WO2016142918A1

WO2016142918A1 - Pyrazole derivatives and relative use for the preparation of 1,3,4-thiadiazoles

Info

Publication number: WO2016142918A1
Application number: PCT/IB2016/051399
Authority: WO
Inventors: Laura Sillani; Serena CARIELLO; Daniele Forgia; Marilena Gusmeroli; Paolo Bellandi
Original assignee: Isagro S.P.A.
Priority date: 2015-03-12
Filing date: 2016-03-11
Publication date: 2016-09-15
Also published as: ITUB20150115A1

Abstract

The present invention relates to pyrazole derivatives having general formula (IV) and their use as intermediates for the preparation of 1, 3, 4-thiadiazoles having general formula (I) having herbicidal properties. The present invention also relates to the preparation process of said compounds having general formula (IV).

Description

PYRAZOLE DERIVATIVES AND RELATIVE USE FOR THE PREPARATION OF 1 , 3, 4-THIADIAZOLES

The present invention relates

derivatives having general formula (IV)

(IV)

and their use as intermediates for the preparation of 1 , 3 , 4-thiadiazoles having general formula (I)

(I)

having herbicidal properties. The present

also relates to the preparation process

compounds having general formula (IV) .

STATE OF THE ART

The present invention relates to

derivatives having general formula (IV)

(IV)

and their use as intermediate compounds for the preparation of compounds having general formula (I)

(I)

The compounds having general formula (I) bear a thiadiazole ring and a pyrazole ring, connected to each other by a sulfinyl (n = 1) or sulfonyl (n = 2) spacer.

These compounds have recently been described by the Applicant in Italian patent application MI2014A001616 for use as herbicides for the control of weeds in agricultural crops.

As of today, except for what has been disclosed by the Applicant, no processes have been described in the state of the art for the preparation of the above compounds having general formula (I) .

Patent US 4097669 discloses various processes for the preparation of 1 , 3 , 4-thiadiazoles substituted in position 2 with a sulfonated residue, having the following chemical structure:

A first synthesis strategy described in patent US 4097669 envisages the reaction between a 5- trifluoromethyl-1, 3, 4-thiadiazole bearing a group X in position 2 and a mercaptan having formula R-SH under basic conditions, wherein X is a chlorine or bromine atom, as indicated in scheme 1. Scheme 1

An alternative way for preparing the desired thiadiazoles described in US 4097669 consists in reacting a 5-trifluoromethyl-1 , 3, 4-thiadiazole bearing a group SH in position 2 with a compound having formula LG-R under basic conditions, wherein LG represents a leaving group, such as halogen, mesyl or tosyl, as indicated in scheme 2.

Scheme 2

The thiadiazoles thus obtained are subsequently subjected to oxidation to provide the corresponding desired sulfonated derivative.

In US 4097669, it is never mentioned that the group R can represent a pyrazole ring optionally substituted, as in the present invention.

Pyrazole derivatives bearing an alkoxyl group in position 5 of the heterocycle, on the other hand, can be prepared, for example, according to the methods described in patent applications US 2005/215797 and US2007/249844.

These methods envisage a first cyclization step by reaction between a mono-substituted hydrazine and a beta-ketoester wherein R₃ represents an alkyl group, and subsequent alkylation of the hydroxyl group in the presence of an alkylating reagent, wherein LG is a leaving group such as, for example, a halogen atom, as indicated in scheme 3. Scheme 3

The above pyrazole derivatives, however, are obtained with low yields and purities, consequently making difficult to use these processes on an industrial level. Furthermore, there does not seem to be any suggestion with respect to the application of the same for the preparation of thiadiazole derivatives bearing a pyrazole ring.

The necessity is therefore felt for providing new intermediates for the preparation of compounds having general formula (I) and also for providing an improved process for the preparation of compounds bearing both a thiadiazole ring and a pyrazole ring, with high yields and purities, using non-toxic reagents and mild reaction conditions.

DESCRIPTION

The Applicant has now surprisingly found that compounds having general formula (I) can be obtained with high yields and purities

(I)

starting from compounds having general formula

(IV) wherein Ri, ]¾, R3, R₄, R5 and n have the meanings specified hereunder. Particularly advantageous results are achieved when the compounds having general formula (IV) are obtained by reacting a mono-substituted hydrazine having general formula R₂NH-NH₂ or a physiologically acceptable salt thereof and a beta- ketoester having general formula (II)

(Π) wherein Ri, R₂, R and R5 have the meanings specified hereunder .

A first object of the present invention therefore relates to compounds having general formula (IV)

(IV)

wherein :

Ri represents a C1-C alkyl group, a C1-C4 haloalkyl group, a C3-C6 cycloalkyl group, a C4-C7 cycloalkylalkyl group, a C6- C10 aryl group or a C7- C12 arylalkyl group, all of these groups being optionally substituted by one or more groups selected from halogen atoms, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxyl group, a C1-C4 haloalkoxyl group, a C1-C4 cycloalkoxyl group, a C1-C4 alkylsulfinyl group, a C1-C4 alkylsulfonyl group, a C6- C10 arylsulfonyl group, a NO2 group, a CN group, a NH₂ group, a C1-C4 alkylamino group, a C2-C5 alkoxycarbonyl group, an amide group, a benzyloxycarbonyl group or a phenoxycarbonyl group;

R₂ represents a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a C4-C7 cycloalkylalkyl group, a C6- C10 aryl group or a C7-C12 arylalkyl group, all of these groups being optionally substituted by one or more halogen atoms;

R5 represents a hydrogen atom or a thiadiazole group having general formula (III)

(III) wherein R represents a hydrogen atom, a C1-C4 alkyl group, a C3-C6 cycloalkyl group or a C4-C7 cycloalkylalkyl group, all of these groups being optionally substituted by one or more halogen atoms.

Examples of a C₁-C4 alkyl group are methyl, ethyl, propyl, butyl.

Examples of a C₁-C4 haloalkyl group are dichloromethyl , difluoromethyl, trichloromethyl , trifluoromethyl, chlorodifluoromethyl, dichloroethyl , trifluoroethyl, tetrafluoroethyl , pentafluoroethyl , tetrafluoroethyl , pentafluoroethyl , tetrafluoropropyl , pentafluoropropyl , dichlorobutyl , difluorobutyl .

Examples of a C3-C6 cycloalkyl group are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl .

Examples of a C4-C7 cycloalkylalkyl group are cyclopropylmethyl , cyclobutylmethyl , cyclopentylmethyl , cyclobutylmethyl .

Examples of a C6-C₁₀ aryl group are phenyl, naphthyl .

Examples of a C7-C₁2 arylalkyl group are benzyl, phenylethyl, phenylpropyl , phenylbutyl, phenylpentyl , phenylhexyl, naphthyl-methyl , naphthylethyl .

Examples of halogen are fluorine, chlorine, bromine, iodine.

Preferred compounds having general formula (I) that can be prepared starting from the intermediate compounds having general formula (IV) of the present invention, are those wherein:

R represents methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl or trifluoromethyl ; Ri represents methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, difluoromethyl, trifluoromethyl, methoxymethyl , aryl or benzyl;

R.₂ represents methyl, ethyl, cyclopropyl, cyclopropylmethyl, aryl or benzyl;

R₃ represents methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl , 2, 2, 2-trifluoroethyl, 1 , 1-2 , 2-tetrafluoroethyl , 1,1,1-2,2, 2-hexafluoroethyl , 1, 1, 1-trifluoropropyl, a methanesulfonic group, a p- toluenesulfonic group, a trifluoromethanesulfonic group, aryl or benzyl.

The above preferred compounds having general formula (I) are obtained starting from compounds having general formula (IV) wherein:

- R5 is H or a thiadiazole group having general formula (III) wherein R is selected from: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl and trifluoromethyl ;

Ri is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, difluoromethyl, trifluoromethyl, methoxymethyl, aryl and benzyl;

R₂ is selected from methyl, ethyl, cyclopropyl, cyclopropylmethyl, aryl, benzyl.

Particularly preferred are compounds having general formula (I) wherein:

- R represents methyl or ethyl;

- Ri represents difluoromethyl or trifluoromethyl ;

- R₂ represents methyl;

- R₃ represents ethyl, difluoromethyl or 2,2,2- trifluoroethyl . The latter more preferred compounds having general formula (I) are obtained starting from compounds having general formula (IV) wherein:

R5 is H or a thiadiazole group having general formula (III) wherein R is selected from: methyl and ethyl ;

Ri is selected from difluoromethyl and trifluoromethyl ;

- R2 represents methyl .

According to another aspect, the present invention relates to a process for the preparation of compounds having general formula (IV) which comprises a cyclization reaction between a mono-substituted hydrazine having general formula R2NH-NH2 or a physiologically acceptable salt thereof and a beta- ketoester having general formula (II), in an acid environment, to give the compound having general formula (IV), as indicated in scheme 4, wherein Ri , R2 and R5 have the meanings defined above and R represents a C1-C4 alkyl group, optionally substituted by one or more halogen atoms.

Scheme 4

(I I) (IV)

The acid environment which allows the formation of the compound having general formula (IV) can be obtained by the addition of an organic or inorganic acid, or with the use of a mono-substituted hydrazine salified with an organic or inorganic acid.

Said hydrazine can be commercially available or it can be prepared according to methods described in literature .

According to a preferred embodiment, the mono- substituted hydrazine having general formula R₂NH-NH₂ is used in non-salified form and dissolved in at least one polar organic solvent, more preferably in an alcoholic solvent selected from methanol, ethanol, propanol, butanol, or mixtures thereof.

The reaction mixture thus formed is brought to a temperature ranging from -10°C to room temperature, preferably ranging from 0°C to 10°C, to which the beta- ketoester having general formula (II) is added.

The beta-ketoester having general formula (II) can be commercially available or it can be prepared according to methods known to skilled persons in the field .

The beta-ketoester having general formula (II) is preferably added to the above reaction mixture in a molar ratio ranging from 0.6 to 2, more preferably from 0.8 to 1.5, even more preferably of about 1 with respect to the quantity of hydrazine.

The mixture is preferably left to react for a period of time ranging from 1 hour to 2 hours at room temperature, and at least one organic or inorganic acid is added.

Acids suitable for the purposes of the present invention are for example: HC1, HBr, H₂SO₄, CF₃COOH, CH₃SO₃H, CF₃SO₃H, p-toluenesulfonic acid, more preferably HC1, HBr and H₂S0₄. Said acid is preferably added in a molar ratio ranging from 0.7 to 1.5, more preferably of about 1 with respect to the quantity of beta-ketoester having general formula (II) .

The reaction mixture is subsequently brought to a temperature ranging from room temperature to the boiling point of the solvent, preferably at a temperature ranging from 60°C to 120°C.

Once the reaction completed, the compound having general formula (IV) can be isolated and purified according to methods well-known to the skilled person. The reaction mixture, for example, can be concentrated under vacuum, diluted with water, and extracted with a solvent immiscible with water. The compound having general formula (IV) can be subsequently recovered by evaporation of the organic solvent and purified by means of classical techniques, such as, for example, crystallization, precipitation or chromatography.

The above compound having general formula (IV) is preferably not subjected to further purification and is used as such in the subsequent synthesis steps.

The Applicant has discovered that, when the cyclization reaction is carried out as described above, i.e. in the presence of specific reagents and experimental conditions, the compound having general formula (IV) can be obtained directly, without having to resort to further purifications, with significantly higher yields and purities with respect to the thiadiazole derivatives described in the art.

These conditions therefore also allow compounds having general formula (I) to be prepared with high yields and purities.

A further object of the present invention therefore relates to the use of compounds having general formula (IV)

(IV) wherein Ri , ]¾ and R5 have the meanings defined above, as intermediates in the preparation of compounds having general formula (I) .

According to a particularly preferred aspect, compounds having general formula (IVa) and (IVb) are used as intermediates in the preparation of compounds having general formula (I)

These compounds correspond to the compounds having general formula (IV), wherein R5 has the meaning of a hydrogen atom or a substituted thiadiazole having general formula (III), respectively, as mentioned above .

According to a further aspect, the present invention therefore relates to a process for the preparation of compounds having general formula (I) starting from the intermediate compounds having general formula (IV) according to Scheme 5 hereunder. According to this reaction scheme, the starting intermediate compound is the compound having general formula (IVa) corresponding to the compound having general formula (IV) wherein R5 is hydrogen.

Scheme 5

According to Scheme 5, the compound having general formula (IVa) is treated with a haloformylation reagent to give the compound having general formula (V)

(IVa) (V)

Said reaction, known as Vilsmeier-Haack haloformylation, is carried out in at least one polar organic solvent, preferably in a polar organic solvent selected from dimethylformamide, xylene, dimethylsulfoxide or mixtures thereof, more preferably in dimethylformamide .

The Vilsmeier reagent is prepared by dissolving, at a temperature ranging from 0°C to 10°C, at least one compound having general formula POX₃ in the above- mentioned polar solvent, wherein X is a chlorine atom or a bromine atom.

The mixture is preferably left to return to room temperature and the compound having general formula (IVa) is added.

According to the present invention, the molar ratio between the quantity of haloformylation reagent having general formula POX₃ and the quantity of compound having general formula (IVa) ranges from 2 to 20, preferably from 4 to 10, and is more preferably about 6.

According to an embodiment of the invention, the halogen atom X present in the compound having general formula (V) can be substituted so as to introduce various functional groups onto the pyrazole ring, according to methods well-known in the art.

Said compound, for example, can be subjected to nitration, as described in patent application US2013/324547, or to fluorination as described in US2004/259734.

The halogen atom X is preferably substituted through a nucleophilic substitution reaction with a group R' to give the compound having general formula (IV) and the carbonyl in position 4 of the pyrazole is subsequently reduced to alcohol, providing the compound having general formula (VII)

(V) (VI) (VII) wherein R' represents a fluorine atom, a nitro group, a methanesulfonic group, a para-toluenesulfonic group, a trifluoromethanesufonic group.

According to another embodiment, the compound having general formula (V) can be subjected directly to a reduction reaction, to lead to the formation of the compound having general formula (VII), wherein R' has the same meanings as X, i.e. it represents a chlorine or bromine atom.

The reduction reaction from aldehyde to alcohol is carried out in at least one organic solvent, preferably in at least one aprotic solvent, more preferably an ethereal solvent such as tetrahydrofuran, dioxane, ethyl ether, tert-butyl-methylether or mixtures thereof .

For this purpose, for example, the reaction mixture is heated at a temperature ranging from 0°C to 10°C, and a metallic hydride is added in portions, preferably a hydride selected from sodium borohydride, calcium borohydride, lithium aluminium hydride, diisobutyl aluminium hydride, bis-methoxyethoxy aluminium hydride, more preferably sodium borohydride.

According to the present invention, the complete conversion from aldehyde to alcohol takes place by preferably introducing said hydride in a molar ratio ranging from 1 to 1.5, with respect to the quantity of starting aldehyde.

Alternatively, the compound having general formula (VII) can be obtained by subjecting said compound having general formula (VI) to a catalytic hydrogenation reaction in the presence of a metallic catalyst such as, for example, Pd/C, Ni Raney.

Said catalytic hydrogenation reaction preferably takes place in at least one polar organic solvent, such as an alcoholic solvent such as, for example, methanol, ethanol, or in ethyl acetate.

The parameters of the above reduction reactions, such as temperature and pressure, can be optionally selected by a skilled person in the field so as to maximize the yield and purity of the desired compound. The hydroxyl group of the alcohol having general formula (VII) thus obtained is subsequently substituted with a group Xi under conditions well-known to the skilled person in the field, to form the corresponding compound having general formula (VIII)

wherein :

Ri, R.2 and R' have the meanings defined above;

Xi represents a chlorine atom, a bromine atom, an alkylsulfonyloxyl group, haloalkylsulfonyloxyl group, an arylsulfonyloxyl group.

Xi preferably represents a chlorine atom, a bromine atom, a methanesulfonic group, a para-toluenesulfonic group, a trifluoromethanesufonic group.

Xi more preferably represents a chlorine atom, a methanesulfonic group, a para-toluenesulfonic group.

According to a particularly preferred embodiment, a halogenating reagent is added to the compound having general formula (VII), more preferably thionyl chloride or oxalyl chloride, to provide a compound having general formula (VIII) wherein Xi represents a chlorine atom.

Said substitution reaction of the OH group with the group Xi can be carried out in the presence or in the absence of an organic or inorganic base, so as to neutralize the acid released during said reaction.

The above substitution reaction is preferably carried out in the absence of a base. Upon completion of the reaction, the reaction mixture is concentrated under vacuum and the compound having general formula (VIII) is used in the subsequent step without further purification .

According to the present invention, said compound having general formula (VIII) is then condensed with a thiadiazole derivative having general formula (IX) in the presence of an organic base such as triethylamine, diethylamine, diisopropylethylamine, pyridine or an inorganic base such as sodium carbonate, potassium carbonate, potassium tert-butylate.

A suitable base for the above condensation reaction is an organic base selected from triethylamine, diethylamine, diisopropylethylamine, pyridine, and is preferably triethylamine, to give the compound having general formula (X)

wherein R, Ri, R₂, R' and Xi have the meanings defined above .

The condensation reaction is preferably carried out in at least one apolar organic solvent, more preferably in at least one chlorinated solvent, even more preferably in chloroform, dichloromethane, dichloroethane or mixtures thereof.

The subsequent step of the process of the present invention envisages reacting the compound having general formula (X) with a reagent having general formula R₃-OH by nucleophilic substitution, to provide the compound having general formula (XI)

wherein R, Ri, R₂, R3 and R' have the meanings defined above .

Preferably, the reagent having formula R₃-OH is dissolved in at least one organic solvent, more preferably in at least one aprotic polar solvent, even more preferably in N-methylpyrrolidone, N,N- dimethylformamide, N, N-dimethylacetamide or mixtures thereof .

An inorganic base, preferably a hydride of an alkaline metal, more preferably sodium hydride, is added to the above reaction mixture, maintaining a temperature ranging from 0°C to 10°C.

According to the present invention, the compound having general formula (X) is then introduced into the solvent-base mixture thus formed, in a molar ratio with respect to the quantity of alkylating reagent ranging from 0.5 to 1.5, preferably ranging from 0.8 to 1.1.

The reaction mixture is then heated at a temperature ranging from room temperature to the boiling point of the solvent, preferably at a temperature ranging from 40°C to 100°C, more preferably at about 80°C.

Once the substitution reaction has been completed, the mixture is preferably concentrated under vacuum and the compound having general formula (XI) is then used directly in the subsequent step.

The desired compounds having general formula (I) are prepared by the oxidation of compounds having general formula (XI)

wherein R, Ri, R₂, R3 have the meanings defined above; n is 1 or 2.

The compound having general formula (XI) is dissolved in at least one apolar organic solvent, preferably in at least one chlorinated solvent, more preferably in chloroform, dichloromethane, dichloroethane or mixtures thereof, maintaining the temperature of the mixture between 0°C and 10°C.

According to the present invention, an oxidizing agent is added, selected from an organic peroxide such as meta-chloroperbenzoic acid, peracetic acid, dibenzoyl peroxide or an inorganic peroxide such as hydrogen peroxide, calcium peroxide, sodium peroxide, preferably meta-chloroperbenzoic acid.

Said oxidizing agent is introduced into the reaction mixture in a molar ratio with respect to the quantity of compound having general formula (XI) ranging from 0.7 to 3, preferably from 0.8 to 2.5.

Once the reaction is complete, the desired compounds can be isolated and purified according to methods well-known to the skilled person. The reaction mixture, for example, can be concentrated under vacuum, diluted with water, and extracted with a solvent immiscible with water. The compounds having general formula (I) can be subsequently recovered by evaporation of the organic solvent and purified by means of classical techniques such as, for example, crystallization, precipitation or chromatography.

In a preferred embodiment, the compound having general formula (IV) wherein R5 is hydrogen (corresponding to the compound having general formula IVa of Scheme 5) is obtained by means of a cyclization reaction between a mono-substituted hydrazine having general formula R₂NH- N¾ or a physiologically acceptable salt thereof and a beta-ketoester having general formula (II) in an acid environment, to give the compound having general formula (IV)

(II) (IV)

wherein Ri, R₂ and R have the meanings defined above;

R5 represents a hydrogen atom.

The cyclization reaction is therefore the following :

As previously indicated, the use of an intermediate having general formula (IV) obtained by means of the above cyclization reaction allows the corresponding compound having general formula (I) to be obtained with high yields and purities.

According to a further aspect, the present invention relates to a process for the preparation of compounds having general formula (I) according to Scheme 6. According to this reaction scheme, the starting intermediate compound is the compound having general formula (XII) corresponding to the compound having general formula (IV) wherein R5 is a thiadiazole radical having general formula (III)

(III) wherein R represents a hydrogen atom, a C₁-C4 alkyl group, a C3-C6 cycloalkyl group or a C4-C7 cycloalkylalkyl group, all of these groups being optionally substituted by one or more halogen atoms.

Scheme 6

According to Scheme 6, the hydroxyl group of the compound having general formula (XII) is alkylated with a group R₃, by reaction with an alkylating reagent having general formula R₃-X, wherein R₃ has the meaning defined above and X represents a leaving group, such as a halogen, a methanesulfonic group, a para- toluenesulfonic group or a trifluoromethanesulfonic group .

Said alkylation reaction is carried out in at least a polar organic solvent, more preferably in at least an aprotic polar solvent, even more preferably in N,N- dimethylformamide, N-methylpyrrolidone or mixtures thereof .

An organic or inorganic base is added to the mixture containing the solvent and alkylating agent, preferably an inorganic base selected from a hydroxide of alkaline metals or a carbonate of alkaline metals, more preferably a carbonate of alkaline metals, such as sodium carbonate or potassium carbonate.

The reaction mixture is then heated at a temperature within the range from room temperature to the boiling point of the solvent, preferably at a temperature within the range from 40°C to 100°C, more preferably at about 80°C.

According to the present invention, the compound having general formula (XI) thus obtained is then subjected to an oxidation reaction to provide the desired compounds having general formula (I) .

For this purpose, an oxidizing agent is added to said compound having general formula (XI), selected from an organic peroxide such as meta-chloroperbenzoic acid, peracetic acid, dibenzoyl peroxide or an inorganic peroxide such as hydrogen peroxide, calcium peroxide, sodium peroxide, preferably meta- chloroperbenzoic acid.

As it will be evident to the skilled person in the field, in the oxidation reaction indicated in Schemes 5 and 6, a molar ratio between said oxidizing agent and said compound having general formula (XI) ranging from 0.7 to 1.5 leads to the formation of a compound having general formula (I), wherein n is equal to 1. Analogously, a molar ratio between said oxidizing agent and said compound having general formula (XI) ranging from 1.5 to 3 leads to the formation of a compound having general formula (I), wherein n is equal to 2.

With the process according to the invention, in

Schemes 5 and 6, the sulfoxides having general formula (I), i.e. the compounds having general formula (I) wherein n is equal to 1, are preferably obtained in racemic form.

The two isomers can be separated by means of techniques well-known to skilled person in the field, such as, for example, chiral resolution, chiral chromatography, distillation, precipitation.

Alternatively, said isomers can be obtained by means of enantioselective reactions, for example by means of enantioselective oxidation from sulfide to sulfoxide (as described in Chem. Comm. 2008, pages 1704-1706, or in Angew. Chem. 2007, vol. 46, pages 4729-4731), or by reduction of the sulfone to sulfoxide .

In a preferred embodiment, the compound having general formula (IV) wherein R5 is a thiadiazole group having general formula (III) (corresponding to the compound having general formula (XII) of Scheme 6), is obtained by means of a cyclization reaction between a mono-substituted hydrazine having general formula R₂NH- N¾ or a physiologically acceptable salt thereof and a beta-ketoester having general formula (II), in an acid environment, to give the compound having general formula (IV)

(II) (IV) wherein Ri, R₂ and R have the meanings defined above; R5 represents a thiadiazole group having general formula (III)

wherein R represents a hydrogen atom, a C₁-C4 alkyl group, a C3-C6 cycloalkyl group or a C4-C7 cycloalkylalkyl group, all of these groups being optionally substituted by one or more halogen atoms.

The cyclization reaction is therefore the following :

As previously indicated, the use of an intermediate having general formula (IV) obtained by means of the above cyclization reaction, allows the corresponding compound having general formula (I) to be obtained with high yields and purities.

As the beta-ketoester having general formula (lib) is not commercially available, it can be prepared according to the methods described hereunder.

According to an embodiment of the present invention, the beta-ketoester having general formula (lib) can be prepared in two steps. The first step envisages the condensation of a thiadiazole derivative having general formula (IX) and an acrylate having general formula (XIII), forming a thiadiazole derivative bearing an ester group having general formula (XIV) . Said compound is subsequently acylated with a reagent having general formula RiC(0)X, wherein Ri has the meaning defined above, X is a chlorine or bromine atom, to provide the desired beta-ketoester having general formula (lib) .

According to another embodiment of the present invention, the beta-ketoester having general formula (lib) is preferably prepared according to the method described in Advanced Synthesis and Catalysis 2009, vol. 351, pages 3269-3278, or by the condensation of the beta-ketoester having general formula (Ila) with a thiadiazole derivative having general formula (IX) in the presence of formaldehyde:

wherein R, Ri and R have the meanings indicated above.

A diluted solution of formaldehyde in water is added to a solution of beta-ketoester having general formula (Ila) in a polar solvent, preferably in water.

According to the present invention, a diluted solution of formaldehyde is used, having a concentration preferably ranging from 20% to 50% in water .

The molar ratio of the above-mentioned formaldehyde with respect to the quantity of the above-mentioned beta-ketoester having general formula (Ila) preferably ranges from 0.5 to 1.5, and is more preferably about 1.

The compound having general formula (IX) is added to the reaction mixture thus formed, in a molar ratio ranging from 0.2 to 0.8, preferably ranging from 0.4 to 0.6, more preferably about 0.5, with respect to the quantity of beta-ketoester having general formula (Ha) .

The reaction is then preferably brought to a temperature ranging from room temperature to 100°C, more preferably ranging from 40°C to 80°C.

Some examples are provided hereunder for illustrative and non-limiting purposes of the present invention .

EXPERIMENTAL PART

Example 1

Preparation of 2- [ (l-methyl-3-trifluoromethyl-5- (2, 2, 2- trifluoroethoxy) -pyrazol-4-yl ) sulfinyl] -5-methyl-l, 3, 4- thiadiazole [Compound (I), R = CH₃, Ri = CF₃, R₂ = CH₃, R₃ = CH₂CF₃, n = 1] a) Preparation of l-methyl-3- (trifluoromethyl) -1H- pyrazol-5-ol [compound having general formula (IVa)]

10 g (54.34 mmoles) of ethyl trifluoroacetoacetate (Ila) were added dropwise to a solution under nitrogen of 2.9 ml (54.34 mmoles) of methylhydrazine in 40 ml of ethanol, maintaining a temperature of about 4-5°C with an ice bath; after about lh 30 at room temperature, 2 ml of concentrated hydrochloric acid were added.

The mixture was heated to reflux temperature for 13 hours.

After control in GC-MS and LC-MS, the mixture was concentrated at reduced pressure, then diluted with water; the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and washed with water and with a saturated solution of sodium chloride.

After anhydrification on sodium sulfate, filtration and evaporation of the solvent at reduced pressure, 8.9 g of the desired product were obtained as a yellow solid. The raw product thus obtained was treated with hexane, filtered and dried in air, obtaining 7.8 g (46.98 mmoles) of the desired product as a white solid. Yield 86.5%. LC-MS [M+H] = 167.

b) Preparation of 5-chloro-l-methyl-3- (trifluoro- methyl ) -lff-pyrazole-4-carbaldehyde [compound having general formula (V) ]

24.3 ml (265.62 mmoles) of phosphorous oxychloride were added dropwise to 7 ml (88.54 mmoles) of N,N- dimethylformamide, maintaining a temperature of about 4-5°C with an ice bath; 7.35g (44.27 mmoles) of 1- methyl-3- (trifluoromethyl) -lJJ-pyrazol-5-ol (IVa) were then added at room temperature.

The mixture was heated to reflux temperature for 1 hour .

After control in GC-MS and LC-MS, the mixture was carefully poured into water and ice; the aqueous phase was extracted three times with chloroform. The organic phases were combined and washed with a saturated solution of NaHCC>3, water and a saturated solution of NaCl.

After anhydrification on sodium sulfate, filtration and evaporation of the solvent at reduced pressure, 7.4 g of the desired product were obtained (34.9 mmoles) as a brown solid. Yield 79.4%.

LC-MS [M+H] = 213.

c) Preparation of 5-fluoro-1-methyl-3-

(trifluoromethyl) -lff-pyrazole-4-carbaldehyde [compound having general formula (VI), R' = F]

4.8 g (82.55 mmoles) of KF were added at room temperature to a solution under nitrogen of 7 g (33.02 mmoles) of 5-chloro-l-methyl-3- (trifluoromethyl) -1H- pyrazole-4-carbaldehyde (V) in 80 ml of dimethylsulfoxide .

The mixture was heated to 120-130°C for 5 hours. After control in GC-MS and LC-MS, the mixture was poured into water; the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and washed with water and with a saturated solution of NaCl .

After anhydrification on sodium sulfate, filtration and evaporation of the solvent at reduced pressure, 5.3 g of the desired product were obtained (27.04 mmoles) as a brown oil. Yield 82%.

LC-MS [M+H] = 197.

d) Preparation of [ 5-fluoro-1-methyl-3- ( trifluoromethyl ) -lH-pyrazole-4-yl ] methanol [ compound having general formula (VII)]

1.06 g (28.06 mmoles) of sodium borohydride were added in portions to a solution under nitrogen of 5 g (25.51 mmoles) of 5-fluoro- l-methyl-3- (trifluoro- methyl ) -lff-pyrazole-4-carbaldehyde (VI) in 80 ml of THF, maintaining a temperature of about 4-5°C with an ice bath.

The mixture was left at about 10°C for 5 hours. After control in GC-MS, the mixture was concentrated at reduced pressure and poured into water; the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and washed with a saturated solution of NaHCC>3, water and a saturated solution of NaCl .

After anhydrification on sodium sulfate, filtration and evaporation of the solvent at reduced pressure, 4.9 g of the desired product were obtained (24.75 mmoles) as a brown oil. Yield 97%.

GC-MS [m/z] = 198. e) Preparation of 5-fluoro-4- ( chloromethyl ) - 1-methyl-3- (trifluoromethyl) -lH-pyrazole [compound having general formula (VIII) ]

2.17 ml (29.70 mmoles) of thionyl chloride were added dropwise, at room temperature, to a solution under nitrogen of 4.9 g (24.75 mmoles) of [5-fluoro-1- methyl-3- (trifluoromethyl) -lH-pyrazol-4-yl ] methanol (VII) in 85 ml of dichloromethane .

The mixture was left under magnetic stirring at room temperature for 2 hours .

After control in GC-MS, the mixture was concentrated at reduced pressure, azeotroping with toluene to remove the excess thionyl chloride.

5.3 g of the desired product (24.75 mmoles) were obtained as a brown oil. Quantitative yield.

GC-MS [m/z] = 216. f ) Preparation of 2- ({ [ 5-fluoro-l-methyl-3- (trifluoromethyl ) -lff-pyrazol-4-yl ] methyl } thio ) -5-methyl-l , 3,4- thiadiazole [compound having general formula (X) ]

3.20 ml (23.09 mmoles) of triethylamine were added dropwise at room temperature to a suspension under nitrogen of 3.05 g (23.09 mmoles) of 5-methyl-l, 3, 4- thiadiazole-2-thiol (IX) in 30 ml of chloroform; 5.0 g (23.09 mmoles) of 5-fluoro-4- (chloromethyl) -l-methyl-3- (trifluoromethyl) -lH-pyrazole (VIII) dissolved in 10 ml of chloroform were then added. 4.8 ml (34.64 mmoles) of triethylamine were finally added dropwise.

The mixture was left under magnetic stirring at room temperature for a night.

After control in GC-MS and LC-MS, the mixture was diluted with water and the phases were then separated; the aqueous phase was re-extracted twice with dichloromethane. The organic phases were combined and washed with water and with a saturated solution of sodium chloride.

After anhydrification on sodium sulfate, filtration and evaporation of the solvent at reduced pressure, 6.48 g of the desired product were obtained (20.78 mmoles) as a brown oil. Yield 90%.

LC-MS [M+H] = 313. g) Preparation of 2-methyl-5- ( { [ l-methyl-5- ( 2 , 2 , 2- trifluoroethoxy) -3- ( trifluoromethyl ) -lH-pyrazol-4- yl ] methyl } thio ) -1 , 3 , 4-thiadiazole [ compound having general formula (XI)]

1.15g (48.08 mmoles) of sodium iodide were added in portions to a flask containing 4.15 ml (57.69 mmoles) of trifluoroethanol, maintaining a temperature of about 4-5°C with an ice bath and leaving the mixture to react at this temperature for about 30 minutes.

The mixture thus prepared was added to a solution under nitrogen of 6 g (19.23 mmoles) of 2- ( { [5-fluoro- l-methyl-3- (trifluoromethyl) -lH-pyrazol-4-yl ] methyl } - thio) -5-methyl-l, 3, 4-thiadiazole (X) in 20 ml of N- methyl-2-pyrrolidone at room temperature.

The mixture was heated at 80°C for 6 hours.

After control in GC-MS and LC-MS, the mixture was poured into water; the aqueous phase was extracted three times with ethyl acetate. The organic phases were joined and washed with water and a saturated solution of sodium chloride.

After anhydrification on sodium sulfate, filtration and evaporation of the solvent at reduced pressure, 7.16 g of the desired product were obtained (18.27 mmoles) as a brown oil. Yield 95%.

LC-MS [M+H] = 393. h) Preparation of 2- [ ( l-methyl-3-trifluoromethyl-5- (2,2, 2-trifluoroethoxy) -pyrazol-4-yl ) sulfinyl] -5- methyl- 1, 3, 4-thiadiazole [Compound having general formula ( I ) ]

4.4 g (19.58 mmoles) of 4-chloro-perbenzoic acid at 77% were added to 7.0 g (17.8 mmoles) of 2-methyl-5- ( { [ 1-methy1-5- (2,2, 2-trifluoroethoxy) -3- ( trifluorome- thyl ) -lH-pyrazol-4-yl ] methyl } thio ) -1 , 3 , 4-thiadiazole (XI), dissolved in 35 ml of chloroform, maintaining a temperature of about 4-5°C with an ice bath; the mixture was then left under magnetic stirring at room temperature for a night.

After control in LC-MS, the mixture was diluted with water and the phases were then separated; the aqueous phase was re-extracted twice with dichloromethane . The organic phases were combined and washed with an aqueous solution of NaHS0₃ at 5%, a saturated solution of NaHC0₃, water and a saturated solution of NaCl .

After anhydrification on sodium sulfate, filtration and evaporation of the solvent at reduced pressure, 7.1 g of the desired product were obtained (17.4 mmoles) as a yellow oil. The raw product thus obtained was purified by flash chromatography (eluent hexane/ethyl acetate 6:4), obtaining 6.0 g (14.77 mmoles) of the desired product as a yellow solid. Yield 83.0%.

LC-MS [M+H] = 409.

Example 2

Preparation of 2-methyl-5- ( { [ l-methyl-5- ( 2 , 2 , 2- trifluoroethoxy) -3- ( trifluoromethyl ) -lH-pyrazol-4-yl ] - methyl } thio ) -1 , 3 , 4-thiadiazole [Compound having general formula (XI), R = CH₃, Ri = CF₃, R₂ = CH₃, R₃ = CH₂CF₃] a) Preparation of 4, 4, 4-trifluoro-2- {[ (5-methyl-l, 3, 4- thiadiazol-2-yl ) thio] methyl } -3-ethyl-oxobutanoate

[compound having general formula (lib)]

10 g (75.7 mmoles) of 5-methyl-l, 3, 4-thiadiazole-2- thiol (IX) were added at room temperature to a mixture under nitrogen of 12.3 g (151.5 mmoles) of a solution of formaldehyde at 37% in water and 27.8 g (151.5 mmoles) of ethyl trifluoroacetoacetate (Ila) in 70 ml of water.

The mixture was heated to 60°C for 24 hours.

After control in LC-MS, the mixture was extracted three times with ethyl acetate. The organic phases were combined and washed with water and with a saturated solution of sodium chloride. After anhydrification on sodium sulfate, filtration and evaporation of the solvent at reduced pressure, 27.7 g of the desired product were obtained as a colourless oil. The raw product thus obtained was purified by flash chromatography (eluent heptane/ethyl acetate 8:2), obtaining 15.1 g (46.04 mmoles) of the desired product as a yellow solid. Yield 60.8%.

LC-MS [M+H] = 329.

b) Preparation of l-methyl-4- { [ (5-methyl-l, 3, 4- thiadiazol-2-yl ) thio ] methyl } -3- (trifluoromethyl) -1H- pyrazol-5-ol [compound having general formula (XII)]

8 g (24.4 mmoles) of 4 , 4 , 4-trifluoro-2- {[( 5-methyl- 1,3, 4-thiadiazol-2-yl ) thio ] methyl } -3-ethyl-oxobutanoate (lib), dissolved in 10 ml of ethanol, were added dropwise to a solution under nitrogen of 1.3 ml (24.4 mmoles) of methylhydrazine in 30 ml of ethanol, maintaining a temperature of about 4-5°C with an ice bath; after about lh 30' at room temperature, 2 ml of concentrated hydrochloric acid were added.

The mixture was heated to reflux temperature for 5 hours .

After control in LC-MS, the mixture was concentrated at reduced pressure, then diluted with water; the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and washed with water and a saturated solution of sodium chloride .

After anhydrification on sodium sulfate, filtration and evaporation of the solvent at reduced pressure, 6.7 g of the desired product were obtained as a yellow solid. Yield 88.5%.

LC-MS [M+H] = 311

c) Preparation of 2-methyl-5- ( { [ l-methyl-5- ( 2 , 2 , 2- trifluoroethoxy) -3- ( trifluoromethyl ) -lH-pyrazol-4-yl ] - methyl } thio ) -1 , 3 , 4-thiadiazole [compound having general generale (XI ) ]

4.9 g (19.4 mmoles) of 2 , 2 , 2-trifluoroethyl-4- methylbenzenesulfonate were added to a mixture of 4.0 g (12.9 mmoles) of l-methyl-4- { [ (5-methyl-l, 3, 4- thiadiazol-2-yl ) thio] methyl } -3- (trifluoromethyl) -1H- pyrazol-5-ol (XII) and 2.7 g (19.4 mmoles) of potassium carbonate in 50 ml of N, N-dimethylformamide, left under magnetic stirring at room temperature for 30 minutes.

The mixture was heated at 80°C for 4 hours.

After control in LC-MS, the mixture was poured into water; the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and washed with water and with a saturated solution of sodium chloride.

After anhydrification on sodium sulfate, filtration and evaporation of the solvent at reduced pressure, 3.5 g (8.92 mmoles) of the desired product were obtained as a brown solid. The raw product thus obtained was purified by flash chromatography (eluent heptane/ethyl acetate 7:3), obtaining 1.5 g (3.87 mmoles) of the desired product as a yellow solid. Yield 30%.

LC-MS [M+H] = 393.

Example 3

Preparation of 2-methyl-5- ( { [ l-methyl-5- ( 2 , 2 , 2- trifluoroethoxy) -3- ( trifluoromethyl ) -lH-pyrazol-4-yl ] - methyl } thio ) -1 , 3 , 4-thiadiazole [compound having general formula (XI) ]

1.2 ml (16.7 mmoles) of trifluoroethanol were added dropwise to a suspension under nitrogen of 0.7 g (16.7 mmoles) of sodium hydride in 15 ml of N,N- dimethylformamide, maintaining a temperature of about 4-5°C with an ice bath and leaving the mixture to react at this temperature for about 1 hour.

5 g (15.2 mmoles) of 2- ( { [ 5-chloro-l-methyl-3- (trifluoromethyl) -lH-pyrazol-4-yl ] methyl } thio ) -5- methyl-1, 3, 4-thiadiazole (X), dissolved in 5 ml of N,N- dimethylformamide were added to the mixture thus prepared, maintaining a temperature of about 4-5°C with an ice bath.

The mixture was heated at 80°C for 6 hours.

After anhydrification on sodium sulfate, filtration and evaporation of the solvent at reduced pressure, 7.16 g (18.27 mmoles) of the desired product were obtained as a brown oil. Yield 95%.

LC-MS [M+H] = 393

Example 4

Preparation of 4 , 4 , 4-trifluoro-2- {[( 5-methyl- 1,3, 4-thiadiazol-2-yl ) thio ] methyl } -3-butyl-oxobutanoate [compound having general formula (lib), R = CH₃, Ri = CF₃, R₄ = CH2CH2CH2CH3 ]

a) Preparation of 3- [ (5-methyl-l, 3, 4-thiadiazol-2- yl ) thio ] butyl propanoate [compound having general formula (XIV) ]

10.6 g (83.2 mmoles) of butyl acrylate (XIII) and 11.0 ml (79.4 mmoles) of triethylamine were added, at room temperature, to a solution under nitrogen of 10. Og (75.6 mmoles) of 5-methyl-l , 3, 4-thiadiazole-2-thiol (IX) in 300 ml of MeOH.

The mixture was heated to reflux temperature for 8 hours .

After control in GC-MS, the solvent was removed at reduced pressure, obtaining 18.3 g of the desired product (70.4 mmoles), as a yellow oil. Yield 93%.

GC-MS [m/z] = 260.

b) Preparation of 4, 4, 4-trifluoro-2- {[ (5-methyl-l, 3, 4- thiadiazol-2-yl ) thio] methyl } -3-butyl-oxobutanoate

[compound having general formula (lib)]

18.6 g (70.4 mmoles) of 3- [ (5-methyl-l, 3, 4- thiadiazol-2-yl ) thio ] butyl propanoate (XIV) were added to a suspension, under nitrogen, of 8.5 g (75.8 mmoles) of tBuOK in 250ml of tetrahydrofuran .

After about 15 minutes at room temperature, trifluoroacetylchloride was bubbled into the reaction mixture which was maintained at 50°C for 8 hours.

After control in LC-MS, the mixture was extracted three times with ethyl acetate. The organic phases were combined and washed with water and with a saturated solution of sodium chloride.

After anhydrification on sodium sulfate, filtration and evaporation of the solvent at reduced pressure, 23.7 g of the desired product were obtained as a brown oil. The raw product thus obtained was purified by flash chromatography (eluent heptane/ethyl acetate 8:2), obtaining 15.0 g (42.13 mmoles) of the desired product as a solid. Yield 55.5%.

LC-MS [M+H] = 356

Claims

1. Use of a compound having general formula (IV)

(IV)

as intermediate for preparing 1 , 3 , 4-thiadiazoles having general formula (I)

(I) wherein in said general formulae (IV) and (I) :

Ri represents a C1- C alkyl group, a C1- C4 haloalkyl group, a C₃-C6 cycloalkyl group, a C4-C₇ cycloalkylalkyl group, a C6- C10 aryl group or a C₇- C12 arylalkyl group, said groups being optionally substituted by one or more groups selected from halogen atoms, a C1- C4 alkyl group, a C1- C4 haloalkyl group, a C1- C4 alkoxyl group, a C1- C4 haloalkoxyl group, a C1- C4 cycloalkoxyl group, a C1- C4 alkylsulfinyl group, a C1- C4 alkylsulfonyl group, a Ce^~ Cio arylsulfonyl group, a NO2 group, a CN group, a N¾ group, a C1- C4 alkylamino group, a C2-C5 alkoxycarbonyl group, an amide group, a benzyloxycarbonyl group or a phenoxycarbonyl group;

R₂ represents a C1- C4 alkyl group, a C₃-C6 cycloalkyl group, a C4-C7 cycloalkylalkyl group, a C6- C10 aryl group, or a C7- C12 arylalkyl group, said groups being optionally substituted by one or more halogen atoms ;

- R₃ represents a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C3-C6 cycloalkyl group, a C4-C7 cycloalkylalkyl group, a C6- C10 aryl group, a C7-C12 arylalkyl group, a C1-C4 alkylsulfonyl group, a C1-C4 haloalkylsulfonyl group, a C6- C10 arylsulfonyl group, said groups being optionally substituted by one or more halogen atoms;

(III)

wherein R represents a hydrogen atom, a C1-C4 alkyl group, a C3-C6 cycloalkyl group or a C4-C7 cycloalkylalkyl group, said groups being optionally substituted by one or more halogen atoms;

- n is equal to 1 or 2.

2. Use of a compound having general formula (IV) according to the previous claim, wherein:

R5 is H or a thiadiazole group having general formula (III) wherein R is selected from: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl and trifluoromethyl ;

Ri is selected from: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, difluoromethyl, trifluoromethyl, methoxymethyl , aryl and benzyl; R.₂ is selected from: methyl, ethyl, cyclopropyl, cyclopropylmethyl , aryl, benzyl.

3. Use of a compound having general formula (IV) according to claim 1, wherein:

- R.5 is H or a thiadiazole group having general formula (III) wherein R is selected from: methyl and ethyl ;

Ri is selected from: difluoromethyl and trifluoromethyl ;

- R₂ is methyl.

4. A process for preparing 1 , 3 , 4-thiadiazoles having general formula (I)

which comprises: a) reacting a compound having general formula

(IV)

with an alkylating agent having general formula

form the compound having general formula (XI)

b) oxidizing said compound having general formula (XI) to obtain said compound having general formula (I) ; wherein in said general formulae (I), (IV) and (XI) :

Ri represents a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C3-C6 cycloalkyl group, a C4-C7 cycloalkylalkyl group, a C6- C10 aryl group or a C7- C12 arylalkyl group, said groups being optionally substituted by one or more groups selected from halogen atoms, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxyl group, a C1-C4 haloalkoxyl group, a C1-C4 cycloalkoxyl group, a C1-C4 alkylsulfinyl group, a C1-C4 alkylsulfonyl group, a Ce^~ C10 arylsulfonyl group, a NO2 group, a CN group, a NH₂ group, a C1-C4 alkylamino group, a C2-C5, alkoxycarbonyl group, an amide group, a benzyloxycarbonyl group or a phenoxycarbonyl group;

R₂ represents a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a C4-C7 cycloalkylalkyl group, a C6- C10 aryl group, or a C7- C12 arylalkyl group, said groups being optionally substituted by one or more halogen atoms;

R₃ represents a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C3-C6 cycloalkyl group, a C4-C7 cycloalkylalkyl group, a C6- C10 aryl group, a C7-C12 arylalkyl group, a C1-C4 alkylsulfonyl group, a C1-C4 haloalkylsulfonyl group, a C6- C10 arylsulfonyl group, said groups being optionally substituted by one or more halogen atoms;

R5 represents a thiadiazole group having general formula (III)

(III) wherein R represents a hydrogen atom, a C1-C₄ alkyl group, a C3-C6 cycloalkyl group, or a C4-C7 cycloalkylalkyl group, said groups being optionally substituted by one or more halogen atoms;

- X represents a group selected from: halogen, a methanesulfonic group, a para-toluenesulfonic group and a trifluoromethanesulfonic group;

n is equal to 1 or 2.

5. A process for preparing 1 , 3 , 4-thiadiazoles having general formula (I)

which comprises:

a) reacting a compound having general formula (IVa) with a haloformylation agent having general formula PO(X)3 to form a compound having general formula (V)

b) subjecting said compound having general formula (V) to a nucleophilic substitution of the group X with a group R' to form a compound having general formula (VI) R2 R2

I I

R1 CHO R1 CHO

(V) (VI) c) reducing said compound having general formula (VI) to form a compound having general formula (VII)

(VI) (VII)

d) subjecting said compound having general formula (VII) to a substitution reaction of the OH group with a group Xi to form a compound having general formula (VIII)

(VII) (VIII)

e) reacting said compound having general formula

(VIII) with a compound having general formula (IX) in the presence of a base to form a compound having general formula (X)

(VII I) (IX) (X) f) reacting said compound having general formula (X) with a compound having general formula R₃OH in the presence of an inorganic base to form a compound having general formula (XI) :

g) oxidizing said compound having general formula (XI) to form said compound having general formula (I) ;

wherein in said general formulae (I), (IV) -(XI) :

R represents a hydrogen atom, a C1-C alkyl group, a C3-C6 cycloalkyl group or a C4-C7 cycloalkylalkyl group, said groups being optionally substituted by one or more halogen atoms;

- Ri represents a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C3-C6 cycloalkyl group, a C4-C7 cycloalkylalkyl group, a C6- C10 aryl group, or a C7- C12 arylalkyl group, said groups being optionally substituted by one or more groups selected from halogen atoms, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxyl group, a C1-C4 haloalkoxyl group, a C1-C4 cycloalkoxyl group, a C1-C4 alkylsulfinyl group, a C1-C4 alkylsulfonyl group, a Ce^~ Cio arylsulfonyl group, a NO2 group, a CN group, a N¾ group, a C1-C4 alkylamino group, a C2-C5 alkoxycarbonyl group, an amide group, a benzyloxycarbonyl group or a phenoxycarbonyl group;

R₂ represents a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a C4-C7 cycloalkylalkyl group, a C6- C10 aryl group, or a C7- C12 arylalkyl group, said groups being optionally substituted by one or more halogen atoms ;

- R' is selected from: a fluorine atom, a nitro group, a methanesulfonic group, a para-toluenesulfonic group, a trifluoromethanesulfonic group;

Xi represents a chlorine atom, a bromine atom, a C1-C4 alkylsulfonyloxyl group, a C1-C4 haloalkyl- sulfonyloxyl group, a C6- C10 arylsulfonyloxyl group;

X represents a halogen selected from a chlorine atom and a bromine atom;

n is equal to 1 or 2.

6. The process according to the previous claim, wherein said reduction phase c) comprises reacting said compound having general formula (VI) with a metal hydride .

7. The process according to the claim 5, wherein said reduction phase c) comprises subjecting said compound having general formula (VI) to catalytic hydrogenation .

8. The process according to one or more of claims 5-7, wherein said base in said phase e) is selected from: an organic base, preferably selected from: triethylamine, diethylamine, diisopropylethylamine, pyridine and mixtures thereof.

an inorganic base, preferably selected from: sodium carbonate, potassium carbonate, potassium tert-butylate and mixtures thereof.

9. The process according to one or more of claims 5-8, wherein said inorganic base in said phase f) is a hydride of an alkaline metal, preferably sodium hydride .

10. The process according to one or more of claims 5-9, wherein said oxidation phase g) comprises reacting said compound having general formula (XI) with at least one oxidizing agent selected from:

an organic peroxide, preferably selected from: metachloroperbenzoic acid, peracetic acid, dibenzoyl peroxide and mixtures thereof;

an inorganic peroxide, preferably selected from: hydrogen peroxide, calcium peroxide, sodium peroxide and mixtures thereof.

11. The process according to claim 5, wherein, in said phase b) , said compound having general formula (V) is subjected to a reduction reaction to form said compound having general formula (VII) wherein R' represents a chlorine or bromine atom, said compound having general formula (VII) thus obtained being subsequently subjected to said subsequent phases d) - g) .

12. A compound having general formula (IV)

(IV)

wherein: Ri represents a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C3-C6 cycloalkyl group, a C4-C7 cycloalkylalkyl group, a C6- C10 aryl group or a C7- C12 arylalkyl group, said groups being optionally substituted by one or more groups selected from halogen atoms, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxyl group, a C1-C4 haloalkoxyl group, a C1-C4 cycloalkoxyl group, a C1-C4 alkylsulfinyl group, a C1-C4 alkylsulfonyl group, a Ce^~ C10 arylsulfonyl group, a NO2 group, a CN group, a NH₂ group, a C1-C4 alkylamino group, a C2-C5 alkoxycarbonyl group, an amide group, a benzyloxycarbonyl group or a phenoxycarbonyl group;

R5 represents a thiadiazole group having general formula (III)

(III)

wherein R represents a hydrogen atom, a C1-C4 alkyl group, a C3-C6 cycloalkyl group or a C4-C7 cycloalkylalkyl group, said groups being optionally substituted by one or more halogen atoms.

13. A process for preparing a compound having general formula (IV)

(IV)

which comprises:

a) reacting, in an acid environment, a monosubstituted hydrazine having general formula R₂NH-NH₂ or a physiologically acceptable salt thereof and a beta- ketoester having general formula (II) to form said compound having general formula (IV)

(II) (IV) wherein :

- Ri represents a C₁-C4 alkyl group, a C₁-C4 haloalkyl group, a C3-C6 cycloalkyl group, a C4-C7 cycloalkylalkyl group, a C6-C₁₀ aryl group or a C7-C₁₂ arylalkyl group, all of these groups being optionally substituted by one or more groups selected from halogen atoms, a C₁-C4 alkyl group, a C₁-C4 haloalkyl group, a C₁-C4 alkoxyl group, a C₁-C4 haloalkoxyl group, a C₁-C4 cycloalkoxyl group, a C₁-C4 alkylsulfinyl group, a C₁-C4 alkylsulfonyl group, a C6-C₁₀ arylsulfonyl group, a NO₂ group, a CN group, a NH₂ group, a C₁-C4 alkylamino group, a C₂-C5 alkoxycarbonyl group, an amide group, a benzyloxycarbonyl group or a phenoxycarbonyl group;

R₂ represents a C₁-C4 alkyl group, a C3-C6 cycloalkyl group, a C4-C7 cycloalkylalkyl group, a C6-C₁₀ aryl group, or a C7-C₁₂ arylalkyl group, said groups being optionally substituted by one or more halogen atoms ;

- R represents a C₁-C4 alkyl group, optionally substituted by one or more halogen atoms;

R5 represents a thiadiazole radical having general formula (III)

(III) wherein R represents a hydrogen atom, a C₁-C4 alkyl group, a C3-C6 cycloalkyl group or a C4-C7 cycloalkylalkyl group, said groups being optionally substituted by one or more halogen atoms.

14. The process according to the previous claim, wherein said compound having general formula (II) is obtained by means of a process which comprises:

a) reacting a compound having general formula (IX) with an acrylate compound having general formula (XIII) to obtain a compound having general formula (XIV)

b) reacting said compound having general formula (XIV) with a compound having general formula RiC(0)X to obtain a compound having general formula (lib),

(lib) wherein Ri and R have the meaning indicated in claim 13 and R represents a hydrogen atom, a C₁-C4 alkyl group, a C3-C6 cycloalkyl group or a C4-C7 cycloalkylalkyl group, said groups being optionally substituted by one or more halogen atoms .

15. The process according to claim 13, wherein said compound having general formula (II) is obtained by means of a process which comprises:

a) reacting a compound having general formula (Ila) with a compound having general formula (IX) in the presence of formaldehyde to obtain a compound having general formula (II)

wherein Ri and R have the meaning indicated in claim 13 and R represents a hydrogen atom, a C₁-C4 alkyl group, a C3-C6 cycloalkyl group or a C4-C7 cycloalkylalkyl group, all of these groups being optionally substituted by one or more halogen atoms .