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WO1997048668A2 - Preparation de 3-aryle-5-haloalkyl-pyrazoles substitues a activite herbicide - Google Patents

Preparation de 3-aryle-5-haloalkyl-pyrazoles substitues a activite herbicide Download PDF

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Publication number
WO1997048668A2
WO1997048668A2 PCT/US1997/010525 US9710525W WO9748668A2 WO 1997048668 A2 WO1997048668 A2 WO 1997048668A2 US 9710525 W US9710525 W US 9710525W WO 9748668 A2 WO9748668 A2 WO 9748668A2
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Prior art keywords
formula
compound
set forth
alkyl
halogen
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PCT/US1997/010525
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English (en)
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WO1997048668A3 (fr
Inventor
Bruce C. Hamper
Michael K. Mao
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Monsanto Company
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Priority claimed from US08/667,256 external-priority patent/US5880290A/en
Priority claimed from US08/667,135 external-priority patent/US5869688A/en
Priority claimed from US08/667,103 external-priority patent/US5698708A/en
Priority to HU0104324A priority Critical patent/HUP0104324A3/hu
Priority to NZ333414A priority patent/NZ333414A/xx
Priority to JP10503274A priority patent/JP2000512656A/ja
Application filed by Monsanto Company filed Critical Monsanto Company
Priority to BR9710711A priority patent/BR9710711A/pt
Priority to EP97931231A priority patent/EP0923520A2/fr
Priority to PL97330718A priority patent/PL330718A1/xx
Priority to AU34919/97A priority patent/AU720882B2/en
Publication of WO1997048668A2 publication Critical patent/WO1997048668A2/fr
Publication of WO1997048668A3 publication Critical patent/WO1997048668A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16—Halogen atoms or nitro radicals

Definitions

  • the present invention generally relates to the preparation of substituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity, and specifically, to novel processes for preparing C,. 5 alkyl esters of 5-[l-(C, .j alkyl)- 4-halo-5-(C,. 3 haloalkyl)-lH-pyrazole-3-yl]-2,4-dihalo-benzoic acids such as isopropyl 5-[4-bromo-i-methyl-5- (trifluoromethyl) -lH-pyrazole-3-yl]-2-chloro-4- fluorobenzoate.
  • the invention is preferably directed to the preparation of such 3-aryl-5-haloalkyl-pyrazoles
  • the invention also relates to the individual process steps for forming phenyl-diketones, forming and alkylating pyrazoles, brominating pyrazoles and other heterocyclic compounds, oxidizing alkyl-substituted benzene compounds, and esterifying carboxyiic acids.
  • aryl-pyrazole compounds are known and used as chemical intermediates, pharmaceuticals and herbicides.
  • Exemplary U.S. Patents include No.'s 3,326,662 to Tomoyoshi et al., 3,948,937 to Johnson et al. , 4,008,249 to Fischer, deceased et al. , 4,072,498 to Moon et al., 4,260,775 to Plath et al., 4,468,871 to Ebel et al., 4,752,326 to Ohyama et al., 5,032,165 to Miura et al., 5,045,106 to Moedritzer et al.
  • a variety of 3-aryl-5- haloalkyl pyrazoles are disclosed in U.S. Patent No.'s 5,281,571 and 5,489,571 to Woodard et al.
  • the resulting aryl-pyrazole is subjected to further process steps, including N-alkylation and halogenation of the pyrazole moiety, oxidation of the methyl group on the phenyl moiety to form a benzoic acid, and formation of benzoic acid derivatives thereof.
  • the present invention is directed to a process for preparing a compound of Formula Illb
  • Ar which has a fully halogenated ⁇ -carbon.
  • Ar is phenyl or substituted phenyl
  • R 2 is c,.-, haloalkyl
  • Z is halogen.
  • the invention is also directed to a process for preparing a compound of Formula IIId
  • (illb) is condensed with hydrazine in a reaction mixture to form an alkyl-pyrazole-precursor intermediate.
  • the hydrazine is present in the reaction mixture in a stoichiometric excess amount relative to the phenyl-diketone.
  • the amount of excess hydrazine is at least about 15 mole percent of the sum of the molar amount of unreacted phenyl-diketone and the molar amount of intermediate formed.
  • Excess hydrazine is then removed from the reaction mixture, and the intermediate is alkylated with an alkylating agent.
  • Ar is phenyl or substituted phenyl
  • R' is alkyl or alkyl substituted with halogen, amino, nitro, cyano, hydroxy, carboxy, alkoxy, thio, mercaptoalkyl or alkylthio
  • R 2 is alkyl, hydroxy, alkoxy, acyl, carboxyiic acid and aldehyde, amide and ester derivatives thereof, halogen, haloalkyl, amino, nitro, cyano, mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylphosphinyl or alkylphosphonyl.
  • a phenyl-diketone of Formula Illb is condensed with hydrazine in a reaction mixture to form an alkyl- pyrazole-precursor intermediate.
  • Hydrazine is present in the reaction mixture in a stoichiometric excess amount relative to the phenyl-diketone.
  • the reaction mixture has an organic phase and an aqueous phase, and hydrazine is removed from the reaction mixture by removing the aqueous phase from the reaction mixture.
  • the intermediate is then alkylated with an alkylating agent.
  • Ar, R 1 and R 2 are defined in this process as in the process immediately preceding.
  • the invention is directed as well to a process for preparing an alkylated pyrazole compound of Formula Hie
  • R 2 i ⁇ alkyl, hydroxy, alkoxy, acyl, carboxyiic acid and aldehyde, amide and ester derivatives thereof, halogen, haloalkyl, amino, nitro, cyano, mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylphosphinyl or alkylphosphonyl.
  • R 2 is preferably an electron withdrawing group and most preferably a haloalkyl.
  • the invention is additionally directed to a process for regioselectively alkylating a 3 (5)-aryl-5 (3) - haloalkylpyrazole.
  • the amount of 3-aryl isomer formed is at least about 90% of the total amount of 1- alkyl-3 (5) -aryl-5(3) -haloalkyl-pyrazole formed.
  • Ar is phenyl or substituted phenyl
  • R ! is C,. 5 alkyl
  • R 2 is C,. 3 haloalkyl.
  • the invention is directed, moreover, to a process for brominating a heterocyclic substrate.
  • the heterocyclic substrate is reacted with a bromide salt under oxidizing conditions.
  • the invention is further directed to a process for directly oxidizing an alkyl-substituted benzene substrate.
  • the substrate is reacted with molecular oxygen in the presence of metal salt catalyst and benzoyl peroxide.
  • the invention is directed to processes for esterifying a carboxyiic acid substrate. In a first esterification protocol, the carboxyiic acid is reacted with a halogenating agent, and the resulting acid halide is esterified to form the corresponding carboxyiic acid ester.
  • the esterification reagent used in this process is formed by mixing an alcohol and an acylhalide.
  • a carboxyiic acid substrate is esterified with a trialkylorthoester of Formula
  • R 10 is C -3 3 5 alkyl and R 11 is hydrogen or alkyl.
  • the present invention is also directed to processes for preparing a compound of Formula I
  • (If) is halogenated to form an acid halide and the acid halide is then esterified with an esterification reagent.
  • the esterification reagent is formed by mixing an alcohol of Formula R ,0 OH and an acylhalide.
  • R 1 is C, 5 alkyl
  • R 2 is C,. 3 haloalkyl
  • R 3 , R 5 and R 6 are halogen
  • R 10 is C 3 . 5 alkyl.
  • R 1 , R 2 , R 3 , R 5 , R 6 and R 10 are defined as in the immediately preceding process and R 11 is hydrogen or alkyl.
  • R l , R 2 , R 5 , R 6 and R 10 are defined as in the immediately preceding process and R 3 is bromo.
  • R 1 , R 2 R 5 , R 6 and R 10 are as defined in the immediately preceding process.
  • R 3 is halogen.
  • (ia) is acylated with a haloacylhalide having a fully halogenated ⁇ -carbon and represented structurally as Formula Al o
  • the resulting compound of Formula lb is condensed with hydrazine to form an alkyl-pyrazole-precursor intermediate.
  • the intermediate is alkylated with an alkylating agent to form a compound of Formula Id, which is oxidized to form a compound of Formula Ie, which is halogenated to form a compound of Formula If, which is esterified to form a compound of Formula I.
  • R 1 , R 2 , R 3 , R 5 , R 6 and R 10 are defined as in the process immediately preceding.
  • a compound of Formula Ia is acylated with a haloacetylhalide or an alkyl haloacetate to form a phenyl diketone of Formula lb.
  • the phenyl-diketone is condensed with hydrazine in a reaction mixture to form an alkyl- pyrazole-precursor intermediate.
  • the reaction mixture has an organic phase and an aqueous phase, and hydrazine is present in the reaction mixture in a stoichiometric excess amount relative to the compound of Formula lb.
  • the reaction mixture is heated to dissolve into the organic phase any amount of precipitate which may have formed and to separate the aqueous phase from the organic phase. Excess hydrazine is then removed from the reaction mixture by removing the aqueous phase from the reaction mixture.
  • the intermediate is alkylated with an alkylating agent under acidic conditions to form a compound of Formula Id, which is subsequently oxidized with molecular oxygen in the presence of metal salt catalyst, halide salt and acetone promoter and benzoyl peroxide to form a compound of Formula Ie, which is then halogenated to form a compound of Formula If, which is then esterified to form a compound of Formula I.
  • R 1 , R 2 , R 3 , R 5 , R 6 and R 10 are as defined for the immediately preceding process.
  • the present invention is further directed to a process for preparing a compound of Formula II
  • the compound of Formula lib is then condensed with hydrazine in a reaction mixture to form an alkyl-pyrazole-precursor intermediate.
  • Hydrazine is present in the reaction mixture in a stoichiometric excess amount relative to the compound of Formula lb.
  • the reaction mixture which has an organic phase and an aqueous phase, is then heated to dissolve into the organic phase any amount of precipitate which may have formed. Such heating also facilitates separation of the aqueous phase from the organic phase layers.
  • Excess hydrazine is removed from the reaction mixture by removing the aqueous phase.
  • the intermediate is then alkylated with a methylating agent under acidic conditions to form a compound of Formula Hd,
  • the compound of Formula Hd is oxidized with molecular oxygen in the presence of metal salt catalyst, halide salt, acetone and benzoyl peroxide to form a compound of Formula He,
  • the compound of Formula He is brominated with a bromide salt under oxidizing conditions to form a compound of Formula Hf
  • the present invention includes novel process steps for forming phenyl-diketones, forming and alkylating pyrazoles, brominating pyrazoles and other heterocyclic compounds, oxidizing alkyl-substituted benzene compounds, and esterifying carboxyiic acids. These steps may be combined to prepare 3-aryl-5-haloalkyl pyrazoles, or alternatively, used in subcombinations or individually to prepare intermediates or other compounds.
  • the bromination, oxidation and esterification processes presented herein are particularly suited to a broader range of substrates, as detailed below.
  • the methods presented herein confer significant advantages over the prior art methods in terms of cost, reliability, selectivity, yield and throughput. Specific advantages for particular process steps are discussed below.
  • the 3-aryl-5-haloalkyl pyrazoles prepared by the methods of the present invention may be used to provide outstanding control of broadleaf and narrowleaf weeds such as gallium, blackgrass, pigweed, cocklebur, velvetleaf and hemp sesbania in various crops such as corn, soybean, wheat, barley, rice and nuts. They are also effective in forestry against undesirable trees and vines.
  • the 3-aryl-5-haloalkyl pyrazoles may be applied in a variety of application modes and may be used as herbicidal compositions, as co-herbicides, or in combination with safeners, fungicides, insecticides, nematicides and/or other disease control agents.
  • the herbicidal compound prepared according to the preferred embodiment of the invention isopropyl 5-[4-bromo-l-methyl-5- (trifluoromethyl)-lH-pyrazole-3-yl]-2-chloro-4- fluorobenzoate, is especially effective for preemergent control of broadleaf and narrowleaf weeds associated with small-grain crops such as wheat.
  • alkyl As used herein, the terms “alkyl”, “alkenyl”, or “alkynyl”, whether used alone or in compound form (e.g., haloalkyl, alkoxy, alkoxyalkyl, etc.), refers to both linear and/or branched-chain moieties.
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl and cycloalkenylalkyl members include the following: methyl, ethyl, the isomeric propyls, butyls, pentyls, hexyls, heptyls, octyl ⁇ , nonyls, decyls, etc.; vinyl, allyl, crotyl, methallyl, the isomeric butenyls, pentenyls, hexenyls, heptenyls, octenyls; ethynyl, the isomeric propynyls, butynyls, pentynyls, hexynyls, etc.; the alkoxy, polyalkoxy, alkoxyalkyl and polyalkoxyalkyl analogs of
  • methoxy, ethoxy, propoxys, butoxys, pentoxys and hexoxys and corresponding polyalkoxys and alkoxyalkyls e.g., methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, tertbutoxymethyl, pentoxymethyl, hexoxymethyl, etc.
  • haloalkyl refers to alkyl radicals substituted with one or more halogen (chloro, fluoro, bromo or idodo) atoms. Polyhaloalkyl members may have the same or mixed types of halogen atoms.
  • a "perhaloalkyl” refers to an alkyl in which each of the hydrogen atoms is substituted with halogen atoms.
  • a haloalkyl which is "fully halogenated" at a particular carbon atom has halogen atoms in place of all the hydrogen atoms normally bonded to that carbon.
  • Representative mono-, di- and tri- haloalkyl members include: chloromethyl, chloroethyl, bromomethyl, bromoethyl, iodomethyl, iodoethyl, chloropropyl, bromopropyl, iodopropyl, 1,1,-dichloromethyl, 1,ldibromomethyl, 1,1-dichloropropyl,
  • heterocyclic refers to a closed-ring structure in which one or more of the atoms in the ring is other than carbon.
  • exemplary heterocyclic members include: alkylthiodiazolyl; piperidyl; piperidylalkyl; dioxolanylalkyl, thiazolyl; alkylthiazolyl; benzothiazolyl; halobenzothiazolyl; furyl; alkyl-substituted furyl; furylalkyl; pyridyl; alkylpyridyl; alkyloxazolyl; tetrahydrofurylalkyl; 3-cyanothienyl; thienylalkyl; alkyl- substituted thienyl; 4,5-polyalkylene-thienyl; piperidinyl; alkylpiperidinyl; pyridyl; di- or tetrahydropyridinyl; alkyltetra
  • R 1 is C,_ 5 alkyl
  • R 2 is C,. 3 haloalkyl
  • R 3 , R s and R 6 are halogen and R 10 is C ⁇ _ 5 alkyl.
  • the haloalkyl R 2 is preferably fully halogenated at the carbon nearest the pyrazole ring.
  • the processes are used to prepare isopropyl 5-[4-bromo-l-methyl-5-(trifluoromethyl)-1H- pyrazole-3-yl]-2-chloro-4-fluorobenzoate, structurally represented as the compound of Formula II,
  • a preferred overall process for producing compounds of Formula I starts with substituted acetophenones of Formula la,
  • Process A relates to the acylation of acetophenones to form phenyl-diketones.
  • the acetophenones used in the acylation step are, as described below, preferably 2,4- dihalo-5-methyl-acetophenones
  • the present invention encompasses using acetophenones in which the phenyl moiety is unsubstituted or has other substituents.
  • an acetophenone of the Formula Ilia may be converted to a phenyl-diketone of the Formula Illb according to the reaction:
  • Ar is phenyl or substituted phenyl and R 2 is a C,. 3 haloalkyl and is fully halogenated at the carbon which is nearest the carbonyl once the phenyl-diketone is formed.
  • substituted phenyl refers to a radical having the Formula Ar-1,
  • R 4 is selected from the group consisting of: C, .8 alkyl; C 3 .» cycloalkyl, cycloalkenyl, cycloalkylalkyl or cycloalkenylalkyl; C 2 . 8 alkenyl or alkynyl; benzyl; the aforementioned members substituted with halogen, amino, nitro, cyano, hydroxy, alkoxy, alkylthio,
  • mercaptoalkyl alkoxyalkyl or polyalkoxyalkyl; carbamyl; amino, nitro or cyano; halogen; hydroxy; C,. l0 heterocycle containing 0, S(0) m and/or NR 8 heteroatoms; C ⁇ aryl, aralkyl, or alkaryl;
  • X is O, S(0) m , NR 8 , or CR 8 R 9 ;
  • Y is O, S(0) m , NR 8 ;
  • m is 0-2;
  • n is 1-5; and
  • R 8 and R 9 are selected from the group consisting of: hydrogen; C Ui alkyl; C 3-8 cycloalkyl, cycloalkenyl, cycloalkylalkyl or cycloalkenylalkyl; C 2 .
  • the substituted phenyl of the present invention more preferably includes compounds of the Formula Ar-2,
  • R s is hydrogen or halogen
  • R 6 is hydrogen, halogen, nitro, cyano or YR 8
  • R 7 is hydrogen, lower alkyl, haloalkyl
  • R 5 is halogen
  • R 6 is x
  • R 7 is lower alkyl, haloalkyl, or ⁇ cw where W is hydrogen, hydroxy, halogen, or -OC,. 5 alkyl.
  • the acetophenones of Formula IHa are known in the art.
  • 2,4-dihalo-5-methyl-acetophenones of Formula Ia may be prepared from commercially available 2,4- dihalogenated toluene.
  • the substituted toluene may be acylated using an acylating agent such as an acyl halide, an anhydride or a ketene in the presence of a Lewis acid or Bronstead acid at temperatures ranging from about -50°C to about 200°C and preferably from about 0°C to about 100°C.
  • the amount of acylating agent preferably ranges from one molar equivalent to an excess, and preferably an excess of about 2 molar equivalents relative to the amount of substituted toluene.
  • the acylation reaction may be carried out neat or in any inert solvent. Prefered solvents include nitrobenzene, carbon disulfide, organic acids or halogenated hydrocarbons.
  • the reaction may be carried out under pressure, with pressures ranging from about lxio 5 Pa (about 1 psig) to about 1.7 x 10 s Pa (about 10 psig) . Reaction time varies depending on reagent concentrations, temperature, etc.
  • phenyl-diketones of Formula Illb from such acetophenones may be carried out substantially as described below for preparing compounds of Formula lb and Formula lib.
  • phenyl-diketones of Formula lb are prepared from acetophenones of Formula Ia according to the reaction
  • acylating a compound of Formula Ia with an acylating agent.
  • a suitable acylating agent is a haloacylhalide structurally represented as the compound of Formula Al,
  • the haloacylhalide preferably has a fully halogenated ⁇ -carbon, such that after acylation and after subsequent formation of the pyrazole ring, the R 2 carbon nearest the pyrazole ring is fully halogenated.
  • the complete halogenation of this carbon favorably affects the herbicidal activity of compounds of Formula I.
  • the full halogenation of this R 2 carbon also facilitates synthesis of the desired regioisomer, as noted below (Process B) .
  • the haloacylhalide is preferably a haloacetylhalide, more preferably a trihaloacetylhalide, even more preferably a trihaloacetylchloride and most preferably trifluoroacetylchloride.
  • Another suitable acylating agent is an alkyl haloacetate, with alkyl trihaloacetates being preferred and methyl or ethyl trifluoroacetate being most preferred.
  • Haloacylhalides and alkyl haloacetates are equally preferred as acylating agents in terms of reactivity or yield, but the use of haloacylhalides presently offer a cost advantage over alkyl trihaloacetates.
  • Compounds of Formula lb may be prepared in any anhydrous solvent or mixture of solvents, including ether, alcohols, dimethylsulfoxide, toluene, benzene, etc, with alcohol being a preferred solvent.
  • the reaction is preferably carried out in the presence of a strong base such as an alkali alkoxide, alkali amide or alkali hydride, with alkali alkoxides such as sodium methoxide being preferred.
  • a strong base such as an alkali alkoxide, alkali amide or alkali hydride
  • alkali alkoxides such as sodium methoxide being preferred.
  • the use of alcohol/alkali alkoxide solvent mixtures generally results in better yields, and higher substrate payloads.
  • acylating agent 1.2 to 1.5 molar equivalents relative to the amount of acetophenone to be reacted
  • an excess of a 75% methanol/25% sodium methoxide solution about 1.5 molar equivalents of sodium methoxide relative to the amount of acetophenone
  • the initial temperature of methanol/sodium methoxide solution, prior to mixing ranges from about -20°C to about 60°C, more preferably from about -10°C to about 20°C and is most preferably about -5°C.
  • the temperature is controlled during the mixing and before addition of the acetophenone to be less than about 60°C and more preferably less than about 40°C.
  • the substituted acetophenone is then added to the reagent mixture, followed by the further addition of methanol/sodium methoxide solvent (another 1.5 molar equivalents relative to the amount of acetophenone) .
  • the reaction proceeds at atmospheric pressure and at temperatures ranging from about 25°C to about 75°C, more preferably from about 50°C to about 70°C and most preferably at about 60°C.
  • the reaction time varies from about a few minutes to several days, depending primarily on the concentration of the reagents and the reaction temperature. Yields of greater than about 90% are typically achieved using reaction times of about 45 minutes at 60 °C.
  • the haloacylhalide is preferably premixed with the alkoxide / alcohol solution prior to adding the acetophenone substrate
  • the order of combining the acylating agent, substrate, and solvent or solvent mixture is not narrowly critical.
  • the reaction could also be effected by premixing the acetophenone substrate with a basic solvent and then adding the acylating agent, or as a further alternative, by adding the acylating agent and acetophenone at the same time.
  • One consideration in determining a preference of order relates to controlling exotherms which result upon combination of reagent, substrate and solvents.
  • Formula lb may, if desired, be isolated and/or purified.
  • the resulting compound is precipitated out of solution by cooling the reaction mixture to about 50°C, neutralizing with a mineral acid solution such as a 10% Hcl solution, and further cooling to about 10°C.
  • the precipitated product can then be isolated by filtration, and, if desired, purified by methods known in the art, such as crystallization.
  • phenyl-diketone of Formula lb will be subsequently used in Process B
  • several alternative work-up schemes may be suitably employed to replace the solvent system used in Process A (e.g. alcohol/alkali alkoxide) with the system to be subsequently used in Process B (e.g. aromatic solvents)
  • the compound of Formula lb may be precipitated and isolated as described above, and the isolated phenyl-diketone precipitate can be reslurried into the solvent to be used for Process B, without further drying or purification. More preferably, the reaction mixture is worked up without isolating the phenyl- diketone product.
  • the work-up preferably includes neutralizing the reaction mixture with a mineral acid solution as a 10% Hcl solution and stripping the alcohol at temperatures ranging from about 45°C to about 50°C under a slight vacuum. At least about 50% of the alcohol should be removed, preferably at least about 80% is removed and most preferably at least about 90% is removed.
  • the aromatic solvent is then added and the aqueous layer is removed.
  • a variation of this method includes first stripping the alcohol under reduced pressure, cooling the reaction mixture to about ambient temperature, adding the aromatic solvent, washing with an aqueous mineral acid solution, further washing with deionized water and removing the resulting aqueous phase.
  • the organic phase contains the desired phenyl-diketone product and is used in Process B, as described below.
  • a phenyl-diketone of Formula lib is prepared from an acetophenone of Formula Ha according to the reaction:
  • This reaction is carried out substantially as described above for preparing compounds of Formula lb, using either trifluoroacetylchloride, methyl trifluoroacetate or ethyl trifluoroacetate as the acylating agent.
  • Trifluoroacetylchloride is presently less expensive than methyl or ethyl trifluoroacetate, and is therefore preferred with respect to cost, but the aforementioned acylating agents are otherwise equally preferred.
  • the preparation of compounds of Formula lib is further exemplified in Example 1 (Process A) .
  • Process B relates to the cyclization of phenyl- diketones and subsequent alkylation to form alkylated 3(5)- aryl-5(3)-haloalkyl pyrazoles.
  • an aryl- pyrazole of Formula Illb may be converted to an alkylated 3- aryl-pyrazole of Formula Hid according to the reaction
  • Ar is phenyl or substituted phenyl as defined for Process A;
  • R 1 is alkyl or alkyl substituted with halogen, amino, nitro, cyano, hydroxy, carboxy, alkoxy, thio, mercaptoalkyl or alkylthio;
  • R 2 is alkyl, hydroxy, alkoxy, acyl, carboxyiic acid and aldehyde, amide and ester derivatives thereof, halogen, haloalkyl, amino, nitro, cyano, mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylphosphinyl or alkylphosphonyl.
  • R 1 is preferably C ⁇ 5 alkyl and R 2 is preferably a C,. 3 haloalkyl.
  • This reaction is effected by condensing a compound of Formula Hlb with hydrazine and preferably with an excess of hydrazine, removing any excess hydrazine, and alkylating, as described in detail below for preparing compounds of Formula Id and Hd. If desired, an intermediate compound of the Formula Hie
  • Ar and R 2 are as defined above for compounds of Formulae Hlb and Hid, may be formed by condensing the phenyl-diketone of Formula Hlb under acidic conditions or adding an acid to the reaction mixture after the condensation.
  • the alkylation reaction may be carried out regioselectively, under acidic conditions, without deprotonating the N-hydrogen of Formula Hie, to form the 3- aryl-isomer of Formula Hie, wherein Ar and R 1 are as defined above for compounds of Formulae Hlb and Hid and wherein R 2 is alkyl, hydroxy, alkoxy, acyl, carboxyiic acid and aldehyde, amide and ester derivatives thereof, halogen, haloalkyl, amino, nitro, cyano, mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylphosphinyl or alkylphosphonyl.
  • Process B particularly relates to the regioselective preparation of 3-aryl-5-haloalkyl pyrazoles of Formula Id according to the overall reaction:
  • R 1 is C,. 5 alkyl
  • R 2 is C 1-3 haloalkyl
  • R 5 and R 6 are halogen.
  • a phenyl-diketone of Formula lb is condensed with hydrazine in a reaction mixture to form one or more intermediates, discussed in detail below and collectively referred to as alkyl-pyrazole-precursor intermediates.
  • An alkylating agent is then added to the reaction mixture and reacts with the alkyl-pyrazole-precursor intermediate(s) to form, in the general case, a mixture of two isomers, collectively represented by Formula Ic,
  • the predominant product formed is the l-alkyl-3-aryl-5-haloalkyl-pyrazole (Formula Id) rather than the l-alkyl-5-aryl-3-haloalkyl-pyrazole, referred to hereinafter as the 3-aryl isomer and the 5-aryl isomer, respectively.
  • the hydrazine is preferably unsubstituted hydrazine. While alkyl-substituted hydrazines such as methyl-hydrazine could be used in the present invention to form an alkylated pyrazole in a single step, the regioisomer resulting therefrom is predominantly the 5-aryl isomer rather than the desired 3-aryl isomer. Hydrazine may be reacted with the phenyl-diketone of Formula lb in any suitable solvent or mixture of solvents, including both organic and aqueous solvents. Based on availability and cost, hydrazine is preferably used in the reaction as an aqueous solution.
  • the phenyl-diketone is preferably in an organic solution.
  • Aromatic solvents having a relatively high boiling point such as toluene, xylene, cymene, cumene and ethyl benzene are preferred, with toluene being a most preferred solvent for the phenyl- diketone.
  • the reaction is most preferably effected by adding an aqueous hydrazine solution to a toluene solution containing the phenyl-diketone to form a two-phase reaction mixture in which the phenyl-diketone is in an organic phase and hydrazine in an aqueous phase.
  • the toluene solution is preferably at about ambient temperature when the hydrazine solution is added. Sufficient hydrazine solution is added to provide a stoichiometric excess amount of hydrazine in the reaction mixture relative to the phenyl-diketone.
  • the stoichiometric excess amount is the residual amount of hydrazine which would remain after all of the phenyl-diketone has completely reacted with hydrazine.
  • the stoichiometric excess amount of hydrazine in the reaction mixture or reaction zone at any given time is the difference between the molar amount of hydrazine present at that time and the molar amount of phenyl-diketone present at that time.
  • the amount of excess hydrazine present in the reaction mixture is preferably at least about 1 mole percent of a reference amount, the reference amount being the sum of the molar amount of unreacted phenyl-diketone and the molar amount of alkyl-pyrazole-precursor intermediate formed.
  • the amount of excess hydrazine is more preferably at least about 15 mole percent of the reference amount, and is most preferably about 20 mole percent of the reference amount.
  • the amount of excess hydrazine preferably ranges from about 5 to about 50 mole percent and more preferably from about 10 to about 25 mole percent.
  • the use of excess hydrazine maximizes the conversion of the phenyl-diketone to alkyl-pyrazole-precursor intermediate, thereby resulting in improved yields.
  • the reaction mixture is stirred to facilitate the inter-phase reaction between hydrazine and the phenyl-diketone.
  • the reaction mixture may also contain some unreacted acetophenone carried over from the previous step (Process A) .
  • the reaction is preferably effected at atmospheric pressure and at temperatures ranging from about 0°C to about 60°C, more preferably at temperatures ranging from about 30°C to about 50°C and most preferably at a temperature of about 40°C. Reaction times vary from about a few minutes to several days depending on the concentration of the reagents and the reaction temperature. At 40°C, the reaction is completed, as determined by gas chromatography, within about 30 minutes.
  • one or more intermediate compounds are believed to result from condensation of the phenyl-diketone (Formula lb) with hydrazine.
  • phenyl-diketone Formmula lb
  • hydrazine For example, 3-aryl-5-hydroxy-pyrazolines of Formula Bl or 3(5) -aryl-pyrazoles of Formula B2
  • aryl- pyrazole intermediates of Formula B2 may be obtained by allowing the aforementioned condensation reaction to proceed under acidic conditions (e.g. using an acetic acid solvent as in Example 2) or, alternatively, by adding acid to the reaction mixture after the condensation reaction is completed.
  • the phenyl-diketone reagent and the resulting intermediate(s) remain preferentially in the organic phase of the reaction mixture, while hydrazine remains in the aqueous phase thereof. However, some resulting intermediate may precipitate out of solution.
  • the excess hydrazine and the resulting alkyl-pyrazole-precursor intermediates are preferably separated from each other before alkylating the intermediates to form alkylated pyrazole compounds of Formulas Ic or Id.
  • Such separation minimizes the explosive danger which would exist if the resulting intermediate(s) were alkylated in the presence of hydrazine.
  • the separation may be effected by any means known in the art, but is preferably effected by phase separation (in two-phase reaction mixtures) or by liquid-liquid solvent extraction methods (in single-phase reaction mixtures) . Excess hydrazine is preferably removed from the reaction mixture without isolating the resulting intermediate(s) .
  • the excess hydrazine is removed from the reaction mixture by first heating the reaction mixture to redissolve into the organic phase any amount of precipitate which may have formed during the reaction. Such heating also facilitates separation of the aqueous phase from the organic phase into separate aqueous and organic layers. If desired, other solvents may be added to the two-phase system to either increase the partition coefficients or sharpen phase separation.
  • the aqueous phase layer which includes hydrazine, is then removed from the reaction mixture.
  • the remaining organic phase may be further washed with an aqueous solution, such as a brine (NaCl) solution. This wash solution is also separated and removed from the organic solution.
  • the resulting intermediate(s) and the excess hydrazine may be separated from each other by removing organic phase containing the resulting intermediate(s) from the reaction mixture.
  • reaction can be carried out in a single- phase organic system, in which anhydrous hydrazine is reacted with a phenyl-diketone of Formula lb and the excess hydrazine is removed by extraction with water.
  • reaction is instead carried out in a single phase aqueous solution, the resulting intermediate(s) may be separated by extraction with an organic solvent.
  • the phase separation and liquid-liquid extraction work-up steps described herein are less cumbersome than isolation or purification techniques (e.g. precipitation and/or crystallization) and safer than distillation methods.
  • an alkylating agent is added to the reaction mixture to alkylate the alkyl-pyrazole-precursor intermediate(s) .
  • the resulting alkylated pyrazole is represented generally by Formula Ic.
  • Suitable alkylating agents include alkyl halides, alkyl sulfonates and mono- or di-alkylsulfates, with dialkylsulfates being preferred.
  • R 1 is a methyl group, dimethylsulfate, methyliodide, and methylbromide are preferred alkylating agents.
  • Dimethylsulfate should be used in at least an equimolar amount relative to the phenyl- diketone of Formula lb, as the ⁇ econd methyl group is not reactive enough to alkylate the intermediate(s) .
  • the alkylating agents are preferably added to the reaction mixture in molar excess relative to the amount phenyl- diketone being reacted, the molar excess ranging from about 1.01 to about 1.3 molar equivalents, more preferably from about 1.05 to about 1.25 molar equivalents and most preferably from about 1.1 to about 1.2 molar equivalents.
  • the alkylating agents should generally be added slowly to the reaction mixture to help avoid large exothermic excursions.
  • the percentage of the 3-aryl isomer obtained under acidic conditions is consistently greater than about 90% of the total amount of aryl-pyrazole product, and frequently greater than about 95%, whereas under non-acidic conditions, the percentage of 3-aryl isomer obtained ranged from about 55% to about 80%.
  • this selectivity is believed to arise from the fact that intermediates such as the compound of Formula B2 exist predominantly (greater than about 90%) in the 5-aryl tautomeric form (Formula B3) and only marginally (less than about 10%) in the 3-aryl form (Formula B4) :
  • the nitrogen is believed to be deprotonated, leaving a very reactive electron pair for alkylation. Since the deprotonated nitrogen is predominantly the nitrogen closest to the aryl group, the 5-aryl isomer dominates under basic conditions. In contrast, when the alkylation is carried out under acidic conditions, no deprotonation occurs and the other nitrogen (ie, the nitrogen lacking hydrogen) is relatively more reactive. Hence, the alkylation is selective to form the 3-aryl isomer under acidic conditions. Acidic conditions are also preferred over basic conditions with regard to the stability of the reaction for particular R 2 constituents, such as CF 2 C1. (Example 4).
  • the selective preparation of the 3-aryl isomer is also favorably influenced by the electron-withdrawing capability of the R 2 group.
  • Electron withdrawing R 2 moieties which enhance selective alkylation include substituted alkyl, acyl, carboxyiic acid and aldehyde, amide and ester derivatives thereof, halogen, haloalkyl (Example 3) , nitro, cyano, mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylphosphinyl or alkylphosphonyl.
  • the R 2 group is preferably a haloalkyl group and most preferably a haloalkyl group which is fully halogenated at the carbon closest to the pyrazole ring.
  • the aryl group has relatively little effect on regioselectivity.
  • Preferred solvents for the alkylation reaction include toluene, xylene, cymene, acetone, dimethylsulfoxide, dimethylformamide, dioxane, etc, with toluene being most preferred.
  • the alkylation is most preferably effected by reacting the intermediate(s) with a dialkylsulfate in anhydrous toluene under reflux conditions.
  • the toluene solvent may be neutral prior to the reaction, but acidic conditions are immediately generated as the alkylation reaction proceeds under reflux. For example, where dimethylsulfate is used as the alkylating agent, methyl- sulfonic acid is generated as soon as methylation of the intermediate(s) begins.
  • a small amount of acid such as p-toluene sulfonic acid can be added.
  • the reaction is preferably carried out under atmospheric pressure and at a temperature ranging from about 60°C to about 120°C, and most preferably at about 105°C.
  • water is removed from the reaction mixture as a toluene/water azeotrope.
  • the azeotrope is preferably condensed and the condensate separated, with the toluene being returned to the reaction mixture.
  • the progress of the reaction may be monitored using gas chromatography, and, if necessary, additional alkylating agent may be added to effect complete conversion to the alkylated pyrazole.
  • Reaction times may range from about a few minutes to several days depending on the concentration of the reagents and the reaction temperature. Overall yields ranging from about 70% to about 85% are typically achieved using reaction times of about 16 hours at a temperature of about 105°C.
  • the product may be isolated and purified by methods known in the art, including precipitation and filtration, concentration, extraction, crystallization or chromatographic methods.
  • the reaction product mixture is preferably worked up by cooling to about 50 °C and then washing in succession with caustic solutions (5% NaOH, then 10% NaOH) to destroy any excess dimethylsulfate and to neutralize the organic phase.
  • the product mixture is then further washed with a brine solution (10%) .
  • the toluene solvent is then replaced with methanol by stripping toluene in vacuo and adding methanol.
  • the 3-aryl regioisomer is isolated by adding water (16:1 methanol:H 2 0) , cooling to a temperature of about 5 °C to about 10 °C, and centrifuging to crystallize the desired 3-aryl isomer while leaving the undesired 5-aryl isomer in solution.
  • the alkylated 3- aryl-pyrazole of Formula Hd is prepared from the phenyl diketone of Formula lib according to the reaction:
  • Process C relates to the oxidation of alkyl- substituted benzene compounds to form the corresponding benzoic acids.
  • the substrate for this reaction is preferably a 2,4-dihalo-5-pyrazole toluene
  • the oxidation method of the present invention is more generally applicable to other alkyl-substituted benzene substrates, including for example, unsubstituted toluene, substituted toluene, substituted toluene where at least one substituent is a substituted or unsubstituted heterocyclic ring having up to 6 ring members, and substituted toluene where at least one substituent is pyrazole or substituted pyrazole.
  • the oxidization method of the present invention may be used to prepare a substituted-benzoic acid pyrazole of Formula IHg from a substituted-toluene of Formula IHf according to the reaction
  • R 5 and R 6 are halogen and Pyr is a substituted or unsubstituted pyrazole.
  • substituted pyrazole as used herein means a substituted pyrazole of Formula Pyr-1,
  • R 1 is hydrogen, alkyl or alkyl substituted with halogen, amino, nitro, cyano, hydroxy, carboxy, alkoxy, thio, mercaptoalkyl or alkylthio
  • R 2 is alkyl, hydroxy, alkoxy, acyl, carboxyiic acid and aldehyde, amide and ester derivatives thereof, halogen, haloalkyl, amino, nitro, cyano, mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylphosphinyl or alkylphosphonyl
  • R 3 is hydrogen or halogen.
  • the substituted pyrazole is more preferably the l-alkyl-5-aryl isomer of Formula Pyr-2,
  • R 1 is hydrogen or C ⁇ . s alkyl
  • R 2 is hydrogen or C 1-3 haloalkyl
  • R 3 is hydrogen or halogen
  • Substituted-toluenes of Formula IHf are oxidized to form benzoic acids of Formula IHg substantially as detailed below for preparing compounds of Formula Ie and He.
  • benzoic acid compounds of Formula Ie are prepared by oxidizing 2,4- dihalo-5-pyrazole-toluene compounds of Formula Id according to the reaction:
  • R l is C ⁇ alkyl
  • R 2 is C,. 3 haloalkyl
  • R 5 and R 6 are halogen.
  • the reaction is preferably carried out as a direct oxidation by reacting the compound of Formula Id with molecular oxygen in the presence of metal salt catalyst or mixtures thereof, catalyst promoter and free radical initiator.
  • metal salt catalysts such as cobalt salts, manganese salts, nickel salts, cesium salts and zirconium salts may be used individually or in combination.
  • salts examples include cobalt (II) acetate, cobalt formate, cobalt hexylate, cobalt chloride, cobalt carbonate, cobalt acetylacetonate, manganese (II) acetate, manganese chloride, cesium (III) acetate, zirconium (IV) acetylacetonate, zirconium chloride, nickel chloride, etc.
  • Cobalt acetate, Co(0Ac) 2 , manganese acetate, Mn(OAc) 2 or co- catalysts thereof are preferred catalysts.
  • the total amount of a single catalyst or of a combination of catalysts in a mixture can range from about less than 1% to about 100% molar equivalents relative to the compound of Formula Id.
  • a catalyst promoter is used in conjunction with the metal salt catalyst.
  • Preferred catalyst promoters include alkyl halides, halide salts, lithium salts, carboxylate salts, with halide salts such as alkali halides and ammonium halides being more preferred. Bromide compounds such as sodium bromide, hydrogen bromide and ammonium bromide are most preferred as catalyst promoters.
  • the amount of halide salt promoter preferably ranges from about 0.1 mole % to about 10 mole % relative to the compound of Formula Id.
  • a ketone such as acetone may be used as a catalyst promoter or as a co-promoter with the halide salt promoter. Without being bound by theory, it appears that acetone hastens the typically slow induction period of the reaction, thereby shortening the total reaction time by as much as 20% to 30%.
  • benzoyl peroxide is a preferred initiator.
  • the use of benzoyl peroxide makes the reaction more robust, dependable and reliable relative to the use of hydrogen peroxide, which is substantially less reliable and often erratic with regard to initiating the oxidation.
  • it is believed that the benzoyl peroxide makes the reaction less sensitive to impurities which commonly stall the reaction.
  • the amount of benzoyl peroxide used preferably ranges from about 0.1 mole % to about 10 mole % relative to the substituted toluene compound of Formula Id, more preferably from about 0.1 mole % to about 5 mole % and most preferably from about 0.3 mole % to about 0.7 mole %.
  • the reaction is preferably carried out in any suitable solvent which does not interfere with the course of the reaction; however, the reactior. can also be carried out neat.
  • Preferred solvents include aliphatic carboxyiic acids and anhydrides such as acetic acid and acetic anhydride. Acetic acid is a most preferred solvent.
  • the substrate compound of Formula Id is preferably combined with the catalyst, promoter and initiator in a suitable reactor and mixed.
  • a most preferred reaction mixture includes the substrate and the following combination of co-catalysts, catalyst promoters and initiator in acetic acid: from about 0.9 to about 1.1 mole percent Co(OAc) 2 , from about 0.09 to about 0.11 mole percent Mn(0Ac) 2 , from about 2.7 to about 3.3 mole percent sodium bromide, from about 4.5 to about 5.5 mole percent acetone and from about 0.6 to about 0.8 mole percent benzoyl peroxide.
  • oxygen is supplied to the reaction mixture in stoichiometric excess as pure 0 2 , as air, or as a mixture of oxygen or air in other gasses. Without being bound by theory, the rate of reaction appears to be mass transfer limited. As such, the mixture should be well mixed or agitated during the reaction to maximize oxygen dispersion.
  • the reaction may proceed at atmospheric pressure, or, if desired, in a pressurized atmosphere.
  • oxygen pressure preferably ranges from about 1x10 s Pa to about 70xl0 5 Pa (about 1 atm to about 1000 psig) and more preferably from about 1x10 s Pa to about 18xl0 5 Pa (about 1 atmosphere to about 250 psig) .
  • the oxygen pressure is most preferably about 1.7 x 10 5 Pa (about 10 psig).
  • the above-recited pressure values represent the partial pressure of oxygen in the air. While higher pressures favorably influence the reaction rate, the capital costs required to effect such pressurization may negate any overall benefit to conducting the reaction at higher pressures.
  • the reaction preferably proceeds at temperatures ranging from about 80°C to the boiling point of the solvent. When acetic acid is used as the solvent, the reaction temperature preferably ranges from about 80°C to about 120°C, with a temperature of about 110°C being preferred. Reaction times may range from about a few minutes to several days depending on the concentration of the reagents and the reaction temperature. Yields of about 90% are typically achieved in about 5 to 50 hours at a temperature of about 110°C.
  • the product may be isolated and purified using conventional methods. However, where the resulting benzoic acid of Formula Ie will be used in subsequent steps of the overall process, the product is preferably not isolated from solution prior to the next step (Process D) . When use in the subsequent step is anticipated, the reaction mixture is kept at a temperature of greater than about 70 °C to minimize the potential for product precipitation.
  • the benzoic acid of Formula He is prepared from the aryl-pyrazole of Formula Hd according to the reaction:
  • This reaction is carried out substantially as described above for preparing compounds of Formula Ie, and is further exemplified in Example 1 (Process C) .
  • the methyl group on the aryl member of Formula Hd is oxidized preferentially relative to the methyl on the pyrazole member.
  • the reaction should be discontinued once all of the aryl-methyl has been reacted. For example, once all of the substrate compound has reacted, as determined by HPLC sampling, the reaction may be terminated by cutting off oxygen supply and, if the system is pressurized, venting the reactor.
  • Process D relates to the halogenation of heterocyclic compounds.
  • the substrate for this reaction is preferably a l-alkyl-3-aryl-5-haloalkylpyrazole
  • the bromination method of the present invention is more generally applicable to other heterocyclic substrates, including heterocyclic compounds having up to 6 ring-members, unsubstituted pyrazoles, or substituted pyrazoles.
  • the bromination method of the present invention may be used to prepare a phenyl-substituted pyrazole of Formula IHh from a compound of Formula Hid according to the reaction
  • Ar is phenyl or substituted phenyl as defined in Process A;
  • R 1 is hydrogen, alkyl or alkyl substituted with halogen, amino, nitro, cyano, hydroxy, carboxy, alkoxy, thio, mercaptoalkyl or alkylthio;
  • R 2 is alkyl, hydroxy, alkoxy, acyl, carboxyiic acid and aldehyde, amide and ester derivatives thereof, halogen, haloalkyl, amino, nitro, cyano, mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylphosphinyl or alkylphosphonyl. More preferably, R 1 is hydrogen or C,. s alkyl and R 2 is C, 3 haloalkyl. The bromination of such substrates is carried out substantially as described below for preparing compounds of Formula If and
  • Process D relates, more preferably, to the halogenation l-alkyl-3-aryl-5-haloalkyl pyrazoles to form 4- halo pyrazoles.
  • the halogenated pyrazoles of Formula If are prepared by halogenating a compound of Formula Ie according to the reaction
  • R 1 is C,_ 5 alkyl
  • R 2 is C,. 3 haloalkyl
  • R 3 , R 5 and R 6 are halogen.
  • Suitable halogenating agents known in the art include chlorine, N-chlorosuccinimide, sulfuryl chloride, bromine, N-bromosuccinimide, etc.
  • the amount of halogenating reagent can range from les ⁇ than one molar equivalent to an excess, relative to the 3-aryl pyrazole compounds of Formula Ie.
  • Any inert solvent may be used, including organic acids, inorganic acids, hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, ethers, sulfides, sulfoxides and sulfones.
  • Reaction temperatures may range from about 10°C to about 100°C and the reaction period will vary depending on reagent concentrations, temperature, etc.
  • R 3 is preferably a bromo group
  • Process D relates, in a preferred embodiment, to the bromination of heterocyclic compounds such as a l-alkyl-3-aryl-5-haloalkyl pyrazole.
  • a compound of Formula Ie may be brominated to prepare a brominated pyrazole of Formula If (with R 3 as bromo) , by reacting the compound of Formula Ie with a bromonium ion.
  • the bromonium ion is preferably generated by oxidizing a bromide salt.
  • Both organic and inorganic bromide salts are suitable, with inorganic bromide salts such as alkali bromides (e.g. sodium bromide) being preferred.
  • Preferred oxidizing agents include, independently, aqueous sodium hypochlorite and chlorine gas.
  • the bromonium ion may, alternatively, be present as bromonium chloride, BrCl, formed for example by mixing Br 2 (g) and Cl 2 (g) .
  • bromonium ion generated from a bromide salt under oxidizing conditions is generally more reactive and more selective than liquid bromine. Reaction times using this system are shorter than those using liquid bromine by an order of magnitude.
  • the bromination reagents used herein are generally less expensive than liquid bromine, and the present method minimizes the quantity of bromide waste which is generated.
  • the reaction may be carried out in any suitable solvent, but is preferably conducted using aliphatic acid solutions such as acetic acid.
  • aliphatic acid solutions such as acetic acid.
  • the use of an acetic acid solution helps minimize undesired side reactions, such as halogenation of the benzoic acid to an acid halide.
  • excess sodium bromide is added to an acetic acid solution containing a compound of Formula Ie.
  • the total amount of sodium bromide in the reaction mixture preferably ranges from about 1.0 to about 1.6 molar equivalents relative to the amount of benzoic acid substrate of Formula Ie, more preferably from about 1.15 to about 1.5 molar equivalents with about 1.4 equivalents being most preferred.
  • the reagent compound of Formula Ie is supplied directly from the previous oxidation step, the existing mixture may already contain a relatively small amount of NaBr which was used as a promoter during oxidation. In such a case, the amount of NaBr already existing in solution should be accounted for in determining the amount of NaBr to add.
  • the sodium bromide is preferably added as an aqueous solution formed by dissolving the NaBr in distilled or deionized water (about 17 to about 25 molar equivalents H 2 0, with about 21 molar equivalents being preferred) .
  • the reaction mixture should be well mixed while adding NaBr and during the subsequent reaction to achieve good bromination yield and minimize side reactions.
  • the sodium bromide is preferably added slowly to minimize the formation of large lump precipitates and to minimize significant temperature departures below about 70 °C.
  • the oxidation agent is added and the reaction mixture is heated to the desire reaction temperature, which preferably ranges from about ambient temperature to about 100°C, more preferably from about 70°C to about 90 °C, and most preferably from about 75 °C to about 85 °C.
  • the amount of excess chlorine preferably ranges from about 1.0 to about 1.5 molar equivalents relative to the amount of heterocyclic substrate of Formula Ie.
  • the amount of excess chlorine preferably ranges from about 1.0 to about 1.3 molar equivalents relative to the amount of substituted toluene substrate of Formula Id (Process C) , with about 1.15 molar equivalents being most preferred.
  • the chlorine reacts with aqueous sodium bromide to form bromonium ion, Hcl and NaCl, and the bromonium ion brominates the substrate.
  • the reaction following the addition of chlorine gas is fairly exothermic. As the reaction progresses, the reaction mixture typically becomes more viscous, and may require higher temperatures and/or the addition of more water to facilitate proper mixing. If the reaction does not reach completion, as determined by HPLC or fluorine NMR, additional chlorine (about 0.1 molar equivalent) may be added.
  • sodium hypochlorite When sodium hypochlorite is used as the oxidizing reagent, excess sodium hypochlorite is added after the sodium bromide has been added and mixed with the substrate compound.
  • the NaOCl i ⁇ preferably added as an aqueous solution while the reaction mixture is stirred and maintained at about 70 °C.
  • the amount of excess NaOCl preferably ranges from about 1.0 to about 3.0 molar equivalents relative to the amount of heterocyclic substrate of Formula Ie.
  • the amount of excess hypochlorite When the oxidized aryl-pyrazole product resulting from Process C is subsequently brominated in the instant process without being isolated, the amount of excess hypochlorite preferably ranges from about 1.5 to about 3.5 molar equivalents relative to the amount of substituted toluene substrate of Formula Id
  • the reaction then proceeds as described above with respect to using chlorine as the oxidizing agent.
  • the sodium hypochlorite and chlorine gas are equally preferred as oxidizing agents based on performance. However, preference between these oxidizing agents may be based on other factors, such as availability. Other oxidizing agents known to those skilled in the art may also be used.
  • the bromination reaction is preferably carried out at atmospheric pressure. Reaction times may vary from a few minutes to several days, with yields of greater than about 90% resulting in about 2-4 hours at temperatures ranging from about 75°C to about 85°C. When the reaction is completed, the reaction mixture is cooled to about ambient temperature or slightly greater.
  • the excess oxidizing agent is then destroyed and the desired brominated pyrazole product is precipitated out of solution.
  • residual oxidizing agent may be destroyed and a precipitated product formed by adding an aqueous solution of reducing agent such as aqueous sodium sulfite solution to the reaction mixture. Additional water may be added to fully precipitate the desired product and to aid mixing.
  • the precipitated product may then be filtered from solution, washed with deionized water and dried.
  • the resulting halogenated pyrazole compound of Formula If will be used in the subsequent esterification step, the product should be thoroughly dried.
  • the brominated- aryl-pyrazole of Formula Hf is prepared from the compound of Formula He according to the reaction:
  • Process E relates to the esterification of carboxyiic acids. While the substrate for this reaction is preferably a 2,4-dihalo-5-pyrazole benzoic acid, the esterification methods of the present invention are more generally applicable to other carboxyiic acids, including aliphatic carboxyiic acids, long-chain fatty acids, heterocyclic carboxyiic acids, substituted and unsubstituted benzoic acids, and benzoic acids substituted with at least one substituent being a(n) (un)substituted heterocyclic ring having up to 6 ring members.
  • the esterification methods presented herein may be used to prepare a benzoic acid ester of Formula IHi from a compound of Formula IHg according to the reaction
  • a 2,4-dihalo-5- pyrazole-benzoic acid ester of Formula I is prepared by esterifying a compound of Formula If according to either of two protocols which effect the reaction:
  • R 1 is C,_ 5 alkyl
  • R 2 is C,. 3 haloalkyl
  • R 3 , R 5 and R 6 are halogen
  • R 10 is C,. 5 alkyl.
  • a benzoic acid of Formula If is reacted with a halogenating agent to form a corresponding acid halide.
  • the acid halide is then stirred with an excess of esterification reagent formed by premixing an esterifying alcohol with an acyl halide.
  • the benzoic acid of Formula is esterified with a trialkylorthoester.
  • the acid halide intermediate is prepared by methods known in the art.
  • An exemplary method includes reacting the benzoic acid substrate with a halogenating agent such as thionyl chloride, phosphorus pentachloride, oxalyl chloride, etc.
  • a halogenating agent such as thionyl chloride, phosphorus pentachloride, oxalyl chloride, etc.
  • Inert solvents such as toluene, which do not interfere with the halogenation reaction, may be used, and the reaction may be promoted by adding a catalytic amount of an amine base such as triethylamine, pyridine or dimethylformamide, etc.
  • the benzoic acid substrate is halogenated by mixing the substrate with excess halogenating agent (1.1-1.7 equivalents) in a toluene solution at ambient temperature, adding a few drops of dimethylformamide, slowly heating to about 75°C and reacting at that temperature for about 1 to 3 hours. Other reaction temperatures and periods may be appropriate.
  • the toluene solvent and excess halogenating agent are removed by stripping in vacuo while maintaining the temperature at about 75°C.
  • the acid halide intermediate is reacted with an esterification reagent formed by mixing a small amount of an acylhalide with an alcohol of Formula R 10 OH.
  • the acyl halide is preferably a C,_ 3 acyl halide, and more preferably an acetyl halide.
  • the halide member of the acyl halide should generally be the same halide as the acid halide intermediate being esterified, and is preferably chloride.
  • a most preferred acyl halide is acetyl chloride.
  • the amount of acyl halide added to form the esterification agent preferably ranges from about 0.1% to about 10%, more preferably from about 2% to about 5%, and is most preferably about 4%, by weight, relative to amount of alcohol added to form the esterification agent.
  • acyl halides such as acetyl chloride are believed to scavenge any trace H 2 0 /hich may be present in the alcohol reagent stock, thereby eliminating a potentially competing reaction when the esterifying alcohol is subsequently reacted with the acid halide intermediate being esterified.
  • the acetyl halide appears to react preferentially with water rather than with the alcohol, particularly where the alcohol is a hindered alcohol such as isopropanol.
  • the use of a acylhalide/alcohol esterification reagent allows for the use of less expensive alcohol grades (ie, grades having from about 1% to about 2% water) while providing for improved yields and purity of the resulting ester product.
  • Hcl gas result ⁇ from the esterification reaction and should be scrubbed during the reaction.
  • the reaction period varies, but yields greater than about 90% are obtained by reacting at about 75°C for about one to two hours.
  • the resulting esterification product is also of high purity (greater than about 90%) , which simplifies product workup and results in improved payloads and cycle times.
  • the resulting benzoic acid ester product can be isolated by removing excess alcohol in vacuo or by precipitating the product.
  • the reaction mixture is preferably heated to and maintained at a temperature of about 80°C to about 90°C while the alcohol solvent and other volatiles are stripped under reduced pressure.
  • the remaining mixture containing the product is then cooled to ambient temperature.
  • the product may be precipitated by cooling to about 50°C and adding water, and then isolated by filtering.
  • the benzoic acid ester of Formula I is prepared by reacting the benzoic acid of Formula If with a trialkylorthoester of Formula FI,
  • R 10 is C,. s alkyl and R" is hydrogen or alkyl.
  • R 10 is preferably C 3 . 5 alkyl.
  • R 11 is preferably hydrogen such that the trialkylorthoester is a trialkylorthoformate.
  • trialkylorthoesters such as trialkylorthoformates provide excellent yield of the desired alkyl esters.
  • the benzoic acid is esterified with the trialkylorthoester in neat or in a suitable solvent.
  • aromatic hydrocarbon solvents such as toluene, xylene and cymene and relatively high-boiling ethers such as methoxyethylether, diethoxyether or dioxane are suitable solvents.
  • the benzoic acid substrate is mixed with excess trialklyorthoester (about 1.1 to about 1.5 molar equivalents with about 1.3 molar equivalents being preferred) and heated to a reaction temperature ranging from about 80°C to about 150°C, more preferably from about 130°C to about 140°C, and most preferably at about 135°C. Volatile by-products begin to be driven out of the reaction mixture as the reaction mixture is heated above about 110°C.
  • the reaction is preferably carried out at atmospheric pressure.
  • the reaction time varies depending on the temperature and the concentration of reactants; yields of about 90% are typically obtained using at a temperature of about 135°C fo- about 1 to 2 hours.
  • the esterified product may be isolated as a melt by stripping away excess trialkylorthoformate, solvent and volatile by-products, and then cooling.
  • the esterified product may be precipitated by cooling to about 50°C, adding isopropanol and then adding water.
  • the precipitated product is isolated by filtering, optionally rewashing with additional isopropanol/water, and drying.
  • the esterified aryl-pyrazole of Formula II is prepared from the compound of Formula Hf according to the reaction:
  • This reaction may be effected substantially as described above using either of the two esterification protocols for preparing compounds of Formula I.
  • a preferred esterification reagent for preparing the isopropyl ester is formed by mixing about 4% acetyl chloride, by weight, with isopropanol.
  • the trialkylorthoester esterification reagent is preferably triisopropylorthoformate, where, with reference to Formula FI, R 10 is isopropanol (-CH(CH 3 ) 2 ) and R u is hydrogen.
  • the formation of the isopropyl ester of Formula II is further exemplified in Example 1 (Processes E-l and E-2) for the acylhalide/alcohol and trialkylorthoester protocols, respectively.
  • Process steps for preparing compounds of Formulas 1 or II are preferably carried out in the order of Processes A-E as presented above: diketone formation (Process A) , cyclization (condensation) and alkylation (Process B) , oxidation (Process C) , halogenation (Process D) and esterification (Process E) .
  • Processes A-E diketone formation
  • Processes B cyclization
  • alkylation Process B
  • oxidation Process C
  • halogenation Processes E
  • the exact order is not narrowly critical, and may be varied by persons skilled in the art.
  • aryl-pyrazole compounds may be prepared by forming a phenyl diketone from an acetophenone (Process A) , condensing the phenyl-diketone and alkylating to form an alkylated pyrazole (Process B) , halogenating the pyrazole moiety (Process D) , oxidizing the methyl group on the phenyl moiety (Process C) and esterifying (Process E) .
  • Compounds of Formula I are prepared according to this embodiment by acylating a compound of Formula Ia (Process A)
  • the pyrazole moiety could be halogenated after the oxidation and esterification steps.
  • the aryl-pyrazoles are prepared by forming a phenyl diketone (Process A) , condensing the phenyl-diketone and alkylating to form an alkylated pyrazole (Process B) , oxidizing the methyl group on the phenyl moiety to form a benzoic acid pyrazole (Process C) , esterifying the benzoic acid (Process E) , and halogenating the pyrazole moiety (Process D) .
  • Compounds of Formula I are prepared by acylating a compound of Formula Ia (Process A) to form a compound of Formula lb,
  • aryl-pyrazoles may be prepared by first oxidizing a methyl-acetophenone to form a carboxyiic acid- acetophenone (Process C) , esterifying (Process E) , forming a phenyl diketone (Process A) , condensing the phenyl-diketone and alkylating to form an alkylated pyrazole (Process B) and halogenating the pyrazole moiety (Process D) .
  • compounds of Formula I may be prepared by oxidizing a compound of Formula Ia (Process C)
  • an aryl-pyrazole may be prepared by first forming a phenyl-diketone (Process A) , oxidizing (Process C) a methyl group on the phenyl moiety of the phenyl-diketone, esterifying (Process E) , forming an alkylated pyrazole (Process B) and halogenating (Process D) .
  • a compound of Formula I may be prepared by acylating a compound of Formula Ia (Process A)
  • an aryl-pyrazole may be prepared by first oxidizing a methyl-acetophenone to form a carboxyiic acid- acetophenone (Process C) , then forming a phenyl diketone (Process A) , and condensing the phenyl-diketone and alkylating to form an alkylated pyrazole (Process B) , halogenating the pyrazole moiety (Process D) and esterifying (Process E) .
  • compounds of Formula I may be prepared by oxidizing a compound of Formula Ia (Process C)
  • an aryl-pyrazole may be prepared by first forming a phenyl-diketone (Process A) , oxidizing (Process C) , forming an alkylated pyrazole (Process B) , halogenating (Process D) , and esterifying (Process E) .
  • 3-aryl-pyrazoles of Formula I may be prepared by acylating a compound of Formula Ia (Process A)
  • halogenation step could, in these last two examples, be carried out after the esterification.
  • compounds of Formula I may be prepared by acylating a compound of Formula Ia (Process A)
  • aryl-pyrazoles of Formula I may be prepared by oxidizing a compound of Formula Ia (Process C)
  • Example 1 Preparation of isopropyl 5-[4-bromo-l-methyl-5- (trifluoromethyl)-lH-pyrazole-3-yl]-2-chloro-4- fluorobenzoate.
  • Trifluoroacetyl chloride (2.6 kg, 1.5 molar equiv. relative to the compound of Formula Ha) was bubbled into a solution containing 25% sodium methoxide in methanol (4.24 kg NaMeO, 1.5 molar equiv. relative to the compound of Formula Ha) at -5°C. The addition was controlled so that the temperature did not exceed 40°C, despite the resulting exotherm. Total addition time was about 1.5 hours. The 4-chloro-2-fluoro-5- methyl-acetophenone of Formula Ha (2.434 kg, 13.092 mole) was then added.
  • Toluene (11.62 kg) was added as a solvent and the aqueous layer was removed.
  • the toluene solution which contained the product compound of Formula lib, was washed with DI water (6.63 kg) and used directly in Process B without further processing.
  • the solution was further cooled to about 10°C, resulting in a precipitated product.
  • the precipitate was isolated by filtration and then washed with DI water until filtrate pH was greater than about 2.
  • the isolated precipitate was reslurried in toluene (about 11 kg) without further drying.
  • reaction mixture was, when necessitated, heated to 70°C to redissolve precipitated intermediates and/or to facilitate separation of the organic and aqueous phases into distinct layers.
  • the water layer was removed and the toluene solution was washed with a 10% aqueous brine solution (2 X 2.77 kg). The aqueous brine solution was then removed and discarded.
  • Dimethylsulfate (1.94 kg, about 1.2 equiv.) was added slowly to the toluene solution containing the alkyl- pyrazole-precursor intermediates, prepared as described above, the speed of addition being controlled so as to minimize large exotherms.
  • the solution was heated to reflux at 105°C while azeotroping to remove water. The reaction progress was monitored by gas chromatography. In experimental runs where the reaction did not go to completion, additional dimethyl sulfate (about 150 to 170 grams) was added.
  • Glacial acetic acid (11.00 kg, 184 moles) was then added, followed in succession by the addition of benzoyl peroxide (22.87 g, 0.094 moles supplied as 32.67 g of a hydrated solid comprising 70% benzoyl peroxide) and acetone (27.66 g, 0.49 moles) .
  • benzoyl peroxide 22.87 g, 0.094 moles supplied as 32.67 g of a hydrated solid comprising 70% benzoyl peroxide
  • acetone 27.66 g, 0.49 moles
  • a slurry containing 5-[l-methyl-5-(trifluoromethyl)-1H- pyrazole-3-yl]-2-chloro-4-fluorobenzoic acid in about four parts acetic acid was prepared as described in Process C.
  • Reagent grade isopropanol (5.53 kg, 10.6 molar equiv.) was mixed with acetyl chloride (221 g) to form an esterification agent. An exotherm and evolution of HCI gas was observed. The esterification agent was added to the acid chloride intermediate at 75°C. The reaction mixture was stirred and maintained at a temperature of 75°C during the reaction, and HCI off gas was scrubbed. Reaction progress was monitored by gas chromatography and was complete within about 2 hours.
  • the reaction mixture was then cooled to about 50°C.
  • the product was isolated by filtration, resulting in a tan to white waxy solid with a purity of greater than about 92% and a yield of about 90% to about 94%.
  • an alternative method for product work-up included stripping the product mixture under reduced pressure and at temperatures ranging from about 80° to about 90°C to remove solvent and all volatiles. The melt was then cooled to ambient temperatures to form a brick-like solid.
  • He was prepared from 1,1,1-trifluoro-4-[2-chloro-4-fluoro-5- methylphenyl-l-yl]-2,4-dibutanone.
  • the dibutanone (20.6 g) was dissolved in 100 ml of acetic acid in a 500 ml flask equipped with a magnetic stirrer. Hydrazine (2.85 g) was added all at once and an exotherm to 45°C was observed. The solution was heated to 110°C and maintained at that temperature for 15 minutes. The reaction mixture was then cooled to room temperature and poured into water (200 ml) , resulting in a white solid precipitate. The precipitated product was isolated by filtering, and then air dried overnight.
  • the percent of 3-aryl isomer selectively formed over the 5-aryl isomer ranged from about 55% to about 80% of the total N-methyl pyrazoles products prepared, with the better selectivity being obtained using less reactive methylating agents, such as methyl bromide, and lower temperatures.
  • significantly improved selectivity resulted by running the reaction under acidic conditions.
  • a dimethylsulfate methylating agent in refluxing toluene forming methyl-sulfonic acid a ⁇ the reaction proceeds
  • about 96% of the alkylated aryl-pyrazole product was the desired 3-aryl isomer.
  • the regiochemical assignment of the alkylated haloalkyl pyrazoles was determined by comparison of the l3 C nmr chemical shifts of the 3 and 5 carbons of the pyrazole rings. Briefly, for the aryl sub ⁇ tituent, the C3 carbon of the 3-aryl isomer has greater hydrazone character and appears at about 143 ppm, whereas the C5 carbon of the 5-aryl isomer has greater ene- hydrazine character and appears upfield at about 133 ppm.
  • Example 4 Preparation of 3 (5) -aryl-5 (3) - difluorochloromethyl-pyrazole; decomposition of the same while alkylating under basic conditions and succe ⁇ ful alkylation of the same under acidic conditions.
  • the aryl-pyrazole of Formula Hie was alkylated under basic conditions (K 2 C0 3 , Mel) .
  • the basic alkylation resulted in decomposition without any alkylated pyrazole products being formed.
  • the incompatibility of the CF 2 C1 group with base was confirmed by treatment of the intermediate (Formula Hie) with carbonate in the absence of an alkylating agent. In this case, decomposition occurred in less than one hour at room temperature.

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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)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des procédés de préparation de 3-aryle-5-haloalkyle-pyrazoles substitués, et spécifiquement de préparation d'esters alcoyliques C1-5 d'acides 5-[1-(alkyle C1-5)-4-halo-5-(haloalkyle C1-3)-1H-pyrazole-3-yl]-2,4-dihalo-benzoïques tels que isopropyl 5-[4-bromo-1-méthyl-5-(trifluorométhyl)-1H-pyrazole-3-yl]-2-chloro-4-fluorobenzoate. Les procédés décrits comprennent de nouvelles approches de formation de phényl-dicétones, de formation et d'alkylation de pyrazoles, de bromation de composés hétérocycliques, d'oxydation de composés benzéniques à substitution alkyle, et d'estérification d'acides carboxyliques. On peut combiner ces procédés afin de préparer des 3-aryle-5-haloalkyle pyrazoles ou alternativement les utiliser dans des sous-combinaisons ou individuellement pour préparer des intermédiaires ou d'autres composés utiles.
PCT/US1997/010525 1996-06-20 1997-06-16 Preparation de 3-aryle-5-haloalkyl-pyrazoles substitues a activite herbicide WO1997048668A2 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AU34919/97A AU720882B2 (en) 1996-06-20 1997-06-16 Preparation of substituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity
PL97330718A PL330718A1 (en) 1996-06-20 1997-06-16 Method of obtaining substituted 3-aryl-5-halogenoalkyl pyrazoles exhibiting herbicidal activity
EP97931231A EP0923520A2 (fr) 1996-06-20 1997-06-16 Preparation de 3-aryle-5-haloalkyl-pyrazoles substitues a activite herbicide
NZ333414A NZ333414A (en) 1996-06-20 1997-06-16 Preparation of substituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity
JP10503274A JP2000512656A (ja) 1996-06-20 1997-06-16 除草剤活性を有する置換された３―アリール―５―ハロアルキル―ピラゾールの製法
HU0104324A HUP0104324A3 (en) 1996-06-20 1997-06-16 Preparation of substituted 3-aryl-5-halogenalkyl-pyrazoles having herbicidal activity
BR9710711A BR9710711A (pt) 1996-06-20 1997-06-16 Prepara-Æo de 3-aril-5-haloalquil-pirazÄis substitu¡dos tendo atividade herbicida

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US08/667,256 US5880290A (en) 1994-01-31 1996-06-20 Preparation of substituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity
US08/667,135 1996-06-20
US08/667,103 1996-06-20
US08/667,103 US5698708A (en) 1996-06-20 1996-06-20 Preparation of substituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity
US08/667,135 US5869688A (en) 1994-07-20 1996-06-20 Preparation of substituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity
US08/667,256 1996-06-20

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5866723A (en) * 1991-09-25 1999-02-02 Monsanto Company Benzoyl derivatives and synthesis thereof
JP2003513076A (ja) * 1999-10-29 2003-04-08 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド 置換ピラゾールの合成方法

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Publication number Priority date Publication date Assignee Title
DK2999694T3 (en) * 2013-05-22 2017-06-19 Bayer Cropscience Ag PROCEDURE FOR PREPARING 3,5-BIS (FLUORAL COOL) PYRAZOLD DERIVATIVES FROM ALFA, ALFA DIHALOGENAMINES
CN114874144B (zh) * 2022-03-28 2024-07-05 曲靖师范学院 一种制备4-溴代n-芳基吡唑类化合物的工艺

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2578654A (en) * 1950-01-28 1951-12-18 Shell Dev Preparation of tertiary-alkyl-substituted benzene carboxylic acids
FR1504431A (fr) * 1965-11-09 1967-12-08 Inst Francais Du Petrole Procédé d'oxydation du paraxylène en deux étapes
US3426035A (en) * 1966-02-03 1969-02-04 Dow Chemical Co Halogenation of aromatic compounds
DE2922591A1 (de) * 1979-06-02 1980-12-04 Basf Ag Verfahren zur herstellung von pyrazolen
US4870109A (en) * 1985-05-20 1989-09-26 Eli Lilly And Company Control of ectoparasites
US5281571A (en) * 1990-10-18 1994-01-25 Monsanto Company Herbicidal benzoxazinone- and benzothiazinone-substituted pyrazoles
US5532416A (en) * 1994-07-20 1996-07-02 Monsanto Company Benzoyl derivatives and synthesis thereof
JPH072798A (ja) * 1993-06-17 1995-01-06 Sumika Fine Chem Kk ５−ハロゲノピリミジン誘導体の製造方法
US5587485A (en) * 1994-07-20 1996-12-24 Monsanto Company Heterocyclic- and carbocyclic- substituted benzoic acids and synthesis thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5866723A (en) * 1991-09-25 1999-02-02 Monsanto Company Benzoyl derivatives and synthesis thereof
JP2003513076A (ja) * 1999-10-29 2003-04-08 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド 置換ピラゾールの合成方法
JP4861585B2 (ja) * 1999-10-29 2012-01-25 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド 置換ピラゾールの合成方法

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HUP0104324A2 (hu) 2002-02-28
NZ333414A (en) 2000-05-26
AU3491997A (en) 1998-01-07
PL330718A1 (en) 1999-05-24
CA2258215A1 (fr) 1997-12-24
HUP0104324A3 (en) 2002-04-29
BR9710711A (pt) 1999-08-17
WO1997048668A3 (fr) 1998-04-02
CN1228075A (zh) 1999-09-08
EP0923520A2 (fr) 1999-06-23
JP2000512656A (ja) 2000-09-26

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