4-AMINO-6- (SUBSTITUTED PHENYL) PICOLINATES AND 6-AMINO-2- (SUBSTITUTED PHENYL) -4-PYRIMIDINCARBOXYL

专利摘要:
Arylalkyl esters of 4-amino-6- (substituted phenyl) picolinates and 6-amino-2- (substituted phenyl) -4-pyrimidinecarboxylates and their use as herbicides The present invention relates to arylalkyl esters of 4-aminopicolinic acids and 6 -amino-4-pyrimidinecarboxylates, which are weed control herbicides especially those common to rice and wheat crop systems and pasture management programs.
公开号:BR102012001641B1
申请号:R102012001641-9
申请日:2012-01-24
公开日:2019-04-02
发明作者:Joseph D. Eckelbarger；Carla N. Yerkes；Christian T. Lowe；Jeffrey B. Epp；Katherine A. Guenthenspberger；Thomas L. Siddall；Paul R. Schmitzer
申请人:Dow Agrosciences Llc；
IPC主号:

专利说明:

[001] The present invention relates to certain new esters of 4-amino-6- (substituted phenyl) -picolinic acids and 6-amino-2- (substituted phenyl) -4-pyrimidinecarboxylic acids and the use of these compounds as herbicides for weed control especially those species common to rice and wheat cropping systems and pasture management programs.
[002] Various picolinic acids and their pesticidal properties have been described in the art. U.S. Patent 6,784,137 B2 and U.S. Patent 7,314,849 B2 disclose a genus of 4-amino-6-arylpicolinic acids and their derivatives and their use as selective herbicides particularly for rice and cereals such as wheat and barley. WO 2005/063721 A1, WO 2007/082076 A1, US Patent 7 863 220 B2, US Patent 7 300 907 B2, US Patent 7 642 220 B2, and US Patent 7 786 044 B2 disclose certain 6-amino-2-substituted acids -4-pyrimidinecarboxylic and its derivatives and their use as herbicides. It has now been discovered that certain esters of 4-amino-6- (substituted phenyl) picolinic acids and 6-amino-2- (substituted phenyl) -4-pyrimidinecarboxylic acids can provide superior weed control especially in rice growing systems and wheat and pasture management programs.
[003] Certain arylalkyl esters of 4-amino-6- (substituted phenyl) picolinic acids and 6-amino-2- (substituted phenyl) -4-pyrimidine carboxylic acids are superior herbicides with a broad spectrum of weed-type weed control. broadleaf, grass, and sedge especially in rice and wheat crop systems and pasture management programs. The compounds have
Petition 870180167466, of 12/26/2018, p. 7/83
2/70 additionally excellent toxicological or environmental profiles.
[004]
The invention includes compounds of Formula IA:
R ³ where [005] Y represents C1-C8 alkyl, C3-C6 cycloalkyl, or substituted phenyl with 1 - 4 substituents independently selected from halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, nitro, NR ¹ R ² , or where two adjacent substituents are taken together as -O (CH2) nOor -O (CH2) n- where n = 1 or 2;
[006] Z represents halogen, C1-C3 alkoxy, or C2-C4 alkenyl;
[007] R ¹ and R ² independently represent H, C1-C6 alkyl, or
C1-C6 acyl;
[008] R ³ represents C7-C11 unsubstituted or substituted arylalkyl.
Preferred compounds include those in which Y represents substituted phenyl, Z represents Cl, -CH = CH2 or OCH3, R ¹ and R ² represent H, R ³ represents unsubstituted or ortho-, meta-, or para-monosubstituted benzyl .
[0010] The invention also includes compounds of Formula IB:
Petition 870180167466, of 12/26/2018, p. 8/83
3/70

R ³ where
X = H or F;
[0011] Y represents halogen, C1-Cs alkyl, C3-C6 cycloalkyl, or substituted phenyl with 1 - 4 substituents independently selected from halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, nitro, NR ¹ R ² , or where two adjacent substituents are taken together as O (CH2) nO- or -O (CH2) n- where n = 1 or 2;
[0012] Z represents halogen or C2-C4 alkenyl;
[0013] R ¹ and R ² independently represent H, C1-C6 alkyl, or C1-C6 acyl;
[0014] R ³ represents C7-C11 unsubstituted or substituted arylalkyl.
Preferred compounds include those in which X represents H or F, Y represents substituted phenyl, Z represents Cl, R ¹ and R ² represent H, R ³ represents unsubstituted or ortho-, meta-, or para-monosubstituted benzyl.
[0016] The invention includes herbicidal compositions containing a herbicidally effective amount of a compound of Formula IA or IB in a mixture with an agriculturally acceptable adjuvant or vehicle. The invention also includes a method of using the compounds and compositions of the present invention to eliminate or control undesirable vegetation by applying a herbicidal amount of the compound to the vegetation or vegetation site as well as to the soil prior to application.
Petition 870180167466, of 12/26/2018, p. 9/83
4/70 emergence of vegetation or irrigation or flood water before or after the emergency. The invention further includes a method for the selective post-emergence control of undesirable vegetation in the presence of rice, wheat or forage, which includes applying to said undesirable vegetation an herbicidally effective amount of a compound of the present invention. The invention also includes a method of preparing the compounds of the present invention.
The herbicidal compounds of the present invention are arylalkyl esters of 4-amino-6- (substituted phenyl) picolinic acids and 6 amino-2- (substituted phenyl) -4-pyrimidine-carboxylic acids and their derivatives. The picolinic acids from which the esters of Formula IB are derived are a new class of compounds having herbicidal activity. Various compounds of picolinic acids are described in US Patent 6,784,137 B2 and US Patent 7,314,849 B2, including but not limited to 4 amino-3- chloro-6- (4-chloro-2-fluoro-3-methoxy-phenyl) acid picolinic acid, 4 amino-3- chloro-5-fluor-6- (4-chloro-2-fluoro-3-methoxyphenyl) picolinic acid and 4-amino-3-chloro-6- (2,4-dichloro-3- methoxyphenyl) -picolinic. Pyrimidinecarboxylic acids, from which the esters of Formula IA are derived, are also a new class of compounds having herbicidal activity. Various pyrimidinecarboxylic acid compounds are described in WO 2005/063721 A1, WO 2007/082076 A1, U.S. Patent 7 863 220 B2, U.S. Patent 7 300 907 B2, U.S. Patent 7 642 220 B2, and U.S. Patent 7 786 044 B2. These picolinic acids and pyrimidine carboxylic acids control annual grasses, broadleaf weeds, and nuts in rice and wheat, but the arylalkyl esters of the present invention demonstrate greater efficiency than known esters, especially against weeds prominent in crop systems and wheat and pasture management programs.
[0018] Preferred ester groups are those that produce levels
Petition 870180167466, of 12/26/2018, p. 10/83
5/70 higher weed control than an equivalent rate of acid from methyl esters. Preferred ester groups include the unsubstituted benzyl ester and ortho-, meta- and paramonosubstituted benzyl esters.
[0019] The arylalkyl esters of 6-amino-2- (substituted phenyl) -4-pyrimidinecarboxylic acids can be prepared by reacting the pyrimidinecarboxylic acid with an arylalkyl halide in the presence of a base.
Layout 1

[0020] Arylalkyl esters of picolinic acids can be prepared by coupling picolinic acid with an alcohol using any number of suitable activating agents such as those used for peptide couplings such as dicyclohexylcarbodiimide (DCC) or carbonyl diimidazole (CDI) or by reacting the corresponding acid with an appropriate arylalkyl alcohol in the presence of an acid catalyst. Alternatively, arylalkyl esters can be prepared by reacting picolinic acid with an arylalkyl halide in the presence of a base.

[0021] It is recognized that some reagents and reaction conditions
Petition 870180167466, of 12/26/2018, p. 11/83
6/70 disclosed here or in the chemistry literature for the preparation of compounds of Formula IA or IB may not be compatible with certain functionalities present in the intermediates. In these cases, the incorporation of protection / deprotection sequences or interconversions of functional groups in the synthesis will assist in obtaining the desired products. The use and choice of protection groups will be apparent to a specialist in chemical synthesis.
[0022] The terms alkyl, alkenyl and alkynyl, as well as derivative terms such as alkoxy, acyl and alkylthio, in this context, include in their scope portions of straight chain and branched chain. Unless specifically indicated otherwise, each may be unsubstituted or substituted with one or more substituents selected from, but not limited to, halogen, alkoxy, alkylthio, or aminoalkyl. As long as the substituents are sterically compatible and the chemical bonding and deformation energy rules are met. The terms alkenyl and alkynyl are intended to include one or more unsaturated bonds.
[0023] The term arylalkyl, in this context, refers to a substituted phenyl alkyl group having a total of 7 to 11 carbon atoms, such as benzyl (-CH2C6H5), 2-methylnaphthyl (-CH2C10H7) and 1- or 2-phenethyl (-CH2CH2C6H5 or -CH (CH3) C6H5). The phenyl group can itself be unsubstituted or substituted with one or more substituents independently selected from halogen, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, C1 -C6 alkylthio, C (O) OC1-C6alkyl, or where two adjacent substituents are taken together as -O (CH2) nOem that n = 1 or 2, provided that the substituents are sterically compatible and the rules of chemical bonding and deformation energy are satisfied.
[0024] Unless specifically limited otherwise, the
Petition 870180167466, of 12/26/2018, p. 12/83
7/70 halogen term includes fluorine, chlorine, bromine, and iodine.
[0025] Formula IA or IB compounds have been found to be useful as pre-emergence and post-emergence herbicides for rice and cereal crop systems and for pasture management programs. The term herbicide is used here to mean an active ingredient that eliminates, controls, or otherwise adversely modifies the growth of plants. A herbicidally effective control of vegetation control is an amount of active ingredient that causes an adverse modifying effect and that includes deviations from natural development, elimination, regulation, desiccation, retardation, and the like. The terms plants and vegetation include germinating seeds, emerging new plants, parts of plants above and below ground such as buds, roots, tubers, rhizomes and the like, and established vegetation.
[0026] Herbicidal activity is shown by the compounds of the present invention when they are applied directly to the plant or plant location at any stage of growth or before planting or emergence. The observed effect depends on the plant species to be controlled, the growth stage of the plant, the parameters of application of dilution and the size of the spray drops, the particle size of the solid components, the environmental conditions at the time of use, the specific compound used, the specific adjuvants and vehicles used, the type of soil, water quality, and the like, as well as the quantity of chemical product applied. These and other factors can be adjusted as known in the art to promote selective herbicide action. It is generally preferable to apply post-emergence Formula IA or IB compounds by spraying or applying relatively immature undesirable vegetation with water to obtain maximum weed control. [0027] Application rates of 1 to 500 grams per hectare (g / ha) are generally used in foliar and water application operations
Petition 870180167466, of 12/26/2018, p. 13/83
8/70 post-emergency. Preferred rates of application are 10 to 300 g / ha. For pre-emergence applications, rates of 5 to 500 g / ha are generally employed. Preferred rates of application are 30 to 300 g / ha. The higher projected rates generally provide nonselective control over a wide variety of undesirable vegetation. The lower rates typically provide selective control and can be used at the crop location.
[0028] The herbicidal compounds of the present invention are often applied in conjunction with one or more other herbicides to control a greater variety of undesirable vegetation. When used in conjunction with other herbicides, the compounds currently claimed can be formulated with the other herbicide or herbicides, mixed in tank with the other herbicide or herbicides or applied sequentially with the other herbicide or herbicides. Some of the herbicides that can be used in conjunction with the compounds of the present invention include: 2,4-D salts, esters and amines, acetochlor, acifluorfen, alachlor, amidosulfuron, aminopyralid, aminotriazole, ammonium thiocyanate, aniliphos, atrazine, azimsulfuron, benfuresate, bensulfuron-methyl, bentazon, bentiocarb, benzobicyclon, benzofenap, bifenox, bispyribasodic, bromobutide, butachlor, cafenstrol, carfentrazone-ethyl, clodinafop-propargil, chlorimuron, chlorprofam, clodimethopram, clinodimide cyclosulfamuron, cycloxidim, cyhalophope-butyl, cumiluron, daimuron, diclosulam, diflufenican, diflufenzopyr, dimepiperate, dimetamethrin, diquat, dithiopir, EK2612, EPTC, esprocarb, ET-751, ethoxypropyl, phenoxypropyl, phenoxypropylene, ethoxypropyl isoxadifen-ethyl, fentrazamide, flazassulfuron, florassulam, fluazifop, fluazifop-P-butyl, flucetosulfuron, flufenacet, flufenpir-ethyl, flumetsulam, flumioxa zin, flupirsulfuron, fluroxypyr, fomesafen, foramsulfuron, glufosinate,
Petition 870180167466, of 12/26/2018, p. 14/83
9/70 glufosinate-P, glyphosate, halosulfuron-methyl, haloxifop-methyl, haloxifop-R, haloxifop-R-methyl, imazametabenz, imazamox, imazapic, imazapir, imazaquin, imazetapir, imazosulfuron, indanofan, isabanone, isaban, ixanazone, isabanone , MCPB, mefenacet, mesosulfuron, mesotrione, metamifop, metazosulfuron, metolachlor, metosulam, metsulfuron, molinate, monosulfuron, MSMA, orthosulfamuron, orizaline, oxadiargyl, oxadiazon, oxaziclomefone, pimethaxoxamoxin, pyrophaoxamoxy, phaoxamine, poxy , pretilachlor, profoxidim, prohexadione-calcium, propachlor, propanil, propisoclor, propyzamide, propirissulfuron, prosulfuron, pirabuticarb, piraclonil, pirazogil, pyrazolynate, pyrazosulfuron-ethyl, pyrazoxyfen, piribenzoxim, pyridate, piriftalid, pyriminobac-methyl, pirimissulfan, primisulfuron, pyroxsulam , quinoclamine, quinclorac, quizalofop-P-ethyl, S-3252, setoxidim, simazine, symmetry, s-metolachlor, sulcotrione, sulfentrazone, sulfosate, tefuril triona, tenilchlor, thiazopyr, thiobencarb, triclopyr, triclopyr-esters and amines, trifluralin, trinexapacetyl, tritosulfuron, and other 4-amino-6- (substituted phenyl) picolinates and 6 amino-2- (substituted phenyl) -4-pyrimidinacarboxylates and their salts and esters.
[0029] The compounds of the present invention can additionally be used to control undesirable vegetation in many crops that have become tolerant of or resistant to them and other herbicides by genetic manipulation or by mutation and selection. The herbicidal compounds of the present invention can, in addition, be used in conjunction with glyphosate, glufosinate, dicamba, imidazolinones, aryloxyphenoxypropionates or 2,4-D in glyphosate-tolerant, glufosinate-tolerant, dicamba-tolerant, imidazolinone-tolerant cultures aryloxyphenoxy-propionate or 2.4D tolerant. It is generally preferable to use the compounds of the invention in combination with herbicides that are selective for the crop being
Petition 870180167466, of 12/26/2018, p. 15/83
10/70 treated and that complement the spectrum of weeds controlled by these compounds in the application rate employed. In addition, it is generally preferable to apply the compounds of the invention and other complementary herbicides at the same time, either as a combined formulation or as a tank mixture. Similarly, the herbicidal compounds of the present invention can be used in conjunction with acetolactate synthase (ALS) inhibitors in cultures tolerant to acetolactate synthase inhibitors or with 4-hydroxyphenyl dioxigenase pyruvate (HPPD) inhibitors in cultures tolerant to 4 pyruvate inhibitors. -hydroxyphenyl dioxigenase.
[0030] The compounds of the present invention can generally be used in combination with herbicide safeners known as benoxacor, bentiocarb, brassinolide, cloquintocet (mexyl), ciometrinil, cyprosulfamide, daimuron, diclormid, diciclonon, dietholate, dimepiperate, disulfoton-ethenol , fenclorim, flurazol, fluxofenim, furilazol, harpin proteins, isoxadifen-ethyl, mefenpir-diethyl, mefenato, MG 191, MON 4660, naphthalic anhydride (NA), oxabetrinil, R29148 and M-phenylsulfonylbenzoic acid amides, to increase your selectivity. They can additionally be used to control undesirable vegetation in many crops that have become tolerant or resistant to them or other herbicides by genetic manipulation or by mutation and selection. For example, corn, wheat, rice, soybeans, sugar beet, cotton, canola, and other crops that have become tolerant or resistant to compounds that are acetolactate synthase inhibitors in sensitive plants can be treated. Many glyphosate and glufosinate tolerant cultures can be treated as well, alone or in combination with these herbicides. Some crops have become tolerant to auxinic herbicides and ACCase herbicides such as 2,4- (dichlorophenoxy) acetic acid (2,4-D) and dicamba and aryloxyphenoxypropionates. These herbicides can be used to treat
Petition 870180167466, of 12/26/2018, p. 16/83
11/70 such resistant crops or other auxin tolerant crops. Some cultures have become tolerant to 4-hydroxyphenyl dioxigenase pyruvate inhibitor herbicides, and these herbicides can be used to treat these resistant cultures.
[0031] Although it is possible to use the compounds of Formula IA or IB directly as herbicides, it is preferable to use them in mixtures containing a herbicidally effective amount of the compound together with at least one agriculturally acceptable adjuvant or vehicle. Suitable adjuvants or vehicles should not be phytotoxic to valuable crops, particularly at the concentrations used in applying weed control compositions in the presence of crops, and should not react chemically with Formula IA or IB compounds or other ingredients in the composition. These mixtures can be designed for direct application to weeds or their location, or they can be concentrated or formulations that are normally diluted with additional vehicles and adjuvants before application. They can be solids such as powders, granules, water-dispersible granules, or wettable powders, or liquids such as, for example, emulsifiable concentrates, solutions, emulsions or suspensions. They can also be supplied as a premix or mixed in a tank.
[0032] Suitable agricultural adjuvants and vehicles that are useful in preparing herbicidal mixtures of the invention are well known to those of skill in the art. Some of these adjuvants include, but are not limited to, concentrated oil (mineral oil (85%) + emulsifiers (15%)); nonylphenol ethoxylate; benzylcocoalkylimethyl quaternary ammonium salt; blend of petroleum hydrocarbon, alkyl esters, organic acid, and anionic surfactant; C9-C11 alkyl polyglycoside; phosphate alcohol ethoxylate; natural primary alcohol ethoxylate (C12C16); di-s-butylphenol EO-PO block copolymer; polysiloxane-methyl
Petition 870180167466, of 12/26/2018, p. 17/83
12/70 cap; nonylphenol ethoxylate + urea ammonium nitrate; emulsified methylated seed oil; ethoxylate (8EO) of tridecyl alcohol (synthetic); tallow amine ethoxylate (15 EO); PEG (400) dioleate-99.
[0033] Liquid vehicles that can be used include water and organic solvents. The organic solvents typically used include, but are not limited to, petroleum or hydrocarbon fractions such as mineral oil, 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, flaxseed oil, palm oil, peanut oil , safflower oil, sesame oil, tung oil and the like; esters of the above vegetable oils; esters of monoalcohols or dihydric, trihydric, or other lower polyalcohols (containing 4-6 hydroxy), such as 2-ethyl hexyl stearate, n-butyl oleate, isopropyl myristate, propylene glycol dioleate, dioctyl succinate, dibutyl adipate, dioctyl phthalate and the like; esters of mono-, di- and polycarboxylic acids and the like. Specific organic solvents include toluene, xylene, petroleum naphtha, crop oil, acetone, methyl ethyl ketone, cyclohexanone, trichlorethylene, perchlorethylene, ethyl acetate, amyl acetate, butyl acetate, propylene glycol monomethyl ether and diethylene glycol monomethyl ether , methyl alcohol, ethyl alcohol, isopropyl alcohol, amyl alcohol, ethylene glycol, propylene glycol, glycerin, M-methyl-2-pyrrolidinone, Μ, Μ-dimethyl alkylamides, dimethyl sulfoxide, liquid fertilizers and the like. Water is generally the vehicle of choice for diluting concentrates.
[0034] Suitable solid vehicles include talc, pyrophyllite, silica, atapulgite, kaolin, kieselguhr, chalk, diatomaceous earth, lime (lime), calcium carbonate, bentonite, Fuller earth, cotton seed husks, trio flour, flour soybeans, pumice, wood flour, almond shell flour, lignin, and the like.
Petition 870180167466, of 12/26/2018, p. 18/83
[0035] It is usually desirable to incorporate one or more surfactants in the compositions of the present invention. Such surfactants are advantageously used in both solid and liquid compositions, especially those designed to be diluted with a vehicle, before application. Surfactants can be anionic, cationic or non-ionic and in character and can be used as emulsifying agents, wetting agents, suspending agents, or for other purposes. Surfactants conventionally used in the art of formulation and which can also be used in the present formulations are described, among others, in McCutcheon's Detergents and Emulsifiers Annual, MC Publishing Corp., Ridgewood, New Jersey, 1998 and McCutcheon Detergents and Emulsifiers Annual. in Encyclopedia de Surfactants, (Encyclopedia of Surfactants) Vol. I-III, Chemical Publishing Co., New York, 1980-81. Typical surfactants include salts of alkyl sulfates, such as diethanolammonium lauryl sulfate; alkylarylsulfonate salts, such as calcium dodecylbenzenesulfonate; alkylphenol-alkylene oxide addition products, such as nonylphenol-Cw ethoxylate; alcohol-alkylene oxide addition products, such as tridecyl alcohol-Cw ethoxylate; soaps, such as sodium stearate; alkylnaphthalene sulfonate salts, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as sodium di (2-ethylhexyl) sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as trimethylammonium lauryl chloride; polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; salts of mono- and dialkyl phosphate esters; vegetable or seed oils such as soybean oil, rapeseed / canola oil, olive oil, castor oil, sunflower seed oil, coconut oil, corn oil, cottonseed oil, linseed oil, palm, peanut oil, safflower oil, sesame oil, tung oil and
Petition 870180167466, of 12/26/2018, p. 19/83
Similar 14/70; and esters of the above vegetable oils, particularly methyl esters.
[0036] Often, some of these materials, such as vegetable oils or seed oils and their esters, can be used interchangeably as an agricultural adjuvant, as a liquid vehicle or as a surfactant.
[0037] Other adjuvants commonly used in agricultural compositions include compatibilizing agents, defoamers, sequestering agents, neutralizers and buffers, corrosion inhibitors, dyes, odorants, spreading agents, penetration aids, tackiness agents, dispersants, thickeners, depressants of freezing point, antimicrobial agents, and the like. The compositions can also contain other compatible components, for example, other herbicides, plant growth regulators, fungicides, insecticides, and the like and can be formulated with liquid fertilizers or solid fertilizer carriers such as ammonium nitrate, urea and the like.
[0038] The concentration of the active ingredient in the herbicidal compositions of this invention is generally from 0.001 to 98 weight percent. Concentrations of 0.01 to 90 weight percent are often employed. In compositions designed to be employed as concentrates, the active ingredient is generally present in a concentration of 5 to 98 weight percent, preferably 10 to 90 weight percent. Such compositions are typically diluted with an inert carrier, such as water, before application. The diluted compositions usually applied to weeds or the weed site generally contain 0.0001 to 1 weight percent of active ingredient and preferably contain 0.001 to 0.05 weight percent.
[0039] The present compositions can be applied to herbs
Petition 870180167466, of 12/26/2018, p. 20/83
15/70 weeds or their location by the use of conventional soil or aerial sprinklers, sprayers and granule applicators, by addition to irrigation water or flood water from rice fields, and by other conventional means known to those skilled in the art.
[0040] The following Examples are presented to illustrate the various aspects of this invention and are not to be considered as limitations on the claims.
Examples [0041] General: Microwave heating was performed using a Biotage Initiator ™ microwave reactor. Microwave reactions were carried out in closed reaction vessels with magnetic stirring and temperature controlled via infrared (IR) detection.
Example 1. Preparation of benzyl 4-amino-3-chloro-6- (4chloro-2-fluoro-3-methoxyphenyl) -5-fluoropicolinate (Compound 1)
[0042] To a solution of 4-amino-3-chloro-6- (4-chloro-2-fluor-3methoxyphenyl) -5-fluoropicolinic acid (prepared by the methods described in US patent 7 314 849 B2; 100 milligrams (mg ), 0.29 millimoles (mmol)) in tetrahydrofuran (THF; 1 milliliter (mL)) was added carbonyl diimidazole (51 mg, 0.32 mmol). The reaction mixture was stirred at room temperature for 30 minutes (min) when the evolution of carbon dioxide (CO2) ceased. Benzyl alcohol (62 mg, 0.58 mmol) was added, and the reaction mixture was heated in a microwave oven at 90 ° C for 20 min. The reaction mixture was purified by silica gel chromatography (applied directly to an Isco 40 column
Petition 870180167466, of 12/26/2018, p. 21/83
16/70 grams (g) RediSep® eluting with 0-100% diethyl ether (Et2Ü) in hexanes) to provide a white solid (147 mg, 78%): mp 132-133 ° C, ¹ H NMR (400 MHz, DMSO-cfe) δ 7.50 - 7.33 (m, 6H), 7.29 (dd, J = 8.5, 7.1 Hz, 1H), 7.13 (s, 2H), 5.37 (s, 2H), 3.92 (s, 3H); ESIMS m / z 439 ([M + H] ⁺ ).
Example 2. Preparation of 4-chlorobenzyl 4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropicolinate (Compound 2)
[0043] A suspension of 4-amino-3-chloro-6- (4-chloro-2-fluoro3-methoxyphenyl) -5-fluoropicolinic acid (150 mg, 0.43 mmol), 1- (bromomethyl) -4methylbenzene ( 159 mg, 0.86 mmol), potassium carbonate (K2CO3; 118 mg, 0.86 mmol) and sodium iodide (NaI; 6 mg, 0.04 mmol) in N, Ndimethylformamide (DMF; 1 mL) was heated in a microwave oven at 100 ° C for 5 min. The reaction mixture was then diluted with Et2O, washed with brine, dried over sodium sulfate (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with a 0-70% ethyl acetate (EtOAc) / hexanes gradient) to provide a white solid (148 mg, 73%): mp 143 ° C; ¹ H NMR (400 MHz, DMSO-cfe) δ 7.50 - 7.42 (m, 5H), 7.28 (dd, J = 8.5, 7.1 Hz, 1H), 7.08 (s , 2H), 5.37 (s, 2H), 3.93 (d, J = 0.8 Hz, 3H); ESIMS m / z 475 ([M + H] ⁺ ).
Compounds 3-16 of Table 1 were synthesized as in Example 2.
Example 3. Preparation of 4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) 2,4-dichlorobenzyl picolinate (Compound 17)
Petition 870180167466, of 12/26/2018, p. 22/83
17/70

Cl [0044] Acid
4-amino-3-chloro-6- (4-chloro-2-fluoro-3 methoxyphenyl) picolinic (prepared by the methods described in the U patent.
S. 7 314 849 B2; 828 mg, 2.5 mmols) was dissolved in DMF (4 ml).
Sodium hydride (NaH, 60% dispersion in mineral oil; 154 mg, 3.85 mmols) was added gradually. To the mixture was added 2,4-dichloro
1- (chloromethyl) benzene (586 mg, 3.0 mmol). The reaction mixture was allowed to stir for 24 hours (h). Water was added to the reaction mixture, and the aqueous phase was extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried with Na2SO4, filtered, and concentrated. Purification by normal phase chromatography gave a white solid (440 mg, 35%): mp 165-168 ° C, ¹ H NMR (400 MHz, CDCb) δ 7.68 (dd, J = 8.6, 7.8 Hz, 1H), 7.54 (d, J = 8.3
Hz, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 7.23 (d, J = 1.8 Hz, 1H), 7.21 (d, J = 1.6 Hz, 1H), 5.50 (s, 2H), 4.83 (s, 2H), 3.97 (d, J = 0.8 Hz, 3H) ; ESIMS m / z 489 ([M-H]).
Compounds 18 and 19 of Table 1 were synthesized as in Example 3.
Example 4. Preparation of 4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropicolinate of 4-trifluoromethoxybenzyl (Compound 20)
Petition 870180167466, of 12/26/2018, p. 23/83
18/70
[0045] A suspension of 4-amino-3-chloro-6- (4-chloro-2-fluoro-
3- methoxyphenyl) -5-fluoropicolinic (200 mg, 0.573 mmol), 1- (bromomethyl) -
4- (trifluoromethoxy) benzene (161 mg, 0.630 mmol) and K2CO3 (119 mg, 0.859 mmol) in DMF (2 mL) was heated to 50 ° C overnight. The reaction mixture was then concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 0-80% EtOAc / hexane gradient) to provide a white solid (154 mg, 51.4%): mp 155-156 ° C; ¹ H NMR (400 MHz, DMSO-cfe) δ 7.60 (d, J = 8.7 Hz, 2H), 7.47 (dd, J = 8.5, 1.5 Hz, 1H), 7, 41 (d, J = 8.0 Hz, 2H), 7.29 (dd, J = 8.5, 7.1 Hz, 1H), 7.14 (s, 2H), 5.41 (s, 2H ), 3.95 - 3.90 (m, 3H); ESIMS m / z 523 ([M + H] ⁺ ), 521 ([MH] ^- ).
Compounds 21-34 of Table 1 were synthesized as in Example 4.
Example 5. Preparation of benzyl 6-amino-2- (4-chloro-2-fluor-3methoxyphenyl) -5-vinylpyrimidine-4-carboxylate (Compound 35)

[0046] 6-Amino-2- (4-chloro-2-fluor-3-methoxyphenyl) -5vinylpyrimidine-4-carboxylic acid (prepared by the methods described in US patent 7 786 044 B2; 0.150 g, 0.463 mmol), ( bromomethyl) benzene
Petition 870180167466, of 12/26/2018, p. 24/83
19/70 (0.103 g, 0.602 mmol), and lithium carbonate (LI2CO3; 0.044 g, 0.602 mmol) were combined in DMF (1.5 mL) and heated to 60 ° C overnight. The cooled reaction mixture was concentrated and then partitioned between EtOAc and water. The organic phase was dried, concentrated and purified by column chromatography (eluting with a gradient of EtOAc / hexanes) to provide 6-amino-2- (4-chloro-2-fluoro-3methoxyphenyl) -5-vinylpyrimidine-4-carboxylate benzyl as a white solid (0.154 g, 80%): mp 119-121 ° C; ¹ H NMR (400 MHz, CDCb) δ 7.67 (dd, J = 8.5, 7.5 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.42 - 7.32 (m, 3H), 7.21 (dd, J = 8.6, 1.7 Hz, 1H), 6.70 (dd, J = 17.8, 11.6 Hz, 1H), 5.60 ( dd, J = 7.7, 1.0 Hz, 1H), 5.57 (s, 1H), 5.39 (s, 2H), 5.35 (s, 2H), 4.00 (d, J = 0.8 Hz, 3H); ESIMS m / z 414 ([M + H] ⁺ ).
Example 6. Preparation of 4-methoxybenzyl 4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) picolinate (Compound 36)
[0047] To a solution of 4-amino-3-chloro-6- (4-chloro-2-fluoro-3methoxyphenyl) picolinic acid (600 mg, 1.81 mmol) in THF (10 mL) were added triphenylphosphine (475 mg, 1.81 mmol), diethyl azodicarboxylate (0.29 mL, 1.81 mmol), and 4-methoxybenzyl alcohol (0.34 mL, 2.72 mmol). The reaction mixture was stirred for 48 h. Additional triphenylphosphine (475 mg, 1.81 mmol) was added to the reaction, and the reaction mixture was stirred for 24 hours. The reaction mixture was concentrated to dryness and was purified by silica gel chromatography (eluting with a 0-100% EtOAc / hexane gradient) to provide an off-white solid (170 mg, 26%): mp 73-83 ° C ; ¹ H NMR (400 MHz, CDCh)
Petition 870180167466, of 12/26/2018, p. 25/83
20/70 δ 7.66 (dd, J = 8.6, 7.8 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.22 (dd, J = 8.7, 1 , 8 Hz, 1H), 7.16 (d, J = 1.7 Hz, 1H), 6.94 - 6.87 (m, 2H), 5.38 (s, 2H), 4.80 (s , 2H), 3.96 (d, J = 0.8 Hz, 3H), 3.81 (s, 3H); ESIMS m / z 451 ([M + H] ⁺ ), 449 ([MH] -).
Compound 37 from Table 1 was synthesized as in Example
6.
Example 7. Preparation of benzyl 4-amino-3-chloro-6- (2,4-dichloro-3methoxyphenyl) -picolinate (Compound 38)
[0048] Methyl 4-amino-3-chloro-6- (2,4-dichloro-3-methoxyphenyl) picolinate (Compound C, prepared by the methods described in US Patent 7,314,849 B2; 500 mg, 1.4 mmol ) was dissolved in benzyl alcohol (10 ml), treated with titanium (IV) isopropoxide (ca 100 pL) and heated to 85-90 ° C. After two hours, another portion of titanium (IV) isopropoxide (100 pL) was added and heating continued for another 18 hours. The volatiles were removed under high vacuum, and the residue was purified by silica gel chromatography (eluting with 5% Et2O-30% dichloromethane (CH2Cb) -65% hexane). The material was further purified by reverse phase high performance liquid chromatography (RP-HPLC; eluting with 70% acetonitrile) to provide the title compound (375 mg, 61%): mp 107-108 ° C; ¹ H NMR (400 MHz, CDCh) δ 7.50 - 7.26 (m, 8H), 6.97 (s, 1H), 5.42 (s, 2H), 4.85 (s, 2H), 3.91 (s, 3H); ESIMS m / z 437 ([M + H] ⁺ ).
Compound 39 from Table 1 was synthesized as in Example
7.
Petition 870180167466, of 12/26/2018, p. 26/83
21/70
Example 8. Preparation of benzyl 4-amino-3-chloro-6- (4-chloro-2-fluoro-3- (1-fluoroethyl) phenyl) -5-fluoropicolinate (Compound 40)
[0049] Step______A. Methyl 4-amino-3-chloro-6- (4-chloro-2-fluor-3- (1-fluoroethyl) phenyl) -5-fluoropicolinate (Compound H). 2- (4-Chloro-2fluor-3- (1-fluoroethyl) phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolan (510 mg, 1.7 mmol, 1.0 equivalent ( equiv)) and methyl 4-amino-3,6-dichloro-5fluoropicolinate (prepared by the methods described in US patent 6 784 137 B2; 400 mg, 1.7 mmol, 1.0 equiv) were sequentially added to a container of 5 ml Biotage microwave, followed by cesium fluoride (CsF; 510 mg, 3.3 mmol, 2.0 equiv), palladium (II) acetate (19 mg, 0.084 mmol, 0.05 equiv), and 3.3 ', 3''sodium phosphinatri-yltribenzenesulfonate (95 mg, 0.17 mmol, 0.10 equiv). A 3: 1 water-acetonitrile mixture (3.2 mL) was added and the resulting brown mixture was heated in a microwave oven at 150 ° C for 5 minutes. The cooled reaction mixture was diluted with water (150 ml) and extracted with CH2Cl2 (4 x 50 ml). The combined organic extracts were dried over magnesium sulfate (MgSO4), filtered by gravity, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (eluting with a gradient of 5% acetonitrile to 100% acetonitrile) to provide the desired product, 4-amino-3-chloro-6- (4-chloro-2-fluorine) Methyl 3- (1 fluoroethyl) phenyl) -5-fluoropicolinate as a brown semi-solid (220 mg, 35%): IR (thin film) 3475 (w), 3353 (m), 3204 (w), 3001 (w ), 2955 (w), 1738 (s), 1711 (s), 1624 (s) cm ^-1 ; ¹ H NMR (300 MHz,
Petition 870180167466, of 12/26/2018, p. 27/83
22/70
CDCb) δ 7.50 (m, 1H), 7.30 (m, 1H), 7.21 (d, J = 2 Hz, 1H), 6.16 (dq, J = 46, 7 Hz, 1H) , 4.96 (br s, 2H), 3.97 (s, 3H), 1.75 (dd, J = 23.7 Hz, 3H); ESIMS m / z 379 ([M + H] ⁺ ).
[0050] Step B. 4-Amino-3-chloro-6- (4-chloro-2-fluoro-3- (1 fluoroethyl) phenyl) -5-fluoropicolinic acid. A 2 molar aqueous solution (M) of sodium hydroxide (NaOH; 580 pL, 1.2 mmol, 4.0 equiv) was added to a stirred suspension of 4-amino-3-chloro-6- (4-chloro- Methyl 2-fluor-3- (1 fluoroethyl) phenyl) -5-fluoropi-cholinate (110 mg, 0.29 mmol, 1.0 equiv) in methyl alcohol (1.9 mL) at 23 ° C. The pale yellow homogeneous solution was stirred at 23 ° C for 20 hours. The reaction mixture was adjusted approximately to pH = 4 via addition in drops of concentrated hydrochloric acid (HCl) and concentrated via rotary evaporation. The residue was suspended in water and vacuum filtered to provide the desired product, 4-amino-3-chloro-6- (4-chloro-2-fluoro-3- (1-fluoroethyl) phenyl) -
5-fluoropicolinic as a white powder (55 mg, 50%): IR (thin film) 3319 (m), 3193 (w), 2983 (w), 1719 (m), 1629 (s) cm ^-1 ; ¹ H NMR (300 MHz, DMSO-cfe) δ 7.58 (t, J = 9 Hz, 1H), 7.49 (d, J = 9 Hz, 1H), 6.99 (br s, 2H), 6.15 (dq, J = 44, 7 Hz, 1H), 1.71 (dd, J = 23, 7 Hz, 3H); ESIMS m / z 365 ([M + H] ⁺ ).
[0051] Stage______C. Benzyl 4-amino-3-chloro-6- (4-chloro-2-fluor-3- (1-fluoroethyl) phenyl) -5-fluoropicolinate. Triethylamine (190 pL, 1.4 mmol, 2.0 equiv) and benzyl bromide (120 pL, 1.0 mmol, 1.5 equiv) were sequentially added to a stirred solution of 4 amino-3- chloro-6- acid (4-chloro-2-fluor-3- (1-fluoroethyl) phenyl) -5-fluoropicolinic (0.25 g, 0.69 mmol, 1.0 equiv) in THF (3.4 mL) at 23 ° C . The resulting cloudy pale yellow solution was stirred at 23 ° C for 18 hours. The reaction mixture was diluted with water (150 ml) and extracted with CH2Cl2 (3 x 70 ml). The combined organic layers were dried (MgSO4), filtered by gravity, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography
Petition 870180167466, of 12/26/2018, p. 28/83
23/70 (eluting with a gradient of 5% acetonitrile to 100% acetonitrile) to provide the desired product, benzyl 4-amino-3-chloro-6- (4-chloro-2-fluoro3- (1-fluoroethyl) phenyl) Benzyl-5-fluoropicolinate as a yellow semi-solid (160 mg, 52%): IR (thin film) 3485 (m), 3393 (m), 3196 (w), 3035 (w), 2983 (w), 1737 (s), 1622 (s) cm ^-1 ; ¹ H NMR (300 MHz, CDCb) δ 7.23 - 7.57 (m, 7H), 6.18 (dq, J = 45, 6 Hz, 1H), 5.45 (s, 2H), 4, 94 (br s, 2H), 1.78 (ddd, J = 23.7, 1 Hz, 3H); ESIMS m / z 453 ([M + H] ⁺ ).
Example 9. Preparation of benzyl 4-amino-3-chloro-6- (4-chloro-3-ethoxy-2-fluorophenyl) -5-fluoropicolinate (Compound 41)
[0052] Step A. Methyl 4-amino-3-chloro-6- (4-chloro-3-ethoxy-2-fluorophenyl) -5 fluoropicolinate (Compound A). 2- (4-Chloro-3-ethoxy-2fluorophenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolan (500 mg, 1.7 mmol, 1.0 equiv) and 4-amino- Methyl 3,6-dichloro-5-fluoropicolinate (400 mg, 1.7 mmol, 1.0 equiv) was sequentially added to a 5 ml Biotage microwave container, followed by CsF (510 mg, 3.3 mmol, 2.0 equiv), palladium (II) acetate (19 mg, 0.084 mmol, 0.05 equiv), and 3.3 ', 3' '- sodium phosphinathriyltribenzene sulfonate (95 mg, 0, 17 mmol, 0.10 equiv). A 3: 1 water-acetonitrile mixture (3.2 ml) was added, and the resulting brown mixture was heated in a bench microwave at 150 ° C for 5 min. The cooled reaction mixture was diluted with water (150 ml) and extracted with CH2Cl2 (4 x 50 ml). The combined organic extracts were dried (MgSO4), filtered by gravity, and concentrated by rotary evaporation. The residue was
Petition 870180167466, of 12/26/2018, p. 29/83
24/70 purified by silica gel column chromatography (eluting with 33% EtOAc / hexane) to provide the desired product, 4-amino-3-chloro-6- (4 chloro-3-ethoxy-2-fluorophenyl) -5 -methyl fluoropicolinate as a brown powder (450 mg, 63%): mp 170-172 ° C; IR (thin film) 3485 (m), 3380 (s), 2951 (w), 1739 (s), 1610 (s) cm ^-1 ; ¹ H NMR (300 MHz, CDCb) δ 7.20 - 7.30 (m, 2H), 4.95 (br s, 2H), 4.19 (q, J = 7 Hz, 2H), 3.98 (s, 3H), 1.43 (t, J = 7 Hz, 3H); ESIMS m / z 377 ([M + H] ⁺ ).
[0053] Step B. 4-Amino-3-chloro-6- (4-chloro-3-ethoxy-2-fluorophenyl) -5-fluoropicolinic acid. A 2 M aqueous solution of NaOH (900 pL, 1.8 mmol, 4.0 equiv) was added to a stirred suspension of 4 amino-3- chloro-6- (4-chloro-3-ethoxy-2-fluorophenyl) - Methyl 5-fluoropicolinate (170 mg, 0.45 mmol, 1.0 equiv) in methyl alcohol (3.0 mL) at 23 ° C. The resulting heterogeneous white mixture was stirred at 23 ° C for 4 hours. The reaction mixture was adjusted to approximately pH = 4 via the drop addition of concentrated HCl and then concentrated via rotary evaporation. The residue was suspended in water and vacuum filtered to provide the desired product, 4-amino-3-chloro-6- (4-chloro-3-ethoxy-2-fluorophenyl) -5-fluoropicolinic acid as a white powder (140 mg, 88%): mp 163-165 ° C; IR (thin film) 3486 (m), 3377 (s), 3155 (w), 2981 (w), 2935 (w), 1718 (s), 1614 (s) cm ^-1 ; ¹ H NMR (300 MHz, DMSO-cfe) δ 7.45 (dd, J = 9, 2 Hz, 1H), 7.28 (dd, J = 9, 7 Hz, 1H), 7.01 (br s , 2H), 4.15 (q, J = 7 Hz, 2H), 1.33 (t, J = 7 Hz, 3H); ESIMS m / z 363 ([M + H] ⁺ ).
[0054] Step C. Benzyla 4-amino-3-chloro-6- (4-chloro-3-ethoxy-2-fluorophenyl) -5 fluoropicolinate. Triethylamine (290 pL, 2.1 mmols, 2.0 equiv) and benzyl bromide (190 pL, 1.6 mmol, 1.5 equiv) were sequentially added to a stirred solution of 4-amino3-chloro-6- acid (4-chloro-3-ethoxy-2-fluorophenyl) -5-fluoropicolinic (0.38 g, 1.1 mmol, 1.0 equiv) in THF (7.0 mL) at 23 ° C. The resulting cloudy brown solution was stirred at 23 ° C for 18 hours. The reaction mixture was diluted with water (150 ml) and extracted with CH2Cl2 (3 x 70 ml). The
Petition 870180167466, of 12/26/2018, p. 30/83
25/70 combined organic extracts were dried (MgSÜ4), filtered by gravity, and concentrated by rotary evaporation. The residue was purified by RP-HPLC (eluting with a gradient of 5% acetonitrile to 100% acetonitrile) to provide the desired product, 4-amino-3-chloro-6 (4-chloro-3-ethoxy-2-fluorophenyl) Benzyl-5-fluoropicolinate as a white powder (230 mg, 49%): mp 122-124 ° C; IR (thin film) 3477 (s), 3372 (s), 3194 (w), 3036 (w), 2992 (m), 2943 (w), 2900 (w), 1729 (s), 1616 (s) cm ¹ ; ¹ H NMR (300 MHz, CDCb) δ 7.49 - 7.32 (m, 5H), 7.29 - 7.21 (m, 2H),
5.43 (s, 2H), 4.91 (br s, 2H), 4.19 (q, J = 7 Hz, 2H), 1.43 (t, J = 7 Hz, 3H); ESIMS m / z 453 ([M + H] ⁺ ).
Example 10. Preparation of benzyl 4-amino-3-chloro-6- (4cyclopropylphenyl) -5-fluoropicolinate (Compound 42)
[0055] Step_______A. Ethyl 4-amino-3-chloro-6- (4-cyclopropylphenyl) -5 fluoropicolinate. Methyl 4-cyclopropylphenylboronic acid (250 mg, 1.5 mmol, 1.2 equiv) and methyl 4-amino-3,6-dichloro-5-fluoropicolinate (300 mg, 1.3 mmol, 1.0 equiv) were sequentially added to a 5 ml Biotage microwave container, followed by CsF (380 mg,
2.5 mmols, 2.0 equiv), palladium (II) acetate (14 mg, 0.063 mmol, 0.05 equiv), and 3.3 ', 3' '- fosfinatri-il-tribenzenesulfonate sodium ( 71 mg, 0.13 mmol, 0.10 equiv). A 3: 1 water-acetonitrile mixture (2.5 mL) was added, and the resulting brown mixture was heated in a bench microwave at 150 ° C for 5 minutes. The cooled reaction mixture was diluted with water (150 ml) and extracted with CH2Cl2 (4 x 50 ml). The combined organic extracts were dried (MgSO4), filtered by gravity, and concentrated by rotary evaporation. The residue was
Petition 870180167466, of 12/26/2018, p. 31/83
26/70 purified by RP-HPLC (eluting with a gradient of 5% acetonitrile to 100% acetonitrile) to provide the desired product, methyl 4-amino-3-chloro-6 (4-cyclopropylphenyl) -5-fluoropicolinate as a white powder (310 mg, 78%): mp 116-119 ° C; IR (thin film) 3475 (s), 3357 (s), 3089 (w), 3013 (w), 2954 (w), 1724 (m), 1607 (m) cm ^-1 ; ¹ H NMR (300 MHz, CDCb) δ 7.81 (m, 2H), 7.15 (m, 2H), 4.85 (br s, 2H), 3.98 (s, 3H), 1.94 (m, 1H), 1.01 (m, 2H), 0.74 (m, 2H); ESIMS m / z 321 ([M + H] ⁺ ).
[0056] Step B. 4-Amino-3-chloro-6- (4-cyclopropylphenyl) -5 fluoropicolinic acid. A 2 M aqueous solution of NaOH (600 pL, 1.2 mmol, 2.0 equiv) was added to a stirred suspension of 4-amino-3-chloro-
Methyl 6- (4-cyclopropylphenyl) -5-fluoropicolinate (190 mg, 0.59 mmol, 1.0 equiv) in methyl alcohol (3.0 mL) at 23 ° C. The resulting heterogeneous white mixture was stirred at 23 ° C for 3 hours. The reaction mixture was adjusted to approximately pH = 4 via dropping concentrated HCl and then concentrated via rotary evaporation. The residue was suspended in water and vacuum filtered to provide the desired product, 4-amino-3-chloro-6- (4-cyclopropylphenyl) -5-fluoropicolinic acid as a white powder (170 mg, 94% yield): mp 147-149 ° C; IR (thin film) 3463 (s), 3339 (s), 3202 (m), 3084 (w), 3007 (w), 1721 (m), 1630 (s) cm ^-1 ; ¹ H NMR (300 MHz, DMSO-cfe) δ 7.70 (m, 2H), 7.17 (m, 2H), 6.81 (br s, 2H), 1.96 (m, 1H), 0 .99 (m, 2H), 0.71 (m, 2H); ESIMS m / z 307 ([M + H] ⁺ ).
[0057] Stage_______C. Benzyl 4-amino-3-chloro-6- (4-cyclopropylphenyl) -5 fluoropicolinate. Triethylamine (220 pL, 1.6 mmol, 2.0 equiv) and benzyl bromide (140 pL, 1.2 mmol, 1.5 equiv) were sequentially added to a stirred solution of 4-amino3-chloro-6- acid (4-chloro-3-ethoxy-2-fluorophenyl) -5-fluoropicolinic (0.24 g, 0.78 mmol, 1.0 equiv) in THF (5.2 ml) at 23 ° C. The cloudy yellow-pale solution was stirred at 23 ° C for 72 hours. The reaction mixture was diluted with water (150 ml) and extracted with CH2Cl2 (3 x 70 ml). The extracts
Petition 870180167466, of 12/26/2018, p. 32/83
27/70 combined organics were dried (MgSÜ4), filtered by gravity, and concentrated by rotary evaporation. The residue was purified by RPHPLC (eluting with a gradient of 5% acetonitrile to 100% acetonitrile) to provide the desired product, benzyl 4-amino-3-chloro-6- (4-cyclopropylphenyl) 5-fluoropicolinate as a white powder (180 mg, 58%): mp 129-131 ° C; IR (thin film) 3389 (s), 3229 (w), 3194 (w), 3083 (w), 3068 (w), 3033 (w), 3008 (w), 1737 (s), 1616 (s) cm ^-1 ; ¹ H NMR (300 MHz, CDCl3) δ 7.83 (m, 2H), 7.48 (m, 2H), 7.33 - 7.42 (m, 3H), 7.15 (m, 2H),
5.43 (s, 2H), 4.82 (br s, 2H), 1.94 (m, 1H), 1.01 (m, 2H), 0.75 (m, 2H); ESIMS m / z 497 ([M + H] ⁺ ).
Example 11: Preparation of benzyl 4-amino-3-bromo-6- (4-chloro-2-fluoro-3-methoxy-phenyl) -5-fluoropicolinate (Compound 43)
[0058] Step A. A mixture of 4,5,6-methyl trichloropicolinate (prepared by the methods described in US patent 6 784 137 B2; 25 g, 0.10 moles (mol)) and benzyl alcohol (100 g, 0 , 2 mol) in a round bottom flask with three 250 mL necks was heated under nitrogen to 100 ° C. Titanium isopropoxide (0.6 g, 0.02 mol) was added. After 4 hours at 100 ° C, the almost colorless solution was cooled and transferred to a 250 ml round bottom flask with a single neck. The excess benzyl alcohol was removed in vacuo to remove an off-white solid (31 g, 94%): mp 125-126.5 ° C; ¹ H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H, pyridine H), 7.42 (m, 2H, phenyl), 7.31 (m, 3H, phenyl), 5.40 (s, 2H, CH2Ph); ¹³ C { ¹ H} NMR (101 MHz, CDCh) δ 162.0 (CO2R), 150.4, 145.0, 144.9, 134.7, 133.1, 128.3 (CH phenyl), 125 , 4 (CH pyridine),
Petition 870180167466, of 12/26/2018, p. 33/83
28/70
67.88 (Cl-hPh).
[0059] Step B. A 250 mL three-necked flask equipped with a reflux condenser and nitrogen inlet (N2) was loaded with 4,5,6-benzyl trichloropicolinate (17.77 g, 56.10 mmols) , 2- (4-chloro-2-fluoro-3-methoxyphenyl) -1,3,2-dioxaborinane (19.20 g, 79.0 mmols) and CsF (17.04 g, 112.0 mmols). Acetonitrile (100 ml) and water (30 ml) were added. The reaction mixture was evacuated / and filled with N2 (5x). Dichlorobis (triphenylphosphine) palladium (II) (Pd (PPh3) 2Cl2 solid 1.724 g, 2.456 mmols) was added. The solution was evacuated / filled with N2 (5x) and then stirred at reflux for 90 min. A white solid precipitated when cooling to room temperature. The solid was filtered, washed with water and air-dried (18.66 g, 75%): ¹ H NMR (400 MHz, CDCh) δ 8.23 (s, 1H, pyridine H), 7.52 - 7, 32 (m, 5H, phenyl), 7.27 (dd, Jh-h = 8.4 Hz, Jf-h = 1.7 Hz, 1H, aromatic), 7.10 (dd, Jh-h = 8, 4 Hz, Jf-h = 6.8 Hz, 1H, aromatic),
5.44 (s, 2H, CH2Ph), 3.98 (d, Jf-h = 1.3 Hz, 3H, OMe); ¹³ C { ¹ H} NMR (101 MHz, CDCl3) δ 163.0, 153.7, 153.5 (d, Jf-c = 253 Hz, C2 '), 146.0,
144.5 (d, Jf-c = 13 Hz), 144.1, 135.0, 134.2, 129.9 (d, Jf-c = 3 Hz), 128.5, 126.1, 125, 8 (d, Jf-c = 14 Hz), 125.3 (d, Jf-c = 3 Hz), 124.9 (d, Jf-c = 2 Hz), 67.9 (CH2), 61.5 (d, Jf-c = 4 Hz, OMe). Anal. Calcd for C20H13Cl3FNO3: C, 54.51; H, 2.97; N, 3.18. Found: C, 54.60; H, 3.08; N, 3.16.
[0060] Step C. A 250 mL bottle with three necks was equipped with a distillation head, an N2 inlet, a mechanical stirrer and a thermocouple. The flask was loaded with CsF (21.07 g, 139.0 mmols). Anhydrous DMSO (100 ml) was added, and the suspension was evacuated / filled (5x) with N2. The suspension was heated to 80 ° C for 30 minutes. DMSO (30 mL) was distilled under vacuum to remove any residual water. Solid benzyl 4,5-dichloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) picolinate (15.34 g, 34.8 mmols)
Petition 870180167466, of 12/26/2018, p. 34/83
29/70 was added, and the solution was evacuated / filled with N2 (5x). The reaction mixture was heated to 105 ° C under N2. After 6 hours at 105 ° C, analysis of an aliquot by GC showed no peak for the monofluoro intermediate. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into ice water (400 g) and was extracted with EtOAc (3 x 200 ml). The combined organic extracts were washed with saturated NaHCO3 solution (satd), water (5 x 100 mL) and brine. The extracts were dried (MgSO4) and concentrated under reduced pressure to provide a brown solid (12.97 g). The solid was purified by flash chromatography (330 g silica column; 0-20% EtOAc gradient) to provide a white solid (9.95 g; 70%): mp 114-116 ° C; ¹ H NMR (400 MHz, CDCh) δ 8.01 (dd, Jf-h = 9.4, 5.5 Hz, 1H, pyridine H), 7.53 - 7.20 (m, 7H, phenyl), 5.44 (s, 2H, C ^ Ph), 3.99 (d, Jf-h = 1.2 Hz, 3H, OMe); ¹³ C NMR (101 MHz, CDCh) δ 162.8 (d, Jf-c = 3 Hz, CO2Bn), 156.2 (dd, Jf-c = 267, 12 Hz), 153.9 (d, Jf- c = 255 Hz), 148.0 (dd, Jf-c = 269, 11 Hz), 145.4 (t, Jf-c = 7 Hz), 144.7 (d, Jf-c = 13 Hz),
144.6 (dd, Jf-c = 13, 2 Hz), 135.2 (s), 130.6 (d, Jf-c = 3 Hz), 125.6 (d, Jf-c = 4 Hz) , 125.4 (d, Jf-c = 2 Hz), 122.0 (d, Jf-c = 14 Hz), 115.0 (d, Jf-c = 16 Hz), 67.9 (s, CH2Ph ), 61.6 (d, Jf-c = 5 Hz, OMe); ¹⁹ F { ¹ H} NMR (376 MHz, CDCh) δ -123.90 (d, Jf-f = 19.7 Hz, F4), -128.37 (d, Jf-f = 33.5 Hz, F2 '), -139.64 (dd, Jf-f = 33.5, 19.7 Hz, F5), Anal, Calcd for C20H13CF3NO3: C, 58.91; H, 3.21; N, 3.43, Found: C, 59.03; H, 3.20; N, 3.39.
[0061] Step_______D. Benzyl 4,5-difluoro-6- (4-chloro-2-fluoro-3methoxyphenyl) picolinate (4.99 g, 12.2 mmol) was suspended in DMSO (100 mL). Ammonia was bubbled through the solution for 30 min. After stirring overnight, the reaction mixture was poured into ice water (500 ml). The product was extracted into EtOAc (3 x 150 ml). The combined organic extracts were washed with water (5 x
Petition 870180167466, of 12/26/2018, p. 35/83
30/70
100 mL) and brine, dried (MgSÜ4) and concentrated under reduced pressure to provide a white solid (4.99 g, 101%); ¹ H NMR (400 MHz, CDCb) δ 7.52 (d, Jf-h = 6.5 Hz, 1H, pyridine H3), 7.45 - 7.38 (m, 2H), 7.37 - 7, 17 (m, 5H), 5.38 (s, 2H, CtePh), 4.67 (br s, 2H, NH2), 3.94 (d, Jf-h = 1.1 Hz, 3H, OMe); ¹³ C { ¹ H} NMR (101 MHz, CDCb) δ 164.4 (CÜ2R), 153.9 (d, Jf-c = 254 Hz), 147.6 (d, Jf-c = 256 Hz), 144 , 4 (d, Jf-c = 14 Hz), 144.0 (d, Jf-c = 5 Hz), 142.2 (d, Jf-c = 12 Hz), 140.4 (d, Jf-c = 15 Hz), 135.6 (s), 129.5 (d, Jf-c = 3 Hz), 128.5 (CH), 128.3 (CH), 128.3 (CH), 125.6 (d, Jf-c = 3 Hz, CH), 125.2 (d, Jf-c = 4 Hz, CH), 123.3 (dd, Jf-c = 14, 4 Hz), 113.1 (d , Jf-c = 4 Hz, C3), 67.3 (s, CH2Ph), 61.5 (d, Jfc = 4 Hz, OMe); ¹⁹ F { ¹ H} NMR (376 MHz, CDCb) δ -128.54 (dd, J = 30.7, 5.2 Hz, F2 '), -141.84 (dd, J = 30.8, 6 , 5 Hz, F5), HRMS-ESI (m / z) [M] ⁺ calculated for C20H15CIF2N2O3, 404.0739; found, 404.0757.
[0062] Step E. M-Bromosuccinamide (NBS; 580 mg, 3.3 mmol, 1.1 equiv) was added to a stirred suspension of 4-amino-6- (4-chloro-2-fluor-3-methoxyphenyl) - Benzyl 5-fluoro-picolinate (1.2 g, 3.0 mmol, 1.0 equiv) in 1,2-dichloroethane (15 mL) at 23 ° C. The resulting bright yellow mixture was stirred at 23 ° C for 72 hours. The brown reaction mixture was concentrated by N2 stream and the residue was purified by silica gel column chromatography (eluting with 29% EtOAc / hexane) to provide the desired product, 4-amino-3-bromo-6 (4 benzyl chloro-2-fluoro-3-methoxyphenyl) -5-fluoropicolinate as a brown powder (1.3 g, 93%): mp 144-146 ° C; IR (thin film) 3370 (s), 3225 (w), 3190 (w), 3093 (w), 3066 (w), 3037 (w), 2948 (w), 1731 (s), 1616 (s) cm ¹ ; ¹ H NMR (400 MHz, CDCb) δ 7.47 (m, 2H), 7.41 - 7.33 (m, 3H), 7.26 - 7.22 (m, 2H), 5.42 (s , 2H), 4.98 (br s, 2H), 3.96 (d, J = 1 Hz, 3H); ESIMS m / z 485 ([M + H] ⁺ ).
Example 12: Preparation of benzyl (E) -4-amino-6- (4-chloro-2-fluor3-methoxy-phenyl) -3- (2-chlorovinyl) -5-fluoropicolinate (Compound 44)
Petition 870180167466, of 12/26/2018, p. 36/83
31/70
[0063] Step A. Tributyltin hydride (2.0 mL, 7.3 mmols, 1.0 equiv) and ethinyltrimethylsilane (2.1 mL, 15 mmols, 2.0 equiv) were combined, 2,2'-azobis (2-methylpropionitrile) (AIBN; 60 mg, 0.36 mmol, 0.05 equiv) was added, and the resulting pure colorless solution was heated to 80 ° C. On heating an exotherm to ~ 110 ° C was observed. The reaction mixture was cooled back to 80 ° C and stirred for 20 hours. The reaction mixture was cooled to 23 ° C to provide the desired crude product, (E)-trimethyl (2- (tributylstannyl) vinyl) silane, as a pale yellow oil (2.8 g, 99% crude yield): ¹ H NMR (400 MHz, CDCl3) δ 6.96 (d, J = 22.5 Hz, 1H), 6.60 (d, J = 22.5 Hz, 1H), 1.54 - 1.44 ( m, 6H), 1.35 - 1.23 (m, 6H), 0.91 - 0.82 (m, 15H), 0.03 (s, 9H). [0064] Step B. (E)-trimethyl (2- (tributylstannyl) vinyl) silane (1.1 g, 2.7 mmol, 1.1 equiv) was added to a stirred mixture of 4-amino-3-bromo-6 - Benzyl (4-chloro-2-fluor-3-methoxyphenyl) -5-fluoropicolinate (Compound 43; 1.2 g, 2.5 mmol, 1.0 equiv) and tetrakis (triphenylphosphine) palladium (0) (290 mg, 0.25 mmol, 0.10 equiv) in DMF (8.3 mL) at 23 ° C. The reaction mixture was heated to 90 ° C, resulting in a homogeneous dark yellow solution, and the reaction mixture was heated for 20 hours. The cooled reaction mixture was diluted with water (400 ml) and extracted with Et2Ü (4 x 100 ml). The organic layer was dried (MgSÜ4), filtered by gravity, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (gradient from 5% acetonitrile to 100% acetonitrile) to provide the desired product, (E) -4-amino-6- (4-chloro-2-fluorine-3Petition 870180167466, of 12/26/2018, page 37/83
32/70 methoxyphenyl) -5-fluorine-3- (2- (trimethylsilyl) vinyl) benzyl picolinate, as a light brown oil (460 mg, 38%): IR (thin film) 3483 (w), 3376 (m ), 3206 (w), 3069 (w), 2955 (s), 2897 (w), 1732 (s), 1619 (s) cm-1; 1H NMR (400 MHz, CDCl ₃ ) δ 7.44 - 7.27 (m, 7H), 6.94 (d, J = 20 Hz, 1H), 6.28 (d, J = 20 Hz, 1H) , 5.33 (s, 2H), 4.62 (br s, 2H), 3.95 (d, J = 1 Hz, 3H), 0.09 (s, 9H); ESIMS m / z 503 ([M + H] ⁺ ).
[0065] Step C. M-chlorosuccinimide (NCS; 190 mg, 1.4 mmol, 2.0 equiv) was added to a stirred solution of (E) -4-amino-6- (4-chloro2-fluorine-3 -methoxyphenyl) -5-fluorine-3- (2- (trimethylsilyl) vinyl) benzyl picolinate (350 mg, 0.70 mmol, 1.0 equiv) in DMF (7.0 mL) at 23 ° C. The homogeneous pale green solution was heated to 50 ° C and stirred for 24 hours. The cooled reaction mixture was diluted with water (400 ml) and extracted with Et2Ü (4 x 100 ml). The combined organic layers were dried (MgSÜ4), filtered by gravity, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (gradient from 5% acetonitrile to 100% acetonitrile) to provide the desired product, (E) - 4-amino-6- (4-chloro-2-fluor-3-methoxyphenyl) ) -3- (2-chlorovinyl) -5-benzyl fluoropicolinate as a brown powder (70 mg, 22% yield): mp 133-135 ° C; IR (thin film) 3486 (s), 3345 (s), 3215 (w), 3069 (w), 3037 (w), 2953 (w), 1719 (s), 1616 (s) cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 - 7.43 (m, 2H), 7.41 - 7.33 (m, 3H), 7.27 (m, 2H), 6.89 ( d, J = 14 Hz, 1H), 6.45 (d, J = 14 Hz, 1H), 5.37 (s, 2H), 4.62 (br s, 2H), 3.97 (d, J = 1 Hz, 3H); ESIMS m / z 465 ([M + H] ⁺ ).
Petition 870180167466, of 12/26/2018, p. 38/83
33/70
Table 1. Example compound structures
Number of Structure compoundnh ₂ F Jx , Clγ 3 y N Κχ / Οχ. O cr ^OF _x NH2 Cl _X CN 4 N X / O ^ xYO Cl ^O Fl ' _x NH2 -ClO χγ γ' 5 JsXNyJ γΛ,O cr ° x FFx, NH2 xCl/ -CF ₃ γ ^ γ-6 J <x -Jx N X / Ox ^ γΛO cr ^O F NH2F _x , ClO 7Ύγ , -Y Jx,N /O O cr ° x F
Petition 870180167466, of 12/26/2018, p. 39/83
34/70
Number ofcompound Structure F nh ₂ .Cl8 / ¼. /N // O ^O Cl'F F NH2 / Cl9if ^ í / L /N /OO Clcr ^O F F NH2 / Cl r ^^ i] 10 án.N x / O ^ AJ O O/cV ^O F 1/.. NH2 / Cl X ^ / / ί ^^ χ 11 J <x / k N X / O ^ AA O cr ^O F F NH2 Cl12 Xx / kN XO / ^ '' ^ Cl / /A.O cr 1 F ^O
Petition 870180167466, of 12/26/2018, p. 40/83
35/70
Number ofcompound Structure NH2Fx..ClV ^ / jl 13 / V. Z ''N VZ ° .O J / ^ xO Cl 'F ^O N ^H 2FCl > 1 14 .J <X. // - ^ X. JJ laugh N O Cr'' F ^O NH2F _x Cl15rí ^ V N 'X / Ox ^'Cçx O/ Jcv 'F ^O NH2 O F ^ClII 1st 16 N χΖ'Ό'χχ / - Χχ ^ / Αχ ^O crF ^O NH2 / -Cl___.Cl γ'Ίτ 18 / <ϊχN Xx / O ^ O CrF ^O
Petition 870180167466, of 12/26/2018, p. 41/83
36/70
Number of Structure compoundnh ₂ , .Cl Y 19 / ¼. TheN /O. O cY ^O '' FF „ NH2 ClAT THE γ ^ γ 21ΓΎ NΧ-ΥχχO ^O FF- NH2 , Cl 22 xY> x-LN X / O ^Ύχ OJ.Cl '' ^O F Cl F NH2 Cl γ ^ γ| Ί 23 χΥ JxN O Cr ' ^O FF NH2 .Cl, F^Y:; | Y24 Yx χΥ N/ ^ Xx-O CV ^O F
Petition 870180167466, of 12/26/2018, p. 42/83
37/70
Number of Structure compoundnh ₂ F A/ Cl γΥYY 25 . / -¼ AY N Y-O ' /THEO FClFO NH2F YCl Y Y YY 26 / -¼ Y N Υγΐ / ¼O cf ₃ Cl 'F ^O NH2FCl YY YYyY 27jY / -¼ A'N/ -O ^ AJ YO cr ^O YF NH2 Cl γΥγ 28Ύ NO/--O cr ^O FF _x NH2 Cl YYYY 29ΥΥ -¼NO-xY , ^O li γΥOOCl ^O F
Petition 870180167466, of 12/26/2018, p. 43/83
38/70
Number ofcompound Structure NH2FC/ ClXx / Cl V ^ AThe ⁷ '30ίΓΎ Az AN Χχ / Οχχ ^ / 1 A / AO crF ^O N ^F _x , Cl/ Sx V> rA ^ 'χ _γ χ ^/ 31 A> A N rz-O-xx ^ A / AO Cl 'F ^O NH2F, / ClJrA ^ THE 32/ V Air.N VzO , / Air v / Y / YO ClFçy ^X O ^{O 1} nh ₂To ^N 11 A ^ THE / V. O / Air JJ33 THE rz N Π THEO cr I F^O NH I Oat 34AA A ^ /'N A / Ox ^A ^ A A AOTHE/ClTHE ^O
Petition 870180167466, of 12/26/2018, p. 44/83
39/70
Number ofcompound Structure 37 nh ₂ rY ^Cl OJ Cl F ° 39 NH2n °° Cl F°
Table 2. Analytical data for Compounds in Table 1
Composition number Appearance Federal Police(° C) ESIMSm / z ¹ H NMR (field strength, solvent) Other data fromNMR 3 White solid 139 453 ([M + H] ⁺ ) (400 MHz, DMSO-cfe) δ 7.45 (dd, J = 8.5, 1.6 Hz, 1H),7.34 (d, J = 8.0 Hz, 2H), 7.28(dd, J = 8.5, 7.1 Hz, 1H),7.20 (d, J = 7.9 Hz, 2H), 7.07 (s, 2H), 5.32 (s, 2H), 3.92 (d,J = 0.8 Hz, 3H), 2.30 (s, 3H)4 White solid 151 464 ([M + H] ⁺ ) (400 MHz, DMSO-cfe) δ 7.92 - 7.84 (m, 2H), 7.65 (d, J = 8.5 Hz, 2H), 7.47 (dd, J = 8.5, 1.6 Hz, 1H), 7.30 (dd, J = 8.5, 7.1 Hz, 1H), 7.10 (s, 2H), 5.48 (s, 2H), 3.93 ( d, J = 0.9 Hz, 3H)
Petition 870180167466, of 12/26/2018, p. 45/83
40/70
Composition number Appearance Federal Police(° C) ESIMSm / z ¹ H NMR (field strength, solvent) Other data fromNMR 5 White solid 183-184 469 ([M + H] ⁺ ), 467 ([MH] ^- ) (400 MHz, DMSO-cfe) δ 7.43 (d, J = 8.4 Hz, 1H), 7.29 -7.12 (m, 4H), 6.88 (d, J = 8.7 Hz, 2H), 4.59 (d, J = 4.4 Hz, 2H), 3.90 (s, 3H), 3.71 (s, 3H)6 White solid 118-119 507 ([M + H] ⁺ ), 505 ([MH] ^- ) (400 MHz, DMSO-cfe) δ 7.79 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.47 (dd, J = 8 , 5, 1.5 Hz, 1H), 7.31 (dd, J = 8.5, 7.1 Hz, 1H), 7.15 (s, 2H), 5.49 (s, 2H), 3 .93 (d, J = 0.7 Hz, 3H)7 Yellow solid o 170-175 449 ([M + H] ⁺ ), 447 ([MH] ^- ) (400 MHz, CDCl3) δ 8.03 7.94 (m, 2H), 7.70 - 7.59 (m, 2H), 7.51 (dd, J = 10.6, 4.8 Hz, 2H ), 7.22 (dd, J = 7.7, 1.6 Hz, 2H), 5.63 (s, 2H), 4.95 (s, 2H), 3.96 (d, J = 0, 8 Hz, 3H)8 White solid 135 453 ([M + H] ⁺ ), 451 ([MH] ^- ) (400 MHz, DMSO-cfe) δ 7.50 - 7.38 (m, 2H), 7.33 - 7.18 (m, 4H), 7.13 (s, 2H), 5.39 (s, 2H), 3.92 (d, J = 0.7 Hz, 3H), 2.35 (s, 3H)9 White solid 183-184 474 ([M + H] ⁺ ), 472 ([MH] ^- ) (400 MHz, DMSO-cfe) δ 7.62 (dd, J = 7.0, 2.3 Hz, 1H),7.57 - 7.37 (m, 4H), 7.30(dd, J = 8.5, 7.1 Hz, 1H),7.14 (s, 2H), 5.45 (s, 2H),3.92 (s, 3H)
Petition 870180167466, of 12/26/2018, p. 46/83
41/70
Composition number Appearance Federal Police(° C) ESIMSm / z ¹ H NMR (field strength, solvent) Other data fromNMR 10 White solid 135-136 469 ([M + H] ⁺ ) (400 MHz, DMSO-cfe) δ 7.46 (dd, J = 8.5, 1.5 Hz, 1H), 7.43 - 7.33 (m, 2H), 7.29(dd, J = 8.5, 7.1 Hz, 1H),7.11 (s, 2H), 7.05 (d, J = 8.0Hz, 1H), 6.96 (td, J = 7.4, 0.9Hz, 1H), 5.34 (s, 2H), 3.92 (d, J = 0.5 Hz, 3H), 3.81 (s, 3H)11 White solid 150 453 ([M + H] ⁺ ), 451 ([MH] ^- ) (400 MHz, DMSO-cfe) δ 7.46 (dd, J = 8.5, 1.5 Hz, 1H),7.32 - 7.21 (m, 4H), 7.17 (d, J = 7.2 Hz, 1H), 7.13 (s, 2H),5.34 (s, 2H), 3.92 (d, J = 0.7Hz, 3H), 2.31 (s, 3H)12 White solid 147-148 474 ([M + H] ⁺ ), 472 ([MH] ^- ) (400 MHz, DMSO-cfe) δ 7.55(s, 1H), 7.51 - 7.39 (m, 4H),7.30 (dd, J = 8.5, 7.1 Hz,1H), 7.15 (s, 2H), 5.40 (s,2H), 3.93 (d, J = 0.7 Hz, 3H)13 White solid 164-165 469 ([M + H] ⁺ ), 467 ([MH] ^- ) (400 MHz, DMSO-cfe) δ 7.47 (dd, J = 8.5, 1.5 Hz, 1H),7.36 - 7.25 (m, 2H), 7.14 (s,2H), 7.02 (d, J = 7.4 Hz, 2H),6.96 - 6.88 (m, 1H), 5.35 (s,2H), 3.93 (d, J = 0.7 Hz, 3H),3.74 (s, 3H)
Petition 870180167466, of 12/26/2018, p. 47/83
42/70
Composition number Appearance Federal Police(° C) ESIMSm / z ¹ H NMR (field strength, solvent) Other data fromNMR 14 Colorless oil453 ([M + H] ⁺ ), 451 ([MH] ^- ) (400 MHz, DMSO-cfe) δ 7.50 - 7.43 (m, 3H), 7.41 - 7.35 (m, 2H), 7.35 - 7.26 (m, 2H), 7, 07 (s, 2H), 6.08 (q, J = 6.5 Hz, 1H), 3.93 (d, J = 0.9 Hz, 3H), 1.61 (d, J = 6.6 Hz, 3H) ¹⁹ F NMR (376 MHz, DMSOd ₆ ) δ -129.03 (d, J = 28.1 Hz), -137.77 (d, J = 28.1 Hz) 15 White solid 84-85 453 ([M + H] ⁺ ), 451 ([MH] ^- ) (400 MHz, DMSO-cfe) δ 7.47 (dd, J = 8.5, 1.6 Hz, 1H),7.36 - 7.18 (m, 6H), 7.05 (s, 2H), 4.53 (t, J = 6.8 Hz, 2H),3.93 (d, J = 1.0 Hz, 3H), 3.02 (t, J = 6.8 Hz, 2H)16 White solid 182 498 ([M + H] ⁺ ), 496 ([MH] ^- ) (400 MHz, DMSO-cfe) δ 8.02 - 7.95 (m, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.46 (dd, J = 8.5, 1.6 Hz, 1H), 7.30 (dd, J = 8.5, 7.1 Hz, 1H), 7.09 (s, 2H), 5.47 (s, 2H), 3.93 ( d, J = 1.0 Hz, 3H), 3.86 (s, 3H)18 White solid 100-108 457 ([M + H] ⁺ ), 455 ([MH] ^- ) (400 MHz, CDCl3) δ 7.64 (dd, J = 8.6, 7.8 Hz, 1H),7.44 - 7.32 (m, 4H), 7.22(dd, J = 8.7, 1.8 Hz, 1H),7.17 (d, J = 1.6 Hz, 1H), 5.40(s, 2H), 4.85 (s, 2H), 3.96 (d, J = 0.9 Hz, 3H)
Petition 870180167466, of 12/26/2018, p. 48/83
43/70
Composition number Appearance Federal Police(° C) ESIMSm / z ¹ H NMR (field strength, solvent) Other data fromNMR 19 White solid 110-113 435 ([M + H] ⁺ ), 433 ([MH] ^- ) (400 MHz, CDCl3) δ 7.71 (dd, J = 8.6, 7.8 Hz, 1H),7.49 (dd, J = 5.4, 3.4 Hz, 2H), 7.40 - 7.34 (m, 2H),7.33 - 7.28 (m, 1H), 7.23 (dd, J = 8.7, 1.7 Hz, 1H),7.18 (d, J = 1.6 Hz, 1H), 6.21 (q, J = 6.6 Hz, 1H), 4.80 (s,2H), 3.97 (d, J = 0.8 Hz, 3H),1.72 (d, J = 6.6 Hz, 3H)21 White solid 207-208 484 ([M + H] ⁺ ), 482 ([MH] ^- ) (400 MHz, acetone-cfe) δ 8.33 - 8.25 (m, 2H), 7.85 -7.77 (m, 2H), 7.40 (ddd, J = 15.3, 8.5, 4.1 Hz, 2H), 6.52 (s, 1H), 5.59 (s, 2H) , 3.99 (d, J = 1.1 Hz, 3H)22 White solid 107-108 485 ([MH] ^- ) (400 MHz, DMSO-cfe) δ 7.48 (dd, J = 8.5, 1.6 Hz, 1H),7.34 (s, 4H), 7.27 (dd, J =8.5, 7.1 Hz, 1H), 7.09 (s,2H), 4.52 (t, J = 6.6 Hz, 2H),3.93 (d, J = 0.8 Hz, 3H), 3.01 (t, J = 6.6 Hz, 2H)23 White solid 160-161 457 ([M + H] ⁺ ), 455 ([MH] ^- ) (400 MHz, DMSO-cfe) δ 7.50 - 7.41 (m, 2H), 7.34 - 7.26 (m, 3H), 7.20 (s, 1H), 7.14 (s, 2H), 5.40 (s, 2H), 3.92 (d, J = 0.6 Hz, 3H)
Petition 870180167466, of 12/26/2018, p. 49/83
44/70
Composition number Appearance Federal Police(° C) ESIMSm / z ¹ H NMR (field strength, solvent) Other data fromNMR 24 White solid 143-144 457 ([M + H] ⁺ ) (400 MHz, DMSO-cfe) δ 7.55 - 7.50 (m, 2H), 7.46 (dd, J = 8.5, 1.5 Hz, 1H), 7.31 - 7.20 ( m, 3H), 7.13 (s, 2H), 5.36 (s, 2H), 3.92 (s, 3H)25 White solid 169 457 ([M + H] ⁺ ), 455 ([MH] ') (400 MHz, DMSO-cfe) δ 7.57 (dt, J = 9.4, 4.7 Hz, 1H), 7.45 (ddd, J = 9.4, 4.6, 1.7 Hz, 2H), 7.26 (ddd, J = 15.6, 7.3, 2.8 Hz, 3H), 7.13 (s, 2H), 5.42 (s, 2H), 3.92 (d , J = 0.5 Hz, 3H)26 White solid 133-134 507 ([M + H] ⁺ ), 505 ([MH] ^- ) (400 MHz, DMSO-cfe) δ 7.84 - 7.69 (m, 3H), 7.61 (t, J = 7.5 Hz, 1H), 7.48 (dd, J = 8.5, 1.5 Hz, 1H), 7.29 (dd, J = 8.5, 7.1 Hz, 1H), 7.15 (s, 2H), 5.53 (s, 2H), 3.92 ( d, J = 0.6 Hz, 3H)27 White solid 75-76 481 ([M + H] ⁺ ), 479 ([MH] ^- ) (400 MHz, DMSO-cfe) δ 7.46 (dd, J = 8.5, 1.5 Hz, 1H),7.37 (d, J = 8.1 Hz, 2H), 7.32- 7.23 (m, 3H), 7.12 (s, 2H),5.32 (s, 2H), 3.92 (d, J = 0.7 Hz, 3H), 2.88 (dt, J = 13.7,6.8 Hz, 1H), 1.19 (d, J = 6.9Hz, 6H)
Petition 870180167466, of 12/26/2018, p. 50/83
45/70
Composition number Appearance Federal Police(° C) ESIMSm / z ¹ H NMR (field strength, solvent) Other data fromNMR 28 White solid 142-143 489 ([M + H] ⁺ ), 487 ([MH] ') (400 MHz, acetone-cfe) δ 8.06 (s, 1H), 8.00 - 7.90 (m, 3H), 7.65 (dd, J = 8.5, 1.7 Hz, 1H) , 7.59 - 7.51 (m, 2H), 7.40 (ddd, J = 15.3, 8.5, 4.1 Hz, 2H), 6.49 (s, 2H), 5.61 (s, 2H), 4.00 (d, J = 1.1 Hz, 3H)29 White solid 144-145 497 ([M + H] ⁺ ), 495 ([MH] ^- ) (400 MHz, acetone-cfe) δ 8.19 (dd, J = 1.7, 1.2 Hz, 1H), 8.01 (dt, J = 7.8, 1.4 Hz, 1H), 7 , 79 (ddd, J = 7.7, 1.7, 1.2 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.43 (dd, J = 8.5 , 1.5 Hz, 1H), 7.37 (dd, J = 8.5, 6.7 Hz, 1H), 6.50 (s, 2H), 5.53 (s, 2H), 4.00 (d, J = 1.1 Hz, 3H), 3.90 (s, 3H)30 White solid 167-168 485 ([MH] ^- ) (400 MHz, acetone-cfe) δ7.51 (d, J = 8.2 Hz, 1H), 7.43 (dd, J = 8.5, 1.6 Hz, 1H),7.37 - 7.30 (m, 2H), 7.26 (dd, J = 8.1, 2.0 Hz, 1H),6.49 (s, 2H), 5.43 (s, 2H), 4.00 (d, J = 1.1 Hz, 3H)31 White solid 145 485 ([M + H] ⁺ ), 483 ([MH] ^- ) (400 MHz, acetone-cfe) δ7.50 - 7.39 (m, 3H), 7.33 (ddd, J = 8.4, 7.9, 4.4 Hz, 3H), 6.48 (s, 2H), 5.38 ( s,2H), 4.00 (d, J = 1.1 Hz, 3H)
Petition 870180167466, of 12/26/2018, p. 51/83
46/70
Composition number Appearance Federal Police(° C) ESIMSm / z ¹ H NMR (field strength, solvent) Other data fromNMR 32 SolidColorless 161 497 ([M + H] ⁺ ), 495 ([MH] ') (400 MHz, acetone-cfe) δ 8.02 (dd, J = 7.8, 1.3 Hz, 1H), 7.78 (dd, J = 7.8, 0.6Hz, 1H), 7.65 (td, J = 7.6, 1.4Hz, 1H), 7.54 - 7.35 (m, 3H), 6.50 (s, 1H), 5.82 (s, 2H), 4.01 (d, J = 1.1 Hz, 3H ), 3.91 (s, 3H)33 White solid 145-147 417 ([M + H] ⁺ ) (400 MHz, CDCl3) δ 7.65 -7.15 (m, 9H), 5.45 (d, J = 4.1 Hz, 2H), 5.40 (s, 2H), 3.99 (d, J = 1.0 Hz, 3H), 3.81 (d, J = 7.2 Hz, 3H) ¹⁹ F NMR (376 MHz, CDCl3) δ -129.38 (s) 34 Clear oil431 ([M + H] ⁺ ) (400 MHz, CDCl3) δ 7.59 (dd, J = 8.6, 7.5 Hz, 1H),7.35 - 7.15 (m, 6H), 5.63 (s,2H), 4.63 (td, J = 7.0, 4.0 Hz,2H), 3.98 (d, J = 0.9 Hz, 3H),3.75 (s, 3H), 3.15 - 3.07 (m, 2H) ¹⁹ F NMR (376 MHz, CDCl3) δ -129.46 (s) 37 Yellow oil o435 ([M + H] ⁺ ), 433 ([MH] ^- ) (400 MHz, CDCl3) δ 7.67 (dd, J = 8.6, 7.9 Hz, 1H),7.29 (dd, J = 15.8, 3.6 Hz, 4H), 7.25 - 7.20 (m, 2H),7.19 (d, J = 1.6 Hz, 1H), 4.81 (s, 2H), 4.62 (t, J = 7.2 Hz,2H), 3.97 (d, J = 0.7 Hz, 3H),3.12 (t, J = 7.1 Hz, 2H)
Petition 870180167466, of 12/26/2018, p. 52/83
47/70
Composition number Appearance Federal Police(° C) ESIMSm / z ¹ H NMR (field strength, solvent) Other data fromNMR 39 White crystals 90-91.5 421 ([M + H] ⁺ ) (400 MHz, CDCl3) δ 7.73 -7.11 (m, 9H), 5.45 (s, 2H),4.81 (s, 2H), 3.97 (d, J = 0.6Hz, 3H)
Example 13. Evaluation of General Post-emergence Herbicidal Activity ^[0066] Seeds or pyrenes of the desired test plant species were planted in a Sun Gro Metro-Mix® ³⁶⁰ planting mix ^, which typically has a pH of 6.0 to 6, 8 and an organic matter content of 30 percent, in plastic pots with a surface area of 84.6 square centimeters (cm ² ). When required to ensure good germination and healthy plants, a fungicide and / or other chemical or physical treatment was applied. The plants were grown for 7-31 days (d) in a greenhouse with a photoperiod of approximately 15 hours (h) which was maintained at 23-29 ° C during the day and 22-28 ° C at night. Nutrients and water were added regularly and supplementary lighting was provided with 1000 watt metal halide top lamps as needed. The plants were subjected to tests when they reached the first or second stage of true leaf.
^[0067] Treatments consisted of esters of compounds 33 and 39 and F and G. Compound F is methyl 6-amino-2- (4-chloro-2-fluoro-3-methoxyphenyl) -5methoxypyrimidine-4-carboxylate; and compound G is methyl 4-amino-3-chloro-6- (4-chloro-2-fluor-3-methoxyphenyl) picolinate. A heavy amount, determined by the highest rate to be tested, of each test compound was placed in a 25 ml glass vial and dissolved in 4 ml of a 97: 3 v / v (volume / volume) mixture of
Petition 870180167466, of 12/26/2018, p. 53/83
48/70 acetone and dimethyl sulfoxide (DMSO) to obtain concentrated stock solutions. If the test compound did not readily dissolve, the mixture was heated and / or sonicated. The concentrated stock solutions obtained were diluted with 20 mL of an aqueous mixture containing acetone, water, isopropyl alcohol, DMSO, concentrated crop oil Atplus 411F, and Triton® X-155 surfactant ^{in a} 48,5: 39: 10 ^ratio : 1.5: 1.0: 0.02 v / v to obtain spray solutions containing the highest application rates. Additional application rates were obtained by serial dilution of the high rate solution in a solution containing 2 ml of a 97: 3 v / v (volume / volume) mixture of acetone and DMSO and 10 ml of an aqueous mixture containing acetone, water , isopropyl alcohol, DMSO, concentrated crop oil Atplus 411F, and Triton X-155 surfactant in a 48.5: 39: 10: 1.5: 1.0: 0.02 v / v ratio to obtain 1 / 2X ratios , 1 / 4X, 1 / 8X and 1 / 16X of the high rate. Compost amounts are based on an application volume of 12 mL at a rate of 187 liters per hectare (L / ha). Formulated compounds were applied to plants with a Mandel top trail sprayer equipped with 8002E nozzles calibrated to apply 187 L / ha over an application area of 0.503 square meters (m ² ) at a spray height of 43 cm (18 inches) above the average height of the canopy of the plants. Control plants were sprayed in the same way with white solvent.
[0068] The treated plants and the control plants were placed in a greenhouse as described above and watered by sub-irrigation to avoid washing out the test compounds. After 14 d, the condition of the test plants compared to that of untreated plants was determined visually, classified on a scale from 0 to 100 percent, where 0 corresponds to no damage and 100 corresponds to complete death.
[0069] Some of the tested compounds, application rates
Petition 870180167466, of 12/26/2018, p. 54/83
49/70 employees, plant species tested and results are shown in Tables 3 and 4.
Table 3: Activity of Herbicidal Compounds in Post-emergent Applications with Different Rates (14 Days after application (DAA))
Compound number Application fee(g ai / ha) Visual Damage (%) IPOHE G 35 65 G 17.5 50 G 8.75 40 39 35 80 39 17.5 75 39 8.75 70
Table 4: Activity of Herbicidal Compounds in Postemergent Applications (70 g ai / ha and 14 DAA)
Compound number Visual Damage (%) ORYSA THREE IPOHE VIOTR STEME F 75 70 80 80 90 33 30 45 100 100 100
IPOHE = Ipomoea hederacea (Ipomeia)
ORYSA = Oryza sativa (Rice)
STEME = Stellaria media (Esparguta, vulgar)
TRZAS = Triticum aestivum (Wheat, spring)
VIOTR = Viola tricolor (Pansy, wild) g ai / ha = grams of active ingredient per hectare DAA = days after application
Example 14. Post-emergence herbicidal activity assessment in
Petition 870180167466, of 12/26/2018, p. 55/83
50/70 cereal crops ^[0070] Seeds of the desired test plant species were planted in a Sun Gro Metro-Mix® 360 planting mix, which typically has a pH of 6.0 to 6.8 and a content of matter organic 30 p _{or cen} t _o , in plastic pots with a surface area of 84.6 cm ² . When required to ensure good germination and healthy plants, a fungicide and / or other chemical or physical treatment was applied. The plants were grown for 7-36 d in a greenhouse with an approximate 14 hour photoperiod that was maintained at 18 ° C during the day and 17 ° C at night. Nutrients and water were added regularly and supplementary lighting was provided with 1000 watt metal halide top lamps as needed. The plants were subjected to tests when they reached the second or third stage of true leaf.
[0071] Treatments consisted of esters of compounds 33, 34, 39, 40 and 42 and B, F, G and H. Compound B is methyl 4-amino-3-chloro-6- (4cyclopropylphenyl) -5-fluoropicolinate; Compound F is methyl 6-amino-2 (4-chloro-2-fluor-3-methoxy-phenyl) -5-methoxypyrimidine-4-carboxylate; Compound G is methyl 4-amino-3-chloro-6- (4-chloro-2-fluoro-3methoxyphenyl) picolinate; and compound H is methyl 4-amino-3-chloro-6- (4-chloro-2-fluoro-3- (1-fluoroethyl) phenyl) -5-fluoropicolinate. A heavy amount, determined by the highest rate to be tested, of each test compound was placed in a 25 ml glass vial and dissolved in 8 ml of a 97: 3 v / v mixture of acetone and DMSO to obtain solutions of concentrated stock. If the test compound did not readily dissolve, the mixture was heated and / or sonicated. The concentrated stock solutions obtained were diluted with 16 mL of an aqueous mixture containing acetone, water, isopropyl alcohol, DMSO, Agri-dex concentrated crop oil, and Triton X-77 surfactant in a ratio of 64.7: 26.0: 6.7: 2.0: 0.7: 0.01 v / v to obtain
Petition 870180167466, of 12/26/2018, p. 56/83
51/70 spray solutions containing the highest application rates. Additional application rates were obtained by serial dilution of the high rate solution in a solution containing 4 ml of a 97: 3 v / v mixture of acetone and DMSO and 8 ml of an aqueous mixture containing acetone, water, isopropyl alcohol, DMSO , Agridex concentrated crop oil, and Triton X-77 surfactant in a ratio of 48.5: 39.0: 10.0: 1.5: 1.0: 0.02 v / v to obtain 1 / 2X ratios, 1 / 4X, 1 / 8X and 1 / 16X of the high rate. Compost amounts are based on an application volume of 12 mL at a rate of 187 L / ha. Formulated compounds were applied to plants with a Mandel top trail sprayer equipped with 8002E nozzles calibrated to apply 187 L / ha over an application area of 0.503 m ² at a spray height of 18 inches (43 cm) above average height of the plant canopy. Control plants were sprayed in the same way with white.
[0072] The treated plants and the control plants were placed in a greenhouse as described above and watered by sub-irrigation to avoid washing out the test compounds. After 20-22 d, the condition of the test plants compared to that of untreated plants was visually determined and rated on a scale of 0 to 100 percent where 0 corresponds to no damage and 100 corresponds to complete death.
[0073] Some of the compounds tested, application rates employed, plant species tested and results are shown in Tables 5-10.
Petition 870180167466, of 12/26/2018, p. 57/83
52/70
Table 5: Activity of Herbicidal Compounds wheat cultivation systems (35 g ae / ha and 21 DAA)
Compound number Visual Damage (%) POLCO SINAR B 62 70 42 95 93
Table 6: Activity of Herbicidal Compounds in wheat cultivation systems (35 g ae / ha and 21 DAA)
Compound number Visual Damage (%) SINAR KCHSC SASKR MATCH POLCO G 80 87 80 75 85 39 95 95 90 95 95
Table 7: Activity of Herbicidal Compounds in wheat cultivation systems with varying rates (21 DAA)
Compound number Application fee(g ae / ha) Visual Damage(%) CIRAR G 17.5 80 G 8.75 70 39 17.5 95 39 8.75 90
Petition 870180167466, of 12/26/2018, p. 58/83
53/70
Table 8: Activity of Herbicidal Compounds in wheat cultivation systems (8.75 g ae / ha and 21 DAA)
Compound number Visual Damage (%) SINAR VERPE PESGL H 87 80 0 40 98 95 65
Table 9: Activity of Herbicidal Compounds in wheat cultivation systems (35 g ae / ha and 21 DAA)
Compound number Visual Damage (%) MATCH AVEFA F 10 20 33 40 40 34 20 40
Table 10: Activity of Herbicidal Compounds in wheat cultivation systems (17.5 g ae / ha and 21 DAA)
Compound number Visual Damage (%) LOLMU SETVI F 60 85 33 80 93 34 70 80
AVEFA = Avena fatua (Oats, wild)
CIRAR = Cirsium arvense (Canadian thistle)
KCHSC = Kochia scoparia (Kochia)
Petition 870180167466, of 12/26/2018, p. 59/83
54/70
LOLMU = Lolium multiflorum (ryegrass, Italian)
MATCH = Matricaria chamomilla (Chamomile, wild) PESGL = Pennisetum glaucum (Foxtail, yellow) POLCO = Polygonum convolvulus (Buckwheat, wild
SASKR = Salsola kali (Thistle, Russian)
SETVI = Setaria viridis (Foxtail, green) SINAR = Brassica sinapis (Mustard, wild) VERPE = Veronica persica (Verônica) g ae / ha = equivalent g of acid per hectare DAA = days after application
Example 15. Post-emergence herbicidal activity evaluation on pastures ^[0074] Seeds of the desired test plant species were planted in a Sun Gro Metro-Mix® 360 planting mix, which typically has a pH of 6.0 to 6, 8 and an organic matter content of 30 percent, in plastic pots with a surface area of 139.7 cm ² . When required to ensure good germination and healthy plants, a fungicide and / or other chemical or physical treatment was applied. The plants were grown with an approximate 14 hour photoperiod that was maintained at 24 ° C during the day and 21 ° C at night. Nutrients and water were added regularly and supplementary lighting was provided with 1000 watt metal halide top lamps as needed. The plants were subjected to tests when they reached the stage of 4 or 6 true leaves depending on the species.
[0075] Treatments consisted of esters of compounds 39 and G. Compound G is methyl 4-amino-3-chloro-6- (4-chloro-2-fluor-3methoxyphenyl) picolinate. A heavy amount, determined by the highest rate to be tested, of each test compound was placed in
Petition 870180167466, of 12/26/2018, p. 60/83
55/70 a 25 ml glass vial and dissolved in 8 ml of a 97: 3 v / v mixture of acetone and DMSO to obtain concentrated stock solutions. If the test compound did not readily dissolve, the mixture was heated and / or sonicated. The concentrated stock solutions obtained were diluted with 16 mL of an aqueous mixture containing acetone, water, isopropyl alcohol, DMSO, Agri-dex concentrated crop oil, and Triton X-77 surfactant in a ratio of 64.7: 26.0: 6.7: 2.0: 0.7: 0.01 v / v to obtain spray solutions containing the highest application rates. Additional application rates were obtained by serial dilution of the high rate solution in a solution containing 4 ml of a 97: 3 v / v mixture of acetone and DMSO and 8 ml of an aqueous mixture containing acetone, water, isopropyl alcohol, DMSO , Agri-dex concentrated crop oil, and Triton X-77 surfactant in a 48.5: 39.0: 10.0: 1.5: 1.0: 0.02 v / v ratio to obtain 1 / 2X, 1 / 4X, 1 / 8X and 1 / 16X of the high rate. Compost amounts are based on an application volume of 12 mL at a rate of 187 L / ha. Formulated compounds were applied to plants with a Mandel top trail sprayer equipped with 8002E nozzles calibrated to apply 187 L / ha over an application area of 0.503 m ² at a spray height of 18 inches (43 cm) above average height of the plant canopy. Control plants were sprayed in the same way with white.
[0076] The treated plants and the control plants were placed in a greenhouse as described above and watered by sub-irrigation to avoid washing out the test compounds. After 35 d, the condition of the test plants compared to that of untreated plants was determined visually and rated on a scale of 0 to 100 percent where 0 corresponds to no damage and 100 corresponds to complete death.
[0077] Some of the tested compounds, application rates
Petition 870180167466, of 12/26/2018, p. 61/83
56/70 employees, plant species tested and results are shown in Tables 11 and 12.
Table 11: Activity of Herbicidal Compounds in Pasture Cultivation Systems with Different Rates (35 DAA)
Compound number Application fee(g ae / ha) Visual Damage (%) CIRAR G 35 60 G 17.5 40 39 35 95 39 17.5 100
Table 12: Activity of Herbicidal Compounds in Pasture Cultivation Systems with Different Rates (35 DAA)
Compound number Application fee(g ae / ha) Visual Damage (%) SOOSS G 140 50 G 70 30 39 140 100 39 70 85
CIRAR = Cirsium arvense (Canadian thistle)
SOOSS = Solidago L. spec (Golden rod) g ae / ha = g equivalent of acid per hectare
DAA = days after application
Example 16. Evaluation of herbicidal activity in post-emergence foliar application on no-till rice [0078] Seeds or pyrenes of the desired test plant species were planted in a soil matrix prepared by mixing a clay soil (43 percent silt, 19 percent clay, and 38 percent sand, with a pH of 8.1 and an organic matter content of 1.5 percent) and
Petition 870180167466, of 12/26/2018, p. 62/83
57/70 river sand in a ratio of 80 to 20. The soil matrix was contained in plastic pots with a surface area of 139.7 cm ² . When required to ensure good germination and healthy plants, a fungicide and / or other chemical or physical treatment was applied. The plants were grown for 10-17 d in a greenhouse with an approximate photoperiod of 14 h which was maintained at 29 ° C during the day and 26 ° C at night. Nutrients and water were added regularly and supplementary lighting was provided with 1000 watt metal halide top lamps as needed. The plants were subjected to tests when they reached the second or third stage of true leaf.
[0079] Treatments consisted of esters of compounds 1-4, 6-8, 10, 11, 13-16, 20-31, 35, 38, 41 and 42 and A-E. Compound A is methyl 4-amino-3-chloro-6- (4-chloro-3-ethoxy-2-fluorophenyl) -5-fluoropicolinate; compound B is 1-methyl 4-amino-3-chloro-6- (4-cyclopropylphenyl) -5-fluoropicolinate; compound C is methyl 4-amino-3-chloro-6- (2,4-dichloro-3methoxyphenyl) picolinate; compound D is methyl 6-amino-2- (4-chloro-2-fluoro-3-methoxyphenyl) -5-vinylpyrimidine-4-carboxylate; and compound E is methyl 4-amino-3-chloro-6- (4-chloro-2-fluor-3-methoxyphenyl) -5-fluoropicolinate. Heavy amounts of technical grade compounds were placed in 25 ml glass vials and dissolved in a 97: 3 v / v acetone-DMSO volume to obtain 12X stock solutions. If the test compound did not readily dissolve, the mixture was heated and / or sonicated. The concentrated stock solutions were added to the spray solutions so that the final concentrations of acetone and DMSO were 16.2% and 0.5%, respectively. Spray solutions were diluted to the appropriate final concentrations with the addition of 10 mL of a 1.5% (v / v) aqueous mixture of Agri-dex concentrated crop oil. Generally, multiple concentrations of spray solutions
Petition 870180167466, of 12/26/2018, p. 63/83
58/70 were formulated and tested using the same stock solution. The final spray solutions contained 1.25% (v / v) of Agri-dex concentrated crop oil. Compound amounts are based on an application volume of 12 mL at a rate of 187 L / ha. Spray solutions were applied to the plants with a Mandel top track sprayer equipped with 8002E nozzles calibrated to apply 187 L / ha over an application area of 0.503 square meters (m ² ) at a spray height of 18 inches (43 cm) ) above the average canopy height of the plant. Control plants were sprayed in the same way with white solvent.
[0080] The treated plants and the control plants were placed in a greenhouse as described above and watered by sub-irrigation to avoid washing out the test compounds. After 3 weeks, the condition of the test plants compared to that of untreated plants was determined visually and rated on a scale of 0 to 100 percent where 0 corresponds to no damage and 100 corresponds to complete death.
[0081] Applying the well accepted probit analysis as described by J. Berkson in Journal of the American Statistical Society, 48, 565 (1953) and by D. Finney in Probit Analysis Cambridge University Press (1952), the data obtained can be used to calculate GR50 and GR80 values, which are defined as growth reduction factors that correspond to the effective dose of herbicide needed to kill or control 50 percent or 80 percent, respectively, of a target plant.
[0082] Some of the application rates and relationships employed, plant species tested and results are shown in Tables 13-18.
Table 13: Activity of Herbicidal Compounds in rice culture systems (17.5 g ae / ha and 21 DAA; visual damage may represent data
Petition 870180167466, of 12/26/2018, p. 64/83
59/70 obtained in several trials)
Compost number Visual Damage (%) ECHCG ECHCO AESSAND SEBEX CYPEs CYPIR SCPJU THE 60 50 0 20 60 80 20 41 95 95 100 99 100 100 90
Table 14: Activity of Herbicidal Compounds in rice culture systems (8.75 g ae / ha and 21 DAA; visual damage can represent data obtained in several tests)
Compound number Visual Damage (%) ECHCO CYPIR B 50 60 42 85 100
Table 15: Activity of Herbicidal Compounds in rice culture systems (8.75 g ae / ha and 21 DAA; visual damage may represent data obtained in several tests)
Compound number Visual Damage (%) ECHCO BRAPP CYPDI SCPJU Ç 84 74 96 90 38 90 90 100 100
Petition 870180167466, of 12/26/2018, p. 65/83
60/70
Table 16: Activity of Herbicidal Compounds in rice culture systems (8.75 g ae / ha 21 DAA; visual damage may represent data obtained in several tests)
Compound number Visual Damage (%) ECHCG ECHCO D 87 79 35 95 90
Table 17: Activity of Herbicidal Compounds in rice culture systems (8.75 g ae / ha and 21 DAA; visual damage can represent data obtained in several tests)
Compound number Visual Damage (%) CYPDI SCPJU AND 89 61 1 100 93 8 99 99 25 100 100 26 100 100 10 100 91 11 99 97 23 100 100 13 95 80 29 100 100 3 100 99 2 100 100 24 100 100 6 100 100
Petition 870180167466, of 12/26/2018, p. 66/83
61/70
Compound number Visual Damage (%) CYPDI SCPJU 16 94 85 4 80 80 20 100 100 21 100 100 27 100 100 31 100 100 30 99 0 15 100 90 22 100 90 28 100 100 7 70 60 14 95 50
Table 18: Growth Reduction Calculations for Compounds in
Rice Culture Systems
Species Number ofcompound GR50 GR80 GR90 g ae / ha ECHCG AND 3.7 17.1 38.11 <4.38 <4.38 6.1 POLPY AND 30.7 > 70 > 701 <8.75 19.7 46.7 BRAPP AND <4.38 22.7 84.31 <4.38 9.9 26.0 ECHCO AND <4.38 14.6 55.61 2.4 7.8 14.4
AESSE = Aeschynomene sensitive SW./L. (angiquinho)
BRAPP = Brachiaria platyphylla (GRISEB.) NASH (papuãPetição 870180167466, of 12/26/2018, page 67/83
62/70 do-swamp)
CYPDI = Cyperus difformis L. (junquinho)
CYPES = Cyperus esculentus L. (yellow junction)
CYPIR = Cyperus would L. (rice flatsedge)
ECHCG = Echinochloa crus-galli (L.) P. BEAUV. (barnyard grass)
ECHCO = Echinochloa colonum (L.) LINK (grass grass or wild rice (junglerice))
POLPY = Polygonum pensylvanicum L. (Pennsylvania smartweed)
SCPJU = Scirpus juncoides ROXB. (Japanese reed)
SEBEX = Sesbania exaltata (RAF.) CORY / RYDB. (sesbania hemp) g ae / ha = gram-equivalent of acid per hectare
DAA = days after application
GR50 = concentration of compost needed to reduce the growth of a plant by 50% compared to the untreated plant
GRs0 = concentration of compost necessary to reduce the growth of a plant by 80% compared to the untreated plant
GR90 = concentration of compost necessary to reduce the growth of a plant by 90% in relation to the untreated plant Example 17. Evaluation of herbicidal activity for water application in transplanted irrigated rice [0083] Seeds of weeds or pyrenes of the plant species test samples were planted in a drenched soil (mud) prepared by mixing a non-sterilized mineral soil (28 percent silt, 18 percent clay, and 54 percent sand, with a pH of 7.3 to 7.8 and a organic matter content of 1.0 percent) and water in a ratio of 100 kilograms (kg) of soil to 19 liters (L) of water. The prepared sludge was distributed in 250 ml aliquots in pots
Petition 870180167466, of 12/26/2018, p. 68/83
63/70 480 ml non-perforated plastics with a surface area of 91.6 cm ² leaving a top space of 3 cm in each pot. Rice seeds were planted in a Sun Gro MetroMix 306 planting mix, which typically has a pH of 6.0 to 6.8 and an organic matter content of 30 percent, in plastic seedling production trays. Seedlings in the second or third leaf growth stage were transplanted in 650 mL of mud contained in 960 mL unperforated plastic pots with a surface area of 91.6 cm ² four days before herbicide application. The flooded rice field was created by filling the 3 cm of top space of the pots with water. When required to ensure good germination and healthy plants, a fungicide and / or other chemical or physical treatment was applied. The plants were grown for 4-14 d in a greenhouse with an approximate photoperiod of 14 h that was maintained at 29 ° C during the day and 26 ° C at night. Nutrients were added as Osmocote (17: 6: 10, Nitrogen: Phosphorus: Potassium (N: P: K) + minor nutrients) at a rate of 2 grams (g) per pot. Water to maintain the flood, and supplementary lighting was provided with 1000 watt metal halide top lamps as needed. The plants were subjected to tests when they reached the second or third stage of true leaf.
[0084] Treatments consisted of esters of compounds 1-4, 633, 35-39, 41 and 42 and A-G. Compound A is methyl 4-amino-3-chloro-6- (4-chloro-3-ethoxy-2-fluorophenyl) -5-fluoropicolinate; compound B is 4-amino-
Methyl 3-chloro-6- (4-cyclopropylphenyl) -5-fluoropicolinate; compound C is
Methyl 4-amino-3-chloro-6- (2,4-dichloro-3-methoxyphenyl) picolinate; compound D is methyl 6-amino-2- (4-chloro-2-fluor-3-methoxyphenyl) -5-vinylpyrimidine4-carboxylate; compound E is methyl 4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropicolinate; compound F is 6-amino2- (4-chloro-2-fluor-3-methoxyphenyl) -5-methoxypyrimidine-4-carboxylate
Petition 870180167466, of 12/26/2018, p. 69/83
64/70 methyl; and compound G is methyl 4-amino-3-chloro-6- (4-chloro-2-fluoro-3methoxyphenyl) picolinate. Heavy amounts of technical grade compounds were placed in individual 120 ml glass bottles and dissolved in 20 ml of acetone to obtain concentrated stock solutions. If the test compound did not readily dissolve, the mixture was heated and / or sonicated. The concentrated stock solutions obtained were diluted with 20 mL of an aqueous mixture containing 2.5% concentrated crop oil Agridex (v / v). The final application solutions contained 1.25% (v / v) of Agri-dex concentrated crop oil. Generally, multiple concentrations were tested using the same stock solution. Applications were made by injecting an appropriate amount of the application solution into the paddy water layer. Control plants were treated in the same way with solvent (white).
[0085] The treated plants and the control plants were placed in a greenhouse as described above and water was added when necessary to maintain a flood of the plants. After 3 weeks, the condition of the test plants compared to that of untreated plants was determined visually and rated on a scale of 0 to 100 percent where 0 corresponds to no damage and 100 corresponds to complete death.
[0086] Applying the well accepted probit analysis as described by J. Berkson in Journal of the American Statistical Society, 48, 565 (1953) and by D. Finney in Probit Analysis Cambridge University Press (1952), the data obtained can be used to calculate GR50 and GR80 values, which are defined as growth reduction factors that correspond to the effective dose of herbicide needed to kill or control 50 percent or 80 percent, respectively, of a target plant.
[0087] Some of the tested compounds, application rates
Petition 870180167466, of 12/26/2018, p. 70/83
65/70 employees, plant species tested and results are shown in Tables 19-28.
Table 19: Activity of Herbicidal Compounds in rice culture systems (35 g ae / ha and 21 DAA; visual damage may represent data obtained in several tests)
Compound number Visual Damage (%) ECHCG SCPJU THE 40 60 41 95 100
Table 20: Activity of Herbicidal Compounds in rice culture systems (17.5 g ae / ha and 21 DAA; visual damage can represent data obtained in several tests)
Compound number Visual Damage (%) ECHCG B 10 42 70
Table 21: Activity of Herbicidal Compounds in rice culture systems (35 g ae / ha and 21 DAA; visual damage may represent data obtained in several tests)
Compound number Visual Damage (%) ECHCG SCPJU F 0 50 33 40 100
Table 22: Activity of Herbicidal Compounds in Culture Systems
Petition 870180167466, of 12/26/2018, p. 71/83
66/70 rice (35 g ae / ha and 21 DAA; visual damage may represent data obtained in several tests)
Compound number Visual Damage (%) ECHCG SCPJU Ç 36 83 38 99 100
Table 23: Activity of Herbicidal Compounds in rice culture systems (35 g ae / ha and 21 DAA; visual damage may represent data obtained in several tests)
Compound number Visual Damage (%) ECHCG D 54 35 76
Table 24: Activity of Herbicidal Compounds in rice culture systems (35 g ae / ha and 21 DAA; visual damage may represent data obtained in several tests)
Compound number Visual Damage (%) FIMMI G 61 39 100 36 100
Petition 870180167466, of 12/26/2018, p. 72/83
67/70
Table 25: Activity of Herbicidal Compounds in rice culture systems (35 g ae / ha and 21 DAA; visual damage can represent data obtained in several tests)
Compound number Visual Damage (%) CYPRO G 47 39 80 17 100
Table 26: Activity of Herbicidal Compounds in rice culture systems (35 g ae / ha and 21 DAA; visual damage can represent data obtained in several tests)
Compound number Visual Damage (%) ECHCG G 74 39 100 18 100 17 98 19 90 37 98
Petition 870180167466, of 12/26/2018, p. 73/83
68/70
Table 27: Activity of herbicidal compounds in rice culture systems (17.5 g ae / ha at 21 DAA; visual damage may represent data obtained in several tests)
Compound number Visual Damage (%) ECHCG SCPJU AND 26 75 1 87 99 8 100 100 9 100 100 25 10 90 26 20 100 10 70 100 32 60 100 11 97 99 12 100 100 23 60 95 13 98 98 29 10 60 3 78 99 2 97 99 24 70 100 6 60 95 16 90 99 31 50 85 20 50 0 27 10 80 21 10 80 4 95 95 30 50 85 14 10 70
Petition 870180167466, of 12/26/2018, p. 74/83
69/70
Compound number Visual Damage (%) ECHCG SCPJU 15 30 70 22 0 40 28 10 50 7 80 90
Table 28: Growth reduction calculations for compounds in rice growing systems
Species Compound number GR50 GR80 GR90 g ae / ha ECHCG AND 33.2 58.5 78.71 10.9 21.8 31.2 SCPJU AND 9.6 20.0 29.51 <8.75 4.4 10.8 LEFCH AND 59.9 99.4 130.01 50.4 78.6 99.1 FIMMI AND 14.4 21.7 26.81 <17.5 <17.5 <17.5
CYPRO = Cyperus rotundus L. (tiririca)
ECHCG = Echinochloa crus-galli (L.) P. BEAUV. (capimarroz)
FIMMI = Fimbristylis miliacea (L.) VAHL (cuminho)
LEFCH = Leptochloa chinensis (L.) NEES (Chinese sprangletop)
SCPJU = Scirpus juncoides ROXB. (jonquil) g ae / ha = gram-equivalent of acid per hectare
DAA = days after application
GR50 = concentration of compost needed to reduce the growth of a plant by 50% compared to the untreated plant
Petition 870180167466, of 12/26/2018, p. 75/83
70/70
GRso = concentration of compost required to reduce plant growth by 80% compared to untreated plant
GR90 = concentration of compost necessary to reduce the growth of a plant by 90% in relation to the untreated plant.

权利要求:
Claims (6)
[1]
1. Compound, characterized by the fact that it presents the
Formula IB:
o _s 3
R ³ in which
X represents H or F;
Y represents C1-C8 alkyl, C3-C6 cycloalkyl, or substituted phenyl with 1-4 substituents independently selected from halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, nitro, NR ¹ R ² , or where two adjacent substituents are taken together as -O (CH2) nOor -O (CH2) n-, where n = 1 or 2;
Z represents halogen or C2-C4 alkenyl;
R ¹ and R ² independently represent H, C1-C6 alkyl, or C1-C6 acyl; and
R ³ represents benzyl substituted with 1-4 substituents independently selected from halogen, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, C1-C6 alkylthio, C (O) OC1-Cealquila, or where two adjacent substituents are taken together as -O (CH2) nOsendo n = 1 or 2.
[2]
2. Compound according to claim 1, characterized by the fact that X represents H.
[3]
3. Compound according to claim 1, characterized by the fact that X represents F.
[4]
Compound according to claim 1, characterized
Petition 870180167466, of 12/26/2018, p. 77/83
2/2 because Z represents Cl.
[5]
5. Compound according to claim 1, characterized by the fact that R ¹ and R ² represent H.
[6]
6. Herbicidal composition, characterized by the fact that it comprises a herbicidally effective amount of a compound, as defined in claim 1, in admixture with an agriculturally acceptable adjuvant or vehicle.

类似技术:

---

公开号 | 公开日 | 专利标题

---

BR102012001641B1|2019-04-02|4-AMINO-6- | PICOLINATES AND 6-AMINO-2- | -4-PYRIMIDINCARBOXYLATES AND HERBICIDE COMPOSITION

---

RU2672587C2|2018-11-16|4-amino-6-|picolinates and 6-amino-2-|pyrimidine-4-carboxylates and their use as herbicides

---

US20010047099A1|2001-11-29|4-aminopicolinates and their use as herbicides

---

EP1498413A1|2005-01-19|4-Aminopicolinates and their use as herbicides

---

WO2010099279A1|2010-09-02|N-alkoxyamides of 6-|-4-aminopicolinates and 2-|-6-amino-4-pyrimidinecarboxylates and their use as selective herbicides for crops

---

RU2652132C2|2018-04-25|4-amino-6-|-picolinates and 6-amino-2-|-pyrimidine-4-carboxylates and their application as herbicides

---

CN108774179B|2020-01-21|Substituted pyrimidine-4-formic acid derivative and weeding composition and application thereof

---

BR112020013958A2|2020-12-01|herbicidal compounds

---

CN109293640B|2020-05-19|Substituted nitrogen-containing heteroaromatic formamide derivative and weeding composition and application thereof

---

CA2921977A1|2015-03-26|Agricultural chemicals

---

NZ613477B2|2015-05-28|Arylalkyl esters of 4-amino-6-|picolinates and 6-amino-2-|-4-pyrimidinecarboxylates and their use as herbicides

---

EP0843666A1|1998-05-27|4-substituted 5-polycyclylpyrimidine herbicides

---

CA3146886A1|2021-02-18|2-phenoxy-pyrimidine derivatives as herbicidal compounds

---

NZ712512B2|2021-02-02|4-amino-6-|-picolinates and 6-amino-2-|-pyrimidine-4-carboxylates and their use as herbicides

同族专利:

---

公开号 | 公开日

---

EP2667716A1|2013-12-04|

---

PL2899182T3|2018-07-31|

---

US9169217B2|2015-10-27|

---

CA2825878C|2016-10-18|

---

JP2016074722A|2016-05-12|

---

CL2013002114A1|2013-12-06|

---

KR20150024446A|2015-03-06|

---

CA2825878A1|2012-08-02|

---

CN103442570B|2016-01-13|

---

EP2899182A1|2015-07-29|

---

JP5873880B2|2016-03-01|

---

BR102012001641A2|2014-04-22|

---

UA108922C2|2015-06-25|

---

UY33878A|2012-09-28|

---

CO6731127A2|2013-08-15|

---

CN103442570A|2013-12-11|

---

EP2667716A4|2014-06-11|

---

MX2013008608A|2013-08-12|

---

US20120190551A1|2012-07-26|

---

WO2012103042A1|2012-08-02|

---

HK1207640A1|2016-02-05|

---

DK2899182T3|2018-04-16|

---

CA2925262C|2018-09-11|

---

EP2899182B1|2018-01-10|

---

JP2014505072A|2014-02-27|

---

KR101542313B1|2015-08-06|

---

TWI596088B|2017-08-21|

---

US8883688B2|2014-11-11|

---

AR085019A1|2013-08-07|

---

AU2012209278B2|2015-04-16|

---

RU2566760C2|2015-10-27|

---

CA2925262A1|2012-08-02|

---

HK1187782A1|2014-04-17|

---

RU2013139370A|2015-03-10|

---

BR112013019007A2|2016-07-12|

---

CL2016000212A1|2016-12-09|

---

US20150025238A1|2015-01-22|

---

TW201309646A|2013-03-01|

---

ES2657385T3|2018-03-05|

---

ECSP13012789A|2013-09-30|

---

KR20130121954A|2013-11-06|

---

NZ613477A|2015-02-27|

---

MX336673B|2016-01-27|

---

ZA201305581B|2014-09-25|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US3285925A|1962-03-06|1966-11-15|Dow Chemical Co|Amino-trichloropicolinic acid compounds|

---

US3325272A|1965-06-23|1967-06-13|Dow Chemical Co|Plant growth control methods and compositions|

---

US6297197B1|2000-01-14|2001-10-02|Dow Agrosciences Llc|4-aminopicolinates and their use as herbicides|

---

AR037228A1|2001-07-30|2004-11-03|Dow Agrosciences Llc|ACID COMPOUNDS 6- -4-AMYNOPYCOLINIC, HERBICIDE COMPOSITION THAT UNDERSTANDS AND METHOD TO CONTROL UNWANTED VEGETATION|

---

TWI370816B|2003-04-02|2012-08-21|Dow Agrosciences Llc|6-alkyl or alkenyl-4-aminopicolinates and their use as herbicides|

---

TWI355894B|2003-12-19|2012-01-11|Du Pont|Herbicidal pyrimidines|

---

UA84724C2|2003-12-19|2008-11-25|Э. И. Дю Пон Де Немур Энд Компани|Pyrimidine derivatives, herbicidal mixtures and compositions based thereon, method for controlling undesired vegetation|

---

CN101171237B|2005-05-06|2011-04-20|杜邦公司|Method for preparation of optionally 2-substituted 1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acids|

---

EP1971579B1|2006-01-13|2010-07-28|Dow AgroSciences LLC|2--6-amino-5-halo-4-pyrimidinecarboxylic acids and their use as herbicides|

---

EP1973881B1|2006-01-13|2009-10-28|Dow Agrosciences LLC|6--4-aminopicolinates and their use as herbicides|

---

BRPI0706884A2|2006-02-02|2011-04-12|Du Pont|method of inhibiting cotton plant foliage growth, mixing to cause prolonged defoliation of cotton plant and agricultural compositions|

---

CA2646143A1|2006-04-10|2007-10-25|E. I. Du Pont De Nemours And Company|Herbicidal mixtures|

---

WO2008073369A1|2006-12-12|2008-06-19|E. I. Du Pont De Nemours And Company|Herbicidal mixtures|

---

ES2400405T3|2007-08-13|2013-04-09|Dow Agrosciences Llc|2- -6-amino-5-chloro-4-pyrimidinecarboxylates and their use as herbicides|

---

WO2009029735A1|2007-08-30|2009-03-05|Dow Agrosciences Llc|2--6-amino-5-alkoxy, thioalkoxy and aminoalkyl-4-pyrimidinecarboxylates and their use as herbicides|

---

MX2010003464A|2007-10-02|2010-04-27|Dow Agrosciences Llc|2-substituted-6-amino-5-alkyl, alkenyl or alkynyl-4-pyrimidinecar boxylic acids and 6-substituted-4-amino-3- alkyl, alkenyl or alkynyl picolinic acids and their use as herbicides.|

---

EP2191720A1|2008-11-29|2010-06-02|Bayer CropScience AG|Herbicide-safener combination|

---

GB0902474D0|2009-02-13|2009-04-01|Syngenta Ltd|Chemical compounds|

---

GB0907625D0|2009-05-01|2009-06-10|Syngenta Ltd|Method of controlling undesired vegetation|

---

GB201008290D0|2010-05-18|2010-06-30|Syngenta Ltd|Chemical compounds|

---

TWI529163B|2011-01-25|2016-04-11|陶氏農業科學公司|Process for the preparation of 4-amino-5-fluoro-3-halo-6-picolinates|MX2012011821A|2010-04-12|2012-11-30|Supernus Pharmaceuticals Inc|Methods for producing viloxazine salts and novel polymorphs thereof.|

---

EP2667717A4|2011-01-25|2015-10-14|Dow Agrosciences Llc|6-amino-2-substituted-5-vinylsilylpyrimidine-4-carboxylic acids and esters and 4-amino-6-substituted-3-vinylsilylpyridine-2-carboxylic acids and esters as herbicides|

---

US8912120B2|2012-07-24|2014-12-16|Dow Agrosciences, Llc.|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6- pyridine-2-carboxylic acid or a derivative thereof and synthetic auxin herbicides|

---

US9644469B2|2012-07-24|2017-05-09|Dow Agrosciences Llc|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6- pyridine-2-carboxylic acid or a derivative thereof and VLCFA and lipid synthesis inhibiting herbicides|

---

US8796177B2|2012-07-24|2014-08-05|Dow Agrosciences Llc|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6-pyridine-2-carboxylic acid or a derivative thereof and acetyl-CoA carboxylaseinhibitors|

---

US20140031224A1|2012-07-24|2014-01-30|Dow Agrosciences Llc|Safened herbicidal compositions including 4-amino-3-chloro-5-fluoro-6-pyridine-2-carboxylic acid or a derivative thereof for use in rice|

---

US8883682B2|2012-07-24|2014-11-11|Dow Agrosciences, Llc.|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6-pyridine-2-carboxylic acid or a derivative thereof and auxin transport inhibitors|

---

US8791048B2|2012-07-24|2014-07-29|Dow Agrosciences Llc|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6- pyridine-2-carboxylic acid or a derivative thereof and clomazone|

---

US8916499B2|2012-07-24|2014-12-23|Dow Agrosciences, Llc.|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6- pyridine-2-carboxylic acid or a derivative thereof and a protoporphyrinogen oxidase inhibitor|

---

US8889591B2|2012-07-24|2014-11-18|Dow Agrosciences, Llc.|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6-pyridine-2-carboxylic acid or a derivative thereof and bromobutide, daimuron, oxaziclomefone or pyributicarb|

---

US8809232B2|2012-07-24|2014-08-19|Dow Agroscience Llc|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6- pyridine-2-carboxylic acid or a derivative thereof and halosulfuron, pyrazosulfuron and esprocarb|

---

US8841233B2|2012-07-24|2014-09-23|Dow Agrosciences Llc|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6- pyridine-2-carboxylic acid or a derivative thereof and 4-hydroxyphenyl-pyruvate dioxygenaseinhibitors|

---

US8846570B2|2012-07-24|2014-09-30|Dow Agrosciences, Llc.|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6-pyridine-2-carboxylic acid or a derivative thereof and microtubule inhibiting herbicides|

---

US8912121B2|2012-07-24|2014-12-16|Dow Agrosciences, Llc.|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6-pyridine-2-carboxylic acid or a derivative thereof and certain PS II inhibitors|

---

US8871681B2|2012-07-24|2014-10-28|Dow Agrosciences Llc|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6- pyridine-2-carboxylic acid or a derivative thereof and certain sulfonylureas|

---

US8871680B2|2012-07-24|2014-10-28|Dow Agrosciences, Llc.|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6- pyridine-2-carboxylic acid or a derivative thereof and a di-methoxy-pyrimidine and derivatives thereof|

---

US8895470B2|2012-07-24|2014-11-25|Dow Agrosciences, Llc.|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6- pyridine-2-carboxylic acid or a derivative thereof and glyphosate or glufosinate|

---

US8901035B2|2012-07-24|2014-12-02|Dow Agrosciences, Llc.|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6- pyridine-2-carboxylic acid or a derivative thereof and cellulose biosynthesis inhibitor herbicides|

---

US8906826B2|2012-07-24|2014-12-09|Dow Agrosciences, Llc.|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6- pyridine-2-carboxylic acid or a derivative thereof and imidazolinones|

---

US8906825B2|2012-07-24|2014-12-09|Dow Agrosciences, Llc.|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6- pyridine-2-carboxylic acid or a derivative thereof and triazolopyrimidine sulfonamides|

---

TW201427596A|2012-08-07|2014-07-16|Dow Agrosciences Llc|Herbicidal composition|

---

RU2653855C2|2012-12-13|2018-05-15|ДАУ АГРОСАЙЕНСИЗ ЭлЭлСи|Process for preparation of 4-amino-5-fluoro-3-chloro-6-picolinates|

---

WO2014100147A1|2012-12-21|2014-06-26|Dow Agrosciences Llc|Herbicidal compositions comprising 4-amino-3-chloro-6--5-fluoropyridine-2-carboxylic acid or a derivative thereof and flurtamone, diflufenican, or picolinafen|

---

NZ710092A|2013-01-25|2020-05-29|Dow Agrosciences Llc|Herbicidal compositions comprising 4-amino-3-chloro-6-pyridine-2-carboxylic acid|

---

UA116460C2|2013-01-25|2018-03-26|ДАУ АГРОСАЙЄНСІЗ ЕлЕлСі|Herbicidal compositions comprising 4-amino-3-chloro-6- pyridine-2-carboxylic acid|

---

CN105120662B|2013-01-25|2018-05-04|美国陶氏益农公司|Include the Herbicidal combinations of the chloro- 6- of 4- amino -3-pyridine-2-carboxylic acids|

---

JP2016516697A|2013-03-12|2016-06-09|ダウ アグロサイエンシィズ エルエルシー|Herbicidal composition comprising 4-amino-3-chloro-5-fluoro-6-pyridine-2-carboxylic acid|

---

NZ712866A|2013-03-14|2020-03-27|Dow Agrosciences Llc|Broadleaf crop control with 6-arylpicoline carboxylic acids, 2-arylpyrimidine carboxylic acids, or salts or esters thereof|

---

US9113629B2|2013-03-15|2015-08-25|Dow Agrosciences Llc|4-amino-6--picolinates and 6-amino-2--pyrimidine-4-carboxylates and their use as herbicides|

---

ES2712103T3|2013-03-15|2019-05-09|Dow Agrosciences Llc|New carboxylates of 4-aminopyridine and 6-aminopyrimidine as herbicides|

---

US9730445B2|2013-03-15|2017-08-15|Dow Agrosciences Llc|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6- pyridine-2-carboxylic acid or a derivative thereof and fungicides|

---

US8841234B1|2013-03-15|2014-09-23|Dow Agrosciences, Llc.|Herbicidal compositions comprising 4-amino-3-chloro-5-fluoro-6- pyridine-2-carboxylic acid or a derivative thereof and fungicides|

---

JP6434522B2|2013-09-05|2018-12-05|ダウ アグロサイエンシィズ エルエルシー|Method for producing borated arenes|

---

US9603364B2|2013-12-12|2017-03-28|Dow Agrosciences Llc|4-amino-6--picolinates and their use as herbicides|

---

TW201625354A|2014-06-16|2016-07-16|陶氏農業科學公司|Methods for producing borylated arenes|

---

AU2016297470B2|2015-07-17|2019-03-21|Corteva Agriscience Llc|Control of aquatic weeds using combinations of halauxifen, florpyrauxifen and other aquatic herbicides|

---

TWI726900B|2015-08-04|2021-05-11|美商陶氏農業科學公司|Process for fluorinating compounds|

---

CN109485600A|2017-09-11|2019-03-19|山东先达农化股份有限公司|Compound of fluorine-containing chloropyridine oxime ester structure and its preparation method and application and a kind of herbicide|

---

CN108774179B|2018-05-29|2020-01-21|青岛清原化合物有限公司|Substituted pyrimidine-4-formic acid derivative and weeding composition and application thereof|

---

CN108586357B|2018-07-05|2020-01-21|青岛清原化合物有限公司|Substituted pyrimidineformyl oxime derivatives, preparation method thereof, herbicidal composition and application|

---

CN109042671B|2018-08-22|2022-03-01|安徽辉隆集团银山药业有限责任公司|Chlorofluoropyridine ester dispersible oil suspending agent and application thereof|

---

CN112110852A|2019-06-20|2020-12-22|青岛清原化合物有限公司|Substituted picolinic acid pyridine methylene ester derivative and preparation method, herbicidal composition and application thereof|

---

CN110959618A|2019-11-05|2020-04-07|安徽众邦生物工程有限公司|Weeding composition containing halauxifen-methyl and sulfentrazone|

---

CN112841201B|2019-11-12|2021-10-22|江苏清原农冠杂草防治有限公司|Weeding composition containing pyrimidine benzyl carboxylate compounds and PPO inhibitor and application thereof|

---

EP3679794A1|2019-11-27|2020-07-15|Bayer AG|Herbicidal compositions|

法律状态:
2014-04-22| B03A| Publication of an application: publication of a patent application or of a certificate of addition of invention|

---

2014-07-01| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

---

2018-07-24| B07A| Technical examination (opinion): publication of technical examination (opinion)|

---

2018-07-31| B15K| Others concerning applications: alteration of classification|Ipc: A01N 43/40 (2006.01), C07D 213/79 (2006.01), C07D |

---

2018-10-09| B07A| Technical examination (opinion): publication of technical examination (opinion)|

---

2019-02-05| B09A| Decision: intention to grant|

---

2019-04-02| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 24/01/2012, OBSERVADAS AS CONDICOES LEGAIS. (CO) 20 (VINTE) ANOS CONTADOS A PARTIR DE 24/01/2012, OBSERVADAS AS CONDICOES LEGAIS |

优先权:

---

申请号 | 申请日 | 专利标题

---

US201161435925P| true| 2011-01-25|2011-01-25|

---

US61/435,925|2011-01-25|

---