EA037646B1 - Process for the preparation of substituted triazoles - Google Patents

Abstract

The invention relates to a process for the preparation of a triazole compound of formula Ifrom oxirane of formula II

Description

The present invention relates to a method for providing triazole compounds by reacting substituted oxiranes with 1H-1,2,4-triazole under basic conditions.

Substituted oxiranes are valuable intermediates for the synthesis of triazole compounds with pesticidal, in particular fungicidal, action. Triazole compounds that are available via an oxirane intermediate are, for example, described in WO 2013/010862 (PCT / EP 2012/063526), WO 2013/010894 (PCT / EP 2012/063635), WO 2013/010885 (PCT / EP 2012 / 063620), WO 2013/024076 (PCT / EP 2012/065835), WO 2013/024075 (PCT / EP 2012/065834), WO 2013/024082 (PCT / EP 2012/065850), WO 2013/024077 (PCT / EP 2012/065836), WO 2013/024081 (PCT / EP 2012/065848), WO 2013/024080 (PCT / EP 2012/065847), WO 2013/024083 (PCT / EP 2012/065852) and EP 2559688 (EP 11177556.5 ), which are directed to specific fungicidal substituted 2- [2-halo-4phenoxyphenyl] -1- [1,2,4] triazol-1-ylethanol compounds. WO 2013/007767 (PCT / EP 2012/063626) is directed to fungicidal substituted 2- [2-haloalkyl-4-phenoxyphenyl] -1- [1,2,4] triazole-1ylethanol compounds, which can also be synthesized via the corresponding oxirane intermediate compound. A common method for the synthesis of oxiranes from carbonyl compounds such as aldehydes and ketones is by reaction with trimethylsulfonium iodide in the presence of a base (JACS 1965, 87, p. 1353 et seq.). This reagent is very expensive and not suitable for industrial scale. An alternative reagent is trimethyl sulfonium methyl sulfate, which can be obtained from dimethyl sulfide and dimethyl sulfate (Heterocycles 8, 1977, p. 397 et seq.). However, this reagent (melting point 100 to 104 ° C) is very hygroscopic and difficult to handle in solid form (Synth. Communications, 15, 1985, p. 753). For example, accurate dosing of the specified reagent is possible only when air humidity is excluded. J. Agric. Food Chem. 2009, 57, 4854-4860 certain derivatives of 2-arylphenyl- (ether) -3- (1H-1,2,4-triazol-1-yl) propan-2ol were synthesized via oxirane.

Synthetic Communications 15, 1985, p. 749 et seq. Generally describes the reaction of trimethylsulfonium methyl sulfate with aldehydes and ketones using a 50% NaOH solution. However, it is noted that a satisfactory yield cannot be achieved with every ketone or aldehyde, in particular aldehydes that are more reactive are reacted. According to this document, NaOH and large amounts of water are used as the base for the reaction, since the base is added as a 50% aqueous solution. In addition, the process uses a large excess of base and preferably methylene chloride, which is not suitable for an industrial process and also due to environmental concerns.

A.A. Afonkin et al. in Russian Journal of Organic Chemistry, vol. 44, No. 12, 2008, p. 1776-1779 discloses the synthesis of certain electron-rich aryl (heteroaryl) oxiranes both under interfacial transfer conditions and under homogeneous conditions using trimethylsulfonium methyl sulfate as a reagent. In this reference, aldehydes in the reaction are described as generally more reactive than ketones. NaOH is used as a 50% aqueous solution, i.e. high amounts of water are present.

DE 3733755 is directed to a process for the preparation of 2- (4-chlorophenylethyl) -2-tert-butyloxyrane from the corresponding ketone using trimethylsulfonium methyl sulfate in the presence of potassium hydroxide, dimethyl sulfide and water. According to this document, the amount of water present in the reaction mixture must be between 1.0 and 1.5 mol per mol of ketone, otherwise the yields are not high enough. Such limited amounts of water are nevertheless disadvantageous for an industrial process.

Therefore, the methods known from the literature are sometimes not suitable for efficient synthesis of substituted oxiranes, since the yield is insufficient and / or the reaction conditions and parameters, such as water content and / or the ratio of reactants and ingredients to each other, are not suitable for scale, increased to industrially relevant quantities. In particular, since some oxiranes are valuable intermediates for the synthesis of triazole compounds with promising fungicidal activity, there is an ongoing need for improved methods that make such intermediates and target compounds readily available.

The aim of the present invention was to optimize the synthesis of triazole active compounds using these oxiranes.

Surprisingly, a highly efficient synthesis has now been found for the conversion of specific compounds containing an oxo group to oxiranes, which are useful as intermediates in the synthesis of certain pesticidal triazole compounds.

Process for the preparation of compounds of formula IIa

o in which RG is optionally substituted aryl or heteroaryl and R ¹ is as defined below;

including the following stage:

- 1 037646 (i) reaction of an oxo compound of formula IIIa

with trimethylsulfonium methyl sulfate of formula IV (CH ₃ ) ₃ S ⁺ CH ₃ SO ₄ '

IV in aqueous solution in the presence of a base.

In particular, compound IIa is oxirane compound II and compound IIIa is oxo compound III.

Method for preparing compounds II

includes the following stage:

(i) the reaction of an oxo compound of formula III

with trimethylsulfonium methyl sulfate of formula IV

IV (CH ₃ ) ₃ S ⁺ CH ₃ SO ₄ 'in aqueous solution in the presence of KOH, where used from 1 to 4, preferably from more than 1.5 to 4 EQ. water relative to 1 eq. compounds III, where the variables R ¹ , R ³ , R ⁴ , n and m take the following values:

R ^{1 is} selected from C ₁ -C ₆ -αalkyl, C ₂ -C _6- alkenyl, C ₂ -C ₆ -αalkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₆ - alkyl, phenyl, phenyl-C1-C ₄ -alkyl, phenyl-C ₂ -C ₄ -alkenyl or phenyl-C ₂ -C ₄ -alkynyl;

where the aliphatic fragments of the radical R ^{1 are} not additionally substituted or carry one, two, three or up to the maximum possible number of the same or different groups R ^12a , which are independently selected from R ^12a halogen, OH, CN, nitro, C1-C ₄ -alkoxy, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ halocycloalkyl and C _{1 -C 4} haloalkoxy;

where the cycloalkyl and / or phenyl moieties of the radical R ^{1 are} not additionally substituted or carry one, two, three, four, five, or up to the maximum number of the same or different groups R ^12b , which are independently selected from R ^12b halogen, OH, CN, nitro, _C1-C4 alkyl, _C1-C4 alkoxy,

C1-C ₄ -haloalkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -galogentsikloalkila and _C1-C4 -galogenalkoksi;

R ^{3 is} independently selected from halogen, CN, NO _2, OH, SH, _C1-C6 alkyl, _C1-C6 alkoxy,

C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyloxy, NH ₂ , NH (C ₁ -C ₄ -alkyla), N (C ₁ -C ₄ -αalkyl) ₂ , NH (C ₃ -C ₆ -cycloαalkyl), N (C ₃ -C ₆ -cycloαalkyl) ₂ , S (O) _p (C ₁ -C ₄ -αalkyl), C (= O ) _(C1-C4 alkyl), C (= O) (OH), C (= O) (O-C1-C4-alkyl), C (= O) (NH (C1-C4 αlkila)), C (= O) (N (C1-C4-alkyl) 2), C (= O) (NH (C ₃ -C ₆ -cycloalkyl)) and C (= O) - (N (C ₃ -C ₆ -cycloalkyl ) ₂ ); where each of R ³ is unsubstituted or up to 3a.

optionally substituted with one, two, three, or four R;

* 2,

R ^{3a is} independently selected from halogen, CN, NO _: where p is 0, 1 or 2;

OH, _C1-C4 alkyl, _C1-C4 -haloalkyl,

C ₃ -C ₈ -tsikloαlkila, C ₃ -C ₈ -galogentsikloalkila, _C1-C4 alkoxy and _C1-C4 -galogenalkoksi;

R ^{4 is} independently selected from substituents as defined for R ³ , wherein said R ⁴ is unsubstituted or further substituted with one, two, three or four R ^4a , where each R ^{4a is} independently selected from substituents as defined for R ^3a ;

n takes the value 0, 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, or 5.

More specifically, compounds II and III are as follows:

wherein R is selected from halogen and _(C1-C2) haloalkyl, in particular Cl, Br, F or CF3, in particular Cl or CF3;

R ¹ , R ³ , R ⁴ and m are as defined and preferably defined herein;

n1 can be 0, 1, 2, or 3.

Compounds of formula III have formula IIIA

- 2 037646 in which R ¹ means C _g C ₆ -alkyl or C ₃ -C ₈ -cycloalkyl and R ⁴ means F or Cl.

R ¹ means C ₁ -C ₆ -alkyl, in particular C ₁ -C ₄ -alkyl, in particular selected from CH ₃ , C2H5, n-C ₃ H ₇ ,

CH (CH ₃ ) 2, n-butyl, isobutyl and tert-butyl, more preferably selected from CH ₃ , C2H5, CH (CH ₃ ) 2 and C (CH3) h.

R ¹ is C ₃ -C ₈ -cycloalkyl, in particular C ₃ -C ₆ -cycloalkyl, such as C ₃ H5 (cyclopropyl), C4H7 (cyclobutyl), cyclopentyl or cyclohexyl.

R ¹ means C3H5 (cyclopropyl) or C4H7 (cyclobutyl).

R ⁴ means F or Cl, in particular Cl.

In particular, R ^{1 is} selected from CH ₃ , CH (CH ₃ ) 2 and cyclopropyl, and R ⁴ is Cl.

This option refers to formulas II and I, respectively:

with the above values of R ¹ and R ⁴ .

In process step (i), the oxo compound of formula III is reacted with trimethylsulfonium methyl sulfate of formula IV

in aqueous solution in the presence of a base.

Preferably, the process uses 1 to 4 equivalents, in particular 1.2 to 3.5 equivalents, in particular 1.5 to 3.3 equivalents, of water relative to 1 equiv. compounds III. May be beneficial if more than 1.5 eq is present. water, in particular from more than 1.5 to 4 eq. water, especially from more than 1.5. up to 3.5 equiv. water, even more preferably from more than 1.5 to 2.5 EQ. water per mole of compound III. In particular, ratios of 1.6 to 3.8, in particular 1.7 to 3.3 eq., In particular 1.8 to 2.8, or 1.9 to 2.5 eq., May be favorable. water per mole of compound III.

Reagent IV is preferably used in an amount of from 1.1 to 2.5, in particular from 1.2 to 2, in particular from 1.3 to 1.6 eq. IV for 1 eq. (mol) of compound III.

In general, the reagent of Formula IV can be prepared from dimethyl sulfide and dimethyl sulfate. Reagent IV is prepared in situ by adding dimethyl sulfate to a reaction mixture containing dimethyl sulfide. Dimethyl sulfide is usually used in excess.

As reagent IV, an aqueous solution of trimethylsulfonium III methyl sulfate is preferably used, containing from 33 to 37 wt.%, Preferably from 34 to 36 wt.%, In particular from 34 to 35.3 wt.%, Also in particular from 34.3 to 35.9 wt% trimethylsulfonium cation.

In particular, the solution of reagent IV contains 33 to 37 wt%, preferably 34 to 36 wt%, in particular 34 to 35.3 wt%, also in particular 34.3 to 35.9 wt% trimethylsulfonium cation. Accordingly, the amount of trimethyl sulfonium methyl sulfate in this reagent, measured as the sum of the trimethyl sulfonium cations and methyl sulfate anions, is from about 80 to 90 wt%, preferably from about 83 to 88 wt%, in particular from about 83 to 86 wt%. Quantification, for example, can be performed using quantitative NMR spectroscopy.

The viscosity of an aqueous solution of reagent IV is relatively low. The solutions are stable at room temperature, in particular at 25 ° C, and can be stored for a longer time. In particular, the reagent solution does not crystallize during storage for longer periods of time, such as several weeks, for example up to 12 weeks, at temperatures between 10 ° C and 25 ° C.

The reagent can be prepared by adding dimethyl sulfate to water and dimethyl sulfide. Dimethyl sulfide is usually used in excess, usually from 2 to 8, more preferably from 4 to 6, in particular from 4.5 to 5.5, equiv.

In the preparation of an aqueous solution of reagent IV, preferably 1.3 to 2.2 equivalents are used, more preferably 1.45 to 2.0 equivalents. water relative to dimethyl sulfate.

The temperature of the reaction mixture during the addition of dimethyl sulfate is preferably room temperature, in particular from 25 to 40 ° C.

The aqueous reagent is separated as a lower phase and can be used further as such.

As follows from the prior art, it has not been possible to provide stable aqueous solutions of reagent IV that can be used in the process for the synthesis of oxiranes from compounds containing an oxo group. At this time, it has surprisingly been found that a stable aqueous solution of reagent IV can be provided if the water content is kept within specific ranges as defined above with respect to dimethyl sulfate.

The use of an aqueous solution of reagent IV is also very effective in higher scale reaction conditions because it is stable and because it contains a certain amount of reagent so that reagent IV can be easily and accurately dosed into the reaction mixture.

The base used in step (i) is preferably selected from KOH and NaOH. In a preferred embodiment, KOH is used, and in particular it is used in solid form,

- 3 037646 preferably in the form of solid pellets, flakes, microgranules and / or powder. It is preferred if at least 3 eq is used. base, preferably at least 3.2 eq., especially at least 3.4 eq. for 1 eq. compounds III. It may be preferred if the amount of base is 3 to 6 equivalents, in particular 3 to 5 equivalents. per 1 mole of compound III.

The base, in particular the solid KOH, is used in such a way that the range of water present in the reaction mixture required according to the invention is maintained. Therefore, during the reaction, some of the base is dissolved in the reaction solution, and some is still present in solid form.

Dimethyl sulfide is also used as a solvent in step (i). An additional solvent is also used. In particular, an aprotic organic solvent such as, for example, diethyl ether, methyl tert-butyl ether, chlorobenzene, xylene or toluene is suitable.

The reaction temperature in step (i) is preferably kept at a maximum of 50 ° C, in particular a maximum of 45, more preferably a maximum of 40 ° C. Usually also preferred is a reaction temperature of at least 20 ° C, in particular at least room temperature, in particular at least 25 ° C. In a further embodiment, the temperature is at least 30 ° C. It may be preferred if the temperature is at least 35 ° C.

Oxiranes of formula II can be obtained in high yields. Preferably, the yields are at least 60%, more preferably 70%, even more preferably at least 75%, even more preferably at least 80%.

The order in which the reagents are added to the reaction mixture varies. In one embodiment, a base is first added to the solution of compound III and the solvent, and then reagent IV is added. According to another embodiment, reagent IV is first added to the solution of compound III and then the base is added. According to a further embodiment, a solution of compound III and reagent IV are added to the base at the same time. In the latter embodiment, the base is preferably suspended in a sufficient amount of solvent and stirred during the addition of the reactants.

The oxirane of formula II obtained according to the method (step (i)) can be further converted to a triazole of formula I.

Therefore, the method includes the following stage:

(ii) reacting an oxirane of formula II with 1H-1,2,4-triazole and an inorganic base to give compounds of formula I wherein R ^{1 is} selected from C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl;

R ^{3 is} independently selected from halogen, CN, NO ₂ , OH, SH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyloxy, NH ₂ , NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ , NH (C ₃ -C ₆ -cycloalkyl) , N (C ₃ -C ₆ -cycloalkyl) ₂ , S (O) _p (C ₁ -C ₄ -alkyl), C (= O) (C ₁ -C ₄ alkyl), C (= O) (OH) , C (= O) (O-C ₁ -C ₄ -alkyl), C (= O) (NH (C ₁ -C ₄ -alkyl)), C (= O) (N (C ₁ -C ₄ - alkyl) ₂ ), C (= O) (NH (C ₃ -C ₆ -cycloalkyl)) and C (= O) - (N (C ₃ -C ₆ -cycloalkyl) ₂ ), where p takes the value 0, 1 or 2;

each of R ³ is unsubstituted or further substituted with one, two, three or four R ^3a , where R ^{3a is} independently selected from halogen, CN, NO ₂ , OH, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -halogenoalkyl, Q-Q cycloalkyl, C ₃ -C ₈ halocycloalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ haloalkoxy;

R ^{4 is} independently selected from substituents as defined for R ³ , wherein said R ⁴ is unsubstituted or further substituted with one, two, three or four R ^4a , where each R ^{4a is} independently selected from substituents as defined for R ^3a ;

n takes the value 0, 1, 2, 3, or 4;

m takes the value 0, 1, 2, 3, 4, or 5.

In step (ii) oxirane is reacted with 1H-1,2,4-triazole and an inorganic base.

The inorganic base used in step (ii) is preferably selected from NaOH, KOH, Na ₂ CO ₃ and K ₂ CO ₃ , in particular from NaOH and KOH. In one embodiment, NaOH is used. According to a further embodiment, KOH is used.

In accordance with a special embodiment, the sodium salt of 1H-1,2,4-triazole is used as the base, wherein said sodium salt is prepared using a triazole and a base before

- 4 037646 respectfully chosen from NaOH, NaH and Na-alcoholates. See also DE 3042302.

The amount of base used in step (ii) is preferably equal to or less than 1 equivalent, in particular less than 1 equivalent, more preferably equal to or less than 0.8 equiv., Even more preferably equal to or less than 0.6 equiv. for 1 eq. compounds II. Also preferred are amounts of base that are equal to or less than 0.4 equivalents, in particular equal to or less than 0.2 equivalents, especially equal to or less than 0.1 equivalents. for 1 eq. compounds II. Preferably, at least 0.1 equivalents are used, more preferably at least 0.2 equivalents, in particular at least 0.3 equivalents, in particular at least 0.4 equivalents. base for 1 eq. compounds II.

It was found that higher yields of compounds I can be achieved using less than 1 eq. bases with respect to compound II. In particular embodiments of the invention, NaOH is used as a base, preferably in the amount indicated above, in particular in an amount of 0.1 to 0.55 equivalents. with respect to the oxirane of formula II.

In order to advantageously shorten the reaction times, temperatures of at least 100 ° C, more preferably at least 110 ° C, in particular at least 120 ° C are suitable. Also, one embodiment is heating the reaction mixture in a vessel with a reflux condenser. Preferably, the reaction temperature does not exceed 150 ° C, in particular does not exceed 140 ° C. In particular, the reaction is carried out at a temperature of from 120 to 140 ° C.

The amount of 1H-1,2,4-triazole used in step (ii) is usually at least 1 eq. per mole of oxirane II. According to one embodiment, 1H-1,2,4-triazole is used in excess relative to oxirane II. Preferred amounts are from more than 1 to 2 equivalents, more preferably from more than 1 to 1.8 equivalents, even more preferably from more than 1 to 1.6 equivalents. Generally for economic reasons, it may be preferable to use at least 1.1 eq., Especially from 1.15 to 1.5 eq. triazole with respect to oxirane II.

The solvent used in step (ii) is preferably selected from dimethylformamide, dimethylacetamide, N-methylpyrrolidone. Most preferred is dimethylformamide.

One by-product that can form when R ¹ is isopropyl is the following compound II, in particular IIa:

where R ³ , R ⁴ , n and m are as defined above.

In particular, in formula IIa, R ³ is CF ₃ or Cl and R ⁴ is Cl.

According to the reaction conditions, the formation of a by-product can be suppressed or avoided and higher yields can be obtained.

Usually, one additional undesirable by-product of the synthesis of compounds I, which may occur in undesirable amounts, is the symmetric triazole I, which is formed together with the target triazole of formula I, sometimes in a large excess compared to the target compound I, which leads, therefore, to lower yields of the target product of the formula I where R ¹ , R ³ , R ⁴ , n and m are defined above.

In particular, Ia can occur when R ³ is CF ₃ or Cl, R ⁴ is Cl and R ¹ is as defined and preferably defined herein:

Specific by-products Ia that can be formed during the implementation of the process according to the invention, depending on the substituents in the reactants, are summarized in table. S1. Each line from lines S1-1 - S1-320 table. S1 corresponds to the by-product Ia containing the substituents specified in the corresponding line.

- 5 037646

Table S1

I No. R ⁴ R ^J R ¹ Sl-1 Cl CF ₃ H Sl-2 Cl CF ₃ CH ₃ Sl-3 Cl CF ₃ CH ₂ CH ₃ Sl-4 Cl CF ₃ CH ₂ CH ₂ CH ₃ Sl-5 Cl CF ₃ CH (CH ₃ ) ₂ Sl-6 Cl CF ₃ C (CH ₃ ) ₃ Sl-7 Cl CF ₃ CH (CH ₃ ) CH ₂ CH ₃ Sl-8 Cl CF ₃ CH ₂ CH (CH ₃ ) ₂ Sl-9 Cl CF ₃ CH ₂ CH ₂ CH ₂ CH ₃ Sl-10 Cl CF ₃ CF ₃ Sl-11 Cl CF ₃ chf ₂ Sl-12 Cl CF ₃ ch ₂ f Sl-13 Cl CF ₃ CHC1 ₂ Sl-14 Cl CF ₃ CH ₂ C1 Sl-15 Cl CF ₃ CH ₂ OH Sl-16 Cl CF ₃ CH ₂ CH ₂ OH Sl-17 Cl CF ₃ CH ₂ CH ₂ CH ₂ OH Sl-18 Cl CF ₃ CH (CH ₃ ) CH ₂ OH Sl-19 Cl CF ₃ CH ₂ CH (CH ₃ ) OH SI-20 Cl CF ₃ CH ₂ CH ₂ CH ₂ CH ₂ OH Sl-21 Cl CF ₃ CH (CH ₃ ) CN SI-22 Cl CF ₃ ch ₂ ch ₂ cn SI-23 Cl CF ₃ ch ₂ cn SI-24 Cl CF ₃ ch ₂ ch ₂ cn SI-25 Cl CF ₃ ch ₂ ch ₂ ch ₂ cn, SI-26 Cl CF ₃ CH (CH ₃ ) CH ₂ CN SI-27 Cl CF ₃ CH ₂ CH (CH ₃ ) CN SI-28 Cl CF ₃ ch ₂ ch ₂ ch ₂ ch ₂ cn SI-29 Cl CF ₃ CH ₂ OCH ₃ Sl-30 Cl CF ₃ CH ₂ OCH ₂ CH ₃ Sl-31 Cl CF ₃ CH (CH ₃ ) OCH ₃ Sl-32 Cl CF ₃ CH (CH ₃ ) OCH ₂ CH ₃ Sl-33 Cl CF ₃ CH ₂ CH ₂ OCH ₂ CH ₃ Sl-34 Cl CF ₃ CH ₂ OCF ₃ Sl-35 Cl CF ₃ ch ₂ ch ₂ ocf ₃ Sl-36 Cl CF ₃ CH ₂ OCC1 ₃ Sl-37 Cl CF ₃ CH ₂ CH ₂ OCC1 ₃ Sl-38 Cl CF ₃ CH = CH ₂ Sl-39 Cl CF ₃ CH ₂ CH = CH ₂ SI-40 Cl CF ₃ CH ₂ CH = CHCH ₃ Sl-41 Cl CF ₃ CH ₂ C (CH ₃ ) = CH ₂ SI-42 Cl CF ₃ CH ₂ C (CH ₃ ) = CHCH ₃ SI-43 Cl CF ₃ CH ₂ C (CH ₃ ) = C (CH ₃ ) ₂ SI-44 Cl CF ₃ CH = CHCH ₃ SI-45 Cl CF ₃ C (CH ₃ ) = CH ₂ SI-46 Cl CF ₃ CH = C (CH ₃ ) ₂ SI-47 Cl CF ₃ C (CH ₃ ) = C (CH ₃ ) ₂ SI-48 Cl CF ₃ C (CH ₃ ) = CH (CH ₃ ) SI-49 Cl CF ₃ C (C1) = CH ₂ Sl-50 Cl CF ₃ C (H) = CHC1 Sl-51 Cl CF ₃ C (C1) = CHC1 Sl-52 Cl CF ₃ CH = CC1 ₂ Sl-53 Cl CF ₃ C (C1) = CC1 ₂ Sl-54 Cl CF ₃ C (H) = CH (F) Sl-55 Cl CF ₃ C (H) = CF ₂ Sl-56 Cl CF ₃ C (F) = CF ₂ Sl-57 Cl CF ₃ C (F) = CHF Sl-58 Cl CF ₃ CH = CHCH ₂ OH Sl-59 Cl CF ₃ CH = CHOCH ₃ SI-60 Cl CF ₃ CH = CHCH ₂ OCH ₃ Sl-61 Cl CF ₃ CH = CHCH ₂ OCF ₃ SI-62 Cl CF ₃ CH = CHCH ₂ OCC1 ₃ SI-63 Cl CF ₃ CH = CH (C ₃ H ₅ ) SI-64 Cl CF ₃ CH = CH (C ₄ H ₇ ) SI-65 Cl CF ₃ CH = CH (1-C1-C ₃ H ₄ ) SI-66 Cl CF ₃ CH = CH (1-FC ₃ H ₄ ) SI-67 Cl CF ₃ CH = CH (1-C1-C ₄ H ₆ ) Sl-68 Cl CF ₃ CH = CH (1-FC ₄ H ₆ )

- 6 037646

SI-69 Cl CF ₃ C = CH SI-70 Cl CF ₃ C = CCH ₃ Sl-71 Cl CF ₃ CH ₂ C = CCH ₃ SI-72 Cl CF ₃ CH ₂ C = CH SI-73 Cl CF ₃ CH ₂ C = CCH ₂ CH ₃ SI-74 Cl CF ₃ C = CCH (CH ₃ ) ₂ SI-75 Cl CF ₃ C = CC (CH ₃ ) ₃ SI-76 Cl CF ₃ C = C (C ₃ H ₅ ) SI-77 Cl CF ₃ C = C (C ₄ H ₇ ) SI-78 Cl CF ₃ C = C (I-C1-C ₃ H ₄ ) SI-79 Cl CF ₃ C = C (1-C1-C ₄ Nb) Sl-80 Cl CF ₃ CbCCI Sl-81 Cl CF ₃ CbCBr SI-82 Cl CF ₃ C = C-I Sl-83 Cl CF ₃ CH ₂ C = CC1 SI-84 Cl CF ₃ CH ₂ C = CBr Sl-85 Cl CF ₃ CH ₂ C = CI Sl-86 Cl CF ₃ C = CCH ₂ OCH ₃ Sl-87 Cl CF ₃ C = CCH (OH) CH ₃ Sl-88 Cl CF ₃ C = CCH (OCH ₃ ) CH ₃ Sl-89 Cl CF ₃ C = COCH ₃ SI-90 Cl CF ₃ CH ₂ C = COCH ₃ Sl-91 Cl CF ₃ C = CCH ₂ OCC1 ₃ SI-92 Cl CF ₃ C = CCH ₂ OCF ₃ SI-93 Cl CF ₃ C = CCH ₂ (C ₃ H ₅ ) SI-94 Cl CF ₃ C = CCH ₂ (C ₄ H ₇ ) SI-95 Cl CF ₃ C = C (I-C1-C ₃ H ₄ ) SI-96 Cl CF ₃ C = C (1-FC ₃ H ₄ ) SI-97 Cl CF ₃ C = C (1-C1-C ₄ Nb) SI-98 Cl CF ₃ C = C (1-FC ₄ H ₆ ) SI-99 Cl CF ₃ C ₃ H ₃ (cyclopropyl) Sl-100 Cl CF ₃ C ₄ H ₇ (cyclobutyl) Sl-101 Cl CF ₃ C5H9 (cyclopentyl) Sl-102 Cl CF ₃ cyclohexyl Sl-103 Cl CF ₃ CH (CH ₃ ) -C ₃ H ₅ (CH (CH ₃ ) cyclopropyl) Sl-104 Cl CF ₃ CH ₂ -C ₃ H ₅ (CH ₂ cyclopropyl) Sl-105 Cl CF ₃ 1 - (C1) -cyclopropyl Sl-106 Cl CF ₃ 1 - (P) -cyclopropyl Sl-107 Cl CF ₃ 1- (CH ₃ ) cyclopropyl Sl-108 Cl CF ₃ 1 - (CX) -cyclopropyl Sl-109 Cl CF ₃ 2- (C1) -cyclopropyl Sl-110 Cl CF ₃ 2- (P) -cyclopropyl

- 7 037646

Sl-111 Cl CF ₃ 1 - (C1) -cyclobutyl Sl-112 Cl CF ₃ 1 - (P) -cyclobutyl Sl-113 Cl CF ₃ 2- (C1) -cyclobutyl Sl-114 Cl CF ₃ 3 - (C1) -cyclobutyl Sl-115 Cl CF ₃ 2- (P) -cyclobutyl Sl-116 Cl CF ₃ 3- (P) -cyclobutyl Sl-117 Cl CF ₃ 3,3 -C1 ₂ -cyclobutyl Sl-118 Cl CF ₃ 3,3-P ₂ -cyclobutyl Sl-119 Cl CF ₃ 2- (CH ₃ ) - cyclopropyl Sl-120 Cl CF ₃ 1 - (CH ₃ ) -cyclobutyl Sl-121 Cl Cl 2- (CH ₃ ) -cyclobutyl Sl-122 Cl Cl 3 - (CH ₃ ) -cycle shoe Sl-123 Cl Cl 3.3- (CH ₃ ) ₂ cyclobutyl Sl-124 Cl Cl 2- (CX) -cyclopropyl Sl-125 Cl Cl 1 -cyclopropylcyclopropyl Sl-126 Cl Cl 2-cyclopropylcyclopropyl Sl-127 Cl Cl CH (CH ₃ ) (cyclobutyl) Sl-128 Cl Cl CH ₂ - (cyclobutyl) Sl-129 Cl Cl CH ₂ CH ₂ (cyclopropyl) Sl-130 Cl Cl CH ₂ CH ₂ (cyclobutyl) Sl-131 Cl Cl CH ₂ - (1-C1cyclopropyl) Sl-132 Cl Cl CH ₂ - (1-F-cyclopropyl) Sl-133 Cl Cl CH ₂ - (1-C1cyclobutyl) Sl-134 Cl Cl CH ₂ - (1-Fcyclobutyl) Sl-135 Cl Cl CHCH ₃ - (1-C1cyclopropyl) Sl-136 Cl Cl C (CH ₃ ) ₂ - (1-F-cyclopropyl) Sl-137 Cl Cl SbN ₅ Sl-138 Cl Cl 4-C1-C ₆ H ₄ Sl-139 Cl Cl 4-OCH ₃ -C ₆ H ₄ Sl-140 Cl Cl 4-CH ₃ -C ₆ H4 Sl-141 Cl Cl 4-FC ₆ H ₄ Sl-142 Cl Cl 2,4-F ₂ -C ₆ H ₃ Sl-143 Cl Cl 2,4-C1 ₂ -C ₆ H ₃ Sl-144 Cl Cl 2-CH ₃ -C ₆ H4 Sl-145 Cl Cl 2-CF ₃ -C ₆ H ₄

- 8 037646

Sl-146 Cl Cl 4-CH ₃ -C ₆ H4 Sl-147 Cl Cl 4-CF ₃ -C ₆ H ₄ Sl-148 Cl Cl 2-OCH ₃ -C ₆ H ₄ Sl-149 Cl Cl 2-OCF ₃ -C ₆ H ₄ Sl-150 Cl Cl 4-OCH ₃ -C ₆ H ₄ Sl-151 Cl Cl 4-OCF ₃ -C ₆ H ₄ Sl-152 Cl Cl 2,4,6-F ₃ -C ₆ H ₂ Sl-153 Cl Cl 2,4,6-Cl ₃ -C ₆ H ₂ Sl-154 Cl Cl ch ₂ c ₆ h ₅ Sl-155 Cl Cl CH ₂ - (4-Cl) -C ₆ H ₄ Sl-156 Cl Cl CH ₂ - (4-CH ₃ ) -C ₆ H ₄ Sl-157 Cl Cl CH ₂ - (4-OCH ₃ ) -C ₆ H ₄ Sl-158 Cl Cl CH ₂ - (4-F) -C ₆ H ₄ Sl-159 Cl Cl CH ₂ - (2,4-Cl ₂ ) -C ₆ H ₃ Sl-160 Cl Cl CH ₂ - (2,4-F ₂ ) -C ₆ H ₃ Sl-161 Cl Cl H Sl-162 Cl Cl CH ₃ Sl-163 Cl Cl CH ₂ CH ₃ Sl-164 Cl Cl CH ₂ CH ₂ CH ₃ Sl-165 Cl Cl CH (CH ₃ ) ₂ Sl-166 Cl Cl C (CH ₃ ) ₃ Sl-167 Cl Cl CH (CH ₃ ) CH ₂ CH ₃ Sl-168 Cl Cl CH ₂ CH (CH ₃ ) ₂ Sl-169 Cl Cl ch ₂ ch ₂ ch ₂ ch ₃ Sl-170 Cl Cl CF ₃ Sl-171 Cl Cl chf ₂ Sl-172 Cl Cl ch ₂ f Sl-173 Cl Cl chci ₂ Sl-174 Cl Cl ch ₂ ci Sl-175 Cl Cl ch ₂ oh Sl-176 Cl Cl ch ₂ ch ₂ oh Sl-177 Cl Cl CH ₂ CH ₂ CH ₂ OH Sl-178 Cl Cl CH (CH ₃ ) CH ₂ OH Sl-179 Cl Cl CH ₂ CH (CH ₃ ) OH Sl-180 Cl Cl ch ₂ ch ₂ ch ₂ ch ₂ oh Sl-181 Cl Cl CH (CH ₃ ) CN Sl-182 Cl Cl ch ₂ ch ₂ cn Sl-183 Cl Cl ch ₂ cn Sl-184 Cl Cl ch ₂ ch ₂ cn Sl-185 Cl Cl ch ₂ ch ₂ ch ₂ cn, Sl-186 Cl Cl CH (CH ₃ ) CH ₂ CN Sl-187 Cl Cl CH ₂ CH (CH ₃ ) CN Sl-188 Cl Cl ch ₂ ch ₂ ch ₂ ch ₂ cn Sl-189 Cl Cl CH ₂ OCH ₃ Sl-190 Cl Cl CH ₂ OCH ₂ CH ₃ Sl-191 Cl Cl CH (CH ₃ ) OCH ₃ Sl-192 Cl Cl CH (CH ₃ ) OCH ₂ CH ₃

- 9 037646

Sl-193 Cl Cl CH ₂ CH ₂ OCH ₂ CH ₃ Sl-194 Cl Cl CH ₂ OCF ₃ Sl-195 Cl Cl ch ₂ ch ₂ ocf ₃ Sl-196 Cl Cl CH ₂ OCC1 ₃ Sl-197 Cl Cl CH ₂ CH ₂ OCC1 ₃ Sl-198 Cl Cl CH = CH ₂ Sl-199 Cl Cl CH ₂ CH = CH ₂ SI-200 Cl Cl CH ₂ CH = CHCH ₃ Sl-201 Cl Cl CH ₂ C (CH ₃ ) = CH ₂ SI-202 Cl Cl CH ₂ C (CH ₃ ) = CHCH ₃ SI-203 Cl Cl CH ₂ C (CH ₃ ) = C (CH ₃ ) ₂ SI-204 Cl Cl CH = CHCH ₃ SI-205 Cl Cl C (CH ₃ ) = CH ₂ SI-206 Cl Cl CH = C (CH ₃ ) ₂ SI-207 Cl Cl C (CH ₃ ) = C (CH ₃ ) ₂ SI-208 Cl Cl C (CH ₃ ) = CH (CH ₃ ) SI-209 Cl Cl C (C1) = CH ₂ Sl-210 Cl Cl C (H) = CHC1 Sl-211 Cl Cl C (C1) = CHC1 Sl-212 Cl Cl CH = CC1 ₂ Sl-213 Cl Cl C (C1) = CC1 ₂ Sl-214 Cl Cl C (H) = CH (F) Sl-215 Cl Cl C (H) = CF ₂ Sl-216 Cl Cl C (F) = CF ₂ Sl-217 Cl Cl C (F) = CHF Sl-218 Cl Cl CH = CHCH ₂ OH Sl-219 Cl Cl CH = CHOCH ₃ SI-220 Cl Cl CH = CHCH ₂ OCH ₃ Sl-221 Cl Cl CH = CHCH ₂ OCF ₃ SI-222 Cl Cl CH = CHCH ₂ OCC1 ₃ SI-223 Cl Cl CH = CH (C ₃ H ₅ ) SI-224 Cl Cl CH = CH (C ₄ H ₇ ) SI-225 Cl Cl CH = CH (1-C1-C ₃ H ₄ ) SI-226 Cl Cl CH = CH (1-FC ₃ H ₄ ) SI-227 Cl Cl CH = CH (1-C1-C ₄ H ₆ ) SI-228 Cl Cl CH = CH (1-FC ₄ H ₆ ) SI-229 Cl Cl C = CH Sl-230 Cl Cl C = CCH ₃ Sl-231 Cl Cl CH ₂ C = CCH ₃ Sl-232 Cl Cl CH ₂ C = CH Sl-233 Cl Cl CH ₂ C = CCH ₂ CH ₃ Sl-234 Cl Cl C = CCH (CH ₃ ) ₂ Sl-235 Cl Cl C = CC (CH ₃ ) ₃ Sl-236 Cl Cl C = C (C ₃ H ₅ ) Sl-237 Cl Cl C = C (C ₄ H ₇ ) Sl-238 Cl Cl C = CCI-C1-C ₃ H ₄ ) Sl-239 Cl Cl C = C (1-C1-C ₄ Nb)

- 10 037646

SI-240 Cl Cl C = CC1 Sl-241 Cl Cl C = CBr SI-242 Cl Cl C = C-I SI-243 Cl Cl CH ₂ C = CC1 SI-244 Cl Cl CH ₂ C = CBr SI-245 Cl Cl CH ₂ C = CI SI-246 Cl Cl C = CCH ₂ OCH ₃ SI-247 Cl Cl C = CCH (OH) CH ₃ SI-248 Cl Cl C = CCH (OCH ₃ ) CH ₃ SI-249 Cl Cl C = COCH ₃ Sl-250 Cl Cl CH ₂ C = COCH ₃ Sl-251 Cl Cl C = CCH ₂ OCC1 ₃ SI-252 Cl Cl C = CCH ₂ OCF ₃ Sl-253 Cl Cl C = CCH ₂ (C ₃ H ₅ ) SI-254 Cl Cl C = CCH ₂ (C ₄ H ₇ ) Sl-255 Cl Cl C = C (I-C1-C ₃ H ₄ ) Sl-256 Cl Cl C = C (1-FC ₃ H ₄ ) Sl-257 Cl Cl C = C (1-C1-C ₄ Nb) Sl-258 Cl Cl C = C (1-FC ₄ H ₆ ) Sl-259 Cl Cl C ₃ H ₅ (cyclopropyl) SI-260 Cl Cl C ₄ H ₇ (cyclobutyl) Sl-261 Cl Cl C5H9 (cyclopentyl) SI-262 Cl Cl cyclohexyl SI-263 Cl Cl CH (CH ₃ ) -C ₃ H ₅ (CH (CH ₃ ) cyclopropyl) SI-264 Cl Cl CH ₂ -C ₃ H ₅ (CH ₂ cyclopropyl) SI-265 Cl Cl 1 - (C1) -cyclopropyl SI-266 Cl Cl 1 - (P) -cyclopropyl SI-267 Cl Cl 1- (CH ₃ ) cyclopropyl SI-268 Cl Cl 1 - (CM) -cyclopropyl SI-269 Cl Cl 2- (C1) -cyclopropyl SI-270 Cl Cl 2- (P) -cyclopropyl Sl-271 Cl Cl 1 - (C1) -cyclobutyl SI-272 Cl Cl 1 - (P) -cyclobutyl SI-273 Cl Cl 2- (C1) -cyclobutyl SI-274 Cl Cl 3 - (C1) -cyclobutyl SI-275 Cl Cl 2- (P) -cyclobutyl SI-276 Cl Cl 3- (P) -cyclobutyl SI-277 Cl Cl 3,3 -C1 ₂ -cyclobutyl SI-278 Cl Cl 3,3-P ₂ -cyclobutyl SI-279 Cl Cl 2- (CH ₃ ) cyclopropyl SI-280 Cl Cl 1 - (CH ₃ ) -cyclobutyl

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S1-281 C1 C1 2- (CHs) -cyclobutyl S1-282 C1 C1 3 - (CHs) -cyclobutyl S1-283 C1 C1 3.3- (CH ₃ ) ₂ cyclobutyl S1-284 C1 C1 2- (STU) -cyclopropyl S1-285 C1 C1 1 -cyclopropylcyclopropyl S1-286 C1 C1 2-cyclopropylcyclopropyl S1-287 C1 C1 CH (CH ₃ ) (cyclobutyl) S1-288 C1 C1 CH ₂ - (cyclobutyl) S1-289 C1 C1 CH ₂ CH ₂ (cyclopropyl) S1-290 C1 C1 ch ₂ ch ₂ - (cyclobutyl) S1-291 C1 C1 CH ₂ - (1-C1-cyclopropyl) S1-292 C1 C1 CH ₂ - (1-Fcyclopropyl) S1-293 C1 C1 CH ₂ - (1-C1-cyclobutyl) S1-294 C1 C1 CH ₂ - (1-Fcyclobutyl) S1-295 C1 C1 SNSNz- (1-C1- cyclopropyl) S1-296 C1 C1 C (CH ₃ ) ₂ - (1-Fcyclopropyl) S1-297 C1 C1 from _{6 to 5} S1-298 C1 C1 4-C1-C ₆ H ₄ S1-299 C1 C1 4-OCHs-C ₆ H ₄ S1-300 C1 C1 4-СНz-С ₆ Н4 S1-301 C1 C1 4-FC ₆ H ₄ S1-302 C1 C1 2,4-F ₂ -C ₆ H ₃ S1-303 C1 C1 2,4-C1 ₂ -C ₆ Ns S1-304 C1 C1 2-СНз-С ₆ Н4 S1-305 C1 C1 2-CF ₃ -C ₆ H ₄ S1-306 C1 C1 4-СНz-С ₆ Н4 S1-307 C1 C1 4-CF ₃ -C ₆ H ₄ S1-308 C1 C1 2-OCHs-C ₆ H ₄ S1-309 C1 C1 2-OCF ₃ -C ₆ H ₄ S1-310 C1 C1 4-OCHs-C ₆ H ₄ S1-311 C1 C1 4-OCF ₃ -C ₆ H ₄ S1-312 C1 C1 2,4,6-F ₃ -C ₆ H ₂ S1-313 C1 C1 2,4,6-C1s-C ₆ H ₂ S1-314 C1 C1 sn ₂ s ₆ n ₅ S1-315 C1 C1 CH ₂ - (4-C1) -C ₆ H ₄ S1-316 C1 C1 CH ₂ - (4-CHs) -C ₆ H ₄ S1-317 C1 C1 CH ₂ - (4-OCH ₃ ) -C ₆ H ₄ S1-318 C1 C1 CH ₂ - (4-F) -C ₆ H ₄ S1-319 C1 C1 CH ₂ - (2,4-C1 ₂ ) -C ₆ Hs S1-320 C1 C1 CH ₂ - (2,4-F ₂ ) -C ₆ H ₃

The reaction conditions of the invention make it possible to reduce the amount of I in favor of the desired product I. Consequently, the yield of triazole I can be significantly improved in comparison with the conventional methods of the prior art.

In addition, it has been found that if the reaction product I obtained in step (ii) is crystallized as described in accordance with the invention, the product can be obtained in high yield and purity.

Therefore, the compounds I obtained in step (ii) are crystallized from a suitable solvent such as, for example, toluene, aliphatic alcohol, acetonitrile, ethyl acetate and / or cyclohexane, in particular toluene and / or aliphatic alcohol.

In particular, the aliphatic alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or any mixture thereof. In particular, the aliphatic alcohol is selected from methanol and ethanol.

Typically, for the crystallization step, a significant portion of the solvent, in particular dimethylformamide, as described above, is first evaporated, preferably under reduced pressure. Preferably, at least 55% of the solvent is removed, more preferably at least 60% of the solvent, in particular at least 70% of the solvent. In particular, 12 037646 may be preferred if at least 80%, in particular at least 90% of a solvent such as

DMF. The solvent can then be recycled for reuse in process step (ii), if necessary, after preliminary further rectification.

Water is then added and an appropriate suitable solvent such as ether, for example diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methylene chloride and / or toluene, in particular toluene. Ethyl acetate may also be suitable for use as a solvent. The product I is then preferably obtained by crystallization directly from a concentrated, eg toluene-containing reaction mixture. It is also preferred and suitable for crystallization of the products according to the invention to replace the solvent with, for example, methanol or ethanol (see above).

Seed crystals are added to carry out the crystallization step.

By using a crystallization step in process steps (ii), the formation of undesired symmetric triazole I can be reduced to a level equal to or less than 10%, more preferably equal to or less than 8%, even more preferably equal to or less than 5%, even more preferably equal to or less than 2%.

Preferably, the ratio of the isolated compound I to I is at least 20: 1, more preferably at least 30: 1, even more preferably 50: 1, in particular 70: 1. In particular, the ratio of compound I to I is at least 30: 1.

You can also carry out the general methods of further reactions of oxiranes II to obtain the final products I.

For example, the epoxy ring of compound II can be opened by reaction with alcohols R ² OH, preferably under acidic conditions, to give compounds V

The resulting compounds V are then reacted with halogenating agents or sulfonating agents such as PBr ₃ , PCl ₃ , mesyl chloride, tosyl chloride or thionyl chloride to give compounds VI, wherein LG 'is a nucleophilically substituted leaving group such as halogen, alkylsulfonyl, alkylsulfonyloxy and arylsulfonyloxy, preferably chlorine, bromine or iodine, particularly preferably bromine or alkylsulfonyl. Compounds VI are then reacted with 1H-1,2,4-triazole to give compounds I as is known in the art and / or described above:

For the preparation of compounds of Formula I wherein the alcohol group is derivatized to an ether group, resulting in compounds of Formula I-1

where the variables R ¹ , R ² , R ⁴ , n and m are defined and preferably defined herein;

R ² is hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₈ -tsikloαlkil, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₆ -alkul, phenyl, phenyl-C1-C ₄ -alkyl, phenyl-C ₂ -C ₄ -alkenyl or phenyl-C ₂ -C ₄ alkynyl;

where aliphatic fragments of the radical R ^{2 are} not additionally substituted or carry one, two, three or up to the maximum possible number of identical or different groups R ^12a , which are independently selected from:

R ^12a halogen, OH, CN, nitro, C 1 C ₄ -alkoxy, C ₃ -C ₈ -tsikloαlkila, C ₃ -C ₈ and C 1 -gαlogentsikloαlkila S4galogenalkoksi;

where the cycloalkyl and / or phenyl moieties of the radical R ^{2 are} not further substituted or carry one, two, three, four, five, or up to the maximum number of the same or different groups R ^12b , which are independently selected from:

R ^12b halogen, OH, CN, nitro, _C1-C4 alkyl, _C1-C4 alkoxy, _C1-C4 -haloalkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -galogentsikloalkila and C1-C _4- haloalkoxy;

you can carry out the following stage:

(i ii) derivatizing a compound of formula I from step (i) under basic conditions with R ² -LG, where LG is a nucleophilically substituted leaving group;

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LG is a nucleophilically substituted leaving group such as halogen, alkylsulfonyl, alkylsulfonyloxy and arylsulfonyloxy, preferably chlorine, bromine or iodine, particularly preferably bromine. Preferably, in step (iii) a base is used, such as, for example,

NaH.

Suitable solvents are, for example, ethers, in particular cyclic ethers. Possible solvents are, for example, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me-THF), diethyl ether, TBME (tert-butyl methyl ether), CPME (cyclopentyl methyl ether), DME (1,2-dimethoxyethane) and 1,4-dioxane. Moreover, solvents that may be suitable are, for example, diisopropyl ether, di-n-butyl ether and / or diglyme. Often the use of THF or 2-methyl-THF is particularly suitable. In addition, it may also be suitable to use combinations of two or more different solvents, such as, for example, any combination of the solvents listed above or any one of the listed ethers with aliphatic hydrocarbons such as n-hexane, heptane, or aromatic hydrocarbons, such as toluene or xylenes.

The person skilled in the art is familiar with the reaction in step (ii) and can vary the reaction conditions in a manner similar to known syntheses.

In accordance with an aspect, the invention relates to a process for the preparation of a triazole compound of Formula I

comprising the following step: (iia) reacting an oxirane of formula II

with 1H-1,2,4-triazole and an inorganic base, where 0.1-0.8 equiv. the specified base for 1 eq. compounds II, which leads to compounds of formula I, where

R ^{1 is} selected from C ₁ -C ₆ -alkyl or C ₃ -C ₈ -cycloalkyl;

R ^{3 is} independently selected from halogen, CN, NO ₂ , OH, SH, C ₁ -C ₆ alkyl, C ₁ -C ₆ α-alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyloxy, NH2, NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ , NH (C ₃ -C ₆ -cycloalkyl), N (C ₃ -C ₆ -cycloalkyl) ₂ , S (O) _p (C ₁ -C ₄ -αalkyl), C (= O) (C1-C ₄ alkyl), C (= O) (OH), C (= O) (O-C1-C4-alkyl), C (= O) (NH (C1-C4-alkyl)), C (= O) (N (C1-C4-alkyl) 2), C (= O) (NH (C ₃ -C ₆ -cycloalkyl)) and C (= O) - (N (C ₃ -C ₆ -cycloalkyl) ₂ ), where p is 0, 1 or 2;

each R ³ is not substituted or additionally substituted with one, two, three or four R ^3a, wherein R ^3a is independently selected from halogen, CN, NO2, OH, _C1-C4 alkyl, C1-C ₄ -haloalkyl, C ₃ - C ₈ -cycloalkyl, C ₃ -C ₈ -galogentsikloalkila, _C1-C4 alkoxy and _C1-C4 -galogenalkoksi;

R ^{4 is} independently selected from substituents as defined for R ³ , wherein said R ⁴ is unsubstituted or further substituted with one, two, three or four R ^4a , where each R ^{4a is} independently selected from substituents as defined for R ^3a ;

n takes the value 0, 1, 2, 3, or 4;

m takes the value 0, 1, 2, 3, 4, or 5.

For the preparation of compounds of formula I in which the alcohol group is derivatized (resulting in compounds OR ² , compounds I-1, see above), the following step can subsequently be carried out:

(iiia) derivatizing a compound of formula I from step (iia) under basic conditions with R ² -LG, where LG is a nucleophilically substituted leaving group;

where the variables R ¹ , R ³ , R ⁴ , n and m are defined and preferably defined herein.

Reaction steps (ii) and (iii) are described in detail above and also apply accordingly to this aspect of the invention, namely to the corresponding steps (iia) and (iiia), provided that it is characteristic that the inorganic base is used in an amount less than 1 eq. for 1 eq. compounds II.

The oxyrane II used in the process according to the invention can be prepared according to the process according to the invention described above, or can also be provided in analogy to known methods, for example, by the reaction of the corresponding oxo-containing compound III with trimethylsulf (ox) onium halides ((CH ₃ ) ₃ S ⁺ OHal ^- ), preferably with trimethylsulfonium iodide, preferably in the presence of a base such as sodium hydroxide (see also JACS 1965, 87, p. 1353).

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The starting oxo-containing compounds III for the processes of the invention can be synthesized as described in the aforementioned literature and patent applications. Usually, a person skilled in the art can obtain them in various ways by analogy with known methods of the prior art (cf. J. Agric. Food Chem. (2009), 57, 4854-4860; EP 0275955 A1; DE 4003180 A1; EP 0113640 A2;

EP 0126430 A2). The following are pathways for the synthesis of precursors.

In the first method, for example, in a first step phenols A are reacted with derivatives B, where X ¹ is I or Br, in particular Br (= bromo derivatives III), preferably in the presence of a base, to give compounds C.

[prefer / □ 3x tel / R ³ ) n

О Н χ base] р * хх -р хх m

AB ^with

X = F or CI

The resulting compounds C, where in particular X is Br, are then converted into Grignard reagents by reaction with transmetallation reagents such as isopropyl magnesium halides and then reacted with acetyl chloride, preferably under anhydrous conditions and preferably in the presence of a catalyst such as CuCl, CuCl ₂ , AlCl ₃ , LiCl and their mixtures, to obtain acetophenones D

The second method for obtaining precursors is as follows. In the first step, the halogen derivative E, in which X ² is halogen, in particular F, and X ³ is halogen, in particular Br, is reacted with a transmetallation reagent such as, for example, isopropyl magnesium bromide, and then with an acyl chloride reagent R1COCl ( e.g. acetyl chloride), preferably under anhydrous conditions and optionally in the presence of a catalyst such as CuCl, CuCl ₂ , AlCl ₃ , LiCl and mixtures thereof, to give ketones F

The ketones F are then reacted with phenols A, preferably in the presence of a base, to give compounds III, where R ¹ is as defined and preferably defined, respectively, herein.

Compounds III can also be prepared in analogy to the first method described for compounds D (preferred conditions for the process step, see above). This is illustrated as follows:

Alternatively, compounds III can be synthesized by Friedel Crafts acylation as follows:

Ethers H can be synthesized by nucleophilic substitution of group X in compound G (Angewandte Chemie, International Edition, 45 (35), 5803-5807; 2006, US 20070088015 A1, Journal of the American Chemical Society, 134 (17), 7384-7391 ; 2012). The Lewis acid catalyzed addition of the acid halide will then advantageously lead to compounds III (Journal of Chemical Research, Synopses, (8), 245; 1992, WO 2010/096777 A1).

If individual compounds cannot be obtained directly using the routes described above, they can be obtained by derivatizing other compounds.

If the product is isolated from the reaction mixture in any of the reaction steps of the process according to the invention or other methods described, as appropriate, such isolation can be carried out using techniques known generally to a person skilled in the art. Typically, the reaction mixture is extracted with a suitable organic solvent (for example, aromatic

- 15 037646 hydrocarbons such as toluene and xylenes) and the residue, if necessary, is purified by recrystallization and / or chromatography.

In the definitions of the variables provided in this document, collective terms are used that are usually characteristic of the substituents in question. The term C _n -C _m indicates the number of carbon atoms possible in each occurrence in a given substituent or substituent moiety.

The term halogen refers to fluorine, chlorine, bromine and iodine.

The term C ₁ -C ₆ -alkyl refers to a straight or branched chain saturated hydrocarbon group containing from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl , 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2 -methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl , 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Similarly, the term C ₂ -C ₄ -alkyl refers to a straight or branched chain alkyl group of 2 to 4 carbon atoms such as ethyl, propyl (n-propyl), 1-methylethyl (isopropyl), butyl, 1 -methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl).

The term C ₁ -C ₆ -halogenoalkyl refers to an alkyl group containing from 1 to 6 carbon atoms as defined above, some or all of the hydrogen atoms in this group being replaced by halogen atoms as mentioned above. Examples are C1-C2-haloalkyl groups such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 2-fluoroethyl, 1- -difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl.

The term C ₂ -C ₆ alkenyl refers to a straight or branched unsaturated hydrocarbon radical containing from 2 to 6 carbon atoms and a double bond at any position. Examples are C ₂ -C ₄ alkenyl groups such as ethenyl, 1-propenyl, 2-propenyl (allyl), 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl.

The term C ₂ -C ₆ alkynyl refers to a straight or branched unsaturated hydrocarbon radical containing from 2 to 6 carbon atoms and at least one triple bond. Examples are C ₂ -C ₄ alkynyl groups such as ethynyl, prop-1-ynyl, prop-2-ynyl (propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, 1- methylprop-2-ynyl.

The term C ₃ -C ₈ -cycloalkyl refers to monocyclic saturated hydrocarbon radicals containing from 3 to 8 carbon atoms - ring members, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The term C3-C ₈ -cycloalkyl-Cl-C ₄ -alkyl refers to an alkyl of 1 to 4 carbon atoms (as defined above), where one hydrogen atom of the alkyl radical is replaced by a cycloalkyl radical of 3 to 8 carbon atoms ( according to the above definition).

The term C ₁ -C ₆ alkoxy refers to a straight or branched chain alkyl group of 1 to 6 carbon atoms that is attached via oxygen at any position in the alkyl group. Examples are C1-C ₄ alkoxy groups such as methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.

The term Cl-C ₆ -halogenoalkoxy refers to a Cl-C ₆ alkoxy radical as defined above, wherein some or all of the hydrogen atoms in this group may be replaced by halogen atoms as mentioned above. Examples are C1-C ₄ -galogenalkoksi groups such as OCH2F, OCHF2, OCF _3, OCH ₂ Cl OCHCl _2, OCCl _3, hlorftormetoksi, dihlorftormetoksi, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, OC2F5, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy, 2 chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 2-bromopropoxy, 3-bromopropoxy, 3,3,3-trifluoropropoxy, 3 , 3,3-trichloropropoxy, OCH ₂ -C ₂ F ₅ , OCF ₂ -C ₂ F ₅ , 1-fluoromethyl-2-fluoroethoxy, 1-chloromethyl-2-chloroethoxy, 1-bromomethyl-2-bromoethoxy, 4-fluorobutoxy, 4 -chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy.

The term phenyl _C1-C6 alkyl refers to alkyl having 1 to 6 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical replaced by a phenyl radical. Likewise, the terms phenyl-C ₂ -C ₆ -alkenyl and phenyl-C ₂ -C ₆ -alkynyl refer to alkenyl and alkynyl, respectively, where one hydrogen atom of the aforementioned radicals is replaced by a phenyl radical.

The meanings and preferred values described below for the variables R ¹ , R ² , R ³ , R ⁴ , n and m apply to compounds and precursors of compounds I, and to by-products in any of the methods of the invention detailed above.

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R ¹ in accordance with the present invention means hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, phenyl, phenyl- C1-C4-alkyl, phenyl-C2-C4-alkenyl or phenyl-C2-C4-alkynyl, where the aliphatic moieties of the radical R ¹ can carry one, two, three or up to the maximum possible number of the same or different groups R ^12a , which independently selected from each other from halogen, OH, CN, nitro, C1-C4 alkoxy, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ halocycloalkyl and C1-C ₄ haloalkoxy; and where the cycloalkyl and / or phenyl moieties of the radical R ¹ can carry one, two, three, four, five, or up to a maximum number of the same or different groups R ^12b , which are independently selected from halogen, OH, CN, nitro, C1 -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C _{1 -C 4} -haloalkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -halogenocycloalkyl and Ci -C ₄ -haloalkoxy.

In accordance with one embodiment, R ¹ is H.

According to a further embodiment of the invention, R ^{1 is} selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkyl -C ₁ -C ₄ -alkula, phenyl, phenyl-C1-C ₄ -alkyl, phenyl-C ₂ -C ₄ alkenyl and phenyl-C ₂ -C ₄ -alkynyl, where R ¹ in each case unsubstituted or substituted by R ^12a and / or R ¹² as defined and preferably defined herein. Specific embodiments of the invention can be found in table. P1.

According to one particular embodiment, R ¹ is C1-C6 alkyl, in particular C1-C4 alkyl such as CH3, C2H5, CH (CH3) 2 or C (CH3) 3. A further embodiment of the invention relates to compounds in which R ¹ _{is C 1 -C 6} -alkyl, in particular C 1 -C 4 -alkyl, which is substituted by one, two or three or up to the maximum possible number of the same or different R ^12a groups as defined and is preferably defined herein. According to a particular embodiment of the invention, R ¹ is C1-C6 haloalkyl, in particular C1-C4 haloalkyl, more preferably C1-C2 haloalkyl such as CF3 or CHF2. According to a further special embodiment, R ¹ is C1-C4-alkoxy-C1-C6-alkyl, in particular C 1 C ₄ -alkoxy-C ₁ -C ₄ -alkyl such as CH2-OCH3. Moreover, specific embodiments of the invention can be found in table. P1.

According to another embodiment, R ¹ is C3-C8 cycloalkyl-C1-C6 alkyl, in particular C3-C6 cycloalkyl-C1-C4 alkyl. A further embodiment of the invention relates to compounds in which R ¹ is _{C 3} -C ₈ -cycloalkyl-C ₁ -C ₆ -alkyl, in particular C _{3 -C 6} -cycloalkyl-C ₁ -C ₄ -alkyl, which is substituted with one, two or three or up to the maximum possible number of the same or different R ^12a groups in the alkyl moiety and / or substituted with one, two, three, four or five or up to the maximum possible number of the same or different R ^12b groups in the cycloalkyl moiety. R ^12a and R ^12b in each occurrence are as defined and preferably defined herein. Specific embodiments of the invention can be found in table. P1.

According to another embodiment, R ¹ is C2-C6 alkenyl, in particular C2-C4 alkenyl, such as CH = CH2, CH2CH = CH2, CH = CHCH3 or C (CH3) = CH2. A further embodiment of the invention relates to compounds in which R ¹ is _{C 2} -C ₆ alkenyl, in particular C _{2 -C 4} alkenyl, which is substituted by one, two or three or up to the maximum possible number of the same or different R ^12a groups, as defined and preferably defined herein. According to a particular embodiment of the invention, R ¹ is C2-C6-haloalkenyl, in particular C2-C4-haloalkenyl. According to a further special embodiment, R ¹ is a C3-C ₈ -cycloalkyl-C ₂ -C ₆ -alkenyl or C ₃ -C ₈ -galogentsikloalkil-C2-C6-alkenyl, in particular C3-C6 cycloalkyl-C2 -C4 alkenyl or C3-C6 halocycloalkylC2-C4 alkenyl. Moreover, specific embodiments of the invention can be found in table. P1.

According to another embodiment, R ¹ is C2-C6 alkynyl, in particular C2-C4 alkynyl such as CbCH. C = CCH3, CH2-C = CH or CH2-C = C-CH3. A further embodiment of the invention relates to compounds wherein R ¹ is C2-C ₆ -alkynyl, in particular C2-C4-alkynyl which is substituted by one, two or three or up to the maximum possible number of identical or different groups R ^12a, as defined and is preferably defined herein. According to a particular embodiment of the invention, R ¹ is C2-C6-haloalkynyl, in particular C2-C4-haloalkynyl. According to a further special embodiment of the invention, R ¹ is C3-C ₈ -cycloalkyl-C ₂ -C ₆ -alkynyl or C ₃ -C ₆ -halocycloalkyl-C ₂ C ₆ -alkynyl, in particular C ₃ -C ₆ -cycloalkyl —C ₂ —C ₄ alkynyl or C ₃ —C ₆ halocycloalkyl — C ₂ —C ₄ alkynyl. Moreover, specific embodiments of the invention can be found in table. P1.

According to yet another embodiment, R ¹ is phenyl-C 1 -C 4 -alkyl, in particular phenyl-C 1 -C 2 -alkyl, such as benzyl, wherein the alkyl moiety is in each case unsubstituted or carries one, two or three R ^12a , as defined and preferably defined herein, in particular selected from halogen, in particular F and Cl, C1-C4 alkoxy, in particular OCH3, and CN, and where phenyl is in each case unsubstituted or carries one, two or three R ^12b, as defined and preferably defined herein, in particular selected from halogen, in particular Cl and F, C1-C4-alkoxy, especially OCH3, _C1-C4-alkyl, in particular CH3 or C2H5, and CN ... Specific embodiments of the invention

- 17 037646 can be found in table. P1.

According to another embodiment, R ¹ is phenyl-C2-C4 alkenyl, in particular phenyl-C2-C3 alkenyl, such as phenylethenyl, in which the alkenyl moiety is unsubstituted at each occurrence or carries one, two or three R ^12a as defined and preferably defined herein, in particular selected from halogen, in particular F and Cl, C1-C4 alkoxy, in particular OCH3, and CN, and where phenyl is in each case unsubstituted or carries one, two or three R ^12b as defined and preferably defined herein, in particular selected from halogen, in particular Cl and F, C1-C4 alkoxy, in particular OCH3, C1-C4 alkyl, in particular CH3 or C2H5, and CN. According to another embodiment, R ¹ is phenyl-C2-C4 alkynyl, in particular phenyl-C2-C3 alkynyl, such as phenylethynyl, in which the alkynyl moiety is in each case unsubstituted or carries one, two or three R ^12a as defined and preferably defined herein, in particular selected from halogen, in particular F and Cl, C1-C4 alkoxy, in particular OCH3, and CN, and where phenyl is in each case unsubstituted or carries one, two or three R ^12b, as defined and preferably defined herein, in particular selected from halogen, in particular Cl and F, _{C1-C4-alkoxy,} especially OCH3, _C1-C4 alkyl, in particular CH3 or C2H5, and CN. Specific embodiments of the invention can be found in table. P1.

According to another embodiment, R ¹ is C3-C8 cycloalkyl, in particular C3-C6 cycloalkyl, such as C3H5 (cyclopropyl), C4H7 (cyclobutyl), cyclopentyl or cyclohexyl. An additional embodiment of the invention relates to compounds in which R ¹ is C3-C ₈ -cycloalkyl, in particular C ₃ -C ₆ -cycloalkyl, such as C ₃ H ₅ (cyclopropyl) or C 4 H 7 (cyclobutyl), which is substituted with one, two , three, four or five, or up to the maximum possible number of the same or different R ^12b groups as defined and preferably defined herein. According to a particular embodiment of the invention, R ¹ is C3-C8-halocycloalkyl, in particular C3-C6-halocycloalkyl, such as halocyclopropyl, in particular 1-E-cyclopropyl or 1-Cbcyclopropyl. According to a further special embodiment of the invention, R ¹ is C3-C ₈ -cycloalkyl-C ₃ -C ₈ -cycloalkyl, in particular C ₃ -C ₆ -cycloalkyl-C ₃ -C ₆ -cycloalkyl, wherein each of said cycloalkyl- cycloalkyl moieties are unsubstituted or bears one, two or three R ^12b as defined and preferably defined herein, such as 1-cyclopropyl-cyclopropyl or 2-cyclopropyl-cyclopropyl. Specific embodiments of the invention can be found in table. P1.

According to another embodiment, R ¹ is phenyl, where phenyl is unsubstituted or carries one, two, three, four or five independently selected R ^12b as defined and preferably defined herein, in particular selected from halogen, in particular , Cl and F, _C1-C4 alkoxy, in particular OCH3, C ₁ -C ₄ alkyl, in particular CH3 or _C2 H5, and CN. Specific embodiments of the invention can be found in table. P1.

In a further embodiment, R ^{1 is} selected from hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, and C ₃ -C ₆ cycloalkyl, wherein R ¹ is not in each case substituted or substituted by R ^12a and / or R ^12b as defined and preferably defined herein. In each case, the substituents may also have preferred meanings for the corresponding substituent as defined above. Specific embodiments of the invention can be found in table. P1.

Particularly preferred embodiments of R ¹ in accordance with the invention are shown in table. P1, in which each line of lines P1-1 to P1-160 corresponds to one particular embodiment of the invention, and in which lines P1-1 to P1-160 also represent, in any combination, a preferred embodiment of the present invention.

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Table P1

line R ¹ P1-1 H P1-2 SNz P1-3 CH ₂ CH ₃ P1-4 CH ₂ CH ₂ CH ₃ R1-5 CH (CH ₃ ) ₂ R1-6 C (CH ₃ ) s R1-7 CH (CHs) CH ₂ CH ₃ P1-8 CH ₂ CH (CH ₃ ) ₂ R1-9 CH ₂ CH ₂ CH ₂ CHs P1-10 CF ₃ R1-11 chf ₂ P1-12 ch ₂ f R1-13 SNS1 ₂ P1-14 CH ₂ C1 P1-15 CH ₂ OH R1-16 CH ₂ CH ₂ OH P1-17 CH ₂ CH ₂ CH ₂ OH P1-18 CH (CHs) CH ₂ OH R1-19 CH ₂ CH (CHs) OH P1-20 CH ₂ CH ₂ CH ₂ CH ₂ OH P1-21 CH (CH ₃ ) CN P1-22 ch ₂ ch ₂ cn P1-23 ch ₂ cn R1-24 ch ₂ ch ₂ cn R1-25 CH ₂ CH ₂ CH ₂ CN, P1-26 CH (CH ₃ ) CH ₂ CN P1-27 CH ₂ CH (CH ₃ ) CN P1-28 CH ₂ CH ₂ CH ₂ CH ₂ CN P1-29 CH ₂ OCH ₃ P1-30 CH ₂ OCH ₂ CH ₃ P1-31 CH (CHs) OCHs P1-32 CH (CHs) OCH ₂ CHs P1-33 CH ₂ CH ₂ OCH ₂ CHs P1-34 CH ₂ OCF ₃ P1-35 ch ₂ ch ₂ ocf ₃ P1-36 СН ₂ ОСС1з P1-37 CH ₂ CH ₂ OCC1z P1-38 ch = ch ₂ P1-39 CH ₂ CH = CH ₂ P1-40 CH ₂ CH = CHCH3 P1-41 CH ₂ C (CHs) = CH ₂ P1-42 CH ₂ C (CHs) = CHCHs P1-43 CH ₂ C (CHs) = C (CHs) ₂ P1-44 CH = SNCH3 P1-45 C (CHs) = CH ₂ P1-46 CH = C (CHs) ₂ P1-47 C (CHs) = C (CHs) ₂ P1-48 C (CHs) = CH (CHs) P1-49 C (C1) = CH ₂ P1-50 C (H) = CHC1 P1-51 C (C1) = CHC1 P1-52 CH = CC1 ₂ P1-53 C (C1) = CC1 ₂ P1-54 C (H) = CH (F) P1-55 C (H) = CF ₂ P1-56 C (F) = CF ₂ P1-57 C (F) = CHF P1-58 CH = CHCH ₂ OH R1-59 СН = СНОСНз P1-60 CH = CHSN ₂ OCHs P1-61 CH = CHCH ₂ OCF ₃ P1-62 СН = СССН ₂ ОСС1з P1-63 СН = СН (СзН ₅ ) P1-64 CH = CH (C ₄ H ₇ )

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Pl-65 CH = CH (1-C1-C ₃ H ₄ ) Pl-66 CH = CH (1-FC ₃ H ₄ ) Pl-67 CH = CH (1-C1-C ₄ H ₆ ) Pl-68 CH = CH (1-FC ₄ H ₆ ) Pl-69 cxch Pl-70 CCCNs Pl-71 CH ₂ CXCCH ₃ Pl-72 CH ₂ OCH Pl-73 CH ₂ C = CCH ₂ CH ₃ Pl-74 C = CCH (CH ₃ ) ₂ Pl-75 C = CC (CH ₃ ) ₃ Pl-76 CXC (C ₃ H ₅ ) Pl-77 C = C (C ₄ H ₇ ) Pl-78 CXCCI-C1-C ₃ H ₄ ) Pl-79 C = C (1-C1-C ₄ Nb) Pl-80 excel Pl-81 CXCBr Pl-82 CXC-I Pl-83 ch _{2 excc1} Pl-84 sn ₂ exsvg Pl-85 CH ₂ CXC-I Pl-86 CXCCH ₂ 0CH ₃ Pl-87 CXCCH (OH) CH ₃ Pl-88 CXCCH (0CH ₃ ) CH ₃ Pl-89 СХСОСНз Pl-90 CH ₂ CXC0CH ₃ Pl-91 CXCCH ₂ OCCI ₃ Pl-92 cxcch ₂ ocf ₃ Pl-93 CXCCH ₂ (C ₃ H ₅ ) Pl-94 C = CCH ₂ (C ₄ H ₇ ) Pl-95 oxen-ci-c ₃ h ₄ ) Pl-96 oxen-fc ₃ h ₄ ) Pl-97 C = C (1-C1-C ₄ Nb) Pl-98 oxen-fc ₄ h ₆ ) Pl-99 C ₃ H ₅ (cyclopropyl) Pl-100 C ₄ H ₇ (cyclobutyl) Pl-101 C5H9 (cyclopentyl) Pl-102 cyclohexyl Pl-103 CH (CH ₃ ) -C ₃ H ₅ (CH (CH ₃ ) -cyclopropyl) Pl-104 CH ₂ -C ₃ H ₅ (CH ₂ cyclopropyl) Pl-105 1 - (C1) -cyclopropyl Pl-106 1 - (P) -cyclopropyl Pl-107 1 - (CH ₃ ) -cyclopropyl Pl-108 1 - (CH) -cyclopropyl

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P1-109 2- (C1) -cyclopropyl P1-110 2- (P) -cyclopropyl P1-111 1 - (C1) -cyclobutyl P1-112 1 - (P) -cyclobutyl P1-113 2- (C1) -cyclobutyl R1-114 3 - (C1) -cyclobutyl P1-115 2- (P) -cyclobutyl P1-116 3- (P) -cyclobutyl R1-117 3,3 -C1 ₂ -cyclobutyl P1-118 3,3 -P ₂ -cycle shoe R1-119 2- (CH ₃ ) -cyclopropyl P1-120 1 - (CHs) -cyclobutyl P1-121 2- (CH ₃ ) -cyclobutyl P1-122 3 - (CHs) -cyclobutyl P1-123 3.3 - (CH ₃ ) ₂ -cyclobutyl P1-124 2- (SK) -cyclopropyl P1-125 1-cyclopropyl-cyclopropyl P1-126 2-cyclopropyl-cyclopropyl P1-127 CH (CH ₃ ) (cyclobutyl) P1-128 CH ₂ - (cyclobutyl) P1-129 CH ₂ CH ₂ - (cyclopropyl) P1-130 CH ₂ CH ₂ - (cyclobutyl) R1-131 CH ₂ - (1 -C1-cyclopropyl) R1-132 CH ₂ - (1-F-cyclopropyl) R1-133 CH ₂ - (1-C1-cycle shod) R1-134 CH ₂ - (1-F-cyclobutyl) R1-135 CHCH3- (1-C1-cyclopropyl) R1-136 C (CH ₃ ) ₂ - (1 -F-cyclopropyl) R1-137 from _{6 to 5} R1-138 4-C1-C ₆ H ₄ R1-139 4-OCHs-C ₆ H ₄ P1-140 4-CHs-C ₆ H ₄ P1-141 4-FC ₆ H ₄ P1-142 2,4-F ₂ -C ₆ H ₃ P1-143 2,4-C1 ₂ -C ₆ Ns P1-144 2-CHs-C ₆ H ₄ P1-145 2-CF ₃ -C ₆ H ₄ P1-146 4-CHs-C ₆ H ₄ P1-147 4-CF ₃ -C ₆ H ₄ P1-148 2-OCHs-C ₆ H ₄ P1-149 2-OCF ₃ -C ₆ H ₄ P1-150 4-OCHs-C ₆ H ₄ P1-151 4-OCF ₃ -C ₆ H ₄ P1-152 2,4,6-F ₃ -C ₆ H ₂ P1-153 2,4,6-C1s-C ₆ H ₂ P1-154 sn ₂ s ₆ n ₅ P1-155 CH ₂ - (4-C1) -C ₆ H ₄ P1-156 CH ₂ - (4-CHs) -C ₆ H ₄ P1-157 CH ₂ - (4-OCHs) -C ₆ H ₄ P1-158 CH ₂ - (4-F) -C ₆ H ₄ P1-159 CH ₂ - (2,4-C1 ₂ ) -C ₆ Hs P1-160 CH ₂ - (2,4-F ₂ ) -C ₆ H ₃

R ² in compounds 1-1 obtained in accordance with the present invention, or in their precursors, means C1-C6-αalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C3-C8-cycloalkyl- C1C6-alkyl, phenyl, phenyl-C1-C4-alkyl, phenyl-C2-C4-alkenyl or phenyl-C2-C4-alkynyl, where the aliphatic groups of the radical R ² can carry one, two, three or up to the maximum possible number of the same or different groups R ^12a , which are independently selected from halogen, OH, CN, nitro _{, C 1} C ₄ alkoxy, C _{3 -C 8} cycloalkyl, C ₃ -C ₈ halocycloalkyl and _{C 1 -C 4} haloalkoxy; and where the cycloalkyl and / or phenyl moieties of the radical R ² can carry one, two, three, four, five, or up to a maximum number of the same or different groups R ^12b , which are independently selected from halogen, OH, CN, nitro, C1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, _{C 1} -C ₄ -haloalkyl, C _{3 -C 8} -cycloalkyl, Q- ^ halocycloalkyl and _{C 1 -C 4} -haloalkoxy.

According to a further embodiment of the invention, R ^{2 is} selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkyl -C ₁ -C ₄ -alkyl, phenyl, phenyl-C1-C ₄ -alkyl, phenyl-C ₂ -C ₄ alkenyl and phenyl-C ₂ -C ₄ -alkynyl, where R ² in each case are unsubstituted or substituted by R ^12a and / or R ^12b as defined and preferably defined herein. Specific embodiments of the invention can be found in table. P2.

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According to one particular embodiment, R ² is C1-C6 alkyl, in particular C1-Cd alkyl such as CH3, C2H5, CH (CH3) 2, CH2CH2CH3, CH2CH2CH2CH3, CH2CH (CH3) 2. An additional embodiment of the invention relates to compounds in which R ² _{is C 1} -C ₆ -alkyl, in particular C 1 -C 4 -alkyl, which is substituted by one, two or three or up to the maximum possible number of the same or different groups R 12 ^a , such as defined and preferably defined herein. According to a particular embodiment of the invention, R ² is C1-C6-haloalkyl, in particular C1-C4-haloalkyl, more preferably C1-C2-haloalkyl. According to a further special embodiment, R ² represents a _C1-C4 -alkoksiS1-C ₆ -alkyl, in particular C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, such as CH2OCH3, or CH ₂ CH ₂ OCH ₃ . In accordance with another particular embodiment, R ² is hydroxy-C1-C6-alkyl, in particular _{hydroxy-C1-C4} alkyl, such as CH ₂ CH ₂ OH. Moreover, specific embodiments of the invention can be found in table. P2

According to another embodiment, R ² is C3-C8 cycloαalkyl-C1-C6 alkyl, in particular C3-C6 cycloalkyl-C1-C4 alkyl. An additional embodiment of the invention relates to compounds in which R ² is C3-C ₈ -cycloalkyl-C ₁ -C ₆ -alkyl, in particular C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl, more preferably C ₃ -C ₆ -cycloalkyl-C ₁ -C ₂ -alkyl, which is substituted with one, two or three or up to the maximum possible number of the same or different R ^12a groups in the alkyl moiety and / or is substituted with one, two, three, four or five, or up to the maximum possible number of the same or different R ^12b groups in the cycloalkyl moiety. R ^12a and R ^12b in each occurrence are as defined and preferably defined herein. Specific embodiments of the invention can be found in table. P2.

According to another embodiment, R ² is C2-C6 alkenyl, in particular C2-C4 alkenyl, such as CH2CH = CH2, CH2C (CH3) = CH2 or CH2CH = CHCH3. A further embodiment of the invention relates to compounds in which R ² is C2-C6 alkenyl, in particular C2-C4 alkenyl, which is substituted with one, two or three or up to the maximum possible number of the same or different R ^12a groups as defined and preferably as defined herein. According to a particular embodiment of the invention, R ² is _{C 2} -C ₆ -haloalkenyl, in particular C _{2 -C 4} -haloalkenyl, such as CH ₂ C (Cl) = CH ₂ and CH ₂ C (H) = CHCl. According to a further special embodiment of the invention, R ² is C ₃ -C ₈ -cycloalkyl-C ₂ -C ₆ -alkenyl or C ₃ -C ₈ -halocycloalkyl-C ₂ -C ₆ -alkenyl, in particular C ₃ -C ₆ -cycloalkyl-C ₂ -C ₄ -alkenyl or C ₃ -C ₆ -halocycloalkyl-C ₂ -C ₄ -alkenyl. Moreover, specific embodiments of the invention can be found in table. P2.

According to another embodiment, R ² is C2-C6 alkynyl, in particular C2-C4 alkynyl, such as CH2C ^ CH or CH2C ^ CCH3. A further embodiment of the invention relates to compounds in which R ² is _{C 2} -C ₆ alkynyl, in particular C _{2 -C 4} alkynyl, which is substituted by one, two or three or up to as many as possible identical or different R ^12a groups, as defined and preferably defined herein. According to a particular embodiment of the invention, R ² is C2-C6 haloalkynyl, in particular C2C4 haloalkynyl. According to a further special embodiment of the invention, R ² is C3-C ₈ -cycloalkyl-C ₂ -C ₆ -alkynyl or C ₃ -C ₈ -halocycloalkyl-C ₂ -C ₆ -alkynyl, in particular C ₃ C ₆ -cycloalkyl —C ₂ —C ₄ alkynyl or C ₃ —C ₆ halocycloalkyl — C ₂ —C ₄ alkynyl. Specific embodiments of the invention can be found in table. P2.

According to another embodiment, R ² is phenyl-C1-C4-alkyl, in particular phenyl-C1-C2-alkyl, such as benzyl, wherein the alkyl moiety is in each case unsubstituted or carries one, two or three R ^12a , as defined and preferably defined herein, in particular selected from halogen, in particular F and Cl, C1-C4 alkoxy, in particular OCH3, and CN, and where phenyl is in each case unsubstituted or carries one, two or three R ^12b, as defined and preferably defined herein, in particular selected from halogen, in particular Cl and F, C1-C4-alkoxy, especially OCH3, _C1-C4-alkyl, in particular CH3 or C ₂ H ₅ , and CN. Specific embodiments of the invention can be found in table. P2.

According to another embodiment, R ² is phenyl-C2-C4-alkenyl, in particular phenyl-C2-C3-alkenyl, such as phenylethenyl, in which the alkenyl moiety is in each case unsubstituted or carries one, two or three R ^12a as defined and preferably defined herein, in particular selected from halogen, in particular F and Cl, C1-C4 alkoxy, in particular OCH3, and CN, and where phenyl is in each case unsubstituted or carries one, two or three R ^12b, as defined and preferably defined herein, in particular selected from halogen, in particular Cl and F, C1-C4alkoxy, especially OCH3, _C1-C4-alkyl, in particular CH3 or C ₂ H _5, and CN.

According to another embodiment, R ² is phenyl-C2-C4 alkynyl, in particular phenyl-C2-C3 alkynyl, such as phenylethynyl, in which the alkynyl moiety is in each case unsubstituted or carries one, two or three R ^12a as defined and preferably defined herein, in particular selected from halogen, in particular F and Cl, C1-C4 alkoxy, in particular OCH3, and CN, and where phenyl is in each case unsubstituted or carries one, two or three R ^12b, as defined and preferred 22 037 646 Tel'nykh defined herein, in particular selected from halogen, in particular Cl and F, _{C1-C4-alkoxy,} especially OCH3, _C1-C4-alkyl, in particular CH3 or C2H5 and CN.

According to another embodiment, R2 is C ₃ -C ₈ cycloalkyl, in particular C ₃ -C ₆ cycloalkyl, such as C ₃ H ₅ (cyclopropyl), C 4 H 7 (cyclobutyl), cyclopentyl or cyclohexyl. An additional embodiment of the invention relates to compounds in which R2 is C ₃ -C ₈ -cycloalkyl, in particular C ₃ -C ₆ -cycloalkyl, such as C3H5 (cyclopropyl) or C ₄ H ₇ (cyclobutyl), which is substituted with one, two , three, four or five, or up to the maximum possible number of the same or different R ^12b groups as defined and preferably defined herein. According to a particular embodiment of the invention, R ² is C3-C8-halocycloalkyl, in particular C3-C6-halocycloalkyl, such as halocyclopropyl, in particular 1-E-cyclopropyl or 1-C1-cyclopropyl. According to a further special embodiment of the invention, R ² is C3-C ₈ -cycloalkyl-C ₃ -C ₈ -cycloalkyl, in particular C ₃ -C ₆ -cycloalkyl-C ₃ -C ₆ -cycloalkyl, wherein each of said cycloalkyl- cycloalkyl moieties are unsubstituted or bears one, two or three R ^12b as defined and preferably defined herein.

According to another embodiment, R ² is phenyl, where phenyl is unsubstituted or carries one, two, three, four or five independently selected R ^12b as defined and preferably defined herein, in particular selected from halogen, in particular Cl and F, _{C1-C4-alkoxy,} especially OCH3, _C1-C4-alkyl, in particular CH3 or C2H5, and CN.

In a further embodiment, R ^{2 is} selected from C ₁ -C ₆ alkyl, C _{2 -C 6} alkenyl, and C ₂ -C ₆ alkynyl, wherein R ^{2 is} in each case unsubstituted or substituted with R ^12a and / or R ^12b as defined and preferably defined herein. In each case, the substituents may also have preferred meanings for the corresponding substituent as defined above. Specific embodiments of the invention can be found in table. P2.

R ^12a are optional substituents for any aliphatic moiety of the radical R ¹ and / or R ² and can be independently defined for R ¹ and R ² .

R ^12a according to the invention is independently selected from halogen, OH, CN, nitro, C ₁ -C ₄ alkoxy, C _{3 -C 8} cycloalkyl, C ₃ -C ₈ halocycloalkyl and C _{1 -C 4} haloalkoxy.

According to one embodiment, R ^{12a is} independently selected from halogen, OH, CN, C1-C2 alkoxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, and C1-C2 haloalkoxy. In particular, R ^12a are independently selected from F, Cl, OH, CN, C1-C2 alkoxy, cyclopropyl, 1-F-cyclopropyl, 1-O-cyclopropyl, and _C1-C2 -galogenalkoksi.

R ^12b are optional substituents for any cycloalkyl and / or phenyl moiety of the radical R ¹ and / or R ² and can be independently defined for R ¹ and R ² .

R ^12b according to the invention is independently selected from halogen, OH, CN, nitro, C ₁ -C ₄ -alkyl, C _{1 -C 4} -alkoxy, C _{1 -C 4} -halogenoalkyl, C ₃ -C ₈ -cycloalkyl, C ₃ - C ₈ -halocycloalkyl; and C1-C4-haloalkoxy.

In accordance with one embodiment, R ^{12b is} independently selected from halogen, CN, nitro, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, and C1-C2 -halogenoalkoxy. In particular, R ^{12b is} independently selected from F, Cl, OH, CN, nitro, CH3, OCH ₃ , cyclopropyl, 1-E-cyclopropyl, 1-Cbcyclopropyl and halomethoxy.

Particularly preferred embodiments of R ² in accordance with the invention are shown in table. P2, in which each line of lines P2-1 to P2-87 corresponds to one particular embodiment of the invention, and in which lines P2-1 to P2-87 also represent a preferred embodiment of the present invention in any combination.

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Table P2

line R ² P2-1 SNz P2-2 CH ₂ CH ₃ P2-3 CH (CH ₃ ) ₂ P2-4 CH ₂ CH ₂ CH ₃ P2-5 CH ₂ CH ₂ CH ₂ CHs P2-6 CH ₂ CH (CHs) ₂ P2-7 CF ₃ . P2-8 chf ₂ P2-9 cfh ₂ P2-10 CC1 ₃ . P2-11 SNS1 ₂ P2-12 CC1H ₂ P2-13 CH ₂ CF3 P2-14 ch ₂ chf ₂ P2-15 CH ₂ CC1z P2-16 CH ₂ SNS1 ₂ P2-17 CH ₂ CH ₂ OCH ₂ CHs P2-18 CH (CHs) OCH ₂ CHs P2-19 CH (CHs) OCHs P2-20 CH ₂ OCHs P2-21 CH ₂ CH ₂ OCHs P2-22 CH ₂ OCF ₃ P2-23 ch ₂ ch ₂ ocf ₃ P2-24 СН ₂ ОСС1з P2-25 CH ₂ CH ₂ OCC1z P2-26 CH ₂ CH ₂ OH P2-27 CH ₂ OH P2-28 CH ₂ CH ₂ CH ₂ OH, P2-29 CH (CHs) CH ₂ OH P2-30 CH ₂ CH (CHs) OH P2-31 CH ₂ CH ₂ CH ₂ CH ₂ OH P2-32 ch ₂ cn, P2-33 ch ₂ ch ₂ cn, P2-34 ch ₂ ch ₂ ch ₂ cn, P2-35 CH (CH ₃ ) CH ₂ CN, P2-36 CH ₂ CH (CH ₃ ) CN, P2-37 ch ₂ ch ₂ ch ₂ ch ₂ cn P2-38 CH = CH ₂ P2-39 C (CH ₃ ) = CH ₂ P2-40 CH = CHCH ₃ P2-41 CH ₂ CH = CH ₂ P2-42 CH ₂ CH = CHCH ₃ P2-43 CH ₂ C (CH ₃ ) = CH ₂ P2-44 C (CHs) = CH (CHs) P2-45 C (CHs) = C (CHs) ₂ P2-46 CH = C (CHs) ₂

- 24 037646

P2-47 CH = C (C1) ₂ P2-48 C (CHs) = CH ₂ P2-49 CH ₂ C (C1) -CH ₂ P2-50 CH ₂ C (H) = CHC1 P2-51 CH = CHCH ₂ OH P2-52 CH = C (CH ₃ ) OH P2-53 СН = СНОСНз P2-54 CH = CHSN ₂ OCHs P2-55 CH ₂ CH = CHCH ₂ OCH3 P2-56 CH = CHOCF ₃ P2-57 CH = CHCH ₂ OCF ₃ P2-58 СН = СНОСС1з P2-59 СН = СССН ₂ ОСС1з P2-60 CH ₂ CH = CH (CH ₅ ) P2-61 CH ₂ CH = CH (C ₄ H ₇ ) P2-62 CH ₂ CH = CH (1-C1-C ₃ H ₄ ) P2-63 CH ₂ CH = CH (1-FC ₃ H ₄ ) P2-64 s = cn P2-65 CH ₂ C = CH P2-66 CH ₂ C = CCHs P2-67 СН ₂ С = СН _{2 СНз} P2-68 CH ₂ C = CC1 P2-69 ch ₂ c = cf P2-70 CH ₂ C = C-1 P2-71 CH ₂ C = CCH ₂ OH P2-72 CLOCCH3 P2-73 CH ₂ C = COCH3 P2-74 CH ₂ C = СССН ₂ ОСНз P2-75 C = COCF ₃ P2-76 CH ₂ C = COCF ₃ P2-77 С = СОСС1з P2-78 СН ₂ С = СОСС1з P2-79 CH ₂ - (cyclopropyl) P2-80 CH ₂ - (cyclobutyl) P2-81 CH ₂ - (1-C1-cyclopropyl) P2-82 CH ₂ - (1-P-cyclopropyl) P2-83 sn ₂ s ₆ n ₅ P2-84 CH ₂ - (4-C1) -C ₆ H ₄ P2-85 CH ₂ - (4-F) -C ₆ H ₄ P2-86 CH ₂ - (4-CHs) -C ₆ H ₄ P2-87 CH ₂ - (4-OCHs) -C ₆ H ₄

Particularly preferred variants of the combination of radicals R ¹ and R ² in accordance with the invention are shown in table. A, in which each line of lines A-1 to A-56 corresponds to one particular embodiment of the invention, and in which lines A-1 to A-56 also in any combination represent a preferred variant of the combinations of radicals R ¹ and R ^{2 of the} present invention.

- 25 037646

Table A

line R ¹ R ² A-1 H SNz A-2 CH ₃ SNz A-3 CH ₂ CH ₃ SNz A-4 CH (CH ₃ ) ₂ SNz A-5 C ₃ H ₅ (cyclopropyl) SNz A-6 C4H7 (cyclobutyl) SNz A-7 SASSNz SNz A-8 C (CH ₃ ) s SNz A-9 CF ₃ SNz A-10 chf ₂ SNz A-11 CH = CHCH ₃ SNz A-12 C (CH ₃ ) = CH ₂ SNz A-13 1- (C1) cyclopropyl SNz A-14 1- (F) - cyclopropyl SNz A-15 n CH ₂ CH ₃ A-16 SNz CH ₂ CH3 A-17 CH ₂ CH3 CH ₂ CH3 A-18 CH (CH ₃ ) ₂ CH ₂ CH3 A-19 C ₃ H ₅ (cyclopropyl) CH ₂ CH3 A-20 C4H7 (cyclobutyl) CH ₂ CH3 A-21 SASSNz CH ₂ CH3 A-22 C (CH ₃ ) s CH ₂ CH3 A-23 CF ₃ CH ₂ CH3 A-24 chf ₂ CH ₂ CH ₃ A-25 CH = CHCH ₃ CH ₂ CH3 A-26 C (CH ₃ ) = CH ₂ CH ₂ CH3 A-27 1- (C1) cyclopropyl CH ₂ CH3 A-28 1- (F) - cyclopropyl CH ₂ CH ₃ A-29 n CH ₂ -CH = CH ₂

- 26 037646

A-30 SNz CH ₂ -CH = CH ₂ A-31 CH ₂ CH ₃ CH ₂ -CH = CH ₂ A-32 CH (CH ₃ ) ₂ CH ₂ -CH = CH ₂ A-33 C ₃ H ₅ (cyclopropyl) CH ₂ -CH = CH ₂ A-34 s ₄ n ₇ (cyclobutyl) CH ₂ -CH = CH ₂ A-35 CCCNs sn ₂ -sn = sn ₂ A-36 C (CH ₃ ) s sn ₂ -sn = sn ₂ A-37 CF ₃ sn ₂ -sn = sn ₂ A-38 chf ₂ sn ₂ -sn = sn ₂ A-39 CH = CHCH ₃ sn ₂ -sn = sn ₂ A-40 C (CH ₃ ) = CH ₂ sn ₂ -sn = sn ₂ A-41 1- (C1) cyclopropyl sn ₂ -sn = sn ₂ A-42 1- (F) - cyclopropyl sn ₂ -sn = sn ₂ A-43 n CH ₂ -C = CH A-44 SNz sn ₂ -s = s-n A-45 CH ₂ CH ₃ CH ₂ -C = CH A-46 CH (CH ₃ ) ₂ CH ₂ -C = CH A-47 C ₃ H ₅ (cyclopropyl) sn ₂ -s = s-n A-48 C ₄ n ₇ (cyclobutyl) CH ₂ -C = CH A-49 CCCNs sn ₂ -s = s-n A-50 C (CH ₃ ) s sn ₂ -s = s-n A-51 CF ₃ CH ₂ -C = CH A-52 chf ₂ sn ₂ -s = s-n A-53 CH = CHCH ₃ sn ₂ -s = s-n A-54 C (CH ₃ ) = CH ₂ CH ₂ -C = CH A-55 1- (C1) - cyclopropyl sn ₂ -s = s-n A-56 1- (F) - cyclopropyl CH ₂ -C = CH

According to the invention, zero, one, two, three or four R ³ may be present, namely for n being 0, 1, 2, 3 or 4,

In accordance with one embodiment, n is 0.

In a further embodiment, n is 1. In accordance with another further embodiment, n is 1 or 2.

In accordance with another further embodiment, n is 2 or 3. In accordance with one particular embodiment of the invention, n is 2, in accordance with a further special embodiment, n is 3.

In accordance with one embodiment of the invention, one R is attached to the 2-position (R ³¹ ). According to one particular embodiment of the invention, n is 1, according to a further special embodiment, n is 2.

In accordance with one embodiment of the invention, one R ^{3 is} attached to the 3-position (R ³² ). According to one particular embodiment of the invention, n is 1, according to a further special embodiment, n is 2.

According to a further embodiment of the invention, one R is attached to the 5-position (R ³⁴ ). According to one particular embodiment of the invention, n is 1, according to a further special embodiment, n is 2.

In accordance with yet another further embodiment, n is 1, 2, or 3 and one R ³ is at position 2 or 6.

According to a further embodiment of the invention, the two R ^{3 are} attached at 2,3-positions. According to one particular embodiment of the invention, n is 2, according to a further special embodiment, n is 3.

According to a further embodiment of the invention, the two R ^{3 are} attached at 2,5-positions. According to one particular embodiment of the invention, n is 2, according to a further special embodiment, n is 3.

According to a further embodiment of the invention, the two R ^{3 are} attached at 2,6-positions. In accordance with one particular embodiment of the invention, n takes the value 2, in accordance with a further special embodiment, n takes

- 27 037646 value 3.

In accordance with a further embodiment of the invention, two R ^{3 are} attached in

3.5-position. According to one particular embodiment of the invention, n is 2, according to a further special embodiment, n is 3.

For each R ³ (or R ³¹ , R ³² , R ³⁴ , R ^35, respectively) that is present in the compounds according to the invention, the following embodiments and preferences apply regardless of the meaning of any other R ³ (or R ³¹ , R ³² , R ³³ , R ³⁴ , R ^35, respectively), which may be present on the phenyl ring. In addition, the individual embodiments and preferences given herein for R ³ (or R ³¹ , R32, R ³³ , R ³⁴ , R ^35, respectively) apply independently for each case n = 1, n = 2, n = 3 and n = 4.

In accordance with the invention, each R ^{3 is} independently selected from halogen, CN, NO2, OH, SH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ - alkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyloxy, NH2, NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ , NH (C ₃ -C ₆ -cycloalkyl), N (C ₃ -C ₆ -cycloalkyl) ₂ , S (O) _p (C ₁ -C ₄ alkyl), C (= O) (C1-C ₄ -alkyl), C (= O) ( OH), C (= O) (O-C1-C ₄ -alkyl), C (= O) (NH (C ₁ -C ₄ -alkyl)),

C (= O) (N (C ₁ -C ₄ -alkyl) ₂ ), C (= O) (NH (C ₃ -C ₆ -cycloalkyl)) and C (= O) - (N (C ₃ -C ₆ -cycloalkyl) ₂ ); where each of R ³ is unsubstituted or further substituted by one, two, three or four R ^3a ; wherein R ^3a is independently selected from halogen, CN, NO2, OH, _C1-C4 alkyl, C1-C ₄ -haloalkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -galogentsikloalkila, _C1-C4 alkoxy and _C1-C4 -galogenalkoksi.

In accordance with one embodiment R ^{3 is} independently selected from halogen, CN, NO2, _C1-C4 alkyl, _C1-C4 -haloalkyl, _C1-C4 alkoxy, _C1-C4 -galogenalkoksi, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -haloalkenyl, C ₂ -C ₄ -alkynyl, C ₂ -C ₄ -haloalkynyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -halocycloalkyl, S (C ₁ -C ₂ -alkyl), S (O) (C ₁ -C ₂ -alkyl), S (O) ₂ (C ₁ -C ₂ -alkyl), C (= O) (C1-C ₂ -alkyl), C (= O) (OH) and C (= O) (O-C1-C2-alkyl).

According to a further embodiment, R ^{3 is} independently selected from halogen, CN, NO ₂ , OH, SH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C _6- alkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloαalkyloxy, NH2, NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ , NH (C ₃ - C ₆ -cycloalkyl), N (C ₃ -C ₆ cycloalkyl) ₂ , S (O) _p (C ₁ -C ₄ -alkyl) (p = 0, 1 or 2), C (= O) (C1-C ₄ -alkyl), C (= O) (OH), C (= O) (O-C ₁ -C ₄ alkyl), C (= O) (NH (C ₁ -C ₄ -alkyl)), C ( = O) (N (C ₁ -C ₄ -alkyl) ₂ ), C (= O) (NH (C ₃ -C ₆ -cycloαalkyl)) and C (= O) (N (C ₃ -C ₆ -cycloαalkyl ) ₂ ); where each of R ³ is unsubstituted or further substituted by one, two, three or four R ^3a , where R ^3a is as defined and preferably defined herein.

According to yet another further embodiment, R ^{3 is} independently selected from halogen, CN, NO2, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy , C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, C2-C4-haloalkynyl, C3-C6-cycloalkyl, C ₃ -C ₆ -halogenocycloalkyl, S (C ₁ -C ₂ -alkyl), S (O) (C ₁ -C ₂ -alkyl), S (O) ₂ (C ₁ -C ₂ -alkyl), C (= O) (C ₁ -C ₂ alkyl), C (= O) (OH ) and C (= O) (O-C ₁ -C ₂ -alkyl).

In accordance with yet a further embodiment of R ^{3 is} independently selected from F, Cl, Br, CN, _C1-C4 alkyl, _C1-C4 -haloalkyl, _C1-C4 alkoxy, _C1-C4 -galogenalkoksi, S (C ₁ -C ₄ -alkyl), S (O) (C ₁ -C ₄ -alkyl) and S (O) ₂ (C ₁ -C ₄ -alkyl).

According to one particular embodiment, R ³ is halogen, in particular Br, F or Cl, in particular F or Cl.

According to a further special embodiment, R ³ is CN.

According to a further special embodiment, R ³ is C ₁ -C ₆ -alkyl, in particular _{C 1 -C 4} -alkyl, such as CH3.

According to a further special embodiment, R ³ is C ₁ -C ₆ -haloalkyl, in particular C1-C ₄ -haloalkyl, such as CF ₃ , CHF2, CH2F, CCl ₃ , CHCl ₂ or CH ₂ Cl.

According to a further special embodiment, R ³ is C ₁ -C ₆ alkoxy, in particular C1-C ₄ alkoxy, in particular C1-C ₂ alkoxy, such as OCH3 or OCH2CH3.

According to a further special embodiment, R ³ is C ₁ -C ₆ -haloalkoxy, in particular C1-C ₄ -haloalkoxy, in particular C1-C ₂ -haloalkoxy, such as OCF3, OCHF2, OCH2F, OCCl3, OCHCl2 or OCH2Cl, in particular OCF3, OCHF2, OCCl3 or OCHCl2.

According to a further further embodiment, R ³ is C ₂ -C ₆ alkenyl or C ₂ -C ₆ haloalkenyl, in particular C ₂ -C ₄ alkenyl or C ₂ -C ₄ haloalkenyl such as CH = CH ₂ .

According to a further further embodiment, R ³ is C2-C6 alkynyl or C ₂ -C ₆ haloalkynyl, in particular C ₂ -C ₄ alkynyl or C ₂ -C ₄ haloalkynyl such as G ^ CH.

In accordance with yet another additional embodiment, R ^{3 is} selected from C (= O) (C1-C4-alkyl), C (= O) (OH), C (= O) (O-C1-C4-alkyl), C (= O) (NH (C1-C4-alkyl)), C (= O) (M (C1-C4 alkyl) 2), C (= O) (NH (C3-C6-cycloalkyl)) and C (= O ) (N (C3-C6-cycloαalkyl) 2), in particular selected from C (= O) (C1-C2-alkyl), C (= O) (OH), C (= O) (O-C1-C2 -alkyl), C (= O) (NH (C1-C2-alkyl)), C (= O) (N (C1-C2 alkyl) 2), C (= O) (NH (C3-C6-cycloalkyl)) and C (= O) (N (C3-C6-cycloαalkyl) 2). According to one particular embodiment of the invention, R ³ is C (= O) (OH) or C (= O) (O — C1 — C4 alkyl), in particular C (= O) (OCH3).

In accordance with yet a further embodiment of R ³ is selected from eight _(C1-C2 alkyl), S (O) (C ₁ -C ₂ alkyl) and S (O) ₂ (C ₁ -C ₂ -alkyl), in particular SCH3, S (O) (CH ₃ ) and S (O) ₂ (CH ₃ ).

R ^{3a is} independently selected from halogen, CN, NO2, OH, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy, c in particular selected from halogen, CN, C1-C2 alkyl, C1-C2 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C2 alkoxy and C1-C2 haloalkoxy. In particular, R ^{3a is} independently selected from F, Cl, CN, OH, CH3, halomethyl, cyclopropyl, halocyclopropyl, OCH3 and halomethoxy.

Particularly preferred embodiments of R ³ in accordance with the invention are shown in table. P3, in which each line of lines P3-1 to P3-16 corresponds to one particular embodiment of the invention, and in which lines P3-1 to P3-16 also represent a preferred embodiment of the present invention in any combination with each other. Thus, for each R ³ that is present in the compounds according to the invention, these particular embodiments and preferences apply regardless of the meaning of any other R ³ that may be present on the phenyl ring:

Table P3

No. R ³ RZ-1 C1 RZ-2 F RZ-Z CN RZ-4 no ₂ RZ-5 SNz RZ-6 CH ₂ CH ₃ RZ-7 CF ₃ RZ-8 chf ₂ RZ-9 Oso RZ-10 OCH ₂ CH ₃ RZ-11 OCF ₃ RZ-12 ochf ₂ P3-13 SCH ₃ RZ-14 SOCH3 RZ-15 SO2CH3 RZ-16 CO ₂ CH ₃

Particularly preferred embodiments of (R ³ ) n in accordance with the invention are shown in table. P33, wherein each line of lines P33-1 to P33-60 corresponds to one particular embodiment of the invention, and in which lines P33-1 to P33-60 also represent a preferred embodiment of the present invention in any combination.

Table P33

No. (R ³ ) _n RZZ-1 _ * RZZ-2 2-C1 RZZ-Z 3-C1 RZZ-4 2-F RZZ-5 3-F RZZ-6 2-CN RZZ-7 3-CN RZZ-8 2-NO ₂ RZZ-9 3-NO ₂ RZZ-10 2-SCH3 RZZ-11 3-SCH3 RZZ-12 2-SOCH3 P33-13 3-SOCH3 RZZ-14 2-SO ₂ CH ₃ RZZ-15 3-SO ₂ CH ₃ RZZ-16 2-CO ₂ CH ₃ RZZ-17 s-s ₂ sn ₃ RZZ-18 2,3-C1 ₂ RZZ-19 2,5-C1 ₂ RZZ-20 3,5-Cl ₂ RZZ-21 2,6-Cl ₂ RZZ-22 2,3-F ₂ P33-23 2,5-F ₂ RZZ-24 3,5-F ₂ RZZ-25 2.6-F ₂ RZZ-26 2-F-3-C1 RZZ-27 2-F-6-C1

- 29 037646

RZZ-28 2-C1-3-F RZZ-29 2-CHs RZZ-ZO 3-CHs P33-31 2-CH ₂ CHs P33-32 s-sn ₂ sn ₃ RZZ-ZZ 2-CF ₃ P33-34 3-CF3 P33-35 2-CHF ₂ P33-36 3-CHF ₂ P33-37 2-OCHs P33-38 Z-OSN3 P33-39 2-OCH ₂ CHs RZZ-40 s-osn ₂ sn ₃ RZZ-41 2-OCF3 RZZ-42 3-OCF3 P33-43 2-OCHF ₂ RZZ-44 3-OCHF ₂ RZZ-45 2,3- (CHs) ₂ RZZ-46 2.6- (CHs) ₂ RZZ-47 2,3- (CH ₂ CHs) ₂ RZZ-48 2.6- (CH ₂ CHs) ₂ RZZ-49 2,3- (CF ₃ ) ₂ RZZ-50 2.6- (CF ₃ ) ₂ RZZ-51 2,3- (CHF ₂ ) ₂ RZZ-52 2.6- (CHF ₂ ) ₂ P33-53 2,3- (OCHs) ₂ RZZ-54 2.6- (OCHs) ₂ RZZ-55 2,3- (OCH ₂ CH ₃ ) ₂ RZZ-56 2.6- (OCH ₂ CHs) ₂ RZZ-57 2,3- (OCF ₃ ) ₂ RZZ-58 2.6- (OCF ₃ ) ₂ RZZ-59 2,3- (OCHF ₂ ) ₂ RZZ-60 2.6- (OCHF ₂ ) ₂

Each R ⁴ according to the present invention is independently selected from halogen, CN, NO2, OH, SH, C1-C6 alkyl, C1-C6-α-alkoxy, C2-C6-alkenyl, C2-C6-α-alkyl, C3-C8-cycloαalkyl , C3-C8-cycloalkyloxy, NH2, NH (C1-C4-αalkyl), N (C1-C4-alkyl) 2, NH (C3-C6-cycloalkyl), N (C3-C6-cycloαalkyl) 2, S (O ) p (C1-C4-αalkyl), C (= O) (C1-C4-alkyl), C (= O) (He), C (= O) (O-C1-C4-alkyl), C (= 0) (NH (C1-C4-alkyl)), C (= 0) (N (C1-C4-αalkyl) 2), C (= O) (NH (C3-C6-cycloαalkyl)) and C (= O ) - (N (C3-C6-cycloalkyl) 2); wherein each of R ⁴ is unsubstituted or additionally substituted with one, two, three or four R ^4a, independently selected from halogen, CN, NO2, OH, C1-C4 alkyl, C1-C ₄ -haloalkyl, C ₃ -C ₈ - cycloalkyl, C ₃ -C ₈ -halocycloalkyl _{, C 1 -C 4} -alkoxy and C 1 -C ₄ -haloalkoxy.

According to the invention, zero, one, two, three, four or five R ⁴ may be present, namely for m being 0, 1, 2, 3, 4 or 5. In particular, m means 0, 1, 2, 3 or 4.

In accordance with one embodiment, m is 0.

According to a further embodiment, m means 1, 2, 3 or 4, in particular 1, 2 or 3, in particular 1 or 2. According to one special embodiment of the invention, m means 1, according to a further special embodiment m means 2.

In accordance with another additional embodiment, m is 2, 3, or 4.

In accordance with another additional embodiment, m is 3.

In accordance with one embodiment of the invention, one R ^{4 is} attached to the para position (position 4).

According to a further embodiment of the invention, one R ^{4 is} attached to the meta position (position 3).

According to a further embodiment of the invention, one R ^{4 is} attached to the ortho position (position 2).

According to a further embodiment of the invention, the two R ^{4 are} attached at 2,4-positions.

According to a further embodiment of the invention, the two R ^{4 are} attached at 2,3-positions.

According to a further embodiment of the invention, the two R ^{4 are} attached at 2,5-positions.

According to a further embodiment of the invention, the two R ^{4 are} attached at 2,6-positions.

In accordance with a further embodiment of the invention, the two R ^{4 are} attached at the 3,4-positions.

According to a further embodiment of the invention, two R ^{4 are} attached in

- 30 037646

3.5-position.

According to a further embodiment of the invention, three R ^{4 are} attached in

2,4,6-provisions.

For each R ⁴ that is present in the compounds according to the invention, the following embodiments and preferences apply regardless of the meaning of any other R ⁴ that may be present on the phenyl ring. In addition, the individual embodiments and preferences given herein for R ⁴ apply independently for each case m = 1, m = 2, m = 3, m = 4, and m = 5.

According to one embodiment, R ^{4 is} independently selected from halogen, CN, NO ₂ , OH, SH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C _6- alkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyloxy, NH2, NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ , NH (C ₃ - C ₆ -cycloalkyl), N (C ₃ -C ₆ -cycloalkyl) ₂ , S (O) _p (C ₁ -C ₄ -alkyl) (p = 0, 1 or 2), C (= O) (C1- C ₄ -alkyl), C (= O) (OH), C (= O) (O-C1C ₄ -alkyl), C (= O) (NH (C ₁ -C ₄ -alkyl)), C (= O) (N (C ₁ -C ₄ -alkyl) ₂ ), C (= O) (NH (C ₃ -C ₆ -cycloalkyl)) and C (= O) - (N (C ₃ -C ₆ -cycloalkyl ) ₂ ); where each of R ⁴ is unsubstituted or further substituted with one, two, three or four independently selected R ^4a , where R ^4a is as defined and preferably defined herein.

In accordance with a further embodiment of R ⁴ is independently selected from halogen, CN, NO2, _C1-C4 alkyl, C1-C ₄ alkoxy, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C ₃ - C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyloxy, NH2, NH (C ₁ -C ₄₂ -alkyl), N (C ₁ -C ₂ -alkyl) ₂ , S (O) _p (C ₁ -C ₂ - alkyl) (p = 0, 1 or 2), C (= O) (C ₁ -C ₂ -alkyl), C (= O) (OH) and C (= O) (O-C ₁ -C ₂ - alkyl), where each of R ⁴ is unsubstituted or further substituted with one, two, three or four independently selected R ^4a , where R ^4a is as defined and preferably defined herein.

In a further embodiment, R ^{4 is} independently selected from halogen, CN, NO2, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₂ -C ₄ -alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, C2-C4-haloalkynyl, C3-C6-cycloalkyl, C3-C6halogenocycloalkyl, S (C ₁ -C ₂ -alkyl), S (O) (C ₁ -C ₂ -alkyl), S (O) ₂ (C ₁ -C ₂ -alkyl), C (= O) (C ₁ -C ₂ -alkyl), C (= O) (OH) and C (= O) (O-C1-C ₂ -alkyl).

In accordance with a further embodiment of R ⁴ is independently selected from halogen, CN, NO2, _{C1-C2-alkyl, C1-C2} -haloalkyl, _C1-C2 alkoxy, _C1-C2 -galogenalkoksi, S (C ₁ - C ₂ -alkyl), S (O) (C ₁ -C ₂ -alkyl), S (O) ₂ (C ₁ -C ₂ -alkyl), C (= O) (OH) and C (= O) ( O-C1-C ₂ -alkyl).

In accordance with a further embodiment of R ^{4 is} independently selected from F, Cl, Br, CN, _C1-C4 alkyl, _C1-C4 -haloalkyl, I-C4-alkoxy, _C1-C4 -galogenalkoksi, S (C ₁ -C ₄ -alkyl), S (0) (C1-C ₄ -alkyl) and S (O) ₂ (C ₁ -C ₄ -alkyl).

According to another special embodiment, R ^{4 is} independently selected from halogen, in particular from Br, F and Cl, in particular from F and Cl.

According to a further special embodiment, R ⁴ is CN.

According to one further embodiment, R ⁴ is NO2.

In accordance with one further embodiment, R ⁴ is OH.

In accordance with one further embodiment, R ⁴ is SH.

According to a further special embodiment, R ⁴ is C ₁ -C ₆ -alkyl, in particular _{C 1 -C 4} -alkyl, such as CH3. Further suitable alkyls are ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

According to a further particular embodiment R ⁴ is C1-C6galogenalkil, in particular _{C1-C4-haloalkyl,} such as CF _3, CHF2, CH2F, CCl _3, CHCl ₂ or CH ₂ Cl.

According to a further special embodiment, R ⁴ is C1-C6 alkyl, preferably C1-C4 alkyl substituted with OH, more preferably CH2OH, CH2CH2OH, CH2CH2CH2OH, CH (CH3) CH2OH, CH2CH (CH3) OH, CH2CH2CH2CH2OH. In a particular embodiment, R ⁴ is CH2OH. According to a further particular embodiment R ⁴ is _C1-C6 alkyl, preferably _C1-C4 alkyl substituted by CN, more preferably CH2CN, CH2CH2CN, CH2CH2CH2CN, CH ( CH3) CH2CN, CH2CH (CH3) CN, CH2CH2CH2CH2CN ... In a particular embodiment, R ⁴ is CH2CH2CN. In a further special embodiment, R ⁴ is CH (CH3) CN. According to a further specific embodiment, R ⁴ is C1-C4 alkoxy-C1-C6 alkyl, more preferably C1-C4 alkoxy-C1-C4 alkyl. In a particular embodiment, R ⁴ is CH2OCH ₃ . In a further special embodiment, R ⁴ is CH2CH2OCH3. In a further special embodiment, R ⁴ is CH (CH3) OCH ₃ . In a further special embodiment, R ⁴ is CH (CH3) OCH2CH3. In a further special embodiment, R ⁴ is CH2CH2OCH2CH3. According to a further specific embodiment, R ⁴ is C1-C4 haloalkoxy-C1-C6 alkyl, more preferably C1-C4 alkoxy C1-C4 alkyl. In a particular embodiment, R ⁴ is CH2OCF3. In a further special embodiment, R ⁴ is CH2CH2OCF3. In a further special embodiment, R ⁴ is CH2OCCl3. In a further special embodiment, R ⁴ is CH2CH2OCCl3.

According to a further special embodiment, R ⁴ is C ₁ -C ₆ alkoxy, in

- 31 037646 particular _{C1-C4-alkoxy,} in particular C1-C2-alkoxy such as OCH3 or OCH2CH3.

According to a further special embodiment, R ⁴ is Ci-C ₆ haloalkoxy, in particular C1-C ₄ haloalkoxy, in particular C1-C2 haloalkoxy such as OCF3,

OCHF2, OCH2F, OCC13, OCHC12 or OCH2C1, in particular OCF3, OCHF2, OCC13 or OCHC12.

According to a further further embodiment, R ⁴ is C ₂ -C ₆ alkenyl or C ₂ -C ₆ haloalkenyl, in particular C ₂ -C ₄ alkenyl or C ₂ -C ₄ haloalkenyl such as CH = CH ₂ , CH2CH = CH2, CH = CHCH ₃ or C (CH ₃ ) = CH ₂ .

According to a further special embodiment, R ⁴ is C2-C6 alkenyl, preferably C2-C4 alkenyl substituted with OH, more preferably CH = CHOH, CH = CHCH2OH, QCH ^ CHOH, CH = C (CH3) OH. In a particular embodiment, R ⁴ is CH = CHOH. In a further special embodiment, R ⁴ is CH = CHCH2OH. According to a further particular embodiment R ⁴ is C 1 C ₄ -alkoxy-C ₂ -C ₆ -alkenyl, more preferably a C1-C4-alkoxy-C2-C4-alkenyl. In a particular embodiment, R ⁴ is CH = CHOCH3. In a further special embodiment, R ⁴ is CH = CHCH2OCH3. According to a further special embodiment, R ⁴ is C1-C4 haloalkoxy-C2-C6 alkenyl, more preferably C1-C4 haloalkoxy-C2-C4 alkenyl. In a particular embodiment, R ⁴ is CH = CHOCF3. In a further special embodiment, R ⁴ is CH = CHCH2OCF3. In a further special embodiment, R ⁴ is CH = CHOCCl3. In a further special embodiment, R ⁴ is CH = CHCH2OCCl3. According to a further particular embodiment R ⁴ is a _C3-C8 -tsikloαlkil-C ₂ -C ₆ -alkenyl, preferably C3-C6 cycloalkyl-C2-C4-alkenyl. According to a further special embodiment, R ⁴ is C ₃ -C ₆ halocycloalkyl-C ₂ -C ₄ alkenyl, preferably C ₃ -C ₈ halocycloalkyl C _{2 -C 6} alkenyl.

According to another further embodiment, R ⁴ is C ₂ -C ₆ alkynyl or C ₂ -C ₆ haloalkynyl, in particular C ₂ -C ₄ alkynyl or C ₂ -C ₄ haloalkynyl such as C = CH , CH2CCH or CH2CCCH3.

According to a further specific embodiment, R ⁴ is C2-C6 alkynyl, preferably C2-C4 alkynyl substituted with OH, more preferably CCOH, CH2CCOH. In a particular embodiment, R ⁴ is CCOH. In a further special embodiment, R ⁴ is CH2CCOH. According to a further special embodiment, R ⁴ is C1-C4 alkoxy-C2-C6 alkynyl, more preferably C1-C4 alkoxy-C2-C4 alkynyl. In a particular embodiment, R ⁴ is CCOCH3. In a further special embodiment, R ⁴ is CH2CCOCH3. According to a further special embodiment, R ⁴ is _{C 1} -C ₄ haloalkoxy-C _{2 -C 6} alkynyl, more preferably C ₁ -C ₄ haloalkoxy-C ₂ -C ₄ alkynyl. In a particular embodiment, R ⁴ is CCOCF3. In a further special embodiment, R ⁴ is CH2CCOCF3. In a further special embodiment, R ⁴ is CCOCCl3. In a further special embodiment, R ⁴ is CH2CCOCCl3. According to a further special embodiment, R ⁴ is C3-C8 cycloalkyl-C2-C6 alkynyl, preferably C3-C6 cycloalkyl-C2-C4 alkynyl. According to a further particular embodiment R ⁴ is _C3-C6 -galogentsikloalkil-C ₂ -C ₄ -alkynyl, preferably C ₃ -C ₈ halocycloalkyl-C ₂ -C ₆ -alkynyl.

According to one other embodiment, R ⁴ is C ₃ -C ₈ -cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl or cyclobutyl. In a particular embodiment, R ⁴ is cyclopropyl. In a further special embodiment, R ⁴ is cyclobutyl. In a further special embodiment, R ⁴ is cyclopentyl. In a further special embodiment, R ⁴ is cyclohexyl.

According to one other embodiment, R ⁴ is C ₃ -C ₈ -cyclo-alkoxy, preferably C ₃ -C ₆ -cycloalkoxy. In a particular embodiment, R ⁴ is O-cyclopropyl.

According to a particular embodiment, R ⁴ is C3-C8 halocycloalkyl, more preferably fully or partially halogenated C3-C6 cycloalkyl. In a particular embodiment, R ⁴ is wholly or partially halogenated cyclopropyl. In a further special embodiment, R ⁴ is 1-C1-cyclopropyl. In a further special embodiment, R ⁴ is 2-C1-cyclopropyl. In a further special embodiment, R ⁴ is 1-E-cyclopropyl. In a further special embodiment, R ⁴ is 2-Fcyclopropyl. In a further special embodiment, R ⁴ is wholly or partially halogenated cyclobutyl. In a further special embodiment, R ⁴ is 1-Cl cyclobutyl. In a further special embodiment, R ⁴ is 1-E-cyclobutyl. In a further special embodiment, R ⁴ is 3,3-C12 cyclobutyl. In a further special embodiment, R ⁴ is 3,3-E2-cyclobutyl. According to a particular embodiment, R ⁴ is a _{C3-C8-cycloalkyl,} substituted by _C1-C4 alkyl, more preferably a C ₃ -C ₆ -cycloalkyl, substituted by C1-C ₄ -alkyl. In a particular embodiment, R ⁴ is 1-CH3-cyclopropyl. According to a particular embodiment, R ⁴ is C 3 C ₈ - 037 646 32 cycloalkyl substituted by CN, more preferably a C ₃ -C ₆ -cycloalkyl substituted by CN. In a particular embodiment, R ⁴ is l-CN-cyclopropyl. According to a further special embodiment, R ⁴ is C3-C8 cycloαalkyl-C3-C8 cycloalkyl, preferably C3-C6 cycloalkyl-C3-C6 cycloalkyl. In a particular embodiment, R ⁴ is cyclopropyl-cyclopropyl. In a particular embodiment, R ⁴ is 2-cyclopropylcyclopropyl. According to a further special embodiment, R ⁴ is Q- ^ cycloalkyl-C3-C ₈ -halocycloalkyl, preferably C ₃ -C ₆ -cycloalkyl-C ₃ -C ₆ -halocycloalkyl.

According to one other embodiment, R ⁴ is C3-C8 cycloalkyl-C1-C4 alkyl, preferably C3-C6 cycloalkyl-C1-C4 alkyl. In a particular embodiment, R ⁴ is CH (CH3) (cyclopropyl). In a further special embodiment, R ⁴ is CH2 (cyclopropyl).

According to a further preferred embodiment, R ⁴ is Q-Q cycloalkyl-C ₁ -C ₄ -alkyl, where the alkyl moiety may be substituted by one, two, three or up to as many as the same or different R ^a groups as defined and preferably as defined herein, and the cycloalkyl moiety may be substituted with one, two, three, or up to the maximum possible number of the same or different R ^b groups as defined and preferably defined herein.

According to a particular embodiment, R ⁴ is C3-C8 cycloalkyl-C1-C4 haloalkyl, C3-C6 cycloalkyl-C1-C4 haloalkyl. According to a particular embodiment, R ⁴ is _C3-C8 -galogentsikloalkul-C ₁ -C ₄ -alkyl, C ₃ -C ₆ -galogentsikloalkil-C ₁ -C ₄ alkyl. In a particular embodiment, R ⁴ is wholly or partially halogenated cyclopropyl-C1-C4 alkyl. In a further special embodiment, R ⁴ is 1-C1-cyclopropyl-C1-C ₄ -alkyl. In a further special embodiment, R ⁴ is 1-T-cyclopropyl-C ₁ -C ₄ -alkyl.

In accordance with one other embodiment, R ⁴ is NH2.

In accordance with one other embodiment, R ⁴ is NH (C1-C4 alkyl). According to a special embodiment, R ⁴ is NH (CH3). According to a special embodiment, R ⁴ is NH (CH2CH3). According to a specific embodiment, R ⁴ is NH (CH2CH ₂ CH ₃ ). According to a special embodiment, R ⁴ is NH (CH (CH3) 2). According to a special embodiment, R ⁴ is NH (CH2CH ₂ CH ₂ CH ₃ ). According to a particular embodiment, R ⁴ is NH (C (CH ₃ ) ₃ ).

In accordance with one other embodiment, R ⁴ is N (C1-C4 alkyl) 2. According to a specific embodiment, R ⁴ is N (CH3) ₂ . According to a particular embodiment, R ⁴ is N (CH2CH3) 2. According to a specific embodiment, R ⁴ is N (CH2CH ₂ CH ₃ ) ₂ . According to a specific embodiment, R ⁴ is N (CH (CH3) 2) 2. According to a specific embodiment, R ⁴ is N (CH2CH ₂ CH ₂ CH ₃ ) ₂ . According to a particular embodiment, R ⁴ is NH (C (CH ₃ ) ₃ ) ₂ .

According to one other embodiment, R ⁴ is NH (C ₃ -C ₈ -cycloalkyl), preferably NH (C ₃ -C ₆ -cycloalkyl). According to a special embodiment, R ⁴ is NH (cyclopropyl). According to a particular embodiment, R ⁴ is NH (cyclobutyl). According to a specific embodiment, R ⁴ is NH (cyclopenmyl). According to a special embodiment, R ⁴ is NH (cyclohexyl).

According to one other embodiment, R ⁴ is N (C3-C8 cycloαalkyl) 2, preferably N (C3-C6 cycloalkyl) 2. According to a particular embodiment, R ⁴ is N (cyclopropyl) 2. According to a particular embodiment, R ⁴ is N (cyclobutyl) 2. According to a particular embodiment, R ⁴ is N (cyclopenmyl) 2. According to a particular embodiment, R ⁴ is N (cyclohexyl) ₂ .

In accordance with another additional embodiment, R ^{4 is} selected from C (= O) (C1-C ₄ -alkyl), C (= O) (OH), C (= O) (O-C1-C ₄ -alkyl) , C (= O) (NH (C ₁ -C ₄ -alkyl)),

C (= O) (N (C ₁ -C ₄ -alkyl) ₂ ), C (= O) (NH (C ₃ -C ₆ -cycloalkyl)) and C (= O) (N (C ₃ -C ₆ -cycloalkyl) ₂ ), in particular selected from C (= O) (C1-C ₂ -alkyl), C (= O) (OH), C (= O) (O-C1-C ₂ -alkyl), C (= O) (NH (C ₁ -C ₂ -alkyl)), C (= O) (N (C ₁ -C ₂ -alkyl) ₂ ), C (= O) (NH (C ₃ -C ₆ - cycloalkyl)) and C (= O) (N (C ₃ -C ₆ -cycloalkyl) ₂ ). According to one particular embodiment of the invention, R ⁴ is C (= O) (OH) or C (= O) (O — C ₁ -C ₄ alkyl), in particular C (= O) (OCH ₃ ).

In accordance with one other embodiment, R ⁴ is C (= O) (- C1-C4 alkyl). According to a special embodiment, R ⁴ means C (= O) CH3. According to a further special embodiment, R ⁴ is C (= O) CH2CH3. According to a further special embodiment, R ⁴ means C (= O) CH2CH ₂ CH ₃ . According to a further special embodiment, R ⁴ is C (= O) CH (CH3) 2. According to a further special embodiment, R ⁴ is C (= O) C (CH3) ₃ .

In accordance with one other embodiment, R ⁴ is C (= O) OH.

According to one other embodiment, R ⁴ is C (= O) (—O — C1 — C4 alkyl). According to a special embodiment, R ⁴ means C (= O) OCH3. According to a further special embodiment, R ⁴ is C (= O) OCH2CH3. According to a further special embodiment, R ⁴ is C (= O) OCH2CH2CH3. According to a further special embodiment, R ⁴ means C (= O) OCH (CH ₃ ) ₂ . According to a further special embodiment, R ⁴ means C (= O) OC (CH ₃ ) ₃ .

In accordance with one other embodiment, R ⁴ is C (= O) -NH (C1-C4-αalkyl). According to a particular embodiment, R ⁴ is C (= O) NHCH3. According to a further special embodiment, R ⁴ is C (= O) NHCH2CH3. According to a further special embodiment, R ⁴ is C (= O) NHCH2CH ₂ CH ₃ . According to a further special embodiment, R ⁴ is C (= O) NHCH (CH ₃ ) ₂ . According to a further special embodiment, R ⁴ is C (= O) NHC (CH3) 3.

In accordance with one other embodiment, R ⁴ is C (= O) -N (C1-C4 -alkyl) 2. According to a particular embodiment, R ⁴ is C (= O) N (CH3) ₂ . According to a further special embodiment, R ⁴ is C (= O) N (CH2CH3) 2. According to a further special embodiment, R ⁴ is C (= O) N (CH2CH2CH3) 2. According to a further special embodiment, R ⁴ is C (= O) N (CH (CH3) ₂ ) ₂ . According to a further special embodiment, R ⁴ means C (= O) N (C (CH3) 3) 2.

In accordance with one other embodiment, R ⁴ is C (= O) -NH (C ₃ -C ₆ cycloalkyl). According to a particular embodiment, R ⁴ is C (= O) NH (cyclopropyl). According to a further special embodiment, R ⁴ is C (= O) NH (cyclobutyl). According to a further special embodiment, R ⁴ is C (= O) NH (cyclopentyl). According to a further special embodiment, R ⁴ is C (= O) NH (cyclohexyl).

In accordance with one other embodiment, R ⁴ is C (= O) -N (C3-C6 cycloalkyl) 2. According to a particular embodiment, R ⁴ is C (= O) N (cyclopropyl) 2. According to a further special embodiment, R ⁴ is C (= O) N (cyclobutyl) 2. According to a further special embodiment, R ⁴ is C (= O) N (cyclopentyl) 2. According to a further special embodiment, R ⁴ is C (= O) N (cyclohexyl) ₂ .

According to another further embodiment, R ^{4 is} selected from 8 (C1-C2 alkyl), S (O) (C1-C2 alkyl) and S (O) 2 (C1-C2 alkyl), in particular SCH3, S ( O) (CH3) and S (O) 2 (CH3). According to a specific embodiment, R ^{4 is} selected from S (C1-C ₂ -gαlogena-alkyl), S (O) (C ₁ -C ₂ haloalkyl) and S (O) ₂ (C ₁ -C ₂ -haloalkyl) such as SO2CF3.

Particularly preferred embodiments of R ⁴ in accordance with the invention are shown in table. P4, in which each line of lines P4-1 to P4-16 corresponds to one particular embodiment of the invention, and in which lines P4-1 to P4-16 also represent a preferred embodiment of the present invention in any combination with each other. Thus, for each R ⁴ that is present in the compounds according to the invention, these particular embodiments and preferences apply regardless of the meaning of any other R ⁴ that may be present on the phenyl ring:

Table P4

No. R ⁴ P4-1 C1 P4-2 F P4-3 CN P4-4 no ₂ P4-5 SNz P4-6 CH ₂ CH ₃ P4-7 CF ₃ P4-8 chf ₂ P4-9 Oso P4-10 OCH ₂ CH ₃ P4-11 OCF ₃ P4-12 ochf ₂ P4-13 SCH ₃ P4-14 SOCH3 P4-15 SO ₂ CH ₃ P4-16 CO ₂ CH3

Particularly preferred embodiments of (R ⁴ ) m in accordance with the invention are shown in table. P44, in which each line of lines P44-1 to P44-155 corresponds to one particular embodiment of the invention, and in which lines P44-1 to P44-155 also represent a preferred embodiment of the present invention in any combination.

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Table P44

No. (R ⁴ ) m R44-1 _ * R44-2 2-C1 R44-3 3-C1 R44-4 4-C1 R44-5 2-F R44-6 3-F R44-7 4-F R44-8 2-CN R44-9 3-CN R44-10 4-CN R44-11 2-NO ₂ P44-12 3-NO2 R44-13 4-NO2 R44-14 2-SCH3 R44-15 3-SCH3 R44-16 4-SCH3 P44-17 2-SOCH3 R44-18 3-SOCH3 R44-19 4-SOCH3 P44-20 2-SO ₂ CH ₃ P44-21 3-SO ₂ CH ₃ P44-22 4-SO ₂ CH ₃ P44-23 2-CO ₂ CH ₃ P44-24 3-CO ₂ CH ₃ R44-25 4-CO ₂ CH ₃ P44-26 2,3-C1 ₂ P44-27 2,4-Cl ₂ P44-28 2,5-Cl ₂ P44-29 3,4-Cl ₂ R44-30 3,5-Cl ₂ P44-31 2,6-Cl ₂ P44-32 2,3-F ₂ P44-33 2,4-F ₂ P44-34 2,5-F ₂ P44-35 3,4-F ₂ P44-36 3,5-F ₂ P44-37 2.6-F ₂ P44-38 2-F-3-C1 P44-39 2-F-4-C1 P44-40 3-F-4-C1 P44-41 2-F-6-C1 P44-42 2-C1-3-F

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P44-43 2-C1-4-F P44-44 3-C1-4-F P44-45 2,3,4-C1 ₃ P44-46 2,4,5-C1 ₃ P44-47 3,4,5-C1 ₃ P44-48 2,4,6-C1 ₃ P44-49 2,3,4-F ₃ P44-50 2,4,5-F ₃ P44-51 3,4,5-F ₃ P44-52 2,4,6-F ₃ P44-53 2,3-4-F ₃ P44-54 2,4-F ₂ -3-Cl P44-55 2,6-F ₂ -4-Cl P44-56 2,5-F ₂ -4-Cl P44-57 2,4-Cl ₂ -3-F P44-58 2,6-Cl ₂ -4-F P44-59 2,5-Cl ₂ -4-F P44-60 2-CHs P44-61 Z-CH3 P44-62 4-CHs P44-63 2-CH ₂ CH ₃ P44-64 3-CH ₂ CH ₃ P44-65 4-CH ₂ CH ₃ P44-66 2-CF ₃ P44-67 3-CF ₃ P44-68 4-CF ₃ P44-69 2-CHF ₂ P44-70 3-CHF ₂ P44-71 4-CHF ₂ P44-72 2-OCH3 P44-73 Z-OSN3 P44-74 4-OCHs P44-75 2-OCH ₂ CH ₃ P44-76 3-OCH ₂ CH ₃ P44-77 4-OCH ₂ CHs P44-78 2-OCF3 P44-79 3-OCF3 P44-80 4-OCF3 P44-81 2-OCHF ₂ P44-82 3-OCHF ₂ P44-83 4-OCHF ₂ P44-84 2,3- (CH ₃ ) ₂ P44-85 2,4- (CHs) ₂ P44-86 3.4- (CHs) ₂

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P44-87 2.6- (CHs) ₂ P44-88 2,3- (CH ₂ CHs) ₂ P44-89 2,4- (CH ₂ CHs) ₂ P44-90 3,4- (CH ₂ CHs) ₂ P44-91 2.6- (CH ₂ CHs) ₂ P44-92 2,3- (CF ₃ ) ₂ P44-93 2,4- (CF ₃ ) ₂ P44-94 3.4- (CF ₃ ) ₂ P44-95 2.6- (CF ₃ ) ₂ P44-96 2,3- (CHF ₂ ) ₂ P44-97 2,4- (CHF ₂ ) ₂ P44-98 3,4- (CHF ₂ ) ₂ P44-99 2.6- (CHF ₂ ) ₂ P44-100 2,3- (OCH ₃ ) ₂ P44-101 2,4- (OCH ₃ ) ₂ P44-102 3.4- (OCHs) ₂ P44-103 2.6- (OCHs) ₂ P44-104 2.3 (OCH ₂ CH ₃ ) ₂ P44-105 2.4 (OCH ₂ CH ₃ ) ₂ P44-106 3.4 (OCH ₂ CH ₃ ) ₂ P44-107 2.6 (OCH ₂ CH ₃ ) ₂ P44-108 2,3- (OCF ₃ ) ₂ P44-109 2,4- (OCF ₃ ) ₂ P44-110 3.4- (OCF ₃ ) ₂ P44-111 2.6- (OCF ₃ ) ₂ P44-112 2,3- (OCHF ₂ ) ₂ P44-113 2,4- (OCHF ₂ ) ₂ P44-114 3,4- (OCHF ₂ ) ₂ P44-115 2.6- (OCHF ₂ ) ₂ P44-116 2,3,4- (CH ₃ ) h P44-117 2,4,5- (CH ₃ ) h P44-118 3,4,5- (CH ₃ ) h P44-119 2,4,6- (CH ₃ ) h P44-120 2,3,4 (CH ₂ CH ₃ ) h P44-121 2,4,5 (CH ₂ CH ₃ ) h P44-122 3.4.5 (CH ₂ CH ₃ ) h P44-123 2,4,6-

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(CH ₂ CH ₃ ) ₃ P44-124 2,3,4- (CF ₃ ) ₃ P44-125 2,4,5- (CF ₃ ) ₃ P44-126 3,4,5- (CF ₃ ) ₃ P44-127 2,4,6- (CF ₃ ) ₃ P44-128 2,3,4- (CHF ₂ ) ₃ P44-129 2,4,5- (CHF ₂ ) ₃ P44-130 3,4,5- (CHF ₂ ) ₃ R44-131 2,4,6- (CHF ₂ ) ₃ R44-132 2,3,4- (OCH ₃ ) ₃ R44-133 2,4,5- (OCH ₃ ) ₃ R44-134 3,4,5- (OCH ₃ ) ₃ R44-135 2,4,6- (OCH ₃ ) ₃ R44-136 2,3,4 (OCH ₂ CH ₃ ) ₃ R44-137 2.4.5 (OCH ₂ CH ₃ ) ₃ R44-138 3.4.5 (OCH ₂ CH ₃ ) ₃ R44-139 2,4,6 (OCH ₂ CH ₃ ) ₃ P44-140 2,3,4- (OCF ₃ ) ₃ P44-141 2,4,5- (OCF ₃ ) ₃ P44-142 3,4,5- (OCF ₃ ) ₃ P44-143 2,4,6- (OCF ₃ ) ₃ P44-144 2,3,4 (OCHF ₂ ) ₃ P44-145 2,4,5 (OCHF ₂ ) ₃ P44-146 3.4.5 (OCHF ₂ ) ₃ P44-147 2,4,6 (OCHF ₂ ) ₃ P44-148 2-CF ₃ -4-Cl P44-149 2-CF ₃ -4-F P44-150 2-Cl-4-CF ₃ P44-151 2-F-4-CF ₃ P44-152 2-CN-4-C1 P44-153 2-CN-4-F P44-154 2-C1-4-CN P44-155 2-F-4-CN

In particular, in the process according to the invention, compounds III.a are used to prepare compounds P.a, which can then be further reacted to give compounds Ia and, optionally, further reacted to give the corresponding compounds I-1 (containing OR2, see . above):

where the substituents are as defined and preferably defined above.

In particular, the substituents have the following preferred meanings. In this case, the specific meanings of the respective substituents are in each case independently, but also in any combination with each other, separate embodiments of the present invention.

According to one particular embodiment of the invention, in compounds I (or I-1), II and III, respectively, R ¹ is C1-C4 alkyl, C3-C6 cycloalkyl or C2-C4 alkynyl. Preferably R ¹ is C 1 -C 4 alkyl, C ₃ cycloalkyl or C ₃ alkynyl. In one particular embodiment, R ¹ is CH3. In a further special embodiment, R ¹ is C2H5. In yet another additional special embodiment, R ¹ is n- (C3H7). In another additional special embodiment, R ¹ is iso- (C3H ₇ ). In yet another additional special embodiment, R ¹ is C (CH ₃ ) ₃ . In yet another additional embodiment, R ¹ is cyclopropyl. In yet another additional embodiment, R ¹ means

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C-Clh.

According to one particular embodiment of the invention, in compounds I-1, R ² is C1-C3 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, in particular hydrogen, C1-C3 alkyl, C2-C4 alkenyl or C2- C4 alkynyl. Preferably, R ² is _C1-C3 alkyl. In a further special embodiment, R ² is CH3. In another additional special embodiment, R ² is C2H5. In yet another additional special embodiment, R ² is n- (C3H7). In yet another additional special embodiment, R ² is iso- (C3H ₇ ). In another additional special embodiment, R ² is CH2CH = CH2 (allyl). In another additional special embodiment, R ² is CH2C (CH ₃ ) = CH ₂ . In yet another additional special embodiment, R ² is CH ₂ C ^ CH.

According to one particular embodiment of the invention, in compounds I (or I-1), II and III, respectively, R ³ is Cl or CF3. In one embodiment, R ³ is Cl. In a further embodiment, R ³ is CF3.

According to one particular embodiment of the invention, in compounds I (or I-1), II and III, respectively, R ⁴ is Cl or F. In one embodiment, R ⁴ is Cl. In a further embodiment, R ⁴ is F.

In particular, using the method according to the invention, the following compounds I.1 - I.18 and I.19 - I.31 can be advantageously obtained:

Compound 1.1: 2- [2-chloro-4- (4-chlorophenoxy) phenyl] -1- (1,2,4-triazol-1-yl) pent-3-in-2-ol;

compound I.2: 1- [2-chloro-4- (4-chlorophenoxy) phenyl] -1-cyclopropyl-2- (1,2,4-triazol-1-yl) ethanol;

compound I.3: 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -1- (1,2,4-triazol-1-yl) propan-2-ol;

compound I.4: 1- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -1-cyclopropyl-2- (1,2,4-triazol-1yl) ethanol;

compound I.5: 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -3-methyl-1 - (1,2,4-triazol-1-yl) butan2-ol;

compound I.6: 1- [2- [2-chloro-4- (4-chlorophenoxy) phenyl] -2-methoxypent-3-ynyl] -1,2,4-triazole;

compound I.7: 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -1- (1,2,4-triazol-1-yl) butan-2-ol;

compound I.8: 1- [2- [2-chloro-4- (4-chlorophenoxy) phenyl] -2-cyclopropyl-2-methoxyethyl] -1,2,4triazole;

compound I.9: 1- [2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-methoxypropyl] -1,2,4-triazole;

compound I.10: 2- [2-chloro-4- (4-chlorophenoxy) phenyl] -3,3-dimethyl-1- (1,2,4-triazol-1-yl) butan-2-ol;

compound I.11: 1- [2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-cyclopropyl-2-methoxyethyl] 1,2,4-triazole;

compound 1.12: 1- [2- [2-chloro-4- (4-chlorophenoxy) phenyl] -2-methoxy-3,3-dimethylbutyl] -1,2,4-triazole;

compound I.13: 1- [2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-methoxybutyl] 1,2,4-triazole; compound 1.14: 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -1- (1,2,4-triazol-1-yl) pent-3-in-2-ol; compound I.15: 1- [2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-methoxypent-3-ynyl] -1,2,4triazole;

compound 1.16: 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -1- (1,2,4-triazol-1-yl) but-3-yn-2-ol;

compound 1.17: 2- [2-chloro-4- (4-chlorophenoxy) phenyl] -1- (1,2,4-triazol-1-yl) propan-2-ol;

compound I.18: 2- [2-chloro-4- (4-fluorophenoxy) phenyl] -1- (1,2,4-triazol-1-yl) propan-2-ol;

compound I.19: 2- [2-chloro-4- (4-chlorophenoxy) phenyl] -3-methyl-1- (1,2,4-triazol-1-yl) butan-2-ol;

compound I.20: 1- [2- [2-chloro-4- (4-chlorophenoxy) phenyl] -2-methoxypropyl] -1,2,4-triazole;

compound I.21: 1- [2- [2-chloro-4- (4-chlorophenoxy) phenyl] -2-methoxybutyl] -1,2,4-triazole;

compound I.22: 1- [2- [2-chloro-4- (4-chlorophenoxy) phenyl] -2-methoxypentyl] -1,2,4-triazole;

compound I.23: 2- [2-chloro-4- (4-chlorophenoxy) phenyl] -1,1,1-trifluoro-3 - (1,2,4-triazol-1-yl) propan-2-ol ;

compound I.24: 2- [2-chloro-4- (4-chlorophenoxy) phenyl] -3-fluoro-1- (1,2,4-triazol-1yl) butan-2-ol hydrochloride;

compound I.25: 2- [2-chloro-4- (4-chlorophenoxy) phenyl] -1- (1,2,4-triazol-1-yl) pent-4-in-2-ol;

compound I.26: 2- [2-chloro-4- (4-chlorophenoxy) phenyl] -1-methoxy-3- (1,2,4-triazol-1-yl) propan-2-ol;

compound I.27: 2- [2-chloro-4- (4-fluorophenoxy) phenyl] -1-methoxy-3- (1,2,4-triazol-1-yl) propan-2-ol;

compound I.28: 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -1- (1,2,4-triazol-1-yl) pentan-2-ol;

compound I.29: 2- [4- (4-fluorophenoxy) -2- (trifluoromethyl) phenyl] -1- (1,2,4-triazol-1-yl) propan-2-ol;

compound I.30: 2- [2-chloro-4- (4-chlorophenoxy) phenyl] -1- (1,2,4-triazol-1-yl) butan-2-ol;

compound I.31: 2- [2-chloro-4- (4-chlorophenoxy) phenyl] -1- (1,2,4-triazol-1-yl) pentan-2-ol.

In particular, using the method according to the invention, the following compounds IC.1 to IC.7 can be advantageously obtained:

compound IC.1: 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -1- (1,2,4-triazol-1-yl) propan-2-ol;

compound 1C.2: 1- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -1-cyclopropyl-2- (1,2,4-triazol-1yl) ethanol;

compound IC.3: 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -3-methyl-1- (1,2,4-triazol-1- 39 037646 yl) butan-2-ol ;

compound 1C.4: 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -1- (1,2,4-triazol-1-yl) butan-2-ol;

connection 1C.5? 1- [2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-methoxypropyl] -1,2,4triazole;

compound 1C.6: 1- [2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-cyclopropyl-2-methoxyethyl] 1,2,4-triazole;

compound 1C.7: 1- [2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-methoxybutyl] 1,2,4-triazole.

Compounds I contain chiral centers and are usually obtained in the form of racemates. The R- and S-enantiomers of the compounds can be separated and isolated in pure form using methods known to the person skilled in the art, for example, using chiral HPLC. In addition, components I can be present in different crystalline modifications, which can differ in biological activity.

The compounds according to the invention can be present in various crystalline modifications. In addition, when using the crystallization step according to the invention, solvates can be formed, in particular, of any one of the compounds I.1 to I.18. In particular, the solvate is formed using an aliphatic alcohol as described above, in particular methanol or ethanol.

Examples and shapes

The following figures and examples further illustrate the present invention, but do not limit the invention in any way.

FIG. 1 shows an X-ray powder diffraction diagram of Form A of compound I.3.

FIG. 2 shows an X-ray powder diffraction chart of Form A of compound I.5. Analytics.

X-ray powder diffraction patterns of Forms A and B were recorded using a Panalytical X'Pert Pro diffractometer with reflection geometry in the range 2θ = 3-35 ° with a step width of 0.0167 ° and using CuKa radiation (1.54178 A) at 25 ° C. The recorded 2θ values were used to calculate the d values. Peak intensities (linear intensity readings) were plotted against the 2θ angle (x axis in ° 2θ).

Single crystal X-ray diffraction data were collected at 100K on a Bruker AXS CCD Detector instrument using graphite-monochromatic CuKa radiation (λ = 1.54178 A). The structure was determined by direct methods, refined and generalized using Fourier methods using the SHELX software package (G.M. Sheldrick, SHELX-97, University of Gottingen 1997). Correction of adsorption was performed using the SADABS software.

DSC was performed on a Mettler Toledo DSC 823e module. The sample was placed in rolled but vented aluminum crucibles. The sample weight was 3 mg. Heat behavior was analyzed over the range 30-200 ° C using a heating rate of 10 ° C / min and a nitrogen flow of 150 ml / min. Melting points and polymorphic transitions were confirmed on a Mettler Hot Stage in combination with an optical microscope.

A) Obtaining reagent IV.

Example A1.

Preparation of an aqueous solution of trimethylsulfonium methyl sulfate (11.3 wt%, water).

304 g of dimethyl sulfide and 30 g of water (1.67 mol) were stirred at 25 ° C. Then, 146 g of dimethyl sulfate (1.15 mol) was added over 60 minutes, while the temperature was raised to 35 ° C. The mixture was then stirred for 2 hours at 35 to 38 ° C. To ensure phase separation, the mixture was cooled to 30 ° C and not stirred. Received 246 g of the lower aqueous phase.

The water content of the solution was measured by Karl Fischer titration and was 11.3% by weight. The content of trimethylsulfonium methyl sulfate was quantified at 85.3 wt%; (SMe ₃ ) ⁺ : 35 wt% (qty-NMR in D ₂ O, fumaric acid di-Na salt as internal standard). The viscosity of the solution at 25 ° C was 18.3 mPa-s.

Characterization: 1H-NMR (400 MHz, D2O): δ / ppm. = 2.9 (s, 9H), 3.72 (s, 3H), 4.66 (s, H ₂ O).

Example A2.

Preparation of an aqueous solution of trimethylsulfonium methyl sulfate (14.9 wt%, water).

304 g of dimethyl sulfide and 41.3 g of water (2.3 mol) were stirred at 25 ° C. Then, 146 g of dimethyl sulfate (1.15 mol) was added over 60 minutes, while the temperature was raised to 35 ° C. The mixture was then stirred for 2 hours at 35 to 38 ° C. To ensure phase separation, the mixture was cooled to 30 ° C and not stirred. Received 259 g of the lower aqueous phase.

The water content of the solution was measured by Karl Fischer titration and was 14.9% by weight. The content of trimethylsulfonium methyl sulfate was quantified at 83.2 wt%; (SMe ₃ ) ⁺ : 34 wt% (qty-NMR in D2O, fumaric acid di-Na salt as internal standard). The viscosity of the solution at 25 ° C was 12.5 mPa-s.

Example A3.

Preparation of an aqueous solution of trimethylsulfonium methyl sulfate (11.2 wt%, water).

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144 g of dimethyl sulfide, 30 g of water (1.67 mol) and 236 g of toluene were stirred at 25 ° C. Then, 146 g of dimethyl sulfate (1.15 mol) was added over 60 minutes while the temperature was raised to 46 ° C.

The mixture was then stirred for 2 h at 30 ° C. To ensure phase separation, the mixture was cooled to 30 ° C and not stirred. Received 245 g of the lower aqueous phase.

The water content of the solution was measured by Karl Fischer titration and was 11.2% by weight. The content of trimethylsulfonium methyl sulfate was quantified at 84.5 wt%; (SMe ₃ ) ⁺ : 34.8 wt% (qty-NMR in D2O, fumaric acid di-Na salt as internal standard).

Comparative example.

Preparation of an aqueous solution of trimethylsulfonium methyl sulfate (6.5 wt%, water).

304 g of dimethyl sulfide and 15.0 g of water (0.83 mol) were stirred at 25 ° C. Then, 146 g of dimethyl sulfate (1.15 mol) was added over 60 minutes, while the temperature was not more than 35 ° C. The mixture was then stirred for 2 hours at 35 to 38 ° C. To ensure phase separation, the mixture was cooled to 30 ° C and not stirred. Received 237 g of the lower aqueous phase.

The water content in the solution was measured by Karl Fischer titration and was 6.5 wt%. The content of trimethylsulfonium methyl sulfate was quantified at 89.6 wt%; (SMe ₃ ) ⁺ : 37.2 wt% (qty-NMR in D2O, fumaric acid di-Na salt as internal standard). The viscosity of the solution at 30 ° C was 35.1 mPa-s. The solution was not stable at 25 ° C. Long mirror crystals formed.

C) Synthesis of oxiranes.

Example B1.

Synthesis of 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-methyloxyrane.

1- [4- (4-Chlorophenoxy) -2- (trifluoromethyl) phenyl] ethanone (0.87 mol) dissolved in 372 g of dimethyl sulfide, together with 250 g of aqueous trimethylsulfonium methyl sulfate (86 wt%, prepared according to example A1) was prepared at 23 ° C. With vigorous stirring, 15 g of KOH pellets, 85 wt% (2.65 mol) were added. This resulted in an increase in temperature of about 5 ° C. Stirring was then continued for 10 hours at 38 ° C. A sample of the reaction mixture showed complete conversion of the ketone (HPLC). Thereafter, 1350 g of a 20 wt% NaCl solution was added at 30 ° C. After separation of the aqueous phase, the dimethyl sulfide solution was concentrated by solvent distillation at temperatures up to 98 ° C. There was obtained 324 g of 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-methyloxyrane with a purity of approximately 90 wt.% (Q. HPLC); output> 99%.

Determination of characteristics.

A sample of the crude product was dissolved at 40 ° C in diisopropyl ether and cooled to -5 ° C. The product was obtained as a crystalline compound. Melting point: 60 ° C.

-NMR (400 MHz, CDCl ₃ ): δ / ppm. = 1.63 (s, 3H), 2.92 (d, 1H), 3.02 (d, 1H), 6.95 (d, 2H), 7.13 (m, 1H), 7.22 ( s, 1H), 7.34 (d, 2H) 7.64 (d, 1H);

13C-NMR (125 MHz, CDCl ₃ ): δ / ppm. = 24.82 (q), 55.41 (t), 57.27 (s), 115.94 (d), 120.63 (d, 2C) 121.48 (d), 123.91 (s) , 128.60 (s), 129.36 (s), 130.05 (d, 2C), 131.04 (d), 134.59 (s), 154.50 (s), 156.56 (s ).

Example B2.

Synthesis of 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-cyclopropyloxyrane.

1- [4- (4-Chlorophenoxy) -2- (trifluoromethyl) phenyl] cyclopropylmethanone (0.80 mol) dissolved in 343 g of dimethyl sulfide, together with 263.4 g of aqueous trimethylsulfonium methyl sulfate (86 wt.%, Obtained according to with example A1), was prepared at 23 ° C. 212 g KOH pellets, 85 wt% (3.21 mol) were added with vigorous stirring. This led to an increase in temperature by about 5-7 ° C. Stirring was then continued for 8 hours at 38 ° C. A sample of the reaction mixture showed complete conversion of the ketone (HPLC). Thereafter, 1236 g of a 20 wt% NaCl solution were added at 30 ° C. After separation of the aqueous phase, the dimethyl sulfide solution was concentrated by distillation of the solvent at temperatures up to 90 ° C. There was obtained 332 g of the product (2- [4- (4-chlorophenoxy) -2 (trifluoromethyl) phenyl] -2-cyclopropyloxyrane) with a purity of 82 wt% (q.v. HPLC); yield> 95%.

Determination of characteristics.

A sample of the crude product was dissolved at 60 ° C in isopropanol and cooled to 10 ° C. The product was obtained as a crystalline compound. Melting point: 45 ° C.

¹³ C-NMR (125 MHz, CDCl ₃ ): δ / ppm. = 1.06 (t), 2.17 (t), 15.87 (d), 53.09 (t), 58.46 (s), 115.47 (d), 121.20 (d, 2C ), 121.65 (d), 124.01 (s), 127.59 (s), 128.4 (s), 130.16 (d, 2C), 132.10 (d), 133.52 ( s), 154.26 (s), 156.27 (s).

Example B3.

Synthesis of 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-isopropyloxyrane.

1- [4- (4-Chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-methylpropan-1-one (0.078 mol) dissolved in 62 g of dimethyl sulfide, together with 22.2 g of aqueous trimethyl sulfonium methyl sulfate (80 wt. %, obtained in accordance with example A1) was prepared at 27 ° C. With vigorous stirring, 15.4 g of KOH pellets, 85 wt% (0.23 mol) were added. This led to an increase in temperature by about 5-7 ° C. Then

- 41 037646 stirring was continued for 3.5 hours at 38 ° C. A sample of the reaction mixture showed complete conversion of the ketone (HPLC). Thereafter, 45 g of water was added at 25 ° C. After separation of the aqueous phase, the dimethyl sulfide solution was diluted with a small amount of toluene and washed again with 105 g of water. The organic phase was then concentrated by distillation of the solvent at 50 ° C. and up to a pressure of 2 mbar. Received 30 g of 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2 isopropyloxyrane with a purity of approximately 81% (% area, HPLC); the yield is approximately 88%.

Determination of characteristics.

A sample of the crude product was analyzed by NMR spectroscopy.

¹³ C-NMR (125 MHz, CDCl ₃ ): δ / ppm. = 17.32 (q), 17.55 (q), 31.57 (d), 52.93 (t), 62.71 (s), 116.28 (d), 120.73 (d, 2C ) 121.69 (d), 123.95 (s), 127.41 (s), 129.41 (s), 130.12 (d, 2C), 131.97 (d), 134.12 (s ), 154.67 (s), 156.56 (s).

¹ H-NMR (400 MHz, CDCl ₃ ): δ / ppm. = 0.85-0.95 (dd, 6H), 2.22-2.35 (md, 1H), 2.78 (d, 1H), 3.20 (d, lH), 6.98 (d , 2H), 7.10 (m, 1H), 7.23 (s, 1H), 7.35 (d, 2H) 7.55 (d, 1H).

Example B4.

Synthesis of 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-methyloxyrane.

1- [4- (4-Chlorophenoxy) -2- (trifluoromethyl) phenyl] ethanone (0.13 mol) dissolved in 55 g of dimethyl sulfide, together with 45 g of aqueous trimethyl sulfonium methyl sulfate (80 wt.%, 17 wt.% H ₂ O, obtained in accordance with example A2) was prepared at 23 ° C. With vigorous stirring, 25 g of KOH pellets, 85 wt% (0.38 mol) were added. This resulted in an increase in temperature of about 5 ° C. Stirring was then continued for 8 hours at 38 ° C. A sample of the reaction mixture showed complete conversion of the ketone (HPLC). Thereafter, 199 g of a 20 wt% NaCl solution was added at 30 ° C. After separation of the aqueous phase, the dimethyl sulfide solution was concentrated by solvent distillation at temperatures up to 90 ° C. There was obtained 56 g of 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2methyloxirane with a purity of 77 wt.% (Q.v. HPLC); yield> 95%.

Example B5.

Synthesis of 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-methyloxyrane.

1- [4- (4-Chlorophenoxy) -2- (trifluoromethyl) phenyl] ethanone (0.45 mol), dissolved in 280 g of toluene, together with 129 g of aqueous trimethylsulfonium methyl sulfate (86 wt.%, Obtained in accordance with example A1) was prepared at 24 ° C. 89 g of KOH pellets, 85 wt% (0.38 mol) were added with vigorous stirring. This resulted in an increase in temperature of about 4 ° C. Stirring was then continued for 21 hours at 38 ° C. A sample of the reaction mixture showed complete conversion of the ketone (HPLC). Thereafter, 500 g of a 20 wt% NaCl solution was added at 30 ° C. After separation of the aqueous phase, the toluene solution was concentrated by distillation of the solvent at temperatures up to 98 ° C and a pressure of 50 mbar. There was obtained 163 g of 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-cyclopropyloxyrane with a purity of about 89 wt.% (Q. HPLC); yield> 95%.

Example B6.

Synthesis of 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-methyloxyrane.

1- [4- (4-Chlorophenoxy) -2- (trifluoromethyl) phenyl] ethanone (0.128 mol) dissolved in 55.4 g of dimethyl sulfide was prepared at 22 ° C. With vigorous stirring, 25.4 g of KOH pellets, 85 wt% (0.385 mol) were added. Then 42.1 g of aqueous trimethylsulfonium methyl sulfate (85.6 wt%, prepared according to Example A1) were added. This led to an increase in temperature by about 2-3 ° C. Stirring was then continued for 8 hours at 38 ° C. A sample of the reaction mixture showed complete conversion of the ketone (HPLC). Thereafter, 199 g of a 20 wt% NaCl solution was added at 30 ° C. After separation of the aqueous phase, the dimethyl sulfide solution was concentrated by solvent distillation at temperatures up to 90 ° C. There was obtained 49.7 g of 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2methyloxirane with a purity of about 82 wt.% (Q. HPLC); the yield is approximately 97%.

Example B7.

Synthesis of 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-cyclopropyloxyrane.

1- [4- (4-Chlorophenoxy) -2- (trifluoromethyl) phenyl] cyclopropylmethanone (0.122 mol) dissolved in 52 g of dimethyl sulfide was prepared at 22 ° C. With vigorous stirring, 32.2 g of KOH pellets, 85 wt% (0.488 mol) were added. Then added 40.1 g of aqueous trimethylsulfonium methyl sulfate (85.6 wt.%, Obtained in accordance with example A1). This led to an increase in temperature by about 3-5 ° C. Stirring was then continued for 8 hours at 38 ° C. A sample of the reaction mixture showed complete conversion of the ketone (HPLC). Thereafter, 187 g of a 20 wt% NaCl solution were added at 30 ° C. After separation of the aqueous phase, the dimethyl sulfide solution was concentrated by solvent distillation at temperatures up to 90 ° C. There was obtained 50.0 g of 2- [4- (4-chlorophenoxy) -2 (trifluoromethyl) phenyl] -2-methyloxyrane with a purity of about 82 wt.% (Q. HPLC); the yield is approximately 91%.

C) Synthesis of triazoles.

Example C1. 2- [4- (4-Chlorophenoxy) -2- (trifluoromethyl) phenyl] -1- (1,2,4-triazol-1-yl) propan-2-ol (co

- 42 037646 unity I.3).

235.3 g (95.4 wt%; 0.683 mol) 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-methyloxyrane was prepared in 496 g of DMF and heated to 60 ° C. Then 60.6 g (99 wt.%; 0.869 mol) of triazole and 13.4 g (0.335 mol) of NaOH powder were added one after another with stirring. The reaction mixture was heated to 125 ° C and then stirred for a total of 4 hours at this temperature. The HPLC sample showed almost complete conversion to the desired product (triazol-1-yl / triazol-4-yl ratio approximately 10: 1). Approximately 80% of the DMF was evaporated at 65 ° C / 4 mbar. To the concentrated reaction mixture were added 714 g of toluene and 400 g of water. Then the aqueous phase was separated at 60 ° C. The toluene phase was washed again with 200 g of water. The aqueous phase was separated and the toluene solution was concentrated at 70 ° C./50 mbar until the solution contained approximately 50% product. The precipitated solids were redissolved by heating to 80 ° C. The solution was cooled from 80 to 0 ° C at a rate of 5 K / h with stirring. The suspension of solids, which was easily agitated, was separated by suction filtration and washed 2 times with 2x100 g fresh and cold toluene. The solid compound was dried at 25 ° C / 50 mbar.

Yield: 456 g (98 wt%; triazol-4-yl isomer: not detected); 82% of theoretical.

Melting point: 126-127 ° C.

The crystalline material thus obtained was analyzed by DSC and by X-ray powder diffractometry (XRPD). The X-ray powder diffractogram is depicted in FIG. 1. Reflections are summarized in table. one.

1H-NMR (400 MHz, CDCl ₃ ): δ / ppm. = 1.64 (s, 3H), 4.55 (s, 0H), 4.44 (d, 1H), 4.62 (d, 1H), 6.92-7.61 (m, 7H), 7.87 (s, 1H), 8.02 (s, 1H)

13C-NMR (125 MHz, CDCl ₃ ): δ / ppm. = 27.8 (q), 59.02 (t), 74.77 (s), 118.21 (d), 120.50 (d), 120.82 (d, 2C), 123.95 (CF3 ), 128.96 (s), 129.54 (s), 130.09 (d, 2C), 130.42 (d), 137.30 (s), 144.34 (d), 151.46 ( d), 154.24 (s), 156.49 (s).

Single crystals of Form A of compound I.3 were obtained by evaporating a solution of the title compound in acetonitrile at ambient temperature. Single crystal X-ray diffraction data were collected as described above and crystallographic parameters were calculated based on them. The crystallographic parameters calculated in this way are summarized in table. 2.

Example C2. 1- [4- (4-Chlorophenoxy) -2- (trifluoromethyl) phenyl] -1-cyclopropyl-2- (1,2,4-triazol-1yl) ethanol.

12.8 g (98 wt%; 0.182 mol) of triazole and 2.86 g (0.07 mol) of NaOH powder were added to 217.5 ml of 22.8 wt% DMF solution of 2- [4- (4-chlorophenoxy ) -2- (trifluoromethyl) phenyl] -2-cyclopropyloxyrane (0.14 mol) at 25 ° C. After heating to 125 ° C, the reaction mixture was stirred at this temperature for a total of 10 hours.The HPLC sample showed almost complete conversion to the target product (triazol-1-yl / triazol-4-yl ratio approximately 7.3: 1) ... Approximately 90% of the DMF was evaporated at 125 ° C / 60 mbar. To the concentrated reaction mixture were added 140 g of toluene and 86 g of water at 40 ° C. Then the aqueous phase was separated at 80 ° C. The toluene solution was concentrated up to 86 ° C / 40 mbar. Received approximately 133 g of distillate. The residue was cooled to 60 ° C. and 25 g of methanol was added. After cooling to 45 ° C, seed crystals were added and the reaction mixture was kept at 45 ° C for 30 minutes. The mixture was then cooled to 0 ° C over 5 hours and stirred for 12 hours. The slightly agitated solid suspension was separated by suction filtration and washed once with 21 g of 0 ° C methanol. The solid compound was dried at 55 ° C and 15 mbar.

Yield: 42.4 g (94.6 wt.%; Approximately 3 wt.% MeOH; ratio of triazol-1-yl / triazol-4-yl approximately 39: 1); 68% of theoretical.

Melting point: 86-87 ° C.

-NMR (400 MHz, CDCl ₃ ): δ / ppm. = 0.28-0.42 (m, 4H), 1.38-1.43 (m, 1H), 4.2-4.4 (s, br., OH), 4.49 (d, 1H ), 4.76 (d, 1H), 6.92-7.76 (br, 7H), 7.92 (s, 1H), 8.0 (s, 1H);

13C-NMR (125 MHz, CDCl ₃ ): δ / ppm. = -0.12 (t), 1.61 (t), 18.91 (d), 58.78 (t), 75.09 (s), 118.14 (d), 120.34 (d) , 120.9 (d, 2C) ,, 123.97 (CF3), 129.20 (s), 129.53 (s), 130.08 (d, 2C), 130.92 (d), 137, 06 (s), 144.18 (d), 151.84 (d), 154.24 (s), 156.44 (s).

Example C2a. Crystallization of 1- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -1-cyclopropyl-2 (1,2,4-triazol-1-yl) ethanol.

206.5 g of a toluene solution of 1- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -1-cyclopropyl-2 (1,2,4-triazol-1-yl) ethanol (41.8 wt. %; 0.204 mol), obtained as described in example C2, was concentrated up to 60 ° C / 10 mbar. The residue was cooled to 50 ° C and dissolved in a mixture of 50 g ethanol and 9 g water. After cooling to 30 ° C, seed crystals were added and the reaction mixture was kept at 30 ° C for 60 minutes. The mixture was then cooled to 0 ° C at a rate of 2.5 K / min over 5 hours and stirred at 0 ° C for 4 days. The suspension of solids, which was easily stirred, was separated by suction filtration and washed once with 39 g of ethanol at 0 ° C.

- 43 037646

The solid compound was dried at 60 ° C / 10 mbar.

76.4 g (93.7 wt%; triazol-1-yl / triazol-4-yl ratio of about 44: 1) of colorless crystals were obtained, containing ethanol in a molar ratio of the product to about 1/3 (found with 1H- NMR spectroscopy); crystallization yield 83%.

Melting point: 81.5 ° C.

Example C3. 2- [4- (4-Chlorophenoxy) -2- (trifluoromethyl) phenyl] -3-methyl-1- (1,2,4-triazol-1-yl) butan-2ol (compound I.5).

2- [4- (4-Chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-isopropyloxyrane (92.9 g, 76.9 wt%, 0.217 mol) was dissolved in 180.6 g of DMF. To this solution were added 27.4 g (98 wt%; 0.391 mol) of triazole and 4.7 g (0.117 mol) of NaOH powder at 25 ° C. After heating to 125 ° C., the reaction mixture was stirred at this temperature for a total of 22.5 hours. The HPLC sample showed that there was still oxirane and the ratio of triazole products was 10.3: 1 (triazol-1-yl / triazol-4-yl). Adding an additional 0.3 eq. triazole and stirring for another 2 hours at 125 ° C. did not improve the conversion. Approximately 79% of the DMF was evaporated at up to 60 ° C / 4 mbar. To the concentrated reaction mixture were added 413 g of toluene and 205 g of water at 80 ° C. Then the aqueous phase was separated at 55 ° C. The toluene solution was concentrated at up to 90 ° C / 40 mbar until a residue of 108 g remained. 111 g of methanol were added to the residue at 60 ° C. The resulting solution was cooled to -1 ° C at a rate of 5 ° C / h. Seed crystals were added at 45 ° C. The suspension of solids, which was easily agitated, was separated by suction filtration and washed once with 25 g of fresh and cold (0 ° C.) methanol. The solid compound was dried at 55 ° C and 50 mbar.

Yield: 64.8 g (96.9 wt%; triazol-1-yl / triazol-4-yl ratio approximately 100: 1); 73% of theoretical. The crystals were found to contain residual methanol by 1 H-NMR.

Melting point: 114-115 ° C.

1H-NMR (400 MHz, CDCl ₃ ): δ / ppm. = 0.87 (d 3H), 1.2 (d, 3H), 2.38 (m, 1H), 4.3-4.65 (s, br., 0H), 4.58 (d, 1H ), 4.75 (d, 1H), 6.85-7.54 (m, 7H), 7.7 (s, 1H), 7.8 (s, 1H);

¹³ C-NMR (125 MHz, CDCl ₃ ): δ / ppm. = 16.83 (q), 17.44 (q), 37.00 (d), 57.70 (t), 80.43 (s), 117.98 (d), 120.13 (d), 120.87 (d, 2C) ,, 123.75 (CF3), 129.54 (s), 130.10 (d, 2C), 130.20 (d), 130.82 (s), 136.65 (s), 143.83 (d), 151.69 (d), 154.20 (s), 156.06 (s)

Example C4. 2- [4- (4-Chlorophenoxy) -2- (trifluoromethyl) phenyl] -3-methyl-1- (1,2,4-triazol-1-yl) butan-2ol (compound I.5).

The preparation of compound I.5 was carried out as described in experiment C.3, except that no seed crystals were added during cooling of the solution of compound I.5 in methanol at 45 ° C. The crystalline material thus obtained was analyzed by DSC and by X-ray powder diffractometry (XRPD). The X-ray powder diffractogram is depicted in FIG. 2. Reflections are summarized in table. 3.

Single crystals of compound I.5 Form A were prepared by dissolving the thus obtained compound I.5 in 3-propanol and allowing the heptane to diffuse into this solution at ambient temperature. Single crystal X-ray diffraction data were collected as described above and the crystallographic parameters were calculated from them. The crystallographic parameters calculated in this way are summarized in table. four.

D) Comparative examples regarding the amount of base used.

Base and triazole in the amounts specified in the table. D was added to a 20-25% solution of the corresponding oxirane II in DMF. At 125 ° C., the product of formula I was obtained. After evaporation of more DMF, the residue was partitioned between toluene and water. The yield was determined after azeotropic drying and concentration by quantitative HPLC from a toluene solution.

Table D

example 1 eq. oxirane II EKV. triazole eq. foundations pace. / duration output 1triazolyl D1 K ^{1 =} cyclopropyl (R ³ ) _n = 2-CF ₃ (R ⁴ ) m = 4-Cl 1.3 NaOH / 0.5 125 ° C / 10h 82% D2 R ^{i =} CH3 (R ³ ) n = 2-CF ₃ (R ⁴ ) _m = 4-Cl 1.3 NaOH / 1.3 125 ° C / 6h 86% D3 R ^{1 =} L (HKnonponHn 1.3 NaOH / 1.3 125 ° C / 12h 75%

- 44 037646

(R ³ ) n = 2-CF3 (R ⁴ ) m = 4-Cl D4 R = CH ₃ (R ³ ) n = 2-CF3 (R ⁴ ) m = 4-Cl 1.3 KOH / 0.3 125 ° C / 5.5 h 93% D5 r ⁴ = ch ₃ (R ³ ) n = 2-CF3 (R ⁴ ) m = 4-Cl 1.3 NaOH / 0.3 125 ° C / 5h 91% D6 R = CH ₃ (R ³ ) n = 2-CF3 (R ⁴ ) m = 4-Cl 1.3 KOH / 1.3 125 ° C / 6h 89% D7 R ^{i =} iIHKgonponHg (R ³ ) n = 2-CF3 (R ⁴ ) m = 4-Cl 1.3 KOH / 1.3 125 ° C / 16h 56% D8 R ^{i =} ijHKgonponHg (R ³ ) n = 2-CF3 (R ⁴ ) m = 4-Cl 1.3 KOH / 0.3 125 ° C / 12h 76%

E1) Comparative example.

To 1- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] cyclopropylmethanone (0.13 mol) dissolved in 55 g of dimethyl sulfide together with 42 g of aqueous trimethylsulfonium methyl sulfate (86 wt%, obtained in accordance with example A1), 15.7 g of NaOH pellets (98 wt%) (0.385 mol) were added at 22 ° C with vigorous stirring. This resulted in a temperature increase of about 5-6 ° C. Stirring was then continued for 20 hours at 38 ° C. A sample of the reaction solution showed incomplete conversion of the ketone (detection by HPLC). Then 199 g of a 20 wt% NaCl solution was added at 30 ° C. After separation of the aqueous phase, the dimethyl sulfide solution was concentrated by solvent distillation at temperatures up to 90 ° C. 59.7 g of product was obtained (purity of the product approximately 47% by weight, as determined by quantitative HPLC) 2- [4- (4-chlorophenoxy) -2 (trifluoromethyl) phenyl] -2-methyloxyrane; yield: 66%.

E2) Comparative example.

The use of 50% aqueous KOH leads to incomplete conversion of the reagents.

To 1- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] cyclopropylmethanone (0.13 mol) dissolved in 55 g of dimethyl sulfide together with 42 g of aqueous trimethylsulfonium methyl sulfate (86 wt%, obtained in accordance with example A1), 15.743 g of 50% aqueous KOH (0.385 mol) was added at 22 ° C with vigorous stirring. This resulted in a temperature increase of about 5-6 ° C. Stirring was then continued for 32 hours at 38 ° C. A sample of the reaction solution showed incomplete conversion of the ketone (detection by HPLC). Then 199 g of a 20 wt% NaCl solution was added at 30 ° C. After separation of the aqueous phase, the dimethyl sulfide solution was concentrated by solvent distillation at temperatures up to 90 ° C. There was obtained 53.5 g (purity of the product approximately 34.5 wt.%, Determined by quantitative HPLC) of 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2 methyloxirane. Yield: 44%.

Claims (6)

CLAIM 1. A method of obtaining a triazole compound of formula I comprising the following step: (iia) reacting an oxirane of formula II with 1H-1,2,4-triazole and an inorganic base, where 0.1-0.8 equiv. the specified base for 1 eq. compounds II, which leads to compounds of formula I, where R ^{1 is} selected from C ₁ -C ₆ alkyl or _{C 3 -C 8} cycloalkyl; R ^{3 is} independently selected from halogen, CN, NO2, OH, SH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C 3 -C ₈ -cycloalkyl, Cs-C ₈ -cycloalkyloxy, NH2, NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ , NH (Cs-C ₆ -cycloalkyl), N (Cs- C ₆ -cycloalkyl) ₂ , S (O) _p (C ₁ -C ₄ -alkyl), C (= O) (C1-C ₄ alkyl), C (= O) (OH), C (= O) ( O-C1-C4-alkyl), C (= O) (NH (C1-C4-alkyl)), C (= O) (N (C1-C4-alkyl) 2), C (= O) (NH ( Cs-C ₆ -cycloalkyl)) and C (= O) - (N (Cs-C ₆ -cycloalkyl) ₂ ), where p is 0, 1 or 2; each R ³ is not substituted or additionally substituted with one, two, three or four R ^3a, wherein R ^3a is independently selected from halogen, CN, NO2, OH, C1-C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, - 45 037646 C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -galogentsikloalkila, _C1-C4 alkoxy and _C1-C4 -galogenalkoksi; R ^{4 is} independently selected from substituents as defined for R ³ , wherein said R ⁴ is unsubstituted or further substituted with one, two, three or four R ^4a , where each R ^{4a is} independently selected from substituents as defined for R ^3a ; n takes the value 0, 1, 2, 3, or 4; m takes the value 0, 1, 2, 3, 4, or 5. 2. The method according to claim 1, in which the product obtained in stage (iia)? crystallized from toluene and / or aliphatic alcohol. 3. The method of claim 2, wherein the aliphatic alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or any mixture thereof. 4. A process according to any one of claims 1 to 3, wherein the base used in step (iia) is selected from NaOH, KOH, Na ₂ CO ₃ and K ₂ CO ₃ . 5. A process according to any one of claims 1 to 4, wherein the base used in step (iia) is selected from NaOH and KOH. 6. The method according to any one of claims 1 to 5, in which the amount of base used in stage (iia) is from 0.1 to 0.6 EQ. for 1 eq. compounds II.