Field of the invention
The present invention provides processes for preparation of substituted pyrazole compounds of formula II, that can be used as intermediates for preparation of substituted piperidine urea compounds useful for the treatment of dilated cardiomyopathy (DCM).

Formula II
R2 is independently selected from F, C1-C4 alkyl, C1-C4 haloalkyl, R3 is independently selected from H, F, C1-C4 alkyl, C1-C4 haloalkyl,
R4 is C1-C4 alkyl, R6 is H or a protecting group, or salt thereof and
R7 is a group selected from H, Cl or trialkylsilyl.

Background of the invention
4-Methylsulphonyl substituted piperidine urea compounds of formula I are being developed for the treatment of dilated cardiomyopathy (DCM), a disease that leads to heart failure and severe complications such as stroke, arrhythmias, and sudden cardiac death.

Formula I
wherein R1 is a 5 to 6-membered heteroaryl ring having at least one nitrogen atom and is optionally substituted with one or more group independently selected from halo, cyano, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy.
WO2016/118774 discloses preparation of 4-methylsulphonyl substituted piperidine urea compounds using reagents like N-Fluorodibenzenesulfonimide, (NFSI), diethylaminosulfur trifluoride, n-butyllithium that are strong, expensive reagents and are not viable for commercial scale ups.
There is a need in the art to replace these reagents for preparation of 4-methylsulphonyl substituted piperidine urea compounds of formula I. The present invention provides processes for preparation of substituted pyrazole compounds that can be used as intermediates for preparation of compounds of formula I.

Object of the invention
The present invention provides processes for preparation of substituted pyrazole compounds of formula II, that can be used as intermediates for the substituted piperidine urea compounds useful for treatment of dilated cardiomyopathy (DCM).

Formula II
R2 is independently selected from F, C1-C4 alkyl, C1-C4 haloalkyl; R3 is independently selected from H, F, C1-C4 alkyl, C1-C4 haloalkyl,
R4 is C1-C4 alkyl, R6 is H or a protecting group and
R7 is a group selected from H, Cl or trialkylsilyl.

Summary of the invention
A first aspect of the present invention provides a process for preparation of a compound of formula II,

Formula II
R2 is independently selected from F, C1-C4 alkyl, C1-C4 haloalkyl, R3 is independently selected from H, F, C1-C4 alkyl, C1-C4 haloalkyl, R4 is C1-C4 alkyl,
R6 is H or a protecting group and R7 is a group selected from H, Cl or trialkylsilyl.
comprising the steps of:
a) reacting a compound of formula VII, with elemental sulfur in presence of a base, a catalyst and a reducing agent to give a compound of formula VI,

Formula VII Formula VI
wherein R3 and R4, R7 are as defined above, L1 is a leaving group;
b) reacting the compound of formula VI with a compound of formula VIII to give a compound of formula V;

Formula VIII Formula V
wherein R3 and R4, R7 are as defined above, L2 is a leaving group,
c) converting the compound of formula V to the compound of formula II.
A second aspect of the present invention provides a process for preparation of a compound of formula II

Formula II
wherein R2 , R3, R4, R6 and R7 are as defined above.
comprising the steps of:
a) fluorinating a compound of formula V, to give a compound of formula IV;

Formula V Formula IV
b) oxidizing the compound of formula IV to give a compound of formula III

Formula III
c) converting the compound of formula III to the compound of formula II.
A third aspect of the present invention provides a process for preparation of a compound of formula II, wherein the steps of fluorination and oxidization are carried without isolating a compound of formula IV.
A fourth aspect of the present invention provides a process for preparation of a compound of formula IV

Formula IV
comprising the step of fluorinating a compound of formula V,

Formula V
to obtain a compound of formula IV.
wherein R3, R4, R6 and R7 are as defined above.
A fifth aspect of the present invention provides a process for preparation of a compound of formula III

Formula III
comprising the step of oxidizing the compound of formula IV

Formula IV
to obtain a compound of formula III.
wherein R3, R4, R6 and R7 are as defined above.
A sixth aspect of the present invention provides a process for preparation of a compound of formula VI,

Formula VI
comprising the steps of:
a) reacting a compound of formula VII,

Formula VII
wherein R3, R4, R7 and L1 are as defined above
with elemental sulfur in presence of a base, a catalyst and a reducing agent to give a compound of formula VI.
A seventh aspect of the present invention provides a process for preparation of a compound of formula V,

Formula V
wherein R3, R4, R6 and R7 are as defined above;
comprising the step of reacting the compound of formula VI with a compound of formula VIII to obtain a compound of formula V,

Formula VI Formula VIII
wherein R3, R4, R6 and R7 are as defined above; L2 is a leaving group.
An eighth aspect of the present invention provides a compound of formula II and salts thereof.

Formula II
wherein R6 is H or salt thereof.
An ninth aspect of the present invention provides a process for using a compound of formula II and salts thereof for preparation of compound of formula I.
A tenth aspect of the present invention provides a pyrazole compound of formula III

Formula III
wherein R3, R4 and R6 are as defined above.
Detailed description of the invention
The term “C1-C4 alkyl” in the present invention refers to methyl, ethyl, isopropyl, n-butyl, iso-butyl, tert-butyl, or the like.
The term “C1-C4 haloalkyl” in the present invention refers to alkyl group substituted by one or more halogens. Examples of C1-C4 haloalkyl include, but not limited to fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, or the like.
The term “C1-C4 alkoxy” in the present invention refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy or the like.
The term “ambient temperature” in the present invention refers to the temperature in the range of 5°C to 35°C.
The term “heteroaryl” in the present invention refers to 5-6 membered heteroaromatic ring having at least one nitrogen atom as a ring member.
The term “salt” in the present invention refers to hydrochloride, hydrobromide, mesylate, tosylate or the like
The term “protecting group” in the present invention refers to the groups used in the art and serve the function of blocking amino moiety while the reactions are carried out at other sites of the molecule. Examples of amino protecting groups include, but not limited to acyl, alkoxycarbonyl, alkenyloxycarbonyl and aralkyloxycarbonyl groups such as carbobenzyloxy, tert.-butoxycarbonyl, trityl, pthaloyl, and the like.
The term “deprotection” in the present invention refers to the process of removal of protecting group. The step of deprotection is carried out by a procedure known in the art or as described in Protecting Groups by Carey & Sundberg, which is included as a reference. The step can be carried out using an acid such as hydrochloric acid, hydrobromic acid, acetic acid or trifluoroacetic acid, or a base such as sodium hydroxide or potassium hydroxide.
The term “leaving group” in the present invention refers to an atom or a group of atoms which can be displaced during the reaction. The leaving group includes but are not limited to organosulphonyl groups, acyloxy groups, alkoxy groups, alkoxy carbonyl groups (e.g., ethoxy carbonyl or the likes); halogens (e.g., iodine, bromine, chlorine or fluorine); amido; azido; isocyanato; substituted or unsubstituted thiolates (e.g., thiomethyl or thiophenyl). The examples of leaving groups include mesyl, tosyl, bromo, iodo, and the like.
The term “reducing agent” in the present invention refers to Zinc/acetic acid, Zinc/alcoholic potassium hydroxide, sodium borohydride, triphenylphosphine, tributylphosphine, tris(2-carboxyethyl)phosphine, or the like.
A catalyst, used in the step of formation of compound of formula VI, is selected from the salts of copper or iron. The catalyst includes copper powder, copper chloride (CuCl), copper bromide (CuBr), copper iodide (CuI), iorn chloride (FeCl3), iron bromide (FeBr3)or the like.
The term “base” in the present invention refers to inorganic or organic bases. Examples of inorganic bases includes potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium hydride, potassium hydride, or the like. Examples of organic bases includes sodium ethoxide, sodium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, n-butylamine, t-butylamine, pyridine, methyl lithium, n-butyl lithium, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diethylamide or the like.
The step of fluorination in the present invention is carried out in presence of electrophilic fluorinating agents. Examples of electrophilic fluorinating agents includes N-fluoro-o-benzenedisulfonimide, N-fluorobenzenesulfonimide, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), N-fluoro-pyridinium salts such as 1-fluoropyridinium triflate, 1-fluoropyridinium tetrafluoroborate, 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, 1-fluoro-2,4,6-trimethylpyridinium triflate, 1-fluoro-2,6-dichloropyridinium triflate, 2,6-dichloro-1-fluoropyridinium tetrafluoroborate, 2-fluoro-1,3-dimethylpyridinium p-toluenesulfonate, 2-fluoro-1-methylpyridinium p-toluenesulfonate, N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate). Preferably, the fluorinating agents are selected from a group consisting of 1-fluoropyridinium triflate, 1- fluoropyridinium tetrafluoroborate, 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, 1-fluoro-2,4,6-trimethylpyridinium triflate, 1-fluoro-2,6- dichloropyridinium triflate, 2,6-dichloro-1-fluoropyridinium tetrafluoroborate, , 1-fluoro-4-methylpyridinium triflate, 1-fluoro-4-methylpyridinium tetrafluoroborate.
The step of oxidation is carried out using an oxidant, optionally in the presence of a catalyst to oxidize sulfide to sulfone. Examples of the oxidant includes hydrogen peroxide/sodium tungstate, peracetic acid, benzyl hydroperoxide, ethylbenzene hydroperoxide, cumyl hydroperoxide, sodium hypochlorite, oxalic acid dihydrate/ hydrogen peroxide (H2O2), meta-chloroperoxybenzoic acid (mCPBA), urea-hydrogen peroxide adduct, Permanganate/manganese dioxide, ruthenium chloride hydrate/sodium periodate, oxone, and the like, optionally in the presence of catalyst, for example, ammonium molybdate or alkali metal tungstate.
The step of alkylation is carried out using alkylating agent in the presence of a base. Examples of the alkylating agent includes bromoalkane, chloroalkane, iodoalkane, diazoalkane, dialkylcarbonate, dialkylsulfonate, and the like.
In an embodiment of first aspect, the present invention provides a process for preparation of a compound of formula IIA,

Formula IIA
wherein R6 and R7 are as defined above, comprising the steps of:
a) reacting a compound of formula VIIA with an elemental sulfur in presence of base, a catalyst and a reducing agent to give a compound of formula VIA,

Formula VIIA Formula VIA
R7 and L1 are defined above;
b) reacting the compound of formula VIA with a compound of formula VIII to give a compound of formula VA,

Formula VIII Formula VA
wherein R6 and R7 are as defined above;
c) converting the compound of formula VA to the compound of formula IIA.
In another embodiment of first aspect of the present invention the step a) is carried out in the presence of a base selected from a group consisting of potassium carbonate, sodium carbonate, cesium carbonate or the like.
In another embodiment of first aspect of the present invention, the step a) is optionally carried out in the presence an additive agent, selected from a group that includes potassium iodide, sodium iodide or dimethylaminopyridine (DMAP) or the like.
In another embodiment of first aspect of the present invention, the step a) is carried out in a solvent. Examples of solvents includes dimethylformamide, dimethylacetamide, sulfolane, ethyl methyl ketone, acetone, methyl isopropyl ketone, methyl isobutyl ketone, methyl n-butyl ketone, methyl t-butyl ketone, methyl isoamyl ketone, dimethyl sulfoxide, hexamethylphosphoric triamide, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol, dimethyl ether, diethylether, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, ethyl acetate, acetonitrile, or mixture(s) thereof.
In another embodiment of first aspect of the present invention, the step a) is carried out in presence of a catalyst selected from a group consisting of CuCl, CuBr, CuI or the like.
In another embodiment of first aspect of the present invention, the step a) is carried out in presence of a reducing agent selected from a group consisting of triphenylphosphine, tributylphosphine, tris(2-carboxyethyl)phosphine, or the like.
In another embodiment of first aspect of the present invention, the step b) is carried out in presence of base.
In another embodiment of first aspect of the present invention, the reaction does not involve isolation of the compound of formula VI or VIA.
In another embodiment of first aspect, the present invention provides a process for preparing t-butyl-4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine carboxylate comprising the steps of:
a) reacting 3-(difluoromethyl)-4-iodo-1-methyl-1H-pyrazole with elemental sulfur in presence of a base, a catalyst and reducing agent to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiol;
b) reacting 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiol with tert-butyl 4-{[(methanesulfonyl)oxy]methyl}piperidine-1-carboxylate to give tert-butyl 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]sulfanyl} methyl)piperidine-1-carboxylate;
c) converting tert-butyl 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]sulfanyl}methyl)piperidine-1-carboxylate to t-butyl-4-{1-[3-(difluoromethyl) -1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl} piperidine carboxylate.
In an embodiment of second aspect, the present invention provides a process for preparation of a compound of formula IIA

Formula IIA
wherein R6 and R7 are as defined above, comprising the steps of:
a) fluorinating a compound of formula VA to give a compound of formula IVA;

Formula VA Formula IVA
b) oxidizing the compound of formula IVA to give a compound of formula IIIA;

Formula IIIA
c) converting the compound of formula IIIA to the compound of formula IIA.
The compound of formula III/IIIA is converted to a compound of formula II/IIA by the step of alkylation.
In another embodiment of second aspect, the step of fluorination is carried out in presence of an electrophilic fluorinating agent.
In another embodiment of second aspect, the step of fluorination is carried out in the presence of N-fluoro-pyridinium salts.
In another embodiment of second aspect of the present invention, the compound of formula IVA may not be isolated.
In another embodiment of second aspect of the present invention, the compound of formula IIIA may not be isolated.
In another embodiment of second aspect of the present invention, the step of oxidation may precede step of fluorination.
In another embodiment of second aspect, the present invention provides a process for preparation tert-butyl-4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine-1-carboxylate comprising the steps of:
a) fluorinating tert-butyl 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]sulfanyl}methyl)piperidine-1-carboxylate in presence of N-fluoro-pyridinium salts to obtain tert-butyl 4-[{[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]sulfanyl}(fluoro)methyl]piperidine-1-carboxylate;
b) oxidizing tert-butyl 4-[{[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]sulfanyl}(fluoro)methyl]piperidine-1-carboxylate to tert-butyl-4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoromethyl}piperidine-1-carboxylate.
c) converting tert-butyl-4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoromethyl}piperidine-1-carboxylate to tert-butyl-4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine-1-carboxylate.
In another embodiment of second aspect, the present invention provides a process that does not involve isolation of either tert-butyl 4-[{[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]sulfanyl}(fluoro)methyl]piperidine-1-carboxylate or 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylate.
In an embodiment of third aspect, the present invention provides a process for preparation of a compound of formula IIA, wherein the steps of fluorination and oxidization are carried out without isolation of the compound of formula IVA.
In another embodiment of sixth aspect, the present invention involves a step of hydrolysis of compound of formula IIA, wherein R7 is Cl or alkylsilyl group, to a compound of formula IIA, wherein R7 is hydrogen.
In another embodiment of sixth aspect, the present invention involves a step of deprotection of the compound of formula IIA, wherein R6 is a protecting group, to a compound of formula IIA, wherein R6 is hydrogen.
In an embodiment, the present invention provides a compound of formula IIB and salts thereof.

Formula IIB
In another embodiment, the present invention provides 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine and salts thereof.
In an embodiment, the present invention provides a process for using a compound of formula IIB or salt thereof for preparation of compound of formula I.
In another embodiment of first aspect, the present invention involves isolation of a compound of formula IIC as a solid compound

FORMULA IIC
wherein R6 is tert-butyloxycarbonyl and R7 is hydrogen.
The compound of formula IIC is isolated in crystalline and/or amorphous form. The isolation of the compound of formula IIC is carried out using crystallization in a suitable solvent or mixture of solvents at a temperature of about -20? to 30?.
The solvents used in the crystallization can be selected from the group consisting of methanol, ethanol, propanol, 2-propanol, tetrahydrofuran, acetonitrile, cyclohexane, hexane, heptane, toluene, water or the like and the mixture thereof.
In an embodiment, the present invention provides a pyrazole compound of formula IIIA

Formula IIIA
wherein R6 is as defined above.
In another embodiment, the present invention provides tert-butyl-4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylate.
In another embodiment, the present invention provides a process for using a compound of formula IIIA for preparation of compound of formula I.
An fourteenth aspect of the present invention provides compound of formulae II, IIA, IIB, IIC, III and/or IIIA as impurity in the compound of formula I.
In another embodiment, the present invention provides compounds of formulae IIA, VIA, VIC, VA, IVA and IIIA.

Formula VIA Formula VA

Formula IVA

Formula IIIA Formula IIA
The present invention provides a process for using a compounds of formulae VI, VIA, IV, IVA for preparation of compound of formula I.
The compound of formulae II and III can be converted to the compound of formula I using the methods known or taught in WO 2016118774, which is included as a reference.
The compound of formula VII and VIII, used as a starting material can either be obtained commercially or be prepared by the method as disclosed in PCT Pub. No. 2009/000442 and US Pub. No. 2010/29650. The compound of formula VI can also be obtained commercially or can be prepared by the method as disclosed in Chinese Pub. No. 105622469. Pyrazole carboxylic acid used as a raw material can either be obtained commercially or be prepared by the method described in US Pat. No. 9650345. These patent references have been cited as references in the present invention.
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 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiol
3-(Difluoromethyl)-4-iodo-1-methyl-1H-pyrazole (50g) was added to mixture of potassium carbonate (52g), copper iodide(3.56g), sulfur powder (18.2g) in dimethylformamide (250ml) at a temperature of about 50ºC in 10 to 20 minutes. The reaction mixture was stirred at a temperature of about 110°C for 4 to 5 hours. The reaction mixture was allowed cooled to a temperature of about 20°C. A mixture of triphenylphosphine (125g), in water (125ml) and dioxane (325ml), was added to the reaction mixture. Hydrochloric acid (35%; 42ml) was slowly added to the reaction mass while maintaining the temperature of reaction mixture to below 30°C. After completion of the addition, the reaction mixture was stirred at a temperature of about 40°C. The reaction mixture was concentrated at a temperature of about 80°C to obtain a residue. Water (700ml) and dichloromethane (150ml ) were added to the residue and stirred for about 15minutes. The pH of the mixture was adjusted to 4.5-5 and layers were separated. Aqueous layer was again extracted with dichloromethane (60ml). The organic layers were combined and filtered and washed with water. A solution of potassium hydroxide (20%; 80ml) was added to the organic layer. The organic layer was washed with water, passed through sodium sulfate bed and concentrated to obtain the desired compound. Yield: 85 % ; Purity: 93 %
Example 2: Preparation of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiol
3-(Difluoromethyl)-4-iodo-1-methyl-1H-pyrazole (50g) was added to mixture of sodium carbonate (52g), copper iodide(3.56g), sulfur powder (18.2g) in dimethylsulfoxide (250ml) at a temperature of about 50ºC in 10 to 20 minutes. The reaction work up was done as per the example 3. Yield: 60 % ; Purity: 93 %
Example 3: Preparation of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiol
3-(Difluoromethyl)-4-iodo-1-methyl-1H-pyrazole (50g) was added to mixture of sodium methoxide (30g), copper iodide(3.56g), sulfur powder (18.2g) in sulfolane (250ml) at a temperature of about 50ºC in 10 to 20 minutes. The reaction mixture was stirred at a temperature of about 110°C for 4 to 5 hours. The reaction work up was proceeded as per the example 2. Yield: 60 % ; Purity: 93 %
Example 4: Preparation of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiol
3-(Difluoromethyl)-4-iodo-1-methyl-1H-pyrazole (50g) was added to mixture of potassium carbonate (52g), copper iodide(3.56g), sulfur powder (18.2g) in sulfolane (250ml) at a temperature of about 50ºC in 10 to 20 minutes. The reaction mixture was stirred at a temperature of about 110°C for 4 to 5 hours. The reaction was proceeded as per the example 2. Yield: 65 %; Purity: 93 %
Example 5: Preparation of tert-butyl 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]sulfanyl}methyl)piperidine-1-carboxylate
3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiol (13g) was added to a mixture of tert-butyl 4-{[(methanesulfonyl)oxy]methyl}piperidine-1-carboxylate (20g) and potassium carbonate (20.6g) in acetonitrile (200ml). The reaction mixture was stirred at a temperature of 60ºC for one hour. The progress of the reaction was monitored by gas chromatography. After completion of reaction, the reaction was cooled to room temperature and filtered. The filtered mass was washed with dichloromethane (100ml). The organic layer was washed with a dilute solution of hydrochloric acid (1N; 200ml).The organic layer was concentrated to obtain the title compound. Yield: 70 %; Purity: 97 %
Example 6: Preparation of tert-butyl 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]sulfanyl}methyl)piperidine-1-carboxylate
3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiol (13g) was added to a mixture of tert-butyl 4-{[(methanesulfonyl)oxy]methyl}piperidine-1-carboxylate (20g) and sodium methoxide (15g) in acetonitrile (200ml). The reaction mixture was stirred at a temperature of 60ºC for one hour. The reaction was proceeded as per the example 8. Yield: 70 %; Purity: 97 %
Example 7: Preparation of tert-butyl-4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4yl]sulfanyl](fluoro)methyl}piperidine-1-carboxylate
1-Fluoro-2, 4, 6 tri methyl pyridinium triflate (0.8648 mmol) was added to a solution of tert-butyl 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]sulfanyl}methyl)piperidine-1-carboxylate (0.8648 mmol) in dichloromethane (15 ml) at a temperature of about 30 to 35°C under nitrogen atmosphere. The reaction mass was refluxed at 40°C for 10-11 hours. The progress of the reaction was monitored by high performance liquid chromatography (HPLC). The reaction mixture was cooled to 0 °C. A solution of ruthenium chloride hydrate (0.012 mmol) in tetrahydrofuran (6 ml) was added to the reaction mixture at 0 °C. The progress of the reaction was monitored with HPLC. After completion of the reaction, the mixture was quenched by water. Layers were separated, filtered and concentrated to isolate desired compound. GCMS: 402 [M+Na]+ Yield: 85%; Purity: 95%
Example 8: Preparation of tert-butyl-4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylate
Sodium meta periodate (3.44 mmol) in water was added to the reaction mixture containing tert-butyl-4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4yl]sulfanyl](fluoro)methyl}piperidine-1-carboxylate (1.5mmol) in tetrahydrofuran (6 ml) at 0 °C. The reaction mixture was stirred for 1-2 hour at 0°C. The reaction mass was quenched with water (15ml) and extracted with dichloromethane (10ml). The resultant two phase mixture was separated using a separating funnel and the aqueous layer was extracted twice with dichloromethane (10ml). The organic layers were combined and washed with water (10ml). The final organic layer was concentrated to get the title compound. The product was analysed by HPLC chromatography. MS (ES, m/z): 434 [M+Na]+; Yield: 90%; Purity: 95%
Example 9: Preparation of tert-butyl-4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4yl]sulfanyl](fluoro)methyl}piperidine-1-carboxylate
2,6-Dichloro-1-fluoropyridinium tetrafluoroborate (0.9 mmol) was added to a solution of tert-butyl 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]sulfanyl}methyl)piperidine-1-carboxylate (0.8648 mmol) in dichloromethane (15 ml) at a temperature of about 30 to 35°C under nitrogen atmosphere. The reaction mass was refluxed at 40°C for 10-11 hours. The progress of the reaction was monitored by high performance liquid chromatography (HPLC). The reaction mixture was cooled to 0 °C. A solution of ruthenium chloride hydrate (0.012 mmol) in tetrahydrofuran (6 ml) was added to the reaction mixture at 0 °C. The progress of the reaction was monitored with HPLC. After completion of the reaction, the mixture was quenched by water. Layers were separated, filtered and concentrated to isolate desired compound. GCMS: 402 [M+Na]+ ; Yield: 80%; Purity: 90%
Example 10: Preparation of tert-butyl-4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylate
1-Fluoro-2, 4, 6 tri methyl pyridinium triflate (0.8648 mmol) was added to a solution of tert-butyl 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]sulfanyl}methyl)piperidine-1-carboxylate (0.8648 mmol) in dichloromethane (15 ml) at a temperature of about 30 to 35°C under nitrogen atmosphere. The reaction mass was refluxed at 40°C for 10-11 hours. The progress of the reaction was monitored by high performance liquid chromatography (HPLC). The reaction mixture was cooled to 0 °C. A solution of ruthenium chloride hydrate (0.012 mmol) in tetrahydrofuran (6 ml) was added to the reaction mixture at 0 °C. Sodium meta periodate (3.44 mmol) in water was added to the reaction mixture maintaining the temperature at 0 °C. The reaction mixture was stirred for 1-2 hour at 0°C. The reaction mass was quenched with water (15ml) and extracted with dichloromethane (10ml). The final organic layer was concentrated to get the title compound. The product was analysed by HPLC chromatography. MS(ES, m/z): 434 [M+Na]+
Yield: 80%; Purity: 90%.
Example 11: Preparation of tert-butyl-4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylate
1-Fluoropyridinium triflate (0.9 mmol) was added to a solution of tert-butyl 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]sulfanyl}methyl)piperidine-1-carboxylate (0.8648 mmol) in dichloromethane (15 ml) at a temperature of about 30 to 35°C under nitrogen atmosphere. The reaction mass was refluxed at 40°C for 10-11 hours. The progress of the reaction was monitored by high performance liquid chromatography (HPLC). The reaction mixture was proceeded with oxidation as per the example 15. MS (ES, m/z): 434 [M+Na]+; Yield: 70 %; Purity: 90%
Example 11: Preparation of tert-butyl-4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylate
1-Fluoropyridinium tetrafluoroborate (0.8648 mmol) was added to a solution of tert-butyl4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]sulfanyl}methyl)piperidine-1-carboxylate (0.8648 mmol) in dichloromethane (15 ml) at a temperature of about 30 to 35°C under nitrogen atmosphere. The reaction mass was refluxed at 40°C for 10-11 hours. The progress of the reaction was monitored by high performance liquid chromatography (HPLC). The reaction mixture was cooled to 0 °C. The reaction mixture was proceeded with oxidation as per the example 15. MS (ES, m/z): 434 [M+Na]+ Yield: 70 %; Purity: 90%
Example 12: Preparation of tert-butyl-4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylate
1-Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (0.8648 mmol) was added to a solution of tert-butyl 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]sulfanyl}methyl)piperidine-1-carboxylate (0.8648 mmol) in dichloromethane (15 ml) at a temperature of about 30 to 35°C under nitrogen atmosphere. The reaction mass was refluxed at 40°C for 10-11 hours. The progress of the reaction was monitored by high performance liquid chromatography (HPLC). The reaction mixture was cooled to 0 °C. The reaction mixture was proceeded with oxidation as per the example 15. MS: 434 [M+Na]+; Yield: 70 %; Purity: 85%
Example 13: Preparation of tert-butyl-4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine-1-carboxylate
Potassium tertiarybutoxide (1M; 14.6ml) was dropwise added to a solution of tert-butyl-4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl} piperidine-1-carboxylate (2 gm, 0.0048 mol) in THF (45 ml) under nitrogen atmosphere. The reaction mixture was cooled to -30 °C followed by addition of sodium hydride (0.28gm, 0.0065 mol) was added to the reaction mixture and stirred for 20 minutes at -30 °C. A solution of methyl iodide (0.75gm, 0.0053 mol) in THF (5ml) was added to the reaction mixture while maintaining the temperature at -30 °C for 10min and then stirred for 30min at -30 °C. The reaction was monitored using (HPLC). After completion of the reaction, acetonitrile (50ml) was added to the reaction mixture and the pH of the reaction mixture was adjusted to 6 using a solution of acetic acid (2ml). The reaction mixture was concentrated under reduced pressure to obtain a residue. Dichloromethane (20ml) was added to the residue filtered through hyflo gel .The residue was washed with dichloromethane (4x10ml). The filtrate was combined and concentrated under reduced pressure to give the desired product. The crude product was recrystallized using ethanol and cyclohexane to get the pure product. Purity: 99 % (HPLC); Yield: 65%.
Example 14: Preparation of tert-butyl-4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine-1-carboxylate
LiHMDS (1M; 14.6ml) was dropwise added to a solution of tert-butyl-4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl} piperidine-1-carboxylate (2 gm, 0.0048 mol) in THF (45 ml) under nitrogen atmosphere. The reaction mixture was cooled to -78 °C and stirred for 20 minutes. A solution of methyl iodide (0.75gm, 0.0053 mol) in THF (5ml) was added to the reaction mixture while maintaining the temperature at -78 °C for 10 minutes and then stirred for 30 minutes at -78 °C. The reaction was monitored using (HPLC). After completion of the reaction, saturated ammonium chloride (20ml) and dichloromethane (20ml) was added. Layers were separated, organic layer was washed with water and was concentrated under reduced pressure to obtain a residue. The residue was crystallized using isopropyl alcohol and cyclohexane.
Yield: 75%; Purity: 99%; (HPLC).
Example 15: Preparation of 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl} piperidine
Aqueous hydrochloride (3.5N; 24ml) was added to a solution of tert-butyl-4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl} piperidine-1-carboxylate (2.5g) in acetonitrile (10ml). The reaction mixture was stirred at 70ºC for one hour. The progress of the reaction was monitored by gas chromatography. After completion of the reaction dichloromethane (15ml) was added to the reaction mixture and layers were separated. The pH of aqueous layer was maintained to 12-13 using 20% NaOH (18ml) and extracted two times with dichloromethane (25ml). The organic layer was concentrated to obtain given compound.
Purity: 99%; Yield: 95%

WE CLAIM:
1. A process for preparation of a compound of formula II,

Formula II
wherein;
R2 is independently selected from F, C1-C4 alkyl and C1-C4 haloalkyl, R3 is independently selected from H, F, C1-C4 alkyl and C1-C4 haloalkyl, R4 is C1-C4 alkyl, R6 is H or a protecting group and R7 is a group selected from H, Cl and trialkylsilyl,
comprising the steps of:
a) reacting a compound of formula VII with elemental sulfur in presence of a base, a catalyst and a reducing agent to give a compound of formula VI;

Formula VII Formula VI
wherein R3, R4 and R7 are as defined above, and L1 is a leaving group;
b) reacting the compound of formula VI with a compound of formula VIII to give a compound of formula V;

Formula VIII Formula V
wherein L2 is a leaving group; R6 is as defined above,
c) fluorinating the compound of formula V, to give a compound of formula IV;

Formula IV Formula III
d) oxidizing the compound of formula IV to give a compound of formula III
e) converting the compound of formula III to the compound of formula II.

2. The process as claimed in claim 1, wherein steps of fluorination and oxidation are carried out without isolation of the compound of formula IV.
3. A process for preparation of a compound of formula II

Formula II
wherein R2 , R3, R4, R6 and R7 are as defined above, comprising the steps of:
a) fluorinating a compound of formula V to give a compound of formula IV;

Formula V Formula IV
b) oxidizing the compound of formula IV to give a compound of formula III

Formula III
c) converting the compound of formula III to the compound of formula II.
4. The process as claimed in claim 1, and 3, wherein the step of converting the compound of formula III to a compound of formula II is carried out using alkylating agent in presence of a base.
5. The process as claimed in claim 1, wherein the catalyst is selected from a group consisting of copper powder, copper chloride, copper bromide, and copper iodide.
6. The process as claimed in claim 1, wherein the base is selected from a group consisting of potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate and cesium bicarbonate.
7. The process as claimed in claim 1, wherein the reducing agent is selected from a group consisting of zinc/acetic acid, zinc/alcoholic potassium hydroxide, sodium borohydride, potassium borohydride, lithium aluminum hydride, triphenylphosphine/HCl, and tris(2-carboxyethyl)phosphine, borane.
8. A compound of formula VI,

Formula VI
wherein, R3 is independently selected from H, F, C1-C4 alkyl, C1-C4 haloalkyl, R4 is C1-C4 alkyl, and R7 is a group selected from H, Cl or trialkylsilyl.
9. A compound of formula IV,

Formula IV
wherein R2 is independently selected from F, C1-C4 alkyl, C1-C4 haloalkyl;
R3 is independently a member selected from H, F, C1-C4 alkyl, C1-C4 haloalkyl,
R4 is C1-C4 alkyl, R6 is H or a protecting group or a salt thereof and R7 is a group selected from H, Cl or rialkylsilyl.