Process for the preparation of amino-pyrazoles

Abstract

The present invention discloses an efficient preparation of 3-amino-1-((2,6-di-substituted)phenyl)pyrazoles.

Claims

1. Process for preparation of a compound of formula (I) ##STR00021## wherein R.sup.1, R.sup.2 and R.sup.3 represent independently of one another halogen, cyano, nitro, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenoxy, (C.sub.2-C.sub.6)alkynoxy, (C.sub.3-C.sub.6)cycloalkoxy, phenyl(C.sub.1-C.sub.6)alkyl, aryl, cyano(C.sub.1-C.sub.6)alkyl, halogen(C.sub.1-C.sub.6)alkyl with 1-9 identical or different halogen atoms, halogen(C.sub.3-C.sub.6)cycloalkyl with 1-9 identical or different halogen atoms, halogen(C.sub.1-C.sub.6)alkoxy with 1-9 identical or different halogen atoms, (C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylthio, halogen(C.sub.1-C.sub.6)alkylthio with 1-9 identical or different halogen atoms, (C.sub.1-C.sub.6)alkylsulfinyl, halogen(C.sub.1-C.sub.6)alkylsulfinyl with 1-9 identical or different halogen atoms, (C.sub.1-C.sub.6)alkylsulfonyl, halogen(C.sub.1-C.sub.6)alkcylsulfonyl with 1-9 identical or different halogen atoms, n represents a number from the group consisting of 0, 1 and 2, where for n >1 R.sup.3 may be identical or different and R.sup.4 and R.sup.5 represent independently of one another hydrogen, cyano, nitro, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkoxy, phenyl(C.sub.1-C.sub.6)alkyl, aryl, heteroaryl, cyano(C.sub.1-C.sub.6)alkyl, halogen(C.sub.1-C.sub.6)alkyl with 1-9 identical or different halogen atoms, halogen(C.sub.1-C.sub.6)alkoxy with 1-9 identical or different halogen atoms, (C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylthio, halogen(C.sub.1-C.sub.6)alkylthio with 1-9 identical or different halogen atoms, (C.sub.1-C.sub.6)alkylsulfinyl, halogen(C.sub.1-C.sub.6)alkylsulfinyl with 1-9 identical or different halogen atoms, (C.sub.1-C.sub.6)alkylsulfonyl, halogen(C.sub.1-C.sub.6)alkylsulfonyl with 1-9 identical or different halogen atoms comprising (i) reacting, a compound of formula (IV) or a salt thereof ##STR00022## in which R.sup.1, R.sup.2, R.sup.3 and n have the above mentioned meanings, with a compound of formula (V) as either E- or Z-isomer ##STR00023## in which-R.sup.4 and R.sup.5 have the above mentioned meanings, in the presence of a catalytic amount of base, to obtain a compound of formula (III) ##STR00024## in which-R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and n have the above mentioned meanings, and (ii) said compound of formula (III) is, cyclized in the presence of an acid to provide a compound of formula (II) ##STR00025## in which-R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and n have the above mentioned meanings, and (iii) said compound of formula (II) is, converted in the presence of an oxidant, a catalytic amount of an iodide source and an organic acid, to a compound of formula (I).

2. Process according to claim 1 wherein R.sup.1 represents fluoro R.sup.2 represents fluoro n represents 0, R.sup.4 represents hydrogen and R.sup.5 represents hydrogen.

3. Process according to claim 2 additionally comprising reacting the compound obtained by the process according to claim 2 with a compound of formula (VI) ##STR00026## wherein M represents halogen, hydroxy, alkoxy, alkylsulphanyl, acyloxy, N-heterocyclyl or represents hydroxyl, to obtain the compound of formula (VII) ##STR00027##

4. Process according to claim 1, comprising (ii) and (iii).

5. Process according to claim 4, comprising (iii).

6. The compound of formula ##STR00028## and/or a salt thereof.

7. Process for preparation of the compound according to claim 6 wherein the compound of formula ##STR00029## or a salt thereof is reacted with acrylonitrile of formula ##STR00030## in the presence of a catalytic amount of base.

8. Process according to claim 1, wherein R.sup.1, R.sup.2 and R.sup.3 represent independently of one another bromo, chloro, fluoro, cyano, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.3)alkylthio, n represents a number from the group consisting of 0 and 1, where for n=1 R.sup.3 is preferred in position 4 and R.sup.4 and R.sup.5 represent independently of one another hydrogen, cyano, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, trifluoromethyl, (C.sub.1-C.sub.3)alkylthio.

9. Process according to claim 1, wherein R.sup.1, R.sup.2 and R.sup.3 represent independently of one another chloro, fluoro, tifluoromethyl, n represents a number from the group consisting of 0 and 1, where for n=1 R.sup.3 is in position 4 and R.sup.4 and R.sup.5 represent hydrogen.

10. Process according to claim 1, wherein R.sup.1, R.sup.2 and R.sup.3 represent independently of one another halogen, cyano, nitro, (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.3)alkoxy, phenyl(C.sub.1-C.sub.3)alkyl, aryl, cyano(C.sub.1-C.sub.3)alkyl, halogen(C.sub.1-C.sub.3)alkyl with 1-7 identical or different halogen atoms, halogen(C.sub.1-C.sub.3)alkoxy with 1-7 identical or different halogen atoms, (C.sub.1-C.sub.3)alkoxycarbonyl(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkylthio, halogen(C.sub.1-C.sub.3)alkylthio with 1-7 identical or different halogen atoms, (C.sub.1-C.sub.3)alkylsulfinyl, (C.sub.1-C.sub.3)alkylsulfonyl, n represents a number from the group consisting of 0, 1 and 2, where for n>1, R.sup.3 may be identical or different and R.sup.4 and R.sup.5 represent independently of one another hydrogen, cyano, (C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.3)alkoxy, phenyl(C.sub.1-C.sub.3)alkyl, aryl, heteroaryl, cyano(C.sub.1-C.sub.3)alkyl, halogen(C.sub.1-C.sub.3)alkyl with 1-7 identical or different halogen atoms, halogen(C.sub.1-C.sub.3)alkoxy with 1-7 identical or different halogen atoms, (C.sub.1-C.sub.3)alkoxycarbonyl(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkylthio, halogen(C.sub.1-C.sub.3)alkylthio with 1-9 identical or different halogen atoms.

Description

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

(1) In a preferred embodiment of the invention R.sup.1, R.sup.2 and R.sup.3 represent independently of one another halogen, cyano, nitro, (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, (C.sub.2-C.sub.3)alkynyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.3)alkoxy, phenyl(C.sub.1-C.sub.3)alkyl, aryl, cyano(C.sub.1-C.sub.3)alkyl, halogen(C.sub.1-C.sub.3)alkyl with 1-7 identical or different halogen atoms, halogen(C.sub.1-C.sub.3)alkoxy with 1-7 identical or different halogen atoms, (C.sub.1-C.sub.3)alkoxycarbonyl(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkylthio, halogen(C.sub.1-C.sub.3)alkylthio with 1-7 identical or different halogen atoms, (C.sub.1-C.sub.3)alkylsulfinyl, (C.sub.1-C.sub.3)alkylsulfonyl, n represents a number from the group consisting of 0, 1 and 2, where for n>1 R.sup.3 may be identical or different and R.sup.4 and R.sup.5 represent independently of one another hydrogen, cyano, (C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.3)alkoxy, phenyl(C.sub.1-C.sub.3)alkyl, aryl, heteroaryl, cyano(C.sub.1-C.sub.3)alkyl, halogen(C.sub.1-C.sub.3)alkyl with 1-7 identical or different halogen atoms, halogen(C.sub.1-C.sub.3)alkoxy with 1-7 identical or different halogen atoms, (C.sub.1-C.sub.3)alkoxycarbonyl(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkylthio, halogen(C.sub.1-C.sub.3)alkylthio with 1-9 identical or different halogen atoms.

(2) When R.sup.1, R.sup.2, R.sup.3, R.sup.4 or R.sup.5 represent aryl, it is a phenyl or naphthyl group, and is unsubstituted or is substituted with 1-3 substituents independently chosen from the following list: C.sub.1-3-alkyl groups (which may be straight-chained, cyclic, or branched), C.sub.1-3-haloalkyl groups (which may be straight-chained, cyclic, or branched), C.sub.1-3-alkoxy groups (which may be straight-chained, cyclic, or branched), halogens, nitro groups, nitrile groups, or groups of the structure C(O)NR.sup.aR.sup.b (where R.sup.a and R.sup.b are independently chosen between H and a C.sub.1-3-alkyl group (which may be straight-chained or branched)).

(3) When R.sup.4 or R.sup.5 represent heteroaryl, it is a 4-, 5-, or 6-membered ring containing 1-4 heteroatoms independently chosen between O, N, and S, and is in particular selected from the group consisting of

(4) ##STR00008##
which may be connected to the rest of the molecule through any of the ring carbon atoms. This heterocycle is unsubstituted or is substituted with 1-3 substituents independently chosen from the following list: C.sub.1-3-alkyl groups (which may be straight-chained, cyclic, or branched), C.sub.1-3-haloalkyl groups (which may be straight-chained, cyclic, or branched), C.sub.1-3-alkoxy groups (which may be straight-chained or branched), nitriles, nitro groups, halogens, or groups of the structure C(O)NR.sup.aR.sup.b (where R.sup.a and R.sup.b are independently chosen between H or a C.sub.1-3-alkyl group (which may be straight-chained or branched)).

(5) In a particular preferred embodiment of the invention R.sup.1, R.sup.2 and R.sup.3 represent independently of one another bromo, chloro, fluoro, cyano, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.3)alkylthio, n represents a number from the group consisting of 0 and 1, where for n=1 R.sup.3 is preferred in position 4 and R.sup.4 and R.sup.5 represent independently of one another hydrogen, cyano, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, trifluoromethyl, (C.sub.1-C.sub.3)alkylthio.

(6) In a very particular preferred embodiment of the invention R.sup.1, R.sup.2 and R.sup.3 represent independently of one another chloro, fluoro, trifluoromethyl, n represents a number from the group consisting of 0 and 1, where for n=1 R.sup.3 is in position 4 and R.sup.4 and R.sup.5 represent hydrogen.

(7) In another very particular preferred embodiment of the invention R.sup.1 represents fluoro, R.sup.2 represents fluoro, n represents 0, R.sup.4 represents hydrogen and R.sup.5 represents hydrogen.

(8) 3-Amino-1-((2,6-di-substituted)phenyl)pyrazoles of formula (I) are prepared from 5-amino-1-((2,6-di-substituted)phenyl)dihydropyrazoles of formula (II)

(9) ##STR00009##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and n have the same definitions as provided above for the compounds of formula (I) via oxidation with an oxidative system consisting of an oxidant, an iodide source and an acid.

(10) The oxidation of dihydropyrazoles of formula (II) to pyrazoles of formula (I) may be performed neat or in the presence of a solvent. In reactions where a solvent is used, solvents such as amides (e.g. DMF, DMAc, NMP), nitriles (e.g. MeCN, PrCN), alcohols (e.g. MeOH, EtOH, (i)-PrOH, (n)-BuOH), ethers (e.g. Et.sub.2O, 2-methyltetrahydrofuran, THF, MTBE), esters (e.g. MeOAc, EtOAc, (i)-PrAc, BuOAc), carbonates (e.g. dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate), aromatic hydrocarbons or halogenated derivatives thereof (e.g. toluene, xylene, chlorobenzene), hydrocarbons or halogenated derivatives thereof (e.g. methylcyclohexane, heptane, dichloromethane, dichloroethane), sulfoxides (e.g. dimethylsulfoxide, sulfolane), ketones (e.g. acetone, methylisobutylketone), or water may be used either singly or as a mixture of two or more thereof. The use of nitriles, alcohols, water, or mixtures thereof is preferred. Especially preferred is the use of MeOH, EtOH, (i)-PrOH, (n)-BuOH, MeCN, PrCN, water, or mixtures of two or more of these solvents.

(11) When the oxidation is performed in a solvent or a mixture of solvents, the concentration of the dihydropyrazoles of formula (II) in the resulting mixture may lie between 1%-50% (w/w), although a range from 10%-40% (w/w) is preferred.

(12) The oxidant may be an inorganic peroxide, such as H.sub.2O.sub.2 or an organic peroxide like alkyl hydroperoxides or alkylaryl hydroperoxides. Preferred oxidant is H.sub.2O.sub.2. In general 1 equiv. of the dihydropyrazoles of formula (II) is reacted with 0.9 equiv. to 5 equiv. of the oxidant, preferably with 1-3 equiv. and more preferably with 1-2 equiv. of the oxidant.

(13) The iodide source may be an inorganic iodide salt, such as NaI, KI, CsI or AgI or another iodide containing compound like HI. Preferred iodide source is NaI, KI or HI. The reaction stoichiometry between the dihydropyrazoles of formula (II) and the iodide source may range from 0.01 equiv. to 0.5 equiv., although a range from 0.02-0.5 equiv. is preferred and a range from 0.02-0.1 equiv. is particularly preferred.

(14) The acid may be a mineralic acid (e.g. HI), carboxylic acid (e.g. formic acid, acetic acid) or a sulfonic acid (e.g. MsOH, pTsOH). Preferred acid is a carboxylic acid or HI. In general 1 equiv. of the dihydropyrazoles of formula (II) is reacted with 0.1 equiv. to 1 equiv. of the acid, preferably with 0.2-1 equiv. and more preferably with 0.2-0.8 equiv. of the acid.

(15) The reaction may be carried out between 40 C. and 180 C., and is preferably carried out between 10 C. and 120 C. and particular preferably between 10 C. and 90 C.

(16) The reaction may be carried out between 0.1 bar and 10 bar pressure, and is preferably carried out between 0.8 bar and 1.2 bar.

(17) 5-Amino-1-((2,6-di-substituted)phenyl)dihydropyrazoles of formula (II) are prepared from -cyanoethyl hydrazines of formula (III)

(18) ##STR00010##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and n have the same definitions as provided above for the compounds of formula (II) via acid-mediated cyclization.

(19) The cyclization of -cyanoethyl hydrazines of formula (III) to dihydropyrazoles of formula (II) may be performed neat or in the presence of a solvent. In reactions where a solvent is used, solvents such as amides (e.g. DMF, DMAc, NMP), nitriles (e.g. MeCN, PrCN), alcohols (e.g. MeOH, EtOH, (i)-PrOH, (n)-BuOH), ethers (e.g. Et.sub.2O, 2-methyltetrahydrofuran, THF, MTBE), esters (e.g. MeOAc, EtOAc, (i)-PrAc, BuOAc), carbonates (e.g. dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate), aromatic hydrocarbons or halogenated derivatives thereof (e.g. toluene, xylene, chlorobenzene), hydrocarbons or halogenated derivatives thereof (e.g. methylcyclohexane, heptane, dichloromethane, dichloroethane), sulfoxides (e.g. dimethylsulfoxide, sulfolane), ketones (e.g. acetone, methylisobutylketone), or water may be used either singly or as a mixture of two or more thereof. The use of no solvent or the use of nitriles, alcohols, ethers, esters, water, or mixtures thereof is preferred. Especially preferred is the use of nitriles, ethers, esters or water, or mixtures of two or more of these solvents.

(20) When the cyclization is performed in a solvent or a mixture of solvents, the concentration of the dihydropyrazoles of formula (II) in the resulting mixture may lie between 1%-50% (w/w), although a range from 10%-40% (w/w) is preferred.

(21) The acid may be a mineral acid (e.g., HCl, H.sub.2SO.sub.4, H.sub.3PO.sub.4) or an organic acid (e.g., CF.sub.3CO.sub.2H, CH.sub.3SO.sub.3H, CF.sub.3SO.sub.3H, pTsOH, MsOH). Preferred acid is a mineral acid like HCl or H.sub.2SO.sub.4. In general 1 equiv. of the -cyanoethyl hydrazine of formula (III) is reacted with 0.01 equiv. to 10 equiv. of the acid, preferably with 0.1-5 equiv. and more preferably with 0.1-2 equiv. of the acid.

(22) The reaction may be carried out between 40 C. and 180 C., and is preferably carried out between 10 C. and 150 C. and particular preferably between 40 C. and 120 C.

(23) The reaction may be carried out between 0.1 bar and 10 bar pressure, and is preferably carried out between 0.8 bar and 1.2 bar.

(24) -Cyanoethyl hydrazines of formula (III) are prepared from (2,6-di-substituted)phenyl hydrazines of formula (IV) and acrylonitriles of formula (V)

(25) ##STR00011##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and n have the same definitions as provided above for the compounds of formula (III) via base-catalyzed Michael addition.

(26) The reaction may be performed using a free hydrazine of formula (IV) or using a salt of such a hydrazine. When such a salt is used, it may be a hydrochloride, hydrobromide, sulfate, acetate, trifluoroacetate, methanesulfonate, or 4-toluenesulfonate salt of a hydrazine of formula (IV). Preferred is the use of a free hydrazine or a hydrochloride salt thereof. Many of these hydrazines of formula (IV) are commercially available or easy to synthesize, e.g. via diazotization of the corresponding phenyl halide and subsequent reduction.

(27) One skilled in the art will further be aware that acrylonitriles of formula (V) can exist as E- or Z-isomers, and that these isomers can interconvert. If desired, these isomers can generally be separated by standard isolation techniques (e.g., chromatography, recrystallization, distillation). The present invention includes the use of either of these isomeric forms and mixtures thereof. Many of these acrylonitriles of formula (V) are commercially available.

(28) The Michael addition of (2,6-di-substituted)phenyl hydrazines of formula (IV) and acrylonitriles of formula (V) may be performed neat or in the presence of a solvent. In reactions where a solvent is used, solvents such as amides (e.g. DMF, DMAc, NMP), nitriles (e.g. MeCN, PrCN), alcohols (e.g. MeOH, EtOH, (i)-PrOH, (n)-BuOH), ethers (e.g. Et.sub.2O, 2-methyltetrahydrofuran, THF, MTBE), esters (e.g. MeOAc, EtOAc, (i)-PrAc, BuOAc), carbonates (e.g. dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate), aromatic hydrocarbons or halogenated derivatives thereof (e.g. toluene, xylene, chlorobenzene), hydrocarbons or halogenated derivatives thereof (e.g. methylcyclohexane, heptane, dichloromethane, dichloroethane), sulfoxides (e.g. dimethylsulfoxide, sulfolane) or ketones (e.g. acetone, methylisobutylketone) may be used either singly or as a mixture of two or more thereof. The use of no solvent or of nitriles as solvents is preferred.

(29) When the Michael addition is performed in a solvent or a mixture of solvents, the concentration of the dihydropyrazoles of formula (II) in the resulting mixture may lie between 1%-50% (w/w), although a range from 10%-40% (w/w) is preferred.

(30) The base may be an inorganic base (e.g., NaOH, KOH) as water containing solution or neat or an organic base (e.g., Et.sub.3N, DIPEA, alkoxides). Preferred base is an inorganic base like NaOH or KOH. In general 1 equiv. of the phenyl hydrazine of formula (IV) is reacted with about 1 equiv. of the acrylonitrile of formula (V) in the presence of 0.01 equiv. to 0.8 equiv. of the base, preferably in the presence of 0.01-0.5 equiv. and more preferably in the presence of 0.01-0.2 equiv. of the base.

(31) The reaction may be carried out between 40 C. and 180 C., and is preferably carried out between 10 C. and 120 C. and particular preferably between 10 C. and 100 C.

(32) The reaction may be carried out between 0.1 bar and 10 bar pressure, and is preferably carried out between 0.8 bar and 1.2 bar.

(33) The present invention is also directed to a process for the preparation of the compound of formula (VII)

(34) ##STR00012##
which can be obtained by reacting the compound of formula (Ia)

(35) ##STR00013##
obtained by a process according to the present invention,
with a compound of formula (VI)

(36) ##STR00014##
in which M represents halogen, hydroxy, alkoxy, alkylsulphanyl, acyloxy, N-heterocyclyl (e.g. imidazolyl) or represents hydroxyl and preferably represents halogen, more preferably chlorine.

(37) Compounds of formula (VI) can be preactivated or be activated in situ. Compounds of formula (VI) can be employed, for example, as acid halides (e.g. M=chlorine). In this case, the reaction is advantageously carried out at elevated temperatures without base or at lower temperatures in the presence of a base such as, for example, triethylamine or sodium hydroxide. However, it is also possible to use carboxylic acids (M=OH) in the presence of coupling reagents such as, for example dicyclohexylcarbodiimide and additives such as 1-hydroxy-1-H-benzotriazole (W. Knig, R. Geiger, Chem. Ber. 1970, 103, 788). Use may furthermore be made of coupling reagents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1,1-carbonyl-1H-imidazole, O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate and similar compounds. Suitable coupling reagents for carrying out the preparation process are, in principle, all compounds which allow an amide bond to be formed (cf., for example, E. Valeur, M. Bradley Chem. Soc. Rev. 2009, 38, 606; S.-Y. Han, Y.-A. Kim Tetrahedron 2004, 60, 2447). Use may furthermore also be made of symmetric or mixed anhydrides for preparing the compound of formula (VII) (G. W. Anderson, J. E. Zimmerman, F. M. Calahan, J. Am. Chem. Soc. 1967, 89, 5012). Here, various chloroformic esters may be employed, for example isobutyl chloroformate and sec-butyl chloroformate. Isovaleryl chloride and pivaloyl chloride, for example, may likewise be used (cf. WO 2014/53450 A1).

(38) The compound of formula (VII) is known to be useful for controlling animal pests including arthropods, insects and nematodes, cf. WO 2014/053450 A1.

EXAMPLES

Example 1: Synthesis of 3-(N-amino-2,6-difluoro-anilino)propanenitrile

(39) ##STR00015##

(40) A solution of (2,6-difluorophenyl)hydrazine (88.6 g, 0.62 mol) in 250 mL MeCN was treated with 2.6 mL (0.05 mol) NaOH (50%) and heated to 50 C. Subsequently, acrylonitrile (34.3 g, 0.65 mol) was added dropwise over a period of 20 min. The temperature was kept below 60 C. After stirring for 1 h at 50 C., most of the MeCN was distilled off. The reaction was diluted with 200 mL of water extracted three times with 150 mL EtOAc. The combined organic phases were washed once with brine, dried over Na.sub.2SO.sub.4 and the solvent was evaporated to give 3-(N-amino-2,6-difluoro-anilino)propanenitrile (110.0 g, 90% yield, 96.2% HPLC-purity) as white solid.

(41) .sup.1H NMR (CD.sub.3CN) (ppm)=7.1-7.2 (m, 1H), 6.9-7.0 (m, 2H), 4.1 (br s, 2H), 3.4 (t, 2H), 2.7 (t, 2H).

Example 2: Synthesis of 2-(2,6-difluorophenyl)-3,4-dihydropyrazol-5-amine

(42) ##STR00016##

(43) A solution of 3-(N-amino-2,6-difluoro-anilino)propanenitrile (110.0 g, 0.56 mol) in 200 mL MeCN was treated with 94 mL aq. HCl (32%) and heated to reflux for 5 h. The reaction mixture was cooled to 50 C. and 192 mL aq. NaOH (20%) were added. After stirring for 15 min at 50 C., the phases were separated and the organic phase was dried over Na.sub.2SO.sub.4. The solvent of the organic phase was removed under vacuum and the remaining solid was recrystallized from toluene to give 2-(2,6-difluorophenyl)-3,4-dihydropyrazol-5-amine (104.9 g, 95% yield, 96.8% HPLC-purity) as a light beige solid.

(44) .sup.1H NMR (CD.sub.3CN) (ppm)=7.0-7.1 (m, 1H), 6.8-6.9 (m, 2H), 4.4 (br s, 2H), 3.6 (t, 2H), 2.8 (t, 2H).

Example 3: Synthesis of 2-(2,6-difluorophenyl)-3,4-dihydropyrazol-5-amine via 3-(N-amino-2,6-difluoro-anilino)propanenitrile as One-Pot Procedure

(45) ##STR00017##

(46) A solution of (2,6-difluorophenyl)hydrazine (35.4 g, 0.25 mol) in 100 mL MeCN was treated with 1.0 mL (0.02 mol) NaOH (50%) and heated to 50 C. Subsequently, acrylonitrile (13.7 g, 0.26 mol) was added dropwise over a period of 20 min. The temperature was kept below 60 C. After stirring for 1 h at 50 C., 38 mL aq. HCl (32%) were added and the reaction was heated to reflux for 5 h. The reaction mixture was cooled to 50 C. and 77 mL aq. NaOH (20%) were added. After stirring for 15 min at 50 C., the phases were separated and the organic phase was dried over Na.sub.2SO.sub.4. The solvent of the organic phase was removed under vacuum and the remaining solid was recrystallized from toluene to give 2-(2,6-difluorophenyl)-3,4-dihydropyrazol-5-amine (41.9 g, 85% yield, 96.5% HPLC-purity) as a light beige solid.

(47) .sup.1H NMR (CD.sub.3CN) (ppm)=7.0-7.1 (m, 1H), 6.8-6.9 (m, 2H), 4.4 (br s, 2H), 3.6 (t, 2H), 2.8 (t, 2H).

Comparative Example 3: Synthesis of 2-(2,6-difluorophenyl)-3,4-dihydropyrazol-5-amine

(48) ##STR00018##

(49) A solution of acrylonitrile (345 mg, 6.4 mmol) in 5 mL EtOH was treated with NaOMe (1.94 g, 10.7 mmol) at room temperature and stirred for 30 min. Then, (2,6-difluorophenyl)hydrazine (1.0 g, 5.4 mmol) was added and the reaction mixture heated to reflux overnight. The reaction mixture was cooled to room temperature and 20 mL water were added. After extraction with DCM (320 mL) the combined organic phases were dried over Na.sub.2SO.sub.4 and evaporated. 2-(2,6-difluorophenyl)-3,4-dihydropyrazol-5-amine (770 mg, 32% yield, 44.3% HPLC-purity) was obtained as brown oil.

(50) .sup.1H NMR (CD.sub.3CN) (ppm)=7.0-7.1 (m, 1H), 6.8-6.9 (m, 2H), 4.4 (br s, 2H), 3.6 (t, 2H), 2.8 (t, 2H).

Example 4: Synthesis of 1-(2,6-difluorophenyl)pyrazol-3-amine (Ia)

(51) ##STR00019##

(52) To a solution of 2-(2,6-difluorophenyl)-3,4-dihydropyrazol-5-amine (10.0 g, 50.7 mmol), KI (420 mg, 2.5 mmol) and AcOH (1.5 g, 25.0 mmol) in 50 mL MeCN was added H.sub.2O.sub.2 (3.5 g, 53.2 mmol, 50%) at 40 C. over a period of 1 h. The temperature was kept below 65 C. After stirring for 1 h at 50 C., the reaction was quenched with 9 mL aq. NaOH (20%) and 4 mL aq. NaHSO.sub.3 (40%). Then most of the MeCN was distilled off and a suspension was formed. Filtration and subsequent recrystallization of the solid gave 1-(2,6-difluorophenyl)pyrazol-3-amine (7.8 g, 80% yield, 96.7% HPLC-purity) as a beige solid.

(53) .sup.1H NMR (CD.sub.3CN) (ppm)=7.5 (d, 1H), 7.4-7.5 (m, 1H), 7.1-7.2 (m, 2H), 5.8 (d, 1H), 4.1 (br s, 2H).

Example 5: Synthesis of N-[1-(2,6-difluorophenyl)pyrazol-3-yl]-2-(trifluoromethyl)benzamide (VII)

(54) ##STR00020##

(55) To a solution of 1-(2,6-difluorophenyl)pyrazol-3-amine (56.0 g, 0.29 mmol) in 425 mL toluene 2-(trifluoromethyl)benzoyl chloride (60.4 g, 0.29 mmol) was added at 50 C. over a period of 2 h and stirred for another 1 h at 50 C. After subsequent heating to reflux for 6 h the reaction mixture was cooled down, the precipitating solid was filtered and washed twice with 100 mL toluene. N-[1-(2,6-difluorophenyl)pyrazol-3-yl]-2-(trifluoromethyl)benzamide (96.8 g, 91% yield, 99.7% HPLC-purity) was obtained as brown solid.

(56) .sup.1H NMR (CD.sub.3CN) (ppm)=9.2 (br. s, 1H), 7.8 (d, 1H), 7.6-7.7 (m, 4H), 7.4-7.5 (m, 1H), 7.2 (t, 2H), 7.0 (d, 1H).