BR112017002773B1 - PROCESSES FOR THE PREPARATION OF 5-FLUORO-1H-PYRAZOLES AND DERIVATIVES AND USE OF THE INTERMEDIATE 3-PERFLUOROETHYL-4-PERFLUOROMETHYL-5-FLUORO-PYRAZOLE - Google Patents

Abstract

PROCESS FOR THE PREPARATION OF 5-FLUORO-lH-PYRAZOLES FROM HEXAFLUOROPROPENE. An innovative process for the preparation of 5-fluoro-1H-pyrazoles of general formula (I) as described herein and further reactions with this compound.

Description

5-Fluoro-1H-pyrazoles, in particular 5-Fluoro-1-methyl-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole, are important building blocks for the preparation of crop protection chemicals such as those described in the paper WO 2010051926, WO 2012/069366, WO 2012/0803876 and WO 2012/107343.

State of the art

For the dimerization of hexafluoropropene (HFP) the perfluoro-4-methyl-2-pentene catalyst and different processes were used.

Perfluoro-2-methyl-2-pentene is commercially available (Fa. Daikin) and P&M Invest (Russia). However, the compound is toxic.

Alternatively, it can be prepared via dimerization of hexafluoropropene (see, for example, US 5,254,774; R. Haszeldiner et al, Journal of the Chemical Society D: Chemical Communications (1970), (21), 1444-1445.

Document DE 4228592 describes the preparation of perfluoro-4-methyl-2-pentene in the presence of N,N,N,N-Tetramethylethylenediamine and Potassium fluoride.

Pazenok et al. describes the preparation of perfluoro-4-methyl-2-pentene in the presence of ammonium and phosphonium perfluorocyclobutane ylides (Pazenok et al., Tetrahedron Letters, (1996), 52(29), 9755-9758).

US 5,254,774 describes the preparation of hexafluoropropene oligomers in the presence of potassium cyanide.

Document US 2,918,501 describes the preparation of internally unsaturated perfluoroolefins in the presence of fluoride in different solvents such as amides, phenylamine or sulfoxides.

For the transformation of perfluoro-4-methyl-2-pentene into perfluoro-2-methyl-2-pentene usually fluorides are used (Brunskill et al, Chem. Com. 1970, 1444).

Also 'Proton Sponge' hydrofluoride was used to generate hexafluoropropene carbanions (Chambers et al, J. of Fluorine Chemistry (1994), 69(1), 103-108).

US 4,377,717 discloses the production of perfluoro-2-methyl-2-pentene by heating hexafluoropropylene in the presence of activated carbon.

Document US 4,093,670 (DE 2706603 Al) discloses the production of perfluoro-4-methyl-2-pentene. (E)-(CF3) 2CFCF=CF(CF3) was isomerized to the more stable perfluoro-2-methyl-2-pentene after heating for 3 h at 40° in MeCN in the presence of 0.00025 mol each of KF and 18 -tails-6 ether. In other examples the 18-crown-6 ether was replaced by benzo-15-crown-5 ether and dibenzo- and dicyclohexyl-18-crown-6 ether.

Document CN 103483139 discloses a method of preparing perfluoro-2-methyl-2-pentene. The method allows perfluoro-2-methyl-2-pentene to be prepared through a catalytic isomerization reaction of a perfluoro-4-methyl-2-pentene feedstock.

A method of preparing perfluoro-2-methyl-2-penten-)3~enolate is described in: V. Snegirev et al Izvestiya Akademii Nauk SSR, Seriya Khimicheskaya (1986), No. 1, pp. 106-119; and T.Martini, J.Fluor.Chem. (1976), 8, 535-540.

Scherer 46 et al (1981) J. of Organic Chemistry 23792381 and Chambers et al 51 (1995) Tetrahedron 48, 13167-13176 reveal dimerization processes of CF2=CF(CF3).

It is known that 5-fluoro-1-methyl-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole can be prepared by treating the hexafluoropropene dimer with water-free N,N-dimethylhydrazine in diethyl ether at -50 °C followed by heating the intermediate to 120 °C, Knunyants et al. Izv. Akad. Nauk SSSR (1990) 2583-2589:

However, this two-step transformation requires low temperatures for the first step and results in the formation of CH3F during thermal elimination in the second step, making this process expensive, non-environmentally friendly, and particularly difficult for industrialization.

Starting from perfluoro-2-methyl-2-penten and phenylhydrazine, in the presence of triethylamine at -50 °C 1-Phenylpyrazole was shown to be obtainable in 90% yield (document SU 1456419).

Chi et al. J.Fluor.Chem. 98 (1999) 29, reported that the reaction of perfluoro-2-methyl-2-pentene (3) with phenylhydrazine in CH3CN gave a mixture of isomeric pyrazoles a and b in a 4:1 ratio.

Furin et al Russian J. Org. Chem. 37 (2001) 11, 16211628 (Scheme 5) prepared a compound of formula (II) by reacting compound (3) with PrCONHNH2:

Wayne et al. document WO 2010/123999 (alkylation of unsubstituted pyrazole, pages 31 and 35) describe alkylation steps, however, they do not disclose an alkylation of a compound of formula (4), that is, of a substituted pyrazole.

WO 2011012620 describes processes for the alcylation of pyrazoles.

Document EP 2 184 273 discloses a process for preparing a compound of formula (IV).

The problem to be solved by this invention was to identify a simple and selective process for preparing 5-fluoro-1H-pyrazoles from available fluoroalkenes and monosubstituted hydrazines, which should, in particular, be reasonable for an industrial scale process. As an additional advantage, this process should have a favorable safety profile, e.g., replacement of hazardous monomethylhydrazine with less hazardous reagents (e.g., hydrazide), and production of undesired residual material.

summary

A first aspect of the present invention relates to a process for the synthesis of 5-fluoro-1H-pyrazoles of general formula (I) wherein R1 represents C1-C4-alkyl, preferably methyl; comprising the steps of - reacting intermediate (3) with C1-C4-alkyl-CONHNH2 to prepare 3-perfluoroethyl-4-perfluoromethyl-5-fluoropyrazole (intermediate (4)) (in this document referred to as step 3); and - reacting intermediate (4) with a C1-C1-alkylating agent, preferably a methylating agent to prepare a compound of formula (I) (herein referred to as step 4). In a preferred embodiment of the first aspect of the present invention, the process is characterized by the steps of: - reacting hexafluoropropene (intermediate (1)) in the presence of a catalyst to form its perfluoro-4-methyl-2-pentene dimer (intermediate (2)) (in this document referred to as step 1); and isomerizing perfluoro-4-methyl-2-pentene to perfluoro-2-methyl-2-pentene (intermediate (3)) (in this document referred to as step 2); react a compound (3) with C1-C4-alkyl-CONHNH2 to prepare 3-perfluoroethyl-4-perfluoromethyl-5-fluoro-pyrazole (intermediate (4)) - reacting intermediate (4) with a (C1-C4)-alkylating agent, preferably a methylating agent, to prepare a compound of formula (I).

A further aspect relates to a process for preparing a compound of formula (IV) wherein R1 is C1-C4-alkyl, preferably methyl; and Ai is C-R2; and R2 is hydrogen, fluorine, chlorine, bromine, CN, NO2, optionally halogenated C1-Cβ-alkyl, optionally halogenated C1-C4-alkoxy, optionally halogenated C1-C4-alkylsulfonyl, optionally halogenated C1-C4-alkylsulfinyl or N-cyclopropylaminocarbonyl (-C(=0)-NH-cyclopropyl); preferably hydrogen, fluorine, chlorine, bromine, CN, NO2, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n-propoxy, 1-methylethoxy, fluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy , trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, pentafluoroethoxy, methylsulfonyl, methylsulfinyl, trifluoromethylsulfonyl, trifluoromethylsulfinyl or N-cyclopropylaminocarbonyl, more preferably hydrogen, fluorine, chlorine, bromine, CN, NO2, methyl , fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, or pentafluoroethoxy, preferably hydrogen, fluorine, chlorine, bromine, most preferably chlorine; and A2 is C-R3 or nitrogen; and R3 is hydrogen, methyl, fluorine or chlorine, preferably hydrogen; and T represents one of the T1-T9 groups listed below, where the bond to the pyrazole leader group [N2C3R1(C2F5)(CF3)] is marked with an asterisk *, or *-C(=0)-NH-T9; and R6 independently of one another represents halogen, cyano, nitro, amino or optionally substituted C1-Ce-alkyl, C1-Ce-alkyloxy, C1-Ce-alkylcarbonyl, C1-Cβ-alkylsulfanyl, C1-Ce-alkylsulfinyl, Ci- Cε- alkylsulfonyl, n represents the values 0-2, preferably 0, with the proviso that n is 0 or 1 in T5, T6 and T8, and with the proviso that n is 0 in T7; and Q is hydrogen, cyano, hydroxy, formyl or one of the groups Ci-Cβ-alkyl, Cs-Cε-alkenyl, C3-C6-alkynyl, Ca-Cg-cycloalkyl, C3-C9-heterocycloalkyl, Ci-Ci-alkoxy, C4-C15-alkylcycloalkyl, C^-Cys-cycloalkylalkyl, C1-Cε-hydroxyalkyl, Ce-aryl-C1-Cs-alkyl, C5-C6-heteroaryl-C1-C3-alkyl, C1-C1-aminoalkyl, aminocarbonyl -C1-C4-alkyl or C1-C4-alkyl-amino-C1-C4-alkyl which are optionally substituted with one, two, three, four or five, preferably with one or two, more preferably with one, substituents independently selected from from the group consisting of hydroxy, nitro, amino, halogen, C1-C3-alkoxy, cyano, hydroxycarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkylcarbamoyl, C4-C6-cycloalkylcarbamoyl and optionally independently with one, two or three substituents selected from the group consisting of halogen, cyano, nitro, hydroxycarbonyl, C1-Cz-alkylcarbamoyl, C1-C2-alkyl, C1-C2-halogenated alkyl and phenyl substituted with C1-C2~alkoxy; preferably Q is C3-C6-cycloalkyl, or Ca-Ce-cycloalkyl which is substituted with at least one substituent selected from the group consisting of chlorine, fluorine, bromine, iodine, cyano and hydroxy, or Cg-aryl-Ci-C3 ~alkyl; more preferably cyclopropyl, 1-cyano-cyclopropyl or benzyl (-CH2-CeHs); comprising the steps as described in paragraph 0 or paragraph 0.

A preferred embodiment relates to the process for preparing a compound of formula (IV) as described above, wherein a compound of formula (IV) is a compound of formula (II), preferably of formula (II') (see, e.g. paragraph 0).

Another preferred embodiment relates to the process for preparing a compound of formula (IV) described above, wherein a compound of formula (IV) is compound (Ia) (see, for example, paragraph 0).

Another preferred embodiment relates to the process for preparing a compound of formula (IV), wherein the compound of formula (IV) is a compound of formula (II) as described herein, further comprising the steps of: - react compound (I) with a cyano donor to prepare the intermediate of formula (6) wherein R1 is optionally halogenated C1-C4-alkyl or optionally halogenated cyclopropyl, preferably methyl (herein referred to as Step 5); and - reacting the compound (6) with an inorganic base in a first hydrolysis step followed by addition of an inorganic acid in a second hydrolysis step to prepare the intermediate of formula (7) wherein R1 is C1-Cj-alkyl, preferably methyl (herein referred to as Step 6); and - reacting a compound of formula (8) or its salt (8') with an activated form (7') of the compound (7) wherein R1, Ai, A∑, and Q are as defined for compound (IV) and GS is any leaving group (herein referred to as Step 8), to prepare a compound of formula (II).

Another preferred embodiment relates to the process for preparing a compound of formula (IV) described above, wherein a compound of formula (IV) is a compound of formula (III).

Another preferred embodiment relates to the process for preparing a compound of formula (III) wherein a compound of formula (III) is a compound of formula III', preferably the compound (Ilia) or the compound (Illb) (see , for example, paragraphs 0 to 0 and 0).

Another preferred embodiment relates to the process for preparing a compound of formula (III), comprising the steps as described in paragraph 0 or paragraph 0 and further comprising the steps of reacting a compound of formula (I) with a compound of formula (11) by means of nucleophilic substitution of the fluoride in the ring position of a compound of formula (I) (herein referred to as Step 9) wherein R1 is C1-C1-alkyl, preferably methyl; and U represents bromine, iodine, triflate, boronic acid, boronic ester or trifluoroboronate; and the five-membered cycles of E3-E3, carbon and nitrogen represent the five-membered heterocycles selected from the group consisting of wherein R6 independently of one another represents halogen, cyano, nitro, amino or optionally substituted C1-Cg-alkyl, C1-Cg-alkyloxy, C1-Cg-alkylcarbonyl, C1-Cθ-alkylsulfanyl, C1-Cg-alkylsulfinyl, Ci- Cβ-alkylsulfonyl, n represents the values 0-2, preferably 0, with the proviso that n is 0 or 1 in T5, T6 and T8 and provided that n is 0 in T7; to prepare a compound of formula (12); and reacting a compound of formula (12) and a compound of formula (13) (herein referred to as Step 10) wherein R1, Ai, A2, and Q are as defined for a compound of formula (III) (or IV, respectively) and U and the five-membered cycles of E1-E3, carbon, and nitrogen are as defined for the compound (11); and M represents bromine, iodine or triflate when U represents a boronic acid, boronic ester or trifluoroboronate; or M represents a boronic acid, boronic ester or trifluoroboronate when U represents bromine, iodine or triflate; to prepare a compound of formula (III).

Another preferred embodiment relates to the process for preparing a compound of formula (IV) as described above, wherein a compound of formula (IV) is a compound of formula (III''), preferably of formula (III'' ') (see, for example, paragraph 0).

Another preferred embodiment refers to the process for preparing a compound of formula (III''), preferably of formula (III'''), as described above, characterized by the steps as described in paragraph 0 or paragraph 0, optionally further comprising steps 9 and 10 as described above; or optionally further comprising the steps of reacting a compound of formula (I) and an azide donor to prepare intermediate (14) (herein referred to as Step 11) wherein R1 is as defined for a compound of formula (III); and reacting the intermediate (14) with an intermediate of formula (15) to give an intermediate (III''*) (herein referred to as Step 12) wherein R1, R6, Ai, and A2 are as defined for compound (III), n is 0 or 1 and GP is any carboxylic group protecting group such as C1-Cg-alkyl (e.g., methyl).

Another preferred embodiment relates to a process as described above, wherein R1 is methyl.

Another preferred embodiment relates to a process as described above, in which the catalyst in Step 1 and the fluoride donor in Step 2 are identical.

Another preferred embodiment refers to any of the processes as described above, wherein steps 3 and 4 are carried out in the same solvent, preferably acetonitrile or methylene chloride, more preferably methylene chloride.

Another preferred embodiment relates to a process as described above, wherein steps 3 and 4 are carried out in the same solvent selected from the group consisting of acetonitrile or methylene chloride.

Use of intermediate (4) for the preparation of the compound selected from the group consisting of a compound of formula (I), (6), (6a), (7), (7a), (I), (Ia), (II), (lia), (III), (III'), (Illa), (III"), (III'"), (Illb), and (IV).

Another aspect relates to the use of a compound of formula (I), preferably compound (Ia), prepared according to a process comprising steps as described in paragraph 0 or paragraph 0 for preparing a compound of formula ( II).

Another aspect relates to the use of a compound of formula (I), preferably compound (Ia), prepared according to a process comprising steps as described in paragraph 0 or paragraph 0 for preparing a compound of formula ( III) or (III').

Another aspect relates to the use of a compound of formula (I), preferably compound (Ia), prepared according to a process comprising steps as described in paragraph 0 or paragraph 0 for preparing a compound of formula ( IV).

Definitions

The term "alkyl" as used herein refers to linear, branched or cyclic saturated hydrocarbyl groups. The Ci-Ce-alkyl definition covers the broadest range defined herein for an alkyl group. Preferred alkyl groups are C1-C4-alkyl, more preferred C1-C3-alkyl, even more preferred C1-C2-alkyl.

Specifically, this definition covers, for example, the meanings of methyl, ethyl, n-, isopropyl, n-, iso-, see- and t-butyl, n-pentyl, n-hexyl, 1,3-dimethylbutyl and 3, 3-dimethylbutyl.

The term "cycloalkyl" as used herein refers to a monocyclic saturated hydrocarbyl group that has 3 to 9 (Ca-Cg-cycloalkyl) and preferably 3 to 6 carbon ring members (Cβ-Cε-cycloalkyl), e.g. example, (but not limited to) cyclopropyl, cyclopentyl and cyclohexyl. This definition also applies to cycloalkyl as part of a composite substituent, e.g., cycloalkylalkyl, etc., unless defined elsewhere.

The term "halogen" as used herein refers to elements of the 7th main group of the periodic table and their radicals, preferably fluorine, chlorine, bromine and iodine and their radicals. More preferable halogens are chlorine and fluorine.

The term "halogenated alkyl" or "halogenated cyclopropyl" or other "halogenated" groups or similar "halogenated" groups as used herein refers to alkyl/cycloalkyl/cyclopropyl etc. moieties, wherein at least one (1) atom of Hydrogen attached to a carbon atom is replaced by a halogen, preferably selected from F, Cl, I, or Br, more preferably selected from F or Cl. Thus, the halogenated form of an alkyl moiety that has n carbon atoms and thus 2n+1 hydrogen, can have between 1 and 2n+1 halogen substitutions, i.e., 1, 2, or 3 hydrogens of a methyl moiety. are each replaced by a halogen, 1, 2, 3, 4 or 5 hydrogens of an ethyl moiety are each replaced by a halogen, 1, 2, 3, 4, 5, 6 or 7 hydrogens of a propyl moiety are each replaced by a halogen, or 1, 2, 3, 4, 5, 6, 7, 8 or 9 hydrogens of a butyl moiety are each replaced by a halogen. In a preferred embodiment, all hydrogens of an alkyl moiety are replaced by halogen (perhalogenated moiety). More preferably, all halogens of a perhalogenated moiety are selected from Cl or F or a combination thereof. Even more preferably, all hydrogens of an alkyl moiety are substituted by F. Thus, the halogenated form of a cyclopropyl moiety having 5 hydrogens may have 1, 2, 3, 4 or 5 halogen substitutions, preferably selected from F. or Cl or combinations thereof, more preferably the moiety is perfluorinated cyclopropyl.

According to the invention, "alkoxy" is straight-chain or branched -O-alkyl, preferably having 1 to 6 or even 1 to 4 carbon atoms, such as, for example, methoxy, ethoxy, n-propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. It is also preferably alkoxy groups that have 1 to 4 carbon atoms.

According to the invention, "heterocycloalkyl" is a carbocyclic ring system with at least one ring in which at least one carbon atom is replaced by a heteroatom, preferably by a heteroatom from the group consisting of N, 0, S, P, B, Si, Se and which is saturated, unsaturated or heteroaromatic where the bond to the central structure of a compound described herein is located on a ring atom. Unless otherwise defined, the heterocyclic ring preferably comprises 3 to 9 ring atoms, in particular, 3 to 6 ring atoms, of which 1 to 5 ring atoms are carbon atoms with the proviso that one or more, preferably 1 to 4, in particular 1, 2 or 3, ring atoms are heteroatoms in the heterocyclic ring. Preferably, a ring heteroatom is selected from the group consisting of N, 0 and S, where, however, two oxygen atoms should not be directly adjacent. Heterocyclic rings usually comprise no more than 4 nitrogen atoms, and/or no more than 2 oxygen atoms and/or no more than 2 sulfur atoms. If the heterocyclyl radical or heterocyclic ring is optionally substituted, it can be fused with other carbocyclic or heterocyclic rings. In the case of optionally substituted heterocyclyl, the invention also covers polycyclic systems such as, for example, 8-azabicyclo[3.2.1]octanyl or 1-azabicyclo[2.2.1]heptyl. In the case of optionally substituted heterocyclyl, the invention also covers spirocyclic systems, such as, for example, 1-oxa-5-azaspiro[2,3]hexyl.

According to the invention, "alkylcycloalkyl" is a mono-, bi- or tricyclic cycloalkyl group that is substituted by one or more alkyl group(s), preferably in which the sum of carbon atoms in the cycloalkyl and alkyl part of the substituent is between 4 to 15 or 4 to 9 carbon atoms, such as, for example, ethylcyclopropyl, isopropylcyclobutyl, 3-methylcyclopentyl and 4-methylcyclohexyl. It is also preferably alkylcycloalkyls having 4, 5 or 7 carbon atoms, such as, among others, ethylcyclopropyl or 4-methylcyclohexyl. Preferably, the alkyl part of an alkylcycloalkyl substituent is C1 or a C2 alkyl (-CH3 or -C2H5).

According to the invention, "cycloalkylalkyl" is an alkyl group that is substituted by one or more mono-, bi- or tricyclic cycloalkyl group(s), preferably in which the sum of carbon atoms in the cycloalkyl and alkyl part of the substituent is between 4 to 15, more preferably between 4 and 9 carbon atoms, such as, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and cyclopentylethyl. It is also preferably cycloalkylalkyls having 4, 5 or 7 carbon atoms such as, among others, cyclopropylmethyl or cyclobutylmethyl. Preferably, the alkyl part of a cycloalkylalkyl substituent is C1 or a C2 alkylene (-CH2- or -C2H4-).

According to the invention, "aryl" is an aromatic hydrocarbyl (aryl) group. Preferably, an aryl group refers to Ce-Cyl-aryl, that is, an aryl group having between 6 and 14 ring carbon atoms. Also according to the invention "heteroaryl" refers to an aromatic group comprising at least one atom of the ring heteroatom individually selected from the group consisting of 0, N, P and S (e.g. 1, 2, 3, 4 or even more ring heteroatom atom(s) although heteroaryl with 1, 2, 3 or 4 ring heteroatom atoms are preferred). The definition of C5-Ci4-heteroaryl refers to an aryl group comprising at least one ring heteroatom atom individually selected from the group consisting of 0, N, P and S while the sum of ring atoms including the at least one atom of the ring heteroatom as defined above, is between 5 and 14. For example, the term Cs-heteroaryl includes furan (1 ring oxygen atom and 4 ring carbon atoms) or imidazole (2 ring nitrogen atoms and 3 ring carbon atoms). More preferred aryl compounds are Cβ-aryl, Cs-heteroaryl or Cε-heteroaryl. Examples are phenyl, cycloheptatrienyl, cyclooctatetraenyl, naphthyl and anthracenyl; 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyrrolyl, 3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 1,2,4-oxadiazol- 3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-triazol-3- yl, 1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl and 1,3,4-triazol-2-yl; 1-pyrrolyl, 1-pyrazolyl, 1,2,4-triazol-l-yl, 1-imidazolyl, 1,2,3-triazol-l-yl, 1,3,4-triazol-l-yl; 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl and 1,2,4-triazin-3-yl.

According to the invention, "Arylalkyl" and "heteroarylalkyl" are an alkyl group (alkylene chain) that is substituted by one or more aryl group(s) or one or more heteroaryl group(s), respectively. The alkylene chain preferably has between 1 and 6 carbon atoms (Ci-Ce-alkylene chain), preferably between 1 and 3 carbon atoms. The definition of Cv-Cso-arylalkyl group covers the broadest range defined herein for an arylalkyl group having a total of 7 to 20 atoms in the combination of the aryl ring system and the alkylene chain. Preferred arylalkyls are Cv-Cg-arylalkyl, for example, Ce-aryl-Ci-Cg-alkyl such as benzyl (-CH2-C6H5), phenylethyl (-CH2-CH2-C6H5) or phenylpropyl (-(CH2)3-C6H5 ) . The definition of Ce-20-heteroarylalkyl group encompasses the broader range defined herein for a heteroarylalkyl group having a total of 6 to 20 atoms in the combination of the heteroaryl ring system and the alkylene chain, wherein at least 1 Ring atom in the heteroaryl ring system is a heteroatom. Preferred heteroarylalkyls are Ce-Cg-arylalkyl, for example, Cs-heteroaryl-Ci-Ca-alkyl such as pyrrol-2-yl-methyl (-CH2-C4NH4) or Ce-heteroaryl-Ci-Cs-alkyl such as 2- pyridin-2-yl-methyl (-CH2-C5NH4).

According to the invention, "Alkylaryl" is an aryl group that is substituted by one or more alkyl group(s), preferably C1-Cg-alkyl group(s), more preferably C1-Ca-alkyl group(s). The definition of a C7-C2o-alkylaryl group encompasses the broader range defined herein for an alkylaryl having a total of 7 to 20 atoms in the aryl ring system and alkyl group(s), preferably Cv-Cg-alkylaryl, such as Ci-Cg-alkyl-Ce-aryl.

Specifically, this definition encompasses, for example, the meanings of tolyl (-C6H4-CH3), ethylphenyl (-C6H4-C2H5), or 2,3-, 2,4-, 2,5-, 2,6-, 3 ,4- or 3,5-dimethylphenyl.

Similarly, an "alkylheteroaryl" group is a heteroaryl group as defined herein that is substituted by one or more alkyl group(s). The definition of a C6-C2o-alkylheteroaryl group encompasses the broadest range defined herein for an alkylheteroaryl having a total of 6 to 20 atoms in the heteroaryl ring system and alkyl group(s), which individually are preferably group(s). ) C1-Cε-alkyl, more preferably C1-C3-alkyl group(s). Preferably alkylheteroalkyl is Ce-Cg-alkylheteroaryl. For example, C1-Cs-alkyl-Cβ-heteroaryl, such as 2-methyl-pyridyl (-C5NH3-CH3), 2-ethyl-pyridyl, 2,3-dimethyl-pyridyl or 2-methyl-3-ethyl-pyridyl .

According to the invention, "alkylcarbonyl" is a straight-chain or branched alkyl-C(=0), preferably having 2 to 7 carbon atoms (-C(=0)-Ci-Ce-alkyl), such as methylcarbonyl , ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, sec-butylcarbonyl and tert-butylcarbonyl. Preferred alkylcarbonyls have 1 to 4 carbon atoms (Ci~Ca-alkyl-C(=0)).

According to the invention, "alkylaldehyde" is a straight or branched chain alkyl substituted with a group C(=O)H (-alkyl-CH(=0)), preferably having 2 to 7 carbon atoms (-Ci -Ce-alkyl-CH (=0) ) . Preferred alkylcarbonyls have 2 to 4 carbon atoms (-C1-C3-alkyl-CH(=O)).

According to the invention, "aminoalkyl", "alkylaminoalkyl" (secondary amine) and "aminocarbonylalkyl", respectively, refer to amino (-NH2), aminoalkyl (-NHalkyl) and (-C (=0)-NH2), respectively, substituted alkylene chains. Preferably, alkyl in the three listed amino substituents is C1-Cs-alkyl, more preferably C1-C1-alkyl, for example, C1-alkylamino refers to -CH2-NH2, Cyl-alkylamino-C1-alkyl refers to -CH2- NH-CH3, and Cyl-alkylcarbonylamino refers to -CH2-C(=0)-NH2.

"Optionally substituted" groups as used herein are preferably substituted by 1, 2, 3, 4, 5, preferably by 1 or 2 independently selected from the group consisting of hydroxy, nitro, amino, halogen, C1-C3-alkoxy , cyano, hydroxycarbonyl, C1-C4- alkoxycarbonyl, C1-C4-alkylcarbamoyl, C4-C6- cycloalkylcarbamoyl and phenyl.

The person skilled in the art is aware that the terms "one" or "an" as used in the present application may, depending on the situation, mean "one (1)", "one (1) or more" or "at least one (1)".

Chemical structures and combinations of modalities that are against natural laws and that the person skilled in the art would therefore exclude based on their specialist knowledge are not included in this document. Ring structures that have three or more adjacent oxygen atoms, for example, are excluded.

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

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

Detailed Description

In the following, the invention and various embodiments of the invention are described in more detail. It is obvious to one skilled in the art that all modalities may be present separately or in combination.

Surprisingly, 5-fluoro-1H-pyrazoles of general formula (I) where R1 is C1-C1-alkyl, preferably methyl, can be prepared with high purity and in a short and simple process by reacting a compound (3) with C1-C4-alkyl-C0NHNH2 to prepare 3-perfluoroethyl- 4-perfluoromethyl-5-fluoro-pyrazole (intermediate (4)) and further reacting intermediate (4) with a C1-C4-alkylating agent, preferably a methylating agent, to prepare a compound of formula (I): wherein R1 represents C1-C4-alkyl, preferably methyl.

Wayne et al. document WO 2010/123999 (alkylation of unsubstituted pyrazole, pages 31 and 35) describe alkylation steps. However, the alkylation of non-symmetrically substituted pyrazoles usually proceeds with the formation of two regioisomers. The composition of the mixture depends on the nature of the substrate, alkylating reagents and reaction conditions. Surprisingly, the alkylation of this electron-poor pyrazole proceeds in good yield and high regioselectivity (see, for example, WO 2011012620).

In a preferred embodiment, 5-fluoro-1H-pyrazoles of general formula (I) can be prepared with high purity and in a short and simple process by reacting hexafluoropropene (intermediate (1)) with perfluoro-4-methyl- 2- pentene (intermediate (2)), isomerize intermediate (2) to perfluoro-2-methyl-2-pentene (intermediate (3)), react intermediate (3) with C1-C1-alkyl-CONHNH∑ to prepare 3-perfluoroethyl-4-perfluoromethyl-5-fluoro-pyrazole (intermediate (4)) and further reacting intermediate (4) with a C1-C4-alkylating agent, preferably a methylating agent, to prepare a compound of formula ( D:

The terms "catalyst" and "alkylating agent" are as defined in paragraphs 0 and 0. Step 1: Hexafluoropropene Dimerization

Typically, the reaction is carried out in the presence of a catalyst such as a fluoride (F_) donor (e.g. Mein F, BUIN F, NaF, KHF2, KF or CsF. Preferred catalysts are KHF2, KF and CsF, more preferably KF or CsF.

Typically dimethoxyethane), acetonitrile, DMF (dimethylformamide), DMA (dimethylacetamide),N-methylpyrrolidone, sulfolane, benzonitrile, dimethoxyethane, diethyleneglycoldimethylether. The reaction temperature is between 10 °C and 50 °C, preferably between 20 °C and 40 °C.

The reaction time is dependent on the size of the reaction and is typically between 1 min and 30 h.

Although the purification steps for Dimer (2) and/or removal or solvent exchange after Step 1 may occur before Step 2, Step 1 and Step 2 can be performed as a one pot reaction.

A "one pot reaction", as long as not otherwise stated, refers to two reaction steps (e.g., Step 3 and Step 4) that are carried out without interim purification steps after the first reaction step and before carrying out the second step and/or without the need to change the solvent.

"No purification steps" as used in the present application refers to the absence of purification steps selected from the group consisting of removing more than 10% of the solvent from a reaction mixture by evaporation, for example, under reduced pressure and/or or heating, crystallization of an intermediate or compound resulting from a reaction step in a solvent other than the solvent of the reaction mixture, or chromatography.

"Solvent exchange" as used in the present application means that no large amount of a solvent of a different type is added to a reaction mixture. "No large amount" refers to a volume of less than 50 vol % based on the volume of a solvent in a reaction mixture. For example, the addition of 5 ml of acetonitrile to a reaction mixture comprising 200 ml of methylene chloride is not a solvent change even if part of the solvent of the reaction mixture, such as 50 vol% of the solvent of a mixture of reaction, was removed by, for example, phase separation. However, the addition of more than 100 ml of acetonitrile (solvent of a different type) to a reaction mixture comprising 200 ml of methylene chloride as solvent is considered a change of solvent even if methylene chloride is not removed before addition. of acetonitrile. Also considered as a solvent exchange is the removal of at least 95 vol% of a first solvent (e.g., acetonitrile) in a reaction mixture after the first reaction step by, e.g., phase separation, followed by addition of a solvent of a different type, for example dichloromethane.

Although not mandatory, a one pot reaction is preferably carried out in the same reaction vessel. Step 2: Isomerization of perfluoro-4-methyl-2-pentene (Inactive Dimer) to perfluoro-2-methyl-2-pentene

Typically, isomerization is carried out in the presence of a fluoride donor. NaF, KF, KHF2, AIF3 or Cs F may be used in combination with an auxiliary catalyst comprising one or more ethylene glycoldimethyl ether, sulfolane, 15-crown ether-5 and 18-crown ether-6, quaternary ammonium salts such as tetraalkylammonium, difluorhydrates (e.g. alkaline difluorhydrates such as KHF2 hydrochloride or hydrobromide) or tetra-C1-Cg-alkylphosphonium salts or tetraphenylphosphonium salts such as PhíP Cl, PhuP Br, PhíP Br or PhíP HF2.

Preferred fluoride donors are NaF, KF, KHF2, CsF, AIF3 most preferably KF.

Isomerization usually occurs at a high temperature between 25 and 60 °C at normal pressure, but the reaction can be carried out under pressure of up to 6 bar and a temperature between 60 and 80 °C.

Typically, the solvents are polar solvents such as glyme, acetonitrile, DMF, DMA, benzonitrile, dimethoxyethane or diethyleneglycoldimethylether or combinations thereof. More preferable solvents are acetonitrile, DMF or DMA.

The reaction time is usually between 1 h and 10 h as well as between 2 h and 8 h.

In a preferred embodiment, the solvent in Step 1 and Step 2 is the same, preferably acetonitrile.

In another preferred embodiment, Step 3 and Step 4 are reacted as a one pot reaction and the solvent in Step 3 and Step 4 is the same, preferably acetonitrile or methylene chloride, more preferably methylene chloride.

Although the purification steps for intermediate (3) and/or solvent exchange after Step 2 may occur before Step 3; Step 1 to Step 3; or Step 2 and Step 3 can be carried out as a one pot reaction, i.e. without purification steps for intermediate (2) and/or intermediate (3) before carrying out Step 3 and/or without the need to change the solvent before performing Step 2 and Step 3 or before performing Step 3, respectively.Step 3: Reaction of perfluoro-2-methyl-2-pentene (3) with (C1-C4)-alkyl-CONHNH2

Generally, the reaction is carried out in a solvent. Typical solvents are - alkanes, such as hexanes preferably cyclohexane or methylcyclohexane; - haloalkanes, preferably dichloromethane, dichlorethane; - alcohols, preferably methanol, ethanol, or isopropanol; - nitriles, preferably acetonitrile, or butyronitrile; - amides, preferably DMF, or dimethylacetamide; - ethers preferably diethyl ether, methyl tert-butyl ether, dimethoxyethane, diglyme, - benzene, toluene, dichlorobenzene, chlorobenzenes.

Most preferred solvents are CH3CN, DMF, dichloromethane, ethanol.

The reaction temperature should vary between 10 and 60 °C, preferably between 20 and 40 °C.

Typically, the reaction can be carried out under standard pressure (around 1.013 bar, for example, between 0.7 and 1.3 bar). However, in the case of volatile reactants such as MeBr and Mel, the reaction can also be carried out under higher pressure such as between 2 and 6 bar.

Typically, the ratio between intermediate (3) and Acylhydrazine is between 1:1 and 1:2, preferably between 1:1.3 and 1:1.5.

Preferably, the C1-C4-alkyl-CONHNH2 is C3H7-CONHNH2.

The reaction time is not of critical importance and may depend on the reaction volume, preferably within the range of 1 h to 10 h, more preferably within the range of 1 h to 5 h.

Although the purification steps for intermediate (4) and/or solvent removal or exchange after Step 3 may occur before Step 4, Step 1 to Step 4 or Step 2 to Step 4 or Step 3 and Step 4 may be performed as a one pot reaction, that is, without purification steps for the dimer (2) and/or intermediate (3) and/or intermediate (4) before carrying out Step 4 and/or without the need to remove or exchange the solvent before performing Step 4. Step 4: Reaction of intermediate (4) with an alkylating agent

The reaction of intermediate (4) with a C1-C4-alkylating agent, preferably a methylating agent, to prepare a compound of formula (I) is herein referred to as step 4.

Typical alkylating agents are alkyl bromides, alkyl iodides or dialkylsulfates or trialkylphosphates such as CH3Cl, CHaBr, CH3I, (ÇHaíaSOí or (CH3O3PO). In a preferred embodiment, the alkylating agent is CHjBr, CH3I, (CH3)2SO4.

Typically, the ratio between intermediate (4) and the alkylating agent is between 1:1 and 1:2, preferably between 1:1.1 and 1:1.5.

The alkylation reaction can be carried out in different solvents such as - alkanes, such as hexanes, for example, cyclohexane or methylcyclohexane; - haloalkanes, preferably dichloromethane, dichlorethane; - alcohols, preferably methanol, ethanol, or isopropanol; - nitriles, preferably acetonitrile, or butyronitrile; - amides, preferably dimethylformamide, or dimethylacetamide; - ethers such as diethyl ether, methyl tert-butyl ether, dimethoxyethane, diglyme, - benzene, toluene, dichlorobenzene, chlorobenzenes - lactams such as N-methylpyrrolidone (NMP).

The most preferred solvents are dimethylformamide (DMF), N-methylpyrrolidone (NMP), dichloromethane (CH2 Cl2) or acetonitrile (CH3 CN).

In a preferred embodiment, the alkylation reaction is carried out in the presence of a weak organic or inorganic base. Preferred bases are LÍ2CÕ3, Na2CO3, K2CO3, NEts.

Generally, the reaction time is not of critical importance and may depend on the reaction volume, the reactivity of the alkylating reagents is preferably within the range of 3 h to 20 h, more preferably within the range of 1 h to 5 h.

Usually, alkylation occurs at normal pressure, for example, around standard pressure (around 1.013 bar, for example, between 0.7 and 1.3 bar). However, in the case of volatile reactants such as CHsBr, the reaction can also be carried out under higher pressure such as between 2 and 6 bar.

A particularly preferred embodiment of the present invention relates to a process for preparing the compound of formula (Ia) starting from perfluoro-2-methyl-2-pentene (3) or hexafluoropropene (1) comprising the steps described in this document above. Step 5

In a step 5, the compound of formula (I), preferably the compound (Ia), can be transformed into its CN analogue of formula (6) or (6a), respectively. wherein R1 is (C1-C4)-alkyl, preferably, a compound of formula (6) is a compound of formula (6a):

By reacting the compound (I), preferably the compound (Ia), with a CN donor such as alkaline cyanides (e.g., NaCN, KCN, CsCN, or CuCN).

Typical solvents are acetonitrile, DMF, DMA, N-methylpyrrolidone (NMP), Sulfolane, dimethoxyethane, diglyme. Preferred solvents are acetonitrile, DMF or DMA.

Typically, the temperature for this reaction is between 30°C and 120°C, preferably between 40°C and 110°C, more preferably above 60°C such as between 60°C and 120°C or between 60°C and 100°C. °C.

Generally, reaction time is not of critical importance and may depend on the reaction volume. Preferably, the reaction time is between 2 h and 8 h, more preferably between 4 and 8 h. Step 6

In a step 6, a compound of formula (6), preferably (6a), can be transformed into its carboxylic acid analogue of formula (7), preferably formula (7a), respectively, according to hydrolysis steps known in the art. technique: wherein R1 is C1-C4-alkyl, preferably a compound of formula (7) is a compound of formula (7a):

The conversion of a cyano group (-CN) to a carboxylic group (-COOH) is generally carried out under acidic or basic conditions.

For acid hydrolysis, preference is given to mineral acids, e.g. H2SO4, HC1, HSO3CI, HF, HBr, HI, H3PO4 or organic acids, e.g. CF3COOH, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid. The reaction can be accelerated by adding catalysts, for example, FeCla, AICI3, BF3, SbCla, NaH2PO4. The reaction can also be carried out without adding acid, just in water.

Basic hydrolysis is carried out in the presence of inorganic bases such as alkali metal hydroxides, e.g. lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal carbonates, e.g. Na2CC>3, K2CO3 and alkali metal acetates , for example, NaOAc, KOAc, LiOAc, and alkali metal alkoxides, for example, NaOMe, NaOEt, NaOt-Bu, KOt-Bu of organic bases such as trialkylamines, alkylpyridines, phosphazenes and 1,8-diazabicyclo[5.4.0 ]undecene (DBU). Preference is given to inorganic bases, for example, NaOH, KOH, Na∑CCh or K2CO3. To generate the protonated acid form of formula (7) or (7a), respectively, a following acidification step should follow.

Typically, suitable inorganic acids for carrying out acidification after completion of basic hydrolysis are any acid that is stronger than the deprotonated form of a compound of formula (7) or (7a), respectively. Preference is given to mineral acids, e.g. H2SO4, HC1, HF, HBr, HI, H3PO4 or organic acids, e.g. CF3COOH, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid. Preferred acids for these acidifications are HC1 or H2SO4.

The reaction step can be carried out in substance or in a solvent. Preference is given to carrying out the reaction in a solvent. Suitable solvents are, for example, selected from the group comprising water, alcohols such as methanol, ethanol, isopropanol or butanol, aliphatic and aromatic hydrocarbons, for example n-hexane, benzene or toluene, which may be replaced by fluorine atoms. and chlorine, such as methylene chloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers, for example, diethyl ether, diphenyl ether, methyl tert-butyl ether, isopropyl ethyl ether, dioxane, diglyme, dimethyl glycol, dimethoxyethane (DME) or THF; nitriles such as methyl nitrile, butyl nitrile or phenyl nitrile; amides such as dimethylformamide (DMF) or N-methylpyrrolidone or mixtures of such solvents, particular preference being given to water, acetonitrile, dichloromethane and alcohols (ethanol). Preferably, the reaction is carried out in water. The process step of the invention is generally carried out under standard pressure. Alternatively, however, it is also possible to work under vacuum or under high pressure (e.g. reaction in an autoclave with aqueous HCl).

The reaction time can, according to batch size and temperature, be selected within a range between 1 hour and several hours such as between 1 h and 30 h, preferably between 3 h and 20 h.

Preference is given to conversion via basic hydrolysis followed by acidification.

The process step of the invention is preferably carried out within a temperature range of 20°C to 150°C, more preferably at temperatures of 30°C to 110°C, most preferably at 30°C to 80°C.

Generally the reaction time can, according to batch size and temperature, be selected within a range between 1 hour and several hours such as between 1 and 30 h, preferably between 3 and 20 h.

Compounds of formula (II)

The present invention also relates to a process for producing an insecticidal compound of formula (II), preferably of formula (II'), more preferably of formula (Ila), based on the preparation of compounds of formula (I). Compounds of formula (II) are, for example, known from WO 2010/051926. wherein R1 is C1-C1-alkyl, preferably methyl; and Ai is C-R2; and R2 is hydrogen, fluorine, chlorine, bromine, CN, NO2, optionally halogenated C1-Cε-alkyl, optionally halogenated C1-C4-alkoxy, optionally halogenated C1-C4-alkylsulfonyl, optionally halogenated C1-C4-alkylsulfinyl or N-cyclopropylaminocarbonyl (-C(=0)-NH-cyclopropyl); preferably hydrogen, fluorine, chlorine, bromine, CN, NO2, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n-propoxy, 1-methylethoxy, fluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy , trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, pentafluoroethoxy, methylsulfonyl, methylsulfinyl, trifluoromethylsulfonyl, trifluoromethylsulfinyl or N-cyclopropylaminocarbonyl, more preferably hydrogen, fluorine, chlorine, bromine, CN, NO2, methyl , fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, or pentafluoroethoxy, preferably hydrogen, fluorine, chlorine, bromine, most preferably chlorine; and A2 is C-R3 or nitrogen; and R3 is hydrogen, methyl, fluorine or chlorine, preferably hydrogen; and Q is hydrogen, cyano, hydroxy, formyl or one of the groups Ci-Cβ-alkyl, Ca-Cε-alkenyl, C3-C6-alkynyl, Ca-Cg-cycloalkyl, Cg-Cg-heterocycloalkyl, Ci-Cí-alkoxy, C4-Ci5-alkylcycloalkyl, C4-C15- cycloalkylalkyl, Ci-Ce-hydroxyalkyl, Cε-aryl-Ci-Ca-alkyl, Cs-Cε-heteroaryl-Ci-Ca-alkyl, C1-C4- aminoalkyl, aminocarbonyl-Ci- C4-alkyl or C1-C4-alkylamino-C1-C4-alkyl which are optionally substituted with one, two, three, four or five, preferably with one or two, more preferably with one, substituents independently selected from the group consisting of hydroxy, nitro, amino, halogen, C1-C3-alkoxy, cyano, hydroxycarbonyl, C1-C4-alkoxycarbonyl, C1-C1-alkylcarbamoyl, C1-Ce-cycloalkylcarbamoyl and optionally independently with one, two or three substituents selected from from the group consisting of halogen, cyano, nitro, hydroxycarbonyl, C1-C2-alkylcarbamoyl, C1-C2-alkyl, C1-C2-halogenated alkyl and phenyl substituted with C1~C2-alkoxy; preferably Q is C3-C6-cycloalkyl, or Ca-Ce-cycloalkyl which is substituted with at least one substituent selected from the group consisting of chlorine, fluorine, bromine, iodine, cyano and hydroxy, or Cε-aryl-Ci-Ca -alkyl; more preferably cyclopropyl, 1-cyano-cyclopropyl or benzyl (-CH2-C6H5); preferably, a compound of formula (II) is a compound of formula (II'): wherein A1 and A2 and Q are as defined for a compound of formula (II), characterized by the fact that the process comprises steps 3 and 4 as described in paragraphs 0 and 0 to 0.

In a preferred embodiment, the compound of formula (II) is the compound (IIa) defined by the following substituents:

The innovative and inventive process for preparing a compound of formula (II), preferably (II'), more preferably (lia), is characterized by the fact that the process comprises steps 3 and 4 as described in paragraphs 0 and 0 to 0 In a preferred embodiment, the process is characterized by the fact that it comprises steps 1 to 4 described in paragraphs 0 to 0. In another preferred embodiment, the process comprises in addition to steps 3 and 4 or in addition to steps 1 to 4 optionally Step 5 and Step 6 as described in paragraphs 0 to 0 and optionally, by the subsequent Step 8 described below. Optionally, the compound (8) in Step 8 can be produced by the reaction indicated in Step 7 which is described below: wherein R1 and Ai and A2 and Q have the meanings described for the compounds of formula (II). GS is any desired leaving group, e.g., halogen or anhydrous.

Typically, an amine derivative of formula (8) not only refers to the amine, but also to its salt form (8)H+ W wherein W" is selected from ", Cl", Br", J", HSO4", CH3COO", BFr, CH3SO3", Toluenesulfonic acid, CF3COO" or CF3SO3-. where W is selected from ", Cl”, Br_, J”, HSO4-, CH3COO”, BFr, CH3SO3-, Toluenesulfonic acid, CF3COO- or CF3SO3-.

Thus, a preferred embodiment refers to the Step 8 reaction in which the compound of formula (8) is present in its salt form (8) H+ W~, wherein W~ is selected from ~, Cl', Br -, J", HSO4-, CH3COO-, BF4-, CH3SO3-, Toluenesulfonic acid,CF3COO- or CF3SO3-.

In a more preferred embodiment, a compound of formula (8) is compound (8a) and/or its salt (8a'): wherein W" (in the case of compound (8a' )) is selected from the group consisting of F", Cl-, Br", J", HSO4-, CH3COO-, BF4-, CH3SO3-, Toluenesulfonic acid- , CF3COO- or CF3SO3-. Step 8

In Step 8, compounds according to the invention of type (II), preferably (II'), more preferably (Ia), can be synthesized by reacting amines of general structure (8) (or their salts) with the intermediate (7') which is an activated form of the carboxylic acid derivative of formula (7), preferably of formula (7a). The reaction can be carried out with or without solvents. At this stage, a suitable base can likewise be used. wherein R1 is hydrogen, optionally halogenated C1-C4-alkyl or optionally halogenated cyclopropyl, preferably methyl.

An activated form of carboxylic acid derivative of formula 7, preferably formula (7a), which is indicated in the reaction scheme of Step 8 above to have any GS leaving group in the -C(=O)GS group, comprises a) analogues of formula (7) or (7a), respectively, wherein the OH of the COOH group is replaced by a suitable leaving group such as halogen; b) anhydrides of compounds of formula (7) or (7a), respectively; or c) compounds of formula (7) or (7a), respectively in the presence of a coupling reagent the presence of which activates the compound of formula (7) or (7a), respectively, within the meaning of the present invention, such as dicyclohexylcarbodiimide or 1 -hydroxybenzotriazole. The person skilled in the art is aware of suitable leaving groups for the preparation of anhydrides of a carboxylic acid or coupling reagents suitable for acid/amine reactions and the preparation of such compounds. Preferred leaving groups are carboxylic acid halides such as carboxylic acid chlorides or fluorides.

Cyclic carboxylic acid halides, as among others represented by the general structure (7'), can be prepared simply by reacting a heterocyclic carboxylic acid of the compound (7) with halogenating reagents such as thionyl chloride, thionyl bromide, phosphoryl chloride, oxalyl chloride, phosphorus trichloride, etc. (Houben-Weyl (1952) vol. VIII, p.463 ff.).

Amine derivatives of formula (7) and their salts are known in the art, are commercially available or can be prepared in a known manner (see, for example, WO 2010/051926).

The synthesis of carboxamides represented by formula (II), preferably (II'), more preferably (Ia), can, however, also be carried out using coupling reagents such as dicyclohexylcarbodiimide and additives such as 1-hydroxybenzotriazole (König et al. al. Chem. Ber. (1970), 788-798). It is also possible to use coupling reagents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1,1'-carbonyl-1H-imidazole and similar compounds.

Coupling reagents that are used to carry out the synthesis process are all those that are suitable for the preparation of an ester or amide linkage (cf., e.g., Bodansky et al., Peptide Synthesis, 2nd ed., Wiley & Sons, New York, 1976; Gross, Meienhofer, The Peptide: Analysis, Synthesis, Biology (Academic Press, New York, 1979).

Furthermore, mixed anhydrides can also be used for the synthesis of (II), preferably (II'), more preferably (IIa) (see, for example, Anderson et al, J. Am. Chem. Soc (1967), 5012 -5017). In this process it is possible to use various chloroformates, such as, for example, isobutyl chloroformate, isopropyl chloroformate. Similarly, diethylacetyl chloride, trimethylacetyl chloride and the like can be used for this.

In general, Step 8 may be carried out optionally/if appropriate in the presence of a suitable diluent/solvent and optionally/if appropriate in the presence of a suitable basic reaction aid.

The process according to the invention can be carried out in the presence of a diluent/solvent. Useful diluents for this purpose include all inert organic solvents, preferably aliphatic, alicyclic or aromatic hydrocarbons, for example petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons, for example, chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane or trichloroethane; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; ketones such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; nitriles such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoramide, more preferably chlorobenzene and toluene are used.

Preferred diluents are aliphatic, alicyclic or aromatic hydrocarbons, for example petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; and halogenated hydrocarbons, for example, chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane or trichloroethane; for example, toluene or chlorobenzene.

The solvent that can be used is any solvent that does not adversely affect the reaction, such as, for example, water. Aromatic hydrocarbons such as benzene or toluene are suitable; halogenated hydrocarbons such as dichloromethane, chloroform or tetrachloromethane, open-chain or cyclic ethers such as diethyl ether, dioxane, tetrahydrofuran or 1,2-dimethoxyethane; esters such as ethyl acetate and butyl acetate; ketones such as, for example, acetone, methyl isobutyl ketone and cyclohexanone; amides such as dimethylformamide and dimethylacetamide; nitriles such as acetonitrile; and other inert solvents such as 1,3-dimethyl-2-imidazolidinone; Solvents can be used separately or in combination of two or more.

The base (basic reaction aid) used may be an acid acceptor such as an organic base such as triethylamine, ethyldiisopropylamine, tri-n-butylamine, pyridine and 4-dimethylaminopyridine; furthermore, the following bases may, for example, be used: alkali metal hydroxides, such as, for example, sodium hydroxide and potassium hydroxide; carbonates such as sodium hydrogen carbonate and potassium carbonate; phosphates such as dipotassium hydrogen phosphate and disodium phosphate; alkali metal hydrides, such as sodium hydride; alkali metal alcoholates, such as sodium methanolate and sodium ethanolate. These bases can be used in proportions of from 0.01 to 5.0 mol equivalents based on (8) and (7'). Furthermore, silver(I) cyanide can also be used as a base and activator (see, for example, Journal of Organic Chemistry. 1992, 57, 4394-4400; Journal of Medicine Chemistry 1992, 35, 3905-3918; Journal of Organic Chemistry 2003, 68, 1843-1851).

However, in a preferred embodiment of the present invention, step 8 is carried out in the absence of an acid acceptor and the leaving group is Cl or F, more preferably Cl.

In the context of the invention, "in the absence of an acid acceptor" means in the absence of an acid acceptor other than the amine reactant (8) or, in other words, "in the absence of an additional acid acceptor wherein "additional" means in addition to the amine derivative of formula (8) (or its salts (8') which are part of the reaction. An "additional acid acceptor" in the sense of the present invention may be a base in addition to the amine compound according to invention or compounds that reduce the potency of a formed acid such as salts, for example silver cyanide (AgCN), which are capable of transforming strong acids that are formed during the reaction (leaving group anion plus hydrogen cation) into insoluble salts and weak acids (e.g., HCl formed (if the leaving group is chlorine) react with AgCN to insoluble AgCl and weak base HCN).

Surprisingly, the carboxamides of formula (II) can be prepared in the absence of an acid acceptor in good yields with high purity and selectivity. An additional advantage of the process according to the invention is that the final treatment is simpler, since an acid acceptor is not necessary. This results in less or no wastage of water, an easier purification process without prior isolation by adding an aliphatic alcohol in the same reaction vessel, and the process can be carried out at a higher concentration. The resulting product was then obtained with a surprising purity greater than 90% or even close to 100%, and with less reagent and effort, while previous conditions in the presence of an acid acceptor generally lead to a purity close to less than 90%. %. The process according to the invention becomes more economically viable.

Thus, a preferred embodiment relates to a reaction for producing compounds of formula (Ia) wherein leaving group GS refers to F, Cl, Br or I, preferably F or Cl, and in the absence of an acid acceptor other than compound (8a).

The suitable reaction temperature is in the range of -20°C to the boiling point of the particular solvent. In general, the reaction temperature is between 70°C to 150°C, preferably between 80°C to 140°C, for example, 100°C or around 100°C such as 80°C to 130°C or 80°C to 120°C.

The reaction time is between 1 min and 96 h depending on the choice of volume, reagents, solvents and reaction temperature.

For the Step 8 process, generally between 0.8 and 1.5 mol, preferably 0.8 to 1.4 mol, 0.9 to 1.4 mol, equimolar amounts or 1 to 1.2 mol of amine derivative of formula (8) or its salt, preferably (8a) or (8a'), are used per mole of the pyrazol-carboxamide derivatives (1').

A preferred embodiment refers to a reaction of a compound (8a) or its salt (8a'), respectively, with the compound (7'), wherein X is Cl and wherein the proportion of the compound (8a) (or its salt (8a')) and (7') where X is Cl is between 1:1 or 1:1.3, preferably between 1:1 to 1:2 such as between 1:1 to 1:1 or even 1 :1.

Depending on the choice of volume, reagents, solvents and reaction temperature, the reaction time can vary between one minute and 96 h. Typically, the reaction time is up to 15 hours, but the reaction can also be terminated even earlier in the case of complete conversion. Preference is given to reaction times of 5-10 hours.

The Step 8 reaction is generally carried out under standard pressure. However, it is possible to work under high or reduced pressure - generally between 0.1 bar and 10 bar. It is preferable to work under reduced pressure to remove HC1 from the reaction volume.

The Step 8 reaction can generally be carried out under atmosphere. However, it is preferred to carry out the process under protective gas such as argon or nitrogen.

Furthermore, the person skilled in the art will understand that it is also possible to react a compound of formula (7') with a compound of formula (8*), wherein the -C(=O)-NH-Q moiety of the compounds of formula (8) is replaced by a C(=O)-OH or C(=O)-GP moiety in a compound of formula (8*), where GP represents any protecting group of a carboxylic group (e.g., a methylester, i.e. , GP represents -O-methyl). The deprotection of the carboxylic moiety of the resulting compound (II*) from a reaction with a compound {8*) and/or activation of the carboxylic moiety and/or coupling with an amine to arrive at a compound of formula (II) are well known to a technician. Compounds of the general structure (II*) can be synthesized by reacting an amine of the general structure (7) with activated carboxylic acid derivatives of the general structure (8*). In this sense, the same conditions apply to the choice of solvent, reaction conditions, reaction time and reagents as for the synthesis of (II), described above. Step 7

Compounds of general structure (8) can be synthesized by reacting an amine of general structure (10) with activated carboxylic acid derivatives of general structure (9). In this sense, the same conditions apply for the choice of solvent, reaction conditions, reaction time and reagents as for the synthesis of (II), preferably (II'), more preferably (Ia), described in Step 8 above.

Compounds of formula (III)

The present invention also relates to a process for producing an insecticidal compound of formula (III) or (III') based on the preparation of compounds of formula (I). wherein R1 is (C1-C4)-alkyl, preferably methyl; and Ai is C-R2; R2 is hydrogen, fluorine, chlorine, bromine, CN, NO2, optionally halogenated C1-Cε-alkyl, optionally halogenated C1-C4-alkoxy, optionally halogenated C1-C4-alkylsulfonyl, optionally halogenated C1-C4-alkylsulfinyl or N-cyclopropylaminocarbonyl ( -C(=O)-NH- cyclopropyl); preferably hydrogen, fluorine, chlorine, bromine, CN, NO2, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n-propoxy, 1-methylethoxy, fluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy , trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, pentafluoroethoxy, methylsulfonyl, methylsulfinyl, trifluoromethylsulfonyl, trifluoromethylsulfinyl or N-cyclopropylaminocarbonyl, more preferably hydrogen, fluorine, chlorine, bromine, CN, NO2, methyl , fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, or pentafluoroethoxy, preferably hydrogen, fluorine, chlorine, bromine, most preferably chlorine; and A2 is C-R3 or nitrogen; R3 is hydrogen, methyl, fluorine or chlorine, preferably hydrogen; and Q is hydrogen, cyano, hydroxy, formyl or one of the groups Ci-Cβ-alkyl, Cs-Cε-alkenyl, C3-C6-alkynyl, Ca-Cg-cycloalkyl, Cs-Cg-heterocycloalkyl, Ci-C4-alkoxy, C4-Ci5-alkylcycloalkyl, C4-C15- cycloalkylalkyl, Ci-Cβ-hydroxyalkyl, Cβ-aryl-Ci-Ca-alkyl, Cs-Ce-heteroaryl-Ci-Cs-alkyl, C1-C4- aminoalkyl, aminocarbonyl-Ci- C4-alkyl or C1-C4-alkyl-amino-C1-C4-alkyl which are optionally substituted with one, two, three, four or five, preferably with one or two, more preferably with one, substituents independently selected from the group consisting of hydroxy, nitro, amino, halogen, C1-C3-alkoxy, cyano, hydroxycarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkylcarbamoyl, C4~C6-cycloalkylcarbamoyl and optionally independently with one, two or three substituents selected from from the group consisting of halogen, cyano, nitro, hydroxycarbonyl, C1-C2-alkylcarbamoyl, C1-C2-alkyl, C1-C∑-halogenated alkyl and phenyl substituted with C1-C2-alkoxy; preferably Q is Ca-Cg-cycloalkyl, or Ca-Cs-cycloalkyl which is substituted with at least one substituent selected from the group consisting of chlorine, fluorine, bromine, iodine, cyano and hydroxy, or Ce-aryl-Ci-Ca -alkyl; more preferably cyclopropyl, 1-cyano-cyclopropyl or benzyl (-CH2-C6H5); T represents one of the 5-membered heteroaromatics T1-T8 listed below, where the bond to the pyrazole leader group is marked with an asterisk *, wherein R6 independently of each other represents halogen, cyano, nitro, amino or optionally substituted C1-Cg-alkyl, C1-Ce-alkyloxy, C1-Cβ-alkylcarbonyl, C1-Cβ-alkylsulfanyl, C1-Ce-alkylsulfinyl, Ci- Ce-alkylsulfonyl, n represents the values 0-2, preferably 0, with the proviso that n is 0 or 1 in T5, T6 and T8 and provided that n is 0 in T7; preferably, a compound of formula (III) is a compound of formula (III') wherein Ai and A∑ and T and Q have the meanings described above for a compound of formula (III) characterized by the fact that the process comprises steps 3 and 4 as described in paragraphs 0 and 0 to 0.

For the sake of clarification, if n in any formula described herein is 0 (zero), ring carbon atoms with a free valence are then replaced by hydrogen.

In a preferred embodiment, the compound of formula (III) is the compound (Ilia) defined by the following substituents:

The innovative and inventive process for preparing a compound of formula (III), preferably (III'), more preferably (Ilia), is characterized by the fact that the process comprises steps 3 and 4 as described in paragraphs 0 and 0 to 0 In a preferred embodiment, the process is characterized by the fact that it comprises steps 1 to 4 described in paragraphs 0 to 0. In a further preferred embodiment, the process comprises in addition to steps 3 and 4 or in addition to steps 1 to 4 the subsequent Step 9 and Step 10:

The radicals Ai, Az, R1 and Q have the meanings described for compound (III). Preferably, R1 is methyl. The five-membered cycles of E1-E3, carbon and nitrogen represent the five-membered heterocycles defined under T. U represents bromine, iodine or triflate if M represents a boronic acid, boronic ester or trifluoroboronate. U represents a boronic acid, boronic ester or trifluoroboronate if M represents bromine, iodine or triflate. Step 9

Compounds of the general structure (12) can be prepared by processes known in the literature by, for example, nucleophilic substitution of F in the aromatic ring (document WO 2007-107470; Sakya et al., Tetrahedron Letters 2003, 44, 7629-7632) from the appropriate starting materials (I), preferably (Ia), and (11). Step 10

Compounds of formula (III) or (III'), preferably the compound (Ilia), can be prepared by using palladium-catalyzed reactions with reaction partners (12) and (13) (see, for example, document WO 2005 /040110 or document WO 2009/089508). Compounds of general structure (13) are commercially available or can be prepared by processes known to those skilled in the art.

Furthermore, the person skilled in the art is aware that it is alternatively possible to react a compound of formula (12) with a compound of formula (13*), wherein the -C(=O)-NH-Q moiety of the compounds of formula (13) is replaced by a C(=0)-OH or C(=O)-GP moiety in a compound of formula (13*), where GP represents any protecting group of a carboxylic group (for example, an alkyl ester such as methyl ester , i.e. GR represents -O-methyl). The deprotection of the carboxylic moiety of the resulting compound (III*) from a reaction with a compound (13*) and/or activation of the carboxylic moiety and/or coupling with an amine to arrive at a compound of formula (III) are well known to a technician.

In summary, compounds of general structure (III) can be synthesized by reacting an amine of general structure (10) with activated carboxylic acid derivatives of general structure (III*). In this sense, the same conditions apply to the choice of solvent, reaction conditions, reaction time and reagents as for the synthesis of (II), described in Step 8 above.

Compounds of formula (III'')

In another preferred embodiment, the invention relates to a process for preparing a compound of formula (III''), preferably of formula (III'''), for example, known from document WO 2012/107434: wherein R1, R6, n, Ai, A2, and Q are as defined for the compound (III), preferably; preferably, a compound of formula (III''') is a compound of formula (III''') wherein R6, n, Ai, A2 and Q are as defined for a compound of formula (III), preferably wherein n is 0 characterized by the fact that the process comprises steps 3 and 4 as described in paragraphs 0 and 0 to 0.

In a preferred embodiment, the compound of formula (111'''') is the compound (Illb) defined by the following substituents:

The process for preparing a compound of formula (III''), preferably (III'''), more preferably (IIIb), is characterized by the fact that the process comprises steps 3 and 4 as described in paragraphs 0 and 0 to 0. In a preferred embodiment, the process is characterized by the fact that it comprises steps 1 to 4 described in paragraphs 0 to 0. In a further preferred embodiment, the process comprises in addition to steps 3 and 4 or in addition to steps 1 to 4 optionally the subsequent Step 9 and Step 10 as described in paragraphs 0 to 0 or optionally the subsequent Step 11 and Step 12. Steps 11 and 12 are known in the art (see, for example, document WO 2012/107434). Step 11

In a step 11, a compound of formula (I), preferably of formula (Ia), can be transformed into its azide analogue of formula (14) or (14a), respectively: wherein R1 is hydrogen, optionally halogenated C1-C1-alkyl or optionally halogenated cyclopropyl, preferably methyl, preferably a compound of formula (14) is compound (14a) , by reacting the compound (I), preferably the compound (la), with an azide-donor such as an alkali metal azide (for example, NaNa).

Preferably, the reaction is carried out in a polar aprotic solvent such as tetrahydrofuran (THF), ethyl acetate (EtOAc), acetone, dimethylformamide (DMF), acetonitrile or dimethyl sulfoxide (DMSO). A preferred solvent is DMSO.

Typically, the reaction temperature is between 0 °C and 60 °C, preferably between 10 °C and 30 °C, more preferably between 20 °C and 30 °C.

The reaction time may, among others, depend on the reaction volume and is usually between 0.5 h and 30 h. Step 12

In a step 12, an intermediate of formula (14), preferably of formula (14a), is reacted with an intermediate of formula (15) to give an intermediate of formula (III'''*) or preferably a compound of formula ( III'''*) where R1 is methyl, respectively: wherein R1, R6, Ai, and A2 are as defined for compound (III), n is 0 or 1 and GP is any carboxylic group protecting group such as C1-Ce-alkyl (e.g., methyl). Preferably, R1 in a compound of formula (III''''*) is methyl (compound of formula (III'''*)}. More preferably, R1 in formula (III'''*) is methyl in the formula ( III''*) is 0.

The compounds of formula (15) are commercially available or can be prepared according to methods known in the art.

Typically, the solvent for the Step 12 reaction is a polar protic solvent such as water, formic acid, n-butanol, isopropanol, nitromethane, ethanol, methanol, acetic acid or combinations thereof. Preferably, the solvent is n-butanol, isopropanol, ethanol, water or combinations thereof.

The reaction is carried out in the presence of copper or a copper catalyst such as copper sulfate or copper(I) iodide, optionally in the presence of a base such as N-ethyldiisopropylamine. However, also other bases - organic are suitable. In case of a Cu(II) catalyst, a reducing agent such as sodium ascorbate can be used. In case of Cu(0) catalyst, such as an amine salt, an oxidizing agent can be used (see, for example, Angewandte Chemie, International Edition (2009), 48(27),4900-4908 and references cited , Lutz., Angew. Chem. Int. Ed. 2008, 47, 2182 - 2184 and references cited, and Bock et al., Eur. J. Org. Chem. (2006), 51-68 and references cited).

Starting from a compound of formula (III''*}, compounds of formula (III), (III'), (III''), (III'''), (Illb), (III'''') , (IV) or (IV') can be readily prepared according to methods known in the art (see, for example, WO 2012/107434).

The compound of formula (III'''') can be prepared by reacting a compound of formula (III''*) in which O-GP is Ci-Ce-alkoxy via hydrolysis. For example, in the case where -O-GP is methoxy or ethoxy, the hydrolysis can be carried out with water and a base, such as potassium hydroxide or lithium hydroxide, in the absence or presence of a solvent, such as, for example, example, tetrahydrofuran or methanol. In the case where R is, for example, tert-butoxy, the hydrolysis is carried out in the presence of acid, such as trifluoroacetic acid or hydrochloric acid. The reaction is carried out at a temperature of from -120 °C to 130 °C, preferably from -100 °C to 100 °C. wherein R1, R6, n, Ai, and A2 are as defined for compound (III), preferably R1 is methyl and n is 0.

Compounds of the general structure (III) can be synthesized by reacting an amine of the general structure (10) with activated carboxylic acid derivatives of the general structure (III''''). In this sense, the same conditions apply for the choice of solvent, reaction conditions, reaction time and reagents as for the synthesis of (II) described in Step 8 above.

Compounds of formula (IV)

One aspect of the present invention relates to a process for preparing a compound of formula (IV), preferably of formula (IV'): wherein R1 is C1-C1-alkyl, preferably methyl; and Ai is C-R2; and R2 is hydrogen, fluorine, chlorine, bromine, CN, NO2, optionally halogenated C1-Ce-alkyl, optionally halogenated C1-C1-alkoxy, optionally halogenated C1-C1-alkylsulfonyl, optionally halogenated C1-C1-alkylsulfinyl or N-cyclopropylaminocarbonyl (-C(=O)-NH- cyclopropyl); preferably hydrogen, fluorine, chlorine, bromine, CN, NO2, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n-propoxy, 1-methylethoxy, fluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy , trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, pentafluoroethoxy, methylsulfonyl, methylsulfinyl, trifluoromethylsulfonyl, trifluoromethylsulfinyl or N-cyclopropylaminocarbonyl, more preferably hydrogen, fluorine, chlorine, bromine, CN, NO2, methyl , fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, or pentafluoroethoxy, preferably hydrogen, fluorine, chlorine, bromine, most preferably chlorine; and A2 is C-R3 or nitrogen; and R3 is hydrogen, methyl, fluorine or chlorine, preferably hydrogen; and T represents one of the 5-membered heteroaromatics T1-T9 listed below, where the bond to the pyrazole leader group is marked with an asterisk * or *-C(=0)-NE TS ; and R6 independently of each other represents halogen, cyano, nitro, amino or optionally substituted C1-Ce-alkyl, C1-Cg-alkyloxy, C1-Cb-alkylcarbonyl, C1-Ce-alkylsulfanyl, C1-Cg-alkylsulfinyl, C1- Cg-alkylsulfonyl, n represents the values 0-2, preferably 0, with the proviso that n is 0 or 1 in T5, T6 and T8 and provided that n is 0 in T7. Q is hydrogen, cyano, hydroxy, formyl or one of the groupings Ci-Cg-alkyl, Ca-Cg-alkenyl, C3-C6-alkynyl, Cs-Cg-cycloalkyl, Ca-Cg-heterocycloalkyl, Ci-Cq-alkoxy, C4 -C15-alkylcycloalkyl, C4-C15- cycloalkylalkyl, C1-Ce-hydroxyalkyl, Cs-aryl-C1-Cβ-alkyl, Cs-Ce-heteroaryl-C1-Ca-alkyl, C1-C4- aminoalkyl, aminocarbonyl-C1-C4 -alkyl or C1-C4-alkyl-amino-C1-C4-alkyl which are optionally substituted with one, two, three, four or five, preferably with one or two, more preferably with one, substituents independently selected from the group consisting of hydroxy, nitro, amino, halogen, C1-C3-alkoxy, cyano, hydroxycarbonyl, C1-C4_alkoxycarbonyl, C1-C4-alkylcarbamoyl, C4-C6-cycloalkylcarbamoyl and optionally independently with one, two or three substituents selected from the group consisting of halogen, cyano, nitro, hydroxycarbonyl, C1-C2-alkylcarbamoyl, Ci-Ca-alkyl, Ci-C2-halogenated alkyl and phenyl substituted with Ci-C∑-alkoxy; preferably Q is Cj-Ce-cycloalkyl, or Cs-Ce-cycloalkyl which is substituted with at least one substituent selected from the group consisting of chlorine, fluorine, bromine, iodine, cyano and hydroxy, or Cg-aryl-Ci-Ca -alkyl; more preferably cyclopropyl, 1-cyano-cyclopropyl or benzyl (-CH2-C6H5); Preferably, a compound of formula (IV) is a compound of formula (IV'): wherein T, Ai, A2 and Q are as defined for a compound of formula (IV), preferably wherein T is selected from T3, T8 or T9 wherein the process is characterized by the fact that the process comprises the steps 3 and 4 as described in paragraphs 0 and 0 to 0. In a preferred embodiment, the process is characterized by the fact that it comprises steps 1 to 4 described in paragraphs 0 to 0.

A preferred embodiment relates to a process for the preparation of compound (IV) where R1 - in all formulas disclosed herein in which R1 is present - represents methyl.

Another preferred embodiment relates to a process for preparing compound (IV) where n - in all formulas disclosed herein in which n is present - represents 0.

Another preferred embodiment relates to a process for the preparation of compound (IV) where Ai - in all formulas disclosed herein in which Ai is present - represents C-R2, wherein R2 represents hydrogen, fluorine, chlorine or bromine , most preferably where R2 represents chlorine.

Another preferred embodiment relates to a process for the preparation of compound (IV) where A2 - in all formulas disclosed herein in which A2 is present - represents C-R3 in which R3 represents hydrogen.

Another preferred embodiment relates to a process for preparing the compound (IV) where T - in formula (IV) and all additional formulas disclosed herein in which T is present - represents T3, T8 or T9.

Another preferred embodiment relates to a process for the preparation of compound IV where Q - in all formulas disclosed herein in which Q is present - represents optionally substituted Ca-Cs-cycloalkyl or Ce-aryl-Ci-Ca-alkyl with cyano even more preferred Q represents Cj-cycloalkyl or benzyl optionally substituted with cyano, even more preferred Q represents cyclopropyl (e.g. 1-cyano-cyclopropyl) or benzyl substituted with cyano.

Another preferred embodiment relates to a process for the preparation of compound (IV) where R1 - in all the formulas disclosed in the present document in which R1 is present - represents methyl and n - in all the formulas disclosed in the present document in which n is present present - represents 0 and Ai - in all formulas disclosed herein where Ai is present - represents C-Cl and A2 - in all formulas disclosed herein where A2 is present - represents C-H and where T - in the formula (IV) and all additional formulas disclosed herein in which T is present - represents T3, T8 or T9, and Q in all formulas disclosed herein in which Q is present represents Cj-Cs-cycloalkyl or Ce-aryl -Ci-Cs- alkyl optionally substituted with cyano.

Another preferred embodiment relates to a process for the preparation of compound IV where R1 - in all formulas disclosed herein in which R1 is present - represents methyl and T - in all formulas disclosed in this document in which T is present - represents T3, T8 or T9 and n - in all formulas disclosed herein in which n is present - represents 0 and Ai - in all formulas disclosed in this document in which Ai is present - represents C-Cl and A2 - in all formulas disclosed herein in which A2 is present - represents C-H and Q - in all formulas disclosed herein in which Q is present - represents cyclopropyl (e.g. 1-cyano-cyclopropyl) or benzyl substituted with cyano.

The present invention also relates to a process for preparing a compound of formula (6), preferably of formula (6a), comprising steps 3 and 4 as described in paragraphs 0 and 0 to 0. In a preferred embodiment, the process is characterized by the fact that it comprises steps 1 to 4 described in paragraphs 0 to 0.

The present invention also relates to a process for preparing a compound of formula (6), preferably of formula (6a), comprising steps 3 and 4 as described in paragraphs 0 and 0 to 0. Or comprising steps 1 to 4 described in paragraphs 0 to 0 and step 5 as described in paragraphs 0 to 0.

The present invention also relates to a process for preparing a compound of formula (7), preferably of formula (7a), comprising steps 3 and 4 as described in paragraphs 0 and 0 to 0. In a preferred embodiment, the process is characterized by the fact that it comprises steps 1 to 4 described in paragraphs 0 to 0.

The present invention also relates to a process for preparing a compound of formula (7), preferably of formula (7a), comprising steps 3 and 4 as described in paragraphs 0 and 0 to 0 or comprising steps 1 to 4 described in paragraphs 0 to 0 and steps 5 and 6 as described in paragraphs 0 to 0.

The present invention also relates to a process for the preparation of a compound (I), (II), (III) or (IV), in which Step 3 and Step 4 are carried out in the same solvent, preferably acetonitrile. or methylene chloride, more preferably methylene chloride.

The present invention also relates to a process for preparing a compound (I), (II), (HI) or (IV), wherein Step 3 and Step 4 are carried out as a one pot reaction in the same solvent, preferably acetonitrile or methylene chloride, more preferably methylene chloride.

The present invention also relates to a process for preparing a compound (I), (II), (III) or (IV), in which Step 2, Step 3 and Step 4 are carried out in the same solvent.

The present invention also relates to a process for preparing a compound (I), (II), (III) or (IV), in which Step 2, Step 3 and Step 4 are carried out as one one pot reaction in the same solvent.

In one aspect, the present invention also relates to the use of compounds of formula (1) prepared by a process comprising at least steps 3 and 4 as described herein to prepare a compound of formula (II), preferably of formula ( read).

Furthermore, the present invention also relates to the use of compounds of formula (1) prepared by a process comprising at least steps 3 and 4 as described herein to prepare a compound of formula (III), preferably of formula (III '), more preferably of formula (Illa).

Furthermore, the present invention also relates to the use of compounds of formula (1) prepared by a process comprising at least steps 3 and 4 as described herein to prepare a compound of formula (III''), preferably of formula (III'''), more preferably of formula (Illb).

Furthermore, the present invention also relates to the use of compounds of formula (1) prepared by a process comprising at least steps 3 and 4 as described herein to prepare a compound of formula (IV), preferably of formula (IV). ').Example 1 (Step 1)Preparation of Perfluoro-2-methyl-4-pentene (intermediate (2) In a suspension of 5 g of CsF in 100 ml of acetonitrile (CH3CN) 300 g of hexafluoropropene (HEP) were slowly introduced to maintain the reactor temperature below 30 °C. After the introduction of HFP, the mixture was heated for 8 h at 50-55 °C and cooled to 10 °C. The lower layer was separated and distilled in a yield of 260 g of Perfluoro-2-methyl-4-pentene. Yield 87%. Mp 50 °C. Example 2 (Step 2) Preparation of Perfluoro-2-methyl-2-pentene (intermediate (3) Perfluoro-2-methyl-4- Pentene 210 g and 1 g of dry CsF in 300 ml of CH3CN were heated for 8 h at 50-55 °C. The mixture was cooled to 5-10 °C and the phases were separated. The bottom phase 195 g (93 %) (pure perfluoro-2-methyl-2-pentene) was used without purification for the preparation of perfluoro-2-methyl-2-penten-)-3-triethylammonium-enolate according to example 3. Example 3 (Step 3) Preparation of 5-Fluoro-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole (intermediate (4)) A solution of 15 g (50 mmol) of perfluoro-2-methyl-2-pentene and 10.1 g of triethylamine in 40 ml of acetonitrile were mixed together and stirred for 30 min. 5.1 g (50 mmol) of propionylhydrazine was added at 0 °C to the mixture and the mixture was heated for 4 h at 40 °C. 100 ml of water was added to the reaction mixture and the product was extracted with methylene chloride. The extract was washed with water and evaporated. The residue was distilled under reduced pressure. mp 60-61 °C /I mbar. Yield 9.5 g. 1H-NMR (400 MHz, da-acetonitrile): δ = 8.2 ppm. 19F-NMR (400 MHz, CDCI3): δ = -56.3 (3F), -85.9 (3F), -113.9 (2F), 128.8 (F) ppm. Example 4 (Step 4; Preparation of N-methyl-3-pentafluoroethyl-4-trifluoromethyl-5-fluoropyrazole (compound (la)) 27.2 g (0.1 mol) of 3-pentafluoroethyl-4-trifluoromethyl-5- fluorpyrazole, 27.6 g of potassium carbonate and 28 g of methyl iodide in 200 ml of DMF were stirred at RT for 3 h. GC shows that 78% of the desired product along with 22% isomer. The mixture was diluted with water, the product was extracted with Ethyl acetate and the organic extract was washed with water and dried over MgSCH - The solvent was removed in vacuo at 300 mbar to give an oil. The mixture was distilled in vacuo to give the pure isomer with point boiling 50-55 °C / 10 mbar.19F NMR δ: 53.7 (3F), 83.9 (3F), 112.1 (2F), 125.1 (IF) ppm. Yield 20.3 g 71%, Example 5 (Step 5) Preparation of 5-Cyano-1-methyl-3-pentafluoroethyl-4-trifluoromethyl-lyf-pyrazole (intermediate (6a)) 28.6 g (0.1 mol) of 5-fluoro-1-methyl-3-pentafluoroethyl-4-trifluoromethylpyrazole (compound (Ia)) and 9.7 g (0.15 mol) of potassium cyanide are suspended in 150 ml of acetonitrile and then heated under reflux for 5 h under a protective gas atmosphere. After cooling, the precipitate (KCN, KF) was filtered off, and the solvent was removed under vacuum at 300 mbar to give a brown oil (27.8 g, 95%) which was used for the next step without any purification. 1H-NMR (400 MHz, ds-acetonitrile) : δ — 4.11 (s, 3H, CH3) ppm 19F-NMR (400 MHz, CDCI3) : δ = -56.7 (3F), -111.4 ( 3F), - 111.6 (2F) ppm. GC-MS: Retention time 2.67 min; mass (m/z); 224 (M)+.

Example 6 (Step 6) Preparation of 1-Methyl-3-pentafluoroethyl-4-trifluoromethyl-1-pyrazol-5-carboxylic acid (intermediate (7a)) 29.3 g (0.1 M) of 5-cyano-1-methyl-3-pentafluoroethyl-4-trifluoromethylpyrazole (compound (6a)) and 110 g of 10% NaOH were heated in an oil bath at 100° C for 6 h until a clear solution formed. After cooling to 5°C, the reaction mixture was slowly acidified to pH 1 by adding 37% HCl to give white crystals which were filtered off, washed with 40 ml of cold water and dried yielding 28 g (7a) of 1-methyl-3-pentafluoroethyl-4-trifluoromethylpyrazol-5-carboxylic acid) as a white solid with mp 120-122°C. 1H-NMR (400 MHz, da-acetonitrile) δ = 4.08 (s, 3H, CH3) ppm; HPLC-MS a): logP = 1.86; mass (m/z): 313.0 (M+H)+.

Example 7 (step 9) Preparation of 4-bromo-2'-methyl-51-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-1,3'-bipyrazole (intermediate (12)) 2.00 g (6 .99 mmol) of 5-fluoro-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole (compound (Ia)), 1.03 g (6.99 mmol) of 4-bromo- lH-pyrazole (compound of formula (11)) and 1.93 g of potassium carbonate are suspended in 50 ml of tetrahydrofuran p.a. The reaction mixture is heated under reflux for 16 h. The cooled reaction mixture is filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel column chromatography. This gives 0.69 g of 4-bromo-2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-21H-1,3'-bipyrazole as a colorless solid. 1H-NMR (400 MHz, da-acetonitrile): δ = 8.00 (s, 1H), 7.91 (s, 1H), 3.71 (s, 3H). HPLC-MSa>: logP = 4.14, mass (m/z) = 413 [M+H]+.

Example 8 (step 10) Preparation of 2-Chloro-N1-cyano-cyclopropyl-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H1,3'-bipyrazol-4 - yl]benzamide (compound (Illa)) 150 mg (0.36 mmol) of 4-bromo-2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'Hl, 3'-bipyrazole, 126 mg (0.36 mmol) of 2-chloro-N-(1-cyanocyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzamide, 21 mg (0.01 mmol) tetrakis( triphenylphosphin)palladium and 1.1 ml of 1 M aqueous sodium bicarbonate were mixed with 10.5 ml of isopropanol and heated under reflux for 3 h. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate. The organic phase was washed twice with water, dried over NasSO4, and filtered. The solvent is removed under reduced pressure. The residue was purified via silica gel column chromatography, yielding 98 mg of 2-chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)- 21H-1,31-bipyrazol-4-yl]benzamide as colorless solid. 1H-NMR (400 MHz, da-Acetonitrile): δ d3-Acetonitrile): δ = 8.27 (s, 1H), 8.25 (s, 1H), 7.75 (d, 1H), 7.70 (dd, 1H), 7.62 (s, 1H), 7.51 (d, 1H), 3.75 (s, 3H), 1.56-1.60 (m, 2H), 1.33- 1.36 (m, 2H). HPLC-MSa> : logP = 3.72, Mass (m/z) = 553.1 [M+H] + .

Example 9 (step 11) Preparation of 5-Azido-1-methyl-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole (intermediate (14), R1 = methyl) 5-Fluoro-1-methyl-3-pentafluoroethyl-4 -trifluoromethyl-1H-pyrazole (prepared according to steps 1 to 4; 7 mmol) is added to a mixture of dimethyl sulfoxide (DMSO) (10 ml). ) is then added to the mixture, which is kept at room temperature. The mixture is stirred overnight at RT. After the reaction is complete, a mixture of water (100 ml) and diethyl ether (100 ml) is added. The phases are separated and the aqueous phase extracted twice with diethyl ether.This compound is used without further purification.

Example 10 (step 12) Preparation of 2-Chloro-5-[1-(2-methyl-5-pentafluoroethyl-4-trifluoromethyl-2H-pyrazol-3-yl)-1H-[1,2, 3]triazol-4-yl]-benzoic acid (see intermediate (III''*)) 2-Chloro-5-ethynyl-benzoic acid methyl ester (1.13g, 5.8 mmol) and 5-Azido-1- Methyl-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole (1.80 g, 5.8 mmol) is suspended in a mixture of water and t-BuOH (30 ml). Sodium ascorbate (0.600 ml of 1 M sol. in water, freshly prepared) is added to the mixture followed by copper (II) sulfate pentahydrate (0.015 g). The resulting heterogeneous mixture is stirred vigorously for 96 hours. The reaction mixture is diluted with water and the product extracted with ethyl acetate. The organic phase is washed with brine, dried over magnesium sulfate and evaporated. The residue is subjected to silica gel column chromatography (c-HEX/EtOAc=3:1) providing the desired product 2-chloro-5-[1-(2-methyl-5-pentafluoroethyl-4-) acid methyl ester trifluoromethyl-2H-pyrazol-3-yl)-1H-[1,2,3]triazol-4-yl]-benzoic acid (53% yield). XH-RMN (400 MHz, CDC3): Δ = 8.47 (S, 1h), 8.12 (is, 1h), 8.0 (D, 1h), 7.62 (D, 1h), 3, 98 (s, 3H), 3.87 (s, 3H) ppm. LC-MS RT 2.12, 504 (M+H+), 545 (M+CH3CN+H+)

Example 11 (step 13) Preparation of 2-Chloro-5-[1-(2-methyl-5-pentafluoroethyl-4-trifluoromethyl-2H-pyrazol-3-yl)-1H-[L2,3]triazol-4 Acid -yl]- benzoic (see compound of formula (III'''')) (see intermediate (III''*)) (see compound of formula (III'''') 2-Chloro-5-[1-(2-methyl-5-pentafluoroethyl-4-trifluoromethyl-2H-) acid methyl ester pyrazol-3-yl)-1H-[1,2,3]triazol-4-yl]-benzoic acid (1.53 g, 3.0 mmol) is suspended in a mixture of water and tetrahydrofuran (1:3, 50 ml) and lithium hydroxide (0.22 g, 9.1 mmol) is added. The resulting mixture is stirred vigorously for 5 hours at 60 °C. The reaction mixture is diluted with water and acidified with hydrogen chloride (2 N).The aqueous phase is extracted twice with EtOAc, dried over MgSCM and concentrated in vacuo to provide the desired product 2-chloro-5-[1-(2-methyl-5-pentafluoroethyl-4-trifluoromethyl-2H-) acid. pyrazol-3-yl)-1H-[1,2,3]triazol-4-yl]-benzoic acid. This compound was used without further purification. HI-NMR (400 MHz, CDCl3): δ = 8.52(s , 1H), 8.18 (E, 1H), 8.09 (d, 1H), 7.66 (d, 1H), 3.88 (s, 3H) ppm. LC-MS RT 2.08, 488 (M+H+) .

Example 12 (step 8) Preparation of N-[4-chloro-3-(benzylcarbamoyl)phenyl]-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-carboxamide (compound (IIa )) 560 mg (1.79 mmol) of 1-methyl-3-pentafluoroethyl-4-trifluoromethylpyrazol-5-carboxylic acid was suspended in 10 ml of dichloromethane. The suspension was cooled to 0 °C and then subsequently mixed with 0.02 ml of N,N-dimethylformamide and 188 μl (2.15 mmol; 1.2 eq) oxalyl chloride. The reaction mixture was first stirred for 0.5 h at 0 °C and then for 3 h at room temperature. The solvent was removed under reduced pressure in a rotary evaporator. The resulting 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-carbonyl chloride was used for the subsequent synthesis step without additional final treatment. 88.7 mg (0.34 mmol) of 5-amino-N-benzyl-2-chlorobenzamide, 2.77 mg (0.02 mmol) of N,N-dimethylpyridine-4-amine (DMPA) are dissolved in 2 .5 ml of ethyl acetate. The solution is cooled to 0 °C using an ice bath and mixed with 119 μl (0.68 mmol) of W-ethyldiisopropylamine. 75.0 mg (0.22 mmol) of 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-carbonyl chloride are suspended in 2.5 ml of ethyl acetate and then added to the cooled reaction solution. The reaction mixture is heated for four hours at 50 °C and then stirred for 16 hours at room temperature. The reaction solution is diluted with 10.0 ml of ethyl acetate. The organic phase is washed three times with 1 M hydrochloric acid, twice with 1 M sodium hydroxide solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and filtered and solvent is removed under reduced pressure in a rotary evaporator. This gives 140 mg (0.17 mmol) of N-[4-chloro-3-(benzylcarbamoyl)phenyl]-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-carboxamide ( 97 %) as white solid. 1H-NMR (400 MHz, ds-acetonitrile): δ = 9.29 (bs, 1H), 7.78 (d, 1H), 7.67 (dd, 1H), 7.48 (d, 1H), 7.21-7.52 (m, 6H), 4.54 (d, 2H), 3.97 (s, 3H) ppm. HPLC-MSa): logP = 3.90 mass (m/z) = 555.1 [M+H] + . 1 The indicated mass is the peak of the isotope pattern of the [M+H]+ ion with the highest intensity. a) Note regarding determination of logP values and mass detection: The given logP values were determined in accordance with EEC Directive 79/831 Annex V.A8 by means of HPLC (High Performance Liquid Chromatography) on a column phase inversion (C18). Agilent 1100 LC System; 50*4.6 Zorbax Eclipse Plus C18 1.8 micron; eluent A: acetonitrile (0.1% formic acid); eluent B: water (0.09% formic acid); linear gradient from 10% acetonitrile to 95% acetonitrile in 4.25 min, then 95% acetonitrile for an additional 1.25 min; oven temperature 55 °C; flow rate: 2.0 ml/min. Mass detection is carried out via an Agilend MSD system.

Claims (15)

1. Process for the synthesis of 5-fluoro-1H-pyrazoles of general formula (I) characterized by the fact that R1 represents (C1-C4)-alkyl; and the process comprises the steps of - reacting intermediate (3) with (C1-C4)-alkylCONHNH2 to prepare 3-perfluoroethyl-4-perfluoromethyl-5-fluoro-pyrazole (intermediate (4)) - reacting intermediate (4) with a (C1-C4)-alkylating agent, preferably a methylating agent to prepare a compound of formula (I) (herein referred to as step 4). 2. Process for the synthesis of 5-fluoro-1H-pyrazoles of general formula (I), according to claim 1, characterized in that it comprises the steps of reacting hexafluoropropene (intermediate (1)) in the presence of a catalyst to form its perfluoro-4-methyl-2-pentene dimer (intermediate (2)) - isomerize perfluoro-4-methyl-2-pentene into perfluoro-2-methyl-2-pentene (intermediate (3)) - reacting a compound (3) with (C1-C4)-alkyl-CONHNH2 to prepare 3-perfluoroethyl-4-perfluoromethyl-5-fluoro-pyrazole (intermediate (4)) - reacting intermediate (4) with a (C1-C4) alkylating agent, preferably a methylating agent, to prepare a compound of formula (I). 3. Process, characterized by the fact that it is for the preparation of a compound of formula (IV) wherein R1 is C1-C4-alkyl; and A1 is C-R2; and R2 is hydrogen, fluorine, chlorine, bromine, CN, NO2, C1-C6-optionally halogenated alkyl, C1-C4-optionally halogenated alkoxy, C1-C4-optionally halogenated alkylsulfonyl, C1-C4-optionally halogenated alkylsulfinyl or N-cyclopropylaminocarbonyl (-C(=O)-NH-cyclopropyl); preferably hydrogen, fluorine, chlorine, bromine, CN, NO2, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n-propoxy, 1-methylethoxy, fluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy , trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, pentafluoroethoxy, methylsulfonyl, methylsulfinyl, trifluoromethylsulfonyl, trifluoromethylsulfinyl or N-cyclopropylaminocarbonyl, more preferably hydrogen, fluorine, chlorine, bromine, CN, NO2, methyl , fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, or pentafluoroethoxy, preferably hydrogen, fluorine, chlorine, bromine, the most preferable being chlorine; and A2 is C-R3 or nitrogen; and R3 is hydrogen, methyl, fluorine or chlorine, preferably hydrogen; and T represents one of the T1-T9 groups listed below, where the bond to the pyrazole leader group is marked with an asterisk *, *-C(=O)-NH-T9; and R6 independently of each other represents halogen, cyano, nitro, amino or optionally substituted C1-C6-alkyl, C1-C6-alkyloxy, C1-C6-alkylcarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6 - alkylsulfonyl, and n represents the values 0-2, preferably 0, with the proviso that n is 0 or 1 in T5, T6 and T8 and provided that n is 0 in T7; and Q is hydrogen, cyano, hydroxy, formyl or one of the groups C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C9-cycloalkyl, C3-C9-heterocycloalkyl, C1-C4-alkoxy, C4-C15-alkylcycloalkyl, C4-C15-cycloalkylalkyl, C1-C6-hydroxyalkyl, C6-aryl-C1-C3-alkyl, C5-C6-heteroaryl-C1-C3-alkyl, C1-C4-aminoalkyl, aminocarbonyl-C1- C4-alkyl or C1-C4-alkyl-amino-C1-C4-alkyl which are optionally substituted with one, two, three, four or five, preferably with one or two, more preferably with one, substituents independently selected from the group consisting of hydroxy, nitro, amino, halogen, C1-C3-alkoxy, cyano, hydroxycarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkylcarbamoyl, C4-C6-cycloalkylcarbamoyl and optionally independently with one, two or three substituents selected from from the group consisting of halogen, cyano, nitro, hydroxycarbonyl, C1-C2-alkylcarbamoyl, C1-C2-alkyl, C1-C2-halogenated alkyl and phenyl substituted with C1-C2-alkoxy; preferably Q is C3-C6-cycloalkyl, or C3-C6-cycloalkyl which is substituted with at least one substituent selected from the group consisting of chlorine, fluorine, bromine, iodine, cyano and hydroxy, or C6-aryl-C1-C3 -alkyl; more preferably cyclopropyl, 1-cyano-cyclopropyl or benzyl (-CH2-C6H5); said process comprising defined in claim 1 or 2. 4. Process according to claim 3, characterized by the fact that a compound of formula (IV) is a compound of formula (II) wherein R1, A1, R2, A2, R3 and Q are as defined in claim 3, preferably of formula (II') wherein A1, R2, A2, R3 and Q are as defined in this claim for compounds of formula (II). 5. Process according to claim 3 or 4, characterized in that a compound of formula (IV) is compound (IIa) 6. Process, according to any one of claims 3 to 5, characterized by further comprising the steps of: - reacting the compound (I) with a cyano donor to prepare the intermediate of formula (6) wherein R1 is (C1-C4)-alkyl; and - reacting the compound (6) with a strong inorganic base in a first hydrolysis step followed by addition of an inorganic acid in a second hydrolysis step to prepare the intermediate of formula (7) wherein R1 is (C1-C4)-alkyl; and - reacting a compound of formula (8) or its salt (8') with an activated form (7') of the compound (7) wherein R1, A1, A2, and Q are as defined in claim 3 and GS is any leaving group, to prepare a compound of formula (II). 7. Process according to claim 3, characterized by the fact that a compound of formula (IV) is a compound of formula (III) wherein R1 is (C1-C4)-alkyl; and A1 is C-R2; R2 is hydrogen, fluorine, chlorine, bromine, CN, NO2, C1-C6-optionally halogenated alkyl, C1-C4-optionally halogenated alkoxy, C1-C4-optionally halogenated alkylsulfonyl, C1-C4-optionally halogenated alkylsulfinyl or N-cyclopropylaminocarbonyl ( -C(=O)-NH-cyclopropyl); preferably hydrogen, fluorine, chlorine, bromine, CN, NO2, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n-propoxy, 1-methylethoxy, fluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy , trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, pentafluoroethoxy, methylsulfonyl, methylsulfinyl, trifluoromethylsulfonyl, trifluoromethylsulfinyl or N-cyclopropylaminocarbonyl, more preferably hydrogen, fluorine, chlorine, bromine, CN, NO2, methyl , fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, or pentafluoroethoxy, preferably hydrogen, fluorine, chlorine, bromine, the most preferable being chlorine; and A2 is C-R3 or nitrogen; R3 is hydrogen, methyl, fluorine or chlorine, preferably hydrogen; and Q is hydrogen, cyano, hydroxy, formyl or one of the groups C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C9-cycloalkyl, C3-C9-heterocycloalkyl, C1-C4-alkoxy, C4-C15-alkylcycloalkyl, C4-C15-cycloalkylalkyl, C1-C6-hydroxyalkyl, C6-aryl-C1-C3-alkyl, C5-C6-heteroaryl-C1-C3-alkyl, C1-C4-aminoalkyl, aminocarbonyl-C1- C4-alkyl or C1-C4-alkyl-amino-C1-C4-alkyl which are optionally substituted with one, two, three, four or five, preferably with one or two, more preferably with one, substituents independently selected from the group consisting of hydroxy, nitro, amino, halogen, C1-C3-alkoxy, cyano, hydroxycarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkylcarbamoyl, C4-C6-cycloalkylcarbamoyl and optionally independently with one, two or three substituents selected from from the group consisting of halogen, cyano, nitro, hydroxycarbonyl, C1-C2-alkylcarbamoyl, C1-C2-alkyl, C1-C2-halogenated alkyl and phenyl substituted with C1-C2-alkoxy; preferably Q is C3-C6-cycloalkyl, or C3-C6-cycloalkyl which is substituted with at least one substituent selected from the group consisting of chlorine, fluorine, bromine, iodine, cyano and hydroxy, or C6-aryl-C1-C3 -alkyl; more preferably cyclopropyl, 1-cyano-cyclopropyl or benzyl (-CH2-C6H5); T represents one of the 5-membered heteroaromatics T1-T8 listed below, where the bond to the pyrazole leader group is marked with an asterisk *, wherein R6 independently of each other represents halogen, cyano, nitro, amino or optionally substituted C1-C6-alkyl, C1-C6-alkyloxy, C1-C6-alkylcarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1- C6-alkylsulfonyl, n represents the values 0-2, preferably 0, with the proviso that n is 0 or 1 in T5, T6 and T8 and provided that n is 0 in T7. 8. Process according to claim 7, characterized by the fact that a compound of formula (III) is the compound of formula (III') more preferably the compound (IIIa) or the compound (IIIb), which is the compound of formula (III where n is 0, A1 represents C-Cl, A2 represents CH and Q represents cyanocyclopropyl. 9. Process, according to claim 7 or 8, characterized by comprising Steps 1 to 4, as defined in claim 1, and further comprising the steps of - reacting a compound of formula (I) with an intermediate of formula (11 ) by means of nucleophilic substitution of the fluoride at the ring position of a compound of formula (I) (herein referred to as Step 9) wherein R1 is (C1-C4)-optionally halogenated alkyl or optionally halogenated cyclopropyl; and U represents bromine, iodine, triflate, boronic acid, boronic ester or trifluoroboronate; and the five-membered cycles of E1-E3, carbon and nitrogen represent the five-membered heterocycles selected from the group consisting of wherein R6 independently of each other represents halogen, cyano, nitro, amino or optionally substituted C1-C6-alkyl, C1-C6-alkyloxy, C1-C6-alkylcarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1- C6-alkylsulfonyl, n represents the values 0-2, preferably 0, with the proviso that n is 0 or 1 in T5, T6 and T8 and provided that n is 0 in T7; to prepare an intermediate of formula (12); and - reacting a compound of formula (12) and a compound of formula (13) (herein referred to as Step 10) wherein R1, A1, A2, and Q are as defined for a compound of formula (III) and U represents bromine, iodine, triflate, boronic acid, boronic ester or trifluoroboronate; and the five-membered cycles of E1-E3, carbon and nitrogen represent the five-membered heterocycles selected from the group consisting of wherein R6 independently of each other represents halogen, cyano, nitro, amino or optionally substituted C1-C6-alkyl, C1-C6-alkyloxy, C1-C6-alkylcarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1- C6-alkylsulfonyl, n represents the values 0-2, preferably 0, with the proviso that n is 0 or 1 in T5, T6 and T8 and provided that n is 0 in T7; and M represents bromine, iodine or triflate when U represents a boronic acid, boronic ester or trifluoroboronate; or M represents a boronic acid, boronic ester or trifluoroboronate when U represents bromine, iodine or triflate to prepare a compound of formula (III). 10. Process according to claim 3, characterized by the fact that a compound of formula (IV) is a compound of formula (III'') preferably of formula (III''') 11. Process according to claim 10, characterized by the steps as defined in claim 1 or 2, optionally further comprising the steps as defined in claim 9; or optionally further comprising the steps of reacting a compound of formula (I) and an azide donor to prepare intermediate (14) wherein R1 is as defined for a compound of formula (III); and - reacting the intermediate (14) with an intermediate of formula (15) to give an intermediate (III''*) (herein referred to as Step 12) wherein R1, R6, A1, and A2 are as defined for the compound (III), n is 0 or 1, and GP is any carboxylic group protecting group such as C1-C6-alkyl (e.g., methyl). 12. Process according to any one of claims 1 to 11, characterized by the fact that R1 is methyl. 13. Process according to any one of claims 1 to 12, characterized in that steps 3 and 4 are carried out in the same solvent, preferably acetonitrile or methylene chloride, more preferably methylene chloride. 14. Process according to any one of claims 1 to 13, characterized in that steps 3 and 4 are carried out in the same solvent selected from the group consisting of acetonitrile or methylene chloride. 15. Use of intermediate (4), characterized in that it is for the preparation of a compound selected from the group consisting of a compound of formula (I), (6), (7), (I), (Ia), ( II), (IIa), (III), (III'), (IIIa), (III''), (III'''), (IIIb), and (IV), which are as defined in any of claims 1 to 14, a compound of formula (6a) and a compound of formula (7a)