CN1355786A - Substituted arylmalonic acid dinitriles as intermediates for preparation of herbicides - Google Patents

Substituted arylmalonic acid dinitriles as intermediates for preparation of herbicides Download PDF

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CN1355786A
CN1355786A CN00808905A CN00808905A CN1355786A CN 1355786 A CN1355786 A CN 1355786A CN 00808905 A CN00808905 A CN 00808905A CN 00808905 A CN00808905 A CN 00808905A CN 1355786 A CN1355786 A CN 1355786A
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alkyl
amino
alkynyl
carbonyl
alkenyl
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A·施尼德
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Syngenta Participations AG
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/34—Nitriles
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/33—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring with cyano groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/26—Radicals substituted by halogen atoms or nitro radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Agronomy & Crop Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compounds of formula (I), as intermediates for the preparation of known, herbicidally active 3-hydroxy-4-aryl-5-oxopyrazoline derivatives. A process for their preparation and their use in the preparation of herbicides.

Description

Be used to prepare the substituted aryl Malononitrile compound of the intermediate of weedicide
The present invention relates to new substituted aryl Malononitrile compound, they are used in total method of the known 3-hydroxy-4-aryl-5-oxopyrazoline derivative with weeding activity of preparation as intermediate, and this total method has beyond thought advantage.The invention still further relates to preparation and their purposes aspect preparation 3-hydroxy-4-aryl-5-oxopyrazoline derivative of these intermediates.
Arylprop dintrile and utilize their method of palladium complex preparation at for example Chem.Commun.1984,932 and JP-A-60 197 650 on the books.And J.Am.Chem.Soc.121, the method for utilizing palladium catalyst arylation malonic ester has also been described in 1473 (1999).
Have now found that the substituted aryl Malononitrile compound that a class is new, they are especially suitable for use as the intermediate of the proper method of preparation weedicide 3-hydroxy-4-aryl-5-oxopyrazoline derivative.
Therefore, the present invention relates to formula I compound:R wherein0Be halogen independently of one another, C1-C 6Alkyl, C2-C 6Alkenyl, C2-C 6Alkynyl, C1-C 6Haloalkyl, cyano group-C1-C 6Alkyl, C2-C 6Halogenated alkenyl, cyano group-C2-C 6Alkenyl, C2-C 6The halo alkynyl, cyano group-C2-C 6Alkynyl, hydroxyl, hydroxyl-C1-C 6Alkyl, C1-C 6Alkoxyl, nitro, amino, C1-C 6Alkyl is amino, two (C1-C 6Alkyl) amino, C1-C 6Alkyl-carbonyl-amino, C1-C 6Alkyl sulfonyl-amino, C1-C 6Alkyl amino sulfonyl, C1-C 6The alkyl carbonyl, C1-C 6Alkyl carbonyl-C1-C 6Alkyl, C1-C 6Alkoxyl carbonyl-C1-C 6Alkyl, C1-C 6Alkyl carbonyl-C2-C 6Alkenyl, C1-C 6The alkoxyl carbonyl, C1-C 6Alkoxyl carbonyl-C2-C 6Alkenyl, C1-C 6Alkyl carbonyl-C2-C 6Alkynyl, C1-C 6Alkoxyl carbonyl-C2-C 6Alkynyl, cyano group, carboxyl, phenyl or contain 1 or 2 heteroatomic aromatic ring that is selected from nitrogen, oxygen and sulphur, wherein rear two kinds of aromatic rings can be by C1-C 3Alkyl, C1-C 3Haloalkyl, C1-C 3Alkoxyl, C1-C 3Halogenated alkoxy, halogen, cyano group or nitro replace; Perhaps R0With adjacent substituting group R1、R 2And R3Form together saturated or undersaturated C3-C 6Hydrocarbon bridge, this hydrocarbon bridge can be interrupted by 1 or 2 hetero atom that is selected from nitrogen, oxygen and sulphur and/or by C1-C 4Alkyl replaces; R1，R 2And R3Be hydrogen independently of one another, halogen, C1-C 6Alkyl, C2-C 6Alkenyl, C2-C 6Alkynyl, C3-C 6Cycloalkyl, C1-C 6Haloalkyl, C2-C 6Halogenated alkenyl, C1-C 6Alkoxyl carbonyl-C2-C 6Alkenyl, C1-C 6Alkyl carbonyl-C2-C 6Alkenyl, cyano group-C2-C 6Alkenyl, nitro-C2-C 6Alkenyl, C2-C 6The halo alkynyl, C1-C 6Alkoxyl carbonyl-C2-C 6Alkynyl, C1-C 6Alkyl carbonyl-C2-C 6Alkynyl, cyano group-C2-C 6Alkynyl, nitro-C2-C 6Alkynyl, C3-C 6Halogenated cycloalkyl, hydroxyl-C1-C 6Alkyl, C1-C 6Alkoxy-C1-C 6Alkyl, C1-C 6Alkylthio group-C1-C 6Alkyl, cyano group, C1-C 4The alkyl carbonyl, C1-C 6The alkoxyl carbonyl, hydroxyl, C1-C 10Alkoxyl, C3-C 6Alkenyloxy, C3-C 6Alkynyloxy group, C1-C 6Halogenated alkoxy, C3-C 6The halo alkenyloxy, C1-C 6Alkoxy-C1-C 6Alkoxyl, sulfydryl, C1-C 6Alkylthio group, C1-C 6The alkyl halide sulfenyl, C1-C 6The alkyl sulfinyl, C1-C 6The alkyl sulfonyl base, nitro, amino, C1-C 6Alkyl is amino, two (C1- C 6Alkyl) amino or phenoxy group, phenyl ring wherein can be by C1-C 3Alkyl, C1-C 3Haloalkyl, C1-C 3Alkoxyl, C1-C 3Halogenated alkoxy, halogen, cyano group or nitro replace; R2Can also be phenyl, naphthyl maybe can contain 1 or 2 the heteroatomic 5-or the 6-unit aromatic ring that are selected from nitrogen, oxygen and sulphur, and wherein said benzyl ring, naphthyl ring body system and 5-or 6-unit aromatic ring can be by halogen, C3-C 8Cycloalkyl, hydroxyl, sulfydryl, amino, cyano group, nitro or formoxyl replace; And/or described benzyl ring, naphthyl ring body system and 5-or 6-unit aromatic ring can be replaced by following group: C1-C 6Alkyl, C1-C 6Alkoxyl, hydroxyl-C1-C 6Alkyl, C1-C 6Alkoxy-C1-C 6Alkyl, C1-C 6Alkoxy-C1-C 6Alkoxyl, C1-C 6Alkyl carbonyl, C1-C 6Alkylthio group, C1-C 6Alkyl sulfinyl, C1-C 6Alkyl sulfonyl base, list-C1-C 6Alkyl is amino, two (C1-C 6Alkyl) amino, C1-C 6Alkyl-carbonyl-amino, C1-C 6Alkyl carbonyl (C1-C 6Alkyl) amino, C2-C 6Alkenyl, C3-C 6Alkenyloxy, hydroxyl-C3-C 6Alkenyl, C1-C 6Alkoxy-C2-C 6Alkenyl, C1-C 6Alkoxy-C3-C 6Alkenyloxy, C2-C 6Alkenyl carbonyl, C2-C 6Alkenyl thio, C2-C 6Alkenyl sulfinyl, C2-C 6Alkenyl sulfonyl, list-or two-(C2-C 6Alkenyl) amino, C1-C 6Alkyl (C3-C 6Alkenyl) amino, C2-C 6Alkenyl carbonyl is amino, C2-C 6Alkenyl carbonyl (C1-C 6Alkyl) amino, C2-C 6Alkynyl, C3-C 6Alkynyloxy group, hydroxyl-C3-C 6Alkynyl, C1-C 6Alkoxy-C3-C 6Alkynyl, C1-C 6Alkoxy-C4-C 6Alkynyloxy group, C2-C 6Alkynyl carbonyl, C2-C 6Alkynes sulfenyl, C2-C 6Alkynyl sulfinyl, C2-C 6Alkynyl sulfonyl, list-or two-(C3-C 6Alkynyl) amino, C1-C 6Alkyl (C3-C 6Alkynyl) amino, C2-C 6Alkynyl carbonyl amino or C2-C 6Alkynyl carbonyl (C1-C 6Alkyl) amino; And/or described benzyl ring, naphthyl ring body system and 5-or the 6-unit aromatic ring C that can be replaced by halogen1-C 6Alkyl, C1-C 6Alkoxyl, hydroxyl-C1-C 6Alkyl, C1-C 6Alkoxy-C1-C 6Alkyl, C1-C 6Alkoxy-C1-C 6Alkoxyl, C1-C 6Alkyl carbonyl, C1-C 6Alkylthio group, C1-C 6Alkyl sulfinyl, C1-C 6Alkyl sulfonyl base, list-C1-C 6Alkyl is amino, two (C1-C 6Alkyl) amino, C1-C 6Alkyl-carbonyl-amino, C1-C 6Alkyl carbonyl (C1-C 6Alkyl) amino, C2-C 6Alkenyl, C3-C 6Alkenyloxy, hydroxyl-C3-C 6Alkenyl, C1-C 6Alkoxy-C2-C 6Alkenyl, C1-C 6Alkoxy-C3-C 6Alkenyloxy, C2-C 6Alkenyl carbonyl, C2-C 6Alkenyl thio, C2-C 6Alkenyl sulfinyl, C2-C 6Alkenyl sulfonyl, list-or two-(C2-C 6Alkenyl) amino, C1-C 6Alkyl (C3-C 6Alkenyl) amino, C2-C 6Alkenyl carbonyl is amino, C2-C 6Alkenyl carbonyl (C1-C 6Alkyl) amino, C2-C 6Alkynyl, C3-C 6Alkynyloxy group, hydroxyl-C3-C 6Alkynyl, C1-C 6Alkoxy-C3-C 6Alkynyl, C1-C 6Alkoxy-C4-C 6Alkynyloxy group, C2-C 6Alkynyl carbonyl, C2-C 6Alkynes sulfenyl, C2-C 6Alkynyl sulfinyl, C2-C 6Alkynyl sulfonyl, list-or two-(C3-C 6Alkynyl) amino, C1-C 6Alkyl (C3-C 6Alkynyl) amino, C2-C 6Alkynyl carbonyl amino or C2-C 6Alkynyl carbonyl (C1-C 6Alkyl) the amino replacement; And/or described benzyl ring, naphthyl ring body system and 5-or 6-unit aromatic ring can be by formula COOR50、CONR 51、 SO 2NR 53R 54Or SO2OR 55Group replace, R wherein50、R 51、R 52、R 53、R 54And R55Be C independently of one another1-C 6Alkyl, C2-C 6Alkenyl or C3-C 6Alkynyl or be halogen-, hydroxyl-, alkoxyl-, sulfydryl-, amino-, cyano group-, nitro-, alkylthio group-, alkyl sulfinyl-or the C of alkyl sulfonyl base-replacement1-C 6Alkyl, C2-C 6Alkenyl or C3-C 6Alkynyl; And n is 0,1 or 2.
In above-mentioned definition, halogen is interpreted as being meant fluorine, chlorine, bromine or iodine, preferred fluorine, chlorine or bromine.
Alkyl in the substituting group definition for example is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-or the tertiary butyl, and the various isomer of amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl and dodecyl.
Haloalkyl preferably has the chain length of 1-6 carbon atom.Haloalkyl for example is methyl fluoride, difluoromethyl, difluoro chloromethyl, trifluoromethyl, chloromethyl, dichloromethyl, dichlorofluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoro ethyl, 2-chloroethyl, 2,2-two fluoro ethyls, 2,2-Dichloroethyl, 2,2,2-three chloroethyls or pentafluoroethyl group, preferred trichloromethyl, difluoro chloromethyl, difluoromethyl, trifluoromethyl or dichlorofluoromethyl.
Alkoxy base preferably has the chain length of 1-6 carbon atom.Alkoxyl group for example is meant methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, or pentyloxy and hexyloxy isomer, preferred methoxyl group, oxyethyl group or positive propoxy.
Halogenated alkoxy for example is fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, 2,2,2-trifluoro ethoxy, 1,1,2,2-tetrafluoro oxyethyl group, 2-fluorine oxyethyl group, 2-chloroethoxy or 2,2,2-three chloroethoxies.
The alkenyl example that can mention is vinyl, allyl group, methylallyl, 1-methyl ethylene, but-2-ene-1-base, pentenyl and 2-hexenyl; Preferred chain length is the alkenyl of 3-6 carbon atom.
The alkynyl example that can mention is ethynyl, propargyl, 1-methyl propargyl, 3-butynyl, fourth-2-alkynes-1-base, 2-methyl fourth-3-alkynes-2-base, fourth-3-alkynes-2-base, 1-pentynyl, penta-4-alkynes-1-base and 2-hexin base; Preferred chain length is the alkynyl of 3-6 carbon atom.
Suitable halogenated alkenyl comprises the alkenyl that is replaced one or many by halogen, and halogen wherein is in particular bromine or iodine, and refers to fluorine or chlorine especially, described group for example is 2-and 3-fluorine propenyl, 2-and chlorallylene base, 2-and 3-bromopropenyl, 2,2-two fluoro-1-methyl ethylenes, 2,3,3-trifluoro-propenyl, 3,3,3-trifluoro-propenyl, 2,3,3-tri chloropropene base, 4,4,4-trifluoro but-2-ene-1-base and 4,4,4-trichlorine but-2-ene-1-base.By halo replace once, the alkenyl of twice or three times preferably has 3-6 carbon atom chain length.Kiki alkenyl group can be replaced by halogen on saturated or undersaturated carbon atom.
Alkoxyalkyl preferably has 1-6 carbon atom.For example, alkoxyalkyl is methoxymethyl, methoxy ethyl, ethoxyl methyl, ethoxyethyl group, n-propoxymethyl, positive propoxy ethyl, isopropoxy methyl or isopropoxy ethyl.
Halogenated alkoxy for example is fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, 2,2,2-trifluoro ethoxy, 1,1,2,2-tetrafluoro oxyethyl group, 2-fluorine oxyethyl group, 2-chloroethoxy or 2,2,2-three chloroethoxies.
Alkenyloxy for example is an allyloxy, and first is for allyloxy and but-2-ene-1-base oxygen base.
Suitable halo alkenyloxy comprises the alkenyloxy that is replaced one or many by halogen, and halogen wherein is in particular bromine or iodine, and refers to fluorine or chlorine especially.Described group for example is 2-and 3-fluorine propenyloxy group, 2-and chlorallylene oxygen base, 2-and 3-bromopropylene oxygen base, 2,3,3-trifluoro propene oxygen base, 2,3,3-tri chloropropene oxygen base, 4,4,4-trifluoro but-2-ene-1-base oxygen base and 4,4,4-trichlorine but-2-ene-1-base oxygen base.
Alkynyloxy group for example is alkynes propoxy-and 1-methyl alkynes propoxy-.
Suitable naphthenic substituent contains 3-8 carbon atom, and is for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group.They can be replaced one or many by halogen (preferred fluorine, chlorine or bromine).
Alkyl-carbonyl is ethanoyl or propionyl particularly.
Alkoxy carbonyl for example is methoxycarbonyl, ethoxy carbonyl, positive propoxy carbonyl, isopropoxy carbonyl or tert-butoxycarbonyl, pentyloxy carbonyl or hexyloxy carbonyl isomer; Preferred methoxycarbonyl or ethoxy carbonyl.
Alkylthio preferably has the chain length of 1-6 carbon atom.For example, alkylthio is methylthio group, ethylmercapto group, rosickyite base, butylthio, penta sulfenyl or own sulfenyl, perhaps their branched chain isomer, but preferred methylthio group or ethylmercapto group.
Halogenated alkylthio is for example 2,2,2-trifluoro ethylmercapto group or 2,2,2-trichlorine ethylmercapto group.
Alkyl sulphinyl for example is a methylsulfinyl, ethyl sulfinyl, n-propyl sulfinyl; the sec.-propyl sulfinyl, normal-butyl sulfinyl, isobutyl-sulfinyl; sec-butyl sulfinyl or tertiary butyl sulfinyl, preferable methyl sulfinyl or ethyl sulfinyl.
Alkyl sulphonyl for example is methylsulfonyl, ethylsulfonyl, n-propyl alkylsulfonyl, different third alkylsulfonyl, normal-butyl alkylsulfonyl, isobutyl-alkylsulfonyl, sec-butyl alkylsulfonyl or tertiary butyl alkylsulfonyl; Preferred methylsulfonyl or ethylsulfonyl.
Alkylamino for example is a methylamino, ethylamino, n-propyl amino, sec.-propyl amino or butyl-, amyl group-or hexyl-amine isomer.
Dialkyl amido for example is a dimethylamino, first and second amino, diethylamino, n-propyl-methylamino, dibutylamino or diisopropylaminoethyl.
Alkylthio alkyl for example is methylthiomethyl, methylmercaptoethyl, ethylmercapto group methyl, ethylmercapto group ethyl, positive rosickyite ylmethyl, positive rosickyite base ethyl, iprotiazem ylmethyl or iprotiazem base ethyl.
R 2Phenyl in the definition and naphthyl and R 1, R 2And R 3Phenoxy group in the definition can be the replacement form.Substituting group optionally can be positioned in ortho position, a position and/or the contraposition in this case, and to naphthalene nucleus, substituting group can also be positioned on 5-, 6-, 7-and/or the 8-position.
R 0And R 2The suitable example that contains 1 or 2 heteroatomic 5-that is selected from nitrogen, oxygen and sulphur or 6-unit aromatic ring in the definition is pyrryl (pyrrolidyl), pyridyl, pyrimidyl, triazinyl, thiazolyl, triazolyl, thiadiazolyl group, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, furyl, thienyl, pyrazolyl, benzoxazolyl, benzothiazolyl, quinoxalinyl, indyl and quinolyl.In addition, these heteroaryls can also be substituted.
The corresponding meaning that above provides also is applicable to the substituting group with the array mode definition, for example alkoxyl group-alkoxyl group, alkyl-sulfuryl amino, alkyl-amino-sulfonyl, phenyl-alkyl, naphthyl-alkyl and heteroaryl-alkyl.
In the definition of alkyl-carbonyl and alkoxy carbonyl, given carbon number bound does not comprise carbonylic carbon atom under every kind of particular case.
The formula I compound that preferred definition is following, wherein the definition cotype I of n; R 0Be halogen independently of one another, C 1-C 6Alkyl, C 1-C 6Haloalkyl, hydroxyl, C 1-C 6Alkoxyl group, nitro, amino, C 1-C 6Alkylamino, two (C 1-C 6Alkyl) amino, C 1-C 6Alkyl-carbonyl-amino, C 1-C 6Alkyl sulfonyl-amino, C 1-C 6Alkyl amino sulfonyl, C 1-C 4Alkyl-carbonyl, C 1-C 6Alkoxy carbonyl or carboxyl; And R 1, R 2And R 3Be hydrogen independently of one another, halogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 3-C 6Cycloalkyl, C 1-C 6Haloalkyl, C 2-C 6Halogenated alkenyl, C 2-C 6The halo alkynyl, C 3-C 6Halogenated cycloalkyl, C 1-C 6Alkoxy-C 1-C 6Alkyl, C 1-C 6Alkylthio-C 1-C 6Alkyl, cyano group, C 1-C 4Alkyl-carbonyl, C 1-C 6Alkoxy carbonyl, hydroxyl, C 1-C 10Alkoxyl group, C 3-C 6Alkenyloxy, C 3-C 6Alkynyloxy group, C 1-C 6Halogenated alkoxy, C 3-C 6The halo alkenyloxy, C 1-C 6Alkoxy-C 1-C 6Alkoxyl group, sulfydryl, C 1-C 6Alkylthio, C 1-C 6Halogenated alkylthio, C 1-C 6Alkyl sulphinyl, C 1-C 6Alkyl sulphonyl, nitro, amino, C 1-C 4Alkylamino or two (C 1-C 4Alkyl) amino.
Also preferred these formulas I compound, wherein R 1, R 2And R 3Be hydrogen independently of one another, halogen, C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 2-C 4Alkenyl, C 2-C 4Halogenated alkenyl, C 2-C 4Alkynyl, C 3-C 6Cycloalkyl, C 1-C 4Alkyl-carbonyl, C 1-C 6Alkoxy carbonyl, hydroxyl, C 1-C 4Alkoxyl group, C 3-or C 4Alkenyloxy, C 3-or C 4Alkynyloxy group, C 1-C 4Halogenated alkoxy, nitro or amino.
Preferred R wherein equally also 1Be C 2-C 6The formula I compound of alkyl.
Same preferred wherein n is 0 formula I compound.Wherein, preferred especially these formulas I compound, wherein R 1Be C 2-C 4Alkyl, C 1-C 4Alkoxyl group, C 2-C 4Alkynyl or C 3-C 6Cycloalkyl, and R 3Be C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 2-C 4Alkynyl or C 3-C 6Cycloalkyl.
Equally preferred R wherein 1Be C 2-C 6The formula I compound of alkynyl.
Also preferred these formulas I compound, wherein R 1And R 3Be C independently of one another 2-C 6Alkyl, C 2-C 6Alkynyl, C 1-C 10Alkoxyl group or C 3-C 6Cycloalkyl.Wherein, preferred especially R 1Be C 2-C 6Alkyl and R 3Be C 2-C 6Alkyl, C 2-C 6Alkynyl or C 1-C 10The compound of alkoxyl group.
Chem.Commun.1984,932 and JP-A-60 197 650 in a kind of method of palladium catalysis synthesizing aryl propane dinitrile has been described, comprise making unsubstituted or the mono-substituted aryl halide of 2-or 4-position carries out C-C with the propane dinitrile negatively charged ion and is connected productive rate 56-95%.For example, wherein mention use (PPh 3) 2PdCl 2And Pd (PPh 3) 4As palladium complex and use tetrahydrofuran (THF) as reaction medium, and JP-A-60 197 650 required wideer scope, also mentions and uses two (trialkyl phosphine)-and two (tri-alkoxies-and triple phenoxyl-phosphine)-Palladous chloride (II) title complex and as the glycol dimethyl ether and the dimethyl formamide of reaction medium.In these two pieces of documents, the aryl halide of specifically mentioning has only unsubstituted or mono-substituted aryl iodide and 4-position by cyano group activatory bromobenzene.
Surprisingly, have now found that propane dinitrile and the list that contains in a large number leavings group in addition-or the C-C of many-substituted aryl derivative be connected and can in the presence of various palladium (II) or palladium (O) title complex, in multiple reaction medium, carry out easily, and product yield and purity are all very high.
The advantage of the inventive method is: a) variation range of reaction medium and reaction conditions is wide, b) the volumetric concentration height (up to 10%) of reactant, c) the palladium catalyst quantity of Shi Heing is many, d) can use have the various leavings groups that comprise sterically hindered (low activity) leavings group and extensively (especially on 2-and 6-position) benzene derivative of replacing as initial compounds, e) initial compounds easily obtains, f) catalyzer that uses is commercially available product, perhaps easy-to-use commercially available palladium salt (concentrated hydrochloric acid solution (20%) and corresponding ligand " on the spot " preparation that for example add the Palladous chloride (II) of solubility promoter N,N-DIMETHYLACETAMIDE (DMA), g) reactions steps is simple, propane dinitrile negatively charged ion that for example will " on the spot " generates and palladium catalyst react with aryl halide or aromatic yl sulphonate, h) post-treating method is simply effective, the C-C that can high purity obtains formula I connects product (embodiment P17), i) the general extra-high-speed of product yield, and j) this method can be used as in the successive reaction step of preparation formula III3-hydroxy-4-aryl-5-oxopyrazoline derivative step by step, thereby also is superior from economic angle and ecological aspect.
Therefore, this preparation method is particularly suitable for mass preparation formula I arylprop two carbonitrile derivatives.
The method of preparation I compound of the present invention is included under the palladium catalyst existence formula II compound and propane dinitrile negatively charged ion is reacted in inert solvent:
Figure A0080890500181
R wherein 0, R 1, R 2, R 3With n suc as formula defining among the I, and X is a leavings group.The propane dinitrile negatively charged ion is preferably by propane dinitrile and alkali " on the spot " preparation.
The preparation of formula I compound is illustrated by following reaction process 1.Reaction process 1 According to reaction process 1, formula I compound is pressed and describedly made by formula II compound: the first step of reaction is under 0-100 ℃ temperature, and at alkali (for example alkali metal alcoholates such as sodium tert-butoxide) and palladium catalyst (for example independent palladium catalyst for preparing, close palladium (II) as molybdenyl dichloride (tricyclohexyl phosphine)) exist down, formula II compound is fed in the propane dinitrile solution that appropriate solvent is for example made in aromatic hydrocarbons, ether or the methyl-sulphoxide (as dimethylbenzene or tetrahydrofuran (THF)).Pass through reacting by heating solution then to 30-250 ℃ of beginning linked reaction, temperature of reaction depends on solvent for use.
For the C-C ligation that formula II compound and propane dinitrile negatively charged ion carry out in the presence of palladium catalyst, suitable leavings group is a halogen, R 10S (O) 2O-(R wherein 10Be C 1-C 4Alkyl, preferable methyl, C 1-C 4Haloalkyl, preferred halogenated methyl or n-C 4F 9, aryl, preferred phenyl, or by the phenyl of halogen, methyl or halogenated methyl list-to three-replace) and single-, two-or three-aryl methoxy.
Single, two-and three-aryl methoxy group in the preferred phenyl of aryl, it can be for example by methyl substituted once to three times, and substituting group is preferably placed on 2-, the 4-and/or 6-position of phenyl ring.
The example of these leavings groups has mesyloxy (methanesulfonates), trifluoro-methanesulfonyl oxy (triflate), right-tosyloxy (tosylate), CF 3(CF 2) 3S (O) 2O-(nine fluorine fourth sulphonates), phenylbenzene methoxy base, two (aminomethyl phenyl) methoxyl group, three benzyloxies (trityl) and three (aminomethyl phenyl) methoxyl group.
Preferred especially these leavings groups, wherein X is chlorine, bromine, iodine, CF 3S (O) 2O-(triflate), CF 3(CF 2) 3S (O) 2O-(nine fluorine fourth sulphonates), right-tolyl-S (O) 2O-(tosylate), (C 6H 5) 2CHO-, (CH 3-C 6H 4) 2CHO-, (C 6H 5) 3CO-(three benzyloxies) or (CH 3-C 6H 4) 3CO-.Wherein, more preferred wherein X is the leavings group of chlorine, bromine or iodine.
Be fit to the palladium catalyst that the C-C ligation is used between formula II compound and propane dinitrile negatively charged ion and be generally palladium (II) or palladium (O) title complex, for example dihalide palladium (II), acid chloride (II), palladous sulfate (II), dichloride two (triphenyl phosphine) are closed palladium (II), dichloride two (three cyclopentyl phosphines) and are closed that palladium (II), dichloride two (tricyclohexyl phosphine) close palladium (II), two (dibenzalacetones) close palladium (O) or four (triphenyl phosphines) close palladium (O).
In the particularly advantageous version of the inventive method, palladium catalyst can pass through also that palladium (II) or palladium (O) compound cooperate with required ligand and " on the spot " preparation, for example by together adding palladium (II) salt that will cooperate (as palladium chloride (II) (PdCl 2) or acid chloride (II) (Pd (OAc) 2)) and required ligand (triphenyl phosphine (PPh for example 3) or tricyclohexyl phosphine (PCy 3)) and selected solvent, propane dinitrile and alkali prepare.Advantageously, the palladium salt palladium chloride (II) that price is suitable can also be with the 20%PdCl that forms in concentrated hydrochloric acid 2The solution form is used (embodiment P4 and P17) in the presence of the N,N-DIMETHYLACETAMIDE (DMA) that has as solubility promoter, comparatively Ang Gui palladium diacetate (II) then is dissolved in for example tetrahydrofuran (THF) basically.With palladium salt is benchmark, and the amount of the required ligand that adds in reaction medium is 10 molar excess at the most.Reacting by heating medium elder generation " on the spot " forms palladium (II) or palladium (O) title complex that the C-C linked reaction needs then, and then beginning C-C linked reaction.
The suitable ligand example that is used for palladium (II) and palladium (O) title complex is three methylphosphines, triethylphosphine, three (tertiary butyl) phosphine, three cyclopentyl phosphines, tricyclohexyl phosphine (PCy 3), three (methylcyclohexyl) phosphine, methyl (tetramethylene) phosphine, the tertiary butyl (pentamethylene) phosphine, triphenyl phosphine (PPh 3), three (aminomethyl phenyl) phosphine, 1,2-(diphenyl phosphine) hexanaphthene, 1,2-(diphenyl phosphine) pentamethylene, 2,2 ＇-(diphenyl phosphine) biphenyl, 1, two (diphenyl phosphine) ethane, 1 of 2-, two (diphenyl phosphine) propane, 1 of 3-, two (diphenyl phosphine) butane, 3 of 4-, two (diphenyl phosphine) tetramethyleneimine, 2,2 of 4-'-(diphenyl phosphine)-dinaphthalene (BINAP), 1,1 '-two (diphenyl phosphine) ferrocene, 1,1 '-two (di-t-butyl phosphino-) ferrocene, phenyl ether be two-diphenyl phosphine:
Figure A0080890500211
R 10Be hydrogen or dimethylamino, and R 11Be the cyclohexyl or the tertiary butyl.The phenylbenzene derivative that these electron riches of back and spatial volume are big is that the specific palladium catalyst of preparation the present invention is the specially suitable phosphine ligand that so-called Buchwald catalyzer is used.These catalyzer with as the alkalimetal hydride of alkali or alkali metal phosphate and equally also be particularly suitable for propane dinitrile of the present invention as the toluene of solvent or dimethylbenzene combination and be connected with the C-C that polysubstituted aryl derivatives carries out.
Described ligand and palladium complex are known, and be documented in the many pieces of reference, J.Am.Chem.Soc.121 for example, 4369-4378 (1999), EP-A-0564406, EP-A-0646590 and " palladium reagent and catalyzer " ' Palladium Reagents andCatalysts ', J.Tsuji editor, John Wiley ﹠amp; Sons, 1995.
Usually use have single-and two-tooth dentate, uncle or two tertiary amines, phosphine and arsine as palladium (O) title complex of ligand.N-in these ligands, P-and/or As atom can be replaced by straight or branched aliphatic group identical or different, that contain 1-18 carbon atom (preferred 1-12 carbon atom, especially 1-8 carbon atom).
Same suitable also has unsubstituted or C 1-C 4The C of alkyl-replacement 5-C 7Cycloalkyl, unsubstituted or C 1-C 4The C of alkyl-replacement 6-C 10Aryl, especially phenyl and alkyl phenyl, and unsubstituted or by C 1-C 4The benzyl that alkyl replaces.
Two aliphatic groups with heteroatoms N, P and/or As bonding can form unsubstituted or C 1-C 4The C of alkyl-replacement 4-or C 5-hydrocarbon bridge, thus 5-or 6-unit heterocycle formed with heteroatoms.
Under the situation of bidentate ligands, two N, P and/or As atom are by aliphatic, unsubstituted or C 1-C 4The C of alkyl-replacement 2-C 5Hydrocarbon chain (divalence) connects.
Described aliphatic series, bivalent hydrocarbon chain can randomly be interrupted by 1 or 2 heteroatoms (for example O, N and/or S), and/or can be the parts of ring or ring system.Preferred phosphine ligand, especially alkalescence and the big phosphine ligand of spatial volume, thricyclohexyl-or tri-tert-phosphine for example, its reason is can significantly reduce subsequently the concentration (reducing 3-10 times) of corresponding palladium complex, and can not lose their catalytic activity.
The consumption of palladium catalyst is the 0.001-50mol% of formula II compound amount, preferred 0.01-10mol%, especially 0.1-3mol%.
(suitable solvent of the step 1) of reaction process 1 and palladium-catalysis C-C ligation (step 2 in the reaction process 1) of carrying out with formula II compound is aliphatic series to be used to form the propane dinitrile negatively charged ion, alicyclic or aromatic hydrocarbons, pentane for example, hexane, sherwood oil, hexanaphthene, methylcyclohexane, benzene, toluene and dimethylbenzene, the aliphatic halogenated hydrocarbons class, methylene dichloride for example, chloroform and two-or tetrachloroethane, nitrile, acetonitrile for example, propionitrile and benzonitrile, ethers, ether for example, dibutyl ether, t-butyl methyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, diglyme, tetrahydrofuran (THF) is with diox, alcohols, methyl alcohol for example, ethanol, propyl alcohol, butanols, ethylene glycol, glycol ether, the glycol monomethyl methyl-or single ethyl-ether and diglycol monotertiary methyl or single ethyl ether, ketone, as acetone and methyl iso-butyl ketone (MIBK), ester or lactone, for example ethyl acetate or methyl acetate and valerolactone, the N-substituted lactams, N-Methyl pyrrolidone (NMP) for example, amides, N for example, dinethylformamide (DMF) and N,N-DIMETHYLACETAMIDE (DMA), acyclic ureas, N for example, N '-dimethyl ethylidene-urea (DMEU), sulfoxide class, for example mixture of methyl-sulphoxide or these solvents.Wherein, special preferred aromatic hydrocarbons, ether and methyl-sulphoxide.
The anionic suitable alkali of preparation propane dinitrile is nucleophilicity weak base, tricresyl phosphate-an alkali metal salt for example, the hydride of basic metal and alkaline-earth metal, the amide of basic metal and alkaline-earth metal and alkali metal alcoholates, for example Tripotassium phosphate, potassium tert.-butoxide or sodium tert-butoxide, di-isopropyl lithamide (LDA) and potassium cyanide or sodium cyanide.The preferred excessive 2-10 equivalent of the consumption of described alkali is a benchmark with the amount of propane dinitrile.(alkali/group of solvents of the step 1) in the reaction process 1 is combined into for example alkali metal alcoholates/aliphatic series, alicyclic or aromatic hydrocarbon, for example sodium tert-butoxide/dimethylbenzene to be particularly suitable for producing the propane dinitrile negatively charged ion.The dihalide two (tricyclic alkyl phosphine) that is combined as that is particularly suitable for leavings group X in the palladium catalyst of C-C ligation (step 2 in the reaction process 1) and the formula II compound is closed palladium (II) and halogen, for example, dichloride two (tricyclohexyl phosphine) is closed palladium (II) and bromide.
The anionic formation of propane dinitrile should be at 0-100 ℃, carry out under preferred 20-80 ℃ the temperature of reaction, the reaction that described negatively charged ion and formula II compound carry out in the presence of palladium catalyst then should be carried out under 30-250 ℃ temperature of reaction, preferred 50-200 ℃, particularly 80-160 ℃, this depends on used reaction medium and reaction pressure.
The C-C linked reaction of propane dinitrile negatively charged ion and formula II compound can randomly be carried out under the high pressure of 1.1-10 crust.For the reaction of under the temperature that is higher than the solvent for use boiling point, carrying out, for example, be particularly suitable in closed system, under high pressure, carrying out for using under the toluene situation in 140 ℃ of reactions of carrying out.
Owing to be used for the consumption seldom (easily decompose) of the palladium catalyst of C-C ligation, therefore should be with them in the final stage of reagent feed order and under inert atmosphere, join (step 2 of reaction process 1) (embodiment P17) in the reaction mixture.
Wherein X perhaps can utilize currently known methods (for example Sandmeyer reaction) to be prepared via diazonium salt by corresponding formula VIII substituted aniline for for example formula II compound of halogen is known:
Figure A0080890500231
R wherein 0, R 1, R 2, R 3Definition cotype I with n.
Wherein X is for example R 10S (O) 2O-or single-, two-or the formula II compound of three-aryl methoxy can prepare by corresponding formula IX phenol according to standard method:
Figure A0080890500232
R wherein 0, R 1, R 2, R 3Definition cotype I with n.
The substituted aniline of formula VIII is known, perhaps can prepare with currently known methods, for example prepares with olefin alkylation aniline as described in EP-A-0362667.
Equally, formula IX compound also can be known, perhaps can use for example corresponding formula VIII aniline or its diazonium salt by so-called Phenolic Boiling preparation.
Following reaction process 2 is for example understood the possible method of preparation formula II compound.Reaction process 2
Figure A0080890500241
Formula I substituted aryl dintrile of the present invention is especially suitable for use as the intermediate that 3-hydroxy-4-aryl-5-oxopyrazoline derivative that the preparation formula III replaces is used:
Figure A0080890500242
R wherein 0, R 1, R 2, R 3With the definition cotype I of n, and R 4And R 5Then be hydrogen independently of one another, C 1-C 12Alkyl, C 1-C 12Haloalkyl, C 2-C 8Alkenyl, C 2-C 8Alkynyl, C 1-C 10Alkoxy-C 1-C 8Alkyl is many-C 1-C 10Alkoxy-C 1-C 8Alkyl, C 1-C 10Alkylthio-C 1-C 8Alkyl, C 3-C 8Cycloalkyl, C 3-C 8Halogenated cycloalkyl, 4-to 8-unit heterocyclic radical, phenyl, α-or betanaphthyl, phenyl-C 1-C 6Alkyl, α-or betanaphthyl-C 1-C 6Alkyl, 5-or 6-heteroaryl or 5-or 6-heteroaryl-C 1-C 6Alkyl, aromatic ring wherein and hetero-aromatic ring can be by halogen, C 1-C 6Alkyl, C 1-C 6Haloalkyl, C 1-C 6Alkoxyl group, C 1-C 6Halogenated alkoxy, nitro or cyano group replace, perhaps R 4And R 5The nitrogen-atoms that connects with their institutes keys forms saturated or undersaturated 5-to 8-unit heterocycle, this heterocycle 1) can by oxygen, sulphur or-NR 7-be interrupted, and/or by halogen, C 1-C 10Alkyl, C 1-C 10Haloalkyl, hydroxyl, C 1-C 6Alkoxyl group, C 1-C 6Alkoxy-C 1-C 6Alkoxyl group, C 1-C 6Halogenated alkoxy, sulfydryl, C 1-C 6Alkylthio, C 3-C 7Cycloalkyl, heteroaryl, heteroaryl-C 1-C 6Alkyl, phenyl, phenyl-C 1-C 6Alkyl or benzyloxy replace, and wherein back 3 substituent phenyl ring itself can also be by halogen, C 1-C 6Alkyl, C 1-C 6Haloalkyl, C 1-C 6Alkoxyl group, C 1-C 6Halogenated alkoxy or nitro replace, what and/or 2) can contain a tool 2-6 carbon atom condenses or screws togather alkylidene group or alkenylene chain, this chain randomly is interrupted by oxygen or sulphur, described alkylidene group of at least one annular atoms bridge joint or alkenylene chain in the perhaps described saturated or unsaturated heterocycle; R7 is hydrogen, C 1-C 4Alkyl, C 1-C 6Alkyl-carbonyl, C 1-C 6Alkyl sulphonyl, C 3-C 6Alkenyl or C 3-C 6Alkynyl; And G is a hydrogen, metal ion Equivalent or ammonium ion, sulfonium ion or phosphonium ion, the preparation method of wherein said formula III compound comprise at first carry out step a) or b) one of: a) hydrolyzing type I compound:
Figure A0080890500251
R wherein 0, R 1, R 2, R 3The same with the definition of n, production IV compound: Then, adopt known standard method, carry out following reaction: a according to mode well known in the art 1) with the gained compound with the esterification of formula VII alcohol:
R 6-OH (VII) is R wherein 6Be C 1-C 6Alkyl, C 1-C 6Haloalkyl or benzyl, the aryl malonic acid esters of production V: R wherein 0, R 1, R 2, R 3, R 6The same with the definition of n, perhaps a 2) utilize carboxylic acid halides the gained compound to be converted into the halo carbonyl ketene of formula X:
Figure A0080890500261
R wherein 0, R 1, R 2, R 3The same with the definition of n, and Hal is halogen, perhaps b) with formula VII compound:
R 6-OH (VII) is R wherein 6As above definition, directly alcoholysis formula I compound:
Figure A0080890500262
R wherein 0, R 1, R 2, R 3The same with the definition of n, production V compound:
Figure A0080890500263
R wherein 0, R 1, R 2, R 3, R 6It is the same with the definition of n,
Choose wantonly in the presence of alkali subsequently, (method modification a adds a to make formula V compound or formula X compound 2) react in inert organic solvents with the compound of formula VI, VIa or VIb: R wherein 4And R 5Definition the same, and HHal is a hydrogen halide, randomly transforming the wherein G that is obtained by salt then is that the formula III compound of metal ion Equivalent or ammonium cation is converted into wherein that G is the corresponding salt of sulphur or the cationic formula III compound of phosphorus, perhaps be converted into corresponding formula III compound by handling with Bronsted acid (Br nsted acid), wherein G is a hydrogen.
The implication of the corresponding group that compound provides among the formula I is applicable to radicals R in the formula III compound 4And R 5Interior halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthio alkyl, cycloalkyl and halogenated cycloalkyl.
Many alkoxyl group-alkyl for example are methoxymethoxy-methyl, oxyethyl group methoxy base-methyl, ethoxy ethoxy-methyl, positive propoxy oxyethyl group-methyl, isopropoxy oxyethyl group-methyl, methoxymethoxy-ethyl, oxyethyl group methoxy base-ethyl, ethoxy ethoxy-ethyl, positive propoxy oxyethyl group-methyl, positive propoxy oxyethyl group-ethyl, isopropoxy oxyethyl group-methyl, isopropoxy oxyethyl group-ethyl or (oxyethyl group) 3-ethyl.
Phenyl and naphthyl can be the replacement forms, in this case as required substituting group can be positioned at the ortho position-, a position-and/or contraposition on, and, can also be positioned on 5-, 6-, 7-and/or the 8-position for the naphthalene nucleus system.Substituent optimum position is ortho position and the contraposition with respect to the ring link position.For example, the substituting group of phenyl and naphthyl is C 1-C 4Alkyl, halogen, C 1-C 6Haloalkyl, C 1-C 6Alkoxyl group, C 1-C 6Halogenated alkoxy, nitro, cyano group, amino, C 1-C 4Alkylamino and two (C 1-C 4Alkyl) amino.
R 4With R 5Heterocyclic radical in the definition is preferably 4-to the 8-unit ring that contains 1 or 2 heteroatoms (for example N, S and/or O).They are generally saturated.
R 4And R 5Heteroaryl in the definition is generally 5-or the 6-membered aromatic heterocycle that preferably contains 1-3 heteroatoms (for example N, S and/or O).
The heterocyclic radical that is fit to and the example of heteroaryl are pyrrolidyl, piperidyl, pyranyl ， alkyl dioxin, azetidinyl, oxetanyl, pyridyl, pyrimidyl, triazinyl, thiazolyl, triazolyl, thiadiazolyl group, imidazolyl oxazolyl ， isoxazolyl, pyrazinyl, furyl, thienyl, morpholinyl, piperazinyl, pyrazolyl benzoxazolyl, benzothiazolyl, quinoxalinyl, indyl and quinolyl.These heterocyclic radicals and heteroaryl can also be substituted in addition, for example by halogen, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, C 1-C 6Haloalkyl, C 1-C 6Halogenated alkoxy, nitro or cyano group replace.
For the substituting group G in the formula III compound, metal ion Equivalent (for example basic metal or alkaline-earth metal ions) and ammonium ion are for example sodium, potassium, magnesium, calcium and ammonium cation, for example triethyl ammonium and ammonium methyl positively charged ion.The sulphur positively charged ion comprises for example three (C 1-C 4Alkyl) sulphur positively charged ion, and can make by for example transforming corresponding alkali metal salt, for example transform by cationite.
For example, " R 4And R 5The nitrogen-atoms that connects with their institutes keys forms saturated or undersaturated 5-to 8-unit heterocycle, this heterocycle 1) can by oxygen, sulphur or-NR 7-be interrupted, and/or by halogen, C 1-C 10Alkyl, C 1-C 10Haloalkyl, hydroxyl, C 1-C 6Alkoxyl group, C 1-C 6Alkoxy-C 1-C 6Alkoxyl group, C 1-C 6Halogenated alkoxy.Sulfydryl, C 1-C 6Alkylthio, C 3-C 7Cycloalkyl, heteroaryl, heteroaryl-C 1-C 6Alkyl, phenyl, phenyl-C 1-C 6Alkyl or benzyloxy replace, and wherein back 3 substituent phenyl ring itself can also be by halogen, C 1-C 6Alkyl, C 1-C 6Haloalkyl, C 1-C 6Alkoxyl group, C 1-C 6Halogenated alkoxy or nitro replace, what and/or 2) can contain a tool 2-6 carbon atom condenses or screws togather alkylidene group or alkenylene chain, this chain randomly is interrupted by oxygen or sulphur, described alkylidene group of at least one annular atoms bridge joint or alkenylene chain in the perhaps described saturated or unsaturated heterocycle " substituting group definition expression formula III compound in following heterocyclic system:
Figure A0080890500281
In above-mentioned polycyclic system, the abbreviation figure: The expression group:
Figure A0080890500291
Substituent R 4And R 5The 5-to 8-that can form together unit's heterocycle and have 2-6 carbon atom condense or screw togather alkylidene group or the alkenylene chain therefore can be by the heteroatoms interruption once or twice.
The purposes of formula I compound in the 3-hydroxy-4-aryl-5-oxopyrazoline derivative of preparation formula III reaction process 3 illustrated.Reaction process 3
Formula I arylprop dintrile form formula IV arylprop diacid hydrolysis reaction (reaction process 3, route a) carry out according to known standard method, for example, in dilute sulphuric acid in about 50 ℃ of following heating a few hours.
The follow-up esterification that gained formula IV arylprop diacid forms formula V aryl malonic acid esters also is to carry out according to the known standard method, for example reacts (reaction process 3, route a with excessive formula VII alcohol in the presence of catalytic amount acid 1).
On the other hand, similar WO97/02243 is described, randomly in the presence of catalyzer such as diethylformamide or triphenyl phosphine, and randomly in the presence of alkali such as pyridine or triethylamine, under-20 ℃ to 200 ℃ temperature, utilize carboxylic acid halides, for example oxalyl chloride, thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride or phosgene can also be converted into the arylprop diacid of formula IV corresponding formula X halo carbonyl ketene, wherein R 0, R 1, R 2, R 3The same with the definition of n, and Hal is halogen, preferred chlorine or bromine (reaction process 3, route a 2).
By in the presence of catalytic amount acid, to choose wantonly and at high temperature carry out alcoholysis (Pinner reaction) with formula VII alcohol, aftertreatment in water-bearing media subsequently can also be converted into the arylprop dintrile of formula I the aryl malonic acid esters (reaction process 3, route b) of formula V.This alcoholysis reaction is recorded in for example Chem.Rev.61, among 179 (1961).
Condensation reaction between formula V aryl malonic acid esters and formula VI hydrazine derivative or its salt formula VIa or VIb compound, can according to for example WO92/16510 or the described similar mode of WO97/02243, in organic solvent such as dimethylbenzene, randomly for example carry out in the presence of the triethylamine at alkali, according to the alkali that uses in post-treating method and the condensation reaction, generate required formula III target compound (G=H) or its salt (G=basic metal or alkaline-earth metal ions Equivalent or ammonium ion).Corresponding sulfonium salt and microcosmic salt can be produced by the salt transform mode, for example use cationite.
Condensation reaction between formula V compound and formula VI compound also can be carried out under the situation that alkali-free exists, but with formula VIa or VIb compound (replacing formula VI compound) between the identical condensation reaction carried out then should in the presence of alkali (equimolar amount), carry out.
The condensation reaction of formula X halo carbonyl ketene and formula VI hydrazine derivative or its salt formula VIa or VIb compound formation formula III compound according to for example with the described similar fashion of WO97/02243, randomly carry out in the presence of alkali such as alkaline carbonate, pyridine or triethylamine in organic solvent such as toluene or dimethylbenzene, temperature of reaction is-20 ℃ to 250 ℃.
If the initial substance that uses is not an enantiomer-pure; the formula III compound that obtains in the aforesaid method is generally racemic modification or non-enantiomer mixture form; if necessary subsequently; can be separated with currently known methods according to their physico-chemical property; for example with optically-active soda ash, acid or metal complexes salify after carry out the fractional crystallization method; perhaps use chromatographic process, for example adopt the cellulosic high pressure liquid chromatography of ethanoyl (HPLC).
According to substituent R 0-R 5Different with G, the formula III compound can exist with the form of geometrical isomer and/or optically active isomer and isomer mixture (atropisomer) or with tautomer and tautomers mixture form.
The compound of formula VI, VIa and VIb or known, perhaps can use with for example WO95/00521 and WO99/47525 in the similar mode of currently known methods described prepare.The alcohol of formula VII is known.
The following example is used for further explaining the present invention, but the present invention is not had any restriction.Preparation embodiment: embodiment P1:2, the preparation of 6-diethyl-4-methyl bromobenzene
Under 4 ℃, in 4 hours,, dropwise add the 200ml aqueous solution of 8.83g (0.128mol) Sodium Nitrite in the suspension of 6-diethyl-4-monomethylaniline in 500ml 48% Hydrogen bromide, heat gained brown solution to 80 ℃ then to 20g (0.1225mol) 2.After stirring 1 hour under this temperature, reaction mixture to 20 ℃ adds the dilution of 1 premium on currency, and then with hexane extraction three times.The organic phase twice that the salt water washing merges, after dried over sodium sulfate in 60 ℃ of vacuum concentration.Obtain the 27.5g crude product, and then by silica gel chromatography (500g silica gel; Eluent: purifying hexane) obtains the required title compound of 19.89g (71% theoretical yield) colorless oil. 1H-NMR (CDCl3): 6.89ppm (s, 2H); 2.75ppm (q, 4H); 2.27ppm (s, 3H); 1.22ppm (t, 6H). embodiment P2:2, the preparation of 6-diethyl-4-methyl iodobenzene
Order adds 100g 4-methyl-2 in the solution of 91.4ml sulfuric acid in 370ml water, 6-Diethyl Aniline and 480g ice.In formed reaction mixture, dropwise adding the solution of 44.6g Sodium Nitrite in 110ml water under 0-5 ℃, last 45 minutes subsequently, then dropwise add the 150ml aqueous solution of 136.4g potassiumiodide again.20 ℃ were stirred after 15 hours, were 3 liters t-butyl methyl ether (TBME) abstraction reaction mixture three times with total amount; The organic phase that merges is respectively washed one time with 8% hydrochloric acid and water, and then dry and concentrated.Obtain the 137.75g crude product, obtain the required title compound of 57.8g colourless liquid form by distillation purifying (125 ℃/5m of boiling point millibar). 1H-NMR(CDCl 3)：6.90ppm(s，2H)；2.75ppm(q，4H)；2.30ppm(s，3H)；1.23ppm(t，6H)。The preparation of embodiment P3:4-aminomethyl phenyl propane dinitrile
The 0.18g propane dinitrile is dissolved in 15ml dimethylbenzene, in this solution, slowly drips the 0.72g sodium tert-butoxide.The yellow suspension of 20 ℃ of stirring formation 1 hour.Add 0.43g 4-toluene bromide and 0.035g dichloride two (triphenyl phosphine) then and close palladium (II) (Pd (PPh 3) 2Cl 2), and under 150 ℃ of outside temperatures, further stir and spend the night.For aftertreatment, in reaction mixture, add 25ml water and 25ml 1N hydrochloric acid thereafter, and use ether extraction.With the ether phase of dried over sodium sulfate merging, and then concentrate.Obtain the 0.72g crude product; HPLC (high pressure liquid chromatography/Nucleosil; Eluent: acetonitrile/water+0.1% trifluoroacetic acid (TFA)) record wherein that the content of required title compound is 54%, the result is that the productive rate of neat compounds is 97% theoretical yield.The preparation of embodiment P4:4-aminomethyl phenyl propane dinitrile
The 0.18g propane dinitrile is dissolved in 13ml dimethylbenzene, and in gained solution, slowly drips the 0.72g sodium tert-butoxide.The yellow suspension of 20 ℃ of stirring formation 1 hour.Add 0.43g 4-toluene bromide and 0.2ml 20% palladium chloride (II) (PdCl then 2) concentrated hydrochloric acid solution in DMA (about 0.01mol), and 65g triphenyl phosphine (PPh 3) the 2ml xylene solution.Stirring formed yellow suspension under 150 ℃ of outside temperatures spends the night.For aftertreatment, in reaction mixture, add 25ml water and 25ml 1N hydrochloric acid thereafter, and use ether extraction.With the ether phase of dried over sodium sulfate merging, and then concentrate.Obtain the 0.91g crude product; HPLC (Nucleosil; Eluent: acetonitrile/water+0.1% trifluoroacetic acid (TFA)) record wherein that the content of required title compound is 40.5%, the result is that the productive rate of neat compounds is 97% theoretical yield.Embodiment P5:2,4, the preparation of 6-trimethylphenyl propane dinitrile
The 13.2g propane dinitrile is dissolved in the 500ml tetrahydrofuran (THF), in gained solution, slowly adds 12g sodium hydride (NaH, 60%).20 ℃ were stirred formed yellow suspension 1 hour.Add 25g mesityl iodine and 0.738g dichloride two (tricyclohexyl phosphine) then and close palladium (II) (Pd (PCy 3) 2Cl 2), and under 80 ℃ of outside temperatures, further stir this yellow suspension and spend the night.For aftertreatment, in reaction mixture, add 500ml water and 500ml 1N hydrochloric acid then, and use ether extraction.Ether phase with dried over sodium sulfate merges concentrates then.Obtain the 32.2g crude product.By silica gel chromatography purifying (eluent: ethyl acetate/hexane 1/10), obtain the required title compound of 16g (86% theoretical yield).Embodiment P6:2, the preparation of 6-diethyl-4-aminomethyl phenyl propane dinitrile
The 0.66g propane dinitrile is dissolved in the 30ml tetrahydrofuran (THF), in this solution, slowly adds 0.6g sodium hydride (60%).20 ℃ were stirred formed yellow suspension 1 hour.Add 1.46g 2 then, 6-diethyl-4-methyl iodobenzene and 0.11g dichloride two (tricyclohexyl phosphine) are closed palladium (II) (Pd (PCy 3) 2Cl 2), and under 80 ℃ of outside temperatures, further stir this yellow suspension and spend the night.For aftertreatment, in reaction mixture, add 25ml water and 25ml 1N hydrochloric acid subsequently, and use ether extraction.Ether phase so that dried over sodium sulfate merges concentrates then.Obtain the 1.9g crude product.By silica gel chromatography purifying (eluent: ethyl acetate/hexane 1/10), obtain the required title compound of 0.62g (58% theoretical yield). 1H-NMR (CDCl 3): 7.05ppm (s, 2H); 5.32ppm (s, 1H); 2.85ppm (q, 4H); 2.37ppm (s, 3H); 1.35ppm (t, 6H). embodiment P7:2, the preparation of 6-diethyl-4-aminomethyl phenyl propane dinitrile
The 0.66g propane dinitrile is dissolved in 30ml methyl-sulphoxide (DMSO), in this solution, slowly adds 0.6g sodium hydride (60%).20 ℃ were stirred formed yellow suspension 1 hour.Add 1.18g 2 then, 6-diethyl-4-methyl bromobenzene and 0.07g dichloride two (tricyclohexyl phosphine) are closed palladium (II) (Pd (PCy 3) 2Cl 2), and under 150 ℃ of outside temperatures, further stir this yellow suspension and spend the night.For aftertreatment, in reaction mixture, add 25ml water and 25ml 1N hydrochloric acid subsequently, and use ether extraction.Ether phase so that dried over sodium sulfate merges concentrates then.Obtain the 1.5g crude product.By silica gel chromatography purifying (eluent: ethyl acetate/hexane 1/10), obtain the required title compound of 0.88g (83% theoretical yield).Embodiment P8:2, the preparation of 6-diethyl-4-aminomethyl phenyl propane dinitrile
The 0.18g propane dinitrile is dissolved in 15ml dimethylbenzene, and in this solution, adds the 0.72g sodium tert-butoxide.20 ℃ were stirred formed yellow suspension 1 hour.Add 0.59g 2 then, 6-diethyl-4-methyl bromobenzene and 0.035g dichloride two (triphenyl phosphine) are closed palladium (II) (Pd (PPh 3) 2Cl 2), and under 150 ℃ of outside temperatures, further stir this yellow suspension and spend the night.For aftertreatment, in reaction mixture, add 25ml water and 25ml 1N hydrochloric acid subsequently, and use ether extraction.Ether phase so that dried over sodium sulfate merges concentrates then.Obtain the 0.92g crude product.By silica gel chromatography purifying (eluent: ethyl acetate/hexane 1/10), obtain the required title compound of 0.47g (89% theoretical yield).Embodiment P9:4-bromo-2, the preparation of 6-Diethyl Aniline
Under 10 ℃,, dropwise add the 50ml glacial acetic acid solution of 27ml (0.5mol) bromine in the solution of 6-Diethyl Aniline in the 200ml glacial acetic acid to 74.6g (0.5mol) 2.20 ℃ are stirred 1 hour so that complete reaction; In reaction mixture impouring mixture of ice and water, regulate with sodium hydroxide solution and to be alkalescence, and then with twice of ethyl acetate extraction.The organic phase that merges also concentrates with hypo solution and salt water washing, dried over sodium sulfate.Obtain 112.4g crude product oily matter, and then distillation purifying (boiling point 129-131 ℃/1 millibar), the required title compound of 92g (81% theoretical yield) oily form obtained. 1H-NMR (CDCl 3): 7.07ppm (s, 2H); 3.60ppm (broad peak, 2H); 2.50ppm (q, 4H); 1.25ppm (t, 6H).Embodiment P10:4-phenyl-2, the preparation of 6-Diethyl Aniline
With 912mg (0.004mol) 4-bromo-2,6-Diethyl Aniline, 732mg (0.006mol) phenylo boric acid and 1820mg (0.012mol) cesium fluoride (CsF) place 20ml degassing diox, add 18mg (0.00008mol) Pd (OAc) 2And 47mg (0.00012mol) (2 ＇-dicyclohexyl phosphino-biphenyl-2-yl) solution of dimethylamine in the 1ml diox; 20 ℃ were stirred 16 hours.With in the reaction mixture impouring dilute solution of sodium hydroxide, use twice of ethyl acetate extraction then.Organic phase salt water washing, dried over sodium sulfate also concentrates.Obtain 1.0g crude product oily matter, and then silica gel column chromatography, 742mg (82% theoretical yield) oily neat compounds obtained. 1H-NMR (CDCl 3): 7.55ppm (m, 2H); 7.39ppm (m, 2H); 7.25ppm (m, 1H); 7.21ppm (s, 2H); 3.70ppm (broad peak, 2H); 2.60ppm (q, 4H); 1.28ppm (t, 6H). embodiment P11:1,4-two bromo-2, the preparation of 6-diethylbenzene
Put into 5.7g (0.025mol) 4-bromo-2 in 10ml water and 10ml 48% Hydrogen bromide, the 6-Diethyl Aniline dropwise adds 5.25ml (0.02625mol) 5M sodium nitrite solution then under about 0 ℃.In ice bath, stirred 30 minutes, then stirred 45 minutes in 100 ℃ again.The thin up reaction mixture, and with twice of ethyl acetate extraction.Organic phase salt water washing, dried over sodium sulfate also concentrates.Obtain 6.48g oily crude product, and then silica gel column chromatography, the required product of 3.62g (50% theoretical yield) oily form obtained. 1H-NMR(CDCl 3)：7.20ppm(s，2H)；2，75ppm(q，4H)；1.22ppm(t，6H)。Embodiment P12:4-(2-pyridyl)-1-bromo-2, the preparation of 6-diethylbenzene
Under-70 ℃, in the 7ml tetrahydrofuran (THF), put into 790mg (0.005mol) 2-bromopyridine, and dropwise add 6.7ml (0.010mol) 1.5M tert-butyl lithium pentane solution.In bathing, stirred 15 minutes CO2; Dropwise add the solution of 1.12g (0.005mol) zinc bromide in the 8ml tetrahydrofuran (THF) then, no longer continuing the stirring reaction material under the refrigerative situation.Add 1.46g (0.005mol) 1 at 20 ℃ subsequently, 4-two bromo-2,6-diethylbenzene and 288mg (0.00025mol) four (triphenyl phosphine) closes palladium (O), then bathes at 60 ℃ and continues under the temperature to stir material 1.5 hours.In reaction mixture impouring ammonium chloride saturated solution, use twice of ethyl acetate extraction.The organic phase that merges also concentrates with salt water washing, dried over sodium sulfate.Obtain 1.79g oily crude product, behind silica gel column chromatography, get the required title compound of 700mg (48% theoretical yield) oily form. 1H-NMR (CDCl 3): 7.74ppm (m, 2H); 7.70ppm (s, 2H); 7.23ppm (m, 1H); 2.87ppm (q, 4H); 1.30ppm (t, 6H). embodiment P13: preparation 4-phenyl-1-bromo-2,6-diethylbenzene (4-bromo-3,5-diethyl biphenyl)
Emulsification 609mg (0.0027mol) 4-phenyl-2 in 2ml water, the 6-Diethyl Aniline, and under 0 ℃, add 2ml hydrogen bromide solution (48%).To wherein adding 0.568ml (0.002842mol) 5M sodium nitrite solution, in ice bath, stirred 30 minutes then, then stirred 45 minutes in 100 ℃ again.Reaction mixture is with frozen water dilution and with twice of ethyl acetate extraction.The organic phase water and the salt water washing that merge, dried over sodium sulfate and concentrated.Obtain the 730mg crude product, behind silica gel column chromatography, obtain the required title compound of 347mg (44% theoretical yield), fusing point 72-74 ℃. 1H-NMR (CDCl 3): 7.58ppm (m, 2H); 7.43ppm (m, 2H); 7.35ppm (m, 1H); 7.28ppm (s, 2H); 2.87ppm (q, 4H); 1.28ppm (t, 6H). embodiment P14:2, the preparation of 6-diethyl-4-phenyl phenylpropyl alcohol dintrile
84mg (0.00128mol) propane dinitrile is dissolved in 7ml degassing dimethylbenzene, adds 84mg (0.00349mol) sodium tert-butoxide, and stirred 30 minutes in 20 ℃.Add 336mg (0.00116mol) 4-phenyl-1-bromo-2 then, 6-diethylbenzene and 16.3mg (0.0000232mol) dichloride two (triphenyl phosphines) close palladium (II), stir 17 hours in 150 ℃.In reaction mixture impouring frozen water, use hcl acidifying, use ethyl acetate extraction again twice.The organic phase water and the salt water washing that merge concentrate after the dried over sodium sulfate.Obtain the required title compound of 315mg (99% theoretical yield). 1H-NMR(CDCl 3)：7.35-7.50ppm(m，3H)；7.40ppm(s，2H)；5.35ppm(s，1H)；2.93ppm(q，4H)；1.39ppm(t，6H).
Similar front embodiment is described, also makes following compounds (embodiment P15 and P16): 2, and 6-diethyl-4-(2-pyridyl)-phenyl propane dinitrile, 1H-NMR (CDCl 3): 8.72ppm (m, 1H); 7.82ppm (s, 2H); 7.77ppm (m, 2H); 7.28ppm (m, 1H); 5.37ppm (s, 1H); 2.95ppm (q, 4H); 1.41ppm (t, 6H); With 2,6-dimethyl-4-(4-pyridyl)-phenyl propane dinitrile, 1H-NMR (CDCl 3): 8.70ppm (d, 2H); 7.47ppm (d, 2H); 7.40ppm (s, 2H); 5.39ppm (s, 1H); 2.64ppm (s, 6H). embodiment P17:2, the preparation of 6-diethyl-4-methyl-phenyl-propane dinitrile
In 2.5 liters of sulfonation flasks that have internal thermometer, argon gas joint and reflux condensing tube or a still head, put into 198.8g (2.06mol) sodium tert-butoxide and 600ml dimethylbenzene, add 50.4g (0.76mol) propane dinitrile melts in 60 ℃ in formed solution then, temperature of reaction is increased to 103 ℃.In the presence of gentle argon gas stream, distillate the trimethyl carbinol that about 50ml produces in 80 ℃ in 70 minutes, under uniform temp, add 496g 2,6-diethyl-4-methyl bromobenzene (31.4% xylene solution) then.Reaction soln is subsequently in 130 ℃ of heating 2 hours.
Meanwhile, under argon atmospher, in another 100ml round-bottomed flask, put into the 1.98g tricyclohexyl phosphine; Utilize syringe to add the mixture of 35ml anhydrous dimethyl benzene and 27ml N,N-dimethylacetamide (DMA), and the gained solution that outgases.Add 0.73g 20% Palladous chloride (II) solution (concentrated hydrochloric acid) by syringe then, 20 ℃ were stirred the gained yellow suspension 1 hour.Under 105 ℃, the catalyst solution of preparation in this way in syringe joins above-mentioned reaction soln, was down stirred formed suspension 2 hours at 120-130 ℃ then.Sample thief shows 100% reaction with gas chromatographic analysis, and no coupling product or starting raw material exist.For aftertreatment, reaction mixture is cooled to 40 ℃, add the 800ml mixture of ice and water.Tell water (about 1.4 liters), utilize rotatory evaporator to steam 365ml water/xylene mixture.Then water further is cooled to 15 ℃, adds 142g 32% hydrochloric acid soln then so that the pH value reaches 5-5.5.Have the crystallization crude product to separate out, and it can be easy to leach.Use the 250ml water washing then.The resulting 163g of vacuum-drying (112% theoretical yield) crude product in 60 ℃ of loft drier obtains the required title compound of 143.8g (99% theoretical yield), purity 98.8%.

Claims (24)

1. formula I compound:
Figure A0080890500021
R wherein0Be halogen independently of one another, C1-C 6Alkyl, C2-C 6Alkenyl, C2-C 6Alkynyl, C1-C 6Haloalkyl, cyano group-C1-C 6Alkyl, C2-C 6Halogenated alkenyl, cyano group-C2-C 6Alkenyl, C2- C 6The halo alkynyl, cyano group-C2-C 6Alkynyl, hydroxyl, hydroxyl-C1-C 6Alkyl, C1-C 6Alkoxyl, nitro, amino, C1-C 6Alkyl is amino, two (C1-C 6Alkyl) amino, C1-C 6Alkyl-carbonyl-amino, C1-C 6Alkyl sulfonyl-amino, C1-C 6Alkyl amino sulfonyl, C1-C 6The alkyl carbonyl, C1-C 6Alkyl carbonyl-C1-C 6Alkyl, C1-C 6Alkoxyl carbonyl-C1-C 6Alkyl, C1-C 6Alkyl carbonyl-C2-C 6Alkenyl, C1-C 6The alkoxyl carbonyl, C1-C 6Alkoxyl carbonyl-C2-C 6Alkenyl, C1-C 6Alkyl carbonyl-C2-C 6Alkynyl, C1-C 6Alkoxyl carbonyl-C2-C 6Alkynyl, cyano group, carboxyl, phenyl or contain 1 or 2 heteroatomic aromatic ring that is selected from nitrogen, oxygen and sulphur, wherein rear two kinds of aromatic rings can be by C1-C 3Alkyl, C1-C 3Haloalkyl, C1-C 3Alkoxyl, C1-C 3Halogenated alkoxy, halogen, cyano group or nitro replace; Perhaps R0With adjacent substituting group R1、R 2And R3Form together saturated or undersaturated C3-C 6Hydrocarbon bridge, this hydrocarbon bridge can be interrupted by 1 or 2 hetero atom that is selected from nitrogen, oxygen and sulphur and/or by C1-C 4Alkyl replaces; R1，R 2And R3Be hydrogen independently of one another, halogen, C1-C 6Alkyl, C2-C 6Alkenyl, C2-C 6Alkynyl, C3-C 6Cycloalkyl, C1-C 6Haloalkyl, C2-C 6Halogenated alkenyl, C1-C 6Alkoxyl carbonyl-C2-C 6Alkenyl, C1-C 6Alkyl carbonyl-C2-C 6Alkenyl, cyano group-C2-C 6Alkenyl, nitro-C2-C 6Alkenyl, C2-C 6The halo alkynyl, C1-C 6Alkoxyl carbonyl-C2-C 6Alkynyl, C1-C 6Alkyl carbonyl-C2-C 6Alkynyl, cyano group-C2-C 6Alkynyl, nitro-C2-C 6Alkynyl, C3-C 6Halogenated cycloalkyl, hydroxyl-C1-C 6Alkyl, C1-C 6Alkoxy-C1-C 6Alkyl, C1-C 6Alkylthio group-C1-C 6Alkyl, cyano group, C1-C 4The alkyl carbonyl, C1-C 6The alkoxyl carbonyl, hydroxyl, C1-C 10Alkoxyl, C3-C 6Alkenyloxy, C3-C 6Alkynyloxy group, C1-C 6Halogenated alkoxy, C3-C 6The halo alkenyloxy, C1-C 6Alkoxy-C1-C 6Alkoxyl, sulfydryl, C1-C 6Alkylthio group, C1-C 6The alkyl halide sulfenyl, C1-C 6The alkyl sulfinyl, C1-C 6The alkyl sulfonyl base, nitro, amino, C1-C 6Alkyl is amino, two (C1- C 6Alkyl) amino or phenoxy group, phenyl ring wherein can be by C1-C 3Alkyl, C1-C 3Haloalkyl, C1-C 3Alkoxyl, C1-C 3Halogenated alkoxy, halogen, cyano group or nitro replace; R2Can also be phenyl, naphthyl maybe can contain 1 or 2 the heteroatomic 5-or the 6-unit aromatic ring that are selected from nitrogen, oxygen and sulphur, and wherein said benzyl ring, naphthyl ring body system and 5-or 6-unit aromatic ring can be by halogen, C3-C 8Cycloalkyl, hydroxyl, sulfydryl, amino, cyano group, nitro or formoxyl replace; And/or described benzyl ring, naphthyl ring body system and 5-or 6-unit aromatic ring can be replaced by following group: C1-C 6Alkyl, C1-C 6Alkoxyl, hydroxyl-C1-C 6Alkyl, C1-C 6Alkoxy-C1-C 6Alkyl, C1-C 6Alkoxy-C1-C 6Alkoxyl, C1-C 6Alkyl carbonyl, C1-C 6Alkylthio group, C1-C 6Alkyl sulfinyl, C1-C 6Alkyl sulfonyl base, list-C1-C 6Alkyl is amino, two (C1-C 6Alkyl) amino, C1-C 6Alkyl-carbonyl-amino, C1-C 6Alkyl carbonyl-(C1-C 6Alkyl) amino, C2-C 6Alkenyl, C3-C 6Alkenyloxy, hydroxyl-C3-C 6Alkenyl, C1-C 6Alkoxy-C2-C 6Alkenyl, C1-C 6Alkoxy-C3-C 6Alkenyloxy, C2-C 6Alkenyl carbonyl, C2-C 6Alkenyl thio, C2-C 6Alkenyl sulfinyl, C2-C 6Alkenyl sulfonyl, list-or two-(C2-C 6Alkenyl) amino, C1-C 6Alkyl (C3-C 6Alkenyl) amino, C2-C 6Alkenyl carbonyl is amino, C2-C 6Alkenyl carbonyl (C1-C 6Alkyl) amino, C2-C 6Alkynyl, C3-C 6Alkynyloxy group, hydroxyl-C3-C 6Alkynyl, C1-C 6Alkoxy-C3-C 6Alkynyl, C1-C 6Alkoxy-C4-C 6Alkynyloxy group, C2-C 6Alkynyl carbonyl, C2-C 6Alkynes sulfenyl, C2-C 6Alkynyl sulfinyl, C2-C 6Alkynyl sulfonyl, list-or two-(C3-C 6Alkynyl) amino, C1-C 6Alkyl (C3-C 6Alkynyl) amino, C2-C 6Alkynyl carbonyl amino or C2-C 6Alkynyl carbonyl (C1-C 6Alkyl) amino; And/or described benzyl ring, naphthyl ring body system and 5-or 6-unit aromatic ring can be by the C of halogen-replacement1-C 6Alkyl, C1-C 6Alkoxyl, hydroxyl-C1-C 6Alkyl, C1-C 6Alkoxy-C1-C 6Alkyl, C1-C 6Alkoxy-C1-C 6Alkoxyl, C1-C 6Alkyl carbonyl, C1-C 6Alkylthio group, C1-C 6Alkyl sulfinyl, C1-C 6Alkyl sulfonyl base, list-C1-C 6Alkyl is amino, two (C1-C 6Alkyl) amino, C1-C 6Alkyl-carbonyl-amino, C1-C 6Alkyl carbonyl (C1-C 6Alkyl) amino, C2-C 6Alkenyl, C3-C 6Alkenyloxy, hydroxyl-C3-C 6Alkenyl, C1-C 6Alkoxy-C2-C 6Alkenyl, C1-C 6Alkoxy-C3-C 6Alkenyloxy, C2-C 6Alkenyl carbonyl, C2-C 6Alkenyl thio, C2-C 6Alkenyl sulfinyl, C2-C 6Alkenyl sulfonyl, list-or two-(C2-C 6Alkenyl) amino, C1-C 6Alkyl (C3-C 6Alkenyl) amino, C2-C 6Alkenyl carbonyl is amino, C2-C 6Alkenyl carbonyl (C1-C 6Alkyl) amino, C2-C 6Alkynyl, C3-C 6Alkynyloxy group, hydroxyl-C3-C 6Alkynyl, C1-C 6Alkoxy-C3-C 6Alkynyl, C1-C 6Alkoxy-C4-C 6Alkynyloxy group, C2-C 6Alkynyl carbonyl, C2-C 6Alkynes sulfenyl, C2-C 6Alkynyl sulfinyl, C2-C 6Alkynyl sulfonyl, list-or two-(C3-C 6Alkynyl) amino, C1-C 6Alkyl (C3-C 6Alkynyl) amino, C2-C 6Alkynyl carbonyl amino or C2-C 6Alkynyl carbonyl (C1-C 6Alkyl) the amino replacement; And/or described benzyl ring, naphthyl ring body system and 5-or 6-unit aromatic ring can be by formula COOR50、CONR 51、 SO 2NR 53R 54Or SO2OR 55Group replace, R wherein50、R 51、R 52、R 53、R 54And R55Be C independently of one another1-C 6Alkyl, C2-C 6Alkenyl or C3-C 6Alkynyl or be halogen-, hydroxyl-, alkoxyl-, sulfydryl-, amino-, cyano group-, nitro-, alkylthio group-, alkyl sulfinyl-or the C of alkyl sulfonyl base-replacement1-C 6Alkyl, C2-C 6Alkenyl or C3-C 6Alkynyl; And n is 0,1 or 2.
2. according to the compound of claim 1, wherein each R0 is halogen independently of one another, C 1-C 6Alkyl, C 1-C 6Haloalkyl, hydroxyl, C 1-C 6Alkoxyl group, nitro, amino, C 1-C 6Alkylamino, two (C 1-C 6Alkyl) amino, C 1-C 6Alkyl-carbonyl-amino, C 1-C 6Alkyl sulfonyl-amino, C 1-C 6Alkyl amino sulfonyl, C 1-C 4Alkyl-carbonyl, C 1-C 6Alkoxy carbonyl or carboxyl; And R 1, R 2And R 3Be hydrogen independently of one another, halogen, C 1-C 6Alkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 3-C 6Cycloalkyl, C 1-C 6Haloalkyl, C 2-C 6Halogenated alkenyl, C 2-C 6The halo alkynyl, C 3-C 6Halogenated cycloalkyl, C 1-C 6Alkoxy-C 1-C 6Alkyl, C 1-C 6Alkylthio-C 1-C 6Alkyl, cyano group, C 1-C 4Alkyl-carbonyl, C 1-C 6Alkoxy carbonyl, hydroxyl, C 1-C 10Alkoxyl group, C 3-C 6Alkenyloxy, C 3-C 6Alkynyloxy group, C 1-C 6Halogenated alkoxy, C 3-C 6The halo alkenyloxy, C 1-C 6Alkoxy-C 1-C 6Alkoxyl group, sulfydryl, C 1-C 6Alkylthio, C 1-C 6Halogenated alkylthio, C 1-C 6Alkyl sulphinyl, C 1-C 6Alkyl sulphonyl, nitro, amino, C 1-C 4Alkylamino or two (C 1-C 4Alkyl) amino.
3. according to the compound of claim 2, R wherein 1, R 2And R 3Be hydrogen independently of one another, halogen, C 1-C 4Alkyl, C 1-C 4Haloalkyl, C 2-C 4Alkenyl, C 2-C 4Halogenated alkenyl, C 2-C 4Alkynyl, C 3-C 6Cycloalkyl, C 1-C 4Alkyl-carbonyl, C 1-C 6Alkoxy carbonyl, hydroxyl, C 1-C 4Alkoxyl group, C 3-or C 4-alkenyloxy, C 3-or C 4-alkynyloxy group, C 1-C 4Halogenated alkoxy, nitro or amino.
4. according to the compound of claim 1, R wherein 1Be C 2-C 6Alkyl.
5. according to the compound of claim 1, wherein n is 0.
6. according to the compound of claim 5, R wherein 1Be C 2-C 4Alkyl, C 1-C 4Alkoxyl group, C 2-C 4Alkynyl or C 3-C 6Cycloalkyl, and R 3Be C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 2-C 4Alkynyl or C 3-C 6Cycloalkyl.
7. according to the compound of claim 1, R wherein 1Be C 2-C 6Alkynyl.
8. according to the compound of claim 1, R wherein 1And R 3Be C independently of one another 2-C 6Alkyl, C 2-C 6Alkynyl, C 1-C 10Alkoxyl group or C 3-C 6Cycloalkyl.
9. compound according to Claim 8, wherein R 1Be C 2-C 6Alkyl and R 3Be C 2-C 6Alkyl, C 2-C 6Alkynyl or C 1-C 10Alkoxyl group.
10. the method for preparing the formula I compound of claim 1, this method are included under the palladium catalyst existence formula II compound and propane dinitrile negatively charged ion are reacted in inert solvent:
Figure A0080890500051
R wherein 0, R 1, R 2, R 3With definition in n such as the claim 1, and X is a leavings group.
11. according to the method for claim 10, the X in its Chinese style II compound is a halogen, R 10S (O) 2O-(R wherein 10Be methyl, halogenated methyl, n-C 4F 9, phenyl or by the phenyl of halogen, methyl or halogenated methyl list-to three-replace) or single-, two-or three-aryl methoxy.
12. according to the method for claim 11, wherein X is a chlorine, bromine, iodine, CF 3S (O) 2O-(triflate), CF 3(CF 2) 3S (O) 2O-(nine fluorine fourth sulphonates), right-tolyl-S (O) 2O-(tosylate), (C 6H 5) 2CHO-, (CH 3-C 6H 4) 2CHO-, (C 6H 5) 3CO-(three benzyloxies) or (CH 3-C 6H 4) 3CO-.
13. according to the method for claim 12, wherein X is chlorine, bromine or iodine.
14., wherein use palladium (II) or palladium (O) title complex as palladium catalyst according to the method for claim 10.
15., wherein use dihalide palladium (II), acid chloride (II), palladous sulfate (II), dichloride two (triphenyl phosphine) to close palladium (II), dichloride two (three cyclopentyl phosphines) and close that palladium (II), dichloride two (tricyclohexyl phosphine) close palladium (II), two (dibenzalacetones) close palladium (O) or four (triphenyl phosphines) close palladium (O) as palladium catalyst according to the method for claim 14.
16. according to the method for claim 10, palladium catalyst is wherein prepared by palladium (II) or palladium (O) compound " on the spot " by cooperating with required ligand.
17. according to the method for claim 10, wherein the consumption of palladium catalyst is 0.001-50mol%, preferred 0.01-10mol%, especially 0.1-3mol% are benchmark with the amount of formula II compound.
18. according to the method for claim 10, wherein use aliphatic, alicyclic or aromatic hydrocarbon, aliphatic halogenated hydrocarbons, nitrile, ether, alcohol, ketone, ester or lactone, the N-substituted lactams, acid amides, acyclic urea, the mixture of sulfoxide or these solvents is as solvent.
19. according to the method for claim 18, wherein use aromatic hydrocarbons, ether or methyl-sulphoxide.
20. according to the method for claim 10, wherein use tricresyl phosphate-an alkali metal salt, the hydride of basic metal or alkaline-earth metal, the amide of basic metal or alkaline-earth metal or alkali metal alcoholates are as alkali.
21. according to the method for claim 20, wherein alkali with propane dinitrile equivalent or the normal excessive use of 2-10.
22. according to the method for claim 10, wherein the anionic formation of propane dinitrile is to carry out under 0-100 ℃ temperature, and the reaction of it and formula II compound then is to carry out under 30-250 ℃ temperature of reaction.
23., wherein carry out under the high pressure that is reflected at the 1.1-10 crust of propane dinitrile negatively charged ion and formula II compound according to the method for claim 10.
24. the formula I compound of claim 1 is as the application of intermediate in the 3-hydroxy-4-aryl-5-oxopyrazoline derivative that the preparation formula III replaces:
Figure A0080890500071
R wherein 0, R 1, R 2, R 3With the definition of n with claim 1, and R 4And R 5Then be hydrogen independently of one another, C 1-C 12Alkyl, C 1-C 12Haloalkyl, C 2-C 8Alkenyl, C 2-C 8Alkynyl, C 1-C 10Alkoxy-C 1-C 8Alkyl is many-C 1-C 10Alkoxy-C 1-C 8Alkyl, C 1-C 10Alkylthio-C 1-C 8Alkyl, C 3-C 8Cycloalkyl, C 3-C 8Halogenated cycloalkyl, 4-to 8-unit heterocyclic radical, phenyl, α-or betanaphthyl, phenyl-C 1-C 6Alkyl, α-or betanaphthyl-C 1-C 6Alkyl, 5-or 6-unit's heteroaryl or 5-or the heteroaryl-C of 6-unit 1-C 6Alkyl, aromatic ring wherein and hetero-aromatic ring can be by halogen, C 1-C 6Alkyl, C 1-C 6Haloalkyl, C 1-C 6Alkoxyl group, C 1-C 6Halogenated alkoxy, nitro or cyano group replace, perhaps R 4And R 5The nitrogen-atoms that connects with their institutes keys forms saturated or undersaturated 5-to 8-unit heterocycle, this heterocycle 1) can by oxygen, sulphur or-NR 7-be interrupted, and/or by halogen, C 1-C 10Alkyl, C 1-C 10Haloalkyl, hydroxyl, C 1-C 6Alkoxyl group, C 1-C 6Alkoxy-C 1-C 6Alkoxyl group, C 1-C 6Halogenated alkoxy, sulfydryl, C 1-C 6Alkylthio, C 3-C 7Cycloalkyl, heteroaryl, heteroaryl-C 1-C 6Alkyl, phenyl, phenyl-C 1-C 6Alkyl or benzyloxy replace, and the benzyl ring itself in wherein back 3 substituting groups can also be by halogen, C 1-C 6Alkyl, C 1-C 6Haloalkyl, C 1-C 6Alkoxyl group, C 1-C 6Halogenated alkoxy or nitro replace, what and/or 2) can contain a tool 2-6 carbon atom condenses or screws togather alkylidene group or alkenylene chain, this chain randomly is interrupted by oxygen or sulphur, described alkylidene group of at least one annular atoms bridge joint or alkenylene chain in the perhaps described saturated or unsaturated heterocycle; R 7Be hydrogen, C 1-C 4Alkyl, C 1-C 6Alkyl-carbonyl, C 1-C 6Alkyl sulphonyl, C 3-C 6Alkenyl or C 3-C 6Alkynyl; And G is a hydrogen, metal ion Equivalent or ammonium ion, sulfonium ion or phosphonium ion, the preparation method of wherein said formula III compound comprise carry out step a) or b earlier) one of: a) hydrolyzing type I compound:
Figure A0080890500081
R wherein 0, R 1, R 2, R 3The same with the definition of n, production IV compound:
Figure A0080890500082
Carry out following reaction: a according to mode well known in the art then 1) with the gained compound with the esterification of formula VII alcohol:
R 6-OH (VII) is R wherein 6Be C 1-C 6Alkyl, C 1-C 6Haloalkyl or benzyl, the aryl malonic acid esters of production V:
Figure A0080890500091
R wherein 0, R 1, R 2, R 3, R 6The same with the definition of n, perhaps a 2) utilize carboxylic acid halides the gained compound to be converted into the halo carbonyl ketene of formula X:
Figure A0080890500092
R wherein 0, R 1, R 2, R 3, R 6The same with the definition of n, and Hal is halogen,
Perhaps
B) with formula VII compound:
R 6-OH????(VII)
R wherein 6As above definition,
Direct alcoholysis formula I compound:
Figure A0080890500093
R wherein 0, R 1, R 2, R 3The same with the definition of n, production V compound:
Figure A0080890500094
R wherein 0, R 1, R 2, R 3, R 6It is the same with the definition of n,
Choose wantonly in the presence of alkali then, the compound of formula V compound or formula X compound and formula VI, VIa or VIb reacted in inert organic solvents:
Figure A0080890500101
R wherein 4And R 5Definition the same, and HHal is a hydrogen halide, randomly transforming the wherein G that is obtained by salt then is that the formula III compound of metal ion Equivalent or ammonium cation is converted into wherein that G is the corresponding salt of sulphur or the cationic formula III compound of phosphorus, perhaps by be converted into corresponding formula III compound with the Bronsted acid treatment, wherein G is a hydrogen.
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CN105061209A (en) * 2015-07-17 2015-11-18 河北九天医药化工有限公司 Synthetic method of 2-diester methylmalonate compounds
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