WO2022218987A1 - Procédé de préparation de dérivés de n-aryl-formamidine fongicides - Google Patents

Procédé de préparation de dérivés de n-aryl-formamidine fongicides Download PDF

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WO2022218987A1
WO2022218987A1 PCT/EP2022/059764 EP2022059764W WO2022218987A1 WO 2022218987 A1 WO2022218987 A1 WO 2022218987A1 EP 2022059764 W EP2022059764 W EP 2022059764W WO 2022218987 A1 WO2022218987 A1 WO 2022218987A1
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formula
alkyl
compound
methyl
process according
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Martin Zeller
Jean-Philippe KRIEGER
Miroslav Terinek
Amgad Salah Moussa
Daniel Meyer
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Syngenta Crop Protection Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

  • the present invention relates to a process for the preparation of N-aryl formamidine derivatives suitable for use, e.g., as active ingredients, which have microbiocidal activity, in particular, fungicidal activity.
  • N-aryl formamidine derivatives For instance, a process for the preparation of N-aryl formamidine derivatives is described in WO 2015/155075 by reaction of the corresponding amine derivatives with N-alkyl formamides in the presence of a suitable condensing agent, especially phosphorus oxychloride, in a solvent.
  • a suitable condensing agent especially phosphorus oxychloride
  • R 1 and R 2 independently of each other are hydrogen, halogen, cyano, OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, NH(CI-C 4 alkyl), N(CI-C 4 alkyl) 2 , CO(Ci-C 4 alkyl), C0 2 (Ci-C 4 alkyl), C0 2 H, CONH(CI-C 4 alkyl), CON(CI-C 4 alkyl) 2 , S0 2 NH(Ci-C 4 alkyl), S0 2 N(Ci-C 4 alkyl) 2 , Ci-C 4 haloalkyl, Ci-C 4 alkoxy, Ci- C 4 haloalkoxy, Ci-C 4 alkoxyCi- 4 alkyl or C 2 -C 4 alkynyl;
  • R 3 is Ci-C 4 alkyl, Ci-C 4 alkoxy-Ci-C 4 alkyl or phenyl, wherein any of said groups may be substituted by one or more substituents selected from the group consisting of halogen, cyano, OH, NH 2 , Ci-C 4 alkyl or Ci-C 4 haloalkyl;
  • R 4 and R 5 independently of each other are hydrogen, Ci-C 4 alkyl or C3-C6 cycloalkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 6-membered saturated cyclic group;
  • A is N or CH
  • Y is O or Ci-C 2 alkylene, optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, OH, NH 2 , Ci-C 4 alkyl or Ci-C 4 haloalkyl; and n is 0 or 1 ; said process comprising the step of reacting a compound of formula (II): wherein A, Y, n, R 1 , R 2 and R 3 are as defined for the compound of formula (I), with a N-alkyl formamide of formula HC(0)NR 4 R 5 (III), wherein R 4 and R 5 are as defined for the compound of formula (I), in the presence of at least one condensing agent of formula (IV): wherein X 1 and X 2 , equal to or different from each other, are chlorine, C1-C2 alkoxy or C1-C2 chloroalkoxy.
  • the compounds of formula (I) can be used in the agricultural sector and related fields of use, e.g., as active ingredients for controlling plant pests or on non-living materials for the control of spoilage microorganisms or organisms potentially harmful to man.
  • the compounds of formula (I) are distinguished by excellent activity at low rates of application, by being well tolerated by plants and by being environmentally safe. They have very useful curative, preventive and systemic properties and can be used for protecting numerous cultivated plants.
  • the compounds of formula (I) can be used to inhibit or destroy the pests that occur on plants or parts of plants (fruit, blossoms, leaves, stems, tubers, roots) of different crops of useful plants, while at the same time protecting also those parts of the plants that grow later, e.g., from phytopathogenic microorganisms.
  • the compounds of formula (I) have, for practical purposes, a very advantageous level of biological activity for protecting plants against diseases that are caused by fungi.
  • the compound of formula (I) is particularly suitable for use as a fungicide.
  • fungicide as used herein means a compound that controls, modifies, or prevents the growth of fungi. According to this particular aspect of the invention, the use may exclude methods for the treatment of the human or animal body by surgery or therapy.
  • the compounds of formula (I) are for example, effective against fungi and fungal vectors of disease as well as phytopathogenic bacteria and viruses.
  • halogen refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo), preferably fluorine, chlorine or bromine.
  • cyano means a -CN group.
  • amino means an -NH2 group.
  • hydroxy means an -OH group.
  • Ci-C6alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • the terms “Ci- C 4 alkyl” and “Ci-C2alkyl” are to be construed accordingly.
  • Ci-C6alkylene refers to the corresponding definition of Ci-C6alkyl, Ci-C 4 alkyl or Ci-C2alkyl, respectively, except that such radical is attached to the rest of the molecule by two single bonds.
  • Ci-ealkyl include, but are not limited to, methyl, ethyl, iso-propyl, n-propyl and tert-butyl.
  • C1-C4 alkoxy refers to a radical of the formula -OR a where R a is a Ci-C 4 alkyl radical as generally defined above. Examples of Ci-C 4 alkoxy include, but are not limited to, methoxy, ethoxy and propoxy.
  • Ci-C 4 alkoxyCi- 4 alkyl refers to radical of the formula Rb-0-R a - where Rb is a Ci-C 4 alkyl radical as generally defined above, and R a is a Ci-C 4 alkylene radical as generally defined above.
  • C 2 -C 4 alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond that can be of either the (E)- or ( ⁇ -configuration, having from two to four carbon atoms, which is attached to the rest of the molecule by a single bond.
  • C3-C 4 alkenyl is to be construed accordingly. Examples of C 2 -C 4 alkenyl include, but are not limited to, ethenyl and prop-1 -enyl.
  • C2-C6alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to four carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • C3-C6alkynyl is to be construed accordingly.
  • Examples of C2-C6alkynyl include, but are not limited to, ethynyl, prop-1 -ynyl, propargyl (prop-2-ynyl), but-1-ynyl and 3-methyl-but-1-ynyl.
  • Ci-C 4 haloalkoxy refers to a Ci-C 4 alkoxy group as defined above substituted by one or more of the same or different halogen atoms.
  • Examples of Ci-C 4 haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy and trifluoroethoxy.
  • Ci-C 4 haloalkyl refers to a Ci-C 4 alkyl radical as generally defined above substituted by one or more of the same or different halogen atoms.
  • Ci-C 4 haloalkyl include, but are not limited to fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl and trifluoroethyl.
  • Cs-Cscycloalkyl refers to a stable, monocyclic or bi-cyclic ring radical which is saturated or partially unsaturated and contains 3 to 8 carbon atoms. C3-C6cycloalkyl is to be construed accordingly.
  • Examples of Cs-Cscycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • aryl refers to an aromatic ring system consisting solely of carbon and hydrogen atoms which may be mono-, bi- or tricyclic. Examples of such ring systems include phenyl, naphthalenyl, anthracenyl, indenyl or phenanthrenyl.
  • n, A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and Y apply generally to the compounds of any of formulae (l-A), (I-A1), (I-A2) or (l-B), as well as to the compounds of any of formula (II), (III), (lll-A), (III- A1), (V), (VI), (VII), (VIII) or (IX).
  • the compound of formula (I) is prepared according to the process of the invention, said process comprising the step of reacting a compound of formula (II) with a N-alkyl formamide of formula (III) in the presence of at least one condensing agent of formula (IV). This reaction is shown in Scheme 1 .
  • the compound of formula (I) as obtained by the process of the invention is in any of its tautomeric forms with different (E)/(Z)-configurations.
  • n 1 and Y is O.
  • R 1 and R 2 independently of each other are hydrogen, halogen, cyano, OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, NH(CI-C 4 alkyl), N(CI-C 4 alkyl) 2 , CO(Ci-C 4 alkyl), C0 2 (Ci-C 4 alkyl), C0 2 H, CONH(CI-C 4 alkyl), CON(CI-C 4 alkyl) 2 , S0 2 NH(Ci-C 4 alkyl), S0 2 N(Ci-C 4 alkyl) 2 , Ci-C 4 haloalkyl, Ci-C 4 alkoxy, Ci- C 4 haloalkoxy, Ci-C 4 alkoxyCi- 4 alkyl or C 2 -C 4 alkynyl;
  • R 3 is Ci-C 4 alkyl, Ci-C 4 alkoxy-Ci-C 4 alkyl, phenyl or phenylCi-C 2 alkyl, wherein any of said groups may be substituted by one or more substituents selected from the group consisting of halogen, cyano, OH, NH 2 , Ci-C 4 alkyl or Ci-C 4 haloalkyl;
  • R 4 and R 5 independently of each other are hydrogen, Ci-C 4 alkyl or C3-C6 cycloalkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 6-membered saturated cyclic group; and A is N or CH.
  • R 1 is hydrogen, halogen, cyano, OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, NH(CI-C4 alkyl), N(CI-C4 alkyl) 2 , CO(Ci-C 4 alkyl), C0 2 (Ci-C 4 alkyl), C0 2 H, CONH(CI-C 4 alkyl), CON(CI-C 4 alkyl) 2 , S0 2 NH(Ci- C4 alkyl), S0 2 N(CI-C4 alkyl) 2 , C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ci-C4alkoxyCi-4alkyl or C 2 -C 4 alkynyl;
  • R 3 is C1-C4 alkoxy-Ci-C 4 alkyl, optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, OH, NH 2 , C1-C4 alkyl or Ci-C 4 haloalkyl; and R 4 and R 5 independently of each other are hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 6-membered saturated cyclic group.
  • A is CH, n is 1 , Y is O and R 1 is methyl.
  • R 2 is hydrogen, halogen, cyano, OH, NH 2 , C1-C4 alkyl, C3-C6 cycloalkyl, NH(CI-C4 alkyl), N(CI-C4 alkyl) 2 , CO(Ci-C 4 alkyl), C0 2 (Ci-C 4 alkyl), C0 2 H, CONH(CI-C 4 alkyl), CON(CI-C 4 alkyl) 2 , S0 2 NH(Ci- C4 alkyl), S0 2 N(CI-C4 alkyl) 2 , C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ci-C4alkoxyCi-4alkyl or C 2 -C 4 alkynyl;
  • R 3 is phenyl, optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, OH, NH 2 , C1-C4 alkyl or C1-C4 haloalkyl; and
  • R 4 and R 5 independently of each other are hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 6-membered saturated cyclic group.
  • A is CH, n is 1 and Y is CR 6 R 7 , wherein R 6 and R 7 , equal to or different from each other, are selected from the group consisting of hydrogen, halogen, cyano, OH, NH 2 , Ci-C 4 alkyl or Ci-C 4 haloalkyl.
  • R 1 and R 2 independently of each other are hydrogen, halogen, cyano, OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, NH(CI-C 4 alkyl), N(CI-C 4 alkyl) 2 , CO(Ci-C 4 alkyl), C0 2 (Ci-C 4 alkyl), C0 2 H, CONH(CI-C 4 alkyl), CON(CI-C 4 alkyl) 2 , S0 2 NH(Ci-C 4 alkyl), S0 2 N(Ci-C 4 alkyl) 2 , Ci-C 4 haloalkyl, Ci-C 4 alkoxy, Ci- C 4 haloalkoxy, Ci-C 4 alkoxyCi- 4 alkyl or C 2 -C 4 alkynyl;
  • R 3 is Ci-C 4 alkyl, Ci-C 4 alkoxy-Ci-C 4 alkyl or phenyl, wherein any of said groups may be substituted by one or more substituents selected from the group consisting of halogen, cyano, OH, NH 2 , Ci-C 4 alkyl or Ci-C 4 haloalkyl;
  • R 4 and R 5 independently of each other are hydrogen, Ci-C 4 alkyl or C3-C6 cycloalkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 6-membered saturated cyclic group; and
  • R 6 and R 7 are selected from the group consisting of hydrogen, halogen, cyano, OH, NH 2 , Ci-C 4 alkyl or Ci-C 4 haloalkyl.
  • R 1 and R 2 independently of each other are hydrogen, halogen, cyano, OH, NH 2 , methyl, ethyl, cyclopropyl, NH(CI-C 2 alkyl), N(CI-C 2 alkyl) 2 , CO(Ci-C 2 alkyl), C0 2 (Ci-C 2 alkyl), C0 2 H, CONH(CI-C 2 alkyl), CON(CI-C 2 alkyl) 2 , S0 2 NH(Ci-C 2 alkyl), S0 2 N(Ci-C 2 alkyl) 2 , Ci-C 4 fluoroalkyl, Ci- C 4 alkoxy, Ci-C 2 haloalkoxy or C 2 -C 4 alkynyl.
  • R 1 and R 2 independently of each other are hydrogen, halogen, cyano, OH, NH 2 , methyl, ethyl, cyclopropyl, NHMe, NMe 2 , COMe, 0O 2 Me, C0 2 H, CONHMe, CONMe 2 , S0 2 NHMe, S0 2 NMe 2 , CHF 2 , CF3, OMe, OCHF 2 or acetylenyl.
  • R 1 and R 2 independently of each other are hydrogen, halogen, cyano, methyl, ethyl, cyclopropyl, CHF 2 , CF3, OMe, or OCHF 2 .
  • R 3 is Ci-C 4 alkoxy-Ci-C 4 alkyl or phenyl, wherein any of said groups may be substituted by one or more substituents selected from the group consisting of halogen, cyano, OH, NH 2 , Ci-C 4 alkyl or Ci-C 4 haloalkyl.
  • R 4 and R 5 independently of each other are hydrogen, C1-C3 alkyl or C3-C5 cycloalkyl. More preferably, R 4 and R 5 independently of each other represent hydrogen, methyl, ethyl, isopropyl or cyclopropyl. Even more preferably, R 4 is hydrogen or methyl and R 5 is methyl or ethyl.
  • compound (l-A) is selected from compounds A.01 , A.02, A.03, A.04, A.05, A.06, A.07, A.08, A.09, A.10, A.11 , A.12, A.13, A.14, A.15, A.16 or A.17 as defined in Table A below.
  • compound (l-B) is selected from compounds B.01 , B.02 or B.03 as defined in Table B below.
  • N-alkyl formamides of formula (III) suitable for use in the process of the invention include compounds wherein R 4 and R 5 independently of each other are hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl. More preferably, in the N-alkyl formamide of formula (III) R 4 and R 5 independently of each other are hydrogen, methyl, ethyl or isopropyl. Even more preferably, the N-alkyl formamide of formula (III) is N-ethyl-N-methylformamide.
  • condensing agents of formula (IV) suitable for use in the process of the invention include compounds where X 1 and X 2 , equal to or different from each other, are chlorine, methoxy, ethoxy or trichloromethoxy such as, for instance, phosgene (COCI2), diphosgene (CIC(0)0CCl3), triphosgene (Cl3C0C(0)0CCl3), methyl chloroformate (CIC(0)0CH3), and ethyl chloroformate (CIC(0)0CH2CH3).
  • the condensing agent of formula (IV) is phosgene or diphosgene.
  • the compound of formula (I) is advantageously prepared via reaction of a compound of formula (II) with a N-alkyl formamide of formula (III) in the presence of phosgene, wherein the molar ratio between phosgene and the compound of formula (II) is from 1 :1 to 2:1 , preferably from 1.05:1 to 1.3:1 , more preferably from 1.1 :1 to 1.3:1.
  • the compound of formula (I) is advantageously prepared via reaction of a compound of formula (II) with a N-alkyl formamide of formula (III) in the presence of a condensing agent of formula (IV), wherein the molar ratio between the N-alkyl formamide of formula (III) and the compound of formula (II) is from 1 :1 to 2:1 , preferably from 1.05:1 to 1.3:1.
  • R 4 and R 5 independently of each other are hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 6-membered saturated cyclic group; and
  • A is an anion selected from chloride, methoxide, ethoxide and trichloromethoxide.
  • R 4 and R 5 independently of each other are hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl. More preferably, in the salt of formula (lll-A) R 4 and R 5 independently of each other are hydrogen, methyl, ethyl or isopropyl.
  • R 4 and R 5 independently of each other are hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 3- to 6-membered saturated cyclic group.
  • R 4 and R 5 independently of each other are hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl. More preferably, in the salt of formula (III-A1) R 4 and R 5 independently of each other are hydrogen, methyl, ethyl or isopropyl.
  • the process of the invention may be carried out in a batch-mode or in a continuous mode, e.g. using one or more pipe reactors or one or more continuous stirred-tank reactors.
  • the process is carried out using one or more continuous stirred- tank reactors.
  • continuous stirred-tank reactor is intended to denote a reaction vessel equipped with means for stirring.
  • the process is carried out in the presence of at least one solvent.
  • suitable solvents include, for instance, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, xylene, ethylbenzene, chlorobenzene, a,a,a-trifluorotoluene, methylcyclohexane, dichloromethane, chloroform, acetonitrile, propionitrile, 1 ,2-dichlorobenzene and 1 ,2-dichloroethane and mixtures thereof.
  • the solvent is a water-immiscible solvent.
  • water immiscible solvent is intended to be construed broadly to include liquids which are partially miscible with water on agitation but which on settling separate into two layers to form a liquid/liquid interface.
  • the solvent is selected from the group consisting of toluene, acetonitrile and mixtures thereof.
  • the process of the invention is usually carried out at a temperature from 0°C to 60°C, preferably from 0°C to 40°C, more preferably from 0°C to 35°C. Very good results have been obtained when the process of the invention is carried out at a temperature from 0°C to 35°C.
  • the process of the invention is usually carried out at a pressure from 1 atm to 5 atm.
  • Typical reaction times are usually in the range from 1 to 16 hours. Very good results have been obtained when the process of the invention is carried out at reaction times from 1 to 3 hours.
  • a reaction mixture is generally provided by the process of the invention, said reaction mixture comprising a compound of formula (I) and at least one solvent as defined above.
  • the process of the invention typically further comprises the step of isolating the compound of formula (I) from the reaction mixture.
  • the compound of formula (I) is advantageously isolated from the reaction mixture by addition of water, typically by an extractive work-up procedure.
  • the compound of formula (I) may be isolated from the reaction mixture by addition of an aqueous acidic medium, typically by an extractive work-up procedure.
  • the aqueous acidic medium typically comprises, preferably consists of, water and one or more acids selected from the group consisting of acetic acid, citric acid, sulfuric acid and hydrochloric acid.
  • the aqueous acidic medium comprises, preferably consists of, water and hydrochloric acid.
  • the process of the invention may further comprise a work-up extractive procedure, wherein said workup extractive procedure typically comprises the following steps:
  • reaction mixture comprising a compound of formula (I) and at least one solvent as defined above;
  • a base preferably a base selected from the group consisting of alkali hydroxides, e.g. sodium hydroxide or potassium hydroxide;
  • the solvents used in steps (i) and (v) of the work-up extractive procedure may be equal to or different from each other.
  • the solvent is as defined above. More preferably, in steps (i) and (v) of the work-up extractive procedure, the solvent is toluene.
  • a compound of formula (II) may be prepared from a compound of formula (V), wherein A, Y, n, R 1 , R 2 and R 3 are as defined for the compound of formula (I).
  • the process of the invention may further comprise the step of reacting an intermediate compound of formula (V) with an acid or a base to obtain a compound of formula (II). This reaction is shown in Scheme 2.
  • a compound of formula (V) may be reacted with an acid, typically hydrochloric acid, or a base, typically sodium hydroxide or potassium hydroxide, in a reaction medium comprising water and, optionally, at least one solvent, typically dioxane.
  • compound (V) is selected from compounds C.01 , C.02, C.03, C.04, C.05, C.06, C.07, C.08, C.09, C.10, C.11 , C.12, C.13, C.14, C.15, C.16, C.17, C.18, C.19 or C.20 as defined in Table C below.
  • a compound of formula (II) may be prepared from a compound of formula (VI), wherein A, Y, n, R 1 , R 2 and R 3 are as defined for the compound of formula (I).
  • the process of the invention may further comprise the step of reacting an intermediate compound of formula (VI) with ammonium chloride in the presence of iron to obtain a compound of formula (II). This reaction is shown in Scheme 3.
  • a compound of formula (VI) may be reacted with ammonium chloride in a reaction medium comprising water and at least one solvent, typically ethanol, in the presence of iron.
  • the reaction is typically carried out at a temperature from 70°C to 100°C. See, for instance, the process for the preparation of 5-bromo-2-methyl-6-(1-methyl-2-propoxy-ethoxy)pyridin-3-amine as described in WO 2015/155075.
  • a compound of formula (VI), wherein n is 1 and Y is O may be prepared from a compound of formula (VII), wherein A, R 1 and R 2 are as defined for the compound of formula (I), via reaction with a compound of formula (VIII), wherein R 3 is as defined for the compound of formula (I).
  • the process of the invention may further comprise the step of reacting an intermediate compound of formula (VII) with a compound of formula (VIII) to obtain a compound of formula (VI), wherein n is 1 and Y is O. This reaction is shown in Scheme 4.
  • a compound of formula (VII) may be reacted with a compound of formula (VIII) in the presence of a base and diisopropyl diazodicarboxylate in a reaction medium comprising at least one solvent.
  • the reaction is typically carried out at a temperature from 30°C to 50°C.
  • suitable bases include inorganic bases and organic bases.
  • Preferred bases are selected from the group consisting of phosphines (e.g. triphenylphosphine), tertiary amines, substituted or non-substituted pyridine, bycyclic amines and mixtures thereof.
  • a compound of formula (VI), wherein n is 1 and Y is O may be prepared from a compound of formula (VII), wherein A, R 1 and R 2 are as defined for the compound of formula (I), via reaction with a compound of formula (IX), wherein R 3 is as defined for the compound of formula (I) and R x is fluorine, C1-C4 alkyl, C 2 -C 4 alkenyl or phenyl, wherein any of said C1-C4 alkyl, C 2 -C 4 alkenyl or phenyl may be substituted by one or more substituents selected from the group consisting of halogen, NO 2 , C1-C4 alkyl or C1-C4 haloalkyl.
  • This reaction is shown in Scheme
  • R x in the compound (IX) is fluorine, methyl, ethyl, ethenyl, phenyl, 4-methylphenyl or 4- nitrophenyl.
  • compound (VI) is selected from compounds D.01 , D.02, D.03, D.04, D.05, D.06, D.07, D.08, D.09, D.10, D.11 , D.12, D.13, D.14, D.15, D.16, D.17, D.18, D.19 or D.20 as defined in Table D below.
  • the present invention further relates to intermediate compounds of any of formula (lll-A), (III-A1), (V), (VI), (VII), (VIII) and (IX).
  • the intermediates so obtained may be characterized by any suitable analytical techniques such as NMR and IR spectroscopy.
  • Preferred groups and values for the substituents n, A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and Y in the compounds of formula (I) are, in any combination thereof, as set out above in Tables A and B.
  • an asymmetric carbon atom in any of compounds A.01 to A.17 means that these compounds may occur in chiral enantiomeric forms, i.e. , (R)- and (S)-enantiomers as depicted below.
  • the presence of an asymmetric carbon atom in any of compounds B.01 to B.03 means that these compounds may occur in chiral enantiomeric forms, i.e., (R)- and (S)-enantiomers as depicted below.
  • Enantiomerically pure final compounds may be obtained from racemic starting materials as appropriate via standard physical separation techniques, such as reverse phase chiral chromatography, or through stereoselective synthetic techniques, e.g., by using chiral starting materials.
  • the compounds of formula (I) may be prepared according to the synthetic techniques described above.
  • the reaction mixture was stirred for further 2 hours after finishing feeding of the 5-bromo-2-methyl-6-(1-methyl-2-propoxy-ethoxy)pyridin-3-amine solution.
  • the reaction mixture was then dosed into a stirred mixture of water (120 g) and 30% sodium hydroxide (29 g; assay 30%; 218 mmol) during 20 minutes. Agitation was stopped and phases were allowed to separate. The aqueous phase was split off and discarded.
  • the organic phase was extracted with 32% hydrochloric acid (8.1 g; assay 32%; 71 mmol) in water (60 g). Phases were allowed to separate. The aqueous phase was split off, and the organic phase was washed with water (20 g).
  • the reaction mixture was stirred for further 2 hours after finishing feeding of 5-bromo-2-methyl-6-(1-methyl-2-propoxy- ethoxy)pyridin-3-amine solution.
  • Water (200 g) was dosed over 15 minutes to the reaction mixture followed by the addition of aquous ammonia (2 g; assay 25%). The mixture was warmed to 30 °C. To get a sharp phase separation methanol (15 g) was added. Phases were allowed to separate. The organic phase was washed with water (40 g). Both aqueous phases were combined and fresh toluene (160 g) was added. The mixture was neutralised to pH 8.5-9.5 by adding 30% sodium hydroxide (47.0 g; assay 30%; 353 mmol).
  • the reaction mixture was stirred for another 1 hour after finishing feeding of the 5-bromo-2-methyl-6-(1-methyl-2-propoxy- ethoxy)pyridin-3-amine solution.
  • Water (200 g) was dosed over 15 minutes to the reaction mixture followed by the addition of aueqous ammonia (2 g; assay 25%).
  • the mixture was warmed to 30 °C.
  • methanol (16.6 g) was added. Phases were allowed to separate.
  • the organic phase was washed with water (20 g). Both aqueous phases were combined, neutralised to pH 8.5-9.5 by adding 30% sodium hydroxide (40.9 g; assay 30%; 307 mmol) and extracted with fresh toluene (150 g). Phases were allowed to separate.
  • the reaction mixture was then fed into a mixture of water (330 g) and sodium bicarbonate (2 g) during 1 hour.
  • 30% sodium hydroxide 53.9 g; assay 30%; 404 mmol
  • a pH of 7.5 to 9.0 was maintained during feeding of the reaction mass.
  • the resulting mixture was extracted with ethyl acetate (250 g).
  • the aqueous phase was split off and discarded.
  • the organic phase was washed twice with water (100 g), dried (Na 2 SC> 4 ) and evaporated.
  • the resulting organic phase was extracted with 32% hydrochloric acid (5.5 g; assay 32%; 48 mmol) in water (300 g).
  • the aqueous phase was split off, neutralised with 30% sodium hydroxide (7 g; assay 30%; 53 mmol) and extracted with fresh toluene (170 g).
  • the aqueous phase was split off and discarded.
  • the remaining organic phase was evaporated to dryness.
  • Purified N'-[5-bromo-2-methyl-6- (1-methyl-2-propoxy-ethoxy)-3-pyridyl]-N-ethyl-N-methyl-formamidine (12.3 g; assay 91.1%; 30 mmol) was obtained.
  • reaction mixture was then fed into a mixture of water (200 g) and 30% sodium hydroxide (60 g, assay 30%; 450 mmol) during 30 maintaining the internal temperature at 1°C.
  • the resulting mixture was extracted with ethyl acetate (120 g).
  • the aqueous phase was split off and discarded.
  • the organic phase was washed twice with water (100 g), dried with Na 2 SC> 4 and evaporated to dryness.
  • N'-[5-Bromo-2-methyl-6-(1- methyl-2-propoxy-ethoxy)-3-pyridyl]-N-ethyl-N-methyl-formamidine (21.3 g; assay 96.2%; isolated yield 88.2%) was obtained as a brownish oil.
  • the process of the invention as notably embodied by the processes according to any of Examples 1 to 4 surprisingly provides a compound of formula (I) at very high isolated yields, advantageously at low molar ratios between phosgene and the compound of formula (II).
  • the process of the invention surprisingly provides a compound of formula (I) at a very high isolated yield in association with a high assay at a relatively low molar ratio of 1.3:1 between phosgene and the compound of formula (II).
  • Example 3 the process of the invention surprisingly provides a compound of formula (I) at a higher isolated yield in association with a higher assay, in comparison with the process of Example 2, at a lower molar ratio of 1.0:1 between phosgene and the compound of formula (III).
  • the stability was assessed on the basis of mass balance analysis: the sum of N-ethyl-N-methyl-formamide and the Vilsmeier reagent was considered and compared to the amount of standard. Hydrolysis, caused by the introduction of moisture during sample preparation or in the setup itself, was not considered to be a thermal decomposition pathway during this study. As shown in Table 2 below, the phosgene-derived Vilsmeier reagent advantageously proved to be stable over 21 hours at 10°C.
  • the reaction mixture was stirred at 10°C for about 21 hours and samples were withdrawn regularly, diluted with CDC and analyzed by 1 H qNMR to monitor the stability of the formed Vilsmeier reagent.
  • the stability was assessed on the basis of mass balance analysis: the sum of N-ethyl-N-methyl-formamide and the Vilsmeier reagent was considered and compared to the amount of standard.
  • Hydrolysis caused by the introduction of moisture during sample preparation or in the setup itself, was not considered to be a thermal decomposition pathway during this study. As shown in Table 3 below, the phosphoroxychloride-derived Vilsmeier reagent did show a decay of about 20% over 20 hours at 10°C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

La présente invention concerne un procédé de préparation de dérivés de N-aryl-formamidine appropriés pour une utilisation, par exemple, en tant que principes actifs, qui ont une activité microbiocide, en particulier, une activité fongicide.
PCT/EP2022/059764 2021-04-15 2022-04-12 Procédé de préparation de dérivés de n-aryl-formamidine fongicides WO2022218987A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015155075A1 (fr) 2014-04-11 2015-10-15 Syngenta Participations Ag Dérivés fongicide de n'- [2-méthyl -6- [2-alcoxy-éthoxy]-3-pyridyl]-n-alkyl-formamidine destinés à être utilisés dans l'agriculture
WO2017063973A1 (fr) * 2015-10-14 2017-04-20 Syngenta Participations Ag Compositions fongicides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015155075A1 (fr) 2014-04-11 2015-10-15 Syngenta Participations Ag Dérivés fongicide de n'- [2-méthyl -6- [2-alcoxy-éthoxy]-3-pyridyl]-n-alkyl-formamidine destinés à être utilisés dans l'agriculture
WO2017063973A1 (fr) * 2015-10-14 2017-04-20 Syngenta Participations Ag Compositions fongicides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SCOTT MALCOLM K. ET AL: "Antisecretory activity of human, dog, and rat metabolites of fenoctimine", vol. 30, no. 5, 1 May 1987 (1987-05-01), pages 894 - 899, XP055836970, ISSN: 0022-2623, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/jm00388a025> DOI: 10.1021/jm00388a025 *

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