Patent Application
20130184465
The present invention relates to a process using specific magnesium reagents for providing thio-triazolo group-containing compounds, in particular pesticidal compounds of the triazole class having phytopathogenic activity, and for the synthesis of precursors therefor. The invention furthermore relates to intermediates and to their preparation.
Magnesium amides and their use are, in principle, known from the literature: See for example WO 2007/082911 and the literature cited therein, for example M.-X. Zhang, P.-E. Eaton, Angew. Chem. Int. Ed. 2002, 41, 2169-2171. The use of lithium salts together with Grignard reagents is known from EP 1 582 523. WO 2007/082911 is particularly directed to mixed magnesium and lithium amides.
Important pesticidal compounds carry a thio-triazolo group. Specific thio-triazole compounds that are known as active ingredients having pesticidal, in particular fungicidal activity, are known, for example, from WO 96/38440. Also WO 2009/077471 (PCT/EP2008/067483), WO 2009/077443 (PCT/EP2008/067394) WO 2009/077500 (PCT/EP2008/067545), WO 2009/077497 (PCT/EP2008/067539), EP 09178224, EP 09178291, EP09178288 describe further specific thio-triazolo compounds. Therein, preparation routes for the disclosed compounds are explained.
In particular, it is known from the literature, for example, to introduce the thio-group into the respective triazole compounds using a strong base such as n-BuLi and sulfur powder. Alternatively, the triazole compounds are reacted with sulfur in the presence of an aprotic polar solvent, such as, for example, an amide (such as dimethylformamide (DMF)) or N-alkylpyrrolidone (such as N-octylpyrrolidone, N-dodecylpyrrolidone or N-methylpyrrolidone (NMP)). See also WO 99/19307, WO 97/06151, WO 97/05119 and WO 96/41804. The disadvantages of these methods are that the yield of the desired products is often not satisfying and that the reaction conditions often do not allow commercial scales. Regarding the reaction using n-BuLi, a further disadvantage is that the reagent is quite expensive and that the reaction has to be carried out at low temperatures, which necessitates special cooling equipment. Upscales are thus elaborate and expensive.
Consequently, the methods known from the literature are sometimes not suitable for the efficient synthesis of substituted thio-triazoles because the yield is not sufficient and/or the reaction conditions and parameters such as temperature and/or reactants are not suitable for an upscale to industrially relevant amounts. For example the reaction that involves strong bases often result in a high amount of side products and low yields of the desired products. Inter alia because some thio-triazolo compounds are promising fungicidally active compounds, there is an ongoing need for alternative processes, that are preferably improved at least in some regards and that make the thio-triazolo compounds as easily available as possible.
It has now surprisingly been found a highly efficient general synthesis for the introduction of sulfur into triazolo group-containing compounds involving the use of a magnesium amide reagent. The inventive process represents a new and general method for obtaining compounds containing a thio-triazolo group.
Thus, according to one aspect the present invention provides a process for the preparation of a thio-triazolo group-containing compound of the formula (I)
wherein the variables are defined as follows:
A key step in the process according to the invention is the deprotonation of the respective triazole compounds (IV) using magnesium amide reagent, thereby resulting in the formation of a compound (IIIa) (see below).
Accordingly, another aspect of the present invention is a process for the preparation of a compound (IIIa)
comprising the step
(i) reacting a triazolo compound of formula (IV)
Compound (IIIa) is usually not isolated from the reaction mixture but directly further reacted to the desired end products (see below). Thus, it represents an intermediate of the overall reaction.
In particular, according to one aspect, compound (IIIa) can be further reacted with a suitable electrophile to result directly in a target thio-triazolo group containing compound of formula (I)
Alternatively, according to the invention, compound (IIIa) can be transformed into a magnesium thiolate (IIa)
using sulfur. Intermediate (IIa) can be further reacted to a target compound (I) by protonating the magnesium thiolate (IIa) or by reacting the same with a suitable electrophilic compound.
Compound (IIa) is usually not isolated from the reaction mixture but directly further reacted according to the invention. Thus, it represents an intermediate of the overall reaction.
Another aspect of the present invention is a compound of formula (IIIa), wherein Q is NR1R2 or X3.zLiX2 and the synthesis and use thereof. Still another aspect of the present invention is a compound of formula (IIa), wherein Q is NR1R2 or X3.zLiX2 and the synthesis and use thereof.
The thio-triazolo groups of the general formula (I) can be present in two tautomeric forms (especially, in case “Y” is hydrogen)—the “thiol” form of the formula (Ia) or in the “thiono” form of the formula (Ib)
However, for the sake of simplicity, generally only one of the two forms, mostly the “thiol” form is shown here.
In some of the definitions of the symbols in the formulae given herein, collective terms are used which are generally representative of the following substituents:
halogen: fluorine, chlorine, bromine and iodine;
alkyl and the alkyl moieties of composite groups such as, for example, alkylamino: saturated straight-chain or branched hydrocarbon radicals having 1 to 4, 6, 8 or 12 carbon atoms, for example C1-C6-alkyl, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl;
haloalkyl: alkyl as mentioned above, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above; in particular C1-C2-haloalkyl, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl or 1,1,1-trifluoroprop-2-yl alkenyl and also the alkenyl moieties in composite groups, such as alkenyloxy: unsaturated straight-chain or branched hydrocarbon radicals having 2 to 4, 2 to 6 or 2 to 8 carbon atoms and one double bond in any position. According to the invention, it may be preferred to use small alkenyl groups, such as (C2-C4)-alkenyl; on the other hand, it may also be preferred to employ larger alkenyl groups, such as (C5-C8)-alkenyl. Examples of alkenyl groups are, for example, C2-C6-alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl;
haloalkenyl: alkenyl as defined above, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as described above under haloalkyl, in particular by fluorine, chlorine or bromine;
alkadienyl: unsaturated straight-chain or branched hydrocarbon radicals having 4 to 6 or 4 to 8 carbon atoms and two double bonds in any position;
alkynyl and the alkynyl moieties in composite groups: straight-chain or branched hydrocarbon groups having 2 to 4, 2 to 6 or 2 to 8 carbon atoms and one or two triple bonds in any position, for example C2-C6-alkynyl, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and I-ethyl-1-methyl-2-propynyl;
haloalkynyl: alkynyl as defined above, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as described above under haloalkyl, in particular by fluorine, chlorine or bromine;
cycloalkyl and also the cycloalkyl moieties in composite groups: mono- or bicyclic saturated hydrocarbon groups having 3 to 8, in particular 3 to 6, carbon ring members, for example C3-C6-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
halocycloalkyl: cycloalkyl as defined above, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as described above under haloalkyl, in particular by fluorine, chlorine or bromine;
cycloalkenyl: monocyclic monounsaturated hydrocarbon groups having preferably 3 to 8 or 4 to 6, in particular 5 to 6, carbon ring members, such as cyclopenten-1-yl, cyclopenten-3-yl, cyclohexen-1-yl, cyclohexen-3-yl, cyclohexen-4-yl and the like;
halocycloalkenyl: cycloalkenyl as defined above, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as described above under haloalkyl, in particular by fluorine, chlorine or bromine;
alkoxy: an alkyl group as defined above which is attached via an oxygen, preferably having 1 to 8, more preferably 2 to 6, carbon atoms. Examples are: methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy, and also for example, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy or 1-ethyl-2-methylpropoxy;
haloalkoxy: alkoxy as defined above, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as described above under haloalkyl, in particular by fluorine, chlorine or bromine. Examples are OCH2F, OCHF2, OCF3, OCH2Cl, OCHCl2, OCCl3, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, OC2F5, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 2-bromopropoxy, 3-bromopropoxy, 3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy, OCH2—C2F5, OCF2—C2F5, 1-(CH2F)-2-fluoroethoxy, 1-(CH2Cl)-2-chloroethoxy, 1-(CH2Br)-2-bromoethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy; and also 5-fluoropentoxy, 5-chloropentoxy, 5-bromopentoxy, 5-iodopentoxy, undecafluoropentoxy, 6-fluorohexoxy, 6-chlorohexoxy, 6-bromohexoxy, 6-iodohexoxy or dodecafluorohexoxy.
alkylene: divalent unbranched chains of CH2 groups. Preference is given to (C1-C6)-alkylene, more preference to (C2-C4)-alkylene; furthermore, it may be preferred to use (C1-C3)-alkylene groups. Examples of preferred alkylene radicals are CH2, CH2CH2, CH2CH2CH2, CH2(CH2)2CH2, CH2(CH2)3CH2 and CH2(CH2)4CH2;
a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered saturated or partially unsaturated heterocycle which contains 1, 2, 3 or 4 heteroatoms from the group consisting of O, N and S, where the heterocycle in question may be attached via a carbon atom or, if present, via a nitrogen atom. According to the invention, it may be preferred for the heterocycle in question to be attached via carbon, on the other hand, it may also be preferred for the heterocycle to be attached via nitrogen. In particular:
The finding of the present invention is that, ultimately, it offers a very general method for introducing sulfur into triazole groups. Therefore, R in principle can be any organic group that allows carrying out the reaction steps according to the inventive process ultimately resulting in thio-group-containing triazole groups. If necessary, some reactive groups within the “organic group” can be protected via suitable protecting groups. It is within the skill of a person of the art to choose suitable groups and it is general knowledge of the skilled person how to insert and remove such groups.
Important pesticidal compounds carry a thio-triazolo group. In particular, there are compounds of formula (I) known that are effective against phytopathogenic fungi. According to one aspect of the present invention, compounds of formula (I) are active compounds for controlling phytopathogenic fungi. Thus, compounds that can advantageously be synthesized using the new inventive process are for example fungicidal compounds of the triazole compound class.
For example, the inventive process has shown to be very useful for the synthesis of fungicidal thio-triazole compounds of the triazole compound class that contain an epoxide group. Compounds that contain labile functional groups such as an epoxide group can often not be efficiently and/or economically be synthesized via prior art processes. Such compounds are for example described in WO 96/38440, WO 2009/077471 (PCT/EP2008/067483), WO 2009/077443 (PCT/EP2008/067394) WO 2009/077500 (PCT/EP2008/067545) and WO 2009/077497 (PCT/EP2008/067539), EP 09178224, EP 09178291 and EP09178288, wherein these documents also describe the fungicidal activity of said compounds. In said patent applications, also the respective triazole compounds (without sulfur group) and their synthesis are disclosed.
In the following, the meaning of the substituents of the compounds used according to the invention is further defined. Thereby, in each case the substituents are meant to have the given meanings and preferred meaning on their own or in any combination with the meanings or preferred meanings of any other substituent.
Accordingly, in one aspect of the inventive process, R in the compounds (I) and the precursors thereof, in particular in compounds (IV), has the following meaning (1):
wherein # shall mean the point of attachment to the triazolo group and A and B are as defined as follows:
In group (1) particular preference is given to the following meanings of the substituents, in each case on their own or in combination.
According to one embodiment, A and B independently stand for unsubstituted phenyl or substituted phenyl containing one, two, three or four independently selected substituents L.
According to one specific embodiment, A is unsubstituted phenyl.
According to a further embodiment, A is phenyl, containing one, two, three or four, in particular one or two, independently selected substituents L, wherein L is as defined or as preferably defined herein. According to one aspect of this embodiment, one of the substituents is in 4-position (para) of the phenyl ring. According to a further aspect, L is in each case independently selected from F, Cl, Br, nitro, phenyl, phenoxy, methyl, ethyl, iso-propyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, trichloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethoxy, difluoromethoxy and trifluorochloromethyl. According to another specific aspect, L is in each case independently selected from F, Cl and Br, in particular F and Cl.
According to another embodiment, A is monosubstituted phenyl, containing one substituent L, wherein L is as defined or as preferably defined herein. According to one aspect, said substituent is in para-position.
According to a specific embodiment, A is 3-fluorophenyl.
According to another embodiment, A is phenyl, containing two or three independently selected substituents L.
According to another preferred embodiment of the invention, A is phenyl which is substituted by one F and contains a further substituent L, where the phenyl may additionally contain one or two substituents L selected independently of one another, wherein L is as defined or preferably defined herein. According to a preferred embodiment, A is a group A-1
in which # is the point of attachment of the phenyl ring to the oxirane ring; and
In one embodiment, L2 is selected from the group consisting of F, Cl, methyl, methoxy, CF3, CHF2, OCF3, OCF3 and OCHF2. According to a more specific embodiment, L2 is F or Cl.
In one embodiment, L3 is independently selected from the group consisting of F, Cl, methyl, methoxy, CF3, CHF2, OCF3, OCF3 or OCHF2. According to a more specific embodiment, L3 is independently F or Cl.
According to a preferred embodiment, m=0. According to a further preferred embodiment, m=1.
In the formula A-1, the fluorine substituent is, according to a preferred embodiment, in the 4-position.
According to still another embodiment, A is disubstituted phenyl, containing exactly two substituents L that are independently selected from each other, wherein L is as defined or as preferably defined herein. In particular, L is in each case independently selected from F, Cl, Br, C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, in particular selected from F, Cl, C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, in particular selected from F, Cl, methyl, trifluoromethyl and methoxy. According to a further aspect of this embodiment, the second substituent L is selected from methyl, methoxy and chloro. According to another aspect, one of the substituents is in the 4-position of the phenyl ring. According to another specific aspect, A is phenyl containing one F and exactly one further substituent L as defined or preferably defined herein.
According to yet a further preferred embodiment, A is disubstituted phenyl which contains one F and a further substituent L selected from the group consisting of Cl, C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy, in particular selected from the group consisting of Cl, methyl, trifluoromethyl and methoxy. The second substituent L is specifically selected from the group consisting of methyl, methoxy and chlorine. According to one aspect thereof, one of the substituents is located in the 4-position of the phenyl ring.
According to another specific embodiment, A is 2,4-disubstituted phenyl. According to still another specific embodiment, A is 2,3-disubstituted phenyl. According to still another specific embodiment, A is 2,5-disubstituted phenyl. According to still another specific embodiment, A is 2,6-disubstituted phenyl. According to still another specific embodiment, A is 3,4-disubstituted phenyl. According to still another specific embodiment, A is 3,5-disubstituted phenyl.
According to a further preferred embodiment of the invention, A is phenyl which is substituted by exactly two F. According to one aspect, A is 2,3-difluoro-substituted. According to a further aspect, A is 2,4-difluoro-substituted. According to yet a further aspect, A is 2,5-difluoro-substituted. According to yet a further aspect, A is 2,6-difluoro-substituted. According to yet a further aspect, A is 3,4-difluoro-substituted. According to yet a further aspect, A is 3,5-difluoro-substituted.
According to a further embodiment, A is trisubstituted phenyl containing exactly three independently selected substitutents L, wherein L is as defined or preferably defined herein. According to yet a further embodiment, A is phenyl which is substituted by exactly three F. According to one aspect, A is 2,3,4-trisubstituted, in particular 2,3,4-trifluoro-substituted. According to another aspect, A is 2,3,5-trisubstituted, in particular 2,3,5-trifluoro-substituted. According to still another aspect, A is 2,3,6-trisubstituted, in particular 2,3,6-trifluoro-substituted. According to still another aspect, A is 2,4,6-trisubstituted, in particular 2,4,6-trifluoro-substituted. According to still another aspect, A is 3,4,5-trisubstituted, in particular 3,4,5-trifluoro-substituted. According to still another aspect, A is 2,4,5-trisubstituted, in particular 2,4,5-trifluoro-substituted.
According to a preferred embodiment, B is phenyl, that is unsubstituted or phenyl which contains one, two, three or four independently selected substituents L, wherein L is as defined or preferably defined herein.
According to one embodiment of the invention, B is unsubstituted phenyl.
According to a further embodiment, B is phenyl which contains one, two, three or four independently selected substituents L, wherein L is as defined or preferably defined herein.
According to a further embodiment, B is phenyl which contains one, two or three, preferably one or two, independently selected substituents L, wherein L is as defined or preferably defined herein. According to a specific aspect, L is in each case independently selected from F, Cl, Br, methyl, methoxy and trifluoromethyl. According to still another embodiment, B is phenyl, which contains one, two or three, preferably, one or two, halogen substituents.
According to a further embodiment, B is phenyl which contains one, two, three or four substituents L, wherein L is independently selected from F, Cl, Br, methyl, ethyl, iso-propyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, trichloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethoxy, difluoromethoxy and difluorochloromethyl. According to a specific aspect, L is in each case independently selected from F, Cl and Br.
According to still a further embodiment, B is unsubstituted phenyl or phenyl which contains one, two or three substituents independently selected from halogen, NO2, amino, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylamino, C1-C4-dialkylamino, thio and C1-C4-alkylthio.
According to a further embodiment, B is a phenyl ring that is monosubstituted by one substituent L, where according to a special aspect of this embodiment, L is located in the ortho-position to the point of attachment of the phenyl ring to the oxirane ring. L is as defined or preferably defined herein. According to a further specific embodiment, B is monochloro-substituted phenyl, in particular 2-chlorophenyl.
According to a further embodiment, B is phenyl, which contains two or three, in particular two, independently selected substitutents L, wherein L is as defined or preferably defined herein.
According to a further embodiment of the invention, B is a phenyl ring which contains a substituent L in the ortho-position and furthermore has one further independently selected substituent L. According to one aspect, the phenyl ring is 2,3-disubstituted. According to a further aspect, the phenyl ring is 2,4-disubstituted. According to yet a further aspect, the phenyl ring is 2,5-disubstituted. According to yet a further aspect, the phenyl ring is 2,6-disubstituted.
According to a further embodiment of the invention, B is a phenyl ring which contains a substituent L in the ortho-position and furthermore contains two further independently selected substituents L. According to one aspect, the phenyl ring is 2,3,5-trisubstituted. According to a further aspect, the phenyl ring is 2,3,4-trisubstituted. According to yet a further aspect, the phenyl ring is 2,4,5-trisubstituted.
In a further embodiment, B is phenyl which contains one substituent L in the 2-position and one, two or three further independently selected substituents L. According to a preferred embodiment, B is a group B-1
in which # denotes the point of attachment of the phenyl ring to the oxirane ring; and
According to a preferred embodiment, L1 is F. According to another preferred embodiment, L1 is Cl. According to a further preferred embodiment, L1 is methyl. According to yet a further preferred embodiment, L1 is methoxy. According to yet a further preferred embodiment, L1 is CF3. According to yet a further preferred embodiment, L1 is OCF3 or OCHF2. According to a preferred embodiment, in the compounds of the formula I according to the invention, B is thus phenyl which contains a substituent selected from the group consisting of F, Cl, CH3, OCH3, CF3, CHF2, OCF3 and OCHF2 in the 2-position and one or two further independently selected substituents L.
According to a further preferred embodiment, L2 is F. According to another preferred embodiment, L2 is Cl. According to a further preferred embodiment, L2 is methyl. According to yet a further preferred embodiment, L2 is methoxy. According to yet a further preferred embodiment, L2 is CF3. According to yet a further preferred embodiment, L2 is OCF3 or OCHF2.
According to a preferred embodiment, L3 is F. According to another preferred embodiment, L3 is Cl. According to a further preferred embodiment, L3 is methyl. According to yet a further preferred embodiment, L3 is methoxy. According to yet a further preferred embodiment, L3 is CF3. According to yet a further preferred embodiment, L3 is OCF3 or OCHF2.
According to a preferred embodiment, m=0; i.e. B is a disubstituted phenyl ring. According to a preferred aspect, B is a 2,3-disubstituted phenyl ring. According to a further preferred aspect, the phenyl ring B is 2,4-disubstituted. According to yet a further preferred aspect, the phenyl ring B is 2,5-disubstituted. According to yet a further preferred aspect, the phenyl ring is 2,6-disubstituted.
According to a further preferred embodiment, m=1; i.e. B is a trisubstituted phenyl ring. According to a preferred aspect, the phenyl ring B is 2,3,5-trisubstituted. According to another preferred further aspect, the phenyl ring B is 2,3,4-trisubstituted. According to yet a further preferred embodiment, the phenyl ring B is 2,4,5-trisubstituted.
Unless indicated otherwise, in group (1) L independently has the following preferred meanings:
According to one embodiment, L is independently selected from the group consisting of halogen, cyano, nitro, cyanato (OCN), C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, S-A6, C(═O)A7, C(═S)A7, NA8A9; where A6, A7, A8, A9 are as defined below:
Furthermore preferably, L is independently selected from the group consisting of halogen, NO2, amino, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylamino, thio and C1-C4-alkylthio.
Furthermore preferably, L is independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and C1-C4-haloalkylthio, in particular halogen, C1-C4-alkyl and C1-C4-haloalkyl.
According to a further preferred embodiment, L is independently selected from the group consisting of F, Cl, Br, CH3, C2H5, i-C3H7, t-C4H9, OCH3, OC2H5, CF3, CCl3, CHF2, CClF2, OCF3, OCHF2 and SCF3, in particular selected from the group consisting of F, Cl, CH3, C2H5, OCH3, OC2H5, CF3, CHF2, OCF3, OCHF2 and SCF3. According to one aspect, L is independently selected from the group consisting of F, Cl, CH3, OCH3, CF3, OCF3 and OCHF2. It may be preferred for L to be independently F or Cl.
According to one preferred embodiment, A and B are as defined as follows:
A phenyl, which is unsubstituted or substituted by one, two or three substituents L that may be the same or different, independently selected from F, Cl, Br, nitro, phenyl, phenoxy, methyl, ethyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, trichloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethoxy, difluoromethoxy and trifluoromethylthio; and
B phenyl, that is substituted by one, two or three substituents L that may be the same or different, independently selected from F, Cl, Br, methyl, ethyl, iso-propyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, trichloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethoxy, difluoromethoxy and trifluoromethylthio.
In specific groups (1) A and B are defined as follows:
A is phenyl, 4-chlorophenyl, 2,4-chlorophenyl, 2-chlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 4-methylphenyl, 3-bromo-4-fluorophenyl, 4-bromophenyl, 3,4-dichlorophenyl, 4-tert-butyl-phenyl, 3-chlorophenyl, 3,5-dichlorophenyl or 4-trifluoromethoxyphenyl and B is 2-chlorophenyl. In one specific group (1) A is 4-flourphenyl and B is 2-chlorophenyl.
A is 4-fluorophenyl and B is 2-difluoromethoxyphenyl.
A is phenyl, 4-chlorophenyl, 2,4-chlorophenyl, 2-chlorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-fluorophenyl, 3-bromo-4-fluorophenyl, 4-bromophenyl, 3,4-dichlorophenyl, 4-tert-butyl-phenyl, 3-chlorophenyl, 3,5-dichlorophenyl or 4-trifluoromethoxyphenyl, and B is 2-fluorophenyl.
A is phenyl, 4-chlorophenyl, 2,4-chlorophenyl, 2-chlorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-fluorophenyl, 3-bromo-4-fluorophenyl, 4-bromophenyl, 3,4-dichlorophenyl, 4-tert-butyl-phenyl, 3-chlorophenyl, 3,5-dichlorophenyl or 4-trifluoromethoxyphenyl, and B is 2-bromophenyl.
In further specific groups (1) A and B are defined as follows:
A is 2,4-difluorophenyl and B is 2-chlorophenyl.
A is 3,4-difluorophenyl and B is 2-chlorophenyl.
A is 2,4-difluorophenyl and B is 2-fluorophenyl.
A is 3,4-difluorophenyl and B is 2-fluorophenyl.
A is 2,4-difluorophenyl and B is 2-trifluoromethylphenyl.
A is 3,4-difluorophenyl and B is 2-trifluoromethylphenyl.
A is 3,4-difluorophenyl and B is 2-methylphenyl
In further specific groups (1) A and B are defined as follows:
A is phenyl and B is 2,4-dichlorophenyl.
A is phenyl and B is 2-fluoro-3-chlorophenyl.
A is phenyl and B is 2,3,4-trichlorophenyl.
A is 4-fluorophenyl and B is 2,4-dichlorophenyl.
A is 4-fluorophenyl and B is 2-fluoro-3-chlorophenyl.
A is 4-fluorophenyl and B is 2,3,4-trichlorophenyl.
A is 2-chlorophenyl and B is 2,4-dichlorophenyl.
A is 2-chlorophenyl and B is 2-fluoro-3-chlorophenyl.
A is 2-chlorophenyl and B is 2,3,4-trichlorophenyl.
The meanings described above of the variables A, B and L for groups (1) apply for R=group (1) in compounds (I) and, unless indicated otherwise, correspondingly to the precursors of the compounds (I) and side products.
The precursors for compounds (I)-(1), such as the respective compounds (IV)-(1) can be synthesized as described in the above mentioned patent applications.
The compounds (IV)-(1) can be prepared in an advantageous manner from compounds of the formula (XI)
in which Z is a leaving group, such as, for example, halogen (for example Cl or Br) or OSO2Rxx, where Rxx is C1-C6-alkyl, C1-C6-haloalkyl, aryl or substituted aryl; OSO2Rxx is in particular a mesylate, triflate, phenyl or toluenesulfonate group. To obtain compounds of the formula (IV)-(1), compounds of the formula (XI), are reacted with 1,2,4-triazole and a base such as, for example, sodium hydride, for example in DMF. See also, for example, EP 0 421 125 A2.
Compounds of the formula (XI) can be obtained from compounds (XI), wherein Z is a hydroxy group by introducing the leaving group Z by methods known to the person skilled in the art. Thus, the respective hydroxy compound is reacted, for example, with Ryy—SO2Y, where Ryy is as defined for formula (XI) and Y is halogen, where Ryy—SO2Y is, for example, mesyl chloride, in the presence of a base (for example NEt3) (see also EP386557). To obtain compounds (XI), in which Z is halogen, the corresponding hydroxy compound can be reacted with C(Hal)4 (Hal=Br or Cl) with PPh3, for example in CH2Cl2. Alternatively, SOCl2/pyridine can be used (see also WO 2005/056548). The hydroxy compounds of the formula (XI) (Z═OH) can be obtained from α,β-disubstituted acroleins of the type of the formula
by initial epoxidation, for example with H2O2 in the presence of a base such as, for example, NaOH or by reaction with a peracid (for example MCPBA=m-chloroperoxybenzoic acid) or tert-butyl hydroperoxide). The resulting aldehyde can then be reduced to the hydroxy compound, for example with NaBH4 (see also EP 0 386 557A1). Processes for epoxidation and reduction of the aldehyde group are well known to the person skilled in the art. The double bond can be present either in the (E) or in the (Z) configuration. This is indicated by the zig-zag bond between B and the double bond. The acrolein compounds can be synthesized, for example, analogously to the procedure described in DE3601927. According to one alternative, they can be prepared via an aldol synthesis according to the scheme below:
Another way to prepare the compounds (XI) consists in converting the double bond in compounds of the formula
to the epoxide. Suitable epoxidation methods are known to the person skilled in the art. It is possible, for example, to use hydrogen peroxide/maleic anhydride for this purpose. The double bond may be present either in (E) or in (Z) configuration. This is indicated by the zigzag bond between B and the double bond. These compounds can be obtained from compounds
by reacting, for example, with acetic acid/H2SO4 in a suitable organic solvent such as, for example, an ether, such as Et2O or 1,4-dioxane, to form the double bond. Suitable methods are known to the person skilled in the art. These compounds can be obtained, for example, by a Grignard reaction according to the following scheme:
See also EP 409049.
According to the inventive process, the pure enantiomers or a mixture of enantiomers (racemic or enantiomerically enriched) of the reactants, in particular of compounds of formula (IV), can be used. According to a preferred embodiment, the racemic mixture is used. Depending on the use of the respective reactant, in particular of compound of formula (IV), it is possible to obtain compounds of formula (I) having a certain stereochemistry. For example, the following different stereoisomers of compounds (I)-(1) can be obtained using the inventive process:
compound (I)-(1)-a1):
Formula (I)-(1), wherein A is 4-fluoro-phenyl and B is 2-chlorophenyl; Y is SH:
With respect to the fungicidal activity of the end products, it may be preferred, if the “trans” diastereomers are synthesized in the inventive process.
According to one specific embodiment of the present invention, R in compounds (IIa) and (IIIa) is a group (1) as defined above, including the specific embodiments thereof. In particular, compounds (IIa)-(1) and compounds (IIIa)-(1),
according to the invention compiled in tables 1a to 257a in combination with rows 1 to 2313 of table A below are suitable for the synthesis of the respective fungicides of formula (I) and are obtained by the inventive process. The groups mentioned for a substituent in the tables are furthermore per se, independently of the combination in which they are mentioned, a particularly preferred aspect of the substituent in question.
One undesired side product in the synthesis of compounds (I)-(1) that may occur in undesired amounts with prior art processes and that can be reduced or even avoided using the new inventive process is the cyclizised hydroxy compound IA:
wherein A and B are as defined and preferably defined as for compounds (I)-(1). In conventional processes, for example using high temperature or n-butyllithium as a base, product IA may occur to up to 100%, leading, consequently, to very low yields of the desired product of formula (I). According to the inventive process, in particular when carrying out the process steps (ii) and (iii-1), more particular steps (i), (ii) and (iii-1), in case R has the meaning (1), side product IA is formed preferably to equal or less than 10%, more preferably equal or less than 8%, even more preferably equal or less than 5%, even more preferably equal or less than 3%.
Another undesired side product in the synthesis of compounds (I)-(1) that may occur in undesired amounts with prior art processes and that can be reduced or even avoided using the new inventive process is the cyclizised hydroxy compound IB:
wherein A and B are as defined and preferably defined as for compounds (I)-(1). In conventional processes, for example using high temperature or n-butyllithium as a base, product IB may occur to up to 100%, leading, consequently, to very low yields of the desired product of formula (I). According to the inventive process, in particular when carrying out the process steps (ii) and (iii-1), more particular steps (i), (ii) and (iii-1), in case R has the meaning (1), side product IA is formed preferably to equal or less than 10%, more preferably equal or less than 8%, even more preferably equal or less than 5%, even more preferably equal or less than 3%.
According to another embodiment of the present invention, the organic group R in the compounds (I) and the precursors thereof carries a free hydroxy group and compounds (1) are from the triazole class of fungicides. In a particular embodiment thereof, R stands for a group of formula (2):
wherein R11 and R22 have the following meanings:
wherein R33 and R44 independently are selected from the group of hydrogen and the meaning for L as defined above.
According to one embodiment, R11 and R12 are preferably independently selected from C1-C4-alkyl and phenyl, wherein the alkyl and phenyl group independently may contain one, two, three or four substitutents, independently selected from F, Cl, Br, methoxy, ethoxy, propoxy, isopropoxy, C1-C2-alkoximino, cyclopropyl, cyclobutyl, cyclopentyl and/or cyclohexyl. Specifically, R11 stands for C1-C4-alkyl that is substituted by one or two substituents independently selected from F, Cl, methoxy, cyclopropyl, cyclopentyl and/or cyclohexyl and R12 stands for phenyl, that is substituted by one, two, three or four substituents independently selected from F, Cl, Br and methoxy. In one specific embodiment, R11 is 1-ethyl that is 1-substituted by cyclopropyl and R12 is 4-chlorophenyl. According to another specific embodiment, R11 is n-butyl and R12 is 2,4-dichlorophenyl.
According to another embodiment, R11 and R12 are preferably independently selected from C1-C4-alkyl, phenyl-C1-C4-alkyl and C3-C6-cycloalkyl, preferably phenyl-C1-C4-alkyl and C3-C6-cycloalkyl, wherein the alkyl, phenyl and cycloalkyl groups independently may contain one, two, three or four substitutents, independently selected from F, Cl, Br, CN, methyl, ethyl, propyl, isopropyl and/or tert-butyl. Specifically, R11 stands for phenyl-C1-C4-alkyl that is substituted in the phenyl moiety by one, two, three or four substituents independently selected from F, Cl and methoxy and R12 stands for C3-C6-cycloalkyl, that is substituted by one, two, three or four substituents independently selected from F, Cl, Br and methoxy. In one specific embodiment, R11 is 2-chlorophenylmethyl and R12 is 1-chlorocyclopropyl.
According to still another embodiment, R11 and R12 are preferably independently selected from C1-C4-alkyl and phenyl-C1-C4-alkyl, wherein the alkyl and phenyl groups may contain one, two, three or four substitutents, independently selected from F, Cl, Br, CN, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxyvarbonyl, methoxyiminomethyl, 1-methoximinoethyl and nitro. Specifically, R11 stands for C1-C4-alkyl that may be substituted by one or two substituents, independently selected from methyl, ethyl, propyl, isopropyl and tert-butyl and R12 stands for phenyl-C1-C4-alkyl, that is substituted in the phenyl moiety by one, two, three or four substituents independently selected from F, Cl, Br, CN, methyl, trifluoromethyl and methoxy. In one specific embodiment R11 is tert-butyl and R12 is 2-(4-chlorophenyl)-1-ethyl.
According to still another embodiment, R11 and R12 are preferably independently selected from phenyl, wherein the phenyl moieties may contain one, two, three or four substitutents, independently selected from F, Cl, Br, CN, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxyvarbonyl, methoxyiminomethyl, 1-methoximinoethyl and nitro. Specifically, R11 and R12 independently stand for phenyl, that may contain one, two or three substitutents, independently selected from F, Cl and Br. In one specific embodiment R11 is 2-fluorophenyl and R12 is 4-fluorophenyl.
According to still another embodiment, preferably R11 and R22, together with the carbon atom to which they are attached, form a five- or six-membered saturated ring, that can be unsubstituted or substituted by one, two or three substituents L′, wherein L′ stands for L as defined above or stands for a group
wherein R33 and R44 independently are selected from the group of hydrogen, C1-C4-alkyl and phenyl, wherein the alkyl and phenyl groups may contain one, two, three or four substitutents, independently selected from F, Cl, Br, CN, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy and nitro. Specifically, R11 and R22, together with the carbon atom to which they are attached, form a five-membered saturated ring, that is substituted by one, two or three substituents L′, wherein L′ stands for C1-C4-alkyl or for a group
wherein R33 and R44 independently are selected from the group of hydrogen, C1-C4-alkyl and phenyl, wherein the alkyl and phenyl groups may contain one, two, three or four substitutents, independently selected from F, Cl, CN, methyl, isopropyl, tert-butyl and methoxy. In one specific embodiment R11 and R22, together with the carbon atom to which they are attached, form a five-membered saturated ring, that is substituted in 5-position by two methyl groups and contains a group
wherein R33 is hydrogen and R44 is 4-chlorophenyl in 2-position.
According to still another embodiment, R11 and R22, together with the carbon atom to which they are attached, form a five- or six-membered saturated ring, that can be un-substituted or substituted by one, two or three substituents, independently selected from F, Cl, Br, CN, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, nitro, benzyl, wherein the phenyl moiety itself may contain on, two, three or four substituents, independently selected from F, Cl, CN, methyl, isopropyl, tert-butyl and methoxy. In one specific embodiment R11 and R22, together with the carbon atom to which they are attached, form a five-membered saturated ring, that is substituted in 5-position by two methyl groups and contains a 4-chlorobenzyl group in 2-position. Regarding compounds (I)-(2) and the synthesis of precursors thereof see also WO 96/16048, WO 96/38423, EP378953, EP655443, DE 4030039, DE 3337937, DE3315681, U.S. Pat. No. 4,414,210.
According to another embodiment of the present invention, R stands for a group of formula (3):
wherein R55, R66 and R77 have the following meanings:
R55 phenyl-C1-C8-alkyl, phenyl or a five- or six-membered saturated, partially unsaturated or aromatic heterocycle which contains one, two, three or four heteroatoms from the group consisting of O, N and S; where the aliphatic and/or aromatic and/or heterocyclic groups for their part may carry one, two, three or four identical or different groups selected from halogen, cyano, nitro, C1-C8-alkyl, C1-C8-haloalkyl, C1-C8-alkoxy, C1-C8-haloalkoxy, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkenyl, C3-C8-cycloalkoxy, C3-C8-halocycloalkoxy, C1-C8-alkylcarbonyl, C1-C8-alkylcarbonyloxy, C1-C8-alkoxycarbonyl, amino, C1-C8-alkylamino, di-C1-C8-alkylamino, phenyl, halophenyl, phenyloxy, halophenyloxy;
According to one embodiment, R55 is phenyl, that is unsubstituted or substituted by one, two, three or four substituents independently selected from halogen, C1-C6-alkyl, C1-C6-haloalkyl, phenoxy-C1-C6-alkyl and halophenyloxy, and R66 and R77 are independently selected from hydrogen, methyl, ethyl, n-propyl and n-butyl. Specifically, R55 is phenyl, that contains one, two or three substituents independently selected from F, Cl and halophenoxy, wherein the phenoxy moiety contains one or two halogen atoms selected from Cl and F; and R66 is hydrogen and R77 is C1-C4-alkyl. In one specific embodiment R55 is 4-(4-chlorophenoxy)-2-chlorophenyl, R66 is hydrogen and R77 is methyl. In another specific embodiment R55 is 2,4-dichlorophenyl, R66 is hydrogen and R77 is n-propyl.
Regarding compounds (I)-(3) and the synthesis of precursors thereof see also WO 96/41804 and Pestic. Sci, 1980, 11, 95 and Research Disclosure 1989, 297,13.
According to another embodiment of the present invention, R stands for a group of formula (4):
wherein R222, R333 and R444 have the following meanings:
R222 and R333 are independently selected from hydrogen, cyano, C1-C6-alkyl and C1-C6-haloalkyl, wherein the alkyl moieties may be unsubstituted or substituted by one, two, three or four substituents L as defined or preferably defined above for compounds, wherein R is a group (1). In particular, R222 and R333 are independently selected from hydrogen, cyano and C1-C4-alkyl, wherein the alkyl moiety may contain one, two, three or four substituents independently selected from F, Cl, CN, C1-C4-alkoxy and C1-C4-haloalkoxy. q is one, two three or five, preferably one or two, and R444 are independently selected from L as defined or preferably defined above for compounds, wherein R is a group (1), in particular independently selected from F, Cl, CN, methyl, isopropyl, tert-butyl and methoxy, more specifically independently selected from Cl and F. According to one specific embodiment, R222, is hydrogen, R333 is methyl, substituted by 1,1,2,2-tetrafluoroethoxy, and R444 is 2,4-dichlorophenyl. According to another specific embodiment, R222 is cyano, R333 is n-butyl and R444 is 4-chlorophenyl. According to still another specific embodiment, R222 is hydrogen, R333 is n-propyl and R444 is 2,4-dichlorophenyl. Regarding compounds (I)-(4) and the synthesis of precursors thereof see also DE19528300, DE19529089.
According to another embodiment of the present invention, R stands for a group of formula (5):
wherein # shall mean the point of attachment to the triazolo group and Q1, Q2, R555, R666, R777 and R888 are as defined as follows:
For compounds (I)-(5) and their precursors (in particular wherein the triazole group does not contain SH or a derivatized sulfur group) and the preparation of the same, see WO2010/029001, WO2010/029002, WO 2010/029000, WO 2010/029003, WO2010/031721, WO 2010/031847, WO 2010/031848, WO 2010/031842 (PCT/EP 2009/062122) and/or WO 2010/040718 (PCT/EP2009/062909).
Y in the compounds (I) is hydrogen, halogen, (C1-C8-alkyl, (C1-C8)-haloalkyl, (C2-C8)-alkenyl, (C2-C8)-haloalkenyl, (C2-C8)-alkynyl, (C2-C8)-haloalkynyl, (C6-C10)-aryl, a five-, six-, seven-, eight-, nine- or ten-membered, in particular five- or six-membered, aromatic heterocycle that contains one, two, three or four heteroatoms from the group consisting of O, N and S, C(═S)R9, SO2R10 or CN; wherein
According to one embodiment, Y in compounds (I) is hydrogen.
According to a further embodiment of the invention, Y in compounds (I) is (C1-C8-alkyl, (C2-C8)-alkenyl or CN.
According to a further embodiment of the invention, Y in compounds (I) is C1-C8-alkyl, preferably C1-C5-alkyl or C1-C4-alkyl. According to one specific embodiment, Y in compounds (I) is C3-alkyl, according to another specific embodiment, Y in compounds (I) is C5-alkyl. Particular examples of preferred Y are methyl, ethyl, iso-propyl, n-butyl or n-pentyl.
According to still a further embodiment of the invention Y in compounds (I) is (C2-C8)-alkenyl, in particular (C3-C6)-alkenyl such as Y=allyl.
According to still a further embodiment of the invention Y in compounds (I) is CN.
One key step of the present invention is providing a triazole magnesium compound of formula (IIIa)
by means of a process comprising the step
The present invention, thus, provides a use of a reagent (R1R2N)MgQ (Va), wherein the variables are defined or preferably defined herein, for the synthesis of thio-triazolo group-containing compounds of the formula (I) as defined or preferably defined herein.
According to one aspect of the invention, the amide reagent (R1R2N)MgQ (Va) is used, wherein Q is (C1-C10)-alkyl, (C2-C10)-alkenyl, (C2-C10)-alkynyl, (C3-C8)-cycloalkyl, (C6-C10)-aryl, wherein the aryl is unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen and (C1-C4)-alkyl, NR1R2 or X1, wherein X1 is halogen.
According to another aspect of the invention, the amide reagent (R1R2N)MgQ (Va) is used, wherein Q is X3.zLiX2, wherein X3, X2 are independently halogen (=amide reagent (Vb)).
Also both, amide reagents (Va) and (Vb), in any suitable weight ratio can be used according to the present invention.
In the R1R2N group, R1 and R2 are, according to one embodiment, in particular independently selected from (C1-C6)-alkyl, Si(A1A2A3), (C3-C6)-cycloalkyl and (C6-C10)-aryl, wherein A1, A2, A3 are preferably independently selected from C1-C4-alkyl, trimethylsilyl and phenyl. The groups in R1 and R2 may independently from each other bear one, two or three identical or different Ra groups, wherein Ra is in each case preferably independently selected from halogen, C1-C4-alkyl, C1-C4-alkoxy and C1-C4-haloalkoxy.
Particularly suitable are R1R2N groups, wherein R1 and R2 are independently selected from methyl, ethyl, isopropyl, n-butyl, sec-butyl, tert-butyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tris(trimethylsilyl)silyl, more particularly selected from trimethylsilyl, isopropyl and tert-butyl.
According to another embodiment of the invention in the R1R2N group, R1 and R2, together with the nitrogen atom to which they are bonded, form a five- or six-membered saturated or partially unsaturated, in particular saturated, heterocyclyl, which is bonded via N and, if it is a six-membered heterocyclyl, which may contain one or two additional heteroatoms selected from O, N and S. According to one embodiment, R1 and R2 form a five-membered ring. According to another embodiment, R1 and R2 form a six-membered ring. According to one embodiment, the heterocyclyl is unsubstituted. According to another embodiment, the heterocyclyl carries one, two, three or four substituents, preferably selected from the group of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and C6-C10-aryl.
Particularly suitable are R1R2N groups, wherein R1 and R2 together with the nitrogen atom to which they are bonded, form six-membered saturated heterocyclyl, which is bonded via N and which may contain one or two additional heteroatoms selected from O, N and S, and which carries one, two, three or four substituents, selected from the group of halogen, C1-C4-alkyl, C1-C4-haloalkyl and C6-C10-aryl, in particular halogen, C1-C4-alkyl, C1-C4-haloalkyl and phenyl. More particularly, R1 and R2 and the nitrogen form TMP (2,2,6,6-tetramethylpiperidine), piperidine, pyrrolidine, morpholine, thiomorpholine and N-alkyl- or N-aryl-piperazine, in particular TMP (2,2,6,6-tetramethylpiperidine), piperidine, pyrrolidine, morpholine, thiomorpholine, N-alkyl- or N-phenyl-piperazine.
According to one embodiment of the invention Q is (C1-C10)-alkyl, (C2-C10)-alkenyl, (C2-C10)-alkynyl, (C3-C8)-cycloalkyl or (C6-C10)-aryl, wherein the aryl is unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen and (C1-C4)-alkyl. In particular, Q is (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl or phenyl, optionally containing one, two or three substituents selected from Cl, F, methyl and ethyl. According to one embodiment, Q is (C1-C6)-alkyl, in particular (C2-C4)-alkyl. Specific examples for Q are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl. It may be preferred according to the invention to use reagents, wherein Q is iso-propyl, n-butyl or cyclopentyl. According to another embodiment, Q is (C2-C6)-alkenyl, in particular vinyl. According to still another embodiment, Q is unsubstituted phenyl.
According to another embodiment of the invention, Q is X2, wherein X2 is halogen, in particular Cl or Br.
According to another embodiment, Q is NR1R2, wherein R1 and R2 are preferably defined as given above.
According to another embodiment, Q is X3.zLiX2, wherein X3, X2 are independently halogen (=amide reagent (Vb)), in particular Cl.
The magnesium amide reagents used according to the present invention can generally be prepared by reacting a organomagnesium halide QMgX1 or a diorganomagnesium compound Q2Mg, wherein Q is (C1-C10)-alkyl, (C2-C10)-alkenyl, (C2-C10)-alkynyl, (C3-C8)-cycloalkyl, (C6-C10)-aryl, wherein the aryl is unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen and (C1-C4)-alkyl, with the respective amine.
In particular, the synthesis of the reagent (Va) wherein Q is (C1-C10)-alkyl, (C2-C10)-alkenyl, (C2-C10)-alkynyl, (C3-C8)-cycloalkyl, (C6-C10)-aryl, wherein the aryl is unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen and (C1-C4)-alkyl, can be carried out starting from (n-butyl)2Mg or any similar dialkyl magnesium compound, that is commercially available with 1.0 equivalent of the respective amine, see for example M.-X. Zhang, P. E. Eaton, Angew. Chem. Int. Ed. 2002, 41, 2169.
The synthesis of the reagent (Va) wherein Q is NR1R2 can be carried out starting from (n-butyl)2Mg or any similar dialkyl magnesium compound, that is commercially available with 0.5 equivalents of the respective amine, see for example P. E. Eaton, C.-H. Lee, Y. Xiong, J. Am. Chem. Soc. 1989, 111, 8016.
The synthesis of the reagent (Va) wherein Q is halogen can for example be carried out starting from EtMgBr or any similar organomagnesium halide, that is commercially available with 1.0 equivalent of the respective amine, see for example F. C. Frostick, C. R. Hauser, J. Am. Chem. Soc. 1949, 71, 1350.
The synthesis of the reagent (Vb) wherein Q is halide can for example be carried out starting from iPrMgCl.LiCl or any similar organomagnesium halide, that is commercially available with 1.0 equivalents of the respective amine, see for example A. Krasovskiy, V. Krasovskaya, P. Knochel, Angew. Chem. Int. Ed. 2006, 45, 2958.
The synthesis of the reagent (Vb) wherein Q is NR1R2 can for example be carried out starting from iPrMgCl.LiCl or any similar organomagnesium halide, that is commercially available with 0.5 equivalents of the respective amine, see for example G. C. Clososki, C. J. Rohbogner, P. Knochel, Angew. Chem. Int. Ed. 2007, 46, 7681.
If, according to the above mentioned aspect of the invention, the amide reagent (R1R2N)MgX3.zLiX2 (Vb) is used, z is >0, preferably in the range from 0.001 to 5, more particularly in the range from 0.5 to 2, even more particularly in the range from 0.9 to 1.2 and it may be preferred if z is about 1.
According to one embodiment of the inventive process, zLiX2 is added to the reaction mixture of step (i). According to an alternative, before contacting the magnesium amide reagent (Va) with a compound of formula (I), it is brought together with the respective amount of LiX2, thereby forming an addition product (R1R2N)MgX3.zLiX2 (Vb). According to this alternative, (R1R2N)MgX3.zLiX2 (Vb) is then used in step (i). The use of LiX2 together with magnesium amide reagents is generally known in the art, see for example Angew. Chem. Int. Ed. 2006, 45, 159 and WO 2007/082911 and the literature cited therein.
According to still another aspect of the invention, the magnesium amide reagent (Va) or (Vb), respectively, is used in catalytic amounts, and the reagent is recycled in situ.
The process step (i) according to the invention can be carried out in any organic solvent that is suitable for magnesium amide reagents. In general, the use of ethers is advantageous. Possible solvents are for example tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (2-Me-THF), diethyl ether, TBME (tert-butyl methyl ether), CPME (cyclopentyl methyl ether), DME (1,2-dimethoxyethane) and 1,4-dioxane. Further solvents that may be suitable are, for example, diisopropyl ether, di-n-butyl ether and/or diglyme. Often, the use of THF or 2-methyl-THF is particularly suitable. Furthermore, it may also be suitable to use combinations of two or more different solvents, such as for example any combination of the solvents listed above or any one of the listed ethers with aliphatic hydrocarbons like n-hexane, heptane or aromatic hydrocarbons like toluene or xylenes.
As mentioned above, one advantage of the inventive process is, that it can be carried out in a large temperature range. This especially applies to step (i). In particular, there is no need for strongly cooling the reaction mixture, although it is sometimes beneficial to run the reaction under slight cooling. On the other hand, it can also be advantageous to work at elevated temperatures. This can be favourable in order to achieve higher conversion of the reagents to the products. Suitable temperature ranges are −40° C. to 80° C., in particular −30° C. to 60° C., more particularly −20° C. to 20° C. It may be preferred to carry out the reaction at temperatures of −20° C. to 0° C. It may be also preferred to work at temperatures of 0° C. to 20° C.
The reaction components in step (i) are usually employed in amounts such that 1 to 10 moles, in particular 1,1 to 5, more particularly 1,2 to 3 moles of magnesium amide reagent are used per mole of the compound (IV). It may be preferred if 1 to 2,5 moles of the magnesium amide reagent are used per mole of the compound (IV).
Compounds of formula (IIIa), wherein Q is NR1R2 or X3.zLiX2 are novel. Accordingly, a further aspect of the present invention is a compound of formula (IIIa)
wherein Q is NR1R2 or X3.zLiX2, as defined and preferably defined above and R is as defined or preferably defined above, wherein it is preferred if R is one of sub-groups (1), (2), (3), (4) or (5) as defined and preferably defined above. According to one specific embodiment, R in compounds (IIIa) is a group (1) as defined above, including the specific embodiments thereof.
A further aspect of the present invention is a use of a compound of formula (IIIa) as defined and preferably defined herein, for the synthesis of a thio-triazolo group-containing compound of the formula (I) as defined herein.
The process of the present invention may be described as the synthesis of thio-triazolo group containing compounds (I), particularly pesticidal compounds of the triazole class having phytopathogenic activity,
by a process comprising either step (ii) together with step (iii-1) or (iii-2); or comprising step (iv):
with sulfur, wherein R and Q are as defined above, in order to obtain a compound of formula (IIa)
and
According to step (ii), a compound (IIIa) is reacted with sulfur, thereby forming magnesium thiolates of formula (IIa). Sulfur (Ss) is preferably used as a powder. The reaction components are usually employed in amounts such that 1 to 20 moles, in particular 1.2 to 10, more particularly 1.3 to 5 moles of sulfur are used per mole of the compound (IIIa). It may be preferred if 1 to 4 moles of sulfur are used per mole of the compound (IIIa).
Suitable solvents for step (ii) are all inert organic solvents, where preferably ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether and 1,2-dimethoxyethane can be used. Furthermore, it may also be suitable to use combinations of two or more different solvents, such as for example any combination of the solvents listed above or any one of the listed ethers with aliphatic hydrocarbons like n-hexane, heptane or aromatic hydrocarbons like toluene or xylenes.
The reaction temperature is preferably between −40° C. and 80° C., in particular between −30° C. and 60° C. It may be preferred to work at temperatures of −20° C. to 20° C.
The reaction is generally carried out under atmospheric pressure.
Usually, the reaction mixture resulting from step (ii) is directly used for subsequent steps (iii-1) or (iii-2). However, in case a work-up is suitable, it can be carried out according to procedures generally known to the person skilled in the art.
According to step (iii-1), the respective compound (IIa) is protonated in order to obtain compounds of formula (I), wherein Y is hydrogen (in the following also called compounds (I.1):
Suitable reagents for the protonation are for example hydrohalic acids, such as hydrogen fluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide, carbonic acid, sulfuric acid, phosphoric acid and nitric acid. The latter acids are generally used in an aqueous medium. Also organic acids can be used for step (iii-1), for example formic acid and alkanoic acids, such as acetic acid, trifluoroacetic acid, trichloroacetic acid and propionic acid, and also glycolic acid, lactic acid, succinic acid, citric acid, benzoic acid and other arylcarboxylic acids, cinnamic acid, oxalic acid, alkylsulfonic acids (sulfonic acids having straight-chain or branched alkyl radicals of 1 to 20 carbon atoms), arylsulfonic acids or aryldisulfonic acids (aromatic radicals, such as phenyl and naphthyl, which carry one or two sulfonic acid groups), alkylphosphonic acids (phosphonic acids having straight-chain or branched alkyl radicals of 1 to 20 carbon atoms), arylphosphonic acids or aryldiphosphonic acids (aromatic radicals, such as phenyl and naphthyl, which carry one or two phosphoric acid radicals), where the alkyl or aryl radicals may carry further substituents, for example p-toluenesulfonic acid, salicylic acid, p-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid etc.
Furthermore, the protonation step (iii-1) of the inventive process may be carried out using other protonating agents, such as alcohols, for example (C1-C6)-alcohols, in particular methanol, ethanol, isopropanol or isobutanol. Also water as such may be used. It may be preferred to use water, if appropriate in the presence of an organic or inorganic acid such as, for example, acetic acid, dilute sulfuric acid or dilute hydrochloric acid.
According to step (iii-2), the respective compound (IIa) is reacted with the respective electophilic reagent Y1-LG in order to obtain compounds of formula (I), wherein Y is Y1, which is (C1-C8)-alkyl, (C1-C8)-haloalkyl, (C2-C8)-alkenyl, (C2-C8)-haloalkenyl, (C2-C8)-alkynyl, (C2-C8)-haloalkynyl, C(═S)R9, SO2R10 or CN; wherein R9 and R10 are as defined and preferably defined above.
LG stands for a leaving group, such as, for example, halogen, such as Cl, Br or I, or alkyl or arylsulfonates like methanesulfonate, benzenesulfonate, 4-toluenesulfonate, 2-nitrobenzenesulfonate, 4-nitrobenzenesulfonate and 4-bromobenzenesulfonate, or perfluorinated alkylsulfonates like trifluoromethanesulfonate or nonafluorobutanesulfonate. Cl, Br and I are mostly preferably used.
In order to obtain target compounds, wherein Y is C1-C8-alkyl, preferably C1-C5-alkyl or C1-C4-alkyl, in particular C3-alkyl or C5-alkyl, specifically methyl, ethyl, iso-propyl, n-butyl or n-pentyl, a compound (IIa) is preferably reacted with the corresponding alkyl halide.
Target compounds (I) with Y being (C2-C8)-alkenyl, in particular (C3-C6)-alkenyl such as Y=allyl, are similarly accessible by reacting compounds (IIa) with the respective (C2-C8)-alkenyl-LG, LG preferably being Br, Cl or I, wherein one particularly suitable reagent is prop-2-enyl bromide.
For target compounds, wherein Y═CN the reagent BrCN is suitable for the inventive process.
In general, from 1 to 3 equivalents, preferably from 1 to 2.5 equivalents, of reagent Y1-LG are employed per mole of the compound of the formula II.
Suitable solvents for steps (iii-1) and (iii-2) are all inert organic solvents, where preferably ethers such as tetrahydrofuran, dioxane, diethyl ether and 1,2-dimethoxyethane can be used. Further solvents that may be suitable are, for example, diisopropyl ether, di-n-butyl ether and/or diglyme. Often, the use of THF or 2-methyl-THF is particularly suitable. Furthermore, it may also be suitable to use combinations of two or more different solvents, such as for example any combination of the solvents listed above or any one of the listed ethers with aliphatic hydrocarbons like n-hexane, heptane or aromatic hydrocarbons like toluene or xylenes.
The reaction of step (iii-1) or (iii-2) is generally carried out under atmospheric pressure. The protonation step (iii-1) or the trapping reaction using an electrophile Y1-LG (iii-2), respectively, may be carried out at temperatures of −30° C. to 80° C., preferably −10° C. to 60° C., more preferably 0° C. to 40° C. In some cases it may be preferred, if temperatures of −30° C. to 40° C., preferably −10° C. to 20° C., more preferably 0° C. to 40° C. are used.
Work-up of the reaction mixture resulting from reaction step (iii-1) or (iii-2), respectively, is carried out by procedures known in a general manner to the person skilled in the art. Usually, the reaction mixture is extracted with a suitable organic solvent (for example aromatic hydrocarbons such as toluene and xylenes) and the residue is, if appropriate, purified by recrystallization and/or chromatography.
According to one embodiment of step (iv), an inventive magnesium compound (IIIa) is reacted with a disulfide R3—S—S—R3, in order to obtain a compound of formula (I), wherein Y is R3 and R3 is (C1-C8-alkyl, (C1-C8)-haloalkyl, (C2-C8)-alkenyl, (C2-C8)-haloalkenyl, (C2-C8)-alkynyl, (C2-C8)-haloalkynyl, (C6-C10)-aryl, a five-, six-, seven-, eight-, nine- or ten-membered, in particular five- or six-membered, aromatic heterocycle that contains one, two, three or four heteroatoms from the group consisting of O, N and S, C(═S)R9 or CN, in particular (C1-C8)-alkyl, (C1-C8)-haloalkyl, (C2-C8)-alkenyl, (C2-C8)-haloalkenyl, (C2-C8)-alkynyl, (C2-C8)-haloalkynyl, C(═S)R9 or CN. Preferably, R3 is (C1-C5)-alkyl, in particular methyl, ethyl, iso-propyl, n-propyl, n-butyl or n-pentyl, (C3-C6)-alkenyl, in particular allyl, or CN. According to a specific embodiment thereof, dirhodane NC—S—S—CN is used in order to result in compounds (I) with Y═CN.
According to a further embodiment of step (iv), an inventive magnesium compound (IIIa) is reacted with a reagent (VII) R4—S—SO2—R4, in order to obtain a compound of formula (I), wherein Y is R4 and R4 is (C1-C8-alkyl, (C1-C8)-haloalkyl, (C2-C8)-alkenyl, (C2-C8)-haloalkenyl, (C2-C8)-alkynyl, (C2-C8)-haloalkynyl, (C6-C10)-aryl, a five-, six-, seven-, eight-, nine- or ten-membered, in particular five- or six-membered, aromatic heterocycle that contains one, two, three or four heteroatoms from the group consisting of O, N and S, C(═S)R9 or CN, in particular (C1-C8)-alkyl, (C1-C8)-haloalkyl, (C2-C8)-alkenyl, (C2-C8)-haloalkenyl, (C2-C8)-alkynyl, (C2-C8)-haloalkynyl, C(═S)R9 or CN. Preferably, R4 is (C1-C5)-alkyl, in particular methyl, ethyl, iso-propyl, n-propyl, n-butyl or n-pentyl, (C3-C6)-alkenyl, in particular allyl or CN.
According to still a further embodiment of step (iv), an inventive magnesium compound (IIIa) is reacted with a reagent (VIII) R5—S-Hal, wherein Hal is halogen, in particular Cl or Br, in order to obtain a compound of formula (I), wherein Y is R5, wherein R5 is halogen, (C1-C8-alkyl, (C1-C8)-haloalkyl, (C2-C8)-alkenyl, (C2-C8)-haloalkenyl, (C2-C8)-alkynyl, (C2-C8)-haloalkynyl, (C6-C10)-aryl or a five-, six-, seven-, eight-, nine- or ten-membered, in particular five- or six-membered, aromatic heterocycle that contains one, two, three or four heteroatoms from the group consisting of O, N and S, or CN. Specific examples are Y═R5═CN or CCl3. One further particular reagent is SHal2 (R5=Hal), in order to obtain a compound of formula (I), wherein Y is Halogen, in particular Cl. According to still a further embodiment a reagent BrSCN is used in order to obtain a compound (I), wherein Y═R5═CN.
Accordingly, a further aspect of the present invention is a use of a compound of formula (IIa) as defined and preferably defined herein, for the synthesis of a thio-triazolo group-containing compound of the formula (I) as defined herein.
Suitable solvents for step (iv) and are all inert organic solvents, where preferably ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether and 1,2-dimethoxyethane can be used. Furthermore, it may also be suitable to use combinations of two or more different solvents, such as for example any combination of the solvents listed above or any one of the listed ethers with aliphatic hydrocarbons like n-hexane, heptane or aromatic hydrocarbons like toluene or xylenes. The reaction temperature is preferably between −30° C. and 80° C., in particular between −10° C. and 60° C. It may be preferred to work at temperatures of −5° C. to 20° C. or 0° C. to 40° C.
The reaction is generally carried out under atmospheric pressure.
The electrophile, in particular the disulfide or BrSCN, is usually employed in equivalent amounts compared to of the compound (IIIa) and/or (IIIb) or in excess, such that usually 1 to 8 moles, in particular 2 to 6 or 3 to 5 moles are used per mole of the compound (IIIa) and/or (IIIb).
In case a work-up is suitable, it can be carried out according to procedures generally known to the person skilled in the art. Usually, the reaction mixture is extracted with a suitable organic solvent, and the residue is, if appropriate, purified by recrystallization and/or chromatography.
Furthermore, it is possible by means of the inventive process as described above to insert a group S-M1, (Y=M1 in compounds (I)) wherein M1 is as defined below.
Compounds of formula (IIa), wherein Q is NR1R2 or Xe.zLiX2 are novel. Accordingly, a further aspect of the present invention is compound of formula (IIa)
wherein Q is NR1R2 or Xe.zLiX2 wherein R1 and R2, Xe, X2 and z are in particular as defined and preferably defined above (Xe, X2 are preferably Cl), and R is as defined or preferably defined above, wherein R=group (1), (2), (3), (4) or (5) is preferred.
According to another aspect of the present invention, thio-triazolo-group containing compounds (I), particularly pesticidal compounds of the triazole class having phytopathogenic activity of formula (I)
are synthesized from a compound of formula (IIa)
by means of the inventive process comprising the step (iii-1) or (iii-2) as defined above.
According to another aspect of the present invention, compounds of formula (IIa) can be obtained by a process comprising the step of reacting a compound (IIIa) with sulfur according to step (ii) as defined above.
According to one embodiment of the inventive process, step (i), then step (ii) and then (iii-1) or (iii-2) are carried out. Thus, according to this embodiment, the inventive process comprises the steps (i), (ii) and, subsequently, (iii-1) or (iii-2).
According to another embodiment of the inventive process, step (i), then step (iv) is carried out. Thus, according to this embodiment, the inventive process comprises the steps (i) and (iv).
A further advantage of the inventive process is that thio-triazolo compounds (I) are accessible in a one-pot reaction. Furthermore, if desired, the reaction can be carried out without cooling or at slightly elevated temperatures and that the conversion to the desired products is high. Thereby, only few side-products or even no significant side-products are formed. The process is thus very economic.
Still a further advantage of the inventive process is that the magnesium amide reagent (Va) or (Vb), respectively, can, according to another aspect of the invention, be used in catalytic amounts, and the reagent can be recycled in situ through reaction with an organomagnesium compound.
The novel compounds according to the invention contain chiral centers and are generally obtained in the form of racemates or as diastereomeric mixtures of erythro and threo forms. The erythro and threo diastereomers of the compounds according to the invention can be separated and isolated in pure form, for example, on the basis of their different solubilities or by column chromatography. Using known methods, such uniform pairs of diastereomers can be used to obtain uniform enantiomers.
Accordingly, the invention provides both the pure enantiomers or diastereomers and mixtures thereof. This applies to the compounds according to the invention. The scope of the present invention includes in particular the (R) and (S) isomers and the racemates of the compounds according to the invention, which have centers of chirality. Suitable compounds according to the invention also include all possible stereoisomers (cis/trans isomers) and mixtures thereof.
The compounds according to the invention may be present in various crystal modifications. They are likewise provided by the present invention.
Furthermore, in the inventive process, the reactants used, contain chiral centers and are generally used in the form of racemates or as diastereomeric mixtures of erythro and threo forms. The erythro and threo diastereomers of these compounds can be separated and isolated in pure form, for example, on the basis of their different solubilities or by column chromatography. Using known methods, such uniform pairs of diastereomers can be used to obtain uniform enantiomers.
Accordingly, the invention provides both the use of pure enantiomers or diastereomers and mixtures thereof. The scope of the present invention includes in particular the use of the (R) and (S) isomers and the racemates of the respective reactants, which have centers of chirality. Suitable compounds used according to the invention also include all possible stereoisomers (cis/trans isomers) and mixtures thereof.
The compounds used according to the invention may be present in various crystal modifications. They are likewise possible to be used in the inventive process.
In order to obtain compounds of formula (I) that contain a derivatized sulfur group (Y other that hydrogen), the compounds of formula (I), wherein Y=hydrogen (compounds (1.1)) can be further reacted according to processes known in the art.
For example, by further reaction of compounds (I.1) with R8A-LG, where R8A is as defined below and LG is a leaving group such as, for example, halogen, such as Cl, Br or I, or perfluoroalkylsulfonate, e.g. trifluoromethylsulfonate or nonafluorobutanesulfonate, it is possible to prepare various compounds of the formula (I) carrying a S—R8A group instead of “S—H”. To prepare compounds containing a group SR8A where R8A is C1-C8-alkyl, preferably C1-C5-alkyl or C1-C4-alkyl, in particular C3-alkyl or C5-alkyl, specifically methyl, ethyl, iso-propyl, n-butyl or n-pentyl, a compound (1.1) is reacted with the corresponding alkyl halide (see also WO 96/38440). Further, the following S-residues may be formed from the respective SH-derivative of formula (I):
S—R8A, where
in which
According to an embodiment of the invention Y in compounds (I) is derivatized into Na, ½ Cu or an ammonium cation of the formula (E), wherein Z1 and Z2 preferably are independently selected from hydrogen and C1-C4-alkyl and Z3 and Z4 are preferably independently selected from hydrogen, C1-C4-alkyl, benzyl and phenyl; where the phenyl groups are in each case unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen and C1-C4-alkyl. It may be preferred, if in group (E), Z1, Z2, Z3 and Z4 are independently selected from hydrogen and C1-C4-alkyl, in particular hydrogen, methyl and ethyl. One particular suitable group (E) is HN(Et)3.
Compounds of the formula I which contain a group S—C(═O)NA3AA4A can be synthesized analogously to the process described in WO 99/21853.
Compounds of the formula I which contain a group DII can be synthesized analogously to the process described in WO 99/05149.
Compounds of the formula I which contain a group S—SO2R6A can be synthesized analogously to the process described in WO 97/44332.
Compounds of the formula I which contain a group S—CN can be synthesized analogously to the process described in WO 99/44331.
Compounds of the formula I which contain a group DI can be synthesized analogously to the process described in WO 97/43269.
Compounds of the formula I which contain a group S—C(═O)R5A where R5A=C1-C8-alkyl, C1-C8-haloalkyl, C1-C8-alkoxy or C1-C8-haloalkoxy can be synthesized analogously to the process described in WO 97/42178.
Compounds of the formula I which contain a group SM1 can be synthesized analogously to the process described in WO 97/41107.
According to one aspect of the present invention, one of the steps for derivatizing the sulfur in the triazole ring as detailed above is carried out following the process of the present invention, wherein Y═H. According to one specific aspect, following the synthesis of compounds (I)-(1) with Y═H according to the process of the present invention, one of the steps for derivatizing the sulfur in the triazole ring is carried out. This represents a very useful approach for the synthesis of further fungicidal compounds, in particular where SH is derivatized into SR8A, R8A being C1-C8-alkyl, in particular C1-C5-alkyl, C2-C8-alkenyl or CN (see specific examples above). According to one further specific aspect, following the synthesis of compounds (I)-(1) with Y═H according to the process of the present invention, the step of derivatizing the sulfur in the triazole ring is derivatized into SMS, wherein M1 is as defined and preferably defined above. See WO 97/41107.
The following examples further illustrate the present invention and do not restrict the invention in any manner.
A solution of (2RS, 3SR)-2-[3-(2-chloro-phenyl)-2-(2,4-difluoro-phenyl)-oxiranylmethyl]-[1,2,4]triazole (0.5 g, 1.44 mmol) in 4 mL of THF was cooled to 0° C. A solution of the respective Mg amide base in THF (1.73 mol, 1.2 eq.) was injected while cooling with ice. The solution was then agitated at that temperature for 60 minutes. Then, sulfur (92 mg, 2.88 mmol) was added at once. Stirring was continued for another 60 min at 0° C. Then, the reaction mixture was quenched through the addition of 5% HCl and extracted with TBME. The crude reaction mixtures were analyzed by HPLC,
A solution of (2RS, 3SR)-2-[3-(2-chloro-phenyl)-2-(2,4-difluoro-phenyl)-oxiranylmethyl]-[1,2,4]triazole (4.0 g, 11.5 mmol) in 16 mL of THF was cooled to 0° C. A solution of TMPMgCl.LiCl in THF (1.1 aloft in THF, 12.5 mL, 13.8 mmol) was injected within 5 minutes while cooling with ice. The solution was then agitated at that temperature for 60 minutes. Then, sulfur (0.75 g, 23.4 mmol) was added portionwise over 5 minutes. Stirring was continued for another 60 min at 0° C. Then, the reaction mixture was poured onto ice cold 4% HCl (20 ml) and 20 ml TBME were added. The phases were separated and the aqueous phase was extracted with TBME (20 mL). The combined organic phases were washed with water and brine and dried over Na2SO4. All volatiles were removed under reduced pressure and the raw residue was recrystallized from xylene (isomer mixture). The crystals were filtered off, rinsed with xylenes and n-hexane and dried at a pressure of <20 mbar overnight to give the product as a powder (3.68 g, purity 93.4% by HPLC, 78.7% yield).
1H NMR (CDCl3, 500 MHz): δ(ppm)=13.31 (bs, 1H); 8.24 (s, 1H); 7.55-7.61 (m, 2H); 7.45-7.50 (m, 2H); 7.34 (q, J=9.5 Hz, 1H); 7.27 (dt, 3.0 Hz, a 12.5 Hz, 1H); 7.05 (ddd, a 3.0 Hz, 9.5 Hz, J=10.5 Hz, 1H); 4.46 (d, 18.0 Hz, 1H); 4.39 (s, 1H); 4.12 (d, 18.0 Hz, 1H).
Melting point: 180° C.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10183605.4 | Sep 2010 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2011/066777 | 9/27/2011 | WO | 00 | 3/27/2013 |
| Number | Date | Country | |
|---|---|---|---|
| 61387996 | Sep 2010 | US |
