Disubstituted 5(3)-pyrazole carboxylates and a process for their preparation from enolates and Fluoroalkylaminoreagents (FAR) reagents

The present invention relates to disubstituted 5(3)-pyrazole carboxylates and a novel process for their preparation. It is known from WO 2012/126766 that N-alkyl-3-haloalkyl-4-(methylsulfmyl)-5-pyrazole carboxylates are important precursors for the synthesis of pyrazole carboxyamides which possess strong insecticidal activity. The chemical synthesis of a pyrazole with CSF -group in position 3 and SMe-group in position 4 was described in WO 2012/126766 . This synthesis however requires multi step transformations with moderate yield and tedious isolation and purification.

The utilization of Fluoroalkylaminoreagents (FAR) for synthesis of diverse substituted pyrazoles have been already published for example in Pazenok et al, European Journal of Organic Chemistry 2015(27), 6052- 6060; Pazenok et al, European Journal of Organic Chemistry 2013(20), 4249-4253; WO 2014/033164 and WO 2008/022777.

In the light of the prior art described above, it is an object of the present invention to provide a process that does not have the aforementioned disadvantages and hence gives a route to disubstituted 5(3)-pyrazole carboxylates derivatives in high yields.

The object described above was achieved by a process for the preparation of disubstituted 5(3)-pyrazole carboxylates of the formula (la) or (lb),

(la) (lb) wherein

R ¹ is selected from H, (Ci-C ₆ )alkyl, phenyl or 2-pyridyl,

R ² is selected from H, (Ci-Ci2)alkyl or (C3-C8)cycloalkyl,

R ³ is selected from (Ci-Ci2)alkyl, (Ci-C3)haloalkyl, (C3-C8)cycloalkyl, (C6-Ci2)aryl, (Ci-

C ₃ )alkyl(C ₆ -Ci2)aryl and (C ₆ -Ci2)aryl(Ci-C ₆ )alkyl, R ⁴ is selected from (Ci-C ₆ )haloaLkyl and (Ci-C3)haloalkoxy(Ci-C6)haloalkyl and n is 0, 1 or 2, comprising a step (A), wherein a,a-difhioroalkylamino reagents (FAR) of the formula (III),

wherein

R ⁴ is defined as above and

R ⁶ and R ⁷ are each independently selected from (Ci-Ce)alkyl, (C>,-Cx)cycloalkyl, (C6-Ci2)aryl or together with the nitrogen atom to which they are bonded may form a five- or six-membered ring, are first converted into compounds of the formula (VI) in the presence of a Lewis Acid [L]

[LF]

^R \ ₊

N— R

- ⁴ // where R ⁴ , R ⁶ and R ⁷ are defined as for formula (III) and [LF] is an anion formed from the Lewis Acid [L] and one fluorine atom from compound (III), and then the compounds of the formula (VI) are reacted with enolates of the formula (II), wherein

R ⁵ is selected from (Ci-Ci2)aLkyl or (C3-C8)cycloaLkyl, R ³ and n are defined as above, m is 1 or 2 and

Cat ^m+ is selected from alkaline metal cations (with m = 1), alkaline earth metal cations (with m =2), organic ammonium cations (with m =1) or organic phosphonium cations (with m =1), to form compounds of formula (IV),

wherein n, [LF] , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are defined as above, and further comprising a step (B), wherein cyclization with an hydrazine of the formula (V)

NH2 -NH-R ¹ (V), wherein R ¹ is defined as above, takes place to form the compounds of formula (la) or (lb).

Preferred is a process according to the invention, where the radicals in formula (la), (lb), (II), (III), (IV), (V) and (VI) are defined as follows:

R ¹ is selected from H, (Ci-C ₆ )alkyl, phenyl or 2-pyridyl,

R ² is selected from H, (Ci-C ₆ )alkyl or (C ₃ -C ₆ )cycloalkyl, R ³ is selected from (Ci-C ₆ )alkyl, (Ci-C ₃ )haloalkyl, (C ₃ -C ₆ )cycloalkyl, (G-Oparyl, (Ci - C ₃ )alkyl(C ₆ -C ₉ )aryl and (C ₆ -C ₉ )aryl(Ci-C ₃ )alkyl,

R ⁴ is selected from (Ci-C ₆ )haloalkyl and (Ci-C ₃ )haloalkoxy(Ci-C ₆ )haloalkyl,

R ⁵ is selected from (Ci-C6)alkyl or (C ₃ -C ₆ )cycloalkyl, n is 0, 1 or 2, R ⁶ and R ⁷ are each independently selected from (Ci-C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, (C ₆ -Ci ₂ )aryl or R ⁶ and R ⁷ together with the nitrogen atom to which they are bonded may form a five- or six-membered ring, m is 1 and

Cat ^m+ is selected from alkaline metal cations, preferably from Li ⁺ , Na ⁺ , K ⁺ and Cs ⁺ , organic ammonium cations, preferably (R ⁸ ) ₄ N ⁺ or organic phosphonium cations, preferably (phenyl) ₄ P ⁺ , wherein

R* are each independently selected from (Ci-C ₆ )alkyl. More pre ferred is a process according to the invention, where the radicals in formula (la), (lb), (II), (III), (IV), (V) and (VI) are defined as follows:

R ¹ is selected from H, (C 1 -Cr,)alkyl or phenyl,

R ² is selected from H or (Ci -Ce)alkyl,

R ³ is selected from (Ci-C ₆ )alkyl,

R ⁴ is selected from (G-G)haloalkyl and (Ci-C3)haloaIkoxy(Ci-C6)haloalkyl, wherein the halogen is selected from fluoro and/or chloro,

R ⁵ is selected from (Ci-Ce)alkyl, n is 0, 1 or 2,

R ⁶ and R ⁷ are each independently selected from (G-G)alkyl, m is 1 and

Cat ^m+ is selected from Li ⁺ , Na ⁺ , K ⁺ , Cs ⁺ or Me4N ⁺ .

Even more preferred is a process according to the invention, where the radicals in formula (la), (lb), (II), (III), (IV), (V) and (VI) are defined as follows:

R ¹ is selected from H, methyl, ethyl or phenyl

R ² is selected from H, methyl or ethyl,

R ³ is selected from methyl or ethyl

R ⁴ is selected from difluoromethyl (CF ₂ H), chlorofluoromethyl (CHFC1), 1 ,2,2,2- tetrafluoroethyl (CF ₃ CFH), pentafluoroethyl (C ₂ F ₅ ) and trifluoromethoxyfluoromethyl (CF ₃ OCFH),

R ⁵ is selected from (Ci-C3)alkyl, n is 2, R ⁶ and R ⁷ are methyl, m is 1 and

Cat+ is selected from Li ⁺ , Na ⁺ or K ⁺ .

Most preferred is a process according to the invention, where the radicals in formula (la), (lb), (II), (III), (IV), (V) and (VI) are defined as follows:

R ¹ is selected from H, methyl or phenyl,

R ² is selected from H, methyl or ethyl,

R ³ is methyl, R ⁴ is selected from difluoromethyl (CF ₂ H), chlorofluoromethyl (CHFC1), 1 ,2,2,2- tetrafluoroethyl (CF ₃ CFH), pentafluoroethyl (C ₂ F ₅ ) and trifluoromethoxyfluoromethyl (CF ₃ OCFH),

R ⁵ is selected from methyl or ethyl, n is 2, R ⁶ and R ⁷ are methyl, m is 1 and

Cat ^m+ is Na ⁺ or K ⁺ .

In a particularly preferred embodiment of the present invention n is 2 for the compounds of the general formula (la), (lb), (II) and (IV). In a preferred embodiment of the invention the process is carried out in the presence of one or more suitable solvents. Suitable solvents will be specified below for the respective process steps.

Surprisingly, the pyrazoles of the formula (la) or (lb) can be prepared under the inventive conditions only in several steps with good yields and in high purity, which means that the process according to the invention overcomes the abovementioned disadvantages of the preparation processes previously described in the prior art.

A further object of the present invention are intermediates of the general formula (IV)

wherein n, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are defined as above and [LF] is an anion formed from a Lewis Acid [L] and one fluorine atom. [LF] stands preferred for BF f, AlCLF , SbCLF , SbF _f ;, PF ₆ or ZnCLF , more preferred for BF4 , AlCLF or

SbF ₆ , even more preferred for BF ₄ or AlCLF and most preferred [LF] is BF4 .

Respectively the Lewis Acid [L] from which [LF] is formed, is preferably selected from BF ₃ , AICL, SbCL, SbFs, PF ₅ or ZnCF or any mixtures of those, more preferred from BF ₃ , AICL or SbFs, even more preferred from BF ₃ or AICL and most preferred the Lewis Acid is BF ₃ .

An object of the present invention are also disubstituted 5(3)-pyrazole carboxylates of the formula (la) or

(lb),

(la) (lb) wherein

R ¹ is selected from H, (G-G,)alkyl, phenyl or 2-pyridyl,

R ² is selected from (Ci-Ci ₂ )alkyl or (G-G)cycloalkyl,

R ³ is selected from (Ci-Ci ₂ )alkyl, (Ci-C ₃ )haloalkyl, (C ₃ -Cs)cycloalkyl, (C ₆ -Ci ₂ )aryl, (Ci-

C ₃ )alkyl(C ₆ -Ci ₂ )aryl and (C ₆ -G ₂ )aryl(G-C ₆ )alkyl,

R ⁴ is selected from (Ci-C6)haloalkyl and (Ci-C ₃ )haloalkoxy(Ci-C ₆ )haloalkyl and n is 0, 1 or 2.

Preferred are disubstituted 5(3)-pyrazole carboxylates of the formula (la) or (lb), wherein R ¹ is selected from H, (G-C6)alkyl, phenyl or 2-pyridyl,

R ² is selected from (G-G,)alkyl or (C ₃ -C ₆ )cycloalkyl,

R ³ is selected from (G-Ce)alkyl, (G-C3)haloalkyl, (G-G,)cycloalkyl, (G-G)aryl, (G -

C ₃ )alkyl(C ₆ -C ₉ )aryl and (C ₆ -C ₉ )aryl(Ci-C ₃ )alkyl,

R ⁴ is selected from (G-G )haloalkyl and (Ci-C ₃ )haloalkoxy(Ci-C ₆ )haloalkyl and n is 0, 1 or 2.

More preferred are disubstituted 5(3)-pyrazole carboxylates of the formula (la) or (lb), wherein R ¹ is selected from H, (G-C6)alkyl or phenyl,

R ² is selected from (G-Ce)alkyl, R ³ is selected from (G-Ce)alkyl, R ⁴ is selected from (Ci-C ₆ )haloalkyl and (Ci-C3)haloalkoxy(Ci-C6)haloalkyl, wherein the halogen is selected from fluoro and/or chloro and n is 0, 1 or 2.

Even more preferred are disubstituted 5(3)-pyrazole carboxylates of the formula (la) or (lb), wherein R ¹ is selected from H, methyl, ethyl or phenyl

R ² is selected from methyl or ethyl,

R ³ is selected from methyl or ethyl

R ⁴ is selected from difluoromethyl (CF ₂ H), chlorofluoromethyl (CHFC1), 1 , 2,2,2- tetrafluoroethyl (CF ₃ CFH), pentafluoroethyl (C ₂ F ₅ ) and trifluoromethoxyfluoromethyl (CF ₃ OCFH) and n is 2.

Most preferred are disubstituted 5(3)-pyrazole carboxylates of the formula (la) or (lb), wherein R ¹ is selected from H, methyl or phenyl,

R ² is selected from methyl or ethyl,

R ³ is methyl,

R ⁴ is selected from difluoromethyl (CF ₂ H), chlorofluoromethyl (CHFC1), 1, 2,2,2- tetrafluoroethyl (CF ₃ CFH), pentafluoroethyl (C ₂ F ₅ ) and trifluoromethoxyfluoromethyl (CF ₃ OCFH) and n is 2.

In a particularly preferred embodiment of the present invention n is 2 for the compounds of the general formula (la), (lb) and (IV). General definitions

In the context of the present invention, the term "halogen" (Hal), unless defined differently, comprises those elements which are selected from the group comprising fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine.

Alkyl groups in the context of the present invention, unless defined differently, are linear or branched saturated hydrocarbyl groups. The definition Ci-Cn-aLkyl encompasses the widest range defined herein for an alkyl group. Specifically, this definition encompasses, for example, the meanings of methyl, ethyl, n-, isopropyl, n-, iso-, sec- and t-butyl, n-pentyl, n-hexyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, n-heptyl, n- nonyl, n-decyl, n-undecyl or n-dodecyl.

The term Alkoxy, either on its own or else in combination with further terms, for example haloalkoxy, is understood in the present case to mean an O-alkyl radical, where the term "alkyl" is as defined above.

Cycloalkyl groups in the context of the present invention are monocyclic, saturated hydrocarbyl groups having 3 to 8 and preferably 3 to 6 carbon ring members, for example (but not limited to) cyclopropyl, cyclopentyl and cyclohexyl. This definition also applies to cycloalkyl as part of a composite substituent, for example cycloalkylalkyl etc., unless defined elsewhere.

Aryl groups in the context of the present invention, unless defined differently, are aromatic hydrocarbyl groups. The definition C .12-aryl encompasses the widest range defined herein for an aryl group having 6 to 12 skeleton atoms. The aryl groups may be mono- or bicyclic. Specifically, this definition encompasses, for example, the meanings of phenyl, cycloheptatrienyl, cyclooctatetraenyl, naphthyl and anthracenyl.

Arylalkyl groups (aralkyl groups) in the context of the present invention, unless defined differently, are alkyl groups which are substituted by aryl groups. Specifically, this definition encompasses, for example, the meanings of benzyl and phenylethyl.

Alkylaryl groups (alkaryl groups) in the context of the present invention, unless defined differently, are aryl groups which are substituted by one or more alkyl groups, which may have 1 to 6 carbon atoms in the alkyl chain. Specifically, this definition encompasses, for example, the meanings oftolyl or 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl.

Halogen-substituted radicals, for example haloalkyl, are mono- or polyhalogenated, up to the maximum number of possible substituents. In the case of polyhalogenation, the halogen atoms may be identical or different. Unless stated otherwise, optionally substituted radicals may be mono- or polysubstituted, where the substituents in the case of polysubstitutions may be the same or different.

Haloalkyl groups in the context of the present invention are straight -chain or branched alkyl groups having 1 to 6 and preferably 1 to 3 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as specified above, for example (but not limited to) C ₁ -C ₃ - haloalkyl such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1 - chloroethyl, 1 -bromoethyl, 1 -fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2- fluoroethyl, 2-chloro,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and l,l,l-trifluoroprop-2-yl. This definition also applies to haloalkyl as part of a composite substituent, for example haloalkylalkoxy, haloalkoxyhaloalkyl, haloalkylaminoalkyl etc., unless defined elsewhere. Preference is given to alkyl groups substituted by one or more halogen atoms, for example trifluoromethyl (CF ₃ ), difluoromethyl (CHF ₂ ), CF ₃ CFH, CF ₃ CH ₂ , CF ₂ C1 CF ₃ CF ₂ , CF ₃ CC1 ₂ .

The term intermediate used in the context of the present invention describes the substances which occur in the process according to the invention and are prepared for further chemical processing and are consumed or used therein in order to be converted to another substance. The intermediates can often be isolated and intermediately stored or are used without prior isolation in the subsequent reaction step. The term "intermediate" also encompasses the generally unstable and short-lived intermediates which occur transiently in multistage reactions (staged reactions) and to which local minima in the energy profde of the reaction can be assigned.

The inventive compounds may be present as mixtures of any different isomeric forms possible, especially of stereoisomers, for example E and Z isomers, threo and erythro isomers, and optical isomers, but if appropriate also of tautomers. Both the E and the Z isomers are disclosed and claimed, as are the threo and erythro isomers, and also the optical isomers, any mixtures of these isomers, and also the possible tautomeric forms.

Process description

The process according to the invention is illustrated in Scheme 1 :

Step (A)

In step (A), FAR,s of the formula (III) are first converted into compounds of the formula (VI) in the presence of a Lewis Acid [L], and then reacted with compounds of the formula (II).

Preferred compounds of the general formula (III) are l,l,2,2-tetrafluoroethyl-N,N-dimethylamine (TFEDMA), 1 ,1 ,2,2-tetrafluoroethyl-N,N-diethylamine, 1 ,1 ,2-trifluoro-2-(trifluoromethyl)ethyl-N,N- dimethylamine, l,l,2-trifluoro-2-(trifluoromethyl)ethyl-N,N-diethylamine (Ishikawa’s reagent), 1 ,1 ,2- trifluoro-2-chloroethyl-N,N-dimethylamine and 1 ,l,2-trifluoro-2-chloroethyl-N,N-diethylamine (Yarovenko’s reagent), l,l,2-triiluoro-N,N-dimethyl-2-(trilluoromethoxy)ethanamine. Compounds of the general formula (III) are used as iminoacylating reagents. Preference is given to 1,1,2,2-tetrafluoroethyl- N,N-dimethylamine (TFEDMA), l,l,2-trifluoro-2-chloroethyl-N,N-dimethylamine and l ,l ,2-trifluoro-N,N- dimethyl-2-(trifluoromethoxy)ethanamine. a,a-Dihaloamines such as TFEDMA, Ishikawa’s or Yarovenko reagents are commercially available or can be prepared according to ( Yarovenko et al., Zh. Obshch. Khim. 1959, 29, 2159, Chem. Abstr. 1960, 54, 9724h or Petrov et al, J. Fluor. Chem. 109 (2011) 25-31). l,l,2-trifhioro-N,N-dimethyl-2- (trifluoromethoxy)ethanamine is available according to S. Pazenok et al. Organic Letters (2017), 19(18), 4960-4963. In the process according to the invention, the a,a-difluoroalkylamine (III) is first reacted with a Lewis acid [L] to form the compounds of formula (VI). The activation of a,a-difluoroalkylamines with Lewis acids is generally described in W02008/022777.

Suitable Lewis Acids [L] according to the invention comprise all organic and inorganic, preferably inorganic, electronpair acceptors known by any person skilled in the art. Preferably the Lewis Acid is selected from BF3, A1CL, SbCL, SbFs, PF5 or ZnCF or any mixtures of those, more preferred from BF3, A1CL or SbFs, even more preferred from BF ₃ or A1CL and most preferred the Lewis Acid is BF ₃ .

The Lewis acids can be used as a substance as such or as a stable solution in a suitable solvent, which is preferably the solvent used for step (A) in general. Within the reaction of compounds of the formula (111) with the Lewis Acids to form compounds of formula

(VI) an anion [LF] is formed from the Lewis Acid [L] and one fluorine atom of compound (III). [LF] stands preferred for BF f, A1CLF , SbCLF , SbFe , PF ₆ or ZnCLF , more preferred for BF f, A1CLF or SbFe , even more preferred for BF f or A1CLF and most preferred [LF] is BF f.

According to the invention, 1 mol of the Lewis acid [L] is reacted with equimolar amounts of the a,a- difluoralkylamine of the formula (III).

The activated FAR (VI) is than reacted with compounds of formula (II) to obtain compounds of formula (IV).

In this step the compound of the formula (II) is preferably added to compound (VI) dissolved in a suitable solvent. Compounds of formula (II) can be prepared from the cheap and available chemicals like methylalkylsulphones and oxalic acid esters according to Sokolov, M. P. et al; Journal of Organic Chemistry USSR (English Translation); vol. 22; (1986); p. 644-647. Preferred compounds of the formula (II) are sodium 3-methoxy-l -(methylsulfonyl)-3-oxoprop-l -en-2-olates, sodium 3-ethoxy-l - (methylsulfonyl)-3-oxoprop-l -en-2-olates, sodium 3 -ethoxy- 1 -(phenylsulfonyl)-3-oxoprop-l -en-2-olates, potassium 3-methoxy-l -(methylsulfonyl)-3-oxoprop-l-en-2-olates, potassium 3-ethoxy-l-(methylsulfonyl)- 3 -oxoprop- 1 -en-2 -dates .

For the process according to the invention 1 to 2 mol, preferred 1 tol,5 mol, most preferred 1 to 1,2 mol of the activated FAR of the formula (VI) is reacted with 1 mol compound of formula (II). According to the invention, the step (A) is preferably effected at temperatures of -20°C to +60°C, more preferably at temperatures of -20°C to +40°C, even more preferably at -10 to 20°C and under standard pressure. Due to the hydrolytic sensitivity of the a,a-difluoroaLkylamines, the reaction is preferably conducted in anhydrous conditions under inert gas atmosphere. The reaction time is not critical and may, according to the batch size and temperature, be selected within a range between a few minutes and several hours.

The reaction of compound (II) with the activated FAR (VI) is preferably effected in the presence of a base. Preference is given to organic bases, such as tri(Ci-C4)alkylamines, pyridines, (Ci-C alkylpyridines, for example picolines, and l ,8-diazabicyclo[5.4.0]undecene (DBU) or alkali metal hydroxides, for example lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal carbonates, for exampleNa2C03 or K2CO3 and alkali metal (Ci-C alkoxides, for example NaOMe, NaOEt, NaOt-Bu or KOt-Bu, or alkali metal fluorides, for example KF. Also mixtures of those bases could be used. Most preferable are organic bases like pyridine and (Ci-C alkypyridines or KF.

According to the invention preferably 1 to 5 mol, more preferably 1 ,5 to 4 mol and even more preferably 2 to 3,5 mol of the base are used for 1 mol of compound of the formula (II).

Step (A) is preferably carried out in the presence of one or more solvents. Suitable solvents for step (A) are, for example, aliphatic, alicyclic or aromatic hydrocarbons, for example petroleum ether, n-hexane, n- heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, and halogenated hydrocarbons, for example chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane or trichloroethane, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,2-diethoxyethane or anisole, esters such as ethylacetate or isopropylacetat, nitriles such as acetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N- methylformanilide, N-methylpyrrolidone or hexamethylphosphoramide; sulphoxides such as dimethyl sulphoxide or sulphones such as sulpholane. Particular preference is given to THF, acetonitrile, methyl tert- butyl ether, dichloromethane, toluene, xylene, chlorobenzene, n-hexane, cyclohexane or methylcyclohexane, and very particular preference to acetonitrile, THF, methyl tert-butyl ether or dichloromethane.

The formed intermediates of the formula (IV) can be used in the cyclization step (B) without prior workup. Alternatively, the intermediates can be isolated by suitable workup, characterized and optionally further purified. Step (B):

In the cyclization step (B) compounds of formula (IV) are reacted with hydrazines of formula (V).

The reaction is preferably effected at temperatures of -20 °C to +80 °C, more preferably at temperatures of +0 °C to +70 °C, even more more preferably at +20 to + 50°C and under standard pressure. The reaction time is not critical and may, according to the batch size be selected within a relatively wide range.

According to the invention preferably 1 mol to 2 mol, more preferably 1 to 1,5 mol of the hydrazine are used for the conversion 1 mol of the compound of formula (IV).

Step (B) is preferably carried out in the presence of one or more solvents. More preferably the cyclization step (B) is effected without changing the solvent after step (A).

Suitable solvents are, for example, aliphatic, alicyclic or aromatic hydrocarbons, for example petroleum ether, n-hexane, n-heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, and halogenated hydrocarbons, for example chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane or trichloroethane, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,2-diethoxyethane or anisole; alcohols such as methanol, ethanol, isopropanol or butanol, esters such as ethylacetate or isopropylacetat, nitriles such as acetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoramide; sulphoxides such as dimethyl sulphoxide or sulphones such as sulpholane. Particular preference is given to acetonitrile, THF, methyl tert-butyl ether, ethanol, isopropylacetate, dichloromethane, toluene, xylene, chlorobenzene, n-hexane, cyclohexane or methylcyclohexane, and very particular preference to acetonitrile, THF, ethanol, isopropylacetate, toluene or xylene.

After the reaction has ended, the compounds of the general formula (I) can be isolated and purified by suitable methods known to any person skilled in the art. For example, the solvents could be removed and the product could be isolated by filtration. Alternatively the product could first be extracted with an organic solvent and washed with water, which is preferably acidified with an acid, preferably with HC1 or H ₂ SO ₄ , then the solvent can be removed under reduced pressure and the product can be purified via crystallization.

Starting from compounds of the general formula (IV) two different isomers of the general formula (la) or (lb) can be formed during step (B). The regioselectivity of the cyclization step (B) can be influenced by the choice of the solvents and substrates, especially of the hydrazine according to the general formula (V). The compounds of the fonnula (I) where R ² = (Ci-Ci2)alkyl or (C3-C8)cycloalkyl can be converted in a further step (C) to pyrazole acids of the formula (I) with R ² = H according to state of the art procedures as for example described in WO 2013/113829.

Scheme 2: Step (O

(la) (lb) (la) with R ² =H

(lb) with R ² =H

The process of the present invention preferably consists of steps A and B or steps A and B and C.

Examples:

The invention is illustrated by but not limited to the following examples:

Example 1 r(Z/E)-l-(difluoromethyl)-4-ethoxy-3-hvdroxy-2-methyl-4-oxo- but-2-envbdenel-dimethyl- ammoniumtetrafluoroborate

BF ₃ .0Et ₂ (0,12 ml, 1,0 mmol) was added to a solution of l,l,2,2-tetrafluoroethyl-N,N-dimethylamine (TFEDMA) (0,12 ml, 1,0 mmol) in dry dichloromethane (1 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before the dichloromethane was removed under reduced pressure. The solid residue was then taken up in acetonitrile (1 ml) and (0,216 g, 1 ,0 mmol) of sodium 3- ethoxy-l-(methylsulfonyl)-3-oxoprop-l-en-2-olate and (0,316 g, 4 mmol) pyridine was added in CD ₃ CN (2 ml) and the mixture was stirred at room temperature for 10 h. The solvent was evaporated in vacuum and the residue then analysed by H, ¹³ C and ¹⁹ F NMR.

¾ NMR (600 MHz, CD ₃ CN -d ₃ ) d ppm 1.29 (br t, .7=7.13 Hz, 4 H) 3.22 (s, 3 H) 3.44 (br s, 6 H) 4.24 (q, 7=7.23 Hz, 3 H) 6.90 - 7.09 (m, 1 H) 8.99 - 9.34 (m, 1 H)

¹³ C NMR (151 MHz, CD3CN -d ₃ ) d ppm 14.20 (s, 1 C) 46.42 (s, 1 C) 46.65 - 47.52 (m, 1 C) 62.96 (s, 1 C) 104.90 - 105.03 (m, 1 C) 111.25 (t, 7=248.91 Hz, 1 C) 165.03 - 165.52 (m, 1 C) 166.44 (s, 1 C) 177.33 (s, 1 C).

¹⁹ F NMR (CDCE, 282 MHz): d ppm -117.3 (CHF ₂ , J _F-H = 53.6 Hz), -150 (BF ₄ ) Example 2

Ethyl 5-(difluoromethyl)-2-methyl-4-methylsulfonyl-pyrazole-3-carb oxylate

BF ₃ CH3CN complex (17 wt.% solution) (2,17 g, 20 mmol) was added to a solution of TFEDMA (2,86 g, 20 mmol) in 25 ml CH3CN under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before (3,2 g, 15 mmol) of sodium 3-ethoxy-l-(methylsulfonyl)-3-oxoprop-l-en-2-olate and (4,7 g, 60 mmol) pyridine were added at 10°C and the mixture was stirred at room temperature for 10 h. The mixture was cooled to -10°C and (1 ,38 g 30 mmol) of methylhydrazine was added to the reaction mixture. The formed suspension was stirred for 4 h at RT and 100 ml of water were added. The product was extracted with ethylacetate, the organic solution washed with 10 ml (10 wt.%) HC1 and water and the organic solvent was evaporated to furnish a pale yellow solid, which was recrystallized from methycyclohexane.

Yield 3,18 g, 75 % of theory.

¾ NMR (DMSO-de, 600 MHz): d ppm 7.25 (t, J = 53.3 Hz, 1H) 4.43 (q, J = 12 Hz, 2H) 4.09 (s, 3H) 1.36 (t, J= 7.1 Hz, 3H)

¹³ C NMR (151 MHz, DMSO-i/e) d ppm 13.63 (s, 1 C) 40.46 (s, 1 C) 44.92 (s, 1 C) 63.25 (s, 1 C) 108.90 (t, J= 236.56 Hz, 1 C) 122.47 (s, 1 C) 135.77 (s, 1 C) 143.14 (t, 7=24.85 Hz, 1 C) 157.63 (s, 1 C)

¹⁹ F NMR (CFCls _, 282 MHz): d ppm -115.06, (d)

Example 3

5-(difluoromethyl)-2-methyl-4-methylsulfonyl-pyrazole-3-c arboxylic acid

Ethyl 5-(difluoromethyl)-2-methyl-4-methylsulfonyl-pyrazole-3-carb oxylate (2,83 g, 10 mmol) in toluene (15 ml) was mixed with an 8N aqueous sodium hydroxide solution (100 ml) and stirred at 50°C for 3 h. The phases were separated and the water phase was acidified to pH 1 with 6N HC1. The formed precipitate was filtered off and dried. Yield 2,3 g, 90 %, colourless solid, m.p.l68°C.

¾ NMR (DMSO-de, 600 MHz): d ppm 7.24 (t, J= 53.3 Hz, 1H) 4.08 (s, 3H) 3,39 (s, 3H)

¹³ C NMR (151 MHz, DMSO-i/e): d ppm: 40.4 (s, 1 C) 44.92 (s, 1 C) 109.0 (t, J= 236.56 Hz, 1 C) 121.9 (s, 1 C) 137.5 (s, 1 C) 143.0 (t, 7=24.85 Hz, 1 C) 159.3 (s, 1 C)

¹⁹ F NMR (CFCE _, 282 MHz): d ppm -114.61, (d) Example 4

Ethyl 5-(difluoromethylVl-methyl-4-methylsulfonyl-pyrazole-3-carbo xylate

BF ₃ CH ₃ CN complex (17 wt. % solution) (2,17 g, 20 mmol) was added to a solution of TFEDMA (2,86 g, 20 mmol) in 25 ml C¾CN under argon in a Teflon flask. The solution was stirred at room temperature for

15 min, before the (3,2 g, 15 mmol) of sodium 3 -ethoxy- l-(methylsulfonyl)-3-oxoprop-l-en-2-olate and (4,7 g, 60 mmol) of pyridine were added at 10°C and the mixture was stirred at room temperature for 10 h. The solvent and volatile products were removed in vaccum (20 mbar) and the residue was taken up in 30 ml ethanol. The solution was cooled to 10°C and (1,38 g, 30 mmol) of methylhydrazine was added to the reaction mixture within 30 min. The formed suspension was stirred for 4 h at RT and 100 ml of water were added. The product was extracted with ethylacetate, the organic solution was washed with 10 ml (10 wt.%) HC1 and water and the organic solvent was evaporated to furnish a pale yellow solid, which was recrystallized from methycyclohexane.

Yield 3,3 g., 78 % of theory. ¾ NMR (600 MHz, DMSO-i/e) d ppm 1.32 (s, 3 H) 3.50 (s, 3 H) 4.11 (s, 3 H) 4.34 - 4.38 (m, 2 H) 7.42 - 7.61 (m, 1 H).

¹³ C NMR (151 MHz, DMSO-ifc) d ppm 13.99 (s, 1 C) 40.49 (s, 1 C) 44.60 (s, 1 C) 62.12 (s, 1 C) 123.87 (s, 1 C) 136.88 (s, 1 C) 140.54 - 141.18 (m, 1 C) 159.97 (s, 1 C) Example 5

Ethyl 5-(difluoromethylVl-methyl-4-methylsulfonyl-pyrazole-3-carbo xylic acid

Ethyl 5-(difluoromethyl)-l-methyl-4-methylsulfonyl-pyrazole-3-carb oxylate (2,83 g, 10 mmol) in toluene (15 ml) was mixed with an 8N aqueous sodium hydroxide solution (30 ml) and stirred at 50°C for 3 h. The phases were separated and the water phase was acidified to pH 1 with 6N HC1. The formed precipitate was filtered off and dried.

Yield 2, 4 g, 95 %, colourless solid, m.p. 186°C.

¾ NMR (600 MHz, DMSO-i/e) d ppm 3.50 (s, 3 H) 4.09 (s, 3 H) 7.40 - 7.66 (m, 1 H) 13.17 - 14.78 (m, 1 H)

¹³ C NMR (151 MHz, DMSO-i/e) d ppm 40.46 (t, .7=3.46 Hz, 1 C) 44.50 (s, 1 C) 107.21 (t, J= 236.26 Hz, 1 C) 123.66 (s, 1 C) 136.68 (t, .7=25.15 Hz, 1 C) 142.02 (s, 1 C) 161.55 (s, 1 C)

¹⁹ F NMR (CFCE, 282 MHz) d ppm -115, 44, (d)

Example 6

Ethyl 5-(difhioromethyl)-4-methylsulfonyl-2-phenyl-pyrazole-3-carb oxylate

BF ₃ CH ₃ CN complex (17 wt. % solution) (3,26 g, 30 mmol) was added to a solution of TFEDMA (4,3 g, 30 mmol) in 25 ml CH ₃ CN under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before (3,2 g, 15 mmol) of sodium 3-ethoxy-l-(methylsulfonyl)-3-oxoprop-l-en-2-olate and (4,7 g,

60 mmol) pyridine were added at 10°C and the mixture was stirred at room temperature for 10 h. The mixture was cooled to -10°C and (3,2 g, 30 mmol) of Phenylhydrazine was added to the reaction mixture. The formed suspension was stirred for 4 h at room temperature and 100 ml of water were added. The product was extracted with ethylacetate, the organic solution washed with 10 ml (10 wt.%) HC1 and water and the organic solvent was evaporated to furnish a pale yellow solid, which was recrystallized from ethanol/water.

Yield 4,17 g., 81 % of theory.

¾ NMR (600 MHz, DMSO-i/e) d ppm 1.11 (t, .7=7.13 Hz, 3 H) 3.45 (s, 3 H) 4.28 (q, 7=7.16 Hz, 2 H) 7.33 - 7.35 (m, 1 H) 7.55 - 7.58 (m, 2 H) 7.59 - 7.62 (m, 2 H) 7.60 - 7.63 (m, 1 H) ¹³ C NMR (151 MHz, DMSO-i/e) d ppm 13.66 (s, 1 C) 40.49 (s, 1 C) 44.95 (s, 1 C) 63.28 (s, 1 C) 108.92 (s,

1 C) 122.48 (t, 7=3.61 Hz, 1 C) 135.79 (s, 1 C) 142.97 - 143.38 (m, 1 C) 157.65 (s, 1 C)

Example 7

5 -(Difluoromethyl)-4-methylsulfonyl-2-phenyl-pyrazole-3 -carboxylic acid

Ethyl 5-(difluoromethyl)-4-methylsulfonyl-2-phenyl-pyrazole-3-carb oxylate (3.44 g, 10 mmol) in toluene (15 ml) was mixed with an 8N aqueous sodium hydroxide solution (142 ml) and stirred at 40°C for 3 h. The phases were separated and water phase acidified to pH 1 with 6N HC1. The precipitate was filtered off and dried. Yield 3g, 95 % of colourless solid, m.p. l87°C

¾ NMR (600 MHz, DMSO-i/e) d ppm 3.50 (s, 3 H) 4.09 (s, 3 H) 7.40 - 7.66 (m, 1 H) 13.17 - 14.78 (m, 1 H).

¹³ C NMR (151 MHz, DMSO-i/e) d ppm 40.46 (t, .7=3.46 Hz, 1 C) 44.50 (s, 1 C) 107.21 (t, J= 236.26 Hz, 1 C) 123.66 (s, 1 C) 136.68 (t, .7=25.15 Hz, 1 C) 142.02 (s, 1 C) 161.55 (s, 1 C)