FIELD OF THE INVENTION
The present invention relates to an industrially advantageous, improved and safe process for preparation of 1-{2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidine-4-carbothioamide.

BACKGROUND OF THE INVENTION
1-{2-[5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidine-4-carbothioamide, formula I, is used as an important intermediate for synthesizing the agrochemical and pharmaceutical products.

Formula I
US Patent No. 9,604,962 describes a process for preparation of compound of
formula I by reacting 1-{2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl} piperidine-4-carbonitrile having structural formula II with hydrogen sulfide gas to obtain compound of formula I having 3% of its regioisomer.

Formula II
The said patent suffers from the drawback such that the direct supply of hydrogen sulfide gas to the reaction vessel is prone to leakage the gas during its supply. The leakage and exposure to hydrogen sulfide gas can cause safety and health hazards to the people employed in the process. So, the said process for preparation of compound of formula I is unsafe and tedious.
Therefore, there is urgent need for development of an industrially advantageous, efficient and safe process for preparation of compound of formula I.

OBJECT OF THE INVENTION
The main object of the present invention is to provide an industrially advantageous, efficient and safe process for preparation of a compound of formula I.

Formula I

SUMMARY OF THE INVENTION
In first aspect, the present invention relates to a process for preparation of a compound of formula I,

Formula I
comprising the steps of:
a) reacting a compound of formula V,

Formula V
wherein R is selected from H, alkyl or aryl
with a compound of formula IV in a solvent to obtain compound of formula III

Formula IV

Formula III

wherein n is 0 or 1; m is 1-3; X1 is leaving group and X2 is selected from H, halogen, alkyl, haloalkyl or aryl
b) converting compound of formula III to compound of formula II;

Formula II
wherein R3 is substituted pyrazole ring;
c) reacting compound of formula II,

Formula II
with salt of sulfide to obtain the compound of formula I.

In second aspect, the present invention relates to process for preparation of compound of formula I,

Formula I
comprising the steps of:
a) reacting compound of formula V,

Formula V
wherein R is selected from H, alkyl or aryl;
with a compound of formula IV,

Formula IV
wherein n is 0 or 1; m is 1-3; X1 is leaving group and X2 is selected from H, halogen, alkyl, haloalkyl or aryl.
in a solvent to obtain the compound of formula III; and

Formula III
wherein n is 0 or 1; m is 1-3 and X2 is selected from H, halogen, alkyl, haloalkyl or aryl.
b) converting the compound of formula III to compound of formula I.

In third aspect, the present invention relates to process for preparation of compound of formula I,

Formula I
comprising the steps of:
a) reacting compound of formula II,

Formula II
with salt of sulfide to obtain a reaction mixture; and
b) isolating the compound of formula I; from step a) reaction mixture.

Formula I

DETAILED DESCRIPTION OF THE INVENTION
As used herein, a halogen is defined as group comprises of fluorine, chlorine, bromine and iodine.
As used herein, an alkyl is defined as a group comprises C1 to C8 carbon in aliphatic straight or branched chain.
As used herein, a leaving group is defined as a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage includes halogen, ester, azide or the like.
As used herein, an aryl is defined substituted or unsubstituted benzene, pyridine or pyrazole ring.
As used herein, a base is selected from inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydride or the like. The base can also be selected from organic bases such as triethylamine, tertiary butyl amine, butyl lithium or the like.
The conversion of formula III to compound of formula II can be carried out by coupling reaction in the presence of a base.
The coupling reaction may be carried out by any process known in the art.
In an embodiment of the first aspect, the present invention provides a process for preparation of a compound of formula I:

Formula I
comprising the steps of:
a) reacting piperidine-4-carboxamide with chloroacetyl chloride in an aprotic solvent to obtain 1-(2-chloroacetyl) piperidine-4-carbonitrile;
b) converting 1-(2-chloroacetyl) piperidine-4-carbonitrile to a compound of formula II

Formula II
by reacting it with 5-methyl-3-trifluoromethylpyrazole in presence of a base;
c) reacting a compound of formula II with a salt of sulfide to obtain the compound of formula I.
The aprotic solvent may be selected from the group comprising of sulfolane, dimethylformamide, diethylformamide, dimethylacetamide, N-methylpyrrolidone, N-vinylpyrrolidone, hexamethylphosphoramide, acetonitrile, dimethylsulfoxide, propylene carbonate, 1,3-Dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone, dimethylurea, tetramethylurea, di-t-butylurea, and a like or mixture thereof.
The step a) of the process may be carried out in presence of an additional solvent selected from dichloromethane, carbon tetrachloride, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, hexane, heptane, cyclohexane, toluene, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, acetonitrile or mixtures thereof.
The step a) of the process is carried out at a temperature in the range of 0ºC to 60ºC or preferably in the range of 5ºC to 50ºC or more preferably in the range of 10ºC to 50ºC.
In an embodiment of the third aspect, the present invention provides a process for preparation of a compound of formula I:

Formula I

comprising the steps of:
a) reacting a compound of formula II

Formula II
with a salt of sulfide to obtain the compound of formula I;
b) isolating the compound of formula I from the reaction mixture of step a).
The salt of sulfide is selected from alkali metal hydrosulfide, alkali metal sulfide, and inorganic sulfide or hydrate thereof.
The alkali metal hydrosulfide is selected from sodium hydrosulfide and potassium hydrosulfide etc. The alkali metal sulfide is selected from sodium sulfide and potassium sulfide. The inorganic sulfide is such as ammonium sulfide, sodium sulfide, potassium sulfide and alike.
It is advantageous to use the salt of sulfide. The salt of sulfide in-situ generated hydrogen sulfide gas. The in-situ generated hydrogen sulfide gas can be used in a controlled manner for reaction as compared to direct use of hydrogen sulfide gas.
Therefore, the risk that may be faced during the supply of hydrogen sulfide gas to the reaction vessel is diminished.
Optionally, the reaction of formula II with salt of sulfide can be carried out in the presence of amine or ammonium salt.
The salt of amine can be selected from hydrochloride or hydrobromide; wherein amine can be selected from aliphatic amine such as methylamine, diethylamine, methoxamine, trimethylamine, propylamine, isopropylamine, butylamine, isobutylamine and aromatic amine such as pyridine, aniline and their derivatives.
The ammonium salt can be selected from ammonium chloride, ammonium nitrate, ammonium sulfate and alike.
The reaction of compound of formula II with salt of sulfide is carried out in the presence of solvent. The solvent can be selected from ether, alcohol, ketone, amide and water or mixture thereof.
The ether solvent can be selected from 1,4-dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran and alike or mixture thereof.
The alcohol solvent can be selected from ethanol, methanol, propanol, isopropanol and alike or mixture thereof.
The ketone solvent can be selected from acetone, methyl isobutyl ketone, methyl ethyl ketone and alike or mixture thereof.
The amide solvent can be selected from dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and alike or mixture thereof.
The reaction is carried out at a temperature in the range of 40ºC to 60ºC. The time taken for completion of the reaction is from 5 hours to 10 hours.
After completion of the reaction, the reaction mass is cooled to a temperature below 30ºC. Thereafter, the reaction mixture is diluted with water and stirred for 20 to 50 minutes to obtain a reaction mixture. The resulting reaction mixture is filtered to obtain the compound of formula I.
In an embodiment, the present invention provides a compound of formula I having more than 3% of regio-isomer impurity.

Regioisomer Impurity
The compound of formula I can be analysed by any one of chromatographic techniques such as Thin layer chromatography (TLC), High pressure liquid chromatography (HPLC), Ultra-pressure liquid chromatography (UPLC) and the like.
The compound of formula V, IV, II and 5-methyl-3-trifluoromethylpyrazole which are used as a starting material can be prepared by any method known in the art or can be obtained commercially.
It is against this and other backgrounds, which shall be filed in a detailed manner in complete specifications, in due course, the present invention is brought out and explained in following non-limiting examples.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention.
Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
EXAMPLES
Example 1: Preparation of 1-(2-chloroacetyl) piperidine-4-carbonitrile
Chloroacetyl chloride (201 g) was added dropwise to a slurry of piperidine-4-carboxamide (91 g), N,N-dimethyl formamide (315g) and dichloromethane (789 g moles) at a temperature of 20°C over the period of one and half hours. After complete addition of chloroacetyl chloride, temperature of the reaction mass was increased to 50°C to obtain a clear homogeneous solution. After the reaction completion, the reaction mass was cooled to 20°C and washed with brine solution and sodium bicarbonate solution to remove side products. Then the organic layer was concentrated to get the titled compound.
Yield: 80%
Purity (GC): 90%.

Example 2: Preparation of 1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbonitrile
A solution of 5-methyl-3-trifluoromethylpyrazole (9.3 g, 62 mmol) and 45% aqueous potassium hydroxide solution (7.79 g, 62 mmol) in N,N-dimethylformamide (25 mL) was cooled to 5°C and 1-(2-chloroacetyl)-4-piperidinecarbonitrile (11.2 g, 60 mmol) was added. The reaction mixture was stirred for 8 hours at 5-10° C., then diluted with water (100 mL), and filtered. The filtered cake was washed with water and dried at 50° C. in a vacuum-oven to give the titled compound as a solid.

Example 3: Preparation of 1-{2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl] acetyl}piperidine-4-carbothioamide (formula I)
1-{2-[5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidine-4-carbonitrile (25g), water (100ml), 1,4-dioxane (99.51ml), sodium hydrosulfide hydrate (55g) and diethylamine hydrochloride (63.87g) were added to the reactor to obtain a reaction mixture. The reaction mixture was heated at 55°C under stirring for 8 to 10 hours. After completion of the reaction, monitored by HPLC, the reaction mixture was cooled to a temperature below 30°C and thereafter adding water (500ml), further stirred the reaction mixture for 30 minutes. Then the reaction mixture is filtered to obtain 28.6g of title compound. The filtrate was taken for next crop product recovery. The titled compound was analyzed by HPLC having following results.
Purity (HPLC) : 95.43%
Regioisomer Impurity : 3.91%
Unreacted starting intermediate : 0.58%

Example 4: Preparation of 1-{2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl] acetyl}piperidine-4-carbothioamide (formula I)
1-{2-[5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidine-4-carbonitrile (25g), water (100ml), 1,4-dioxane (99.51ml), sodium hydrosulfide hydrate (55g) were added to the reactor to obtain a reaction mixture. The reaction mixture was heated at 55°C under stirring for 8 to 10 hours. After completion of the reaction, monitored by HPLC, the reaction mixture was cooled to a temperature below 30°C and thereafter adding water (500ml), further stirred the reaction mixture for 30 minutes. Then the reaction mixture is filtered to obtain 28.6g of title compound. The filtrate was taken for next crop product recovery. The titled compound was analyzed by HPLC having following results.
Purity (HPLC) : 94.43%
Regioisomer Impurity : 4.01%
Unreacted starting intermediate : 0.58%

Example 5: Preparation of 1-{2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl] acetyl}piperidine-4-carbothioamide (formula I)
1-{2-[5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidine-4-carbonitrile (25g), water (100ml), 1,4-dioxane (99.51ml), sodium sulfide (60g) and diethylamine hydrochloride (63.87g) were added to the reactor to obtain a reaction mixture. The reaction mixture was heated at 55°C under stirring for 8 to 10 hours. After completion of the reaction, monitored by HPLC, the reaction mixture was cooled to a temperature below 30°C and thereafter adding water (500ml), further stirred the reaction mixture for 30 minutes. Then the reaction mixture is filtered to obtain 28.6g of title compound. The filtrate was taken for next crop product recovery. The titled compound was analysed by HPLC having following results.
Purity (HPLC) : 94.43%
Regioisomer Impurity : 3.71%
Unreacted starting intermediate : 0.68%

We Claims:
1. A process for preparation of compound of formula I,

Formula I
comprising the steps of:
a) reacting compound of formula V,

Formula V
wherein R is selected from H, alkyl or aryl
with compound of formula IV in a solvent,

Formula IV
to obtain compound of formula III,

Formula III
wherein n is 0 or 1; m is 1-3; X1 is leaving group and X2 is selected from H, halogen, alkyl, haloalkyl or aryl
b) converting compound of formula III to compound of formula II;

Formula II
c) reacting compound of formula II, with salt of sulfide to obtain the compound of formula I.
2. A process for preparation of compound of formula I,

Formula I
comprising the steps of:
a) reacting compound of formula V,

Formula V
wherein R is selected from H, alkyl or aryl;
with a compound of formula IV,

Formula IV
wherein n is 0 or 1; m is 1-3; X1 is leaving group and X2 is selected from H, halogen, alkyl, haloalkyl or aryl.
in a solvent to obtain the compound of formula III; and

Formula III
wherein n is 0 or 1; m is 1-3 and X2 is selected from H, halogen, alkyl, haloalkyl or aryl.
b) converting the compound of formula III to compound of formula I.

3. A process for preparation of compound of formula I,

Formula I
comprising the steps of:
a) reacting compound of formula II,

Formula II
with salt of sulfide to obtain a reaction mixture; and
b) isolating the compound of formula I; from reaction mixture of step a).
4. The process as claimed in claim 1 and 2, wherein the solvent used in step a) is an aprotic organic solvent selected from a group comprising of sulfolane, dimethylformamide, diethylformamide, dimethylacetamide, N-methylpyrrolidone, N-vinylpyrrolidone, hexamethylphosphoramide, acetonitrile, dimethylsulfoxide, propylene carbonate, 1,3-Dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone, dimethylurea, tetramethylurea, di-t-butylurea, or a mixture thereof.
5. The process as claimed in claim 1 and 2, wherein step a) reaction is carried out in presence of an additional solvent selected from dichloromethane, carbon tetrachloride, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, hexane, heptane, cyclohexane, toluene, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, and acetonitrile or a mixtures thereof.
6. The process as claimed in claim 1 and 2, wherein step a) reaction is carried out at a temperature selected in the range of 0ºC to 60ºC.
7. The process as claimed in claim 1 and 3, wherein salt of sulfide is selected from a group consisting of sodium hydrosulfide, potassium hydrosulfide, sodium sulfide, potassium sulfide, ammonium sulfide or hydrates thereof.
8. The process as claimed in claim 1 and 3, wherein the reaction of formula II with salt of sulfide is carried out in presence ammonium chloride, ammonium nitrate, ammonium sulfate, salts of methylamine, diethylamine, methoxamine, trimethylamine, propylamine, isopropylamine, butylamine, isobutylamine, pyridine and aniline.
9. The process as claimed in claim 1 and 3, wherein reaction of compound of formula II with salt of sulfide is carried out in the presence of a solvent selected from 1,4-dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, ethanol, methanol, propanol, isopropanol, acetone, methyl isobutyl ketone, methyl ethyl ketone, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone; and water or a mixture thereof.
10. The process as claimed in claim 1 and 3, wherein reaction of compound of formula II with salt of sulfide is carried out at a temperature selected in the range of 40ºC to 60ºC.