Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B39/00—Halogenation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C17/00—Preparation of halogenated hydrocarbons
  • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C17/00—Preparation of halogenated hydrocarbons
  • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
  • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C17/00—Preparation of halogenated hydrocarbons
  • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
  • C07C17/18—Preparation of halogenated hydrocarbons by replacement by halogens of oxygen atoms of carbonyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
  • C07C201/06—Preparation of nitro compounds
  • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
  • C07C37/62—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
  • C07C41/01—Preparation of ethers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
  • C07C41/01—Preparation of ethers
  • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
  • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; 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
  • C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—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 no double bonds between ring members or between ring members and non-ring members 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
  • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • 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
  • C07D207/33—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 ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
• • 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
  • 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
  • C07D215/16—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 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
  • C07D215/18—Halogen atoms or nitro radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/12—Radicals substituted by halogen atoms or nitro or nitroso radicals

Definitions

• the present invention relates to a method for producing a fluorine-containing compound by introducing fluorine atoms into an oxygen-containing compound having a ketone group, an aldehyde group, a hydroxyl group, or the like, using a deoxyfluorinating agent.
• Fluorine atoms have a high electronegativity and are as small as hydrogen atoms. This characteristic allows fluorine atoms to bond stably with many atoms, and organic compounds into which fluorine has been introduced tend to have improved heat resistance, chemical resistance, light resistance, water resistance, etc. compared to before the introduction.
• carbon-fluorine bonds have a short bond distance, are rigid, and have low polarizability. Due to this characteristic of carbon-fluorine bonds, organic compounds into which carbon-fluorine bonds have been introduced have reduced reactivity and improved stability as a compound.
• Useful organic compounds can be synthesized by fluorinating organic compounds, so a variety of fluorinating agents have been developed.
• Non-Patent Document 1 reports that by protecting the NH in the pyrrole ring of an acylpyrrole compound, a deoxyfluorination reaction occurs with DAST, and a difluoroalkylpyrrolic compound is synthesized. DAST also functions as a deoxyfluorinating agent for carboxylic acids and aldehydes.
• Patent Document 1 reports that DAST produces retinoyl fluoride from retinoic acid and 15,15-difluoroaxerophthene from retinal.
• Non-Patent Document 2 reports the use of a salt of a glyme- coordinated alkali metal ion and SF5- ([M(G4)n][ SF5 ]) as a deoxyfluorination agent, which is a more stable and easier-to-use complex of SF4.
• This document reports that a deoxyfluorinated product was obtained by reacting 3-phenyl-1-propanol with [Cs(G4) 2 ][ SF5 ] in THF, but the yield was low and further improvement is required.
• the present invention aims to provide a method for producing fluorine-containing compounds by introducing fluorine atoms into a wide variety of oxygen-containing compounds having a ketone group, an aldehyde group, a hydroxyl group, etc., using SF 5 -, which has been stabilized by forming a salt with a glyme-coordinated alkali metal ion, as a deoxyfluorinating agent under relatively mild conditions.
• the present inventors have discovered that deoxyfluorination using a salt of a glyme-coordinated alkali metal ion and SF 5 - as a deoxyfluorination agent in a specific solvent can deoxyfluorinate a wide variety of oxygen-containing compounds under relatively mild conditions, thereby completing the present invention.
• the present invention relates to a method for producing a fluorine-containing compound, comprising the steps of: deoxyfluorinating an oxygen-containing compound having an aldehyde group, a ketone group, a carboxy group, or a hydroxy group in one or more solvents selected from the group consisting of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, tetraethylene glycol dimethyl ether, dimethylacetamide, hexamethylphosphite triamide, and acetonitrile, using a deoxyfluorination agent represented by the formula (I) below, thereby producing a fluorine-containing compound.
• the oxygen-containing compound is represented by the following general formula (S1):
• R 1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and R 11 is an aliphatic hydrocarbon group having 1 to 30 carbon atoms which may have a substituent, an alkoxy group which may have a substituent, an aliphatic heterocyclic group which may have a substituent, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent]
• the fluorine-containing compound is a compound represented by the following general formula (P1):
• R 12 is an aliphatic hydrocarbon group having 1 to 30 carbon atoms which may have a substituent, an alkoxy group which may have a substituent, an aliphatic heterocyclic group which may have a substituent, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent]
• the fluorine-containing compound is a compound represented by the following general formula (P2):
• R 12 is the same as in general formula (S2)]
• the oxygen-containing compound is represented by the following general formula (S3):
• R 13 is an aliphatic hydrocarbon group having 1 to 30 carbon atoms which may have a substituent
• the fluorine-containing compound is a compound represented by the following general formula (P3):
• R 13 is the same as in general formula (S3)]
• the method for producing a fluorine-containing compound according to the present invention makes it possible to deoxyfluorinate a wide variety of oxygen-containing compounds having an aldehyde group, a ketone group, a carboxy group, or a hydroxy group under relatively mild conditions, thereby producing a variety of fluorine-containing compounds.
• C p1-p2 (p1 and p2 are positive integers satisfying p1 ⁇ p2) means a group having a carbon number of p1 to p2.
• optionally substituted group includes both unsubstituted and substituted groups.
• compound (n) means a compound represented by formula (n).
• the "C 1-30 aliphatic hydrocarbon group” includes all of a C 1-30 alkyl group which may have a substituent, a C 2-30 alkenyl group which may have a substituent, and a C 2-30 alkynyl group which may have a substituent.
• the "C 1-30 aliphatic hydrocarbon group” may be a straight chain, a branched chain, or a cyclic group.
• a "substituted C p1-p2 aliphatic hydrocarbon group” is a group in which one or more, preferably 1 to 3, hydrogen atoms bonded to carbon atoms of a C p1-p2 aliphatic hydrocarbon group are substituted with other functional groups.
• the substituents may be the same or different.
• a "C 1-30 alkyl group” is an alkyl group having 1 to 30 carbon atoms, which may be linear or branched, or may be a group containing a cyclic structure.
• Examples of C1-30 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl
• a "C 1-10 alkyl group” is an alkyl group having 1 to 10 carbon atoms, which may be linear or branched, or may be a group containing a cyclic structure.
• a "C 2-10 alkyl group” is an alkyl group having 2 to 10 carbon atoms, which may be linear or branched.
• Examples of a C 1-10 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
• C 1-6 alkyl group is an alkyl group having 1 to 6 carbon atoms, which may be linear or branched, or may be a group containing a cyclic structure.
• Examples of C 1-6 alkyl groups include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
• a "substituted C p1-p2 alkyl group” is a group in which one or more, preferably 1 to 3, of the hydrogen atoms bonded to a carbon atom of a C p1-p2 alkyl group are substituted with other functional groups.
• the C p1-p2 alkyl group has two or more substituents, the substituents may be the same or different.
• C2-30 alkenyl groups include those groups listed as C2-30 alkyl groups in which at least one single bond between carbon atoms is replaced with a double bond.
• Specific examples of C2-30 alkenyl groups include vinyl, propenyl, 2-propenyl, butenyl, 1-methylpropenyl, 2-methylpropenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl groups.
• a "substituted C p1-p2 alkenyl group” is a group in which one or more, preferably 1 to 3, hydrogen atoms bonded to carbon atoms of a C p1-p2 alkenyl group are substituted with other functional groups.
• the substituents may be the same or different.
• C 1-30 alkoxy group refers to a group in which an oxygen atom is bonded to the bonding terminal of an alkyl group having a linear, branched, or cyclic structure having 1 to 30 carbon atoms.
• alkyl group moiety in the C 1-30 alkoxy group include the same as those in the above-mentioned C 1-30 alkyl group.
• C 1-10 alkoxy group refers to a group in which an oxygen atom is bonded to the bonding terminal of an alkyl group having a linear, branched, or cyclic structure having 1 to 10 carbon atoms.
• alkyl group moiety in the C 1-10 alkoxy group include the same as those in the above-mentioned C 1-10 alkyl group.
• a "substituted C p1-p2 alkoxy group” is a group in which one or more, preferably 1 to 3, hydrogen atoms bonded to a carbon atom of a C p1-p2 alkoxy group are substituted with other functional groups.
• the substituents may be the same or different.
• C1-10 acyl group refers to a group in which a carbonyl group is bonded to a C1-9 alkyl group.
• the alkyl group moiety in the C1-10 acyl group is preferably a linear or branched alkyl group having 1 to 9 carbon atoms, more preferably a linear or branched alkyl group having 1 to 6 carbon atoms, even more preferably a linear or branched alkyl group having 1 to 3 carbon atoms, and particularly preferably an acetyl group.
• a "substituted C p1-p2 acyl group” is a group in which one or more, preferably 1 to 3, of the hydrogen atoms bonded to the carbon atom of the C p1-p2 acyl group are substituted with other functional groups.
• the C p1-p2 acyl group has two or more substituents, the substituents may be the same or different.
• an "aliphatic heterocyclic group” is a group containing an aliphatic heterocycle, that is, a group in which 1 to 3 carbon atoms forming the cyclic structure of an aliphatic hydrocarbon group containing a cyclic structure are replaced with atoms other than carbon atoms.
• the aliphatic heterocyclic group may be a group containing a nitrogen atom (nitrogen-containing aliphatic heterocyclic group), a group containing an oxygen atom (oxygen-containing aliphatic heterocyclic group), or a group containing a sulfur atom (sulfur-containing aliphatic heterocyclic group).
• the aliphatic heterocyclic group may contain two or more types of atoms other than carbon atoms.
• Examples of the aliphatic heterocyclic group include a pyrrolidyl group, a piperidyl group, a piperazyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a tetrahydrothiophenyl group, a thianyl group, a morpholyl group, a thiomorpholyl group, a dioxanyl group, and a dithianyl group.
• a "substituted aliphatic heterocyclic group” is a group in which one or more, preferably 1 to 3, of the hydrogen atoms bonded to the carbon atoms that form the ring structure of the aliphatic heterocyclic group are substituted with other functional groups.
• the substituents may be the same or different.
• an "aryl group” is a cyclic group having aromaticity, the ring of which is composed only of carbon atoms.
• a “C 6-14 aryl group” is an aromatic hydrocarbon group having 6 to 14 carbon atoms, with a C 6-12 aryl group being particularly preferred.
• Examples of the C 6-14 aryl group include a phenyl group, a naphthyl group, an anthryl group, and a 9-fluorenyl group, with a phenyl group being particularly preferred.
• a "substituted aryl group” is a group in which one or more, preferably 1 to 3, hydrogen atoms bonded to a carbon atom of the aryl group are substituted with another functional group.
• the substituents may be the same or different from each other.
• substituents examples include a C 1-6 alkyl group, a C s-6 alkenyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a nitro group, an aldehyde group, a C 1-10 acyl group, an amino group which may have a substituent, a C 6-14 aryl group which may have a substituent, and a C 6-14 heteroaryl group which may have a substituent.
• a C 1-6 alkyl group examples include a C 1-6 alkyl group, a C s-6 alkenyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a
• Examples of the "optionally substituted C 6-14 aryl group” include a phenyl group, a naphthyl group, an anthryl group, a 2-methylphenyl group, a 4-methylphenyl group, a 3,5-dimethylphenyl group, a 2,6-dimethylphenyl group, a 2,4-dimethylphenyl group, a 2-trifluoromethylphenyl group, a 2-methoxyphenyl group, a 4-methoxyphenyl group, a 2,4-dimethoxyphenyl group, a 3,5-dimethoxyphenyl group, a 2-methylthiophenyl group, a 4-methylthiophenyl group, a 2,4-dimethylthiophenyl group, a 3,5-dimethylthiophenyl group, a 4-chlorophenyl group, a 4-bromophenyl group, a 4-nitrophenyl group, a 4-aminophenyl group, a 4-
• a "heteroaryl group” is a cyclic group having aromaticity, the ring of which is composed of carbon atoms and atoms other than carbon atoms.
• the heteroaryl group may be a group containing a nitrogen atom (nitrogen-containing heteroaryl group), a group containing an oxygen atom (oxygen-containing heteroaryl group), or a group containing a sulfur atom (sulfur-containing heteroaryl group).
• the aromatic ring may contain two or more types of atoms other than carbon atoms.
• Examples of C 5-14 nitrogen-containing heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, benzimidazolyl, benzotriazolyl, quinolyl, isoquinolyl, quinazolyl, and carbazolyl groups.
• Examples of C 5-14 oxygen-containing heteroaryl groups include furanyl, pyranyl , benzopyranyl, and xanthenyl groups.
• Examples of C 5-14 sulfur-containing heteroaryl groups include thienyl groups.
• Examples of C 5-14 heteroaryl groups containing two or more heteroatoms include oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl groups.
• a "substituted heteroaryl group” is a group in which one or more, preferably 1 to 3, hydrogen atoms bonded to a carbon atom of the heteroaryl group are substituted with another functional group.
• the heteroaryl group has two or more substituents, the substituents may be the same or different.
• substituents examples include a C 1-6 alkyl group, a C s-6 alkenyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, a C 1-10 acyl group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a trihalomethyl group, a nitro group, an aldehyde group, an amino group which may have a substituent, a C 6-14 aryl group which may have a substituent, and a C 6-14 heteroaryl group which may have a substituent.
• a C 1-6 alkyl group examples include a C 1-6 alkyl group, a C s-6 alkenyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, a C 1-10 acyl group, a halogen atom (a fluorine atom, a chlorine atom,
• aromatic group includes both an aryl group (aromatic hydrocarbon group) which may have a substituent, and a heteroaryl group (heterocyclic group) which may have a substituent.
• the deoxygenation fluorination agent used in the present invention (hereinafter, sometimes referred to as the "deoxygenation fluorination agent of the present invention”) is a compound represented by the following general formula (E1).
• the SF 5 -ion functions as a nucleophilic reagent for the carbon atom of a ketone group or a carbon atom bonded to a hydroxyl group, thereby bonding a fluorine atom in place of the oxygen atom bonded to these carbon atoms.
• the SF 5 -ion forms a salt with a glyme-coordinated alkali metal ion, and therefore the thermal stability and low pressure resistance are improved.
• SF 4 is unlikely to be eliminated even in a low pressure environment, and thermal decomposition at about 100°C is also suppressed. Therefore, in addition to allowing the deoxygenation fluorination reaction to proceed under relatively mild conditions, the structural restrictions on the substrate to be deoxygenated are relaxed.
• the deoxygenation fluorination agent of the present invention can use a wide variety of oxygen-containing compounds having an aldehyde group, a ketone group, a carboxy group, or a hydroxy group as a substrate.
• M represents a cesium ion, a potassium ion, or a rubidium ion.
• G4 represents tetraethylene glycol dimethyl ether (tetraglyme) (CAS No.: 143-24-8), and n represents an integer of 1 to 4.
• a compound in which M is a cesium ion in the general formula (E1) ([Cs(G4)n][SF 5 ]) is preferred, and a compound in which M is a cesium ion and n is 2 ([Cs(G4) 2 ][SF 5 ]) is particularly preferred.
• the method for producing a fluorine-containing compound according to the present invention is a method for producing a fluorine-containing compound by deoxyfluorinating an oxygen-containing compound having an aldehyde group, a ketone group, a carboxy group, or a hydroxy group in one or more solvents selected from the group consisting of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), tetraethylene glycol dimethyl ether (tetraglyme) (G4), dimethylacetamide (DMA), hexamethyl phosphorous triamide (HMPA), and acetonitrile (MeCN) using the deoxyfluorinating agent of the present invention.
• DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
• tetraethylene glycol dimethyl ether tetraglyme
• DMA dimethylacetamide
• HMPA hex
• the deoxyfluorinating agent of the present invention is stable at room temperature, but is easily decomposed when the temperature is raised in the solvent.
• the deoxyfluorinating agent is decomposed even at about 60° C. in tetrahydrofuran (THF) or dimethyl ether (DME), but is stable up to about 80° C. in MeCN, and is hardly decomposed at room temperature to 120° C. in DMPU, G4, DMA, and HMPA.
• a fluorine-containing compound can be efficiently produced by using one or more solvents selected from the group consisting of DMPU, G4, DMA, HMPA, and MeCN as a solvent for carrying out the deoxyfluorination reaction.
• the solvent used in the method for producing a fluorine-containing compound according to the present invention may be one type of solvent or a mixed solvent of two or more types of solvents.
• the deoxyfluorination reaction can be carried out by adding the substrate compound and the deoxyfluorinating agent of the present invention to a solvent consisting of one or more selected from the group consisting of DMPU, G4, DMA and HMPA, and maintaining the mixture at room temperature to 120°C for a predetermined period of time.
• the temperature of the reaction system may be changed stepwise within the range of room temperature to 120°C.
• the amount of the substrate compound and the deoxyfluorinating agent of the present invention to be added to the reaction system is preferably 0.5 to 100 molar equivalents of the deoxyfluorinating agent of the present invention per mole of the substrate compound, more preferably 0.5 to 50 molar equivalents, and even more preferably 0.5 to 10 molar equivalents.
• the substrate compound used in the method for producing a fluorine-containing compound according to the present invention is not particularly limited as long as it is an oxygen-containing compound having an aldehyde group, a ketone group, a carboxy group, or a hydroxy group.
• the oxygen-containing compound may have at least one of an aldehyde group, a ketone group, a carboxy group, and a hydroxy group, and may have two or more of an aldehyde group, a ketone group, a carboxy group, and a hydroxy group.
• the functional groups may be the same, or two or more of the aldehyde groups, ketone groups, carboxy groups, and hydroxy groups may be combined.
• the method for producing a fluorine-containing compound according to the present invention can produce a compound represented by the following general formula (P1) as a fluorine-containing compound when the oxygen-containing compound used as the substrate is a compound represented by the following general formula (S1).
• R 1 is a hydrogen atom or a C 1-6 alkyl group.
• R 1 is a C 1-6 alkyl group, it may be a C 1-6 alkyl group having no substituent, or may be a C 1-6 alkyl group having a substituent.
• the substituent is not particularly limited as long as it is a group that does not inhibit deoxyfluorination by the deoxyfluorination agent of the present invention.
• substituents examples include a C 1-6 alkoxy group, a C 1-6 alkylthio group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a trihalomethyl group, a nitro group, an amino group which may have a substituent, and the like.
• the amino group which may have a substituent is a group in which one or two hydrogen atoms of the amino group are substituted with a C 1-6 alkyl group, a C 1-10 acyl group, and the like, and specific examples thereof include a dimethylamino group, a diethylamino group, a methylamino group, an acetylamino group, and an acetylmethylamino group.
• R 1 is preferably a hydrogen atom or an unsubstituted C 1-6 alkyl group, more preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, or an isopropyl group, and further preferably a hydrogen atom or a methyl group.
• R 11 is a C 1-30 aliphatic hydrocarbon group which may have a substituent, an alkoxy group which may have a substituent, an aliphatic heterocyclic group which may have a substituent, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent.
• R 11 is a C 1-30 aliphatic hydrocarbon group which may have a substituent
• the substituent is not particularly limited as long as it is a group which does not inhibit deoxyfluorination by the deoxyfluorinating agent of the present invention.
• the substituent include a C 1-6 alkoxy group, a C 1-6 alkylthio group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a trihalomethyl group, a nitro group, an amino group which may have a substituent, an aryl group which may have a substituent, and a heteroaryl group which may have a substituent.
• the amino group which may have a substituent the same groups as those exemplified as the substituents of R 1 can be used.
• R 11 is a C 1-30 aliphatic hydrocarbon group which may have a substituent
• the C 1-30 aliphatic hydrocarbon group which may have a substituent is preferably a C 1-10 alkyl group which may have a substituent or a C 2-10 alkenyl group which may have a substituent, more preferably a C 1-10 alkyl group which may have an optionally substituted aryl group or an optionally substituted heteroaryl group as a substituent, or a C 2-10 alkenyl group which may have an optionally substituted aryl group or an optionally substituted heteroaryl group as a substituent, and even more preferably a C 1-10 alkyl group which may have an optionally substituted phenyl group as a substituent, or a C 2-10 alkenyl group which may have an optionally substituted phenyl group as a substituent.
• a methyl group, an ethyl group, a propyl group, or a vinyl group which may have an optionally substituted phenyl group as a substituent is particularly preferred.
• the phenyl group which may have a substituent include a phenyl group which has, as a substituent, one or more groups selected from the group consisting of a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a nitro group, an amino group, a dimethylamino group, a methylamino group, an acetylamino group, a methoxy group, a vinyl group, a propenyl group, a 1-methylvinyl group, and a hydroxy group, and a phenyl group which has no substituent.
• a halogen atom a fluorine atom, a chlorine atom, a bromine atom, or an iodine
• R 11 is an alkoxy group which may have a substituent
• the alkoxy group is preferably a C 1-10 alkoxy group, more preferably a C 1-10 alkoxy group in which the alkyl group moiety is linear or branched, and still more preferably a C 1-6 alkoxy group in which the alkyl group moiety is linear.
• R 11 is an alkoxy group which may have a substituent
• the substituent is not particularly limited as long as it is a group which does not inhibit deoxyfluorination by the deoxyfluorinating agent of the present invention.
• the substituent include a C 1-6 alkoxy group, a C 1-6 alkylthio group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a nitro group, an aryl group which may have a substituent, and a heteroaryl group which may have a substituent.
• R 11 is an alkoxy group which may have a substituent
• the alkoxy group which may have a substituent is preferably a C 1-10 alkoxy group which may have a substituent, more preferably a C 1-10 alkoxy group in which the alkyl group moiety is linear or branched and which may have a substituent, and even more preferably a C 1-6 alkoxy group in which the alkyl group moiety is linear and which may have a substituent.
• a C 1-6 alkoxy group in which the alkyl group moiety is linear and which may have one or more substituents selected from the group consisting of a C 1-6 alkoxy group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a nitro group, and a phenyl group which may have a substituent is preferred, a C 1-6 alkoxy group having a phenyl group which may have a substituent as a substituent, a C 1-6 alkoxy group having a phenyl group which does not have a substituent as a substituent, or a C 1-6 alkoxy group which does not have a substituent is more preferred, and a C 1-6 alkoxy group having a phenyl group which does not have a substituent as a substituent is even more preferred.
• the aliphatic heterocyclic group is preferably a nitrogen-containing aliphatic heterocyclic group, more preferably a pyrrolidyl group, a piperidyl group, a piperazyl group, or a morpholyl group, and even more preferably a pyrrolidyl group or a piperidyl group.
• the nitrogen atom forming the heterocycle may be protected with a protecting group.
• those used as protecting groups for amines such as a tert-butoxycarbonyl (Boc) group, a benzyloxycarbonyl group (Cbz group), a 9-fluorenylmethyloxycarbonyl group (Fmoc group), an allyloxycarbonyl group (Alloc group), or a 2,2,2-triethoxycarbonyl group (Troc group), may be appropriately used.
• R 11 is an aliphatic heterocyclic group which may have a substituent
• substituents include a C 1-6 alkyl group, a C s-6 alkenyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a trihalomethyl group, a nitro group, an amino group which may have a substituent, an aryl group which may have a substituent, and a heteroaryl group which may have a substituent, etc.
• the amino group which may have a substituent the same groups as those exemplified as the substituents of R 1 can be used.
• the aliphatic heterocyclic group which may have a substituent is preferably a nitrogen-containing aliphatic heterocyclic group which may have a substituent and whose nitrogen atom may be protected by a protecting group, more preferably a pyrrolidyl group or piperidyl group which may have a substituent and whose nitrogen atom may be protected by a protecting group, still more preferably a pyrrolidyl group or piperidyl group which may have a substituent and whose nitrogen atom may be protected by a Boc group or a Cbz group, and still more preferably a pyrrolidyl group which may have a substituent and whose nitrogen atom may be protected by a Boc group or a Cbz group.
• R 11 is an aryl group which may have a substituent
• the aryl group is preferably a phenyl group which may have a substituent or a naphthyl group which may have a substituent, and more preferably a phenyl group which may have a substituent.
• R 11 is an aryl group which may have a substituent
• substituents include a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 1-6 alkoxy group, a C 2-6 acyl group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a nitro group, an amino group which may have a substituent, a hydroxy group, an aryl group, a heteroaryl group, etc.
• the amino group which may have a substituent the same groups as those exemplified as the substituents of R 1 can be used.
• R 11 is an aryl group which may have a substituent
• the aryl group which may have a substituent is preferably a phenyl group which may have a substituent, and more preferably a phenyl group which may have one or more substituents selected from the group consisting of a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 1-6 alkoxy group, a C 2-6 acyl group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a nitro group, an amino group, a dimethylamino group, a methylamino group, an acetylamino group, a phenyl group, a halogenated phenyl group (a phenyl group substituted with a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iod
• the heteroaryl group is preferably a pyrrolyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, an indolyl group, an isoindolyl group, a quinolyl group, an isoquinolyl group, a furanyl group, or a thienyl group, and more preferably a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a pyridyl group, an indolyl group, a quinolyl group, a furanyl group, or a thienyl group.
• R 11 is a heteroaryl group which may have a substituent
• substituents include a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 1-6 alkoxy group, a C 2-6 acyl group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a nitro group, an amino group which may have a substituent, a hydroxy group, an aryl group, a heteroaryl group, and the like, and among these, one or more substituents selected from the group consisting of a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 1-6 alkoxy group, a C 2-6 acyl group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), an amino group which may have a substituent, a hydroxy group
• R 11 is a heteroaryl group which may have a substituent
• the heteroaryl group which may have a substituent is preferably a pyrrolyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolyl group, a furanyl group, or a thienyl group, and these heteroaryl groups may have a substituent.
• a pyrrolyl group As compound (S1), a pyrrolyl group , a pyrazolyl group, an imidazolyl group, a pyridyl group, an indolyl group, a quinolyl group, a furanyl group, or a thienyl group which may have one or more substituents selected from the group consisting of a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 1-6 alkoxy group, a C 2-6 acyl group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), an amino group, a dimethylamino group, a methylamino group, an acetylamino group, a phenyl group, and a halogenated phenyl group, is more preferable, and a pyrrolyl group, a pyrazolyl group
• the method for producing a fluorine-containing compound according to the present invention can produce a compound represented by the following general formula (P2) as a fluorine-containing compound when the oxygen-containing compound used as a substrate is a compound represented by the following general formula (S2).
• R 12 is an optionally substituted C 1-30 aliphatic hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, or an optionally substituted heteroaryl group.
• the optionally substituted C 1-30 aliphatic hydrocarbon group, the optionally substituted alkoxy group, the optionally substituted aliphatic heterocyclic group, the optionally substituted aryl group, and the optionally substituted heteroaryl group can each be the same as the groups exemplified for R 11 above, and the groups preferred for R 11 above are preferably used.
• the method for producing a fluorine-containing compound according to the present invention can produce a compound represented by the following general formula (P3) as a fluorine-containing compound when the oxygen-containing compound used as a substrate is a compound represented by the following general formula (S3).
• R 13 is a C 1-30 aliphatic hydrocarbon group which may have a substituent.
• the same groups as those exemplified for R 11 above can be used, and the groups which are preferred for R 11 above are preferably used.
• the hydroxy group in compound (S3) may be protected with a protecting group.
• the protecting group may be appropriately selected from known protecting groups used as protecting groups for alcohols. Specific examples of the protecting group include trialkylsilyl group, tetrahydropyranyl group (THP group), methoxymethyl ether group (MOM group), trityl group (Tr group), and tert-butyl group. Examples of the trialkylsilyl group include trimethylsilyl group (TMS group), triethylsilyl group (TES group), triisopropylsilyl group (TIPS group), and tritert-butylsilyl group (TBS group).
• the NMR apparatus used in the analyses in the examples was a JNM-ECS400 (400 MHz) or ECZ500R (500 MHz) manufactured by JEOL Ltd.
• the reference value for C 6 F 6 was set to ⁇ 162 PPM.
• the unit of yield (%) described in the examples is mol %.
• the silyl-protected alcohol the following compound (1) was used.
• the solvents used were G4, THF, DME, diethylene glycol dimethyl ether (CAS No.: 111-96-6) (G2), acetonitrile (MeCN), dimethylformamide (DMF), N-methylpyrrolidone (NMP), DMPU, DMA, HMPA, and dimethylsulfoxide (DMSO).
• compound (1) (0.1 mmol) as a starting material (substrate) and 1,4-difluorobenzene (0.5 mmol, 5 ⁇ L) as an internal standard were dissolved in a solvent (0.5 mL) in a glass vial to prepare a substrate solution.
• solid Cs(G4)2SF5 (0.15 mmol, 1.5 equivalents relative to the substrate) was charged, and the substrate solution was added using a syringe and mixed well to prepare a reaction mixture that was a homogeneous solution.
• the resulting reaction mixture was transferred to an NMR tube containing an FEP-inlet and sealed with a PTFE plug. The NMR tube was then heated to 60° C. to carry out the reaction. The progress of the reaction was monitored by 19 F NMR.
• Table 1 shows the reaction time for each reaction, the conversion rate (fluorination rate) (%) of the substrate compound, and the yield (%) calculated from the NMR measurement data.
• fluorine-containing compounds were obtained with a high yield of over 70% after 72 hours of reaction.
• MeCN was used as the solvent, the conversion rate was low after 22 hours of reaction, but decomposition of Cs(G4)2SF5 did not progress and by-products were small.
• DMPU was the most suitable reaction solvent for the deoxyfluorination reaction using Cs(G4)2SF5, as it produced few by-products and had a very high yield.
• fluorine-containing compounds were not obtained in THF or DME, in which Cs(G4)2SF5 is easily decomposed.
• Example 2 Various substrate compounds were subjected to deoxyfluorination reactions using Cs(G4)2SF5 as a deoxyfluorination agent and DMPU as a reaction solvent to synthesize fluorine-containing compounds.
• the substrate compound (0.05 mmol) and 1,4-difluorobenzene (0.5 mmol, 5 ⁇ L) as an internal standard were dissolved in DMPU (0.4 mL) in a glass vial to prepare a substrate solution.
• solid Cs(G4)2SF5 (0.1-0.2 mmol, 2-4 equivalents relative to the substrate) was charged, and the substrate solution was added using a syringe and mixed well to prepare a reaction mixture that was a homogeneous solution.
• the reaction mixture obtained was transferred to an NMR tube containing an FEP inlet and sealed with a PTFE plug. The NMR tube was then heated to a predetermined temperature to carry out the reaction. The progress of the reaction was monitored by 19 F NMR.
• the reaction products were isolated as follows.
• the starting material (0.2 mmol) was placed in a PTFE round-bottom test tube containing a stirrer in a glove box filled with argon gas.
• a solution was prepared by dissolving Cs(G4)2SF5 (0.4-0.8 mmol, 2-4 equivalents relative to the substrate) in DMPU (1.5 mL), and the solution was placed in the round-bottom test tube.
• the PTFE round-bottom test tube was sealed with a screw cap and reacted at a predetermined temperature for a predetermined time.
• the reaction crude liquid was then cooled to room temperature, and water (10 mL) was added, and the product was extracted using dichloromethane solvent.
• the obtained organic layer was washed with water and saturated saline, and dehydrated with magnesium sulfate. Furthermore, the solvent was distilled off to obtain a crude product.
• the obtained crude product was purified by silica gel column chromatography.
• SF 5 - stabilized by forming a salt with a glyme-coordinated alkali metal ion is used as a deoxyfluorination agent, and therefore deoxyfluorination can be carried out under relatively mild conditions for a wide variety of oxygen-containing compounds having a ketone group, an aldehyde group, a hydroxyl group, etc. Therefore, the present invention is useful for synthesizing a wide variety of fluorine-containing compounds.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Priority Applications (3)

Applications Claiming Priority (2)

Publications (1)

Family

ID=90830785

Family Applications (1)

Country Status (4)

Citations (4)

• 2023
  • 2023-10-25 CN CN202380074253.0A patent/CN120091986A/zh active Pending
  • 2023-10-25 EP EP23882689.5A patent/EP4610245A1/en active Pending
  • 2023-10-25 JP JP2024553106A patent/JP7778957B2/ja active Active
  • 2023-10-25 WO PCT/JP2023/038549 patent/WO2024090485A1/ja not_active Ceased

Patent Citations (4)

Non-Patent Citations (4)

Also Published As

Similar Documents

Legal Events