WO2020037109A1 - Procédés de fluoration - Google Patents

Procédés de fluoration Download PDF

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Publication number
WO2020037109A1
WO2020037109A1 PCT/US2019/046627 US2019046627W WO2020037109A1 WO 2020037109 A1 WO2020037109 A1 WO 2020037109A1 US 2019046627 W US2019046627 W US 2019046627W WO 2020037109 A1 WO2020037109 A1 WO 2020037109A1
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substituted
alkyl
heteroaryl
cycloalkyl
group
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PCT/US2019/046627
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English (en)
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Melanie S. Sanford
Sydonie D. SCHIMLER
James W. Ringer
Douglas Bland
Patrick R. MELVIN
Devin FERGUSON
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Dow Agrosciences Llc
The Board Of Regents Of The University Of Michigan
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Publication of WO2020037109A1 publication Critical patent/WO2020037109A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • 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
    • C07D213/26—Radicals substituted by halogen atoms or nitro radicals
    • 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
    • C07D213/61—Halogen atoms or nitro radicals
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids

Definitions

  • DFT Difluoropyridinyl triazolothione
  • reagents include, but certainly are not limited to: phenylsulfur trifluoride, dialkylaminosulfur trifluorides, and bis(2- methoxyethyl)aminosulfur trifluoride.
  • phenylsulfur trifluoride dialkylaminosulfur trifluorides
  • bis(2- methoxyethyl)aminosulfur trifluoride can be costly, and in certain reactions are inefficient in terms of yield, atom economy, and reaction rate; and may produce unwanted, toxic and/or difficult to handle by-products or impurities.
  • DFT is also known by its chemical name: 4-((6-(2-(2,4-difluorophenyl)- l, l-difluoro-2-hydroxy-3-(5-thioxo-4, 5-dihydro- 1H- 1, 2, 4-triazol- l- yl) propyl) pyridin-3 -yl) oxy) benzonitrile .
  • the current disclosure describes a method of preparing
  • heteroaromatic alcohol ketone, aldehyde or ester. More specifically, the method employs 1, G-sulfonyldiimidazole (SDI), to create sulfuryl fluoride (SO2F2) in situ, along with fluoride anion to convert starting aromatic or heteroaromatic alcohol, aldehyde or ester into the monoiluoromethyl or difluoromethyl substituted product.
  • SDI 1, G-sulfonyldiimidazole
  • SO2F2 sulfuryl fluoride
  • the disclosure provides for processes that affect fluorination in mild conditions.
  • the mild conditions comprise room temperature with a low loading of an acid.
  • the mild conditions comprise room temperature with a low loading of the Lewis acid, tetramethyl ammonium fluoride.
  • the conditions comprise room temperature with the acid, hydrofluoric acid.
  • the conditions comprise room temperature with the acid, hydrogen fluoride.
  • the disclosure provides for a process to make the difluoromethyl substituted heteroaromatic synthon for DFT.
  • the substituted heteroaromatic part of the synthon is a pyridinyl moiety 3-aryloxy substituted (aryl ether) which itself is 4-substituted by a cyano functional group.
  • the DFT synthon is a 4-(pyridin-3- yloxy) benzonitrile group.
  • process to make DFT or methods of manufacture of DFT, or a salt thereof, are provided.
  • the present disclosure provides methods to arrive at the a-iluorinated pyridinyl compound which is a synthon in the synthesis of DFT. And it is presently contemplated that these methods can be extended into an otherwise distinct method or process to make (or manufacture) the entire DFT molecule made when the remaining
  • nucleophilic addition reactions the synthetic steps of which is just one such example that are disclosed in the‘775 application, are employed to add in the difluorophenyl and triazolothione pieces for DFT.
  • substantially purified or free of impurities refers to a mixture in which one small organic molecule of interest far exceeds the amount of minerals, metal, and / or other small organic molecules as impurities, and at least 95% by dry weight is the small organic molecule of interest.
  • Fluoride salt refers to a combination of a cation and fluoride anion.
  • Typical fluoride salts include metal cations and so, some examples include, but are not limited to: sodium fluoride (NaF), potassium fluoride (KF), rubidium fluoride (RbF), cesium fluoride (CsF), potassium fluoride (KF), tetrabutyl ammonium fluoride, iron trifluoride (FeFa), manganese difluoride (MnFa), cobalt difluoride (C0F2), copper difluoride (CUF2) and calcium difluoride (CaF 2 ).
  • Pg or protecting group refers to any organic functional group which is a mask or as is traditional known in the art, is a group that“protects” a certain organic functional group with the ability to form that certain
  • TMS, TBDMS, TBDPS, Ms, Ns, Tf, Fmoc, Boc, Cbz, Troc, Alloc, acetyl including acetamide where R methyl or trifluoroacetamide where
  • aminosulfonyl aminosulfonyloxy, aminosulfonylamino, amidino, aryl,
  • heterocyclylthio substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
  • salt refers to salts which are suitable for use in agriculture, i.e. they affect humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio in agriculture. These salts are well known in the art. Salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases.
  • acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide,
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH 2 -), n-propyl (CH3CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH3CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), f-butyl ((CH 3 ) 3 C-), n-pentyl (CH3CH 2 CH 2 CH 2 CH 2 -), and neopentyl ((CFhJsCCFE-).
  • C x alkyl refers to an alkyl group having x number of carbon atoms.
  • C x alkenyl refers to an alkenyl group having x number of carbon atoms.
  • Alkynyl refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (-C o C-) unsaturation. Examples of such alkynyl groups include acetylenyl (-C o CH), and propargyl (-CH2C o CH). C x alkynyl refers to an alkynyl group having x number of carbon atoms.
  • Substituted alkyl refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino,
  • aminocarbonylamino acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,
  • heterocyclic substituted heterocyclic, heterocyclyloxy, substituted
  • heterocyclyloxy heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
  • the substituted alkyl groups include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.
  • Alkyl aryl refers to an alkyl group having from 1 to 8, preferably 1 to 5, or more preferably 1 to 3 carbon atoms in length and is substituted specifically at any one of the carbons along the chain with an aryl group.
  • Alkenyl aryl refers to an alkenyl or alkene group having from 1 to 8, preferably 1 to 5, or more preferably 1 to 3 carbon atoms in length and is substituted specifically at any one of the carbons along the chain with an aryl group.
  • the aryl group can include heteroatoms or not.
  • Alkynyl aryl refers to an alkynyl or alkyne group having from 1 to 8, preferably 1 to 5, or more
  • Cycloalkyl or“Cyclyl alkyl” refers to a saturated or partially saturated, but not aromatic, group having from 3 to 10 ring carbon atoms and no heteroatoms. Cycloalkyl encompasses single ring systems.
  • Substituted alkenyl refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,
  • aminosulfonyl aminosulfonyloxy, aminosulfonylamino, amidino, aryl,
  • heterocyclylthio substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.
  • Substituted alkynyl refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,
  • aminosulfonyl aminosulfonyloxy, aminosulfonylamino, amidino, aryl,
  • Ar and/or“aryl” refers to any group which is aromatic. This group must be cyclic; and does not contain heteroatoms.
  • Alkoxy refers to the group -O-alkyl or the group -O-phenyl wherein the phenyl and alkyl are defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, f-butoxy,
  • Substituted alkoxy refers to the group -0-(substituted alkyl) or -0-(substituted phenyl) wherein substituted phenyl and alkyl are defined herein.
  • Preferred substituted alkyl groups in -0-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-,
  • heterocyclic-C(O)- and substituted heterocyclic-C(O)-, wherein alkyl
  • substituted alkyl alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,
  • Acyl includes the“acetyl” group CH 3 C(0)-.
  • heteroaryl -NR 30 C(O)heterocyclic, and -NR 30 C(O)substituted heterocyclic wherein R 30 is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
  • heterocyclic and substituted heterocyclic are as defined herein.
  • aminoacyl refers to the groups H-C(N)-, alkyl-C(N)-, substituted alkyl-C(N)-, alkenyl-C(N)-, substituted alkenyl-C(N)-, alkynyl-C(N)-, substituted alkynyl-C(N)-, cycloalkyl-C(N)-, substituted cycloalkyl-C(N)-, aryl-C(N)-, substituted aryl-C(N)-, heteroaryl-C(N)-, substituted heteroaryl-C(N)-,
  • heterocyclic-C(N)- and substituted heterocyclic-C(N)-, wherein alkyl,
  • substituted alkyl alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,
  • alkyl-C(0)0- alkenyl-C(0)0-, substituted alkenyl-C(0)0-, alkynyl-C(0)0-, substituted alkynyl-C(0)0-, aryl-C(0)0-, substituted aryl-C(0)0-,
  • heterocyelic-C(0)0- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and
  • Amino refers to the group -NH2.
  • Substituted amino refers to the group -NR 31 R 32 where R 31 and R 32 are independently selected from the group consisting of hydrogen, hydroxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and substituted sulfonyl and wherein R 31 and R 32 are optionally joined, together with the nitrogen bound thereto to form a
  • R 31 and R 32 are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • R 31 is hydrogen and R 32 is alkyl
  • the substituted amino group is sometimes referred to herein as alkylamino.
  • R 31 and R 32 are alkyl
  • the substituted amino group is sometimes referred to herein as dialkylamino.
  • R 31 or R 32 is hydrogen but not both.
  • R 31 nor R 32 are hydrogen.
  • Aminocarbonyl refers to the group -C(0)NR 33 R 34 where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
  • heterocyclic and substituted heterocyclic are as defined herein.
  • Aminoacyl carbonyloxy refers to the group -C(NR 33 )OR 34 where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
  • heterocyclic group and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Aminothiocarbonyl refers to the group -C(S)NR 33 R 34 where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
  • heterocyclic group and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Aminocarbonylamino refers to the group -NR 30 C(O)NR 33 R 34 where R 30 is hydrogen or alkyl and R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl,
  • heterocyclic or substituted heterocyclic group and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Aminothiocarbonylamino refers to the group -NR 30 C(S)NR 33 R 34 where R 30 is hydrogen or alkyl and R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl,
  • heterocyclic or substituted heterocyclic group and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Aminocarbonyloxy refers to the group -0-C(0)NR 33 R 34 where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
  • heterocyclic group and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Aminosulfonyl refers to the group -S0 2 NR 33 R 34 where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted hetero
  • heterocyclic and substituted heterocyclic are as defined herein.
  • Aminosulfonyloxy refers to the group -0-S0 2 NR 33 R 34 where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
  • heterocyclic group and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Aminosulfonylamino refers to the group -NR 30 -SO2NR 33 R 34 where R 30 is hydrogen or alkyl and R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl,
  • heterocyclic or substituted heterocyclic group and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • heterocyclic and substituted heterocyclic are as defined herein.
  • Substituted aryl refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,
  • heterocyclic substituted heterocyclic, heterocyclyloxy, substituted
  • heterocyclyloxy heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, a monosaccharide (which may be covalently bonded to the aryl group thru any oxygen atom on the saccharide), and substituted alkylthio, wherein said substituents are defined herein.
  • Aryloxy refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.
  • Substituted aryloxy refers to the group -0-(substituted aryl) where substituted aryl is as defined herein.
  • Arylthio refers to the group -S-aryl, where aryl is as defined herein.
  • Substituted arylthio refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.
  • Carboxy or“carboxyl” or“carboxylate” refers to -COOH or salts thereof.
  • Carboxyl ester or“carboxy ester” refers to the
  • heteroaryl -C(0)0-heterocyelic, and -C(0)0-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. [0051] “(Carboxyl ester)amino” refers to the
  • R 30 is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
  • heterocyclic and substituted heterocyclic are as defined herein.
  • heteroaryl -0-C(0)0-heterocyelic, and -0-C(0)0-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Cyano refers to the group -C o N.
  • Cycloalkyl refers to a saturated or unsaturated but nonaromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems.
  • C x cycloalkyl refers to a cycloalkyl group having x number of ring carbon atoms.
  • suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
  • One or more the rings can be aryl, heteroaryl, or heterocyclic provided that the point of attachment is through the non-aromatic, non-heterocyclic ring saturated carbocyclic ring.
  • “Substituted cycloalkyl” refers to a cycloalkyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,
  • heterocyclyloxy substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
  • Cycloalkyloxy refers to -O-cycloalkyl.
  • Substituted cycloalkyloxy refers to -0-(substituted cycloalkyl).
  • Cycloalkylthio refers to -S-cycloalkyl.
  • Substituted cycloalkylthio refers to -S-(substituted cycloalkyl).
  • Halo or“halogen” refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.
  • Heteroaryl refers to an aromatic group of from 4 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring.
  • Such heteroaryl groups can have a single ring ( e.g ., pyridinyl or furyl) or multiple condensed rings ( e.g ., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and / or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N 0), sulfinyl, or sulfonyl moieties.
  • Preferred heteroaryls include 5 or 6 membered heteroaryls such as pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
  • Substituted heteroaryl refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of
  • Heteroaryloxy refers to -O-heteroaryl.
  • Substituted heteroaryloxy refers to the group -0-(substituted heteroaryl) .
  • Heteroarylthio refers to the group -S-heteroaryl.
  • Substituted heteroarylthio refers to the group -S-(substituted heteroaryl) .
  • Heterocycle or“heterocyclic” or“heterocycloalkyl” or
  • heterocyclyl refers to a saturated or partially saturated, but not aromatic, group having from 2 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen.
  • C x cycloalkyl or heterocycloalkyl refers to a group having x number of ring carbon atoms excluding the ring heteroatoms.
  • Heterocycle encompasses single ring or multiple condensed rings, including fused, bridged and spiro ring systems. In fused ring systems, one or more the rings can be cycloalkyl, aryl or heteroaryl provided that the point of attachment is through the non-aromatic ring.
  • the nitrogen and / or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, sulfonyl moieties.
  • “Substituted heterocyclic” or“substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
  • Heterocyclyloxy refers to the group -O-heterocycyl.
  • Substituted heterocyclyloxy refers to the group -0-(substituted heterocycyl) .
  • Heterocyclylthio refers to the group -S-heterocycyl.
  • Substituted heterocyclylthio refers to the group -S-(substituted heterocycyl) .
  • heterocycle and heteroaryl include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, dexahydroindole, dihydro pyridine, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, imidazolinone, piperidine, piperazine, indo
  • Niro refers to the group -NO2.
  • Phthalimide functional groups are well known in the art and can be generated by covalently bonding a nitrogen atom to a C6H 4 (CO)2 group.
  • Polyethylene glycol refers to the group -0-(CH 2 CH 2 -0) n -E, wherein E is either H or CH3, where n is between 2-20,000.
  • Spirocyclic ring system refers to a ring system with two rings that has a single ring carbon atom in common to both rings. Herein used the term bicyclic can incorporate up to four heteroatoms in either ring.
  • Bicyclic ring or“Bicyclic ring system” refers to a ring system with two rings that has two ring carbon atoms in common, and which can located at any position along either ring.
  • bicyclic ring system can incorporate up to four heteroatoms in either ring.
  • alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Substituted sulfonyl includes groups such as methyl-S0 2 -, phenyl-S0 2 -, and 4-methylphenyl-S0 2 -.
  • Preferred substituted alkyl groups on the substituted alkyl-S0 2 - include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.
  • heteroaryl -SO-heterocyclic, -SO-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Substituted sulfinyl includes groups such as methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-.
  • Preferred substituted alkyl groups on the substituted alkyl-SO- include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, dilluromethyl, fluoromethyl and the like.
  • heteroaryl -OS0 2 -heterocyclic, -OS0 2 -substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • substitution or“substitution” or“substitutied” generally refers groups which are covalently bonded to an atom to replace a hydrogen atom.
  • the atom in this general context can be a carbon atom or a heteroatom, for example a nitrogen atom.
  • Thioacyl refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-,
  • heterocyclic-C(S)- and substituted heterocyclic-C(S)-, wherein alkyl,
  • substituted alkyl alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Forml refers to the group -C(0)H.
  • Alkylthio refers to the group -S-alkyl wherein alkyl is as defined herein.
  • Substituted alkylthio refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein.
  • Preferred substituted alkyl groups on -S-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.
  • references to or depiction of a certain element such as hydrogen or H is meant to include all isotopes of that element.
  • an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
  • Compounds comprising radioisotopes such as tritium, 14 C, 32 P and 35 S are thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein.
  • the compounds described herein may exist as solvates, especially hydrates, and unless otherwise specified, all such solvates and hydrates are intended. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds.
  • Compounds of the present technology may exist as organic solvates as well, including DMF, ether, and alcohol solvates, among others. The identification and preparation of any particular solvate is within the skill of the ordinary artisan of synthetic organic or medicinal chemistry.
  • any substituted functional group is substituted at from one to three different positions, and those one to three substituting groups are capable of each independently being substituted at one to three positions, wherein any and each substituting group is independently selected from the group consisting of: halogen, hydroxyl, Ci-Cs alkyl, substituted Ci-Cs alkyl, Ci- Ce alkenyl, substituted Ci-Cs alkenyl, Ci-Cs alkynyl, substituted Ci-Cs alkynyl, acyl, acylamino, aminocarbonylamino, aminoacyl, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminoacyl carbonyloxy,
  • any and all heteroaryl and heterocycloalkyl substituents may contain up to four heteroatoms selected from the group consisting of: O, N, and S but may not contain the heteroatom-heteroatom bonds: O-O, O-S and S-S. It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g ., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substituents is three.
  • each of the above definitions is constrained by a limitation that each functional group is substituted (at from one to three positions) and that any and all of those substituent groups may be substituted one more time (at from one to three positions).
  • the definitions presented herein are not intended to include impermissible substitution patterns (e.g ., methyl substituted with 5 fluoro groups) . Such impermissible substitution patterns are well known to the skilled artisan.
  • the term“about,” when referring to a value can be meant to encompass variations of, in some aspects, ⁇ 100% in some aspects ⁇ 50%, in some aspects ⁇ 20%, in some aspects ⁇ 10%, in some aspects ⁇ 5%, in some aspects ⁇ 1%, in some aspects ⁇ 0.5%, and in some aspects ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.
  • substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • substituent“alkoxycarbonylalkyl” refers to the group (alkoxy)-C(0)-(alkyl)-.
  • the disclosure provides for a process of fluorinating an aromatic a- hydroxy, keto, aldehyde or ester organic compound, the process comprising mixing the aromatic compound with SDI, tetramethyl ammonium fluoride, a fluoride salt and an acid (a Lewis acid or otherwise).
  • the disclosure provides for a total synthesis of DFT. In some aspects, the disclosure provides for a process of manufacturing DFT wherein the process returns an amount of DFT made is greater than or equivalent to five hundred (500) grams. In some aspects, the process of manufacturing DFT returns greater than or equivalent to one ( 1) kilogram of DFT.
  • the present disclosure provides for processes that make sulfuryl fluoride in situ by combining 1, G-thiocarbonyldiimidazole (SDI) and tetramethyl fluoride (N(CH 3 ) 4 F). Accordingly, the present disclosure provides for processes that fluorinate a compound of formula II, as described herein, with I, G-thiocarbonyldiimidazole (SDI) and tetramethyl fluoride (N(CH 3 ) 4 F).
  • the present disclosure provides for a process to make a compound of formula I:
  • Y is hydrogen or fluorine
  • each of U, J, E, Z, and T is independently selected from the group consisting of: CH, CR 1 , and N, wherein up to 3 of U, J, E, Z, and T may be N; each R 1 is independently selected from the group consisting of: hydrogen, halogen, carboxy ester, carboxylate, amino, substituted amino, hydroxyl, thiol, alkylthio, substituted alkylthio, Ci-Cs alkoxy, Ci-Cs substituted alkoxy, Ci-Cs alkyl, Ci-Cs substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, Ci-Cs alkynyl, Ci-Cs substituted alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 substituted cycloalkyl, C 3 -C 8 heterocycloalkyl, C 3 -C 8 substituted heterocycloalkyl, C 3 -C 7 heteroaryl, C
  • R 1 groups may be covalently bonded together to form a cycloalkyl, heterocycloalkyl, heteroaryl, or phenyl ring;
  • heterocyclic groups contain up to three heteroatoms selected from the group consisting of: oxygen, sulfur and nitrogen.
  • each of U, J, E, Z, and T is independently selected from the group consisting of: CH, CR 1 , and N. wherein up to 3 of U, J, E, Z, and T may be N; each R 1 is independently selected from the group consisting of: hydrogen, halogen, carboxy ester, carboxylate, amino, substituted amino, hydroxyl, thiol, alkylthio, substituted alkylthio, Ci-Cs alkoxy, Ci-Cs substituted alkoxy, Ci-Cs alkyl, Ci-Cs substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, Ci-Cs alkynyl, Ci-Cs substituted alkynyl, C 3 -Cs cycloalkyl, C3-C8 substituted cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 substituted heterocycloalkyl, C 3 -C7 heteroaryl, C 3 -
  • R 2 is selected from the group consisting of: hydrogen, Ci-Cs alkyl, Ci- Cs substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, Ci-Cs alkynyl, Ci-Cs substituted alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 substituted cycloalkyl, C 3 - Cs heterocycloalkyl, C 3 -C 8 substituted heterocycloalkyl, C 3 -C7 heteroaryl, C 3 - C7 substituted heteroaryl, phenyl, and substituted phenyl;
  • R 1 groups may be covalently bonded together to form a cycloalkyl, heterocycloalkyl, heteroaryl, or phenyl ring;
  • heterocyclic groups contain up to three heteroatoms selected from the group consisting of: oxygen, sulfur and nitrogen.
  • each R 1 is independently selected from the group consisting of:
  • R 2 is selected from the group consisting of: hydrogen, Ci-Cs alkyl, Ci- Cs substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, Ci-Cs alkynyl, Ci-Cs substituted alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 substituted cycloalkyl, C 3 - Cs heterocycloalkyl, C 3 -C 8 substituted heterocycloalkyl, C 3 -C7 heteroaryl, C 3 - C7 substituted heteroaryl, phenyl, and substituted phenyl;
  • R 1 groups may be covalently bonded together to form a cycloalkyl, heterocycloalkyl, heteroaryl, or phenyl ring;
  • heterocyclic groups contain up to three heteroatoms selected from the group consisting of: oxygen, sulfur and nitrogen.
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, Z, and T is CH, E is CR 1 where R 1 is substituted amino.
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, Z, and T is CH, E is CR 1 where R 1 is cyano.
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, Z, and T is CH, E is CR 1 where R 1 is Ci-Cs substituted alkyl.
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, Z, and T is CH, E is CR 1 where R 1 is Ci-Cs alkoxy or Ci-Cs substituted alkoxy.
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, Z, and T is CH, E is CR 1 where R 1 is C 3 -C7 heteroaryl. [0121] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, and Z is CH, T is N, E is
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, T, and Z is CH, J is N, E is
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, T, and Z is CH, J is CR 1 where R 1 is substituted amino, E is N.
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, T, and Z is CH, J is CR 1 where R 1 is cyano, E is N.
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, T, and Z is CH, J is CR 1 where R 1 is Ci-Cs alkoxy or Ci-Cs substituted alkoxy, E is N.
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, and Z is CH, T is CR 1 where R 1 is substituted amino, E is N.
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, and Z is CH, T is CR 1 where R 1 is C 3 -C7 heteroaryl, E is N.
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, and Z is CH, T is CR 1 where R 1 is Ci-Cs alkoxy or Ci-Cs substituted alkoxy, E is N.
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, and Z is CH, T is CR 1 where R 1 is cyano, E is N.
  • the disclosure provides a process for preparing a
  • the disclosure provides a process for preparing a compound of
  • the disclosure provides a process for preparing a compound of
  • the disclosure provides a process for preparing a compound of formula I, as described herein, wherein E is N and X isJ .
  • the disclosure provides a process for preparing a compound of formula I, as described herein, wherein E is N and X isJ .
  • each of U, J, Z, and T is CH; E is N and X is ⁇ k H .
  • the disclosure provides a process for preparing a compound of formula I, as described herein, wherein each of U, J, Z, and T is CH; E is N and
  • X isJ .
  • the disclosure provides a process for preparing a compound of formula I, as described herein, wherein each of U, J and T is CH;
  • the disclosure provides a process for preparing a compound of formula I, as described herein, wherein each of U,
  • the disclosure provides for a process of to make a
  • the disclosure provides for a process of to make a
  • OH compound of formula I wherein Y is H, X is J , each of U, J, and Z is CH, and E is N. [0133] In some aspects, the disclosure provides for a process of to make a
  • the disclosure provides for a process of to make a
  • the disclosure provides for a process of to make a
  • the disclosure provides for a process of to make a
  • the disclosure provides for a process of to make a
  • the disclosure provides for a process of to make a compound of formula III or V wherein R 2 is Ci-Cs alkyl or Ci-Cs substituted alkyl.
  • the disclosure provides for a process of to make a compound of formula III or V wherein R 2 is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, J, Z, and T is CH, E is CR 1 where R 1 is substituted amino.
  • the disclosure provides for a process of to make a compound of formula III or V wherein R 2 is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, J, Z, and T is CH, E is CR 1 where R 1 is cyano.
  • the disclosure provides for a process of to make a compound of formula III or V wherein R 2 is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, J, Z, and T is CH, E is CR 1 where R 1 is Ci-Cs substituted alkyl.
  • the disclosure provides for a process of to make a compound of formula III or V wherein R 2 is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, J, Z, and T is CH, E is CR 1 where R 1 is Ci-Cs alkoxy or Ci-Cs substituted alkoxy.
  • the disclosure provides for a process of to make a compound of formula III or V wherein R 2 is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, J, Z, and T is CH, E is CR 1 where R 1 is C3-C7 heteroaryl.
  • the disclosure provides for a process of to make a compound of formula III or V wherein R 2 is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, J, and Z is CH, T is N, E is N.
  • the disclosure provides for a process of to make a compound of formula III or V wherein R 2 is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, T, and Z is CH, J is N, E is N.
  • the disclosure provides for a process of to make a compound of formula III or V wherein R 2 is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, T, and Z is CH, J is CR 1 where R 1 is substituted amino, E is N.
  • the disclosure provides for a process of to make a compound of formula III or V wherein R 2 is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, T, and Z is CH, J is CR 1 where R 1 is cyano, E is N.
  • the disclosure provides for a process of to make a compound of formula III or V wherein R 2 is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, T, and Z is CH, J is CR 1 where R 1 is Ci-Cs alkoxy or Ci-Cs substituted alkoxy, E is N.
  • the disclosure provides for a process of to make a compound of formula V wherein m is 1. In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 2. In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 3. In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 4.
  • the disclosure provides for a process of to make a compound of formula V wherein m is 1, R 2 is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, and R 1 is Ci-Cs alkoxy or Ci-Cs substituted alkoxy.
  • the disclosure provides for a process of to make a compound of formula V wherein m is 2, R 2 is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, and one R 1 is amino or substituted amino.
  • the disclosure provides for a process of to make a compound of formula V wherein m is 2, R 2 is C3-C7 heteroaryl or C3-C7 substituted heteroaryl, and one R 1 is amino or substituted amino.
  • the disclosure provides for a process of to make a compound of formula V wherein m is 2, R 2 is phenyl or substituted phenyl, and one R 1 is amino or substituted amino.
  • the disclosure provides for a process of to make a compound of formula V wherein m is 2, R 2 is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, and one R 1 is halogen while the other R 1 is cyano. In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 2, R 2 is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, and one R 1 is halogen while the other R 1 is amino or substituted amino.
  • the disclosure provides for a process of to make a compound of formula V wherein m is 2, R 2 is C3-C8 heterocycloalkyl or C3-C8 substituted heterocycloalkyl, and one R 1 is halogen while the other R 1 is Ci-Cs alkoxy or Ci-Cs substituted alkoxy.
  • the disclosure provides for a process of to make a compound of formula V wherein m is 2, R 2 is C3-C8 heterocycloalkyl or C3-C8 substituted heterocycloalkyl, and one R 1 is Ci-Cs alkyl or Ci-Cs substituted alkyl while the other R 1 is Ci-Cs alkoxy or Ci-Cs substituted alkoxy.
  • the disclosure provides for a process of to make a compound of formula V wherein m is 2, R 2 is Ci-Cs alkyl or Ci-Cs substituted alkyl, and one R 1 is carboxy ester while the other R 1 is Ci-Cs alkoxy or Ci-Cs alkyl.
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein E is N, each of U, J, and T is CH, and Z is CR 1 where R 1 is selected from the group consisting of: hydrogen, halogen, carboxy ester, amino, substituted amino, hydroxyl, Ci-Cs alkyl, Ci-Cs
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein E is N, each of U, T, and Z is CH, and J is CR 1 where R 1 is selected from the group consisting of: hydrogen, halogen, amino, substituted amino, Ci-Cs alkoxy, Ci-Cs substituted alkoxy, Ci-Cs alkyl, Ci-Cs substituted alkyl, Ci-Cs alkenyl, and cyano.
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein E is N, each of T, J, and Z is CH, and U is CR 1 where R 1 is selected from the group consisting of: hydrogen, halogen, carboxy ester, Ci-Cs alkoxy, Ci-Cs substituted alkoxy, Ci-Cs alkyl, Ci-Cs substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, Ci-Cs alkynyl, Ci-Cs substituted alkynyl, C3-C7 heteroaryl, C3-C7 substituted heteroaryl, phenyl, and substituted phenyl.
  • R 1 is selected from the group consisting of: hydrogen, halogen, carboxy ester, Ci-Cs alkoxy, Ci-Cs substituted alkoxy, Ci-Cs alkyl, Ci-Cs substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted al
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein the organic acid is hydrogen fluoride.
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein the organic acid is hydrofluoric acid. In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein the organic acid is formic acid. In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein the organic acid is p-toluenesulfonic acid. In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein the organic acid is trifluoroacetic acid.
  • the disclosure provides for a process of to make a compound of formula I, III, or V wherein the fluoride salt is potassium fluoride. In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein the fluoride salt is tetramethylammonium fluoride. In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein the fluoride salt is sodium fluoride.
  • the disclosure provides a process substantially as shown in Example 1.
  • the disclosure provides for a total synthesis of DFT.
  • processes to make DFT, or methods of manufacture of DFT, or a salt thereof where the process of method comprises: fluorination of a ethyl 2-(5-(4-cyanophenoxy)pyridin-2-yl)-2-oxoacetate derivative using
  • tetramethylammonium fluoride 1, G-thiocarbonyldiimidazole (SDI), a fluoride salt and an acid
  • nucleophilic addition to the fluorinated ethyl 2-(5-(4-cyanophenoxy)pyridin-2-yl)-2-oxoacetate- l,3-difluorobenzyl derivative with a triazole or triazolothione nucleophile 1, G-thiocarbonyldiimidazole (SDI), a fluoride salt and an acid
  • the disclosure provides for a process to make DFT, or method of manufacture of DFT, or a salt thereof, the process comprising:
  • Metal is a metal or metalloid that makes a nucleophilic organometallic reagent of the difluoro compound, and wherein R 1 is selected from the group consisting of:
  • the disclosure provides for a process to make DFT, or method of manufacture of DFT, or a salt thereof, the process comprising:
  • R 1 is selected from the group consisting of:
  • Metal is a metal or metalloid that makes a nucleophilic
  • organometallic reagent of the difluoro compound is organometallic reagent of the difluoro compound.
  • the disclosure provides for processes where the Metal or metalloid is selected from the group consisting of: magnesium, lithium, copper, zinc, and boron.
  • the disclosure provides for a process of
  • the process returns an amount of DFT made is greater than or equivalent to five hundred (500) grams. In some aspects, the process of manufacturing DFT returns greater than or equivalent to one ( 1) kilogram of DFT. In some aspects, the disclosure provides for a process of manufacturing DFT wherein the process returns five hundred (500) grams or one ( 1) kg of DFT where the amount of each of the staring materials, i.e. , , trimethylsulfoxonium iodide, and 1H- 1,2,4- triazole is such that it corresponds with the amounts needed based on the reaction stoichiometry and % yield disclosed in the addition reactions disclosed in the Examples section herein, and assuming that any following steps, if needed, are nearly quantitative, i.e. any deprotection and/or reduction and/or
  • the amount of each of the starting material compounds may be calculated or adjusted according to the expected yield, as described above, from those reactions.
  • the disclosure provides a process substantially as shown below:
  • the disclosure provides a process for preparing the compounds disclosed herein by deoxyfluorination reactions, the process
  • the mixtures are stirred in each reaction chamber. In some aspects, a mixture is stirred in one chamber.
  • the mixing of the contents of both chambers occurs at room temperature. In some aspects, the mixing of the contents of both
  • the mixing of the contents of both chambers occurs initially at -78°C, -25°C, 0°C, 5°C, 10°C, or 15°C and then the mixture is allowed to warm to room temperature or above.
  • the mixing of the contents of both chambers occurs at 30°C. In some aspects, the mixing of the contents of both chambers occurs from 20- 120°C. In some aspects, the mixing of the contents of both chambers occurs at 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 1 10, 1 15, or 120°C for 2 hours or more. In some aspects, the mixing of the contents of both chambers occurs for 2 hours, and some aspects, for 3 hours. In some aspects, the mixing of the contents of both chambers occurs for 4 hours. In some aspects, the mixing of the contents of both chambers occurs for 6 hours or for 8 hours. In some aspects, the mixing of the contents of both chambers occurs for 12 hours.
  • the mixing of the contents of one of the chambers occurs at 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 1 10, 1 15, or 120°C.
  • aprotic organic solvent is mixed in the reaction chamber containing the compound of formula II and N(CH3) 4 F. In some aspects, aprotic organic solvent is mixed both chambers. In some aspects, aprotic organic solvent is mixed in the reaction chamber containing the 1, 1'- thiocarbonyldiimidazole (SDI), the fluoride salt, and the acid. [0171] In some aspects, the aprotic organic solvent is the same in both chambers. In some aspects, the aprotic organic solvent is different in each chamber. Regardless, there is no limitation on the identity of which aprotic organic solvent may be used in each of the chambers, i.e.
  • the aprotic organic solvent is acetonitrile (ACN).
  • the aprotic organic solvent is tetrahydrofuran (THF).
  • the aprotic organic solvent is 2-methyl - tetrahydrofuran (2-methyl THF).
  • the disclosure provides a process on an industrial scale comprising a-iluorination of an aromatic compound with 1, 1’- sulfonyldiimidazole (SDI) and tetramethylammonium fluoride (N(CH3) 4 F), where deoxyfluorination of the aromatic or heteroaromatic alcohol, ketone, aldehyde or ester provides the corresponding monoiluoromethyl or difluoromethyl substituted aromatic compound.
  • the disclosure provides a process on an industrial scale comprising the synthesis of DFT, wherein a- iluorination of a 4-(pyridin-3-yloxy)benzonitrile derivative provides a product that is a synthon for DFT. That product is then used in the total synthesis at an industrial scale with difluorophenyl and triazolothionyl derivatives to make DFT.
  • the disclosure provides a process for preparing the solvate of any one of the product or reactant compounds disclosed herein.
  • Such solvates may have desirable properties such as enhanced solubility or even less impurities, e.g. minute amounts of regio-isomers can be present even in commercial shelf-reagents and preparing a solvate of such a reagent or when purifying a product may be advantageous.
  • the fluorination process is affected by a general methodology, such an exemplary method is specifically demonstrated where benzaldehyde, SDI, KF, formic acid, DMF solvent and Me 4 NF are mixed at room temperature. Next, ether as an aprotic extraction solvent is added and the compound is extracted in the organic layer three (3) times. The combined organic layers are washed with water, dried with MgS0 4 , filtered and the solvent is removed in vacuo. The resulting mixture is purified by either flash or HPLC chromatography.
  • an exemplary fluorination process is carried out where SDI and the fluoride salt, in the above case, KF, are mixed separately from the aromatic compound of formula II, IV, or VI and Me 4 NF.
  • the acid in the above case, formic acid, is added to the SDI/KF mixture.
  • the aprotic solvent, in the above case, DMF is added to the compound of formula II, IV, or VI/ Me 4 NF mixture. Then the two mixtures are mixed together at room temperature. An extraction solvent is added after some time, the organic layers taken and the combined organic layer washed with water, dried and chromatographed.
  • aromatic compounds can be functionalized with the desired or appropriate R 1 group by electrophilic aromatic substitution reactions.
  • benzyl derivatives can be functionalized by reacting the benzyl derivative with an electrophilic partner in the presence of a Lewis acid.
  • a Lewis acid such as one or more functional groups on them.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from
  • NaHCOa sodium bicarbonate
  • HATU l-[Bis(dimethylamino) methylene]- 1H- 1,2,3- trl zolo[4,5-b]pyridinium 3-oxid
  • LAH lithium aluminum hydride
  • HPLC-MS analysis was carried out with gradient elution.
  • Medium pressure liquid chromatography (MPLC) was performed with silica gel columns in both the normal phase and reverse phase.
  • Chamber A 2 equiv SDI, 4 equiv KF
  • Chamber B 4 equiv Me 4 NF, DMF
  • Chamber B 4 equiv Me 4 NF, DMF
  • Chamber B 4.0 equiv Me 4 NF, DMF
  • Chamber A 2.0 equiv SDI, 4.0 equiv KF
  • Chamber B 4.0 equiv Me 4 NF, DMF
  • Each aspect and embodiment described above can also have included or incorporated therewith such variations or aspects as disclosed in regard to any or all of the other aspects and
  • phrase“consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology.
  • the phrase“consisting of’ excludes any element not specified.

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Abstract

La présente technologie concerne des réactions de fluoration. De façon spécifique, l'Invention concerne des procédés utiles pour fabriquer le composé fongicide, la TFD. Plus largement, l'invention concerne également des procédés utiles pour la désoxyfluoration au niveau de la position α-aromatique d'un composé donné.
PCT/US2019/046627 2018-08-17 2019-08-15 Procédés de fluoration WO2020037109A1 (fr)

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