The present invention provides a process for preparation of pyrazole derivatives of
formula I.
I
RSrV
N—N
V
Formula I wherein R1 represents hydrogen, alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or an arylalkyl group which is optionally substituted;
R2 represents a hydrogen, alkyl group having 1 to 6 carbon atoms optionally substituted by halogen, a cycloalkyl group having 3 to 6 carbon atoms or an arylalkyl group which is optionally substituted, or an aryl group which is optionally substituted;
R3 represents an alkyl group having 1 to 6 carbon atoms, which is substituted by at least one halogen atom; Wherein halogen atom is selected from fluorine, chlorine, bromine and iodine.
Background of the invention
The pyrazole derivatives, particularly N-alkylated pyrazole derivatives are valuable intermediates in the field of medicine and agricultural chemicals.
N-alkylated pyrazole derivatives have been prepared in literature by decarboxylation reactions of 4-carboxylic acid pyrazoles.
Bull. Chem. Soc. Jpn., 1986, 2631-2632 reports reaction of 5-Methyl-l-phenyl-3-(trifluoromethyl)-lH -pyrazole-4-carboxylic acid with copper powder in quinoline to yield merely 32% of 5-methyl-l-phenyl-3-trifluoromethyl pyrazole.

Eur. J. Med. Chem., 2008, 2386-2394 reports similar decarboxylation by heating 5-amino-l-phenyl-3-(trifluoromethyl)- lH-pyrazole-4-carboxylic acid at its melting point for one hour to give 5-amino-l-phenyl-3-(trifluoromethyl)- 1H-pyrazole in a low yield of 30 %.
WO 2014/033164 describes preparation of 3,5-bis(haloalkyl)-pyrazole compounds by decarboxylation of 3,5-bis(haloalkyl)-pyrazole-4-carboxylic acid derivatives using a copper reagent in presence of a base like quinoline, pyridines, alkylpyridines, phenanthroline, N-methylmorpholine, 2-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide at elevated temperature.
The present invention provides an efficient and a simple method for the decarboxylation of pyrazole-4-carboxylic acid derivatives.
WO 2016/118774 discloses use of N-alkylated iodopyrazole derivatives for preparation of piperidine urea compounds used for treating dilated cardiomyopathy. It also discloses the preparation of N-alkylated iodopyrazole using iodine in presence of n-butyl lithium.
The use of n-butyllithium limits the viability of the above process on commercial scale. There is a need in the art to develop an alternate commercially viable process for preparation of N-alkylated iodopyrazole derivatives.
Object of the invention
The main object of the present invention is to provide simple, cost effective and industrially applicable processes for preparation of N-alkylated halogen-containing
pyrazole compounds of formula I.
I
Formula I

wherein R represents hydrogen, alkyl group having 1 to 6 carbon atoms, a
cycloalkyl group having 3 to 6 carbon atoms or an arylalkyl group which is
optionally substituted;
R2 represents a hydrogen, alkyl group having 1 to 6 carbon atoms optionally
substituted by halogen, a cycloalkyl group having 3 to 6 carbon atoms or an
arylalkyl group which is optionally substituted, or an aryl group which is optionally
substituted;
R3 represents an alkyl group having 1 to 6 carbon atoms, which is substituted by at
least one halogen atom;
wherein halogen atom is selected from fluorine, chlorine, bromine and iodine.
Summary of the invention
First aspect of the present invention provides a process for preparation of
compound of formula I,
I
RSrV
N—N
V
Formula I wherein R1 represents hydrogen, alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or an arylalkyl group which is optionally substituted;
R2 represents a hydrogen, alkyl group having 1 to 6 carbon atoms optionally substituted by halogen, a cycloalkyl group having 3 to 6 carbon atoms or an arylalkyl group which is optionally substituted, or an aryl group which is optionally substituted;
R3 represents an alkyl group having 1 to 6 carbon atoms, which is substituted by at least one halogen atom; wherein halogen atom is selected from fluorine, chlorine, bromine and iodine,

comprising the steps of:
a) decarboxylating a compound of formula III
COOH
2

Formula III using copper reagent in the presence of aliphatic amine, to obtain a compound of formula II, and
3 ^V r,2

w
N—N
V
Formula II b) iodinating compound of formula II to obtain compound of formula I. A second aspect of the present invention provides a process for preparation of
compound of formula I,
I
,2
Formula I wherein R\ R2, R3 are as defined above; comprising the step of:
a) iodinating of compound of formula II
N—N
V
Formula II to obtain compound of formula I, wherein iodination is carried out in presence of an organic acid.

A third aspect of the present invention provides a process for preparation of compound of formula II,
„3
fU. >^v ^R
w
N—N
V
Formula II
wherein i?7, R2, R3 are as defined above;
comprising the step of:
a) decarboxylating a compound of formula III

Formula III using copper reagent in presence of an aliphatic amine. A fourth aspect of the present invention provides a process for preparation of compound of formula II,
N—N
V
Formula II wherein R\ R2, R3 are as defined above; comprising the step of:
a) decarboxylating a compound of formula III
/ s ^
y\ 1
N- —N
\ 1
rn iula R III
COOH R3.
using copper reagent in the presence of aliphatic amine;

wherein, the aliphatic amine is recycled back to the reactor for continuous decarboxylation. Detailed description of the invention
The term "copper reagent" in the present invention refers to copper powder, cuprous oxide, cupric oxide, copper chloride, and copper iodide or mixture thereof.
The term "aliphatic amine" in the present invention refers to straight chain or branched chain alkyl amine. Examples of aliphatic amine includes methylamine, ethylamine, triethylamine, diethylmethylamine, isopropylamine, disopropylamine, diisopropylmethylamine, diisopropylethylamine, n-butylamine, tertiary butylamine, tributylamine, or the like.
The term "organic acid" in the present invention refers to a lower alkyl sulfonic acids as well as aryl sulfonic acids and carboxylic acids. Examples of organic acid includes acetic acid, oxalic acid, pyruvic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or the like.
In an embodiment of the present invention, the step of decarboxylation involves use of copper powder, cuprous oxide, copper powder in the presence of tributyl amine, triethylamine, diisopropylethylamine and diisopropylmethylamine or mixture thereof.
In an embodiment of the present invention, the step of decarboxylation is carried out in presence of copper oxide, copper powder or a mixture thereof at a temperature of about 130°C to 230°C.
In another embodiment of the present invention, the aliphatic amine is recycled back into the reactor.
In another embodiment of the present invention, the step of decarboxylation is carried out in a polar aprotic solvent. Examples of polar aprotic solvents includes acetone, methyl ethyl ketone, ethyl acetate, N,N-dimethylformamide, acetonitrile, dimethylsulfoxide, N,N-dimethylacetamide, sulfolane, dimethoxyethane, dioxane or the like.

In a preferred embodiment of the present invention, the step of decarboxylation is carried out in sulfolane.
In an embodiment of the present invention, the step of iodination is carried out using iodine and potassium iodate in the presence of organic acid.
In another embodiment of the present invention, the step of iodination is carried out using iodine in presence of potassium iodate, sulfuric acid and acetic acid at a temperature of about 20°C to 100°C
In another preferred embodiment of the present invention, the step of iodination is carried out using iodine and potassium iodate in presence of acetic acid.
In a particular embodiment, the present invention provides a process for preparation of 3-(difluoromethyl)-l-methyl-lH-pyrazole comprising the step of decarboxylation of 3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid using copper powder and copper oxide in presence of tributyl amine in sulfolane.
In another particular embodiment, the present invention provides a process for preparation of 3-(difluoromethyl)-4-iodo-l-methyl-lH-pyrazole comprising the step of iodination of 3-(difluoromethyl)-l-methyl-lH-pyrazole using iodine and potassium iodate in presence of acetic acid and sulphuric acid.
The compounds of formula I and II are important intermediates for the preparation of 4-methylsulphone-substituted piperidine urea compounds known or taught in WO 2016118774, which is included as a reference.
The compounds of formula I and formula II are isolated by using techniques known in the art for example distillation, evaporation, column chromatography and layer separation or combination thereof.
Unless stated to the contrary, any of the words "comprising" and "comprises" 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 completion of the reaction can 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) and alike.
The compound of formula III used as a starting material can be obtained commercially or can be prepared by the method as disclosed in US Patent No. 9,650,345 B2.
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.
EXAMPLES Example 1A: Preparation of 3-(difluoromethyl)-l-methyl-lH-pyrazole
Tributyl amine (TBA) (90g) was added to a mixture of 3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid (170g), copper powder (10.8g), copper oxide (9.67g) in sulfolane (252g) at a temperature of about 20 to 50°C. The reaction mixture was stirred at a temperature of 150°C. During decarboxylation carbon dioxide gas was released and the product mixture was collected in another vessel. The collected product mixture consisted of two layers i.e., lower layer and upper layer. The layers were separated and upper layer which consisted of TBA was recycled back to reactor. Dichloromethane (150ml) was added to the lower layer. The organic layer was washed twice with an aqueous solution of hydrochloric acid solution (IN, 150ml). The layers were separated and the organic layer was washed twice with water (150ml). The organic layer was separated and concentrated to get the titled compound. Yield: 70 % Purity: 95 % (by HPLC)

Example IB: Preparation of 3-(difluoromethyl)-l-methyl-lH-pyrazole
Triethyl amine (50g) was added to a mixture of 3-(difluoromethyl)-l-methyl-1H-pyrazole-4-carboxylic acid (170g), copper powder (10.8g), copper oxide (9.67g) in sulfolane (252g) at a temperature of about 20 to 50°C. The reaction mixture was stirred at a temperature of 150°C. During decarboxylation carbon dioxide gas was released and the product mixture was collected in another vessel. The collected product mixture consisted of two layers i.e., lower layer and upper layer. The layers were separated and upper layer which consisted of TBA was recycled back to reactor. Dichloromethane (150ml) was added to the lower layer. The organic layer was washed twice with an aqueous solution of hydrochloric acid solution (IN, 150ml). The layers were separated and the organic layer was washed twice with water (150ml). The organic layer was separated and concentrated to get the titled compound. Yield: 70 % Purity: 95 % (by HPLC)
Example 1C: Preparation of 3-(difluoromethyl)-l-methyl-lH-pyrazole
Diisopropylethyl amine (75g) was added to a mixture of 3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid (170g), Copper powder (10.8g), copper oxide (9.67g) in sulfolane (252g) at a temperature of about 20 to 50°C. The reaction mixture was stirred at a temperature of 150°C. During decarboxylation carbon dioxide gas was released and the product mixture was collected in another vessel. The collected product mixture consisted of two layers i.e., lower layer and upper layer. The layers were separated and upper layer which consisted of TBA was recycled back to reactor. Dichloro methane (150ml) was added to the lower layer. The organic layer was washed twice with an aqueous solution of hydrochloric acid solution (IN, 150ml). The layers were separated and the organic layer was washed twice with water (150ml). The organic layer was separated and concentrated to get the titled compound.

Yield: 70 %
Purity: 95 % (by HPLC)
Example ID: Preparation of 3-(difluoromethyl)-l-methyl-lH-pyrazole
Diisopropyl amine (50g) was added to a mixture of 3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid (170g), copper powder (10.8g), Copper oxide (9.67g) in sulfolane (252g) at a temperature of about 20 to 50°C. The reaction mixture was stirred at a temperature of 150°C. During decarboxylation carbon dioxide gas was released and the product mixture was collected in another vessel. The collected product mixture consisted of two layers i.e., lower layer and upper layer. The layers were separated and upper layer which consisted of TBA was recycled back to reactor. Dichloromethane (150ml) was added to the lower layer. The organic layer was washed twice with an aqueous solution of hydrochloric acid solution (IN, 150ml). The layers were separated and the organic layer was washed twice with water (150ml). The organic layer was separated and concentrated to get the titled compound. Yield: 70 % Purity: 95 % (by HPLC)
Example 2: Preparation of 3-(difluoromethyl)-4-iodo-l-methyl-lH-pyrazole
Concentrated sulphuric acid (98 %; 64.37g) was added dropwise over a period of 20 minutes to a mixture of 3-(difluoromethyl)-l-methyl-lH-pyrazole (73.5g), Iodine (67.5g), potassium iodate (31g) and acetic acid (816g) at a temperature of about 25 to 30°C. The reaction temperature was allowed to rise to 45°C. The reaction mixture was stirred at a temperature of about 60 °C for one hour. After completion of the reaction, the reaction mixture was quenched with water (500 ml) at a temperature of about 25 to 30°C. Dichloromethane (200ml) was added to the reaction mass. The organic layer was neutralized with an aqueous solution of

sodium bisulfate (100ml). The organic layer was washed twice with water (500ml).
The organic layer was concentrated to get the titled compound.
Yield: 83 %
Purity: 96 % (by HPLC)
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.

WE CLAIM:

1. A process for preparation of a compound of formula I,
I
2

Formula I
wherein R1 represents hydrogen, alkyl group having 1 to 6 carbon atoms optionally substituted by halogen, a cycloalkyl group having 3 to 6 carbon atoms or an arylalkyl group which is optionally substituted;
R2 represents a hydrogen, alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or an arylalkyl group which is optionally substituted, or an aryl group which is optionally substituted;
R3 represents an alkyl group having 1 to 6 carbon atoms, which is substituted by at least one halogen atom;
wherein halogen atom is selected from fluorine, chlorine, bromine and iodine.
comprising the steps of: a) decarboxylating a compound of formula III using copper reagent in the presence of aliphatic amine to obtain a compound of formula II; and


N —N
V
Formula III Formula II

b) iodinating compound of formula II to obtain the compound of formula I.
2. A process for preparation of a compound of formula II,

N—N
V
Formula II
wherein R1 represents hydrogen, alkyl group having 1 to 6 carbon atoms optionally substituted by halogen, a cycloalkyl group having 3 to 6 carbon atoms or an arylalkyl group which is optionally substituted;
R2 represents a hydrogen, alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or an arylalkyl group which is optionally substituted, or an aryl group which is optionally substituted;
R3 represents an alkyl group having 1 to 6 carbon atoms, which is substituted by at least one halogen atom;
wherein halogen atom is selected from fluorine, chlorine, bromine and iodine. comprising the step of ecarboxylating a compound of formula III
COOH R3
Formula III using copper reagent in presence of an aliphatic amine.
3. A process for preparation of a compound of formula II,
w
N—N
V
Formula II wherein R\ R2, R3 are as defined above; comprising the step of: decarboxylating a compound of formula III

Formula III using copper reagent in the presence of aliphatic amine; wherein, the aliphatic amine is recycled back to the reactor for continuous decarboxylation.
4. A process for preparation of a compound of formula I,
I

Formula I wherein R\ R2, R3 are as defined above; comprising the step of: iodinating compound of formula II
RSCVR2
N—N
V
Formula II to obtain the compound of formula I, wherein iodination is carried out in presence of an organic acid.
5. The process as claimed in claim 1, 2 and 3 wherein, the "copper reagent" is selected from a group consisting of copper powder, cuprous oxide, cupric oxide , copper chloride and copper iodide or a mixture thereof.
6. The process as claimed in claim 1, 2 and 3 wherein, the "aliphatic amine" is straight chain or branched chain alkyl amine selected from a group consisting of

methylamine, ethylamine, triethylamine, diethylmethylamine, isopropylamine, disopropylamine, diisopropylmethylamine, diisopropylethylamine, n-butylamine, tertiary butylamine and tributylamine or a mixture thereof.
7. The process as claimed in claim 1 and 4, wherein, the step of iodination is carried out using iodine and potassium iodate in presence of organic acid.
8. The process as claimed in claim 7, wherein, organic acid is a lower alkyl sulfonic acids, an aryl sulfonic acids or a carboxylic acid selected from a group consisting of acetic acid, oxalic acid, pyruvic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid or a mixture thereof.