WO2017195894A1 - Procédé de production d'un composé de type 2-acétylpyridine - Google Patents

Procédé de production d'un composé de type 2-acétylpyridine Download PDF

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WO2017195894A1
WO2017195894A1 PCT/JP2017/018068 JP2017018068W WO2017195894A1 WO 2017195894 A1 WO2017195894 A1 WO 2017195894A1 JP 2017018068 W JP2017018068 W JP 2017018068W WO 2017195894 A1 WO2017195894 A1 WO 2017195894A1
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group
compound
formula
producing
alkyl
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宇都宮　朋久
中村　俊之
陽介 中山
義之 楠岡
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Nissan Chemical Corp
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Nissan Chemical Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

Definitions

  • the present invention relates to a process for producing 2-acetylpyridine compounds useful as medical pesticides or their production intermediates.
  • Certain 2-acetylpyridine compounds are known to be useful as intermediates for physiologically active compounds (see, for example, Patent Document 1 and Patent Document 2).
  • a method for synthesizing a 2-acetylpyridine compound a method using a 2-halopyridine compound and a vinyltin compound (for example, see Patent Document 3 and Patent Document 4) is known.
  • Patent Document 5 and Non-Patent Document 1 methods for introducing an acetyl group into a pyridine ring are known.
  • Patent Document 5 a bisacetylpyridine compound into which two acetyl groups are introduced is generated, and when a monoacetylpyridine compound is produced from a pyridine compound having a plurality of reaction points as a raw material, There is a concern that the bisacetylpyridine compound is mixed as an impurity. Furthermore, in the method described in Non-Patent Document 1, a lot of palladium catalyst is used, and the removal work when the palladium catalyst is mixed into the product is not easy. Moreover, it is not suitable for industrial use from the viewpoint of environmental load due to the disposal of the metal catalyst.
  • the present inventor has found a simple method for producing a 2-alkoxyvinylpyridine compound and a 2-acetylpyridine compound, and has completed the present invention. That is, the present invention relates to the following [1] to [11].
  • X and Y are each independently a hydrogen atom, hydroxyl group, halogen atom, cyano, nitro, C 1 -C 6 alkyl, halo (C 1 -C 6 ) alkyl, C 1 -C 6 alkoxy , Halo (C 1 -C 6 ) alkoxy, C 2 -C 8 alkenyl, halo (C 2 -C 8 ) alkenyl, C 2 -C 8 alkynyl, halo (C 2 -C 8 ) alkynyl, C 1 -C 6
  • X represents a halogen atom
  • Y represents a hydrogen atom, a halogen atom or C 1 -C 6 alkyl
  • Y is a method for producing a 2-alkoxyvinylpyridine compound according to [2], wherein Y represents a halogen atom or C 1 -C 6 alkyl.
  • Y represents a halogen atom, The method for producing a 2-alkoxyvinylpyridine compound according to [3].
  • [5] The method for producing a 2-alkoxyvinylpyridine compound according to any one of [1] to [4], wherein R represents (C 1 -C 6 ) alkyl optionally substituted with a hydroxyl group.
  • the phosphine-based ligand is 1,3-bis (diphenylphosphino) propane, 1,1′-bis (diphenylphosphino) ferrocene or 1,4-bis (diphenylphosphino) butane [1]
  • the method for producing a 2-alkoxyvinylpyridine compound according to any one of [1] to [9] comprising a step of adding water.
  • the present invention can provide an industrial process for producing 2-acetylpyridine compounds useful as medical pesticides or their production intermediates.
  • this invention includes all the optically active forms, a racemate, or a diastereomer.
  • n- means normal
  • i- means iso
  • s- means secondary and t- means tertiary
  • m- means meta.
  • a halogen atom in this invention a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom are mentioned. In the present specification, the notation “halo” also represents these halogen atoms.
  • C a -C b alkyl represents a linear or branched hydrocarbon group having a carbon number of a to b
  • X and Y in the formula (1) Is usually C 1 -C 6 alkyl
  • R in the formula (2) is usually C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl.
  • halo (C a ⁇ C b) alkyl hydrogen atoms bonded to carbon atoms by halogen atom wherein the meaning of is as defined above is optionally substituted C a ⁇ C b represents alkyl and is usually halo (C 1 -C 6 ) alkyl.
  • fluoromethyl group chloromethyl group, bromomethyl group, iodomethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 3-fluoropropyl group, 3-chloropropyl group, difluoromethyl group, trifluoro Methyl group, dichloromethyl group, trichloromethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, chlorodifluoromethyl group, bromodifluoromethyl group, Specific examples include pentafluoroethyl group, heptafluoropropyl group, heptafluoroisopropyl group, 4-chlorobutyl group, 4-fluorobutyl group and the like.
  • (C a -C b ) alkyl optionally substituted with a hydroxyl group means that the number of carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a hydroxyl group is from a to b.
  • the alkyl having the above meaning is usually (C 1 -C 8 ) alkyl optionally substituted with a hydroxyl group, preferably (C 1 -C 6 ) alkyl optionally substituted with a hydroxyl group, Each selected range of carbon atoms is selected.
  • C a -C b alkoxy represents an alkyl-O— group having the above-mentioned meaning consisting of a to b carbon atoms, usually C 1 -C 6 alkoxy, C 1 -C 4 alkoxy is preferred.
  • Specific examples include methoxy group, ethoxy group, n-propyloxy group, i-propyloxy group, n-butyloxy group, i-butyloxy group, s-butyloxy group, tert-butyloxy group, pentyloxy group, hexyloxy group, etc. As mentioned.
  • halo (C a -C b ) alkoxy represents a haloalkyl-O— group having the above-mentioned meaning consisting of a to b carbon atoms, usually halo (C 1- C 6 ) alkoxy, preferably halo (C 1 -C 4 ) alkoxy.
  • difluoromethoxy group trifluoromethoxy group, chlorodifluoromethoxy group, bromodifluoromethoxy group, 2-fluoroethoxy group, 2-chloro-1,1,2-trifluoroethoxy group, 1,1,2,2-tetrafluoro
  • difluoromethoxy group trifluoromethoxy group, chlorodifluoromethoxy group, bromodifluoromethoxy group, 2-fluoroethoxy group, 2-chloro-1,1,2-trifluoroethoxy group, 1,1,2,2-tetrafluoro
  • ethoxy group and a 1,1,2,3,3,3-hexafluoropropyloxy group.
  • C a -C b alkenyl refers to a straight or branched chain having 1 to 2 carbon atoms, and one or more double bonds in the molecule.
  • halo (C a -C b ) alkenyl refers to a straight chain composed of a to b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom, or It represents an unsaturated hydrocarbon group which is branched and has one or more double bonds in the molecule, and is usually halo (C 2 -C 8 ) alkenyl, preferably halo (C 2- C 6 ) alkenyl.
  • these halogen atoms may be the same as or different from each other.
  • C a -C b alkynyl refers to a linear or branched chain consisting of a to b carbon atoms, and one or more triple bonds in the molecule. Represents an unsaturated hydrocarbon group, usually C 2 -C 8 alkynyl, preferably C 2 -C 6 alkynyl.
  • ethynyl group 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group, 1- Specific examples include hexynyl group, 3-hexynyl group, 3-methyl-1-pentynyl group, 4-methyl-1-pentynyl group, 3,3-dimethyl 1-butynyl group and the like.
  • halo (C a -C b ) alkynyl refers to a straight chain composed of a to b carbon atoms in which a hydrogen atom bonded to a carbon atom is arbitrarily substituted with a halogen atom. Or an unsaturated hydrocarbon group which is branched and has one or more triple bonds in the molecule, and is usually halo (C 2 -C 8 ) alkynyl, preferably halo (C 2- C 6 ) Alkynyl. At this time, when substituted by two or more halogen atoms, these halogen atoms may be the same as or different from each other.
  • C a -C b alkylcarbonyl represents a carbonyl group to which an alkyl group having from a to b carbon atoms is bonded, and is usually a C 1 -C 6 alkylcarbonyl.
  • C 1 -C 4 alkylcarbonyl is preferred.
  • C a -C b alkoxycarbonyl represents a carbonyl group to which an alkoxy group having a carbon number of a to b is bonded, and is usually C 1 -C 6 alkoxycarbonyl. C 1 -C 4 alkoxycarbonyl is preferred.
  • the 2-acetylpyridine compound represented by the formula (4) can be produced by the method represented by the following reaction formula 1.
  • Compound (3) comprises a compound (1) and a compound (2) in a solvent or without a solvent, in the presence of a palladium catalyst having a phosphine-based ligand and a basic compound. Some can be produced by reacting in the presence of water.
  • the palladium catalyst having a phosphine-based ligand used in this reaction include tetrakis (triphenylphosphine) palladium (0), bis (tri-tert-butylphosphine) palladium (0), bis (tricyclohexylphosphine) palladium.
  • Preferred examples include dichlorobis (triphenylphosphine) palladium (II) and tetrakis (triphenylphosphine) palladium (0). More preferably, dichlorobis (triphenylphosphine) palladium (II) is mentioned.
  • a complex formed by mixing a catalyst precursor and a phosphine ligand can be used as a palladium catalyst having a phosphine ligand.
  • the complex can be prepared in a reaction system, and in some cases, it can be prepared separately and added to the reaction system.
  • Catalyst precursors used in this reaction include dichlorobis (acetonitrile) palladium (II), dichlorodiaminepalladium (II) dichlorobis (benzonitrile) palladium (II), dichloro (1,5-cyclooctadiene) palladium (II), Allyl palladium chloride dimer (II), bis (2-methylallyl) palladium chloride dimer (II), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), acetylacetone palladium (0) II), palladium (II) acetate, palladium (II) trifluoroacetate, palladium (II) trifluoromethanesulfonate, palladium (II) chloride, palladium-supported carbon and the like.
  • Preferred examples include palladium (II) chloride and palladium (II) acetate. More preferably, palladium (II) acetate is mentioned.
  • Examples of the phosphine ligand used in this reaction include trimethylphosphine, tri-n-butylphosphine, tri-t-butylphosphine, triethoxyphosphine, triphenylphosphine, tris (4-methylphenyl) phosphine, and tris (4-methoxyphenyl).
  • triphenylphosphine 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane or 1,1′-bis (diphenylphosphino) ferrocene, more preferably 1 , 3-bis (diphenylphosphino) propane.
  • the amount of the phosphine-based ligand used is 10 molar equivalents or less, preferably 5 molar equivalents or less, more preferably 3 molar equivalents or less, and 0.01 molar equivalents or more with respect to the catalyst precursor. , Preferably 0.1 molar equivalent or more, more preferably 1 molar equivalent or more.
  • the usage-amount of a phosphine-type ligand is 1 molar equivalent or less with respect to a compound (1), Preferably it is 0.1 molar equivalent or less, More preferably, it is 0.02 molar equivalent or less. Yes, it is 0.000001 molar equivalent or more, preferably 0.0001 molar equivalent or more, more preferably 0.002 molar equivalent or more.
  • the range of the usage-amount of the palladium catalyst which has a phosphine-type ligand the above-mentioned upper limit and lower limit can be combined arbitrarily.
  • Examples of basic compounds used in this reaction include organic bases and inorganic bases.
  • Examples of the organic base include aromatic amines such as pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, triethylamine, tri-n-butylamine, di (isopropyl) ethylamine, 1,8-diazabicyclo.
  • aromatic amines such as pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, triethylamine, tri-n-butylamine, di (isopropyl) ethylamine, 1,8-diazabicyclo.
  • aliphatic amines such as [5.4.0] -7-undecene and 1,4-diazabicyclo [2.2.2] octane.
  • inorganic bases include tetramethylammonium hydroxide, trimethylbenzylammonium hydroxide and tetrabutylammonium hydroxide, quaternary ammonium hydroxides, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide.
  • the amount of the basic compound used is 20 molar equivalents or less, preferably 10 molar equivalents or less, more preferably 5 molar equivalents or less, and 0.01 molar equivalents or more, relative to compound (1). Preferably it is 0.1 molar equivalent or more.
  • the upper limit and lower limit described above can be combined arbitrarily.
  • This reaction can be performed by adding water as necessary.
  • the amount of water added is 100 molar equivalents or less, preferably 10 molar equivalents or less, more preferably 4 molar equivalents or less, and 0.01 molar equivalents or more, relative to compound (1).
  • Preferably it is 0.1 molar equivalent or more, more preferably 1 molar equivalent or more.
  • About the range of the usage-amount of water, the upper limit and lower limit described above can be combined arbitrarily.
  • the reaction temperature is usually ⁇ 90 to 200 ° C., preferably 60 to 200 ° C., more preferably 100 to 160 ° C. While the reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, it is generally 1 minute to 100 hours, preferably 10 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • a solvent can be used as necessary.
  • the solvent used is not particularly limited as long as it does not inhibit the progress of the reaction.
  • aliphatic hydrocarbon solvents such as hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, heptane
  • Aromatic hydrocarbon solvents such as benzene, xylene, toluene, chlorobenzene, nitrobenzene, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, Alcohol solvents such as ethylene glycol monomethyl ether, 1,3-propanediol monomethyl ether, diethylene glycol, diethyl ether, tetrahydrofuran, cyclopentyl methyl ether, tertiary buty
  • Ether solvents such as methyl acetate, ethyl acetate, butyl acetate, methyl propionate, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, propionitrile, etc.
  • amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, propionitrile, etc.
  • examples thereof include nitrile solvents, ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone, and dimethyl sulfoxide.
  • alcohol solvent, amide solvent and dimethyl sulfoxide more preferably methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, ethylene Glycol monomethyl ether, 1,3-propanediol monomethyl ether, diethylene glycol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide, more preferably 1-butanol, ethylene glycol, 1, 2-Propanediol or dimethyl sulfoxide, more preferably 1,2-propanediol.
  • solvents can be used in a mixture of two or more.
  • Compound (4) can be produced by hydrolyzing compound (3) in the presence of an acid in a solvent or without a solvent.
  • the acid used in this reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid.
  • hydrochloric acid, sulfuric acid or phosphoric acid more preferably hydrochloric acid or sulfuric acid.
  • the usage-amount of an acid is 10 molar equivalent or less with respect to a compound (3), Preferably it is 5 molar equivalent or less, 0.01 molar equivalent or more, Preferably it is 0.1 molar equivalent or more.
  • the amount of acid used in the second step is 10 molar equivalents or less with respect to the compound (1), The amount is preferably 5 molar equivalents or less, 0.01 molar equivalents or more, and preferably 0.1 molar equivalents or more.
  • the above-mentioned upper limit and lower limit can be combined arbitrarily.
  • the reaction temperature is usually ⁇ 90 to 200 ° C., preferably 0 to 100 ° C., more preferably 0 to 80 ° C. While the reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, it is generally 1 minute to 100 hours, preferably 10 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • a solvent can be used as necessary.
  • the solvent used is not particularly limited as long as it does not inhibit the progress of the reaction.
  • aliphatic hydrocarbon solvents such as hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, heptane
  • Aromatic hydrocarbon solvents such as benzene, xylene, toluene, chlorobenzene, nitrobenzene, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, Alcohol solvents such as ethylene glycol monomethyl ether, 1,3-propanediol monomethyl ether, diethylene glycol, diethyl ether, tetrahydrofuran, cyclopentyl methyl ether, tertiary buty
  • Ether solvents such as methyl acetate, ethyl acetate, butyl acetate, methyl propionate, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, propionitrile, etc.
  • amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, propionitrile, etc.
  • Examples include nitrile solvents, ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone, dimethyl sulfoxide, and water.
  • alcohol solvent amide solvent, dimethyl sulfoxide or water
  • methanol ethanol, 1-propanol, 2-propanol, 1-butanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol , Ethylene glycol monomethyl ether, 1,3-propanediol monomethyl ether, diethylene glycol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or water, more preferably 1-butanol, ethylene
  • examples include glycol, 1,2-propanediol, dimethyl sulfoxide or water. These solvents can be used in a mixture of two or more.
  • the first step and the second step can be performed in an inert gas atmosphere such as nitrogen or argon if necessary.
  • the reaction mixture after completion of the reaction is directly concentrated or dissolved in an organic solvent, and the organic layer obtained after washing with water is concentrated, or poured into ice water and extracted with an organic solvent.
  • the desired compound can be obtained by carrying out normal post-treatment such as concentrating the obtained organic layer.
  • it can be separated and purified by any purification method such as recrystallization, column chromatograph, thin layer chromatograph, liquid chromatographic fractionation, distillation or the like.
  • the compound (3) obtained in the first step can be used continuously in the second step without purification and isolation after the completion of the reaction.
  • Performing the first step and the second step continuously means performing the second step on the product produced in the first step without performing the isolation / purification operation.
  • the reaction container which performs a 1st process and a 2nd process may respectively be the same, or may differ.
  • the solvent used when the first step and the second step are continuously performed is not particularly limited as long as it does not inhibit the progress of the reaction, and examples thereof include the same solvent as that in the first step.
  • Some of the compounds (1) used here are known compounds, and some are available as commercial products.
  • other methods known in the literature for example, a method described in International Publication No. 2002/22583, a method of converting a 2-pyridone compound into a 2-chloropyridine compound, described in US Pat. No. 4,703,123, Synthesis according to a method of reductively substituting a halogen atom on the pyridine ring with a hydrogen atom, a method described in International Publication No. 2009/114589, substituting an amino group of a 3-aminopyridine compound with a halogen atom, etc. Can do.
  • Some of the compounds (2) used here are known compounds, and some of them are commercially available.
  • a method of adding an alcohol to an alkyne compound described in JP-A No. 04-198144, an acetal compound to an alcohol described in International Publication No. 2009/063926 Can be synthesized according to a method of desorbing.
  • the present invention is an excellent industrial production method for 2-alkoxyvinylpyridine compounds or 2-acetylpyridine compounds. Specifically, the yield can be improved, the conversion rate can be improved, and by-products can be reduced as compared with the conventional production method.
  • the quantitative analysis described in the synthesis example is a quantitative analysis by an internal standard method using high performance liquid chromatography (HPLC), and was performed under the following analysis conditions A, B, or C.
  • the peak area ratio described in the synthesis example is a ratio of each peak area calculated according to the following calculation formula with the total area of the peaks detected in the HPLC chromatogram being 100%. .
  • Each peak area ratio area of each peak / total area of peaks ⁇ 100
  • Synthesis example 2 4-[(1- (3,5-dichloropyridin-2-yl) vinyl) oxy] butan-1-ol [hereinafter abbreviated as compound (3-1). ] 2,3,5-trichloropyridine (3.0 g) was suspended in 1,2-propanediol (6.0 g), and the resulting reaction mixture was mixed with water (0.3 g), sodium carbonate (1.91 g), tetramethylene glycol. 4.76 g of monovinyl ether, 27.2 mg of 1,3-bis (diphenylphosphino) propane and 7.4 mg of palladium acetate were sequentially added, the inside of the reaction vessel was replaced with nitrogen, and the reaction was stirred at 120 ° C. for 16 hours.
  • Synthesis example 3 1.0 g of 2,3,5-trichloropyridine and 1.03 g of sodium hydrogen carbonate were suspended in 3.0 g of n-butanol, and 1.91 g of tetramethylene glycol monovinyl ether, 1,3- Bis (diphenylphosphino) propane (135.6 mg) and palladium acetate (24.6 mg) were sequentially added, and the mixture was reacted by stirring at 120 ° C. for 15 hours under a nitrogen atmosphere. After cooling the obtained reaction liquid to room temperature, this reaction liquid was analyzed by HPLC (analysis condition C). As a result, the peak area ratio of the compound (3-1) was 48.4% (conversion rate: 76.7%).
  • Synthesis Examples 4-7 In accordance with the steps described in Synthesis Example 3, the reaction was performed by changing the basic compound as appropriate. Table 1 shows the peak area ratio and conversion rate of the compound (3-1) calculated from the HPLC analysis results after the reaction was stopped.
  • Synthesis example 8 1.0 g of 2,3,5-trichloropyridine and 1.03 g of sodium hydrogen carbonate were suspended in 3.0 g of 1-butanol, and 1.91 g of tetramethylene glycol monovinyl ether, 1,3- Bis (diphenylphosphino) propane (67.8 mg) and palladium acetate (12.3 mg) were sequentially added, and the mixture was reacted by stirring at 120 ° C. for 24 hours under a nitrogen atmosphere. The obtained reaction solution was cooled to room temperature and then analyzed by HPLC (analysis condition C). As a result, the peak area ratio of the compound (3-1) was 66.6% (conversion rate: 99.2%).
  • Synthesis Example 9 According to the process described in Synthesis Example 8, the reaction was carried out by changing the solvent as needed. Table 2 shows the peak area ratio and conversion rate of the compound (3-1) calculated from the HPLC analysis results after the termination of the reaction, and the yield of the compound (4-1) calculated from the quantitative analysis results. In the column of “-” in Synthesis Example 11, the operation after confirming the peak area ratio of the compound (3-1) was not performed.
  • Synthesis Example 11 According to the process described in Synthesis Example 10, the reaction was performed by changing the solvent as appropriate.
  • Table 3 shows the peak area ratio and conversion rate of the compound (3-1) calculated from the HPLC analysis results after the reaction was stopped, and the yield of the compound (4-1) calculated from the quantitative analysis results.
  • Synthesis Example 12 (First step) 2.0 g of 2,3,5-trichloropyridine and 1.28 g of sodium carbonate were suspended in 4.0 g of 1,2-propanediol, and 3.18 g of tetramethylene glycol monovinyl ether was added to the resulting reaction mixture. 18.1 mg of 3-bis (diphenylphosphino) propane and 5 mg of palladium acetate were sequentially added, and the mixture was reacted by stirring at 120 ° C. for 21 hours under a nitrogen atmosphere. The obtained reaction solution was cooled to room temperature and then analyzed by HPLC (analysis condition B). As a result, the peak area ratio of the compound (3-1) was 83.4% (the conversion rate was 99.3%).
  • Synthesis Example 13 and Synthesis Example 14 In accordance with the process described in Synthesis Example 12, the reaction was carried out by changing the ligand as appropriate.
  • Table 4 shows the peak area ratio and conversion rate of the compound (3-1) calculated from the HPLC analysis results after the reaction was stopped, and the yield of the compound (4-1) calculated from the quantitative analysis results.
  • DPPP is “1,3-bis (diphenylphosphino) propane”
  • DPPF is “1,1′-bis (diphenylphosphino) ferrocene”
  • DPPB is “1,4- Represents bis (diphenylphosphino) butane.
  • Synthesis Example 16 According to the process described in Synthesis Example 15, the reaction was carried out by changing the amount of water added as appropriate. Table 5 shows the conversion rate calculated from the HPLC analysis results after the reaction was stopped and the yield of the compound (4-1) calculated from the quantitative analysis results. In the table, “equivalent” represents the molar equivalent of water relative to 2,3,5-trichloropyridine.
  • Synthesis Example 17 75.0 g of 2,3,5-trichloropyridine and 47.9 g of sodium carbonate were suspended in 150.0 g of 1,2-propanediol and 27.0 g of water, and tetramethylene glycol monovinyl ether 119 was added to the resulting reaction mixture. .3 g, 1,3-bis (diphenylphosphino) propane 678.0 mg, and palladium acetate 184.5 mg were sequentially added, and the mixture was reacted by stirring at 120 ° C. for 12 hours in a nitrogen atmosphere. After cooling the obtained reaction liquid to room temperature, this reaction liquid was analyzed by HPLC (analysis condition B). As a result, the peak area ratio of the compound (3-1) was 80.4% (conversion rate: 99.1%).
  • Synthesis Example 18 In accordance with the first step described in Synthesis Example 12, 10.02 g of 2,3,5-trichloropyridine was reacted to synthesize compound (3-1) (reaction time 15 hours), and 30 g of toluene was added to the reaction solution. And washed with 50 g of water to obtain 55.03 g of a toluene solution of the compound (3-1).
  • Synthesis Example 20 According to the process described in Synthesis Example 19, the reaction was performed by changing the amount of acid. The yield of compound (4-1) calculated from the quantitative analysis results is shown in Table 6.
  • Synthesis Example 21 and Synthesis Example 22 A method according to the first step of Synthesis Example 12 using 4.04 g of 2,5-dichloro-3-methylpyridine (Synthesis Example 21) or 4.00 g of 2,5-dichloropyridine (Synthesis Example 22) as a raw material
  • Table 7 shows the peak area ratio (analysis condition B) and conversion rate of the 2-alkoxyvinylpyridine compound obtained by the above, and the peak area ratio (analysis condition B) of the 2-acetylpyridine compound after completion of the second step.
  • the 2nd process was performed with the following method. To the reaction solution in the first step, 12.1 g of toluene was added and washed with 20 g of water. 13.0 ml of 2% by mass hydrochloric acid was added to the organic layer and stirred at room temperature for 3 hours.
  • the present invention is extremely useful as a method for easily producing a 2-alkoxyvinylpyridine compound or a 2-acetylpyridine compound. It should be noted that the entire contents of the specification, claims, and abstract of Japanese Patent Application No. 2016-097353 filed on May 13, 2016 are incorporated herein as the disclosure of the specification of the present invention. Is.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé industriel et sûr de production d'un composé de type 2-acétylpyridine. L'invention porte sur un procédé de production d'un composé de type 2-acétylpyridine représenté par la formule (4) par hydrolyse d'un composé représenté par la formule (3), ledit composé étant obtenu par réaction d'un composé de type 2-chloropyridine représenté par la formule (1) et d'un composé de type éther de vinyle représenté par la formule (2) l'un avec l'autre. (Dans les formules, chacun parmi X et Y représente, indépendamment, un atome d'hydrogène, un atome d'halogène, un groupe cyano, un groupe nitro, un groupe C1-C6-alkyle, un groupe halogéno-(C1-C6)alkyle ou analogue ; et R représente un groupe C1-C8-alkyle ou analogue.)
PCT/JP2017/018068 2016-05-13 2017-05-12 Procédé de production d'un composé de type 2-acétylpyridine Ceased WO2017195894A1 (fr)

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CN110790700B (zh) * 2019-11-13 2023-06-20 怀化金鑫新材料有限公司 一种2-乙酰基吡啶的合成方法

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