Title: Method for Preparing Substituted Heterocyclic Compounds

Field of the Invention

The present invention relates to a novel process for the preparation of substituted heterocyclic compound of Formula I or of salts thereof.

Formula I

Background of the Invention

Substituted heterocyclic compounds of Formula I or of salts thereof are important starting materials for a number of active pharmaceutical ingredients and crop protection active ingredients.

Processes for the preparation of substituted pyrazole compounds are described widely in literature, e.g. W02003051820; W02008102678; WO2008145257; W0200853043;

W0200900442; W02008022777; WO2009133178; WO2009133179; W0201009990;

WO201154732; WO2012163905; W02015003289; WO2015063793; WO2016152831 ; CN102718712; CN102731402; CN102766096; CN103351339; CN103360313;

CN103787977; CN104016920; CN104163800; CN104326891 ; CN104326891 ; CN 105218448; EP1997808; GB200908435; JP2013006780 and Angew. Chem. Int. Ed. 2010,

49, 7790 -7794.

The processes described in the prior art though provide moderate to good yields, however, result in a mixture of regioisomeric pyrazoles. Another drawback of these processes is the use of reactants as methylhydrazine or substituted hydrazines, which are highly carcinogenic in nature and are difficult to handle. Moreover, the existing methodologies have a higher number of reaction steps, thereby making it unfavourable to ran them on a commercial scale. Therefore, there is a need for a simple and regioselective process for the synthesis of substituted pyrazoles. Accordingly, the present invention provides a regioselective,

industrially feasible, and cost-effective process for the preparation of a substituted heterocyclic compound of Formula I.

Objective and Summary of the Invention:

It is an objective of the present invention to provide a simple, regioselective, industrially feasible, safe and cost-effective process for the preparation of substituted heterocyclic compounds of Formula I or of salts thereof.

Surprisingly, the present invention provides a solution to these objectives by offering a novel high yielding and economically attractive process overcoming at least one of the shortcomings of the processes described in the prior art.

The objective was achieved according to the present invention by finding a novel process for preparing substituted heterocyclic compounds of Formula I or of salts thereof

Formula I

wherein R1 is selected from hydrogen, halogen, cyano, nitro, CHO, COOR3, CONR3, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, CVCVcycloalkyl, CYCVcyclohaloalkyl, C3-C10-cycloalkylalkyl, Ci-C6-haloalkyl, C2-C6-haloalkenyl, C2-C6-haloalkynyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, Ci-C6-alkoxy-Ci-C4-alkyl, CVCVcyc loal kox y, Ci-C6-hydroxyalkyl, C3-C8-halocycloalkyl, Ci-C6-haloalkoxycarbonyl, Ci-C6-alkylthio, Ci-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, Ci-C6-haloalkylthio, Ci-C6-haloalkylsulfinyl, Ci-C6-haloalkylsulfonyl, C3-C8-cycloalkylthio, Ci-C6-alkylamino, Ci-C6-dialkylamino, C3-C8-cycloalkylamino, C3-C8-cycloalkyl-Ci-C6-alkylamino, Ci-C6-alkylcarbonyl, Ci-C6-alkoxycarbonyl, C1-C6-alkylaminocarbonyl, Ci-C6-dialkylaminocarbonyl, Ci-C6-alkoxycarbonyloxy, C1-C6-alkylaminocarbonyloxy, Ci-C6-dialkylaminocarbonyloxy, 5- to 11- membered spirocyclic ring or 3- to 10- membered carbocyclic/ heterocyclic ring; wherein Formula I may be substituted by one or more R1;

X is selected from NR2 or PR2;

R2 is selected from hydrogen, Ci-C6-alkyl, CYCYcycloalkyl, aryl or heterocyclic ring; wherein each group of R2 is optionally substituted with one or more R1;

R3 is selected from hydrogen, Ci-C6-alkyl, CVCYcycloalkyl;

which comprises reacting a compound of Formula II or of salts thereof

R1— =N

Formula II

with a compound of Formula III or of salts thereof

Formula I I I

in the presence of a catalyst and optionally in the presence of a solvent.

Detailed Description of the Invention:

The definitions provided herein for the terminologies used in the present disclosure are for illustrative purpose only and in no manner limit the scope of the present invention disclosed in the present disclosure.

As used herein, the terms “comprises”, “comprising”, “includes”, “including”, “has”, “having”, “contains”,“containing”, “characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process or method.

The transitional phrase“consisting of’ excludes any element, step or ingredient not specified. If in the claim, such would close the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase“consisting of’ appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.

The transitional phrase“consisting essentially of’ is used to define a composition or method that includes materials, steps, features, components or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components or elements do not materially affect the basic and novel characteristic(s) of the claimed invention. The term “consisting essentially of’ occupies a middle ground between “comprising” and “consisting of’.

Further, unless expressly stated to the contrary,“or” refers to an inclusive“or” and not to an exclusive“or”. For example, a condition A“or” B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B is true (or present).

Also, the indefinite articles“a” and“an” preceding an element or component of the present invention are intended to be non-restrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore“a” or“an” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.

Carbon-based radical refers to a monovalent molecular component comprising a carbon atom that connects the radical to the remainder of the chemical structure through a single bond. Carbon-based radicals can optionally comprise saturated, unsaturated and aromatic groups, chains, rings and ring systems, and heteroatoms. Although carbon-based radicals are not subject to any particular limit in size, in the context of the present invention they typically comprise 1 to 16 carbon atoms and 0 to 3 heteroatoms. Of note are carbon-based radicals selected from Ci-C6 alkyl, Ci-C6 haloalkyl and phenyl optionally substituted with 1-3 substituents selected from C1-C3 alkyl, halogen and nitro.

The meaning of various terms used in the description shall now be illustrated.

The term“alkyl”, used either alone or in compound words such as“alkylthio” or“haloalkyl” or -N(alkyl) or alkylcarbonylalkyl or alkylsuphonylamino includes straight-chain or branched Ci to C24 alkyl, preferably Ci to C15 alkyl, more preferably Ci to C10 alkyl, most preferably Ci to C6 alkyl. Representative examples of alkyl include methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, l ,l-dimethylethyl, pentyl, 1 -methylbutyl, 2-

methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1 -ethylpropyl, hexyl, l ,l-dimethylpropyl,

1.2-dimethylpropyl, l-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, l,2-dimethylbutyl, l ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,

3.3-dimethylbutyl, l-ethylbutyl, 2-ethylbutyl, l,l ,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1-ethyl- 1 -methylpropyl and l-ethyl-2-methylpropyl or the different isomers. If the alkyl is at the end of a composite substituent, as, for example, in alkylcycloalkyl, the part of the composite substituent at the start, for example the cycloalkyl, may be mono- or polysubstituted identically or differently and independently by alkyl. The same also applies to composite substituents in which other radicals, for example alkenyl, alkynyl, hydroxyl, halogen, carbonyl, carbonyloxy and the like, are at the end.

The term“cycloalkyl” means alkyl closed to form a ring. Representative examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. This definition also applies to cycloalkyl as a part of a composite substituent, for example cycloalkylalkyl etc., unless specifically defined elsewhere.

The term“cycloalkylalkyl” means cycloalkyl substituent on alkyl, for example, cyclopropyl or cyclobutyl or cyclopentyl are substituted on any carbon of Ci-C6 alkyl. Representative examples of cycloalkylalkyl include cyclopropyl methyl, cyclopropyl ethyl.

As used herein, the term“combined” refers to the act of“mixing”,“intermixing” or“putting together” for the purposes of bringing two or more chemical compounds in close contact so as to promote a chemical reaction. For example certain substrates, reagents or ingredients, reagents as described in the summary of the invention are“combined” with each other in an appropriate vessel, container or apparatus in such a fashion that the substrates, reagents or ingredients can chemically react with one another so that a new product can be formed.

The present invention relates to a novel process for the preparation of substituted heterocyclic compounds of Formula I or of salts thereof

Formula I

wherein R1 is selected from hydrogen, halogen, cyano, nitro, CHO, COOR3, CONR3, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, CVCVcycloalkyl, CVCVcyclohaloalkyl, C3-C10-cycloalkylalkyl, Ci-C6-haloalkyl, C2-C6-haloalkenyl, C2-C6-haloalkynyl, Ci-C6-alkoxy, Ci-

C6-haloalkoxy, Ci-C6-alkoxy-Ci-C4-alkyl, CVCVcyc loal kox y, Ci-C6-hydroxyalkyl, C3-C8-halocycloalkyl, Ci-C6-haloalkoxycarbonyl, Ci-C6-alkylthio, Ci-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, Ci-C6-haloalkylthio, Ci-C6-haloalkylsulfinyl, Ci-C6-haloalkylsulfonyl, C3-C8-cycloalkylthio, Ci-C6-alkylamino, Ci-C6-dialkylamino, C3-C8-cycloalkylamino, C3-C8-cycloalkyl-Ci-C6-alkylamino, Ci-C6-alkylcarbonyl, Ci-C6-alkoxycarbonyl, C1-C6-alkylaminocarbonyl, Ci-C6-dialkylaminocarbonyl, Ci-C6-alkoxycarbonyloxy, C1-C6-alkylaminocarbonyloxy, Ci-C6-dialkylaminocarbonyloxy, 5- to 11- membered spirocyclic ring or 3- to 10- membered carbocyclic/ heterocyclic ring; wherein Formula I may be substituted by one or more R1;

X is selected from NR2 or PR2;

R2 is selected from hydrogen, Ci-C6-alkyl, C3-C8-cycloalkyl, aryl or heterocyclic ring; wherein each group of R2 is optionally substituted with one or more R1;

R3 is selected from hydrogen, Ci-C6-alkyl, C3-C8-cycloalkyl;

which comprises reacting a compound of Formula II or of salts thereof

R1-ºN

Formula II

with a compound of Formula III or of salts thereof

Formula I I I

in the presence of a catalyst and optionally in the presence of a solvent.

According to one aspect of the present invention, the compound of Formula I or of salts thereof is produced through an intermediate of Formula V, which may be optionally isolated
Formula V

wherein M represents a transition metal selected from Cu, Co, Zn, Pd, Pt, preferably Cu; and R1 is as defined above.

The catalyst is selected from the group comprising of one or more of the species of copper powder, anhydrous copper(II) acetate, copper(II) acetate monohydrate, copper(I) oxide, copper(II) oxide, copper(I) chloride, copper(II) chloride, iron(II) chloride, iron(III) chloride, zinc(II) chloride, nickel(II) acetate, cobalt(II) chloride anhydrous, cobalt(II) chloride hexahydrate, cobalt(II) chloride dihydrate, cobalt(II, III) oxide hexahydrate, cobalt(II) bromide, cobalt(II) fluoride, cobalt(II) iodide, cobalt(II) oxide, cobalt(III) oxide, cobalt(II) acetate anhydrous, cobalt(II) acetate tetrahydrate and the like. The preferred catalyst is selected from copper compounds such as copper oxides and/or copper salts. The catalyst can be utilized in catalytic or stoichiometric amounts either independently or in combinations.

The solvent is selected from the group comprising of aliphatic, alicyclic or aromatic hydrocarbons, halogenated solvents, ethers, polar aprotic and aprotic dipolar solvents and the like; aliphatic hydrocarbons are selected from but not limited to hexane, heptane, octane and the like; alicyclic hydrocarbons like cycloalkanes are selected from but not limited to cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like; aromatic hydrocarbons are selected from but not limited to toluene, xylene, mesitylene, benzene and the like; ethers are selected from but not limited to diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, monoglyme, diglyme, methoxy-methane, methoxy-ethane, ethoxy-ethane, di-methoxyethane, di-ethoxyethane and the like; halogenated hydrocarbons are selected from but not limited to dichloromethane, chloroform, dichloroethane and the like; polar aprotic solvents are selected from but not limited to N,N-dimethylmethanamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, 1, 3-dimethyl-3, 4,5,6-tetrahydro-2(lH)-pyrimidinone, hexamethyl phosphor triamide and the like.

The reaction of a compound of Formula II or of salts thereof with a compound of Formula III or of salts thereof may be carried out in an autoclave oxygen under pressure or autogenous

pressure, or atmospheric pressure or reduced pressure. The reaction is preferably carried out in the presence of inert solvents and at reflux temperature.

According to a preferred embodiment, to a solution of a compound of Formula II or of salts thereof, in a suitable solvent, a solution of compound of Formula III or of salts thereof, in a suitable solvent and a catalyst are added. The reaction can be carried out at a temperature between 35 °C to 150 °C, wherein said reaction may be carried out in presence of oxygen/ air, under reduced pressure or at atmospheric pressure or under pressure conditions. The reaction mixture is usually stirred for 16 h to 48 h, to obtain a compound of Formula I or of salts thereof. The stoichiometry of the catalyst used is in the range of 1 mol% to 100 mol%, preferably 10 mol% to 30 mol%. Compounds of Formulae VI, VII, VIII or of salts thereof are undesired products whereas water, acetic acid and acetic anhydride are by-products. These impurities and by-products can be removed by reaction work-up techniques such as acid base treatment or/and crystallization or/and distillation.

Yet another embodiment of the present invention provides a novel process for preparing substituted heterocyclic compound of Formula I or of salts thereof, having a purity of more than 99%, when measured by GC method.

Another embodiment of the present invention provides a process for the synthesis of pyrazole carboxamide fungicide precursors, especially for preparing pyrazolylcarboxanilide fungicides from heterocyclic compounds of Formula I or of salts thereof.

Another embodiment of the present invention provides a process for the synthesis of pyrazole-4-carboxamides such as benzovindiflupyr, bixafen, fluindapyr, fluxapyroxad, furametpyr, inpyrfluxam, isopyrazam, penflufen, penthiopyrad, sedaxane, isoflucypram and pydiflumetofen.

According to one embodiment of the present invention, compounds of Formula la are produced through an intermediate of Formula Va which may be optionally isolated,

wherein Hal is selected from fluorine, chlorine, bromine or iodine.

According to the present invention, after completion of the reaction, isolation of the desired product is carried out by using suitable conventional techniques of reaction work-up such as separation/ solvent extraction/ triturating, acid-base wash, chromatography, filtration, sedimentation, centrifugation and/or washing.

A specific embodiment of the present invention provides a novel and efficient synthesis of compounds of Formula I or of salts thereof, having impurities of less than 10%, wherein the impurities are selected from the group comprising of Formulae VI, VII, VIII, IX, and X or of salts thereof.

Formula VI Formula VII Formula VI I I Formula IX Formula X

A specific embodiment of the present invention provides a novel and efficient synthesis of compounds of Formula I or of salts thereof, having impurities of less than 10%, wherein the impurities are selected from the group comprising of Formulae VIA, VIIA, VIIIA, IXA, and XA or of salts thereof.

Formula VIA Formula VIIA Formula VIIIA Formula IXA Formula XA

A specific embodiment of the present invention provides a substantially pure methyl-3-(dihalomethyl)-l -methyl- lH-pyrazole-4-carboxylate compound of Formula 1A

Formula 1 A

comprising impurities of less than 10%, wherein the impurities are selected from the group comprising of Formulae VI, VII, VIII, IX, and X or of salts thereof.

Formula VI Formula VII Formula VI I I Formula IX Formula X

The term "substantially pure" methyl-3-(dihalo methyl)- 1 -methyl- lH-pyrazole-4-carboxylate of Formula 1A means that any impurities are less than 10%, preferably less than 8%, more preferably less than 5%, as per GC, wherein the impurities are selected from the group comprising of Formulae VI, VII, VIII, IX, and X or of salts thereof.

A specific embodiment of the present invention provides a process for preparing methyl-3-(dihalomethyl)-l -methyl- lFl-pyrazole-4-carboxylate compound of Formula 1A

Formula 1 A

comprising reacting 2,2-dihaloacetonitrile with methyl-3-(methylamino)acrylate in the presence of a catalyst and optionally in the presence of a solvent.

The present invention is further described in greater detail as illustrated in the following non limiting examples. It should be understood that variation and modification of the process are possible within the ambit of the invention broadly disclosed herein.

Examples

Example-1: Preparation of methyl-3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylate Copper(I) oxide (1.12 g, 7.82 mmol) and anhydrous copper(II) acetate (0.16 g, 0.869 mmol) were added to a solution of 2,2-difLuoroacetonitrile (0.669 g, 8.69 mmol) in toluene (17.3 ml). The reaction mixture was heated to 40 °C for 1 h. A solution of methyl-3 -(methylamino)acrylate (1.0 g, 9.69 mmol) in toluene (5.76 ml) was slowly added to it. The reaction mixture was stirred further for 16 h at 65-70 °C, cooled to 25-30 °C and then filtered through a celite bed. The filtrate was washed with 10% aqueous citric acid solution (5.0 ml), 10% aqueous sodium bicarbonate solution (5.0 ml). Organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain methyl-3 -(difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylate (0.6 g, 36.3%, 3.16 mmol).

400 MHz): d 7.87 (s, 1H), 7.07 (t, / = 54 Hz, 1H), 3.94 (s, 3H), 3.82 (s, 3H).

13C NMR (CDCb, 100 MHz): d 39.6, 51.6, 106.8, 109.2, 111.5, 112.9, 134.9, 145.9, 146.2, 146.4, 162.1.

GC-MS: 190.1

Example-2: Preparation of methyl-3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylate A 100 ml autoclave was charged with methyl-3-(methylamino)acrylate (1.50 g, 12.38 mmol), 2, 2 -diflu oro acetonitrile (1.00 g, 13.00 mmol), anhydrous copper(II) acetate (0.67 g, 3.71 mmol) and toluene (25.0 ml) at 25 °C. 02-pressure (1 bar) was applied under vigorous stirring. The reaction mixture was stirred vigorously at 90 °C for 20 h. It was cooled to 25 °C and filtered through a celite bed. The filtrate was washed with 10% aqueous citric acid solution (20.0 ml). The aqueous citric acid layer was washed twice with ethyl acetate (100.0 ml). The combined organic layers were washed with water (20.0 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain methyl-3-(difluoromethyl)-l -methyl- lH-pyrazole-4-carboxylate (1.91 g, 81 % yield, 10.04 mmol).

Example-3: Preparation of methyl-3-(dichloromethyl)-l -methyl-lH-pyrazole-4-carboxylate To a solution of 2,2-dichloro acetonitrile (23.9 g, 217.0 mmol) in toluene (461 ml) was added anhydrous copper(II) acetate (39.4 g, 217.0 mmol), and mild vacuum (703 Torr) was applied at 25-30 °C. The reaction mixture was heated to 65-70 °C and a solution of methyl-3-(methylamino)acrylate (25.0 g, 217.0 mmol) in toluene (115.0 ml) was added to it over 1 h.

After complete addition, the reaction mixture was stirred for 16 h at 65-70 °C under vacuum conditions (703 Torr). The reaction mixture was then cooled to 25-30 °C and filtered through a celite bed. The filtrate was washed with 10% aqueous citric acid solution (416.0 ml), 10% sodium bicarbonate solution (383.0 ml) and water (250.0 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain methyl-3-(dichloromethyl)-l -methyl- lH-pyrazole-4-carboxylate (28.0 g, 57.7% yield, 125.53 mmol). 3H NMR (CDCb, 400 MHz): d 7.82 (s, 1H), 7.39 (s, 1H), 3.97 (s, 3H), 3.85 (s, 3H).

13C NMR (CDCb, 100 MHz): d 39.6, 51.4, 62.3, 109.9, 134.5, 151.1 , 162.1.

GC-MS: 221.9, 224.0

Example-4: Preparation of Impurity (X)

The aqueous layer obtained in Example-3 was stirred for 16 h to obtain a precipitate. The precipitate was filtered, washed with water (50.0 ml) and dried under vacuum to obtain mixture of solid isomers i.e. (£>Z)-methyl-4,4-dichloro-2-((methylamino)methylene)-3-oxobutanoate (4.0 g, 8.2% yield, 17.70 mmol).

Isomer- 1 (Major):

3H NMR (CDCb, 400 MHz): d 10.86 (br s, 1H), 8T4(d, J= 14 Hz, 1H), 7.49 (s, 1H), 3.75 (s, 3H), 3.23 (d, J = 4.8 Hz, 3H).

13C NMR (CDCb, 100 MHz): d 36.7, 37.0, 51.3, 51.4, 68.6, 163.5, 186.5.

Isomer-2 (Minor):

3H NMR (CDCb, 400 MHz): d 9.38 (br s, 1H), 8.22 (d, / = 14.8 Hz, 1H), 7.11 (s, 1H), 3.82 (s, 3H), 3.23 (d, J = 4.8 Hz, 3H)

13C NMR (CDCb, 100 MHz): d 36.6, 36.8, 51.2, 51.3, 51.5, 95.3, 165.95.

LCMS: 225.9 [M+l]

Example-5: Preparation of methyl-3-(4-chlorophenyl)-l -methyl-lH-pyrazole-4-carboxylate To a solution of 4-chlorobenzonitrile (1.0 g, 7.27 mmol) in toluene (12.0 ml) anhydrous copper(II) acetate (1.22 g, 6.72 mmol) was added, and the resulting mixture was heated to 50 °C for 1 h. To this reaction mixture, a solution of methyl- 3 -(methylamino) acrylate (0.82 g, 7.12 mmol) in toluene (12.0 ml) was added over 15 min at the same temperature. The reaction mixture was stirred for 20 h at 95 °C, cooled to 25 °C and filtered through a celite bed. The filtrate was washed with 10% aqueous citric acid solution (12.0 ml). The aqueous layer obtained by this procedure was extracted twice with ethyl acetate (56.0 ml). The

combined organic layers were washed twice with water (40.0 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain methyl-3-(4-chlorophenyl)-l -methyl- lH-pyrazole-4-carboxylate (1.14 g, 62.6% yield, 4.55 mmol).

3H NMR (CDCb, 400 MHz): d 7.94 (s, 1H), 7.74 (d, / = 11.2 Hz, 2H), 7.37 (d, J =11.2 Hz, 2H), 3.94 (s, 3H), 3.77 (s, 3H)

13C NMR (CDCb, 100 MHz): d 39.3, 51.2, 111.3, 128.0, 130.4, 130.7, 134.4, 135.8, 152.0, 163.2

GC-MS: 250.0, 252.0

Example-6: Preparation of methyl 3-isopropyl- 1 -methyl- lH-pyrazole-4-carboxylate

To a solution of isobutyronitrile (1.0 g, 14.47 mmol) in toluene (12.0 ml) anhydrous copper(II) acetate (3.42 g, 18.83 mmol) was added, and the resulting mixture was heated to 50 °C for 1 h. To this reaction mixture, a solution of methyl-3 -(methylamino)acrylate (1.81 g, 14.47 mmol) in toluene (12.0 ml) was added slowly. The reaction mixture was stirred for 20 h at 95 °C, cooled to 25 °C and filtered through a celite bed. The filtrate was washed with 10% aqueous citric acid solution (25.0 ml). The aqueous layer was extracted twice with ethyl acetate (56.0 ml). The combined organic layers were washed twice with water (40.0 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain methyl 3-vinyl-lH-pyrazole-4-carboxylate (0.73 g, 28% yield, 4.01 mmol).

3H NMR (CDCb, 400 MHz): d 7.75 (s, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.46-3.57 (m, 1H), 1.27 (s, 6H).

13C NMR (CDCb, 100 MHz): d 21.8, 26.7, 38.9, 50.9, 110.4, 134.6, 160.6, 163.8.

GC-MS: 182.1

Example-7: Preparation of methyl- 1 -methyl-3 -vinyl- lH-pyrazole-4-carboxylate

To a solution of acrylonitrile (1.0 g, 18.85 mmol) in toluene (12.0 ml) was added anhydrous copper(II) acetate (3.48 g, 19.16 mmol) and heated to 50 °C for 1 h. To this reaction mixture, a solution of methyl-3-(methylamino)acrylate (2.36 g, 18.85 mmol) in toluene (12.0 ml) was added slowly over 15 min. Reaction mixture was stirred for 20 h at 95 °C, cooled to 25 °C and filtered through a celite bed. Filtrate was washed with 10% aqueous citric acid solution (33.0 ml). Aqueous layer was washed twice with ethyl acetate (56.0 ml). Combined organic layers were washed twice with water (40.0 ml), dried over anhydrous sodium sulphate and

concentrated under reduced pressure to obtain methyl- 1 -methyl-3 -vinyl- lH-pyrazole-4-carboxylate (1.10 g, 35.0% yield, 6.62 mmol).

¾ NMR (CDCb, 400 MHz): 8.01 (s, 1H), 7.40 (d, / = 4 Hz, 1H), 7.18 (d, J = 16.0 Hz, 1H), 6.00 (d, / = 12 Hz, 1H), 3.79 (s, 3H), 3.68 (s, 3H)

GC-MS: 166.1

Example-8: Preparation of Impurity (IXA)

Tin(II) chloride dihydrate (1.960 g, 8.69 mmol) and toluene (12.0 ml) were mixed together followed by the addition of methyl-3 -(methylamino)acrylate (1.042 g, 8.69 mmol) in toluene (12.0 ml) at 25 °C. The reaction mixture was stirred for 16 h at 70 °C. It was then cooled to 25 °C and filtered through a celite bed. The filtrate was washed with 6% aqueous NaHCCb solution (13.0 ml). The organic layer was washed twice with water (20.0 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude solid. This crude solid was triturated with n-hexane (23.0 ml) and purified on combiflash chromatography (FCC) to obtain pure dimethyl-4-(2-methoxy-2-oxoethyl)-l -methyl- 1,4-dihydropyridine-3,5-dicarboxylate (1.50 g, 61 % yield, 8.70 mmol).

JH NMR (CDCb, 400 MHz): d 7.08 (s, 2H), 4.13 (t, J = 5.2 Hz, 1H), 3.69 (s, 6H), 3.55 (s, 3H), 3.14 (s, 3H), 2.41 (d, / = 5.2 Hz, 2H)

13C NMR (CDCb, 100 MHz): d 29.0, 40.8, 41.3, 51.1 , 51.2, 105.5, 140.1, 167.0, 171.8 GCMS: 252.1, 210.1 , 150.1

LCMS: 284.0 [M+l], 210.0

Example-9: Preparation of Impurity (VIA) and (VIIA)

To a solution of methyl-3-(methylamino)acrylate (5.0 g, 43.43 mmol) in toluene (115.0 ml) was added anhydrous copper(II) acetate (7.90 g, 43.43 mmol) at 25 °C. The reaction mixture was stirred for 16 h at 65-70 °C under vacuum (703 Torr) and then cooled to 25 °C. It was then filtered through a celite bed. The filtrate was washed with 10% aqueous citric acid solution (75.0 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a mixture of Impurity (VIA) and VIIA. These components were separated on neutral alumina by flash column chromatography.

Impurity VIA

JH NMR (CDCb, 400 MHz): d 8.77 (br s, 1H), 7.38 (d, J = 13.8 Hz, 1H), 7.17 (d, / = 12.2

Hz, 1H), 6.00 (d, J = 15.6 Hz, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.10 (d, / = 4.8 Hz, 3H) LCMS: 199.75 [M+l ]

Impurity VIIA

NMR (CDCb, 400 MHz): d 8.18 (d, / = 2.4 Hz, 1H), 7.84 (dd, J1 = 2.8 Hz, J2 = 2.4 Hz, 1H), 6.52 (d, J = 4.8 Hz, 1H), 3.85 (s, 3H), 3.58 (s, 3H)

LCMS: 167.75 [M+l ]

Example- 10: Preparation of Impurity (VIIIA)

Ethyl-2, 2-difluoroacetate (150.0 g, 1209 mmol) was charged in ethyl alcohol (1500 ml) at 25 °C. The solution was cooled to 0-5 °C, and then ammonia gas was bubbled in slowly for 30 min. The reaction mixture was stirred for 2 h at 25 °C. Excess solvent was removed under reduced pressure to obtain the crude solid. The crude solid was triturated in n-hexane (458.0 ml) at 15-20 °C and filtered to obtain pure 2,2-difluoroacetamide (110.0, 96% yield, 1209 mmol).

400 MHz): d 6.37 (br s, 2H), 5.89 (t, / = 54 Hz, 1H)

13C NMR (CDCb, 100 MHz): d 165.1, 164.9, 164.6, 110.6, 108.1, 105.6

GCMS: 95.0, 44.0, 32.0

Claims:

1. A process for preparing substituted heterocyclic compound of Formula I or of salts thereof

Formula I

wherein R1 is selected from hydrogen, halogen, cyano, nitro, CHO, COOR3, CONR3, Ci- C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, CYCYcycloalkyl, CYCYcyclohaloalkyk C3-C10- cycloalkylalkyl, Ci-C6-haloalkyl, C2-C6-haloalkenyl, C2-C6-haloalkynyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, Ci-C6-alkoxy-Ci-C4-alkyl, CYCYcycloalkoxy, Ci-C6-hydroxyalkyl, C3-C8-halocycloalkyl, Ci-C6-haloalkoxycarbonyl, Ci-C6-alkylthio, Ci-C6-alkylsulfmyl, Ci-C6-alkylsulfonyl, Ci-C6-haloalkylthio, Ci-C6-haloalkylsulfinyl, C1-C6- haloalkylsulfonyl, C3-C8-cycloalkylthio, Ci-C6-alkylamino, Ci-C6-dialkylamino, C3-C8- cycloalkylamino, C3-C8-cycloalkyl-Ci-C6-alkylamino, Ci-C6-alkylcarbonyl, C1-C6- alkoxycarbonyl, Ci-C6-alkylaminocarbonyl, Ci-C6-dialkylaminocarbonyl, C1-C6- alkoxycarbonyloxy, Ci-C6-alkylaminocarbonyloxy, Ci-C6-dialkylaminocarbonyloxy, 5- to 11- membered spirocyclic ring or 3- to 10- membered carbocyclic/ heterocyclic ring; wherein Formula I may be substituted by one or more R1;

X is selected from NR2 or PR2;

R2 is selected from hydrogen, Ci-C6-alkyl, C3-C8-cycloalkyl, aryl or heterocyclic ring; wherein each group of R2 is optionally substituted with one or more R1;

R3 is selected from hydrogen, Ci-C6-alkyl, C3-C8-cycloalkyl;

which comprises reacting a compound of Formula II or of salts thereof

R1— =N

Formula II

with a compound of Formula III or of salts thereof

Formula I I I

in the presence of a catalyst and optionally in the presence of a solvent.

2. The process as claimed in claim 1, wherein the solvent is selected from one or more of aliphatic, alicyclic or aromatic hydrocarbons, halogenated solvents, ethers, polar aprotic and aprotic dipolar solvents.

3. The process as claimed in claim 1, wherein the catalyst is selected from one or more of copper powder, anhydrous copper(II) acetate, copper(II) acetate monohydrate, copper(I) oxide, copper(II) oxide, copper(I) chloride, copper(II) chloride, iron(II) chloride, iron(III) chloride, zinc(II) chloride, nickel(II) acetate, cobalt(II) chloride, cobalt(II) chloride hexahydrate, cobalt(II) bromide, cobalt(II) fluoride, cobalt(II) iodide, cobalt(II) oxide, cobalt(III) oxide, cobalt(II, III) oxide, cobalt(II) acetate anhydrous and cobalt(II) acetate tetrahydrate.

4. The process as claimed in claim 1 , wherein said reaction is carried out at temperature in the range of 50 °C to 150 °C.

5. The process as claimed in claim 1 , wherein said reaction is carried out at temperature in the range of 70 °C to 90 °C.

6. The process for preparing compound of Formula I or of salts thereof as claimed in claim 1, having impurities of less than 10%, wherein impurities are selected from compounds of Formulae VIA, VIIA, VIIIA, IXA, and XA or of salts thereof.

Formula VIA Formula VIIA Formula VII IA Formula IXA Formula XA

7. Substantially pure methyl-3-(dihalomethyl)-l-methyl-lH-pyrazole-4-carboxylate compound of Formula 1A

Formula 1 A

having impurities of less than 10%, wherein the impurities are selected from the group comprising compounds of Formulae VI, VII, VIII, IX, and X or of salts thereof.

Formula VI Formula VII Formula VI I I Formula IX Formula X

A process for preparing methyl-3-(dihalomethyl)-l-methyl-lH-pyrazole-4-carboxylate compound of Formula 1 A or of salts thereof

Formula 1 A

comprising reacting 2,2-dihaloacetonitrile with methyl- 3- (me thylamino) acrylate in the presence of a catalyst and optionally in the presence of a solvent.

9. The process as claimed in claim 8, wherein the solvent is selected from one or more of aliphatic, alicyclic or aromatic hydrocarbons, halogenated solvents, ethers, polar aprotic and aprotic dipolar solvents.

10. The process as claimed in claim 8, wherein the catalyst is selected from one or more of copper powder, anhydrous copper(II) acetate, copper(II) acetate monohydrate, copper(I) oxide, copper(II) oxide, copper(I) chloride, copper(II) chloride, iron(II) chloride, iron(III) chloride, zinc(II) chloride, nickel(II) acetate, cobalt(II) chloride, cobalt(II) chloride hexahydrate, cobalt(II) bromide, cobalt(II) fluoride, cobalt(II) iodide, cobalt(II) oxide, cobalt(III) oxide, cobalt(II, III) oxide, cobalt(II) acetate anhydrous and cobalt(II) acetate tetrahydrate.