WO2012103047A1 - Process for the preparation of 4-amino-5-fluoro-3-halo-6-(substituted)picolinates - Google Patents
Process for the preparation of 4-amino-5-fluoro-3-halo-6-(substituted)picolinates Download PDFInfo
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- WO2012103047A1 WO2012103047A1 PCT/US2012/022291 US2012022291W WO2012103047A1 WO 2012103047 A1 WO2012103047 A1 WO 2012103047A1 US 2012022291 W US2012022291 W US 2012022291W WO 2012103047 A1 WO2012103047 A1 WO 2012103047A1
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- 0 *C(c(cc1N)nc(*)c1F)=O Chemical compound *C(c(cc1N)nc(*)c1F)=O 0.000 description 4
- OAAANLFMSUVBAS-UHFFFAOYSA-N CC(C)OC(c(c(Cl)c1N)nc(Cl)c1F)=O Chemical compound CC(C)OC(c(c(Cl)c1N)nc(Cl)c1F)=O OAAANLFMSUVBAS-UHFFFAOYSA-N 0.000 description 1
- MUCAKBKIVUFYQH-UHFFFAOYSA-N CC(C)OC(c(cc1Cl)nc(Cl)c1Cl)=O Chemical compound CC(C)OC(c(cc1Cl)nc(Cl)c1Cl)=O MUCAKBKIVUFYQH-UHFFFAOYSA-N 0.000 description 1
- YRGNDQQIUXCCAI-UHFFFAOYSA-N CC(C)OC(c(cc1F)nc(F)c1F)=O Chemical compound CC(C)OC(c(cc1F)nc(F)c1F)=O YRGNDQQIUXCCAI-UHFFFAOYSA-N 0.000 description 1
- WNZCDFOXYNRBRB-UHFFFAOYSA-N COc(c(Cl)ccc1-c(nc(C(OCc2ccccc2)=O)c(Cl)c2N)c2F)c1F Chemical compound COc(c(Cl)ccc1-c(nc(C(OCc2ccccc2)=O)c(Cl)c2N)c2F)c1F WNZCDFOXYNRBRB-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/83—Thioacids; Thioesters; Thioamides; Thioimides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
Definitions
- the present invention concerns a process for the preparation of 4-amino-5-fluoro-3- halo-6-(substituted)picolinates. More particularly, the present invention concerns a process for the preparation of 4-amino-5-fluoro-3-halo-6-(substituted)picolinates in which the 5- fluoro substituent is introduced by a halogen exchange early in the process scheme.
- U.S. Patent 6,297,197 B l describes inter alia certain 6-(alkoxy or aryloxy)-4-amino- 3-chloro-5-fluoropicolinate compounds and their use as herbicides.
- U.S. Patents 6,784,137 B2 and 7,314,849 B2 describe inter alia certain 6-(aryl)-4-amino-3-chloro-5-fluoropicolinate compounds and their use as herbicides.
- U.S. Patent 7,432,227 B2 describes inter alia certain 6-(alkyl)-4-amino-3-chloro-5-fluoropicolinate compounds and their use as herbicides.
- the present invention concerns a process for the preparation of 4-amino-5-fluoro-3- halo-6-(substituted)picolinates from 4,5,6-trichloropicolinates. More particularly, the present invention concerns a process for the preparation of a 4-amino-5-fluoro-3-halo-6- (substituted)picolinate of the Formula I
- W represents CI, Br or I
- R represents C1-C4 alkyl, cyclopropyl, C2-C4 alkenyl or phenyl substituted with from 1 to 4 substituents independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy;
- R 1 represents C1-C12 alkyl or an unsubstituted or substituted C7-C11 arylalkyl; which comprises the following steps: a) fluorinating a 4,5,6-trichloropicolinate of Formula A
- R 1 is as previously defined; with a source of fluoride ion to produce a 4,5,6-trifluoropicolinate of Formula B wherein R 1 is as previously defined; b) aminating the 4,5,6-trifluoropicolinate of Formula B with ammonia to produce a 4- amino-5,6-difluoropicolinate of Formula C
- R 1 is as previously defined; c) exchanging the fliioro substituent in the 6-position of the 4-amino-5,6-difluoro- picolinate of Formula C with an iodo, bromo or chloro substituent by treating with an iodide, bromide or chloride source to produce a 4-amino-5-fluoro-6-halopicolinate of Formula D
- W and X independently represent CI, Br and R 1 is as previously defined; and e) coupling the 4-amino-3,6-dihalo-5-fluoropicolinate of Formula E with an aryl, alkyl or alkenyl metal compound of the Formula F
- R-Met F wherein R is as previously defined and Met represents Zn-halide, Zn-R, tri-
- the present invention concerns a process for the preparation of a 4-amino-5-fluoro-3-halo-6-(substituted)picolinate of the Formula I
- W represents CI, Br or I
- R represents C1-C4 alkyl, cyclopropyl, C2-C4 alkenyl, or phenyl substituted with from 1 to 4 substituents independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy;
- R 1 represents C1-C12 alkyl or an unsubstituted or substituted C7-C11 arylalkyl; which comprises the following steps: a) fluorinating a 4,5,6-trichloropicolinate of Formula A
- R 1 is as previously defined; with a source of fluoride ion to produce a 4,5,6-trifluoropicolinate of Formula B
- R 1 is as previously defined; b) aminating the 4,5,6-trifluoropicolinate of Formula B with ammonia to produce a 4- amino-5,6-difluoropicolinate of Formula C
- R 1 is as previously defined; c) exchanging the fliioro substituent in the 6-position of the 4-amino-5,6-difluoro picolinate of Formula C with an iodo, bromo or chloro substituent by treating with an iodide, bromide or chloride source to produce a 4-amino-5-fluoro-6-halopicolinate of Formula D
- R-Met F wherein R is as previously defined and Met represents Zn-halide, Zn-R, tri- (C 1 -C4 alkyl)tin, copper, or B(OR 2 )(OR 3 ), where R 2 and R 3 are independent of one another, hydrogen, C 1 -C4 alkyl, or when taken together form an ethylene or propylene group in the presence of a transition metal catalyst to produce the 4-amino-5-fluoro-6-(substituted)- picolinate of Formula G.
- W represents CI, Br or I
- R represents C1-C4 alkyl, cyclopropyl, C2-C4 alkenyl or phenyl substituted with from 1 to 4 substituents independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy;
- R 1 represents C1-C12 alkyl or an unsubstituted or substituted C7-C11 arylalkyl; which comprises the following steps: a) coupling a 4,5,6-trichloropicolinate of Formula A wherein R 1 is as previously defined; with an aryl, alkyl or alkenyl metal compound of the Formula F
- R-Met F wherein R is as previously defined and Met represents Zn-halide, Zn-R, tri-
- R 1 is as previously defined; c) aminating the 4,5-difluoro-6-(substituted)picolinate of Formula J with ammonia to produce a 4-amino-5-fluoro-6-(substituted)picolinate of Formula K wherein R and R 1 are as previously defined; and d) halogenating the 4-amino-5-fluoro-6-(substituted)picolinate of Formula K with a halogen source to produce the 4-amino-5-fluoro-3-halo-6-(substituted)picolinate of Formula I.
- ester substituent R 1
- R 1 may optionally be exchanged with a different R 1 substituent.
- esters including unsubstituted or substituted C7-C11 arylalkyl esters, can be prepared by direct esterification or transesterification reactions using techniques which are well known in the art.
- Another aspect of the present invention is the novel intermediates produced during the present process, viz-, compounds selected from the group consisting of : a)
- R represents C1-C4 alkyl, cyclopropyl, C2-C4 alkenyl or phenyl substituted with from 1 to 4 substituents independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy and R 1 represents C1-C12 alkyl or an unsubstituted or substituted C7-C11 arylalkyl; b)
- X represents I, Br, CI or F
- Y 1 represents H, CI, Br, or I with the proviso that when X is CI, Y 1 is H, Br or I
- R 1 represents C1-C12 alkyl or an unsubstituted or substituted C7-C11 arylalkyl
- Y 2 represents H, Br or I
- R represents C1-C4 alkyl, cyclopropyl, C2-C4 alkenyl or phenyl substituted with from 1 to 4 substituents independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy, and R 1 represents C1-C12 alkyl or an unsubstituted or substituted C7-C11 arylalkyl; and d)
- R represents C1-C4 alkyl, cyclopropyl, C2-C4 alkenyl, or phenyl substituted with from 1 to 4 substituents independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy, and R 1 represents C1-C12 alkyl or an unsubstituted or substituted C7-C11 arylalkyl.
- alkyl alkenyl and “alkynyl,” as well as derivative terms such as “alkoxy,” “acyl,” “alkylthio” and “alkylsulfonyl,” as used herein, include within their scope straight chain, branched chain and cyclic moieties. Unless specifically stated otherwise, each may be unsubstituted or substituted with one or more substituents selected from but not limited to halogen, hydroxy, alkoxy, alkylthio, Ci-Ce acyl, formyl, cyano, aryloxy or aryl, provided that the substituents are sterically compatible and the rules of chemical bonding and strain energy are satisfied.
- alkenyl and alkynyl are intended to include one or more unsaturated bonds.
- arylalkyl refers to a phenyl substituted alkyl group having a total of 7 to 11 carbon atoms, such as benzyl (-CH2C6H5), 2-methylnaphthyl (-CH2C1 0 H7) and 1- or 2-phenethyl (-CH 2 CH 2 C6H 5 or -CH(CH 3 )C 6 H 5 ).
- substituents independently selected from halogen, nitro, cyano, Ci-C 6 alkyl, Ci-C 6 alkoxy, halogenated Ci-C 6 alkyl, halogenated Ci-C 6 alkoxy, Ci-C 6 alkylthio, C(0)OCi-C6alkyl, or where two adjacent substituents are taken together as -0(CH 2 )
- halogen refers to fluorine, chlorine, bromine and iodine.
- the 6-phenyl groups substituted with from 1 to 4 substituents independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy may be of any orientation, but 4-substituted phenyl, 2,4-disubstituted phenyl, 2,3,4-trisubstituted phenyl, 2,4,5-trisubstituted phenyl, and 2,3,4,6-tetrasubstituted phenyl isomers are preferred.
- the 4-amino-5-fluoro-3-halo-6-(substituted)picolinates are prepared from 4,5,6- trichloropicolinates by a series of steps involving fluorine exchange, amination, halogen exchange, halogenation and transition metal assisted coupling. The individual steps may be performed in different sequences.
- the 4,5,6-trichloropicolinate starting materials are known compounds; see, for example, Example 3 in U.S. Patent 6,784,137 B2.
- Higher esters, including unsubstituted or substituted C7-C11 arylalkyl esters, can be prepared by direct esterification or
- the fluorinated picolinate is prepared by reacting the corresponding chlorinated picolinate with at least one equivalent of fluoride ion source for each ring chlorine substituent to be exchanged.
- Typical fluoride ion sources are alkali metal fluorides which include sodium fluoride (NaF), potassium fluoride (KF) and cesium fluoride (CsF), with KF and CsF being preferred.
- Fluoride salts such as tetrabutylammonium fluoride (n-Bu 4 NF) may also be used.
- the reaction is carried out in a polar aprotic solvent or reaction medium such as,
- DMSO dimethylsulf oxide
- ⁇ N-methylpyrrolidinone
- ⁇ NN-dimethylformamide
- HMPA hexamethylphosphoramide
- Additives such as crown ethers or phase transfer agents which are known to increase the rate of fluoride exchange may also be used.
- the temperature at which the reaction is conducted is not critical but usually is from 70 °C to 180 °C and preferably from 80 °C to 120 °C. Depending upon which solvent is employed in a particular reaction, the optimum temperature will vary. Generally speaking the lower the temperature the slower the reaction will proceed.
- the present reaction is typically conducted in the presence of vigorous agitation sufficient to maintain an essentially uniformly dispersed mixture of the reactants.
- an amount of alkali metal fluoride which will supply at least an equimolar amount of fluorine atoms based on the number of chlorine atoms to be exchanged in the starting material, i. e. , at least an equimolar amount of alkali metal fluoride.
- an amount of alkali metal fluoride which will supply at least an equimolar amount of fluorine atoms based on the number of chlorine atoms to be exchanged in the starting material, i. e. , at least an equimolar amount of alkali metal fluoride.
- a 4-fluoropicolinate is allowed to react with ammonia to replace the fluorine atom with an amino group.
- reaction is carried out in an inert solvent, preferably, a polar aprotic solvent or reaction medium such as DMSO, NMP, DMF, HMPA or sulfolane.
- a polar aprotic solvent or reaction medium such as DMSO, NMP, DMF, HMPA or sulfolane.
- aqueous ammonium hydroxide can be used, with or without use of an organic solvent.
- the temperature at which the reaction is conducted is not critical but usually is from 0 °C to 45 °C and preferably from 10 °C to 30 °C.
- the 4-fluoropicolinate is dissolved in the solvent, and the ammonia is added to the reaction mixture with cooling. Excess ammonia gas is typically bubbled into the reaction mixture.
- a typical reaction generally requires from 0.5 to 5 hours and is usually conducted at ambient atmospheric pressure.
- the amine-containing products or intermediates obtained by any of these processes can be recovered by conventional means, such as evaporation or extraction, and can be purified by standard procedures, such as recrystallization or chromatography. Purification of the amine-containing products or intermediates can also be affected by protonation with an acid to form a salt which is isolated in higher purity by crystallization, precipitation or extraction.
- a variety of acids such as hydrochloric acid, hydrobromic acid, nitric acid, acetic acid or sulfuric acid, can be used. Anhydrous hydrochloric acid is a preferred acid.
- the purified salt is then neutralized with a base to form the neutral amine-containing product or intermediate.
- Inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or sodium bicarbonate may be used.
- Organic bases such as triethylamine are preferred. Purification of the amine-containing product or intermediate may be performed in this manner immediately after the amination step, or after subsequent reactions, e.g,. halogenation, coupling, have been preformed.
- the 6-iodinated, 6-brominated or 6-chlorinated picolinate is prepared by reacting the corresponding 6- fluorinated picolinate with at least one equivalent of iodide, bromide or chloride.
- the halogen exchange reaction is carried out in the presence of a large excess of anhydrous hydrogen iodide (HI), hydrogen bromide (HBr) or hydrogen chloride (HC1).
- HI anhydrous hydrogen iodide
- HBr hydrogen bromide
- HC1 hydrogen chloride
- the reaction is typically performed in the absence of water to minimize the formation of byproducts.
- the halogen exchange generally requires from 5 to 50 equivalents of HI, HBr or HC1, preferably from 10 to 20 equivalents.
- the reaction is carried out in an inert solvent, preferably, a polar solvent such as dioxane or acetic acid.
- the temperature at which the reaction is conducted is not critical but usually is from 75 °C to 150 °C and preferably from 100 °C to 125 °C.
- the reaction is typically performed in a sealed pressure reactor which is capable of containing HI, HBr or HC1 gas.
- a typical reaction generally requires from 0.5 to 5 hours.
- halogenation reaction a chlorine, bromine or iodine atom is introduced into the 3-position of the picolinate by reacting the 3-unsubstituted picolinate with a halogen source in an inert solvent.
- the chlorine source can be chlorine (Cl 2 ) itself or reagents such as sulfuryl chloride, N-chlorosuccinimide or l,3-dichloro-5,5- dimethylhydantoin.
- chlorine or sulfuryl chloride a large excess of chlorinating agent is used.
- chlorine gas the reaction is performed in an inert solvent, preferably, a solvent such as dichloromethane, dichloromethane-water or acetic acid.
- sulfuryl chloride the reaction can be performed in an inert solvent, such as dichloromethane or in neat sulfuryl chloride.
- the temperature at which the reaction is conducted is not critical but usually is from 0 °C to 45 °C and preferably from 10 °C to 30 °C. A typical reaction generally requires from 0.5 to 5 hours.
- the chlorination reaction is usually conducted at ambient atmospheric pressure.
- the reaction is carried out using a stoichiometric amount of chlorinating reagent.
- chlorinating agent used is N-chlorosuccinimide or l,3-dichloro-5,5- dimethylhydantoin
- the reaction is carried out using a stoichiometric amount of chlorinating reagent.
- l,3-dichloro-5,5-dimethylhydantoin both chlorines in the hydantoin are found to react.
- the reaction is performed in an inert polar solvent, such as DMF or acetonitrile.
- the temperature at which the reaction is conducted is not critical but usually is from 20 °C to 85 °C and preferably from 50 °C to 80 °C.
- acetonitrile is used as solvent, it is convenient to carry out the reaction at the reflux temperature.
- a typical reaction generally requires from 0.5 to 5 hours.
- the chlorination reaction is usually conducted at ambient atmospheric pressure.
- the bromine source can be bromine (Br 2 ) itself or reagents such as sulfuryl bromide, N-bromosuccinimide or l,3-dibromo-5,5- dimethylhydantoin.
- Br 2 is used as the brominating agent, a large excess can be employed, and the reaction is performed in an inert solvent, preferably, a solvent such as dichloromethane, dichloromethane-water or acetic acid.
- the temperature at which the reaction is conducted is not critical but usually is from 0 °C to 45 °C and preferably from 10 °C to 30 °C. A typical reaction generally requires from 0.5 to 5 hours.
- the bromination reaction is usually conducted at ambient atmospheric pressure.
- the reaction is carried out using a stoichiometric amount of brominating reagent.
- the reaction is performed in an inert polar solvent, such as DMF or acetonitrile.
- the temperature at which the reaction is conducted is not critical but usually is from 20 °C to 85 °C and preferably from 50 °C to 80 °C.
- acetonitrile is used as solvent, it is convenient to carry out the reaction at the reflux temperature.
- a typical reaction generally requires from 0.5 to 5 hours.
- the bromination reaction is usually conducted at ambient atmospheric pressure.
- the iodine source can be iodine (I 2 ) itself or reagents such as iodine monochloride or N-iodosuccinimide. Periodic acid may be used in conjunction with I 2 .
- I 2 is used as the iodinating agent, a large excess of I 2 can be employed, and the reaction is performed in an inert solvent, preferably, a solvent such as dichloromethane, dichloromethane-water, methyl alcohol or acetic acid.
- the temperature at which the reaction is conducted is not critical but usually is from 0 °C to 45 °C and preferably from 10 °C to 30 °C. A typical reaction generally requires from 0.5 to 5 hours.
- the iodination reaction is usually conducted at ambient atmospheric pressure.
- a 6-iodo, bromo or choropicolinate is reacted with an aryl, alkyl or alkenyl metal compound where the metal is a Zn-halide, Zn-R, tri-(Ci-C4 alkyl)tin, copper, or B(OR 2 )(OR 3 ), where R 2 and R 3 are independent of one another, hydrogen, CrC 4 alkyl, or when taken together form an ethylene or propylene group, in the presence of a transition metal catalyst.
- Catalyst is a transition metal catalyst, in particular a palladium catalyst such as palladium diacetate or bis(triphenylphosphine)palladium(II) dichloride, or a nickel catalyst such as nickel(II) acetylacetonate or bis(triphenylphosphine)nickel(II) dichloride.
- catalysts can be prepared in situ from metal salts and ligands, such as palladium acetate and triphenylphosphine or nickel(II) chloride and triphenylphosphine. These in situ catalysts can be prepared by prior reaction of metal salt and ligand, followed by addition to the reaction mixture, or by separate addition of the metal salt and ligand directly to the reaction mixture.
- coupling reactions are carried out in the absence of oxygen using an inert gas, such as nitrogen or argon.
- an inert gas such as nitrogen or argon.
- Additional amounts of ligand may optionally be added to increase catalyst stability and activity.
- additives such as Na 2 CC>3, K2CO 3 , KF, CsF and NaF are typically added to the coupling reaction.
- the coupling reaction generally requires from 1 to 5 equivalents of such additive, preferably from 1 to 2 equivalents.
- Water may optionally be added to the coupling reaction to increase the solubility of these additives.
- the coupling reaction generally requires from 1 to 3 equivalents of an aryl, alkyl or alkenyl metal compound, preferably from 1 to 1.5 equivalents.
- the reaction is carried out in an inert solvent, such as toluene, tetrahydrofuran (THF), dioxane or acetonitrile.
- the temperature at which the reaction is conducted is not critical but usually is from 25 °C to 150 °C and preferably from 50 °C to 125 °C.
- a typical reaction generally requires from 0.5 to 24 hours. No particular order of addition of reactants is typically required. It is often operationally simpler to combine all reactants except the catalyst and then deoxygenate the reaction solution.
- the catalyst can be added to commence the coupling reaction.
- the Met portion of the aryl, alkyl or alkenyl metal compound is a Zn-halide, Zn-R or copper
- protection of reactive functional groups may be necessary.
- an amino substituent -NHR or -NH 2
- protection of these reactive groups may be required.
- a variety of groups are known in the art for protection of amino groups from reaction with organometallic reagents. Examples of such protecting groups are described in rd
- the products obtained by any of these processes can be recovered by conventional means, such as evaporation or extraction, and can be purified by standard procedures, such as recrystallization or chromatography.
- Methyl 4,5,6-trichloropicolinate 14.19 grams (g), 59.0 millimoles (mmol) was slurried in 2-propanol (150 milliliters (mL)) in a 250 mL round bottom flask equipped with a Dean-Stark trap and a reflux condenser. Sulfuric acid (98% H 2 SO 4 ; 8.07 g, 82 mmol) was added, and the reaction mixture was heated to reflux. After 20 hours (h) at reflux, the majority of the 2-propanol (100 mL) was distilled overhead. The pot solidified upon cooling to room temperature.
- CDCI3 ⁇ 162.0 (C0 2 R), 150.4, 145.0, 144.9, 134.7, 133.1, 128.3 (phenyl CH), 125.4 (pyridine CH), 67.88 ( H 2 Ph).
- a 22 L round bottom flask was fitted with a thermocouple, mechanical stirrer and a Dean-Stark trap which was connected to a nitrogen bubbler.
- the vessel was purged with nitrogen and then 4,5,6-trichloropicolinate (2547 g, 10.07 mol), pyridinium p-toluene sulfonate (PPTS; 130 g, 0.52 mol), benzyl alcohol (2249 g, 20.8 mol) and xylenes (10278 g) were added.
- PPTS pyridinium p-toluene sulfonate
- benzyl alcohol 2249 g, 20.8 mol
- xylenes 10278 g
- the total amount of distillate collected was 4750 g (415 g was water). After the water stopped distilling overhead, a reactor sample was taken and analyzed by high-performance liquid chromatography (HPLC) to ensure less than 1.5 area of starting carboxylic acid remained. The reaction was allowed to cool to room temperature and stirred overnight. Xylenes (4000 g) were removed by vacuum distillation. The solution was cooled to 85-100 °C and then vacuum transferred to a 30 L jacketed crystallization vessel that had been fitted with a mechanical stirrer and thermocouple. The vacuum was released with nitrogen and a nitrogen bubbler was placed on the crystallization vessel. To the xylene solution was added isopropyl alcohol (IPA; 6200 g) over 15 minutes (min).
- IPA isopropyl alcohol
- the resulting slurry was allowed to cool slowly to room temperature and then cooled further to 5 °C.
- the solid was collected by filtration, and the cake was washed with cold (5-10 °C) IPA (3731 g).
- the solid was dried in air to a constant weight providing white crystals (2765 g, gas chromatography (GC) internal standard purity 96.5 %, 84.3%).
- a 250 mL three-neck flask was equipped with a mechanical stirrer, a Dean-Stark trap with nitrogen inlet and a thermocouple. The flask was purged with nitrogen and CsF (23.38 g, 154 mmol) was added. Anhydrous DMSO (124 mL) was added, and the suspension was evacuated/backfilled (5x) with nitrogen. The suspension was heated at 80 °C for 30 min. DMSO (20 mL) was distilled off under vacuum at 75 °C to remove any residual water.
- Propan-2-yl 4,5,6-trichloropicolinate (13.45 g, 50.1 mmol) was added against a nitrogen purge.
- the reaction mixture was evacuated/backfilled (3x) and heated at 100 °C for 1 h with vigorous stirring.
- a second 250 mL three-neck flask was equipped with a mechanical stirrer, a Dean- Stark trap with nitrogen inlet and a thermocouple.
- the flask was purged with nitrogen and CsF (24.41 g, 0.160 mmol) was added.
- Anhydrous DMSO (30 mL) was added, and the suspension was evacuated/backfilled (5x) with nitrogen.
- the suspension was heated to 80 °C for 30 min.
- DMSO (22 mL) was distilled off under vacuum at 75 °C to remove residual water.
- the cooled reaction mixture in the first flask was cannula filtered into the second flask under nitrogen.
- the reaction mixture was evacuated/backfilled (5x) and then heated to 100 °C for 1 h and then for an additional 90 min at 110 °C. Analysis of an aliquot by GC showed 96% propan-2-yl 4,5,6-trifluoropicolinate with only 1.4% propan-2-yl 5-chloro-4,6- difluoropicolinate present.
- the crude product solution was used directly in the amination step without further purification.
- the product can be isolated by aqueous workup, extraction with EtOAc and drying to give a light tan oil:
- a 250 mL three-neck flask was equipped with a distillation head, a nitrogen inlet, a mechanical stirrer and a thermocouple.
- the flask was charged with CsF (14.2 g, 93.0 mmol)
- Anhydrous DMSO (80 mL) was added, and the suspension was evacuated/backfilled (5x) with nitrogen.
- the suspension was heated at 80 °C for 30 min.
- DMSO (20 mL) was distilled off under vacuum to remove any residual water.
- Solid propan-2-yl 4,5-dichloro-6-(4-chloro- 2-fluoro-3-methoxyphenyl)picolinate (10.44 g, 26.6 mmol) was added, and the solution was evacuated/backfilled with nitrogen (5x). The reaction mixture was heated to 105 °C under nitrogen. After 4 h at 105 °C, analysis of an aliquot by GC showed a 91:6 ratio of difluoro to monofluoro products. The reaction mixture was allowed to cool to room temperature.
- a second 250 mL three-neck flask was equipped with a mechanical stirrer, a distillation head with a nitrogen inlet and a thermocouple.
- the flask was purged with nitrogen and CsF (7.5 g, 49.4 mmol) was added.
- Anhydrous DMSO (20 mL) was added, and the suspension was evacuated/backfilled (5x) with nitrogen.
- the suspension was heated at 80 °C for 30 min.
- DMSO (15 mL) was distilled off under vacuum to remove residual water.
- the cooled reaction mixture in the first flask was cannula filtered into the second flask under nitrogen.
- the reaction mixture was evacuated/backfilled (5x) and then heated to 100 °C for 2 h.
- the reaction mixture was poured into ice-water (400 g) and was extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with satd NaHCC>3 solution, water (5 x 100 mL) and brine. The extracts were dried (MgS0 4 ) and concentrated under reduced pressure to give a tan solid (12.97 g).
- a 22 L straight wall jacketed reactor was fitted with an overhead stirrer, condenser, nitrogen inlet and outlet, and a stoppered solids loading port.
- the reactor was purged with nitrogen for 2 days.
- the loading port was opened, and benzyl 4,5-dichloro-6-(4-chloro-2- fluoro-3-methoxyphenyl)picolinate (2032 g, 4.12 mol, 89.3% purity) was quickly added to the reactor.
- CsF (2500 g, 16.46 mol) was quickly poured into the reactor.
- the reactor was next loaded with anhydrous ( ⁇ 100 ppm water) DMSO (8869 g). The mixture was heated to 110 °C for 2 h.
- the reaction mixture from Example la was filtered to remove Cs salts, and the salts were washed with DMSO (50 mL).
- the DMSO washing solution was added to the DMSO solution (150 mL) which had been saturated with ammonia for 15 min.
- the flask was kept in a cold bath which kept the temperature near 16 °C.
- Ammonia was bubbled through the reaction mixture for 30 min, during which time a white precipitate formed. After 90 min, analysis of an aliquot by GC showed a single major peak for the 4-amino product.
- the reaction mixture was quenched by addition of satd aq ammonium chloride (NH 4 C1) solution (100 mL) followed by water (400 mL).
- Propan-2-yl 4,5-difluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (4.89 g, 13.9 mmol) was dissolved in DMSO (100 mL). Ammonia was bubbled through the solution for a total of 100 min over the course of 48 h. The reaction mixture was poured into ice- water (500 mL). The product was extracted into EtOAc (3 x 250 mL).
- Benzyl 4,5-difluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (4.99 g, 12.2 mmol) was slurried in DMSO (100 mL). Ammonia was bubbled through the solution for 30 min. After stirring overnight, the reaction mixture was poured into ice-water (500 mL). The product was extracted into EtOAc (3 x 150 mL).
- Propan-2-yl 4-amino-5,6-difluoropicolinate (4.25 g, 19.7 mmol) was dissolved in hydrochloric acid (HC1, 4 M in dioxane; 65 mL) in a 100 mL Hastalloy stirred Parr reactor. The reactor was heated to 100 °C for 2 h. Upon standing at room temperature overnight, a yellow crystalline solid formed. This solid was not soluble in EtOAc, but did dissolve upon shaking with satd aq NaHCC>3 solution (500 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2 x 250 mL).
- Propan-2-yl 4-amino-6-chloro-5 -fluoropicolinate (1.191 g, 5.12 mmol) was almost completely dissolved in CH 2 C1 2 (40 mL). Water (40 mL) was added. Chlorine was bubbled through the solution for 5 min. After 30 min, an aliquot of the reaction mixture was analyzed by GC, showing desired product and only 1.7% starting material. The aqueous layer was separated and extracted with CH 2 C1 2 (50 mL). The combined organic extracts were washed with satd aq NaHCC>3 solution and then brine. The extracts were dried (MgS0 4 ) and concentrated under reduced pressure to yield an orange oil.
- Propan-2-yl 4-amino-6-chloro-5-fluoropicolinate (634 milligrams (mg), 2.73 mmol) was slurried in acetonitrile (11 mL). l,3-Dichloro-5,5-dimethyl-hydantoin (303 mg, 1.54 mmol) was added as a solid, and the reaction mixture was stirred at reflux for 2.5 h.
- Methyl 4-amino-6-chloro-5-fluoropicolinate (1.0 g, 4.9 mmol) was combined with l,3-dibromo-5,5-dimethylhydantoin (1.7 g, 5.9 mmol) in 1,2-dichloroethane (15 mL) and heated at reflux (83 °C) for 4 h. The cooled mixture was stirred with 10% NaHSC>3 solution and EtOAc (30 mL). The organic phase was separated, washed with water (2 x 20 mL), brine (10 mL), dried (Na 2 S0 4 ) and concentrated.
- Methyl 4-amino-6-chloro-5-fluoropicolinate (2.2 g, 10.8 mmol) was dissolved in methyl alcohol (CH 3 OH; 20 mL). The solution was treated with periodic acid (880 mg, 3.9 mmol) and iodine (2.2 g, 8.6 mmol) and then heated to reflux for 20 h. The mixture was cooled, and the volatiles were removed under vacuum. The residue was dissolved in EtOAc (50 mL) and then stirred with 10% NaHSC>3 solution (20 mL) for 10 min. The organic phase was separated and washed with brine (10 mL), dried (Na 2 S0 4 ) and evaporated.
- Propan-2-yl 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (3.065 g, 8.59 mmol) was dissolved in sulfuryl chloride (150 mL). The solution was stirred under nitrogen at room temperature for 8 h. During this time, a white precipitate formed. Hexane (100 mL) was added, and the mixture was stored overnight at -20 °C. The product was filtered, washed with hexane and then slurried in EtOAc (100 mL). The organic suspension was neutralized with satd aq NaHCC>3 solution, which caused all solids to dissolve.
- Benzyl 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate (2.07 g, 5.12 mmol) was slurried in acetonitrile (20 mL) in a scintillation vial.
- l,3-Dichloro-5,5- dimethylhydantoin (554 mg, 2.181 mmol) was added as a solid, and the reaction mixture was stirred at reflux for 1 h. After cooling to room temperature, water (40 mL) was added to precipitate the product. The solid was collected on a Buchner funnel and washed with water.
- the reaction mixture was allowed to cool to room temperature and was then added dropwise to a dilute sodium bisulfite (NaHSC ⁇ ) solution (990 mL, 7.5 g of NaHSC ⁇ ) over 1 h.
- NaHSC ⁇ sodium bisulfite
- the resulting precipitate was isolated by filtration, washed with acetonitrile-water (1:1 v/v, 2 x 50 mL) and then water (2 x 50 mL).
- the solid was dried to give a pale yellow powder (53.44 g, 94%, 96.1% HPLC purity (octanophenone internal standard)).
- Propan-2-yl 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (600 mg, 1.682 mmol) was dissolved in acetic acid (5.6 mL). Sodium acetate (1.5 g, 18.50 mmol) was added followed by iodine monochloride (2.2 g, 13.45 mmol). An exotherm of approximately 10 °C was observed during the addition. The reaction mixture was heated at 80 °C for 20 h. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with water, satd aq NaHCC>3 solution, dried (MgS0 4 ) and then concentrated to dryness.
- the solution was evacuated/backfilled with nitrogen (5x) and then heated at 70 °C under nitrogen for 3 h. After 3 h, the reaction mixture was allowed to cool to room temperature. The aqueous layer was separated. Water (20 mL) was added to the organic layer. The resulting dark brown precipitate was filtered and washed with water. The solid was dissolved in EtOAc (60 mL) and filtered to remove a small amount of black solid. The EtOAc solution was treated with activated carbon (175 mg) and filtered to give a wine- colored solution. Evaporation under reduced pressure gave a dark red solid.
- Propan-2-yl 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (1.50 g, 71% purity by LC area) was added to tetrahydrofuran (THF; 10 mL) and heated to 40 °C to provide a clear yellow solution.
- the solution was allowed to cool to room temperature and HQ (4 M in dioxane; 1.3 mL, 5.2 mmol) was added. After addition of HQ, solids precipitated from the solution and the reaction mixture was cooled to 0 °C. The solids were isolated by vacuum filtration and washed with cold THF (5 mL).
- the salt wet cake was added to THF (10 mL) and water (5 mL). Triethylamine (Et 3 N; 0.8 mL, 5.7mmol) was added to the mixture and the reaction mixture formed a clear biphasic solution.
- the reaction mixture was transferred to a separatory funnel, and the organic layer was separated. Hexanes (20 mL) was added to the organic layer and solids precipitated from solution. The reaction mixture was cooled to 0 °C and allowed to stir for 30 min.
- the salt wet cake was added to dichloromethane (10 mL) and water (5 mL).
- Et 3 N (0.6 mL, 4.3 mmol) was added to the mixture, and the reaction mixture formed a clear biphasic solution.
- the reaction mixture was transferred to a separatory funnel, and the organic layer was separated. Hexanes (20 mL) was added to the organic layer and solids precipitated from solution.
- the reaction mixture was cooled to 0 °C, and the solids were isolated by vacuum filtration and washed with hexanes (10 mL).
- Benzyl 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (3.00 g,7.41mmol) was added to CH 3 OH (35 mL).
- Sodium methoxide 25 wt% in CH 3 OH; 2.0 mL, 8.9mmol ) was added to the reaction mixture and allowed to stir for 24 h.
- Water 50 mL was added to the reaction mixture and the mixture was concentrated under reduced pressure to remove most of the CH 3 OH.
- Methyl 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate_(l .50 g, 67% purity by LC area) was added to THF (10 mL) and dichloromethane (5 mL), and the mixture was heated to 40 °C to provide a clear yellow solution.
- the solution was allowed to cool to room temperature and HC1 (4 M in dioxane; 1.4 mL, 5.6 mmol) was added. After addition of HC1, solids precipitated from the solution, and the reaction mixture was cooled to 0 °C. The solid was isolated by vacuum filtration and washed with cold THF (5 mL).
- the salt wet cake was added to THF (25 mL) and water (10 mL).
- Et 3 N (0.8 mL,5.7mmol) was added to the mixture, and the reaction mixture formed a clear biphasic solution.
- the reaction mixture was transferred to a separatory funnel, and the organic layer was separated and concentrated to a solution of -10 mL.
- Hexanes (20 mL) was added to the organic layer, and solids precipitated from solution.
- the reaction mixture was cooled to 0 °C, and the solids were isolated by vacuum filtration and washed with hexanes (10 mL).
- Methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate (1.25 g, 88% purity by LC area) was added to dichloromethane (15 mL) and THF (3 mL), and the mixture was heated to 40 °C to provide a clear yellow solution. The solution was allowed to cool to room temperature, and HC1 (4 M in dioxane; 0.95 mL,3.8mmol) was added. After addition of HC1, solids precipitated from the solution, and the reaction mixture was cooled to 0 °C. The solid was isolated by vacuum filtration and washed with cold dichloromethane (5 mL).
- the salt wet cake was added to dichloromethane (20 mL) and water (10 mL).
- Et 3 N (0.6 mL,4.3mmol) was added to the mixture, and the reaction mixture formed a clear biphasic solution.
- the reaction mixture was transferred to a separatory funnel, and the organic layer was separated and concentrated under reduced pressure to a solution of -10 mL.
- Hexanes (20 mL) was added to the organic layer and solids precipitated from solution.
- the reaction mixture was cooled to 0 °C, and the solids were isolated by vacuum filtration and washed with hexanes (10 mL).
- This solid was slurried with dichloromethane (30 mL) and water (15 mL), and Et 3 N (1.98 mL,14.2mmol) was added. The solids dissolved to give a two phase mixture. After stirring for 15 min, the mixture was transferred to a separatory funnel and the phases were allowed to separate over 15 min. The organic layer was separated, hexanes (60 mL) was added, and the mixture was cooled to below 10 °C. The solution quickly became cloudy and solids precipitated from the mixture.
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SG2013056056A SG192094A1 (en) | 2011-01-25 | 2012-01-24 | Process for the preparation of 4-amino-5-fluoro-3-halo-6-(substituted)picolinates |
JP2013551280A JP5736059B2 (en) | 2011-01-25 | 2012-01-24 | Process for the preparation of 4-amino-5-fluoro-3-halo-6- (substituted) picolinate |
UAA201310363A UA109697C2 (en) | 2011-01-25 | 2012-01-24 | METHOD OF OBTAINING 4-AMINO-5-FLUORO-3-HALOGEN-6- (SUBSTITUTED) PICOLINATES |
EP12739953.3A EP2667714B9 (en) | 2011-01-25 | 2012-01-24 | Process for the preparation of 4-amino-5-fluoro-3-halo-6-(substituted)picolinates |
BR112013018975A BR112013018975A2 (en) | 2011-01-25 | 2012-01-24 | Process for the preparation of 4-amino-5-fluoro-3-halo-6- (substituted) picolinates |
KR1020137021994A KR101547044B1 (en) | 2011-01-25 | 2012-01-24 | Process for the preparation of 4-amino-5-fluoro-3-halo-6-(substituted)picolinates |
MX2013008605A MX345293B (en) | 2011-01-25 | 2012-01-24 | Process for the preparation of 4-amino-5-fluoro-3-halo-6-(substit uted)picolinates. |
CA2825390A CA2825390A1 (en) | 2011-01-25 | 2012-01-24 | Process for the preparation of 4-amino-5-fluoro-3-halo-6-(substituted)picolinates |
RU2013139338/04A RU2545074C1 (en) | 2011-01-25 | 2012-01-24 | Method of obtaining 4-amino-5-fluoro-3-halogen-6-(substituted)picolinates |
AU2012209283D AU2012209283B8 (en) | 2011-01-25 | 2012-01-24 | Process for the preparation of 4-amino-5-fluoro-3-halo-6-(substituted)picolinates |
CN201280014371.4A CN103429081B (en) | 2011-01-25 | 2012-01-24 | The method preparing 4-amino-5-fluorine-3-halo-6-(replacement) pyridine-2-formic acid esters |
ZA2013/05578A ZA201305578B (en) | 2011-01-25 | 2013-07-23 | Process for the preparation of 4-amino-5-fluoro-3-halo-6-(substituted)picolinates |
IL227648A IL227648B (en) | 2011-01-25 | 2013-07-24 | Process for the preparation of 4-amino-5-fluoro-3-halo-6-(substituted) picolinates |
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3285925A (en) * | 1962-03-06 | 1966-11-15 | Dow Chemical Co | Amino-trichloropicolinic acid compounds |
US3325272A (en) * | 1965-06-23 | 1967-06-13 | Dow Chemical Co | Plant growth control methods and compositions |
US3629424A (en) * | 1967-12-26 | 1971-12-21 | Dow Chemical Co | Cyanofluoropyridines and fungicidal compositions and methods for using the same |
US3803159A (en) * | 1967-12-26 | 1974-04-09 | Dow Chemical Co | Fluorine containing cyanopyridines |
US6297197B1 (en) * | 2000-01-14 | 2001-10-02 | Dow Agrosciences Llc | 4-aminopicolinates and their use as herbicides |
US6784137B2 (en) * | 2001-07-30 | 2004-08-31 | Dow Agrosciences Llc | 6-aryl-4-aminopicolinates and their use as herbicides |
US20090088322A1 (en) * | 2007-10-02 | 2009-04-02 | Dow Agrosciences Llc | 2-substituted-6-amino-5-alkyl, alkenyl or alkynyl-4-pyrimidinecarboxylic acids and 6-substituted-4-amino-3- alkyl, alkenyl or alkynyl picolinic acids and their use as herbicides |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2803592A1 (en) * | 2000-01-06 | 2001-07-13 | Aventis Cropscience Sa | NOVEL DERIVATIVES OF 3-HYDROXYPICOLINIC ACID, PROCESS FOR THEIR PREPARATION AND FUNGICIDAL COMPOSITIONS CONTAINING SAME |
JP4615809B2 (en) * | 2000-01-14 | 2011-01-19 | ダウ・アグロサイエンス・エル・エル・シー | Selective electrochemical reduction of halogenated 4-aminopicolinic acids |
RU2220959C1 (en) * | 2000-01-14 | 2004-01-10 | Дау Агросайенсиз Ллс | 4-aminopicolinates and their application as herbicides |
UA82358C2 (en) * | 2003-04-02 | 2008-04-10 | Дау Агросайенсиз Ллс | 6-alkyl or alkenyl-4-amionopicolinates, herbicidal composition, method for controlling undesirable vegetation |
WO2006062979A1 (en) * | 2004-12-06 | 2006-06-15 | E.I. Dupont De Nemours And Company | Herbicidal 6-cyclopropyl-substitute 4-aminopicolinic acid derivatives |
CA2626103C (en) * | 2006-01-13 | 2013-07-30 | Dow Agrosciences Llc | 6-(poly-substituted aryl)-4-aminopicolinates and their use as herbicides |
US8252938B2 (en) * | 2009-06-08 | 2012-08-28 | Dow Agrosciences, Llc. | Process for the preparation of 6-(aryl)-4-aminopicolinates |
GB0910766D0 (en) * | 2009-06-22 | 2009-08-05 | Syngenta Ltd | Chemical compounds |
GB201008290D0 (en) * | 2010-05-18 | 2010-06-30 | Syngenta Ltd | Chemical compounds |
-
2012
- 2012-01-20 TW TW101102581A patent/TWI529163B/en not_active IP Right Cessation
- 2012-01-24 CA CA2825390A patent/CA2825390A1/en not_active Abandoned
- 2012-01-24 UA UAA201310363A patent/UA109697C2/en unknown
- 2012-01-24 SG SG2013056056A patent/SG192094A1/en unknown
- 2012-01-24 PL PL12739953T patent/PL2667714T3/en unknown
- 2012-01-24 AU AU2012209283D patent/AU2012209283B8/en active Active
- 2012-01-24 MX MX2013008605A patent/MX345293B/en active IP Right Grant
- 2012-01-24 US US13/356,691 patent/US8609855B2/en active Active
- 2012-01-24 AR ARP120100233A patent/AR085021A1/en unknown
- 2012-01-24 BR BR112013018975A patent/BR112013018975A2/en not_active Application Discontinuation
- 2012-01-24 JP JP2013551280A patent/JP5736059B2/en active Active
- 2012-01-24 RU RU2013139338/04A patent/RU2545074C1/en not_active IP Right Cessation
- 2012-01-24 WO PCT/US2012/022291 patent/WO2012103047A1/en active Application Filing
- 2012-01-24 CN CN201280014371.4A patent/CN103429081B/en active Active
- 2012-01-24 KR KR1020137021994A patent/KR101547044B1/en active IP Right Grant
- 2012-01-24 EP EP12739953.3A patent/EP2667714B9/en active Active
- 2012-01-24 BR BR102012001633-8A patent/BR102012001633A2/en not_active Application Discontinuation
-
2013
- 2013-07-23 ZA ZA2013/05578A patent/ZA201305578B/en unknown
- 2013-07-24 IL IL227648A patent/IL227648B/en active IP Right Grant
- 2013-07-25 CO CO13175767A patent/CO6731130A2/en unknown
- 2013-10-09 US US14/049,664 patent/US8927731B2/en active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3285925A (en) * | 1962-03-06 | 1966-11-15 | Dow Chemical Co | Amino-trichloropicolinic acid compounds |
US3325272A (en) * | 1965-06-23 | 1967-06-13 | Dow Chemical Co | Plant growth control methods and compositions |
US3629424A (en) * | 1967-12-26 | 1971-12-21 | Dow Chemical Co | Cyanofluoropyridines and fungicidal compositions and methods for using the same |
US3803159A (en) * | 1967-12-26 | 1974-04-09 | Dow Chemical Co | Fluorine containing cyanopyridines |
US6297197B1 (en) * | 2000-01-14 | 2001-10-02 | Dow Agrosciences Llc | 4-aminopicolinates and their use as herbicides |
US6784137B2 (en) * | 2001-07-30 | 2004-08-31 | Dow Agrosciences Llc | 6-aryl-4-aminopicolinates and their use as herbicides |
US20090088322A1 (en) * | 2007-10-02 | 2009-04-02 | Dow Agrosciences Llc | 2-substituted-6-amino-5-alkyl, alkenyl or alkynyl-4-pyrimidinecarboxylic acids and 6-substituted-4-amino-3- alkyl, alkenyl or alkynyl picolinic acids and their use as herbicides |
US20100041556A1 (en) * | 2007-10-02 | 2010-02-18 | Dow Agrosciences Llc | 2-substituted-6-amino-5-alkyl, alkenyl or alkynyl-4-pyrimidinecarboxylic acids and 6-substituted-4-amino-3-alkyl, alkenyl or alkynyl picolinic acids and their use as herbicides |
Non-Patent Citations (1)
Title |
---|
See also references of EP2667714A4 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8774158B2 (en) | 2010-09-02 | 2014-07-08 | Intel Corporation | Method and apparatus to shorten the duration of initial network selection and handover decisions in multicomm platforms by utilizing alternate fragmented scanning |
WO2014024927A1 (en) * | 2012-08-07 | 2014-02-13 | 日産化学工業株式会社 | Herbicidal composition |
JPWO2014024927A1 (en) * | 2012-08-07 | 2016-07-25 | 日産化学工業株式会社 | Herbicidal composition |
WO2020061146A1 (en) * | 2018-09-19 | 2020-03-26 | Dow Agrosciences Llc | Preparation of halogen analogs of picloram |
US11401242B2 (en) | 2018-09-19 | 2022-08-02 | Corteva Agriscience Llc | Preparation of halogen analogs of picloram |
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