WO2023080193A1 - Procédé de production d'un composé d'indole - Google Patents

Procédé de production d'un composé d'indole Download PDF

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Publication number
WO2023080193A1
WO2023080193A1 PCT/JP2022/041133 JP2022041133W WO2023080193A1 WO 2023080193 A1 WO2023080193 A1 WO 2023080193A1 JP 2022041133 W JP2022041133 W JP 2022041133W WO 2023080193 A1 WO2023080193 A1 WO 2023080193A1
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Prior art keywords
compound
reaction
production method
solvent
toluene
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PCT/JP2022/041133
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English (en)
Japanese (ja)
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大希 山口
佑司 小澤
紘久 齋藤
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日産化学株式会社
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Publication of WO2023080193A1 publication Critical patent/WO2023080193A1/fr

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    • 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
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D209/12—Radicals substituted by oxygen 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
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a method for producing an indole compound.
  • Indole compounds are useful as various fine chemical intermediates, including bioactive substances such as pharmaceuticals and agricultural chemicals.
  • Various methods, such as those disclosed in Patent Documents 1 to 8, are known as methods for producing the indole compound.
  • the yield may be low in the reaction in water and a polar solvent or in the presence of a basic compound.
  • An object of one aspect of the present invention is to provide a method for producing an indole compound in which the target product is obtained in high yield in the indole cyclization reaction using sodium dithionite.
  • a method for producing an indole compound according to one aspect of the present invention provides a compound represented by the following formula (1) under heating in the absence of a solvent or in an organic solvent, an acidic compound and An indole compound represented by the following formula (2) is produced by reacting with sodium dithionite.
  • R 1 represents methyl, methoxy, or ethoxy
  • R 2 represents a halogen atom
  • n represents an integer of 1, 2, 3 or 4.
  • a method for producing an indole compound provides a compound represented by the following formula (1), in the absence of a solvent or in an organic solvent, under heating, to an acidic
  • R 1 represents methyl, methoxy, or ethoxy
  • R 2 represents a halogen atom
  • n is 1, 2, 3; or represents an integer of 4.
  • the target indole compound can be obtained in high yield in the indole cyclization reaction using sodium dithionite.
  • a compound represented by the following formula (1) (hereinafter also referred to as “compound (1)”) is used as a starting material, and the compound represented by the following formula (2) is It is a method for producing an indole compound (hereinafter also referred to as “compound (2)").
  • R 1 represents methyl, methoxy, or ethoxy
  • R 2 represents a halogen atom
  • n is 1, 2, 3; or represents an integer of 4.
  • the following compound (2) is produced using the following compound (1) as a starting material, and the following formula (3) is produced using compound (2) as a starting material. ) (hereinafter also referred to as “compound (3)”).
  • R 1 represents methyl, methoxy, or ethoxy
  • R 2 represents a halogen atom
  • n is 1, 2, 3; or represents an integer of 4.
  • the first production method in the embodiment of the present invention is to produce compound (2) by reacting compound (1) with an acidic compound and sodium dithionite under heating in the absence of a solvent or in an organic solvent. It is a method for producing an indole compound.
  • Compound (1) has a keto-enol tautomer represented by formula (1′) or formula (1′′). The structures of formulas (1′) and (1′′) are shown below. Compound (1) is observed as a mixture of keto-enol tautomers in conventional 1 H-NMR and the like. As used herein, compound (1) also represents one or both of these isomers unless otherwise specified.
  • R 1 represents methyl, methoxy, or ethoxy
  • R 2 represents a halogen atom
  • n represents an integer of 1, 2, 3 or 4.
  • a halogen atom may be fluorine, chlorine, bromine or iodine, and when n is 2 or more, the halogen atoms of R 2 may be the same or different.
  • Compound (1) is preferably a compound represented by the following formula (1A) (hereinafter also referred to as “compound (1A)”).
  • compound (1A) is preferably a compound represented by the following formula (2A) (hereinafter referred to as "compound ( 2A)”).
  • R1 represents methyl, methoxy, or ethoxy
  • R2 represents a halogen atom.
  • a halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom.
  • acids can be used as the acidic compound.
  • acids include mineral acids, aliphatic carboxylic acids and organic sulfonic acids.
  • mineral acids include sulfuric acid, nitric acid, phosphoric acid and hydrochloric acid.
  • aliphatic carboxylic acids include formic acid, acetic acid, trifluoroacetic acid and propionic acid.
  • organic sulfonic acids include methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.
  • the acidic compound is preferably acetic acid or propionic acid from the viewpoint of increasing the yield of compound (2).
  • the amount of the acidic compound used in the first production method can be determined as appropriate within the range in which compound (2) is produced in the first production method.
  • the amount of the acidic compound used in the first production method may be 0.01 to 50 molar equivalents relative to compound (1), and from the viewpoint of increasing the yield of compound (2), 0.1 to 30 molar equivalents. It is preferably a molar equivalent, more preferably 5 to 25 molar equivalents, even more preferably 7.5 to 21 molar equivalents, and even more preferably 9 to 15 molar equivalents.
  • Sodium dithionite acts as a reducing agent in the first production method.
  • the amount of sodium dithionite to be used in the first production method can be appropriately determined within the range in which compound (2) is produced in the first production method.
  • the amount of sodium dithionite used in the first production method may be 1 to 10 molar equivalents relative to compound (1), and from the viewpoint of increasing the yield of compound (2), 2 to 10 molar equivalents. , more preferably 2 to 5 molar equivalents, even more preferably 2 to 3 molar equivalents.
  • components other than the components described above may be further added to the reaction system within the range that compound (2) is produced.
  • One or more other components may be used as long as the compound (2) is produced and the effects of the other components are obtained.
  • the reaction in the first production method may be carried out in an organic solvent.
  • the organic solvent preferably has a boiling point at which the reaction temperature in the first production method can be achieved from the viewpoint of sufficiently advancing the reaction in the first production method.
  • organic solvents include aromatic hydrocarbon solvents and dimethylsulfoxide.
  • the aromatic hydrocarbon solvent is the solvent in the synthesis reaction in the first production method.
  • One or more aromatic hydrocarbon solvents may be used.
  • aromatic hydrocarbon solvents include benzene, toluene, ortho-xylene, meta-xylene, para-xylene, ethylbenzene, chlorobenzene, ortho-dichlorobenzene, meta-dichlorobenzene, para-dichlorobenzene, nitrobenzene and tetrahydronaphthalene.
  • the aromatic hydrocarbon solvent is preferably toluene, ortho-xylene or chlorobenzene from the viewpoint of increasing the yield of compound (2), and more preferably toluene.
  • the amount of the organic solvent used in the first production method may be determined as appropriate within the range in which compound (2) is produced.
  • the amount of the organic solvent used in the first production method may be 0.1 to 20 parts by mass, preferably 1 to 10 parts by mass, relative to 1 part by mass of compound (1). It is more preferably 7 parts by mass, more preferably 3 to 7 equivalents.
  • a base may be used together with an acidic compound.
  • One or more bases may be used. Examples of such bases include sodium formate, sodium acetate, potassium acetate, sodium propionate, potassium propionate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide and potassium hydroxide.
  • Combined use of the base can act favorably for reduction of compound (1).
  • the amount of the base used in the first production method may be 0.01 to 5 molar equivalents relative to compound (1), preferably 0.1 to 2 molar equivalents, and 0.2 to 1 Molar equivalents are more preferred.
  • the reaction temperature in the first production method can be appropriately determined within the range in which the compound (2) is produced under heating in the first production method. If the reaction temperature is too high, the components in the reaction mixture in the first production method may thermally decompose. From the viewpoint of reaction time and yield, the reaction temperature in the first production method is preferably 50° C. or higher, more preferably 70° C. or higher, and even more preferably 80° C. or higher. In addition, the reaction temperature in the first production method is preferably 150° C. or lower, more preferably 130° C. or lower, even more preferably 110° C. or lower, from the viewpoint of suppressing thermal decomposition. °C or less is even more preferable. In addition, the upper limit and the lower limit of the preferable reaction temperature can be combined arbitrarily.
  • the reaction in the first production method may contain additional conditions as long as compound (2) is produced in the first production method.
  • the reaction in the first production method is preferably carried out in an inert gas atmosphere from the viewpoint of suppressing the production of unintended by-products such as oxides.
  • the inert gas may be any gas that does not substantially exhibit activity with respect to the reagents and products in the reaction of the first production method.
  • examples of inert gases include nitrogen gas and noble gases. From the viewpoint of lower cost, the inert gas is preferably nitrogen gas.
  • the end point of the reaction in the first production method can be determined by a conventional method, such as analysis of the reaction solution.
  • the reaction mixture obtained in the first production method can be isolated by a conventional method.
  • a solution of the target compound (2) can be obtained by extracting the reaction mixture with an aromatic hydrocarbon such as toluene.
  • the second production method in the embodiment of the present invention is to produce compound (2) by reacting compound (1) with an acidic compound and sodium dithionite under heating in the absence of solvent or in an organic solvent. and a second step of producing compound (3) from compound (2).
  • R 1 represents methyl, methoxy, or ethoxy
  • R 2 represents a halogen atom
  • n is 1, 2, 3; or represents an integer of 4.
  • the first step is substantially the same as the first manufacturing method in the embodiment of the present invention described above.
  • the product of the first step may be isolated or subjected to the second step in the form of a solution to the extent that the second step, which is the next step, can be performed.
  • the second step is a step of deacetylating or deesterifying compound (2).
  • the second step includes heating compound (2) in the presence of water and an acidic or basic compound.
  • the amount of water to be used in the second step can be appropriately determined within the scope of performing the deacetylation or deesterification reaction of compound (2).
  • the amount of water used in the second step may be 1 to 50 parts by mass per 1 part by mass of compound (2).
  • the acidic compound in the second step is the same as the acidic compound in the first production method described above.
  • the acidic compound in the second step may be the same as or different from the acidic compound in the first production method.
  • the amount of the acidic compound to be used in the second step may be appropriately determined in consideration of the valence of the acid within the range where the deacetylation or deesterification reaction of compound (2) is achieved.
  • the amount of the acidic compound used may be 0.1 to 10 molar equivalents relative to compound (2) as the starting material in the second step. It is preferably ⁇ 5.5 molar equivalents, more preferably 3 to 5 molar equivalents.
  • bases can be used as the basic compound in the second step.
  • One or more bases may be used.
  • bases include lithium hydroxide, sodium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, lithium hydride, sodium hydride, potassium hydride, sodium methoxy sodium ethoxide, sodium isopropoxide and potassium-tert-butoxide.
  • the basic compound is preferably sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate from the viewpoint of operability and economic efficiency of the reaction.
  • the amount of the basic compound to be used in the second production method may be appropriately determined in consideration of the valence of the base within the range where the deacetylation or deesterification reaction of compound (2) is achieved.
  • the amount of the basic compound used in the second step is sodium hydroxide, it may be 0.1 to 10 molar equivalents relative to compound (2) as the starting material in the second step, It is preferably 3 to 9 molar equivalents, more preferably 3 to 7 molar equivalents.
  • the second step is performed by heating the reaction mixture. If the reaction temperature is too high, the components in the reaction mixture may thermally decompose. From the viewpoint of reaction time and yield, the reaction temperature in the second step is preferably 50 to 150°C.
  • the reaction temperature in the second step is preferably high from the viewpoint of sufficiently advancing the deacetylation or deesterification reaction, and preferably low from the viewpoint of suppressing the accompanying decomposition reaction.
  • the reaction temperature in the second step is preferably 90° C. or higher, more preferably 100° C. or higher, and even more preferably 110° C. or higher.
  • the reaction temperature is preferably 150° C. or lower, more preferably 140° C. or lower.
  • the upper and lower limits of the preferred reaction temperature can be combined arbitrarily.
  • an aromatic hydrocarbon as a solvent in the second step.
  • the aromatic hydrocarbon in the second step is the same as the aromatic hydrocarbon in the first production method described above.
  • the aromatic hydrocarbon in the second step may be the same as or different from the aromatic hydrocarbon in the first production method.
  • the aromatic hydrocarbon in the second step is preferably toluene.
  • the second step may include additional conditions to the extent that compound (3) is produced by the deacetylation or deesterification reaction of compound (2).
  • the second step may be performed in an inert gas atmosphere.
  • the endpoint of the reaction in the second step can also be determined by conventional methods, and compound (3) is extracted from the reaction mixture of the second step by conventional methods, for example extraction with an aromatic hydrocarbon such as toluene. can be isolated.
  • the second step can be carried out by a two-step reaction process as shown in the reaction scheme below.
  • R 1 is methoxy or ethoxy.
  • the second step is the hydrolysis reaction of the alkoxy of compound (2) and the decarboxylation of the compound represented by the above formula (4) (hereinafter also referred to as “compound (4)”) produced thereby. It can also be realized by a carbonic acid reaction.
  • hydrolysis reaction For the hydrolysis reaction, it is possible to employ known conditions that enable hydrolysis reaction at methoxy or ethoxy of R 1 .
  • the hydrolysis reaction can be carried out by heating in the presence of an acidic or basic compound in a solvent containing a polar solvent and water.
  • One or more polar solvents may be used, examples of which include lower alcohols.
  • Lower alcohols may be, for example, alcohols having up to 4 carbon atoms, examples of which include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol and 2-methyl-2-propanol is included.
  • the solvent for the hydrolysis reaction may further contain an aromatic hydrocarbon from the viewpoint of stabilizing the reaction temperature.
  • the aromatic hydrocarbon in the dehydrolysis reaction is the same as the aromatic hydrocarbon mentioned above.
  • the aromatic hydrocarbon is preferably toluene from the viewpoint of stabilizing the reaction temperature.
  • the amount of each of the above components used in the hydrolysis reaction can be appropriately determined within the range in which the hydrolysis reaction can be achieved.
  • the acidic compound or basic compound is monovalent, it may be 0.1 to 10 molar equivalents, and 1 to 5 molar equivalents, relative to compound (2), which is the starting material for the hydrolysis reaction. is preferred.
  • the amount of water used in the solvent may be 1 to 50 parts by mass, preferably 1 to 10 parts by mass, per 1 part by mass of compound (2).
  • the amount of the polar solvent used in the solvent may be 0.1 to 20 parts by mass, preferably 1 to 10 parts by mass, per 1 part by mass of compound (2).
  • the amount of the aromatic hydrocarbon used in the solvent may be 0.1 to 20 parts by mass, preferably 1 to 10 parts by mass, per 1 part by mass of compound (2).
  • the heating temperature in the hydrolysis reaction is preferably 50 to 150° C., more preferably 60 to 140° C., from the viewpoint of advancing the hydrolysis reaction and from the viewpoint of suppressing the decomposition of the components in the reaction mixture. is more preferred.
  • the heating temperature can be appropriately set for the same reason as the reaction temperature in the second step described above.
  • reaction product of the hydrolysis reaction (compound (4) above) can be isolated by neutralization of the reaction mixture, or can exist as a salt in the aqueous layer.
  • the compound (4) may be isolated or dissolved in the aqueous layer as a salt.
  • Decarboxylation reaction For the decarboxylation reaction, it is possible to adopt known conditions that can eliminate the carboxy of compound (4).
  • the decarboxylation reaction can be carried out by heating in the presence of an acidic or basic compound in a solvent comprising a polar solvent and water.
  • the polar solvent in the decarboxylation reaction is the same as the polar solvent in the hydrolysis reaction, and may be the same as or different from the polar solvent in the hydrolysis reaction. Further, the solvent for the decarboxylation reaction may further contain an aromatic hydrocarbon from the viewpoint of stabilizing the reaction temperature, as in the hydrolysis reaction, and the aromatic hydrocarbon is preferably toluene.
  • the amount of each of the above components used in the decarboxylation reaction can be appropriately determined within the range in which the decarboxylation reaction can be realized.
  • the acidic compound or basic compound is monovalent, it may be 0.1 to 10 molar equivalents relative to the above compound (4), which is the starting material for decarboxylation, and 0.5 to 7 molar equivalents. Molar equivalents are preferred.
  • the amount of water used in the solvent may be 1 to 50 parts by mass, preferably 3 to 10 parts by mass, per 1 part by mass of compound (2).
  • the amount of the polar solvent used in the solvent may be 0.1 to 20 parts by mass, preferably 1 to 5 parts by mass, per 1 part by mass of compound (2).
  • the amount of the aromatic hydrocarbon used in the solvent may be 0.1 to 20 parts by mass, preferably 1 to 10 parts by mass, per 1 part by mass of compound (2).
  • reaction temperature in the decarboxylation reaction is preferably 50 to 150° C., more preferably 60 to 140° C., from the viewpoints of progressing the decarboxylation reaction and suppressing decomposition of components in the reaction mixture. is more preferred.
  • the reaction temperature in the decarboxylation reaction can be appropriately set for the same reason as the reaction temperature in the second step described above.
  • Compound (3) is produced by the decarboxylation reaction.
  • Compound (3) can be isolated from the reaction mixture by extraction with an aromatic hydrocarbon.
  • Both the hydrolysis reaction and the decarboxylation reaction use an acidic compound or a basic compound, and either the acidic compound or the basic compound may be used as long as the desired reaction proceeds.
  • a basic compound is preferably employed in the hydrolysis reaction, and an acidic compound is preferably employed in the decarboxylation reaction.
  • compound (1) as a starting material is reacted in the presence of sodium dithionite and an acidic compound in the absence of a solvent or in an organic solvent to give the desired 2-methyl-1H- An indole-3-carbonyl compound (compound (2)) is obtained in high yield.
  • compound (2) 2-methyl-1H- An indole-3-carbonyl compound
  • the first and second manufacturing methods described above do not require components containing heavy metals, so waste liquids and waste can be easily treated.
  • the above-mentioned first production method and second production method can be carried out at normal pressure, special equipment such as high pressure equipment is not required, and special operation for its operation is required. do not have.
  • the target compound (2) or compound (3) is produced by using ordinary equipment in the production of organic compounds in a usual manner. It can be produced in high yield.
  • the first production method and the second production method described above suppress the production of by-products and produce the target compound (2) or compound (3) with a high conversion rate and high purity. can be done.
  • compound (3) can be obtained from compound (1) in high yield by further applying a conventional deacetylation or deesterification technique.
  • the compound (2) to the compound (4 ) can give compound (3).
  • the compound (4) is converted into a solid by utilizing the difference in solubility between the raw material (compound (2)) and the product (compound (4)). Isolatable.
  • compound (4) can separate into the aqueous phase as a salt. Therefore, such a second step is advantageous from the viewpoint of facilitating separation of compound (2) and compound (4) and facilitating purification of compound (4).
  • the first production method in the embodiment of the present invention is to react compound (1) with an acidic compound and sodium dithionite under heating in the absence of solvent or in an organic solvent.
  • compound (2) is produced.
  • the second production method in the embodiment of the present invention comprises reacting compound (1) with an acidic compound and sodium dithionite under heating in the absence of a solvent or in an organic solvent to obtain compound (2). and a second step of producing compound (3) from compound (2).
  • the second step then includes heating compound (2) in the presence of water and an acidic or basic compound.
  • the target indole compound can be obtained in high yield in the indole cyclization reaction using sodium dithionite.
  • the acidic compound may be acetic acid or propionic acid. This configuration is much more effective from the viewpoint of increasing the yield of compound (2).
  • the acidic compound may be acetic acid. This configuration is much more effective from the viewpoint of increasing the yield of compound (2).
  • the organic solvent may be one or more selected from the group consisting of aromatic hydrocarbon solvents and dimethylsulfoxide. This configuration is much more effective from the viewpoint of increasing the yield of compound (2).
  • the organic solvent may be an aromatic hydrocarbon solvent. This configuration is much more effective from the viewpoint of increasing the yield of compound (2).
  • the aromatic hydrocarbon solvent may be toluene, ortho-xylene or chlorobenzene. This configuration is much more effective from the viewpoint of increasing the yield of compound (2).
  • the first production method may be carried out in one or more organic solvents selected from the group consisting of toluene, ortho-xylene, chlorobenzene and dimethylsulfoxide. This configuration is much more effective from the viewpoint of increasing the yield of compound (2).
  • the first production method may use toluene or ortho-xylene as a solvent. This configuration is much more effective from the viewpoint of increasing the yield of compound (2).
  • the first production method may use toluene as a solvent. This configuration is much more effective from the viewpoint of increasing the yield of compound (2).
  • the reaction temperature may be 50-150°C. This configuration is much more effective from the viewpoint of suppressing thermal decomposition during the reaction and from the viewpoint of the balance between reaction time and yield.
  • the first production method in the embodiment of the present invention is to produce compound (2) by reacting compound (1) with an acidic compound and sodium dithionite in an aromatic hydrocarbon solvent under heating. It may be something to do.
  • compound (1) may be the compound represented by formula (1A) above
  • compound (2) may be the compound represented by formula (2A) above.
  • R 2 of compound (1A) and compound (2A) may be a fluorine atom, a chlorine atom or a bromine atom.
  • R 2 of compound (1A) may be a fluorine atom
  • R 2 of compound (2A) may be a fluorine atom
  • the first production method in the embodiment of the present invention comprises reacting compound (1A) with acetic acid and sodium dithionite at 80 to 100° C. in the absence of solvent or in an organic solvent to obtain compound (2A ), wherein the organic solvent may be toluene, ortho-xylene, chlorobenzene or dimethylsulfoxide.
  • the first production method in the embodiment of the present invention is to produce compound (2A) by reacting compound (1A) with acetic acid and sodium dithionite in an organic solvent at 80 to 100°C. wherein the organic solvent may be toluene, ortho-xylene, chlorobenzene or dimethylsulfoxide.
  • the first production method in the embodiment of the present invention is to produce compound (2A) by reacting compound (1A) with acetic acid and sodium dithionite in toluene at 80 to 100°C. can be anything.
  • the present invention can promote the development and popularization of pharmaceuticals and agricultural chemicals. In this way, the present invention is expected to contribute to achieving the Sustainable Development Goals (SDGs) for securing healthy life and solving food problems.
  • SDGs Sustainable Development Goals
  • HPLC high-performance liquid chromatography
  • Example 1 Production of 1-(6-fluoro-2-methyl-1H-indol-3-yl)ethanone (hereinafter referred to as compound (2-1)) 3-(4-fluoro-2-nitrophenyl)-4- 0.50 g of hydroxy-3-penten-2-one (hereinafter referred to as compound (1-1)), 1.88 g of acetic acid, 1.09 g of sodium dithionite and 2.50 g of toluene (solvent) were placed in a reactor. In addition, the mixture was stirred at 100° C. for 22 hours under a nitrogen atmosphere. According to HPLC analysis during the reaction, the relative area percentages of compound (2-1) were 78.6% (4 hours) and 80.9% (22 hours).
  • the relative area percentages in Examples and Comparative Examples are the area percentages of the above compounds with respect to the peak area of HPLC analysis in which the peak of the solvent (toluene in this example) is removed from the entire peak of HPLC analysis.
  • the time in parenthesis after that indicates the reaction time when the sample was obtained.
  • the reaction mixture was cooled to 70° C., diluted with 5.0 mL of water, and extracted with 5.7 mL of toluene to obtain a toluene solution containing compound (2-1).
  • the reaction mixture was cooled to 70° C., diluted with 5.0 mL of water, and extracted with 5.7 mL of toluene to obtain a toluene solution containing compound (2-1).
  • As a result of quantitative analysis of this toluene solution it was confirmed to contain 0.29 g of compound (2-1) (yield 72.0%).
  • Example 2 Production of methyl 6-fluoro-2-methyl-1H-indole-3-carboxylate (hereinafter referred to as compound (2-2)) 2-(4-fluoro-2-nitrophenyl)-3-hydroxy-2 -Methyl butenoate (hereinafter referred to as compound (1-2)) 0.50 g, acetic acid 1.77 g, sodium dithionite 1.02 g and toluene (solvent) 2.50 g were added to a reaction vessel and and 100° C. for 22 hours. According to HPLC analysis during the reaction, the relative area percentages of compound (2-2) were 78.7% (4 hours) and 93.7% (22 hours).
  • Example 3 Production of ethyl 6-fluoro-2-methyl-1H-indole-3-carboxylate (hereinafter referred to as compound (2-3)) 2-(4-fluoro-2-nitrophenyl)-3-hydroxy-2 -Ethyl butenoate (hereinafter referred to as compound (1-3)) 0.50 g, acetic acid 1.67 g, sodium dithionite 0.97 g and toluene (solvent) 2.50 g were added to a reaction vessel and and 100° C. for 22 hours. According to HPLC analysis during the reaction, the relative area percentages of compound (2-3) were 78.6% (4 hours) and 93.0% (22 hours).
  • Example 4 Production of compound (2-2) Except for changing acetic acid to 2.18 g of propionic acid, the reaction was carried out under the same conditions as in the method described in Example 2 above to obtain a toluene solution containing compound (2-2). rice field. According to HPLC analysis during the reaction, the relative area percentages of compound (2-2) were 61.7% (4 hours) and 89.9% (22 hours). As a result of quantitative analysis of this toluene solution, it was confirmed to contain 0.31 g of compound (2-2) (yield 75.2%).
  • Example 5 Production of compound (2-1) Except for changing the solvent from toluene to ortho-xylene, the reaction was carried out under the same conditions as described in Example 1 above to obtain an ortho-xylene solution containing compound (2-1). .
  • Example 6 Production of compound (2-2) Except for changing the solvent from toluene to ortho-xylene, the reaction was carried out under the same conditions as described in Example 2 above to obtain an ortho-xylene solution containing compound (2-2). .
  • the relative area percentage of compound (2-2) was 91.4% by HPLC analysis after a reaction time of 22 hours.
  • As a result of quantitative analysis of this ortho-xylene solution it was confirmed to contain 0.35 g of compound (2-2) (yield 85.8%).
  • Example 7 Production of Compound (2-3) An ortho-xylene solution containing compound (2-3) was obtained by carrying out the reaction under the same conditions as in the method described in Example 3 above, except that the solvent was changed from toluene to ortho-xylene. .
  • the relative area percentage of compound (2-3) was 91.1% (22 hours) by HPLC analysis at a reaction time of 22 hours.
  • As a result of quantitative analysis of this ortho-xylene solution it was confirmed to contain 0.35 g of compound (2-3) (yield 85.7%).
  • Example 8 Preparation of 6-fluoro-2-methyl-1H-indole (hereinafter referred to as compound (3-1))
  • Compound (2-2) 0.50 g, sodium hydroxide 0.43 g, water 7.50 g and toluene 1 0.50 g was added to the reaction vessel and stirred for 26 hours under heating and reflux. After completion of the reaction, the reaction mixture was cooled to 40° C. and extracted with 1.7 mL of toluene. After washing the resulting organic layer with 1.5 mL of water, a toluene solution containing compound (3-1) was obtained. As a result of quantitative analysis of this toluene solution, it was confirmed to contain 0.36 g of compound (3-1) (yield 98.8%).
  • Example 9 Production of compound (3-1) 0.50 g of compound (2-1), 2.57 g of a 50% by mass sulfuric acid aqueous solution, and 2.50 g of toluene were added, and the mixture was stirred under reflux with heating for 9 hours. After completion of the reaction, the reaction mixture was cooled to 70° C., diluted with 3.5 mL of water, and extracted with 1.2 mL of toluene. After washing the resulting organic layer with 1.5 mL of water, a toluene solution containing compound (3-1) was obtained. As a result of quantitative analysis of this toluene solution, it was confirmed to contain 0.36 g of compound (3-1) (yield 91.8%).
  • Example 10 and Example 11 Production of Compound (3-1) A reaction was carried out under the same conditions as the method described in Example 9 above, except that the type of raw material, the amount of the 50% by mass sulfuric acid aqueous solution used, and the reaction time were changed. The amount of each reagent used, reaction time and yield are listed in Table 1 below.
  • Example 12 Production of compound (3-1) 0.87 g of sodium hydroxide, 12.50 g of water, and the reaction was carried out under the same conditions as described in Example 8 above, except that the reaction time was changed to 23 hours. A toluene solution containing -1) was obtained. As a result of quantitative analysis of this toluene solution, it was confirmed to contain 0.35 g of compound (3-1) (yield 97.8%).
  • Example 13 Production of compound (3-1) 2.00 g of compound (2-2), 6.01 g of methanol, 2.90 g of 40% by mass sodium hydroxide aqueous solution and 4.27 g of water are added to a reaction vessel, and heated under reflux. Stirred for 16 hours. After completion of the reaction, the reaction mixture was cooled to 30° C., diluted with 13.8 mL of toluene, and extracted with 6.0 mL of water. After washing the obtained aqueous layer with 13.8 mL of toluene, 6.0 mL of water was added. The reaction mixture was cooled to 10° C., 3.52 g of 35 mass % hydrochloric acid was added dropwise, and stirred for 0.5 hours.
  • Example 14 Production of compound (3-1) 1.00 g of compound (2-2), 3.02 g of toluene, 3.02 g of methanol, 2.42 g of 40% by mass sodium hydroxide aqueous solution and 1.55 g of water were added to a reaction vessel and heated. Stirred under reflux for 22 hours. The reaction solution was cooled to room temperature and the organic layer and aqueous layer were separated. After washing the resulting aqueous layer with 3.4 mL of toluene, 3.00 g of water, 4.63 g of 35% by mass hydrochloric acid and 4.63 g of toluene were added to the washed aqueous layer and stirred at 60° C. for 4 hours.
  • Example 16 Preparation of 1-(6-chloro-2-methyl-1H-indol-3-yl)ethanone (hereinafter referred to as compound (2-4)) 3-(4-chloro-2-nitrophenyl)-4- 0.50 g of hydroxy-3-penten-2-one (hereinafter referred to as compound (1-4)), 1.78 g of acetic acid, 1.04 g of sodium dithionite and 2.50 g of toluene (solvent) were placed in a reactor. In addition, the mixture was stirred at 100° C. for 22 hours under a nitrogen atmosphere.
  • reaction mixture was cooled to 70° C., diluted with 5.0 mL of water, and extracted with 5.7 mL of toluene to obtain a suspension containing compound (2-4). This suspension was filtered to obtain a solid and a filtrate. As a result of quantitative analysis of each, it was confirmed that 0.34 g of compound (2-4) was included in total. As a result of quantitative analysis of the aqueous layer, it was confirmed to contain 0.02 g of compound (2-4) (yield 87.1%).
  • Example 17 Production of compound (2-4) A suspension containing compound (2-4) was obtained by carrying out the reaction under the same conditions as in Example 16 except that the solvent was changed from toluene to chlorobenzene. This suspension was filtered to obtain a solid and a filtrate. As a result of quantitative analysis of each, it was confirmed that 0.29 g of compound (2-4) was included in total. As a result of quantitative analysis of the aqueous layer, it was confirmed to contain 0.05 g of compound (2-4) (yield 83.1%).
  • Example 18 Production of methyl 6-bromo-2-methyl-1H-indole-3-carboxylate (hereinafter referred to as compound (2-5)) 2-(4-bromo-2-nitrophenyl)-3-hydroxy-2 -Methyl butenoate (hereinafter referred to as compound (1-5)) 0.50 g, acetic acid 1.42 g, sodium dithionite 0.84 g and toluene (solvent) 2.50 g were added to a reaction vessel and and 100° C. for 22 hours.
  • compound (2-5) 2-(4-bromo-2-nitrophenyl)-3-hydroxy-2 -Methyl butenoate
  • Example 19 Production of compound (2-5) A toluene solution containing compound (2-5) was obtained by carrying out the reaction under the same conditions as in Example 18, except that the amount of toluene was changed to 1.50 g. As a result of quantitative analysis of this toluene solution, it was confirmed to contain 0.38 g of compound (2-5) (yield 88.9%).
  • Example 20 Preparation of ethyl 6-chloro-2-methyl-1H-indole-3-carboxylate (hereinafter referred to as compound (2-6)) 2-(4-chloro-2-nitrophenyl)-3-hydroxy-2 -Ethyl butenoate (hereinafter referred to as compound (1-6)) 0.50 g, propionic acid 1.95 g, sodium dithionite 0.94 g and toluene (solvent) 2.50 g were added to a reaction vessel and a nitrogen atmosphere was added. The mixture was stirred at 100° C. for 22 hours.
  • compound (2-6) 2-(4-chloro-2-nitrophenyl)-3-hydroxy-2 -Ethyl butenoate
  • solvent solvent
  • Example 21 Production of compound (2-6) 0.50 g of compound (1-6), 1.59 g of acetic acid, 0.94 g of sodium dithionite and 2.50 g of toluene (solvent) were added to a reactor and heated to 100°C under a nitrogen atmosphere. and stirred for 44 hours. After completion of the reaction, the reaction mixture was cooled to 70° C., diluted with 5.0 mL of water, and extracted with 5.7 mL of toluene to obtain a suspension containing compound (2-6). This suspension was filtered to obtain a solid and a filtrate. As a result of quantitative analysis of each, it was confirmed that 0.34 g of compound (2-6) was contained in total. As a result of quantitative analysis of the aqueous layer, it was confirmed to contain 0.02 g of compound (2-6) (yield 85.8%).
  • Example 22 Production of compound (2-3) A toluene solution containing compound (2-3) was obtained by carrying out the reaction under the same conditions as in Example 3 except that the solvent was changed from toluene to 2.50 g of dimethylsulfoxide. . As a result of quantitative analysis of this toluene solution, it was confirmed to contain 0.30 g of compound (2-3) (yield 72.2%).
  • Example 23 and Example 24 Production of Compound (2-2) A reaction was carried out under the same conditions as in the method described in Example 2, except that the reaction temperature was changed. Reaction temperatures and yields are listed in Table 2 below.
  • Example 25 Production of compound (2-3) A toluene solution containing compound (2-3) was obtained by carrying out the reaction under the same conditions as in Example 3, except that the reaction temperature was changed to 80°C. As a result of quantitative analysis of this toluene solution, it was confirmed to contain 0.29 g of compound (2-3) (yield 71.1%).
  • Example 26 Production of compound (2-2) 0.70 g of compound (1-2), 2.47 g of acetic acid, 1.43 g of sodium dithionite and 4.90 g of toluene (solvent) were added to a reactor and heated to 100°C under a nitrogen atmosphere. and stirred for 22 hours. The relative area percentage of compound (2-2) during the reaction was 91.7% (21 hours) by HPLC qualitative analysis. After completion of the reaction, the reaction mixture was cooled to 70° C., diluted with 7.0 mL of water, and extracted with 8.0 mL of toluene to obtain a toluene solution containing compound (2-2). As a result of quantitative analysis of this toluene solution, it was confirmed to contain 0.50 g of compound (2-2) (yield 89.0%).
  • Example 27 and 28 Production of Compound (2-2) A reaction was carried out under the same conditions as in the method described in Example 26, except that the amount of sodium dithionite used was changed. According to HPLC qualitative analysis, the relative area percentage of compound (2-2) during the reaction of Example 27 was 90.3% (21 hours), and that of Example 28 was 90.3% (21 hours). The amounts and yields of each reagent used are shown in Table 3 below.
  • Example 29 and Example 30 Production of Compound (2-2) A reaction was carried out under the same conditions as in the method described in Example 26, except that the amount of acetic acid used was changed.
  • the relative area percentages of compound (2-2) during the reaction of Example 29 by HPLC qualitative analysis were 79.0% (21 hours), 87.2% (42 hours), and 92.7% ( 20 hours).
  • the amount of each reagent used, reaction time and yield are listed in Table 4 below.
  • Example 31 and 32 Production of compound (2-2) A toluene solution containing compound (2-2) was obtained by carrying out the reaction under the same conditions as in Example 2, except that the amount of toluene used as a solvent and the reaction time were changed. rice field. The relative area percentage of compound (2-2) during the reaction of Example 31 by HPLC qualitative analysis was 77.8% (4 hours), 92.0% (13 hours), and 79.1% in Example 32. (4 hours) and 92.1% (16 hours). The amount of each reagent used, reaction time and yield are listed in Table 5 below.
  • Example 33 and 34 Production of compound (2-2) A toluene solution containing compound (2-2) was obtained by carrying out the reaction under the same conditions as in Example 31, except that the amount of acetic acid used and the reaction time were changed. According to HPLC qualitative analysis, the relative area percentages of compound (2-2) during the reaction of Example 33 were 66.2% (4 hours) and 90.5% (26 hours), and in Example 34, 70.5%. 2% (4 hours) and 92.5% (23 hours). The amount of each reagent used, reaction time and yield are listed in Table 6 below.
  • Example 35 Production of compound (2-2) The reaction was carried out under the same conditions as in Example 32, except that the amount of sodium dithionite used was changed to 0.79 g and the reaction time was changed to 22 hours to obtain compound (2-2). A toluene solution containing The relative area percentages of compound (2-2) during the reaction by HPLC qualitative analysis were 74.8% (4 hours) and 82.7% (22 hours). As a result of quantitative analysis of the toluene solution, it was confirmed to contain 0.29 g of compound (2-2) (yield 73.0%).
  • the sum of relative area percentages of compound (3-1) and FNPA was 40.5%.
  • the present invention can be used for efficient production of pharmaceuticals and agricultural chemicals, and is expected to contribute to further development and spread of pharmaceuticals and agricultural chemicals.

Abstract

L'invention concerne un procédé de production d'un composé d'indole, au moyen duquel un produit souhaité peut être obtenu à un rendement élevé dans une réaction de cyclisation d'indole à l'aide de dithionite de sodium. Un composé représenté par la formule (1) est mis à réagir avec un composé acide et du dithionite de sodium sous chauffage dans un système sans solvant ou dans un solvant organique pour ainsi produire un composé d'indole représenté par la formule (2). Dans la formule (1) et la formule (2), R1 représente méthyle, méthoxy ou éthoxy, R2 représente un atome d'halogène, et n représente un nombre entier de 1, 2, 3 ou 4.
PCT/JP2022/041133 2021-11-04 2022-11-04 Procédé de production d'un composé d'indole WO2023080193A1 (fr)

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