PICOLINAMIDES AS FUNGICIDES

专利摘要:
picolinamides as fungicides. this description refers to the picolinamides of formula I and their use as fungicides.
公开号:BR112017013608B1
申请号:R112017013608-2
申请日:2015-12-21
公开日:2021-06-22
发明作者:Zachary Buchan；Kyle A. Dekorver；David M. Jones；Jessica Herrick；Jeremy Wilmot；Jared RIGOLI；Brian Loy；Yu Lu；Kevin G. Meyer；Chenglin Yao
申请人:Dow Agrosciences Llc；
IPC主号:

专利说明:

CROSS REFERENCE TO RELATED ORDERS
[0001] This application claims the benefit of Provisional Patent Application Nos. US 62/098,089, filed December 30, 2014, US 62/098,097, filed December 30, 2014, US 62/255,163, filed November 13, 2015, and US 62/255,168, filed 13 of November 2015, which are expressly incorporated by reference herein. BACKGROUND & SUMMARY
[0002] Fungicides are compounds, of natural or synthetic origin, which act to protect and/or cure plants against damage caused by agriculturally relevant fungi. Generally, no single fungicide is useful in all situations. Consequently, research is ongoing to produce fungicides, which may perform better, are easy to use, and cost less.
[0003] The present description refers to picolinamides and their use as fungicides. The compounds of the present description can offer protection against ascomycetes, basidiomycetes, deuteromycetes and oomycetes.
R1 e R11 são independentemente selecionados a partir de hidrogênio ou alquila, opcionalmente substituídos com 0, 1 ou múltiplos R8; Alternativamente, R1 e R11 podem ser empregados juntamente para formar um carbociclo ou heterociclo de 3 - 6 membros saturado ou parcialmente saturado, opcionalmente substituído com 0, 1 ou múltiplos R8; R2 e R12 são independentemente selecionados a partir de hidrogênio ou metila; R3 é selecionado a partir de arila ou heteroarila, cada qual opcionalmente substituído com 0, 1 ou múltiplos R8; R4 é selecionado a partir de alquila, arila, ou acila, cada qual opcionalmente substituída com 0, 1 ou múltiplos R8; R5 é selecionado a partir de alcóxi ou benzilóxi, cada qual opcionalmente substituído com 0, 1, ou múltiplos R8; R6 é selecionado a partir de hidrogênio, alcóxi, ou halo, cada qual opcionalmente substituído com 0,1, ou múltiplos R8; R7 é selecionado a partir de hidrogênio, -C(O)R9, ou - CH2OC(O)R9; R8 é selecionado a partir de hidrogênio, alquila, arila, acila, halo, alquenila, alcóxi, ou heterociclila, cada qual opcionalmente substituído com 0, 1, ou múltiplos R10; R9 é selecionado a partir de alquila, alcóxi, ou arila, cada qual opcionalmente substituído com 0, 1, ou múltiplos R8; R10 é selecionado a partir de hidrogênio, alquila, arila, acila, halo, alquenila, alcóxi, ou heterociclila.[0004] An embodiment of the present description may include the compounds of Formula I:
X is hydrogen or C(O)R5; Y is hydrogen, C(O)R5, or Q; what is R1 and R11 are independently selected from hydrogen or alkyl, optionally substituted with 0, 1 or R8 multiples; Alternatively, R1 and R11 can be employed together to form a saturated or partially saturated 3-6 membered carbocycle or heterocycle, optionally substituted with 0, 1 or multiple R8; R2 and R12 are independently selected from hydrogen or methyl; R3 is selected from aryl or heteroaryl, each optionally substituted with 0, 1 or multiple R8; R4 is selected from alkyl, aryl, or acyl, each optionally substituted with 0, 1 or multiple R8; R5 is selected from alkoxy or benzyloxy, each optionally substituted with 0, 1, or multiple R8; R6 is selected from hydrogen, alkoxy, or halo, each optionally substituted with 0.1, or multiples of R8; R7 is selected from hydrogen, -C(O)R9, or -CH2OC(O)R9; R8 is selected from hydrogen, alkyl, aryl, acyl, halo, alkenyl, alkoxy, or heterocyclyl, each optionally substituted with 0, 1, or multiple R10; R9 is selected from alkyl, alkoxy, or aryl, each optionally substituted with 0, 1, or multiple R8; R10 is selected from hydrogen, alkyl, aryl, acyl, halo, alkenyl, alkoxy, or heterocyclyl.
[0005] Another embodiment of the present description may include a fungicidal composition for the control or prevention of fungal attack comprising the compounds described above and a phytologically acceptable carrier material.
[0006] Yet another embodiment of the present description may include a method for controlling or preventing fungal attack on a plant, the method including the steps of applying a fungicidally effective amount of one or more of the compounds described above to at least one of the fungi , from the plant, and from an area adjacent to the plant.
[0007] It will be understood by those skilled in the art that the following terms may include generic "R" groups within their definitions, for example, "the term alkoxy refers to a substituent -OR". It is likewise understood that within the definitions for the following terms, these "R" groups are included for purposes of illustration and are not to be construed as limiting or being limited by substitutions around Formula I.
[0008] The term "alkyl" refers to a branched, unbranched or saturated cyclic carbon chain, including, but not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
[0009] The term "alkenyl" refers to a branched, unbranched or cyclic carbon chain containing one or more double bonds including, but not limited to, ethenyl, propenyl, butenyl, isopropenyl, isobutenyl, cyclobutenyl, cyclopentenyl, cyclo -hexenyl, and the like.
[00010] The term "aryl" and "Ar" refers to any aromatic ring, mono- or bicyclic, containing the heteroatom.
[00011] The term "heterocyclyl" refers to any aromatic or non-aromatic ring, mono- or bicyclic, containing one or more heteroatoms.
[00012] The term "alkoxy" refers to an -OR substituent.
[00013] The term "hydroxyl" refers to an -OH substituent.
[00014] The term "amino" refers to a -N(R)2 substituent.
[00015] The term "halogen" or "halo" refers to one or more halogen atoms, defined as F, Cl, Br, and I.
[00016] The term "nitro" refers to a -NO2 substituent.
[00017] The term thioalkyl refers to a -SR substituent.
[00018] Throughout the description, reference to the compounds of Formula I is read to likewise include all stereoisomers, for example, diastereomers, enantiomers, and mixtures thereof. In another embodiment, Formula (I) is read as the same to include salts or hydrates thereof. Exemplary salts include, but are not limited to: hydrochloride, hydrobromide, hydroiodide, trifluoroacetate and trifluoromethane sulfonate.
[00019] It is likewise understood by those skilled in the art that additional substitution is permissible, unless otherwise noted, provided the chemical bonding and stress energy rules are satisfied, and the product still exhibits fungicidal activity.
[00020] Another embodiment of the present description is a use of a compound of Formula I, for protecting a plant against attack by a phytopathogenic organism or the treatment of a plant infested by a phytopathogenic organism, comprising the application of a compound of Formula I, or a composition comprising the compound to the soil, a plant, a part of a plant, foliage and/or roots.
[00021] Additionally, another embodiment of the present description is a composition useful for protecting a plant against attack by a phytopathogenic organism and/or treating a plant infested by a phytopathogenic organism comprising a compound of Formula I and a phytologically acceptable carrier material . DETAILED DESCRIPTION
[00022] The compounds of the present description can be applied by any of a variety of known techniques, as the compounds or as formulations comprising the compounds. For example, the compounds can be applied to plant roots or foliage to control various fungi, without damaging the plants' commercial value. The materials can be applied in the form of any of the commonly used formulation types, for example, as solutions, powders, wettable powders, flowable concentrates or emulsifiable concentrates.
[00023] Preferably, the compounds of the present description are applied in the form of a formulation, comprising one or more of the compounds of the compounds of Formula I with a phytologically acceptable carrier. Concentrated formulations can be dispersed in water or other liquids for application, or formulations can be powder or granular type, which can then be applied without further treatment. The formulations can be prepared according to procedures that are conventional in the agricultural chemical arts.
[00024] The present description contemplates all vehicles by which one or more of the compounds can be formulated for release and used as a fungicide. Typically, the formulations are applied as aqueous suspensions or emulsions. Such suspensions or emulsions can be made from water-soluble, water-suspensible, or emulsifiable formulations that are solid, commonly known as wettable powders; or liquids, commonly known as emulsifiable concentrates, aqueous suspensions, or suspension concentrates. As will be readily appreciated, any material to which these compounds can be added can be used, as long as it produces the desired utility without significant interference with the activity of these compounds as antifungal agents.
[00025] Wettable powders, which can be compacted to form water dispersible granules, comprise an intimate mixture of one or more of the compounds of Formula I, an inert carrier and surfactants. The concentration of the compound in the wettable powder can be from about 10 percent to about 90 percent by weight based on the total weight of the wettable powder, more preferably about 25 percent by weight to about 75 percent. In preparing wettable powder formulations, the compounds can be compounded with any finely divided solid, such as prophyllite, talc, chalk, gypsum, Fuller's earth, bentonite, attapulgite, starch, casein, gluten, montmorillonite clays, diatomaceous earth, silicates purified or similar. In such operations, the finely divided vehicle and surfactants are typically mixed with the compound(s) and ground.
[00026] Emulsifiable concentrates of the compounds of Formula I may comprise a convenient concentration, such as from about 1 percent by weight to about 50 percent of the compound, in a suitable liquid, based on the total weight of the concentrate. The compounds can be dissolved in an inert carrier, which is a water-miscible solvent or a mixture of water-immiscible organic solvents, and emulsifiers. Concentrates can be diluted with water and oil to form spray mixtures in the form of oil-in-water emulsions. Useful organic solvents include aromatics, especially the high-boiling naphthalene and olefinic moieties of petroleum such as heavy aromatic naphtha. Other organic solvents can likewise be used, for example terpenic solvents, including rosin derivatives, aliphatic ketones, such as cyclohexanone, and complex alcohols, such as 2-ethoxyethanol.
[00027] Emulsifiers which can be employed to advantage here can be readily determined by those skilled in the art and include various nonionic, anionic, cationic and amphoteric emulsifiers, or a mixture of two or more emulsifiers. Examples of nonionic emulsifiers useful in preparing the emulsifiable concentrates include polyalkylene glycol ethers and condensation products of alkyl and aryl phenols, aliphatic alcohols, aliphatic amines or fatty acids with ethylene oxide, propylene oxides such as ethoxylated alkyl phenols, and carboxylic esters solubilized with the polyol or polyoxyalkylene. Cationic emulsifiers include quaternary ammonium compounds and fatty amine salts. Anionic emulsifiers include the oil-soluble (e.g., calcium) salts of alkylaryl sulfonic acids, oil-soluble salts or sulfated polyglycol ethers, and appropriate phosphated polyglycol ether salts.
[00028] Representative organic liquids that can be employed in preparing the emulsifiable concentrates of the compounds of the present description are aromatic liquids such as xylene, propyl benzene fractions; or mixed naphthalene fractions, mineral oils, substituted aromatic organic liquids such as dioctyl phthalate; kerosene; dialkyl amides of various fatty acids, particularly the dimethyl amides of fatty glycols and glycol derivatives such as n-butyl ether, ethyl ether or methyl ether of diethylene glycol, methyl ether of triethylene glycol, petroleum fractions or hydrocarbons such as oil mineral, aromatic solvents, paraffinic oils, and the like; vegetable oils such as soybean oil, rapeseed oil, olive oil, castor oil, sunflower seed oil, coconut oil, corn oil, cottonseed oil, linseed oil, palm oil, peanut oil, safflower oil, sesame oil, tung oil, and the like; esters of the above vegetable oils; and the like. Mixtures of two or more organic liquids can likewise be employed in preparing the emulsifiable concentrate. Organic liquids include xylene, and propyl benzene fractions, with xylene being more preferred in some cases. Surface-active dispersing agents are typically employed in liquid formulations and in an amount of 0.1 to 20 percent by weight based on the combined weight of the dispersing agent with one or more of the compounds. The formulations may likewise contain other compatible additives, for example plant growth regulators and other biologically active compounds used in agriculture.
[00029] Aqueous suspensions comprise suspensions of one or more water-insoluble compounds of Formula I, dispersed in an aqueous vehicle at a concentration in the range of from about 1 to about 50 percent by weight, based on the total weight of the aqueous suspension . Suspensions are prepared by finely grinding one or more of the compounds, and vigorously mixing the ground material in a vehicle comprised of water and selected surfactants from the same types discussed above. Other components, such as inorganic salts and synthetic or natural gums, can likewise be added to increase the density and viscosity of the aqueous vehicle.
[00030] The compounds of Formula I can likewise be applied as granular formulations, which are particularly useful for soil applications. Granular formulations generally contain from about 0.5 to about 10 percent by weight, based on the total weight of the granular formulation of the compound(s), dispersed in an inert carrier consisting wholly or largely of material. roughly divided inert such as attapulgite, bentonite, diatomite, clay or a similar cheap substance. Such formulations are usually prepared by dissolving the compounds in a suitable solvent and applying them to a granular carrier which has been preformed to the appropriate particle size, in the range of about 0.5 to about 3 mm. A suitable solvent is a solvent in which the compound is substantially or completely soluble. Such formulations can similarly be prepared by making a mass or paste of the vehicle and the compound and solvent, and crushing and drying to obtain the desired granular particle.
[00031] Powders containing the compounds of Formula I can be prepared by intimately mixing one or more of the compounds in powdered form with a suitable dusty agricultural vehicle, such as, for example, kaolin clay, ground volcanic stone, and the like. Powders may suitably contain from about 1 to about 10 percent by weight of the compounds, based on the total weight of the powder.
[00032] The formulations may additionally contain adjuvant surfactants to enhance the deposition, wetting and penetration of the compounds on the target culture and organism. These adjuvant surfactants can optionally be employed as a component of the formulation or as a tank mix. The amount of adjuvant surfactant will typically range from 0.01 to 1.0 percent by volume, based on a volume of spray water, preferably 0.05 to 0.5 percent by volume. Suitable adjuvant surfactants include, but are not limited to ethoxylated nonyl phenols, ethoxylated synthetic or natural alcohols, salts of the sulfosuccinic esters or acids, ethoxylated organosilicones, ethoxylated fatty amines, surfactant mixtures with mineral or vegetable oils, culture oil concentrate mineral (85%) + emulsifiers (15%)); nonylphenol ethoxylate; benzylcocoalkyldimethyl quaternary ammonium salt; mixture of petroleum hydrocarbon, alkyl esters, organic acid, and anionic surfactant; C9-C11 alkylpolyglycoside; phosphate alcohol ethoxylate; natural primary alcohol ethoxylate (C12 - C16); di-sec-butylphenol EO-PO block copolymer; polysiloxane-methyl buffer; nonylphenol ethoxylate + urea ammonium nitrate; emulsified methylated seed oil; tridecyl alcohol ethoxylate (synthetic) (8EO); tallow amine ethoxylate (15 EO); PEG(400)-dioleate-99. The formulations may also include oil-in-water emulsions such as those described in U.S. Patent Application Serial No. 11/495,228, the description of which is expressly incorporated by reference herein.
[00033] The formulations may optionally include combinations that contain other pesticidal compounds. Such additional pesticide compounds may be fungicides, insecticides, herbicides, nematocides, miticides, arthropodicides, bactericides or combinations thereof that are compatible with the compounds of the present description in the medium selected for application, and not antagonistic to the activity of the present compounds. Consequently, in such embodiments, the other pesticide compound is employed as a supplemental toxicant for the same or a different pesticide use. The compounds of Formula I, and the pesticide compound in the combination may generally be present in a weight ratio of from 1:100 to 100:1.
[00034] The compounds of the present description can likewise be combined with other fungicides to form fungicidal mixtures and synergistic mixtures thereof. The fungicidal compounds of the present description are often applied together with one or more other fungicides to control a wider variety of undesirable diseases. When used in conjunction with other fungicide(s), the compounds now claimed may be formulated with the other fungicide(s), tank mixed with the other fungicide(s) (s) or applied sequentially with the other fungicide(s). Such other fungicides may include 2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol, 8-hydroxyquinoline sulfate, amethoctradine, amisulbrom, antimycin, Ampelomyces quisqualis, azaconazole, azoxystrobin, Bacillus subtilis, Bacillus subtilis strain QST713, benalbethyl, benyl avamil, -isopropyl, benzovindiflupyr benzylaminobenzene sulfonate (BABS) salt, bicarbonates, biphenyl, bismerthiazole, bitertanol, bixaphene, blasticidin-S, borax, Bordeaux mixture, boscalide, bromuconazole, bupirimate, calcium polysulfide,captafol,captain, carbendazim, carpropamide, carvone, clazafenone, chlorneb, chlorothalonil, chlozolinate, Coniothyrium minitans, copper hydroxide, copper octanoate, copper oxychloride, copper sulfate, copper sulfate (tribasic), cuprous oxide, cyazofamid, cyflufenamide, cymoxanil, cyprodinilconazole , dazomete, debacarb, diammonium ethylenebis-(dithiocarbamate), dichlofluanid, dichlorophene, diclocymete, diclomezine, dichlorane, di ethofencarb, difenoconazole, difenzoquathione, diflumethorim, dimethomorph, dimoxystrobin, diniconazole,diniconazole-M, dinobutone, dinocap, diphenylamine, dithianone, dodemorph, dodemorph acetate, dodine, dodine free base, edifenphos, ethoxyconazole and enestrobin , etridiazole, famoxadone, fenamidone, fenarimol, fembuconazole, fenfuram, fenhexamide, fenoxanil, fempiclonil, fempropidin, fempropimorph, fempirazamine, fentin, fentin acetate, fentin hydroxide, ferbam, phenoxanil, fluxonazine, fluxonazine , fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, fluthianil, flutolanil, flutriafol, fluxapyroxad, folpet, formaldehyde, fosetyl, fosetyl-aluminum, fuberidazole, furalaxyl, furametpyr, guazatine, hexazatine acetates, chloroalhexyl, imazazole , imazalyl sulfate, imibenconazole, iminoctadine, iminoctadine triacetate, iminoctadine tris(albesylate) na, iodocarb, ipconazole, ipfempyrazolone, iprobenfos, iprodione, iprovalicarb, isoprothiolane, isopirazam, isotianil, kasugamycin, kasugamycin hydrochloride hydrate, kresoxim-methyl, laminarin, mancopper, mancofenam, meniprom, mebepropani, mandipani dinocap, mercuric chloride, mercuric oxide, mercurous chloride, metalaxyl, metalaxyl-M, metam, metam-ammonium, metam-potassium, metam-sodium, metconazole, metasulphocarb, methyl iodide, methyl isothiocyanate, methim, methraminoestrobin , myclobutanil, nabam, nitrothal-isopropyl, nuarimol, octilinone, ofurace, oleic acid (fatty acids), oryisastrobin, oxadixyl, oxine-copper, oxpoconazole fumarate, oxycarboxin, pefurazoate, penconazole, pencichlorone, penflurate penthiopyrad, phenylmercuric acetate, phosphonic acid, phthalide, picoxystrobin, polyoxin B, polyoxins, polyoxorim, potassium bicarbonate, hydroxy sulfate potassium uinolin, probenazole, prochloraz, procymidone, propamocarb, propamocarb hydrochloride, propiconazole, propineb, proquinazid, prothioconazole, pyraclostrobin, pyramethostrobin, pyraoxystrobin, pyrazolophos, pyribencarb, pyributicarb, pyphenoxyquinone, pyrophenoquinone Reynoutria sachalinensis extract, sedaxane, siltiofam, simeconazole, sodium 2-phenylphenoxide, sodium bicarbonate, sodium pentachlorophenoxide, spiroxamine, sulfur, SYP-Z048, tar oils, tebuconazole, tebufloquin, technazene, tetraconazole, thiabendazole, thifazamide -methyl, tyram, tiadinil, tolclophos-methyl, tolylfluanid, triadimephone, triadimenol, triazoxide, tricyclazole, tridemorph, trifloxiestrobin, triflumizole, triforine, triticonazole, validamycin, valifenalate, valifenalate, valifenarium, candidal, vinophilazinexamide, vinoxylazine , Gliocladium spp., Phlebiopsis gigantea, Streptomyces griseoviridis, Trichode rma spp., (RS)-N-(3,5-dichlorophenyl)-2-(methoxymethyl)succinimide, 1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone hydrate, 1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane, 2-(2-heptadecyl-2-imidazolin-1-yl) ethanol, 2,3-dihydro-5-phenyl-1,4-dithi -in 1,1,4,4-tetraoxide, 2-methoxyethylmercuric acetate, 2-methoxyethylmercuric chloride, 2-methoxyethylmercuric silicate, 3-(4-chlorophenyl)-5-methylrhodanine, 4-(2-nitroprope- 1-enyl)phenyl thiocyanateme, ampropylphos, anilazine, azithiram, barium polysulfide, Bayer 32394, benodanil, benquinox, bentaluron, benzamacril; benzamacril-isobutyl, benzamorph, binapacryl, bis(methylmercury) sulfate, bis(tributyltin) oxide, butiobate, cadmium calcium copper zinc chromate sulfate, carbamorph, CECA, clobenthiazone, chloraniform, chlorphenazol, chlorquinox, climbazole, copper bis(3-phenylsalicylate), copper zinc chromate, cufraneb, cupric hydrazinium sulphate, cuprobam, cyclafuramide, cipendazole, ciprofuram, decafentin, diclone, dichlozoline, diclobutrazol, dimethirimol, dinoctone, dinosulfone, dinotherbone, dihydrogen dodicin, drazoxolone, EBP, ESBP, etaconazole, etem, ethyrim, phenaminosulfo, fenapanil, fenitropane, fluotrimazole, furcarbanil, furconazole, furconazole-cis, furmeciclox, furofanate, gliodine, griseofulvin, halacrinate, Ispan and hexium58, Ipanacrinate 39 , mebenil, mecarbinzide, metazoxolone, metfuroxam, methylmercury dicyandiamide, metsulfovax, milneb, mucochloric anhydride, myclozoline, N-3,5-dichlorophenyl-succinimide, N-3 - nitrophenylitaconimide, natamycin, N-ethylmercury-4-toluenesulfonanilide, nickel bis(dimethyldithiocarbamate), OCH, phenylmercuric dimethyldithiocarbamate, phenylmercuric nitrate, phosdiphene, prothiocarb; prothiocarb hydrochloride, pyracarbolide, pyridinitrile, pyroxychlor, pyroxyfur, quinacetol; quinacetol sulfate, quinazamide, quinconazol, rabenzazol, salicylanilide, SSF-109, sultropene, tecoram, thiadifluor, thiophene, thiochlorphenfin, thiophanate, thioquinox, thioximide, triamiphos, triarimol, triazbutyl, triclamide, urbacide, and any combinations thereof.
[00035] Additionally, the compounds described herein can be combined with other pesticides, including insecticides, nematocides, miticides, arthropodicides, bactericides or combinations thereof that are compatible with the compounds of the present description in the medium selected for application, and not antagonistic to the activity of the present compounds to form pesticide mixtures and synergistic mixtures thereof. The fungicidal compounds of the present description can be applied together with one or more other pesticides to control a wider variety of unwanted pests. When used in conjunction with other pesticides, the compounds now claimed may be formulated with the other pesticide(s), tank mixed with the other pesticide(s) or applied. s) sequentially with the other pesticide(s). Typical insecticides include, but are not limited to: 1,2-dichloropropane, abamectin, acephate, acetamiprid, acethione, acetoprol, acrinathrin, acrylonitrile, alanicarb, aldicarb, aldoxycarb, aldrin, allethrin, alosamidine, alexyperbrine, alpha- ecdysone, alpha-endosulfan, amidithion, aminocarb, amitone, amitone oxalate, amitraz, anabasin, atidathione, azadirachtin, azamethiphos, azinphos-ethyl, azinphos-methyl, nitrogenate, bultary hexafluorosilicate, barthrin, bendathione, cyfluthrin, beta-cypermethrin, bifenthrin, bioallethrin, bioethanomethrin, biopermethrin, bistriflurone, borax, boric acid, bronfenvinphos, bromocyclone, bromoDDT, bromophos, bromophos-ethyl, bufencarb, buprofezine, butofanate, butacarboxynate, butacarb, butacarb of calcium, calcium polysulfide, campechlor, carbanolate, carbaryl, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothione, carbosulfan, cartape, c cartape hydrochloride, chlorantraniliprole, chlorbicyclene, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chloroxiphos, chlorfenapyr, chlorfenvinphos, chlorfluazuron, chlormephos, chloroform, chloropicrine, chlorpyriphorine, chlorpyrifoxim II, cinerins, cismethrin, chloethocarb, closantel, clothianidin, copper acetoarsenite, copper arsenate, copper naphthenate, copper oleate, cumaphos, cumitoate, crotamitone, crotoxyphos, crufomate, cryolite, cyanophenolyltranthol, cyanocyanine, cyanophos cycloprothrin, cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyromazine, citioate, DDT, decarbofuran, deltamethrin, demefione, demefione-O, demefione-S, demetone, demetone-methyl, demetone-O, demetone-O-methyl, demetone demetone-S-methyl, demetone-S-methylsulfone, diafenthiuron, dialyphos, diatomaceous earth, diazinone, dicaptone, diclofenthion, dichlorvos, dicresyl, dicrotophos, dicyclanil, d ieldrin, diflubenzuron, dilor, dimefluthrin, dimefox, dimethane, dimethoate, dimethrin, dimethylvinphos, dimethylane, dinex, dinex-diclexin, dinoprop, dinosam, dinotefuran, diofenolane, dioxabenzophos, dioxacarb, dioxonene, DN-disulfone DNOC-ammonia, DNOC-potassium, DNOC-sodium, doramectin, ecdiesterone, emamectin, emamectin benzoate, EMPC, empentrin, endosulfan, endothione, endrin, EPN, epofenonane, eprinomectin, esdevalberate, ethophenothine, esphenethione ethoate-methyl, ethoprophos, ethyl formate, ethyl-DDD, ethylene dibromide, ethylene dichloride, ethylene oxide, ethofemprox, ethrphos, EXD, fanfur, fenamiphos, fenazaflor, fenchlorphos, fenetacarb, fenfluthrine, phenobucarbethione , phempyritrine, phenpropathrin, fensulfothione, phenthione, phenthione-ethyl, fenvalerate, fipronil, flonicamid, flubendiamide, flucofurone, flucycloxuron, flucitrinate, flufenerim, flufenoxuron, flufemprox, fluval innate, phonofos, formetanate, formetanate hydrochloride, formotiona, formparanate, formparanate hydrochloride, phosmethylane, fospirate, phostiethane, furathiocarb, furethrin, gamma-cyhalothrin, gamma-HCH, halfemprox, halofenozide, HCH, HEOD, heptachlor, heptopho iflumurone, HHDN, hydramethylnon, hydrogen cyanide, hydroprene, hykincarb, imidacloprid, imiprothrin, indoxacarb, iodomethane, IPSP, isazophos, isobenzane, isocarbophos, isodrine, isofenphos, isofenphos-thiolane, isoxacarb, isoprotine , jasmolin II, jodfenphos, juvenile hormone I, juvenile hormone II, juvenile hormone III, celevane, cynoprene, lambda-cyhalothrin, lead arsenate, lepimectin, leptophos, lindane, lyrinfos, lufenuron, litidathione, malathion, malonobene, mazidox, mecarba mecarphone, menazone, mephospholane, mercurous chloride, mesulfenphos, metaflumizone, methacrylphos, methamidophos, methidathione, methiocarb, methocrotophos, methomyl, methoprene, methoxychlor, m ethoxyfenozide, methyl bromide, methyl isothiocyanate, methylchloroform, methylene chloride, metoflutrine, metolcarb, methoxadiazone, mevinphos, mexacarbate, milbemectin, milbemycin oxime, mipafox, mirex, molossultape, monomeliptophos, monomethophthion, monomethophthion, monomethophthion , naphthalene, nicotine, nifluridide, nitempiram, nithiazine, nitrilacarb, novalurone, noviflumuron, omethoate, oxamyl, oxidomethone-methyl, oxidoprofos, oxydisulfotone, para-dichlorobenzene, parathion, parathione-methyl, pentochlorphene, phenophenophenophene, penflurone , phorate, phosalone, phospholane, phosmete, phosnichlor, phosphamidone, phosphine, foxim, foxim-methyl, pyrimethophos, pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, potassium arsenite, potassium thiocyanate, pp'-DDT, pralethrin, precocious , precocious II, precocious III, primidophos, profenophos, profluralin, promacil, promecarb, propaphos, propetamphs, propoxur, protidathione, prothiophos, protoate, protrifemb ute, pyraclophos, pyrafluprol, pyrazolophos, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyridaben, pyridalyl, pyridaphenthione, pyrifluquinazone, pyrimidiphene, pyrimitate, pyriprol, pyriproxyfen, quassia, pyridaben, pyridalyl, pyridaphenthione, pyrifluquinazone, pyrimidiphene, pyrimitate, pyriprole, pyriproxyfen, quassia, pyridaben, quinonexalone, methyl riania, sabadila, escradane, selamectin, silafluofen, silica gel, sodium arsenite, sodium fluoride, sodium hexafluorosilicate, sodium thiocyanate, sofamide, spinetoram, spinosad, spiromesifen, spirotetramate, sulcofurone, sulcofurone sulfoloxa, sulfoteluramide , sulfuryl fluoride, sulprofos, taufluvalinate, tazincarb, TDE, tebufenozide, tebufempyrad, tebupyrinfos, teflubenzuron, tefluthrin, temefos, TEPP, teralethrin, terbufos, tetrachloroethane, tetrachlorvinphos, tetraphothiamethyl , thiocarboxime, thiocyclam, thiocyclam oxalate, thiodicarb, thiophanox, thiometone, thiosultape, thiosultape disodium, thiosultape-monosodium, thuringiensin, tolfempyrad, tralomethrin, transfluthrin, transpermethrin, triarathene, triazamate, triazophos, trichlorphone, trichlormetaphos-3, trichloronate, triphenophos, triflumurone, trimetacarb, triprenyl-mcprobe, xiamidothion and any combinations thereof.
[00036] Additionally, the compounds described herein can be combined with herbicides that are compatible with the compounds of the present description in the medium selected for application, and not antagonistic to the activity of the present compounds to form pesticide mixtures and synergistic mixtures thereof. The fungicidal compounds of the present description can be applied together with one or more herbicides to control a wide variety of unwanted plants. When used in conjunction with herbicides, the compounds now claimed can be formulated with the herbicide(s), tank mixed with the herbicide(s) or applied sequentially with the herbicide(s). Typical herbicides include, but are not limited to: 4-CPA; 4-CPB; 4-CPP; 2,4-D; 3,4-DA; 2,4-DB; 3,4-DB; 2,4-DEB; 2,4-DEP; 3,4-DP; 2,3,6-TBA; 2,4,5-T; 2,4,5-TB; acetochlor, acifluorfen, aclonifen, acrolein, alachlor, alidochlor, aloxidim, allyl alcohol, alorac, ametridione, ametrine, amibuzine, amicarbazone, amidosulfuron, aminocyclopyrachlor, aminopyralide, amiprophos-methyl, amiprofos-methyl, amitrol, amurona, sulfamate , atrazine, azafenidin, azinsulfuron, aziprothrin, barbane, BCPC, beflubutamide, benazoline, bencarbazone, benfluralin, benfuresate,bensulfurone,bensulide, bentazone, benzadox, benzfendizone, bencycloram, benzofluorbicyclobenzy,propane, benzophene , bispyribac, borax, bromacil, bromobonil, bromobutide, bromophenoxim, bromoxynil, brompirazone, butachlor, butaphenacyl, butamiphos, butenachlor, butidazole, butyuron, butraline, butroxydim, calcium buturon, butylate, castrolamide caffeine, castrodyl acid cambendichlor, carbasulam, carbetamide, carboxazole chlorprocarb, carfentrazone, CDEA, CEPC, clomethoxyphene, chloramben , chloranocrile, chlorazifop, chlorazine, chlorbromurone, chlorbufam, chloreturone, chlorfenac, chlorfemprope, chlorflurazol, chlorflurenol, chloridazone, chlorimuron, chlornitrofen, chloropone, chlorotolurone, chlorthalsulfurone, chlorphurone, methylsulfurone , cisanilide, cletodim, cliodinate, clodinafop, clofop, clomazone, clomeprop, cloprope, cloproxydim, clopyralide, chloransulam, CMA, copper sulfate, CPMF, CPPC, credazine, cresol, cumilurone, cyanatrine, cyclosulfone, cyclocyanazine , cyhalophop, cyperquat, cyprazine, ciprazole, cypromide, daimuron, dalapone, dazomete, delachlor, desmedipham, desmethrin, di-allate, dicamba, dichlobenil, dichloralurea, dichlormate, dichlorprop, dichlorpropen, dichlorosulfen-P, diet , diphenoxuron, difenzoquat, diflufenican, diflufenzopyr, dimefurone, dimepiperate, dimethachlor, dimethametrine, dimethenamid, dimethenamid-P, d imexane, dimidazone, dinitramine, dinofenate, dinoprop, dinosam, dinoseb, dinoterb, diphenamide, dipropetrin, diquat, disul, dithiopyr, diuron, DMPA, DNOC, DSMA, EBEP, eglinazine, endothal, epronacarb, EPTC, and erflurabin ethametsulfuron, ethidimuron, ethiolate, ethofumesate, ethoxyphene, ethoxysulfuron, etinophen, ethnipromide, etobenzanide, EXD, fenassulam, fenoprop, fenoxaprop, fenoxaprop-P, fenoxasulfone, fenteracol, fentiaprop, flamurone flamurone, sulfurone sulphate, sulphate , florasulam, fluazifop, fluazifop-P, fluazolate, flucarbazone, fluketosulfuron, fluchloralin, flufenacet, flufenican, flufempir, flumetsulam, flumezine, flumichlorac, flumioxazine, flumipropyn, fluometurone, fluometurone, fluorophenopropyl, fluoromoxina, fluuropropoyl, fluoromoxina, fluoropropyne, fluoromoxina , flupyrsulfuron, fluridone, flurochloridone, fluroxypyr, flurtamone, fluthiacet, flumipropene, foransulfuron, phosamine, furyloxifene, glyphosinate, glyphosinate-P, glyphosate, halauxifene, halosaphen, halosulfuron, haloxidine, haloxyfop, haloxyfop-P, hexachloroacetone, hexaflurate, hexazinone, imazametabenz, imazamox, imazapic, imazapyr, imadanzopyrilium, imazapine, imazapyr, imadanzophylazine, inimaze, imazapine iodosulfuone, ioxynil, ipazine, ipfencarbazone, iprimidam, isocarbamide, isocyl, isomethiozine, isonoruron, isopolinate, isopropaline, isoproturone, isourone, isoxaben, isoxachlortol, isoxaflutol, moxaflutol, ma butyl, isoxapyrifapyrifaline MCPA-thioethyl, MCPB, mecoprop, mecoprop-P, medinoterb, mefenacet, mefluidide, mesoprazine, mesosulfuron, mesotrione, metam, metamifop, metamitrone, metazachlor, metazosulfuone, metflurazone, mesoprazine, mesothionecarin, metal methoprothrin, methyl bromide, methyl isothiocyanate, methyldinron, methobenzuron, methobromurone, metolachlor, metho ssulam, metoxuron, metribuzin, metsulfuron, molinate, monalide, monisouron, monochloroacetic acid, monolinuron, monuron, morphanquat, MSMA, naproanilide, napropamide, naptalam, neburone, nicosulfuron, nipyraclofene, nitrofen, nitrocarin, nitrocar , ortho-dichlorobenzene, orthosulfamuron, oryzalin, oxadiargyl, oxadiazone, oxapyrazone, oxasulfuron, oxaziclomephone, oxyfluorfen, paraflurone, paraquat, pebulate, pelargonic acid, pendimethalin, penoxsulam, petloxam-medispham-phenyldox, pentofenofen ethyl, phenobenzuron, phenylmercuric acetate, picloram, picolinaphene, pinoxaden, piperophos, potassium arsenite, potassium azide, potassium cyanate, pretilachlor, primisulfuron, procyazine, prodiamine, profluazol, profluralin, profoxidim, promethinazine, promethinazine, , propaquizafop, propazine, profam, propisochlor, propoxycarbazone, propiris sulfurone, propizamide, prosulfaline, prosulfocarb, prosulfuron, proxane, prinachlor, pidanone, pyraclonil, pyraflufen, pyrasulfotol, pyrazolinate, pyrazosulfuron, pyrazoxifene, pyribenzoxim, pyributicarb, pyrichloride, pyroximyl, pyroximyl, pyroximul quinchlorac, quinmerac, quinocamine, quinonamide, quizalofop, quizalofop-P, rodetanil, kidneysulfurone, saflufenacyl, S-metolachlor, sebuthylazine, secbumetone, sethoxydim, sidurone, simazine, simetone, simetrin, SMA, sodium arsenite, azitrate sodium, sulcotrione, sulphalate, sulfentrazone, sulfometurone, sulfosulfuron, sulfuric acid, sulglicapine, swep, TCA, tebutam, tebutiuron, tefuryltrione, tembotrione, tepraloxidim, terbacil, terbucarb, terbuchlor, tetrazoyl, terbumetone, terbuthia, terbumetone , thidiazimine, thidiazuron, thiencarbazone-methyl, thifensulfuron, thiobencarb, thiocarbazil, thiochlor kidney, topramezone, tralkoxydim, triaphamon, tri-allate, triasulfuron, triaziflam, tribenuron, tricamba, triclopyr, tridiphane, triethazine, trifloxysulfuron, trifluralin, triflusulfuron, trifop, trifopsime, trihydroxytriazine, trichlorine, trimethurone, trimethurone .
[00037] Another embodiment of the present description is a method for controlling or preventing fungal attack. This method comprises applying to the soil, plant, roots, foliage or place of the fungus, or in a place where infestation is to be prevented (for example, applying to the grain or grape plants), a fungicidally effective amount of one or more of the compounds of Formula I. The compounds are suitable for treating various plants at fungicidal levels while exhibiting low phytotoxicity. The compounds can be useful both in a protective and/or eradicating manner.
[00038] The compounds have been found to have significant fungicidal effect particularly for agricultural use. Many compounds are particularly effective for use with agricultural crops and horticultural plants.
[00039] It will be understood by those skilled in the art that the effectiveness of the compound for the foregoing fungi establishes the general utility of the compounds as fungicides.
[00040] The compounds have wide ranges of activity against fungal pathogens. Exemplary pathogens may include but are not limited to causing the agent wheat leaf pustule (Zymoseptoria tritici), wheat brown rust (Puccinia triticina), striped rust (Puccinia striiformis), apple rind (Venturia inaequalis), mold vine powder (Uncinula necator), barley burn (Rhynchosporium dryalis), rice blast (Pyricularia oryzae), soybean blight (Phakopsora pachyrhizi), wheat gluma pustule (Leptosphaeria nodorum), wheat powdery mold (Blumeria. sp. tritici), barley powdery mold (Blumeria graminisf. sp. hordei), cucurbit powdery mold (Erysiphe cichoracearum), cucurbit anthracnose (Colletotrichum lagenariom), beet leaf spot (Cercospora beticola precocious), pest Alternaria solani), and barley spot pustule (Cochliobolus sativus). The exact amount of active material to be applied is dependent not only on the specific active material to be applied, but also on the particular action desired, the fungal species to be controlled, and their stage of growth, as well as the part plant or other product to be contacted with the compost. Thus, all compounds, and formulations containing them, may not be equally effective at similar concentrations or against the same fungal species.
[00041] The compounds are effective in use with plants in a phytologically acceptable and disease-inhibiting amount. The term "phytologically acceptable and disease-inhibiting amount" refers to an amount of a compound that kills or inhibits plant disease for which control is desired, but is not significantly toxic to the plant. This amount will generally be from about 0.1 to about 1000 ppm (parts per million), with 1 to 500 ppm being preferred. The exact concentration of compound required varies with the fungal disease to be controlled, the type of formulation employed, the method of application, the particular plant species, weather conditions, and the like. A suitable application rate is typically in the range of about 0.10 to about 0.01 to 0.45 grams per square meter, g/m2 (4 pounds/acre).
[00042] Any desired range or value produced here can be extended or changed without losing the intended effects, as is evident to the person versed in an understanding of the teachings here.
[00043] The compounds of Formula I can be made using well known chemical procedures. Intermediates not specifically mentioned in this description are commercially available, can be made by routines described in the chemical literature, or can be easily synthesized from commercial starting materials using standard procedures. GENERAL SCHEMES
[00044] The following schemes illustrate methods for generating picolinamide compounds of Formula (I). The following descriptions and examples are provided for illustrative purposes and are not to be construed as limiting in terms of substituents or substitution patterns. Compounds of Formulas 1.1, 1.2, 1.3, and 1.4, where R3 is as originally defined, may be prepared by methods shown in Scheme 1, steps a - c. Compounds of Formula 1.0, where Z is ethoxy (-OCH2CH3, OEt) or pyrrolidine and PG is Bn or PMB, can be treated with a mixture of an organometallic nucleophile, such as phenylmagnesium or phenyl lithium bromide, and a reducing agent , such as lithium borohydride (LiBH4), in a polar, aprotic solvent such as tetrahydrofuran (THF) or diethyl ether (Et2O) at a reduced temperature from about -78°C to about 0°C to providing the compounds of Formula 1.1, wherein R3 is as previously defined, as shown in step a. Alternatively, the compound of Formula 1.0, where Z is OEt and PG is Bn or PMB, can be converted to the aldehyde of Formula 1.2 by treating with a catalyst such as chlorobis(cyclooctene)iridium(I) dimer ( Ir2(coe)4Cl2), and a reducing agent, such as diethylsilane (Et2SiH2), in a halogenated solvent such as dichloromethane (CH2Cl2), as described by Cheng, C.; Brookhart, M. Angew. Chem. Int. Ed. 2012, 51, 9422 - 9424 and shown in step b. Compounds of Formulas 1.3 and 1.4, wherein R3 is as previously defined, can be obtained by treating the aldehyde of Formula 1.2 with a carbon nucleophile, such as phenyl magnesium bromide, in a polar, aprotic solvent, such as THF, at a reduced temperature of about -78°C to about 23°C, as described in step c. Scheme 1

[00046] Compounds of Formulas 2.1, 2.2 and 2.3, where R3 is as originally defined, can be obtained using the methods outlined in Scheme 2, steps a - d. Compounds of Formula 2.1, where R3 is as previously defined and R4 is aryl, can be prepared by treating solutions of compounds of Formula 2.0, where R3 is as originally defined, in a solvent such as toluene, with an organometallic species, such as bis(acetate-O)triphenyl-bismuth(V) (Ph3Bi(OAc)2), in the presence of a catalyst, such as copper(II) acetate (Cu(OAc)2), at an elevated temperature of about 50°C as shown in step a. Alternatively, arylated products of Formula 2.1, wherein R3 is as previously defined, may be prepared by treating compounds of Formula 2.0, wherein R3 is as previously defined, with an aryl fluoride, such as 1,3-difluorobenzene, and an alkoxide base, such as potassium tert-butoxide (KOt-Bu) or sodium hydride (NaH), in a polar, aprotic solvent, such as N,N-dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO) , at an elevated temperature of about 50°C to about 70°C, as shown in step b. Compounds of Formula 2.2, wherein R3 is as previously defined and R4 is alkyl, can be prepared from compounds of Formula 2.0, wherein R3 is as previously defined by treating with a base such as KOt-Bu or NaH, and an electrophile, such as an alkyl halide such as (bromomethyl)cyclopropane, in a polar, aprotic solvent such as DMF, at an elevated temperature of about 50°C, as shown in step c. Compounds of Formula 2.3, where R3 is as previously defined and R4 is acyl, can be prepared from compounds of Formula 2.0 by treating with an electrophile, such as an acyl chloride, in a pyridine solvent at room temperature as shown. in step d. Scheme 2

[00047] Compounds of Formula 3.2, wherein R4 and R8 are as originally defined, can be prepared according to the methods outlined in Scheme 3, steps a - c. Compounds of Formula 3.0, where R4 is as originally defined, may be subjected to a palladium catalyst, such as tetracis(triphenylphosphine)palladium(0) (Pd(PPh3)4), and a secondary amine, such as morpholine, in a polar, aprotic solvent, such as THF, at a temperature of about 23°C to provide the compounds of Formula 3.1, wherein R4 is as originally defined, as shown in step a. Compounds of Formula 3.2, where R4 is as originally defined and R8 is alkyl, can be prepared from compounds of Formula 3.1, where R4 is as originally defined, by treatment with a base such as potassium carbonate (K2CO3), and an alkyl bromide, such as (bromomethyl)cyclohexane, in a polar, aprotic solvent, such as acetone, at a temperature of about 25°C to about 50°C, as shown in step b. Additionally, compounds of Formula 3.2, wherein R4 is as originally defined and R8 is aryl, can be prepared from alcohols of Formula 3.1, wherein R4 is as previously defined, by treatment with a copper catalyst such as Cu(OAc )2, an aryl boronic acid, such as phenyl boronic acid, and a tertiary amine, such as triethylamine (NEt3), in a halogenated solvent, such as CH2Cl2, in the presence of 4Â molecular sieves at a temperature of approximately 23°C , as described by Nie, Z.; Perretta, C.; Lu, J.; Su, Y.; Margosiak, S.; Gajiwala, KS; Cortez, J.; Nikulin, V.; Yager, KM; Appelt, K.; Chu, SJ Med. Chem., 2005, 48 (5), pp 1596-1609, and shown in step c. Scheme 3

[00048] Compounds of Formula 4.2, wherein R3 and R4 are as originally defined, can be prepared according to the methods outlined in Scheme 4, steps a - c. Compounds of Formula 4.2, where R3 and R4 are as previously defined but not alkenyl, can be prepared by treating compounds of Formula 4.0, where R3 and R4 are originally defined, with a catalyst such as palladium on carbon (Pd/C), in the presence of hydrogen gas (H2) in a polar solvent such as ethyl acetate (EtOAc) or MeOH, or with an alternate source of hydrogen, such as cyclohexene, in a polar solvent such as EtOH as shown in step a. Additionally, compounds of Formula 4.0, where R3 is as previously defined and R4 is an aryl chloride, can be subjected to modified hydrogenolysis conditions by exposing an EtOH solution of the aryl chloride to H2 in the presence of Pd/ C and NEt3 to provide the compounds of Formula 4.2, wherein R3 and R4 are as originally defined, but not alkenyl or chloro, as shown in step b. Compounds of Formula 4.2, wherein R3 and R4 are as originally defined, can be obtained by treating compounds of Formula 4.1, wherein R3 and R4 are as originally defined, with an oxidant, such as 2,3-dichloro-5. ,6-dicyano-1,4-benzoquinone (DDQ), in a mixed solvent, such as aqueous CH2Cl2, as indicated in step c. Scheme 4

[00049] Compounds of Formula 5.2, wherein R1, R2, R3, R4, R11, and R12, are as originally defined, can be prepared according to the method outlined in Scheme 5, step a. Alcohols of Formula 5.0, wherein R2, R3, R4, and R12, are as originally defined, can be treated with compounds of Formula 5.1, wherein R1 and R11 are as originally defined, a coupling reagent, such as 3 hydrochloride. -(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDC) or a polymer supported carbodiimide (PS-CDI), and a catalyst, such as N,N-dimethylpyridin-4-amine (DMAP), in a halogenated solvent, such as CH 2 Cl 2 , to provide the compounds of Formula 5.2, wherein R 1 , R 2 , R 3 , R 4 , R 11 , and R 12 are as previously defined, as shown in step a. Scheme 5

[00050] Compounds of Formula 6.4, wherein R1, R2, R3, R4, R6,R11, and R12 are as originally defined, can be prepared according to the methods outlined in Scheme 6, steps a - d. Compounds of Formula 6.0, where R1, R2, R3, R4, R11, and R12 are as originally defined but not alkenyl, can be treated with an acid, such as a 4N solution of HCl in dioxane, in a halogenated solvent such as CH 2 Cl 2 to provide the compounds of Formula 6.1, wherein R 1 , R 2 , R 3 , R 4 , R 11 , and R 12 are as originally defined but not alkenyl as shown in step a. Compounds of Formula 6.2, wherein R1, R2, R3, R4,R11, and R12 are as originally defined, can be prepared by treating the compounds of Formula 6.0, wherein R1, R2, R3, R4, R11, and R12 are as originally defined, with an acid, such as 2,2,2-trifluoroacetic acid, in a halogenated solvent such as CH2Cl2, as shown in step b. Compounds of Formulas 6.1 and 6.2, wherein R1, R2, R3, R4, R11, and R12 are as originally defined, may be treated with compounds of Formula 6.3, wherein R6 is as originally defined, in the presence of a base, such as such as diisopropylethylamine, and a peptide coupling reagent such as benzotriazol-1-yl-oxytripyrrolidinephosphonium hexafluorophosphate (PiBOP) or O-(7-azabenzo-triazol-1-yl)-N,N,N' hexafluorophosphate ,N-tetramethyluronium (HATU), in a halogenated solvent such as CH2Cl2, to provide the compounds of Formula 6.4, wherein R1, R2, R3, R4, R6, R11, and R12 are as previously defined, as shown in step c . Scheme 6

[00051] Compounds of Formula 7.1, wherein R1, R2, R3, R6, R11, and R12 are as originally defined but not alkenyl, and R8 is as originally defined but not alkenyl or chlorine, may be prepared from according to the method outlined in Scheme 7, step a. Compounds of Formula 7.0, wherein R1, R2, R3, R6, R8, R11, and R12 are as originally defined, can be subjected to the hydrogenation conditions described in Scheme 4, step b to provide the compounds of Formula 7.1, wherein R1, R2, R3, R6, R8,R11, and R12 are as previously defined, as described in step a. Scheme 7
[00052] Compounds of Formula 8.1, wherein R1, R2, R3, R4, R6, R7, R11, and R12 are as originally defined, may be prepared according to the method outlined in Scheme 8, steps a or b. Compounds of Formula 8.0, wherein R1, R2, R3, R4, R6, R11, and R12 are as previously defined, can be treated with an appropriate alkyl halide with or without a reagent such as sodium iodide (NaI) and a base of alkali carbonate, such as Na2CO3 or potassium carbonate (K2CO3), in a solvent such as acetone, as shown in step a. Or, alternatively, by treatment with an acyl halide or anhydride in the presence of an amine base, such as pyridine, NEt3, DMAP, or mixtures thereof, in an aprotic solvent, such as CH2Cl2, to provide the compounds of Formula 8.1 , wherein R1, R2, R3, R4, R6, R7, R11, and R12 are as previously defined, as shown in step b. Scheme 8
[00053] Compounds of Formula 9.1 and 9.2, wherein R1, R2, R4, R6, R11, and R12 are as originally defined but not alkenyl, and R8 is as originally defined but not allyloxy or alkenyl may be prepared according to the method outlined in Scheme 9, step a. Compounds of Formula 9.0, wherein R1, R2, R4, R6, R8, R11, and R12 are as originally defined, can be treated with a ruthenium catalyst, such as ruthenium trichloride hydrate, and a hydride source, such as sodium borohydride (NaBH4), in a polar, aprotic solvent such as THF, in the presence of water, at a temperature of about 0°C to provide the compounds of Formula 9.1 and 9.2, as described by Sharma, PK; Kumar, S.; Kumar, P.; Nielson, P. Tet. Lett, 2012, 48, 8704-8708 and shown in step a.
[00054] Compounds of Formula 10.3, wherein R2, R3, R4 and R12 are as originally defined, can be prepared according to the methods outlined in Scheme 10, steps a - c. Compounds of Formula 10.0, where R3 is as originally defined, can be transformed into a Grignard reagent by being subjected to magnesium metal in the presence of a lithium salt such as lithium chloride (LiCl) in a polar, aprotic solvent, such as THF, at an elevated temperature of about 70°C. The subsequent Grignard reagent can then be subjected to an iron catalyst, such as tris(acetylacetonate) iron(III) (Fe(acac)3), and an alkyl chloride, such as allyl chloride, in a polar solvent. , aprotic, such as THF, at an elevated temperature of about 70°C to provide the compounds of Formula 10.1, wherein R 2 , R 3 , R 12 are as originally defined, as described by Mayer, M.; Welter, A.; von Wangelin, AJ ChemCatChem, 2011, 3, pp 1567 - 1571, and as shown in step a. Compounds of Formula 10.2, wherein R2, R3, and R12 are as originally defined, may be prepared from compounds of Formula 10.1, wherein R2, R3, and R12 are as originally defined, by treatment with an ammonium salt such as hydrogen sulfate of tetra n-butylammonium, an epoxidation catalyst such as 1,2:4,5-Bis-O-(isopropylidene)-β-L-erythro-2,3-hexodiulo-2,6-pyranose (enantiomer catalyst Shi epoxidation), a buffering solution, such as 0.05 M Na2B4O7-10H2O in 4 X 10-4 M aqueous Na2 (EDTA), in a polar, aprotic solvent, such as acetonitrile, at a temperature of about 0°C. Followed by slow addition of an oxidant such as Oxone to a solution of Na2(EDTA) and simultaneous slow addition of a solution of a base such as K2CO3 in water as described by Wang, Z.-X.; You, Y.; Frohn, M.; Zhang, J.-R.; Shi, YJ Am. Chem. Soc, 1997, 119, pp 11224 - 11235, and as shown in step b. Additionally, compounds of Formula 10.3, wherein R2, R3, R4 and R12 are as originally defined, may be prepared from the epoxides of Formula 10.2, wherein R2, R3, R12 are as previously defined, by treatment with an acid, such as as sulfuric acid (H2SO4) in a mixture of an alcohol substituted with R4 where R4 is as previously defined, such as cyclopropanol, at a reduced temperature of about 0°C, as described by Aggarwal, VK; Bae, I; Lee, H.-Y. Tetrahedron, 2006, 60(43), pp 9725 - 9733, and shown in step c. EXAMPLES
[00055] Example 1A: Preparation of (1R,2S)-1-(4-fluorophenyl)-2-((4-methoxybenzyl)oxy)propan-1-ol.
[00056] To a solution of (4-fluorophenyl)magnesium bromide (7.08 mL, 5.67 mmol) and lithium borohydride (LiBH4) (2.83 mL, 5.67 mmol, 2.0 molar (M) ) in THF) in anhydrous Et 2 O (11.45 mL) at -15°C was added (S)-ethyl 2-((4-methoxybenzyl)oxy)propanoate (1.35 g, 5.67 mmol) as a solution. to 1M in anhydrous Et2O (5.67 mL) via addition funnel over approximately a 40 minute period (min) at a rate that maintained an internal temperature between -7 and -15°C. The reaction vessel was allowed to slowly warm to room temperature (rt) overnight. The reaction mixture was cooled to 0°C and quenched by slow addition of saturated aqueous ammonium chloride (NH4Cl, 25 mL) followed by water (H2O, 25 mL). The mixture was transferred to a separatory funnel, and the aqueous phase (aq.) was extracted with Et2O (3 x 50 mL). The combined organic phases were dried over magnesium sulphate (MgSO4 ), filtered and concentrated. The resulting residue was purified by flash column chromatography (silica gel (SiO2), 5^25% acetone in hexanes) to give the title compound (214 mg, 13%) as a colorless oil: 1H NMR (400 MHz , CDCl 3 ) δ 7.33 - 7.27 (m, 2H), 7.25 - 7.21 (m, 2H), 7.05 - 6.98 (m, 2H), 6.91 - 6.86 (m, 2 H), 4.85 (t, J = 3.3 Hz, 1 H), 4.57 (d, J = 11.4 Hz, 1 H), 4.46 (d, J = 11 .4Hz, 1H), 3.81 (s, 3H), 3.69 (qd, J = 6.3, 4.0Hz, 1H), 2.53 (d, J = 2.9 Hz, 1H), 1.02 (d, J = 6.3 Hz, 3H); 19F NMR (376 MHz, CDCl 3 ) δ -115.49 (s); ESIMS m/z 603 ([2M+Na]+).
[00057] Example 1B: Preparation of (S)-2-((4-methoxybenzyl)oxy)propanal.
[00058] To a solution of (S)-ethyl 2-((4-methoxybenzyl)oxy)propanoate (5.00 g, 21.0 mmol) in CH2Cl2 (30 mL) at 0°C was added chlorobis(dimer) cyclooctene)iridium(I) (Ir2Cl2(coe)4); 94.0 milligrams (mg), 0.105 mmol) followed by diethylsilane (Et2SiH2; 4.08 mL, 31.5 mmol) for 10 min. The mixture was stirred at 0°C for 30 min, then warmed to rt and stirred for 3 h. The reaction mixture was cooled to 0°C and quenched by addition of aq hydrogen chloride. to 1 normal (N) (HCl; 12 ml). The resulting solution was warmed to rt and stirred for 15 min. The phases were separated, and the aq. was extracted with CH2Cl2 (3 x 30 mL). The combined organic phases were washed with brine, dried over sodium sulfate (Na2SO4), filtered, evaporated and purified by flash column chromatography (SiO2, 2^50% acetone in hexanes) to give the title compound (4.27 g, 100%) as a yellow oil: IR (Thin Film) 2934, 2837, 2865, 1731, 1512 cm-1; 1H NMR (300 MHz, CDCl 3 ) δ 9.64 (d, J = 1.9 Hz, 1H), 7.35 - 7.21 (m, 2H), 6.95 - 6.79 (m, 2H), 4.63 - 4.40 (m, 2H), 3.94 - 3.76 (m, 1H), 3.81 (s, 3H), 1.31 (d, J = 6.9 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 203.58, 159.54, 129.65, 129.37, 113.98, 79.14, 71.75, 55.30, 15.34.
[00059] Example 1C: Preparation of (1S,2S)-2-((4-methoxybenzyl)oxy)-1-phenylpropan-1-ol.
[00060] To a solution of (S)-2-((4-methoxybenzyl)oxy)propanal (3.38 g, 17.4 mmol) in Et2O (58 mL) at -78°C was added phenylmagnesium bromide ( 34.8 mL, 34.8 mmol, 1 M in THF) dropwise. The reaction mixture was stirred and allowed to warm at RT overnight. The reaction was quenched by addition of aq ammonium chloride. sat. (NH4Cl). The mixture was partitioned between H2O and EtOAc, the phases were separated, and the aqueous phase was extracted with EtOAc (2x). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (SiO2, 2±50% acetone in hexanes) provided an inseparable mixture of diastereomers (dr 3:1 SS:RS) of the title compound (3.29 g, 66%) as a yellow oil: 1H NMR (400 MHz, CDCl3; major) δ 7.37 - 7.25 (m, 7H), 6.89 (d, J = 8.6Hz, 2H), 4.62 (d , J = 11.0 Hz, 1 H), 4.44 (dd, J = 7.8, 2.1 Hz, 1 H), 4.41 (d, J = 11.0 Hz, 1 H), 3.82 (s, 3H), 3.60 (dq, J = 7.8, 6.2Hz, 1H), 3.21 (d, J = 2.1Hz, 1H), 1, 05 (d, J = 6.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 159.34, 140.56, 130.21, 129.46, 128.31, 127.25, 126.31, 113.93, 79.66, 78.32, 70 .92, 55.30, 15.56; ESIMS m/z 295 ([M+Na]+).
[00061] Example 1D: Preparation of (1S,2S)-2-((4-methoxybenzyl)oxy)-1-(thiophen-2-yl)propan-1-ol and (1R,2S)-2-(( 4-methoxybenzyl)oxy)-1-(thiophen-2-yl)propan-1-ol.
[00062] To a solution of thiophen-2-yl lithium (4.00 mL, 4.00 mmol, 1 M in THF) and lithium borohydride (LiBH4; 1.30 mL, 2.60 mmol, 2 M in THF) in THF (10 mL) at -10°C was added liquid (S)-2-((4-methoxybenzyl)oxy)-1-(pyrrolidin-1-yl)propan-1-one (0.527 g, 2.00 mmol) (for preparation see: Pellicena, M.; Solsona, JG; Romea, P.; Urpi, F. Tetrahedron 2012, 68, 10338.) dropwise via syringe pump addition for approximately one period of 1 h, at a rate that kept the internal temperature below -5°C. The reaction vessel was allowed to slowly warm to RT overnight. The reaction mixture was quenched by addition of aq. sat. The aqueous phase was extracted with Et2O (3x). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (SiO 2 , 2 x 10% acetone in hexanes) provided the title compounds (0.231 g, 41% and 0.175 g, 31%, respectively) as colorless oils: Major: 1H NMR (300 MHz, CDCl 3 ) δ 7.32 - 7.21 (m, 3H), 7.05 - 6.93 (m, 2H), 6.94 - 6.83 (m, 2H), 5.03 (t, J = 4.2 Hz, 1 H), 4.61 (d, J = 11.4 Hz, 1 H), 4.48 (d, J = 11.3 Hz, 1 H), 3, 81 (s, 3H), 3.88 - 3.73 (m, 1H), 2.59 (d, J = 4.4 Hz, 1H), 1.13 (d, J = 6.3 Hz, 3H); ESIMS m/z 579 ([2M+Na]+); secondary: 1H NMR (300 MHz, CDCl3) δ 7.34 - 7.22 (m, 3H), 7.06 - 6.92 (m, 2H), 6.95 - 6.84 (m, 2 H), 4.73 (dd, J = 7.3, 2.7 Hz, 1 H), 4.63 (d, J = 10.9 Hz, 1 H), 4.44 (d, J = 11 0.0Hz, 1H), 3.82 (s, 3H), 3.67 (dq, J = 7.3, 6.2Hz, 1H), 3.29 (d, J = 2.8 Hz, 1H), 1.14 (d, J = 6.1 Hz, 3H); ESIMS m/z 579 ([2M+Na]+).
[00063] Example 1E: Preparation of (1R,2S)-1-(4-fluoro-2-methoxy-phenyl)-2-((4-methoxybenzyl)oxy)propan-1-ol
[00064] To a reaction flask were added 1-bromo-4-fluoro-2-methoxybenzene (0.4 g, 1.951 mmol) and dry diethyl ether (9.75 ml). The vial was sealed, evacuated and recharged with nitrogen, and cooled to -78°C. Then n-BuLi (2.5M in hexanes, 0.780 ml, 1.951 mmol) was added to the reaction, and the reaction mixture was stirred at -78°C for 1 h. LiBH4 (2.0M in THF, 0.975 ml, 1.951 mmol) was added, followed by dropwise addition of (S)-ethyl 2-((4-methoxybenzyl)oxy)propanoate (0.465 g, 1.951 mmol) as a solution. at 0.5M in dry diethyl ether. The reaction was allowed to gradually warm up to RT as the cooling bath expired overnight. The reaction was quenched by carefully adding 2 mL aq. sat. (observed gas evolution), and allowed to stir for 30 min. At this point, the mixture was transferred to a separatory funnel containing water and extracted 3x with diethyl ether. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO 2 , 5→30% acetone in hexanes) to give the title compound (290 mg, 46%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.42 (dd, J = 8.1, 7.2 Hz, 1H), 7.27 - 7.21 (m, 2H), 6.91 - 6, 85 (m, 2H), 6.66 (td, J=8.4, 2.4Hz, 1H), 6.55 (dd, J=10.9, 2.4Hz, 1H), 5.15 (t, J = 3.5 Hz, 1 H), 4.57 (d, J = 11.6 Hz, 1 H), 4.50 (d, J = 11.6 Hz, 1 H) , 3.86 - 3.78 (m, 4H), 3.76 (s, 3H), 2.65 (dd, J = 3.4, 2.0Hz, 1H), 1.00 ( d, J = 6.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 162.88 (d, J = 244.4 Hz), 159.19, 157.03 (d, J = 9.6 Hz), 130.66, 129.30, 128.47 (d, J = 9.9 Hz), 124.48 (d, J = 3.2 Hz), 113.76, 106.79 (d, J = 20.9 Hz), 98.43 (d, J = 25.9 Hz), 75.79 (d), 70.35, 69.97, 55.45, 55.30, 13.46; ESIMS m/z 663 ([2M+Na]+).
[00065] Example 2A: Preparation of 1-methoxy-2-((1R,2S)-2-((4-methoxybenzyl)oxy)-1-phenoxypropyl)benzene.
[00066] To a solution of (1R,2S)-2-((4-methoxybenzyl)oxy)-1-(2-methoxyphenyl)propan-1-ol (500 mg, 1.654 mmol), N-cyclohexyl- N-methylcyclohexanamine (531 µl, 2.480 mmol) and Cu(OAc)2 (60.1 mg, 0.331 mmol) in toluene (8.267 ml) was added Ph3Bi(OAc)2 (1385 mg, 2.480 mmol). The resulting blue suspension was heated to and stirred at 50°C for 16 h. The reaction was cooled in rt, filtered through a pad of CeliteTM and concentrated. The resulting crude material was purified by flash column chromatography (SiO 2 , 0±30% acetone in hexanes) to yield the title compound (555 mg, 67%) as a yellow oil: 1H NMR (300 MHz, CDCl 3 ) ) δ 7.41 - 7.33 (m, 3 H), 7.18 (q, J = 8.2 Hz, 5 H), 7.08 (d, J = 8.0 Hz, 1 H), 6.89 - 6.81 (m, 7H), 5.73 (d, J = 3.5Hz, 1H), 4.60 - 4.49 (m, 2H), 3.88 - 3 .82 (m, 4H), 3.79 (s, 3H), 1.25 (d, J = 6.4Hz, 3H); 13C NMR (101 MHz, CDCl3) δ158.98, 158.27, 156.42, 129.42, 129.18, 128.47, 127.69, 125.82, 121.56, 120.76, 120, 46, 115.71, 113.59, 110.12, 76.32, 75.29, 70.61, 55.38, 55.27, 14.75; ESIMS m/z779 ([2M+Na]+).
[00067] Example 2B: Preparation of 2-chloro-1-((1R,2S)-1-(4-fluoro-2-methoxyphenyl)-2-((4-methoxybenzyl)oxy)propoxy)-4-methylbenzene.
[00068] To a solution of (1R,2S)-1-(4-fluoro-2-methoxyphenyl)-2-((4-methoxybenzyl)oxy)propan-1-ol (190 mg, 0.593 mmol) in anhydrous DMSO (2.97 mL) was added NaH (29.7 mg, 0.741 mmol, 60% by weight in mineral oil). After stirring for 10 min, 2-chloro-1-fluoro-4-methylbenzene (686 mg, 4.74 mmol) was added, and the reaction mixture was heated at 60 °C for 15 h. The reaction was quenched by slow addition of H2O. The mixture was extracted Et2O (3 x 50 mL) and the combined organic layers were dried by passing through a phase separator. Volatiles were removed under a gentle stream of N 2 and the resulting residue was purified by flash column chromatography (SiO 2 , 0^30% acetone in hexanes) to give the title compound (217 mg, 82%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 9.2, 6.8 Hz, 1H), 7.19 (d, J = 8.7Hz, 2H), 7.14 (d, J = 1.7Hz, 1H), 6.85 - 6.77 (m, 3H), 6.62 - 6.55 (m, 3H), 5.63 (d , J = 3.8 Hz, 1 H), 4.63 (d, J = 11.9 Hz, 1 H), 4.57 (d, J = 11.9 Hz, 1 H), 3.89 ( qd, J = 6.4, 3.9 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 2.19 (s, 3H), 1.25 (d, J = 6.4Hz, 3H); 19F NMR (376 MHz, CDCl 3 ) δ-112.06 (s); ESIMS m/z 467 ([M+Na]+).
[00069] Example 2C: Preparation of 4-((1R,2S)-2-(benzyloxy)-1-(cyclopropylmethoxy)-propyl)-1,1'-biphenyl.
[00070] To a solution of (1R,2S)-1-([1,1'-biphenyl]-4-yl)-2-(benzyloxy) propan-1-ol (272 mg, 0.854 mmol) in anhydrous DMF (2.8 mL) at 0°C was added sodium hydride (NaH; 59.8 mg, 1.50 mmol, 60% by weight in mineral oil). The reaction mixture was stirred at 0°C for 15 min. The mixture was removed from the ice bath, stirred for 15 min, then cooled again to 0°C. The reaction was treated with (bromomethyl)cyclopropane (84 µL, 0.854 mmol) and allowed to stir at 0°C. After 10 min, the reaction vessel was removed from the ice bath and the reaction mixture was allowed to stir and warm at RT overnight. The reaction mixture was carefully quenched by the addition of H2O. The crude reaction mixture was stirred for 10 min, and the phases were separated. The phase here was extracted with Et2O (3x), and the combined organic phases were dried over Na2SO4, filtered and concentrated. The resulting oil was purified by flash column chromatography (SiO 2 , 0±10% acetone in hexanes) to give the title compound (251 mg, 79%) as a colorless oil: 1H NMR (400 MHz, CDCl 3 ) δ 7 .64 - 7.60 (m, 2H), 7.57 (d, J = 8.2Hz, 2H), 7.48 - 7.32 (m, 5H), 7.24 - 7. 19 (m, 3H), 7.10 - 7.06 (m, 2H), 4.46 (d, J = 11.9 Hz, 1H), 4.30 (d, J = 11.9 Hz, 1H), 4.27 (d, J = 6.4Hz, 1H), 3.64 (p, J = 6.2Hz, 1H), 3.28 - 3.20 (m, 2H), 1.32 (d, J = 6.2Hz, 3H), 1.12 - 1.01 (m, 1H), 0.56 - 0.45 (m, 2H), 0 .22 - 0.10 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 141.03, 140.33, 139.54, 138.60, 128.75, 128.18, 128.14, 127.67, 127.30, 127.18, 127 .06, 126.73, 84.36, 78.56, 73.75, 71.47, 16.71, 10.74, 3.18, 2.83; ESIMS m/z 395 ([M+Na]+).
[00071] Example 2D: Preparation of (1R,2S)-1-(4-fluoro-2-methoxy-phenyl)-2-((4-methoxybenzyl)oxy)propyl pivalate.
[00072] To a solution of (1R,2S)-1-(4-fluoro-2-methoxyphenyl)-2-((4-methoxybenzyl)oxy)propan-1-ol (85 mg, 0.265 mmol)) in pyridine Anhydrous (0.858 mL) at 25°C was added pivaloyl chloride (65.3 µL, 0.531 mmol). The reaction mixture was stirred at 25°C for 16 h. The reaction was diluted with toluene, and volatiles were removed by rotary evaporation. The resulting oil was purified by flash column chromatography (SiO 2 , 5→30% acetone in hexanes) to give the title compound (91 mg, 85%) as a colorless oil: 1H NMR (300 MHz, CDCl 3 ) δ 7 .22 (dt, J = 5.8, 2.9 Hz, 3H), 6.88 - 6.82 (m, 2H), 6.67 - 6.54 (m, 2H), 6. 39 (d, J = 3.3 Hz, 1 H), 4.60 (d, J = 11.6 Hz, 1 H), 4.49 (d, J = 11.6 Hz, 1 H), 3 .83 - 3.74 (m, 7H), 1.26 (s, 9H), 1.10 (d, J = 6.5Hz, 3H); 19F NMR (471 MHz, CDCl 3 ) δ-112.37 - - 112.55 (m); ESIMS m/z 427 ([M+Na]+).
[00073] Example 3A: Preparation of 5-fluoro-2-((1R,2S)-2-((4-methoxybenzyl)oxy)-1-phenoxypropyl)phenol.
[00074] The solution of 2-(allyloxy)-4-fluoro-1-((1R,2S)-2-((4-methoxy-benzyl)oxy)-1-phenoxypropyl)benzene (294 mg, 0.696 mmol) and morpholine (72.8 µL, 0.835 mmol) in anhydrous THF (3.48 mL) was added Pd(PPh3)4 (40.2 mg, 0.035 mmol). The mixture was stirred at 25°C for 5 h, then quenched by the addition of water. The mixture was diluted with Et2O, transferred to a separatory funnel and washed with 1N HCl (3 x 50 mL). The organic layer was dried by passing through a phase separator, and volatiles were removed in vacuo. The resulting residue was purified by flash column chromatography (SiO2, 5^15% acetone in hexanes) to give the title compound (228 mg, 86%) as a viscous oil:1H NMR (400 MHz, CDCl3) δ 8 .01 (s, 1H), 7.18 (ddt, J = 9.8, 4.7, 2.4 Hz, 4H), 7.07 (dd, J = 8.5, 6.6 Hz , 1H), 6.91 (t, J = 7.4Hz, 1H), 6.86 - 6.79 (m, 4H), 6.61 (dd, J = 10.3, 2, 5Hz, 1H), 6.54 (td, J = 8.3, 2.6Hz, 1H), 5.01 (d, J = 6.3Hz, 1H), 4.60 (d , J = 11.2 Hz, 1 H), 4.43 (d, J = 11.2 Hz, 1 H), 4.03 (p, J = 6.2 Hz, 1 H), 3.80 ( s, 3H), 1.30 (d, J = 6.2 Hz, 3H); 19F NMR (376 MHz, CDCl 3 ) δ -112.86 (s); ESIMS m/z 381 ([M-H]- ).
[00075] Example 3B: Preparation of 2-(cyclopropylmethoxy)-4-fluoro-1-((1R,2S)-2-((4-methoxybenzyl)oxy)-1-phenoxypropyl)benzene.
[00076] To a mixture of 5-fluoro-2-((1R,2S)-2-((4-methoxybenzyl)oxy)-1-phenoxypropyl)phenol (114 mg, 0.298 mmol), and K2CO3 (82 mg, 0.596 mmol) in acetone (1.49 mL) was added (bromomethyl)cyclopropane (43.4 µL, 0.447 mmol). The reaction mixture was stirred at 25°C for 24 h. Potassium carbonate (82 mg, 0.596 mmol) and (bromomethyl)cyclopropane (43.4 µL, 0.447 mmol), and DMSO (1.49 mL) were then added to the reaction mixture. The reaction was stirred at 50°C for 24 h at which point volatiles were removed under a stream of nitrogen. The resulting residue was purified by flash column chromatography (SiO 2 , 0 30% acetone in hexanes) to give the title compound (104 mg, 80%) as a colorless oil: 1H NMR (400 MHz, CDCl 3 ) δ 7 .34 - 7.28 (m, 1H), 7.22 - 7.14 (m, 4H), 6.84 (dt, J = 11.4, 8.1 Hz, 5H), 6. 57 (dd, J = 12.5, 6.0 Hz, 2H), 5.73 (d, J = 3.3Hz, 1H), 4.60 (s, 2H), 3.94 - 3.78 (m, 3H), 3.78 (s, 3H), 1.34 - 1.23 (m, 4H), 0.68 - 0.62 (m, 2H), 0. 38 (q, J = 4.8 Hz, 2H); 19F NMR (376 MHz, CDCl 3 ) δ-112.62 (s); ESIMS m/z 459 ([M+Na]+).
[00077] Example 3C: Preparation of 1-((1R,2S)-1-(2-chlorophenoxy)-2-((4-methoxybenzyl)oxy)propyl)-4-fluoro-2-phenoxybenzene.
[00078] To a solution of 2-((1R,2S)-1-(2-chlorophenoxy)-2-((4-methoxy-benzyl)oxy)propyl)-5-fluorophenol (197 mg, 0.473 mmol), and phenylboronic acid (144 mg, 1.181 mmol) in anhydrous CH2Cl2 (2.36 mL) were added NEt3 (329 µL, 2.363 mmol), Cu(OAc)2 (94 mg, 0.520 mmol) and 4A molecular sieves. The reaction mixture was stirred at 23°C for 3 days (d), then filtered through Celite™ and concentrated. The resulting residue was purified by flash column chromatography (SiO 2 , 0 30% acetone in hexanes) to give the title compound (102 mg, 44%) as a colorless oil: 1H NMR (400 MHz, CDCl 3 ) δ 7 .50 (dd, J = 8.6, 6.7 Hz, 1H), 7.35 (ddd, J = 10.0, 7.8, 1.8 Hz, 3H), 7.18 (dd , J = 17.1, 8.0 Hz, 3H), 7.07 - 7.01 (m, 1H), 7.01 - 6.97 (m, 2H), 6.84 - 6. 70 (m, 5 H), 6.46 (dd, J = 10.1, 2.4 Hz, 1 H), 5.77 (d, J = 3.9 Hz, 1 H), 4.64 ( d, J = 11.8 Hz, 1H), 4.58 (d, J = 11.8Hz, 1H), 4.05 - 3.97 (m, 1H), 3.77 (s, 3H), 1.33 (d, J = 6.4Hz, 3H); 19F NMR (376 MHz, CDCl 3 ) δ-111.43 (d, J = 2.1 Hz); ESIMS m/z 515 ([M+H]+).
[00079] Example 4A: Preparation of (1R,2S)-1-([1,1'-biphenyl]-4-yl)-1-phenoxypropan-2-ol.
[00080] To a magnetically stirred mixture of 4-((1R,2S)-2-(benzyloxy)-1-phenoxypropyl)-1,1'-biphenyl (72 mg, 0.183 mmol) in ethanol (1.22 mL) and cyclohexene (608 µL) was added Pd/C (78 mg, 0.018 mmol, 2.5 wt%). The reaction mixture was stirred at 70°C for 2 h. The reaction mixture was cooled at rt, filtered through Celite™ and concentrated. The resulting residue was purified by flash column chromatography (SiO 2 , 5→30% acetone in hexanes) to give the title compound (43 mg, 77%) as a white solid. 1H NMR (400 MHz, CDCl 3 ) δ 7.59 - 7.54 (m, 4H), 7.43 (dd, J = 12.1, 5.0Hz, 4H), 7.33 (t, J = 7.3 Hz, 1 H), 7.20 (t, J = 8.0 Hz, 2 H), 6.90 (t, J = 8.1 Hz, 3 H), 5.10 (d , J = 4.7Hz, 1H), 4.20 - 4.12 (m, 1H), 2.00 (s, 1H), 1.29 (d, J = 6.4Hz, 3H ); 13C NMR (101 MHz, CDCl3) δ 157.83, 140.92, 140.61, 136.78, 129.42, 128.78, 127.45, 127.39, 127.31, 127.05, 121 .12, 115.90, 83.43, 71.14, 18.11; ESIMS m/z 631 ([2M+Na]+).
[00081] Example 4B: Preparation of (1S,2S)-1-phenoxy-1-(thiophen-2-yl)propan-2-ol.
[00082] To a solution of 2-((1S,2S)-2-((4-methoxybenzyl)oxy)-1-phenoxypropyl)thiophene (0.223 g, 0.630 mmol) in a mixture of CH2Cl2 (3 mL) and H2O (0.3 mL) at 0 °C was added 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (0.150 g, 0.661 mmol). The reaction mixture was stirred for 30 min. The reaction was quenched by adding 1N aq NaOH. (0.66 mL) and was diluted with CH2Cl2 (10 mL). The phases were separated, and the aq. was extracted with CH2Cl2 (2 x 10 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (SiO 2 , 2±20% acetone in hexanes) provided the title compound (116 mg, 75%) as a colorless oil: IR (Thin Film) 3390, 2923, 2851, 2865, 1597 cm-1; 1H NMR (300 MHz, CDCl 3 ) δ 7.33 - 7.16 (m, 3H), 7.07 (ddd, J = 3.5, 1.2, 0.7 Hz, 1H), 7, 03 - 6.88 (m, 4H), 5.26 (d, J = 4.9Hz, 1H), 4.28 - 4.09 (m, 1H), 2.08 (d, J =4.9Hz, 1H), 1.29 (d, J=6.3Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 157.60, 140.58, 129.43, 126.59, 126.50, 125.94, 121.60, 116.21, 80.60, 70.73, 18 .33.
[00083] Example 5: Preparation of (S)-(1R,2S)-1-phenoxy-1-(p-tolyl)propan-2-yl 2-((tert-butoxycarbonyl)amino)propanoate.
[00084] To a solution of (1R,2S)-1-phenoxy-1-(p-tolyl)propan-2-ol (99 mg, 0.409 mmol) and (1R,2S)-1-phenoxy-1-( p-tolyl)propan-2-ol (99 mg, 0.409 mmol) in CH 2 Cl 2 (2.04 mL) at 0 °C was added (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (Boc-Ala -OH; 85 mg, 0.449 mmol), DMAP (4.99 mg, 0.041 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (EDC; 157 mg, 0.817 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was concentrated. Purification by flash column chromatography (SiO 2 , 5→30% acetone in hexanes) provided the title compound (164 mg, 97%) as a colorless oil: 1H NMR (400 MHz, CDCl 3 ) δ 7.27 ( d, J = 6.8Hz, 3H), 7.19 - 7.11 (m, 4H), 6.87 (t, J = 7.4Hz, 1H), 6.82 (d, J = 7.8 Hz, 2 H), 5.28 - 5.21 (m, 1 H), 5.15 (d, J = 4.8 Hz, 1 H), 4.96 (d, J = 7.2Hz, 1H), 4.29 - 4.19 (m, 1H), 2.31 (s, 3H), 1.42 (s, 9H), 1.35 (d, J =6.4Hz, 3H), 1.14 (d, J=7.2Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.73, 157.95, 137.83, 134.48, 129.33, 129.19, 126.87, 121.09, 115.96, 81.07, 74 .22, 28.31, 21.15, 18.51, 14.93; ESIMS m/z414 ([M+H]+).
[00085] Example 6A: Preparation of (S)-(1R,2S)-1-(4-fluorophenyl)-1-phenoxypropan-2-yl 2-aminopropanoate hydrochloride.
[00086] To a solution of ((S)-(1R,2S)-1-(4-fluorophenyl)-1-phenoxypropan-2-yl 2-((tert-butoxycarbonyl)amino)propanoate (220 mg, 0.527 mmol) was added a 4N solution of HCl in dioxane (1.98 ml, 7.9 mmol) The mixture was stirred for 1 h at rt. title as a viscous, colorless oil, which was used in the next step without further purification: ESIMS m/z 318 ([M+H]+).
[00087] Example 6B: Preparation of (S)-(1R,2S)-1-(4-fluorophenyl)-1-phenoxypropan-2-yl 2-(3-hydroxy-4-methoxypicolinamido)propanoate.
[00088] To a solution of (S)-(1R,2S)-1-(4-fluorophenyl)-1-phenoxypropan-2-yl 2-aminopropanoate hydrochloride (186 mg, 0.526 mmol), 3-hydroxy acid- 4-methoxypicolinic (98 mg, 0.578 mmol) and PyBOP (301 mg, 0.578 mmol) in CH2Cl2 (2.63 mL) was added N,N-diisopropylethylamine (DIEA) (303 µL, 1.74 mmol) . The reaction mixture was stirred overnight at room temperature. The solvent was evaporated, and the crude oil was purified by flash column chromatography (SiO 2 , 5→30% acetone in hexanes) to give the title compound (215 mg, 80%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 12.06 (s, 1H), 8.39 (d, J = 7.7Hz, 1H), 7.97 (d, J = 5.2Hz, 1H), 7, 40 - 7.34 (m, 2H), 7.20 - 7.13 (m, 2H), 7.03 - 6.96 (m, 2H), 6.88 (dd, J = 15, 2, 6.3 Hz, 2H), 6.82 - 6.78 (m, 2H), 5.31 - 5.24 (m, 1H), 5.18 (d, J = 5.2 Hz, 1H), 4.64 (p, J = 7.2Hz, 1H), 3.93 (s, 3H), 1.39 (d, J = 6.4Hz, 3H), 1.33 (d, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.49, 168.69, 163.72, 161.27, 157.58, 155.39, 148.76, 140.48, 133.27, 133.24, 130 .37, 129.41, 128.75, 128.67, 121.41, 115.95, 115.64, 115.43, 109.49, 80.61, 74.32, 56.07, 47.95 , 18.01, 15.20; 19F NMR (376 MHz, CDCl 3 ) δ -113.62 (s); HRMS-ESI (m/z) ([M+H]+) calcd for C25H26FN2O6, 469.1769; found, 469,1777.
[00089] Example 7: Preparation of (S)-(1R,2S)-1-(4-fluoro-2-methoxyphenyl)-1-(p-tolyloxy)propan-2-yl 2-(3-hydroxy -4-methoxypicolinamido)propanoate.
[00090] To a reaction flask were added (S)-(1R,2S)-1-(2-chloro-4-methylphenoxy)-1-(4-fluoro-2-methoxyphenyl)propan-2-yl 2- (3-hydroxy-4-methoxypicolinamido)propanoate (79 mg, 0.144 mmol), NEt3 (60.4 µL, 0.433 mmol)), and 5% Pd/C (61.5 mg, 0.014 mmol). EtOAc (1.44 mL) was added, and the vial was sealed and stirred under approximately 1 atm (balloon) of H 2 in rt for 6.5 h. The reaction mixture was filtered through a pad of Celite™ and the filtrate was concentrated to yield an oil, which was purified by flash column chromatography (SiO 2 , 5^30% acetone in hexanes) to give the title compound (66 mg , 85%) as a white foam: 1H NMR (400 MHz, CDCl 3 ) δ 12.11 (s, 1H), 8.44 (d, J = 7.8Hz, 1H), 7.95 (d, J = 5.2 Hz, 1 H), 7.33 (dd, J = 8.2, 6.8 Hz, 1 H), 6.95 (d, J = 8.3 Hz, 2 H), 6 .85 (d, J = 5.2 Hz, 1 H), 6.69 (t, J = 5.7 Hz, 2 H), 6.63 - 6.55 (m, 2 H), 5.57 (d, J = 4.6 Hz, 1 H), 5.40 - 5.33 (m, 1 H), 4.66 (p, J = 7.2 Hz, 1 H), 3.93 (s , 3H), 3.88 (s, 3H), 2.21 (s, 3H), 1.37 (d, J = 7.2 Hz, 3H), 1.33 (d, J = 6.5Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.43, 168.68, 163.36 (d, J = 246.2 Hz), 157.81 (d, J = 9.8 Hz), 155.53, 155 .36, 148.76, 140.41, 130.49, 130.27, 129.77, 129.04 (d, J = 10.1 Hz), 121.33 (d, J = 3.2 Hz) , 115.43, 109.42, 107.35 (d, J = 21.3 Hz), 98.66 (d, J = 25.9 Hz), 74.65, 73.23, 56.04, 55 .77, 48.01, 20.42, 18.09, 15.00;19F NMR (376 MHz, CDCl 3 ) δ -111.31 (s); HRMS-ESI (m/z) ([M+H]+) calcd for C27H30FN2O7, 513.2032; found, 513.2027.
[00091] Example 8A: Preparation of (S)-(1R,2S)-1-phenoxy-1-(p-tolyl)propan-2-yl 2-(3-(acetoxymethoxy)-4-methoxypicolinamido)propanoate.
[00092] To a suspension of (S)-(1R,2S)-1-phenoxy-1-(p-tolyl)propan-2-yl 2-(3-hydroxy-4-methoxypicolinamido)propanoate (110 mg, 0.237 mmol) and K2CO3 (65.5 mg, 0.474 mmol) in acetone (2.37 mL) was added bromomethyl acetate (30.2 µL, 0.308 mmol) in rt. The reaction mixture was heated to 40°C and stirred overnight. The solvent was evaporated, and the resulting crude material was purified by flash column chromatography (SiO 2 , 5→30% acetone in hexanes) to give the title compound (94 mg, 74%) as a colorless oil:1H NMR ( 400 MHz, CDCl3) δ 8.28 (d, J = 7.8 Hz, 1 H), 8.24 (d, J = 5.4 Hz, 1 H), 7.28 (d, J = 8, 0Hz, 2H), 7.19 - 7.10 (m, 4H), 6.93 (d, J = 5.4 Hz, 1H), 6.87 (t, J = 7.4 Hz , 1H), 6.84 - 6.80 (m, 2H), 5.75 - 5.70 (m, 2H), 5.26 (dt, J = 11.4, 5.7 Hz, 1 H), 5.18 (d, J = 5.0 Hz, 1 H), 4.67 (p, J = 7.2 Hz, 1 H), 3.90 (s, 3 H), 2, 31 (s, 3H), 2.06 (s, 3H), 1.38 (d, J = 6.4Hz, 3H), 1.28 (d, J =7.2Hz, 3H) ; 13C NMR (101 MHz, CDCl3) δ 172.25, 170.27, 162.95, 160.27, 157.96, 145.68, 144.01, 142.49, 137.82, 134.51, 129 .31, 129.19, 126.89, 121.06, 115.98, 109.53, 89.58, 81.10, 74.38, 56.17, 48.16, 21.14, 20.87 , 18.23, 15.00; HRMS-ESI (m/z) ([M+H]+) calcd for C29H33N2O8, 537.2231; found, 537,2235.
[00093] Example 8B: Preparation of (S)-(1R,2S)-1-(2-chloro-4-methyl-phenoxy)-1-(4-fluoro-2-methoxyphenyl)propan-2-yl 2- (3-acetoxy-4-methoxypicolinamido)propanoate.
[00094] To a solution of (S)-(1R,2S)-1-(2-chloro-4-methylphenoxy)-1-(4-fluoro-2-methoxyphenyl)propan-2-yl 2-(3- hydroxy-4-methoxypicolinamido)propanoate (59 mg, 0.108 mmol) in pyridine (539 µL, 6.58 mmol) was added acetic anhydride (539 µL, 5.61 mmol). The reaction was stirred for 1 h and then volatiles were removed in vacuo. The resulting residue was dissolved in toluene, and volatiles were again removed in vacuo. The resulting residue was purified by flash column chromatography (SiO 2 , 5^30% acetone in hexanes) to give the title compound (62 mg). , 98%) as a white foam: 1 H NMR (400 MHz, CDCl 3 ) δ 8.50 (d, J = 6.6 Hz, 1 H), 8.28 (d, J = 5.4 Hz, 1 H ), 7.38 (dd, J = 9.2, 6.7 Hz, 1 H), 7.12 (d, J = 1.7 Hz, 1 H), 6.98 (d, J = 5, 5Hz, 1H), 6.81 - 6.76 (m, 1H), 6.61 (ddd, J = 10.8, 5.5, 2.3Hz, 2H), 6.55 ( d, J = 8.4 Hz, 1 H), 5.63 (d, J = 4.4 Hz, 1 H), 5.42 - 5.35 (m, 1 H), 4.72 - 4, 64 (m, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 2.39 (s, 3H), 2.19 (s, 3H), 1, 35 (d, J = 6.5 Hz, 3H), 1.33 (d, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ171.95, 168.85, 163.47 (d, J = 246.5 Hz), 159.42, 162.34, 157.82 (d, J = 9.7 Hz) ), 150.89, 146.60, 141.58, 137.48, 131.22, 130.67, 129.17 (d, J = 10.1 Hz), 127.84, 122.93, 120, 74 (d, J = 3.4 Hz), 114.38, 109.67, 107.46 (d, J = 21.3 Hz), 98.64 (d, J = 25.9 Hz), 75, 32, 73.02, 56.25, 55.78, 47.97, 20.71, 20.20, 18.44, 14.99; 19F NMR (376 MHz, CDCl 3 ) δ-110.97 (d, J = 2.0 Hz); HRMS-ESI (m/z) ([M+H]+) calcd for C29H31ClFN2O8, 589.1747; found, 589,1749.
[00095] Example 9: Preparation of (S)-(1R,2S)-1-(4-fluoro-2-propoxyphenyl)-1-phenoxypropan-2-yl 2-(3-hydroxy-4-methoxypicolinamido) propanoate and (S)-(1R,2S)-1-(4-fluoro-2-hydroxyphenyl)-1-phenoxypropan-2-yl 2-(3-hydroxy-4-methoxypicolinamido)propanoate
[00096] To a magnetically stirred mixture of (S)-(1R,2S)-1-(2-(allyloxy)-4-fluorophenyl)-1-phenoxypropan-2-yl 2-(3-hydroxy-4-methoxypicoly) - namido)propanoate (91 mg, 0.173 mmol) and ruthenium chloride n-hydrate (3.91 mg, 0.017 mmol) in THF (651 µL) and water (217 µL) was added NaBH4 (13.13 mg, 0.347 mmol) mmol) (Note - rigorous gas evolution) under an N2 atmosphere according to the procedure of Sharma, PK; Kumar, S.; Kumar, P.; Nielsen, P. Tet. Lett,2012, 48, 8704-8708. The reaction mixture was stirred at 0°C for 1 h at which point the reaction was carefully quenched by the addition of water and extracted 3x with CH 2 Cl 2 . The combined organic extracts were dried by passing through a phase separator, and volatiles were removed under a gentle stream of N2. The resulting residue was purified by flash chromatography (SiO2, 5^30% acetone in hexanes) to provide the title compounds (29 mg, 32%) as a colorless oil: 1 H NMR (400 MHz, CDCl 3 ) δ 12.12 (s, 1 H), 8.43 (d, J = 7.8 Hz, 1 H ), 7.96 (d, J = 5.2 Hz, 1 H), 7.32 (dd, J = 8.3, 6.8 Hz, 1 H), 7.20 - 7.13 (m, 2H), 6.86 (dd, J = 10.0, 6.2Hz, 2H), 6.82 - 6.77 (m, 2H), 6.61 - 6.53 (m, 2 H), 5.62 (d, J = 4.5 Hz, 1 H), 5.43 - 5.36 (m, 1 H), 4.66 (p, J = 7.2 Hz, 1 H) , 3.98 (t, J = 6.4 Hz, 2H), 3.94 (s, 3H), 1.96 - 1.86 (m, 2H), 1.37 (d, J = 7.2 Hz, 3H), 1.34 (d, J = 6.5 Hz, 3H), 1.11 (t, J = 7.4 Hz, 3H). 19F NMR (376 MHz, CDCl 3 ) δ -111.41 (s, 1F). 13C NMR (101 MHz, CDCl3) δ 171.38, 168.68, 163.33 (d, J = 246.1 Hz), 157.68, 157.21 (d, J = 10.0 Hz), 155 .36, 148.76, 140.40, 130.49, 129.30, 128.95 (d, J = 10.2 Hz), 121.10 (d, J = 3.2 Hz), 120.99 , 115.53, 109.42, 107.16 (d, J = 21.5 Hz), 99.24 (d, J = 25.9 Hz), 74.64, 73.25, 70.01, 56 .04, 48.01, 22.49, 18.13, 15.03, 10.67. HRMS-ESI (m/z) ([M+H]+) calcd for C28H32FN2O7, 527.2188; found, 527.2188, and (33 mg, 39%) as an oily white solid: 1H NMR (400 MHz, CDCl3) δ 12.44 (s, 1H), 9.00 (s, 1H), 8 .35 (d, J = 7.6 Hz, 1 H), 8.09 (d, J = 5.3 Hz, 1 H), 7.22 (ddd, J = 8.4, 7.0, 3 .6Hz, 3H), 6.97 (d, J = 5.3Hz, 1H), 6.94 (t, J = 7.3Hz, 1H), 6.88 (d, J = 7.8 Hz, 2 H), 6.54 (td, J = 8.4, 2.5 Hz, 1 H), 6.32 (dd, J = 10.0, 2.2 Hz, 1 H) , 5.50 (d, J = 6.9 Hz, 1 H), 5.20 (p, J = 6.1 Hz, 1 H), 4.65 (p, J = 7.1 Hz, 1 H ), 3.99 (s, 3H), 1.51 (d, J = 6.3 Hz, 3H), 1.45 (d, J = 7.1 Hz, 3H). 19F NMR (376 MHz, CDCl 3 ) δ -112.15 (s, 1F). 13C NMR (101 MHz, CDCl3) δ 170.47, 168.33, 163.09 (d, J = 246.5 Hz), 157.25, 156.26, 155.47 (d, J = 11.1 Hz), 149.58, 140.15, 130.12, 129.54, 128.71 (d, J = 10.3 Hz), 121.77, 119.93 (d, J = 3.4 Hz) , 115.76, 109.65, 107.75 (d, J = 21.7 Hz), 103.82 (d, J = 24.0 Hz), 74.78, 56.25, 48.98, 29 .26, 18.55, 16.20. HRMS-ESI (m/z) ([M+H]+) calcd for C25H26FN2O7, 485.1719; found, 485,1717, respectively.
[00097] Example 10A: (E)-4-fluoro-2-methoxy-1-(prop-1-en-1-yl)benzene
[00098] To a suspension of magnesium metal (486 mg, 20.0 mmol) and lithium chloride (933 mg, 22.0 mmol) in THF (20.0 mL) was added 1-bromo-4-fluoro- 2-methoxybenzene (1.93 mL, 15.00 mmol) and the mixture was heated at 70°C for 1 h at which point the reaction was cooled to 0°C and Fe(acac)3 (0.5M in THF, 2.00 mL, 1.00 mmol) was added. After 1 min, allyl chloride (0.814 mL, 10.0 mmol) was added and the reaction was stirred at 0°C for 30 min, then at rt for 1 h. The reaction was then heated to 70°C overnight. The reaction was quenched by addition of sat NaHCO3 . (aq) and diluted with petroleum ether and filtered through a pad of CeliteTM. The biphasic solution was extracted with petroleum ether, and the combined organic phases were dried over Na 2 SO 4 , carefully concentrated in vacuo (25 °C, 250 mbar) and purified by flash column chromatography (SiO 2 , 100% petroleum ether ) to afford the title compound (1.07 g, 52%, 15:1 E:Z) as a colorless oil: 1 H NMR (400 MHz, CDCl 3 ) δ 7.31 (dd, J = 8.4, 6 0.8Hz, 1H), 6.66 - 6.51 (m, 3H), 6.14 (dq, J = 15.9, 6.6 Hz, 1H), 3.82 (s, 3 H), 1.88 (dd, J = 6.6, 1.7 Hz, 3H); 19F NMR (376 MHz, CDCl 3 ) δ -113.30 (s).
[00099] Example 10B: (2S,3S)-2-(4-fluoro-2-methoxyphenyl)-3-methyloxirane
[000100] To a round-bottomed flask was added buffer (Na2B4O7 at 0.05M-10H2O in 4x10-4 M aqueous Na2(EDTA), 26.5 mL), acetonitrile (40.1 mL), (E)-4- fluoro-2-methoxy-1-(prop-1-1en-1-io)benzene (0.55g, 2.65 mmol), tetrabutylammonium hydrogen sulfate (0.036 g, 0.106 mmol) and 1,2,4,5- Bis-O-(isopropylidene)-β-L-erythro-2,3-hexodiulo-2,6-pyranose (Shi epoxidation catalyst enantiomer, 0.205 g, 0.794 mmol) and the reaction mixture was cooled to 0 °C . A solution of Oxone (2.246 g, 3.65 mmol) in aqueous Na2(EDTA) (4 x 10-4 M, 15 mL) and a solution of potassium carbonate (2.122 g, 15.36 mmol) in water 15 mL were simultaneously added dropwise via two syringe pumps over 1.5 h. Upon completion of the syringe pump additions, the reaction was immediately quenched with petroleum ether and water. The mixture was extracted 3x with petroleum ether, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (SiO 2 , 0±10% acetone in hexanes) to give the title compound (455 mg, 85%, 15:1 dr) as a colorless oil: 1H NMR ( 400 MHz, CDCl3) δ 7.06 (dd, J = 8.3, 6.7 Hz, 1H), 6.67 - 6.52 (m, 2H), 3.89 - 3.80 (m , 1H), 3.84 (s, 3H), 2.91 (qd, J = 5.1, 2.1 Hz, 1H), 1.45 (d, J = 5.2 Hz, 3H ); 19F NMR (376 MHz, CDCl 3 ) δ-112.15.
[000101] Example 10C: (1S,2S)-1-cyclopropoxy-1-(4-fluoro-2-methoxy-phenyl)propan-2-ol and (1R,2S)-1-cyclopropoxy-1-(4- fluoro-2-methoxyphenyl)propan-2-ol.
[000102] To a solution of (2S,3S)-2-(4-fluoro-2-methoxyphenyl)-3-methyloxirane (50 mg, 0.274 mmol) in cyclopropanol (1.37 mL) was added sulfuric (1 drop) ). The reaction mixture was stirred at 0°C for 10 min, then quenched by addition of solid K 2 CO 3 . Volatiles were removed under a gentle stream of N2 and the resulting residue was purified by flash chromatography (SiO2, 5^30% acetone in hexanes) to yield the title compounds as two diastereomers: Major (1S,2S) ( 32 mg, 49%): 1H NMR (400 MHz, CDCl3) δ 7.31 (dd, J = 8.4, 6.9 Hz, 1H), 6.69 (td, J = 8.3, 2 .4 Hz, 1 H), 6.62 (dd, J = 10.9, 2.4 Hz, 1 H), 4.62 (d, J = 7.5 Hz, 1 H), 3.82 ( s, 3H), 3.78 (dt, J = 13.2, 4.6Hz, 1H), 3.16 (dq, J =9.1, 3.0Hz, 1H), 2, 62 (s, 1H), 0.99 (d, J = 6.4Hz, 3H), 0.66 - 0.50 (m, 2H), 0.40 (dddd, J = 16.3 , 14.5, 10.4, 6.2 Hz, 2H);19 F NMR (376 MHz, CDCl 3 ) δ-112.05 (s); ESIMS m/z 263 ([M+Na]+). Secondary (1R,2S) (18 mg, 27%): 1H NMR (400 MHz, CDCl3) δ 7.38 (dd, J = 8.4, 7.0 Hz, 1H), 6.70 (td, J = 8.4, 2.4 Hz, 1 H), 6.61 (dd, J = 10.9, 2.4 Hz, 1 H), 4.83 (d, J = 4.2 Hz, 1 H), 4.00 - 3.91 (m, 1H), 3.82 (s, 3H), 3.24 (dq, J = 9.2, 3.0Hz, 1H), 1, 94 (d, J = 6.2 Hz, 1H), 1.00 (d, J = 6.5Hz, 3H), 0.70 - 0.63 (m, 1H), 0.59 - 0.52 (m, 1H), 0.51-0.43 (m, 1H), 0.42 - 0.35 (m, 1H); 19F NMR (376 MHz, CDCl3) δ-112.65 (s); ESIMS m/z 263 ([M+Na]+).
[000103] Example A: Evaluation of Fungicide Activity: Wheat Leaf Pustule (Zymoseptoria tritici; Bayer code SEPTTR):
[000104] The technical grades of the materials were dissolved in acetone, which were then mixed with nine volumes of water containing 110 ppm of Triton X-100. The fungicidal solutions were applied to wheat seedlings using an automated cabin sprayer until drained. All sprayed plants were allowed to air dry before further handling. All fungicides were evaluated using the method mentioned above for their activity vs. all target diseases unless otherwise stated. The activity of wheat leaf pustule and brown rust was also evaluated using trail spray applications, in which case the fungicides were formulated as EC formulations containing 0.1% Trycol 5941 in the spray solutions.
[000105] Wheat plants (Yuma variety) were grown from seed in a greenhouse in a mixture of 50% mineral soil/50% Meter without soil until the first leaf had fully emerged, with 7-10 seedlings per Bowl. These plants were inoculated with an aqueous spore suspension of Zymoseptoria tritici before or after fungicide treatment. After inoculation, the plants were kept at 100% relative humidity (one day in a dark condensation chamber, followed by two to three days in a lighted condensation chamber at 20°C) to allow the spores to germinate and infect the leaf. . The plants were then transferred to a greenhouse at 20°C for disease development. When disease symptoms were fully expressed in the first leaves of untreated plants, infection levels were rated on a scale of 0 to 100 percent disease severity. Percent disease control was calculated using the disease severity ratio in treated plants relative to untreated plants.
[000106] Example B: Evaluation of Fungicide Activity: Brown Wheat Rust (Puccinia triticina; Bayer code PUCCRT):
[000107] Wheat plants (Yuma variety) were grown from seed in a greenhouse in a mixture of 50% mineral soil/50% Meter without soil until the first leaf had fully emerged, with 7 - 10 seedlings per Bowl. These plants were inoculated with an aqueous spore suspension of Puccinia triticina before or after the fungicide treatments. After inoculation the plants were kept in a dark condensation environment at 22°C with 100% relative humidity overnight to allow the spores to germinate and infect the leaf. The plants were then transferred to a greenhouse at 24°C for disease development. Fungicidal formulation, application and disease assessment followed the procedures as described in Example A.
[000108] Example C: Evaluation of Fungicidal Activity: Wheat Gluma Pustule (Leptosphaeria nodorum; Bayer code LEPTNO):
[000109] Wheat plants (Yuma variety) were grown from seed in a greenhouse in a mixture of 50% mineral soil/50% Meter without soil until the first leaf had fully emerged, with 7 - 10 seedlings per Bowl. These plants were inoculated with an aqueous spore suspension of Leptosphaeria nodorum 24 h after fungicide treatments. After inoculation the plants were kept at 100% relative humidity (one day in a dark condensation chamber followed by two days in a lighted condensation chamber at 20°C) to allow the spores to germinate and infect the leaf. The plants were then transferred to a greenhouse at 20°C for disease development. Fungicidal formulation, application and disease assessment followed the procedures as described in Example A.
[000110] Example D: Evaluation of Fungicide Activity: Apple Crust (Venturia inaequalis; Bayer VENTIN code):
[000111] Apple seedlings (variety McIntosh) were grown in a soilless Metro mix, with one plant per pot. Seedlings with two young leaves expanding to the top (older leaves at the base of the plants were pruned) were used in the test. Plants were inoculated with a spore suspension of Venturia inaequalis 24 h after fungicide treatment and kept in a 22°C condensation chamber with 100% relative humidity for 48 h, and then transferred to a greenhouse at 20°C for disease development. Fungicidal formulation, application and disease assessment on the sprayed leaves followed the procedures as described in Example A.
[000112] Example E: Evaluation of Fungicide Activity: Beetroot Leaf Spot (Cercospora beticola; Bayer code CERCBE):
[000113] Beet plants (variety HH88) were grown in soilless Metro mix and pruned regularly to maintain a uniform plant size prior to testing. Plants were inoculated with a spore suspension 24 h after fungicide treatments. The inoculated plants were kept in a condensation chamber at 22°C for 48 h, then incubated in a greenhouse at 24°C under a clear plastic cover with base ventilation until disease symptoms were fully expressed. Fungicidal formulation, application and disease assessment on sprayed leaves followed the procedures as described in Example A.
[000114] Example F: Evaluation of Fungicide Activity: Asian Bean Rust (Phakopsora pachyrhizi; Bayer code PHAKPA):
[000115] Technical grades of materials were dissolved in acetone, which were then mixed with nine volumes of water containing 0.011 % Tween 20. The fungicidal solutions were applied over bean seedlings using an automated cabin sprayer until drained. All sprayed plants were allowed to air dry before further handling.
[000116] Bean plants (Williams 82 variety) were grown in soilless Metro mix, with one plant per pot. Two-week-old seedlings were used for testing. Plants were inoculated 3 days before or 1 day after fungicide treatments. Plants were incubated for 24 h in a dark condensation environment at 22°C and 100% relative humidity, then transferred to a growth environment at 23°C for disease development. Disease severity was evaluated on the sprayed leaves.
[000117] Example G: Evaluation of Fungicidal Activity: Burn of Barley (Rhyncosporium secalis; Bayer RHYNSE code):
[000118] Barley seedlings (Harrington variety) were propagated in soilless Metro mix, with each pot having 8 to 12 plants, and used in the test when the first leaf had fully emerged. Test plants were inoculated by an aqueous spore suspension of Rhyncosporium secalis 24 h after fungicide treatments. After inoculation, the plants were kept in a condensed environment at 20°C with 100% relative humidity for 48 h. The plants were then transferred to a greenhouse at 20°C for disease development. Fungicidal formulation, application and disease assessment on sprayed leaves followed the procedures as described in Example A.
[000119] Example H: Evaluation of Fungicide Activity: Rice Blast (Pyricularia oryzae; Bayer PYRIOR code):
[000120] Rice seedlings (Japonica variety) were propagated in a soilless Metro mixture, with each pot having 8 to 14 plants, and used in the test at 12 to 14 days of age. Test plants were inoculated with an aqueous spore suspension of Pyricularia oryzae 24 h after fungicide treatments. After inoculation, the plants were kept in a condensation environment at 22°C with 100% relative humidity for 48 h to allow the spores to germinate and infect the leaf. The plants were then transferred to a greenhouse at 24°C for disease development. Fungicidal formulation, application and disease assessment on sprayed leaves followed the procedures as described in Example A.
[000121] Example I: Evaluation of Fungicide Activity: Early Tomato Pest (Alternaria solani; code Bayer ALTESO):
[000122] Tomato plants (Variety Outdoor Girl) were propagated in soilless Metro mix, with each pot having a plant, and used at 12 to 14 days of age. Test plants were inoculated with an aqueous spore suspension of Alternaria solani 24 h after fungicide treatments. After inoculation the plants were kept at 100% relative humidity (one day in a dark condensation chamber followed by two to three days in a lighted condensation chamber at 20°C) to allow the spores to germinate and infect the leaf. The plants were then transferred to a 22°C growth environment for disease development. Fungicidal formulation, application and disease assessment on sprayed leaves followed the procedures as described in Example A.
[000123] Example J: Evaluation of Fungicidal Activity: Cucumber Anthracnose (Colletotrichum lagenarium; Bayer COLLLA code):
[000124] Cucumber seedlings (Bush Pickle variety) were propagated in soilless Metro mix, with each pot having a plant, and used in the test at 12 to 14 days of age. Test plants were inoculated with an aqueous spore suspension of Colletotrichum lagenarium 24 h after fungicide treatments. After inoculation, the plants were kept in a condensation environment at 22°C with 100% relative humidity for 48 h to allow the spores to germinate and infect the leaf. The plants were then transferred to a 22°C growth environment for disease development. Fungicidal formulation, application and disease assessment on sprayed leaves followed the procedures as described in Example A.

权利要求:
Claims (11)
[0001]
1. Compound, characterized by the fact that it has Formula 1
[0002]
2. Compound, characterized by the fact that it has the Formula IA:
[0003]
3. Compound according to claim 1, characterized in that R7 is hydrogen.
[0004]
4. Compound according to claim 3, characterized in that R6 is alkoxy.
[0005]
5. Compound according to claim 1, characterized in that R7 is selected from -C(O)R9 or -CH2OC(O)R9.
[0006]
6. Compound according to claim 5, characterized in that R9 is alkyl, optionally substituted with 1 or multiple R8.
[0007]
7. A compound according to claim 2, 3 or 5, characterized in that R1 and R11 are independently selected from hydrogen or alkyl.
[0008]
8. Compound according to claim 2, 3 or 5, characterized in that R3 is aryl, optionally substituted with 1 or multiple R8.
[0009]
9. Compound according to claim 2, 3 or 5, characterized in that R4 is selected from alkyl or aryl, each optionally substituted with 1 or multiple R8.
[0010]
10. A compound according to claim 2, 3 or 5, characterized in that R1 and R11 are independently selected from hydrogen or alkyl, R2 and R12 are independently selected from hydrogen or methyl, R3 is aryl, optionally substituted with 1 or multiple R 8 , and R 4 is selected from alkyl or aryl, each optionally substituted with 1 or multiple R 8 .
[0011]
11. Compound according to claim 10, characterized in that R9 is selected from -CH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH(CH3)2, -CH2CH2CH2CH3 or -cyclopropyl.

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法律状态:
2019-08-27| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-03-02| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-06-22| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 21/12/2015, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201462098097P| true| 2014-12-30|2014-12-30|

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US201462098089P| true| 2014-12-30|2014-12-30|

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US62/098,097|2014-12-30|

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US62/098,089|2014-12-30|

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US201562255163P| true| 2015-11-13|2015-11-13|

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US201562255168P| true| 2015-11-13|2015-11-13|

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US62/255,168|2015-11-13|

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US62/255,163|2015-11-13|

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PCT/US2015/067206|WO2016109304A1|2014-12-30|2015-12-21|Picolinamides as fungicides|

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