyl-1H-1,2,4-triazol-5-one; 1-(4-chloro-5-methylsulfonyl aminophenyl)-4,5-dihydro-3-difluoromethyl-1H-1,2,4-triazol-5-one; 1-(4-chloro-5-methylsulfonylaminophenyl)-4,5-dihydro-3-trifluoromethyl-1H-1,2,4-triazol-5-one, 1-(2,4-dichloro-5-methylsulfonylaminophenyl)-4,5-dihydro-3-trifluoromethyl -1H-1,2,4-triazol-5-one and N-2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]phenyl methanesulfonamide or the like.
In another embodiment of the present invention, the compound of formula II is selected from a group consisting of 4,5-dihydro-3-methyl-1-phenyl-1H-1,2,4-triazol-5-one; 4,5-dihydro-3-ethyl-1-phenyl-1H-1,2,4-triazol-5-one; 4,5-dihydro-3-fluoromethyl-1-phenyl-1H-1,2,4-triazol-5-one; 4,5-dihydro-3-difluoromethyl-1-phenyl-1H-1,2,4-triazol-5-one; 4,5-dihydro-3-(2,2-difluoroethyl)-1-phenyl-1H-1,2,4-triazol-5-one; 4,5-dihydro-3-chloromethyl-1-phenyl-1H-1,2,4-triazol-5-one; 4,5-dihydro-1-phenyl-1H-1,2,4-triazol-5-one; 1-(4-chlorophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one; 4-difluoromethyl-4,5-dihydro-3-methyl-1-phenyl-1H-1,2,4-triazol-5-one; 1-(4-chlorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one; 1-(4-chlorophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one; 4-trifluoromethyl-4,5-dihydro-3-methyl-1-phenyl-1H-1,2,4-triazol-5-one; 1-(4-chlorophenyl)-4-trifluoromethyl-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one; 1-(2-chloro-5-methylsulfonylamino; 4,5-dihydro-1-phenyl-1H-1,2,4-triazol-5-one; 1-(4-chlorophenyl)- 4,5-dihydro-1H-1,2,4-triazol-5-one; 1-phenyl-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one; 1-(5-methylsulfonyl aminophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one; 1-(4-chloro-5-methylsulfonylaminophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one; 1-(5-methylsulfonylaminophenyl)-4,5-dihydro-3-difluoromethyl-1H-1,2,4-triazol-5-one; 1-(4-chloro-5-methylsulfonylaminophenyl)-4,5-dihydro-3-difluoromethyl-1H-1,2,4-triazol-5-one; 1-(5-methylsulfonylaminophenyl)-4,5-dihydro-3-trifluoromethyl-IH-1,2,4-triazol-5-one, 1-(4-chloro-5-methylsulfonyl amino phenyl)-4,5-dihydro-3-trifluoromethyl-IH-1,2,4-triazol-5-one and 1-(2,4-dichloro-5-methylsulfonyl amino phenyl)-4,5-dihydro-3-methyl-4-difluoromethyl-5-oxo-IH-1,2,4-triazol-5-one or the like.
In an embodiment, the process involves a step of filtration of the reaction mixture after chlorination step and the product is isolated as solid, and the filtrate is recycled back into the reaction to avoid any aqueous effluent generation.
In another embodiment, the reaction mixture is extracted in a solvent and the organic layer is concentrated to obtain product. The solvent for extraction are selected from N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile ethylacetate, dichloromethane, acetone, methyl tert-butyl ether, diethyl ether, dichloroethane, tetrachloromethane, toluene and methanol or the like.
In another embodiment, the reaction mixture is extracted in a solvent to get an organic phase and aqueous hydrochloric acid phase, the organic layer is concentrated to obtain product and the aqueous hydrochloric acid phase is recycled back into the reaction to avoid any aqueous effluent generation.
In an embodiment of the present invention, the step of converting 4-chloroaniline to 4-chlorophenyl hydrazine, involves diazotization, reduction, and hydrolysis step.
In an embodiment of the present invention, the step of converting 4-chloroaniline to 4-chlorophenyl hydrazine involves diazotisation using a diazotization agent in an acid, followed by reduction using a reducing agent and a base and then hydrolysis using an acid.
In an embodiment, diazotizing agent is selected from a group consisting of sodium nitrite, potassium nitrite and nitrosyl sulfuric acid or the like.
In an embodiment, a reducing agent is selected from a group consisting of sodium sulphite, sodium bisulphite, ammonium sulphite, ammonium bisulphite, potassium bisulphite and potassium sulphite or a mixture thereof.
In an embodiment, a base is selected from a group consisting of sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and ammonia, or the like and a mixture thereof.
In an embodiment of present invention, acid is selected from a group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid and formic acid or the like.
In another embodiment of the present invention, the diazotisation step of converting 4-chloroaniline to 4-chlorophenyl hydrazine is carried out using sodium nitrite in presence of hydrochloric acid in water.
In another embodiment of the present invention, the step of converting 4-chloroaniline to 4-chlorophenyl hydrazine, after acid hydrolysis and salt formation, is followed by addition of a solvent and a base and a step of extraction with solvent. The solvent is selected from a group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, tert-butanol and n-pentanol or the like.
In another embodiment of the present invention, the step of converting 4-chlorophenyl hydrazine to 2-(4-chlorophenyl)-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-one involves reacting 4-chlorophenyl hydrazine with acetaldehyde in presence of sodium cyanate, sodium hypochlorite and acetic acid in a solvent.
In another embodiment of the present invention, the step of converting 4-chloroaniline to 4-chlorophenyl hydrazine to 2-(4-chlorophenyl)-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-one are carried out in situ, without isolation of 4-chlorophenyl hydrazine.
In another embodiment of the present invention, the step of difluoromethylation of 2-(4-chlorophenyl)-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(4-chlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one is carried by reacting 2-(4-chlorophenyl)-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-one with chlorodifluoromethane (R-22) in presence of a base selected from sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide or the like.
In another embodiment of the present invention, the step of difluoromethylation is carried by using 1-2 molar ratio of R-22, and more preferably 1-1.2 w.r.t 2-(4-chlorophenyl)-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-one. The process provides complete consumption of R-22, which has high ozone depleting potential, thereby reducing its exposure to the environment.
In another embodiment of the present invention, the step of chlorination of 2-(4-chlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one is carried out using chlorine in presence of hydrochloric acid as a solvent.
The use of hydrochloric acid as a solvent not only improves the yield but also provides a safer option compared to the use of DMF as a solvent which results in the formation of an explosive compound in presence of hydrochloric acid generated in the reaction, DMF and chlorine is also not suitable mixture.
In another embodiment of the present invention, the step of nitration of 2-(2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one is carried out using a mixture of nitric acid and oleum.
In another embodiment of the present invention, the step of nitration of 2-(2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one is carried out using a mixture of nitric acid and oleum, prepared by adding nitric acid to oleum having sulfur trioxide content of 20-30% at a temperature of 0-10°C.
In another embodiment of the present invention, the step of nitration of 2-(2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one is carried out using a mixture of nitric acid and oleum, where solution of 2-(2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one in dichloromethane is added to a portion of oleum followed by addition of nitrating mixture. The nitrating mixture is a mixture of nitric acid and oleum.
In another embodiment of the present invention, after nitration step, the reaction mixture is quenched with water in continuously stirred tank reactor (CSTR). The quenching step when carried out in CSTR, reduces the volume of the quenching stage, the high volume at this stage was one of the major challenges in this process. High volume leads to low throughput and better control of exothermicity of the reaction and improved quality of the product.
In another embodiment of the present invention, the step of reduction of 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one is carried out using hydrogen in presence of a hydrogenation catalyst selected from a group consisting of Raney nickel, palladium on carbon, platinum and platinum oxide or the like.
In another embodiment of the present invention, the step of reduction of 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one is carried out using hydrogen in a solvent selected from alkyl or phenyl esters like methyl formate, methyl acetate, ethyl acetate, ethyl propionate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isopropyl butyrate and ethyl benzoate or the like.
In another embodiment of the present invention, the step of reduction of 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one is carried out at 10 to 60°C and preferably at 30-50°C.
In another embodiment of the present invention, the step of reduction of 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one is carried out either in batch or continuous mode.
In another embodiment of the present invention, the step of reduction of 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one is carried by using 0.01-3.0 mole equivalents of catalyst w.r.t. 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one and preferably using 0.02-0.5 mole equivalent of catalyst.
In another embodiment of the present invention, the step of mesylation of 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain N-2,4-dichloro-5-4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl methanesulfonamide is carried out by reacting it with methylsulfonyl chloride in a solvent selected from toluene, xylene, acetonitrile, tetrahydrofuran, 1,4-dioxane and diethylbenzene in presence of catalyst selected from a group consisting of aprotic compounds such as NMP, DMSO, DMF, pyridine or like, and a phase transfer catalyst such as tetramethyl ammonium chloride, benzyltriethylammonium chloride and methyltributylammonium chloride or the like.
In another embodiment of the present invention, the step of mesylation of 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain N-2,4-dichloro-5-4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl methanesulfonamide is carried out by reacting it with methylsulfonyl chloride in a solvent in a continuous flow reactor. In continuous flow reactor, the feed of 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one and methylsulfonyl chloride are continuously and simultaneously supplied to the flow reactor, and substantially pure compound is continuously separated from the continuous flow reactor.
In an embodiment, the present invention provides a process for preparation of N-2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]phenyl methanesulfonamide, comprising the steps of:
a) converting anilines to phenyl hydrazines;
b) converting phenyl hydrazines to 2-(phenyl)-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-ones;
c) difluoromethylation of 2-(phenyl)-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-ones to obtain 2-(phenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-ones;
d) optionally chlorinating 2-(phenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one;
e) nitration of 2-(2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one;
f) reduction of 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one; and
g) mesylation of 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain N-2,4-dichloro-5-4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl methanesulfonamide.
In another embodiment of the present invention, the anilines is either aniline or 4-chloroaniline, likewise, phenyl hydrazines is either phenyl hydrazine or 4-chlorophenyl hydrazine; 2-phenyl-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-ones is either 2-phenyl-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-one or 2-(4-chlorophenyl)-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-one; 2-(chlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-ones is either 2-(4-chlorophenyl-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one or 2-(2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one.
In another embodiment, the present invention provides a process for preparation of N-2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]phenyl methanesulfonamide, comprising the steps of:
a) converting 4-chloro-aniline to 4-chlorophenyl hydrazine;
b) converting 4-chlorophenyl hydrazine to 2-(4-chlorophenyl)-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-one;
c) difluoromethylation of 2-(4-chlorophenyl)-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(4-chlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one;
d) chlorination of 2-(4-chlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one;
e) nitration of 2-(2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one;
f) reduction of 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one; and
g) mesylation of 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain N-2,4-dichloro-5-4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl methanesulfonamide.
The present invention for preparation of the compound of formula I has following advantages over the known methods:
1. The use of mild reaction condition in form of using low temperature range prevents degradation of product and improves yield significantly.
2. The mode of addition of reactant and reagent used in the reaction positively affects the product selectivity. The present inventors observed an improvement in the selectivity with slow and continuous addition of methylsulfonyl chloride to the reaction mixture.
4. The process of present invention helps in efficient recycling and recovery of solvents.
5. The process of present invention is safe at commercial scale.
In another embodiment, the solvent used in the reaction are recovered, recycled and reused.
The compound of N-2,4-dichloro-5-4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triaszol-1-yl)phenyl methane sulfonamide is isolated by any method known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or a mixture thereof.
The completion of the reaction may be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), Gas chromatography (GC), liquid chromatography (LC) and alike.
The present invention provides a process for preparation of compound of formula I, having purity greater than 95% and preferably greater than 98%.
Unless stated to the contrary, any of the words “comprising”, “comprises” and includes mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
Embodiments of the invention are not mutually exclusive but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The following example is given by way of illustration and therefore, should not be construed to limit the scope of the present invention.

EXAMPLES
Example 1: Preparation of 1-(2,4-dichlorophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one
4,5-Dihydro-3-methyl-1-phenyl-1H-1,2,4-triazol-5-one (50 g, 0.29 moles) and aqueous hydrochloric acid (584g, 4.0 moles) were added to a reactor. The reaction mass was heated to a temperature of 50°C, and then aqueous hydrogen peroxide (43.38 g, 0.638moles) was added in an hour to the reaction mass. The reaction was monitored (compound II <0.5%) by liquid chromatography. After completion of reaction, the reaction mixture was cooled to a temperature of 20°C and filtered to get 1-(2,4-dichlorophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one and the aqueous filtrate is recycled back into the next batch.
HPLC purity: 98.9%; Yield: 97%.
Example 2: Preparation of 1-(2,4-dichlorophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one from 4,5-dihydro-1-(4-chloro phenyl)-3-methyl-1H-1,2,4-triazol-5-one.
4,5-Dihydro-1-(4-chloro phenyl)-3-methyl-1H-1,2,4-triazol-5-one (50 g, 0.23 moles) and hydrochloric acid (503g, 4.0 moles) was added to a reactor. The reaction mixture was heated to a temperature of 45-50°C, and then aqueous hydrogen peroxide (50%, 23.8 g, 0.35 moles) was added in an hour to the reaction mass. The reaction was monitored (compound II <0.5%) by HPLC. After completion of reaction, the reaction mixture was cooled to a temperature of 20°C and filtered to get 1-(2,4-dichlorophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one and the aqueous filtrate was recycled back into the next reaction.
HPLC purity: 98.23%; Yield: 95.6%
Example 3: Preparation of 1-(2,4-dichlorophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one using acetic acid and water solvent.
4,5-Dihydro-3-methyl-1-phenyl-1H-1,2,4-triazol-5-one (0.057moles), acetic acid (91g, 1.52 moles) and aqueous HCl (20.6 g, 0.17 moles) was added to a reactor and heated to a temperature of 55 °C, followed by addition of 13.2 g (0.116 moles) of aqueous hydrogen peroxide in 30 minutes. Upon completion of the addition, sample were taken for analysis by HPLC till the starting compound was <0.5%. After completion of the reaction, water (200 g) was added and filtered the reaction mass to isolate 1-(2,4-dichlorophenyl)-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one. HPLC purity:98.3%; Yield: 93%.
Example 4: Preparation of 1-(2,4-dichlorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one
4-Difluoromethyl-4,5-dihydro-3-methyl-1-phenyl-1H-1,2,4-Triazol-5-one (0.25 moles) and aqueous hydrochloric acid (3.5 moles) were added to a reactor and heated to a temperature of 50-55°C and then aqueous hydrogen peroxide (0.50 moles) was added in an hour. The reaction was monitored (compound II <0.5%) by liquid chromatography. After completion of reaction, the mixture was cooled to a temperature of 20°C and filtered to get 1-(2,4-dichlorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one. HPLC purity: 99%; Yield: 92%.
Example 5: Preparation of 1-(2,4-dichlorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one using magnesium chloride catalyst.
4-Difluoromethyl-4,5-dihydro-3-methyl-1-phenyl-1H-1,2,4-triazol-5-one (0.31 moles), manganese chloride (0.006 mole) and an aqueous hydrochloric acid (2.0 moles) was added to a reactor and heated to a temperature of 50°C, and then aqueous hydrogen peroxide (0.63 moles) was added in an hour. The reaction was monitored (compound II <0.5%) by liquid chromatography. After completion of reaction, the mixture was cooled to a temperature of 20°C and filtered to obtain the 1-(2,4-dichlorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one. HPLC purity: 96.7%; Yield: 94%
Example 6: Preparation of 1-(2,4-dichlorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one from 1-(4-chlorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1-phenyl-1H-1,2,4-triazol-5-one
1-(4-Chlorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1-phenyl-1H-1,2,4-triazol-5-one (0.5 moles) and aqueous hydrochloric acid (4.0 moles) was added to a reactor and heated to a temperature of 50-60°C, and then aqueous hydrogen peroxide (0.50 moles) was added in an hour. The reaction was monitored (compound II <0.5%) by liquid chromatography. After completion of reaction, the mixture was cooled to a temperature of 20°C and filtered to get 1-(2,4-dichlorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1H-1,2,4-triazol-5-one. HPLC purity: 97%; Yield: 95%
Example 7: Preparation of 4-chlorophenyl hydrazine
Water (288g), 4-chlorophenyl aniline (125g) were added to a reactor followed by addition of concentrated hydrochloric acid (225g) at 20-30? under stirring. The mixture was cooled 0 to 5°C and a 30% aqueous solution of sodium nitrite (250g) was added in two hours to obtain a reaction mass. The reaction mass was added to a mixture of aqueous solution of sodium carbonate (487g of 15%) and an aqueous solution of sodium bisulfite (570g of 30%) dropwise in 30-40 minutes while maintaining temperature to 30-40°C and pH to 6.3 to 6.5. After complete addition, reaction mass was stirred at 30-40°C for an hour and heated to 90-95°C for 2-3 hours. The reaction mass was cooled to 40-50°C and an aqueous solution of hydrochloric acid (35%; 338g) was added and the mixture was again heated to 90-95 °C for 3 hours. The mixture was cooled to a temperature of 25°C and added t-butanol (370g) to the reaction mass in 2 hours. To the reaction mixture was dropwise added aqueous solution of sodium hydroxide (345g of 48%) at 25-30°C, under nitrogen atmosphere, to adjust the pH of reaction mass 8.2 to 8.7. The layers were separated and extracted with t-butanol. The combined organic layer was taken for further step without purification. Yield: 95% (4-chlorophenyl hydrazine (CPH) in tert. butanol solution)
Example 8: Preparation of 2-(4-chlorophenyl)-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-one
Organic phase (609g) from previous step, having chlorophenyl hydrazine in tert. butanol was charged into a 2000ml RBF. The mixture was cooled to 0-5°C and added a solution of acetaldehyde in tert. butanol (156g, 39g acetaldehyde + 117g aq. 88% t-butanol) in 40-50 minutes. The reaction mass was stirred for 10-15 minutes at same temperature and reaction progress was monitored on HPLC till 4-chlorophenyl hydrazine is <0.5%. An aqueous solution of sodium cyanate (353g, 11%, freshly prepared) was added at 0-5°C in 30-40 minutes. Further, the mixture was maintained at 0-5°C for 10-15 minutes and acetic acid (38.9g) was added dropwise into the mass at 0-5°C in 30-40 minutes. The reaction mass was stirred for 3 hours, and reaction progress was monitored by HPLC. After completion of the reaction, an aqueous sodium hypochlorite (350g, 10-11% solution) was dropwise added in 1.5-2 hours and maintained the reaction mass for 1-2 hour. The reaction was monitored by HPLC, after completion of the reaction, the mixture was heated to recover tert-butanol completely from the reaction mixture. The reaction mass was cooled to 0-5°C and adjusted pH of the reaction mixture to 6.5-7.0 using aqueous HCl (15-16%). The reaction mass was filtered, and wet cake was washed with water (72g). The cake was further washed with dichloromethane (150g). The wet cake was dried at 50-60°C and 10mbar vacuum for 2 hours (yield: 85-86%)
Example 9: Preparation of 2-(4-chlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one
To a vacuum distillation set-up of 2000ml 4 neck RBF equipped with one feet glass column, TP, stopper, a reflux divider, a double surface condenser, DMF (1670g), Example-2 solid (105g, assay 95%), potassium carbonate (54g) was charged at 25-30°C. The mixture was stirred and heated to 120°C and 240-250mbar. The refluxing was started at mass temperature 110-120°C and 240-260mbar vacuum, under TR/TP mode and collected distillate (822g). The distillate was checked for water content to obtain <1000ppm and stopped the heating. The mixture was cooled to 25-40°C and transferred the mixture to a pressure reactor. The reactor was flushed with nitrogen, heated to 160°C and added chlorodifluoromethane in 10 minutes. The mixture was maintained for 2-3 hours at 160°C and checked the progress of the reaction by HPLC. Once conversion achieved, the reaction mass was cooled to 20-30°C and released the pressure of the reactor. The mixture was filtered to remove spent salt and taken ML for DMF removal. Water was added to the concentrated ML, cooled the mixture to 5°C and the mass was filtered to isolate wet cake. The wet cake was washed with water and transferred to next stage (yield 95%).
Example 10: Preparation of 2-(2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one
Aqueous hydrochloric acid (225g of 30%), Example-9 product (25g, 98%), 0.15g iron powder (0.15g) and silica (0.5g or sodium metasilicate) were charged into a 500ml RBF. The mixture was agitated and heated to 65-70°C, followed by purging of chlorine gas (10g) into the reaction mixture in 4-5 hours. The progress of the reaction was checked by HPLC. The mixture was cooled to 60°C, added chloroform (25g) and purged chlorine gas (3g). The mixture was cooled to 20-25°C and added dichloromethane (150g). The mixture was stirred for 30 minutes and filtered to remove inorganic solids. The mother liquor was filtered and taken for layer separation to obtain organic phase and aqueous layer, which was recycled back in the next batch. The organic phase was washed with water and separated phases. The organic phase was concentrated and removed dichloromethane and chloroform. Isopropyl alcohol (60g) was added to the concentrated mass and heated the mixture to 75°C. Then, mixture was slowly cooled to 5 °C in 3 hours and filtered to get the solid (Yield: 90%).
Example 11: Preparation of 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one
Preparation of nitrating mixture:
Oleum (158 g, SO3 content 20.2%) was charged in a round bottom flask, cooled to 0-10°C and dropwise added nitric acid (27g, 87%) while maintaining the mass temperature 0-10°C. After addition completed, the mass was stirred for 10-15 minutes.
Nitration:
Oleum (315 g) was charged in a 1 Litre four neck RBF and cooled to 20°C. Example-4 product (20%, 100g example-4 in 409g dichloromethane) was added in the oleum at 20-30°C in 30-45 minutes. The mass was stirred for 10 minutes, added nitrating mixture dropwise at 20-30°C, and maintained the mass for 3 hours at 20-30°C. The reaction progress was checked on HPLC and cooled the reaction mixture to 0-5°C. Then, simultaneously the cooled reaction mixture, cooled water (1100g) and cooled dichloromethane (400g) were charged in a continuous stirred vessel (A) by maintaining a flow rate of each stream at 5°C. The exit of stirred vessel A was entered into another stirred vessel B operated at 25°C. The exit of vessel B was entered into non stirred vessel C for layer separation. The layers were separated, extracted aqueous layer with DCM (400g) and separated again. The combined organic phase was extracted with aqueous NaCl (15%, also containing 1% sodium bicarbonate, 250g) solution and separated organic phase and aqueous phase. The organic phase was concentrated for dichloromethane removal at 50-55 °C and atmospheric pressure. Ethyl acetate was added in the concentrated mass and further concentrated for complete removal of dichloromethane and obtaining product in ethyl acetate (conc. 15-20%). The product in ethyl acetate was transferred to next step (Yield: 95%).
Example 12: Preparation of 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one
Example-5 solution in ethyl acetate (w/w% 15%, 353g) was charged in a 700ml pressure reactor at 40-45°C and added nickel catalyst (2.38g). The reactor was boxed up and flushed with nitrogen gas and followed by hydrogen gas.
The reaction mixture was heated to 50°C and pressurized with hydrogen gas up to 10 bar and maintained for 8-10 hours. The progress of the reaction was checked by HPLC. After conversion achieved, the reaction mixture was cooled to 30-35°C and filtered to remove the nickel catalyst using hi-flow bed. The spent catalyst was first washed with ethyl acetate and then with water to leave spent catalyst in wet form.
The combined filtrate was taken for distillation where first 80% ethyl acetate was distilled out atmospherically at 70-80°C. Then, 300g toluene (300g) was added to the distillation bottom mass and distilled to remove remaining ethyl acetate followed by toluene removal and isolated product in toluene, that transferred to next step (Yield: 93.6%)
Example 13: Preparation of N-2,4-dichloro-5-4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl methanesulfonamide
Alternate Example 1 (Using NMP catalyst)
A solution of example-6 product (47.5g) in toluene (460g) was charged in a 1000ml RBF and removed residual water (azeotropically) and excess toluene to give concentrated example-6 in toluene (30%, 158g). Then, concentrated example-6 product in toluene was heated to 110-115°C, NMP (0.58g) was added and methyl sulfonyl chloride (27.4g) was then added dropwise at 110-115°C to the above mixture till HCl gas evolution was observed. The reaction mixture was maintained at 110-115°C for 20 hours and monitored reaction by HPLC. The reaction mixture was cooled to 80-85°C and toluene (233g) was added. Then, hot water (315g) was added dropwise to the reaction mixture at 80-85 °C in 1 hours and maintained the mixture for 30 minutes. The reaction mass was separated into layers, heated organic phase to 80-85°C and hot water was added in 30 minutes. The reaction mass was maintained for 30 minutes, and layers were separated. The combined organic phase was gradually cooled to 18°C from 80°C in 8 hours and filtered to get solid product. The solid cake was washed with toluene and dried under reduced pressure at 60-70°C (Yield: 85%).
Alternate Example 2 (Using pyridine)
A solution of example-6 product in toluene (170g, Example-6: 25g) was charged into 250ml RBF and removed residual water (azeotropically) and excess toluene to give concentrated step-6 in toluene (50 g, 50% Example-6 concentrated in toluene). Then, the mixture was heated to 85-90°C, added pyridine (0.25g) and added methyl sulfonyl chloride (15.2g) dropwise at 85-90°C to the above mixture till HCl gas evolution was observed. The reaction mass was maintained at 115-120°C for 24 hours and monitored by HPLC. The reaction mixture was cooled to 80-85°C and added toluene (154g). Then, hot water (175g) was added in the above reaction mixture in 30 minutes at 80-85 °C and maintained for 30 minutes and separated into layers. The aqueous phase was separated, added hot water to the organic phase at 80-85°C, maintained for 30 minutes and separated into layers. The organic phase at 80°C was gradually cooled to 18°C in 8 hours and filtered to get solid product. The solid cake was washed with toluene and dried under reduced pressure at 60-70°C (Yield: 85%).
Alternate Example 3 (Using PTC (Tetramethyl ammonium chloride) catalyst)
A solution of example-6 in toluene (170g, Example-6: 25g) and tetramethyl ammonium chloride (0.75 g) were charged to 250ml RBF and removed residual water (azeotropically) and excess toluene to obtain example-6 concentrated in toluene (50%, 50g). The mixture was heated to 110-115°C and added methane sulfonyl chloride (15.2g) dropwise to the above mixture till the HCl gas evolution was observed. The reaction mixture was maintained at 115-120 °C for 10-12 hours and monitored by HPLC. The reaction mixture was cooled to 80-85 °C, added toluene (154g) and added hot water (175g) in the above mixture in 1 hours at 80-85°C. The mixture was maintained for 30 minutes and separated organic and aqueous phase. The organic phase was added with hot water at 80-85 °C and maintained for 30 minutes. The layers were separated to get organic and aqueous phase. The organic phase was gradually cooled to 18°C from 80°C in 8 hours and filtered to get solid cake. The solid cake was washed with toluene and dried under reduced pressure at 60-70°C (yield: 84%).
,CLAIMS:WE CLAIM
1. A process for preparation of a compound of formula I,

Formula I
wherein R is hydrogen, NR1R2, NO2, NR1SO2CH3; R1 and R2 are independently hydrogen, alkyl, halogenated alkyl, halogenated aryl, aryl, substituted aryl; X’ is chloro and n is an integer from 1-3.
comprising chlorinating a compound of formula II,

Formula II
wherein R is hydrogen, NR1R2, NO2, NR1SO2CH3; R1 and R2 are independently hydrogen, alkyl, halogenated alkyl, halogenated aryl, aryl, substituted aryl; X is chloro, bromo or iodo, and d is an integer from 0-2, provided d=n.
using hydrochloric acid and an oxidising agent.
2. The process as claimed in claim 1 for preparation of N-2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]phenyl methanesulfonamide, comprising the steps of:
a) converting anilines to phenyl hydrazines;
b) converting phenyl hydrazines to 2-(phenyl)-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-ones;
c) difluoromethylation of 2-(phenyl)-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-ones to obtain 2-(phenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-ones;
d) optionally chlorinating 2-(phenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one;
e) nitration of 2-(2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one;
f) reduction of 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one; and
g) mesylation of 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain N-2,4-dichloro-5-4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl methanesulfonamide.
3. The process as claimed in claim 2, the anilines is either aniline or 4-chloroaniline, likewise, phenyl hydrazines is either phenyl hydrazine or 4-chlorophenyl hydrazine; 2-phenyl-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-ones is either 2-phenyl-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-one or 2-(4-chlorophenyl)-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-one; 2-(chlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-ones is either 2-(4-chlorophenyl-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one or 2-(2, 4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one.

4. The process as claimed in claim 1, wherein the oxidising agent is selected from a group consisting of hydrogen peroxide, potassium permanganate, sodium hypochlorite, sodium chlorite, sodium chlorate, sodium dichromate, perchlorate, chlorine dioxide, chlorine, and sodium chloride with hydrogen peroxide.
5. The process as claimed in claim 2, wherein step of converting anilines to phenyl hydrazines involves diazotisation using a diazotization agent in an acid, followed by reduction using a reducing agent and a base, and then hydrolysis using an acid.
6. The process as claimed in claim 2, wherein phenyl hydrazines is reacted with acetaldehyde in presence of sodium cyanate, sodium hypochlorite and acetic acid in a solvent to obtain 2-(phenyl)-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-ones.
7. The process as claimed in claim 2, wherein the step of difluoromethylation involves reaction of 2-phenyl-1,2-dihydro-5-methyl-3H-1,2,4-triazol-3-ones with chlorodifluoromethane (R-22) in presence of a base selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide to obtain 2-phenyl-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-ones.
8. The process as claimed in claim 2, wherein, the step of nitration of 2-(2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-ones to obtain 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one is carried out using a mixture of nitric acid and oleum.
9. The process as claimed in claim 2, wherein the step of reduction of 2-(2,4-dichlorophenyl-5-nitro)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one is carried out using hydrogen in presence of a hydrogenation catalyst selected from a group consisting of Raney nickel, palladium on carbon, platinum and platinum oxide.
10. The process as claimed in claim 2, wherein the step of mesylation of 2-(2,4-dichlorophenyl-5-amino)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one to obtain N-2,4-dichloro-5-4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl methanesulfonamide is carried out by reacting it with methylsulfonyl chloride in presence of a catalyst selected from a group consisting of NMP, DMSO, DMF, pyridine and a phase transfer catalyst selected from a group consisting of tetramethyl ammonium chloride, benzyltriethylammonium chloride and methyltributylammonium chloride.

Dated this 25th day of February, 2022.