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, R4isCi-C4 alkyl, R6 is H or a protecting group and R7 is selected from H, CI 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 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, lithiated compounds that are strong, expensive reagents and are not viable for commercial scale up of 4-methylsulphonyl substituted piperidine urea compounds.
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 of formula II 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 preparation of 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, R4is Ci-C4 alkyl, R6 is H or a protecting group or a salt thereof and R7 is selected from H, CI 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, R4is C1-C4 alkyl, R6 is H or a protecting group or salt thereof; and R7 is selected from H, CI or trialkylsilyl; comprising the steps of:
a) reacting a compound of formula VII with elemental sulfur in presence of base and a catalyst to give a compound of formula VIB,
Formula VII Formula VIB
wherein R3, R4 and R7are as defined above, Li is a leaving group, n is 2-8; b) reacting the compound of formula VIB with a compound of formula VIII to give a compound of formula V;
Formula VIII Formula V
wherein R3, R4, R6 and 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 VIB,
Formula VIB wherein R3, R4 and R7 and n is 2-8; comprising the step of reacting a compound of formula VII with elemental sulfur in presence of base and a catalyst to obtain a compound of formula VIB,
Formula VII wherein R3, R4 and R7 and Li are as defined above.
A third aspect of the present invention provides a process for preparation of a compound of formula V,
Formula V comprising the step of reacting a compound of formula VIB with a compound of formula VIII,

Formula VIB Formula VIII
wherein R3, R4, R6 and R7 are as defined above, L2 is a leaving group.
A fourth aspect of the present invention provides a process for preparation of a compound of formula V,
Formula V comprising the steps of:
a) reacting a compound of formula VII with elemental sulfur in presence of base and a catalyst to give a compound of formula VIB,
Formula VII Formula VIB
wherein R3, R4, R7, n is 2-8 are as defined above and Li is a leaving group, b) reacting the compound of formula VIB with a compound of formula VIII

Formula VIII wherein R6 and L2 are as defined above, to give a compound of formula V.
A fifth aspect of the present invention a compound of formula VIB.
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, difiuoroethyl, 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, 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.
A catalyst, used in the step of formation of compound of formula VIB, is selected from the salts of copper or iron. The catalyst includes copper powder, copper chloride, copper bromide, copper iodide, iron chloride, Iron bromide 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 term "reducing agent" in the present invention refers to Zinc/acetic acid, Zinc/alcoholic potassium hydroxide, sodium borohydride, potassium borohydride, lithium aluminum hydride, triphenylphosphine/HCl, and tris(2-carboxyethyl)phosphine, borane, triphenylphosphine, tributylphosphine, tris(2-carboxyethyl)phosphine, 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, l-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, 1-Fluoro-2,4,6-trimethylpyridinium triflate, l-fluoro-2,6-dichloropyridinium triflate, 2,6-dichloro-1-fluoropyridinium tetrafluoroborate, 2-fluoro-l,3-dimethylpyridinium p-toluenesulfonate, 2-fluoro-l-methylpyridinium p-toluenesulfonate, N-fluoro-N'-(chloromethyl)triethylene diamine bis(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 gent in the presence of a base. The alkylating agent includes but is not limited to bromoalkane, chloroalkane, iodoalkane, diazoalkane, dialkylcarbonate, dialkylsulfonate, and the like.
In an embodiment, 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, and R3 is selected from H, F, C1-C4 alkyl, C1-C4 haloalkyl, R4is C1-C4 alkyl, R6 is H or a protecting group; and R7 is selected from H, CI or trialkylsilyl; comprising the steps of:
a) reacting a compound of formula VII with elemental sulfur in presence of base and a catalyst to give a compound of formula VIB,
Formula VII Formula VIB
wherein R3, R4 and R7 are as defined above, Li is a leaving group and n is 2-8; b) reacting the compound of formula VIB with a compound of formula VIII to give a compound of formula V;
Formula VIII Formula V
wherein R3, R4 and R7 are as defined above, and L2 is a leaving group, c) fluorinating a compound of formula V to give a compound of formula IV;

Formula IV d) oxidizing a compound of formula IV to give a compound of formula III;
Formula III e) alkylating a compound of formula III to give a compound of formula II.
In an embodiment, 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 elemental sulfur in presence of base, and a catalyst to give a compound of formula VIC,

Formula VIIA Formula VIC
wherein R7 and L1 are defined above; b) reacting the compound of formula VIC with a compound of formula VIII to give a compound of formula VA;
Formula VIII Formula VA
wherein L2 is a leaving group andR7 and R6 are as defined above, c) fluorinating a compound of formula VA, to give a compound of formula IVA;
Formula VA Formula IVA
d) oxidizing the compound of formula IVA to give a compound of formula IIIA;
Formula IIIA

e) alkylating a compound of formula IIIA to give a compound of formula IIA.
The step a) of the present invention is carried out in the presence of a base selected from a group comprising of potassium carbonate, sodium carbonate, cesium carbonate or the like.
The step a) of the present invention is carried out in presence of a catalyst selected from a group comprising of Copper chloride, Copper bromide, Copper iodide or the like.
The step b) of the present invention is carried out in presence of a reducing agent.
In another embodiment of first aspect, the present invention provides a process for preparation of compound of formula II, wherein the process does not involve isolation of the intermediate of formula VIB.
In another embodiment, the present invention provides a compound of formula VIC.
Formula VIC In another embodiment of first aspect, the present invention provides a process for preparing t-butyl-4-{l-[3-(difluoromethyl)-l-methyl-lH-pyrazole-4-sulfonyl]-l-fluoroethyl}piperidine carboxylate comprising the steps of:
a) reacting 3-(difluoromethyl)-4-iodo-l-methyl-lH-pyrazole with elemental sulfur in presence of a base, and a catalyst to obtain 4,4'-disulfanediylbis[3-(difluoromethyl)-1 -methyl-1 H-pyrazole];
b) reacting 4,4'-disulfanediylbis[3-(difluoromethyl)-l-methyl-lH-pyrazole] with tert-butyl 4-{[(methanesulfonyl)oxy]methyl}piperidine-l-carboxylate to give tert-butyl 4-({ [3-(difluoromethyl)-l-methyl-1H-pyrazol-4-yl] sulfanyl} methyl)piperidine-1 -carboxylate;

c) converting tert-butyl 4-({ [3-(difluoromethyl)-l-methyl-lH-pyrazol-4-
yl]sulfanyl}methyl)piperidine-l-carboxylate to t-butyl-4-{l-[3-
(difluoromethyl)-1 -methyl- lH-pyrazole-4-sulfonyl] -1 -fluoroethyl}piperidine carboxylate.
The process for conversion of a compound of formula V to a compound of formula II involves the step of fluorination, followed by oxidation and subsequent alkylation to give a compound of formula II.
In a particular example tert-butyl 4-({ [3-(difluoromethyl)-l-methyl-1H-
pyrazol-4-yl]sulfanyl}methyl)piperidine-l -carboxylate is fluorinated using an
electrophilic fluorinating agent to yield tert-butyl-4-{[3-(difluoromethyl)-l-
methyl-lH-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-l-carboxylate, which
upon oxidation and subsequent methylation yields tert-butyl-4-{l-[3-
(difluoromethyl)-1 -methyl- lH-pyrazole-4-sulfonyl] -1 -fluoroethyl }piperidine-1 -
carboxylate. Tert-butyl-4-{l-[3-(difluoromethyl)-l-methyl-lH-pyrazole-4-
sulfonyl]-l-fluoroethyl}piperidine-l-carboxylate upon de-protection gives 4-{l-[3 -(difluoromethyl)-1 -methyl-1 H-pyrazole-4-sulfonyl] -1 -fluoroethyl} piperidine.
The compounds of formula V and VA can be converted to a compound of formula II, by the methods taught in WO 2016118774 or co-filed Indian patent application, which are included as reference.
The compounds of formula II 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 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 VIB 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. 3-(Difluoromethyl)-4-iodo-l-methyl-lH-pyrazole used in the present is prepared using the process as disclosed in Indian patent application

201711042921. These patent references have been cited as references in the present invention.
Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.
EXAMPLES
Example 1: Preparation of 4,4'-disulfanediylbis[3-(difluoromethyl)-l-methyl-lH-pyrazole]
3-(Difluoromethyl)-4-iodo-l-methyl-lH-pyrazole (50g) was added to a mixture of potassium carbonate (52.6g), copper iodide (3.56g) and sulfur powder (18.25g) in dimethylformamide (DMF, 400g). The reaction mixture was heated to a temperature of 110°C and stirred for 3 to 4 hours at the same temperature. The progress of the reaction was monitored by Gas chromatography (GC). The reaction mixture was concentrated at a temperature of about 80°C using reduced pressure of about 50mbar to obtain a residue. Dichloromethane (150ml) was added to the residue and filtered through hyflo super cell. The filter cake was washed with dichloromethane (150ml). Organic layer was washed with water (500mlx2). The organic layer was concentrated to obtain the desired product. GCMS 326+
Example 2: Preparation of 4,4'-disulfanediylbis[3-(difluoromethyl)-l-methyl-lH-pyrazole]
3-(Difluoromethyl)-4-iodo-l-methyl-lH-pyrazole (50g) was added to a mixture of potassium carbonate (52.6g), copper iodide (3.56g) and sulfur powder (18.25g) in sulfolane (400g). The reaction mixture was proceeded as per example 1. GCMS
326+

Example 3: Preparation of tert-butyl 4-({[3-(difluoromethyl)-l-methyl-lH-
pyrazol-4-yl]sulfanyl}methyl)piperidine-l-carboxylate using 4,4'-
disulfanediylbis[3-(difluoromethyl)-l-methyl-lH-pyrazole]
Sodium borohydride (1.78g) was slowly added to a mixture of 4,4'-disulfanediylbis[3-(difluoromethyl)-l-methyl-lH-pyrazole (7.4g), tert-butyl 4-{[(methanesulfonyl)oxy]methyl}piperidine-l-carboxylate (9.7g), potassium carbonate (12.2g) in acetonitrile (100ml) at a temperature of 20°C. The reaction mixture was stirred at a temperature of about 60°C for 1 hour. The progress of the reaction was monitored using GC. After completion of the reaction, the reaction mass was filtered. The residue was washed with dichloromethane (100ml). The filtrate was concentrated to obtain a residue. Dichloromethane (100ml) and water was added to the residue. The organic layer was washed with a dilute solution of hydrochloric acid (IN, 200ml). Organic layer was concentrated to give the desired product.
Example 4: Preparation of tert-butyl-4-{[3-(difluoromethyl)-l-methyl-lH-pyrazole-4-yl]sulfanyl](fluoro)methyl}piperidine-l-carboxylate
l-Fluoro-2, 4, 6 tri methyl pyridinium triflate (0.8648 mmol) was added to a
solution of tert-butyl 4-({ [3 -(difluoromethyl)-l -methyl- lH-pyrazol-4-
yl]sulfanyl}methyl)piperidine-l-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 tert-butyl-4- {[3 -(difluoromethyl)-1 -methyl- lH-pyrazole-
4yl]sulfanyl](fluoro)methyl}piperidine-l-carboxylate. GCMS: 402 [M+Na]+ Yield: 85%; Purity: 95%

Example 5: Preparation of tert-butyl-4-{[3-(difluoromethyl)-l-methyl-lH-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-l-carboxylate
Sodium meta periodate (3.44 mmol) in water was added to the reaction mixture
containing tert-butyl-4- {[3 -(difluoromethyl)-1 -methyl- lH-pyrazole-
4yl]sulfanyl](fluoro)methyl}piperidine-l-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 6: Preparation of tert-butyl-4-{[3-(difluoromethyl)-l-methyl-lH-pyrazole-4-yl]sulfanyl](fluoro)methyl}piperidine-l-carboxylate
2,6-Dichloro-l-fluoropyridinium tetrafluoroborate (0.9 mmol) was added to a
solution of tert-butyl 4-({ [3-(difluoromethyl)-1-methyl-lH-pyrazol-4-
yl]sulfanyl}methyl)piperidine-l-carboxylate (0.8648 mmol) in dichloromethane
(15 ml) at a temperature of about 30 to 35°C under nitrogen atmosphere. The
reaction mass was refiuxed 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 tert-butyl-4- {[3 -(difluoromethyl)-1 -methyl- lH-pyrazole-
4yl]sulfanyl](fluoro)methyl}piperidine-l-carboxylate. GCMS: 402 [M+Na]+ Yield: 80%; Purity: 90%

Example 7: Preparation of tert-butyl-4-{[3-(difluoromethyl)-l-methyl-lH-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-l-carboxylate
l-Fluoro-2, 4, 6 tri methyl pyridinium triflate (0.8648 mmol) was added to a solution of tert-butyl 4-({ [3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl]sulfanyl}methyl)piperidine-l-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 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: 80%; Purity: 90%.
Example 8: Preparation of tert-butyl-4-{[3-(difluoromethyl)-l-methyl-lH-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-l-carboxylate
1-Fluoropyridinium triflate (0.9 mmol) was added to a solution of tert-butyl 4-({[3-(difluoromethyl)-1 -methyl-1 H-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 7. MS (ES, m/z): 434 [M+Na]+ Yield: 70 %; Purity: 90%

Example 9: Preparation of tert-butyl-4-{[3-(difluoromethyl)-l-methyl-lH-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-l-carboxylate
1-Fluoropyridinium tetrafluoroborate (0.8648 mmol) was added to a solution of tert-butyl4-({ [3-(difluoromethyl)-1 -methyl- lH-pyrazol-4-
yl]sulfanyl}methyl)piperidine-l-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 7. MS (ES, m/z): 434 [M+Na]+ Yield: 70 %; Purity: 90%
Example 10: Preparation of tert-butyl-4-{[3-(difluoromethyl)-l-methyl-lH-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-l-carboxylate
l-Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (0.8648 mmol) was added to a solution of tert-butyl 4-({ [3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl]sulfanyl}methyl)piperidine-l-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 7. MS: 434 [M+Na]+ Yield: 70 %; Purity: 85%
Example 11: Preparation of tert-butyl-4-{l-[3-(difluoromethyl)-l-methyl-lH-pyrazole-4-sulfonyl]-l-fluoroethyl}piperidine-l-carboxylate
Potassium tertiarybutoxide (1M; 14.6ml) was dropwise added to a solution of tert-butyl-4- {[3 -(difluoromethyl)-1 -methyl-1 H-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 (5 ml) was added to the reaction mixture while maintaining the temperature at -30 °C for lOmin 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 12: Preparation of tert-butyl-4-{l-[3-(difluoromethyl)-l-methyl-lH-pyrazole-4-sulfonyl]-l-fluoroethyl}piperidine-l-carboxylate
LiHMDS (1M; 14.6ml) was dropwise added to a solution of tert-butyl-4-{[3-(difluoromethyl)-1 -methyl- lH-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 13: Preparation of 4-{l-[3-(difluoromethyl)-l-methyl-lH-pyrazole-4-sulfonyl]-l-fluoroethyl} piperidine
Aqueous hydrochloride (3.5N; 24ml) was added to a solution of tert-butyl-4-{l-[3-(difluoromethyl)-1 -methyl-1 H-pyrazole-4-sulfonyl]-1 -fluoroethyl} piperidine-1-carboxylate (2.5g) in acetonitrile (10ml). The reaction mixture was stirred at 70°C 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 R2 is independently selected from F, C1-C4 alkyl, C1-C4 haloalkyl; and R3 is independently selected from H, F, C1-C4 alkyl, C1-C4 haloalkyl, R4is C1-C4 alkyl, R6 is H or a protecting group; and R7 is selected from H, CI or trialkylsilyl; comprising the steps of:
a) reacting a compound of formula VII with elemental sulfur in presence of a base and a catalyst to give a compound of formula VIB,
Formula VII Formula VIB
wherein R3, R4 R7 are as defined above, Li is a leaving group and n is 2-8, b) reacting the compound of formula VIB with a compound of formula VIII to give a compound of formula V;
Formula VIII Formula V
wherein R3, R4 R7 are as defined above, and L2 is a leaving group,

c) converting the compound of formula V to the compound of formula II. 2. 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) reacting the compound of formula VIB with a compound of formula VIII
Formula VIB Formula VIII
wherein R2 ,R3, R4 R6 and R7 are as defined above, n is 2-8 and L2 is a leaving group, to give a compound of formula V; and

Formula V b) converting the compound of formula V into the compound of formula II.
3. The process as claimed in claims 1, wherein the catalyst is selected from a group
consisting of copper powder, copper chloride, copper bromide, and copper iodide.
4. The process as claimed in claims 1, wherein the base is selected from a group consisting of potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate and cesium bicarbonate.
5. The process as claimed in claims 1 and 2, wherein the conversion of the compound of formula V to the compound of formula II, comprises 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) alkylating the compound of formula III to the compound of formula II.
6. The process as claimed in claim 5, wherein the step of fluorination is carried out in presence of a fluorinating agent selected from a group consisting of 1-fluoropyridinium triflate, 1- fluoropyridinium tetrafluoroborate, l-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, l-fluoro-2,4,6-trimethylpyridinium triflate, l-fluoro-2,6- dichloropyridinium triflate, 2,6-dichloro-l-fluoropyridinium tetrafluoroborate, , l-fluoro-4-methylpyridinium triflate, l-fluoro-4-methylpyridinium tetrafluoroborate.
7. The process as claimed in claim 5, wherein the step of oxidation is carried out in presence of an oxidizing agent selected from a group consisting of hydrogen peroxide/sodium tungstate, peracetic acid, benzyl hydroperoxide, ethylbenzene hydroperoxide, cumyl hydroperoxide, sodium hypochlorite, oxalic acid dihydrate/hydrogen peroxide, meta-chloroperoxybenzoic acid, urea-hydrogen peroxide adduct, Permanganate/manganese dioxide, Ruthenium chloride hydrate/sodium periodate and oxone.
8. The process as claimed in claim 5, wherein the step alkylation is carried out using alkylating agent selected from bromoalkane, chloroalkane, iodoalkane, diazoalkane, dialkylcarbonate, dialkylsulfonate in presence of a base.
9. A compound of formula VIB,
Formula VIB

wherein, R3 is independently selected from H, F, C1-C4 alkyl, C1-C4 haloalkyl, R4 is C1-C4 alkyl, R7 is a group selected from H, CI or trialkylsilyl, and n is 2-8.