WO2019115338A1 - Procédé de préparation de dérivés de (5-cyano-imidazol-1-yl)éthanone et d'intermédiaires utiles à cet effet - Google Patents

Procédé de préparation de dérivés de (5-cyano-imidazol-1-yl)éthanone et d'intermédiaires utiles à cet effet Download PDF

Info

Publication number
WO2019115338A1
WO2019115338A1 PCT/EP2018/083768 EP2018083768W WO2019115338A1 WO 2019115338 A1 WO2019115338 A1 WO 2019115338A1 EP 2018083768 W EP2018083768 W EP 2018083768W WO 2019115338 A1 WO2019115338 A1 WO 2019115338A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
alkyl
cycloalkyl
substituted
compound
Prior art date
Application number
PCT/EP2018/083768
Other languages
English (en)
Inventor
Christoph SÄMANN
Sergii Pazenok
Original Assignee
Bayer Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Publication of WO2019115338A1 publication Critical patent/WO2019115338A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a process for preparing (5-cyano-imidazol-l-yl) ethanone derivatives and to specific intermediates that are particularly useful in this process.
  • Certain 5-substituted imidazolylmethyl derivatives are known to be useful in the field of crop protection, in particular as fungicides.
  • WO 2016/156290 Al discloses such 5-substituted imidazolylmethyl derivatives and several routes to synthesize those.
  • One of said routes is referred to in WO 2016/156290 Al as process M and comprises reacting suitable (5-substituted imidazol-l-yl)ethanone derivatives and Grignard reagents.
  • the respective (5-substituted imidazol- 1 -yl)ethanone derivatives can be obtained according to the procedures referred to in WO 2016/156290 Al as processes J and K.
  • object of the invention is providing an improved process for the synthesis of (5-cyano-imidazol-l- yljethanone derivatives as well as novel compounds that are particularly useful intermediates in such process.
  • (5-cyano-imidazol-l-yl)ethanone derivatives can be synthesized in high yield without introducing any protecting group at one of the imidazole nitrogen atoms by reacting a readily available 4-carbamoyl-5-cyanoimidazole with a suitable ketone and subsequent cleavage of the carbamoyl group from the resulting product.
  • subject of this invention is a process for preparing compounds of formula (I)
  • R 1 represents hydrogen, Ci-Cs-alkyl, Ci-Cs-haloalkyl, C 2 -Cs-alkenyl, C 2 -Cs-haloalkenyl, C 2 -Cs-alkynyl, C 2 -C 8 -haloalkynyl, phenyl-C 2 -Cs-alkynyl, [tri(Ci-Cs-alkyl)silyl]phenyl-C 2 -C 8 -alkynyl, C 3 -C 7 - cycloalkyl, bicycloalkyl, C 3 -C 7 -cycloalkyl-Ci-C 4 -alkyl, C 3 -C 7 -cycloalkyl-C 3 -C 7 -cycloalkyl, C 3 -C 7 - cycloalkenyl, tri(Ci-C 8 -alkyl)silyl-Ci-C 4 -alkyl, tri(
  • R 2 represents hydrogen, Ci-Cs-alkyl, or Ce-Cw-aryl; by reacting in a first step A) an imidazole of formula (II)
  • R 2 is defined as in formula (I); with a ketone of formula (III),
  • R 3 represents chlorine, bromine, iodine, Ci-Cs-alkylsulfonate, or C 6 -Ci 4 -arylsulfonate, wherein the G,- Ci 4 -arylsulfonate is non-substituted or substituted by one or more group(s) selected from halogen, Ci-C 4 -alkyl, and Ci-C 4 -haloalkyl; and
  • R 1 is defined as in formula (I), to yield a compound of formula (IV),
  • R 1 and R 2 are defined as in formula (I), and cleaving in a further step B) the carbamoyl group from the compound of formula (IV). Cleaving of the carbamoyl group from the compound of formula (IV) as used throughout this specification results in the respective compound of formula (I), i.e. the carbamoyl group is replaced by hydrogen.
  • Formula (I) provides a general definition of the (5-cyano-imidazol-l-yl)ethanone derivatives obtainable by the process according to the invention. Preferred definitions of the symbols used in the formulae shown above and below are given below. These definitions apply to the compounds of formula (I) and likewise to all educts and intermediates, e.g. the imidazoles of formula (II), the ketones of formula (III) and the intermediates of formulae (IV) and (V).
  • R 1 preferably represents Ci-Cs-alkyl, Ci-Cs-haloalkyl, C 2 -C 7 -alkenyl, C 2 -C 7 -haloalkenyl, optionally halogen-, cyano-, Ci-C 4 -alkyl-, Ci-C 4 -haloalkyl-, Ci-C 4 -alkoxy-, Ci-C 4 -haloalkoxy-, C 1 -C 4 - alkylthio- or Ci-C 4 -haloalkylthio-substituted C 3 -C 7 -cycloalkyl or optionally halogen-, cyano-, C 1 -C 4 - alkyl-, Ci-C 4 -haloalkyl-, Ci-C 4 -alkoxy-, Ci-C 4 -haloalkoxy-, Ci-C 4 -alkylthio- or Ci-C 4 -haloalkylthio- substituted C 6
  • R 1 more preferably represents Ci-Cs-alkyl, optionally halogen-, cyano-, Ci-C 4 -alkyl-, Ci-C 4 -haloalkyl-, Ci-C 4 -alkoxy-, Ci-C 4 -haloalkoxy-, Ci-C 4 -alkylthio- or Ci-C 4 -haloalkylthio-substituted C 3 -C 7 - cycloalkyl or optionally halogen-, cyano-, Ci-C 4 -alkyl-, Ci-C 4 -haloalkyl-, Ci-C 4 -alkoxy-, C 1 -C 4 - haloalkoxy-, Ci-C 4 -alkylthio- or Ci-C 4 -haloalkylthio-substituted Ce-Cw-aryl.
  • R 1 more preferably represents Ci-C 4 -alkyl, optionally halogen-, cyano-, Ci-C 4 -alkyl-, Ci-C 4 -haloalkyl-, Ci-C 4 -haloalkoxy-, Ci-C 4 -alkoxy-, Ci-C 4 -alkylthio- or Ci-C 4 -haloalkylthio-substituted C 3 -C 6 - cycloalkyl or optionally halogen-, cyano-, Ci-C 4 -alkyl-, Ci-C 4 -haloalkyl-, Ci-C 4 -alkoxy-, C 1 -C 4 - haloalkoxy-, Ci-C 4 -alkylthio- or Ci-C 4 -haloalkylthio-substituted phenyl.
  • R 1 more preferably represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, /c/7-butyl, cyclopropyl, 1 -halocyclopropyl, l-(Ci-C 4 -alkyl)cyclopropyl, or optionally halogen-substituted phenyl.
  • R 1 most preferably represents isopropyl, ieri-butyl, cyclopropyl, l-chlorocyclopropyl, 1- fluorocyclopropyl, 1 -methylcyclopropyl, phenyl or 2,4-difluorophenyl.
  • R 2 preferably represents H, Ci-C 4 -alkyl, or phenyl.
  • R 2 more preferably represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, teri-butyl, or phenyl.
  • R 2 more preferably represents H, methyl, or phenyl.
  • R 2 most preferably represents H.
  • R 3 preferably represents chlorine, bromine, iodine, Ci-C 4 -alkylsulfonate, or C 6 -arylsulfonate, wherein the C 6 -arylsulfonate is non-substituted or substituted by one or more group(s) selected from halogen, Ci-C 4 -alkyl, and Ci-C 4 -haloalkyl.
  • R 3 more preferably represents chlorine, bromine, iodine, methylsulfonate, ethylsulfonate, n- propylsulfonate, isopropylsulfonate, n-butylsulfonate, isobutylsulfonate, ieri-butylsulfonate or phenylsulfonate, wherein the phenylsulfonate is non-substituted or substituted by one or more group(s) selected from fluorine, chlorine, bromine, iodine, methyl, and CF 3 .
  • R 3 more preferably represents bromine, iodine, methylsulfonate, or 4-methylbenzenesulfonate.
  • R 3 more preferably represents bromine or chlorine.
  • R 3 most preferably represents bromine.
  • R 1 represents hydrogen, Ci-Cs-alkyl, Ci-Cs-haloalkyl, C 2 -Cs-alkenyl, C 2 -Cs-haloalkenyl, C 2 -Cs-alkynyl, C 2 -C 8 -haloalkynyl, phenyl-C 2 -Cs-alkynyl, [tri(Ci-C 8 -alkyl)silyl]phenyl-C 2 -Cs-alkynyl, C 3 -C 7 - cycloalkyl, bicycloalkyl, C 3 -C 7 -cycloalkyl-Ci-C 4 -alkyl, C 3 -C 7 -cycloalkyl-C 3 -C 7 -cycloalkyl, C 3 -C 7 - cycloalkenyl, tri(Ci-Cs-alkyl)silyl-Ci-C 4 -alkyl, tri(C
  • Halogen fluorine, chlorine, bromine or iodine. Halogen-substitution is generally indicated by the prefix halo, halogen or halogeno.
  • Alkyl saturated, straight-chain or branched hydrocarbyl radical having 1 to 8, preferably 1 to 6, and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C 6 -alkyl such as methyl, ethyl, propyl (n-propyl), 1 -methylethyl (iso-propyl), butyl (n-butyl), l-methylpropyl (sec-butyl), 2-methylpropyl (iso butyl), l,l-dimethylethyl (tert-butyl), pentyl, l-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2- dimethylpropyl, l-ethylpropyl, l,l-dimethylpropyl, 1 ,2-dimethylpropyl, hexyl, 1 -methylpentyl, 2- methylpentyl, 3 -methylpentyl, 4-methylpentyl,
  • said group is a Ci- C 4 -alkyl group, e.g. a methyl, ethyl, propyl, 1 -methylethyl (isopropyl), butyl, 1 -methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl) or l,l-dimethylethyl (tert-butyl) group.
  • alkyl as part of a composite substituent, for example cycloalkylalkyl, hydroxyalkyl etc., unless defined elsewhere like, for example, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, haloalkyl or haloalkylsulfanyl.
  • Alkenyl unsaturated, straight-chain or branched hydrocarbyl radicals having 2 to 8, preferably 2 to 6, and more preferably 2 to 4 carbon atoms and one double bond in any position, for example (but not limited to) C 2 -C 6 -alkenyl such as vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, isopropenyl, homoallyl, (E)-but- 2-enyl, (Z)-but-2-enyl, (E)-but-l-enyl, (Z)-but-l-enyl, 2-methylprop-2-enyl, l-methylprop-2-enyl, 2- methylprop- 1 -enyl, (E)-l-methylprop-l-enyl, (Z)- 1 -methylprop- 1 -enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)- pent-3-enyl, (E)-
  • Alkynyl straight-chain or branched hydrocarbyl groups having 2 to 8, preferably 2 to 6, and more preferably 2 to 4 carbon atoms and one triple bond in any position, for example (but not limited to) C2-C6- alkynyl, such as ethynyl, prop-l-ynyl, prop-2 -ynyl, but-l-ynyl, but-2-ynyl, but-3-ynyl, l-methylprop-2- ynyl, pent- 1 -ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1- methylbut-2-ynyl, 3-methylbut-l-ynyl, l-ethylprop-2-ynyl, hex- 1 -ynyl, hex-2-ynyl, hex-3
  • said alkynyl group is ethynyl, prop-l-ynyl, or prop-2-ynyl.
  • This definition also applies to alkynyl as part of a composite substituent, for example haloalkynyl etc., unless defined elsewhere.
  • Alkoxy saturated, straight-chain or branched alkoxy radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C 6 -alkoxy such as methoxy, ethoxy, propoxy, 1 -methylethoxy, butoxy, 1 -methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1- methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1 -ethylpropoxy, 1,1- dimethylpropoxy, 1 ,2-dimethylpropoxy, 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-eth
  • Alkylsulfanyl saturated, straight-chain or branched alkylsulfanyl radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C 6 -alkylsulfanyl such as methylsulfanyl, ethylsulfanyl, propylsulfanyl, 1 -methylethylsulfanyl, butylsulfanyl, 1 -methylpropyl- sulfanyl, 2-methylpropylsulfanyl, 1,1-dimethylethylsulfanyl, pentylsulfanyl, 1-methylbutylsulfanyl, 2- methylbutylsulfanyl, 3-methylbutylsulfanyl, 2,2-dimethylpropylsulfanyl, 1 -ethylpropylsulfanyl, 1,1- dimethylpropylsulfanyl, 1,
  • Alkylsulfinyl saturated, straight-chain or branched alkylsulfinyl radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C 6 -alkylsulfinyl such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, 1-methylethylsulfinyl, butylsulfinyl, 1 -methylpropylsulfinyl, 2-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, pentylsulfinyl, 1 -methylbutylsulfinyl, 2- methylbutylsulfinyl, 3 -methylbutylsulfinyl, 2,2-dimethylpropylsulfinyl, 1 -ethylpropylsulfiny
  • Alkylsulfonyl saturated, straight-chain or branched alkylsulfonyl radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C 6 -alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, 1 -methylethylsulfonyl, butylsulfonyl, 1 -methylpropyl- sulfonyl, 2-methylpropylsulfonyl, 1,1-dimethylethylsulfonyl, pentylsulfonyl, 1 -methylbutylsulfonyl, 2- methylbutylsulfonyl, 3 -methylbutylsulfonyl, 2,2-dimethylpropylsulfonyl, 1 -ethylpropyls
  • Monoalkylamino represents an amino radical having one alkyl residue with 1 to 4 carbon atoms attached to the nitrogen atom.
  • Non-limiting examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino and tert-butylamino.
  • Dialkylamino represents an amino radical having two independently selected alkyl residues with 1 to 4 carbon atoms each attached to the nitrogen atom.
  • Non-limiting examples include /V,/V-di methylamino, /V,/V-dicthylamino, /V,/V-di isopropylamino, /V-cthyl-/V-mcthylamino, /V-mcthyl-/V-n-pmpylamino, /V-iso- propyl-N-n-propylamino and /V-tcrt-butyl-/V-mcthylamino.
  • Cycloalkyl monocyclic, saturated hydrocarbyl groups having 3 to 10, preferably 3 to 8 and more preferably 3 to 6 carbon ring members, for example (but not limited to) cyclopropyl, cyclopentyl and cyclohexyl. This definition also applies to cycloalkyl as part of a composite substituent, for example cycloalkylalkyl etc., unless defined elsewhere.
  • Cycloalkenyl monocyclic, partially unsaturated hydrocarbyl groups having 3 to 10, preferably 3 to 8 and more preferably 3 to 6 carbon ring members, for example (but not limited to) cyclopropenyl, cyclopentenyl and cyclohexenyl. This definition also applies to cycloalkenyl as part of a composite substituent, for example cycloalkenylalkyl etc., unless defined elsewhere.
  • Cycloalkoxy monocyclic, saturated cycloalkyloxy radicals having 3 to 10, preferably 3 to 8 and more preferably 3 to 6 carbon ring members, for example (but not limited to) cyclopropyloxy, cyclopentyloxy and cyclohexyloxy. This definition also applies to cycloalkoxy as part of a composite substituent, for example cycloalkoxyalkyl etc., unless defined elsewhere.
  • Haloalkyl straight-chain or branched alkyl groups having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as specified above, for example (but not limited to) Ci-C3-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-fluor
  • Haloalkenyl and haloalkynyl are defined analogously to haloalkyl except that, instead of alkyl groups, alkenyl and alkynyl groups are present as part of the substituent.
  • Haloalkoxy straight-chain or branched alkoxy groups having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as specified above, for example (but not limited to) Ci-C 3 -haloalkoxy such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloro fluoromethoxy, dichloro fluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2- fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluor
  • Haloalkylsulfanyl straight-chain or branched alkylsulfanyl groups having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as specified above, for example (but not limited to) C 1 -C 3 - haloalkylsulfanyl such as chloromethylsulfanyl, bromomethylsulfanyl, dichloromethylsulfanyl, trichloromethylsulfanyl, fluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, chlorofluoromethylsulfanyl, dichlorofluoromethylsulfanyl, chlorodifluoromethylsulfanyl, 1 -chloro- ethylsulfanyl, 1 -bromoethylsulfanyl, 1-
  • Aryl mono-, bi- or tricyclic aromatic or partially aromatic group having 6 to 14 carbon atoms, for example (but not limited to) phenyl, naphthyl, tetrahydronapthyl, indenyl and indanyl.
  • the binding to the superordinate general structure can be carried out via any possible ring member of the aryl residue.
  • Aryl is preferably selected from phenyl, 1 -naphthyl and 2-naphthyl. Phenyl is particularly preferred.
  • Heteroaryl 5 or 6-membered cyclic aromatic group containing at least 1, if appropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are each selected independently of one another from the group S, N and O, and which group can also be part of a bi- or tricyclic system having up to 14 ring members, wherein the ring system can be formed with one or two further cycloalkyl, cycloalkenyl, heterocyclyl, aryl and/or heteroaryl residues and wherein benzofused 5 or 6-membered heteroaryl groups are preferred.
  • the binding to the superordinate general structure can be carried out via any possible ring member of the heteroaryl residue.
  • Examples of 5-membered heteroaryl groups which are attached to the skeleton via one of the carbon ring members are fur-2-yl, fur-3-yl, thien-2-yl, thien-3-yl, pyrrol-2-yl, pyrrol-3-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, imidazol-2-yl, imidazole-4-yl, l,2,4-oxadiazol-3-yl, l,2,4-
  • 6-membered heteroaryl groups are pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazin-3- yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazine-2-yl, l,3,5-triazin-2-yl, 1,2,4- triazin-3-yl and l,2,4,5-tetrazin-3-yl.
  • Examples of benzofused 5-membered heteroaryl groups are indol-
  • Examples of benzofused 6-membered heteroaryl groups are quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5- yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-l-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl.
  • This definition also applies to heteroaryl as part of a composite substituent, for example heteroarylalkyl etc., unless defined elsewhere.
  • the binding to the superordinate general structure can be carried out via a ring carbon atom or, if possible, via a ring nitrogen atom of the heterocyclic group.
  • Saturated heterocyclic groups in this sense are for example (but not limited to) oxiranyl, aziridinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, isoxazolidin-3-yl, isoxazolidin-4-yl, isoxazolidin-5- yl, isothiazolidin-3-yl, isothiazolidin-4-yl, isothiazolidin-5-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, oxazolidin-2-yl, oxazolidin-4-yl, oxazolidin-5-yl, thiazolidin-4-yl, thiazolidin-4-yl,
  • benzofused heterocyclic groups are indolin-l- yl, indolin-2-yl, indolin-3-yl, isoindolin-l-yl, isoindolin-2-yl, 2,3-dihydrobenzofuran-2-yl and 2,3- dihydrobenzofuran-3-yl.
  • This definition also applies to heterocyclyl as part of a composite substituent, for example heterocyclylalkyl etc., unless defined elsewhere.
  • Optionally substituted groups may be mono- or polysubstituted, where the substituents in the case of polysubstitutions may be identical or different.
  • Ring structures having three or more adjacent oxygen atoms, for example, are excluded.
  • step A) of the process according to the invention an imidazole of formula (II)
  • R 1 , R 2 and R 3 are defined as outlined above. It is preferred to react the imidazole of formula (II) and the ketone of formula (III) in a molar ratio of 1 : 0.5 to 1 : 5, preferably 1 : 0.7 to 1 : 4, more preferred 1 : 0.9 to 1 : 3, even more preferred 1 : 1 to 1 : 2, and most preferred 1 : 1.05 to 1 : 1.5.
  • step A) of the process according to the invention in the presence of a solvent, more preferred in the presence of a solvent selected from acetonitrile, acetone, diethyl ether, cyclopentyl methyl ether, /c/7-butyl methyl ether, tetrahydrofuran, methyltetrahydrofuran, in particular 2- methyltetrahydrofuran, toluene, V-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF) and mixtures thereof, most preferred in the presence of acetonitrile or acetone.
  • a solvent selected from acetonitrile, acetone, diethyl ether, cyclopentyl methyl ether, /c/7-butyl methyl ether, tetrahydrofuran, methyltetrahydrofuran, in particular 2- methyltetrahydrofuran, toluene, V-methyl-2-pyrrolidone (NMP),
  • the preferred amount of solvent present in step A) varies depending inter alia from the solvent used and the solubility of the respective imidazole of formula (II) and ketone of formula (III) in said solvent.
  • the amount of solvent shall be sufficient to fully dissolve imidazole of formula (II) and ketone of formula (III) under the reaction conditions. Suitable amounts can be easily determined by one skilled in the art via solubility tests.
  • the weight ratio of solvent to combined amounts of imidazole of formula (II) and ketone of formula (III) is 1 : 1 to 1000 : 1, more preferred 3 : 1 to 500 : 1, more preferred 5 : 1 to 100 : 1, most preferred 5 : 1 to 20 : 1.
  • Step A) is preferably carried out in the presence of a base.
  • a base preferably include alkali metal or alkaline earth metal acetates, amides, carbonates, hydrogencarbonates, hydrides, hydroxides or alkoxides, for example sodium acetate, potassium acetate or calcium acetate, lithium amide, sodium amide, potassium amide or calcium amide, sodium carbonate, potassium carbonate or calcium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or calcium hydrogencarbonate, lithium hydride, sodium hydride, potassium hydride or calcium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium methoxide, ethoxide, n- or i-propoxide, h-, i-, s- or t-butoxide or potassium
  • the base is selected from Na2CC>3, K 2 CO 3 , CS 2 CO 3 , NaOH, KOH, NaOMe, KOMe, KOtBu, NaH and mixtures thereof, more preferably from Na2CC>3, K 2 CO 3 , CS 2 CO 3 and mixtures thereof.
  • the base is Na2CC>3 or K 2 CO3.
  • the preferred amount of base present in step A) may vary within broad limits. However, generally the preferred molar ratio of base to imidazole of formula (II) is 1 : 1 to 10 : 1, more preferred 1.1 : 1 to 5 : 1, more preferred 1.2 : 1 to 2 : 1, most preferred 1.2 : 1 to 1.5 : 1.
  • step A) is carried out at a temperature of 0°C to 50°C, more preferred l0°C to 40°C, and most preferred 20°C to 30°C.
  • reaction time of step A) of the process according to the invention varies depending on the scale of the reaction and the reaction temperature, but is generally between a few, e.g. 5, minutes and 48 hours.
  • Step A) is generally performed under standard pressure (1 atm). However, it is also possible to work under elevated or reduced pressure.
  • the resulting reaction mixture comprising the compound of formula (IV) can be directly used in step B) of the present invention. However, it is preferred to work-up the reaction mixture by procedures generally known in the art. This allows isolation and purification of the compound of formula (IV) before further processing of said compound in step B) of the process according to the invention.
  • any solvent present in the reaction mixture is removed, water is added to form a suspension, the resulting suspension is stirred and the solid filtered. Preferably, the solid is washed with water and dried.
  • the resulting product is of high purity and perfectly suitable for further processing in step B) of the process according to the invention. If desired, the resulting product may be further purified by known techniques, for example recrystallization or chromatography.
  • Imidazoles of formula (II) and ketones of formula (III) are either readily available from commercial sources or obtainable by known methods.
  • the imidazoles of formula (II) can be for example obtained by alkaline hydrolysis of the respective 4,5-dicyanoimidazoles as disclosed in J.P. Ferris et al., J. Org. Chem. 1987, 52, 2355-2361 and P.K. Bridson et al., Heterocycles, 1995, 41, 1271-1274, or in analogy to the methods described therein.
  • the imidazoles of formula (II) are obtained by reacting a compound of formula (VI)
  • R 2 is defined as in formula (I), with an aqueous alkali metal hydroxide solution, preferably aqueous sodium hydroxide.
  • aqueous alkali metal hydroxide solution preferably aqueous sodium hydroxide.
  • the reactants are known compounds that are readily available from commercial sources or can be prepared according to well established methods.
  • a 0.5 to 2 molar aqueous alkali metal hydroxide solution is used, more preferred a 0.5 to 2 molar aqueous sodium hydroxide solution, and most preferred a 0.8 to 1.2 molar aqueous sodium hydroxide solution.
  • this reaction is carried out at a temperature of 20°C to 90°C, more preferred 20°C to 80°C, more preferred 25°C to 70°C, and most preferred 25°C to 50°C.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a few, e.g. 5, minutes and 48 hours.
  • This step is generally performed under standard pressure (1 atm). However, it is also possible to work under elevated or reduced pressure.
  • the resulting reaction mixture comprising the compound of formula (II) can be directly used in step A) of the present invention. However, it is preferred to work-up the reaction mixture by procedures generally known in the art. This allows isolation and purification of the compound of formula (II) before further processing of said compound in step A) of the process according to the invention.
  • the pH (23°C, 1 atm) of the reaction mixture is adjusted to a value of 3 to 8, preferably 4 to 7, more preferred 5 to 7, most preferred 5.5 to 6.5 by addition of an acid.
  • the acid is selected from hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, trifluoromethanesulfonic acid, 4-methylbenzenesulfonic acid and mixtures thereof, preferably from hydrochloric acid and sulfuric acid, more preferred hydrochloric acid.
  • the pH value is adjusted by addition of concentrated hydrochloric acid.
  • the resulting suspension is filtered, the solid washed with water and dried.
  • the resulting product is of high purity and perfectly suitable for further processing in step A) of the process according to the invention.
  • the resulting product may be further purified by known techniques, for example recrystallization or chromatography.
  • step B) of the process according to the invention the compound of formula (IV)
  • R 1 and R 2 are defined as in formula (I), is converted into the desired compound of formula (I) by cleavage of the carbamoyl group.
  • Such cleavage can be achieved by different methods, for example by heating the compound of formula (IV) in an acidic environment and/or in the presence of a catalyst promoting replacement of the carbamoyl group by a hydrogen atom.
  • the cleavage of the carbamoyl group from the compound of formula (IV) in step B) is performed by treating the compound of formula (IV) in a first step Bl) with an acid selected from hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, trifluoromethanesulfonic acid, 4-methylbenzenesulfonic acid and mixtures thereof, to yield a carboxylic acid of formula (V), wherein
  • R 1 and R 2 are defined as in formula (I), and heating in a further step B2) the carboxylic acid of formula (V) in the presence of an organic solvent having a boiling point at 1 bar of from 90 °C to 300 °C or mixtures thereof, to a temperature of from 50
  • the acid used in step Bl) is selected from hydrochloric acid and sulfuric acid, more preferred the acid is sulfuric acid.
  • the acid used in step Bl) is present as aqueous solution, more preferred the acid used in step
  • Bl is aqueous sulfuric acid, preferably an aqueous sulfuric acid comprising 10 to 80 % by weight H2SO4, preferably 20 to 70 % by weight H2SO4, more preferred 30 to 60 % by weight H2SO4, more preferred 35 to 50 % by weight H2SO4, most preferred 35 to 45 % by weight H2SO4.
  • the amount of acid present in step Bl) may vary within broad limits depending in particular from the specific acid used and the reaction temperature. However, generally the preferred molar ratio of acid to compound of formula (IV) is 1 : 1 to 100 : 1, more preferred 2 : 1 to 80 : 1, more preferred 3 : 1 to 70 : 1, more preferred 4 : 1 to 60 : 1, most preferred 5 : 1 to 50 : 1.
  • step Bl) is carried out at a temperature of 20°C to l00°C, more preferred 40°C to 99°C, more preferred 60°C to 97°C, and most preferred 80°C to 90°C.
  • the reaction time of step Bl) varies depending on the scale of the reaction and the reaction temperature, but is generally between a few, e.g. 5, minutes and 48 hours, preferably between 1 and 24 hours.
  • Step Bl) is generally performed under standard pressure (1 atm). However, it is also possible to work under elevated or reduced pressure.
  • the resulting reaction mixture comprising the compound of formula (V) can be directly used in step B2) of the present invention. However, it is preferred to work-up the reaction mixture by procedures generally known in the art. This allows isolation and purification of the compound of formula (V) before further processing of said compound in step B2) of the process according to the invention.
  • the reaction mixture is cooled to a temperature of from 0 °C to 30 °C, preferably 0 °C to 10 °C, for example by pouring the reaction mixture into ice water.
  • the cooled reaction mixture is stirred and the resulting suspension filtered.
  • the solid is washed with water and dried.
  • the resulting product is of high purity and perfectly suitable for further processing in step B2) of the process according to the invention. If desired, the resulting product may be further purified by known techniques, for example recrystallization or chromatography.
  • step B2) the carboxylic acid of formula (V) is heated to a temperature of from 50 °C to 250 °C in the presence of an organic solvent having a boiling point at 1 bar of from 90 °C to 300 °C or mixtures thereof.
  • an organic solvent having a boiling point at 1 bar of from 90 °C to 300 °C or mixtures thereof Such treatment results in the cleavage of the carboxyl group and formation of a compound of formula
  • step B2) the carboxylic acid of formula (V) is heated to a temperature of from 70 °C to 200 °C, more preferred 90°C to l80°C, more preferred l00°C to l50°C, most preferred 1 l0°C to l30°C.
  • the temperature is below the boiling point of the organic solvent(s) present in step B2).
  • the temperature is above said boiling point.
  • the reaction needs to be performed under suitable conditions, like reflux or elevated pressure, for example in an autoclave.
  • the organic solvent is selected from nitrobenzene, dimethylformamide, / V, / V-dimcthylacctamidc, dimethyl sulfoxide, propylene carbonate, acetic anhydride and mixtures thereof.
  • the organic solvent is acetic anhydride.
  • the preferred amount of solvent present in step B2) varies depending inter alia from the solvent used and the solubility of the respective compound of formula (V) in said solvent. Generally, the amount of solvent shall be sufficient to fully dissolve the compound of formula (V) under the reaction conditions. Suitable amounts can be easily determined by one skilled in the art via solubility tests.
  • the weight ratio of solvent to amount of compound of formula (V) is 1 : 1 to 1000 : 1 , more preferred 1 : 1 to 500 : 1, more preferred 2 : 1 to 100 : 1, most preferred 2 : 1 to 10 : 1.
  • reaction time of step B2) of the process according to the invention varies depending on the scale of the reaction and the reaction temperature, but is generally between a few, e.g. 5, minutes and 48 hours.
  • Step B2) is generally performed under standard pressure (1 atm). However, it is also possible to work under elevated or reduced pressure.
  • the resulting reaction mixture comprising the compound of formula (I) can be directly used as such. However, it is preferred to work-up the reaction mixture by procedures generally known in the art. This allows isolation and purification of the compound of formula (I) before any further processing of said compound.
  • any solvent present in the reaction mixture is removed, the remaining product dissolved in a suitable solvent, for example toluene, and the solvent removed again.
  • a suitable solvent for example toluene
  • the resulting product is of sufficient purity. If desired, the resulting product may be further purified by known techniques, for example recrystallization or chromatography.
  • step B2 the crude reaction mixture resulting from heat treatment of the carboxylic acid of formula (V) is treated with oxalic acid, preferably a solution of oxalic acid in an organic solvent, preferably an ether, particularly preferred /c/7-butyl methyl ether.
  • the resulting mixture is than stirred until a precipitate has been formed, and the precipitate isolated, preferably by filtration.
  • the isolated precipitate is washed with an organic solvent, preferably an ether, particularly preferred ieri-butyl methyl ether, and the washed solid suspended in an organic solvent, preferably an ether, particularly preferred teri-butyl methyl ether.
  • the suspension is treated with a base, preferably an alkaline carbonate or hydrogen carbonate, particularly preferred sodium carbonate, potassium carbonate sodium hydrogen carbonate, potassium hydrogen carbonate or a mixture thereof.
  • a base preferably an alkaline carbonate or hydrogen carbonate, particularly preferred sodium carbonate, potassium carbonate sodium hydrogen carbonate, potassium hydrogen carbonate or a mixture thereof.
  • an aqueous solution of the base is used.
  • Resulting phases are separated and the desired compound of formula (I) isolated from the organic phase. This particular work-up provides the compounds of formula (I) in particular high purity.
  • compounds of formula (I) are valuable intermediates in the synthesis of compounds useful in the field of crop protection, in particular the fungicides disclosed in WO 2016/156290 Al .
  • the present invention refers to a process, wherein a compound of formula (I) is synthesized as outlined above and is further reacted to a fungicide using process M disclosed in WO 2016/156290 Al .
  • the present invention refers to a process, wherein a compound of formula (I) is synthesized as outlined above and is further reacted to a fungicide of formula (VII)
  • R 1 is defined as in formula (I);
  • R 4 represents hydrogen or Ci-Cs-alkyl
  • R 5 represents hydrogen or Ci-Cs-alkyl; or R 4 and R 5 form together with the carbon atom to which they are attached a C3-C7-cycloalkyl, wherein the C3-C7-cycloalkyl ring is non-substituted or substituted by one or more Ci-C4-alkyl group(s); and Q represents a 6-membered aromatic cycle of formula (Q-I)
  • U 1 represents CX 1 or N
  • U 2 represents CX 2 or N
  • U 3 represents CX 3 or N
  • U 4 represents CX 4 or N
  • U 5 represents CX 5 or N; wherein X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other represent hydrogen, halogen, nitro, cyano, sulfanyl, pentafluoro-k 6 -sulfanyl, Ci-Cs-alkyl, Ci-Cs-haloalkyl having 1 to 5 halogen atoms, Cs-Cs-cycloalkyl, C 3 -C 7 -halocycloalkyl having 1 to 5 halogen atoms, Ci-Cs- haloalkyl-C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkenyl, C 2 -Cs-alkenyl, C 2 -Cs-alkynyl, C 6 -C 12 - bicycloalkyl, C 3 -C 8 -cycloalkyl-C 2 -Cs-alkenyl, C 3
  • U 1 and U 2 or U 2 and U 3 or U 3 and U 4 form together an additional saturated or unsaturated 4 to 6-membered halogen- or Ci-CValkyl-substitutcd or non-substituted ring; wherein the compound of formula (I) is reacted with a manganese compound of formula (VIII),
  • each X, Y and Z represents independently from each other halogen
  • M 1 represents Mg or Zn; n is 1 or 2; m is 0 or 1 ; n+m is 2;
  • R 4 , R 5 and Q are defined as in formula (VII).
  • R 1 is defined as in formula (I).
  • the preferred, more preferred and most preferred definitions given with regard to formula (I) apply mutatis mutandis.
  • R 4 preferably represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or /c/7-butyl.
  • R 4 more preferably represents hydrogen, methyl or ethyl.
  • R 4 most preferably represents hydrogen.
  • R 5 preferably represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or /c/7-butyl.
  • R 5 more preferably represents hydrogen, methyl or ethyl. R 5 most preferably represents hydrogen.
  • R 4 and R 5 may form together with the carbon atom to which they are attached an optionally Ci-C 4 -alkyl- substituted C 3 -C 7 -cycloalkyl ring.
  • R 4 and R 5 preferably form together with the carbon atom to which they are attached a non-substituted C3-C6-cycloalkyl ring, more preferably a non-substituted CXCk -cycloalkyl ring, most preferably a cyclopropyl ring.
  • Q preferably represents a substituted 6-membered aromatic heterocycle containing one or two nitrogen atoms or a substituted 6-membered aromatic carbocycle. Substituted meaning that the cycle of the given formula comprises at least one of X 1 , X 2 , X 3 , X 4 or X 5 not being hydrogen.
  • Q also preferably represents a, preferably substituted, 6-membered aromatic cycle of formula (Q-I-l) to (Q-I-10)
  • X 1 , X 2 , X 3 , X 4 and X 5 have the same definition as given above. Preferred definitions of X 1 , X 2 , X 3 , X 4 and X 5 are given below.
  • Q more preferably represents a, preferably substituted, phenyl, 3-pyridyl or 4-pyridyl of formula (Q-I- 1) to (Q-I-3)
  • X 1 , X 2 , X 3 , X 4 and X 5 have the same definition as given above. Preferred definitions of X 1 , X 2 , X 3 , X 4 and X 5 are given below.
  • Q more preferably represents a, preferably substituted, phenyl or 3-pyridyl of formula (Q-I-l) or (Q-I-
  • X 1 , X 2 , X 3 , X 4 and X 5 have the same definition as given above. Preferred definitions of X 1 , X 2 , X 3 , X 4 and X 5 are given below.
  • Q most preferably represents a, preferably substituted, phenyl of formula (Q-I-l)
  • X 1 , X 2 , X 3 , X 4 and X 5 have the same definition as given above. Preferred definitions of X 1 , X 2 , X 3 , X 4 and X 5 are given below.
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other preferably represent hydrogen, halogen, nitro, cyano, sulfanyl, pentafluoro ⁇ 6 -sulfanyl, Ci-Cs-alkyl, Ci-Cs-haloalkyl having 1 to 5 halogen atoms, C 3 -C 8 - cycloalkyl, C 3 -C 7 -halocycloalkyl having 1 to 5 halogen atoms, Ci-Cs-haloalkyl-C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkenyl, C 2 -Cs-alkenyl, C 2 -Cs-alkynyl, C 6 -Ci 2 -bicycloalkyl, C 3 -Cs-cycloalkyl-C 2 -C 8 - alkenyl, C 3 -C 8 -cycl
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other more preferably represent hydrogen, halogen, nitro, cyano, sulfanyl, pentafluoro ⁇ 6 -sulfanyl, Ci-Cs-alkyl, C 3 -Cs-cycloalkyl, Ci-Cs-alkoxy, Ci-Cs- alkoxycarbonyl, Ci-C 6 -alkylsulfenyl, or C 3 -C 6 -cycloalkoxy.
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other more preferably represent hydrogen, halogen, Ci-Cs- alkyl, C 3 -C 8 -cycloalkyl or Ci-Cs-alkoxy.
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other more preferably represent hydrogen, fluorine, chlorine, bromine, Ci-C 4 -atkyl, C 3 -C 5 -cycloalkyl or Ci-C 4 -alkoxy.
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other more preferably represent hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, /c/7-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert- butoxy.
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other more preferably represent hydrogen, fluorine, chlorine, bromine, methyl, cyclopropyl, or methoxy.
  • X 1 most preferably represents hydrogen or fluorine.
  • X 2 most preferably represents hydrogen or chlorine.
  • X 3 most preferably represents hydrogen, fluorine or methoxy.
  • X 4 most preferably represents hydrogen, fluorine, chlorine, methyl or methoxy.
  • X 5 more preferably represents hydrogen, fluorine, bromine or cyclopropyl, most preferably fluorine.
  • R 1 represents Ci-Cs-alkyl, optionally halogen-, cyano-, Ci-C 4 -alkyl-, Ci-C 4 -haloalkyl-, Ci-C 4 -alkoxy-, Ci-C 4 -haloalkoxy-, Ci-C 4 -alkylthio- or Ci-C 4 -haloalkylthio-substituted C 3 -C 7 -cycloalkyl or optionally halogen-, cyano-, Ci-C 4 -alkyl-, Ci-C 4 -haloalkyl-, Ci-C 4 -alkoxy-, Ci-C 4 -haloalkoxy-, Ci- C 4 -alkylthio- or Ci-C 4 -haloalkylthio-substituted C 6 -Ci 4 -aryl, and
  • X 1 , X 2 , X 3 , X 4 and X 5 independently from each other represent hydrogen, halogen, Ci-Cs-alkyl, C 3 -C 8 - cycloalkyl or Ci-Cs-alkoxy.
  • R 1 preferably represents Ci-C 4 -alkyl, optionally halogen-, cyano-, Ci-C 4 -alkyl-, Ci-C 4 -haloalkyl-, Ci- C 4 -haloalkoxy-, Ci-C 4 -alkoxy-, Ci-C 4 -alkylthio- or Ci-C 4 -haloalkylthio-substituted C 3 -C 6 -cycloalkyl or optionally halogen-, cyano-, Ci-C 4 -alkyl-, Ci-C 4 -haloalkyl-, Ci-C 4 -alkoxy-, Ci-C 4 -haloalkoxy-, Ci-C 4 -alkylthio- or Ci-C 4 -haloalkylthio-substituted phenyl.
  • R 1 more preferably represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, /c/7-butyl, cyclopropyl, 1 -halocyclopropyl, l-(Ci-C 4 -alkyl)cyclopropyl, or optionally halogen-substituted phenyl.
  • R 1 ’ most preferably represents isobutyl, teri-butyl, cyclopropyl, 1 -chlorocyclopropyl, 1- fluorocyclopropyl, 1 -methylcyclopropyl, phenyl or 2,4-difluorophenyl.
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other preferably represent hydrogen, fluorine, chlorine, bromine, Ci-C4-alkyl, CYCYcycloalkyl or Ci-C4-alkoxy.
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other more preferably represent hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, /c/7-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert- butoxy.
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other more preferably represent hydrogen, fluorine, chlorine, bromine, methyl, cyclopropyl, or methoxy.
  • X 1 most preferably represents hydrogen or fluorine.
  • X 2 most preferably represents hydrogen or chlorine.
  • X 3 most preferably represents hydrogen, fluorine or methoxy.
  • X 4 most preferably represents hydrogen, fluorine, chlorine, methyl or methoxy.
  • X 5 more preferably represents hydrogen, fluorine, bromine or cyclopropyl, most preferably fluorine.
  • X, Y, and Z independently from each other preferably represent chlorine, bromine or iodine, more preferably chlorine or bromine.
  • n is either 1 or 2.
  • n is 1
  • m is 1, i.e. the manganese compound comprises one organic moiety per manganese atom.
  • M 1 preferably represents Mg.
  • z 1 can be any number in the range of 0 to 10. If z 1 is greater than 0, M ' X2 is present and can form a complex with the manganese moiety and optionally present LiZ. Preferably the following equation applies: 0 ⁇ z 1 ⁇ 5, preferably 0 ⁇ z 1 ⁇ 3, more preferred 0 ⁇ z 1 ⁇ 2.
  • z 2 can be any number in the range of 0 to 10. However, preferably z 2 is greater than 0, i.e. at least some LiZ is present. Preferably the following equation applies: 0 ⁇ z 2 ⁇ 5, preferably 0 ⁇ z 2 ⁇ 3, more preferred 0 ⁇ z 2 ⁇ 2.
  • the compound of formula (I) and the manganese compound of formula (VIII) are preferably reacted in a molar ratio of 1 : 0.4 to 1 : 5, more preferred 1 : 0.5 to 1 : 4, most preferred 1 : 0,55 to 1 : 3.
  • the manganese compound of formula (VIII) used is a manganese compound of formula (VIII), wherein n is 1 and m is 1, the molar ratio of compound of formula (I) to manganese compound of formula (VIII) is preferably 1 : 1 to 1 : 5, more preferred 1 : 1.5 to 1 : 4, even more preferred 1 : 1.7 to 1 : 3, most preferred 1 : 2 to 1 : 2.5.
  • the manganese compound of formula (VIII) used is a manganese compound of formula (VIII), wherein n is 2 and m is 0, the molar ratio of compound of formula (I) to manganese compound of formula (VIII) is preferably 1 : 0.4 to 1 : 3, more preferred 1 : 0.5 to 1 : 2, even more preferred 1 : 0.6 to 1 : 1, most preferred 1 : 0.7 to 1 : 0.8.
  • a solvent preferably in the presence of an aprotic solvent, more preferably a solvent selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2- methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, /c/7-butyl methyl ether, toluene, N- methylpyridione (NMP), dimethylformamide (DMF) and mixtures thereof, most preferably selected from diethyl ether, ieri-butyl methyl ether, tetrahydrofuran, toluene, and mixtures thereof.
  • a solvent preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2- methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, /c/7-butyl methyl ether, toluene, N- methylpyridione (NMP), dimethylformamide (
  • this step is carried out at a temperature of -l0°C to 50°C, more preferred -l0°C to 30°C, and most preferred -5°C to 20°C.
  • the reaction time of this step varies depending on the scale of the reaction and the reaction temperature, but is generally between a few, e.g. 5, minutes and 48 hours.
  • This step is generally performed under standard pressure (1 atm). However, it is also possible to work under elevated or reduced pressure.
  • the resulting reaction mixture is quenched with water or an aqueous ammonium halogenide solution, preferably an aqueous NH 4 CI solution, preferably a saturated aqueous NH 4 CI solution.
  • an aqueous ammonium halogenide solution preferably an aqueous NH 4 CI solution, preferably a saturated aqueous NH 4 CI solution.
  • Manganese compounds of formula (VIII) can be obtained as disclosed in P. Knochel et al., Synlett 2015, 26, 514-518 and WO 2007/113294 Al or in analogy to the methods described therein.
  • the manganese compounds of formula (VIII) are obtained by the reaction of a compound of formula (IX)
  • the reactants are known compounds that are readily available from commercial sources or can be prepared according to well established methods.
  • This reaction is preferably conducted under a protective atmosphere, preferably nitrogen or argon atmosphere.
  • the reaction is carried out in the presence of an aprotic solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, /c/7-butyl methyl ether, toluene, and mixtures thereof, most preferably selected from diethyl ether, tetrahydrofuran, toluene and mixtures thereof.
  • any solvent present in the reaction is dried before use.
  • the reaction is carried out in the presence of an activating agent selected from copper salts, nickel salts, iron compounds, cobalt compounds, h, C 2 H 4 Br 2 , Cl(CH 2 ) 2 Br, tert.- BuOLi, BCfi, BF 3 , L1BH 4 , L1AIH 4 , NaAlH 4 , Et 3 Al, DIBAL-H (diisobutyl aluminum hydride), Na[H 2 Al(OCH 2 CH 2 OCH 3 )], Me 3 SiCl, Et 2 Zn, IC1, SnCT and mixtures thereof, preferably selected from I 2 , C 2 H 4 Br 2 , Cl(CH 2 ) 2 Br, tert.
  • an activating agent selected from copper salts, nickel salts, iron compounds, cobalt compounds, h, C 2 H 4 Br 2 , Cl(CH 2 ) 2 Br, tert.
  • an activating agent selected from copper salts, nickel salts, iron compounds, cobalt compounds, h,
  • the reaction is preferably conducted at a temperature of from -10 to 30 °C, more preferred -5°C to 5 °C, and a pressure of from 0.5 to 2 bar.
  • the compound of formula (IX) and the manganese halogenide of formula (X) are reacted in a molar ratio of 1 : 0.4 to 1 : 1, more preferred 1 : 0.5 to 1 : 0.8, most preferred about 1 : 0.55 to 1 : 0.7.
  • the manganese halogenide of formula (X) and LiZ are present in a molar ratio of 1 : 0.5 to 1 : 2, more preferred 1 : 0.7 to 1 : 1.5, most preferred about 1 : 0.8 to 1 : 1.2.
  • the compound of formula (IX) and magnesium are present in a molar ratio of 1 : 1 to 1 : 2, more preferred 1 : 1 to 1 : 1.5, most preferred about 1 : 1.1 to 1 : 1.3.
  • reaction mixture resulting from the reaction of the compound of formula (IX) and the manganese halogenide of formula (X) can be worked-up by procedures generally known in the art, e.g. by evaporation of any organic solvent, preferably under reduced pressure.
  • the resulting manganese compounds of formula (VIII) may be further purified by known techniques, for example crystallization.
  • the resulting reaction mixture comprising the manganese compound of formula (VIII) is directly used in the preparation of a compound of formula (VII).
  • the manganese compounds of formula (VIII) are obtained by reacting a Grignard compound of formula (XI)
  • z 3 is preferably 1 , 2 or 3, more preferably 1 or 2, and most preferably 2.
  • the reactants are known compounds that are readily available from commercial sources or can be prepared according to well established methods.
  • the Grignard compound of formula (XI) can be obtained by reacting the respective halogenide of formula (IX) and magnesium, preferably magnesium turnings, preferably in the presence of an activating reagent like copper salts, nickel salts, iron compounds, cobalt compounds, F, C 2 H 4 Br 2 , Cl(CH 2 ) 2 Br, ter/.-BuOLi, BCF, BF 3 , L1BH 4 , L1AIH 4 , NaAlH 4 , Et 3 Al, DIBAL-H (diisobutyl aluminum hydride), Na[H 2 Al(0CH 2 CH 2 0CH 3 )], Mc-.SiCI, Et 2 Zn, IC1, SnCF and mixtures thereof, preferably I 2 , C 2 H 4 Br 2 , Cl(CH 2 ) 2 Br, tert- BuOLi, BC1 3 , BF 3 , LiBH 4 , L1AIH 4 , NaAlH 4 , Et 3 Al, DIB
  • the reaction product resulting from the synthesis of the Grignard compound of formula (XI) for example in order to isolate, concentrate, dilute or purify the Grignard compound or a solution or suspension thereof.
  • the Grignard reagent is represented by formula (XI).
  • Grignard compounds undergo solvent-dependent equilibrium between different magnesium compounds that can be described by the so-called Schlenck equilibrium.
  • the Schlenck equilibrium for the Grignard reagent according to formula (XI) can be schematically illustrated as follows:
  • formula (XI) encompasses not only the structures as depicted, but also the structures resulting from the Schleck equilibrium as well as the respective solvent adducts.
  • the reaction of the Grignard compound of formula (XI) and manganese lithium complex of formula (XII) is preferably conducted under a protective atmosphere, preferably nitrogen or argon atmosphere.
  • a protective atmosphere preferably nitrogen or argon atmosphere.
  • the reaction is carried out in the presence of an aprotic solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2 -methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, /c/7-butyl methyl ether, toluene, and mixtures thereof, most preferably selected from diethyl ether, tetrahydrofuran, toluene and mixtures thereof.
  • any solvent present is dried before use.
  • the reaction is preferably conducted at a temperature of from -10 to 30 °C, more preferred -5°C to 5 °C, and a pressure of from 0.5 to 2 bar.
  • the Grignard compound of formula (XI) and the manganese lithium complex of formula (XII) are reacted in a molar ratio of 1 : 0.8 to 1 : 1.5, more preferred 1 : 0.9 to 1 : 1.4, more preferred about 1 : 1 to 1 : 1.3, most preferred 1 : 1 to 1 : 1.2.
  • the Grignard reagent of formula (XI) is preferably used as solution in an aprotic solvent, in particular as solution in diethyl ether, tetrahydrofuran, toluene or a mixture thereof, particularly preferred as a 0.2 to 1.0 molar solution in diethyl ether or tetrahydrofuran.
  • the reaction mixture resulting from the reaction of the Grignard compound of formula (XI) and the manganese lithium complex of formula (XII) can be worked-up by procedures generally known in the art, e.g. by evaporation of any organic solvent, preferably under reduced pressure. If desired, the resulting manganese compounds of formula (VIII) may be further purified by known techniques, for example crystallisation. However, preferably the resulting reaction mixture comprising the manganese compound of formula (VIII) is directly used in the preparation of a compound of formula (VII).
  • the reaction time of each of the steps of the processes outlined above varies depending on the scale of the reaction and the reaction temperature, but is generally between a few, e.g. 5, minutes and 48 hours.
  • the invention further relates to novel compounds of formulae (IV) and (V), which are particularly useful in the process according to the invention and form part of the invention.
  • R 1 and R 2 are defined as in formula (I).
  • Another subject of this invention is a compound of formula (V)
  • R 1 and R 2 are defined as in formula (I).
  • V-01 15.0 g, 56.0 mmol, 1 equiv
  • dry AC 2 O 42 mL
  • stirred at 120 °C for 2 h 120 °C for 2 h.
  • the reaction mixture was concentrated in vacuo, the remaining oil dissolved in MTBE (100 mL), filtered and the solvent partly removed in vacuo (ca. 50 mL).
  • the desired compound (TOl) was obtained as a light brown solid in 85% yield with 92% purity (10.5 g, 46.1 mmol).
  • the compounds of formula (I) listed in the following Table 4 have been prepared analogously to example 6. Resulting yields and purities are given in this table. This shows that compounds of formula (I) can be obtained in good to very good yield and excellent purity by the process according to the invention.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de dérivés de 1-(5-cyano-imidazol-1-yl)éthan-2-one de formule (I) par réaction dans une première étape d'un imidazole de formule (II) avec une cétone de formule (III), R1, R2 et R3 étant tels que définis dans la spécification, et par clivage dans une seconde étape du groupe carbamoyle à partir du composé résultant. L'invention concerne également des intermédiaires spécifiques utiles dans ce procédé.
PCT/EP2018/083768 2017-12-12 2018-12-06 Procédé de préparation de dérivés de (5-cyano-imidazol-1-yl)éthanone et d'intermédiaires utiles à cet effet WO2019115338A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP17206668 2017-12-12
EP17206668.0 2017-12-12

Publications (1)

Publication Number Publication Date
WO2019115338A1 true WO2019115338A1 (fr) 2019-06-20

Family

ID=60673166

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2018/083768 WO2019115338A1 (fr) 2017-12-12 2018-12-06 Procédé de préparation de dérivés de (5-cyano-imidazol-1-yl)éthanone et d'intermédiaires utiles à cet effet

Country Status (2)

Country Link
TW (1) TW201936583A (fr)
WO (1) WO2019115338A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007113294A1 (fr) 2006-04-03 2007-10-11 Ludwig-Maximilians-Universität München Procede de synthese de composes d'organoelements
WO2016156294A1 (fr) * 2015-04-02 2016-10-06 Bayer Cropscience Aktiengesellschaft Dérivés de triazole utiles en tant que fongicides
WO2016156290A1 (fr) 2015-04-02 2016-10-06 Bayer Cropscience Aktiengesellschaft Nouveaux dérivés d'imidazole à substitution en position 5

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007113294A1 (fr) 2006-04-03 2007-10-11 Ludwig-Maximilians-Universität München Procede de synthese de composes d'organoelements
WO2016156294A1 (fr) * 2015-04-02 2016-10-06 Bayer Cropscience Aktiengesellschaft Dérivés de triazole utiles en tant que fongicides
WO2016156290A1 (fr) 2015-04-02 2016-10-06 Bayer Cropscience Aktiengesellschaft Nouveaux dérivés d'imidazole à substitution en position 5

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
BRIDSON P K ET AL: "Alkylation of 5-cyanoimidazole-4-carboxamide", HETEROCYCLES COMMUNICATION | SPECIAL I, JAPAN INSTITUTE OF HETEROCYCLIC CHEMISTRY, JP, vol. 41, no. 6, 1 January 1995 (1995-01-01), pages 1271 - 1274, XP009151049, ISSN: 0385-5414 *
J.P. COLLMAN ET AL., JOURNAL OF FLUORINE CHEMISTRY, vol. 201, 2000, pages 189 - 197
J.P. FERRIS ET AL., J. ORG. CHEM., vol. 52, 1987, pages 2355 - 2361
M. SKINNER ET AL., ACS MACRO LETT., vol. 6, 2017, pages 215 - 218
MILTON ORCHIN, JOURNAL OF CHEMICAL EDUCATION, vol. 66, no. 7, 1999, pages 586 - 588
N.B. MAXIMOV ET AL., SYNTHESIS, vol. 9, 2011, pages 1465 - 1471
P. KNOCHEL ET AL., SYNLETT, vol. 26, 2015, pages 514 - 518
P.K. BRIDSON ET AL., HETEROCYCLES, vol. 41, 1995, pages 1271 - 1274
S. B. NOSACHEV ET AL: "Synthesis of new pyrazole derivatives from benzylidenemalononitrile", RUSSIAN JOURNAL OF ORGANIC CHEMISTRY., vol. 45, no. 3, 1 March 2009 (2009-03-01), US, pages 463 - 465, XP055453957, ISSN: 1070-4280, DOI: 10.1134/S107042800903021X *

Also Published As

Publication number Publication date
TW201936583A (zh) 2019-09-16

Similar Documents

Publication Publication Date Title
JP5955961B2 (ja) Ｎ−置換１ｈ−ピラゾール５−カルボニルクロリド化合物を製造するための方法
US9556141B2 (en) Process for preparing N-substituted 1H-pyrazole-5-carboxylate compounds and derivatives thereof
US9006447B2 (en) Method for preparing substituted isoxazoline compounds and their precursors 4-chloro, 4-bromo- or 4-iodobenzaldehyde oximes
CN110997644B (zh) 取代的3-芳基-5-三氟甲基-1,2,4-噁二唑类的制备
TWI832859B (zh) 製備鄰甲醯胺基苯甲醯胺類化合物及其中間產物的方法
US20160229820A1 (en) Process for preparing substituted isatoic acid anhydride compounds and derivatives thereof
JP2016518433A (ja) Ｎ置換１ｈ−ピラゾール−５−カルボン酸化合物及びその誘導体を製造する方法
WO2019115338A1 (fr) Procédé de préparation de dérivés de (5-cyano-imidazol-1-yl)éthanone et d'intermédiaires utiles à cet effet
US20160137624A1 (en) Process for preparing pyridylpyrazole compounds and derivatives thereof from pyridylhydrazine
WO2019091898A1 (fr) Procédé de préparation de dérivés d'imidazole à substitution en position 5 et composés de manganèse utiles à cet effet
CN112469687B (zh) 制备邻甲酰胺基苯甲酰胺类化合物的新方法
WO2015162260A1 (fr) Procédé de préparation d'esters et de dérivés d'anthranilamide
CN114761387A (zh) 取代的芳族羧酰胺的制备

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18826511

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18826511

Country of ref document: EP

Kind code of ref document: A1