US20200231556A1

US20200231556A1 - Preparation of substituted 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles

Info

Publication number: US20200231556A1
Application number: US16/634,337
Authority: US
Inventors: Wassilios Grammenos; Michael Rack; Violeta TERTERYAN-SEISER; Christopher Koradin
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2017-07-28
Filing date: 2018-07-20
Publication date: 2020-07-23
Also published as: BR112020001211B1; KR102573454B1; US11021452B2; EP3658542A1; WO2019020451A1; KR20200033916A; CN110959005A; EP3658543A1; BR112020001211A2; EP3658542B1; IL271971B; US20200157064A1; CN110997644A; WO2019020501A1; CN110997644B; IL271962A; BR112020001273A2; CN110959005B; IL271971A; IL271962B

Abstract

The present invention relates to a process for the preparation of 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles, which are useful as fungicidal compounds or as intermediates for the synthesis of fungicidal oxaciazole compounds, using trifluoroacetyl halides.

Description

The present invention relates to a process for the preparation of substituted 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles (compounds I), which can be obtained through reaction of hydroxyamidine type compounds of formula II with trifluoroacetyl halides.
Certain 3-substituted 5-trifluoromethyl-1,2,4-oxadiazoles are known as fungicides i.a. from EP 276432 A2, EP 3165093 A1, EP 3165094 A1, EP 3167716 A1, WO 2015/185485, WO 2017/055469, WO 2017/055473, WO 2017/076739, WO 2017/076740, WO 2017/076742, WO 2017/076757, WO 2017/076935, WO 2017/081309, WO 2017/081310, WO 2017081311, WO 2017081312, WO 2017/085098, WO 2017/085100, WO2017/093019, WO2017/093348, WO 2017/085100, WO2017/093348, WO2017/102006, WO2017/103219, WO2017/103223, WO2017/109044 and WO2017/118689.
The formation of the 1,2,4-oxadiazole ring system in 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles, which are useful as fungicidally active compounds or as intermediates in the synthesis of fungicides, is described in the references cited above or in WO 2013/008162 by reacting amidoximes of type II with trifluoroacetic anhydride (TFAA) in an organic solvent.
One disadvantage of this reaction lies in the formation of significant amounts of free trifluoroacetic acid (TFA) as a side product. Regulatory restrictions oftentimes require very low residue levels of TFA impurities in commercial agrochemical pesticides. For the sake of receiving a market authorization it is therefore crucial to control and minimize the amount of residual TFA during the process of producing a pesticide.
In contrast to other acids it is particularly difficult to remove free TFA from reaction mixtures, be it in solution or in mixtures that are in a solid state. TFA has a tendency to form cocrystals or clathrates with other solid reaction components. The removal of TFA is oftentimes cumbersome and requires elaborate additional purification steps (e. g. chromatography, distillation, crystallization, etc.). Furthermore, TFA is very corrosive and there is an interest to reduce the excess amounts of TFA furnished during or after the ring closing reaction, for example during workup. The reaction of compound II with TFAA produces one equivalent TFA. In the course of the oxadiazole ring closing/aromatisation reaction one equivalent of water is formed per equivalent of compound II. The water immediately reacts with another equivalent of TFAA, which in turn results in the formation of two additional equivalents TFA. As a result, at least two equivalents TFAA are necessary for a complete conversion of compounds II and in total at least three equivalents TFA are formed per equivalent of compounds II.
Reducing the number of equivalents of TFAA to the minimum required by theory, i.e. to two equivalents based on the amounts of compound II, does not always provide sufficient yield of the desired product. Typically, an excess of TFAA is used to achieve complete conversion of compounds II to compounds I. Hydrolyzation of excess TFAA under aqueous workup conditions produces even more TFA.
Thus, it was an object of the present invention to overcome the disadvantages of the known processes and to provide an improved and more economical and production plant friendly process.
It was now found that 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles can be obtained by the use of trifluoroacetyl halides, in particular trifluoroacetyl chloride (TFAC) or trifluoroacetyl fluoride (TFAF). The use of TFAC or TFAF instead of TFAA has several surprising advantages in relation to the preparation of the above-mentioned compounds.
The process of this invention does not require a large excess of trifluoroacetyl halides in order to achieve high yields of the desired oxadiazoles, which is desirable from both, an economical and an ecological point of view. As a consequence, the total organic carbon content in the production waste water is reduced compared to the prior art processes, which makes the process eco-friendly. Unlike the use of TFAA, the use of trifluoroacetic halides results in the formation of a much smaller amount of TFA, which makes such process more production plant friendly and simplifies the workup procedure. As a result the production costs are significantly lower. Furthermore, the process of this invention provides the desired oxadiazoles in high yields and with reduced amounts of undesired side products. The in-situ preparation of compounds of type II enables a process, which proceeds in a smooth and controlled manner, which is very safe, simple, economical, user-friendly and commercially viable.
Accordingly, the present invention relates to a process for preparing compounds of formula I,
wherein

- A¹is N or CH;
- A²is N or CH;
- R^Ais hydrogen or halogen;
- R is methyl, trichloromethyl, ethyl, iso-propyl, OH, SH, CN, halogen, CH₂F, CHF₂, 2,2,2-trifluoroethyl, cyclopropyl, —COOH, —COOR¹, —C(═W)NR¹R², —CR³R⁴NR¹R², —CR³R⁴OR¹, —CR³(═NR¹), —CR³(═O), —CR³R⁴COOH, —CR³R⁴COR¹, —CR³R⁴C(═W)NR¹R², —OCR³R⁴COOH, —OCR³R⁴COR¹, —OCR³R⁴C(═W)NR¹R², —CR³R⁴NR²C(═W)R¹, —CR³R⁴S(═O)₂R¹, or —CR³R⁴NR²S(═O)₂R¹;
- W is O or S;
- R²is hydrogen, formyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy, C₃-C₁₁-cycloalkyl, C₃-C₈-cycloalkenyl, C₃-C₁₁-cycloalkyl-C₁-C₄-alkyl, phenyl-C₁-C₄-alkyl, phenyl, pyridinyl, —C(═O)—(C₁-C₆-alkyl), —C(═O)—(C₃-C₁₁-cycloalkyl), —C(═O)—(C₁-C₆-alkoxy) and —N(R^2a)₂;
- R^2ais independently selected from the group consisting of hydrogen, OH, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₁₁-cycloalkyl, C₃-C₈-cycloalkenyl, C₁-C₆-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl and C₁-C₆-alkylthio; and wherein any of the aliphatic or cyclic groups in R²are unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, hydroxy, oxo, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy and C₃-C₁₁-cycloalkyl;
- R¹is C₁-C₆-alkyl, C₁-C₆-alkoxy, C₃-C₁₁-cycloalkyl, C₃-C₈-cycloalkenyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxyimino-C₁-C₄-alkyl, C₂-C₆-alkenyloxyimino-C₁-C₄-alkyl, C₂-C₆-alkynyloxyimino-C₁-C₄-alkyl, C₁-C₆-alkylamino, diC₁-C₆-alkylamino, C(═O)—(C₁-C₆-alkyl), C(═O)—(C₁-C₆-alkoxy), phenyl-C₁-C₄-alkyl, phenyl-C₁-C₄-alkenyl, phenyl-C₁-C₄-alkynyl, heteroaryl-C₁-C₄-alkyl, phenyl, naphthyl or a 3- to 10-membered saturated, partially unsaturated or aromatic mono- or bicyclic heterocycle, wherein the ring member atoms of said mono- or bicyclic heterocycle include besides carbon atoms further 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein the heteroaryl group in the group heteroaryl-C₁-C₄-alkyl is a 5- or 6-membered aromatic heterocycle, wherein the ring member atoms of the heterocyclic ring include besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein any of the above-mentioned aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different groups R^1a; or
- R¹and R², together with the nitrogen atom to which R²is attached, and together with interjacent group —C(═W)—, if present, which is located between said nitrogen atom and the group R¹, form a saturated or partially unsaturated mono- or bicyclic 3- to 10-membered heterocycle, wherein the heterocycle includes beside one nitrogen atom and one or more carbon atoms no further heteroatoms or 1, 2 or 3 further heteroatoms independently selected from N, O and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein the heterocycle is unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different groups R^1a; or
- if R²is —N(R^2a)₂, R¹and one of the two groups R^2a, together with the nitrogen atom to which R^2ais attached, and together with interjacent groups, which are located between said nitrogen atom and the group R¹, form a saturated or partially unsaturated mono- or bicyclic 3- to 10-membered heterocycle, wherein the heterocycle includes beside two nitrogen atoms and one or more carbon atoms no further heteroatoms or 1, 2 or 3 further heteroatoms independently selected from N, O and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein the heterocycle is unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different groups R^1a;
- R^1ais halogen, oxo, cyano, NO₂, OH, SH, NH₂, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₃-C₈-cycloalkyl, —NHSO₂—C₁-C₄-alkyl, (C═O)—C₁-C₄-alkyl, C(═O)—C₁-C₄-alkoxy, C₁-C₆-alkylsulfonyl, hydroxyC₁-C₄-alkyl, C(═O)—NH₂, C(═O)—NH(C₁-C₄-alkyl), C₁-C₄-alkylthio-C₁-C₄-alkyl, aminoC₁-C₄-alkyl, C₁-C₄-alkylamino-C₁-C₄-alkyl, diC₁-C₄-alkylamino-C₁-C₄-alkyl, aminocarbonyl-C₁-C₄-alkyl or C₁-C₄-alkoxy-C₁-C₄-alkyl;
- R³, R⁴independently of each other are selected from the group consisting of hydrogen, halogen, cyano, C₁-C₄-alkyl, C₁-C₄-alkenyl, C₁-C₄-alkynyl, C₁-C₄-haloalkyl and C₁-C₄-alkoxy; or
- R³and R⁴together with the carbon atom to which they are bound form a saturated 3- to 7-membered carbocycle or a saturated 3- to 6-membered heterocycle; wherein the saturated heterocycle includes beside carbon atoms 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein said N ring member atom is substituted with the group R^N; wherein
  - R^Nis hydrogen, C₁-C₆-alkyl or halogen;
  - and wherein said S ring member atom is unsubstituted or substituted with 1 or 2 oxo radicals; and wherein one or two of the ring member —CH₂— groups of said saturated carbocycle or of said saturated heterocycle may be replaced by one or two groups independently selected from —C(═O)— and —C(═S)—; and wherein the carbon ring member atoms of the saturated carbocycle or of the saturated heterocycle are unsubstituted or substituted with a total number of 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy and C₃-C₈-cycloalkyl;
    the process comprising:
    reacting a compound of formula II,

wherein A¹, A², R^Aand R is as defined above, with a compound of formula IIa,
wherein Hal is chlorine or fluorine.
The amidoxime compounds II can be obtained from cyano compounds V by treatment with hydroxylamine or a salt thereof, for example the hydrochloride salt, in the presence of a base, preferably triethylamine, in a suitable solvent, such as methanol, at a temperature between 0° C. and 100° C. For related examples see Kitamura, S. et al Chemi. Pharm. Bull. (2001), 49, 268 WO 2013/066838 or WO 2017/055473:
Preferably, the formation of the amidoxime II and its transformation to compounds I takes place in a two-step one-pot reaction without any workup of the amidoxime II.
Compounds of formula III are either commercially available or may be prepared using standard procedures known to a person skilled in the art from readily available starting materials. Such procedures are described in, for example, WO 2013/008162, EP 276432 A2, EP 3165093 A1, EP 3165094 A1, EP 3167716 A1, WO 2015/185485, WO 2017/055469, WO 2017/055473, WO 2017/076739, WO 2017/076740, WO 2017/076742, WO 2017/076757, WO 2017/076935, WO 2017/081309, WO 2017/081310, WO 2017081311, WO 2017081312, WO 2017/085098, WO 2017/085100, WO2017/093019, WO2017/093348, WO2017/102006, WO2017/103219, WO2017/103223, WO2017/109044 and WO2017/118689.
According to a preferred embodiment, compound IIa is trifluoacetyl chloride (TFAC).
In a preferred embodiment, the transformation of a compound of formula II with compounds of formula IIa to produce compounds of formula I is carried out in the presence of an inert organic solvent, wherein the inert organic solvent is not identical with a compound I, II, IIa, III or a base as defined herein.
In a preferred embodiment, said process is carried out in the presence of a base, wherein the base is not identical with a compound I, II, IIa, III or an inert organic solvent as defined herein.
In another preferred embodiment, said process is carried out in the presence of an inert organic solvent, wherein the inert organic solvent is not identical with a compound I, II, IIa, III or a base as defined herein; and in the absence of a base, wherein the base is not identical with a compound I, II, IIa, III or an inert organic solvent as defined herein.
In another preferred embodiment, said process is carried out in the presence of a base, wherein the base is not identical with a compound I, II, IIa, III or an inert organic solvent as defined herein; and in the absence of an inert solvent, wherein the inert organic solvent is not identical with a compound I, II, IIa, III or a base as defined herein.
In another preferred embodiment, said process is carried out in the presence of a base, wherein the base is not identical with a compound I, II, IIa, III or a solvent as defined herein; and in the presence of an inert solvent, wherein the inert organic solvent is not identical with a compound I, II, IIa, III or a base as defined herein.
By “inert organic solvent” is meant an organic solvent which, under the reaction conditions of the process of this invention, does not enter into any appreciable reaction with either the reactants or the products.
In one embodiment, the inert organic solvent is selected from non-halogenated inert organic solvents; preferably from non-halogenated aliphatic hydrocarbons, non-halogenated cycloaliphatic hydrocarbons, non-halogenated aromatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, amides, ethers, esters, ketones, nitriles and any combination thereof.
Examples of suitable non-halogenated aliphatic hydrocarbons include pentane, hexane, heptane, and the like. Preference is given to saturated aliphatic hydrocarbons having from 5 to 10 carbon atoms.
Examples of suitable non-halogenated cycloaliphatic hydrocarbons include cyclopentane, cyclohexane, cycloheptane, and the like. Preference is given to non-halogenated saturated cycloaliphatic hydrocarbons having from 5 to 10 carbon atoms. Cyclohexane is particularly preferred.
Examples of suitable a non-halogenated aromatic hydrocarbons include toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 2-propylbenzene (cumene), 2-isopropyltoluene (o-cymol), 3-isopropyltoluene (m-cymol), 4-isopropyltoluene (p-cymol), 1,3,5-trimethylbenzene (mesitylene), and the like. Preference is given to toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1,3,5-trimethylbenzene (mesitylene), and any combination thereof. Especially preferred among the non-halogenated aromatic hydrocarbons are toluene, o-xylene, m-xylene, p-xylene, and any combination thereof, with toluene being the most preferred.
Examples of suitable halogenated aliphatic hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, 1,1-dichloroethylene, 1,2-dichloroethylene, and the like. Preference is given to dichloromethane and 1,2-dichloroethane and any combination thereof.
Examples of suitable halogenated aromatic hydrocarbons include chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, α,α,α-trifluorotoluene (benzotrifluoride) and the like and any combination thereof.
Examples of suitable amides include N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N-methyl-pyrrolidone, and the like and any combination thereof.
Examples of suitable ethers include cyclic and acyclic ethers such as diethyl ether, diisopropyl ether, n-butyl methyl ether, isobutyl methyl ether, sec-butyl methyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, 1,4-dioxane, and the like and any combination thereof.
Examples of suitable esters include ethyl acetate, n-propylacetate, isopropyl acetate, tert-butyl acetate, and the like and any combination thereof.
Examples of suitable ketones include acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclopropyl methyl ketone and the like, and any combination thereof. Examples of suitable nitriles include acetonitrile, benzonitrile, and the like and any combination thereof.
In a preferred embodiment, the inert organic solvent is selected from non-halogenated aliphatic hydrocarbons, non-halogenated cycloaliphatic hydrocarbons, non-halogenated aromatic hydrocarbons, halogenated aliphatic hydrocarbons and any combination thereof.
In a more preferred embodiment, the inert organic solvent is selected from heptane, cyclohexane, cycloheptane, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1,3,5-trimethylbenzene (mesitylene), chlorobenzene, 1,2-dichloroethane, dichloromethane, tetrahydrofuran, dioxane, ethyl acetate, methyl ethyl ketone and benzotrifluoride and any combination thereof.
In an even more preferred embodiment, the inert organic solvent is selected from heptane, cyclohexane, toluene, dichloromethane and any combination thereof.
Still more preferably, the inert organic solvent is selected from heptane, cyclohexane, toluene and any combination thereof.
Particularly preferred inert organic solvents are non-halogenated aromatic hydrocarbons, especially non-halogenated alkylbenzenes which are mono-, di-, or tri-alkylsubstituted with each alkyl group containing 1 to 3 carbon atoms, and in particular those selected from the group consisting of toluene, o-xylene, m-xylene, p-xylene and any combination thereof. Most preferably, the inert organic solvent is toluene.
The volume ratio of the inert organic solvent to the hydroxyamidine II is generally from 0.01:1 to 20:1, preferably from 0.1:1 to 15:1, more preferably from 0.5:1 to 10:1, and most preferably from 1:1 to 5:1.
In a preferred embodiment of the present invention, the transformation of a compound of formula II with compounds of formula IIa to produce compounds of formula I is carried out in the presence of an organic base.
In one embodiment the base is selected from organic bases such as, for example: tertiary amines, pyridine, substituted pyridines, bicyclic amines and any mixture thereof. Preference is given to tertiary amines, pyridine, substituted pyridines and any mixture thereof. Particular preference is given to pyridine, substituted pyridines and any mixture thereof. Pyridine is especially preferred.
Examples of suitable tertiary amines are tri-(C₁-C₆)-alkylamines such as trimethylamine, triethylamine, tributylamine and diisopropylethylamine; di-(C₁-C₆)-alkyl-phenylamines such as N,N-dimethylaniline and N,N-diethylaniline; N-methyl imidazole, N,N-dimethylaminopyridine and the like.
Examples of suitable substituted pyridines are collidine, lutidines, 2-picoline, 3-picoline, 4-picoline, N,N-dimethyl-4-aminopyridine, 5-ethyl-2-methyl-pyridine and the like.
Examples of suitable bicyclic amines are 1,8-diazabicyclo[5.4.0]undec-7-en, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and the like.
In one embodiment the base is an organic base, which is selected from trimethylamine, triethylamine, tributylamine, diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline, N-methyl imidazole, pyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, N,N-dimethyl-4-aminopyridine, 5-ethyl-2-methyl-pyridine,1,8-diazabicyclo[5.4.0]undec-7-en, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and mixtures thereof.
In another embodiment the base is an organic base, which is selected from trimethylamine, triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, 5-ethyl-2-methyl-pyridine, N,N-dimethylaminopyridine and mixtures thereof.
More preferably the base is an organic base, which is selected from trimethylamine, triethylamine, diisopropylethylamine, pyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, 5-ethyl-2-methyl-pyridine and mixtures thereof.
In another embodiment, the base is selected from alkali metal and alkaline earth metal phosphates; alkali metal and alkaline earth metal formats; alkali metal and alkaline earth metal acetates; alkali metal and alkaline earth metal carbonates; alkali metal and alkaline earth metal citrates; alkali metal and alkaline earth metal sulfates and any combination thereof, even more preferably selected from alkali metal and alkaline earth metal phosphates; alkali metal and alkaline earth metal formats; alkali metal and alkaline earth metal acetates; alkali metal and alkaline earth metal carbonates; alkali metal and alkaline earth metal citrates and any combination thereof, in particular selected from alkali metal and alkaline earth metal phosphates; alkali metal and alkaline earth metal acetates; particularly sodium acetate, potassium acetate; alkali metal and alkaline earth metal carbonates and any combination thereof, most preferably selected from alkali metal and alkaline earth metal acetates; particularly preferred are sodium carbonate and potassium carbonate.
In another embodiment the base is selected from trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, 5-ethyl-2-methyl-pyridine, sodium acetate, potassium acetate, sodium carbonate and potassium carbonate and mixtures thereof.
The molar ratio of the base to hydroxyamidine II is generally from 3:1 to 0.4:1 or from 1:1 to 0.2:1, preferably from 0.02:1 to 0.3:1, more preferably from 0.02:1 to 0.25:1, most preferably from 0.02:1 to 0.2:1.
The process of the present invention can be carried out under atmospheric pressure or under elevated or reduced pressure. Typically, the atmospheric and elevated pressure is employed. In a preferred embodiment the process of the present invention can be carried out at pressure ranges typically from 0.8 atmospheres (atm) to 80 atm, preferably form 1.0 atm to 20 atm, in particular from 1.0 to 7 atm.
The temperature used in the process of the present invention can vary widely and is preferably from −30 to 150° C., more preferably from −10 to 120° C. and even more preferably from 0 to 100° C., 20 to 80° C. or 40 to 70° C.
Typical reaction times are in the range of from 1 to 20 hours, preferably from 2 to 15 hours and more preferably from 3 to 10 hours.
In one preferred embodiment, the transformation of a compound of formula II with compounds of formula IIa to produce compounds of formula I is carried out in the presence of an inert organic solvent, wherein the inert organic solvent is selected from trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, 5-ethyl-2-methyl-pyridine, sodium acetate, potassium acetate, sodium carbonate and potassium carbonate and mixtures thereof; and in the absence of a base, wherein the base is not identical with a compound I, II, IIa, III or an inert organic solvent as defined herein; and at a pressure from 1 to 20 atm; and at a temperature from 0 to 100° C.
In another preferred embodiment, said reaction is carried out in the presence of an inert organic solvent, wherein the inert organic solvent is selected from trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, 5-ethyl-2-methyl-pyridine, sodium acetate, potassium acetate, sodium carbonate and potassium carbonate and mixtures thereof; and in the absence of a base, wherein the base is not identical with a compound I, II, IIa, III or an inert organic solvent as defined herein; and at a pressure from 1 to 7 atm; and at a temperature from 20 to 80° C.
The process of the present invention may optionally be carried out in the presence of at least one phase-transfer catalyst.
Phase transfer catalysts suitable for use in the process of this invention are those well known in the art such as, for example, quaternary ammonium salts. Examples of suitable phase-transfer catalysts are trimethyl(phenyl) ammonium chloride, bromide, iodide or hydroxide and tetra-n-C₁-C₁₂-alkyl-ammonium chlorides, bromides, iodides or hydroxides, preferably tetra-n-C₁-C₈-alkyl-ammonium chlorides, bromides, iodides or hydroxides, e.g. tetramethylammonium chloride, bromide, iodide or hydroxide, tetraethylammonium chloride, bromide, iodide or hydroxide, tetra-n-propylammonium chloride, bromide, iodide or hydroxide, tetra-n-butylammonium chloride, bromide, iodide or hydroxide, tetra-n-pentylammonium chloride, bromide, iodide or hydroxide, tetra-n-hexylammonium chloride, bromide, iodide or hydroxide, tetra-n-heptylammonium chloride, bromide, iodide or hydroxide, tetra-n-octylammonium chloride, bromide, iodide or hydroxide, methyl-tri-n-butylammonium chloride, bromide, iodide or hydroxide, ethyl-trimethylammonium chloride, bromide, iodide or hydroxide, n-propyl-trimethyl ammonium chloride, bromide, iodide or hydroxide, methyl-triethyl ammonium chloride, bromide, iodide or hydroxide and n-butyl-triethylammonium chloride, bromide, iodide or hydroxide. Of these, the use of tetra-n-C₁-C₄-alkyl-ammonium chlorides, bromides, iodides or hydroxides is preferred, in particular tetra-n-butylammonium chloride, bromide, iodide or hydroxide and methyl-tri-n-butylammonium chloride, bromide, iodide or hydroxide.
The phase-transfer catalysts, which are usually solid in pure form, can be used as such or, preferably, in dissolved form. An effective amount of the phase-transfer catalyst may range from 0.001 to 0.5 molar equivalents, preferably 0.001 to 0.2 molar equivalents relative to compound II.
According to one embodiment of said process, a mixture of the E/Z-isomers of compounds of formula II is used, more preferably said mixture comprises an E/Z-isomer ratio of from 0.1:1 to 10:1, even more preferably of from 0.5:1 to 2:1.
According to another embodiment, the E-isomer of compounds of formula II is used.
According to a further embodiment, the Z-isomer of compounds of formula II is used.
The reaction mixture obtained is worked up and the compound I can be isolated in a customary manner, e. g. by an aqueous, extractive workup, in particular extraction with a basic or neutral aqueous medium, and by removing the solvent, e. g. under reduced pressure, or by a combination of these measures. Further purification can be effected, for example, by crystallization, thin-film-evaporation, rectification, sublimation, distillation or by chromatography.
In a further embodiment, a compound of formula I, in which R is methyl, is converted into valuable chemical products or intermediates. Accordingly, compounds of formula I, wherein R is methyl, can be further chlorinated to obtain a compound of formula Ib
wherein the variables A¹, A²and R^Ain compounds I and Ib are as defined or preferably defined herein.
The chlorination of the methyl group R of compounds of formula I can be achieved using suitable chlorinating agents, for example molecular chlorine, N-chlorosuccinimide, trichloroisocyanuric acid, sulfuryl chloride or phosphorus pentachloride. The chlorination is conducted at temperatures between 0° C. and 200° C., preferably between 60° C. and 150° C., under irradiation or in the presence of radical starters, for example azobis(isobutyronitril) or dibenzoyl peroxide. For reference, see J. Am. Chem. Soc. 1951, 73, 455.
In one embodiment, the chlorination is carried out in the presence of at least one inert organic solvent, or mixtures of such solvents. The term “inert organic solvent” means an organic solvent, which does not enter into any appreciable reaction with either the reactants or the products under the reaction conditions of the process of this invention. The inert organic solvent used in the process is preferably selected from halogenated aliphatic hydrocarbons and halogenated aromatic hydrocarbons, such as dichloromethane, tetrachloromethane, dichloroethane, chlorobenzene, homologues of dichlorobenzenes or 1,2,4-trichlorobenzene.
In a particularly preferred embodiment the chlorination step is conducted in substance, for example with the liquid reaction product, which is directly obtained after the reaction of compounds II and IIa and in the absence of a further solvent, as described above.
The chlorination can be performed in the presence or absence of TFA impurities originating from the previous reaction. TFA can be removed during the chlorination process via distillation or separately by distillation before carrying out the chlorination step. After completion of the reaction the reaction mixture is worked up in the usual manner or it can be used directly in the next step.
In a further preferred embodiment, the compound of formula Ib is hydrolyzed to obtain a compound of formula III
wherein the variables A¹, A²and R^Ain compounds Ib and III are as defined or preferably defined herein.
In one embodiment this transformation is carried out in the presence of catalytic amounts of a lewis acid and water to obtain a compound of formula III, as described in WO 2007/063028 A2 on pages 42-43. Preferably, the lewis acid is a metal salt, for example aluminum(III) chloride or iron(III) chloride, particularly iron(III) chloride. The lewis acid is used in sub-stoichiometric or catalytic amounts, for example 0.001 to 0.5 molar equivalents, preferably 0.002 to 0.2 molar equivalents, more preferably 0.005 to 0.1 molar equivalents, based on the amount of the compound of formula Ib.
In one embodiment, the hydrolysis step is carried out in the presence of at least one inert organic solvent, or mixtures of such solvents. The inert organic solvent used in the process of this invention is preferably selected from non-halogenated aliphatic hydrocarbons, non-halogenated cycloaliphatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, amides, ethers, esters, ketones, nitriles.
In a preferred embodiment, the hydrolysis step is carried out in the absence of a solvent, i.e. in substance. Under these conditions the trichloromethyl compound Ib or the crude material comprising Ib, which was obtained from the previous reaction step, is heated to a temperature, where such material is a molten mass.
The amount of water in the hydrolysis step is between 0.8 to 1.5 molar equivalents, preferably between 0.95 to 1.05 molar equivalents, based on the amount of the compound Ib. The reaction is carried out at temperatures between 20° C. and 200° C., preferably between 80° C. and 130° C. After completion of the reaction the reaction mixture is worked up in the usual manner or it can be used directly in the next step.
In an especially preferred embodiment, the compound of formula III is reacted with an amine of formula IV to obtain a compound of formula Ic,
wherein the variables A¹, A², R^A, R¹and R²in compounds of formulae III and IV are as defined or preferably defined herein.
A skilled person will recognize that oxadiazole compounds of type Ic can be accessed by treating benzoic acid chloride of formula III with an amine of formula IV. The reaction is preferably carried out in a suitable inert organic solvent, such as non-halogenated aliphatic hydrocarbons, non-halogenated cycloaliphatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, amides, ethers, esters, ketones, nitriles; for example, N,N-dimethylformamide, dichloromethane or tetrahydrofuran; preferably at a temperature between −20° C. and 200° C., preferably between 0° C. and 80° C., and optionally in the presence of a base such as pyridine, triethylamine or N,N-diisopropylethylamine, or under conditions described in the literature for an amide coupling. For examples, see Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606 and Chinchilla, R., Najera, C. Chem. Soc. Rev. 2011, 40, 5084. After completion of the reaction the reaction mixture is worked up in the usual manner.
In another especially preferred embodiment, the compound of formula Ic is used to obtain a compound of formula Id
wherein the variables A¹, A², R^A, R¹and R²in compounds of formulae Ic and Id are as defined or preferably defined herein.
Compounds of formula Ib can be prepared from compounds of formula Ic through treatment with Lawesson's reagent or phosphorus pentasulfide in an inert organic solvent, such as non-halogenated aliphatic hydrocarbons, non-halogenated cycloaliphatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, amides, ethers, esters, ketones, nitriles; for example toluene, tetrahydrofuran, dioxane or ethyl acetate; at a temperature between 0° C. and 130° C., preferentially between 60° C. and 80° C. For examples, see Eur. J. Med. Chem. 2011, 46(9), 3917-3925; Synthesis 2003, 13, 1929-1958; WO 2006/0123242; WO 2010/086820; WO 2014/0151863. After completion of the reaction the reaction mixture is worked up in the usual manner.
The terms “compounds I”, “compounds II”, “compounds IIa” and “compounds III” refer to compounds of formulae I, II, IIa and III, respectively. In the definitions of the variables given above, collective terms are used which are generally representative for the substituents in question.
The term “C_n-C_m” indicates the number of carbon atoms possible in each case in the substituent or substituent moiety in question.
The term “halogen” refers to fluorine, chlorine, bromine and iodine.
The term “oxo” refers to an oxygen atom ═O, which is bound to a carbon atom or sulfur atom, thus forming, for example, a ketonyl —C(═O)— or sulfinyl —S(═O)— group.
The term “formyl” refers to a group C(═O)H.
The term “C₁-C₆-alkyl” refers to a straight-chained or branched saturated hydrocarbon group having 1 to 6 carbon atoms, for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl.
The term “C₂-C₆-alkenyl” refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and a double bond in any position, 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 “C₂-C₆-alkynyl” refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and containing at least one triple bond, such as ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl.
The term “C₁-C₆-haloalkyl” refers to a straight-chained or branched alkyl group having 1 to 6 carbon atoms (as defined above), wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above, for example chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl, CH₂—C₂F₅, CF₂—C₂F₅, CF(CF₃)₂, 1-(fluoromethyl)-2-fluoroethyl, 1-(chloromethyl)-2-chloroethyl, 1-(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl or nonafluorobutyl.
The term “C₁-C₆-alkoxy” refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms (as defined above) which is bonded via an oxygen, at any position in the alkyl group, for example methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.
The term “C₁-C₆-haloalkoxy” refers to a C₁-C₆-alkoxy group as defined above, wherein some or all of the hydrogen atoms may be replaced by halogen atoms as mentioned above, for example, OCH₂F, OCHF₂, OCF₃, OCH₂Cl, OCHCl₂, OCCl₃, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-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, OCH₂—C₂F₅, OCF₂—C₂F₅, 1-(CH₂F)-2-fluoroethoxy, 1-(CH₂Cl)-2-chloroethoxy, 1-(CH₂Br)-2-bromoethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy.
The terms “phenyl-C₁-C₄-alkyl or heteroaryl-C₁-C₄-alkyl” refer to alkyl having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a phenyl or hetereoaryl radical respectively.
The term “C₁-C₄-alkoxy-C₁-C₄-alkyl” refers to alkyl having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a C₁-C₄-alkoxy group (as defined above). Likewise, the term “C₁-C₄-alkylthio-C₁-C₄-alkyl” refers to alkyl having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a C₁-C₄-alkylthio group.
The term “C₁-C₆-alkylthio” as used herein refers to straight-chain or branched alkyl groups having 1 to 6 carbon atoms (as defined above) bonded via a sulfur atom. Accordingly, the term “C₁-C₆-haloalkylthio” as used herein refers to straight-chain or branched haloalkyl group having 1 to 6 carbon atoms (as defined above) bonded through a sulfur atom, at any position in the haloalkyl group.
The term “C₁-C₄-alkoxyimino” refers to a divalent imino radical (C₁-C₄-alkyl-O—N═) carrying one C₁-C₄-alkoxy group as substituent, e.g. methylimino, ethylimino, propylimino, 1-methylethyl-imino, butylimino, 1-methylpropylimino, 2-methylpropylimino, 1,1-dimethylethylimino and the like.
The term “C₁-C₆-alkoxyimino-C₁-C₄-alkyl” refers to alkyl having 1 to 4 carbon atoms, wherein two hydrogen atoms of one carbon atom of the alkyl radical are replaced by a divalent C₁-C₆-alkoxyimino radical (C₁-C₆-alkyl-O—N═) as defined above.
The term “C₂-C₆-alkenyloxyimino-C₁-C₄-alkyl” refers to alkyl having 1 to 4 carbon atoms, wherein two hydrogen atoms of one carbon atom of the alkyl radical are replaced by a divalent C₂-C₆-alkenyloxyimino radical (C₂-C₆-alkenyl-O—N═).
The term “C₂-C₆-alkynyloxyimino-C₁-C₄-alkyl” refers to alkyl having 1 to 4 carbon atoms, wherein two hydrogen atoms of one carbon atom of the alkyl radical are replaced by a divalent C₂-C₆-alkynyloxyimino radical (C₂-C₆-alkynyl-O—N═).
The term “hydroxyC₁-C₄-alkyl” refers to alkyl having 1 to 4 carbon atoms, wherein one hydrogen atom of the alkyl radical is replaced by a OH group.
The term “aminoC₁-C₄-alkyl” refers to alkyl having 1 to 4 carbon atoms, wherein one hydrogen atom of the alkyl radical is replaced by a NH₂group.
The term “C₁-C₆-alkylamino” refers to an amino group, which is substituted with one residue independently selected from the group that is defined by the term C₁-C₆-alkyl. Likewise the term “diC₁-C₆-alkylamino” refers to an amino group, which is substituted with two residues independently selected from the group that is defined by the term C₁-C₆-alkyl.
The term “C₁-C₄-alkylamino-C₁-C₄-alkyl” refers to refers to alkyl having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a C₁-C₄-alkyl-NH-group which is bound through the nitrogen. Likewise the term “diC₁-C₄-alkylamino-C₁-C₄-alkyl” refers to refers to alkyl having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a (C₁-C₄-alkyl)₂N-group which is bound through the nitrogen.
The term “aminocarbonyl-C₁-C₄-alkyl” refers to alkyl having 1 to 4 carbon atoms, wherein one hydrogen atom of the alkyl radical is replaced by a —(C═O)—NH₂group.
The term “C₂-C₆-alkenyl” refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and a double bond in any position, 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 “C₂-C₆-alkynyl” refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and containing at least one triple bond, such as ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl.
The term “C₃-C₁₁-cycloalkyl” refers to a monocyclic, bicyclic or tricyclic saturated univalent hydrocarbon radical having 3 to 11 carbon ring members that is connected through one of the ring carbon atoms by substitution of one hydrogen atom, such as cyclopropyl (C₃H₅), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, norcaranyl (bicyclo[4.1.0]heptyl) and norbornyl (bicyclo[2.2.1]heptyl). Further examples of bicyclic or tricyclic cycloalkyl radicals are found herein as examples R¹0.1 to R¹0.57.
The term “C₃-C₁₁-cycloalkyl” refers to a monocyclic, bicyclic or tricyclic saturated univalent hydrocarbon radical having 3 to 11 carbon ring members that is connected through one of the ring carbon atoms by substitution of one hydrogen atom, such as cyclopropyl (C₃H₅), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, norcaranyl (bicyclo[4.1.0]heptyl) and norbornyl (bicyclo[2.2.1]heptyl).
The term “C₃-C₁₁-cycloalkyl-C₁-C₆-alkyl” refers to alkyl having 1 to 11 carbon atoms, wherein one hydrogen atom of the alkyl radical is replaced by a C₃-C₁₁-cycloalkyl group as defined above.
The term “C₃-C₁₁-cycloalkoxy” refers to a cyclic univalent hydrocarbon radical having 3 to 11 carbon ring members (as defined above) that is bonded via an oxygen, at any position in the cycloalkyl group, for example cyclopropyloxy.
The terms “—C(═O)—C₁-C₄-alkyl”, “—C(═O)—C₁-C₄-alkoxy” and “—C(═O)—C₃-C₁₁-cycloalkyl” refer to radicals which are attached through the carbon atom of the —C(═O)— group.
The term “aliphatic” refers to compounds or radicals composed of carbon and hydrogen and which are non-aromatic compounds. An “alicyclic” compound or radical is an organic compound that is both aliphatic and cyclic. They contain one or more all-carbon rings which may be either saturated or unsaturated, but do not have aromatic character.
The terms “cyclic moiety” or “cyclic group” refer to a radical which is an alicyclic ring or an aromatic ring, such as, for example, phenyl or heteroaryl.
The term “and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with . . . ” refers to aliphatic groups, cyclic groups and groups, which contain an aliphatic and a cyclic moiety in one group, such as in, for example, C₃-C₈-cycloalkyl-C₁-C₄-alkyl; therefore a group which contains an aliphatic and a cyclic moiety both of these moieties may be substituted or unsubstituted independently of each other.
The term “phenyl” refers to an aromatic ring systems including six carbon atoms (commonly referred to as benzene ring.
The term “heteroaryl” refers to aromatic monocyclic or polycyclic ring systems including besides carbon atoms, 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S.
The term “saturated 3- to 7-membered carbocycle” is to be understood as meaning monocyclic saturated carbocycles having 3, 4 or 5 carbon ring members. Examples include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
The term “3- to 10-membered saturated, partially unsaturated or aromatic mono- or bicyclic heterocycle, wherein the ring member atoms of said mono- or bicyclic heterocycle include besides carbon atoms further 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms”, is to be understood as meaning both, aromatic mono- and bicyclic heteroaromatic ring systems, and also saturated and partially unsaturated heterocycles, for example: a 3- or 4-membered saturated heterocycle which contains 1 or 2 heteroatoms from the group consisting of N, O and S as ring members such as oxirane, aziridine, thiirane, oxetane, azetidine, thiethane, [1,2]dioxetane, [1,2]dithietane, [1,2]diazetidine;
and a 5- or 6-membered saturated or partially unsaturated heterocycle which contains 1, 2 or 3 heteroatoms from the group consisting of N, O and S as ring members such as 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1,2,4-oxadiazolidin-3-yl, 1,2,4-oxadiazolidin-5-yl, 1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazolidin-5-yl, 1,2,4-triazolidin-3-yl, 1,3,4-oxadiazolidin-2-yl, 1,3,4-thiadiazolidin-2-yl, 1,3,4-triazolidin-2-yl, 2,3-dihydrofur-2-yl, 2,3-dihydrofur-3-yl, 2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl, 2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl, 2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl, 2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl, 3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl, 3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl, 4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl, 4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1,3-dioxan-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2-piperazinyl, 1,3,5-hexahydrotriazin-2-yl and 1,2,4-hexahydrotriazin-3-yl and also the corresponding -ylidene radicals; and
a 7-membered saturated or partially unsaturated heterocycle such as tetra- and hexahydroazepinyl, such as 2,3,4,5-tetrahydro[1H]azepin-1-,-2-,-3-,-4-,-5-,-6- or- 7-yl, 3,4,5,6-tetrahydro[2H]azepin-2-,-3-,-4-,-5-,-6- or- 7-yl, 2,3,4,7-tetrahydro[1H]azepin-1-,-2-,-3-,-4-,-5-,-6- or- 7-yl, 2,3,6,7-tetrahydro[1H]azepin-1-,-2-,-3-,-4-,-5-,-6- or- 7-yl, hexahydroazepin-1-,-2-,-3- or- 4-yl, tetra- and hexahydrooxepinyl such as 2,3,4,5-tetrahydro[1H]oxepin-2-,-3-,-4-,-5-,-6- or- 7-yl, 2,3,4,7-tetrahydro[1H]oxepin-2-,-3-,-4-,-5-,-6- or- 7-yl, 2,3,6,7-tetrahydro[1H]oxepin-2-,-3-,-4-,-5-,-6- or- 7-yl, hexahydroazepin-1-,-2-,-3- or- 4-yl, tetra- and hexahydro-1,3-diazepinyl, tetra- and hexahydro-1,4-diazepinyl, tetra- and hexahydro-1,3-oxazepinyl, tetra- and hexahydro-1,4-oxazepinyl, tetra- and hexahydro-1,3-dioxepinyl, tetra- and hexahydro-1,4-dioxepinyl and the corresponding -ylidene radicals.
The term “5- or 6-membered heteroaryl” or the term “5- or 6-membered aromatic heterocycle” refer to aromatic ring systems including besides carbon atoms, 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, for example, a 5-membered heteroaryl such as pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-triazolyl-1-yl, 1,2,4-triazol-3-yl 1,2,4-triazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl and 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl; or a 6-membered heteroaryl, such as pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl and 1,3,5-triazin-2-yl and 1,2,4-triazin-3-yl.
In respect of the variables, the embodiments of the intermediates correspond to the embodiments of the compounds I. Preference is given to those compounds I and, where applicable, also to compounds of all subformulae provided herein, e. g. formulae I.1, I.2, II, Ia, III, wherein the variables have independently of each other or more preferably in combination (any possible combination of 2 or more substituents as defined herein) the following meanings:
According to one embodiment of the invention in compounds of formulae I, II, and III, R is methyl, ethyl, iso-propyl, CH₂F, CHF₂, 2,2,2-trifluoroethyl or cyclopropyl.
According to a further embodiment in compounds of formulae I, II, and III, R is CR³R⁴NR¹R², wherein R³, R⁴and R¹are as defined or preferably defined herein and R²is hydrogen. According to a further embodiment in compounds of formulae I, II, and III, R is C(═O)NR¹R², CR³R⁴C(═O)NR¹R²or CR³R⁴NR²C(═O)R¹, wherein R³, R⁴and R¹are as defined or preferably defined herein and R²is hydrogen.
Further embodiments of the present invention relate to the process for preparing compounds I, wherein group R is defined as follows:
Embodiment R.1: R is COOH, —C(═W)NR¹R², CR³R⁴COOH, CR³R⁴C(═W)NR¹R²or CR³R⁴NR²C(═W)R¹.
Embodiment R.2: R is COOH, —C(═O)NR¹R², CR³R⁴COOH, CR³R⁴C(═O)NR¹R²or CR³R⁴NR²C(═O)R¹.
Embodiment R.3: R is COOH or CR³R⁴COOH.
Embodiment R.4: R is —C(═W)NR¹R², CR³R⁴C(═W)NR¹R²or CR³R⁴NR²C(═W)R¹.
Embodiment R.5: R is —C(═O)NR¹R², CR³R⁴C(═O)NR¹R²or CR³R⁴NR²C(═O)R¹.
Embodiment R.6: R is CR³R⁴NR²R¹.
Embodiment R.7: R is CR³R⁴NR²C(═O)R¹.
Even more preferred embodiments of the present invention relate to the process for preparing compounds I, wherein group R in formulae of compounds I, II and III is defined as follows:
Embodiment R.8: R is CF₂COOH or CF₂C(═O)NR¹R².
Embodiment R.9: R is CH₂COOH or CH₂C(═O)NR¹R².
Embodiment R.10: R is —C(CH₂—CH₂)COOH or —C(CH₂—CH₂)C(═O)NR¹R².
According to a further embodiment, W in compounds of formulae I, II and III is O.
Further embodiments of the present invention relate to the process for preparing compounds I, wherein group R¹in formulae of compounds I, II and III is defined as follows: Embodiment 1.1: R¹is C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, phenyl-C₁-C₄-alkyl, heteroaryl-C₁-C₄-alkyl, phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or 6-membered aromatic heterocycle, wherein the ring includes besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals R^1aas defined or preferably defined herein.
Embodiment 1.2: R¹is phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or 6-membered aromatic heterocycle, wherein the ring includes besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms; and wherein any of the cyclic groups are unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals R^1aas defined or preferably defined herein.
Embodiment 1.3: R¹is C₃-C₈-cycloalkyl or C₃-C₈-cycloalkenyl; and wherein the cyclic group is unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals R^1aas defined or preferably defined herein.
Embodiment 1.4: R¹is C₁-C₆-alkyl; and wherein the alkyl group is unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals R^1aas defined or preferably defined herein.
Embodiment 1.5: R¹is difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl, 3,3,3-trifluoropropyl, CH₂CF₂CF₃or CF₂CF₂CF₅, CH(CH₃)CF₃, CH₂CF₂CH₃, CH₂C(CH₃)₂F, CH₂CH(CH₃)CF₃or CH₂C(CH₃)₂CF₃.
Embodiment 1.6: R¹is C₁-C₆-alkoxyimino-C₁-C₄-alkyl, C₂-C₆-alkenyloxyimino-C₁-C₄-alkyl or C₂-C₆-alkynyloxyimino-C₁-C₄-alkyl.
Embodiment 1.7: R¹is a bicyclic or tricyclic C₄-C₁₁-cycloalkyl which is unsubstituted or substituted with 1, 2 or 3 radicals selected from the group consisting of oxo, hydroxy, halogen and C₁-C₃-alkyl.
Embodiment 1.8: R¹is a bicyclic or tricyclic carbocycle selected from the group consisting of radicals R¹0.1 to R¹0.31 below; wherein each radical may be connected to the remainder of the compounds of formula I through one of the ring carbon atoms by substitution of one hydrogen atom; and wherein R¹is unsubstituted or substituted with 1, 2 or 3 radicals selected from the group consisting of oxo, hydroxy, halogen and C₁-C₃-alkyl.
Embodiment 1.9: R¹is selected from the group consisting of R¹0.32 to R¹0.57 below, particularly from R¹0.32 to R¹0.49, which are further unsubstituted, and wherein “# C” indicates the carbon atom, which is attached to the remainder of the compounds of formula I.
Further embodiments of the present invention relate to the process for preparing compounds I, wherein group R^1ais defined as follows: In one embodiment R^1ais selected from the group consisting of halogen, cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy and C₃-C₈-cycloalkyl.
In another aspect of the invention R^1ais selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy or cyclopropyl.
In another embodiment R^1ais selected from the group consisting of halogen, C₁-C₆-alkyl and C₃-C₈-cycloalkyl; particularly from methyl, ethyl, fluorine and chlorine; more particularly from fluorine and chlorine.
According to a further embodiment in compounds of formulae I, II, and III, R¹is C₁-C₆-alkyl, C₁-C₆-alkoxy, C₃-C₆-cycloalkyl or a 4- to 5-membered saturated or partially unsaturated heterocycle, wherein the ring member atoms of said heterocycle include besides carbon atoms 1 or 2 heteroatoms selected from N and O as ring member atoms; and wherein any of the above-mentioned aliphatic or cyclic groups R¹are unsubstituted or substituted with 1, 2 or 3 of identical or different groups R^1a; wherein R^1ais halogen, oxo, cyano, NO₂, OH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy or C₃-C₈-cycloalkyl.
In another embodiment R²in formulae of compounds I, II and III is hydrogen, formyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, propargyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, phenyl, pyridinyl or —N(R^2a)₂; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C₁-C₆-alkyl and C₁-C₆-alkoxy; more preferably from halogen, in particular the radical is fluorine; and wherein R^2ais independently selected from the group consisting of hydrogen, OH, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₈-cycloalkyl or C₁-C₆-alkoxy.
Further embodiments of the present invention relate to the process for preparing compounds I, wherein group R²in formulae of compounds I, II and III is defined as follows:
Embodiment 2.1: R²independently of each other are hydrogen, formyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, propargyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, phenyl, C₁-C₆-alkylamino or diC₁-C₆-alkylamino; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C₁-C₆-alkyl and C₁-C₆-alkoxy.
Embodiment 2.2: R²independently of each other are hydrogen, formyl, methyl, ethyl, n-propyl, iso-propyl, methoxy, ethyoxy, propyloxy, cyclopropyl, cyclopropyl-CH₂—, allyl, phenyl, 4-F-phenyl, 2-F-phenyl, C₁-C₆-alkylamino or diC₁-C₆-alkylamino.
Embodiment 2.3: R²independently of each other are hydrogen, formyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, propargyl, C₃-C₈-cycloalkyl, C₁-C₆-alkylamino or diC₁-C₆-alkylamino.
Embodiment 2.4: R²independently of each other are hydrogen, formyl, methyl, ethyl, n-propyl, iso-propyl, methoxy, ethyoxy, propyloxy, cyclopropyl, cyclopropyl-CH₂—, allyl, C₁-C₆-alkylamino or diC₁-C₆-alkylamino.
Embodiment 2.5: R²independently of each other are hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl or propargyl, C₁-C₆-alkylamino or diC₁-C₆-alkylamino.
Embodiment 2.6: R²independently of each other are hydrogen, methy, ethyl, methoxy, ethyoxy, propyloxy, C₁-C₆-alkylamino or diC₁-C₆-alkylamino.
Embodiment 2.7: R²is hydrogen.
According to a further embodiment in compounds of formulae I, II, and III, R²is C₁-C₄-alkyl, C₁-C₆-alkoxy or C₃-C₈-cycloalkyl, and wherein any of the aliphatic or cyclic groups in R²are unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from halogen.
In one embodiment R²in formulae of compounds I, II and III is hydrogen, formyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, propargyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, phenyl, pyridinyl or —N(R^2a)₂; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C₁-C₆-alkyl and C₁-C₆-alkoxy; more preferably from halogen, in particular the radical is fluorine; and wherein R^2ais independently selected from the group consisting of hydrogen, OH, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₈-cycloalkyl or C₁-C₆-alkoxy; and R¹is C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl-C₁-C₄-alkyl, heteroaryl-C₁-C₄-alkyl, phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or 6-membered aromatic heterocycle, wherein the ring includes besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms; and wherein any of the aliphatic or cyclic groups in R¹are unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals R^1aas defined or preferably defined herein.
In another aspect R²in formulae of compounds I, II and III is hydrogen, formyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, propargyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, C₁-C₆-alkylamino or diC₁-C₆-alkylamino; and R¹in formulae of compounds I, II and III is C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl-C₁-C₄-alkyl, heteroaryl-C₁-C₄-alkyl, phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or 6-membered aromatic heterocycle, wherein the ring includes besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms; and wherein any of the aliphatic or cyclic groups in R¹are unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals R^1aas defined or preferably defined herein.
In another aspect R²in formulae of compounds I, II and III is hydrogen, formyl, methyl, ethyl, n-propyl, iso-propyl, methoxy, ethyoxy, propyloxy, cyclopropyl, cyclopropyl-CH₂—, allyl, C₁-C₆-alkylamino or diC₁-C₆-alkylamino; and R¹in formulae of compounds I, II and III is C₁-C₆-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl; and wherein any of the aliphatic or cyclic groups in R¹are unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen or C₁-C₆-alkyl.
Further embodiments of the present invention relate to the process for preparing compounds I, wherein groups R³and R⁴in formulae of compounds I, II and III, if present, are defined as follows:
Embodiment 3.1: R³and R⁴independently of each other are hydrogen, halogen, C₁-C₆-alkyl or C₁-C₆-haloalkyl; or R³and R⁴together with the carbon atom to which they are bound form a cyclopropyl ring, wherein the cyclopropyl ring is unsubstituted.
Embodiment 3.2: R³and R⁴independently of each other are hydrogen or C₁-C₄-alkyl; Embodiment 3.3: R³and R⁴independently of each other are hydrogen, methyl or ethyl.
Embodiment 3.4: R³and R⁴are independently of each other hydrogen, fluorine, chlorine, methyl or trifluoromethyl; or R³and R⁴together with the carbon atom to which they are bound form a cyclopropyl ring, wherein the cyclopropyl ring is unsubstituted.
Embodiment 3.5: R³and R⁴are both hydrogen.
Embodiment 3.6: R³is hydrogen and R⁴is methyl.
Embodiment 3.7: R³and R⁴are both methyl.
Embodiment 3.8: R³and R⁴are both fluorine.
Embodiment 3.9: R³and R⁴are both trifluoromethyl.
Embodiment 3.10: R³and R⁴together with the carbon atom to which they are bound a saturated monocyclic 3- to 5-membered saturated heterocycle or saturated carbocycle; and wherein the saturated heterocycle includes beside one or more carbon atoms no heteroatoms or 1 or 2 heteroatoms independently selected from N, O and S as ring member atoms; and wherein the heterocycle or the carbocycle is unsubstituted or substituted 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano and C₁-C₂-alkyl.
Embodiment 3.11: R³and R⁴together with the carbon atom to which they are bound form a 3- or 4-membered carbocylic ring; and wherein the carbocylic ring is unsubstituted.
Embodiment 3.12: R³and R⁴together with the carbon atom to which they are bound form a cyclopropyl ring, wherein the cyclopropyl ring is unsubstituted.
Embodiment 3.13: R³and R⁴together with the carbon atom to which they are bound form a saturated 3-membered heterocycle; wherein the heterocycle includes beside two carbon atoms one heteroatom selected from N, O and S as ring member atoms; and wherein the heterocycle is unsubstituted or substituted 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano and C₁-C₂-alkyl.
Embodiment 3.14: R³is methyl and R⁴is fluorine.
Embodiment 3.15: R³is hydrogen and R⁴is fluorine.
According to a further embodiment in compounds of formulae I, II, and III, R is CR³R⁴NR²C(═O)R¹, wherein R³and R⁴are independently selected from hydrogen and C₁-C₄-alkyl, in particular both are hydrogen; and wherein R¹is C₁-C₆-alkyl, C₁-C₆-alkoxy, C₃-C₆-cycloalkyl or a 4- to 5-membered saturated or partially unsaturated heterocycle, wherein the ring member atoms of said heterocycle include besides carbon atoms 1 or 2 heteroatoms selected from N and O as ring member atoms; and wherein any of the above-mentioned aliphatic or cyclic groups R¹are unsubstituted or substituted with 1, 2 or 3 of identical or different groups R^1a; wherein R^1ais halogen, oxo, cyano, NO₂, OH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy or C₃-C₈-cycloalkyl; and wherein R²is hydrogen, C₁-C₄-alkyl, C₁-C₆-alkoxy or C₃-C₈-cycloalkyl, and wherein any of the aliphatic or cyclic groups in R²are unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from halogen.
According to a further embodiment in compounds of formulae I, II, and III, R is CR³R⁴NR²C(═O)R¹, wherein R³and R⁴are both hydrogen; and wherein R¹is C₃-C₆-cycloalkyl or a 4- to 5-membered saturated or partially unsaturated heterocycle, wherein the ring member atoms of said heterocycle include besides carbon atoms 1 or 2 heteroatoms selected from N and O as ring member atoms; and wherein any of the above-mentioned aliphatic or cyclic groups R¹are unsubstituted or substituted with 1, 2 or 3 of identical or different groups R^1a; wherein R^1ais halogen, oxo, cyano, NO₂, OH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy or C₃-C₈-cycloalkyl; and wherein R²is cyclopropyl.
Further embodiments with regard to the meaning of the variables in compounds of formula I are as follows:
Embodiment E1: A¹and A²are CH and R^Ais hydrogen.
Embodiment E2: A¹and A²are CH and R^Ais fluorine.
Embodiment E3: A¹is N, A²is CH and R^Ais hydrogen.
Embodiment E4: A¹and A²are CH, R^Ais hydrogen, and R is methyl, trichloromethyl, —COOH, OH, SH, cyano, chlorine or bromine.
Embodiment E5: A¹and A²are CH, R^Ais fluorine, and R is methyl, trichloromethyl, —COOH, OH, SH, cyano, chlorine or bromine.
Embodiment E6: A¹is N, A²is CH, R^Ais hydrogen, and R is methyl, trichloromethyl, —COOH, OH, SH, cyano, chlorine or bromine.
Embodiment E7: A¹and A²are CH, R^Ais hydrogen, and R is methyl, trichloromethyl, OH or SH; particularly R is methyl.
Embodiment E8: A¹and A²are CH, R^Ais fluorine, and R is methyl, trichloromethyl, OH or SH; particularly R is methyl.
Embodiment E9: A¹is N, A²is CH, R^Ais hydrogen, and R is methyl, trichloromethyl, OH or SH; particularly R is methyl.
Embodiment E10: the combination of variables A¹, A², R^Acorresponds to any one of the Embodiments E1, E2 or E3 defined above, and R is methyl.
In one embodiment the present invention relates to a process for preparing compounds of formula I, wherein the combination of variables A¹, A², R^Acorresponds to any one of the Embodiments E1, E2 or E3 defined above; and

R is methyl, trichloromethyl, ethyl, iso-propyl, OH, SH, cyano, halogen, CH₂F, CHF₂, 2,2,2-trifluoroethyl, cyclopropyl, —COOH, —COOR¹or —C(═W)NR¹R²;
W is O or S;
R¹C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxyimino-C₁-C₄-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, phenyl-C₁-C₄-alkyl, heteroaryl-C₁-C₄-alkyl, phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or 6-membered aromatic heterocycle, wherein the ring includes besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C₁-C₆-alkyl and C₁-C₆-alkoxy;
R²is hydrogen, formyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, propargyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, phenyl, C₁-C₆-alkylamino or diC₁-C₆-alkylamino; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C₁-C₆-alkyl and C₁-C₆-alkoxy.

In one embodiment the present invention relates to a process for preparing compounds of formula I, wherein the combination of variables A¹, A², R^Acorresponds to any one of the Embodiments E1, E2 or E3 defined above; and

R is —COOH, —COOR¹or —C(═W)NR¹R²;
W is O or S;
R¹is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-methoxyiminoethyl, cyclopropyl, bicyclo[1.1.1]pentan-1-yl, or phenyl; and wherein the phenyl group is unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy and cyclopropyl.
R²is hydrogen, methyl or ethyl.

R is —COOH, —COOR¹or —C(═W)NR¹R²;
W is O or S;
R¹is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-methoxyiminoethyl, cyclopropyl, bicyclo[1.1.1]pentan-1-yl, or phenyl; and wherein the phenyl group is unsubstituted or substituted with 1 radical selected from the group consisting of fluorine and 2-difluoromethoxy-phenyl;
R²is hydrogen, methyl or ethyl.

R is —C(═O)NR¹R²;
R¹is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluoro-phenyl, 4-fluoro-phenyl, or 2-difluoromethoxy-phenyl;
R²is hydrogen.

R is —C(═S)NR¹R²;
R¹is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluoro-phenyl, 4-fluoro-phenyl, or 2-difluoromethoxy-phenyl;
R²is hydrogen.

In a further embodiment the present invention relates to a process for preparing compounds of formula I, wherein

A¹and A²are CH;
R^Ais hydrogen;
R is —C(═O)NR¹R²;
R¹is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluoro-phenyl, 4-fluoro-phenyl, or 2-difluoromethoxy-phenyl;
R²is hydrogen.

A¹and A²are CH;
R^Ais hydrogen;
R is —C(═S)NR¹R²;
R¹is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluoro-phenyl, 4-fluoro-phenyl, or 2-difluoromethoxy-phenyl;
R²is hydrogen.

R is —CF₂COOH, —CF₂COR¹or —CF₂C(═O)NR¹R²;
R¹C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxyimino-C₁-C₄-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, phenyl-C₁-C₄-alkyl, heteroaryl-C₁-C₄-alkyl, phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or 6-membered aromatic heterocycle, wherein the ring includes besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C₁-C₆-alkyl and C₁-C₆-alkoxy;
R²is hydrogen, formyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, propargyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, phenyl, C₁-C₆-alkylamino or diC₁-C₆-alkylamino; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C₁-C₆-alkyl and C₁-C₆-alkoxy.

R is —CF₂COOH, —CF₂COR¹or —CF₂C(═O)NR¹R²;
R¹is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, cyclopropyl, bicyclo[1.1.1]pentan-1-yl, or phenyl; and wherein the phenyl group is unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy and cyclopropyl.
R²is hydrogen, methyl or ethyl.

In another embodiment the present invention relates to a process for preparing compounds of formula I, wherein

A¹and A²are CH;
R^Ais hydrogen or fluorine;
R is —CF₂COOH, —CF₂COR¹or —CF₂C(═O)NR¹R²;
R¹is 1-methyl-cycloprop-1-yl or cyclobutyl;
R²is hydrogen, methyl or ethyl.

A¹and A²are CH;
R^Ais hydrogen;
R is —CF₂COOH, —CF₂COR¹or —CF₂C(═O)NR¹R²;
R¹is 1-methyl-cycloprop-1-yl or cyclobutyl;
R²is hydrogen.

R is —OCF₂COOH, —OCF₂COR¹or —OCF₂C(═W)NR¹R²;
R¹C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxyimino-C₁-C₄-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, phenyl-C₁-C₄-alkyl, heteroaryl-C₁-C₄-alkyl, phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or 6-membered aromatic heterocycle, wherein the ring includes besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C₁-C₆-alkyl and C₁-C₆-alkoxy;
R²is hydrogen, formyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, propargyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, phenyl, C₁-C₆-alkylamino or diC₁-C₆-alkylamino; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C₁-C₆-alkyl and C₁-C₆-alkoxy.

R is —OCF₂COOH, —OCF₂COR¹or —OCF₂C(═W)NR¹R²;
R¹is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, cyclopropyl, bicyclo[1.1.1]pentan-1-yl, or phenyl; and wherein the phenyl group is unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy and cyclopropyl.
R²is hydrogen, methyl or ethyl.

A¹and A²are CH;
R^Ais hydrogen or fluorine;
R is —OCF₂COOH, —OCF₂COR¹or —OCF₂C(═W)NR¹R²;
R¹is methyl or cyclopropyl;
R²is hydrogen, methyl or ethyl.

A¹and A²are CH;
R^Ais hydrogen;
R is —OCF₂COOH, —OCF₂COR¹or —OCF₂C(═W)NR¹R²;
R¹is methyl or cyclopropyl;
R²is hydrogen.

R is —CH₂NR²C(═W)R¹, —CH₂S(═O)₂R¹or —CH₂NR²S(═O)₂R¹;
W is O or S;
R¹is C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxyimino-C₁-C₄-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, phenyl-C₁-C₄-alkyl, heteroaryl-C₁-C₄-alkyl, phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or 6-membered aromatic heterocycle, wherein the ring includes besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C₁-C₆-alkyl and C₁-C₆-alkoxy;
R²is hydrogen, formyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, propargyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, phenyl, C₁-C₆-alkylamino or diC₁-C₆-alkylamino; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C₁-C₆-alkyl and C₁-C₆-alkoxy.

R is —CH₂NR²C(═W)R¹, —CH₂S(═O)₂R¹or —CH₂NR²S(═O)₂R¹;
W is O or S;
R¹is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-methoxyiminoethyl, cyclopropyl, bicyclo[1.1.1]pentan-1-yl, or phenyl; and wherein the phenyl group is unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy and cyclopropyl.
R²is hydrogen, methyl or ethyl.

A¹and A²are CH;
R^Ais hydrogen or fluorine;
R is —CH₂NR²C(═W)R¹, —CH₂S(═O)₂R¹or —CH₂NR²S(═O)₂R¹;
W is O or S;
R¹is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-methoxyiminoethyl, cyclopropyl, bicyclo[1.1.1]pentan-1-yl, or phenyl; and wherein the phenyl group is unsubstituted or substituted with 1 radical selected from the group consisting of fluorine and chlorine;
R²is hydrogen, methyl or ethyl.

A¹and A²are CH;
R^Ais hydrogen or fluorine;
R is —CH₂NR²C(═O)R¹, —CH₂S(═O)₂R¹or —CH₂NR²S(═O)₂R¹;
R¹is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-methoxyiminoethyl, cyclopropyl or bicyclo[1.1.1]pentan-1-yl;
R²is hydrogen.

A¹and A²are CH;
R^Ais hydrogen or fluorine;
R is —CH₂NR²C(═O)R¹or —CH₂NR²S(═O)₂R¹;
R¹is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-methoxyiminoethyl, cyclopropyl or bicyclo[1.1.1]pentan-1-yl;
R²is hydrogen.

A¹and A²are CH;
R^Ais hydrogen or fluorine;
R is —CH₂S(═O)₂R¹;
R¹is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-methoxyiminoethyl, cyclopropyl or bicyclo[1.1.1]pentan-1-yl;
R²is hydrogen.

In further aspects of the present invention the embodiments E.1 to E.210 listed in Table E represent preferred combinations of the embodiments, which are defined above for each of the variables R, R¹, R², R³and R⁴.

TABLE E

	Embodiment	R	R¹	R²	R³, R⁴

E.1	R.1	1.1	2.4	3.4
E.2	R.1	1.2	2.4	3.4
E.3	R.1	1.3	2.4	3.4
E.4	R.1	1.4	2.4	3.4
E.5	R.1	1.5	2.4	3.4
E.6	R.1	1.6	2.4	3.4
E.7	R.1	1.7	2.4	3.4
E.8	R.1	1.8	2.4	3.4
E.9	R.1	1.9	2.4	3.4
E.10	R.1	1.10	2.4	3.4
E.11	R.1	1.1	2.4	3.5
E.12	R.1	1.2	2.4	3.5
E.13	R.1	1.3	2.4	3.5
E.14	R.1	1.4	2.4	3.5
E.15	R.1	1.5	2.4	3.5
E.16	R.1	1.6	2.4	3.5
E.17	R.1	1.7	2.4	3.5
E.18	R.1	1.8	2.4	3.5
E.19	R.1	1.9	2.4	3.5
E.20	R.1	1.10	2.4	3.5
E.21	R.1	1.1	2.4	3.7
E.22	R.1	1.2	2.4	3.7
E.23	R.1	1.3	2.4	3.7
E.24	R.1	1.4	2.4	3.7
E.25	R.1	1.5	2.4	3.7
E.26	R.1	1.6	2.4	3.7
E.27	R.1	1.7	2.4	3.7
E.28	R.1	1.8	2.4	3.7
E.29	R.1	1.9	2.4	3.7
E.30	R.1	1.10	2.4	3.7
E.31	R.1	1.1	2.4	3.8
E.32	R.1	1.2	2.4	3.8
E.33	R.1	1.3	2.4	3.8
E.34	R.1	1.4	2.4	3.8
E.35	R.1	1.5	2.4	3.8
E.36	R.1	1.6	2.4	3.8
E.37	R.1	1.7	2.4	3.8
E.38	R.1	1.8	2.4	3.8
E.39	R.1	1.9	2.4	3.8
E.40	R.1	1.10	2.4	3.8
E.41	R.1	1.1	2.4	3.12
E.42	R.1	1.2	2.4	3.12
E.43	R.1	1.3	2.4	3.12
E.44	R.1	1.4	2.4	3.12
E.45	R.1	1.5	2.4	3.12
E.46	R.1	1.6	2.4	3.12
E.47	R.1	1.7	2.4	3.12
E.48	R.1	1.8	2.4	3.12
E.49	R.1	1.9	2.4	3.12
E.50	R.1	1.10	2.4	3.12
E.51	R.1	1.1	2.7	3.4
E.52	R.1	1.2	2.7	3.4
E.53	R.1	1.3	2.7	3.4
E.54	R.1	1.4	2.7	3.4
E.55	R.1	1.5	2.7	3.4
E.56	R.1	1.6	2.7	3.4
E.57	R.1	1.7	2.7	3.4
E.58	R.1	1.8	2.7	3.4
E.59	R.1	1.9	2.7	3.4
E.60	R.1	1.10	2.7	3.4
E.61	R.1	1.1	2.7	3.5
E.62	R.1	1.2	2.7	3.5
E.63	R.1	1.3	2.7	3.5
E.64	R.1	1.4	2.7	3.5
E.65	R.1	1.5	2.7	3.5
E.66	R.1	1.6	2.7	3.5
E.67	R.1	1.7	2.7	3.5
E.68	R.1	1.8	2.7	3.5
E.69	R.1	1.9	2.7	3.5
E.70	R.1	1.10	2.7	3.5
E.71	R.1	1.1	2.7	3.7
E.72	R.1	1.2	2.7	3.7
E.73	R.1	1.3	2.7	3.7
E.74	R.1	1.4	2.7	3.7
E.75	R.1	1.5	2.7	3.7
E.76	R.1	1.6	2.7	3.7
E.77	R.1	1.7	2.7	3.7
E.78	R.1	1.8	2.7	3.7
E.79	R.1	1.9	2.7	3.7
E.80	R.1	1.10	2.7	3.7
E.81	R.1	1.1	2.7	3.8
E.82	R.1	1.2	2.7	3.8
E.83	R.1	1.3	2.7	3.8
E.84	R.1	1.4	2.7	3.8
E.85	R.1	1.5	2.7	3.8
E.86	R.1	1.6	2.7	3.8
E.87	R.1	1.7	2.7	3.8
E.88	R.1	1.8	2.7	3.8
E.89	R.1	1.9	2.7	3.8
E.90	R.1	1.10	2.7	3.8
E.91	R.1	1.1	2.7	3.12
E.92	R.1	1.2	2.7	3.12
E.93	R.1	1.3	2.7	3.12
E.94	R.1	1.4	2.7	3.12
E.95	R.1	1.5	2.7	3.12
E.96	R.1	1.6	2.7	3.12
E.97	R.1	1.7	2.7	3.12
E.98	R.1	1.8	2.7	3.12
E.99	R.1	1.9	2.7	3.12
E.100	R.1	1.10	2.7	3.12
E.101	R.3	1.1		3.4
E.102	R.3	1.2		3.4
E.103	R.3	1.3		3.4
E.104	R.3	1.4		3.4
E.105	R.3	1.5		3.4
E.106	R.3	1.6		3.4
E.107	R.3	1.7		3.4
E.108	R.3	1.8		3.4
E.109	R.3	1.9		3.4
E.110	R.3	1.10		3.4
E.111	R.3	1.1		3.5
E.112	R.3	1.2		3.5
E.113	R.3	1.3		3.5
E.114	R.3	1.4		3.5
E.115	R.3	1.5		3.5
E.116	R.3	1.6		3.5
E.117	R.3	1.7		3.5
E.118	R.3	1.8		3.5
E.119	R.3	1.9		3.5
E.120	R.3	1.10		3.5
E.121	R.3	1.1		3.7
E.122	R.3	1.2		3.7
E.123	R.3	1.3		3.7
E.124	R.3	1.4		3.7
E.125	R.3	1.5		3.7
E.126	R.3	1.6		3.7
E.127	R.3	1.7		3.7
E.128	R.3	1.8		3.7
E.129	R.3	1.9		3.7
E.130	R.3	1.10		3.7
E.131	R.3	1.1		3.8
E.132	R.3	1.2		3.8
E.133	R.3	1.3		3.8
E.134	R.3	1.4		3.8
E.135	R.3	1.5		3.8
E.136	R.3	1.6		3.8
E.137	R.3	1.7		3.8
E.138	R.3	1.8		3.8
E.139	R.3	1.9		3.8
E.140	R.3	1.10		3.8
E.141	R.3	1.1		3.12
E.142	R.3	1.2		3.12
E.143	R.3	1.3		3.12
E.144	R.3	1.4		3.12
E.145	R.3	1.5		3.12
E.146	R.3	1.6		3.12
E.147	R.3	1.7		3.12
E.148	R.3	1.8		3.12
E.149	R.3	1.9		3.12
E.150	R.3	1.10		3.12
E.151	R.8	1.1	2.4
E.152	R.8	1.2	2.4
E.153	R.8	1.3	2.4
E.154	R.8	1.4	2.4
E.155	R.8	1.5	2.4
E.156	R.8	1.6	2.4
E.157	R.8	1.7	2.4
E.158	R.8	1.8	2.4
E.159	R.8	1.9	2.4
E.160	R.8	1.10	2.4
E.161	R.8	1.1	2.7
E.162	R.8	1.2	2.7
E.163	R.8	1.3	2.7
E.164	R.8	1.4	2.7
E.165	R.8	1.5	2.7
E.166	R.8	1.6	2.7
E.167	R.8	1.7	2.7
E.168	R.8	1.8	2.7
E.169	R.8	1.9	2.7
E.170	R.8	1.10	2.7
E.171	R.9	1.1	2.4
E.172	R.9	1.2	2.4
E.173	R.9	1.3	2.4
E.174	R.9	1.4	2.4
E.175	R.9	1.5	2.4
E.176	R.9	1.6	2.4
E.177	R.9	1.7	2.4
E.178	R.9	1.8	2.4
E.179	R.9	1.9	2.4
E.180	R.9	1.10	2.4
E.181	R.9	1.1	2.7
E.182	R.9	1.2	2.7
E.183	R.9	1.3	2.7
E.184	R.9	1.4	2.7
E.185	R.9	1.5	2.7
E.186	R.9	1.6	2.7
E.187	R.9	1.7	2.7
E.188	R.9	1.8	2.7
E.189	R.9	1.9	2.7
E.190	R.9	1.10	2.7
E.191	R.10	1.1	2.4
E.192	R.10	1.2	2.4
E.193	R.10	1.3	2.4
E.194	R.10	1.4	2.4
E.195	R.10	1.5	2.4
E.196	R.10	1.6	2.4
E.197	R.10	1.7	2.4
E.198	R.10	1.8	2.4
E.199	R.10	1.9	2.4
E.200	R.10	1.10	2.4
E.201	R.10	1.1	2.7
E.202	R.10	1.2	2.7
E.203	R.10	1.3	2.7
E.204	R.10	1.4	2.7
E.205	R.10	1.5	2.7
E.206	R.10	1.6	2.7
E.207	R.10	1.7	2.7
E.208	R.10	1.8	2.7
E.209	R.10	1.9	2.7
E.210	R.10	1.10	2.7

In one embodiment the present invention relates to compounds of the formula II, namely compounds II.A-1 to II.A-315, wherein A¹and A²are CH, R^Ais hydrogen, and R in each of the compounds II.A-1 to II.A-315 is defined as in one corresponding line A-1 to A-315 in Table A below, and wherein # denotes the position, which is bound to the phenyl moiety. This means, for example, that a compound of formula II, wherein R is CO₂H is named II.A-43 in correspondence to the definition in line A-43 in Table A.

TABLE A

	No	R

	A-1	CH₃
	A-2	CCl₃
	A-3	OH
	A-4	SH
	A-5	cyano
	A-6	F
	A-7	Cl
	A-8	Br
	A-9	CH₂CH₃
	A-10	CH(CH₃)₂
	A-11	CH₂F
	A-12	CHF₂
	A-13	2,2,2-trifluoroethyl
	A-14	cyclopropyl
	A-15	CH₂OH
	A-16	C(═O)CH₃
	A-17	CH₂OCH₃
	A-18	CH₂OCH₂CH₃
	A-19	CH₂OCH₂CH₂CH₃
	A-20	CH₂OCH(CH₃)₂
	A-21	CH₂OC(CH₃)₃
	A-22	CH₂OCH₂CH═CH₂
	A-23	CH₂OC(phenyl)₃
	A-24	CH₂OSi(CH₃)₃
	A-25	CH₂OSi(CH₂phenyl)₃
	A-26	CH₂OC(═O)CH₃
	A-27	CH₂OC(═O)CH₂CH₃
	A-28	CH₂OC(═O)CH₂CH₂CH₃
	A-29	CH₂OC(═O)CH(CH₃)₂
	A-30	CH₂OC(═O)C(CH₃)₃
	A-31	CH₂OC(═O)CH₂CH═CH₂
	A-32	CH₂OC(═O)OCH₃
	A-33	CH₂OC(═O)OCH₂CH₃
	A-34	CH₂OC(═O)OCH₂CH₂CH₃
	A-35	CH₂OC(═O)OCH(CH₃)₂
	A-36	CH₂OC(═O)OC(CH₃)₃
	A-37	CH₂OC(═O)OCH₂CH═CH₂
	A-38	CH₂OCH₂OCH₃
	A-39	CH₂OCH₂OCH₂CH₃
	A-40	CH₂OCH₂OCH₂CH₂CH₃
	A-41	CH₂OCH₂OCH(CH₃)₂
	A-42	CH₂OCH₂O-tetrahydropyran-2-yl
	A-43	CO₂H
	A-44	CO₂CH₃
	A-45	CO₂CH₂CH₃
	A-46	CO₂CH₂CH₂CH₃
	A-47	CO₂CH(CH₃)₂
	A-48	CO₂C(CH₃)₃
	A-49	CO₂CH₂CH═CH₂
	A-50	CH₂CO₂H
	A-51	CH₂CO₂CH₃
	A-52	CH₂CO₂CH₂CH₃
	A-53	CH₂CO₂CH₂CH₂CH₃
	A-54	CH₂CO₂CH(CH₃)₂
	A-55	CH₂CO₂C(CH₃)₃
	A-56	CH₂CO₂CH₂CH═CH₂
	A-57	CF₂CO₂H
	A-58	CF₂CO₂CH₃
	A-59	CF₂CO₂CH₂CH₃
	A-60	CF₂CO₂CH₂CH₂CH₃
	A-61	CF₂CO₂CH(CH₃)₂
	A-62	CF₂CO₂C(CH₃)₃
	A-63	CF₂CO₂CH₂CH═CH₂
	A-64	pyrrolidine-2-one-methyl
	A-65	CH₂NH₂
	A-66	CH₂NHNH₂
	A-67	CH₂NH—N(CH₃)₂
	A-68	CH₂NH—NH(CH₃)
	A-69	CH₂NH(CH₃)
	A-70	CH₂NH(CH₂CH₃)
	A-71	CH₂NH(CH₂CH₂CH₃)
	A-72	CH₂NH(CH(CH₃)₂)
	A-73	CH₂NH(C(CH₃)₃)
	A-74	CH₂NH(CH₂CH═CH₂)
	A-75	CH₂NH(OCH₃)
	A-76	CH₂NH(OCH₂CH₃)
	A-77	CH₂NH(OCH₂CH₂CH₃)
	A-78	CH₂NH(OCH(CH₃)₂)
	A-79	CH₂NH(OCH₂CH═CH₂)
	A-80	CH₂NH(cyclopropyl)
	A-81	CH₂NH(cyclobutyl)
	A-82	CH₂NH(cyclopentyl)
	A-83	CH₂NH(cyclohexyl)
	A-84	CH₂N(CH₃)₂
	A-85	CH₂N(CH₃)(CH₂CH₃)
	A-86	CH₂N(CH₃)(CH₂CH₂CH₃)
	A-87	CH₂N(CH₃)(CH(CH₃)₂)
	A-88	CH₂N(CH₃)(C(CH₃)₃)
	A-89	CH₂N(CH₃)(CH₂CH═CH₂)
	A-90	CH₂N(CH₃)(OCH₃)
	A-91	CH₂N(CH₃)(OCH₂CH₃)
	A-92	CH₂N(CH₃)(OCH₂CH₂CH₃)
	A-93	CH₂N(CH₃)(OCH₂CH═CH₂)
	A-94	CH₂N(CH₃)(cyclopropyl)
	A-95	CH₂N(CH₃)(cyclobutyl)
	A-96	CH₂N(CH₃)(cyclopentyl)
	A-97	CH₂N(CH₃)(cyclohexyl)
	A-98	CH₂NH(C(═O)H)
	A-99	CH₂NH(C(═O)CH₃)
	A-100	CH₂NH(C(═O)CH₂CH₃)
	A-101	CH₂NH(C(═O)CH₂CH₂CH₃)
	A-102	CH₂NH(C(═O)CH(CH₃)₂)
	A-103	CH₂NH(C(═O)C(CH₃)₃)
	A-104	CH₂NH(C(═O)CH₂CH═CH₂)
	A-105	CH₂NH(C(═O)OCH₃)
	A-106	CH₂NH(C(═O)OCH₂CH₃)
	A-107	CH₂NH(C(═O)OCH₂CH₂CH₃)
	A-108	CH₂NH(C(═O)OCH₂CH═CH₂)
	A-109	CH₂NH(C(═O)cyclopropyl)
	A-110	CH₂NH(C(═O)cyclobutyl)
	A-111	CH₂NH(C(═O)cyclopentyl)
	A-112	CH₂NH(C(═O)cyclohexyl)
	A-113	CH₂N(CH₃)(C(═O)H)
	A-114	CH₂N(CH₃)(C(═O)CH₃)
	A-115	CH₂N(CH₃)(C(═O)CH₂CH₃)
	A-116	CH₂N(CH₃)(C(═O)CH₂CH₂CH₃)
	A-117	CH₂N(CH₃)(C(═O)CH(CH₃)₂)
	A-118	CH₂N(CH₃)(C(═O)C(CH₃)₃)
	A-119	CH₂N(CH₃)(C(═O)CH₂CH═CH₂)
	A-120	CH₂N(CH₃)(C(═O)OCH₃)
	A-121	CH₂N(CH₃)(C(═O)OCH₂CH₃)
	A-122	CH₂N(CH₃)(C(═O)OCH₂CH₂CH₃)
	A-123	CH₂N(CH₃)(C(═O)OCH₂CH═CH₂)
	A-124	CH₂N(CH₃)(C(═O)cyclopropyl)
	A-125	CH₂N(CH₃)(C(═O)cyclobutyl)
	A-126	CH₂N(CH₃)(C(═O)cyclopentyl)
	A-127	CH₂N(CH₃)(C(═O)cyclohexyl)
	A-128	CH₂N(CH₂CH₃)(C(═O)H)
	A-129	CH₂N(CH₂CH₃)(C(═O)CH₃)
	A-130	CH₂N(CH₂CH₃)(C(═O)CH₂CH₃)
	A-131	CH₂N(CH₂CH₃)(C(═O)—CH₂CH₂CH₃)
	A-132	CH₂N(CH₂CH₃)(C(═O)CH(CH₃)₂)
	A-133	CH₂N(CH₂CH₃)(C(═O)C(CH₃)₃)
	A-134	CH₂N(CH₂CH₃)(C(═O)—CH₂CH═CH₂)
	A-135	CH₂N(CH₂CH₃)(C(═O)OCH₃)
	A-136	CH₂N(CH₂CH₃)(C(═O)OCH₂CH₃)
	A-137	CH₂N(CH₂CH₃)(C(═O)—OCH₂CH₂CH₃)
	A-138	CH₂N(CH₂CH₃)(C(═O)—OCH₂CH═CH₂)
	A-139	CH₂N(CH₂CH₃)(C(═O)cyclopropyl)
	A-140	CH₂N(CH₂CH₃)(C(═O)cyclobutyl)
	A-141	CH₂N(CH₂CH₃)(C(═O)cyclopentyl)
	A-142	CH₂N(CH₂CH₃)(C(═O)cyclohexyl)
	A-143	CH₂N(CH₂CH₂CH₃)(C(═O)H)
	A-144	CH₂N(CH₂CH₂CH₃)(C(═O)CH₃)
	A-145	CH₂N(CH₂CH₂CH₃)(C(═O)—CH₂CH₃)
	A-146	CH₂N(CH₂CH₂CH₃)(C(═O)—CH₂CH₂CH₃)
	A-147	CH₂N(CH₂CH₂CH₃)(C(═O)—CH(CH₃)₂)
	A-148	CH₂N(CH₂CH₂CH₃)(C(═O)—C(CH₃)₃)
	A-149	CH₂N(CH₂CH₂CH₃)(C(═O)—CH₂CH═CH₂)
	A-150	CH₂N(CH₂CH₂CH₃)(C(═O)OCH₃)
	A-151	CH₂N(CH₂CH₂CH₃)(C(═O)—OCH₂CH₃)
	A-152	CH₂N(CH₂CH₂CH₃)(C(═O)—OCH₂CH₂CH₃)
	A-153	CH₂N(CH₂CH₂CH₃)(C(═O)—OCH₂CH═CH₂)
	A-154	CH₂N(CH₂CH₂CH₃)(C(═O)—cyclopropyl)
	A-155	CH₂N(CH₂CH₂CH₃)(C(═O)—cyclobutyl)
	A-156	CH₂N(CH₂CH₂CH₃)(C(═O)—cyclopentyl)
	A-157	CH₂N(CH₂CH₂CH₃)(C(═O)—cyclohexyl)
	A-158	CH₂N(CH(CH₃)₂)(C(═O)H)
	A-159	CH₂N(CH(CH₃)₂)(C(═O)CH₃)
	A-160	CH₂N(CH(CH₃)₂)(C(═O)CH₂CH₃)
	A-161	CH₂N(CH(CH₃)₂)(C(═O)—CH₂CH₂CH₃)
	A-162	CH₂N(CH(CH₃)₂)(C(═O)CH(CH₃)₂)
	A-163	CH₂N(CH(CH₃)₂)(C(═O)C(CH₃)₃)
	A-164	CH₂N(CH(CH₃)₂)(C(═O)—CH₂CH═CH₂)
	A-165	CH₂N(CH(CH₃)₂)(C(═O)OCH₃)
	A-166	CH₂N(CH(CH₃)₂)(C(═O)OCH₂CH₃)
	A-167	CH₂N(CH(CH₃)₂)(C(═O)—OCH₂CH₂CH₃)
	A-168	CH₂N(CH(CH₃)₂)(C(═O)—OCH₂CH═CH₂)
	A-169	CH₂N(CH(CH₃)₂)(C(═O)—cyclopropyl)
	A-170	CH₂N(CH(CH₃)₂)(C(═O)cyclobutyl)
	A-171	CH₂N(CH(CH₃)₂)(C(═O)—cyclopentyl)
	A-172	CH₂N(CH(CH₃)₂)(C(═O)cyclohexyl)
	A-173	CH₂N(OCH₃)(C(═O)H)
	A-174	CH₂N(OCH₃)(C(═O)CH₃)
	A-175	CH₂N(OCH₃)(C(═O)CH₂CH₃)
	A-176	CH₂N(OCH₃)(C(═O)CH₂CH₂CH₃)
	A-177	CH₂N(OCH₃)(C(═O)CH(CH₃)₂)
	A-178	CH₂N(OCH₃)(C(═O)C(CH₃)₃)
	A-179	CH₂N(OCH₃)(C(═O)CH₂CH═CH₂)
	A-180	CH₂N(OCH₃)(C(═O)OCH₃)
	A-181	CH₂N(OCH₃)(C(═O)OCH₂CH₃)
	A-182	CH₂N(OCH₃)(C(═O)OCH₂CH₂CH₃)
	A-183	CH₂N(OCH₃)(C(═O)—OCH₂CH═CH₂)
	A-184	CH₂N(OCH₃)(C(═O)cyclopropyl)
	A-185	CH₂N(OCH₃)(C(═O)cyclobutyl)
	A-186	CH₂N(OCH₃)(C(═O)cyclopentyl)
	A-187	CH₂N(OCH₃)(C(═O)cyclohexyl)
	A-188	CH₂N(OCH₂CH₃)(C(═O)H)
	A-189	CH₂N(OCH₂CH₃)(C(═O)CH₃)
	A-190	CH₂N(OCH₂CH₃)(C(═O)CH₂CH₃)
	A-191	CH₂N(OCH₂CH₃)(C(═O)—CH₂CH₂CH₃)
	A-192	CH₂N(OCH₂CH₃)(C(═O)CH(CH₃)₂)
	A-193	CH₂N(OCH₂CH₃)(C(═O)C(CH₃)₃)
	A-194	CH₂N(OCH₂CH₃)(C(═O)—CH₂CH═CH₂)
	A-195	CH₂N(OCH₂CH₃)(C(═O)OCH₃)
	A-196	CH₂N(OCH₂CH₃)(C(═O)OCH₂CH₃)
	A-197	CH₂N(OCH₂CH₃)(C(═O)—OCH₂CH₂CH₃)
	A-198	CH₂N(OCH₂CH₃)(C(═O)—OCH₂CH═CH₂)
	A-199	CH₂N(OCH₂CH₃)(C(═O)—cyclopropyl)
	A-200	CH₂N(OCH₂CH₃)(C(═O)cyclobutyl)
	A-201	CH₂N(OCH₂CH₃)(C(═O)—cyclopentyl)
	A-202	CH₂N(OCH₂CH₃)(C(═O)—cyclohexyl)
	A-203	CH₂N(OCH₂CH₂CH₃)(C(═O)H)
	A-204	CH₂N(OCH₂CH₂CH₃)(C(═O)CH₃)
	A-205	CH₂N(OCH₂CH₂CH₃)(C(═O)—CH₂CH₃)
	A-206	CH₂N(OCH₂CH₂CH₃)(C(═O)—CH₂CH₂CH₃)
	A-207	CH₂N(OCH₂CH₂CH₃)(C(═O)—CH(CH₃)₂)
	A-208	CH₂N(OCH₂CH₂CH₃)(C(═O)—C(CH₃)₃)
	A-209	CH₂N(OCH₂CH₂CH₃)(C(═O)—CH₂CH═CH₂)
	A-210	CH₂N(OCH₂CH₂CH₃)(C(═O)OCH₃)
	A-211	CH₂N(OCH₂CH₂CH₃)(C(═O)—OCH₂CH₃)
	A-212	CH₂N(OCH₂CH₂CH₃)(C(═O)OCH₂CH₂CH₃)
	A-213	CH₂N(OCH₂CH₂CH₃)(C(═O)—OCH₂CH═CH₂)
	A-214	CH₂N(OCH₂CH₂CH₃)(C(═O)—cyclopropyl)
	A-215	CH₂N(OCH₂CH₂CH₃)(C(═O)—cyclobutyl)
	A-216	CH₂N(OCH₂CH₂CH₃)(C(═O)—cyclopentyl)
	A-217	CH₂N(OCH₂CH₂CH₃)(C(═O)—cyclohexyl)
	A-218	CH₂NHC(═O)NH(CH₃)
	A-219	CH₂NHC(═O)NH(CH₂CH₃)
	A-220	CH₂NHC(═O)NH(CH₂CH₂CH₃)
	A-221	CH₂NHC(═O)NH(CH(CH₃)₂)
	A-222	CH₂NHC(═O)NH(C(CH₃)₃)
	A-223	CH₂NHC(═O)NH(CH₂CH═CH₂)
	A-224	CH₂NHC(═O)NH(OCH₃))
	A-225	CH₂NHC(═O)NH(OCH₂CH₃)
	A-226	CH₂NHC(═O)NH(OCH₂CH₂CH₃)
	A-227	CH₂NHC(═O)NH(OCH₂CH═CH₂)
	A-228	CH₂NHC(═O)NHcyclopropyl
	A-229	CH₂NHC(═O)NHcyclobutyl
	A-230	CH₂NHC(═O)NHcyclopentyl
	A-231	CH₂NHC(═O)NHcyclohexyl
	A-232	C(═O)NH₂
	A-233	C(═O)NH(CH₃)
	A-234	C(═O)NH(CH₂CH₃)
	A-235	C(═O)NH(CH₂CH₂CH₃)
	A-236	C(═O)NH(CH(CH₃)₂)
	A-237	C(═O)NH(C(CH₃)₃)
	A-238	C(═O)NH(CH₂CH═CH₂)
	A-239	C(═O)NH(OCH₃)
	A-240	C(═O)NH(OCH₂CH₃)
	A-241	C(═O)NH(OCH₂CH₂CH₃)
	A-242	C(═O)NH(OCH₂CH═CH₂)
	A-243	C(═O)NHcyclopropyl
	A-244	C(═O)NHcyclobutyl
	A-245	C(═O)NHcyclopentyl
	A-246	C(═O)NHcyclohexyl
	A-247	C(═S)NH₂
	A-248	C(═S)NH(CH₃)
	A-249	C(═S)NH(CH₂CH₃)
	A-250	C(═S)NH(CH₂CH₂CH₃)
	A-251	C(═S)NH(CH(CH₃)₂)
	A-252	C(═S)NH(C(CH₃)₃)
	A-253	C(═S)NH(CH₂CH═CH₂)
	A-254	C(═S)NH(OCH₃)
	A-255	C(═S)NH(OCH₂CH₃)
	A-256	C(═S)NH(OCH₂CH₂CH₃)
	A-257	C(═S)NH(OCH₂CH═CH₂)
	A-258	C(═S)NH(cyclopropyl)
	A-259	C(═S)NH(cyclobutyl)
	A-260	C(═S)NH(cyclopentyl)
	A-261	C(═S)NH(cyclohexyl)
	A-262	C(═O)N(CH₃)₂
	A-263	C(═O)N(CH₃)(CH₂CH₃)
	A-264	C(═O)N(CH₃)(CH₂CH₂CH₃)
	A-265	C(═O)N(CH₃)(CH(CH₃)₂)
	A-266	C(═O)N(CH₃)(C(CH₃)₃)
	A-267	C(═O)N(CH₃)(OCH₃)
	A-268	C(═O)N(CH₃)(OCH₂CH₃)
	A-269	C(═O)N(CH₃)(OCH₂CH₂CH₃)
	A-270	C(═O)N(CH₃)(OCH₂CH═CH₂)
	A-271	C(═O)N(CH₃)(cyclopropyl)
	A-272	C(═O)N(CH₃)(cyclobutyl)
	A-273	C(═O)N(CH₃)(cyclopentyl)
	A-274	C(═O)N(CH₃)(cyclohexyl)
	A-275	C(═S)N(CH₃)₂
	A-276	C(═S)N(CH₃)(CH₂CH₃)
	A-277	C(═S)N(CH₃)(CH₂CH₂CH₃)
	A-278	C(═S)N(CH₃)(CH(CH₃)₂)
	A-279	C(═S)N(CH₃)(C(CH₃)₃)
	A-280	C(═S)N(CH₃)(OCH₃)
	A-281	C(═S)N(CH₃)(OCH₂CH₃)
	A-282	C(═S)N(CH₃)(OCH₂CH₂CH₃)
	A-283	C(═S)N(CH₃)(OCH₂CH═CH₂)
	A-284	C(═S)N(CH₃)(cyclopropyl)
	A-285	C(═S)N(CH₃)(cyclobutyl)
	A-286	C(═S)N(CH₃)(cyclopentyl)
	A-287	C(═S)N(CH₃)(cyclohexyl)

	A-288

	A-289

	A-290

	A-291

	A-292

	A-293

	A-294

	A-295

	A-296

	A-297

	A-298

	A-299

	A-300

	A-301

	A-302

	A-303

	A-304

	A-305

	A-306

	A-307

	A-308

	A-309

	A-310

	A-311

	A-312

	A-313

	A-314

	A-315

In preferred embodiments the present invention relates to the transformation of a compound of formula II with compounds of formula IIa to give compounds of formula I as described herein; and wherein the specific combination of reaction conditions is as defined in embodiments B-1 to B-32 in Table B below. All reactions defined by embodiments B1 to B-32 are carried out with 2 equivalents of trifluoroacetic acid chloride, based on the amount of compound II, with a molar ratio of the base to compound II of 1:1, at atmospheric pressure and whereas the other expressions in embodiments B-1 to B-32 have the following meaning:
Acylating agent IIa: 2 equivalents of trifluoroacetic acid chloride, based on the amount of compound II (ac1), 2 equivalents of trifluoroacetic acid fluoride, based on the amount of compound II (ac2).
Base: pyridine (b1), 2,4,6-collidine (b2), 2,6-lutidine (b3), trimethylamine (b4), triethylamin (b5), diisopropylethylamine (b6), sodium acetate (b7), potassium actetate (b8), tributylamine (b9), 2-picoline (b10), 3-picoline (b11), 4-picoline (b12), 5-ethyl-2-methyl-pyridine (b13), sodium carbonate (b14), potassium carbonate (b15).
Molar ratio of base to compound II: 3:1 (ba1), 1:1 (ba2), 1:50 (ba2).
Solvents: heptane (s1), cyclohexane (s2), toluene (s3), xylene (s4), dichloromethane (s5), 1,2-dichlorobenzene (s6), chlorobenzene (s7), 1,3,5-trimethylbenzene (s8), ethylbenzene (s9), tetrahydrofurane (s10), dioxane (s11), ethyl acetate (s12), methyl ethylketone (s13), benzotrifluoride (s14).
Volume ratio of solvent to compound II: 1:2 (sa1), 1:1 (sa2), 5:1 (sa2).
Pressure: 1 atmosphere (p1), 3 atm (p2), 8 atm (p3), 50 atm (p4).
Temperature: −10° C. (t1), 0° C. (t2), 50° C. (t3), 100° C. (t4).
This means, for example, that a reaction, in which the acylating agent IIa is 2 equivalents of TFAC based on the amount of compound II, in the presence of pyridine as a base in a molar ratio of 1:1 based on the amount of compound II, in toluene as solvent and with a volume ratio of toluene to compound II of 1:1, at atmospheric pressure and a temperature of 50° C., is identified as embodiment B-2.

TABLE B

B-1: b1, s3, t2; B-2: b1, s3, t3; B-3: b1, s5, t2; B-4: b1, s5, t3; B-5: b1, s10, t2; B-6: b1, s10,
t3; B-7: b1, s12, t2; B-8: b1, s12, t3; B-9: b4, s3, t2; B-10: b4, s3, t3; B-11: b4, s5, t2; B-12:
b4, s5, t3; B-13: b4, s10, t2; B-14: b4, s10, t3; B-15: b4, s12, t2; B-16: b4, s12, t3; B-17: b5,
s3, t2; B-18: b5, s3, t3; B-19: b5, s5, t2; B-20: b5, s5, t3; B-21: b5, s10, t2; B-22: b5, s10, t3;
B-23: b5, s12, t2; B-24: b5, s12, t3; B-25: no base, s3, t2; B-26: no base, s3, t3; B-27: no
base, s5, t2; B-28: no base, s5, t3; B-29: no base, s10, t2; B-30: no base, s10, t3; B-31: no
base, s12, t2; B-32: no base, s12, t3.

In further preferred embodiments D-1 to D-32, which are summarized in table D below, the present invention relates to the transformation of a compound selected from the group of compounds II.A-1 to II.A-315 with TFAC to give compounds of formula I; and wherein the specific combination of the reaction conditions in each case is as defined in embodiments B-1 to B-32 of Table B. This means, for example, that a reaction, in which any of compounds II.A-1 to II.A-315 is reacted with TFAC under the conditions as defined in Table B, embodiment B-2, is described in embodiment D-2.

TABLE D

D-1: B-1 & II.A-1 to II-A-315; D-2: B-2 & II.A-1 to II-A-315; D-3: B-3 & II.A-1 to II-A-315; D-4: B-4
& II.A-1 to II-A-315; D-5: B-5 & II.A-1 to II-A-315; D-6: B-6 & II.A-1 to II-A-315; D-7: B-7 & II.A-1
to II-A-315; D-8: B-8 & II.A-1 to II-A-315; D-9: B-9 & II.A-1 to II-A-315; D-10: B-10 & II.A-1 to II-
A-315; D-11: B-11 & II.A-1 to II-A-315; D-12: B-12 & II.A-1 to II-A-315; D-13: B-13 & II.A-1 to II-
A-315; D-14: B-14 & II.A-1 to II-A-315; D-15: B-15 & II.A-1 to II-A-315; D-16: B-16 & II.A-1 to II-
A-315; D-17: B-17 & II.A-1 to II-A-315; D-18: B-18 & II.A-1 to II-A-315; D-19: B-19 & II.A-1 to II-
A-315; D-20: B-20 & II.A-1 to II-A-315; D-21: B-21 & II.A-1 to II-A-315; D-22: B-22 & II.A-1 to II-
A-315; D-23: B-23 & II.A-1 to II-A-315; D-24: B-24 & II.A-1 to II-A-315; D-25: B-25 & II.A-1 to II-
A-315; D-26: B-26 & II.A-1 to II-A-315; D-27: B-27 & II.A-1 to II-A-315; D-28: B-28 & II.A-1 to II-
A-315; D-29: B-29 & II.A-1 to II-A-315; D-30: B-30 & II.A-1 to II-A-315; D-31: B-31 & II.A-1 to II-
A-315; D-32: B-32 & II.A-1 to II-A-315.

The invention is illustrated by the following examples:

EXAMPLE 1: PREPARATION OF N-methyl-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]cyclopropanecarboxamide

5.0 g (17.6 mmol) N-[[4-[(Z)-N′-hydroxycarbamimidoyl]phenyl]methyl]-N-methyl-cyclopropanecarboxamide and 25 g (271 mmol) toluene were placed in a glass reactor and cooled to −22° C. After that 4.6 g (35 mmol) trifluoroacetyl chloride was dosed continuously under vigorous stirring over 10 minutes at −22° C. to the reaction mixture. The reaction mixture was stirred for further 45 minutes at −15° C. to −13° C. Then the reaction mixture was heated up to 25° C. 25 g water was added to the reaction mixture. After phase separation the organic phase was extracted with 20 g water. The solvent of the organic phase was distilled off under reduced pressure (40° C.; 2 kPa). Residue: 3.1 g; HPLC-purity of 76.6%; Yield: 42%.

EXAMPLE 2: PREPARATION OF 2,2-difluoro-N-methyl-2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetamide

20.0 g (78 mmol) 2,2-difluoro-2-[4-[(Z)-N′-hydroxycarbamimidoyl]phenyl]-N-methyl-acetamide and 200 mL dichloromethane were placed in a pressure reactor and cooled to −10° C. Then 21.5 g (162 mmol) trifluoroacetyl chloride was dosed continuously under vigorous stirring over 10 minutes at −10° C. to the reaction mixture. The reaction mixture was stirred for 4 hours at 100° C. and 990 kPa. Then, after the reactor was cooled down to 25° C., the pressure of the reactor was released and 200 g water was added to the reaction mixture. After phase separation the organic phase was extracted once with 200 g of an aqueous solution of sodium hydroxide (5% by weight) and once with 100 g water. The organic phase was dried over magnesium sulfate. The solvent was the removed under reduced pressure (40° C.; 2 kPa). Residue: 17.5 g; HPLC gave a purity of 76.3%; Yield: 66.3%.

EXAMPLE 3: PREPARATION OF 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole

100 g (0.67 mol) N′-hydroxy-4-methyl-benzamidine were suspended in 450 g (5.22 mol) tetrahydro-2-methylfuran (Me-THF). In total, 203 g (1.53 mol) trifluoroacetyl chloride were dosed in between 0° C. and 25° C. in 5 hours. Then, the volatiles were removed in vacuo (60° C., 250 to 5 mbar) to yield 138 g (>99% HPLC purity, 91% yield) 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole.

EXAMPLE 4: PREPARATION OF 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole

100 g (0.67 mol) N′-hydroxy-4-methyl-benzamidine were suspended in 450 g (5.22 mol) Me-THF. In total, 203 g (1.53 mol) trifluoroacetylchloride were dosed 40° C. in 3 hours. The volatiles were removed in vacuo (60° C., 10 to 0.5 kPa) to yield 137 g (>98% HPLC purity, 90% yield) 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole.

EXAMPLE 5: PREPARATION OF N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide—Solvent Screening

0.1 g (0.517 mmol) N′-hydroxy-4-methyl-benzamidine were suspended in 5 g solvent. Then, 1.13-1.26 g (0.0566 mol) ca. 10-12% solution of trifluoroacetyl chloride in Me-THF or ethyl acetate were added at room temperature and stirred for 1 hour. The table below shows the HPLC % of N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide following this procedure and in the presence of several different organic solvents.


	Solvent	HPLC %

	N,N-dimethylformamide	85
	NMP	50
	Tetrahydro-2-methylfuran	96
	Acetonitrile	87
	Tetrahydrofurane	92
	Methyl tert-butylether	35
	Ethyl acetate	85
	Me-Imidazolin	99
	Acetone	44
	Dioxane	73
	DME	96
	Dichloromethane	41

EXAMPLE 6: PREPARATION OF N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide

5 g (0.026 mol) N′-hydroxy-4-methyl-benzamidine were suspended in 20 g (0.232 mol) in Me-THF. 62 g (0.0566 mol) ca. 12% solution of trifluoroacetyl chloride in Me-THF were added at room temperature and stirred for 102 hours. After addition of 140 g of a 4% sodium bicarbonate-solution, phases were separated. The organic phase was washed with water and all volatiles were removed in vacuo (up to 80° C. and 0.5 kPa) to yield 6.6 g (>98% HPLC purity, 93% yield) N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide.

EXAMPLE 7: PREPARATION OF N-(2-fluorophenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide

N-(2-fluorophenyl)-4-[(Z)-N′-hydroxycarbamimidoyl]benzamide (1000 mg, 3.65 mmol) was suspended in Me-THF (10 mL) and trifluoroacetyl chloride (12% solution in Me-THF; 1.9 g, 14.63 mmol) was added dropwise at room temperature and stirred for 10 hours at 60° C. The reaction mass was quenched with water following by adjusting pH to 8 with a 4% sodium bicarbonate solution. The organic phase was separated, washed with water and all volatiles were removed in vacuo (up to 80° C. and 0.5 kPa) to yield 955 mg of the title product.

EXAMPLE 8: PREPARATION OF 4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoic acid

4-[(Z)-N′-hydroxycarbamimidoyl]benzoic acid (500 mg, 3 mmol) was suspended in Me-THF (2 mL) and trifluoroacetyl chloride (12% solution in Me-THF; 6.2 g, 6 mmol) was added dropwise at room temperature and stirred for 20 hours. The reaction mass was quenched with water following by adjusting pH to 8 with a 4% sodium bicarbonate solution. The organic phase was separated, washed with water and all volatiles were removed in vacuo (up to 80° C. and 0.5 kPa) to yield the title product.

EXAMPLE 9: PREPARATION OF N-methyl-L[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]methanesulfonamide

N′-hydroxy-4-[[methyl(methylsulfonyl)amino]methyl]benzamidine (500 mg, 2 mmol) was suspended Me-THF (2 mL) and trifluoroacetyl chloride (12% solution in Me-THF; 16.2 g, 14.63 mmol) was added dropwise at room temperature and stirred for 10 hours at 60° C. The reaction mass was quenched with water following by adjusting pH to 8 with a 4% sodium bicarbonate solution. The organic phase was separated, washed with water and all volatiles were removed in vacuo (up to 80° C. and 0.5 kPa) to yield the title product.

EXAMPLE 10: PREPARATION OF N-methyl-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]cyclopropanecarboxamide

N-[[4-[(Z)-N′-hydroxycarbamimidoyl]phenyl]methyl]-N-methyl-cyclopropanecarboxamide (500 mg, 2 mmol) was suspended in Me-THF (2 mL) and trifluoroacetyl chloride (12% solution in Me-THF; 6.2 g, 6 mmol) was added dropwise at room temperature and stirred for 20 hours. The reaction mass was quenched with water following by adjusting pH to 8 with a 4% sodium bicarbonate solution. The organic phase was separated, washed with water and all volatiles were removed in vacuo (up to 80° C. and 0.5 kPa) to yield the title product.

Claims

1.-15. (canceled)

16. A process for preparing compounds of formula I,

wherein

A¹is CH;

A²is N CH;

R^Ais hydrogen or fluorine;

R is —COOH, —COOR¹or —C(═W)NR¹R²;

W is O or S;

R¹is C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxyimino-C₁-C₄-alkyl, C₃-C₁₁-cycloalkyl, C₃-C₈-cycloalkenyl, phenyl-C₁-C₄-alkyl, heteroaryl-C₁-C₄-alkyl, phenyl or heteroaryl; and wherein the heteroaryl group is a 5- or 6-membered aromatic heterocycle, wherein the ring includes besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring member atoms; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C₁-C₆-alkyl and C₁-C₆-alkoxy;

R²is hydrogen, formyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, propargyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, phenyl, C₁-C₆-alkylamino or diC₁-C₆-alkylamino; and wherein any of the aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, cyano, C₁-C₆-alkyl and C₁-C₆-alkoxy;

the process comprising:

reacting a compound of formula II,

wherein A¹, A², R^Aand R is as defined above, with a trifluoroacetyl halide of formula IIa,

wherein Hal is chlorine or fluorine.

17. The process of claim 16, wherein the process is conducted in the presence of an inert organic solvent.

18. The process of claim 16, wherein Hal in compound IIa is chlorine.

19. The process of claim 16, wherein the process is conducted in the presence of a base selected from trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, 5-ethyl-2-methyl-pyridine, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate and mixtures thereof.

20. The process of claim 16, wherein the process is conducted at a pressure from 1 atm to 20 atm.

21. The process of claim 16, wherein the process is conducted at a temperature from 0° C. to 100° C.

22. The process of claim 16, the process comprising two steps:

i) reacting a compound of formula V,

wherein R is as defined in claim 16, with hydroxylamine or a salt thereof;

ii) reacting the product of step i), a compound of formula II,

wherein R is as defined above, with a trifluoroacetyl halide according to the process as defined in claim 16.

23. The process of claim 16, further comprising the step of reacting the compound of formula I to obtain a compound of formula III

24. The process of 23, further comprising the step of reacting the compound of formula III with a compound of formula IV

R¹—NH—R² IV,

wherein R¹and R²in the compound of formula IV is as defined in claim 16 to obtain a compound of formula Ic

25. The process of claim 24, further comprising the step of reacting the compound of formula Ic to obtain a compound of formula Id

26. The process of claim 24, wherein

R¹is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, cyclopropyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, or phenyl; and wherein the phenyl group is unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy and cyclopropyl;

R²is hydrogen, methyl or ethyl.

27. The process of claim 24, wherein

R¹is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluoro-phenyl, 4-fluoro-phenyl or 2-difluoromethoxy-phenyl;

R²is hydrogen.