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    • 专利摘要:
    The present invention relates to new 4-amino-6- (heterocyclic) picolinic acids and their derivatives and 6-amino-2- (heterocyclic) pyrimidine-4-carboxylates and their derivatives which are useful to control undesirable vegetation. The invention also discloses a herbicidal composition comprising new 4-amino-6- (heterocyclic) picolinic acids and their derivatives and 6-amino-2- (heterocyclic) pyrimidine-4-carboxylates and their derivatives and an agriculturally acceptable adjuvant or vehicle as a method to control undesirable vegetation.
    公开号:BR102014006224B1
    申请号:R102014006224-6
    申请日:2014-03-17
    公开日:2020-06-30
    发明作者:Joseph D. Eckelbarger；Jeffrey B. Epp；Lindsey G. Fischer；Christian T. Lowe；Jeff Petkus；Joshua Roth；Norbert M. Satchivi；Paul Richard Schmitzer；Thomas L. Siddall
    申请人:Dow Agrosciences Llc；
    IPC主号:
    专利说明:

    [0001] [0001] This application claims the benefit of Provisional Patent Application Serial No. US 61 / 790,391, filed on March 15, 2013, the description of which is expressly incorporated herein by reference. Field
    [0002] [0002] The invention relates to herbicidal compounds and compositions and methods for controlling undesirable vegetation. BACKGROUND
    [0003] [0003] The occurrence of undesirable vegetation, for example, weeds, is a constant problem faced by farmers in crops, pasture, and other scenarios. Weeds compete with crops and negatively impact crop production. The use of chemical herbicides is an important tool in the control of undesirable vegetation.
    [0004] [0004] In this context there remains a need for new chemical herbicides that offer a broader spectrum of weed control, selectivity, minimal crop damage, stability in storage, ease of handling, greater activity against weeds, and / or a method to treat tolerance to the herbicide that develops with respect to herbicides currently in use. Summary of the invention
    [0005] [0005] Compounds of Formula (I) are provided here:
    [0006] [0006] where
    [0007] [0007] X is N or Cl, where Y is hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio or C 1 -C 3 haloalkylthio;
    [0008] [0008] R 1 is OR 1 ' or NR 1' R 1 ' , where R 1' is hydrogen, C 1 -C 8 alkyl, or C 7 -C 10 arylalkyl, and R 1 ' and R 1' are independently hydrogen, C 1 -C 12 alkyl, C 3 -C 12 alkenyl, or C 3 -C 12 alkynyl;
    [0009] [0009] R 2 is halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 haloalkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 haloalkylthio, amino, C 1 -C 4 alkylamino, C 2 -C 4 haloalkylamino, formyl, C 1 -C 3 alkylcarbonyl, C 1 - C 3 haloalkylcarbonyl, cyano, or a group of the Formula -CR 17 = CR 18 - SiR 19 R 20 R 21 , where R 17 is hydrogen, F, or Cl; R 18 is hydrogen, F, C 1 , C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl; and R 19 , R 20 , and R 21 are independently C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, phenyl, substituted phenyl, C 1 -C 10 alkoxy, or OH;
    [0010] [00010] R 3 and R 4 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 haloalkenyl, C 3 -C 6 alkynyl, formyl, C 1 -C 3 alkylcarbonyl, C 1 -C 3 haloalkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbamyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 trialkylsilyl, C 1 -C 6 dialkylphosphonyl, or R 3 and R 4 used together with N is a 5- or 6-membered saturated or unsaturated ring, or R 3 and R 4 used together represent = CR 3 ' (R 4' ), where R 3 ' and R 4' are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylamino, or, R 3 ' and R 4' used together with = C represent a 5- or 6-membered saturated ring
    [0011] [00011] A is one of the groups Ar1 to Ar28:
    [0012] [00012] R 5 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C1-C3 alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 alkylthio, C 1 -C 3 haloalkylthio, amino, C 1 -C 4 alkylamino, or C 2 -C 4 haloalkylamino.
    [0013] [00013] R 6 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 alkylthio, C 1 -C 3 haloalkylthio, amino, C 1 -C 4 alkylamino, or C 2 -C 4 haloalkylamino;
    [0014] [00014] R 6 ' is hydrogen or halogen;
    [0015] [00015] R 6 " is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, cyclopropyl, halocyclopropyl, C 2 -C 4 alkenyl, C 2 -C 4 haloalkenyl, C 2 - C 4 alkynyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 alkylthio, C 1 -C 3 haloalkylthio, amino, C 1 -C 4 alkylamino, C 2 -C 4 haloalkylamino, CN or NO2;
    [0016] [00016] R 7 and R 7 ' are independently hydrogen, halogen, C 1 - C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 3 alkoxy;
    [0017] [00017] R 8 and R 8 ' are independently hydrogen, halogen, C 1 - C 1 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 3 alkoxy;
    [0018] [00018] R 9 , R 9 ' , R 9 " and R 9'' are independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 3 alkoxy;
    [0019] [00019] R 10 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 haloalkenyl, C 3 -C 6 alkynyl, formyl, C 1 -C 3 alkylcarbonyl, C 1 -C 3 haloalkylcarbonyl, or C 1 -C 6 trialkylsilyl;
    [0020] [00020] m, when present, is 0, 1, or 2; and
    [0021] [00021] n, when present, is 0, 1, or 2;
    [0022] [00022] or an N-oxide or an agriculturally acceptable salt thereof;
    [0023] [00023] with the proviso that A is different from:
    [0024] [00024] Methods of controlling undesirable vegetation are also provided which comprise applying a compound of Formula (I) or an N-oxide or an agriculturally acceptable salt thereof. DETAILED DESCRIPTION DEFINITIONS
    [0025] [00025] As used here, herbicide and herbicidal active ingredient means a compound that controls undesirable vegetation when applied in an appropriate amount.
    [0026] [00026] As used here, control of, or control of undesirable vegetation means killing or preventing vegetation, or causing some other effect of adverse modification to vegetation, for example, deviations from growth or natural development, regulation, desiccation, delay, and the like .
    [0027] [00027] As used here, an herbicidally effective or vegetation control amount is an amount of herbicidal active ingredient, the application of which controls the relevant undesirable vegetation.
    [0028] [00028] As used here, applying a herbicide or herbicidal composition means releasing it directly to the targeted vegetation or to the locus thereof or to the area where control of unwanted vegetation is desired. Application methods include, but are not limited to, pre-emergently contacting land or water, post-emergently contacting undesirable vegetation or area adjacent to undesirable vegetation.
    [0029] [00029] As used here, plants and vegetation include, but are not limited to, dormant seeds, germ seeds, emerging seedlings, plants emerging from vegetative propagules, immature vegetation, and stabilized vegetation.
    [0030] [00030] As used herein, agriculturally acceptable salts and esters refer to salts and esters that exhibit herbicidal activity, or that are or can be converted to plants, water, or soil in the referenced herbicide. Exemplary agriculturally acceptable esters are those that are or can be hydrolyzed, oxidized, metabolized, or otherwise converted, for example, into plants, water, or earth, into the corresponding carboxylic acid which, depending on the pH, may be in dissociated or not dissociated.
    [0031] [00031] Suitable salts include those derived from alkali or alkaline earth metals and those derived from ammonia and amines. Preferred cations include sodium, potassium, magnesium, and amine cations of the Formula: R 13 R 14 R 15 R 16 N +
    [0032] [00032] where R 13 , R 14 , R 15 and R 16 each independently represent hydrogen or C 1 -C 12 alkyl, C 3 -C 12 alkenyl or C 3 -C 12 alkynyl, each of which is optionally substituted by one or more hydroxy groups, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or phenyl, provided that R 13 , R 14 , R 15 and R 16 are sterically compatible. In addition, any two R 13 , R 14 , R 15 and R 16 together can represent an aliphatic difunctional moiety containing one to twelve carbon atoms and up to two oxygen or sulfur atoms. Salts of the compounds of Formula (I) can be prepared by treating compounds of Formula (I) with a metal hydroxide, such as sodium hydroxide, with an amine, such as ammonia, trimethylamine, diethanolamine, 2-methylthiopropylamine, bisalylamine, 2-butoxyethylamine, morpholine, cyclododecylamine, or benzylamine or with a tetraalkylammonium hydroxide, such as tetramethylammonium hydroxide or choline hydroxide. Amine salts are often preferred forms of the compounds of Formula (I) because they are soluble in water and provide for the preparation of desirable aqueous based herbicidal compositions.
    [0033] [00033] Compounds of Formula (I) include N-oxides. Pyridine N-oxides can be obtained by oxidation of the corresponding pyridines. Suitable oxidation methods are described, for example, in Houben-Weila, Metoden der organischen Chemie [Metods in organic chemistry], expanded volumes and subsequent to the 4th. edition, volume E 7b, p. 565 f.
    [0034] [00034] As used herein, unless otherwise specified, acyl refers to formyl, C 1 -C 3 alkylcarbonyl, and C 1 -C 3 haloalkylcarbonyl. C 1 -C 6 acyl refers to formyl, C 1 -C 5 alkylcarbonyl, and C 1 -C 5 haloalkylcarbonyl (the group contains a total of 1 to 6 carbon atoms).
    [0035] [00035] As used herein, alkyl refers to saturated straight chain or branched, saturated hydrocarbon moieties. Unless otherwise specified, C 1 -C 10 alkyl groups are intended. Examples include methyl, ethyl, propyl, 1-methyl-ethyl, butyl, 1-methyl-propyl, 2-methyl-propyl, 1,1-dimethyl-ethyl, pentyl, 1-methyl-butyl, 2-methyl-butyl, 3-methyl-butyl, 2,2-dimethyl-propyl, 1-ethyl-propyl, hexyl, 1,1-dimethyl-propyl, 1,2-dimethyl-propyl, 1-methyl-pentyl, 2-methyl-pentyl, 3-methyl-pentyl, 4-methyl-pentyl, 1,1-dimethyl-butyl, 1,2-dimethyl-butyl, 1,3-dimethyl-butyl, 2,2-dimethyl-butyl, 2,3-dimethyl- butyl, 3,3-dimethyl-butyl, 1-ethyl-butyl, 2-ethyl-butyl, 1,1,2-trimethyl-propyl, 1,2,2-trimethyl-propyl, 1-ethyl-1-methyl- propyl, and 1-ethyl-2-methyl-propyl.
    [0036] [00036] As used here, "haloalkyl" refers to straight chain or branched alkyl groups, where in these groups the hydrogen atoms can be partially or totally replaced by halogen atoms. Unless otherwise specified, groups C 1 -C 8 are intended. Examples include chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2-difluoroethyl trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, and 1,1,1-trifluoroprop-2-yl .
    [0037] [00037] As used here, alkenyl refers to unsaturated, straight chain, or branched hydrocarbon moieties containing a double bond. Unless otherwise specified, C 2 -C 8 alkenyl is intended. Alkenyl groups can contain more than one unsaturated bond. Examples include ethylene, 1-propenyl, 2-propenyl, 1-methylethyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2- propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1, 1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl- 2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3- pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2- butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl -1- butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl -3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl -1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl -2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, and 1-ethyl-2-methyl-2-propenyl. Vinyl refers to a group having the structure -CH = CH 2 ; 1-propenyl refers to a group with the structure -CH = CH-CH 3 ; and 2-propenyl refers to a group with the structure -CH 2 -CH = CH 2 .
    [0038] [00038] As used herein, alkynyl represents straight or branched chain hydrocarbon moieties containing a triple bond. Unless otherwise specified, C 2 -C 8 alkynyl groups are intended. Alkynyl groups can contain more than one unsaturated bond. Examples include C 2 -C 6 -alkynyl, such as ethynyl, 1-propynyl, 2-propynyl (or propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentinyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-1-butynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl- 2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-methyl-1-pentynyl, 4-methyl-1-pentynyl, 1- methyl-2-pentynyl, 4-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl- 4-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl- 1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, and 1-ethyl-1-methyl-2-propynyl.
    [0039] [00039] As used herein, alkoxy refers to a group of Formula R-O-, where R is alkyl as defined above. Unless otherwise specified, alkoxy groups where R is a C1-C8 alkyl group are desired. Examples include methoxy, ethoxy, propoxy, 1-methyl-ethoxy, butoxy, 1-methyl-propoxy, 2-methyl-propoxy, 1,1-dimethyl-ethoxy, pentoxy, 1-methyl-butyloxy, 2-methyl-butoxy, 3-methyl-butoxy, 2,2-dimethyl-propoxy, 1-ethyl-propoxy, hexoxy, 1,1-dimethyl-propoxy, 1,2-dimethyl-propoxy, 1-methyl-pentoxy, 2-methyl-pentoxy, 3-methyl-pentoxy, 4-methyl-penoxy, 1,1-dimethyl-butoxy, 1,2-dimethyl-butoxy, 1,3-dimethyl-butoxy, 2,2-dimethyl-butoxy, 2,3-dimethyl- butoxy, 3,3-dimethyl-butoxy, 1-ethyl-butoxy, 2-ethylbutoxy, 1,1,2-trimethyl-propoxy, 1,2,2-trimethyl-propoxy, 1-ethyl-1-methyl-propoxy, and 1-ethyl-2-methyl-propoxy.
    [0040] [00040] As used herein, haloalkoxy refers to a group of Formula R-O-, where R is haloalkyl as defined above. Unless otherwise specified, haloalkoxy groups where R is a C1-C8 alkyl group are desired. Examples include chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 2-fluoroethoxy, 2,2-fluoroethoxy trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, and 1,1,1-trifluoroprop-2-oxy .
    [0041] [00041] As used herein, alkylthio refers to a group of Formula R-S- where R is alkyl as defined above. Unless otherwise specified, alkylthio groups where R is a C1-C8 alkyl group are desired. Examples include methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methyl-propylthio, 2-methylpropylthio, 1,1-dimethylethylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3- dimethylbutylthio, 2.2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropylthio, and 1-ethyl-2-methylpropylthio.
    [0042] [00042] As used herein, haloalkylthio refers to an alkylthio group as defined above in which the carbon atoms are partially or completely replaced by halogen atoms. Unless otherwise specified, haloalkylthio groups where R is a C1-C8 alkyl group are desired. Examples include chloromethylthio, bromomethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, trifluoromethylthio, chlorofluoromethylthio, dichlorofluoromethylthio, chlorodifluoromethylthio, 1-chloroethylthio, 1-bromoethylthio, 2,2-fluoroethyl, 2-fluoro trifluoroethylthio, 2-chloro-2-fluoroethylthio, 2-chloro-2-difluoroethylthio, 2,2-dichloro-2-fluoroethylthio, 2,2,2-trichloroethylthio, pentafluoroethylthio, and 1,1,1 -trifluoroprop-2-ylio .
    [0043] [00043] As used herein, aryl, as well as derivative terms such as aryloxy, refers to a phenyl, indanyl or naphthyl group with phenyl being preferred. The term "heteroaryl", as well as derived terms such as "heteroaryloxy", refers to a 5- or 6-membered aromatic ring containing one or more heteroatoms, viz., N, O or S; these heteroaromatic rings can be fused to other aromatic systems. Aryl or heteroaryl substituents may be unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, cyano, formyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 acyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 carbamoyl, hydroxycarbonyl, C 1 -C 6 alkylcarbonyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, provided that the substituents are sterically compatible and the chemical bonding standards and deformation energy are satisfied. Preferred substituents include halogen, C 1 -C 2 alkyl and C 1 -C 2 haloalkyl.
    [0044] [00044] As used here alkylcarbonyl refers to an alkyl group attached to a carbonyl group. C 1 -C 3 alkylcarbonyl and C 1 -C 3 haloalkylcarbonyl refer to groups in which a C 1 -C 3 alkyl group is attached to a carbonyl group (the group contains a total of 2 to 4 carbon atoms).
    [0045] [00045] As used here, alkoxycarbonyl refers to a group of the Formula
    [0046] [00046] As used here, arylalkyl refers to an alkyl group substituted by an aryl group. C 7 -C 10 arylalkyl refers to a group in which the total number of carbon atoms in the group is 7 to 10.
    [0047] [00047] As used herein alkylamino refers to an amino group substituted by one or two alkyl groups, which can be the same or different.
    [0048] [00048] As used herein haloalkylamino refers to an alkylamino group in which the alkyl carbon atoms are partially or completely replaced by halogen atoms.
    [0049] [00049] As used here, C 1 -C 6 alkylaminocarbonyl refers to a group of Formula RNHC (O) - where R is C 1 -C 6 alkyl, and C 1 -C 6 dialkylaminocarbonyl refers to a group of Formula R 2 NC (O) - where each R is independently C 1 -C 6 alkyl.
    [0050] [00050] As used here alkylcarbamyl refers to a carbamyl group substituted in nitrogen with an alkyl group.
    [0051] [00051] As used herein alkylsulfonyl refers to a group of Formula
    [0052] [00052] As used here carbamyl (also referred to as carbamoyl and aminocarbonyl) refers to a group of the Formula
    [0053] [00053] As used here dialkylphosphonyl refers to a group of the Formula
    [0054] [00054] As used here, C 1 -C 6 trialkylsilyl refers to a group of the Formula -SiR3 where each R is independently a C 1 - C 6 alkyl group (the group contains a total of 3 to 18 carbon atoms) .
    [0055] [00055] As used here Me refers to a methyl group; OMe refers to a methoxy group; i -Pr refers to an isopropyl group.
    [0056] [00056] As used herein, the term "halogen" including derivative terms such as "halo" refers to fluorine, chlorine, bromine and iodine.
    [0057] [00057] As used here, plants and vegetation include, but are not limited to, germinating seeds, emerging seedlings, plants emerging from vegetative propagules, immature vegetation, and stabilized vegetation. COMPOUNDS OF FORMULA (I)
    [0058] [00058] The invention provides compounds of Formula (I) as defined above and N-oxides and agriculturally acceptable salts thereof.
    [0059] [00059] In some embodiments, the compound is carboxylic acid or an agriculturally acceptable ester or salt. In some embodiments, the compound is carboxylic acid or its methyl ester.
    [0060] [00060] In some embodiments, compounds of Formula (I):
    [0061] [00061] X is N or Cl, where Y is hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio or C 1 -C 3 haloalkylthio;
    [0062] [00062] R 1 is OR 1 ' or NR 1' R 1 ' , where R 1' is hydrogen, C 1 -C 8 alkyl, or C 7 -C1 0 arylalkyl, and R 1 ' and R 1' are independently hydrogen, C 1 -C 12 alkyl, C 3 -C 12 alkenyl, or C 3 -C 12 alkynyl;
    [0063] [00063] R 2 is halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 haloalkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 haloalkylthio, amino, C 1 -C 4 alkylamino, C 2 -C 4 haloalkylamino, formyl, C 1 -C 3 alkylcarbonyl, C 1 - C 3 haloalkylcarbonyl, cyano, or a group of the Formula -CR 17 = CR 18 - SiR 19 R 20 R 21 , where R 17 is hydrogen, F, or Cl; R 18 is hydrogen, F, Cl, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl; and R 19 , R 20 , and R 21 are independently C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, phenyl, substituted phenyl, C 1 -C 10 alkoxy, or OH;
    [0064] [00064] R 3 and R 4 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 alkenyl, C 3 -C6 haloalkenyl, C 3 -C6 alkynyl, formyl, C 1 - C 3 alkylcarbonyl, C 1 -C 3 haloalkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbamyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 trialkylsilyl, C 1 -C 6 dialkylphosphonyl, or R 3 and R 4 used together with N is a saturated ring of 5 or 6 members, or R 3 and R 4 used together represent = CR 3 ' (R 4' ), where R 3 ' and R 4' are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylamino, or, R 3 ' and R 4' used together with = C represent a ring saturated with 5 or 6 limbs;
    [0065] [00065] A is one of the groups Ar1 to Ar24:
    [0066] [00066] R 5 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 alkylthio, C 1 -C 3 haloalkylthio, amino, C 1 -C 4 alkylamino, or C 2 -C 4 haloalkylamino.
    [0067] [00067] R 6 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 alkylthio, C 1 -C 3 haloalkylthio, amino, C 1 -C 4 alkylamino, or C 2 -C 4 haloalkylamino;
    [0068] [00068] R 6 ' is hydrogen or halogen;
    [0069] [00069] R 6 " is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, cyclopropyl, halocyclopropyl, C 2 -C 4 alkenyl, C 2 -C 4 haloalkenyl, C 2 - C 4 alkynyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 alkylthio, C 1 -C 3 haloalkylthio, amino, C 1 -C 4 alkylamino, C 2 -C 4 haloalkylamino, CN or NO 2 ;
    [0070] [00070] R 7 and R 7 ' are independently hydrogen, halogen, C 1 - C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 3 alkoxy;
    [0071] [00071] R 8 and R 8 ' are independently hydrogen, halogen, C 1 - C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 3 alkoxy;
    [0072] [00072] R 9 , R 9 ' , R 9 " and R 9 " are independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 3 alkoxy;
    [0073] [00073] R 10 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 haloalkenyl, C 3 -C 6 alkynyl, formyl, C 1 -C 3 alkylcarbonyl, C 1 -C 3 haloalkylcarbonyl, or C 1 -C 6 trialkylsilyl;
    [0074] [00074] m, when present, is 0, 1, or 2; and
    [0075] [00075] n, when present, is 0, 1, or 2;
    [0076] [00076] or an N-oxide or agriculturally acceptable salt thereof;
    [0077] [00077] with the proviso that A is different from:
    [0078] [00078] In some modalities, m, when present, is 0 or 1; and n, when present, is 0 or 1. In certain modalities, m, when present, is 0; and n, when present, is 0. In certain modalities, m, when present, is 1; and n, when present, is 1.
    [0079] [00079] In some embodiments, R 1 is OR 1 ' , where R 1' is hydrogen, C 1 -C 8 alkyl, or C 7 -C 10 arylalkyl.
    [0080] [00080] In some embodiments, R 2 is halogen, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, orC 1 -C 4 -alkoxy. In some embodiments, R 2 is halogen, C 2 -C 4 -alkenyl, or C 1 -C 4 -aloxy. In some embodiments, R 2 is Cl, OMe, vinyl, or 1-propenyl. In some embodiments, R 2 is Cl. In some modalities, R 2 is OMe. In some embodiments R 2 is vinyl or 1-propenyl.
    [0081] [00081] In some embodiments, R 3 and R 4 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 haloalkenyl, C 3 -C 6 alkynyl , formyl, C 1 -C 3 alkylcarbonyl, C 1 -C 3 haloalkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbamyl, or R 3 and R 4 used together represent = CR 3 ' (R 4' ), wherein R 3 ' and R 4' are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 1 -C 6 alkoxy, or C 1 -C 6 alkylamino. In some embodiments, R 3 and R 4 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 haloalkenyl, formyl, C 1 -C 3 alkylcarbonyl, C 1 -C 3 haloalkylcarbonyl, or R 3 and R 4 used together represent = CR 3 ' (R 4' ), where R 3 ' and R 4' are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 alkylamino. In some embodiments, at least one of R 3 and R 4 is hydrogen. In some embodiments, R 3 and R 4 are both hydrogen.
    [0082] [00082] In some embodiments, X is N, CH, or CF. In some modalities, X is N. In some modalities, X is CH. In some modalities, X is CF.
    [0083] [00083] In some modalities: Ar is Ar1, Ar3, Ar4, Ar7, Ar9, Ar10, Ar13, Ar15, Ar16, Ar19, Ar21, Ar22, Ar25, or Ar27.
    [0084] [00084] In some modalities: Ar is Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar15, Ar16, Ar17, Ar18, Ar25, Ar26, Ar27, or Ar28.
    [0085] [00085] In some modalities: Ar is Ar1, Ar3, Ar7, Ar9, Ar10, Ar13, Ar15, Ar16, Ar19, Ar21, or Ar22.
    [0086] [00086] In some modalities: Ar is Ar2, Ar4, Ar5, Ar6, Ar8, Ar11, Ar12, Ar14, Ar17, Ar18, Ar20, Ar23, Ar24, Ar26, or Ar28.
    [0087] [00087] In some modalities: Ar is Ar2, Ar5, Ar6, Ar8, Ar11, Ar12, Ar14, Ar17, Ar18, Ar20, Ar23, or Ar24.
    [0088] [00088] In some modalities: Ar is Ar1, Ar2, Ar3, Ar4, Ar6, or Ar7.
    [0089] [00089] In some modalities: Ar is Ar15, Ar16, Ar17, or Ar18.
    [0090] [00090] In some embodiments, R 5 is hydrogen, halogen, C 1 - C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 alkylthio, or C 1 -C 3 haloalkylthio.
    [0091] [00091] In some embodiments, R 5 is hydrogen, halogen, C 1 - C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 3 alkoxy. In some embodiments, R 5 is hydrogen or F. In some embodiments, R 5 is hydrogen. In some modalities, R 5 is F.
    [0092] [00092] In some embodiments, R 6 is hydrogen or halogen. In some embodiments, R 6 is hydrogen or F. In some embodiments, R 6 is hydrogen. In some modalities, R 6 is F.
    [0093] [00093] In some embodiments, R 6 ' is hydrogen or halogen. In some embodiments, R 6 ' is hydrogen or F. In some embodiments, R 6' is hydrogen. In some embodiments, R 6 ' is F.
    [0094] [00094] In some embodiments, R 6 " is hydrogen, halogen, C 1 - C 4 alkyl, C 1 -C 4 haloalkyl, cyclopropyl, C 2 -C 4 alkynyl, CN, or NO 2. In some embodiments, R 6 " is hydrogen, halogen, C 1 -C 4 haloalkyl, or cyclopropyl. In some embodiments, R 6 " is hydrogen or halogen. In some embodiments, R 6" is C 1 -C 4 haloalkyl. In some modalities, R 6 " is CN. In some modalities, R 6" is NO 2 .
    [0095] [00095] In some ways:
    [0096] [00096] R 2 is halogen, C 2 -C 4 -alkenyl, C 2 -C 4 haloalkenyl, or C 1 -C 4 -alkoxy;
    [0097] [00097] R 3 and R 4 are both hydrogen; and
    [0098] [00098] X is N, CH or CF.
    [0099] [00099] In some ways:
    [0100] [000100] R 2 is halogen, C 2 -C 4 -alkenyl, or C 1 -C 4 -alkoxy;
    [0101] [000101] R 3 and R 4 are both hydrogen; and
    [0102] [000102] X is N, CH, or CF;
    [0103] [000103] Ar is Ar1, Ar3, Ar7, Ar9, Ar10, Ar13, Ar15, Ar16, Ar19, Ar21, or Ar22;
    [0104] [000104] R 5 is hydrogen or F;
    [0105] [000105] R 6 is hydrogen or F;
    [0106] [000106] R 6 ' is hydrogen;
    [0107] [000107] R 7 , R 7 ' , R 8 , R 8' , R 9 , R 9 ' , R 9 " , and R 9 ", if applicable to the relevant Ar group, are independently hydrogen or fluorine.
    [0108] [000108] In some modalities:
    [0109] [000109] R 2 is halogen, C 2 -C 4 -alkenyl, or C 1 -C 4 -alkoxy;
    [0110] [000110] R 3 and R 4 are both hydrogen; and
    [0111] [000111] XéN, CH, or CF;
    [0112] [000112] Ar is Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar10, Ar11, Ar12, Ar15, Ar16, Ar25, Ar26, Ar27, or Ar28;
    [0113] [000113] R 5 is hydrogen or F;
    [0114] [000114] R 6 is hydrogen or F;
    [0115] [000115] R 6 ' is hydrogen;
    [0116] [000116] R 7 , R 7 ' , R 8 , R 8' , R 9 , R 9 ' , R 9 " , and R 9 ", if applicable to the relevant Ar group, are independently hydrogen or fluorine.
    [0117] [000117] In some ways:
    [0118] [000118] R 2 is chlorine, methoxy, vinyl, or 1-propenyl;
    [0119] [000119] R 3 and R 4 are hydrogen; and
    [0120] [000120] XéN, CH, or CF.
    [0121] [000121] In some ways:
    [0122] [000122] R 2 it is chlorine;
    [0123] [000123] R 3 and R 4 are hydrogen; and
    [0124] [000124] XéN, CH, or CF.
    [0125] [000125] In some ways:
    [0126] [000126] R 2 is methoxy;
    [0127] [000127] R 3 and R 4 are hydrogen; and
    [0128] [000128] X is N, CH, or CF.
    [0129] [000129] In some ways:
    [0130] [000130] R 2 is vinyl or 1-propenyl;
    [0131] [000131] R 3 and R 4 are hydrogen; and
    [0132] [000132] XéN, CH, or CF.
    [0133] [000133] In some ways:
    [0134] [000134] R 2 is chlorine, methoxy, vinyl, or 1-propenyl;
    [0135] [000135] R 3 and R 4 are hydrogen; and
    [0136] [000136] XéN.
    [0137] [000137] In some ways:
    [0138] [000138] R 2 it is chlorine;
    [0139] [000139] R 3 and R 4 are hydrogen; and
    [0140] [000140] X is CH.
    [0141] [000141] In some ways:
    [0142] [000142] R 2 is chlorine, methoxy, vinyl, or 1-propenyl;
    [0143] [000143] R 3 and R 4 are hydrogen; and
    [0144] [000144] X is CF. EXAMPLE COMPOUNDS
    [0145] [000145] The following table 1 describes exemplary compounds of Formula (I) in which:
    [0146] [000146] R 1 is OR 1 ';
    [0147] [000147] R 3 and R 4 are hydrogen; and
    [0148] [000148] R 1 ' , R 2 , X, Ar, m, R 5 , R 6 , R 6' , R 6 " , R 7 , and R 7 ' , R 8 , R 8' , and R 10 are one the following inflammations: Table 1
    [0149] [000149] For compound 107 R 8 and R 8 ' are replaced and each is F.
    [0150] [000150] ** For compound 108 R 10 is replaced and is Me. METHODS OF PREPARATION OF COMPOUNDS
    [0151] [000151] Exemplary procedures for synthesizing the compounds of Formula (I) are provided below.
    [0152] [000152] The 4-amino-6- (heterocyclic) picolinic acids of Formula (I) can be prepared in several ways. As described in Scheme I, the Formula (II) 4-amino-6-chloropicolinates can be converted to Formula (III) 4-amino-6-substituted-picolinates, where Ar is as defined herein, by coupling Suzuki with an ester or boronic acid, in the presence of a base, such as potassium fluoride, and a catalyst, such as bis (triphenylphosphine) - palladium (ll) dichloride, in a mixture of protic, polar solvent, such as acetonitrile -water, at a temperature, such as 110 ° C, for example, in a microwave reactor (reaction at 1 ). The Formula (III) 4-Amino-6-substituted picolinates can be transformed into the Formula (IV) 5-iodine-4-amino-6-substituted picolinates by a reaction with iodination reagents, such as acid periodic and iodine, in a practical, polar solvent, such as methyl alcohol (reaction b 1 ). The Stille coupling of the 5 (iodine-4-amino-6-substituted-picolinates of Formula (IV) with a stanane, such as tetramethyl tin, in the presence of a catalyst, such as bis (triphenylphosphine) - palladium (ll) dichloride, in a non-reactive solvent, such as 1,2-dichloroethane, at a temperature, such as 120-130 ° C, for example, in a microwave reactor, provides 5- (substituted) -4-amino-6- substituted-picolinates of Formula (1a), where Z 1 is alkyl, alkenyl, alkynyl, haloalkenyl and alkylthio (reaction c 1 ).
    [0153] [000153] Alternatively, the Formula (II) 4-amino-6-chloropicolinates can be transformed into the Formula (V) 5-iodo-4-amino-6-chloropicolinates via a reaction with iodination reagents, such as periodic acid and iodine, in a practical, polar solvent, such as methyl alcohol (reaction b 2 ). Stille coupling of the 5-iodine-4-amino-6-chloropicolinates of Formula (V) with a stannane, such as tetramethyl tin, in the presence of a catalyst, such as bis (triphenylphosphine) -palladium (ll) dichloride, in a non-reactive solvent, such as 1,2-dichloroethane, at a temperature, such as 120-130 ° C, for example, in a microwave reactor, provides 5- (substituted) -4-amino-6-chloropicolinates of Formula (VI), where Z 1 is alkyl, alkenyl, alkynyl, haloalkenyl and alkylthio (reaction c 2 ). The Formula (VI) 5- substituted-4-amino-6-chloropicolinates can be converted to Formula (1a) 5-substituted-4-amino-6-substituted-picolinates, where Ar is as defined herein, by of the Suzuki coupling with an ester or boronic acid, in the presence of a base, such as potassium fluoride, and a catalyst, such as bis (triphenylphosphine)-palladium (ll) dichloride, in a mixture of protic, polar solvent, such like acetonitrile-water, at a temperature, such as 110 ° C, for example, in a microwave reactor (reaction at 2 ). Scheme I
    [0154] [000154] As described in Scheme II, the 4,5,6-trichloropicolinate of Formula (VII) can be converted into a corresponding isopropyl ester of Formula (VIII), by means of a reaction with isopropyl alcohol and concentrated sulfuric acid, for example, at reflux temperature under Dean-Stark conditions (reaction d). The isopropyl ester of Formula (VIII) can be reacted with a fluoride ion source, such as cesium fluoride, in an aprotic, polar solvent, such as dimethyl sulfoxide (DMSO), at a temperature, such as 80 ° C, under Dean-Stark conditions, to produce the isopropyl 4,5,6-trifluoropicolinate of Formula (IX) (reaction e). The isopropyl 4,5,6-trifluoropicolinate of Formula (IX) can be aminated with a nitrogen source, such as ammonia, in an aprotic, polar solvent, such as DMSO, to produce 4-amino-5,6- difluoropicolinate of Formula (X) (reaction f). The fluorine substituent at the 6-position of the 4-amino-5,6-difluoropicolinate of Formula (X) can be exchanged with a chlorine substituent by treatment with a chloride source, such as hydrogen chloride, for example, in dioxane , in a Parr reactor, at a temperature, such as 100 ° C, to produce a Formula (XI) 4-amino-5-fluoro-6-chloro-picolinate (reaction g). The 4-amino-5-fluoro-6-chloropicolinate of Formula (XI) can be transesterified to the corresponding methyl ester of Formula (XII) by reaction with titanium (IV) isopropoxide in methyl alcohol at reflux temperature (reaction h ) . Scheme II
    [0155] [000155] As described in Scheme III, 4-amino-5-fluoro-6-chloropicolinate of Formula (XII) can be transformed into 3-iodo-4-amino-5-fluoro-6-chloropicolinate of Formula (XIII) by reaction with iodination reagents, such as periodic acid and iodine, in a protic, polar solvent, such as methyl alcohol (reaction b 3 ). The Stille coupling of the 3-iodo-4-amino-5-fluoro-6-chloropicolinates of Formula (XIII) with a stanane, such as tributyl (vinyl) stanane, in the presence of a catalyst, such as bis (triphenylphosphine) dichloride - palladium (ll), in a non-reactive solvent, such as 1,2-dichloroethane, at a temperature, such as 120-130 ° C, for example, in a microwave reactor, provides 3- (replaced) - 4-amino-5-fluoro-6-chloropicolinates of Formula (XIV), where R 2 is alkyl, alkenyl, alkynyl, haloalkenyl and alkylthio (reaction C3). Alternatively, the 3-iodo-4-amino-5-fluoro-6-chloropicolinates of Formula (XIII) can be treated with cesium carbonate and a catalytic amount of both copper (l) iodide and 1,10-phenanthroline in the presence polar protic solvent, such as methyl alcohol, at a temperature, such as 65 ° C, to provide the 3- (substituted) -4-amino-5-fluoro-6-chloropicolinic acids of Formula (XIV), where R 2 is alkoxy or haloalkoxy (reaction i 1 ), which can be esterified to methyl esters, for example, by treatment with hydrogen chloride (gas) and methyl alcohol at 50 ° C (reaction j 1 ). The 3- (substituted) -4-amino-5-fluoro-6-chloropicolinates of Formula (XIV) can be converted to 4-amino-6-substituted-picolinates of Formula (lB), where Ar is as defined here, by coupling Suzuki with an ester or boronic acid, in the presence of a base, such as potassium fluoride, and a catalyst, such as bis (triphenylphosphine) -paladium (ll) dichloride, in a practical, polar solvent mixture , such as acetonitrile-water, at a temperature, such as 110 ° C, for example, in a microwave reactor (reaction at 3 ).
    [0156] [000156] Alternatively, the Formula (XII) 4-amino-5-fluoro-6-chloropicolinates can be converted to Formula (XV) 4-amino-5-fluoro-6-substituted picolinates, where Ar is as defined here, by means of Suzuki coupling with an ester or boronic acid, in the presence of a base, such as potassium fluoride, and a catalyst, such as bis (triphenylphosphine) -paladium (ll) dichloride, in a solvent mixture practical, polar, such as acetonitrile-water, at a temperature, such as 110 ° C, for example, in a microwave reactor (reaction at 4 ). The Formula (XV) 4-amino-5-fluoro-6-substituted picolinates can be transformed into the Formula (XVI) 3-iodo-4-amino-5-substituted-picolinate (XVI) by reaction with iodine reagents, such as periodic acid and iodine, in a protic, polar solvent, such as methyl alcohol (reaction b 4 ). Stille coupling of the 3-iodine-4-amino-5-fluoro-6-substituted-picolinates of Formula (XVI) with a stanane, such as tributyl (vinyl) stanane, in the presence of a catalyst, such as bis dichloride ( triphenylphosphine) -palladium (ll), in a non-reactive solvent, such as 1,2-dichloroethane, at a temperature, such as 120-130 ° C, for example, in a microwave reactor, provides 3- (replaced ) -4-amino-5-fluoro-6-substituted-picolinates of Formula (lB), where R 2 is alkyl, alkenyl, alkynyl, haloalkenyl and alkylthio (reaction C4). Alternatively, the Formula (XVI) 3-iodo-4-amino-5-fluoro-6-substituted-picolinates can be treated with cesium carbonate and a catalytic amount of both copper (l) iodide and 1,10-phenanthroline in the presence of a practical polar solvent, such as methyl alcohol, at a temperature, such as 65 ° C, to provide the 3- (substituted) -4-amino-5-fluoro-6-substituted-picolinic acids of Formula (IB) , where R 2 is alkoxy or haloalkoxy (reaction i2), which can be esterified to methyl esters, for example, by treatment with hydrogen chloride (gas) and methyl alcohol, at a temperature, such as 50 ° C ( reaction j 2 ). Scheme III
    [0157] [000157] As described in Scheme IV, the 4-acetamido-6- (trimethylstannyl) picolinates of Formula (XVII) can be converted into 4-acetamido-6-substituted-picolinates of Formula (XVIII), where Ar is as defined here, by coupling Stille with an aryl bromide or aryl iodide, in the presence of a catalyst, such as bis (triphenylphosphine) -palladium (II) dichloride, in a solvent, such as 1,2-dichloroethane , for example, at reflux temperature (reaction k ). 4-Amino-6-substituted-picolinates of Formula (1C), where Ar is as defined herein, can be synthesized from 4-acetamido-6-substituted-picolinates of Formula (XVIII) by means of standard deprotection methods, such as as hydrochloric acid gas in methanol (reaction /). Scheme IV
    [0158] [000158] As described in Scheme V, 2,4-dichloro-5-methoxypyrimidine (XIX) can be transformed into 2,4-dichloro-5-methoxy-6-vinylpyrimidine (XX) by means of a reaction with bromide vinyl magnesium in an aprotic, polar solvent, such as tetrahydrofuran (reaction m). 2,4-Dichloro-5-methoxy-6-vinylpyrimidine (XX) can be transformed into 2,6-dichloro-5-methoxypyrimidine-4-carboxaldehyde (XXI) by means of ozone treatment, for example, in a mixture of dichloromethane solvent: methanol (reaction n). 2,6-Dichloro-5-methoxypimimidine-4-carboxaldehyde (XXI) can be transformed into methyl 2,6-dichloro-5-methoxypyrimidine-4-carboxylate (XXII) through treatment with bromine, for example, in a mixture of methanol solvent: water (reaction o). Methyl 2,6-dichloro-5-methoxypyrimidine-4-carboxylate (XXII) can be converted to methyl 6-amino-2-chloro-5-methoxypyrimidine-4-carboxylate (XXIII) by means of treatment with ammonia (by example, 2 equivalents) in a solvent, such as DMSO (reaction p). Finally, the 6-amino-2-substituted-5-methoxypyrimidine-4-carboxylates of Formula (1D), where Ar is as defined here, can be prepared by coupling Suzuki with an ester or boronic acid, with 6- amino-2-chloro-5-methoxypyrimidine-4-carboxylate (XXIII), in the presence of a base, such as potassium fluoride, and a catalyst, such as bis (triphenylphosphine) -palladium (ll) dichloride, in a mixture of protic, polar solvent, such as acetonitrile-water, at a temperature, such as 110 ° C, for example, in a microwave reactor (reaction at 5 ° C). Scheme V
    [0159] [000159] The compounds of Formulas l-A, l-B, l-C, and l-D obtained by any of these processes, can be recovered by conventional methods and purified by standard procedures, such as by recrystallization or chromatography. The compounds of Formula (I) can be prepared from compounds of Formulas l-A, l-B, l-C, and l-D using standard methods well known in the art. COMPOSITIONS and METHODS
    [0160] [000160] In some embodiments, the compounds provided here are used in mixtures containing an herbicidally effective amount of the compound together with at least one agriculturally acceptable vehicle or adjuvant. Exemplary vehicles or adjuvants include those that are not phytotoxic or significantly phytotoxic to valuable crops, for example, in the concentrations used in application to compositions for selective weed control in the presence of crops, and / or do not react or significantly react chemically with the compounds provided here or other composition ingredients. Such mixtures can be intended for application directly to weeds or their loci or they can be concentrated or formulations that are diluted with adjuvants and additional vehicles before application. They can be solid, such as, for example, powders, granules, water-dispersible granules, or wetting powders, or liquids, such as emulsifiable concentrates, solutions, emulsions or suspensions. They can also be supplied as a premix or tank mix.
    [0161] [000161] Agriculturally suitable vehicles or adjuvants that are useful in preparing the herbicidal mixtures of the description are well known to those skilled in the art. Some of these adjuvants include, but are not limited to, culture oil concentrate (mineral oil (85%) + emulsifiers (15%)); ethoxylated nonylphenol; benzylcocoalkylimethyl quaternary ammonium salt; mixture of petroleum hydrocarbon, alkyl esters, organic acid, and anionic surfactant; C9-C11 alkyl polyglycoside; phosphated alcohol ethoxylate; natural primary alcohol ethoxylate (C 12 -C 16 ); di-sec-butylphenol EO-PO block copolymer; polysiloxane-methyl coating; ethoxylated nonylphenol + ammonium urea nitride; emulsified methylated seed oil; tridecyl alcohol ethoxylate (synthetic) (8EO); tallow amine ethoxylate (15 EO); PEG (400) dioleate-99.
    [0162] [000162] Liquid vehicles that can be used include water and organic solvents. Organic solvents typically employed 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, flax seed 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-ethylhexyl stearate, n- butyl oleate, isopropyl myristate, propylene glycol dioleate, di-octyl succinate, adipate di-butyl, di-octyl phthalate and the like; esters of mono-, di- and poly-carboxylic 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 monomethyl ether diethylene glycol, methyl alcohol, ethyl alcohol, isopropyl alcohol, amyl alcohol, ethylene glycol, propylene glycol, glycerin, N-methyl-2-pyrrolidinone, N, N-dimethyl alkylamides, dimethyl sulfoxide, liquid fertilizers, and the like. In some embodiments, water is the vehicle for diluting concentrates.
    [0163] [000163] Suitable solid vehicles include talc, pyrophyllite clay, silica, atapulgo clay, kaolin clay, diatomite, chalk, diatomaceous earth, lime, calcium carbonate, bentonite clay, Fuller earth , cotton seed husk , wheat flour, soy flour, pumice stone, wood powder, nutshell flour, lignin, and the like.
    [0164] [000164] In some embodiments, one or more surfactants are used in the compositions of the present description. Such surfactants are, in some embodiments, used in both solid and liquid compositions, for example, those intended to be diluted with a vehicle before application. Surfactants can be anionic, cationic or non-ionic in nature and can be used as emulsifying agents, wetting agents, suspending agents, or for other purposes. Surfactants conventionally employed in the formulation technique and which can also be employed in the present formulations are described, among others, in McCutcheon's Detergents and Emulsifiers Annual, MC Publishing Corp., Ridgewood, New Jersey, 1998, and in Encyclopedia of Surfactants, Vol. I-III, Chemical Publishing Co., New York, 1980-81. Typical surfactants include salts of alkyl sulfates, such as lauryl sulfate diethanolammonium; alkylarylsulfonate salts, such as calcium dodecylbenzenesulfonate; alkylphenol-alkylene oxide addition products, such as ethoxylated non-phenol-C18; alcohol-alkylene oxide addition products, such as ethoxylated C16 tridecyl alcohol; soap, such as sodium stearate; alkylnaphthalene sulfonate salts, such as sodium dibutylnaphthalenesulfonate; dialkyl sulfosuccinate salts, such as sodium di (2-ethylhexyl) sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as trimethylammonium lauryl chloride; fatty acids from polyethylene glycol esters, such as polyethylene glycol stearate; blocking copolymers of ethylene oxide and propylene oxide; salts of mono- and dialkyl phosphate esters; seed or vegetable oils such as soybean oil, rapeseed / canola oil, olive oil, castor oil, sunflower seed oil, coconut oil, corn oil, cottonseed oil, flax seed oil , palm oil, peanut oil, safflower oil, sesame oil, tung oil and the like; and esters of the above vegetable oils, for example, methyl esters.
    [0165] [000165] Sometimes, some of these materials, such as seed or vegetable oils and their esters, can be used interchangeably as an agricultural adjuvant, as a liquid vehicle or as a surfactant.
    [0166] [000166] Other adjuvants commonly used in agricultural compositions include compatibilizing agents, antifoaming agents, sequestering agents, neutralizing agents and buffers, corrosion inhibitors, dyes, odorants, blowing agents, penetration aids, adhesion agents, dispersing agents , thickening agents, freezing point reducers, 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 or solid fertilizers, particulate fertilizer vehicles such as ammonium nitrate, urea and the like .
    [0167] [000167] The concentration of the active ingredients in the herbicidal compositions of this invention is generally from about 0.001 to about 98 weight percent. Concentrations of about 0.01 to about 90 weight percent are often employed. In compositions designed to be employed as concentrates, the active ingredient is generally present in a concentration of about 5 to about 98 weight percent, preferably about 10 to about 90 weight percent. Such compositions are typically diluted with an inert carrier, such as water, before application. The diluted compositions normally applied to weeds or weed loci generally contain about 0.0001 to about 1 weight percent active ingredient and preferably contain about 0.001 to about 0.05 weight percent.
    [0168] [000168] The present compositions can be applied to weeds or their loci by the use of conventional grinding or aerial sprinklers, vaporizers, and granule applicators, by the addition to irrigation or running water, and by other conventional methods known to those skilled in the art. technical.
    [0169] [000169] In some embodiments, the compounds and compositions described here are applied as a post-emergence application, pre-emergence application, water application to flooded flooded rice or bodies of water (for example, tanks, lakes and streams), or management application.
    [0170] [000170] In some embodiments, the compounds and compositions provided here are used to control weeds in crops, including but not limited to citrus, apple, rubber, oil, palm, forestry, sown directly, sown by water and planted rice, wheat , barley, oats, rye, sorghum, maize (corn) / maize (maize), pasture, pasture, pasture, fallowland, peat, tree and vine orchards, aquatic, or series harvests, as well as non harvesting facilities, for example, industrial vegetation control (IVM) or rights of way. In some embodiments, compounds and compositions are used to control woody, leafy plants and grass weeds, or weeds.
    [0171] [000171] In some embodiments, the compounds and compositions provided here are used to control undesirable vegetation in rice. In certain embodiments, the undesirable vegetation is Brachiaria platyphylla (Groseb.) Nash ( broadleaf signalgrass, BRAPP), Digitaria sanguinalis (L.) Scop. (large vegetable grass, DIGSA), Echinocloa crus-gali (L.) P. Beauv. (rice grass, ECHCG), Echinocloa colonum (L.) LINK (junglerice, ECHCO), Echinocloa orizoides (Ard.) Fritsch (early morning, ECHOR), Echinocloa orizicola (Vasinger) Vasinger (late morning, ECHPH), Ischaemum rugosum Salisbury. ( saramollagrass, ISCRU), Leptocloa chinensis (L.) Nees (Chinese Sprangletop, LEFCH), Leptocloa fascicularis (Lam.) Gray ( bearded sprangletop, LEFFA), Leptocloa panicoides (Presl.) Hitchc. ( Amazon sprangletop, LEFPA), Panicum dichotomiflorum (L.) Michx. (fall panicum, PANDI), Paspalum dilatatum Poir. (dalisgrass, PASDI), Ciperus difformis L. (small flower flat junction, CIPDI), Ciperus esculentus L. (yellow sedge, CIPES), Ciperus would L. (flat rice junction, CIPIR), Ciperus rotundus L. ( junction of purple rice, CIPRO), Eleocharis species (ELOSS), Fimbristyiis miliacea (L.) Vahl (globe fringerush, FIMMI), Schoenoplectus juncoides Roxb. (Japanese Junco, SCPJU), Schoenoplectus maritimus L. (sea clubrush, SCPMA), Schoenoplectus mucronatus L. (rice field bulrush , SCPMU), Aeschynomene species, (jointvetch , AESSS), Alternanthera philoxeroides (Mart.) Griseb. (avocado seed, ALRPH), Alisma plantago-aquatica L. (common nanica banana, ALSPA), Amaranthus species , (anserines and amaranths, AMASS), Ammannia coccinea Rottb. (redstem, AMMCO), Eclipta alba (L.) Hassk. (American false mark, ECLAL), Heteranthera limosa (SW.) Willd./Vahl ( ducksalad , HETLI), Heteranthera reniformis R. & P. (roundleaf mud plantain, HETRE), Ipomoea hederacea (L.) Jacq. (ipomea ivy leaf, IPOHE), Lindernia dubia (L.) Pennell (low false anagalide, LIDDU), Monochoria korsakowii Regel & Maack (monochoria, MOOKA), Monochoria vaginalis (Burm. F.) C. Presl ex Kuhth ( monochoria , MOOVA), Murdannia nudiflora (L.) Brenan (doveweed, MUDNU), Polygonum pensylvanicum L. (Pennsylvania smartweed, POLPY), Polygonum persicaria L. ( ladysthumb, POLPE), Polygonum hidropiperoides Michx. (mild smartweed, POLHP), Rotala indica (Willd.) Koehne (Indian toothcup, ROTIN), Sagittaria species, (arrowhead, SAGSS), Sesbania exaltata (Raf.) Cori / Rydb. Ex Hill (sesbania hemp, SEBEX), or Sfenoclea zeylanica Gaertn. (gooseweed, SPDZE).
    [0172] [000172] In some embodiments, the compounds and compositions provided here are used to control undesirable vegetation on cereals. In certain embodiments, the undesirable vegetation is Alopecurus myosuroides Huds. ( blackgrass, ALOMY), Apera spica-venti (L.) Beauv. ( windgrass, APESV), Avena fatua L. (wild oats, AVEFA), Bromus tectorum L. (downy barley grass, BROTE), Lolium multiflorum Lam. (Italian ryegrass, LOLMU), Phalaris minor Retz. (birdseed, FAMI), Poa annua L. (field grass, POAAN), Setaria pumila (Poir.) Roemer & JA Schultes (yellow fox tail, SETLU), Setaria viridis (L.) Beauv. (green fox tail, SETVI), Cirsium arvense (L.) Scop. (Canadian thistle, CIRAR ), Galium aparine L. ( catchweed bedstraw, GALAP), Kochia scoparia (L.) Schrad. (kochia, KCHSC), Lamium purpureum L. ( purple deadnettle, LAMPU), Matricaria recutita L. (wild chamomile, MATCH), Matricaria matricarioides (Less.) Porter (pineapple weed, MATMT), Papaver rhoeas L. (poppy common, PAPRH), Polygonum convolvulus L. (wild buckwheat, POLCO), Salsola tragus L. (Russian thistle, SASKR), Stellaria media (L.) Vill. (common chickweed, STEME), Veronica persica Poir. (Persian speedwell, VERPE), Viola arvensis Murr. (field violet, VIOAR), or Viola tricolor L. (wild violet, VIOTR).
    [0173] [000173] In some embodiments, the compounds and compositions provided here are used to control undesirable vegetation in natural pasture and pasture. In certain modalities, the undesirable vegetation is Ambrosia artemisiifolia L. (common American ambrosia, AMBEL), Cassia obtusifolia (sickle pod, CASOB), Centaurea maculosa auct. non Lam. ( spotted knapweed, CENMA), Cirsium arvense (L.) Scop. (Canadian thistle, CIRAR), Convolvulus arvensis L. (morning glory, CONAR), Euphorbia esula L. (leafy euphorbia, EPHES), Lactuca serriola L./Torn. (prickly lettuce, LACSE), Plantago lanceolata L. (goat horn plantain, PLALA), Rumex obtusifolius L. (broadleaf dock, RUMOB), Sida spinosa L. (guanxuma, SIDSP), Sinapis arvensis L. (wild mustard, SINAR ), Sonchus arvensis L. ( perennial sowtistle, SONAR), Solid ago (goldenrod, SOOSS), Taraxacum officinale GH Weber ex Wiggers (dandelion, TAROF), Trifolium repens L. (white clover, TRFRE), or Urtica dioica L. (common nettle, URTDI).
    [0174] [000174] In some embodiments, the compounds and compositions provided here are used to control undesirable vegetation found in row crops. In certain embodiments, the undesirable vegetation is Alopecurus myosuroides Huds. ( blackgrass, ALOMY), Avena fatua L. (wild oats, AVEFA), Brachiaria platyphylla (Groseb.) Nash ( broadleaf signalgrass, BRAPP), Digitaria sanguinalis (L.) Scop. (large vegetable grass, DIGSA), Echinocloa crus-gali (L.) P. Beauv. (rice grass, ECHCG), Echinocloa colonum (L.) Link (junglerice, ECHCO), Lolium multiflorum Lam. (Italian ryegrass, LOLMU), Panicum dichotomiflorum Michx. ( fall panicum, PANDI), Panicum miliaceum L. (wild-proso millet, PANMI), Setaria faberi Herrm. (giant foxtail, SETFA), Setaria viridis (L.) Beauv. (green fox tail, SETVI), Sorghum halepense (L.) Pers. {Johnsongrass, SORHA), Sorghum bicolor (L.) Moench ssp. Arundinaceum (shattercane, SORVU), Ciperus esculentus L. (yellow sedge, CIPES), Ciperus rotundus L. (purple rice joint, CIPRO), Abutilon theophrasti Medik. ( velvetleaf, ABUTH), Amaranthus species (anserines and amaranths, AMASS), Ambrosia artemisiifolia L. (common American ambrosia, AMBEL), Ambrosia psilostachya DC. (western American ambrosia, AMBPS), Ambrosia trifida L. (giant ragweed, AMBTR), Asclepias syriaca L. (common asclépia, ASCSY), Chenopodium album L. ( common Anserinas, CHEAL), Cirsium arvense (L.) Scop. (Canadian thistle, CIRAR), Commelina benghalensis L. ( tropical spiderwort, COMBE), Datura stramonium L. ( jimsonweed, DATST), Daucus carota L. (wild carrot, DAUCA), Euphorbia heterophylla L. ( wild poinsettia, EPHHL) , Erigeron bonariensis L. (Fleabane hairy, ERIBO), Erigeron canadensis L. (Canadian fleabane , ERICA), Helianthus annuus L. (common sunflower, HELAN), Jacquemontia tamnifolia (L.) Griseb. (small flower ipomea, IAQTA), Ipomoea hederacea (L.) Jacq. (ipomea ivy leaf, IPOHE), Ipomoea lacunosa L. (white ipomea, IPOLA), Lactuca serriola L./Torn. (prickly lettuce, LACSE), Portulaca oleracea L. (common purslane, POROL), Sida spinosa L. (guanxuma, SIDSP), Sinapis arvensis L. (wild mustard, SIN AR), Solanum ptychanthum Dunal (eastern blackberry, SOLPT) , or Xantium strumarium L. (common thistle, XANST).
    [0175] [000175] In some modalities, application rates of about 1 to about 4,000 grams / hectare (g / ha) are used in post-emergency operations. In some modalities, rates of about 1 to about 4,000 g / ha are used in pre-emergency operations.
    [0176] [000176] In some embodiments, the compounds, compositions, and methods provided here are used in conjunction with one or more other herbicides to control a wider variety of undesirable vegetation. When used in conjunction with other herbicides, the compounds presently claimed may 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: choline salt 4-CPA, 4-CPB, 4-CPP, 2-D, 2,4-D, 2,4-D esters and amines, 2,4-DB, 3,4-DA, 3,4-DB, 2,4-DEB, 2,4-DEP, 3,4-DP, 2,3,6-TBA, 2,4, 5-T, 2,4,5-TB, acetochlor, acifluorfen, aclonifene, acrolein, alachlor, alidochlor, aloxidim, allyl alcohol, alorac, ametridione, ametrine, amibuzin, amicarbazone, amidosulfurone, aminocyclopyrachlor, aminopyroside, amitropyrine, amiprofol-methyme , ammonium sulfamate, anilophos, anisuron, asulam, atraton, atrazine, azafenidin, azimsulfurone, aziprotrine, barban, BCPC, beflubutamide, benazoline, bencarbazone, benfluralin, benfuresate, bensulfuron-methyl, benzene, benzene, benzene, benzene, benzene , benzipram, benzobicyclon, benzofenape, benzofluor, benzoilprope, benztiazuron, bicyclopyrone, bifenox, bilanafos, bispiribac-sodium, borax, bromacila, bromobonil, bromobutide, bromophenoxim, bromoxynil, butromyron, bromoxyl, butromyron a, butamifos, butenachlor, butidazole, butiuron, butralin, butroxidim, buturon, butylate, cacodylic acid, cafenstrol, calcium chlorate, calcium cyanamide, cambendichlor, carbasulam, carbetamide, carboxazole, chlorprocarb, carfentrazone-CEP, CDF, clone, ethyl chloride , chlorambene, chloranocrila, chlorazifope, chlorazine, chlorobromuron, chlororbam, chloreturon, chlorfenac, chlorfenprope, chlorflurazole, chlorflurenol, chloridazon, chlorimuron, chlorornitrophen, chloropon, chlorotoluron, chloroxuron, chloroxin, chloroxin, chloroxin, chloroxin , cinosulfurone, cisanilide, cletodim, cliodinate, clodinafop-propargyl, clofope, clomazone, clomeprope, cloprope, cloproxidim, clopyralide, chloransulam-methyl, CMA, copper sulphate, CPMF, CPPC, credazine, cyrol, cumiluron, cyclic, cumiluron , ciclosulfamuron, cicloxidim, cicluron, cihalofope-butila, cyperquat, cyprazine, cyprazole, cypromide, daimuron, dalapon, dazomet, delaclor, demedifam, demetrina, di-alate, dicamba, dichlobenyl, dichloralurea, dichlormate, dichlorprope, dichlorprope-P, diclofope, diclosulam, dietamquat, diethyl, diphenopenten, diphenoxuron, difenzoquat, diflufenican, diflufenzopyr, dimethoxy, dimethoxy, dimethoxy, dimethoxy, dimethoxy, dimethoxy, dimethoxy, dimethoxy, dimethoxy, dimethoxy, dimethoxy, dimethyl, dimetho- dimexane, dimidazon, dinitramine, dinofenate, dinoprope, dinosam, dinoseb, dinoterb, diphenamide, dipropetrine, diquat, disul, dithiopir, diuron, DMPA, DNOC, DSMA, EBEP, eglinazine, endotal, epronaz, EPTC, erbonal, esprural, esprural, etbenzamide, etametsulfurone, etidimuron, etiolate, etobenzamide, etobenzamide, etofumesate, ethoxyfen, ethoxysulfurone, ethinophene, etnipromide, etobenzanide, EXD, fenasulam, fenprope, phenoxaprope, phenoxaprop-P-ethyl-phenoxyprophape-P-ethyl phenteracol, fentiaprope, fentrazamide, fenurone, ferrous sulfate, flamprope, flamprope-M, flazasulfurone, florasulam, fluazifope, fluazifop-P-butyl, fluazolate, flucarbazone, flucethosulfurone, fluclo ralin, flufenacete, flufenican, flufenpir-ethyl, flumetsulam, flumezin, flumiclorac-pentila, flumioxazin, flumipropin, fluometuron, fluorodiphen, fluoroglycofen, fluoromidine, fluoronitrophen, fluotiururon, fluorone, fluorone, fluorone, fluorone fluthiacet, fomesafen, foramsulfurone, phosamine, furyloxifene, glufosinate, glufosinate-ammonium, glyphosate, halosafen, halosulfuron-methyl, haloxidine, haloxifop-methyl, haloxipop-P-methyl, halauxifene-methyl, hexachlorametone, hexachlorametone, hexachloroacetone imazapic, imazapyr, imazaquin, imazetapyr, imazosulfurone, indanofan, indaziflam, iodobonyl, iodomethane, iodosulfurone, iofensulfurone, ioxynyl, ipazine, ipfencarbazone, iprimidate, isocarbon, iso, isotonic, isocyl, isocyl, isocyl, isocyl, isocyl, isocyl, isocyl, isocyl, isocyl, isocyl, isocyl, iso isoxaflutol, isoxapyrifope, carbutylate, ketoespiradox, lactophen, lenacil, linuron, MAA, MAM A, MCPA, esters and amines, MCPA-thioethyl, MCPB, mecoprope, mecoprope-P, medinoterb, mefenacet, mefluidide, mesoprazine, mesosulfurone, mesotrione, metam, metamiphope, metamitron, metazachlor, metazosulfurone, metflurzon, metflurzon, metzurazone, metflurazon, methiobencarb, methiozoline, methuron, metometon, metoprotrin, methyl bromide, methyl isothiocyanate, methyldimron, metobenzuron, metobromuron, metolachlor, metosulam, methoxyuron, metribuzin, metsulfurone, molinate, monalon, monalon, monalon, monalon , naproanilide, napropamide, napropamide-M, naptalam, neburon, nicosulfurone, nipyraclofen, nitralin, nitrophen, nitrofluorphene, norflurazon, noruron, OCH, orbencarbe, ortho-dichlorobenzene, orthosulfamuron, oxorzone, oxorzone, oxizone , paraflufen-ethyl, parafluron, paraquat, pebulate, pelargonic acid, pendimethalin, penoxsulam, pentachlorophenol, pentanochlor, pentox azone, perfluidone, petoxamide, fenisofam, fenmedifam, fenmedifam-ethyl, fenobenzuron, phenylmercury acetate, picloram, picolinafen, pinoxaden, piperophos, potassium arsenite, potassium azide, potassium cyanate, prurylamine, procylamine, priamylamine, priamylamine, priamylamine profluazole, profluralin, profoxidim, proglinazine, proexadione-calcium, prometon, promethin, propachlor, propanyl, propaquizafope, propazine, profam, propisochlor, propoxycarbazone, propyrisulfurone, propamide, prosulfaline, prosulfocar, pyridine, pyridine, pyrinamine, proxanhydrone, pyrinone pirasulfotol, pyrazogyl, pyrazolinate, pyrazosulfuron-ethyl, pyrazoxifene, pyribenzoxim, pyributicarb, pyrichloride, pyridafol, pyridate, pyriftalide, piriminobac, pyrimisulfan, piritiobac-methyl, pyroxsulfone, pyroxsulam, quincalac, quincalac, quincalac, quincalac, quincalac, quincalac, quincalac, quincalam ethyl, rhodetanil, rimsulfurone, saflufenacil, S-metolachlor, sebutilazine, secbumeton, setoxidim, siduro n, simazine, simeton, symmetrine, SMA, sodium arsenite, sodium azide, sodium chlorate, sulcotrione, sulfalate, sulfentrazone, sulfometuron, sulfosate, sulfosulfurone, sulfuric acid, sulglicapin, swep, TCA, tebutam, tebutiuron, tefuriliona , tepraloxidim, terbacil, terbucarb, terbuclor, terbumeton, terbuthylazine, terbutrin, tetrafluron, tenil chlor, tiazafluron, tiazopir, tidiazimin, tidiazuron, tiencarbazone-methyl, tifensulfurone, thiobazimide, thiobazamide, triasulfurone, triaziflam, tribenuron, tricamba, esters of triclopyr and amines, tridifan, trietazine, trifloxysulfurone, trifluralin, triflusulfurone, tryptophan, trihydroxytriazine, trimeturon, tripropindan, trpropindan, trpropyl, tritinite, trpropyl and tritone
    [0177] [000177] The compounds and compositions of the present invention can generally be used in combination with known herbicidal protectors, such as benoxacor, bentiocarb, brassinolide, cloquintocet (for example, mexila), ciometrinyl, daimuron, dichlormide, diciclonon, dimepiperate, disulfoton, fenclorazol -ethyl, fenclorim, flurazole, fluxofenim, furilazol, harpina proteins, isoxadifen-ethyl, mefenpir-dietila, MG 191, MON 4660, naphthalic anhydride (NA), oxabetrinil, R29148 and N-phenylsulfonylbenzoic acid amides, to enhance your selectivity.
    [0178] [000178] The compounds, compositions, and methods described here can be used to control undesirable vegetation in crops tolerant to glyphosate, tolerant to glufosinate, tolerant to dicamba, tolerant to phenoxy auxin, tolerant to pyridyloxy auxin, tolerant to aryloxyphenoxypropionate, tolerant to inhibitor acetyl CoA carboxylase (ACCase), tolerant to imidazolinone, tolerant to acetolactate synthase inhibitor (ALS), tolerant to 4-hydroxyphenyl-pyruvate dioxigenase (HPPD) inhibitor, tolerant to protoporphyrinogen oxidase (PPO) inhibitor, tolerant to triazine, and tolerant to bromoxynil (such as, but not limited to, soy, cotton, canola / rapeseed, rice, cereals, corn, peat, etc.), for example, in conjunction with glyphosate, glufosinate, dicamba, phenoxy auxins, pyridyloxy auxins, aryloxyphenoxypropionates, ACCase inhibitors, imidazolinones, ALS inhibitors, HPPD inhibitors, PPO inhibitors, triazines, and bromoxynil. The compositions and methods can be used to control undesirable vegetation in crops that have multiple or combined characteristics that confer tolerance to multiple chemicals and / or inhibitors of multiple modes of action.
    [0179] [000179] The compounds and compositions provided here can also be used to control herbicide resistant or tolerant weeds. Examples of resistant or tolerant weeds include, but are not limited to, biotype resistant or tolerant to acetolactate synthase (ALS) inhibitors, photosystem II inhibitors, acetyl CoA carboxylase (ACCase) inhibitors, synthetic auxins, photosystem I inhibitors, 5- enolpyruvylchiquimate-3-phosphate (EPSP) synthase inhibitors, microtubule assembly inhibitors, lipid synthesis inhibitors, photoporphyrinogen oxidase (PPO) inhibitors, carotenoid biosynthesis inhibitors, very long chain fatty acid inhibitors (VLCFA ), phytoene desaturase (PDS) inhibitors, glutamine synthetase inhibitors, 4-hydroxyphenyl-pyruvate-dioxigenase (HPPD) inhibitors, mitosis inhibitors, cellulose biosynthesis inhibitors, herbicides with multiple modes of action such as quinclorac, and herbicides not classified such as arylaminopropionic acids, difenzoquat, endotall, and organoarsenic acids. Examples of resistant or tolerant weeds include, but are not limited to, biotypes with resistance or tolerance to multiple herbicides, multiple chemical classes, and multiple modes of herbicide action.
    [0180] [000180] The described modalities and the following examples are for illustrative purposes and are not intended to limit the scope of the claims. Other modifications, uses, or combinations with respect to the compositions described here will be evident to a person skilled in the art without departing from the spirit and scope of the claimed object matter. SYNTHESIS OF PRECURSORSPreparation 1: Methyl 4-amino-3,6-dichloropicolinate (Title A)
    [0181] [000181] Prepared as described in Fields and other (s), WO 2001051468 A1. Preparation 2: Methyl 4-amino-3,6-dichloro-5-fluoropicolinate (Title B)
    [0182] [000182] Prepared as described in Fields and other (s), Tetrahedron Letters 2010, 51, 79-81. Preparation 3: 2,6-Dichloro-5-methoxy-4-vinyl pyrimidine
    [0183] [000183] To a solution of commercially available 2,6-dichloro-5-methoxy pyrimidine (100 grams (g), 0.55 moles (mol)) in dry tetrahydrofuran was added, dropwise, 1 molar (M) of vinyl magnesium bromide in tetrahydrofuran solvent (124 g, 0.94 mol) for one hour (h) at room temperature. The mixture was then stirred for 4 hours at room temperature. Excess of Grignard's reagent was quenched by the addition of acetone (200 milliliters (mL)) at the same time that the temperature of the mixture was maintained at a temperature below 20 ° C. Thereafter, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ; 151 g, 0.67 mol) was added at once and stirred overnight. A yellow solid precipitated. The solid was filtered and washed with ethyl acetate (500 ml). The filtrate was concentrated under reduced pressure and the resulting crude compound was diluted with ethyl acetate (2 liters (L)). The resulting dark, undissolved semisolid was filtered off using ethyl acetate. It was also concentrated under reduced pressure to provide a crude compound, which was purified by column chromatography. The compound was eluted with 5% to 10% ethyl acetate in a hexane mixture to provide the title compound (70 g, 60%): melting point 60 to 61 ° C; 1 H NMR (CDCI 3 ) δ 3.99 (s, 3H), 5.85 (d, 1H), 6.75 (d, 1H), 6.95 (dd, 1H). Preparation 4: 2,6-Dichloro-5-methoxy-pyrimidine-4-carbaldehyde
    [0184] [000184] A solution of 2,6-dichloro-5-methoxy-4-vinyl pyrimidine (50 g, 0.24 mol) in dichloromethane: methanol (4: 1, 2L) was cooled to -78 ° C. Ozone gas was bubbled through it for 5 h. The reaction was quenched with dimethyl sulfide (50 mL). The mixture was slowly warmed to room temperature and concentrated under reduced pressure at 40 ° C to provide the title compound (50.5 g, 100%); high performance liquid chromatography (HPLC; 85% acetonitrile buffered with 0.1% volume by volume (v / v) of acetic acid). Preparation 5: methyl 2,6-dichloro-5-methoxy-pyrimidine-4-carboxylate
    [0185] [000185] A solution of 2,6-dichloro-5-methoxy-pyrimidine-4-carbaldehyde (50 g, 0.24 mol) in methanol (1 L) and water (60 ml) was prepared. To the solution, sodium bicarbonate (400 g) was added. 2 M bromine solution (192 g, 1.2 mol) in methanol / water (600 mL, 9: 1) was added dropwise to the pyrimidine solution over 45 minutes (min) at 0 o C while stirring the mixture. Stirring was continued at the same temperature for 1 hour. Later, the mixture was stirred at room temperature for 4 hours. While stirring, the reaction mixture was thereafter poured into a mixture of crushed ice (2 L), sodium disulfide (50 g), and sodium chloride (NaCI; 200 g). The product was extracted with ethyl acetate (1 L x 2), and the combined organic layer was dried over sodium sulfate and filtered. Evaporation of the solvent under reduced pressure produced a coarse material, which solidified on long standing to provide the title compound (50.8 g, 87%); ESIMS m / z 238 ([M + H] + ). Preparation 6: Methyl 6-amino-2-chloro-5-methoxy-pyrimidine-4-carboxylate (Title C)
    [0186] [000186] A solution of 2,6-dichloro-5-methoxy-pyrimidine-4-carboxylate (25 g, 0.1 mol) and dimethyl sulfoxide (DMSO) was prepared. To this solution, at 0 to 5 ° C, a solution of ammonia (2 eq) in DMSO was added. This mixture was stirred at the same temperature 0 to 5 ° C for 10 to 15 minutes. Later, the mixture was diluted with ethyl acetate, and the resulting solid was filtered. The ethyl acetate filtrate was washed with a brine solution and dried over sodium sulfate. At concentration, the crude product was obtained. The crude product was stirred in a minimum amount of ethyl acetate and filtered to obtain the pure compound. The additional pure compound was obtained from the filtrate which, after concentration, was purified by flash chromatography. This produced the title compound (11 g, 50%): melting point 158 ° C; 1 H NMR (DMSO- d 6 ) δ 3.71 (s, 3H), 3.86 (s, 3H), 7.65 (br s, 1H), 8.01 (br s, 1H). Preparation 7: Methyl 4-amino-3,6-dichloro-5-iodopicolinate
    [0187] [000187] Methyl 4-amino-3,6-dichloropicolinate (10.0 g, 45.2 millimoles (mmol)), periodic acid (3.93 g, 17.2 mmol), and iodine (11.44 g , 45.1 mmol) were dissolved in methanol (30 mL) and stirred at reflux at 60 ° C for 27 hours. The reaction mixture was concentrated, diluted with diethyl ether, and washed twice with saturated aqueous sodium disulfide. The aqueous layers were extracted once with diethyl ether, and the combined organic layers were dried over anhydrous sodium sulfate. The product was concentrated and purified by flash chromatography (silica gel, 0-50% ethyl acetate / hexanes) to provide the title compound as a light yellow solid (12.44 g, 79%): melting point 130 , 0 to 131.5 ° C; 1 H NMR (400 MHz, CDCI 3 ) δ 5.56 (s, 2H), 3.97 (s, 3H); 13 C NMR (101 MHz, CDCI 3 ) δ 163.80, 153.00, 152.75, 145.63, 112.12, 83.91, 53.21; EIMS m / z 346. Preparation 8: Methyl 4-amino-3,6-dichloro-5-methylpicolinate (Title D)
    [0188] [000188] A mixture of methyl 4-amino-3,6-dichloro-5-iodopicolinate (8.1 g, 23.4 mmol), tetramethyl stannane (8.35 g, 46.7 mmol), and bis chloride (triphenylphosphine) palladium (ll) (2.5 g, 3.5 mmol) in 1,2-dichloroethane (40 mL) was irradiated in a Biotage Initiator microwave at 120 ° C for 30 minutes, with temperature monitoring by external infrared (IR) sensor on the side. The reaction mixture was loaded directly onto a silica gel cartridge and purified by flash chromatography (silica gel, 0-50% ethyl acetate / hexanes) to afford the title compound as an orange solid (4.53 g, 83%): melting point 133 to 136 ° C; 1 H NMR (400 MHz, CDCI 3 ) δ 4.92 (s, 2H), 3.96 (s, 3H), 2.29 (s, 3H); 13 C NMR (101 MHz, CDCI 3 ) δ 164.34, 150.24, 148.69, 143.94, 117.01, 114.60, 53.02, 14.40; ESIMS m / z 236 ([M + H] + ), 234 ([MH] -). Preparation 9: Methyl 6-amino-2,5-dichloropyrimidine-4-carboxylate (Title E)
    [0189] [000189] Prepared as described in Epp and other (s), WO 2007082076 A1. Preparation 10: Methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (Title F)
    [0190] [000190] Prepared as described in Epp and other (s), WO 2013003740 A1. Preparation 11: Methyl 4-amino-6-chloro-5-fluoro-3-vinylpicolinate (Title G)
    [0191] [000191] 4-amino-6-chloro-5-fluoro-3-methyl iodopicolinato (7.05 g, 21.33 mmol, prepared as described in Epp and the other (s), WO 2013003740 A1) and n viniltri- butyl tin (7.52 ml, 25.6 mmol) were suspended in 1,2-dichloroethane (71.1 ml) and the mixture was degassed with argon for 10 minutes. Bis (triphenylphosphine) palladium (ll) chloride (1.497 g, 2.133 mmol) was then added and the reaction mixture was stirred at 70 ° C overnight (light orange solution). The reaction was monitored by gas chromatography-mass spectrometry (GC-MS). After 20 hours, the reaction mixture was concentrated, adsorbed on Celite, and purified by column chromatography (SiO 2 ; hexanes / ethyl acetate gradient) to provide the title compound as a light brown solid (3.23 g, 65 , 7%): melting point 99 at 100 ° C; 1 H NMR (400 MHz, CDCI 3 ) δ 6.87 (dd, J = 18.1, 11.6 Hz, 1H), 5.72 (dd, J = 11.5, 1.3 Hz, 1H) , 5.52 (dd, J = 18.2, 1.3 Hz, 1H), 4.79 (s, 2H), 3.91 (s, 3H); 19 F NMR (376 MHz, CDCI 3 ) δ -138.79 (s); EIMS m / z 230. Preparation 12: Methyl 4-amino-3,5,6-trichloropicolinate (Title H)
    [0192] [000192] Prepared as described in Finkelstein and other (s), WO 2006062979 A1. Preparation 13: Methyl 4-amino-6-bromo-3-chloro-5-fluoropicolinate (Title I)
    [0193] [000193] Prepared as described in Arndt and other (s), US 20120190857 A1. Preparation 14: 4-amino-3-chloro-5-fluoro-6- (trimethylstannyl) methyl picolinate (Title J)
    [0194] [000194] Methyl 4-amino-6-bromo-3-chloro-5-fluoropicolinate (500 mg, 1.8 mmol), 1,1,1,2,2,2-hexamethyldiestanane (580 mg, 1.8 mmol) and bis (triphenylphosphine)-palladium (ll) chloride (120 mg, 0.18 mmol) were combined in dry dioxane (6 mL), sprayed with a stream of nitrogen for 10 minutes and then heated to 80 ° C for 2 hours. The cooled mixture was stirred with ethyl acetate (25 ml) and saturated NaCl (25 ml) for 15 minutes. The organic phase was separated, filtered through diatomaceous earth, dried (Na 2 SO 4 ) and evaporated. The residue was taken up in ethyl acetate (4 ml), stirred and treated in portions with hexane (15 ml). The milky white solution was decanted from any solids produced, filtered through glass wool and evaporated to provide the title compound as an off-white solid (660 mg, 100%): 1 H NMR (400 MHz, CDCI 3 ) δ 4, 63 (d, J = 29.1 Hz, 1H), 3.97 (s, 2H), 0.39 (s, 4H); 19 F NMR (376 MHz, CDCI 3 ) δ -130.28; EIMS m / z 366. Preparation 15: Methyl 4-acetamido-3-chloro-6- (trimethylstannyl) -picolinate (Title K)
    [0195] [000195] Prepared as described in Balko and other (s), WO 2003011853 A1. Preparation 16: Methyl 4-acetamido-3,6-dichloropicolinate (Title L)
    [0196] [000196] Prepared as described in Fields and other (s), WO 2001051468 A1. Preparation 17: Methyl 4-amino-3-chloro-6-iodopicolinate (Title M)
    [0197] [000197] Prepared as described in Balko and other (s), WO 2007082098 A2. Preparation 18: Methyl 4-acetamido-3-chloro-6-iodopicolinate (Title N)
    [0198] [000198] Prepared as described in Balko and other (s), WO 2007082098 A2. Preparation 19: Methyl 4-amino-6-bromo-3,5-difluoropicolinate (Title O)
    [0199] [000199] Prepared as described in Fields and other (s), WO 2001051468 A1. Preparation 20: Methyl 6-amino-2-chloro-5-vinylpyrimidine-4-carboxylate (Title P)
    [0200] [000200] Prepared as described in Epp and other (s), US20090088322. Preparation 21: 2,2,5-Trifluoro-6-iodobenzo [ d ] [1,3] dioxol
    [0201] [000201] 2,2,6-Trifluorobenzo [ d ] [1,3] dioxol-5-amine (8.0 g, 42 mmol) was added to the concentrated hydrochloric acid (cone HCI; 200 mL), cooled to 5 ° C ° C, stirred vigorously and treated dropwise with a solution of sodium nitrite (4.3 g, 63 mmol) in water (10 mL) over 10 min. Stirring was continued for 30 minutes at 5 to 10 ° C and the mixture was carefully poured into a solution of sodium iodide (19 g, 130 mmol) in water (200 ml), quickly stirred with dichloromethane (100 ml). After 20 minutes, the mixture was treated with 10% sodium bisulfide solution (NaHSO 3 ; 20 ml) and stirred for an additional 20 minutes. The phases were separated and the aqueous phase was extracted with dichloromethane (75 ml). The combined organic phases were washed with saturated NaCl (30 ml), dried (Na 2 SO 4 ) and evaporated. The residue was purified by chromatography on silica with hexane to provide the title compound as a clear liquid (6 g, 51%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.41 (d, J = 5.0 Hz, 1H), 6.90 (d, J = 6.6 Hz, 1H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.63 (s), -95.24 (s); EIMS m / z 302. Preparation 22: 4,4,5,5-Tetramethyl-2- (2,2,6-trifluoroben-zo [ d ] [1,3] dioxol-5-yl) -1,3,2-dioxaborolane
    [0202] [000202] 2,2,5-Trifluoro-6-iodobenzo [ d ] [1,3] dioxol (1.0 g, 3.3 mmol) was dissolved in dry tetrahydrofuran (10 mL), cooled to 5 ° C and treated with isopropylmagnesium chloride-lithium chloride complex solution (1.3 M; 2.7 mL, 3.5 mmol). The mixture was stirred for 1 hour at 5-15 ° C, treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (720 µL, 660 mg, 3.5 mmol) and stirred for 20 min. The reaction was quenched by the addition of saturated ammonium chloride (NH 4 CI; 5 ml) and mixed with ethyl acetate (20 ml) and saturated NaCI (10 ml). The separated organic phase was washed with saturated NaCl (10 ml), dried (Na 2 SO 4 ) and evaporated to provide the title compound as a white solid (1.0 g, 100%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.37 (d, J = 4.3 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 1.35 (s, 12H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.96 (s), -104.21 (s)); EIMS m / z 302. Preparation 23: 2,2,5-Trifluoro-4-iodobenzo [ d ] [1,3] dioxol
    [0203] [000203] Sec-Butyllithium (1.4 M in cyclohexane; 6.1 mL, 8.5 mmol) was added to the dry tetrahydrofuran (15 mL) which was pre-cooled to -40 ° C. The solution was cooled to -75 ° C, treated with 2,2,5-trifluorobenzo [ d ] [1,3] dioxol (1.5 g, 8.5 mmol) and stirred at this temperature for 90 minutes. This solution was quickly transferred via cannula in a stirred solution of iodine (2.8 g, 11 mmol) in tetrahydrofuran (25 mL), and the mixture was cooled to -75 ° C. The mixture was stirred for 1 hour during which time the temperature rose to -20 ° C. The reaction was quenched by the addition of saturated NH4Cl (10 mL) and then combined with 10% NaHSO 3 (15 mL) and ethyl acetate (30 mL). The organic phase was washed with saturated NaCl (10 ml), dried (Na 2 SO 4 ) and evaporated. The material was purified by flash chromatography with hexane to provide the title compound as a clear liquid (1.5 g, 58%): 1 H NMR (400 MHz, CDCI 3 ) δ 6.97 (dd, J = 8, 8, 4.0 Hz, 1H), 6.81 (dd, J = 11.7, 5.4 Hz, 1H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.06, -103.15; EIMS m / z 302. Preparation 24: 5-Bromo-4-chloro-2,2-difluorobenzo [ d ] [1,3] dioxol
    [0204] [000204] 2,2,6,6-Tetramethylpiperidine (2.1 mL, 1.8 g, 12 mmol) was dissolved in dry tetrahydrofuran (15 mL), cooled to -75 ° C and treated with n- butyllithium ( n -BuLi, 2.5 M; 4.8 mL, 12 mmol), and the mixture was stirred for 30 minutes at -75 ° C. 5-Bromo-2,2-difluorobenzo [ d ] [1,3] dioxol (2.0 g, 8.4 mmol) was added, and the mixture was stirred for 2 hours at -75 ° C. 1,1,2-Trichloro-1,2,2-trifluoroethane (2.4 ml, 3.8 g, 20 mmol) was added and stirring was continued for 1.5 hours. Saturated NH 4 Cl (10 ml) was added, and the mixture was stirred with diethyl ether (30 ml) and water (20 ml). The ether phase was washed with saturated NaCl (10 ml), dried (Na 2 SO 4 ) and evaporated in vacuo. The residue was purified by chromatography on silica with hexane and then repurified by reverse phase HPLC using 75% acetonitrile to provide the title compound as a clear liquid (640 mg, 28%): 1 H NMR (400 MHz , CDCI 3 ) δ 7.38 (dd, J = 8.5, 5.1 Hz, 1H), 6.90 (dd, J = 9.0, 4.7 Hz, 1H); EIMS m / z 332. Preparation 25: 2- (4-Chloro-2,2-difluorobenzo [ d ] [1,3] dioxol-5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
    [0205] [000205] 5-Bromo-4-chloro-2,2-difluorobenzo [ d ] [1,3] dioxol (1.0 g, 3.7 mmol) was dissolved in dry tetrahydrofuran (12 mL), cooled to -20 to -30 ° C and treated in portions with isopropylmagnesium chloride-lithium chloride complex solution (1.3 M; 3.1 mL, 4.1 mmol). After 90 minutes at -20 to 0 ° C, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolone (830 µL, 750 mg, 4.1 mmol) was added, and stirring was continued at 0-20 ° C for 90 min. The reaction was quenched by the addition of saturated NH4Cl (10 mL), and the mixture was extracted with ethyl acetate (30 mL). The aqueous phase was extracted again with ethyl acetate (15 ml), and the combined organic phases were washed with saturated NaCl (15 ml), dried (Na 2 SO 4 ) and evaporated to provide the title compound as a white solid ( 1.2 g, ca. 100%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.52 (d, J = 8.1 Hz, 1H), 6.99 - 6.94 (m, 1H) , 1.36 (s, 12H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.62 (s); EIMS m / z 318. Preparation 26: 4-Fluorobenzo [ d ] [1,3] dioxol-2-thione
    [0206] [000206] 3-Fluorobenzene-1,2-diol (5.0 g, 39 mmol) and thiophosgene (3.3 mL, 5.0 g, 42 mmol) were combined in chloroform (50 mL), cooled to 10 ° C and treated dropwise over 30 minutes with sodium hydroxide (10% solution; 36 g, 90 mmol) with vigorous stirring. After stirring for 2 hours at room temperature, the chloroform was removed in vacuo, and the solid formed was collected by filtration and washed with water. The solid was dissolved in ethyl acetate (100 ml), the solution was washed with water (30 ml) and saturated NaCl (30 ml), dried (Na 2 SO 4 ) and evaporated. The crude solid was purified by chromatography on silica with 0 to 30% ethyl acetate-hexane to provide the title compound (1.5 g, 77%): melting point 58 to 59 ° C; 1 H NMR (400 MHz, CDCI 3 ) δ 7.28 (m, 1H), 7.12 (m, 2H); 19 F NMR (376 MHz, CDCI 3 ) δ -131.32; EIMS m / z 170. Preparation 27: 5-Bromo-2,2,4-trifluorobenzo [ d ] [1,3] dioxol
    [0207] [000207] 4-Fluorobenzo [ d ] [1,3] dioxol-2-thione (4.8 g, 28 mmol) was dissolved in dichloromethane (75 mL), cooled to -30 ° C and treated with hydrogen fluoride ( HF) -Pyridine (70 weight percent (% weight) of solution; 18 mL, 20 g, 140 mmol). 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (9.7 g, 34 mmol) was added in portions over 30 min. The mixture was stirred for 2 hours at -20 to -30 ° C and then stirred with 5% NaHSO 3 solution (20 ml) for 10 min. The organic phase was separated, dried (Na 2 SO 4 ), and the dichloromethane was carefully removed by distillation through a 200 mm (mm) Vigreux column at atmospheric pressure. The pressure was reduced to approximately 150 millimeters of mercury (mmHg) when more dichloromethane was taken off. Distillation was continued and the boiling fraction at 45 to 55 ° C was collected to provide the title compound as a clear liquid (3.2 g, 45%): 1 H NMR (400 MHz, CDCI 3 ) δ 7, 28 (dd, J = 8.6, 6.2 Hz, 1H), 6.81 (dd, J = 8.6, 1.3 Hz, 1H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.25 (s), -126.72 (s); ElMS m / z 254. Preparation 28: 4,4,5,5-Tetramethyl-2- (2,2,4-trifluorobenzo [ d ] [1,3] dioxol-5-yl) -1,3,2-dioxaborolane
    [0208] [000208] 5-Bromo-2,2,4-trifluorobenzo [ d ] [1,3] dioxol (4.0 g, 16 mmol) was dissolved in 20 ml of dry tetrahydrofuran, cooled to -20 ° C and treated with isopropylmagnesium chloride-lithium chloride complex (1.3 M in tetrahydrofuran; 13 mL, 17 mmol) in portions over 10 min. After stirring for 30 minutes at -20 to 0 ° C, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.1 g, 17 mmol) was added, and stirring it was continued for 1 h at 10 to 15 ° C. After treatment with saturated NH 4 CI solution (10 ml), the mixture was diluted with ethyl acetate (50 ml). The organic phase was washed with saturated NaCl (15 ml), dried (Na 2 SO 4 ) and evaporated to provide the title compound as a brown solid (3.5 g, 72%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.46 (d, J = 26.5 Hz, 1H), 6.90 (dd, J = 18.5, 4.5 Hz, 1H), 1.35 (s, 12H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.70 (s), -126.00 (s); EIMS m / z 302. Preparation 29: 2- (2,2-Difluoro-4-methylbenzo [ d ] [1,3] dioxol-5-yl) -5,5-dimethyl-1,3,2-dioxaborinane
    [0209] [000209] 5-Bromo-2,2-difluoro-4-methylbenzo [ d ] [1,3] dioxol (Prepared as described in Nakamura, Yuji; Mitani, Shigeru; Tsukuda, Shintar, W02007069777; 1.0 g, 4 , 0 mmol) was combined in dry DMSO (10 mL) with 1,1'-bis (diphenylphosphino) ferrocenodichloro-palladium (ll) complex with dichloromethane (330 mg, 0.40 mmol), potassium acetate (1.2 g, 12 mmol) and 5.5.5 ', 5'-tetramethyl-2,2'-bi (1,3,2-dioxaborinane) (950 mg, 4.2 mmol), heated to 80 ° C for 4 hours and then let it rest overnight. The mixture was stirred with ethyl acetate (50 ml) and water (30 ml). The organic phase was washed with water, washed with saturated NaCl, dried (Na 2 SO 4 ), and evaporated. The residue was purified by chromatography on silica with 5 to 50% ethyl acetate-hexane to provide the title compound (540 mg, 48%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.55 - 7, 48 (m, 1H), 6.88 - 6.79 (m, 1H), 5.51 - 5.47 (m, 1H), 3.83 - 3.64 (m, 5H), 1.02 ( d, J = 4.9 Hz, 7H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.91 (d, J = 7.1 Hz); EIMS m / z 284. Preparation 30: 1-Bromo-2- (2-bromo-1,1,2,2-tetrafluoroethoxy) -3-fluorobenzene
    [0210] [000210] 2-Bromo-6-fluorophenol (10.2 g, 53 mmol), potassium carbonate (7.3 g, 53 mmol), 1,2-dibromo-tetrafluoroethane (21 g, 80 mmol) and 1- butanethiol (1.1 g, 12 mmol) was combined in dry N, N- dimethylformamide (75 mL) and heated to 50 ° C in a stirred pressure reactor. After cooling, the contents were mixed with 1.0 M sodium hydroxide (NaOH; 100 ml) and extracted three times with diethyl ether (80 ml portions). The combined extracts were washed with water (15 mL), 2.0 M NaOH (45 mL), dried (Na 2 SO 4 ) and concentrated by rotary evaporation. The material was purified by chromatography on silica gel eluting with hexane to provide the title compound as a clear liquid (15 g, 76%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.48 - 7.39 ( m, 1H), 7.22 - 7.14 (m, 2H); ElMS m / z 368. Preparation 31: 2,2,3,3,7-Pentafluoro-2,3-dihydrobenzofuran
    [0211] [000211] 1-Bromo-2- (2-bromo-1,1,2,2-tetrafluoroethoxy) -3-fluorobenzene (14 g, 38 mmol), copper powder (12.2 g, 192 mmol) and 2,2'-bipyridine (610 mg, 3.9 mmol) were combined in dry DMSO (55 ml) and heated at 150 ° C for 1.5 hours. Vacuum (approximately 20 mm) was applied to the reactor and the distillate was suspended until the pot temperature reached 100 ° C. The distillate containing the product and DMSO was diluted with 1: 1 diethyl ether-pentane (30 ml) and washed (3x5 ml) with water, dried, and distilled in 1 atmosphere (atm) through a 200 mm Vigreux column to remove the mass of the solvents. Vacuum (approximately 20 mmHg) was applied and the boiling fraction at 60 to 65 ° C was collected to provide the title compound as a clear liquid (5.1 g, 64%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.40-7.31 (m, 2H), 7.25-7.17 (m, 1H); EIMS m / z 210. Preparation 32: 2,2,3,3,7-Pentafluoro-6-iodo-2,3-dihydrobenzofuran
    [0212] [000212] 2,2,3,3,7-Pentafluoro-2,3-dihydrobenzofuran (500 mg, 2.4 mmol) was added in portions to a -70 ° C solution of lithium diisopropylamide (LDA) prepared in dry tetrahydrofuran (7 mL) of diisopropylamine (380 mg, 3.8 mmol) and 2.5 M n -BuLi (1.4 mL, 3.6 mmol). After 40 minutes at -70 ° C a solution of iodine (1.0 g, 4.0 mmol) in tetrahydrofuran (5 ml) was added over 15 min. After 20 minutes at -70 ° C, the mixture was heated to -20 ° C and quenched by the addition of saturated NH 4 CI. The mixture was treated with 10% NaHSO 3 (15 ml), stirred for 10 minutes and extracted twice with diethyl ether (15 ml portions). The combined extracts were dried (Na 2 SO 4 ) and evaporated. The residue was purified by reverse phase HPLC eluting with 85% acetonitrile-water to provide the title compound (200 mg, 25%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.25 (dd, J = 8.1, 4.8 Hz, 1H), 6.63 (dd, J = 8.0, 1.1 Hz, 1H), 4.13 (s, 3H); ElMS m / z 336. Preparation 33: 5-Bromo-2,2-difluoro-4-methoxybenzo [ d ] [1,3] dioxol
    [0213] [000213] A solution of LDA was prepared from diisopropylamine (4.2 g, 41 mmol) and n -BuLi (2.5 M; 15.4 mL, 38 mmol) in dry tetrahydrofuran (100 mL). The solution was cooled to -70 ° C and treated in portions with 5-bromo-2,2-difluorobenzo [ d ] [1,3] dioxol (7.0 g, 30 mmol). After 2 hours at -70 ° C, trimethylborate (4.3 g, 41 mmol) was added in portions, stirred at -70 ° C for 1.5 hours and then allowed to warm to room temperature overnight. The mixture was cooled to -30 to -40 ° C and carefully treated with 28% peracetic acid. The mixture was stirred for 30 minutes at -30 ° C, heated to 5 to 10 ° C, treated with 10% NaHSO 3 solution (100 ml) and stirred for 20 minutes. The mixture was acidified by the addition of 6 M HCI and diluted with saturated NaCI solution (75 ml). The mixture was extracted with ethyl acetate (2 x 100 ml) and the combined extracts were washed with saturated NaCl (50 ml), dried (Na 2 SO 4 ) and evaporated by rotation. The crude phenol was dissolved in dry DMSO (50 ml), treated with 95% NaH (750 mg, 30 mmol) and stirred for 30 minutes to produce a clear solution. methyl lodide (5.0 g, 35 mmol) was added in portions, and the mixture was stirred for 20 hours at 20 ° C. An additional 200 mg of NaH was added and stirring was continued for an additional 1 hour. The mixture was poured into water (100 ml) and extracted with diethyl ether (2 x 75 ml). The combined extracts were washed with water (2 x 20 ml), with saturated NaCl (20 ml), dried (Na 2 SO 4 ) and evaporated. The crude material was purified by chromatography on silica with 0 to 20% ethyl acetate-hexane gradient to provide the title compound as a clear liquid (2.5 g, 31%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.25 (d, J = 8.5 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 4.13 (s, 3H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.66; EIMS m / z 266. Preparation 34: 2- (2,2-Difluoro-4-methoxybenzo [ d ] [1,3] dioxol-5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
    [0214] [000214] 2- (2,2-Difluoro-4-methoxybenzo [ d ] [1,3] dioxol-5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1, 1 g, 4.1 mmol) was dissolved in dry tetrahydrofuran (10 mL), cooled to 0 to 5 ° C and treated in portions with isopropylmagnesium chloride-lithium chloride solution (1.3 M; 3.5 mL, 4.5 mmol). The mixture was stirred for 1 h at 0 to 5 ° C, treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (840 mg, 4.5 mmol) and stirred at 20 ° C for 90 min. The mixture was treated with saturated NH4 Cl (5 ml) and stirred for 10 min. The mixture was extracted with ethyl acetate (30 ml) and the extract was washed with saturated NaCl (10 ml), dried (Na 2 SO 4 ) and evaporated by rotation to provide the title compound as an oil which solidified resting (1.2 g, 93%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.42 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 4.06 (s, 3H), 1.34 (s, 12H); 19 F NMR (376 MHz, CDCI 3 ) δ-50.09; EIMS m / z 314. Preparation 35: 3,5-Difluorobenzene-1,2-diol
    [0215] [000215] 3,5-Difluoro-2-methoxyphenol (1.0 g, 6.3 mmol, Prepared as described in Jones, Lyn H .; Randall, Amy; Beard, Oscar; Selby, Matthew D., Organic & Biomolecular Chemistry 2007 , 5, 3431-3433) was dissolved in dry dichloromethane (11 mL), cooled to -20 to -30 ° C and portioned with boron tribromide solution (BBr 3 ) in dichloromethane (1.0 M; 13 mL, 13 mmol). The cooling bath was removed and the mixture was stirred for 20 h at 20 ° C. The mixture was cooled to -30 ° C, portioned with water (3 ml) and then heated to 20 ° C. 6 M HCI (10 ml) and ethyl acetate (30 ml) were added, and the mixture was stirred for 20 minutes to produce two clear phases. The aqueous phase was extracted with ethyl acetate (20 ml), and the combined organic phases were washed with saturated NaCl (10 ml), dried (Na 2 SO 4 ) and evaporated by rotation to provide the title compound as an o oil. which solidified on standing (720 mg, 78%): 1 H NMR (400 MHz, CDCI 3 ) δ 6.51 (ddd, J = 9.5, 2.8, 2.1 Hz, 1H), 6 , 45 (ddd, J = 10.3, 8.7, 2.9 Hz, 1H), 5.71 (s, 1H), 5.06 (s, 1H); 19 F NMR (376 MHz, CDCI 3 ) δ -119.56, -136.16; EIMS m / z 146. Preparation 36: 4,6-Difluorobenzo [ d ] [1,3] dioxol-2-thione
    [0216] [000216] 3,5-Difluorobenzene-1,2-diol (670 mg, 4.6 mmol) was stirred in dry chloroform (8 mL), treated with thiophosgen (580 mg, 5.0 mmol), cooled to 5 ° C 10 ° C, and treated dropwise with 10% NaOH solution (4.2 g, 11 mmol) over 45 minutes. After 30 min, the volatiles were removed by rotary evaporation and the residual solid was collected by filtration and washed with water. The solid was dissolved in ethyl acetate (30 ml), washed with water (2 x 20 ml), washed with saturated NaCl (1 x 10 ml), dried (Na 2 SO 4 ), and evaporated. The residue was purified by chromatography on silica with a 0 to 20% ethyl acetate-hexane gradient to provide the title compound (710 mg, 82%): 1 H NMR (400 MHz, CDCI 3 ) δ 6.95 (ddd, J = 6.8, 2.3, 1.4 Hz, 1H), 6.89 (td, J = 9.5, 2.3 Hz, 1H); 19 F NMR (376 MHz, CDCI 3 ) δ -109.99 (s), -127.93 (s); EIMS m / z 188. Preparation 37: 2,2,4,6-Tetrafluorobenzo [ d ] [1,3] dioxol
    [0217] [000217] 4,6-Difluorobenzo [ d ] [1,3] dioxol-2-thione (9.0 g, 48 mmol) was dissolved in dry dichloromethane (100 mL) in a polyethylene bottle, cooled from -30 to -35 ° C and treated with 70% pyridine fluoride-hydrogen complex (68 g, 480 mmol). The mixture was maintained at this temperature and treated in portions with N- iodosuccinimide (32 g, 144 mmol) for 1 hour. The mixture was stirred for 3 hours and heated to 5 ° C. After cooling to -30 ° C, the mixture was treated in portions with 20% NaHSO 3 (75 mL) with vigorous stirring. The mixture was filtered through diatomaceous earth to remove dark solids. The separated aqueous phase was extracted with dichloromethane (75 ml), and the combined extracts were washed with water (2 x 50 ml) and washed with saturated NaCl (1 x 50 ml). The solvent was removed by atmospheric distillation through a 300 mm Vigreux column. The residue was distilled at 310 mmHg, and the fraction collected at 40-45 ° C contained the title compound as a clear liquid (1.3 g, 14%): 1 H NMR (400 MHz, CDCI 3 ) δ 6, 71 (m, 1H), 6.68 (m, 1H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.47, -113.41, -131.95; ElMS m / z 194. Preparation 38: 2,2,4,6-Tetrafluoro-5-iodobenzo [ d ] [1,3] dioxol
    [0218] [000218] 2,2,4,6-Tetrafluorobenzo [ d ] [1,3] dioxol (500 mg, 2.6 mmol) was dissolved in dry tetrahydrofuran (7 mL), cooled to -70 ° C, treated dropwise with sec-BuLi (1.3 M; 2.1 mL, 2.7 mmol) and stirred for 1 hour at -70 ° C. This mixture was treated dropwise with a solution of iodine (1.1 g, 4.4 mmol) in tetrahydrofuran (5 ml) over 10 min. After 2 hours at -70 ° C, the mixture was treated with saturated NH 4 CI, extracted with ethyl ether, dried (Na 2 SO 4 ) and evaporated. The material was purified by reverse phase HPLC with 85% acetonitrile-water to provide the title compound (250 mg; 30%): 1 H NMR (400 MHz, CDCI 3 ) δ 6.80 - 6.77 (d , J = 8.7 Hz, 1H), 6.77 - 6.75 (d, J = 8.7 Hz, 1H); 19 F NMR (376 MHz, CDCI 3 ) δ -48.72, -99.73, - 132.62; ElMS m / z 320. Preparation 39: 4,6-Difluorobenzo [ d ] [1,3] dioxol
    [0219] [000219] 3,5-Difluorobenzene-1,2-diol (10 g, 69 mmol) was dissolved in dry N, N- dimethylformamide (100 mL), treated with cesium carbonate (56 g, 170 mmol) and stirred for 30 minutes at 20 ° C. Bromochloromethane (12 g, 90 mmol) was added and the mixture was heated and stirred at 60 ° C for 19 hours. After cooling, the mixture was stirred with water (100 ml) and diethyl ether (100 ml). The aqueous phase was again extracted with ether (50 ml). The combined extracts were washed with water (2 x 20 ml), washed with saturated NaCl (1x10 ml) and dried (Na 2 SO 4 ). The volume of the ether was removed by atmospheric distillation through a 300 mm Vigreux column. The pressure was reduced to 75 mmHg and the product was distilled at 70 to 90 ° C to provide the title compound as a thick oil (3.0 g, 28%): 1 H NMR (400 MHz, CDCI 3 ) δ 6 , 45 (m, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 6.02 (s, 2H); 19 F NMR (376 MHz, CDCI 3 ) δ -117.99, -135.90; EIMS m / z 158. Preparation 40: 4,6-Difluoro-5-iodobenzo [ d ] [1,3] dioxol
    [0220] [000220] 4,6-Difluorobenzo [ d ] [1,3] dioxol (300 mg, 1.9 mmol) and N- iodosuccinimide (640 mg, 2.9 mmol) were combined in dry acetonitrile (5 mL), treated with trifluoroacetic acid (430 mg, 3.8 mmol) and stirred for 20 hours. The mixture was stirred with a solution of NaHSO 3 (100 mg in 2 ml of water) and then stirred with ethyl acetate (30 ml) and saturated NaCl (5 ml). The organic phase was washed with saturated NaCl (5 ml), dried (Na 2 SO 4 ) and evaporated. The material was purified by chromatography on silica with 0 to 5% ethyl acetate-hexane gradient to provide the title compound as a white solid (410 mg, 76%): melting point 65 to 66 ° C. 1 H NMR (400 MHz, CDCI 3 ) δ 6.54 (dd, J = 6.9, 1.6 Hz, 1H), 6.07 (s, 2H); 19 F NMR (376 MHz, CDCI 3 ) δ -99.31, -117.98; EIMS m / z 284. Preparation 41: 4,4,5,5-Tetramethyl-2- (2-methylbenzo [ d ] [1,3] dioxol-5-yl) -1,3,2-dioxaborolane
    [0221] [000221] 5-Bromo-2-methylbenzo [ d ] [1,3] dioxol (1.0 g, 4.7 mmol, Prepared as described in Matyus, Peter; Magyar, Kalman; Pihlavista, Marjo; Gyires, Klara; Haider, Norbert; Wang, Yinghua; Woda, Patrick; Dunkel, Petra; Toth-Sarudy, Eva; Turos, Gyoergy, WO2010029379) was dissolved in dry tetrahydrofuran (10 mL), cooled to -70 ° C and treated with n -BuLi (2.5 M; 2.1 mL, 4.7 mmol) for 5 min. After 1 hour, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 g, 6.0 mmol) was added and the mixture was stirred for 90 minutes at -70 to -30 ° C. After adding saturated NH 4 CI (5 ml), the mixture was stirred with ethyl acetate (40 ml) and saturated NaCl (10 ml), dried (Na 2 SO 4 ) and evaporated. The material was purified by chromatography on silica with a 0 to 30% ethyl acetate-hexane gradient to provide the title compound (730 mg, 59%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.33 (dd, J = 7.7, 1.1 Hz, 1H), 7.18 (d, J = 0.9 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6 , 25 (q, J = 5.0 Hz, 1H), 1.66 (d, J = 4.9 Hz, 3H), 1.32 (s, 12H); EIMS m / z 262. Preparation 42: 2- (Benzo [ d ] [1,3] oxathiol-5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
    [0222] [000222] 5-Bromobenzo [ d ] [1,3] oxathiol (1.0 g, 4.6 mmol, Prepared as described in Cabiddu, Salvatore; Cerioni, Giovanni; Cocco, Maria Teresa; Maccioni, Antonio; Plumitallo, Antonio , Journal of Heterocyclic Chemistry 1982, 19, 135-139) was dissolved in dry tetrahydrofuran (12 mL), cooled to -70 ° C, portioned with n -BuLi (2.5 M; 1.9 mL, 4.8 mmol) and stirred at -70 ° C for 30 min. 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (900 mg, 4.8 mmol) was added and stirring was continued for 1.5 hours during which the temperature rose to - 30 ° C. The mixture was treated with saturated NH 4 CI (5 ml) and extracted with ethyl acetate (2 x 25 ml). The combined extracts were washed with saturated NaCl (10 mL), dried (Na 2 SO 4 ) and evaporated to provide the title compound which was used without further purification (1.2 g, 99%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.62 (d, J = 1.1 Hz, 1H), 7.48 (dd, J = 8.0, 1.3 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 5.69 (s, 2H), 1.32 (s, 12H); EIMS m / z 264. Preparation 43: 2,2-Difluoro-5-methoxy-6-nitrobenzo [ d ] [1,3] dioxol
    [0223] [000223] 2,2,5-Trifluoro-6-nitrobenzo [ d ] [1,3] dioxol (2.5 g, 11 mmol) was dissolved in dry methanol (20 mL), treated with 30% methoxide solution sodium (3.1 g, 17 mmol), and stirred at 20 ° C for 1 hour. After the excess methoxide was neutralized by the addition of acetic acid, the volatiles were removed by rotary evaporation. The residue was taken up in ethyl acetate (50 ml), washed with saturated NaHCO 3 (10 ml), saturated NaCl (10 ml), dried (Na 2 SO 4 ) and evaporated. The material was purified by chromatography on silica with 0 to 30% ethyl acetate-hexane gradient to provide the title compound as a white solid (1.8 g, 70%): melting point 84 to 85 ° C . 1 H NMR (400 MHz, CDCI 3 ) δ 7.71 (s, 1H), 6.89 (s, 1H), 3.98 (s, 3H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.90 (s); EIMS m / z 233. Preparation 44: 2,2-Difluoro-6-methoxybenzo [ d ] [1,3] dioxol-5-amine
    [0224] [000224] 2,2-Difluoro-5-methoxy-6-nitrobenzo [ d ] [1,3] dioxol (1.7 g, 7.3 mmol) was dissolved in ethyl acetate (50 mL) and treated with 5 % palladium on carbon (200 mg) and hydrogen of 2.81 kg / cm 2 (40 psi) - 3.51 kg / cm 2 (50 psi) in a stirrer. After 90 minutes, the catalyst was removed by filtration, the solvent was removed by filtration, and the product dried in vacuo to provide the title compound as a brown solid (1.5 g, qt (quantitative)): 1 H NMR ( 400 MHz, CDCI 3 ) δ 6.63 (s, 1H), 6.50 (s, 1H), 3.82 (s, 3H), 3.76 (d, J = 23.0 Hz, 2H); 19 F NMR (376 MHz, CDCI 3 ) δ -50.32 (s); EIMS m / z 203. Preparation 45: 2,2-Difluoro-5-iodo-6-methoxybenzo [ d ] [1,3] dioxol
    [0225] [000225] 2,2-Difluoro-6-methoxybenzo [ d ] [1,3] dioxol-5-amine (1.4 g, 6.9 mmol) was dissolved in dichloromethane (5 mL) and added in portions to HCI rapidly stirred concentrate (75 mL) to form a loose white suspension. The mixture was cooled to 0 to 5 ° C and treated in portions with sodium nitrite (710 mg, 10 mmol) in water (10 ml). After 40 minutes, this mixture was poured as a thin stream into a solution of sodium iodide (3.1 g, 21 mmol) in water (75 ml) quickly stirred with dichloromethane (50 ml). After 45 min, the mixture was stirred with 15% NaHSO 3 solution (20 ml) for 10 minutes. The separated aqueous phase was extracted with dichloromethane (30 ml), and the combined extracts were washed with saturated NaCl (15 ml), dried (Na 2 SO 4 ) and evaporated. The material was purified by chromatography on silica with 0 to 15% ethyl acetate-hexane gradient to provide the title compound as a white solid (1.8 g, 83%): melting point 50 to 51 ° C ; 1 H NMR (400 MHz, CDCI 3 ) δ 7.45 (s, 1H), 6.69 (s, 1H), 3.86 (s, 3H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.81 (s); EIMS m / z 314. Preparation 46: 2- (2,2-Difluoro-6-methoxybenzo [ d ] [1,3] dioxol-5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
    [0226] [000226] 2,2-Difluoro-5-iodo-6-methoxybenzo [ d ] [1,3] dioxol (1.6 g, 5.0 mmol) was dissolved in dry tetrahydrofuran (15 mL), cooled to 0 to 5 ° C and treated in portions with lithium isopropylmagnesium chloride (1.3 M; 4.1 mL, 5.3 mmol). After 50 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 5.4 mmol) was added and stirring was continued for 40 minutes at 15 to 20 ° C. The mixture was treated with saturated NH 4 CI (10 ml) and then mixed with saturated NaCl (10 ml) and ethyl acetate (20 ml). The organic phase was washed with saturated NaCl (10 mL), dried (Na 2 SO 4 ) and evaporated to provide the title compound as a thick oil which was used without further purification (1.4 g, 89%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.35 (s, 1H), 6.65 (s, 1H), 3.81 (s, 3H), 1.34 (s, 12H); 19 F NMR (376 MHz, CDCI 3 ) δ -50.17 (s); EIMS m / z 314. Preparation 47: 2- (6-Chloro-2,2-difluorobenzo [ d ] [1,3] dioxol-5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
    [0227] [000227] 5-Bromo-6-chloro-2,2-difluorobenzo [ d ] [1,3] dioxol (1.0 g, 3.7 mmol) was dissolved in dry tetrahydrofuran (7 mL), cooled to 0 to 5 ° C and portioned with lithium isopropylmagnesium chloride (1.3 M; 3.0 mL, 3.9 mmol). After 30 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (730 mg, 4.0 mmol) was added, and stirring was continued for 45 min at 10 to 15 ° Ç. Saturated NH4Cl (10 ml) was added and the mixture was stirred with ethyl acetate (20 ml) and saturated NaCl (10 ml). The organic phase was washed with saturated NaCl (10 ml), dried (Na 2 SO 4 ) and evaporated to provide the title compound as a white solid (1.2 g, qt): 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.64 (s, 1H), 7.53 (s, 1H), 1.30 (s, 12H); 19 F NMR (376 MHz, DMSO- d 6 ) 5-48.97 (s); EIMS m / z 318. Preparation 48: 2- (7-Methoxybenzo [ d ] [1,3] dioxol-5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
    [0228] [000228] 6-Bromo-4-methoxybenzo [ d ] [1,3] dioxol (1.5 g, 6.5 mmol, Prepared according to Shirasaka, Tadashi; Takuma, Yuki; Imaki, Naoshi. Synthetic Communications 1990 , 20, 1223-1232) was dissolved in dry tetrahydrofuran (25 ml), cooled to 5 ° C and treated with lithium isopropylmagnesium chloride (1.3 M; 5.2 ml, 6.8 mmol). After 50 minutes at 10 ° C, the temperature was raised to 40 ° C and stirred for 5 hours. The mixture was cooled to 20 ° C, treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, 7.1 mmol) and stirred for 3 hours. The mixture was treated with saturated NH4 Cl (2 ml), followed by 1 M HCl (8 ml) and ethyl acetate (20 ml), and then stirred for 10 min. The organic phase was washed with saturated NaCl (10 ml), dried (Na 2 SO 4 ) and evaporated. The product was purified by flash chromatography with dichloromethane to provide the title compound as a white solid (600 mg; 33%): melting point 86 to 88 ° C; 1 H NMR (400 MHz, CDCl3) δ 7.01 (d, J = 0.5 Hz, 1H), 6.97 (d, J = 0.8 Hz, 1H), 5.98 (s, 2H) , 3.93 (s, 4H), 1.33 (s, 12H); EIMS m / z 278. Preparation 49: 6-Bromo-4-fluorobenzo [ d ] [1,3] dioxol-2-thione
    [0229] [000229] 5-Bromo-3-fluorobenzene-1,2-diol (2.0 g, 9.7 mmol, Prepared according to Lu, Hejun; Tang, Peng Cho; Chen, Yiqian; Wang, Shenglan; Wang, Hua; Zhang, Lei; Li, Jun, WO 2011140936 A1) was dissolved in chloroform (25 ml), treated with thiophosgene (1.2 g, 11 mmol) and cooled to 0 to 5 ° C. Sodium hydroxide (10% aqueous, 8.9 g, 22 mmol) was added dropwise with vigorous stirring over 30 minutes. After 1 hour, the chloroform was removed in vacuo and the pH was adjusted to 2 by the addition of 6 M HCI. The solid that was formed was absorbed in ethyl acetate (120 ml), washed with saturated NaCl (30 ml), dried (Na 2 SO 4 ) and evaporated. The material was purified by flash chromatography using 0 to 30% ethyl acetate-hexane gradient to provide the title compound as a brown solid (1.5 g, 62%): melting point 41 at 42 ° C ; 1 H NMR (400 MHz, CDCI 3 ) δ 7.35 - 7.30 (m, 1H), 7.29 (d, J = 1.6 Hz, 1H); 19 F NMR (376 MHz, CDCI 3 ) δ -128.93; EIMS m / z 248/250. Preparation 50: 6-Bromo-2,2,4-trifluorobenzo [ d ] [1,3] dioxol
    [0230] [000230] 6-Bromo-4-fluorobenzo [ d ] [1,3] dioxol-2-thione (6.9 g, 28 mmol) was dissolved in dry dichloromethane (150 mL), cooled to - 40 ° C and treated with pyridine hydrofluoride (70% HF by weight; 39 g, 273 mmol). N -iodosuccinimide (19 g, 84 mmol) was added in portions while maintaining the temperature below - 30 ° C. The mixture was stirred for 30 minutes at -35 to -0 ° C and then allowed to warm to 20 ° C and stirred for 30 minutes. Applying external cooling to keep the temperature below 35 ° C, the mixture was treated in portions with a solution of NaHSO 3 (8 g) in water (50 ml) and stirred for 15 minutes. The mixture was treated with additional water (200 ml) to dissolve the solids. The organic phase was washed with saturated NaCl (30 ml), and dried (Na 2 SO 4 ). The volume of the solvent was removed by atmospheric distillation through a 7-tray Oldershaw column, and when the pot volume was approximately 50 mL, the distillation was continued through a 200 mm Vigreux column until the titer temperature reached 75 ° Ç. After cooling to room temperature, the pressure was reduced to 50 mmHg and the product was suspended at 75 to 80 ° C by simple title distillation to provide the title compound as a clear pink liquid (5.3 g, 74% ): 1 H NMR (400 MHz, CDCI 3 ) δ 7.11 (dd, J = 9.0, 1.7 Hz, 1H), 7.07 (m, 1H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.56, -132.65; EIMS m / z 254. Preparation 51: 4,4,5,5-Tetramethyl-2- (2,2,7-trifluoroben-zo [ d ] [1,3] dioxol-5-yl) -1,3,2-dioxaborolane
    [0231] [000231] 6-Bromo-2,2,4-trifluorobenzo [ d ] [1,3] dioxol (2.0 g, 7.8 mmol) was dissolved in dry tetrahydrofuran (10 mL), cooled from -5 at 0 ° C and treated in portions with lithium isopropylmagnesium chloride complex (1.3 M; 6.3 mL, 8.2 mmol). The cooling bath was removed and the mixture was stirred for 30 min. 2-lsopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.6 g, 8.4 mmol) was added, the mixture was stirred for 1 hour and then treated with NH 4 CI saturated (5 mL). The mixture was diluted with ethyl acetate (40 ml) and saturated NaCl (10 ml) and the pH was adjusted to 2 by the addition of HCI. The organic phase was washed with saturated NaCl (5 ml), dried (Na 2 SO 4 ) and evaporated to provide the title compound which was used without further purification (2 g, 85%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.36 (d, J = 9.8 Hz, 1H), 7.29 (d, J = 6.5 Hz, 1H), 1.33 (s, 12H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.79, -136.26; EIMS m / z 302. Preparation 52: 3-Bromo-6-fluorobenzene-1,2-diol
    [0232] [000232] 3-Bromo-6-fluoro-2-hydroxybenzaldehyde (9.0 g, 41 mmol, Prepared according to Castro, Alfred C .; Depew, Kristopher M .; Grogan, Michael J .; Holson, Edward B. ; Hopkins, Brian T; Johannes, Charles W .; Keaney, Gregg F .; Koney, Nii O .; Liu, Tao; Mann, David A .; Nevalainen, Marta; Peluso, Stephane; Perez, Lawrence Bias; Snyder, Daniel A. Tibbitts, Thomas T., WO 2008024337 A2) was stirred in 1.0 M NaOH (47 mL) and treated with hydrogen peroxide (6%; 49 g, 86 mmol). External cooling was applied to keep the controlled temperature below 50 ° C. After 2 hours of total stirring, the mixture was stirred with a solution of NaHSO 3 in 50 ml of water and extracted with ethyl acetate (2 x 75 ml). The combined extracts were washed with saturated NaCl (20 ml), dried (Na 2 SO 4 ) and evaporated. The catechol derivative, as a dark orange liquid, was carried on to the next step without further purification (8.9 g, qt): EIMS m / z 206. Preparation 53: 4-Bromo-7-fluorobenzo [ d ] [1,3] dioxol-2-thione
    [0233] [000233] 3-Bromo-6-fluorobenzene-1,2-diol (8.9 g, 43 mmol) was dissolved in chloroform (100 mL), cooled to 0 to 5 ° C and treated with thiophosgene (5.4 g , 47 mmol). aqueous sodium hydroxide solution (10% by weight; 40 g, 99 mmol) was added in portions over 30 minutes with vigorous stirring. Stirring was continued for 60 minutes at 5 to 15 ° C and then more of the chloroform was removed by rotary evaporation. The pH was adjusted to 2 by the addition of 1 M HCI and the precipitated thion was absorbed in ethyl acetate (150 ml). The organic phase was washed with water (25 ml), saturated NaCl (25 ml), dried (Na 2 SO 4 ), and evaporated. The crude product was purified by flash chromatography , eluting with 0 to 20% ethyl acetate-hexane gradient to provide the title compound as a brown solid (6.2 g, 58%): melting point 72 to 76 ° Ç; 1 H NMR (400 MHz, NMR (376 MHz, CDCI 3 ) δ -132.68; EIMS m / z 248. Preparation 54: 4-Bromo-2,2,7-trifluorobenzo [ d ] [1,3] dioxol
    [0234] [000234] 4-Bromo-7-fluorobenzo [ d ] [1,3] dioxol-2-thione (6.1 g, 25 mmol) was dissolved in dry dichloromethane (100 mL), cooled from -30 to -40 ° C and treated with pyridine hydrofluoride (70% by weight; 35 g, 245 mmol). N- Iodosuccinimide was added in portions of -25 to - 35 ° C and the mixture was allowed to warm to 20 ° C and stirred for 2 hours. The dark mixture was cooled to 0 ° C and treated with 15% CDCI 3 ) δ 7.40 (dd, J = 9.2, 4.1 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H); 19 F NaHSO 3 solution (30 mL) with stirring. After 20 min, the mixture was diluted with dichloromethane (75 ml) and water (200 ml) to dissolve the solids. The organic phase was washed with saturated NaCl (25 ml) and dried (Na 2 SO 4 ). The solvent was removed by atmospheric distillation through a 450 mm Vigreux column. The product was coaxed at 30 to 40 mmHg at 80 to 90 ° C to provide the title compound as a clear liquid (3.0 g, 47%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.18 ( dd, J = 9.3, 4.2 Hz, 1H), 6.85 (t, J = 9.3 Hz, 1H); 19 F NMR (376 MHz, CDCI 3 ) 5-49.08, -136.17; EIMS m / z 254. Preparation 55: 4,4,5,5-Tetramethyl-2- (2,2,7-trifluoroben-zo [ d ] [1,3] dioxol-4-yl) -1,3,2-dioxaborolane
    [0235] [000235] 4-Bromo-2,2,7-trifluorobenzo [ d ] [1,3] dioxol (2.0 g, 7.8 mmol) was dissolved in dry tetrahydrofuran (12 mL), cooled to -5 ° C and treated in portions with lithium isopropylmagnesium chloride complex (1.3 M; 6.3 mL, 8.2 mmol). The mixture was stirred for 2 hours at 5 to 15 ° C, treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.6 g, 8.4 mmol) and stirred for 2 hours at 10 to 20 ° C. The mixture was treated with saturated NH 4 Cl (5 ml), stirred for 10 minutes and then stirred with 1 M HCI (10 ml) and ethyl acetate (75 ml). The organic phase was washed with saturated NaCl (10 ml), dried (Na 2 SO 4 ) and evaporated to provide the title compound as a white solid (2.3 g, 98%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.41 (dd, J = 8.7, 5.3 Hz, 1H), 6.88 (dd, J = 9.5, 8.8 Hz, 1H), 1.36 (s, 12H ); 19 F NMR (376 MHz, CDCI 3 ) δ -49.07, -131.31; EIMS m / z 302. Preparation 56: (2,2-Difluoro-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo [ d ] [1,3] dioxol-4-yl) trimethylsilane
    [0236] [000236] (2,2-Difluorobenzo [ d ] [1,3] dioxol-4-yl) trimethylsilane (5.0 g, 22 mmol, Prepared as described in Gorecka, Joanna; Leroux, Frederic; Schlosser, Manfred, European Journal of Organic Chemistry 2004 , 1, 64-68) was added to a stirred solution of sec-BuLi (1.4 M; 10 mL, 14 mmol) in dry tetrahydrofuran (28 mL) cooled to - 75 ° C. After 2 hours at -75 ° C, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.2 g, 23 mmol) was added, and the mixture was stirred for 90 minutes at -75 ° C. The mixture was treated with saturated NH 4 CI (5 ml) and heated to 20 ° C. The mixture was combined with water (75 ml), acidified with 6 M HCI and extracted with diethyl ether (100 ml). The organic phase was washed with saturated NaCl (15 mL), dried (Na 2 SO 4 ) and evaporated to provide the title compound (estimated purity of 60%) which was used without further purification: 1 H NMR (400 MHz, CDCI 3 ) δ 7.39 (d, J = 7.5 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 1.36 (s,, 12H), 0.33 ( s, 9H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.33; EIMS m / z 356. Preparation 57: 4-Bromo-5-fluorobenzene-1,2-diol
    [0237] [000237] CH 2 CI 2 (30 ml) in a 50 ml circular base flask was added 4-bromo-5-fluoro-2-methoxyphenol (2 g, 9.05 mmol). The reaction mixture was cooled to 0 ° C in an ice / water bath. Boron tribromide (1.027 mL, 10.86 mmol) was slowly added via syringe over 5 min, the ice / water bath was removed. The reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. The reaction mixture was placed in an ice / water bath and methanol (30 ml) was slowly added via syringe. Upon removal of the ice / water bath, the reaction mixture was allowed to warm to room temperature. The reaction mixture was transferred to a separatory funnel, diluted with ethyl acetate (200 ml) and washed with water (200 ml). The organic layer was dried over Na 2 SO 4 and filtered. Concentration in the organic solution gave 4-bromo-5-fluorobenzene-1,2-diol as a dark brown oil (1.8 g, 96%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.03 (d , J = 6.5 Hz, 1H), 6.72 (dd, J = 8.3, 3.5 Hz, 1H); 19 F NMR (376 MHz, CDCI 3 ) δ -115.91 (s); ESIMS m / z 207 ([M + H] + ), 206 ([MH] -). Preparation 58: 5-Bromo-6-fluorobenzo [d] [1,3] dioxol
    [0238] [000238] To N, N -dimethylformamide (25 ml) in a 50 ml vial was added 4-bromo-5-fluorobenzene-1,2-diol (2 g, 9.66 mmol), cesium carbonate (4, 72 g, 14.49 mmol) and bromochloromethane (1.875 g, 14.49 mmol). The reaction mixture was allowed to stir at room temperature for 1 hour and was then heated to an external temperature of 80 ° C for 3 hours. On cooling, the reaction mixture was diluted with Et2O (75 ml) and washed with water (50 ml) followed by a wash with saturated NaCl solution (50 ml). The organic layer was dried over MgSO 4 and filtered. The concentration of the organic solution provided 5-bromo-6-fluorobenzo [ d ] [1,3] dioxol as a light orange solid (1.8 g, 85%): 1 H NMR (400 MHz, CDCI 3 ) δ 6, 94 (d, J = 5.9 Hz, 1H), 6.67 (d, J = 7.9 Hz, 1H), 6.00 (s, 2H); 19 F NMR (376 MHz, CDCI 3 ) δ -113.82 (s); ESIMS m / z 220 ([M + H] + ), 218 ([MH] -). Preparation 59: 5-Bromo-2,2-dimethylbenzo [ d ] [1,3] dioxol
    [0239] [000239] To benzene (50 ml) in a 250 ml circular base flask was added 4-bromobenzene-1,2-diol (1 g, 5.29 mmol), 2,2-dimethoxypropane (2.204 g, 21, 16 mmol), and p- toluene sulfonic acid monohydrate (0.050 g, 0.265 mmol). The flask was fitted with a Dean-Stark trap and heated to reflux for 18 hours. Upon cooling, the reaction mixture was transferred to a separating funnel and washed with 2 N NaOH solution (100 ml) and saturated NaCl solution (100 ml). The organic layer was dried with MgS04, filtered, and concentrated to produce 5-bromo-2,2-dimethylbenzo [ d ] [1,3] dioxol as a dark brown oil (767 mg, 63%): 1 H NMR (400 MHz, CDCI 3 ) δ 6.91 - 6.85 (m, 2H), 6.62 - 6.57 (m, 1H), 1.66 (s, 6H); 13 C NMR (101 MHz, CDCI 3 ) δ 146.81 (s), 144.25 (s), 123.64 (s), 121.02 (s), 112.05 (s), 109.40 ( s), 108.46 (s), 25.83 (s); ESIMS m / z 230 ([M + H] + ), 228 ([MH] -). Preparation 60: 2- (2,2-Dimethylbenzo [ d ] [1,3] dioxol-5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
    [0240] [000240] A DMSO (10 mL) was added potassium acetate (1.671 g, 17.03 mmol), 4,4,4,, 4,, 5,5,5, 5'-octamethyl-2,2, -bi (1,3,2-dioxaborolane) (1,729 g, 6.81 mmol), 5-bromo-2,2-dimethylbenzo [ d ] [1,3] dioxol (1.3 g, 5.68 mmol) , and PdCI 2 (dppf) (0.415 g, 0.568 mmol). The reaction was heated to an external temperature of 80 ° C for 18 hours. On cooling, the reaction mixture was poured into ice water (50 ml). The ice water mixture was transferred to a separating funnel and two extractions with ethyl acetate (50 ml) were completed. The organic layers were combined, dried over Na 2 SO 4 , and filtered. The solution was concentrated in 5 g of Celite® using ethyl acetate as a solvent. The impregnated celite was loaded into a Teledyne Isco purification system and purified by silica chromatography using 0 to 30% ethyl acetate: hexanes to produce 2- (2,2-dimethylbenzo [ d ] [1,3] dioxol -5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a red semisolid (767 mg, 49%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.31 ( dt, J = 6.6, 3.3 Hz, 1H), 7.15 (s, 1H), 6.74 (d, J = 7.7 Hz, 1H), 1.66 (s, 6H), 1.32 (s, 12H); 13 C NMR (101 MHz, CDCI 3 ) δ 129.21 (s), 113.78 (s), 108.15 (s), 83.59 (s), 25.86 (s), 24.82 ( s); ESIMS m / z 277 ([M + H] + ), 275 ([MH] -). Preparation 61: 2- (6-Fluorobenzo [ d ] [1,3] dioxol-5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
    [0241] [000241] 2- (6-Fluorobenzo [ d ] [1,3] dioxol-5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane was prepared as described in Preparation 60 of 5 - bromo-6-fluorobenzo [ d ] [1,3] dioxol to provide a brown oil (74%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.08 (d, J = 4.6 Hz, 1H ), 6.55 (t, J = 6.4 Hz, 1H), 5.97 (d, J = 2.1 Hz, 2H), 1.24 (s, 12H); 13 C NMR (101 MHz, CDCI 3 ) δ 131.70, 131.37, 128.34, 113.38, 101.93, 98.12, 97.80, 83.51.24.80; ESIMS m / z 267 ([M + H] + ), 265 ([MH] -). Preparation 62: 2- (2,2-Difluorobenzo [ d ] [1,3] dioxol-5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
    [0242] [000242] To a circular bottle of three necks dried in the oven under nitrogen was added 5-bromo-2,2-difluorobenzo [ d ] [1,3] dioxol (2.516 g, 10.6 mmol) and tetra -hydrous hydrofuran (26 mL). The solution was cooled to 0 ° C. Isopropylmagnesium chloride-lithium chloride complex (1.3 M; 10 mL, 13.0 mmol) was added slowly and stirred for 1 hour. 2-lsopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.2 ml, 10.62 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solution was filtered and concentrated to provide 2- (2,2-difluorobenzo [ d ] [1,3] dioxol-5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a yellow oil (2.54 g, 84%): 1 H NMR (400 MHz, CDCI 3 ) δ 7.56 (dd, J = 8.0, 1.0 Hz, 1H), 7.47 (d, J = 0.6 Hz, 1H), 7.06 (dd, J = 7.9, 0.4 Hz, 1H), 1.34 (s, 12H); 19 F NMR (376 MHz, CDCI 3 ) δ -50.18; ElMS m / z 284. Preparation 63: 2- (Benzo [ d ] [1,3] dioxol-4-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
    [0243] [000243] Benzo [ d ] [1,3] dioxol (3.05 g, 25 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to -108 ° C using a tetrahydrofuran / liquid nitrogen bath. sec-Butyllithium (1.4 M in cyclohexane; 19.64 mL, 27.5 mmol) was added dropwise, keeping the temperature below -100 ° C. The reaction mixture was then stirred at temperatures between -100 ° C and -108 ° C for 2 hours to ensure complete deprotonation. 2-lsopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.65 g, 25.00 mmol) was then added to the reaction mixture dropwise, keeping the temperature below - 100 ° C. The reaction mixture was then allowed to warm to room temperature and partitioned between diethyl ether and water. The organic phase was extracted with water once again and the aqueous phases combined and acidified to pH 4 with HCI. The product was extracted with diethyl ether and the organic phase was dried and concentrated in vacuo. The product was purified by flash chromatography (silica gel) to provide the title compound as a white solid (2.14 g, 34.5%): 1 H NMR (300 MHz, CDCI 3 ) δ 7.21 (dd , J = 7.6, 1.4 Hz, 1H), 6.90 (dd, J = 7.7, 1.5 Hz, 1H), 6.82 (t, J = 7.6 Hz, 1H) , 6.02 (s, 2H), 1.36 (s, 12H); EIMS m / z 248. Preparation 64: 2- (2,2-Difluorobenzo [ d ] [1,3] dioxol-4-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
    [0244] [000244] 2,2-Difluorobenzo [ d ] [1,3] dioxol (6 g, 38.0 mmol) was dissolved in tetrahydrofuran (100 ml) and cooled to -75 ° C. sec- Butyllithium (1.4 M in cyclohexane; 29.8 mL, 41.7 mmol) was added dropwise, keeping the temperature below -65 ° C. The reaction mixture was then stirred at -75 ° C for 1 hour to ensure complete deprotonation. 2-lsopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.06 g, 38.0 mmol) was then added to the reaction mixture dropwise keeping the temperature below - 65 ° Ç. The reaction mixture was then allowed to warm to room temperature and remain at room temperature for 2 hours and was then partitioned between diethyl ether and water. The aqueous phase was acidified to pH 3 with 12 N HCI. The product was extracted with diethyl ether and the organic phase was dried and concentrated in vacuo to provide the title compound as an off-white solid (7.06 g, 65.5%): 1 H NMR (300 MHz, CDCl 3 ) δ 7.43 (dd, J = 7.5, 1.5 Hz, 1H), 7.13 (dd, J = 7.9, 1.5 Hz, 1H), 7.05 (t, J = 7, 7 Hz, 1H), 1.37 (s, 12H); EIMS m / z 284. Preparation 65: 4-Chloro-2,2-difluorobenzo [ d ] [1,3] dioxol
    [0245] [000245] 2,2-Difluorobenzo [ d ] [1,3] dioxol (6.3 g, 39.8 mmol) was dissolved in tetrahydrofuran (66 ml) and cooled to -78 ° C. n -Butillithium (2.5 M solution in hexanes; 16.74 mL, 41.8 mmol) was added dropwise, keeping the temperature below -70 ° C. The reaction mixture was then stirred at -78 ° C for 1 hour to ensure complete deprotonation. 1,2,2-Trifluorotrichloroethane (14.93 g, 80 mmol) was dissolved in tetrahydrofuran (33 mL) and cooled to -65 ° C. The lithiate was transferred via cannula in the 1,2,2-trifluorotrichloroethane solution at a rate that allowed the temperature to remain between -60 ° C and -65 ° C during the addition. The reaction mixture was then allowed to warm to room temperature and partitioned between diethyl ether and water. The organic phase was concentrated and the product was stimulated through 100 g of silica gel using hexane as a solvent to provide the title compound as a clear oil (5.74 g, 74.8%): 1 H NMR ( 400 MHz, CDCI 3 ) δ 7.08 (dd, J = 8.2, 1.4 Hz, 1H), 7.03 (t, J = 8.0 Hz, 1H), 6.97 (dd, J = 7.9, 1.5 Hz, 1H); EIMS m / z 192. Preparation 66: 2- (7-Chloro-2,2-difluorobenzo [ d ] [1,3] dioxol-4-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
    [0246] [000246] 4-Chloro-2,2-difluorobenzo [ d ] [1,3] dioxol (3 g, 15.58 mmol) was dissolved in tetrahydrofuran (50 ml) and cooled to -75 ° C. A / -Butillithium (2.5 M in hexanes; 6.86 mL, 17.14 mmol) was added dropwise keeping the temperature below -65 ° C. The reaction mixture was then stirred at -75 ° C for 1 hour to ensure complete deprotonation. 2-lsopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.19 g, 17.14 mmol) was then added to the reaction mixture dropwise keeping the temperature below -65 ° Ç. The reaction mixture was then allowed to warm to room temperature, added to diethyl ether (200 ml) and extracted with water (2 x 100 ml). The aqueous phases were combined and acidified to pH 4 with concentrated HCI. The product was extracted with diethyl ether and the organic phase was dried and concentrated in vacuo to provide the title compound as an off-white solid (3.82 g, 77%): 1 H NMR (400 MHz, CDCl 3 ) δ 7, 38 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 1.36 (s, 12H); ElMS m / z 318. Preparation 67: 2- (2,2-Difluorobenzo [ d ] [1,3] dioxol-5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
    [0247] [000247] To a solution of 5-bromo-2,2-difluorobenzo [ d ] [1,3] dioxol (1.5 g, 6.3 mmol) in N, N- dimethylformamide (12.7 mL) was added 4,4,4 ', 4, 5,5,5, 5, 2,2--octametil, bi (1,3,2-dioxaborolane) (1.6 g, 6.3 mmol), ethyl potassium (1.9 g, 19.0 mmol), and (1,1'-bis (diphenylphosphine) ferrocene) -dichloropalladium (ll) (0.3 g, 0.32 mmol). The reaction mixture was heated at 80 ° C for 18 hours, then the reaction mixture was diluted with Et2O and washed with water. The organic layers were separated, dried with Na 2 SO 4 , filtered, concentrated in vacuo, and purified by chromatography on silica gel eluting with 0 to 100% acetone in hexanes to produce a brown oil (0.9 g, 50% ): 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.55 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.43 (d, J = 8, 0 Hz, 1H), 1.30 (s, 12H); 19 F NMR (376 MHz, DMSO- d 6 ) δ -49.26 (s); EIMS m / z 284. Preparation 68: 2,3-dihydro-1H-inden-2-yl acetate
    [0248] [000248] Acetyl chloride (87.86 g, 1119.40 mmol) was added dropwise to 2,3-dihydro-1 H -inden-2-ol (15 g, 111.94 mmol) under atmosphere nitrogen at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. The excess acetyl chloride was distilled under reduced pressure. The residue was diluted with ethyl acetate (450 ml), washed with a saturated aqueous NaHCO 3 solution (3 x 50 ml), brine (30 ml), dried over Na 2 SO 4 and concentrated under reduced pressure to provide the compound of the title (16.2 g, 82%) which was used in the next step without further purification. Preparation 69: 5-Bromo-2,3-dihydro-1 H -inden-2-yl acetate
    [0249] [000249] To a solution at 0 ° C of 2,3-dihydro-1 H -inden-2-yl acetate (16 g, 90.09 mmol) in dry DMF (160 mL) was added N- bromosuccinimide (17.8 g, 99.09 mmol) in portion, and the mixture was stirred for 48 hours at room temperature. The reaction mixture was then diluted with ethyl acetate (450 ml), washed with ice water (4 x 50 ml) and brine (100 ml), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography using ethyl acetate / hexane (silica gel, 100 to 200 mesh) to provide the title compound (9.8 g, 42%). Preparation 70: 5-Bromo-2,3-dihydro-1 H -inden-2-ol
    [0250] [000250] To a 0 ° C solution of 5-bromo-2,3-dihydro- 1H -inden-2-yl acetate (9 g, 35.43 mmol) in THF (100 mL) was added dropwise a solution of NaOH (2.12 g, 53.15 mmol) in water (25 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated, neutralized with 6 N HCI solution and extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with brine (50 ml), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / hexane, 100 to 200 mesh silica gel) to provide the title compound (4.5 g, 56%). Preparation 71: 5- (4,4,5,5-Tetramethyl-1,3, 2-dioxaborolan-2-yl) -2,3-dihydro-1 H -inden-2-ol
    [0251] [000251] To a solution of 5-bromo-2,3-dihydro-1 H -inden-2-ol (4.5 g, 21.22 mmol) in dioxane (54 mL) was added bis (pinacolate) diboro (6.44 g, 25.47 mmol) and potassium acetate (8.3 g, 84.90 mmol). The reaction mixture was purged with Argon for 20 minutes then Pd (dppf) Cl2 (0.755 g, 1.061 mmol) was added. The reaction mixture was stirred at 110 ° C for 4 hours, then allowed to cool to room temperature, filtered through a small pad of Celite® and washed with ethyl acetate (100mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / hexane, 100 to 200 mesh silica gel) to provide the title compound (3.8 g, 69%). SUMMARY OF THE COMPOUNDS OF FORMULA (I) Example 1: Methyl 4-amino-3-chloro-6- (1,3-dihydroisobenzofuran-5-yl) -5-fluoropicolinate
    [0252] [000252] Tert-Butyl nitrite (1.3 mL, 11 mmol, 1.5 equiv) was added to a stirred solution of benzoic peroxyanhydride (36 mg, 0.15 mmol, 0.02 equiv), diboro bis ester (pinacol) (1.9 g, 7.4 mmol, 1.0 equiv), and 1,3-dihydroisobenzofuran-5-amine (1.0 g, 7.4 mmol, 1.0 equiv) in acetonitrile (25 ml) at 23 ° C. The resulting homogeneous orange / brown solution was stirred at 23 ° C for 3 hours. Activated carbon was added and the black mixture was filtered by gravity and concentrated by rotary evaporation to provide 1.9 g of dark brown oil, which appeared to be consistent with 2- (1,3-dihydroisobenzofuran-5-yl) - 4,4,5,5-tetramethyl-1,3,2-dioxaborolane of ~ 30% purity, by analysis of 1 H NMR crude.
    [0253] [000253] Ao 2- (1,3-dihydroisobenzofuran-5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane crude (estimated to be 570 mg, 2.3 mmol, 1.1 equiv) methyl 4-amino-3,6-dichloro-5-fluoropicolinate (500 mg, 2.1 mmol, 1.0 equiv), dichloro [bis (triphenylphosphine)] - palladium (ll) ( 150 mg, 0.21 mmol, 0.10 equiv), and sodium carbonate (240 mg, 2.3 mmol, 1.1 equiv) followed by a 1: 1 mixture of water: acetonitrile (7.0 mL) at 23 ° C. The resulting orange / dark brown mixture was heated to 85 ° C and stirred for 4 hours. The cooled reaction mixture was diluted with water (150 ml) and extracted with dichloromethane (4 x 70 ml). The combined organic layers were dried (magnesium sulfate), filtered by gravity, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to produce the title compound as an orange powder (150 mg, 22%): mp 153-156 ° C; IR (pure film) 3468 (m), 3334 (s), 3205 (m), 2952 (m), 2856 (m), 1735 (s), 1623 (s), 1579 (w) cm -1 ; 1 H NMR (400 MHz, CDCI 3 ) δ 7.81-7.86 (m, 2H), 7.33 (d, J = 8 Hz, 1H), 5.16 (br d, J = 4 Hz, 1H), 4.89 (br s, 2H), 3.97 (s, 3H); ESIMS m / z 323 [(M + H) + ]. Example 2 (Coupling 1): Methyl 4-amino-6- (benzo [ d ] [1,3] dioxol-4-yl) -3-chloro-5-fluoropicolinate
    [0254] [000254] Methyl 4-amino-3,6-dichloro-5-fluoropicolinate (1.5 g, 6.28 mmol), 2- (benzo [ d ] [1,3] dioxol-4-yl) -4 , 4,5,5-tetramethyl-1,3,2-dioxaborolane (2.024 g, 8.16 mmol), potassium fluoride (0.875 g, 15.06 mmol; Note: Related examples use cesium fluoride) and bis (triphenylphosphine) palladium (ll) chloride (0.440 g, 0.628 mmol) were combined in acetonitrile (13 ml) and water (4.5 ml). The reaction mixture was then irradiated in a microwave at 110 ° C in a plugged flask for 20 minutes, with temperature monitoring by an external IR sensor on the side of the vessel. The cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried and concentrated to 1.2 g of silica gel. This mixture was applied to the top of a silica gel column and the product was eluted with 7-60% of a hexane / ethyl acetate gradient solvent system to provide the title compound as a white solid (1.4 g , 68.7%): melting point 146 to 148 ° C; 1 H NMR (400 MHz, CDCI 3 ) δ 7.16 - 7.09 (m, 1H), 6.98 - 6.85 (m, 2H), 6.01 (s, 2H), 4.91 ( br s, 2H), 3.98 (s, 3H); ESIMS m / z 325 ([M + H] + ).
    [0255] [000255] The preparation method used in this example is referred to in Table 2 as “Coupling 1”. Example 3 (Coupling 2): methyl 4-amino-3-chloro-6- (2,2,4-trifluoro-benzo- [ d ] [1,3] dioxol-5-yl) picolinate
    [0256] [000256] Methyl 4-acetamido-3,6-dichloropicolinate (600 mg, 2.3 mmol), cesium fluoride (690 mg, 4.5 mmol), 4,4,5,5-tetramethyl-2- ( 2,2,4-trifluorobenzo [ d ] [1,3] dioxol-5-yl) -1,3,2-dioxaborolane (980 mg, 3.0 mmol) and bis (triphenylphosphine) palladium (ll) chloride ( 110 mg, 0.16 mmol) were combined in 1: 1 acetonitrile-water (6 mL) and heated to 115 ° C for 30 minutes using a microwave (Biotage Initiator), with temperature monitoring by an external IR sensor on the side of the vessel. The mixture was stirred with water (10 ml) and ethyl acetate (25 ml). The organic phase was washed with saturated NaCl (5 ml), dried over Na 2 SO 4 and evaporated. The residue was purified by chromatography on silica with 5 to 30% ethyl acetate-hexane to provide a solid which was also purified by reverse phase high performance liquid chromatography eluting with 70/30 / 0.10 v / v / v acetonitrile / water / acetic acid to provide 250 mg of the amide. This material was dissolved in methanol (10 ml), carefully treated with acetyl chloride (2 ml) and heated to reflux for 1 hour. After cooling, the volatiles were removed in vacuo and the residue was stirred with ethyl acetate (15 ml) and saturated NaHCO 3 solution (5 ml) for 15 minutes. The organic phase was washed with saturated NaCl solution (5 ml), dried over Na 2 SO 4 and evaporated in vacuo to provide the title compound as a white solid (195 mg, 24%): melting point 153 to 155 ° Ç; 1 H NMR (400 MHz, CDCI 3 ) δ 7.77 (dd, J = 8.6, 7.1 Hz, 1H), 7.14 (d, J = 1.9 Hz, 1H), 6.97 (dd, J = 8.6, 0.9 Hz, 1H), 4.87 (s, 2H), 4.00 (s, 3H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.37 (s), -138.91 (s); ESIMS m / z 361 ([M + H] + ), 359 ([MH] -).
    [0257] [000257] The preparation method used in this example is referred to in Table 2 as “Coupling 2”. Example 4 (Coupling 3): Methyl 4-amino-3-chloro-6- (2,3-dihydrobenzofuran-6-yl) -5-fluoropicolinate
    [0258] [000258] 3,3 ', 3 "-Phosphinathyltribenzenesulfonate (0.209 g, 0.418 mmol), potassium fluoride (0.365 g, 6.28 mmol), 4-amino-3-chloro-6- (2,3-dihydrobenzofuran- Methyl 6-yl) -5-fluoropicolinate, diacethoxipaladium (0.047 g, 0.209 mmol), and 2- (2,3-dihydrobenzofuran-6-yl) -4,4,5,5-tetramethyl-1,3 , 2-dioxaborolane (0.541 g, 2.196 mmol) were combined in a 5 mL microwave vial. Water (Ratio: 3.00, Volume: 3 mL) and acetonitrile (Ratio: 1,000, Volume: 1 mL) were combined and then added to the microwave vial The reaction vial was capped and placed in a Biotage Initiator microwave reactor for 6 minutes at 150 ° C, with temperature monitoring by an external IR sensor on the side of the vessel. Upon cooling, the product precipitated as a solid, additional material was present in the acetonitrile mixture, the solids were washed with water and dried to produce 4-amino-3-chloro-6- (2,3-dihydrobenzofuran-6- il) methyl -5-fluoropicolinate as a white solid co (250 mg, 37%): melting point 150 to 154 ° C; 1 H NMR (400 MHz, CDCI 3 ) δ 7.42 (dt, J = 7.7, 1.6 Hz, 1H), 7.33 (s, 1H), 7.28 (s, 1H), 4 , 88 (s, 2H), 4.62 (q, J = 8.4 Hz, 2H), 3.98 (d, J = 3.0 Hz, 3H), 3.31 - 3.18 (m, 2H); 13 C NMR (101 MHz, CDCI 3 ) δ 164.99, 160.32, 147.23, 144.65, 140.38, 140.24, 134.32, 134.26, 128.69, 124.76 , 121.43, 121.37, 114.64, 109.71, 109.65, 71.39, 52.90, 29.69; ESIMS m / z 233 ([M + H] + ), 231 ([MH] -).
    [0259] [000259] The preparation method used in this example is referred to in Table 2 as "Coupling 3". Example 5 (Coupling 4): 4-amino-3-chloro-6- (2,2,5-trifluorobenzo [ d ] [1,3] dioxol-4-yl) methyl picolinate
    [0260] [000260] Methyl 4-acetamido-3-chloro-6- (trimethylstannyl) picolinate (710 mg, 1.8 mmol) and 2,2,5-trifluoro-4-iodobenzo [ d ] [1,3] dioxol ( 500 mg, 1.7 mmol) were combined in dry N, N- dimethylformamide (7 mL) and de-aerated with a stream of nitrogen for 25 minutes. Bis (triphenylphosphine)-palladium (ll) chloride (120 mg, 0.17 mmol) and cuprous iodide (32 mg, 0.17 mmol) were added and the mixture was heated at 80 ° C for 5 hours. The mixture was combined with ethyl acetate (30 ml) and water (15 ml) and the separated organic phase was washed with water (10 ml), saturated NaCl (10 ml), dried and evaporated. The residue was purified by chromatography on silica with 0 to 50% and gradient of ethyl acetate-hexane to provide 115 mg of the amide intermediate. This material was dissolved in methanol (25 ml), treated with acetyl chloride (3 to 4 ml) and heated at 60 ° C for 2 hours. The volatiles were removed in vacuo and the residue was stirred with saturated NaHCO 3 (10 ml) and ethyl acetate (20 ml) for 30 minutes. The organic phase was separated, washed with saturated NaCl (5 ml), dried (Na 2 SO 4 ), evaporated to provide the title compound as a white solid (130 mg, 20%): 1 H NMR (400 MHz, DMSO - d 6 ) δ 7.52 (dd, J = 8.9, 4.0 Hz, 1H), 7.22 (dd, J = 11, 0, 9.0 Hz, 1H), 7.06 (d , J = 1.4 Hz, 1H), 6.99 (s, 2H), 3.88 (s, 3H); 19 F NMR (376 MHz, DMSO- d 6 ) δ -48.09, -121.60; ESIMS m / z 361 ([M + H] + ), 359 ([MH] -).
    [0261] [000261] The preparation method used in this example is referred to in Table 2 as “Coupling 4”. Example 6 (Coupling 5): methyl 4-amino-5-fluoro-3-methoxy-6- (2,2,6-trifluorobenzo [ d ] [1,3] dioxol-5-yl) picolinate
    [0262] [000262] To a mixture of methyl 4-amino-6-chloro-5-fluoro-3-methoxypolycolinate (300 mg, 1.279 mmol) in acetonitrile (1 ml) and water (3 ml) was added potassium fluoride (149 mg, 2.56 mmol), palladium (11) acetate (28.7 mg, 0.128 mmol) and tris (3-sulfonatophenyl) phosphine tetrahydrate, sodium salt (150 mg, 0.256 mmol). The reaction mixture was then heated at 120 ° C for 20 minutes in a microwave reactor. The cooled reaction mixture was then diluted with dichloromethane and washed with water. The phases were separated and the organics were concentrated. The residue was purified by reverse phase chromatography (100 g C18) eluted with 50/50 acetonitrile-water (0.1% trifluoroacetic acid) to provide the title compound as an off-white solid (251 mg, 52.5%) .
    [0263] [000263] The preparation method used in this example is referred to in Table 2 as “Coupling 5”. Example 7: Methyl 4-amino-6- (7-bromo-2,2-difluorobenzo [ d ] [1,3] dioxol-4-yl) -3-chloro-5-fluoropicolinate
    [0264] [000264] Methyl 4-amino-3-chloro-6- (2,2-difluoro-7- (trimethylsilyl) benzo [ d ] [1,3] dioxol-4-yl) -5-fluoropicolinate (400 mg, 0.92 mmol) was stirred in 1,2-dichloroethane (5 ml), treated with bromine (1.0 g, 6.5 mmol) and stirred at 20-25 ° C for 4 hours. The solution was stirred with 10% NaHSO 3 solution (30 ml) and extracted with ethyl acetate (35 ml). The organic phase was washed with saturated NaCl (5 ml), dried (Na 2 SO 4 ) and evaporated to provide the title compound as a white solid (370 mg, 92%): melting point 168 to 170 ° C; 1 H NMR (400 MHz, CDCI 3 ) δ 7.35 (m, 1H), 5.02 (s, 1H), 3.99 (s, 3H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.23, -137.58; ESIMS m / z 439 ([M + H] + ), 437 ([MH] -). Example 8: Methyl 4-amino-3-chloro-6- (2,2-difluoro-7-iodobenzo- [d] [1,3] dioxol-4-yl) -5-fluoropicolinate
    [0265] [000265] Methyl 4-amino-3-chloro-6- (2,2-difluoro-7- (trimethylsilyl) benzo [ d ] [1,3] dioxol-4-yl) -5-fluoropicolinate (400 mg, 0.92 mmol) in 1,2-dichloroethane (5 mL) was treated with iodine monochloride (900 mg, 5.5 mmol) and stirred for 20 hours at 20 ° C. The mixture was combined with 10 wt% NaHSO 3 solution (30 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (15 ml), and the combined organic phases were washed with saturated NaCl (10 ml), dried (Na 2 SO 4 ) and evaporated to provide the title compound as a white solid (430 mg, 96%): melting point 156 to 159 ° C; 1 H NMR (400 MHz, CDCI 3 ) δ 7.50 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 5.02 (s, 2H ), 3.99 (s, 3H); 19 F NMR (376 MHz, CDCI 3 ) δ -49.22, -137.49; ESIMS m / z 487 ([M + H] + ), 485 ([MH] -). Example 9 (Hydrolysis): 4-Amino-6- (benzo [ d ] [1,3] dioxol-4-yl) - 3-chloro-5-fluoropicolinic acid
    [0266] [000266] To a reaction vessel containing methyl 4-amino-6- (benzo [ d ] [1,3] dioxol-4-yl) -3-chloro-5-fluoropicolinate (0.150 g, 0.462 mmol) methanol (9.24 ml) and 2 N sodium hydroxide (0.924 ml, 1.848 mmol). The reaction mixture was stirred overnight at room temperature, neutralized to pH 3 with 2 N HCI, and concentrated under a stream of nitrogen. The precipitate that formed was filtered, washed with water, and dried to provide the title compound as a white solid (0.107 g, 74.6%): melting point 171 to 173 ° C; 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.08 - 7.00 (m, 2H), 6.99 - 6.93 (m, 2H), 6.93 (br s, 2H), 6 06 (s, 2H); ESIMS m / z 311.2 ([M + H] + ), 309.1 ([MH] -).
    [0267] [000267] The preparation method employed in this example is referred to in Table 2 as "Hydrolysis". Example 10: Preparation of methyl 4-amino-3-chloro-5-fluoro-6- (2-hydroxy-2,3-dihydro-1 H -inden-5-yl) picolinate
    [0268] [000268] A mixture of 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H -inden-2-ol (3 , 8 g, 14.61 mmol), Title B (3.4 g, 14.61 mmol), and cesium fluoride (CsF; 4.44 g, 29.23 mmol) in acetonitrile / water (75 mL: 25 mL) was purged with Argon for 20 minutes then Pd (PPh 3 ) 2 CI 2 (1.0 g, 1.46 mmol) was added. The reaction mixture was stirred at 110 ° C for 2 hours then cooled to room temperature, filtered through a small pad of Celite® and washed with ethyl acetate (100 ml). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / hexane and 100-200 mesh silica gel) to provide the title compound (1.8 g, 36%). Example 11: Preparation of methyl 4-amino-3-chloro-5-fluoro-6- (2-fluoro-2,3-dihydro-1 H -inden-5-yl) picolinate
    [0269] [000269] To a -78 ° C solution of 4-amino-3-chloro-5-fluoro-6- (2-hydroxy-2,3-dihydro-1 H -inden-5-yl) picolinate methyl (0.5 g, 1.48 mmol) in dichloromethane (15 mL) Deoxo-Fluor® (1.9 g, 8.92 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The mixture was then diluted with dichloromethane (15 ml), washed with a cold solution of saturated NaHCO 3 (2 x 10 ml), brine (10 ml), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / hexane and 230 to 400 mesh silica gel) to provide the title compound (0.145 g, 28%): 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.71 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 6.92 (s, 2H), 5.64 - 5.45 (m, 1H), 3.88 (s, 3 H), 3.39 - 3.09 (m, 4H); ESIMS m / z 339 [(M + H) + ]. Example 12: Preparation of methyl 4-amino-3-chloro-5-fluoro-6- (2-oxo-2,3-dihydro-1 H -inden-5-yl) picolinate
    [0270] [000270] To a 0 ° C solution of 4-amino-3-chloro-5-fluoro-6- (2-hydroxy-2,3-dihydro-1 H -inden-5-yl) methyl picolinate (1.0 g, 2.97 mmol) in dichloromethane (25 mL) pyridinium chlorochromate (1.27 g, 5.95 mmol) was added. The reaction mixture was stirred at room temperature for 6 hours, filtered through a small pad of Celite® and washed with dichloromethane (50 ml). The filtrate was dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / hexane and silica gel, 100 to 200 mesh) to provide the title compound (0.5 g, 56%): ESIMS m / z 335 [(M + H ) + ] Example 13: Preparation of methyl 4-amino-3-chloro-6- (2,2-difluoro-2,3-dihydro-1 H -inden-5-yl) -5-fluoropicolinate
    [0271] [000271] To a -78 ° C solution of 4-amino-3-chloro-5-fluoro-6- (2-oxo-2,3-dihydro-1H-inden-5-yl) methyl picolinate (0.5 g, 1.497 mmol) in dichloromethane (50 mL) was added diethylamino sulfur trifluoride (DAST; 1.4 g, 8.98 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was then diluted with dichloromethane (50 ml), washed with an ice-cold saturated NaHCO 3 solution (2 x 10 ml), brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / hexane and 100 to 200 mesh silica gel) to provide the title compound (0.105 g, 18%): 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.77 (d, J = 6 Hz, 2H), 7.31 (d, J = 8.4 Hz, 1H), 4.89 (s, 2H), 3.98 (s, 3H), 3, 52 - 3.43 (m, 4H); ESIMS m / z 357 [(M + H) + ]. Table 2. Compound Number, Structure, Preparation and Appearance
    [0272] [000272] Herbicidal evaluations were made visually on a scale of 0 to 100 where 0 represents no activity and 100 represents complete plant death. The data are presented as shown in table 4.
    [0273] [000273] Post-Emerging Test I: Seeds of test species were obtained from commercial suppliers and planted in a 12.7 cm (5 ”) round pot containing mixture of landless medium (Metro-Mix 360®, Sun Gro Horticulture ). Post-emergence treatments were planted 8 to 12 days (d) before application and grown in a greenhouse equipped with supplementary light sources to provide a 16-hour photoperiod at 24 to 29 ° C. All the pots were irrigated on the surface.
    [0274] [000274] Approximately 10 milligrams (mg) of each compound were dissolved in 1.3 ml of acetone-DMSO (97: 3, volume by volume (v / v)) and diluted with 4.1 ml concentrated water-isopropanol- harvest oil (78: 20: 2, v / v / v) containing 0.02% Triton X-155. Treatments were serially diluted with the formulation solvent above to provide 1.85, 0.926, 0.462 and 0.231 milligrams per milliliter (mg / mL) of test compound released 2.7 mL / pot (approximately equivalent to 4.0, 2.0 , 1.0, and 0.5 kg / ha, respectively). Formulated compounds were applied using a DeVilbiss® compressed air vaporizer at 0.14 to 0.28 kg / cm2 (2-4 pounds per square inch (psi)). Following the treatment, the pots were returned to the greenhouse for the duration of the experiment. All pots were sub-irrigated as needed to provide ideal growing conditions. All pots were fertilized once a week by sub-irrigation with Peters Peat-Lite Special® fertilizer (20-10-20).
    [0275] [000275] Phytotoxicity ratings were obtained 10 days after post-emergence treatment applications. All assessments were made visually on a scale from 0 to 100 where 0 represents no activity and 100 represents complete plant death and are shown as shown in table 4.
    [0276] [000276] Some of the tested compounds, application rates employed, plant species tested, and the results are given in table 5. Table 5. Post-Emerging Test Herbicidal Activity I on Key Broadleaf and Grass Weed as well as Harvest Species
    [0277] [000277] Pre-emergent Test I: Seeds of test species were planted in round plastic pots (12 cm in diameter) containing sandy clay soil. After planting, all the pots were raised 16 hours before the application of the compost.
    [0278] [000278] The compounds were dissolved in a 97: 3 v / v mixture of acetone and DMSO and diluted to the appropriate concentration in a final application solution containing water, acetone, isopropanol, DMSO and Agri-dex (oil concentrate). crop) at a ratio of 59: 23: 15: 1.0: 1.5 v / v and 0.02% w / v (weight / volume) of Triton X-155 to obtain the spray solution containing the highest application rate . The high application rate was serially diluted with the above application solution to provide compound release at rates of 1 / 2X, 1 / 4X and1 / 8X of the highest rate (equivalent to 4.0, 2.0, 1.0, and 0.5 kg / ha, respectively).
    [0279] [000279] The formulated compound (2.7 mL) was applied evenly pipetted over the soil surface, followed by incorporation with water (15 mL). Following the treatment, the pots were returned to the greenhouse for the duration of the experiment. The greenhouse was programmed for an approximate 15 hour photoperiod that was maintained at about 23 to 29 ° C during the day and 22 to 28 ° C at night. Nutrients and water were added on a regular basis through surface irrigation and supplementary lighting was provided with 1000 Watt overhead metal halide lamps as needed.
    [0280] [000280] Herbicide ratings were obtained 14 days after treatment. All assessments were made with respect to appropriate controls on a scale of 0 to 100 where 0 represents no herbicidal effect and 100 represents death of the plant or absence of emergence from the soil and are shown as shown in table 4.
    [0281] [000281] Some of the compounds tested, application rates employed, plant species tested, and the results are given in table 6. Table 6. Pre-emergent Herbicidal Test Activity on Key Broadleaf and Grass Weed as well as Harvest Species
    [0282] [000282] Post-Emerging Test II : Seeds or seedlings of the desired test plant species were planted in a Sun Gro Metro-Mix® 360 planting mixture, which typically has a pH of 6.0 to 6.8 and a substance content about 30 percent organic, in plastic pots with a surface area of 64 square centimeters (cm 2 ). When required to ensure good germination and healthy plants, a fungicide treatment and / or other chemical or physical treatment was applied. The plants were grown for 7 to 21 days in a greenhouse with a photoperiod of approximately 15 hours that was maintained at about 23 to 29 ° C during the day and 22 to 28 ° C during the night. Nutrients and water were added on a regular basis and supplementary lighting was provided with 1000 Watt overhead metal halide lamps as needed. The plants were used for testing when they reached the first or second stage of real leaf.
    [0283] [000283] A heavy amount, determined by the highest rate to be tested, of each test compound was placed in a 25 m glass vial and dissolved in 4 mL of a 97: 3 v / v mixture of acetone and DMSO to obtain concentrated raw material solutions. If the test compound did not dissolve easily, the mixture was heated and / or sonicated. The concentrated raw material solutions obtained were diluted with 20 mL of an aqueous mixture containing acetone, water, isopropyl alcohol, DMSO, Atplus 411F harvest oil concentrate, and Triton® X-155 surfactant in a 48.5: 39 ratio : 10: 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 12 mL of the high-rate solution in a solution containing 2 mL of a 97: 3 v / v mixture of acetone and DMSO and 10 mL of an aqueous mixture containing acetone, water, isopropyl alcohol, DMSO, Atplus 411F harvest oil concentrate, and Triton X-155 surfactant in a ratio of 48.5: 39: 10: 1.5: 1.0: 0.02 v / v to obtain rates 1 / 2X, 1 / 4X, 1 / 8X and 1 / 16X of the high rate. Compost requirements are based on an application volume of 12 mL at a rate of 187 liters per hectare (L / ha). The formulated compounds were applied to the plant material with an aerial mandarine runner vaporizer equipped with 8002E nozzles calibrated to release 187 L / ha over an application area of 0.503 square meters at a spray height of 18 inches (43 cm) above the average height of canopy plants. Control plants were sprayed in the same way with the blank solvent.
    [0284] [000284] The treated plants and control plants were placed in a greenhouse as described above and watered by sub-irrigation to prevent removal of the test compounds. After 14 days, the condition of the test plants when 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 and are shown as shown in the table 4.
    [0285] [000285] Some of the compounds tested, application rates employed, plant species tested, and the results are given in table 7. Table 7. Post-Emerging Test Herbicidal Activity II on Key Broadleaf Weed and Harvest Species
    [0286] [000286] Post-Emerging Test III. Seeds of the desired test plant species were planted in a Sun Gro MetroMix® 306 planting mixture, which typically has a pH of 6.0 to 6.8 and an organic substance content of about 30 percent, in plastic pots with a surface area of 103.2 square centimeters (cm 2 ). When required to ensure good germination and healthy plants, a fungicide treatment and / or other chemical or physical treatment was applied. The plants were grown for 7 to 36 days (d) in a greenhouse with a photoperiod of approximately 14 hours (h) which was maintained at about 18 ° C during the day and 17 ° C at night. Nutrients and water were added on a regular basis and supplementary lighting was provided with 1000 Watt overhead metal halide lamps as needed. The plants were used for testing when they reached the second or third stage of real leaf.
    [0287] [000287] 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 mixture of acetone and DMSO for obtain concentrated raw material solutions. If the test compound did not dissolve easily, the mixture was heated and / or sonicated. The concentrated raw material solutions obtained were diluted with 20 ml of an aqueous mixture containing acetone, water, isopropyl alcohol, DMSO, Agri-Dex concentrate of harvest oil, and surfactant X-77 in a 48:39:10 ratio: 1.5: 1.5: 0.02 v / v to obtain spray solutions containing the highest application rates. Additional application rates were obtained by serial dilution of 12 mL of the high-rate solution in a solution containing 2 mL of a 97: 3 v / v mixture of acetone and DMSO and 10 mL of an aqueous mixture containing acetone, water, isopropyl alcohol, DMSO, Agri-Dex crop oil concentrate, and X-77 surfactant in a 48: 39: 10: 1.5: 1.5: 0.02 v / v ratio to obtain 1 / 2X rates, 1 / 4X, 1 / 8X and 1 / 16X of the high rate. Compost requirements are based on an application volume of 12 mL at a rate of 187 liters per hectare (L / ha). The formulated compounds were applied to the plant material with an aerial mandarine runner vaporizer equipped with 8002E nozzles calibrated to release 187 L / ha over an application area of 0.503 square meters at a spray height of 18 inches (43 cm) above the average height of canopy plants. Control plants were sprayed in the same way with the blank solvent.
    [0288] [000288] The treated plants and control plants were placed in a greenhouse as described above and watered by sub-irrigation to prevent removal of the test compounds. After 21 days, the condition of the test plants when compared to that of untreated plants was determined visually and rated on a scale from 0 to 100 percent where 0 corresponds to no damage and 100 corresponds to complete death and are shown as shown in the table 4.
    [0289] [000289] 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 damage herbicide of a specific compound at various rates can be used to calculate GR 20 , GR 50 , GR 80 and GR 90 values, which are defined as growth reduction factors that correspond to the effective dose of herbicide required to provide growth reduction plant (GR) of 20 percent, 50 percent, 80 percent and 90 percent, respectively. Probit analysis has been applied to date collected from multiple dose rates of individual compounds using the procedures explained in the following examples. The data for some of the dose rates and analysis of all dose rates are captured in the following tables.
    [0290] [000290] Some of the compounds tested, application rates employed, plant species tested, and results are given in tables 9 to 13. Table 9: Activity of Herbicidal Compounds in Wheat and Barley
    [0291] [000291] Seeds or seedlings of the desired test plant species were planted in a prepared soil matrix by mixing a muddy earth (43 percent mud, 19 percent clay, and 38 percent sand, with a pH of about 8 , 1 and an organic substance content of about 1.5 percent) and 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 treatment and / or other chemical or physical treatment was applied. The plants were grown for 10 to 17 days in a greenhouse with an approximate photoperiod of 14 hours that was maintained at about 29 ° C during the day and 26 ° C at night. Nutrients and water were added on a regular basis and supplementary lighting was provided with 1000 Watt overhead metal halide lamps as needed. The plants were used for testing when they reached the second or third stage of real leaf.
    [0292] [000292] A heavy amount, determined by the highest rate to be tested, of each test compound was placed in 25 mL glass vials and dissolved in a 97: 3 v / v acetone-DMSO volume to obtain 12X raw material solutions . If the test compound did not dissolve easily, the mixture was heated and / or sonicated. The concentrated solutions of raw material 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 an aqueous mixture of 1.5% (v / v) Agri-dex concentrate of harvest oil. The final spray solutions contained 1.25% (v / v) Agri- dex concentrate from harvest oil. Compost requirements are based on an application volume of 12 mL at a rate of 187 L / ha. The formulated compounds were applied to the plant material with an aerial mandarine runway vaporizer equipped with 8002E nozzles calibrated to release 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 height of the canopy plants. Control plants were sprayed in the same way with the blank solvent.
    [0293] [000293] The treated plants and control plants were placed in a greenhouse as described above and watered by sub-irrigation to prevent removal of the test compounds. After 20 to 22 days, 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 and are presented as indicated in table 4.
    [0294] [000294] 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 damage herbicide of a specific compound at various rates can be used to calculate GR 20 , GR 50 , GR 8o and GR 90 values, which are defined as growth reduction factors that correspond to the effective dose of herbicide required to provide reduction in plant growth (GR) of 20 percent, 50 percent, 80 percent and 90 percent, respectively. Probit analysis has been applied to this date collected from multiple dose rates of individual compounds using the procedures explained in the following examples. The data for some of the dose rates and analysis of all dose rates are captured in the following tables.
    [0295] [000295] Some of the rates and application ratios employed, plant species tested, and the results are given in table 14. Table 14. Activity of Herbicidal Compounds in Directly Seeded Rice


    BRAPP: broadleaf signalgass, Beachiaria platyhylla ClPDI: small flower flat junction , Ciperus difformis CIPES: yellow sedge , Ciperus esculentus CIPIR: flat rice junction , Ciperus would DIGSA: large green grass, Digitaria sanguinalis ECHCG: rice grass, Echinocloa crus-gali ECHCO: junglerice, Echinocloa colonum LEFCH: Chinese sprangletop, Leptocloa chinensis SCPJU: Japanese Junco, Schoenoplectus juncoides Roxb. SEBEX: sesbania hemp, Sesbania exaltata ORISK: Oriza sativa ORISJ: Oriza sativa g ia / ha: grams of active ingredient per hectare
    权利要求:
    Claims (17)
    [0001]
    Compound, characterized by the fact that it presents Formula (I):
    [0002]
    Compound according to claim 1, characterized by the fact that Ar is Ar5, Ar6, Ar7, Ar8, Ar15, Ar16, Ar17 or Ar18.
    [0003]
    Compound according to claim 1 or 2, characterized by the fact that R 1 is OR 1 ' .
    [0004]
    Compound according to any one of claims 1 to 3, characterized in that R 2 is halogen, C2-C4-alkenyl, C2-C4 haloalkenyl, or C1-C4-alkoxy.
    [0005]
    Compound according to any one of claims 1 to 4, characterized in that R 2 is Cl, methoxy, vinyl, or 1-propenyl.
    [0006]
    Compound according to any one of claims 1 to 5, characterized in that R 3 and R 4 are both hydrogen.
    [0007]
    Compound according to any one of claims 1 to 6, characterized in that X is N, CH, or CF.
    [0008]
    Compound, according to any one of claims 1 to 7, characterized by the fact that R 5 is hydrogen or halogen.
    [0009]
    Compound according to claim 8, characterized by the fact that R 5 is hydrogen or F.
    [0010]
    Compound according to any one of claims 1 to 9, characterized in that R 6 is hydrogen or F.
    [0011]
    Compound according to any one of claims 1 to 10, characterized in that R 6 ' is hydrogen.
    [0012]
    Compound according to any one of claims 1 to 11, characterized by the fact that: R 2 is halogen, C 2 -C 4 alkenyl, or C 1 -C 4 alkoxy; R 3 and R 4 are hydrogen; and XéN, CH, or CF; A is Ar7, Ar9, Ar10, Ar13, Ar15, Ar16, Ar19, Ar21 or Ar22; R 5 is hydrogen or F; R 6 is hydrogen or F; R 6 ' is hydrogen; R 7 , R 7 ' , R 8 , R 8' , R 9 , R 9 ' , R 9 " , and R 9 ", if applicable to the relevant Ar group, are independently hydrogen or fluorine.
    [0013]
    Compound according to any one of claims 1 to 12, characterized by the fact that: R 2 is chlorine; R 3 and R 4 are hydrogen; and XéN, CH, or CF.
    [0014]
    Compound according to any one of claims 1 to 12, characterized by the fact that: R 2 is methoxy; R 3 and R 4 are hydrogen; and XéN, CH, or CF.
    [0015]
    Compound according to any one of claims 1 to 12, characterized by the fact that: R 2 is vinyl or 1-propenyl; R 3 and R 4 are hydrogen; and XéN, CH, or CF.
    [0016]
    Herbicidal composition, characterized by the fact that it comprises the compound, as defined in any one of claims 1 to 15, and an agriculturally acceptable adjuvant or vehicle.
    [0017]
    Method for controlling undesirable vegetation, characterized in that it comprises applying a herbicidally effective amount of a compound, as defined in any one of claims 1 to 15, or composition, as defined in claim 16.
    类似技术:
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    同族专利:
    公开号 | 公开日
    AU2018220080A1|2018-09-13|
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    RU2672584C2|2018-11-16|
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    CR20150561A|2016-01-12|
    WO2014151008A1|2014-09-25|
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    KR20210125575A|2021-10-18|
    ZA201507019B|2017-01-25|
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    法律状态:
    2015-10-27| B03A| Publication of a patent application or of a certificate of addition of invention [chapter 3.1 patent gazette]|
    2017-06-06| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-07-23| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2019-12-24| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2020-04-14| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-06-30| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 17/03/2014, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201361790391P| true| 2013-03-15|2013-03-15|
    US61/790,391|2013-03-15|
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