Herbicidal compound

Abstract

The present invention relates to a compound having the formula (I): or an agronomically acceptable salt thereof, wherein Q, R 2 , R 3 , R 4 and R 5 are as described herein. The present invention further relates to a composition comprising the compound, a method of using the composition to control weeds, and the use of a compound having the formula (I) as a herbicide.

Description

[0001] The present invention relates to novel herbicidal compounds, methods for their preparation, herbicidal compositions comprising these novel compounds, and their use for controlling weeds, especially in useful plant crops, or for inhibiting plant growth.

[0002] N-(tetrazol-5-yl)- and N-(1,3,4-oxadiazol-2-yl)arylformamides are disclosed, for example, in WO2012 / 028579 and WO2012 / 126932. The present invention relates to novel arylformamides.

[0003] Accordingly, the present invention provides a compound of formula (I):

[0004]

[0005] or an agriculturally acceptable salt thereof,

[0006] wherein: -

[0007] Q is Q 1 or Q 2 ;

[0008]

[0009] R 1a is selected from the group consisting of C 1 -C 4 alkyl-, C 1 -C 4 haloalkyl-, C 1 -C 4 alkoxy-C 1 -C 4 alkyl- and C 1 -C 4 haloalkoxy-C 1 -C 4 alkyl-;

[0010] R 1b is selected from the group consisting of C 1 -C 4 alkyl-, C 1 -C 4 haloalkyl-, C 1 -C 4 alkoxy-C 1 -C 4 alkyl- and C 1 -C 4 haloalkoxy-C 1 -C 4 alkyl-;

[0011] R 2Selected from the group consisting of: halogen, C 1 -C 6 -alkyl-, C 1 -C 3 -alkoxy-, C 1 -C 6 -haloalkyl-, C 1 -C 3 -haloalkoxy- and -S(O) p C 1 -C 6 -alkyl;

[0012] R 3 is C 1 -C 6 -haloalkyl or C 1 -C 6 -alkyl;

[0013] R 4 is selected from the group consisting of: C 1 -C 6 -alkyl-, C 1 -C 6 -haloalkyl-, C 1 -C 6 -alkyl-C(O)-, C 1 -C 6 -haloalkyl-C(O)-, C 3 -C 6 -cycloalkyl-, C 3 -C 6 -cycloalkyl-C 1 -C 3 -alkyl-, C 3 -C 6 -cycloalkyl-C(O)-, C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl-C(O)-, -C(O)-phenyl and -C(O)-heteroaryl, wherein phenyl, heteroaryl or C 3 -C 6 -cycloalkyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, C 1 -C 6 -alkyl (such as methyl), C 1 -C 6 -haloalkyl and C 1 -C 6 -alkoxy;

[0014] R5 selected from the group consisting of: hydrogen, C 1 -C 6 -alkyl-, C 1 -C 6 -haloalkyl and C 1 -C 6 -cycloalkyl; or

[0015] R 4 and R 5 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocycle optionally substituted with an oxo group; and

[0016] p is 0, 1 or 2.

[0017] C 1 -C 6 -alkyl and C 1 -C 4 -alkyl includes, for example, methyl (Me, CH 3 ), ethyl (Et, C 2 H 5 ), n-propyl (n-Pr), isopropyl (i-Pr), n-butyl (n-Bu), i-butyl (i-Bu), sec-butyl and tert-butyl (t-Bu).

[0018] C 3 -C 6 -cycloalkyl- includes cyclopropyl (c-propyl (c-Pr)), cyclobutyl (c-butyl (c-Bu)), cyclopentyl (c-pentyl) and cyclohexyl (c-hexyl).

[0019] Halogen (or halo) encompasses fluorine, chlorine, bromine or iodine. The above correspondingly applies to halogen in the context of other definitions, such as haloalkyl.

[0020] C 1 -C 6 -haloalkyl includes, for example, fluoromethyl-, difluoromethyl-, trifluoromethyl-, chloromethyl-, dichloromethyl-, trichloromethyl-, 2,2,2-trifluoroethyl-, 2,2-difluoroethyl, 1,1-difluoroethyl, 1,1,2,2-tetrafluoroethyl, 2-fluoroethyl-, 2-chloroethyl-, pentafluoroethyl-, 1,1-difluoro-2,2,2-trichloroethyl-, 2,2,3,3-tetrafluoroethyl-, 2,2,2-trichloroethyl-, heptafluoro-n-propyl and perfluoro-n-hexyl. C 1 -C 4Halogenoalkyl includes, for example, fluoromethyl-, difluoromethyl-, trifluoromethyl-, chloromethyl-, dichloromethyl-, trichloromethyl-, 2,2,2-trifluoroethyl-, 2-fluoroethyl-, 2-chloroethyl-, pentafluoroethyl-, 1,1-difluoro-2,2,2-trichloroethyl-, 2,2,3,3-tetrafluoroethyl-, 2,2,2-trichloroethyl- and heptafluoropropyl-.

[0021] C 1 -C 6 Alkyl-S-(alkylthio) is, for example, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio, preferably methylthio or ethylthio.

[0022] C 1 -C 6 Alkyl-S(O)-(alkylsulfinyl) is, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl or tert-butylsulfinyl, preferably methylsulfinyl or ethylsulfinyl.

[0023] C 1 -C 6 Alkyl-S(O) 2 -(alkylsulfonyl) is, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl or tert-butylsulfonyl, preferably methylsulfonyl or ethylsulfonyl.

[0024] In a preferred embodiment of the present invention, R 1a and R 1b are selected from the group consisting of methyl, ethyl and n-propyl.

[0025] In another embodiment of the present invention, Q is Q 1 . Thus, in this embodiment, the compound having formula (I) is a compound having formula (Ia):

[0026]

[0027] wherein R 1a , R 2 , R 3 , R 4 and R 5 are as defined for the compound having formula (I).

[0028] In another embodiment of the present invention, Q is Q 2 . Thus, in this specific embodiment of the present invention, a compound having formula (Ib) is provided

[0029]

[0030] wherein R 1b 、R 2 、R 3 、R 4 and R 5 are as defined for the compounds of formula (I).

[0031] In a preferred embodiment of the present invention, R 2 is selected from the group consisting of: methyl, Cl, -CF 3 and -SO 2 methyl, more preferably Cl.

[0032] In another preferred embodiment of the present invention, R 3 is selected from the group consisting of: -CH 3 、-CF 3 、-CHF 2 and -CF 2 CF 2 H, more preferably -CF 3 or -CHF 2 .

[0033] In an embodiment of the present invention, R 4 is -C(O)-heteroaryl, wherein the heteroaryl is optionally substituted as previously described and is selected from the group consisting of R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f 、R 4g and R 4h :

[0034]

[0035] In a preferred embodiment of the present invention, the heteroaryl is R 4c , which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of: halogen, C 1 -C 6 alkyl (such as methyl), C 1 -C 6 haloalkyl and C 1 -C 6 alkoxy. In an even more preferred embodiment of the present invention, the heteroaryl is R 4c , which is optionally substituted with one halogen, preferably fluorine.

[0036] In another embodiment of the present invention, R 4 is selected from the group consisting of: C 1 -C6 alkyl-(preferably methyl), C 1 -C 6 alkyl-C(O)-(preferably CH 3 CH 2 C(O)-) and C 3 -C 6 cycloalkyl-C(O)-(preferably cPr-C(O)-).

[0037] In another embodiment of the present invention, R 5 is hydrogen or C 1 -C 6 alkyl-(preferably methyl), most preferably hydrogen.

[0038] In one embodiment of the present invention, R 4 is methyl or CH 3 CH 2 C(O)-, and R 5 is hydrogen. In another embodiment of the present invention, R 4 is -C(O)-heteroaryl, wherein the heteroaryl is optionally substituted with one halogen, preferably fluorine, of R 4c , and R 5 is hydrogen.

[0039] In another embodiment of the present invention, R 4 and R 5 together form a 5- or 6-membered saturated heterocycle optionally substituted with an oxo group selected from the group consisting of: -C(O)-CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 OCH 2 CH 2 -, -C(O)CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 -, preferably -C(O)-CH 2 CH 2 CH 2 CH 2 -.

[0040] Compounds having formula (I) (and certain intermediate compounds for the synthesis of compounds having formula (I)) may contain asymmetric centers and may exist as a single enantiomer, as an enantiomeric pair in any ratio, or where there is more than one asymmetric center, contain diastereoisomers in all possible ratios. Typically, one of these enantiomers has enhanced biological activity compared to the other possibilities.

[0041] The invention also includes all possible geometric and tautomeric forms of the compounds having formula (I).

[0042] The invention also includes agriculturally acceptable salts, which the compounds having formula (I) can form with amines (such as ammonia, dimethylamine and triethylamine), alkali metal and alkaline earth metal bases or quaternary ammonium bases. Among the alkali metal and alkaline earth metal hydroxides, oxides, alcoholates, and bicarbonates and carbonates used as salt-forming agents, emphasis is placed on the hydroxides, alcoholates, oxides, and carbonates of lithium, sodium, potassium, magnesium, and calcium, but especially those of sodium, magnesium, and calcium. The corresponding trimethylsulfonium salts can also be used.

[0043] Compounds having formula (I) according to the invention can be used as herbicides per se, but are usually formulated into herbicidal compositions using formulation aids such as carriers, solvents, and surfactants (SFA). Accordingly, the invention further provides a herbicidal composition comprising the herbicidal compound of the invention and an agriculturally acceptable formulation aid. The composition can be in the form of a concentrate, which is diluted before use, although ready-to-use compositions can also be made. The final dilution is usually carried out with water, but water can be replaced or used in addition to water, for example, with liquid fertilizers, micronutrients, biological organisms, oils, or solvents.

[0044] The herbicidal composition generally comprises from 0.1% to 99% by weight, especially from 0.1% to 95% by weight, of the compound having formula I and from 1% to 99.9% by weight of the formulation aid, which preferably includes from 0 to 25% by weight of a surface-active substance.

[0045] These compositions can be selected from a variety of formulation types, many of which are known from the Manual on Development and Use of FAO Specifications for Plant Protection Products, 5th Edition, 1999. These include dustable powders (DP), soluble powders (SP), water-soluble granules (SG), water-dispersible granules (WG), wettable powders (WP), granules (GR) (slow or fast release), soluble concentrates (SL), oil miscible liquids (OL), ultra-low volume liquids (UL), emulsifiable concentrates (EC), dispersible concentrates (DC), emulsions (both water-in-oil (EW) and oil-in-water (EO)), microemulsions (ME), suspension concentrates (SC), aerosols, capsule suspensions (CS) and seed treatment formulations. In any case, the formulation type selected will depend on the specific purpose envisaged and on the physical, chemical and biological properties of the compound of formula (I).

[0046] Dustable powders (DP) can be prepared by mixing a compound of formula (I) with one or more solid diluents (e.g., natural clays, kaolin, pyrophyllite, bentonite, alumina, montmorillonite, kieselguhr, chalk, diatomaceous earth, calcium phosphate, calcium carbonate and magnesium carbonate, sulfur, lime, flour, talc and other organic and inorganic solid carriers) and mechanically grinding the mixture into a fine powder.

[0047] Soluble powders (SP) can be prepared by mixing a compound of formula (I) with one or more water-soluble inorganic salts (such as sodium bicarbonate, sodium carbonate or magnesium sulfate) or one or more water-soluble organic solids (such as polysaccharides) and optionally one or more wetting agents, one or more dispersing agents or a mixture of said agents to improve water dispersibility / water solubility. The mixture is then ground into a fine powder. Similar compositions can also be granulated to form water-soluble granules (SG).

[0048] Wettable powders (WP) can be prepared by mixing a compound of formula (I) with one or more solid diluents or carriers, one or more wetting agents and preferably one or more dispersing agents, and optionally one or more suspending agents to facilitate dispersion in a liquid. The mixture is then ground into a fine powder. Similar compositions can also be granulated to form water-dispersible granules (WG).

[0049] The granule (GR) can be formed in the following ways: by granulating a mixture of the compound of formula (I) with one or more powdery solid diluents or carriers, or by absorbing the compound of formula (I) (or its solution in a suitable reagent) into a porous granular material (such as pumice, attapulgite clay, bleaching earth, kieselguhr, diatomaceous earths or corn cob powder), or by adsorbing the compound of formula (I) (or its solution in a suitable reagent) onto a hard core material (such as sand, silicate, mineral carbonate, sulfate or phosphate) and, if necessary, drying to form from preformed blank granules. Reagents commonly used to assist absorption or adsorption include solvents (such as aliphatic and aromatic petroleum solvents, alcohols, ethers, ketones and esters) and adhesives (such as polyvinyl acetate, polyvinyl alcohol, dextrin, sugar and vegetable oils). One or more other additives can also be included in the granule (such as emulsifiers, wetting agents or dispersants).

[0050] The dispersible concentrate (DC) can be prepared by dissolving the compound of formula (I) in water or an organic solvent (such as a ketone, alcohol or glycol ether). These solutions can contain surfactants (for example to improve water dilution or prevent crystallization in the spray tank).

[0051] The emulsifiable concentrate (EC) or oil-in-water emulsion (EW) can be prepared by dissolving the compound of formula (I) in an organic solvent (optionally containing one or more wetting agents, one or more emulsifiers or a mixture of said reagents). Suitable organic solvents used in the EC include aromatic hydrocarbons (such as alkylbenzenes or alkylnaphthalenes, for example SOLVESSO 100, SOLVESSO 150 and SOLVESSO 200; SOLVESSO is a registered trademark), ketones (such as cyclohexanone or methylcyclohexanone) and alcohols (such as benzyl alcohol, furfuryl alcohol or butanol), N-alkylpyrrolidones (such as N-methylpyrrolidone or N-octylpyrrolidone), dimethylamides of fatty acids (such as C 8 -C 10 dimethylamide of fatty acid) and chlorinated hydrocarbons. The EC product can spontaneously emulsify when added to water, thus producing an emulsion with sufficient stability to allow spraying application through appropriate equipment.

[0052] The preparation of the EW involves obtaining a compound of formula (I) as a liquid (if it is not liquid at room temperature, it can be melted at a reasonable temperature typically below 70 °C) or in solution (by dissolving it in a suitable solvent), and then emulsifying the resulting liquid or solution under high shear into water containing one or more SFAs to produce an emulsion. Suitable solvents for use in the EW include vegetable oils, chlorinated hydrocarbons (such as chlorobenzene), aromatic solvents (such as alkylbenzenes or alkylnaphthalenes), and other suitable organic solvents with low solubility in water.

[0053] Microemulsions (MEs) can be prepared by mixing water with a blend of one or more solvents and one or more SFAs to spontaneously produce a thermodynamically stable isotropic liquid formulation. The compound of formula (I) is initially present in the water or in the solvent / SFA blend. Suitable solvents for use in the ME include those described above for use in the EC or EW. The ME can be an oil-in-water system or a water-in-oil system (which system is present can be determined by conductivity measurements) and can be suitable for mixing water-soluble pesticides and oil-soluble pesticides in the same formulation. The ME is suitable for dilution into water, remaining as a microemulsion or forming a conventional oil-in-water emulsion.

[0054] Suspension concentrates (SCs) can comprise an aqueous or non-aqueous suspension of finely divided insoluble solid particles of a compound of formula (I). The SC can be prepared by ball milling or bead milling a solid compound of formula (I) optionally with one or more dispersants in a suitable medium to produce a fine particle suspension of the compound. One or more wetting agents can be included in the composition, and a suspending agent can be included to reduce the rate of particle sedimentation. Alternatively, the compound of formula (I) can be dry milled and added to water containing the reagents described above to produce the desired final product.

[0055] Aerosol formulations contain a compound of formula (I) and a suitable propellant (such as n-butane). The compound of formula (I) can also be dissolved or dispersed in a suitable medium (such as water or a water-miscible liquid, such as n-propanol) to provide a composition for use in a non-pressurized hand spray pump.

[0056] A capsule suspension (CS) can be prepared in a manner similar to that for preparing an EW formulation, but with an additional polymerization stage such that an aqueous dispersion of oil droplets is obtained, wherein each oil droplet is encapsulated by a polymer shell and contains a compound of formula (I) and optionally a carrier or diluent for the oil droplet. The polymer shell can be produced by an interfacial polycondensation reaction or by a coacervation procedure. These compositions can provide a controlled release of the compound of formula (I) and they can be used for seed treatment. The compound of formula (I) can also be formulated in a biodegradable polymer matrix to provide a slow, controlled release of the compound.

[0057] The compositions can include one or more additives to improve the biological properties of the composition, for example by improving wettability, retention or distribution on the surface; rainfastness on the treated surface; or absorption or flow of the compound of formula (I). Such additives include surfactants (SFA), oil-based spray additives such as certain mineral oils or natural vegetable oils (such as soybean and rapeseed oils), and blends of these with other bioenhancing adjuvants (ingredients that can assist or modify the action of the compound of formula (I)).

[0058] Wetting agents, dispersants and emulsifiers can be cationic, anionic, amphoteric or non-ionic types of SFA.

[0059] Suitable cationic types of SFA include quaternary ammonium compounds (such as cetyltrimethylammonium bromide), imidazolines and amine salts.

[0060] Suitable anionic SFA include alkali metal salts of fatty acids, salts of aliphatic sulfuric acid monoesters (such as sodium lauryl sulfate), salts of sulfonated aromatic compounds (such as sodium dodecylbenzenesulfonate, calcium dodecylbenzenesulfonate, butylnaphthalenesulfonate and mixtures of di-isopropyl-naphthalenesulfonate and tri-isopropyl-naphthalenesulfonate), ether sulfates, alcohol ether sulfates (such as sodium laureth-3-sulfate), ether carboxylates (such as sodium laureth-3-carboxylate), phosphate esters (products from the reaction between one or more fatty alcohols and phosphoric acid (mainly monoesters) or with phosphorus pentoxide (mainly diesters), such as the reaction between lauryl alcohol and tetraphosphoric acid; additionally these products can be ethoxylated), sulfosuccinamates, paraffin or olefin sulfonates, taurates and lignosulfonates.

[0061] Suitable amphoteric types of SFA include betaines, propionates and glycine salts.

[0062] Suitable nonionic types of SFAs include condensation products of alkylene oxides (such as ethylene oxide, propylene oxide, butylene oxide or mixtures thereof) with fatty alcohols (such as oleyl alcohol or cetyl alcohol) or with alkylphenols (such as octylphenol, nonylphenol or octylcresol); partial esters derived from long-chain fatty acids or hexitol anhydrides; condensation products of said partial esters with ethylene oxide; block polymers (comprising ethylene oxide and propylene oxide); alkanolamides; mono-esters (such as polyethylene glycol fatty acid esters); amine oxides (such as lauryl dimethylamine oxide); and lecithin.

[0063] Suitable suspending agents include hydrophilic colloids (such as polysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose) and swelling clays (such as bentonite or attapulgite).

[0064] These herbicidal compounds of the present invention can also be used in a mixture with one or more additional herbicides and / or plant growth regulators. Examples of such additional herbicides or plant growth regulators include acetochlor, acifluorfen (including acifluorfen-sodium), acibenzolar-S-methyl, ametryn, amicarbazone, aminopyralid, aminotriazole, atrazine, butafenacil-M, bensulfuron-methyl (including bensulfuron-methyl-methyl), bentazone, bicyclopyrone, bilanafos, bispyribac-sodium, bixlozone, bromacil, bromoxynil, butachlor, carfentrazone-ethyl, carfentrazone (including carfentrazone-ethyl), chlorimuron-ethyl (including chlorimuron-ethyl-ethyl), chlorotoluron, chlorsulfuron, cinmethylin, clacyfos, clethodim, clodinafop-propargyl (including clodinafop-propargyl), clomazone, clopyralid, cyclopyranil, cyclopyrimorate, cyclosulfamuron, cyhalofop-butyl (including cyhalofop-butyl-butyl), 2,4-D (including its choline salt and 2-ethylhexyl ester), 2,4-DB, desmedipham, dicamba (including its aluminum, aminopropyl, bis-aminopropylmethyl, choline, dichloropropyl, diglycolamine, dimethylamine, dimethylammonium, potassium salt and sodium salt), diclosulam, diflufenican, diflufenzopyr, dimethachlor, dimethenamid-P, diquat dibromide, diuron, epyrifenacil, ethalfluralin, ethofumesate, fenoxaprop-P-ethyl (including fenoxaprop-P-ethyl), fenoxasulfone, fenquinotrione, flufenacet, flazasulfuron, florpyrauxifen (including florpyrauxifen-benzyl), fluazifop-P-butyl (including fluazifop-P-butyl), flucarbazone-sodium (including flucarbazone-sodium), flufenacet, flumetsulam, flumioxazin, flupropacil, fluridone, fluroxypyr (including fluroxypyr-meptyl), fomesafen, foramsulfuron, glufosinate (including its ammonium salt), glyphosate (including its diamine, isopropylammonium and potassium salts), halauxifen (including halauxifen-methyl), haloxyfop-methyl (including haloxyfop-methyl), hexazinone, hydantocidin, imazamox, imazapic, imazapyr, imazethapyr, indaziflam, iodosulfuron-methyl-sodium (including iodosulfuron-methyl-sodium), iofensulfuron (including iofensulfuron-sodium), ioxynil, isoproturon, isoxazolidinone, lancotrione, MCPA, MCPB, mecoprop-P, mesosulfuron-methyl (including mesosulfuron-methyl-methyl), mesotrione, metamitron,Pyrimethanil, methiozolin, metolachlor, metosulam, metamitron, metsulfuron-methyl, napropamide, nicosulfuron, norflurazon, oxadiazon, oxyfluorfen, paraquat dichloride, pendimethalin, penoxsulam, phenmedipham, picloram, pinoxaden, pretilachlor, prosulfuron-methyl, prometryn, propanil, pyraclofos, propyrisulfuron, propyzamide, prosulfocarb, prosulfuron, pyraoxystrobin, pyraflufen (including pyraflufen-ethyl), pyrazosulfuron-ethyl, pyridate, pyribambenz-propyl, pyrimisulfan, pyroxasulfone, pyribenzoxim, quinclorac, quinmerac, quizalofop (including quizalofop-P-ethyl and quizalofop-P-tefuryl), rimsulfuron, pyribenzoxim, sethoxydim, simazine, S-metolachlor, mesotrione, sulfosulfuron, thidiazuron, tefuryltrione, mesotrione, terbuthylazine, terbutryn, tetflupyrolimet, thiencarbazone, thifensulfuron-methyl, tiafenacil, tolpyralate, pyrazolynate, tralkoxydim, triafamone, triallate, tribenuron-methyl (including tribenuron-methyl), triclopyr, trifloxysulfuron (including trifloxysulfuron-sodium), trifludimoxazin, trifluralin, triflusulfuron-methyl, ethyl 3-(2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydro-2H-pyrimidin-1-yl)phenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate, 4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one, 4-hydroxy-1,5-dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one, 5-ethoxy-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one, 4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one, 4-hydroxy-1,5-dimethyl-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]imidazolidin-2-one, (4R)-1-(5-tert-butylisoxazol-3-yl)-4-ethoxy-5-hydroxy-3-methylimidazolidin-2-one, 3-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxopyridazine-4-carbonyl]bicyclo[3.2.1]octane-2,4-dione, 2-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxopyridazine-4-carbonyl]-5-methylcyclohexane-1,3-dione2-[2-(3,4-Dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]cyclohexane-1,3-dione, 2-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]-5,5-dimethyl-cyclohexane-1,3-dione, 6-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]-2,2,4,4-tetramethyl-cyclohexane-1,3,5-trione, 2-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]-5-ethyl-cyclohexane-1,3-dione, 2-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]-4,4,6,6-tetramethyl-cyclohexane-1,3-dione, 2-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]-5-methyl-cyclohexane-1,3-dione, 3-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]bicyclo[3.2.1]octane-2,4-dione, 2-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]-5,5-dimethyl-cyclohexane-1,3-dione, 6-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]-2,2,4,4-tetramethyl-cyclohexane-1,3,5-trione, 2-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]cyclohexane-1,3-dione, 4-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]-2,2,6,6-tetramethyl-tetrahydropyran-3,5-dione, 4-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]-2,2,6,6-tetramethyl-tetrahydropyran-3,5-dione, 4-amino-3-chloro-5-fluoro-6-(7-fluoro-1H-indol-6-yl)pyridine-2-carboxylic acid (including its agrochemically acceptable esters, e.g., methyl 4-amino-3-chloro-5-fluoro-6-(7-fluoro-1H-indol-6-yl)pyridine-2-carboxylate), 3-ethylthio-N-(1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide, 3-(isopropylthiomethyl)-N-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide, 3-(isopropylsulfonylmethyl)-N-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide,3-(Ethylsulfonylmethyl)-N-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide and ethyl 2-[[3-[[3-chloro-5-fluoro-6-[3-methyl-2,6-dioxo-4-(trifluoromethyl)pyrimidin-1-yl]-2-pyridinyl]oxy]acetate.,

[0065] The mixed formulations of the compounds of formula I can also be in the form of esters or salts, as mentioned, for example, in The Pesticide Manual, 16th Edition, British Crop Protection Council, 2012.

[0066] The compounds of formula I can also be used in mixtures with other agrochemicals, such as fungicides, nematicides or insecticides, examples of which are given in the Pesticide Manual.

[0067] The mixing ratio of the compounds of formula I with the mixed formulation is preferably from 1:100 to 1000:1.

[0068] These mixtures can advantageously be used in the above-mentioned formulations (in which case the "active ingredient" refers to the corresponding mixture of the compound of formula I and the mixed formulation).

[0069] The compounds or mixtures of the present invention can also be used in combination with one or more herbicide safeners. Examples of such safeners include cloquintocet-mexyl, cloquintocet (including cloquintocet-mexyl), cyprosulfamide, dichlormid, oxabetrinil (including oxabetrinil-ethyl), mefenpyr-diethyl, flurazole, benoxacor, isoxadifen-ethyl (including isoxadifen-ethyl), mefenpyr (including mefenpyr-diethyl), metcamifen and dichlobenil. Particularly preferred are mixtures of the compounds of formula I with cyprosulfamide, isoxadifen-ethyl, cloquintocet-mexyl and / or metcamifen.

[0070] The safeners of the compounds of formula I can also be in the form of esters or salts, as mentioned, for example, in the Pesticide Manual, 16th Edition (BCPC), 2012. The mention of cloquintocet-mexyl also applies to its lithium, sodium, potassium, calcium, magnesium, aluminium, iron, ammonium, quaternary ammonium, sulfonium or phosphonium salts (as disclosed in WO 02 / 34048), and the mention of oxabetrinil-ethyl also applies to oxabetrinil, etc.

[0071] Preferably, the mixing ratio of the compounds of formula I with the safener is from 100:1 to 1:10, especially from 20:1 to 1:1.

[0072] These mixtures can advantageously be used in the above-mentioned formulations (in which case the "active ingredient" refers to the corresponding mixture of the compound of formula I with the safener).

[0073] The present invention further provides a method for controlling weeds at a locus, which method comprises applying to the locus a composition comprising a compound of formula (I) in an amount effective to control weeds. Furthermore, the present invention further provides a method for selectively controlling weeds at a locus comprising crop plants and weeds, wherein the method comprises applying to the locus a composition according to the invention in an amount effective to control weeds. 'Control' means killing, reducing or delaying growth or preventing or reducing germination. Generally, the plants to be controlled are unwanted plants (weeds). 'Locus' means an area in which plants are growing or will grow. Some crop plants may inherently tolerate the herbicidal action of the compound of formula (I). However, in some cases, it may be necessary to engineer tolerance into the crop plants, for example by genetic engineering. Thus, it is possible for crop plants to be genetically engineered to be tolerant to HPPD-inhibitors. Methods for conferring tolerance to HPPD-inhibitors on crop plants are known, for example, from WO0246387. Thus, in an even more preferred embodiment, the crop plant is transgenic with respect to a polynucleotide comprising a DNA sequence encoding an HPPD enzyme resistant to an HPPD inhibitor, the HPPD enzyme resistant to the HPPD inhibitor being derived from bacteria (more specifically, derived from Pseudomonas fluorescens or Shewanella colwelliana), or derived from plants (more specifically, derived from monocotyledonous plants or even more specifically, derived from species of Hordeum, Zea, Triticum, Oryza, Brachiaria, Cenchrus, Lolium, Festuca, Setaria, Eleusine, Sorghum or Avena). Several HPPD-tolerant soybean transgenic "events" are known and include, for example, SYHT04R (WO2012 / 082542), SYHT0H2 (WO2012 / 082548) and FG72. Other polynucleotide sequences that can be used to provide plants tolerant to the compounds of the present invention are disclosed, for example, in WO2010 / 085705 and WO2011 / 068567. Crop plants in which the compositions according to the invention can be used thus include crops such as cereals, for example barley and wheat, cotton, rape, sunflower, maize, rice, soybean, sugar beet, sugar cane and turf.

[0074] Crop plants can also include trees, such as fruit trees, palm trees, coconut trees or other nut trees. Also included are vines (such as grapes), bush fruit trees, fruit plants and vegetables.

[0075] The application rate of the compounds of formula I can vary within a wide range and depends on the nature of the soil, the application method (pre-emergence or post-emergence; seed dressing; application to the seed furrow; no-till application, etc.), the crop plant, the one or more weeds to be controlled, the prevailing climatic conditions, and other factors governed by the application method, the time of application and the target crop. The compounds of formula I according to the invention are generally applied at a rate of from 10 g / ha to 2000 g / ha, in particular from 50 g / ha to 1000 g / ha.

[0076] Application is generally carried out by spraying the composition, typically by means of a tractor-mounted sprayer for large areas, but other methods such as dusting (for powders), dripping or irrigation can also be used.

[0077] Crop plants are to be understood as also including those crop plants which have been rendered tolerant to herbicides or to classes of herbicides (such as ALS-inhibitors, GS-inhibitors, EPSPS-inhibitors, PPO-inhibitors, ACC enzyme-inhibitors and HPPD-inhibitors) by conventional breeding methods or by genetic engineering. Examples of crop plants which have been rendered tolerant to imidazolinones (such as imazamox), by conventional breeding methods are summer rape (canola). Examples of crop plants which have been rendered tolerant to herbicides by genetic engineering methods include, for example, maize varieties having glyphosate and glufosinate resistance, which are commercially available under the and trademarks.

[0078] Crop plants are also to be understood as including those which have been rendered resistant to harmful insects by genetic engineering methods, such as Bt maize (resistant to the European corn borer), Bt cotton (resistant to the cotton boll weevil) and also Bt potato (resistant to the Colorado beetle). Examples of Bt maize are The Bt 176 maize hybrid (Syngenta Seeds). The Bt toxin is a protein naturally formed by the soil bacterium Bacillus thuringiensis. Examples of toxins or transgenic plants capable of synthesizing such toxins are described in EP-A-451 878, EP-A-374 753, WO 93 / 07278, WO 95 / 34656, WO 03 / 052073 and EP-A-427 529. Examples of transgenic plants containing one or more genes encoding insecticidal resistance and expressing one or more toxins are (maize), Yield (maize), (cotton), (cotton), (potato), and Plant crops or their seed materials can be herbicide-resistant and at the same time insect-feeding resistant ("stacked" transgenic events). For example, the seeds can have the ability to express the insecticidal Cry3 protein while being tolerant to glyphosate.

[0079] Crop plants should also be understood to include those obtained by conventional breeding or genetic engineering methods and containing so-called output traits (such as improved storage stability, higher nutritional value, and improved flavor).

[0080] Other useful plants include, for example, turfgrasses on golf courses, lawns, parks, and roadsides or commercially grown for turf, as well as ornamental plants such as flowers or shrubs.

[0081] These compositions can be used to control unwanted plants (collectively referred to as 'weeds'). The weeds to be controlled can be either monocotyledonous species such as Agrostis, Alopecurus, Avena, Brachiaria, Bromus, Cenchrus, Cyperus, Digitaria, Echinochloa, Eleusine, Lolium, Monochoria, Rottboellia, Sagittaria, Scirpus, Setaria, and Sorghum, or dicotyledonous species such as Abutilon, Amaranthus, Ambrosia, Chenopodium, Chrysanthemum, Conyza, Galium, Ipomoea, Nasturtium, Sida, Sinapis, Solanum, Stellaria, Veronica, Viola, and Xanthium. The weeds can also include plants that can be considered crop plants but grow outside the crop area ('escapes'), or plants that grow from seeds left from a previously cultivated different crop ('volunteers'). Such volunteer or escape plants can be resistant to certain other herbicides.

[0082] The compounds of the present invention can be prepared according to the following scheme.

[0083] The compound having formula (I) can be prepared from the compound having formula (II).

[0084]

[0085] The compound having formula (II) is treated with an amine having formula (III) (for embodiments of the present invention where Q = Q1) or an amine having formula (IV) (for embodiments of the present invention where Q = Q2), N-formyl saccharin, and triethylamine, using N-methylpyrrolidone as a solvent, and treated with a palladium(II) acetate catalyst and a xanthene ligand. The reaction can be carried out using a continuous flow reactor.

[0086] Alternatively, the compound having formula (I) can be prepared from benzoic acid having formula (V).

[0087]

[0088] In a suitable solvent (such as pyridine), benzoic acid of formula (V) and an amine of formula (III) (for embodiments of the present invention where Q = Q1) or an amine of formula (IV) (for embodiments of the present invention where Q = Q2) are treated with an amide coupling reagent (such as thionyl chloride and N-methylimidazole).

[0089] The compound of formula (V) can be prepared by hydrolysis of an ester of formula (VI).

[0090]

[0091] In a suitable solvent (such as a 3:1 mixture of ethanol:water), the ester of formula (VI) is treated with sodium hydroxide to obtain the compound of formula (V).

[0092] In the case where R 2 is not chlorine, the compound of formula (VI) can be prepared from a compound of formula (VI) where R 2 is chlorine.

[0093]

[0094] The method of conversion will depend on the nature of R 2 . Those skilled in the art will be familiar with the methods of converting a chlorine group to an R 2 group. For example, in the case where R 2 is methyl, a Suzuki reaction is carried out, where a compound with R 2 = Cl is treated with trimethylcycloboroxane and a base (such as potassium carbonate) using a suitable catalyst (such as [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride).

[0095] where R 2 = Cl of formula (VI) can be prepared from a compound of formula (II) where R 2 = Cl.

[0096]

[0097] The compound of formula (II) is reacted with a base (such as triethylamine) and a palladium catalyst (such as [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride) in a mixed solvent of methanol and acetonitrile in an autoclave with a carbon monoxide atmosphere.

[0098] In the case where R 5 is not hydrogen, where R2 Compounds of formula (II) where = Cl can be prepared from compounds of formula (VII) and compounds of formula (VII).

[0099]

[0100] In a suitable solvent, a compound of formula (VII) is treated with a compound of formula (VIII) where LG is defined as a leaving group. This reaction may optionally require a base. The requirements and selection of the base will be familiar to the person skilled in the art. For example, when R 5 is an acetyl group, the compound of formula (VIII) is acetyl chloride. For example, when R 5 is a methyl group, the compound of formula (VIII) is methyl iodide and the base is sodium hydride.

[0101] Compounds of formula (VII) can be prepared from compounds of formula (IX) and compounds of formula (X).

[0102]

[0103] In a suitable solvent, a compound of formula (IX) is treated with a compound of formula (X) where LG is defined as a leaving group. This reaction may optionally require a base. The requirements and selection of the base will be familiar to the person skilled in the art. For example, when R4 is an acetyl group, the compound of formula (X) is acetyl chloride. For example, when R 5 is a methyl group, the compound of formula (X) is methyl iodide and the base is sodium hydride.

[0104] Compounds of formula (IX) can be prepared from compounds of formula (XI).

[0105]

[0106] Using toluene as a solvent, a compound of formula (XI) is treated with dichlorodimethylhydantoin and a catalytic amount of isopropylammonium chloride to obtain a compound of formula (IX).

[0107] Compounds of formula (XI) can be commercially available. Alternatively, they can be prepared from 2-amino-4-bromophenol.

[0108]

[0109] The method of transformation will depend on the nature of R 3 For example, when R 3 is -CH 2 CF 3In the case of, 2-amino-4-bromophenol is treated with potassium carbonate and 2,2,2-trifluoroethyl trifluoromethanesulfonate. For example, when R 3 is -CF 2 H, 2-amino-4-bromophenol is treated with sodium bromodifluoroacetate and a base (such as cesium carbonate).

[0110] Accordingly, the present invention further provides a compound having the formula (II)

[0111]

[0112] wherein R 2 , R 3 , R 4 and R 5 are as defined above in the compound having the formula (I). In a preferred embodiment, R 2 is Cl, and R 3 is -CF 3 or -CHF 2 .

[0113] The present invention further provides a compound having the formula (V)

[0114]

[0115] wherein R 2 , R 3 , R 4 and R 5 are as defined above in the compound having the formula (I). In a preferred embodiment, R 2 is Cl, and R 3 is -CF 3 or -CHF 2 .

[0116] The present invention also further provides a compound having the formula (VIa)

[0117]

[0118] wherein "Alk" is C 1 -C 6 alkyl (preferably methyl), and wherein R 2 , R 3 , R 4 and R 5 are as defined above in the compound having the formula (I). In a preferred embodiment, R 2 is Cl, and R 3 is -CF 3 or -CHF 2 .

[0119] The following non-limiting examples provide specific synthetic methods for the representative compounds of the present invention (refer to Tables 1 and 2 provided herein).

[0120] Preparation Example 1: Compound 1.004

[0121] Step 1.

[0122] To a flask containing 5-bromo-2-(trifluoromethoxy)aniline (10 g, 39.1 mmol) was added toluene (100 mL) and diisopropylammonium chloride (1.08 g, 7.81 mmol). The reaction mixture was covered with foil to protect from light. At 0 °C, 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (7.70 g, 39.1 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was quenched by adding saturated aqueous sodium bisulfite solution, then diluted with water and ethyl acetate, and the phases were separated. The organic phase was dried and concentrated in vacuo. The crude material was purified by normal-phase flash chromatography (0 to 5% ethyl acetate in cyclohexane) to afford 3-bromo-2-chloro-6-(trifluoromethoxy)aniline as a pale yellow oil (7.07 g, 21.9 mmol, 56%). 1 1H NMR (methanol): 7.05 (m, 1H), 6.99 (d, 1H).

[0123] Step 2.

[0124] To a flask containing 3-bromo-2-chloro-6-(trifluoromethoxy)aniline (1.00 g, 3.40 mmol) was added acetonitrile (20 mL) and the reaction mixture was placed under a nitrogen atmosphere. 5-Bromovaleryl chloride (1.10 g, 0.79 mL, 5.90 mmol) was added. The reaction mixture was stirred at 50 °C for 6 hours. The reaction mixture was quenched by adding water and concentrated in vacuo to remove the acetonitrile solvent. The reaction residue was taken up in ethyl acetate and water and the phases were separated. The aqueous phase was further extracted with ethyl acetate. The organic phases were combined, dried and concentrated in vacuo. The crude material was purified by normal-phase flash chromatography (0 to 30% ethyl acetate in cyclohexane) to afford an impure product as a pale yellow solid. The crude material was taken up in ethyl acetate and washed with 2 M aqueous sodium hydroxide solution. The organic phase was dried and concentrated in vacuo to afford 5-bromo-N-[3-bromo-2-chloro-6-(trifluoromethoxy)phenyl]valeramide as a pale yellow solid (1.44 g, 2.92 mmol, 85%). 1 1H NMR (chloroform): 7.62 (d, 1H), 7.16 (m, 1H), 6.90 (br s, 1H), 3.45 (t, 2H), 2.47 (br s, 2H), 2.02 - 1.87 (m, 4H).

[0125] Step 3.

[0126] To a flask containing N-[3-bromo-2-chloro-6-(trifluoromethoxy)phenyl]acetamide (1.44 g, 2.92 mmol) was added tetrahydrofuran (14 mL). The reaction mixture was stirred at 0 °C for 10 min under a nitrogen atmosphere. Sodium hydride (60% by mass, 0.129 g, 3.21 mmol) in paraffin oil was added to the reaction mixture. The reaction mixture was stirred at room temperature for 4.5 h. Sodium hydride (60% by mass, 0.0818 g, 2.04 mmol) in paraffin oil was further added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by adding water and concentrated in vacuo to remove the tetrahydrofuran solvent. The residue was taken up in ethyl acetate and water, and the phases were separated. The aqueous phase was further extracted with ethyl acetate. The organic phases were combined, dried and concentrated in vacuo. The crude material was purified by normal-phase flash chromatography (0 to 25% ethyl acetate in cyclohexane) to give 1-[3-bromo-2-chloro-6-(trifluoromethoxy)phenyl]piperidin-2-one as a colorless oil (1.03 g, 2.43 mmol, 83%). 1 1H NMR (chloroform): 7.64 (d, 1H), 7.17 (dq, 1H), 3.64 - 3.50 (m, 1H), 3.49 - 3.38 (m, 1H), 2.58 (dt, 2H), 2.07 - 1.88 (m, 4H).

[0127] Step 4.

[0128] To a vessel containing 1-[3-bromo-2-chloro-6-(trifluoromethoxy)phenyl]piperidin-2-one (0.500 g, 1.34 mmol) was added palladium(II) acetate (0.0301 g, 0.134 mmol), XantPhos (0.160 g, 0.268 mmol), N-formylsaccharin (0.638 g, 3.02 mmol), 1-methyltetrazol-5-amine (1.20 g, 12.1 mmol), and 1-methyl-2-pyrrolidone was added to make the total volume of the vessel 20 mL. To a second vessel containing triethylamine (0.611 g, 6.04 mmol, 0.842 mL) was added 1-methyl-2-pyrrolidone to make the total volume of the vessel 20 mL. These two solutions were injected into a sample loop pumped through a T-tube and then around a 20 mL stainless steel coil heated to 170 °C. The flow rate was set such that the total residence time was 15 minutes. The reaction mixture was concentrated in vacuo to remove the solvent 1-methyl-2-pyrrolidone. The residue was taken up in dichloromethane and saturated aqueous sodium carbonate and the phases were separated. The aqueous phase was further extracted with dichloromethane. The aqueous phase was acidified to pH 5 and extracted with ethyl acetate. The organic phases were combined, dried and concentrated in vacuo. The crude material was purified by normal phase flash chromatography (0 to 10% dichloromethane in methanol) to give an impure product as a glassy solid. The crude material was taken up in ethyl acetate and washed with dilute aqueous HCl. The organic phase was dried and concentrated in vacuo to give 3-acetamido-2-chloro-N-(5-methyl-1,3,4-oxadiazol-2-yl)-4-(trifluoromethoxy)benzamide (Compound 1.004) (0.0486 g, 0.116 mmol, 9%) as a foamy white solid. 1 H NMR (methanol): 7.82 (d, 1H), 7.58 (m, 1H), 4.06 (s, 3H), 3.69 - 3.60 (m, 1H), 3.59 - 3.50 (m, 1H), 2.57 (m, 2H), 2.10 - 1.93 (dt, 4H)

[0129] Preparation Example 2: Compound 1.006

[0130] 3-Bromo-2-chloro-6-(trifluoromethoxy)aniline was prepared as previously described.

[0131] Step 1

[0132] Charge a autoclave with 3-bromo-2-chloro-6-(trifluoromethoxy)aniline (24 g, 76 mmol). Add methanol (144 mL). Add triethylamine (23 g, 228 mmol), and then add allylpalladium(II) chloride dimer (1.13 g, 3.10 mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.44 g, 3.92 mmol). Flush the autoclave three times with nitrogen, and then three times with carbon monoxide. Pressurize the reaction to 20 bar CO and heat at 100 °C for 4 h. Then cool it to room temperature and displace the atmosphere with N 2 Discharge the contents into a conical flask, and filter the reaction mixture through diatomaceous earth and evaporate. Column chromatography gave methyl 3-amino-2-chloro-4-(trifluoromethoxy)benzoate (16 g, 59 mmol, 78%) as a white solid.

[0133] Step 2

[0134] To a flask containing methyl 3-amino-2-chloro-4-(trifluoromethoxy)benzoate (2.08 g, 7.70 mmol), add acetonitrile (60 mL) and cyclopropanecarbonyl chloride (2.41 g, 23.1 mmol). Stir the reaction mixture at 60 °C. After addition, a white solid forms that requires vigorous stirring. After stirring for 2 h, cool the reaction mixture and evaporate the solvent. Stir the obtained solid in cyclohexane (100 ml) and filter, then wash with cyclohexane to give methyl 2-chloro-3-(cyclopropanecarbonylamino)-4-(trifluoromethoxy)benzoate (2.40 g, 7.12 mmol, 92%) as a white solid.

[0135] Step 3

[0136] To a solution of methyl 2-chloro-3-(cyclopropanecarbonylamino)-4-(trifluoromethoxy)benzoate (A, 0.35 g, 1.04 mmol) in THF (9 mL) and water (3 mL). Add lithium hydroxide hydrate (87 mg, 2.1 mmol), and stir the reaction mixture for 16 h. Concentrate the reaction to remove THF. Add 2 M HCl to the solution until a white solid precipitates, which is separated by filtration to give 2-chloro-3-(cyclopropanecarbonylamino)-4-(trifluoromethoxy)benzoic acid (0.296 g, 0.915 mmol, 88%) as a white solid. 1H NMR (400 MHz, methanol) δ ppm 7.87 (d, 1H) 7.43 (d, 1H) 1.85 - 1.96 (m, 1H) 0.84 - 1.02 (m, 4H).

[0137] Step 4

[0138] 2-Chloro-3-(cyclopropanecarbonylamino)-4-(trifluoromethoxy)benzoic acid (1.10 g, 3.4 mmol) and 1-methyltetrazol-5-amine (400 mg, 4.1 mmol) in 2-methylpyridine (8 mL) were stirred under a nitrogen atmosphere for 10 min, then 1-methylimidazole (280 mg, 3.4 mmol) was added, followed by triethylamine (520 mg, 5.1 mmol), and the mixture was stirred at room temperature for 10 min. The reaction mixture was then cooled to 0 °C and thionyl chloride (810 mg, 6.8 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with 2 N HCl and stirred for 30 min. The resulting solid was filtered, washed with ethanol and dried to give 2-chloro-3-(cyclopropanecarbonylamino)-N-(1-methyltetrazol-5-yl)-4-(trifluoromethoxy)benzamide (820 mg, 2.08 mmol, 61%) as a white solid. 1H NMR (methanol): 7.73 (d, 1H), 7.52 (br d, 1H), 4.06 (s, 3H), 1.91 (m, 1H), 1.01 - 0.88 (m, 4H).

[0139] Preparation Example 3: Compound 1.007

[0140] Methyl 3-amino-2-chloro-4-(trifluoromethoxy)benzoate was prepared as described previously.

[0141] Step 1

[0142] Propionyl chloride (2.6 g, 28 mmol) was added to a solution of methyl 3-amino-2-chloro-4-(trifluoromethoxy)benzoate (2.5 g, 9.3 mmol) in acetonitrile (60 mL). The reaction mixture was stirred at 60 °C for 2 h. After 2 h, the mixture was cooled to room temperature and the acetonitrile was removed under reduced pressure. The residue was taken up in ethyl acetate, then washed with sodium bicarbonate solution, dried (MgSO 4 ) and concentrated under reduced pressure. Flash chromatography (0 - 30% EtOAc and cyclohexane) gave methyl 2-chloro-3-(propionylamino)-4-(trifluoromethoxy)benzoate (2.28 g, 7.00 mmol, 76%) as a white solid. 1H NMR (400 MHz, d4-methanol): 7.87 (d, 1H) 7.45 (m, 1H) 3.93 (s, 3H) 2.46 (q, 2H) 1.24 (t, 3H).

[0143] Step 2

[0144] To a stirred solution of methyl 2-chloro-3-(propionylamino)-4-(trifluoromethoxy)benzoate (27.7 g, 85.1 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL) was added lithium hydroxide (6.11 g, 255 mmol) in water (10 mL), and the mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and partitioned between 1 N HCl and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give 2-chloro-3-(propionylamino)-4-(trifluoromethoxy)benzoic acid (25.7 g, 78.3 mmol, 92%) as a white solid. 1H NMR (400 MHz, d6-DMSO): 13.70 (1H, s), 9.82 (1H, s), 7.79 (1H, d), 7.51 (1H, d), 2.35 n (2H, q), 1.11 (H, t).

[0145] Step 3

[0146] At room temperature under a N2 atmosphere, a flask was charged with pyridine (50 mL) and 2-chloro-3-(propionylamino)-4-(trifluoromethoxy)benzoic acid (5.00 g, 16.0 mmol). Then 1-methyltetrazol-5-amine (1.79 g, 17.7 mmol) and 1-methylimidazole (1.33 g, 16.0 mmol) were added, and the reaction mixture was cooled to 0 °C. Thionyl chloride (3.94 g, 32.1 mmol) was added dropwise over 3 h, maintaining the temperature at 0 °C - 10 °C using an infusion pump. After addition was complete, the pH of the reaction mixture was 5.7 and a brown precipitate appeared. The ice bath was removed and the reaction was allowed to stir at room temperature. After 2 h, the reaction mixture became a brown solution. After stirring for another 2 h, the reaction mixture was cooled to 0 °C using an ice bath, and then 25 mL of water (pH = 5.8 - 5.9) was added with stirring. The reaction mixture was acidified to pH = 1.5 - 2 using 2 N HCl. During acidification, a sticky solid precipitated. The suspension was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with cold water (25 mL), dried (Na2SO4) and concentrated under reduced pressure to give a pale orange solid. It was purified by chromatography (30% - 40% ethyl acetate in cyclohexane) to give 2-chloro-N-(1-methyltetrazol-5-yl)-3-(propionylamino)-4-(trifluoromethoxy)benzamide (2.59 g, 6.61 mmol, 41%) as a white solid. 1H NMR (400 MHz, d6-DMSO): 11.92 (1H, s), 9.90 (1H, s), 7.80 (1H, d), 7.61 (1H, d), 4.00 (3H, s), 2.37 (2H, q), 1.12 (3H, t).

[0147] Preparation Example 4: Compound 1.012

[0148] Methyl 3-amino-2-chloro-4-(trifluoromethoxy)benzoate was prepared as previously described.

[0149] Step 1

[0150] Methyl 3-amino-2-chloro-4-(trifluoromethoxy)benzoate (2.0 g, 7.4 mmol) and picolinic acid (1.1 g, 8.9 mmol) were dissolved in pyridine (10 mL). The solution was cooled to 0 °C by ice water. Phosphorus oxychloride (1.70 g, 11.1 mmol) was added dropwise over 4 minutes, and then the reaction was allowed to warm to room temperature and stirred for 3 h, at which time a white precipitate appeared. The reaction mixture was slowly quenched into cold (0 °C) saturated aqueous sodium bicarbonate. After the addition, stirring was continued vigorously for 30 min. The obtained white solid was filtered and washed 3 times with water to give methyl 2-chloro-3-(pyridin-2-carbonylamino)-4-(trifluoromethoxy)benzoate (1.69 g, 4.51 mmol, 61%) as a white solid. 1H NMR (400 MHz, d6-DMSO): 10.69 (1H, s), 8.78 (1H, d), 8.15 - 8.06 (2H, m), 7.91 (1H, d), 7.73 (1H, ddd), 7.62 (1H, d), 3.90 (3H, s).

[0151] Step 2

[0152] A solution of lithium hydroxide hydrate (0.54 g, 13 mmol) in water (8.0 mL) was added to a solution of methyl 2-chloro-3-(pyridin-2-carbonylamino)-4-(trifluoromethoxy)benzoate (1.6 g, 4.3 mmol) in tetrahydrofuran (32 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated to remove THF. The aqueous solution was washed with cyclohexane, then cooled to 0 °C and the pH was adjusted to 3 with 10% aqueous citric acid. The aqueous mixture was extracted 3 times with ethyl acetate, and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 2-chloro-3-(pyridin-2-carbonylamino)-4-(trifluoromethoxy)benzoic acid (1.6 g, 4.3 mmol, 100%) as a white solid. 1H NMR (400 MHz, d6-DMSO): 10.65 (1H, d), 8.77 (1H, d), 8.13 (1H, d), 8.05 (1H, t), 7.88 (1H, d), 7.69 (1H, m), 7.58 (1H, d).

[0153] Step 3

[0154] 2-Chloro-3-(pyridine-2-carbonylamino)-4-(trifluoromethoxy)benzoic acid (1.5 g, 4.2 mmol) and 1-methyltetrazol-5-amine (500 mg, 5.0 mmol) in 3-methylpyridine (15 mL) were stirred under a nitrogen atmosphere for 10 minutes. Triethylamine (630 mg, 6.2 mmol) was added, followed by 1-methylimidazole (340 mg, 4.2 mmol), and the mixture was stirred at room temperature for 30 min. Then the reaction mixture was cooled to 0 °C and thionyl chloride (990 mg, 8.3 mmol) was added dropwise. After stirring at room temperature for 16 h, the reaction mixture was quenched to pH 1-2 with 2N HCl at 0 °C while stirring vigorously for 30 min. The aqueous layer was extracted with ethyl acetate three times and then concentrated under reduced pressure. The solid was recrystallized from ethyl acetate / n-pentane to obtain N-[2-chloro-3-[(1-methyltetrazol-5-yl)carbamoyl]-6-(trifluoromethoxy)phenyl]pyridine-2-carboxamide (1.45 g, 3.17 mmol, 76%) as a white solid. 1H NMR (400 MHz, d6-DMSO): 12.00 (1H, brs), 10.77 (1H, s), 8.78 (1H, d), 8.16 - 8.05 (2H, m), 7.88 (1H, d), 7.72 (1H, ddd), 7.67 (1H, dd), 4.00 (3H, s).

[0155] Preparation Example 5: Compound 1.014

[0156] Step 1

[0157] At room temperature, 2-amino-4-bromophenol (564 mg, 3.00 mmol), KOH (0.218 g, 3.90 mmol), DMSO (10 mL), and 1,2-dibromotetrafluoroethane (1.17 g, 4.50 mmol) were added to a 15 mL thick-walled pressure vessel. The reaction flask was then sealed and heated to 80 °C for 18 h. The reaction mixture was cooled to room temperature. The mixture was washed with H2O (200 mL) and extracted with ethyl acetate (100 mL × 3). The layers were separated and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by chromatography (petroleum ether / ethyl acetate = 30:1) to give 5-bromo-2-(2-bromo-1,1,2,2-tetrafluoroethoxy)aniline (0.215 g, 0.586 mmol, 19.5%) as a brown oil and 5-bromo-2-(1,1,2,2-tetrafluoroethoxy)aniline (0.206 g, 0.715 mmol, yield: 23.8%) as a brown oil. 1H NMR (400 MHz, d6-DMSO) of 5-bromo-2-(1,1,2,2-tetrafluoroethoxy)aniline: 6.97 - 6.76 (3H, m), 6.65 - 6.62 (1H, m), 5.54 (2H, brs).

[0158] Step 2

[0159] Diisopropylamine (0.973 g, 9.63 mmol) was added to a mixture of ammonium chloride (0.511 g, 9.63 mmol) and ethanol (25 mL). The mixture was heated to reflux for 4 h. The reaction mixture was cooled and then concentrated to give a white solid, which was washed with additional ethanol and then dried under vacuum. Under nitrogen, 5-bromo-2-(1,1,2,2-tetrafluoroethoxy)aniline (18.5 g, 64.2 mmol), toluene (300 mL), and diisopropylammonium chloride (1.4 g) were added to a 3-neck flask. The flask was covered with foil and then cooled to 0 °C. 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (11.4 g, 57.8 mmol) was added in portions, and the mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by adding an aqueous saturated sodium bisulfite solution and then diluted with water and ethyl acetate. The residue was purified by chromatography (eluent: petroleum ether / ethyl acetate = 30:1) to give 3-bromo-2-chloro-6-(1,1,2,2-tetrafluoroethoxy)aniline (9.00 g, 27.9 mmol, 43.5%) as a yellow oil. 1H NMR (400 MHz, d6-DMSO): 7.03 (1H, d), 3.92 (1H, d), 6.85 (1H, tt), 5.83 (2H, brs).

[0160] Step 3

[0161] The synthesis was carried out in a Flow syn equipped with a 20 mL stainless steel loop. To loop A was added: palladium(II) acetate (694 mg, 3.10 mmol) in 1-methyl-2-pyrrolidone (190 mL), XantPhos (3.59 g, 6.20 mmol), N-formylsaccharin (14.7 g, 69.8 mmol), and 3-bromo-2-chloro-6-(1,1,2,2-tetrafluoroethoxy)aniline (10 g, 31.0 mmol). To loop B was added triethylamine (19.4 mL, 139.54 mmol), 1-methyl-2-pyrrolidone (190 mL), and water (20.1 mL, 1116.3 mmol). The temperature was set to 170 minutes and the time was set to 15 minutes. In a fixed container, water (1000 ml) and 1 M HCl (1000 ml) were added to the output reaction mixture, followed by ethyl acetate (1000 ml) and the phases were separated. The organic layer was concentrated under reduced pressure. The crude material was purified by reverse phase chromatography: (50%-70% MeCN in a gradient of H2O containing 0.1% formic acid) to afford 3-amino-2-chloro-4-(1,1,2,2-tetrafluoroethoxy)benzoic acid as a white solid (5.13 g, 17.8 mmol, 58%). 1H NMR (400 MHz, methanol) δ ppm 6.25 - 6.62 (m, 1H) 7.01 - 7.26 (m, 2H).

[0162] Step 4

[0163] At room temperature, 3-(ethyliminomethylamino)-N,N-dimethyl-propan-1-amine hydrochloride (4.1 g, 21 mmol) was added to a stirred suspension of 3-amino-2-chloro-4-(1,1,2,2-tetrafluoroethoxy)benzoic acid (5.13 g, 17.8 mmol) and 2,3,4,5,6-pentafluorophenol (3.61 g, 19.6 mmol) in dichloromethane (70 mL). The mixture was stirred at room temperature. Initially heterogeneous, within 5 minutes of adding EDC, the mixture was a homogeneous solution. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched by adding saturated aqueous NaHCO3 (100 mL). The mixture was stirred at room temperature for an additional 5 min. The mixture was filtered through a phase separation cartridge and the organic layer was collected. The filtrate was adsorbed onto silica and the crude product was purified by flash column chromatography (0 - 10% gradient of EtOAc in cyclohexane). The fractions containing the product were combined and concentrated in vacuo to afford (2,3,4,5,6-pentafluorophenyl) 3-amino-2-chloro-4-(1,1,2,2-tetrafluoroethoxy)benzoate (6.36 g, 14.0 mmol, 79%) as a colorless oil, which crystallized upon standing. LCMS: M+H = 452.1 in ES-.

[0164] Step 5

[0165] At room temperature, 1-methyltetrazol-5-amine (1.53 g, 15.4 mmol) was added to a round-bottom flask containing a solution of (2,3,4,5,6-pentafluorophenyl) 3-amino-2-chloro-4-(1,1,2,2-tetrafluoroethoxy)benzoate (3.18 g, 7.01 mmol) in acetonitrile (50 mL), followed by the addition of 2-tert-butylimino-N,N-diethyl-1,3-dimethyl-1,3,2λ5-diazaphosphinan-2-amine (4.4 g, 4.6 mL, 15 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched by the addition of aqueous 2M HCl solution (100 mL). The mixture was stirred at room temperature for an additional 5 minutes. The mixture was transferred to a separatory funnel and diluted with EtOAc (100 mL). The phases were separated. The aqueous phase was extracted with EtOAc (100 mL). The combined organic matter was adsorbed onto C18-silica and purified via reverse-phase column chromatography (gradient of 40%-80% MeCN in H2O containing 0.1% formic acid) to afford 3-amino-2-chloro-N-(1-methyltetrazol-5-yl)-4-(1,1,2,2-tetrafluoroethoxy)benzamide (1.88 g, 4.84 mmol, 69%) as a white solid. 1H NMR (400 MHz, methanol) δ ppm 4.05 (s, 3H) 6.28 - 6.62 (m, 1H) 6.91 - 6.99 (m, 1H) 7.22 - 7.30 (m, 1H).

[0166] Step 6

[0167] At room temperature, propionyl chloride (0.23 g, 0.22 mL, 2.5 mmol) was added to a stirred solution of 3-amino-2-chloro-N-(1-methyltetrazol-5-yl)-4-(1,1,2,2-tetrafluoroethoxy)benzamide (0.3 g, 0.81 mmol) in acetonitrile (6 mL). The stirred mixture was heated to 60 °C overnight. The reaction was cooled to room temperature and quenched by the slow addition of water (2 mL). The mixture was stirred at room temperature for an additional 5 minutes. The mixture was transferred to a separatory funnel and diluted with EtOAc (20 mL) and water (20 mL). The phases were separated. The aqueous phase was extracted with EtOAc (20 mL). The combined organic phase was dried (MgSO 4 ) and filtered. The filtrate was adsorbed onto C18-silica and purified via reverse-phase column chromatography (gradient of 30%-60% MeCN in H 2Purification by gradient in O gave 2-chloro-N-(1-methyltetrazol-5-yl)-3-(propionylamino)-4-(1,1,2,2-tetrafluoroethoxy)benzamide as a white solid (280 mg, 0.626 mmol, 77%). 1H NMR (400 MHz, d4-methanol): 1.16 - 1.28 (m, 3H) 2.41 - 2.53 (m, 2H) 4.06 (s, 3H) 6.21 - 6.53 (m, 1H) 7.49 - 7.57 (m, 1H) 7.73 (d, 1H).

[0168] Preparation Example 6: Compound 1.016

[0169] Step 1.

[0170] To a flask containing 3-chloro-4-methyl-2-nitrophenol (5.33 mmol, 1.00 g) was added acetone (20 mL), water (0.1 mL), potassium carbonate (10.7 mmol, 1.47 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (8.00 mmol, 1.86 g). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo to remove the solvent. The residue was dissolved in water and ethyl acetate. The phases were separated, and the aqueous phase was further extracted with ethyl acetate. The organic phases were combined, washed with water and concentrated in vacuo to give 2-chloro-1-methyl-3-nitro-4-(2,2,2-trifluoroethoxy)benzene as an orange solid (5.39 mmol, 1.450 g, quantitative %), which was used without further purification. 1 1H NMR (chloroform): 7.32 (m, 1H), 6.91 (d, 1H), 4.42 (q, 2H), 2.39 (s, 3H).

[0171] Step 2.

[0172] To a flask containing 2-chloro-1-methyl-3-nitro-4-(2,2,2-trifluoroethoxy)benzene (10.0 mmol, 2.70 g) was added water (41 mL) and pyridine (41 mL). The reaction mixture was stirred at 100 °C until the reaction mixture was a solution. Potassium permanganate (40.0 mmol, 6.33 g) was added in 4 portions at one-hour intervals. The reaction mixture was stirred at 100 °C for an additional 1 hour and then allowed to stand overnight at room temperature. The reaction mixture was cooled to room temperature and the solid was filtered off. The solution was washed with ethyl acetate. The aqueous phase was acidified with 2 M aqueous HCl and the material was extracted with ethyl acetate. The organic phases were combined and concentrated in vacuo to give 2-chloro-3-nitro-4-(2,2,2-trifluoroethoxy)benzoic acid as a white solid (4.37 mmol, 1.31 g), which was used without further purification. 11H NMR (in methanol): δ 8.13 (d, 1H), 7.40 (d, 1H), 4.84 (m, 2H)

[0173] Step 3

[0174] To a flask containing 2-chloro-3-nitro-4-(2,2,2-trifluoroethoxy)benzoic acid (4.37 mmol, 1.31 g), triethyl orthoformate (60.1 mmol, 8.91 g, 10 mL) was added. The reaction mixture was stirred at 140 °C for 1 h. The reaction mixture was concentrated in vacuo to remove triethyl orthoformate. The residue was triturated with ethyl acetate and the solid was dried in vacuo to give ethyl 2-chloro-3-nitro-4-(2,2,2-trifluoroethoxy)benzoate (4.23 mmol, 1.39 g, 97%) as an orange solid, which was used without further purification. 1 1H NMR (in chloroform): δ 8.05 (d, 1H), 7.02 (d, 1H), 4.52 (m, 2H), 4.42 (m, 2H), 1.41 (m, 3H)

[0175] Step 4

[0176] To a flask containing ethyl 2-chloro-3-nitro-4-(2,2,2-trifluoroethoxy)benzoate (2.44 mmol, 0.800 g), ethanol (8 mL), ammonium chloride (14.7 mmol, 0.784 g), water (8 mL) and iron (7.33 mmol, 0.409 g) were added. The reaction mixture was stirred at 95 °C for 1 h. The reaction mixture was cooled to room temperature and the solid was filtered through diatomaceous earth and then washed with water and ethyl acetate. The solution was further diluted with water and ethyl acetate. The phases were separated and the aqueous phase was further extracted with ethyl acetate. The organic phases were combined, washed with water and then with brine, and concentrated in vacuo to give ethyl 3-amino-2-chloro-4-(2,2,2-trifluoroethoxy)benzoate (2.43 mmol, 0.723 g, 100%) as a pale orange solid, which was used without further purification. 1 1H NMR (in chloroform): δ 7.27 (m, 1H), 6.70 (d, 1H), 4.46 - 4.40 (m, 4H), 4.37 (m, 2H), 1.39 (m, 3H)

[0177] Step 5

[0178] Ethyl 3-amino-2-chloro-4-(2,2,2-trifluoroethoxy)benzoate (2.43 mmol, 0.723 g), ethanol (15 mL), sodium hydroxide (7.29 mmol, 0.291 g), and water (5 mL) were added to a flask. The reaction mixture was stirred at room temperature for 6.5 h. The reaction mixture was concentrated in vacuo to remove the ethanol solvent. The aqueous phase was acidified to approximately pH 4 with concentrated HCl and then concentrated in vacuo to remove water. The residue was triturated with ethyl acetate and the resulting solid was dried in vacuo to give 3-amino-2-chloro-4-(2,2,2-trifluoroethoxy)benzoic acid (assumed 2.43 mmol, assumed quantitative %), which was not subjected to further purification and was presented in crude form.

[0179] Step 6

[0180] 2,3,4,5,6-Pentafluorophenol (2.79 mmol, 0.514 g), dichloromethane (33 mL), and 1-3-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.79 mmol, 0.564 g) were added to a flask containing 3-amino-2-chloro-4-(2,2,2-trifluoroethoxy)benzoic acid (2.43 mmol, 0.655 g). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to remove the solvent. The reaction residue was dissolved in ethyl acetate and water. The phases were separated and the aqueous phase was further extracted with ethyl acetate. The organic phases were combined and concentrated in vacuo to give (2,3,4,5,6-pentafluorophenyl) 3-amino-2-chloro-4-(2,2,2-trifluoroethoxy)benzoate as a colorless oil (assumed 2.43 mmol, assumed quantitative %), which was not subjected to further purification and was presented in crude form.

[0181] Step 7

[0182] To a flask containing (2,3,4,5,6-pentafluorophenyl) 3-amino-2-chloro-4-(2,2,2-trifluoroethoxy)benzoate (2.43 mmol, 1.06 g) was added 1-methyltetrazol-5-amine (2.68 mmol, 0.265 g), acetonitrile (21 mL), and 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (5.35 mmol, 1.51 g, 1.60 mL). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was quenched by the addition of 2 M aqueous HCl and then extracted with ethyl acetate. The organic phases were combined, washed with water and concentrated in vacuo to give an off-white solid. The crude material was triturated with dichloromethane and the resulting solid was dried in vacuo to give 3-amino-2-chloro-N-(1-methyltetrazol-5-yl)-4-(2,2,2-trifluoroethoxy)benzamide as a white solid (1.87 mmol, 0.655 g, 77%). 1 1H NMR (methanol): 7.01 (d, 2H), 4.69 (m, 2H), 4.04 (s, 3H)

[0183] Step 8

[0184] To a flask containing 3-amino-2-chloro-N-(1-methyltetrazol-5-yl)-4-(2,2,2-trifluoroethoxy)benzamide (0.570 mmol, 0.200 g) was added acetonitrile (4 mL) and 2-fluoropropanoyl chloride (1.43 mmol, 0.158 g). The reaction mixture was stirred at 60 °C for 1.5 h. The reaction mixture was concentrated in vacuo to remove the solvent. The crude material was purified by normal phase flash chromatography (0 to 5% methanol in dichloromethane) to give 2-chloro-3-(2-fluoropropanoylamino)-N-(1-methyltetrazol-5-yl)-4-(2,2,2-trifluoroethoxy)benzamide (Compound 1.016) as a white solid (0.313 mmol, 0.133 g, 55%). 1H NMR (methanol): 7.71 (d, 1H), 7.26 (d, 1H), 5.25 (m, 0.5H), 5.13 (m, 0.5H), 4.68 (m, 2H), 4.04 (s, 3H), 1.68 (d, 1.5H), 1.62 (d, 1.5H).

[0185] Preparation Example 7: Compound 1.018

[0186] Step 1

[0187] Prepare 3-amino-2-chloro-N-(1-methyltetrazol-5-yl)-4-(2,2,2-trifluoroethoxy)benzamide as described above.

[0188] Step 2

[0189] To a flask containing 3-amino-2-chloro-N-(1-methyltetrazol-5-yl)-4-(2,2,2-trifluoroethoxy)benzamide (0.428 mmol, 0.150 g) was added acetonitrile (6 mL) and acetyl chloride (1.28 mmol, 0.101 g, 0.092 mL). The reaction mixture was stirred at 60 °C for 1.5 h. The reaction mixture was concentrated in vacuo to remove the solvent. The crude material was purified by normal phase flash chromatography (0 to 5% methanol in dichloromethane) to afford 3-acetamido-2-chloro-N-(1-methyltetrazol-5-yl)-4-(2,2,2-trifluoroethoxy)benzamide (Compound 1.018) as a white solid (0.357 mmol, 0.140 g, 83%). 1 1H NMR (methanol): 7.67 (d, 1H), 7.25 (d, 1H), 4.67 (m, 2H), 4.04 (s, 3H), 2.18 (s, 3H).

[0190] Preparation Example 8: Compound 1.028

[0191] Step 1

[0192] To a flask containing 3-chloro-4-methyl-2-nitrophenol (5.33 mmol, 1.00 g) was added acetone (20 mL) and water (0.1 mL). Potassium carbonate (8.00 mmol, 1.11 g) and methyl iodide (10.7 mmol, 1.51 g, 0.664 mL) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to remove the acetone solvent. The residue was dissolved in water and ethyl acetate. The phases were separated, and the aqueous phase was further extracted with ethyl acetate. The organic phases were combined and concentrated in vacuo to afford 3-chloro-1-methoxy-4-methyl-2-nitrobenzene as a yellow solid (4.98 mmol, 1.00 g, 93%), which was used without further purification. 1 1H NMR (chloroform): 7.28 (m, 1H), 6.87 (d, 1H), 3.88 (s, 3H), 2.36 (s, 3H).

[0193] Step 2

[0194] To a flask containing 3-chloro-1-methoxy-4-methyl-2-nitro-benzene (3.97 mmol, 0.800 g) was added water (16 mL) and pyridine (16 mL). The reaction mixture was stirred at 100 °C until the reaction mixture was a solution. Potassium permanganate (11.9 mmol, 1.88 g) was added in 3 portions, at one-hour intervals. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature and the solid was filtered off. The solution was washed with TBME. The aqueous phase was acidified with 2 M aqueous HCl and the material was extracted with ethyl acetate. The organic phases were combined and concentrated in vacuo to afford 2-chloro-4-methoxy-3-nitro-benzoic acid (2.20 mmol, 0.509 g, 55%) as a white solid, which was used without further purification. 1 1H NMR (methanol): 8.11 (d, 1H), 7.29 (d, 1H), 4.00 (s, 3H).

[0195] Step 3

[0196] To a flask containing 2-chloro-4-methoxy-3-nitro-benzoic acid (8.77 mmol, 2.03 g) was added triethyl orthoformate (120 mmol, 17.8 g, 20 mL). The reaction mixture was stirred at 140 °C for 3 h. The reaction mixture was concentrated in vacuo to remove triethyl orthoformate. The residue was triturated with ethyl acetate and the solid was dried in vacuo to afford ethyl 2-chloro-4-methoxy-3-nitro-benzoate (8.77 mmol, 2.28 g, quantitative %) as an orange solid, which was used without further purification.

[0197] Step 4

[0198] To a flask containing ethyl 2-chloro-4-methoxy-3-nitro-benzoate (3.85 mmol, 1.00 g) was added ethanol (10 mL), ammonium chloride (23.1 mmol, 1.24 g), water (10 mL) and iron (11.6 mmol, 0.645 g). The reaction mixture was stirred at 95 °C for 1 h. The reaction mixture was cooled to room temperature and the solid was filtered through diatomaceous earth and then washed with water and ethyl acetate. The solution was further diluted with water and ethyl acetate. The phases were separated and then the aqueous phase was further extracted with ethyl acetate. The organic phases were combined, washed with water and then with brine and concentrated in vacuo to afford ethyl 3-amino-2-chloro-4-methoxy-benzoate (3.76 mmol, 0.864 g, 98%) as an off-white solid, which was used without further purification.

[0199] Step 5

[0200] Ethyl 3-amino-2-chloro-4-methoxybenzoate (3.76 mmol, 0.864 g) was added to a flask along with ethanol (15 mL), sodium hydroxide (11.3 mmol, 0.451 g), and water (5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo to remove the ethanol solvent. The aqueous phase was acidified to approximately pH 4 with concentrated HCl and then concentrated in vacuo to remove water. The residue was dissolved in water and ethyl acetate, and the phases were separated. The organic phase was concentrated in vacuo to afford 3-amino-2-chloro-4-methoxybenzoic acid as an off-white solid (3.67 mmol, 0.740 g, 98%) which was used without further purification.

[0201] Step 6

[0202] 2,3,4,5,6-Pentafluorophenol (4.20 mmol, 0.780 g), dichloromethane (37 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.20 mmol, 0.850 g) were added to a flask containing 3-amino-2-chloro-4-methoxybenzoic acid (3.70 mmol, 0.740 g). The reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated in vacuo to remove the solvent. The reaction residue was dissolved in ethyl acetate and water. The phases were separated, and the aqueous phase was further extracted with ethyl acetate. The organic phases were combined and concentrated in vacuo to afford (2,3,4,5,6-pentafluorophenyl) 3-amino-2-chloro-4-methoxybenzoate as an orange oil (assumed 3.70 mmol, assumed quantitative %) which was used without further purification and was taken as a crude form.

[0203] Step 7

[0204] 1-Methyltetrazol-5-amine (4.07 mmol, 0.403 g), acetonitrile (27 mL), and 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (8.14 mmol, 2.30 g, 2.43 mL) were added to a flask containing (2,3,4,5,6-pentafluorophenyl) 3-amino-2-chloro-4-methoxybenzoate (3.70 mmol, 1.36 g). The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched by the addition of 2 M aqueous HCl and then extracted with ethyl acetate. The organic phases were combined, washed with water, and concentrated in vacuo to afford an orange oil. The crude material was purified by normal-phase flash chromatography (0 to 10% methanol in dichloromethane) to afford 3-amino-2-chloro-4-methoxy-N-(1-methyltetrazol-5-yl)benzamide as a pale orange solid (2.21 mmol, 0.624 g, 60%). 11H NMR (in methanol): 7.04 (d, 1H), 6.91 (d, 1H), 4.03 (s, 3H), 3.94 (s, 3H).

[0205] Step 8

[0206] To a flask containing 2-fluoropropanoic acid (10.9 mmol, 1.00 g) was added thionyl chloride (23.5 mmol, 2.80 g, 1.68 mL). The reaction mixture was stirred at 60 °C for 4 h. The product was distilled to give 2-fluoropropanoyl chloride as a colorless oil (6.81 mmol, 0.753 g, 63%). 1 1H NMR (in chloroform): 5.21 (m, 0.5H), 5.08 (m, 0.5H), 1.74 (d, 1.5H), 1.68 (d, 1.5H)

[0207] Step 9

[0208] To a flask containing 3-amino-2-chloro-4-methoxy-N-(1-methyltetrazol-5-yl)benzamide (0.707 mmol, 0.200 g) was added acetonitrile (8 mL) and 2-fluoropropanoyl chloride (1.41 mmol, 0.209 g). The reaction mixture was heated to 60 °C for 4 h. The reaction mixture was concentrated in vacuo to remove the solvent. The crude material was purified by normal phase flash chromatography (0 to 10% methanol in dichloromethane) to give 2-chloro-3-(2-fluoropropanoylamino)-4-methoxy-N-(1-methyltetrazol-5-yl)benzamide (Compound 1.031) as a yellow solid (0.555 mmol, 0.198 g, 79%). 1 1H NMR (in methanol): 7.69 (d, 1H), 7.17 (d, 1H), 5.25 (m, 0.5H), 5.13 (m, 0.5H), 4.03 (s, 3H), 3.92 (s, 3H), 1.68 (d, 1.5H), 1.61 (d, 1.5H).

[0209] Preparation Example 10: Compound 1.030

[0210] Step 1

[0211] Prepare 3-amino-2-chloro-4-methoxy-N-(1-methyltetrazol-5-yl)benzamide as described above.

[0212] Step 2

[0213] To a flask containing 3-amino-2-chloro-4-methoxy-N-(1-methyltetrazol-5-yl)benzamide (0.531 mmol, 0.150 g) was added acetonitrile (6 mL) and acetyl chloride (1.06 mmol, 0.0833 g). The reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was concentrated in vacuo to remove the solvent. The crude material was triturated with ethyl acetate and the solid was dried in vacuo to give 3-acetamido-2-chloro-4-methoxy-N-(1-methyltetrazol-5-yl)benzamide (Compound 1.033) as a white solid (0.490 mmol, 0.159 g, 92%). 1 H NMR (methanol): 7.66 (d, 1H), 7.16 (d, 1H), 4.04 (s, 3H), 3.92 (s, 3H), 2.17 (s, 3H).

[0214] Preparation Example 11: Compound 2.001

[0215] Step 1

[0216] Prepare 3-bromo-2-chloro-6-(trifluoromethoxy)aniline as outlined previously.

[0217] Step 2

[0218] To a flask containing 3-bromo-2-chloro-6-(trifluoromethoxy)aniline (2.00 g, 6.89 mmol) was added tetrahydrofuran (30 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at -78 °C for 30 minutes. n-Butyllithium (2.5 M in hexanes, 7.57 mmol, 3.00 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at -78 °C for 1 hour. Iodomethane (2.93 g, 20.7 mmol, 1.29 mL) was added to the reaction mixture. The reaction mixture was allowed to warm to 0 °C and stirred for 3 hours. The reaction mixture was carefully quenched by slowly adding it to a saturated aqueous ammonium chloride solution. The mixture was stirred at room temperature for 15 minutes and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried and concentrated in vacuo. The crude material was purified by normal phase flash chromatography (0 to 5% ethyl acetate in cyclohexane) to give an impure product. The crude material was purified by reverse phase flash chromatography (60% to 100% (acetonitrile + 0.1% formic acid) in (water + 0.1% formic acid)) to give 3-bromo-2-chloro-N-methyl-6-(trifluoromethoxy)aniline as a brown oil (0.587 g, 1.93 mmol, 28%). 1 H NMR (chloroform): 7.03 - 6.99 (m, 1H), 6.99 - 6.94 (m, 1H), 3.08 (s, 3H).

[0219] Step 3

[0220] To a flask containing 3-bromo-2-chloro-N-methyl-6-(trifluoromethoxy)aniline (1.36 g, 4.47 mmol) was added tetrahydrofuran (41 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at -78 °C for 1 hour. n-Butyllithium (2.5 M in hexanes, 4.91 mmol, 2.00 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at -78 °C for 45 minutes. Iodomethane (1.90 g, 13.4 mmol, 0.834 mL) was added to the reaction mixture. The reaction mixture was allowed to warm to 0 °C and stirred for 3.5 hours. The reaction mixture was carefully quenched by slowly adding it to an ice-cooled saturated aqueous ammonium chloride solution. The mixture was stirred at 0 °C for 15 minutes and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried and concentrated in vacuo. The crude material was purified by normal-phase flash chromatography (0 to 1% ethyl acetate in cyclohexane) to afford 3-bromo-2-chloro-N,N-dimethyl-6-(trifluoromethoxy)aniline (0.520 g, 1.63 mmol, 37%). 1 1H NMR (chloroform): 7.35 (d, J = 8.9 Hz, 1H), 7.01 (m, 1H), 2.87 (s, 6H).

[0221] Step 4

[0222] To a container containing 3-bromo-2-chloro-N,N-dimethyl-6-(trifluoromethoxy)aniline (0.520 g, 1.63 mmol) was added palladium(II) acetate (0.0367 g, 0.163 mmol), XantPhos (0.195 g, 0.327 mmol), N-formylsaccharin (0.776 g, 3.67 mmol), 5-methyl-1,3,4-oxadiazol-2-amine (1.46 g, 14.7 mmol) and 1-methyl-2-pyrrolidone such that the total volume of the container was 20 mL. To a second container containing triethylamine (0.743 g, 7.35 mmol, 1.02 mL) was added 1-methyl-2-pyrrolidone such that the total volume of the container was 20 mL. The reaction was carried out in a Uniqsis FlowSyn. The two solutions were injected into a sample loop pumped through a T-piece and then around a 20 mL stainless steel coil heated to 170 °C. The flow rate was set such that the total residence time was 20 minutes. The reaction mixture was concentrated in vacuo to remove the solvent 1-methyl-2-pyrrolidone. The residue was purified by reverse phase HPLC to give an impure product. The crude material was purified by normal phase flash chromatography (10% to 80% ethyl acetate in cyclohexane) to give 2-chloro-3-(dimethylamino)-N-(5-methyl-1,3,4-oxadiazol-2-yl)-4-(trifluoromethoxy)benzamide (Compound 2.001) as a pale yellow solid (0.174 g, 0.478 mmol, 29%). 1 1H NMR (methanol): 7.37 - 7.34 (m, 2H), 2.90 (s, 6H), 2.51 (s, 3H).

[0223] The compounds were characterized using NMR as indicated or using LCMS with the following conditions. Using a Sample Organizer (with Sample Manager FTN, H-class QSM, Column Manager, 2x Column Manager Aux, photodiode array, ELSD and QDA SQD 2) on a Waters Aquity UPLC-MS equipped with a Waters HSS C18 column (column length 50 mm, column inner diameter 2.3 mm, particle size 1.8 microns). Analysis was carried out with a four-minute run time according to the following gradient table:

[0224]

[0225] Solvent A: H2O with 0.05% TFA 2 O

[0226] Solvent B: CH3CN with 0.05% TFA 3 CN

[0227] Table 1 - Examples of the herbicidal compounds of the present invention.

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285] Table 2 - Examples of herbicidal compounds of the present invention.

[0286]

[0287]

[0288] Biological examples

[0289] Seeds of various test species were sown in standard soil in pots (Lolium perenne (LOLPE), Amaranthus retoflexus (AMARE), Abutilon theophrasti (ABUTH), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), Ipomoea hederacea (IPOHE)). After one day (pre-emergence) or 8 days (post-emergence) of cultivation under controlled conditions in a greenhouse (at 24 °C / 16 °C, day / night; 14-hour light; 65% humidity), these plants were sprayed with an aqueous spray solution derived from a formulation of an industrial-grade active ingredient in an acetone / water (50:50) solution containing 0.5% Tween 20 (polyoxyethylene sorbitan monolaurate, CAS RN 9005-64-5). Unless otherwise indicated, the compounds were applied at 500 g / h. The test plants were then grown in the greenhouse under controlled conditions (at 24 °C / 16 °C, day / night; 14-hour light; 65% humidity) and watered twice daily. The percentage of damage caused to the test plants was evaluated 13 days pre-emergence and post-emergence. The biological activity is shown in the following table on a five-point scale (5 = 80% - 100%; 4 = 60% - 79%; 3 = 40% - 59%; 2 = 20% - 39%; 1 = 0% - 19%).

[0290] Table B1

[0291]

[0292]

[0293]

[0294]

[0295] Applied at 125 g / ha

[0296] Table B2 - Comparative test

[0297] Seeds of the test species were sown in standard soil in pots. After culturing for one day under controlled conditions in a greenhouse (24 °C / 16 °C, day / night; 14 h of light; 65% humidity), the plants were sprayed with an aqueous spray solution derived from 0.6 ml of acetone and a formulation solution of 45 ml containing 10.6% Emulsogen EL (registration number 61791-12-6), 42.2% N-methylpyrrolidone, 42.2% dipropylene glycol monomethyl ether (CAS RN 34590-94-8), and 0.2% X-77 (CAS RN 11097-66-8) of industrial-grade active ingredients.

[0298] The test plants were then grown in the greenhouse under controlled conditions in the greenhouse (24 °C / 16 °C, day / night; 14 h of light; 65% humidity) and watered twice a day. After 14 days, the test was evaluated (100 = damage to plant integrity; 0 = no damage to the plant).

[0299] Test species: ABUTH (Abutilon theophrasti); BROTE (Bromus tectorum); ECHCG (Echinochloa crus-galli); SINAR (Sinapis arvensis).

[0300]

[0301]

[0302] C1 is compound 4-659 disclosed in WO2012 / 028579. It can be seen that replacing the 4-chloro substituent on the benzene ring with the haloalkoxy group of the present invention provides an unexpected improvement in the observed weed control.

Claims

1. A compound having the formula (I): or an agriculturally acceptable salt thereof, wherein: - Q is Q 1 or Q 2 ; R 1a selected from the group consisting of: C 1 -C 4 -alkyl-, C 1 -C 4 -haloalkyl-, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl- and C 1 -C 4 -haloalkoxy-C 1 -C 4 -alkyl-; R 1b selected from the group consisting of: C 1 -C 4 -alkyl-, C 1 -C 4 -haloalkyl-, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl- and C 1 -C 4 -haloalkoxy-C 1 -C 4 -alkyl-; R 2 selected from the group consisting of: halogen, C 1 -C 6 -alkyl-, C 1 -C 3 -alkoxy-, C 1 -C 6 -haloalkyl-, C 1 -C 3 -haloalkoxy- and -S(O) p C 1 -C 6 -alkyl; R 3 is C 1 -C 6 haloalkyl or C 1 -C 6 alkyl; R 4 is selected from the group consisting of: C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkyl-C(O)-, C 1 -C 6 -haloalkyl-C(O)-, C 3 -C 6 -cycloalkyl-C 1 -C 3 -alkyl-, C 3 -C 6 -cycloalkyl-C(O)-, C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl-C(O)-, -C(O)-phenyl and -C(O)-heteroaryl, wherein said phenyl, heteroaryl or C 3 -C 6 -cycloalkyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of: halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl and C 1 -C 6 -alkoxy, and wherein heteroaryl is selected from the group consisting of R 4a -, R 4b -, R 4c -, R 4d -, R 4e -, R 4f -, R 4g - and R 4h -: R 5 selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl and C 1 -C 6 -cycloalkyl; or R 4 and R 5 together with their attached nitrogen atoms form a 5- or 6-membered saturated heterocycle optionally substituted with oxo groups; and p is 0, 1 or 2.

2. The compound according to claim 1, wherein, R 1a or R 1b is selected from the group consisting of methyl, ethyl, and n-propyl.

3. The compound according to claim 1 or 2, wherein, Q is Q 1 , and R 1a is methyl.

4. The compound according to claim 1 or claim 2, wherein, Q is Q 2 and R 1b is methyl.

5. The compound according to claim 1, wherein, R 2 selected from the group consisting of: methyl, Cl, -CF 3 and -SO 2 methyl.

6. The compound according to claim 5, wherein, R 2 is Cl.

7. The compound according to claim 1, wherein, R 3 is -CF 3 or -CHF 2 。 8. The compound according to claim 1, wherein, R 4 selected from the group consisting of: C 1 -C 6 -alkyl-, C 1 -C 6 -alkyl-C(O)- and C 3 -C 6 -cycloalkyl-C(O)-.

9. The compound according to claim 1, wherein, R 4 is -C(O)-heteroaryl, wherein the heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of: halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl and C 1 -C 6 -alkoxy, and wherein the heteroaryl is selected from the group consisting of R 4a -, R 4b -, R 4c -, R 4d -, R 4e -, R 4f -, R 4g - and R 4h -:

10. The compound according to claim 1, wherein, R 5 is hydrogen or C 1 -C 6 -alkyl.

11. A herbicidal composition comprising the compound according to any one of claims 1 - 10 and an agriculturally acceptable formulation adjuvant.

12. The herbicidal composition according to claim 11, which further comprises at least one additional pesticide.

13. The herbicidal composition according to claim 12, wherein, the additional pesticide is a herbicide or a herbicide safener.

14. A method for controlling weeds at a site, the method comprising applying to the site a composition according to any one of claims 11 to 13 in an amount effective to control the amount of weeds.

15. Use of the compound having the formula (I) according to claim 1 as a herbicide.

16. A compound having the formula (II) wherein R 2 , R 4 and R 5 are as defined in the compound of formula (I) as described in any one of claims 1 to 10 above, and R 3 is C 1 -C 6 haloalkyl.

17. A compound having the formula (V) wherein R 2 , R 4 and R 5 are as defined in the compound of formula (I) as described in any one of claims 1 to 10 above, and R 3 is C 1 -C 6 haloalkyl.

18. A compound having the formula (VIa) wherein "Alk" is C 1 -C 6 alkyl, and R 2 , R 3 , R 4 and R 5 are as defined in the compound of formula (I) as described in any one of claims 1 to 10 above.

19. Compound 1.209 or 1.247:

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