Patent Application
20250081967
The present invention relates to pesticidally active, in particular insecticidally active heterocyclic derivatives containing sulfoximine substituents, to processes for their preparation, to compositions comprising those compounds, and to their use for controlling animal pests, including arthropods and in particular insects or representatives of the order Acarina.
Pesticidally active heterocyclic sulfoximine derivatives have previously been described in the literature, for example, in WO 2015/071180, WO 2016/039441, WO 2018/206348, WO 2019/219689, WO 2019/229089, WO 2019/234158, WO 2020/084075 and WO2020/141136.
It has now surprisingly been found that certain novel sulfoximine-containing phenyl and pyridyl derivatives with a stereogenic sulfur and a cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl group have favorable properties as pesticides and are obtainable in a stereospecific manner by means of a stereoselective oxidation, followed by a stereospecific imination reaction.
The present invention therefore provides compounds of formula I,
wherein
Compounds of formula I which have at least one basic centre can form, for example, acid addition salts, for example with strong inorganic acids such as mineral acids, for example perchloric acid, sulfuric acid, nitric acid, nitrose acid, a phosphorus acid or a hydrohalic acid, with strong organic carboxylic acids, such as C1-C4alkanecarboxylic acids which are unsubstituted or substituted, for example by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid or phthalic acid, such as hydroxycarboxylic acids, for example ascorbic acid, lactic acid, malic acid, tartaric acid or citric acid, or such as benzoic acid, or with organic sulfonic acids, such as C1-C4alkane- or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methane- or p-toluenesulfonic acid. Compounds of formula I which have at least one acidic group can form, for example, salts with bases, for example mineral salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower-alkylamine, for example ethyl-, diethyl-, triethyl- or dimethylpropylamine, or a mono-, di- or trihydroxy-lower-alkylamine, for example mono-, di- or triethanolamine.
The alkyl groups occurring in the definitions of the substituents can be straight-chain or branched and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, hexyl and their branched isomers. Haloalkylsulfanyl, haloalkylsulfinyl, haloalkylsulfonyl and alkoxy radicals are derived from the alkyl radicals mentioned.
The term “cyanoisopropyl” as used herein refers to an isopropyl group (as mentioned above), where one of the hydrogen atoms in this radical may be replaced by a cyano group. Cyanoisopropyl is, for example, 1-cyano-1-methylethyl or 2-cyano-1-methylethyl.
Halogen is generally fluorine, chlorine, bromine or iodine. This also applies, correspondingly, to halogen in combination with other meanings, such as haloalkyl.
Haloalkyl groups refer to a straight-chain or branched saturated C1-Cnalkyl radical having 1 to n carbon atoms, preferably have a chain length of from 1 to 6 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these radicals may be replaced by fluorine, chlorine, bromine and/or iodine. Haloalkyl is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1,1-difluoro-2,2,2-trichloroethyl, 2,2,3,3-tetrafluoroethyl and 2,2,2-trichloroethyl; preferably trichloromethyl, difluorochloromethyl, difluoromethyl, trifluoromethyl and dichlorofluoromethyl.
Alkoxy groups preferably have a preferred chain length of from 1 to 6 carbon atoms. Alkoxy is, for example, methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy and also the isomeric pentyloxy and hexyloxy radicals; preferably methoxy and ethoxy.
The term “cyanoisopropoxy” as used herein refers to an i-propoxy group (as mentioned above), where one of the hydrogen atoms in this radical may be replaced by a cyano group. Cyanoisopropoxy is, for example, 1-cyano-1-methylethoxy or 2-cyano-1-methylethoxy.
The term “C1-Cnhaloalkoxy” as used herein refers to a straight-chain or branched saturated C1-Cnhaloalkyl radical having 1 to n carbon atoms (as mentioned above) which is attached via an oxygen atom similar to C1-Cnalkoxy.
Alkylsulfanyl is for example methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, pentylsulfanyl, and hexylsulfanyl.
Alkylsulfinyl is for example methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, a butylsulfinyl, pentylsulfinyl, and hexylsulfinyl.
Alkylsulfonyl is for example methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl, and hexylsulfonyl.
The term “C1-Cnhaloalkylsulfanyl” as used herein refers to an alkylsulfanyl radical as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and/or iodine. Haloalkylsulfanyl groups preferably have a chain length of from 1 to 4 carbon atoms, for example, any one of fluoromethylthio, difluoromethylthio, trifluoromethylthio, chlorodifluoromethylthio, bromodifluoromethylthio, 2-fluoroethylthio, 2-chloroethylthio, 2-bromoethylthio, 2-iodoethylthio, 2,2-difluoroethylthio, 2,2,2-trifluoroethylthio, 2,2,2-trichloroethylthio, 2-chloro-2-fluoroethylthio, 2-chloro-2,2-difluoroethylthio, 2,2-dichloro-2-fluoroethylthio, pentafluoroethylthio, 2-fluoropropylthio, 3-fluoropropylthio, 2-chloropropylthio, 3-chloropropylthio, 2-bromopropylthio, 3-bromopropylthio, 2,2-difluoropropylthio, 2,3-difluoropropylthio, 2,3-dichloropropylthio, 3,3,3-trifluoropropylthio, 3,3,3-trichloropropylthio, 2,2,3,3,3-pentafluoropropylthio, heptafluoropropylthio, 1-(fluoromethyl)-2-fluoroethylthio, 1-(chloromethyl)-2-chloroethylthio, 1-(bromomethyl)-2-bromoethylthio, 4-fluorobutylthio, 4-chlorobutylthio, or 4-bromobutylthio.
Similar considerations apply to the terms “C1-Cnhaloalkylsulfinyl” and “C1-Cnhaloalkylsulfonyl” which refer to the C1-Cnhaloalkylsulfanyl (as mentioned above), but with the sulfur in a different oxidation state, for example, sulfoxide —S(O)C1-Cnhaloalkyl or sulfone —S(O)2C1-Cnhaloalkyl, respectively. Accordingly, for example, groups such as trifluoromethylsulfinyl, trifluoromethylsulfonyl or 2,2,2-trifluoroethylsulfonyl.
The cycloalkyl groups preferably have from 3 to 6 ring carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term “cyanocyclopropyl” as used herein refers to a cyclopropyl (as mentioned above), where one of the hydrogen atoms in this radical may be replaced by a cyano group. Cyanocyclopropyl is, for example, 1-cyanocyclopropyl or 2-cyanocyclopropyl.
The compounds of formula I according to the invention also include hydrates which may be formed during the salt formation.
The presence of a sulfur stereogenic center (S*) in compounds of formula (I) means that the compounds may occur in optically isomeric forms, i.e. enantiomeric or diastereomeric forms. Preferably, and in absence of an additional asymmetric carbon or sulfur atom, the present invention therefore refers to both enantiomers that result from the presence of the chiral sulfur atom S*, i.e. the present invention covers compounds of formula (I) with either (R) or (S) configuration at said stereogenic sulfur atom, and mixtures thereof (such as pure enantiomers or mixtures of enantiomers, i.e., single enantiomers having an enantiomeric excess). The present invention also refers to individual enantiomers obtained either after separation of a racemic mixture using known resolution methods or obtained by means of a stereoselective synthesis. For example, first and second eluting enantiomers obtained by chromatographic separation using a chiral stationary phase (such as amylose- or cellulose-based CHIRALPAK® columns); or enantiomers that are obtainable in a stereospecific manner by imination of stereogenic sulfinyl derivatives that are produced by steeoselective oxidation of the corresponding sulfanyl compounds are also subject matter of the present invention.
Certain embodiments according to the invention are provided as set out below.
Embodiment 1 provides compounds of formula I, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, as defined above.
Embodiment 2 provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 3a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 3b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 3c provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 4a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 4b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 4c provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 5a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 5b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 5c provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 6a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 6b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 7 provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 8a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 8b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 8c provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 9a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 9b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 9c provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 10a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 10b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 10c provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 10d provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 11a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 11 b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 11c provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 12 provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 13 provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 14 provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 15a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 15b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 16a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 16b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 17a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 17b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 18a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 18b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 19a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 19b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 19c provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 20a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 20b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 20c provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 21a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 21 b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 21c provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 22a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 22b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 22c provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 23a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 23b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 23c provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 23d provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 23e provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 24a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 24b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 24c provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 25a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 25b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 25c provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 25d provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 26a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 26b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 1 wherein:
Embodiment 27 provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to any one of the previous embodiments 1-26b wherein S* is in the R-configuration.
Embodiment 28 provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 27 in which said S* center is in either enantiomerically pure or in an enantiomerically enriched form that is enantiomerically enriched with an (S*) R-enantiomeric excess (e.e.) of at least 40%, for example, at least 50%, 60%, 70% or 80%, preferably at least 90%, more preferably at least 95%, yet more preferably at least 98% and most preferably at least 99%.
Embodiment 29 provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to any one of the previous embodiments 1-26b wherein S* is in the S-configuration.
Embodiment 30 provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to embodiment 29 in which said S* center is in either enantiomerically pure or in an enantiomerically enriched form that is enantiomerically enriched with (S*) S-enantiomeric excess (e.e.) of at least 40%, for example, at least 50%, 60%, 70% or 80%, preferably at least 90%, more preferably at least 95%, yet more preferably at least 98% and most preferably at least 99%.
Embodiment 31 provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to any one of the previous embodiments 1-30 whenever prepared or that are obtainable by a process comprising (A) stereoselectively oxidizing a sulfanyl compound of formula (II)
Embodiment 31a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to any one of embodiments 1-26b comprising compounds of formula I that are the first eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
Embodiment 31 b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to any one of embodiments 1-26b comprising compounds of formula I that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
Embodiment 31c provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to any one of embodiments 1-26b comprising compounds of formula I that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
Embodiment 32 provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to any one of embodiments 31a-31c either in enantiomerically pure form or having an enantiomeric excess (e.e.) of the first eluting enantiomer of at least 40%, for example, at least 50%, 60%, 70% or 80%, preferably at least 90%, more preferably at least 95%, yet more preferably at least 98% and most preferably at least 99%.
Embodiment 33a provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to any one of embodiments 1-26b comprising compounds of formula I that are the second eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
Embodiment 33b provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to any one of embodiments 1-26b comprising compounds of formula I that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
Embodiment 33c provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to any one of embodiments 1-26b comprising compounds of formula I that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
Embodiment 34 provides compounds, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, according to any one of embodiments 33a-33c either in enantiomerically pure form or having an enantiomeric excess (e.e.) of the second eluting enantiomer of at least 40%, for example, at least 50%, 60%, 70% or 80%, preferably at least 90%, more preferably at least 95%, yet more preferably at least 98% and most preferably at least 99%.
A preferred group of compounds of formula I is represented by the compounds of formula I-1
wherein R1, R2, R3, R8, R9, S* and A are as defined under formula I above.
In one preferred group of compounds of formula I-1, A is CH or N; R1 is ethyl, propyl or isopropyl; R2 is C1-C2haloalkyl, C1-C2haloalkylsulfanyl, C1-C2haloalkylsulfinyl or C1-C2haloalkylsulfonyl; R3 is C1-C2alkyl; R9 is hydrogen, methyl or ethyl; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In another preferred group of compounds of formula I-1, A is CH or N; R1 is ethyl; R2 is C1-C2fluoroalkyl, trifluoromethylsulfanyl, trifluoromethylsulfinyl, trifluoromethylsulfonyl, difluoromethylsulfanyl, difluoromethylsulfinyl, or difluoromethylsulfonyl; R3 is methyl; R9 is hydrogen or methyl, preferably R9 is hydrogen; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In compounds of formula I-1 and all of the preferred embodiments of compounds of formula I-1 mentioned above, unless otherwise specified, R1, R2, R3, R8, R9, S* and A are as defined under formula I above; preferably A is CH or N, more preferably A is N; R1 is ethyl; R2 is trifluoromethyl, pentafluoroethyl or trifluoromethylsulfanyl; preferably R2 is trifluoromethyl; R3 is methyl; R9 is hydrogen; R8 is 1-cyano-1-methyl-ethoxy, 1-cyano-1-methyl-ethyl or 1-cyanocyclopropyl.
One group of compounds according to this embodiment are compounds of formula (I-1a) which are compounds of formula (I-1), or any of the preferred embodiments of compounds of formula (I-1), wherein S* is in the R-configuration.
One group of compounds according to this embodiment are compounds of formula (I-1b) which are compounds of formula (I-1), or any of the preferred embodiments of compounds of formula (I-1), wherein S* is in the S-configuration.
One group of compounds according to this embodiment are compounds of formula (I-1c) which are compounds of formula (I-1), or any of the preferred embodiments of compounds of formula (I-1), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-1d) which are compounds of formula (I-1), or any of the preferred embodiments of compounds of formula (I-1), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-1e) which are compounds of formula (I-1), or any of the preferred embodiments of compounds of formula (I-1), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
One group of compounds according to this embodiment are compounds of formula (I-1f) which are compounds of formula (I-1), or any of the preferred embodiments of compounds of formula (I-1), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-1g) which are compounds of formula (I-1), or any of the preferred embodiments of compounds of formula (I-1), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-1h) which are compounds of formula (I-1), or any of the preferred embodiments of compounds of formula (I-1), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
Another group of compounds according to this embodiment are compounds of formula (I-1i) which are compounds of formula (I-1), or any of the preferred embodiments of compounds of formula (I-1), whenever prepared or that are obtainable in a stereospecific manner by imination of stereogenic sulfinyl derivatives that are produced by stereoselective oxidation of the corresponding sulfanyl compounds as further set forth and described in embodiment 31.
Another preferred group of compounds of formula I is represented by the compounds of formula I-2
wherein R1, R2, R3, R8, R9, S* and A are as defined under formula I above.
In one preferred group of compounds of formula I-2, A is CH or N; R1 is ethyl, propyl or isopropyl; R2 is C1-C2haloalkyl, C1-C2haloalkylsulfanyl, C1-C2haloalkylsulfinyl or C1-C2haloalkylsulfonyl; R3 is C1-C2alkyl; R9 is hydrogen, methyl or ethyl; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In another preferred group of compounds of formula I-2, A is CH or N; R1 is ethyl; R2 is C1-C2fluoroalkyl, trifluoromethylsulfanyl, trifluoromethylsulfinyl, trifluoromethylsulfonyl, difluoromethylsulfanyl, difluoromethylsulfinyl, or difluoromethylsulfonyl; R3 is methyl; R9 is hydrogen or methyl, preferably R9 is hydrogen; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In compounds of formula I-2 and all of the preferred embodiments of compounds of formula I-2 mentioned above, unless otherwise specified, R1, R2, R3, R8, R9, S* and A are as defined under formula I above; preferably A is CH or N, more preferably A is N; R1 is ethyl; R2 is trifluoromethyl, pentafluoroethyl or trifluoromethylsulfanyl; preferably R2 is trifluoromethyl; R3 is methyl; R9 is hydrogen; R8 is 1-cyano-1-methyl-ethoxy, 1-cyano-1-methyl-ethyl or 1-cyanocyclopropyl.
One group of compounds according to this embodiment are compounds of formula (I-2a) which are compounds of formula (I-2), or any of the preferred embodiments of compounds of formula (I-2), wherein S* is in the R-configuration.
One group of compounds according to this embodiment are compounds of formula (I-2b) which are compounds of formula (I-2), or any of the preferred embodiments of compounds of formula (I-2), wherein S* is in the S-configuration.
One group of compounds according to this embodiment are compounds of formula (I-2c) which are compounds of formula (I-2), or any of the preferred embodiments of compounds of formula (I-2), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-2d) which are compounds of formula (I-2), or any of the preferred embodiments of compounds of formula (I-2), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-2e) which are compounds of formula (I-2), or any of the preferred embodiments of compounds of formula (I-2), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
One group of compounds according to this embodiment are compounds of formula (I-20 which are compounds of formula (I-2), or any of the preferred embodiments of compounds of formula (I-2), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-2g) which are compounds of formula (I-2), or any of the preferred embodiments of compounds of formula (I-2), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-2h) which are compounds of formula (I-2), or any of the preferred embodiments of compounds of formula (I-2), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
Another group of compounds according to this embodiment are compounds of formula (I-2i) which are compounds of formula (I-2), or any of the preferred embodiments of compounds of formula (I-2), whenever prepared or that are obtainable in a stereospecific manner by imination of stereogenic sulfinyl derivatives that are produced by stereoselective oxidation of the corresponding sulfanyl compounds as further set forth and described in embodiment 31.
Another preferred group of compounds of formula I is represented by the compounds of formula I-3
wherein R1, R2, R3, R8, R9, S* and A are as defined under formula I above.
In one preferred group of compounds of formula I-3, A is CH or N; R1 is ethyl, propyl or isopropyl; R2 is C1-C2haloalkyl, C1-C2haloalkylsulfanyl, C1-C2haloalkylsulfinyl or C1-C2haloalkylsulfonyl; R3 is C1-C2alkyl; R9 is hydrogen, methyl or ethyl; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In another preferred group of compounds of formula I-3, A is CH or N; R1 is ethyl; R2 is C1-C2fluoroalkyl, trifluoromethylsulfanyl, trifluoromethylsulfinyl, trifluoromethylsulfonyl, difluoromethylsulfanyl, difluoromethylsulfinyl, or difluoromethylsulfonyl; R3 is methyl; R9 is hydrogen or methyl, preferably R9 is hydrogen; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In compounds of formula I-3 and all of the preferred embodiments of compounds of formula I-3 mentioned above, unless otherwise specified, R1, R2, R3, R8, R9, S* and A are as defined under formula I above; preferably A is CH or N, more preferably A is N; R1 is ethyl; R2 is trifluoromethyl, pentafluoroethyl or trifluoromethylsulfanyl; preferably R2 is trifluoromethyl; R3 is methyl; R9 is hydrogen; R8 is 1-cyano-1-methyl-ethoxy, 1-cyano-1-methyl-ethyl or 1-cyanocyclopropyl.
One group of compounds according to this embodiment are compounds of formula (I-3a) which are compounds of formula (I-3), or any of the preferred embodiments of compounds of formula (I-3), wherein S* is in the R-configuration.
One group of compounds according to this embodiment are compounds of formula (I-3b) which are compounds of formula (I-3), or any of the preferred embodiments of compounds of formula (I-3), wherein S* is in the S-configuration.
One group of compounds according to this embodiment are compounds of formula (I-3c) which are compounds of formula (I-3), or any of the preferred embodiments of compounds of formula (I-3), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-3d) which are compounds of formula (I-3), or any of the preferred embodiments of compounds of formula (I-3), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-3e) which are compounds of formula (I-3), or any of the preferred embodiments of compounds of formula (I-3), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
One group of compounds according to this embodiment are compounds of formula (I-3f which are compounds of formula (I-3), or any of the preferred embodiments of compounds of formula (I-3), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-3g) which are compounds of formula (I-3), or any of the preferred embodiments of compounds of formula (I-3), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-3h) which are compounds of formula (I-3), or any of the preferred embodiments of compounds of formula (I-3), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
Another group of compounds according to this embodiment are compounds of formula (I-3i) which are compounds of formula (I-3), or any of the preferred embodiments of compounds of formula (I-3), whenever prepared or that are obtainable in a stereospecific manner by imination of stereogenic sulfinyl derivatives that are produced by stereoselective oxidation of the corresponding sulfanyl compounds as further set forth and described in embodiment 31.
Another preferred group of compounds of formula I is represented by the compounds of formula I-4
wherein R1, R2, R3, R4, R8, R9, S* and A are as defined under formula I above.
In one preferred group of compounds of formula I-4, A is CH or N; R1 is ethyl, propyl or isopropyl; R2 is C1-C2haloalkyl, C1-C2haloalkylsulfanyl, C1-C2haloalkylsulfinyl or C1-C2haloalkylsulfonyl; R3 is C1-C2alkyl; R4 is C1-C2alkyl, C1-C2haloalkyl, C1-C2alkoxy or cyclopropyl; R9 is hydrogen, methyl or ethyl; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In another preferred group of compounds of formula I-4, A is CH or N; R1 is ethyl; R2 is C1-C2fluoroalkyl, trifluoromethylsulfanyl, trifluoromethylsulfinyl, trifluoromethylsulfonyl, difluoromethylsulfanyl, difluoromethylsulfinyl, or difluoromethylsulfonyl; R3 is methyl; R4 is methyl, ethyl, methoxy or cyclopropyl; R9 is hydrogen or methyl, preferably R9 is hydrogen; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In another preferred group of of compounds of formula I-4, R4 is ethyl, methoxy or cyclopropyl.
In compounds of formula I-4 and all of the preferred embodiments of compounds of formula I-4 mentioned above, unless otherwise specified, R1, R2, R3, R4, R8, R9, S* and A are as defined under formula I above; preferably A is CH or N, more preferably A is N; R1 is ethyl; R2 is trifluoromethyl, pentafluoroethyl or trifluoromethylsulfanyl; preferably R2 is trifluoromethyl; R3 is methyl; R4 is ethyl, methoxy or cyclopropyl; R9 is hydrogen; R8 is 1-cyano-1-methyl-ethoxy, 1-cyano-1-methyl-ethyl or 1-cyanocyclopropyl.
One group of compounds according to this embodiment are compounds of formula (I-4a) which are compounds of formula (I-4), or any of the preferred embodiments of compounds of formula (I-4), wherein S* is in the R-configuration.
One group of compounds according to this embodiment are compounds of formula (I-4b) which are compounds of formula (I-4), or any of the preferred embodiments of compounds of formula (I-4), wherein S* is in the S-configuration.
One group of compounds according to this embodiment are compounds of formula (I-4c) which are compounds of formula (I-4), or any of the preferred embodiments of compounds of formula (I-4), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-4d) which are compounds of formula (I-4), or any of the preferred embodiments of compounds of formula (I-4), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-4e) which are compounds of formula (I-4), or any of the preferred embodiments of compounds of formula (I-4), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
One group of compounds according to this embodiment are compounds of formula (I-40 which are compounds of formula (I-4), or any of the preferred embodiments of compounds of formula (I-4), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-4g) which are compounds of formula (I-4), or any of the preferred embodiments of compounds of formula (I-4), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-4h) which are compounds of formula (I-4), or any of the preferred embodiments of compounds of formula (I-4), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
Another group of compounds according to this embodiment are compounds of formula (I-4i) which are compounds of formula (I-4), or any of the preferred embodiments of compounds of formula (I-4), whenever prepared or that are obtainable in a stereospecific manner by imination of stereogenic sulfinyl derivatives that are produced by stereoselective oxidation of the corresponding sulfanyl compounds as further set forth and described in embodiment 31.
Another preferred group of compounds of formula I is represented by the compounds of formula I-5
wherein R1, R2, R8, R9, S* and A are as defined under formula I above.
In one preferred group of compounds of formula I-5, A is CH or N; R1 is ethyl, propyl or isopropyl; R2 is C1-C2haloalkyl, C1-C2haloalkylsulfanyl, C1-C2haloalkylsulfinyl or C1-C2haloalkylsulfonyl; R9 is hydrogen, methyl or ethyl; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In another preferred group of compounds of formula I-5, A is CH or N; R1 is ethyl; R2 is C1-C2fluoroalkyl, trifluoromethylsulfanyl, trifluoromethylsulfinyl, trifluoromethylsulfonyl, difluoromethylsulfanyl, difluoromethylsulfinyl, or difluoromethylsulfonyl; R9 is hydrogen or methyl, preferably R9 is hydrogen; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In compounds of formula I-5 and all of the preferred embodiments of compounds of formula I-5 mentioned above, unless otherwise specified, R1, R2, R8, R9, S* and A are as defined under formula I above; preferably A is CH or N, more preferably A is N; R1 is ethyl; R2 is trifluoromethyl, pentafluoroethyl or trifluoromethylsulfanyl; preferably R2 is trifluoromethyl; R9 is hydrogen; R8 is 1-cyano-1-methyl-ethoxy, 1-cyano-1-methyl-ethyl or 1-cyanocyclopropyl.
One group of compounds according to this embodiment are compounds of formula (I-5a) which are compounds of formula (I-5), or any of the preferred embodiments of compounds of formula (I-5), wherein S* is in the R-configuration.
One group of compounds according to this embodiment are compounds of formula (I-5b) which are compounds of formula (I-5), or any of the preferred embodiments of compounds of formula (I-5), wherein S* is in the S-configuration.
One group of compounds according to this embodiment are compounds of formula (I-5c) which are compounds of formula (I-5), or any of the preferred embodiments of compounds of formula (I-5), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-5d) which are compounds of formula (I-5), or any of the preferred embodiments of compounds of formula (I-5), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-5e) which are compounds of formula (I-5), or any of the preferred embodiments of compounds of formula (I-5), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
One group of compounds according to this embodiment are compounds of formula (I-5f which are compounds of formula (I-5), or any of the preferred embodiments of compounds of formula (I-5), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-5g) which are compounds of formula (I-5), or any of the preferred embodiments of compounds of formula (I-5), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-5h) which are compounds of formula (I-5), or any of the preferred embodiments of compounds of formula (I-5), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
Another group of compounds according to this embodiment are compounds of formula (I-5i) which are compounds of formula (I-5), or any of the preferred embodiments of compounds of formula (I-5), whenever prepared or that are obtainable in a stereospecific manner by imination of stereogenic sulfinyl derivatives that are produced by stereoselective oxidation of the corresponding sulfanyl compounds as further set forth and described in embodiment 31.
Another preferred group of compounds of formula I is represented by the compounds of formula I-6
wherein R1, R2, R8, R9, S* and A are as defined under formula I above.
In one preferred group of compounds of formula I-6, A is CH or N; R1 is ethyl, propyl or isopropyl; R2 is C1-C2haloalkyl, C1-C2haloalkylsulfanyl, C1-C2haloalkylsulfinyl or C1-C2haloalkylsulfonyl; R9 is hydrogen, methyl or ethyl; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In another preferred group of compounds of formula I-6, A is CH or N; R1 is ethyl; R2 is C1-C2fluoroalkyl, trifluoromethylsulfanyl, trifluoromethylsulfinyl, trifluoromethylsulfonyl, difluoromethylsulfanyl, difluoromethylsulfinyl, or difluoromethylsulfonyl; R9 is hydrogen or methyl, preferably R9 is hydrogen; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In compounds of formula I-6 and all of the preferred embodiments of compounds of formula I-6 mentioned above, unless otherwise specified, R1, R2, R8, R9, S* and A are as defined under formula I above; preferably A is CH or N, more preferably A is N; R1 is ethyl; R2 is trifluoromethyl, pentafluoroethyl or trifluoromethylsulfanyl; preferably R2 is trifluoromethyl; R9 is hydrogen; R8 is 1-cyano-1-methyl-ethoxy, 1-cyano-1-methyl-ethyl or 1-cyanocyclopropyl.
One group of compounds according to this embodiment are compounds of formula (I-6a) which are compounds of formula (I-6), or any of the preferred embodiments of compounds of formula (I-6), wherein S* is in the R-configuration.
One group of compounds according to this embodiment are compounds of formula (I-6b) which are compounds of formula (I-6), or any of the preferred embodiments of compounds of formula (I-6), wherein S* is in the S-configuration.
One group of compounds according to this embodiment are compounds of formula (I-6c) which are compounds of formula (I-6), or any of the preferred embodiments of compounds of formula (I-6), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-6d) which are compounds of formula (I-6), or any of the preferred embodiments of compounds of formula (I-6), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-6e) which are compounds of formula (I-6), or any of the preferred embodiments of compounds of formula (I-6), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
One group of compounds according to this embodiment are compounds of formula (I-60 which are compounds of formula (I-6), or any of the preferred embodiments of compounds of formula (I-6), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-6g) which are compounds of formula (I-6), or any of the preferred embodiments of compounds of formula (I-6), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-6h) which are compounds of formula (I-6), or any of the preferred embodiments of compounds of formula (I-6), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
Another group of compounds according to this embodiment are compounds of formula (I-6i) which are compounds of formula (I-6), or any of the preferred embodiments of compounds of formula (I-6), whenever prepared or that are obtainable in a stereospecific manner by imination of stereogenic sulfinyl derivatives that are produced by stereoselective oxidation of the corresponding sulfanyl compounds as further set forth and described in embodiment 31.
Another preferred group of compounds of formula I is represented by the compounds of formula I-7
wherein R1, R2, R8, R9, S* and A are as defined under formula I above.
In one preferred group of compounds of formula I-7, A is CH or N; R1 is ethyl, propyl or isopropyl; R2 is C1-C2haloalkyl, C1-C2haloalkylsulfanyl, C1-C2haloalkylsulfinyl or C1-C2haloalkylsulfonyl; R9 is hydrogen, methyl or ethyl; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In another preferred group of compounds of formula I-7, A is CH or N; R1 is ethyl; R2 is C1-C2fluoroalkyl, trifluoromethylsulfanyl, trifluoromethylsulfinyl, trifluoromethylsulfonyl, difluoromethylsulfanyl, difluoromethylsulfinyl, or difluoromethylsulfonyl; R9 is hydrogen or methyl, preferably R9 is hydrogen; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In compounds of formula I-7 and all of the preferred embodiments of compounds of formula I-7 mentioned above, unless otherwise specified, R1, R2, R8, R9, S* and A are as defined under formula I above; preferably A is CH or N, more preferably A is N; R1 is ethyl; R2 is trifluoromethyl, pentafluoroethyl or trifluoromethylsulfanyl; preferably R2 is trifluoromethyl; R9 is hydrogen; R8 is 1-cyano-1-methyl-ethoxy, 1-cyano-1-methyl-ethyl or 1-cyanocyclopropyl.
One group of compounds according to this embodiment are compounds of formula (I-7a) which are compounds of formula (I-7), or any of the preferred embodiments of compounds of formula (I-7), wherein S* is in the R-configuration.
One group of compounds according to this embodiment are compounds of formula (I-7b) which are compounds of formula (I-7), or any of the preferred embodiments of compounds of formula (I-7), wherein S* is in the S-configuration.
One group of compounds according to this embodiment are compounds of formula (I-7c) which are compounds of formula (I-7), or any of the preferred embodiments of compounds of formula (I-7), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-7d) which are compounds of formula (I-7), or any of the preferred embodiments of compounds of formula (I-7), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-7e) which are compounds of formula (I-7), or any of the preferred embodiments of compounds of formula (I-7), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
One group of compounds according to this embodiment are compounds of formula (I-70 which are compounds of formula (I-7), or any of the preferred embodiments of compounds of formula (I-7), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-7g) which are compounds of formula (I-7), or any of the preferred embodiments of compounds of formula (I-7), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-7h) which are compounds of formula (I-7), or any of the preferred embodiments of compounds of formula (I-7), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
Another group of compounds according to this embodiment are compounds of formula (I-6i) which are compounds of formula (I-6), or any of the preferred embodiments of compounds of formula (I-6), whenever prepared or that are obtainable in a stereospecific manner by imination of stereogenic sulfinyl derivatives that are produced by stereoselective oxidation of the corresponding sulfanyl compounds as further set forth and described in embodiment 31.
Another preferred group of compounds of formula I is represented by the compounds of formula I-8
wherein R1, R2, R8, R9, S* and A are as defined under formula I above.
In one preferred group of compounds of formula I-8, A is CH or N; R1 is ethyl, propyl or isopropyl; R2 is C1-C2haloalkyl, C1-C2haloalkylsulfanyl, C1-C2haloalkylsulfinyl or C1-C2haloalkylsulfonyl; R9 is hydrogen, methyl or ethyl; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In another preferred group of compounds of formula I-8, A is CH or N; R1 is ethyl; R2 is C1-C2fluoroalkyl, trifluoromethylsulfanyl, trifluoromethylsulfinyl, trifluoromethylsulfonyl, difluoromethylsulfanyl, difluoromethylsulfinyl, or difluoromethylsulfonyl; R9 is hydrogen or methyl, preferably R9 is hydrogen; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In compounds of formula I-8 and all of the preferred embodiments of compounds of formula I-8 mentioned above, unless otherwise specified, R1, R2, R8, R9, S* and A are as defined under formula I above; preferably A is CH or N, more preferably A is N; R1 is ethyl; R2 is trifluoromethyl, pentafluoroethyl or trifluoromethylsulfanyl; preferably R2 is trifluoromethyl; R9 is hydrogen; R8 is 1-cyano-1-methyl-ethoxy, 1-cyano-1-methyl-ethyl or 1-cyanocyclopropyl.
One group of compounds according to this embodiment are compounds of formula (I-8a) which are compounds of formula (I-8), or any of the preferred embodiments of compounds of formula (I-8), wherein S* is in the R-configuration.
One group of compounds according to this embodiment are compounds of formula (I-8b) which are compounds of formula (I-8), or any of the preferred embodiments of compounds of formula (I-8), wherein S* is in the S-configuration.
One group of compounds according to this embodiment are compounds of formula (I-8c) which are compounds of formula (I-8), or any of the preferred embodiments of compounds of formula (I-8), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-8d) which are compounds of formula (I-8), or any of the preferred embodiments of compounds of formula (I-8), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-8e) which are compounds of formula (I-8), or any of the preferred embodiments of compounds of formula (I-8), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
One group of compounds according to this embodiment are compounds of formula (I-80 which are compounds of formula (I-8), or any of the preferred embodiments of compounds of formula (I-8), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-8g) which are compounds of formula (I-8), or any of the preferred embodiments of compounds of formula (I-8), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-8h) which are compounds of formula (I-8), or any of the preferred embodiments of compounds of formula (I-8), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
Another group of compounds according to this embodiment are compounds of formula (I-8i) which are compounds of formula (I-8), or any of the preferred embodiments of compounds of formula (I-8), whenever prepared or that are obtainable in a stereospecific manner by imination of stereogenic sulfinyl derivatives that are produced by stereoselective oxidation of the corresponding sulfanyl compounds as further set forth and described in embodiment 31.
Another preferred group of compounds of formula I is represented by the compounds of formula I-9
wherein R1, R2, R8, R9, S* and A are as defined under formula I above.
In one preferred group of compounds of formula I-9, A is CH or N; R1 is ethyl, propyl or isopropyl; R2 is C1-C2haloalkyl, C1-C2haloalkylsulfanyl, C1-C2haloalkylsulfinyl or C1-C2haloalkylsulfonyl; R9 is hydrogen, methyl or ethyl; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In another preferred group of compounds of formula I-9, A is CH or N; R1 is ethyl; R2 is C1-C2fluoroalkyl, trifluoromethylsulfanyl, trifluoromethylsulfinyl, trifluoromethylsulfonyl, difluoromethylsulfanyl, difluoromethylsulfinyl, or difluoromethylsulfonyl; R9 is hydrogen or methyl, preferably R9 is hydrogen; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In compounds of formula I-9 and all of the preferred embodiments of compounds of formula I-9 mentioned above, unless otherwise specified, R1, R2, R8, R9, S* and A are as defined under formula I above; preferably A is CH or N, more preferably A is N; R1 is ethyl; R2 is trifluoromethyl, pentafluoroethyl or trifluoromethylsulfanyl; preferably R2 is trifluoromethyl; R9 is hydrogen; R8 is 1-cyano-1-methyl-ethoxy, 1-cyano-1-methyl-ethyl or 1-cyanocyclopropyl.
One group of compounds according to this embodiment are compounds of formula (I-9a) which are compounds of formula (I-9), or any of the preferred embodiments of compounds of formula (I-9), wherein S* is in the R-configuration.
One group of compounds according to this embodiment are compounds of formula (I-9b) which are compounds of formula (I-9), or any of the preferred embodiments of compounds of formula (I-9), wherein S* is in the S-configuration.
One group of compounds according to this embodiment are compounds of formula (I-9c) which are compounds of formula (I-9), or any of the preferred embodiments of compounds of formula (I-9), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-9d) which are compounds of formula (I-9), or any of the preferred embodiments of compounds of formula (I-9), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-9e) which are compounds of formula (I-9), or any of the preferred embodiments of compounds of formula (I-9), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
One group of compounds according to this embodiment are compounds of formula (I-90 which are compounds of formula (I-9), or any of the preferred embodiments of compounds of formula (I-9), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-9g) which are compounds of formula (I-9), or any of the preferred embodiments of compounds of formula (I-9), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-9h) which are compounds of formula (I-9), or any of the preferred embodiments of compounds of formula (I-9), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
Another group of compounds according to this embodiment are compounds of formula (I-9i) which are compounds of formula (I-9), or any of the preferred embodiments of compounds of formula (I-9), whenever prepared or that are obtainable in a stereospecific manner by imination of stereogenic sulfinyl derivatives that are produced by stereoselective oxidation of the corresponding sulfanyl compounds as further set forth and described in embodiment 31.
Another preferred group of compounds of formula I is represented by the compounds of formula I-10
wherein R1, R2, R8, R9, S* and A are as defined under formula I above.
In one preferred group of compounds of formula I-10, A is CH or N; R1 is ethyl, propyl or isopropyl; R2 is C1-C2haloalkyl, C1-C2haloalkylsulfanyl, C1-C2haloalkylsulfinyl or C1-C2haloalkylsulfonyl; R9 is hydrogen, methyl or ethyl; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In another preferred group of compounds of formula I-10, A is CH or N; R1 is ethyl; R2 is C1-C2fluoroalkyl, trifluoromethylsulfanyl, trifluoromethylsulfinyl, trifluoromethylsulfonyl, difluoromethylsulfanyl, difluoromethylsulfinyl, or difluoromethylsulfonyl; R9 is hydrogen or methyl, preferably R9 is hydrogen; R8 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl.
In compounds of formula I-10 and all of the preferred embodiments of compounds of formula I-10 mentioned above, unless otherwise specified, R1, R2, R8, R9, S* and A are as defined under formula I above; preferably A is CH or N, more preferably A is N; R1 is ethyl; R2 is trifluoromethyl, pentafluoroethyl or trifluoromethylsulfanyl; preferably R2 is trifluoromethyl; R9 is hydrogen; R8 is 1-cyano-1-methyl-ethoxy, 1-cyano-1-methyl-ethyl or 1-cyanocyclopropyl.
One group of compounds according to this embodiment are compounds of formula (I-10a) which are compounds of formula (I-10), or any of the preferred embodiments of compounds of formula (I-10), wherein S* is in the R-configuration.
One group of compounds according to this embodiment are compounds of formula (I-10b) which are compounds of formula (I-10), or any of the preferred embodiments of compounds of formula (I-10), wherein S* is in the S-configuration.
One group of compounds according to this embodiment are compounds of formula (I-10c) which are compounds of formula (I-10), or any of the preferred embodiments of compounds of formula (I-10), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-10d) which are compounds of formula (I-10), or any of the preferred embodiments of compounds of formula (I-10), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-10e) which are compounds of formula (I-10), or any of the preferred embodiments of compounds of formula (I-10), that are the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
One group of compounds according to this embodiment are compounds of formula (I-100 which are compounds of formula (I-10), or any of the preferred embodiments of compounds of formula (I-10), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-10g) which are compounds of formula (I-10), or any of the preferred embodiments of compounds of formula (I-10), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
One group of compounds according to this embodiment are compounds of formula (I-10h) which are compounds of formula (I-10), or any of the preferred embodiments of compounds of formula (I-10), that are the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
Another group of compounds according to this embodiment are compounds of formula (I-10i) which are compounds of formula (I-10), or any of the preferred embodiments of compounds of formula (I-10), whenever prepared or that are obtainable in a stereospecific manner by imination of stereogenic sulfinyl derivatives that are produced by stereoselective oxidation of the corresponding sulfanyl compounds as further set forth and described in embodiment 31.
Another preferred group of compounds of formula I are those wherein Q, R3, R4 and X1 are as defined under formula I (above);
Another especially preferred group of compounds of formula I are those represented by the compounds of formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, or I-10 wherein
A preferred group of compounds of formula I are those represented by the (S) absolute configuration at the stereogenic sulfur center (S*).
Another preferred group of compounds of formula I are those either in (S) enantiomerically pure form or with an S-enantiomeric excess (e.e.) of at least 40%, for example, at least 50%, 60%, 70% or 80%, preferably at least 90%, more preferably at least 95%, yet more preferably at least 98% and most preferably at least 99%.
Another preferred group of compounds of formula I are those represented by the (R) absolute configuration at the stereogenic sulfur center (S*).
Another preferred group of compounds of formula I are those either in (R) enantiomerically pure form or with an R-enantiomeric excess (e.e.) of at least 40%, for example, at least 50%, 60%, 70% or 80%, preferably at least 90%, more preferably at least 95%, yet more preferably at least 98% and most preferably at least 99%.
An outstanding preferred group of compounds of formula I are those represented by the (S)- or (R)-enantiomer compounds P1 to P19 as defined in the table Y below:
Another preferred group of compounds of formula I are those comprising the first eluting enantiomers upon chiral resolution by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
Another preferred group of compounds of formula I are those comprising the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
Another preferred group of compounds of formula I are those comprising the first eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
Another preferred group of compounds of formula I are those having an enantiomeric excess (e.e.) of the first eluting enantiomer of at least 40%, for example, at least 50%, 60%, 70% or 80%, preferably at least 90%, more preferably at least 95%, yet more preferably at least 98% and most preferably at least 99%.
Another preferred group of compounds of formula I are those comprising the second eluting enantiomers upon chiral resolution by preparative chromatography using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
Another preferred group of compounds of formula I are those comprising the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC (supercritical fluid chromatography) using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases.
Another preferred group of compounds of formula I are those comprising the second eluting enantiomers upon chiral resolution of the racemate by preparative SFC using immobilized amylose-based (CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
Another preferred group of compounds of formula I are those having an enantiomeric excess (e.e.) of the second eluting enantiomer of at least 40%, for example, at least 50%, 60%, 70% or 80%, preferably at least 90%, more preferably at least 95%, yet more preferably at least 98% and most preferably at least 99%.
An outstanding preferred group of compounds of formula I are those represented by the first eluting (P1-A through P19-A) or the second eluting (P1-B through P19-B) enantiomer compounds P1 to P19 as defined in the table Z below:
Compounds according to the invention may possess any number of benefits including, inter alia, advantageous levels of biological activity for protecting plants against insects or superior properties for use as agrochemical active ingredients (for example, greater biological activity, differential biological activity of enantiomer or enantiomerically enriched composition and racemate, differential biological activity of (R) enantiomer or (R) enantiomerically enriched composition and (S) enantiomer or (S) enantiomerically enriched composition, an advantageous spectrum of activity, an increased safety profile, improved physico-chemical properties, or increased biodegradability or environmental profile). In particular, it has been surprisingly found that certain compounds of formula (I) may show an advantageous safety profile with respect to non-target arthropods, in particular pollinators such as honey bees, solitary bees, and bumble bees. Most particularly, Apis mellifera.
In another aspect the present invention provides a composition comprising an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I), or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, as defined in any of embodiments 1-34 (above) or any of the embodiments under compounds of formulae I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, or I-10 and, optionally, an auxiliary or diluent.
In a further aspect the present invention provides a method of combating and controlling insects, acarines, nematodes or molluscs which comprises applying to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I), or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, as defined in any of embodiments 1-34 (above) or any of the embodiments under compounds of formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, or I-10 (above) or a composition as defined above.
In a yet further aspect, the present invention provides a method for the protection of plant propagation material from the attack by insects, acarines, nematodes or molluscs, which comprises treating the propagation material or the site, where the propagation material is planted, with a composition as defined above.
The process according to the invention for preparing compounds of formula I is carried out by methods known to those skilled in the art. Individual enantiomers can be prepared, for example, by either i) enantioselective transformations, ii) resolution of a racemic or partially enriched mixture by fractional crystallization with an enantiomerically enriched reagent, iii) chromatographic separation of the enantiomers using an enantiomerically enriched stationary phase.
Individual enantiomers can be obtained by chromatographic separation of a racemic mixture on a chiral stationary phase using preparative high-performance liquid chromatography (HPLC, in normal or reversed phase mode), or using preparative supercritical fluid chromatography (SFC).
Compounds of the formula I in form of a first or second eluting enantiomer, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9, S* and A are as defined in formula I above,
can be obtained (scheme 1) upon chiral resolution of the racemic mixture of compounds of the formula I (rac-1), wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I above, for example by preparative SFC using immobilized amylose-based (such as CHIRALPAK® IA, CHIRALPAK® IG) or cellulose-based (such as CHIRALPAK® IC) chiral phases and using supercritical CO2 and an alcohol cosolvent, such as preferably methanol, ethanol or isopropyl alcohol, as the mobile phase.
Racemic mixtures of compounds of the formula I (rac-1), wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I above,
can be prepared (scheme 2) by reacting sulfide compounds of formula II, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I, with a suitable nitrogen source such as, for example, ammonia, ammonium carbamate or ammonium acetate (preferably ammonium carbamate), in the presence of hypervalent iodine reagents, such as diacetoxyiodobenzene, in solvents such as toluene, acetonitrile or methanol, at temperatures between 0 and 100° C., preferably around room temperature, in analogy to descriptions found, for example, in Chem. Commun. 53, 348-351; 2017 (and references cited therein).
Alternatively, racemic mixtures of compounds of the formula I (rac-1), wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I above,
may be prepared (scheme 3) by reacting racemic sulfoxide compounds of formula rac-III, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I above, with a suitable nitrogen source, optionally in the presence of an oxidant, optionally in the presence of a metal catalyst and optionally in a solvent such as acetonitrile, dichloromethane or methanol. Examples of typical imination conditions include, O-dinitrophenylhydroxylamine/Rh2(esp)4, NH2COONH4/Phl(OAc)2, NaN3/H2SO4 or O-mesitylenesulfonyl-hydroxylamine (MSH). Examples of such transformations are described in Chemistry—A European Journal 2021, 27, 17293-17321 (and references therein), Chemical Communications 2014, 50, 9687-9689 and Angewandte Chemie, International Edition 2016, 55, 7203-7207 (and references cited therein).
Of particular interest are methods using a hydroxylamine derivative such as O-(4-nitrobenzoyl)-hydroxylamine triflic acid (also known as O-(4-nitrobenzoyl)-hydroxylammonium triflate or O-(4-nitrobenzoyl)-hydroxylammonium trifluoromethanesulfonate) and an iron catalyst, such as iron(II) sulfate (FeSO4) or iron(II)phthalocyanine (Fe(II)phthalocyanine, FePc), in a solvent such as acetonitrile or dichloromethane, as described in Angewandte Chemie International Edition 2018, 57 324-327.
Compounds of formula rac-III, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I above, may be obtained by means of an oxidation reaction of the corresponding sulfide compounds of formula II, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I, involving reagents such as, for example, m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, oxone, sodium periodate, sodium hypochlorite or tert-butyl hypochlorite amongst other oxidants. The oxidation reaction is generally conducted in the presence of a solvent. Examples of the solvent to be used in the reaction include aliphatic halogenated hydrocarbons such as dichloromethane and chloroform; alcohols such as methanol and ethanol; acetic acid; water; and mixtures thereof. The amount of the oxidant to be used in the reaction is preferably 1 to 1.2 moles, relative to 1 mole of the sulfide compounds II to produce the sulfoxide compounds rac-III.
Compounds of the formula rac-Ia may also serve for the preparation of compounds of formula rac-I as illustrated in scheme 4. Such compounds of the formula rac-Ia, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I above, and wherein R10 is cyano or —C(O)R25, in which R25 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6haloalkoxy,
may be prepared (scheme 4) by submitting compounds of formula rac-III, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I above, to imination reaction conditions using a reagent R10—NH2 (R10 as defined above), as described for example in H. Okamura, C. Bolm, Org. Lett. 2004, 6, 1305-1307; H. Okamura, C. Bolm, Chem. Lett. 2004, 33, 482-487; D. Leca, K. Song, M. Amatore, L. Fensterbank, E. Lacôte, M. Malacria, Chem. Eur. J. 2004, 10, 906-916; or M. Reggelin, C. Zur, Synthesis, 2000, 1-64. Typical imination reagents/conditions may include metal-catalyzed methods [see O. G. Mancheno, C. Bolm, Chem. Eur. J. 2007, 13, 6674-6681] such as R10—N3/FeCl2, R10—NH2/Fe(acac)3/Phl=0, Phl=N—R10/Fe(OTf)2, Phl=N—R10/CuOTf, Phl=N—R10/Cu(OTf)2, Phl=N—R10/CuPF6, Phl(OAc)2/R10—NH2/MgO/Rh2(OAc)4, R01NHOMs/FeCl2 or oxaziridines (e.g. 3-(4-cyano-phenyl)-oxaziridine-2-carboxylic acid tert-butyl ester).
Of particular interest are metal-free imination methods involving R10—NH2 and an oxidant, for example, Phl(OAc)2/R10—NH2 as described in G. Y. Cho, C. Bolm, Tetrahedron Lett. 2005, 46, 8007-8008; or N-bromosuccinimide (NBS)/R10—NH2 and a base such as sodium or potassium ter-butoxide as described in C. Bolm et al., Synthesis 2010, No 17, 2922-2925. Oxidants such as N-iodosuccinimide (NIS) or iodine may be also used alternatively as described, for example, in O. G. Mancheno, C. Bolm, Org. Lett. 2007, 9, 3809-3811. An example of hypochlorite salts being used as oxidant, such as sodium hypochlorite NaOCl or calcium hypochlorite Ca(OCl)2, was described in WO2008/1060.
A compound of the formula rac-Ia, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I above, and wherein R10 is CN, may be transformed into a compound of the formula rac-la wherein R10 is C(O)CF3, by treatment with trifluoroacetic anhydride in a solvent such as dichloromethane as described, for example, in O. G. Mancheno, C. Bolm, Org. Lett. 2007, 9, 3809-3811.
A compound of the formula rac-Ia, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I above, and wherein R10 is C(O)CF3, may be transformed into a compound of the formula rac-Ia (group R10 cleavage) by treatment with a base such as sodium or potassium carbonate in a polar protic solvent such as methanol or ethanol as described, for example, in H. Okamura, C. Bolm, Org. Lett. 2004, 6, 1305-1307.
Conversely, the order of the two oxidation/imination steps disclosed in scheme 4 to prepare compounds of the formula rac-Ia may be inverted as shown in scheme 5.
Oxidation of compounds of formula rac-IV, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I above, and in which R10 is as defined in scheme 4, to provide the compounds of formula rac-Ia (substituents as defined in scheme 4), may be achieved under conditions already described above or may alternatively involve, for example, KMnO4, NaMnO4, mCPBA, NalO4/RuO2, NalO4/RuCl3, H2O2, or oxone. In particular, the use of ruthenium salts in combination with alkali metal periodates and alternatively the use of alkali metal permanganates was described in WO2008/097235 and WO2008/106006.
Compounds of formula rac-IV, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I above, and in which R10 is cyano or —C(O)R25, in which R25 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6haloalkoxy, may be prepared by submitting compounds of formula II, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I, to imination reaction conditions, as described above in scheme 4.
The subgroup of compounds of formula II, wherein R8 is cyanoisopropoxy, more particularly 1-cyano-1-methyl-ethoxy, and wherein Q, R1, R2, G1, G2, X1, R3, R4, R9 and A are as defined in formula I above, may be defined as compounds of formula II-a (scheme 6). Such compounds II-a are either known or may be prepared by methods, or in analogy to methods, described for example in WO2020/084075, JP2019/081800, WO2018/206348 and WO2018/197315.
The subgroup of compounds of formula II, wherein R8 is cyanoisopropyl, more particularly 1-cyano-1-methyl-ethyl, and wherein Q, R1, R2, G1, G2, X1, R3, R4, R9 and A are as defined in formula I above, may be defined as compounds of formula II-b (scheme 6). Such compounds II-b are either known or may be prepared by methods, or in analogy to methods, described for example in WO2019/053182, WO2018/153778 and WO2018/077565.
The subgroup of compounds of formula II, wherein R8 is cyanocyclopropyl, more particularly 1-cyanocyclopropyl, and wherein Q, R1, R2, G1, G2, X1, R3, R4, R9 and A are as defined in formula I above, may be defined as compounds of formula II-c (scheme 6). Such compounds II-c are either known or may be prepared by methods, or in analogy to methods, described for example in WO2019/234158, WO2019/059244, WO2018/108726, WO2018/077565, WO2017/089190, WO2016/121997 and WO2016/071214.
Alternatively, individual enantiomers may be obtained by means of a stereoselective synthesis. Compounds of the formula I in form of an individual enantiomer, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I above, and wherein S* is a stereogenic sulfur atom in R- or S-configuration, in which said S* center is in either enantiomerically pure or in enantiomerically enriched form,
may be prepared (scheme 7) by adapting conditions already described in schemes 3 and 4. Compounds of formula III in form of an individual enantiomer, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I above, and wherein S* is a stereogenic sulfur atom in R- or S-configuration, in which said S* center is in either enantiomerically pure or in enantiomerically enriched form, may be obtained from compounds of the formula II (substituents as defined in schemes 3 and 4) by methods of stereoselective synthesis of chiral sulfinyl compounds, preferably in form of a catalytic enantioselective sulfoxide synthesis, by treatment with an oxidizing agent, for example H2O2 or tBuOOH, in the presence of a metal salt and a chiral ligand. Examples of appropriate metal salt and ligand combinations include Fe(acac)3, V(O)(acac)2 or Cu(acac)2 with a Schiff base formed from salicaldehyde derivatives and chiral amino-alcohols, or salen complexes or Ti(OiPr)4 in combination with a tartrate ester such as diisopropyl or diethyl tartrate. The reaction can be carried out in a solvent or mixture of solvents such as dichloromethane, toluene, chlorobenzene or methanol and optionally in the presence additives such as 4-methyoxybenzoic acid, benzoic acid, triethylamine, diisopropylethylamine or water. Examples of such reactions are described in Chemical Reviews 2020, 120, 4578-4611, Chemistry—A European Journal 2005, 11, 1086-1092, Angewandte Chemie (International Edition in English) 1996, 34, 2640-2642, Journal of Organic Chemistry 2012, 3288-3296 and Synlett 1996, 404-406. Alternatively, a chiral acid such as a binol derived chiral phosphoric acid can be uses as a catalyst in place of a metal complex and ligand as described in Journal of the American Chemical Society 2012, 134, 10765-10768.
Compounds of formula III in form of an individual enantiomer,
wherein
Compounds of the formula I in form of an individual enantiomer, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I above, and wherein S* is a stereogenic sulfur atom in R- or S-configuration, in which said S* center is in either enantiomerically pure or in enantiomerically enriched form, may be obtained from compounds of the formula III in form of an individual enantiomer, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I above, and wherein S* is a stereogenic sulfur atom in R- or S-configuration, in which said S* center is in either enantiomerically pure or in enantiomerically enriched form, by means of an imination step via stereospecific nitrogen transfer, either in the direct mode (conditions analogous as in scheme 3), or by involving a reagent of the formula R10—NH2 (R10 as defined above) and through the intermediacy of compounds of formula Ia, wherein Q, R1, R2, G1, G2, X1, R3, R4, R8, R9 and A are as defined in formula I above, and wherein S* is a stereogenic sulfur atom in R- or S-configuration, in which said S* center is in either enantiomerically pure or in enantiomerically enriched form (conditions analogous as in scheme 4).
In another aspect, the present invention provides a process for the preparation of compound of formula (I)
Related to a process for the preparation of compounds of formula (I) involving steps (A) and (B) above, the preferences and preferred embodiments of the substituents of the compounds of formula (I) described above are also valid for the compounds of formula (II) and (III).
In one particularly preferred embodiment, step (A) comprises oxidation of sulfanyl compounds of formula (II) listed in each step 1 of the Preparatory Examples P1 to P19.
In another particularly preferred embodiment, step (B) comprises reacting sulfinyl enantiomer compounds of formula III listed in Table P(SO) with an imination reagent.
Related to a process for the preparation of compounds of formula (III), step (A) above, examples of suitable and preferred oxidants, suitable and preferred metal catalysts, suitable and preferred chiral ligands, suitable and preferred additives, as well as examples of suitable and preferred reaction conditions (such as solvent (or diluent) and temperature), are given below.
In one embodiment, step (A) comprises
In another embodiment, step (A) comprises
Example of suitable and preferred oxidants for steps (A-1) and (A-2) are inorganic peroxides, such as hydrogen peroxide or organic peroxides, such as tert-butyl hydroperoxide. Preferably the oxidant is hydrogen peroxide or tert-butyl hydroperoxide, even more preferably hydrogen peroxide. The ratio of the oxidant used, compared to the sulfanyl compound of formula (II), is in the range from 8:1 to 0.8:1, preferably between 5:1 and 1:1, more preferably between 3:1 and 1:1.
Example of suitable and preferred metal catalysts for steps (A-1) and (A-2) are iron(III) acetylacetonate (Fe(acac)3) or vanadylacetylacetonat (vanadium(IV)-oxyacetylacetonat, VO(acac)2). Preferably the metal catalyst is iron(III) acetylacetonate. The amount of the metal salt used, compared to the sulfanyl compound of formula (II), is in the range from 0.01 to 10 mol %, preferably from 0.1 to 8 mol %, most preferably from 1 to 6 mol %.
Example of suitable and preferred chiral ligands for steps (A-1) and (A-2) are derived from N,N′-bis(salicylidene)ethylenediamine (salen ligand) or chosen from Schiff bases formed from salicaldehyde derivatives and chiral amino-alcohols. Preferably the chiral ligand is a Schiff base formed from salicaldehyde derivatives and chiral amino-alcohols represented by a compound of formula (R)-Xa or (S)-Xa,
wherein R10 and R11 are, independently of each other, chosen from C1-C4alkyl and halogen, and R12 is tert-butyl, isopropyl, optionally substituted phenyl or optionally substituted benzyl. More preferably the chiral ligand is a compound of formula (R)-Xb or (S)-Xb,
wherein R10 and R11 are, independently of each other, chosen from t-butyl, chloro, bromo and iodo; even more preferably chosen from chloro, bromo and iodo. Particularly preferred ia a chiral ligand compound of formula (R)-Xb or (S)-Xb, wherein R10 equals R11 and is chosen from chloro, bromo and iodo. The ratio of the chiral ligand (preferably a compound of formula (R)-Xb or (S)-Xb) used, compared to the metal catalyst (preferably iron(III) acetylacetonate), is in the range from 10:1 to 0.5:1, preferably 3:1 to 1:1, more preferably around 2:1.
Example of suitable and preferred additives for step (A-2) are carbocyclic acids. Preferably the additive is a benzoic acid, optionally mono-, di- or tri-substituted by methyl, ethyl, isopropyl, methoxy or dimethylamino, optionally in form of a lithium, sodium or potassium salt. More preferably the additive is a methoxybenzoic acid (optionally in form of a lithium, sodium or potassium salt), even more preferably 4-methoxybenzoic acid. The amount of the additive used, compared to the sulfanyl compound of formula (II), is in the range from 0.01 to 10 mol %, preferably from 0.1 to 8 mol %, most preferably from 1 to 5 mol %.
In one embodiment related to the process according to the invention of making compounds of formula (III), step (A), examples of appropriate solvents (or diluents) are aliphatic halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, or aromatic hydrocarbons, halohydrocarbons or alkoxyhydrocarbons such as toluene, xylene, chlorobenzene, methoxybenzene or benzotrifluoride, or mixtures thereof. Preferably the solvent (or diluent) is toluene or chlorobenzene, even more preferably toluene.
In one embodiment related to the process according to the invention of making compounds of formula (III), step (A), the reaction is advantageously carried out in a temperature range from approximately −20° C. to approximately 50° C., preferably from approximately −5° C. to approximately 30° C. In a preferred embodiment, the reaction is carried out in the range between 0° C. and 25° C.
Related to a process for the preparation of compounds of formula (I), step (B) above, examples of suitable and preferred imination reagents, examples of suitable and preferred catalysts, suitable and preferred additives, as well as examples of suitable and preferred reaction conditions (such as solvent (or diluent) and temperature), are given below.
In one embodiment, step (B) comprises
Example of suitable and preferred imination reagents for step (B-1) are O-mesitylenesulfonyl-hydroxylamine (MSH) or hydroxylamine derivatives. Preferably the imination reagent is a hydroxylamine derivative, more preferably an O-acylated hydroxylamine salt represented by a compound of formula (XX),
wherein R2O is tert-butyl, or phenyl mono- or di-substituted by nitro, and X− is a sulfonate or hydrogenosulfate group. More preferably the imination reagent is a compound of formula (XX), wherein R2O is 4-nitrophenyl or 2,4-dinitrophenyl, and X—is a sulfonate group. Even more preferably the imination reagent compound of formula (XX) is chosen from O-(4-nitrobenzoyl)-hydroxylammonium trifluoromethanesulfonate and O-(4-nitrobenzoyl)-hydroxylammonium methanesulfonate. Particularly preferred as imination reagent compound of formula (XX) is O-(4-nitrobenzoyl)-hydroxylammonium trifluoromethanesulfonate. The ratio of the imination reagent used, compared to the sulfinyl compound of formula (III), is in the range from 8:1 to 0.8:1, preferably between 5:1 and 1:1, more preferably between 3:1 and 1:1.
Example of suitable and preferred catalysts for steps (B-1) are iron(II) sulfate (FeSO4), iron(II) acetate (Fe(OAc)2) or iron(II) acetylacetonate (Fe(acac)2) each in combination with either 2,2′-bipyridine or 1,10-phenanthroline, or iron(II)phthalocyanine (Fe(II)phthalocyanine, FePc). Preferably the metal catalyst is iron(II)phthalocyanine. The amount of the catalyst used, compared to the sulfinyl compound of formula (III), is in the range from 0.01 to 10 mol %, preferably from 0.1 to 8 mol %, most preferably from 1 to 5 mol %.
In one embodiment related to the process according to the invention of making compounds of formula (I), step (B), examples of appropriate solvents (or diluents) are acetonitrile, methanol, ethanol, isopropanol, 2,2,2-trifluoroethanol (TFE), hexafluoroisopropanol (HFIP), dichloromethane (DCM), toluene, ethyl acetate, acetic acid, water, or mixtures thereof. Preferably the solvent (or diluent) is acetonitrile, acetic acid or dichloromethane, even more preferably dichloromethane.
In one embodiment related to the process according to the invention of making compounds of formula (I), step (B), the reaction is advantageously carried out in a temperature range from approximately −20° C. to approximately 50° C., preferably from approximately −5° C. to approximately 30° C. In a preferred embodiment, the reaction is carried out in the range between 10° C. and 25° C.
Products obtained by the process according to the invention wherein S* is a stereogenic sulfur atom in R- or S-configuration, in which said S* center is in enantiomerically enriched form have an enantiomer ratio (R:S or S:R, as the case may be) of 50.5:49.5 to 99.5:0.5, preferably of 75:25 to 99:1, more preferably of 85:15 to 98:2.
In one embodiment, the sulfinyl compounds of formula (III) obtained by step (A) of the process according to the invention wherein S* is a stereogenic sulfur atom in R- or S-configuration, in which said S* center is in enantiomerically enriched form have an enantiomer ratio (R:S or S:R, as the case may be) of 50.5:49.5 to 99.5:0.5, preferably of 75:25 to 99:1, more preferably of 85:15 to 98:2.
In another embodiment, the sulfoximine compounds of formula (I) obtained by step (B) of the process according to the invention wherein S* is a stereogenic sulfur atom in R- or S-configuration, in which said S* center is in enantiomerically enriched form have an enantiomer ratio (R:S or S:R, as the case may be) of 50.5:49.5 to 99.5:0.5, preferably of 75:25 to 99:1, more preferably of 85:15 to 98:2.
In a further embodiment, the enantiomer ratio (R:S or S:R, as the case may be) of such sulfinyl compounds of formula (III) obtained by step (A) and the enantiomer ratio (R:S or S:R, as the case may be) of such sulfoximine compounds of formula (I) obtained by step (B) are substantially the same. In one embodiment, the enantiomer ratio of the sulfinyl compounds of formula (III) obtained by step (A) and the enantiomer ratio of sulfoximine compounds of formula (I) obtained by step (B) are within (±) plus or minus one percent of each other; preferably are within (±) plus or minus 0.5 percent of each other; more preferably are within (±) plus or minus 0.1 percent of each other.
Optionally, the enantiomeric purity of such products, the sulfinyl compounds of formula (III) and/or the sulfoximine compounds of formula (I) can be increased by a crystallization process known to those skilled in the art, preferably via crystallization from an organic solvent or a mixture of an organic solvent and water.
Methods for determining the enantiomeric excess are known to those skilled in the art and include for example the use of HPLC on chiral stationary phases and NMR with chiral shift reagents.
The reactants can be reacted in the presence of a base. Examples of suitable bases are alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal hydrides, alkali metal or alkaline earth metal amides, alkali metal or alkaline earth metal alkoxides, alkali metal or alkaline earth metal acetates, alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal dialkylamides or alkali metal or alkaline earth metal alkylsilylamides, alkylamines, alkylenediamines, free or N-alkylated saturated or unsaturated cycloalkylamines, basic heterocycles, ammonium hydroxides and carbocyclic amines. Examples which may be mentioned are sodium hydroxide, sodium hydride, sodium amide, sodium methoxide, sodium acetate, sodium carbonate, potassium tert-butoxide, potassium hydroxide, potassium carbonate, potassium hydride, lithium diisopropylamide, potassium bis(trimethylsilyl)amide, calcium hydride, triethylamine, diisopropylethylamine, triethylenediamine, cyclohexylamine, N-cyclohexyl-N,N-dimethylamine, N,N-diethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, quinuclidine, N-methylmorpholine, benzyltrimethylammonium hydroxide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
The reactants can be reacted with each other as such, i.e. without adding a solvent or diluent. In most cases, however, it is advantageous to add an inert solvent or diluent or a mixture of these. If the reaction is carried out in the presence of a base, bases which are employed in excess, such as triethylamine, pyridine, N-methylmorpholine or N,N-diethylaniline, may also act as solvents or diluents.
The reaction is advantageously carried out in a temperature range from approximately −80° C. to approximately +140° C., preferably from approximately −30° C. to approximately +100° C., in many cases in the range between ambient temperature and approximately +80° C.
A compound of formula I can be converted in a manner known per se into another compound of formula I by replacing one or more substituents of the starting compound of formula I in the customary manner by (an)other substituent(s) according to the invention, and by post modification of compounds of with reactions such as oxidation, alkylation, reduction, acylation and other methods known by those skilled in the art.
Depending on the choice of the reaction conditions and starting materials which are suitable in each case, it is possible, for example, in one reaction step only to replace one substituent by another substituent according to the invention, or a plurality of substituents can be replaced by other substituents according to the invention in the same reaction step.
Salts of compounds of formula I can be prepared in a manner known per se. Thus, for example, acid addition salts of compounds of formula I are obtained by treatment with a suitable acid or a suitable ion exchanger reagent and salts with bases are obtained by treatment with a suitable base or with a suitable ion exchanger reagent.
Salts of compounds of formula I can be converted in the customary manner into the free compounds I, acid addition salts, for example, by treatment with a suitable basic compound or with a suitable ion exchanger reagent and salts with bases, for example, by treatment with a suitable acid or with a suitable ion exchanger reagent.
Salts of compounds of formula I can be converted in a manner known per se into other salts of compounds of formula I, acid addition salts, for example, into other acid addition salts, for example by treatment of a salt of inorganic acid such as hydrochloride with a suitable metal salt such as a sodium, barium or silver salt, of an acid, for example with silver acetate, in a suitable solvent in which an inorganic salt which forms, for example silver chloride, is insoluble and thus precipitates from the reaction mixture.
Depending on the procedure or the reaction conditions, the compounds of formula I, which have salt-forming properties can be obtained in free form or in the form of salts.
The compounds of formula I and, where appropriate, the tautomers thereof, in each case in free form or in salt form, can be present in the form of one of the isomers which are possible or as a mixture of these, for example in the form of pure isomers, such as antipodes and/or diastereomers, or as isomer mixtures, such as enantiomer mixtures, for example racemates, diastereomer mixtures or racemate mixtures, depending on the number, absolute and relative configuration of asymmetric carbon atoms which occur in the molecule and/or depending on the configuration of non-aromatic double bonds which occur in the molecule; the invention relates to the pure isomers and also to all isomer mixtures which are possible and is to be understood in each case in this sense hereinabove and hereinbelow, even when stereochemical details are not mentioned specifically in each case.
Diastereomer mixtures or racemate mixtures of compounds of formula I, in free form or in salt form, which can be obtained depending on which starting materials and procedures have been chosen can be separated in a known manner into the pure diasteromers or racemates on the basis of the physicochemical differences of the components, for example by fractional crystallization, distillation and/or chromatography.
Enantiomer mixtures, such as racemates, which can be obtained in a similar manner can be resolved into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, by chromatography on chiral adsorbents, for example high-performance liquid chromatography (HPLC) on acetyl celulose, with the aid of suitable microorganisms, by cleavage with specific, immobilized enzymes, via the formation of inclusion compounds, for example using chiral crown ethers, where only one enantiomer is complexed, or by conversion into diastereomeric salts, for example by reacting a basic end-product racemate with an optically active acid, such as a carboxylic acid, for example camphor, tartaric or malic acid, or sulfonic acid, for example camphorsulfonic acid, and separating the diastereomer mixture which can be obtained in this manner, for example by fractional crystallization based on their differing solubilities, to give the diastereomers, from which the desired enantiomer can be set free by the action of suitable agents, for example basic agents.
Pure diastereomers or enantiomers can be obtained according to the invention not only by separating suitable isomer mixtures, but also by generally known methods of diastereoselective or enantioselective synthesis, for example by carrying out the process according to the invention with starting materials of a suitable stereochemistry.
Several ways of absolute configuration determination of chiral compounds are known and include many spectroscopic and diffraction methods. Amongst them for example, derivatization with a chiral reagent and analysis by chromatographic techniques, NMR with chiral shift reagents, optical rotatory dispersion, circular dichroism, chemical correlation, and X-ray crystallography, in particular single-crystal X-ray diffraction (XRD).
N-oxides can be prepared by reacting a compound of the formula I with a suitable oxidizing agent, for example the H2O2/urea adduct in the presence of an acid anhydride, e.g. trifluoroacetic anhydride. Such oxidations are known from the literature, for example from J. Med. Chem., 32 (12), 2561-73, 1989 or WO 00/15615.
Compounds wherein R2 is C1-C4haloalkylsulfinyl or C1-C4haloalkylsulfonyl may be prepared from the corresponding compounds wherein R2 is C1-C4haloalkylsulfanyl with suitable oxidation methods described, for example, in WO 19/008115.
It is advantageous to isolate or synthesize in each case the biologically more effective isomer, for example enantiomer or diastereomer, or isomer mixture, for example enantiomer mixture or diastereomer mixture, if the individual components have a different biological activity.
The compounds of formula I and, where appropriate, the tautomers thereof, in each case in free form or in salt form, can, if appropriate, also be obtained in the form of hydrates and/or include other solvents, for example those which may have been used for the crystallization of compounds which are present in solid form.
The compounds of formula I according to the following Tables X, A-1 to A-20 and B-1 to B-20 below can be prepared according to the methods described above. The examples which follow are intended to illustrate the invention and show preferred compounds of formula I.
The Tables A-1 to A-20 below illustrate specific compounds of the invention wherein the stereogenic sulfur atom is in the R-configuration.
Table A-1 provides 12 compounds A-1.001 to A-1.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q1 as
For example, compound A-1.004 has the following structure:
wherein (R) denotes the R-configuration at the stereogenic sulfur center.
Table A-2 provides 12 compounds A-2.001 to A-2.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q1 as
Table A-3 provides 12 compounds A-3.001 to A-3.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q1 as
Table A-4 provides 12 compounds A-4.001 to A-4.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q2 as
Table A-5 provides 12 compounds A-5.001 to A-5.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q2 as
Table A-6 provides 12 compounds A-6.001 to A-6.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q3 as
Table A-7 provides 12 compounds A-7.001 to A-7.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q1 as
Table A-8 provides 12 compounds A-8.001 to A-8.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q1 as
Table A-9 provides 12 compounds A-9.001 to A-9.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q4 as
Table A-10 provides 12 compounds A-10.001 to A-10.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q4 as
Table A-11 provides 12 compounds A-11.001 to A-11.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q5 as
Table A-12 provides 12 compounds A-12.001 to A-12.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q5 as
Table A-13 provides 12 compounds A-13.001 to A-13.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q5 as
Table A-14 provides 12 compounds A-14.001 to A-14.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q2 as
Table A-15 provides 12 compounds A-15.001 to A-15.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q2 as
Table A-16 provides 12 compounds A-16.001 to A-16.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q2 as
Table A-17 provides 12 compounds A-17.001 to A-17.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q2 as
Table A-18 provides 12 compounds A-18.001 to A-18.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q1 as
Table A-19 provides 12 compounds A-19.001 to A-19.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q1 as
Table A-20 provides 12 compounds A-20.001 to A-20.012 of formula (I-R) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q5 as
The Tables B-1 to B-20 below further illustrate specific compounds of the invention wherein the stereogenic sulfur atom is in the S-configuration.
Table B-1 provides 12 compounds B-1.001 to B-1.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q1 as
For example, compound B-17.005 has the following structure:
wherein (S) denotes the S-configuration at the stereogenic sulfur center.
Table B-2 provides 12 compounds B-2.001 to B-2.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q1 as
Table B-3 provides 12 compounds B-3.001 to B-3.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q1 as
Table B-4 provides 12 compounds B-4.001 to B-4.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q2 as
Table B-5 provides 12 compounds B-5.001 to B-5.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q2 as
Table B-6 provides 12 compounds B-6.001 to B-6.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q3 as
Table B-7 provides 12 compounds B-7.001 to B-7.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q1 as
Table B-8 provides 12 compounds B-8.001 to B-8.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q1 as
Table B-9 provides 12 compounds B-9.001 to B-9.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q4 as
Table B-10 provides 12 compounds B-10.001 to B-10.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q4 as
Table B-11 provides 12 compounds B-11.001 to B-11.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q5 as
Table B-12 provides 12 compounds B-12.001 to B-12.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q5 as
Table B-13 provides 12 compounds B-13.001 to B-13.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q5 as
Table B-14 provides 12 compounds B-14.001 to B-14.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q2 as
Table B-15 provides 12 compounds B-15.001 to B-15.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q2 as
Table B-16 provides 12 compounds B-16.001 to B-16.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q2 as
Table B-17 provides 12 compounds B-17.001 to B-17.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q2 as
Table B-18 provides 12 compounds B-18.001 to B-18.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q1 as
Table B-19 provides 12 compounds B-19.001 to B-19.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q1 as
Table B-20 provides 12 compounds B-20.001 to B-20.012 of formula (I-S) wherein R1 is ethyl, and A, R8 and R9 are as defined in Table X, and Q is taken from the group of formula Q5 as
The compounds of formula I according to the invention are preventively and/or curatively valuable active ingredients in the field of pest control, even at low rates of application, which have a very favorable biocidal spectrum and are well tolerated by warm-blooded species, fish and plants. The active ingredients according to the invention act against all or individual developmental stages of normally sensitive, but also resistant, animal pests, such as insects or representatives of the order Acarina, nematodes or molluscs. The insecticidal, nematicidal, molluscicidal or acaricidal activity of the active ingredients according to the invention can manifest itself directly, i.e. in mortality or destruction of the pests, which takes place either immediately or only after some time has elapsed, for example during ecdysis, or indirectly, for example in a reduced oviposition and/or hatching rate, anti-feedant effect, and/or growth inhibition.
Compounds of formula (I) according to the invention may possess any number of benefits including, inter alia, advantageous levels of biological activity for protecting plants against insects or superior properties for use as agrochemical active ingredients (for example, greater biological activity, differential biological activity of enantiomer or enantiomerically enriched composition and racemate, differential biological activity of (R) enantiomer or (R) enantiomerically enriched composition and (S) enantiomer or (S) enantiomerically enriched composition, an advantageous spectrum of activity, an increased safety profile, improved physico-chemical properties, or increased biodegradability or environmental profile). In particular, it has been surprisingly found that certain compounds of formula (I) show an advantageous safety profile with respect to non-target organisms, for example, non-target arthropods, in particular pollinators such as honey bees, solitary bees, and bumble bees. Most particularly, Apis mellifera.
In this regard, certain compounds of formula (I) of the invention can be distinguished from known compounds by virtue of greater efficacy at low application rates, which can be verified by the person skilled in the art using experimental procedures similar to or adapted from those outlined in the biological examples, using lower application rates if necessary, for example 50 ppm, 12.5 ppm, 6 ppm, 3 ppm, 1.5 ppm, 0.8 ppm or 0.2 ppm.
Further it has surprisingly found that that compounds of formula (I) of the invention show advantageous physico-chemical properties for application in crop protection, in particular reduced melting point, reduced lipophilicity and increased water solubility. Such properties have been found to be advantageous for plant uptake and systemic distribution, see for example A. Buchholz, S. Trapp, Pest Manag Sci 2016; 72: 929-939) in order to control certain pest species named below.
Putative metabolites of the compounds of the formula I which may be formed in the practice of the invention in conjunction with one or more of the methods, pests, crops and/or targets described below include the amide compounds of formula I-M1, I-M2, I-M3 and the acid compounds of formula I-M4, I-M5, I-M6, each corresponding to a parent nitrile compound of formula I:
wherein Q, R1, R2, R3, R4, R9, X1, G1, G2, S* and A are as defined under formula I above, or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof. Among the specific putative metabolites there may be mentioned: (1) an amide compound of formula I-M1, I-M2, or I-M3 that corresponds to a parent nitrile selected from the group consisting of the compounds described in Tables A-1 through A-20, Tables B-1 through B-20, Table Y, Table Z and Table P(E); and (2) an acid compound of formula I-M4, I-M5, or I-M6 that corresponds to a parent nitrile selected from the group consisting of the compounds described in Tables A-1 through A-20, Tables B-1 through B-20, Table Y, Table Z and Table P(E).
Examples of the abovementioned animal pests are:
The active ingredients according to the invention can be used for controlling, i.e. containing or destroying, pests of the abovementioned type which occur in particular on plants, especially on useful plants and ornamentals in agriculture, in horticulture and in forests, or on organs, such as fruits, flowers, foliage, stalks, tubers or roots, of such plants, and in some cases even plant organs which are formed at a later point in time remain protected against these pests.
Suitable target crops are, in particular, cereals, such as wheat, barley, rye, oats, rice, maize or sorghum; beet, such as sugar or fodder beet; fruit, for example pomaceous fruit, stone fruit or soft fruit, such as apples, pears, plums, peaches, almonds, cherries or berries, for example strawberries, raspberries or blackberries; leguminous crops, such as beans, lentils, peas or soya; oil crops, such as oilseed rape, mustard, poppies, olives, sunflowers, coconut, castor, cocoa or ground nuts; cucurbits, such as pumpkins, cucumbers or melons; fibre plants, such as cotton, flax, hemp orjute; citrus fruit, such as oranges, lemons, grapefruit or tangerines; vegetables, such as spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, potatoes or bell peppers; Lauraceae, such as avocado, Cinnamonium or camphor; and also tobacco, nuts, coffee, eggplants, sugarcane, tea, pepper, grapevines, hops, the plantain family and latex plants.
The compositions and/or methods of the present invention may be also used on any ornamental and/or vegetable crops, including flowers, shrubs, broad-leaved trees and evergreens.
For example the invention may be used on any of the following ornamental species: Ageratum spp., Alonsoa spp., Anemone spp., Anisodontea capsenisis, Anthemis spp., Antirrhinum spp., Aster spp., Begonia spp. (e.g. B. elatior, B. semperflorens, B. tubereux), Bougainvillea spp., Brachycome spp., Brassica spp. (ornamental), Calceolaria spp., Capsicum annuum, Catharanthus roseus, Canna spp., Centaurea spp., Chrysanthemum spp., Cineraria spp. (C. maritime), Coreopsis spp., Crassula coccinea, Cuphea ignea, Dahlia spp., Delphinium spp., Dicentra spectabilis, Dorotheantus spp., Eustoma grandiflorum, Forsythia spp., Fuchsia spp., Geranium gnaphalium, Gerbera spp., Gomphrena globosa, Heliotropium spp., Helianthus spp., Hibiscus spp., Hortensia spp., Hydrangea spp., Hypoestes phyllostachya, Impatiens spp. (I. Walleriana), Iresines spp., Kalanchoe spp., Lantana camara, Lavatera trimestris, Leonotis leonurus, Lilium spp., Mesembryanthemum spp., Mimulus spp., Monarda spp., Nemesia spp., Tagetes spp., Dianthus spp. (carnation), Canna spp., Oxalis spp., Bellis spp., Pelargonium spp. (P. peltatum, P. Zonale), Viola spp. (pansy), Petunia spp., Phlox spp., Plecthranthus spp., Poinsettia spp., Parthenocissus spp. (P. quinquefolia, P. tricuspidata), Primula spp., Ranunculus spp., Rhododendron spp., Rosa spp. (rose), Rudbeckia spp., Saintpaulia spp., Salvia spp., Scaevola aemola, Schizanthus wisetonensis, Sedum spp., Solanum spp., Surfinia spp., Tagetes spp., Nicotinia spp., Verbena spp., Zinnia spp. and other bedding plants.
For example the invention may be used on any of the following vegetable species: Allium spp. (A. sativum, A. cepa, A. oschaninii, A. Porrum, A. ascalonicum, A. fistulosum), Anthriscus cerefolium, Apium graveolus, Asparagus officinalis, Beta vulgarus, Brassica spp. (B. Oleracea, B. Pekinensis, B. rapa), Capsicum annuum, Cicer arietinum, Cichorium endivia, Cichorum spp. (C. intybus, C. endivia), Citrillus lanatus, Cucumis spp. (C. sativus, C. melo), Cucurbita spp. (C. pepo, C. maxima), Cyanara spp. (C. scolymus, C. cardunculus), Daucus carota, Foeniculum vulgare, Hypericum spp., Lactuca sativa, Lycopersicon spp. (L. esculentum, L. lycopersicum), Mentha spp., Ocimum basilicum, Petroselinum crispum, Phaseolus spp. (P. vulgaris, P. coccineus), Pisum sativum, Raphanus sativus, Rheum rhaponticum, Rosemarinus spp., Salvia spp., Scorzonera hispanica, Solanum melongena, Spinacea oleracea, Valerianella spp. (V. locusta, V. eriocarpa) and Vicia faba.
Preferred ornamental species include African violet, Begonia, Dahlia, Gerbera, Hydrangea, Verbena, Rosa, Kalanchoe, Poinsettia, Aster, Centaurea, Coreopsis, Delphinium, Monarda, Phlox, Rudbeckia, Sedum, Petunia, Viola, Impatiens, Geranium, Chrysanthemum, Ranunculus, Fuchsia, Salvia, Hortensia, rosemary, sage, St. Johnswort, mint, sweet pepper, tomato and cucumber.
The active ingredients according to the invention are especially suitable for controlling Aphis craccivora, Diabrotica balteata, Heliothis virescens, Myzus persicae, Plutella xylostella and Spodoptera littoralis in cotton, vegetable, maize, rice and soya crops. The active ingredients according to the invention are further especially suitable for controlling Mamestra (preferably in vegetables), Cydia pomonella (preferably in apples), Empoasca (preferably in vegetables, vineyards), Leptinotarsa (preferably in potatos) and Chilo supressalis (preferably in rice).
The active ingredients according to the invention are especially suitable for controlling Aphis craccivora, Diabrotica balteata, Heliothis virescens, Myzus persicae, Plutella xylostella and Spodoptera littoralis in cotton, vegetable, maize, rice and soya crops. The active ingredients according to the invention are further especially suitable for controlling Mamestra (preferably in vegetables), Cydia pomonella (preferably in apples), Empoasca (preferably in vegetables, vineyards), Leptinotarsa (preferably in potatos) and Chilo supressalis (preferably in rice).
In a further aspect, the invention may also relate to a method of controlling damage to plant and parts thereof by plant parasitic nematodes (Endoparasitic-, Semiendoparasitic- and Ectoparasitic nematodes), especially plant parasitic nematodes such as root knot nematodes, Meloidogyne hapla, Meloidogyne incognita, Meloidogyne javanica, Meloidogyne arenaria and other Meloidogyne species; cyst-forming nematodes, Globodera rostochiensis and other Globodera species; Heterodera avenae, Heterodera glycines, Heterodera schachtii, Heterodera trifolii, and other Heterodera species; Seed gall nematodes, Anguina species; Stem and foliar nematodes, Aphelenchoides species; Sting nematodes, Belonolaimus longicaudatus and other Belonolaimus species; Pine nematodes, Bursaphelenchus xylophilus and other Bursaphelenchus species; Ring nematodes, Criconema species, Criconemella species, Criconemoides species, Mesocriconema species; Stem and bulb nematodes, Ditylenchus destructor, Ditylenchus dipsaci and other Ditylenchus species; Awl nematodes, Dolichodorus species; Spiral nematodes, Heliocotylenchus multicinctus and other Helicotylenchus species; Sheath and sheathoid nematodes, Hemicycliophora species and Hemicriconemoides species; Hirshmanniella species; Lance nematodes, Hoploaimus species; false rootknot nematodes, Nacobbus species; Needle nematodes, Longidorus elongatus and other Longidorus species; Pin nematodes, Pratylenchus species; Lesion nematodes, Pratylenchus neglectus, Pratylenchus penetrans, Pratylenchus curvitatus, Pratylenchus goodeyi and other Pratylenchus species; Burrowing nematodes, Radopholus similis and other Radopholus species; Reniform nematodes, Rotylenchus robustus, Rotylenchus reniformis and other Rotylenchus species; Scutellonema species; Stubby root nematodes, Trichodorus primitivus and other Trichodorus species, Paratrichodorus species; Stunt nematodes, Tylenchorhynchus claytoni, Tylenchorhynchus dubius and other Tylenchorhynchus species; Citrus nematodes, Tylenchulus species; Dagger nematodes, Xiphinema species; and other plant parasitic nematode species, such as Subanguina spp., Hypsoperine spp., Macroposthonia spp., Melinius spp., Punctodera spp., and Quinisulcius spp.
The compounds of the invention may also have activity against the molluscs. Examples of which include, for example, Ampullariidae; Arion (A. ater, A. circumscriptus, A. hortensis, A. rufus); Bradybaenidae (Bradybaena fruticum); Cepaea (C. hortensis, C. Nemoralis); ochlodina; Deroceras (D. agrestis, D. empiricorum, D. laeve, D. reticulatum); Discus (D. rotundatus); Euomphalia; Galba (G. trunculata); Helicelia (H. itala, H. obvia); Helicidae Helicigona arbustorum); Helicodiscus; Helix (H. aperta); Limax (L. cinereoniger, L. flavus, L. marginatus, L. maximus, L. tenellus); Lymnaea; Milax (M. gagates, M. marginatus, M. sowerbyi); Opeas; Pomacea (P. canaticulata); Vallonia and Zanitoides.
The term “crops” is to be understood as including also crop plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising one or more selectively acting toxins, such as are known, for example, from toxin-producing bacteria, especially those of the genus Bacillus.
Toxins that can be expressed by such transgenic plants include, for example, insecticidal proteins, for example insecticidal proteins from Bacillus cereus or Bacillus popilliae; or insecticidal proteins from Bacillus thuringiensis, such as 6-endotoxins, e.g. Cry1Ab, Cry1Ac, Cry1F, Cry1 Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), e.g. Vip1, Vip2, Vip3 or Vip3A; or insecticidal proteins of bacteria colonising nematodes, for example Photorhabdus spp. or Xenorhabdus spp., such as Photorhabdus luminescens, Xenorhabdus nematophilus; toxins produced by animals, such as scorpion toxins, arachnid toxins, wasp toxins and other insect-specific neurotoxins; toxins produced by fungi, such as Streptomycetes toxins, plant lectins, such as pea lectins, barley lectins or snowdrop lectins; agglutinins; proteinase inhibitors, such as trypsin inhibitors, serine protease inhibitors, patatin, cystatin, papain inhibitors; ribosome-inactivating proteins (RIP), such as ricin, maize-RIP, abrin, luffin, saporin or bryodin; steroid metabolism enzymes, such as 3-hydroxysteroidoxidase, ecdysteroid-UDP-glycosyl-transferase, cholesterol oxidases, ecdysone inhibitors, HMG-COA-reductase, ion channel blockers, such as blockers of sodium or calcium channels, juvenile hormone esterase, diuretic hormone receptors, stilbene synthase, bibenzyl synthase, chitinases and glucanases.
In the context of the present invention there are to be understood by 6-endotoxins, for example Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), for example Vip1, Vip2, Vip3 or Vip3A, expressly also hybrid toxins, truncated toxins and modified toxins. Hybrid toxins are produced recombinantly by a new combination of different domains of those proteins (see, for example, WO 02/15701). Truncated toxins, for example a truncated Cry1Ab, are known. In the case of modified toxins, one or more amino acids of the naturally occurring toxin are replaced. In such amino acid replacements, preferably non-naturally present protease recognition sequences are inserted into the toxin, such as, for example, in the case of Cry3A055, a cathepsin-G-recognition sequence is inserted into a Cry3A toxin (see WO 03/018810). Examples of such toxins or transgenic plants capable of synthesising such toxins are disclosed, for example, in EP-A-0 374 753, WO 93/07278, WO 95/34656, EP-A-0 427 529, EP-A-451 878 and WO 03/052073.
The processes for the preparation of such transgenic plants are generally known to the person skilled in the art and are described, for example, in the publications mentioned above. Cry1-type deoxyribonucleic acids and their preparation are known, for example, from WO 95/34656, EP-A-0 367 474, EP-A-0 401 979 and WO 90/13651.
The toxin contained in the transgenic plants imparts to the plants tolerance to harmful insects. Such insects can occur in any taxonomic group of insects, but are especially commonly found in the beetles (Coleoptera), two-winged insects (Diptera) and moths (Lepidoptera).
Transgenic plants containing one or more genes that code for an insecticidal resistance and express one or more toxins are known and some of them are commercially available. Examples of such plants are: YieldGard® (maize variety that expresses a Cry1Ab toxin); YieldGard Rootworm® (maize variety that expresses a Cry3Bb1 toxin); YieldGard Plus® (maize variety that expresses a Cry1Ab and a Cry3Bb1 toxin); Starlink® (maize variety that expresses a Cry9C toxin); Herculex I® (maize variety that expresses a Cry1Fa2 toxin and the enzyme phosphinothricine N-acetyltransferase (PAT) to achieve tolerance to the herbicide glufosinate ammonium); NuCOTN 33B® (cotton variety that expresses a Cry1Ac toxin); Bollgard I® (cotton variety that expresses a Cry1Ac toxin); Bollgard II® (cotton variety that expresses a Cry1Ac and a Cry2Ab toxin); VipCot® (cotton variety that expresses a Vip3A and a Cry1Ab toxin); NewLeaf® (potato variety that expresses a Cry3A toxin); NatureGard®, Agrisure® GT Advantage (GA21 glyphosate-tolerant trait), Agrisure® CB Advantage (Bt11 corn borer (CB) trait) and Protecta®.
Further examples of such transgenic crops are:
Transgenic crops of insect-resistant plants are also described in BATS (Zentrum für Biosicherheit und Nachhaltigkeit, Zentrum BATS, Clarastrasse 13, 4058 Basel, Switzerland) Report 2003, (http://bats.ch).
The term “crops” is to be understood as including also crop plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising antipathogenic substances having a selective action, such as, for example, the so-called “pathogenesis-related proteins” (PRPs, see e.g. EP-A-0 392 225). Examples of such antipathogenic substances and transgenic plants capable of synthesising such antipathogenic substances are known, for example, from EP-A-0 392 225, WO 95/33818 and EP-A-0 353 191. The methods of producing such transgenic plants are generally known to the person skilled in the art and are described, for example, in the publications mentioned above.
Crops may also be modified for enhanced resistance to fungal (for example Fusarium, Anthracnose, or Phytophthora), bacterial (for example Pseudomonas) or viral (for example potato leafroll virus, tomato spotted wilt virus, cucumber mosaic virus) pathogens.
Crops also include those that have enhanced resistance to nematodes, such as the soybean cyst nematode.
Crops that are tolerance to abiotic stress include those that have enhanced tolerance to drought, high salt, high temperature, chill, frost, or light radiation, for example through expression of NF—YB or other proteins known in the art.
Antipathogenic substances which can be expressed by such transgenic plants include, for example, ion channel blockers, such as blockers for sodium and calcium channels, for example the viral KP1, KP4 or KP6 toxins; stilbene synthases; bibenzyl synthases; chitinases; glucanases; the so-called “pathogenesis-related proteins” (PRPs; see e.g. EP-A-0 392 225); antipathogenic substances produced by microorganisms, for example peptide antibiotics or heterocyclic antibiotics (see e.g. WO 95/33818) or protein or polypeptide factors involved in plant pathogen defence (so-called “plant disease resistance genes”, as described in WO 03/000906).
Further areas of use of the compositions according to the invention are the protection of stored goods and store rooms and the protection of raw materials, such as wood, textiles, floor coverings or buildings, and also in the hygiene sector, especially the protection of humans, domestic animals and productive livestock against pests of the mentioned type.
The present invention also provides a method for controlling pests (such as mosquitoes and other disease vectors; see also http://www.who.int/malaria/vector_control/irs/en/). In one embodiment, the method for controlling pests comprises applying the compositions of the invention to the target pests, to their locus or to a surface or substrate by brushing, rolling, spraying, spreading or dipping. By way of example, an IRS (indoor residual spraying) application of a surface such as a wall, ceiling or floor surface is contemplated by the method of the invention. In another embodiment, it is contemplated to apply such compositions to a substrate such as non-woven or a fabric material in the form of (or which can be used in the manufacture of) netting, clothing, bedding, curtains and tents.
In one embodiment, the method for controlling such pests comprises applying a pesticidally effective amount of the compositions of the invention to the target pests, to their locus, or to a surface or substrate so as to provide effective residual pesticidal activity on the surface or substrate. Such application may be made by brushing, rolling, spraying, spreading or dipping the pesticidal composition of the invention. By way of example, an IRS application of a surface such as a wall, ceiling or floor surface is contemplated by the method of the invention so as to provide effective residual pesticidal activity on the surface. In another embodiment, it is contemplated to apply such compositions for residual control of pests on a substrate such as a fabric material in the form of (or which can be used in the manufacture of) netting, clothing, bedding, curtains and tents.
Substrates including non-woven, fabrics or netting to be treated may be made of natural fibres such as cotton, raffia, jute, flax, sisal, hessian, or wool, or synthetic fibres such as polyamide, polyester, polypropylene, polyacrylonitrile or the like. The polyesters are particularly suitable. The methods of textile treatment are known, e.g. WO 2008/151984, WO 2003/034823, U.S. Pat. No. 5,631,072, WO 2005/64072, WO2006/128870, EP 1724392, WO 2005113886 or WO 2007/090739.
Further areas of use of the compositions according to the invention are the field of tree injection/trunk treatment for all ornamental trees as well all sort of fruit and nut trees.
In the field of tree injection/trunk treatment, the compounds according to the present invention are especially suitable against wood-boring insects from the order Lepidoptera as mentioned above and from the order Coleoptera, especially against woodborers listed in the following tables A and B:
The present invention may be also used to control any insect pests that may be present in turfgrass, including for example beetles, caterpillars, fire ants, ground pearls, millipedes, sow bugs, mites, mole crickets, scales, mealybugs ticks, spittlebugs, southern chinch bugs and white grubs. The present invention may be used to control insect pests at various stages of their life cycle, including eggs, larvae, nymphs and adults.
In particular, the present invention may be used to control insect pests that feed on the roots of turfgrass including white grubs (such as Cyclocephala spp. (e.g. masked chafer, C. lurida), Rhizotrogus spp. (e.g. European chafer, R. majalis), Cotinus spp. (e.g. Green June beetle, C. nitida), Popillia spp. (e.g. Japanese beetle, P. japonica), Phyllophaga spp. (e.g. May/June beetle), Ataenius spp. (e.g. Black turfgrass ataenius, A. spretulus), Maladera spp. (e.g. Asiatic garden beetle, M. castanea) and Tomarus spp.), ground pearls (Margarodes spp.), mole crickets (tawny, southern, and short-winged; Scapteriscus spp., Gryllotalpa africana) and leatherjackets (European crane fly, Tipula spp.).
The present invention may also be used to control insect pests of turfgrass that are thatch dwelling, including armyworms (such as fall armyworm Spodoptera frugiperda, and common armyworm Pseudaletia unipuncta), cutworms, billbugs (Sphenophorus spp., such as S. venatus verstitus and S. parvulus), and sod webworms (such as Crambus spp. and the tropical sod webworm, Herpetogramma phaeopteralis).
The present invention may also be used to control insect pests of turfgrass that live above the ground and feed on the turfgrass leaves, including chinch bugs (such as southern chinch bugs, Blissus insularis), Bermudagrass mite (Eriophyes cynodoniensis), rhodesgrass mealybug (Antonina graminis), two-lined spittlebug (Propsapia bicincta), leafhoppers, cutworms (Noctuidae family), and greenbugs.
The present invention may also be used to control other pests of turfgrass such as red imported fire ants (Solenopsis invicta) that create ant mounds in turf.
In the hygiene sector, the compositions according to the invention are active against ectoparasites such as hard ticks, soft ticks, mange mites, harvest mites, flies (biting and licking), parasitic fly larvae, lice, hair lice, bird lice and fleas.
Examples of such parasites are:
Of the order Anoplurida: Haematopinus spp., Linognathus spp., Pediculus spp. and Phtirus spp., Solenopotes spp.
Of the order Mallophagida: Trimenopon spp., Menopon spp., Trinoton spp., Bovicola spp., Werneckiella spp., Lepikentron spp., Damalina spp., Trichodectes spp. and Felicola spp.
Of the order Diptera and the suborders Nematocerina and Brachycerina, for example Aedes spp., Anopheles spp., Culex spp., Simulium spp., Eusimulium spp., Phlebotomus spp., Lutzomyia spp., Culicoides spp., Chrysops spp., Hybomitra spp., Atylotus spp., Tabanus spp., Haematopota spp., Philipomyia spp., Braula spp., Musca spp., Hydrotaea spp., Stomoxys spp., Haematobia spp., Morellia spp., Fannia spp., Glossina spp., Calliphora spp., Lucilia spp., Chrysomyia spp., Wohlfahrtia spp., Sarcophaga spp., Oestrus spp., Hypoderma spp., Gasterophilus spp., Hippobosca spp., Lipoptena spp. and Melophagus spp.
Of the order Siphonapterida, for example Pulex spp., Ctenocephalides spp., Xenopsylla spp., Ceratophyllus spp.
Of the order Heteropterida, for example Cimex spp., Triatoma spp., Rhodnius spp., Panstrongylus spp.
Of the order Blattarida, for example Blatta orientalis, Periplaneta americana, Blattelagermanica and Supella spp.
Of the subclass Acaria (Acarida) and the orders Meta- and Meso-stigmata, for example Argas spp., Ornithodorus spp., Otobius spp., Ixodes spp., Amblyomma spp., Boophilus spp., Dermacentor spp., Haemophysalis spp., Hyalomma spp., Rhipicephalus spp., Dermanyssus spp., Raillietia spp., Pneumonyssus spp., Sternostoma spp. and Varroa spp.
Of the orders Actinedida (Prostigmata) and Acaridida (Astigmata), for example Acarapis spp., Cheyletiella spp., Ornithocheyletia spp., Myobia spp., Psorergatesspp., Demodex spp., Trombicula spp., Listrophorus spp., Acarus spp., Tyrophagus spp., Caloglyphus spp., Hypodectes spp., Pterolichus spp., Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp., Knemidocoptes spp., Cytodites spp. and Laminosioptes spp.
The compositions according to the invention are also suitable for protecting against insect infestation in the case of materials such as wood, textiles, plastics, adhesives, glues, paints, paper and card, leather, floor coverings and buildings.
The compositions according to the invention can be used, for example, against the following pests: beetles such as Hylotrupes bajulus, Chlorophorus pilosis, Anobium punctatum, Xestobium rufovillosum, Ptilinuspecticornis, Dendrobium pertinex, Ernobius mollis, Priobium carpini, Lyctus brunneus, Lyctus africanus, Lyctus planicollis, Lyctus linearis, Lyctus pubescens, Trogoxylon aequale, Minthesrugicollis, Xyleborus spec., Tryptodendron spec., Apate monachus, Bostrychus capucins, Heterobostrychus brunneus, Sinoxylon spec. and Dinoderus minutus, and also hymenopterans such as Sirexjuvencus, Urocerus gigas, Urocerus gigas taignus and Urocerus augur, and termites such as Kalotermes flavicollis, Cryptotermes brevis, Heterotermes indicola, Reticulitermes flavipes, Reticulitermes santonensis, Reticulitermes lucifugus, Mastotermes darwiniensis, Zootermopsis nevadensis and Coptotermes formosanus, and bristletails such as Lepisma saccharina.
The compounds according to the invention can be used as pesticidal agents in unmodified form, but they are generally formulated into compositions in various ways using formulation adjuvants, such as carriers, solvents and surface-active substances. The formulations can be in various physical forms, e.g. in the form of dusting powders, gels, wettable powders, water-dispersible granules, water-dispersible tablets, effervescent pellets, emulsifiable concentrates, microemulsifiable concentrates, oil-in-water emulsions, oil-flowables, aqueous dispersions, oily dispersions, suspo-emulsions, capsule suspensions, emulsifiable granules, soluble liquids, water-soluble concentrates (with water or a water-miscible organic solvent as carrier), impregnated polymer films or in other forms known e.g. from the Manual on Development and Use of FAO and WHO Specifications for Pesticides, United Nations, First Edition, Second Revision (2010). Such formulations can either be used directly or diluted prior to use. The dilutions can be made, for example, with water, liquid fertilisers, micronutrients, biological organisms, oil or solvents.
The formulations can be prepared e.g. by mixing the active ingredient with the formulation adjuvants in order to obtain compositions in the form of finely divided solids, granules, solutions, dispersions or emulsions. The active ingredients can also be formulated with other adjuvants, such as finely divided solids, mineral oils, oils of vegetable or animal origin, modified oils of vegetable or animal origin, organic solvents, water, surface-active substances or combinations thereof.
The active ingredients can also be contained in very fine microcapsules. Microcapsules contain the active ingredients in a porous carrier. This enables the active ingredients to be released into the environment in controlled amounts (e.g. slow-release). Microcapsules usually have a diameter of from 0.1 to 500 microns. They contain active ingredients in an amount of about from 25 to 95% by weight of the capsule weight. The active ingredients can be in the form of a monolithic solid, in the form of fine particles in solid or liquid dispersion or in the form of a suitable solution. The encapsulating membranes can comprise, for example, natural or synthetic rubbers, cellulose, styrene/butadiene copolymers, polyacrylonitrile, polyacrylate, polyesters, polyamides, polyureas, polyurethane or chemically modified polymers and starch xanthates or other polymers that are known to the person skilled in the art. Alternatively, very fine microcapsules can be formed in which the active ingredient is contained in the form of finely divided particles in a solid matrix of base substance, but the microcapsules are not themselves encapsulated.
The formulation adjuvants that are suitable for the preparation of the compositions according to the invention are known per se. As liquid carriers there may be used: water, toluene, xylene, petroleum ether, vegetable oils, acetone, methyl ethyl ketone, cyclohexanone, acid anhydrides, acetonitrile, acetophenone, amyl acetate, 2-butanone, butylene carbonate, chlorobenzene, cyclohexane, cyclohexanol, alkyl esters of acetic acid, diacetone alcohol, 1,2-dichloropropane, diethanolamine, p-diethylbenzene, diethylene glycol, diethylene glycol abietate, diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenzoate, diproxitol, alkylpyrrolidone, ethyl acetate, 2-ethylhexanol, ethylene carbonate, 1,1,1-trichloroethane, 2-heptanone, alpha-pinene, d-limonene, ethyl lactate, ethylene glycol, ethylene glycol butyl ether, ethylene glycol methyl ether, gamma-butyrolactone, glycerol, glycerol acetate, glycerol diacetate, glycerol triacetate, hexadecane, hexylene glycol, isoamyl acetate, isobornyl acetate, isooctane, isophorone, isopropylbenzene, isopropyl myristate, lactic acid, laurylamine, mesityl oxide, methoxy-propanol, methyl isoamyl ketone, methyl isobutyl ketone, methyl laurate, methyl octanoate, methyl oleate, methylene chloride, m-xylene, n-hexane, n-octylamine, octadecanoic acid, octylamine acetate, oleic acid, oleylamine, o-xylene, phenol, polyethylene glycol, propionic acid, propyl lactate, propylene carbonate, propylene glycol, propylene glycol methyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol, xylenesulfonic acid, paraffin, mineral oil, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, propylene glycol methyl ether, diethylene glycol methyl ether, methanol, ethanol, isopropanol, and alcohols of higher molecular weight, such as amyl alcohol, tetrahydrofurfuryl alcohol, hexanol, octanol, ethylene glycol, propylene glycol, glycerol, N-methyl-2-pyrrolidone and the like.
Suitable solid carriers are, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, limestone, calcium carbonate, bentonite, calcium montmorillonite, cottonseed husks, wheat flour, soybean flour, pumice, wood flour, ground walnut shells, lignin and similar substances.
A large number of surface-active substances can advantageously be used in both solid and liquid formulations, especially in those formulations which can be diluted with a carrier prior to use. Surface-active substances may be anionic, cationic, non-ionic or polymeric and they can be used as emulsifiers, wetting agents or suspending agents or for other purposes. Typical surface-active substances include, for example, salts of alkyl sulfates, such as diethanolammonium lauryl sulfate; salts of alkylarylsulfonates, such as calcium dodecylbenzenesulfonate; alkylphenol/alkylene oxide addition products, such as nonylphenol ethoxylate; alcohol/alkylene oxide addition products, such as tridecylalcohol ethoxylate; soaps, such as sodium stearate; salts of alkylnaphthalenesulfonates, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as sodium di(2-ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryltrimethylammonium chloride, polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono- and di-alkylphosphate esters; and also further substances described e.g. in McCutcheon's Detergents and Emulsifiers Annual, MC Publishing Corp., Ridgewood New Jersey (1981).
Further adjuvants that can be used in pesticidal formulations include crystallisation inhibitors, viscosity modifiers, suspending agents, dyes, anti-oxidants, foaming agents, light absorbers, mixing auxiliaries, antifoams, complexing agents, neutralising or pH-modifying substances and buffers, corrosion inhibitors, fragrances, wetting agents, take-up enhancers, micronutrients, plasticisers, glidants, lubricants, dispersants, thickeners, antifreezes, microbicides, and liquid and solid fertilisers.
The compositions according to the invention can include an additive comprising an oil of vegetable or animal origin, a mineral oil, alkyl esters of such oils or mixtures of such oils and oil derivatives. The amount of oil additive in the composition according to the invention is generally from 0.01 to 10%, based on the mixture to be applied. For example, the oil additive can be added to a spray tank in the desired concentration after a spray mixture has been prepared. Preferred oil additives comprise mineral oils or an oil of vegetable origin, for example rapeseed oil, olive oil or sunflower oil, emulsified vegetable oil, alkyl esters of oils of vegetable origin, for example the methyl derivatives, or an oil of animal origin, such as fish oil or beef tallow. Preferred oil additives comprise alkyl esters of C8-C22 fatty acids, especially the methyl derivatives of C12-C18 fatty acids, for example the methyl esters of lauric acid, palmitic acid and oleic acid (methyl laurate, methyl palmitate and methyl oleate, respectively). Many oil derivatives are known from the Compendium of Herbicide Adjuvants, 10th Edition, Southern Illinois University, 2010.
The inventive compositions generally comprise from 0.1 to 99% by weight, especially from 0.1 to 95% by weight, of compounds of the present invention and from 1 to 99.9% by weight of a formulation adjuvant which preferably includes from 0 to 25% by weight of a surface-active substance. Whereas commercial products may preferably be formulated as concentrates, the end user will normally employ dilute formulations.
The rates of application vary within wide limits and depend on the nature of the soil, the method of application, the crop plant, the pest to be controlled, the prevailing climatic conditions, and other factors governed by the method of application, the time of application and the target crop. As a general guideline compounds may be applied at a rate of from 1 to 2000 l/ha, especially from 10 to 1000 l/ha.
Preferred formulations can have the following compositions (weight %):
The following Examples further illustrate, but do not limit, the invention.
The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.
The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording powders that can be used directly for seed treatment.
Emulsions of any require dilution, which can be use in plant protection, can be obtained from this concentrate by dilution with water.
Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill. Such powders can also be used for dry dressings for seed.
The combination is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.
The finely ground combination is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.
The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
28 parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed. The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns. The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.
Formulation types include an emulsion concentrate (EC), a suspension concentrate (SC), a suspo-emulsion (SE), a capsule suspension (CS), a water dispersible granule (WG), an emulsifiable granule (EG), an emulsion, water in oil (EO), an emulsion, oil in water (EW), a micro-emulsion (ME), an oil dispersion (OD), an oil miscible flowable (OF), an oil miscible liquid (OL), a soluble concentrate (SL), an ultra-low volume suspension (SU), an ultra-low volume liquid (UL), a technical concentrate (TK), a dispersible concentrate (DC), a wettable powder (WP), a soluble granule (SG) or any technically feasible formulation in combination with agriculturally acceptable adjuvants.
“Mp” means melting point in ° C. Free radicals represent methyl groups. 1H NMR measurements were recorded on a Brucker 400 MHz spectrometer, chemical shifts are given in ppm relevant to a TMS standard. Spectra measured in deuterated solvents as indicated. Either one of the LCMS methods below was used to characterize the compounds. The characteristic LCMS values obtained for each compound were the retention time (“Rt”, recorded in minutes) and the measured molecular ion (M+H)+ or (M−H)−. Specific rotation [α]: samples were measured on an Autopol IV polarimeter from Rudolph Research Analytical.
Spectra were recorded on a Mass Spectrometer from Waters (ZQ Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.00 kV, Cone range: 30-60 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 0 L/Hr, Desolvation Gas Flow: 650 L/Hr, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment and diode-array detector. Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 m, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH: gradient: 0 min 0% B, 100% A; 1.2-1.5 min 100% B; Flow (ml/min) 0.85.
Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions, Capillary: 3.00 kV, Cone range: 30 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 50 I/h, Desolvation Gas Flow: 650 I/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment, diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 m, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH, gradient: 10-100% B in 1.2 min; Flow (ml/min) 0.85.
Spectra were recorded on a Mass Spectrometer from Agilent Technologies (6410 Triple Quadruple Mass Spectrometer) equipped with an electrospray source (Polarity: Positive and Negative Polarity Switch, Capillary: 4.00 kV, Fragmentor: 100.00 V, Gas Temperature: 350° C., Gas Flow: 11 L/min, Nebulizer Gas: 45 psi, Mass range: 110-1000 Da, DAD Wavelength range: 210-400 nm). Column: KINETEX EVO C18, length 50 mm, diameter 4.6 mm, particle size 2.6 μm. Column oven temperature 40° C. Solvent gradient: A=Water with 0.1% formic acid: Acetonitrile (95:5 v/v). B=Acetonitrile with 0.1% formic acid. Gradient=0 min 90% A, 10% B; 0.9-1.8 min 0% A, 100% B, 2.2-2.5 min 90% A, 10% B. Flow rate 1.8 mL/min.
Spectra were recorded on a Mass Spectrometer from Waters (Acquity SDS Mass Spectrometer) equipped with an electrospray source (Polarity: Positive and Negative Polarity Switch, Capillary: 3.00 kV, Cone Voltage: 41.00 V, Source temperature: 150° C., Desolvation Gas Flow: 1000 L/Hr, Desolvation temperature: 500° C., Gas Flow® Cone: 50 L/hr, Mass range: 110-800 Da, PDA wavelength range: 210-400 nm. Column: Acquity UPLC HSS T3 C18, length 30 mm, diameter 2.1 mm, particle size 1.8 μm. Column oven temperature 40° C. Solvent gradient: A=Water with 0.1% formic acid: Acetonitrile (95:5 v/v). B=Acetonitrile with 0.05% formic acid. Gradient=0 min 90% A, 10% B; 0.2 min 50% A, 50% B; 0.7-1.3 min 0% A, 100% B; 1.4-1.6 min 90% A, 10% B. Flow rate 0.8 mL/min.
Spectra were recorded on a Mass Spectrometer from Waters (Acquity SDS Mass Spectrometer) equipped with an electrospray source (Polarity: Positive and Negative Polarity Switch, Capillary: 3.00 kV, Cone Voltage: 41.00 V, Source temperature: 150° C., Desolvation Gas Flow: 1000 L/Hr., Desolvation temperature: 500° C., Gas Flow @Cone: 50 L/hr., Mass range: 110-800 Da, PDA wavelength range: 210-400 nm. Column: Acquity UPLC HSS T3 C18, length 30 mm, diameter 2.1 mm, particle size 1.8 μm. Column oven temperature 40° C. Solvent gradient: A=Water with 0.1% formic acid: Acetonitrile (95:5 v/v). B=Acetonitrile with 0.05% formic acid. Gradient=0 min 90% A, 10% B; 0.2 min 50% A, 50% B; 0.7-1.3 min 0% A, 100% B; 1.4-1.6 min 90% A, 10% B. Flow rate 0.6 mL/min.
Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions), Capillary: 3.00 kV, Cone range: 30V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 50 I/h, Desolvation Gas Flow: 650 I/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment, diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 m, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH, gradient: 10-100% B in 2.7 min; Flow (ml/min) 0.85.
This compound was prepared in analogy to methods described in WO2020/084075.
LCMS (method 3): m/z 478 [M+H]+; retention time: 1.54 min.
2-[[6-[5-Cyclopropyl-3-methyl-4-oxo-6-(trifluoromethyl) imidazo[4,5-c]pyridin-2-yl]-5-ethylsulfanyl-3-pyridyl]oxy]-2-methyl-propanenitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2020/084075 to afford the desired compound P1. LCMS (method 4): m/z 509 [M+H]+; retention time: 0.92 min.
The racemic 2-[[6-[5-cyclopropyl-3-methyl-4-oxo-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-5-(ethylsulfonimidoyl)-3-pyridyl]oxy]-2-methyl-propanenitrile (compound P1) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2019/234158.
LCMS (method 6): m/z 405 [M+H]+; retention time: 1.05 min.
1-[5-Ethylsulfanyl-6-[7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazin-6-yl]-3-pyridyl]cyclopropanecarbonitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2019/234158 to afford the desired compound P2. LCMS (method 5): m/z 436 [M+H]+; retention time: 0.82 min.
The racemic 1-[5-(ethylsulfonimidoyl)-6-[7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazin-6-yl]-3-pyridyl]cyclopropanecarbonitrile (compound P2) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2020/084075.
1H NMR (400 MHz, chloroform-d) δ ppm 1.44 (t, J=7.34 Hz, 3H) 1.81 (s, 6H) 3.04 (q, J=7.34 Hz, 2H) 7.02 (dd, J1=7.34; J2=1.65 Hz, 1H) 7.65 (d, J=2.57 Hz, 1H) 8.06 (s, 1H) 8.29 (d, J=7.34 Hz, 1H) 8.32 (d, J=2.57 Hz, 1H) 8.37 (d, J=1.65 Hz, 1H).
2-[[5-Ethylsulfanyl-6-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2020/084075 to afford the desired compound P3. LCMS (method 1): m/z 438 [M+H]+; retention time: 0.88 min.
The racemic 2-[[5-(ethylsulfonimidoyl)-6-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (compound P3) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2018/153778.
LCMS (method 2): m/z 406 [M+H]+; retention time: 1.02 min.
2-[5-Ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2019/234158 to afford the desired compound P4. LCMS (method 2): m/z 437 [M+H]+; retention time: 0.83 min.
The racemic 2-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile (compound P4) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2020/084075.
LCMS (method 1): m/z 436 [M+H]+; retention time: 1.16 min.
2 [[5-Ethylsulfanyl-2-methyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2020/084075 to afford the desired compound P5. LCMS (method 1): m/z 467 [M+H]+; retention time: 0.97 min.
The racemic 2-[[5-(ethylsulfonimidoyl)-2-methyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (compound P5) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2019/234158.
LCMS (method 6): m/z 403 [M+H]+; retention time: 1.18 min.
1-[3-Ethylsulfanyl-4-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]phenyl]cyclopropanecarbonitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2019/234158 to afford the desired compound P6. LCMS (method 2): m/z 434 [M+H]+; retention time: 0.88 min.
The racemic 1-[3-(ethylsulfonimidoyl)-4-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]phenyl]cyclopropanecarbonitrile (compound P6) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2020/084075.
1H NMR (400 MHz, chloroform-d) δ ppm 1.44 (m, 3H) 1.82 (s, 6H) 3.05 (m, 2H) 7.66 (d, J=2.20 Hz, 1H) 8.02 (s, 1H) 8.34 (d, J=2.20 Hz, 1H) 8.39 (s, 1H) 9.10 (s, 1H).
2-[[5-Ethylsulfanyl-6-[7-(trifluoromethylsulfanyl)imidazo[1,2-c]pyrimidin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2020/084075 to afford the desired compound P7. LCMS (method 1): m/z 471 [M+H]+; retention time: 0.89 min.
The racemic 2-[[5-(ethylsulfonimidoyl)-6-[7-(trifluoromethylsulfanyl)imidazo[1,2-c]pyrimidin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (compound P7) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2019/234158.
LCMS (method 5): m/z 450 [M+H]+; retention time: 1.03 min.
1-[5-Ethylsulfanyl-6-[5-methoxy-3-methyl-4-oxo-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]cyclopropanecarbonitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2019/234158 to afford the desired compound P8. LCMS (method 5): m/z 481 [M+H]+; retention time: 0.85 min.
The racemic 1-[5-(ethylsulfonimidoyl)-6-[5-methoxy-3-methyl-4-oxo-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]cyclopropanecarbonitrile (compound P8) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2020/084075.
LCMS (method 1): m/z 422 [M+H]+; retention time: 1.11 min.
2-[[5-Ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2020/084075 to afford the desired compound P9. LCMS (method 1): m/z 453 [M+H]+; retention time: 0.93 min.
The racemic 2-[[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (compound P9) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
A sample of the second eluting enantiomer compound P9-B (crystals from ethanol obtained according to Example P9 step 3, with chemical purity of 99% (%=290 nm) and enantiomeric excess of >99%) was subjected to analysis by single crystal X-ray diffraction. Single crystal intensity data was collected on an Rigaku Oxford Diffraction Supernova X-ray Generator using Cu-Kα radiation at a wavelength of 1.54184 Å, collected at 100K to a resolution of 0.81 Å.
The dataset was refined and reduced using the data collection and processing software CrysAlisPro, the structure solution was completed using SIR92 (Altomare A, Cascarano G, Giacovazzo C, Guagliardi A, Burla M C, Polidori G and Camalli M, J. Appl. Cryst. 27: 435 (1994)) and the structure refinement was competed using the CRYSTALS software package (Betteridge P W, Carruthers J R, Cooper R I, Prout K and Watkin D J, J. Appl. Cryst. 36:1487 (2003)).
Individual enantioner compound P9-B crystallized in the monoclinic space group C2. Unit cell parameters of the single crystal analysis are shown in Table 1.
The X-ray crystal structure of compound P9-B is depicted in
Hence, the second eluting enantiomer P9-B was proved by x-ray crystallography to be (S)-2-[[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile, corresponding to compound (S)—P9 (Table Y) obtained via enantioselective synthesis (Example E2 below).
[a]D20=+13.7° (MeOH, C=0.88).
Similarly, the first eluting enantiomer P9-A was proved by x-ray crystallography to be (R)-2-[[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile, corresponding to compound (R)-P9 (Table Y) obtained via enantioselective synthesis (Example E1 below).
[a]D20=−13.2° (MeOH, C=0.87).
This compound was prepared in analogy to methods described in WO2019/234158.
LCMS (method 1): m/z 404 [M+H]+; retention time: 0.98 min.
1-[5-Ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]cyclopropanecarbonitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2019/234158 to afford the desired compound P10. LCMS (method 1): m/z 435 [M+H]+; retention time: 0.82 min.
The racemic 1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]cyclopropanecarbonitrile (compound P10) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2020/084075.
1H NMR (400 MHz, chloroform-d) δ ppm 1.44 (t, J=7.34 Hz, 3H) 1.81 (s, 6H) 3.04 (q, J=7.34 Hz, 2H) 7.67 (s, 1H) 8.05 (s, 1H) 8.34 (s, 1H) 8.45 (s, 1H) 9.18 (s, 1H).
2-[[5-Ethylsulfanyl-6-[7-(trifluoromethyl)imidazo[1,2-c]pyrimidin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2020/084075 to afford the desired compound P11. LCMS (method 1): m/z 439 [M+H]+; retention time: 0.84 min.
The racemic 2-[[5-(ethylsulfonimidoyl)-6-[7-(trifluoromethyl)imidazo[1,2-c]pyrimidin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (compound P11) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2018/153778.
LCMS (method 2): m/z 406 [M+H]+; retention time: 1.09 min.
A solution of 2-[5-ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile (prepared as described above) (300 mg, 0.74 mmol) in methanol (5 mL) was added at room temperature to a solution of diacetoxy iodobenzene (596 mg, 1.85 mmol) and ammonium carbamate (116 mg, 1.48 mmol) in methanol (4 mL). After stirring for 90 minutes at room temperature, the reaction mixture was evaporated and the residue diluted with dichloromethane. The organic phase was washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash chromatography over silica gel (ethyl acetate in cyclohexane) to afford the desired compound P12.
LCMS (method 2): m/z 437 [M+H]+; retention time: 0.91 min.
The racemic 2-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile_(compound P12) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2020/084075.
LCMS (method 1): m/z 422 [M+H]+; retention time: 1.02 min.
2-[[5-Ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2020/084075 to afford the desired compound P13. LCMS (method 1): m/z 453 [M+H]+; retention time: 0.86 min.
The racemic 2-[[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (compound P13) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2019/234158.
LCMS (method 5): m/z 448 [M+H]+; retention time: 1.13 min.
1-[6-[5-Ethyl-3-methyl-4-oxo-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-5-ethylsulfanyl-3-pyridyl]cyclopropanecarbonitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2019/234158 to afford the desired compound P14. LCMS (method 5): m/z 479 [M+H]+; retention time: 0.92 min.
The racemic 1-[6-[5-ethyl-3-methyl-4-oxo-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-5-(ethylsulfonimidoyl)-3-pyridyl]cyclopropanecarbonitrile (compound P14) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2020/084075.
1H NMR (400 MHz, chloroform-d) δ ppm 1.42 (t, J=7.34 Hz, 3H) 1.88 (s, 6H) 3.03 (q, J=7.34 Hz, 2H) 4.31 (s, 3H) 7.72 (d, J=2.57 Hz, 1H) 8.26 (s, 1H) 8.39 (d, J=2.57 Hz, 1H).
2-[[5-Ethylsulfanyl-6-[7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazin-6-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2020/084075 to afford the desired compound P15. LCMS (method 1): m/z 454 [M+H]+; retention time: 0.89 min.
The racemic 2-[[5-(ethylsulfonimidoyl)-6-[7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazin-6-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (compound P15) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2019/234158.
LCMS (method 2): m/z 404 [M+H]+; retention time: 1.07 min.
1-[5-Ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]cyclopropanecarbonitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2019/234158 to afford the desired compound P16. LCMS (method 2): m/z 435 [M+H]+; retention time: 0.87 min.
The racemic 1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]cyclopropanecarbonitrile (compound P16) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2020/084075.
LCMS (method 1): m/z 436 [M+H]+; retention time: 1.06 min.
2-[[5-Ethylsulfanyl-2-methyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2020/084075 to afford the desired compound P17. LCMS (method 1): m/z 467 [M+H]+; retention time: 0.91 min.
The racemic 2-[[5-(ethylsulfonimidoyl)-2-methyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (compound P17) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2019/234158.
LCMS (method 2): m/z 403 [M+H]1; retention time: 1.00 min.
1-[3-Ethylsulfanyl-4-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]phenyl]cyclopropanecarbonitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2019/234158 to afford the desired compound P18. LCMS (method 2): m/z 434 [M+H]+; retention time: 0.83 min.
The racemic 1-[3-(ethylsulfonimidoyl)-4-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]phenyl]cyclopropanecarbonitrile (compound P18) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
This compound was prepared in analogy to methods described in WO2020/084075.
LCMS (method 4): m/z 466 [M+H]+; retention time: 1.10 min.
2-[[6-[5-Ethyl-3-methyl-4-oxo-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-5-ethylsulfanyl-3-pyridyl]oxy]-2-methyl-propanenitrile (prepared as described above) was treated under analogous conditions as described in step 2 of Example P12 and in analogy to methods described in WO2020/084075 to afford the desired compound P19. LCMS (method 4): m/z 497 [M+H]+; retention time: 0.93 min.
The racemic 2-[[6-[5-ethyl-3-methyl-4-oxo-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-5-(ethylsulfonimidoyl)-3-pyridyl]oxy]-2-methyl-propanenitrile (compound P19) mixture was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
The characteristic measured molecular ion (M+H)+ values in Table P(E) were recorded on a Mass Spectrometer from Waters (QDa) (Polarity: positive and negative ions), Detector Gain 1, Temperature Probe: 500° C., Cone Voltage: 10V, ESI Capillary Positive Voltage 0.8-Negative Voltage 0.8, Sampling Frequency 5 Hz, Mass range: 100 to 850 Da.
Compound (R)-P9 in an enantiomerically enriched form (major (R)-stereoisomer having the absolute configuration depicted in the drawing) was prepared in two steps from 2-[[5-ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile by means of a stereoselective oxidation, followed by a stereospecific imination reaction.
2-[[5-ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (prepared as described above in Example P9, step 1) (300 mg, 0.680 mmol), iron(III)acetylacetonate (12.2 mg, 0.035 mmol), 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-diiodo-phenol (prepared according to Chem Eur J 2005, 11, 1086-1092) (37.1 mg, 0.068 mmol) and 4-methoxybenzoic acid (2.6 mg, 0.017 mmol) were dissolved in toluene (2.7 mL). The solution was cooled to 0° C. and hydrogen peroxide (30% aqueous solution, 0.139 mL, 1.36 mmol) was added. The reaction was stirred at 0° C. for 30 minutes then warmed to 10° C. and stirred overnight, before being warmed to room temperature and stirred for a further 6 hours. The reaction mixture was then poured into a mixture of ethyl acetate and aqueous sodium thiosulfate solution, the layers were separated, and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed with water and a 0.5M aqueous hydrochloric acid solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate in cyclohexane) to afford the title compound.
LCMS (method 6): m/z 438 [M+H]+; retention time: 1.86 min.
Enantiomeric excess was measured according to the following method:
All chiral sulfinyl compounds (R)—SO1 to (R)—SO19 with (R)-enantiomer configuration at sulfur of Table P(SO), in either enantiomerically enriched or up to pure form, can be prepared in analogy by applying the preparation Example E1, step 1 (or an adaptation thereof known by those skilled in the art) on the respective sulfanyl substrates.
Enantioenriched 2-[[5-[(R)-ethylsulfinyl]-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (compound (R)—S09 prepared as described above) (219 mg, 0.482 mmol) and iron(II)phthalocyanine (6.39 mg, 0.011 mmol) were dissolved in dichloromethane (2 mL). O-(4-nitrobenzoyl)-hydroxylamine triflic acid (prepared according to Chem Eur J 2017, 23, 563-567) (326 mg, 0.981 mmol) was added and the mixture stirred at room temperature for 1 hour. Ethyl acetate and 2M aqueous hydrochloric acid were added and the reaction mixture was filtered through a pad of celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic phase was washed with sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound.
LCMS (method 6) m/z 453 [M+H]+; retention time: 1.39 min.
Enantiomeric excess was measured according to the following method:
The first eluting major enantiomer (R)-P9 is corresponding to compound P9-A (Table P(E)) obtained via chiral resolution (Example P9 above).
All chiral sulfoximine compounds (R)-P1 to (R)-P19 with (R)-enantiomer configuration at sulfur of Table Y, in either enantiomerically enriched or up to pure form, can be prepared in analogy by applying the preparation Example E1, step 2 (or an adaptation thereof known by those skilled in the art) on the respective sulfinyl substrates (R)—SO1 to (R)—SO19 of Table P(SO).
Compound (S)—P9 in an enantiomerically enriched form (major (S)-stereoisomer having the absolute configuration depicted in the drawing) was prepared by an analogous method using the opposite enantiomer of the chiral ligand in the sulfoxide formation (Example E1, step 1).
Compound (S)—S09 was prepared from 2-[[5-ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile by an analogous procedure to Example E1, step 1 replacing 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodo-phenol with 2-[(E)-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodo-phenol.
LCMS (method 6): m/z 438 [M+H]+; retention time: 1.87 min.
Enantiomeric excess was measured according to the following method:
All chiral sulfinyl compounds (S)—SO1 to (S)—SO19 with (S)-enantiomer configuration at sulfur of Table P(SO), in either enantiomerically enriched or up to pure form, can be prepared in analogy by applying the preparation Example E2, step 1 (or an adaptation thereof known by those skilled in the art) on the respective sulfanyl substrates.
Compound (S)—P9 was prepared from enantioenriched 2-[[5-[(S)-ethylsulfinyl]-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (compound (S)—S09 prepared as described above) by an analogous procedure to Example E1, step 2.
LCMS (method 6): m/z 453 [M+H]+; retention time: 1.39 min.
Enantiomeric excess was measured according to the following method:
The second eluting major enantiomer (S)—P9 is corresponding to compound P9-B (Table P(E)) obtained via chiral resolution (Example P9 above).
All chiral sulfoximine compounds (S)—P1 to (S)—P19 with (S)-enantiomer configuration at sulfur of Table Y, in either enantiomerically enriched or up to pure form, can be prepared in analogy by applying the preparation Example E2, step 2 (or an adaptation thereof known by those skilled in the art) on the respective sulfinyl substrates (S)—SO1 to (S)—SO19 of Table P(SO).
The following mixtures of the compounds of formula I with active ingredients are preferred (the abbreviation “TX” means “one compound selected from the group consisting of the compounds described in Tables A-1 through A-20, Tables B-1 through B-20, Table Y, Table Z and Table P(E) of the present invention”):
The references in brackets behind the active ingredients, e.g. [3878-19-1] refer to the Chemical Abstracts Registry number. The above described mixing partners are known. Where the active ingredients are included in “The Pesticide Manual” [The Pesticide Manual-A World Compendium; Thirteenth Edition; Editor: C. D. S. TomLin; The British Crop Protection Council], they are described therein under the entry number given in round brackets hereinabove for the particular compound; for example, the compound “abamectin” is described under entry number (1). Where “[CCN]” is added hereinabove to the particular compound, the compound in question is included in the “Compendium of Pesticide Common Names”, which is accessible on the internet [A. Wood; Compendium of Pesticide Common Names, Copyright © 1995-2004]; for example, the compound “acetoprole” is described under the internet address http://www.alanwood.net/pesticides/acetoprole.html.
Most of the active ingredients described above are referred to hereinabove by a so-called “common name”, the relevant “ISO common name” or another “common name” being used in individual cases. If the designation is not a “common name”, the nature of the designation used instead is given in round brackets for the particular compound; in that case, the IUPAC name, the IUPAC/Chemical Abstracts name, a “chemical name”, a “traditional name”, a “compound name” or a “development code” is used or, if neither one of those designations nor a “common name” is used, an “alternative name” is employed. “CAS Reg. No” means the Chemical Abstracts Registry Number.
The active ingredient mixture of the compounds of formula I selected from Tables A-1 through A-20, Tables B-1 through B-20, Table Y, Table Z and Table P(E) with active ingredients described above comprises a compound selected from Tables A-1 through A-20, Tables B-1 through B-20, Table Y, Table Z and Table P(E) and an active ingredient as described above preferably in a mixing ratio of from 100:1 to 1:6000, especially from 50:1 to 1:50, more especially in a ratio of from 20:1 to 1:20, even more especially from 10:1 to 1:10, very especially from 5:1 and 1:5, special preference being given to a ratio of from 2:1 to 1:2, and a ratio of from 4:1 to 2:1 being likewise preferred, above all in a ratio of 1:1, or 5:1, or 5:2, or 5:3, or 5:4, or 4:1, or 4:2, or 4:3, or 3:1, or 3:2, or 2:1, or 1:5, or 2:5, or 3:5, or 4:5, or 1:4, or 2:4, or 3:4, or 1:3, or 2:3, or 1:2, or 1:600, or 1:300, or 1:150, or 1:35, or 2:35, or 4:35, or 1:75, or 2:75, or 4:75, or 1:6000, or 1:3000, or 1:1500, or 1:350, or 2:350, or 4:350, or 1:750, or 2:750, or 4:750. Those mixing ratios are by weight.
The mixtures as described above can be used in a method for controlling pests, which comprises applying a composition comprising a mixture as described above to the pests or their environment, with the exception of a method for treatment of the human or animal body by surgery or therapy and diagnostic methods practised on the human or animal body.
The mixtures comprising a compound of formula I selected from Tables A-1 through A-20, Tables B-1 through B-20, Table Y, Table Z and Table P(E) and one or more active ingredients as described above can be applied, for example, in a single “ready-mix” form, in a combined spray mixture composed from separate formulations of the single active ingredient components, such as a “tank-mix”, and in a combined use of the single active ingredients when applied in a sequential manner, i.e. one after the other with a reasonably short period, such as a few hours or days. The order of applying the compounds of formula I selected from Tables A-1 through A-20, Tables B-1 through B-20, Table Y, Table Z and Table P(E) and the active ingredients as described above is not essential for working the present invention.
The compositions according to the invention can also comprise further solid or liquid auxiliaries, such as stabilizers, for example unepoxidized or epoxidized vegetable oils (for example epoxidized coconut oil, rapeseed oil or soya oil), antifoams, for example silicone oil, preservatives, viscosity regulators, binders and/or tackifiers, fertilizers or other active ingredients for achieving specific effects, for example bactericides, fungicides, nematocides, plant activators, molluscicides or herbicides.
The compositions according to the invention are prepared in a manner known per se, in the absence of auxiliaries for example by grinding, screening and/or compressing a solid active ingredient and in the presence of at least one auxiliary for example by intimately mixing and/or grinding the active ingredient with the auxiliary (auxiliaries). These processes for the preparation of the compositions and the use of the compounds I for the preparation of these compositions are also a subject of the invention.
The application methods for the compositions, that is the methods of controlling pests of the abovementioned type, such as spraying, atomizing, dusting, brushing on, dressing, scattering or pouring—which are to be selected to suit the intended aims of the prevailing circumstances—and the use of the compositions for controlling pests of the abovementioned type are other subjects of the invention. Typical rates of concentration are between 0.1 and 1000 ppm, preferably between 0.1 and 500 ppm, of active ingredient. The rate of application per hectare is generally 1 to 2000 g of active ingredient per hectare, in particular 10 to 1000 g/ha, preferably 10 to 600 g/ha.
A preferred method of application in the field of crop protection is application to the foliage of the plants (foliar application), it being possible to select frequency and rate of application to match the danger of infestation with the pest in question. Alternatively, the active ingredient can reach the plants via the root system (systemic action), by drenching the locus of the plants with a liquid composition or by incorporating the active ingredient in solid form into the locus of the plants, for example into the soil, for example in the form of granules (soil application). In the case of paddy rice crops, such granules can be metered into the flooded paddy-field.
The compounds of the invention and compositions thereof are also be suitable for the protection of plant propagation material, for example seeds, such as fruit, tubers or kernels, or nursery plants, against pests of the abovementioned type. The propagation material can be treated with the compound prior to planting, for example seed can be treated prior to sowing. Alternatively, the compound can be applied to seed kernels (coating), either by soaking the kernels in a liquid composition or by applying a layer of a solid composition. It is also possible to apply the compositions when the propagation material is planted to the site of application, for example into the seed furrow during drilling. These treatment methods for plant propagation material and the plant propagation material thus treated are further subjects of the invention. Typical treatment rates would depend on the plant and pest/fungi to be controlled and are generally between 1 to 200 grams per 100 kg of seeds, preferably between 5 to 150 grams per 100 kg of seeds, such as between 10 to 100 grams per 100 kg of seeds.
The term seed embraces seeds and plant propagules of all kinds including but not limited to true seeds, seed pieces, suckers, corns, bulbs, fruit, tubers, grains, rhizomes, cuttings, cut shoots and the like and means in a preferred embodiment true seeds.
The present invention also comprises seeds coated or treated with or containing a compound of formula I. The term “coated or treated with and/or containing” generally signifies that the active ingredient is for the most part on the surface of the seed at the time of application, although a greater or lesser part of the ingredient may penetrate into the seed material, depending on the method of application. When the said seed product is (re)planted, it may absorb the active ingredient. In an embodiment, the present invention makes available a plant propagation material adhered thereto with a compound of formula I including those selected from Tables A-1 through A-20, Tables B-1 through B-20, Table Y, Table Z and Table P(E). Further, it is hereby made available, a composition comprising a plant propagation material treated with a compound of formula I including those selected from Tables A-1 through A-20, Tables B-1 through B-20, Table Y, Table Z and Table P(E).
Seed treatment comprises all suitable seed treatment techniques known in the art, such as seed dressing, seed coating, seed dusting, seed soaking and seed pelleting. The seed treatment application of the compound formula I (including those selected from Tables A-1 through A-20, Tables B-1 through B-20, Table Y, Table Z and Table P(E)) can be carried out by any known methods, such as spraying or by dusting the seeds before sowing or during the sowing/planting of the seeds.
The Examples which follow serve to illustrate the invention. Certain compounds of the invention can be distinguished from known compounds by virtue of greater efficacy at low application rates, which can be verified by the person skilled in the art using the experimental procedures outlined in the Examples, using lower application rates if necessary, for example 50 ppm, 12.5 ppm, 6 ppm, 3 ppm, 1.5 ppm, 0.8 ppm or 0.2 ppm.
Cotton leaf discs were placed onto agar in 24-well microtiter plates and sprayed with aqueous test solutions prepared from 10′000 ppm DMSO stock solutions. After drying the leaf discs were infested with five L1 larvae. The samples were assessed for mortality, anti-feeding effect, and growth inhibition in comparison to untreated samples 3 days after infestation. Control of Spodoptera littoralis by a test sample is given when at least one of the categories mortality, anti-feedant effect, and growth inhibition is higher than the untreated sample.
The following compounds resulted in at least 80% control at an application rate of 200 ppm: P1, P3, P5, P6, P8, P9, P11, P12, P13, P14, P17, P19, P1-A, P3-A, P5-A, P7-A, P8-A, P9-A, P14-A, P15-A, P19-A, P1-B, P3-B, P5-B, P6-B, P7-B, P9-B, P13-B, P14-B, P16-B, P17-B, P19-B.
24-well microtiter plates with artificial diet were treated with aqueous test solutions prepared from 10′000 ppm DMSO stock solutions by pipetting. After drying, the plates were infested with L2 larvae (10 to 15 per well). The samples were assessed for mortality and growth inhibition in comparison to untreated samples 5 days after infestation.
The following compounds gave an effect of at least 80% in at least one of the two categories (mortality or growth inhibition) at an application rate of 200 ppm: P1, P3, P5, P6, P8, P9, P11, P12, P13, P14, P15, P16, P17, P19.
Maize sprouts placed onto an agar layer in 24-well microtiter plates were treated with aqueous test solutions prepared from 10′000 ppm DMSO stock solutions by spraying. After drying, the plates were infested with L2 larvae (6 to 10 per well). The samples were assessed for mortality and growth inhibition in comparison to untreated samples 4 days after infestation.
The following compounds gave an effect of at least 80% in at least one of the two categories (mortality or growth inhibition) at an application rate of 200 ppm: P1, P2, P3, P5, P7, P8, P9, P11, P12, P13, P14, P15, P18, P19, P1-A, P3-A, P5-A, P6-A, P7-A, P8-A, P9-A, P10-A, P11-A, P12-A, P13-A, P14-A, P15-A, P16-A, P17-A, P18-A, P19-A, P1-B, P3-B, P4-B, P5-B, P6-B, P7-B, P8-B, P9-B, P11-B, P12-B, P13-B, P14-B, P15-B, P17-B, P18-B, P19-B.
Sunflower leaf discs were placed on agar in a 24-well microtiter plate and sprayed with aqueous test solutions prepared from 10′000 ppm DMSO stock solutions. After drying, the leaf discs were infested with an aphid population of mixed ages. The samples were assessed for mortality 6 days after infestation.
The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12, P13, P14, P15, P16, P17, P18, P19, P1-A, P2-A, P3-A, P4-A, P5-A, P6-A, P7-A, P8-A, P9-A, P10-A, P11-A, P12-A, P13-A, P14-A, P15-A, P16-A, P17-A, P18-A, P19-A, P1-B, P2-B, P3-B, P4-B, P5-B, P6-B, P7-B, P8-B, P9-B, P10-B, P11-B, P12-B, P13-B, P14-B, P15-B, P16-B, P17-B, P18-B, P19-B.
Roots of pea seedlings infested with an aphid population of mixed ages were placed directly in the aqueous test solutions prepared from 10′000 DMSO stock solutions. The samples were assessed for mortality 6 days after placing seedlings in test solutions.
The following compounds resulted in at least 80% mortality at a test rate of 24 ppm: P1, P2, P4, P5, P6, P8, P9, P10, P11, P12, P13, P14, P15, P16, P17, P18, P19, P1-A, P2-A, P4-A, P5-A, P6-A, P7-A, P8-A, P9-A, P10-A, P11-A, P12-A, P13-A, P14-A, P15-A, P16-A, P17-A, P18-A, P19-A, P1-B, P2-B, P3-B, P4-B, P5-B, P6-B, P7-B, P8-B, P9-B, P10-B, P11-B, P12-B, P13-B, P14-B, P15-B, P16-B, P17-B, P18-B, P19-B.
Cotton leaf discs were placed on agar in 24-well microtiter plates and sprayed with aqueous test solutions prepared from 10′000 ppm DMSO stock solutions. After drying the leaf discs were infested with adult white flies. The samples were checked for mortality 6 days after incubation.
The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P1, P2, P4, P5, P6, P7, P8, P9, P10, P11, P12, P13, P14, P15, P16, P17, P18, P19, P1-A, P2-A, P4-A, P5-A, P6-A, P7-A, P8-A, P9-A, P10-A, P12-A, P13-A, P14-A, P15-A, P16-A, P17-A, P18-A, P19-A, P1-B, P2-B, P4-B, P5-B, P6-B, P7-B, P8-B, P9-B, P10-B, P11-B, P12-B, P13-B, P14-B, P15-B, P16-B, P17-B, P18-B, P19-B.
Soybean leaf on agar in 24-well microtiter plates were sprayed with aqueous test solutions prepared from 10′000 ppm DMSO stock solutions. After drying the leaf were infested with N-2 nymphs. The samples were assessed for mortality and growth inhibition in comparison to untreated samples 5 days after infestation.
The following compounds gave an effect of at least 80% in at least one of the two categories (mortality or growth inhibition) at an application rate of 200 ppm: P1, P2, P5, P6, P7, P8, P9, P13, P14, P15, P18, P19, P1-A, P7-A, P8-A, P14-A, P19-A, P1-B, P5-B, P7-B, P17-B, P18-B, P19-B.
Sunflower leaf discs were placed on agar in 24-well microtiter plates and sprayed with aqueous test solutions prepared from 10′000 DMSO stock solutions. After drying the leaf discs were infested with a Frankliniella population of mixed ages. The samples were assessed for mortality 7 days after infestation.
The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P1, P7, P11-A, P1-B, P7-B, P19-B.
24-well microtiter plates with artificial diet were treated with aqueous test solutions prepared from 10′000 ppm DMSO stock solutions by pipetting. After drying, Plutella eggs were pipetted through a plastic stencil onto a gel blotting paper and the plate was closed with it. The samples were assessed for mortality and growth inhibition in comparison to untreated samples 8 days after infestation.
The following compounds gave an effect of at least 80% in at least one of the two categories (mortality or growth inhibition) at an application rate of 200 ppm: P7, P10, P1-A, P3-A, P4-A, P5-A, P6-A, P7-A, P8-A, P9-A, P10-A, P11-A, P12-A, P13-A, P14-A, P15-A, P16-A, P17-A, P18-A, P19-A, P1-B, P3-B, P4-B, P5-B, P6-B, P7-B, P8-B, P9-B, P10-B, P11-B, P12-B, P13-B, P14-B, P15-B, P16-B, P17-B, P19-B.
Bean leaf discs on agar in 24-well microtiter plates were sprayed with aqueous test solutions prepared from 10′000 ppm DMSO stock solutions. After drying the leaf discs were infested with a mite population of mixed ages. The samples were assessed for mortality on mixed population (mobile stages) 8 days after infestation.
The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P7, P13, P19-A.
24-well microtiter plates with artificial diet were treated with aqueous test solutions prepared from 10′000 ppm DMSO stock solutions by pipetting. After drying, the plates were infested with L2 larvae (6-8 per well). The samples were assessed for mortality, anti-feeding effect, and growth inhibition in comparison to untreated samples 6 days after infestation. Control of Chilo suppressalis by a test sample is given when at least one of the categories mortality, anti-feedant effect, and growth inhibition is higher than the untreated sample.
For example, the following compounds resulted in at least 80% control at an application rate of 200 ppm: P10, P2-A, P6-A, P8-A, P12-A, P13-A, P14-A, P16-A, P6-B, P8-B, P10-B, P12-B, P13-B, P14-B, P16-B.
Activity of compounds P18-A, P18-B, P15-A, P15-B, P9-A, P9-B, P5-A, P5-B, P14-A, P14-B, P6-A, P6-B, P13-A and P13-B according to the preparatory examples and of compound P13 from WO19/234158, compound P2 from WO20/084075, compound P3 from WO20/084075, compound P4 from WO20/084075, compound P14 from WO19/234158, compound P15 from WO19/234158, respectively compound P1 from WO20/084075 against Diabrotica balteata (Example B3) is summarized in Table B12.
Table B12 shows that single enantiomer compounds P18-A, P18-B, P15-A, P15-B, P9-A, P9-B, P5-A, P5-B, P14-A, P14-B, P6-A, P6-B, P1 3-A and P1 3-B (either first/second eluting following a chiral resolution [Table Z], or enantiopure/enantiomerically enriched following a stereoselective synthesis [Table Y]) according to the invention exert predominantly a substantially better insecticidal action on Diabrotica balteata than the compound from the state of the art.
Example B13: Comparison of the Insecticidal Activity of Single Enantiomer Compounds P18-A/P18-B. P10-A/P10-B. P7-A/P7-B and P16-A/P16-B According to the Invention with the Structurally Comparable Racemic Sulfoximine Compounds from the State of the Art
Activity of compounds P18-A, P18-B, P10-A, P10-B, P7-A, P7-B, P16-A and P16-B according to the preparatory examples and of compound P13 from WO19/234158, compound Y-6.001 from WO19/234158, compound P11 from WO20/084075, respectively compound P6 from WO19/234158 against Bemisia tabaci (Example B6) is summarized in Table B13.
Table B13 shows that single enantiomer compounds P18-A, P18-B, P10-A, P10-B, P7-A, P7-B, P1 6-A and P16-B (either first/second eluting following a chiral resolution [Table Z], or enantiopure/enantiomerically enriched following a stereoselective synthesis [Table Y]) according to the invention exert predominantly a substantially better insecticidal action on Bemisia tabaci than the compound from the state of the art.
Activity of compounds P18-A, P18-B, P15-A, P15-B, P6-A, P6-B, P9-A, P9-B, P5-A, P5-B, P11-A and P11-B according to the preparatory examples and of compound P15 from WO16/026848, compound P2 from WO21/219810, compound 6.009 from WO16/096584, compound P3 from WO21/219810, compound P4 from WO21/219810, respectively compound P13 from WO18/206348 against Myzus persicae (systemic, Example BS5 is summarized in Table B14.
Table B14 shows that single enantiomer compounds P18-A, P18-B, P15-A, P15-B, P6-A, P6-B, P9-A, P9-B, P5-A, P5-B, P11-A and P11-B (either first/second eluting following a chiral resolution [Table Z], or enantiopure/enantiomerically enriched following a stereoselective synthesis [Table Y]) according to the invention exert predominantly a substantially better insecticidal action on Myzus persicae (systemic activity) than the compound from the state of the art.
Activity of compound P2-A, P2-B, P16-A, P16-B, P13-A, P13-B, P1-A, P1-B, P1 0-A and P1 0-B according to the preparatory examples and of compound H-1 from WO18/108726, compound P9 from WO16/096584 or compound 11-13 from EP3252046B31, compound P18 from WO18/197315, compound P7 from WO21/21981 0, respectively compound P16 from WO16/026848 or compound 12-13 from EP3252046B31 against Myzus persicae (feeding/contact, Example B34) is summarized in Table B15.
Table B15 shows that single enantiomer compounds P2-A, P2-B, P16-A, P16-B, P13-A, P13-B, P1-A, P1-B, P10-A and P10-B (either first/second eluting following a chiral resolution [Table Z], or enantiopure/enantiomerically enriched following a stereoselective synthesis [Table Y]) according to the invention exert predominantly a substantially better insecticidal action on Myzus persicae (feeding/contact activity) than the compound from the state of the art.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202111024601 | Jun 2021 | IN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/064778 | 5/31/2022 | WO |
