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

A NOVEL PROCESS FOR THE PREPARATION OF 1-(2-(5-METHYL-3-(TRIFLUOROMETHYL)-1H-PYRAZOL-1-YL) ACETYL) PIPERIDINE-4-CARBOTHIOAMIDE

PIRAMAL PHARMA LIMITED, a company incorporated under the Companies Act, 2013, of Ground Floor, Piramal Ananta, Agastya Corporate Park, Kamani Junction, LBS Marg, Kurla West, Mumbai 400070, State of Maharashtra, India
The following specification particularly describes the nature of this invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to an improved one-pot process for the preparation of 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carbothioamide intermediate of formula (1).

BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.

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

US Patent US8642634B2 describes a process for preparation of compound of formula (1) which is shown in below scheme 1.

The above synthetic Scheme for the preparation of 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carbothioamide (1) has some draw backs, which limits its scope on an industrial scale and some of the drawbacks are listed below:
a) Use of H2S gas at plant level is very cumbersome to handle due to its flammable and highly toxic nature;
b) Exposure to hydrogen sulfide gas can cause safety and health hazards to plant workers;
c) Short-term exposure leads to headache, nausea, convulsions, and eye and skin irritation. At high concentrations, may induce unconsciousness, coma, respiratory paralysis, seizures, even death;
d) H2S gas is heavier than air and accumulates in low lying areas of poorly ventilated spaces and in the presence of air and moisture, it may form sulfuric acid, capable of corroding metals, this may cause serious damages to plant equipment’s including reactors;
e) Considering its poisonous nature, it is not viable to use at plant level.

Hence, there is a continuous need to develop simple, commercially advantageous and industrially viable process for the preparation of 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl) piperidine-4-carbothioamide (1) that reduces the number of reaction steps and in turn increases overall yield of the final product.

The present invention offers an improved, efficient, economic, and production friendly process for preparation of 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carbothioamide (1).
OBJECTS OF THE INVENTION
An object of the invention is to provide a process for the preparation of 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carbothioamide (1).
Another object of the invention is to provide a process for the preparation of 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carbothioamide (1) with good yield and quality.
SUMMARY OF THE INVENTION
The problem addressed by the present invention is therefore that of providing a better process for preparing 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carbothioamide (1), which permits to avoid above reported with reference to the known prior art.
In one aspect, provided herein is an efficient and industrially advantageous process for the preparation of 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carbothioamide (1), in high yield and high purity. The process disclosed herein avoids the tedious procedure of the prior art processes, thereby resolving the problems associated with the processes described in the prior art, which is more convenient to operate on a commercial scale.
DETAILED DESCRIPTION OF THE INVENTION
Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only and is not intended to limit the scope of the present invention.
Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "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 the appended claims. Further the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.
In one of the embodiments, the present invention provides a process for the preparation of 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carbothioamide (1),

comprising;
(a) reducing isonicotinamide (7) with a reducing agent in a solvent and optionally in presence of a catalyst to give piperidine-4-carboxamide (8) ;

(b) reacting piperidine-4-carboxamide (8) with a compound formula (9) in a solvent and in presence of a base to give a compound of formula (10);

(c) reacting the compound formula (10) with 5-Methyl-3-trifluoro methyl -1H-pyrazole (11) in a solvent and in presence of a base to give 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)piperidine-4-carboxamide (12);

(d) reacting 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carboxamide (12) with a thionating agent in a solvent to give of 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carbothioamide (1).

The reduction of compound of formula (7) in step (a) is carried out using reducing agent selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, Fe/CaCl2, FeSO4, Fe powder, Raney Nickel, Pd/C, NaBH4, Potassium Borohydride, SnCl2.2H2O, Zn dust, Sodium Borohydride with Pd/C, thiophenol/trifluoroacetic acid, sodium sulphite, sodium hyposulphite, Na2S, NaBH4, NaBH4/BF3-diethyl ether, NiCl2.6H2O, LiBH4, LiAlH4. The reduction of the compound can be carried out using reducing agent and suitably, in the presence of Lewis acid selected from AlCl3, LiCl, or BF3 etherate; or hydrogen gas or a hydrogen source selected from ammonium formate, hydrazine hydrate, hydrazine glyoxylate, glyoxylic acid or hydrazinium monoformate. Preferably, the reducing agent is Pd/C and hydrogen gas.
The solvent used for reducing compound of formula (7) in step (a) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; a hydrocarbon solvent selected from toluene, hexane, heptane, pet ether, xylene, cyclohexane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone or methyl isobutyl ketone (MIBK); an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water; or a mixture thereof.
The catalyst used in step (a) is selected from Perchloric acid, Acetic acid, HBr, H2SO4, HNO3, HCl, HI, H3PO4, triflic acid, methansulfonic acid, benzenesulfonic acid or p-toluene sulfonic acid; or a mixture thereof.
The solvent used in step (b), step (c) and step (d) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected form acetone, propanone, methyl ethyl ketone or methyl isobutyl ketone; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water or a mixture thereof.
The base used in step (b) and step (c) is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; an alkali metal alkoxides selected from sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or an organic amines selected from triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

The thionating agent is selected from Lawesson's reagent, P2S5, or bistrimethylsylilsulfide.

The Lawesson's reagent, chemically designated as 2, 4-bis (4-methoxyphenyl)-1, 3, 2, 4- dithiadi- phosphetane-2, 4-disulfide is represented by

The whole synthetic scheme of preparation of 5-Methyl-3-(trifluoromethyl)-1H-pyrazole (1) according to the present invention can be represented as below:

According to another specific aspect of the present invention relates to a process for the preparation of 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carbothioamide (1),

comprising;
a) reducing isonicotinamide (7) by using Pd/C and hydrogen gas in methanol and in presence of perchloric acid solution in acetic acid to give piperidine-4-carboxamide (8) ;

b) reacting piperidine-4-carboxamide (8) with chloro acetyl chloride of formula (9) in mixture of water and dichloromethane (DCM) and in presence of potassium carbonate to give 1-(2-chloroacetyl) piperidine-4-carboxamide of formula (10);

c) reacting the 1-(2-chloroacetyl) piperidine-4-carboxamide of formula (10) with 5-Methyl-3-trifluoro methyl -1H-pyrazole (11) in acetonitrile and in presence of potassium carbonate to give 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)piperidine-4-carboxamide (13);

d) reacting 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carboxamide (12) with Lawesson’s reagent in DCM to give of 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carbothioamide (1).

The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1
Preparation of piperidine-4-carboxamide (8)
Isonicotinamide (50 g), (1.5 g) 10% palladium on carbon, (200 ml) methanol and (0.05 g) 0.1N perchloric acid solution in acetic acid were charged in autoclave at room temperature. Nitrogen purging was carried out in autoclave to replace air with nitrogen in the autoclave. Then, nitrogen gas was replaced by hydrogen gas in the autoclave and applied 3.0-3.5 kg/cm2 hydrogen pressure. The reaction mixture was heated to 55-60° C., maintained under pressure 10 to 12 kg/cm2 for 24 hr. The progress of the reaction was monitored for unreacted isonicotinamide by HPLC. After completion of the reaction, it was cooled to room temperature. Filtered the reaction mass through hyflo bed and washed with (50 ml) Methanol. Distilled off the Methanol under vacuum below 55° C temperature to get white solid as product (49 g) [Yield = 93.3%].

Example 2
Preparation of 1-(2-chloroacetyl) piperidine-4-carboxamide (10)
Piperidine-4-carboxamide (8) (20 g), water (25 ml), potassium carbonate (25 g) and dichloromethane (DCM, 50 ml) were charged into 500 ml four necked round bottom flask at room temperature. The obtained reaction mass was cooled to 0-5° C. A solution of chloro acetyl chloride (compound 9; 21.5 g) in dichloromethane (DCM, 50 ml) was added slowly into the reaction mass below 5° C and stirred for 2-3 h at 0-5° C. The progress of the reaction was monitored for unreacted piperidine-4-carboxamide (8) by HPLC. After completion of the reaction, it was cooled to room temperature. Filtered the reaction mass through hyflo bed, washed with DCM and dried under vacuum at 40° C for 10 h to get the title compound (31 g) [Yield = 97.3 %].

Example 3
Preparation of 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carboxamide (13)
1-(2-chloroacetyl)piperidine-4-carboxamide (10) (30 g), acetonitrile (60 ml), 5-Methyl-3-trifluoro methyl -1H-pyrazole (11) (17.6 g) and potassium carbonate (10.2 g) were charged into 500 ml four necked round bottom flask at room temperature. The obtained reaction mass was heated to 40-45 °C for 2 hours. The progress of the reaction was monitored for unreacted 1-(2-chloroacetyl) piperidine-4-carboxamide (10) by HPLC. The solvent was distilled out from reaction mass under vacuum, then water (30 ml) and MTBE (30 ml) was added. The obtained mixture was cooled to 0-5° C for 1 h. The obtained solid was filtered and dried to get title compound (30 g) [Yield: 53%].

Example 4
Preparation of 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carbothioamide (1)
1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carboxamide (13) (10 g), Lawesson's reagent (8.3 g) and dichloromethane (DCM, 100 ml) were charged into the reactor. The reaction mixture was stirred overnight at room temperature. The progress of the reaction was monitored by TLC/HPLC. After completion of reaction, solvent was distilled out and an aqueous sodium bicarbonate solution (100 ml) added, stirred for 1 h at room temperature. Filtered the solid, washed with water and then dried to get title compound (8 g) [Yield=76%].

,CLAIMS:We claim:
1. A process for the preparation of 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carbothioamide (1),

comprising;
a) reducing isonicotinamide (7) with a reducing agent in a solvent and optionally in presence of a catalyst to give piperidine-4-carboxamide (8);

b) reacting piperidine-4-carboxamide (8) with a compound of formula (9) in a solvent and in presence of a base to give a compound of formula (10);

c) reacting the compound of formula (10) with 5-Methyl-3-trifluoro methyl -1H-pyrazole (11) in a solvent and in presence of a base to give 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)piperidine-4-carboxamide (12);

d) reacting 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carboxamide (12) with a thionating agent in a solvent to give 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carbothioamide (1).

2. The process as claimed in claim 1, wherein the reducing agent used in step (a) is selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, Fe/CaCl2, FeSO4, Fe powder, Raney Nickel, Pd/C, NaBH4, Potassium Borohydride, SnCl2.2H2O, Zn dust, Sodium Borohydride with Pd/C, thiophenol/trifluoroacetic acid, sodium sulphite, sodium hyposulphite, Na2S, NaBH4, NaBH4/BF3-diethyl ether, NiCl2.6H2O, LiBH4, LiAlH4; or hydrogen gas or a hydrogen source selected from ammonium formate, hydrazine hydrate, hydrazine glyoxylate, glyoxylic acid or hydrazinium monoformate.
3. The process as claimed in claim 1, wherein the solvent used for reducing the compound of formula (7) in step (a) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; a hydrocarbon solvent selected from toluene, hexane, heptane, pet ether, xylene, cyclohexane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone or methyl isobutyl ketone (MIBK); an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water; or a mixture thereof.

4. The process as claimed in claim 1, wherein the catalyst used in step (a) is selected from Perchloric acid, Acetic acid, HBr, H2SO4, HNO3, HCl, HI, H3PO4, triflic acid, methansulfonic acid, benzenesulfonic acid or p-toluene sulfonic acid; or a mixture thereof.

5. The process as claimed in claim 1, wherein the solvent used in step (b), step (c) and step (d) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; a hydrocarbon solvent selected from toluene, hexane, heptane, pet ether, xylene, cyclohexane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone or methyl isobutyl ketone (MIBK); an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water; or a mixture thereof.

6. The process as claimed in claim 1, wherein the base used in step (b) and step (c) is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; an alkali metal alkoxides selected from sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or an organic amines selected from triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

7. The process as claimed in claim 1, wherein in step (d), the thionating agent is selected from Lawesson's reagent, P2S5, or bistrimethylsylilsulfide.

8. The process as claimed in claim 7, wherein the Lawesson's reagent is chemically known as 2, 4-bis (4-methoxyphenyl)-1, 3, 2, 4- dithiadi- phosphetane-2, 4-disulfide.

9. A process for the preparation of 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carbothioamide (1),

comprising;
a) reducing isonicotinamide (7) by using Pd/C and hydrogen gas in methanol and in presence of perchloric acid solution in acetic acid to give piperidine-4-carboxamide (8) ;

b) reacting piperidine-4-carboxamide (8) with chloro acetyl chloride of formula (9) in mixture of water and dichloromethane (DCM) and in presence of potassium carbonate to give 1-(2-chloroacetyl) piperidine-4-carboxamide of formula (10);

c) reacting the 1-(2-chloroacetyl) piperidine-4-carboxamide of formula (10) with 5-Methyl-3-trifluoro methyl -1H-pyrazole (11) in acetonitrile and in presence of potassium carbonate to give 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)piperidine-4-carboxamide (12);

d) reacting 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carboxamide (12) with Lawesson’s reagent in DCM to give of 1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl) piperidine-4-carbothioamide (1).