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WO2003082860A1 - Procedes de production de compose indole - Google Patents

Procedes de production de compose indole Download PDF

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Publication number
WO2003082860A1
WO2003082860A1 PCT/JP2003/003963 JP0303963W WO03082860A1 WO 2003082860 A1 WO2003082860 A1 WO 2003082860A1 JP 0303963 W JP0303963 W JP 0303963W WO 03082860 A1 WO03082860 A1 WO 03082860A1
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formula
compound represented
fluoro
producing
group
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PCT/JP2003/003963
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English (en)
Japanese (ja)
Inventor
Kenzo Fukuda
Yasuo Kondo
Norio Tanaka
Atsushi Irimata
Tomohisa Utsunomiya
Yasuo Shirai
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Nissan Chemical Industries, Ltd.
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Priority to AU2003220912A priority Critical patent/AU2003220912A1/en
Publication of WO2003082860A1 publication Critical patent/WO2003082860A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • 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
    • C07D209/30—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

Definitions

  • the present invention relates to a method for producing an indole compound useful as various fine chemical intermediates including physiologically active substances such as pharmaceuticals and agricultural chemicals, and a novel 2--2-mouth phenylaceton as an intermediate in the production method.
  • physiologically active substances such as pharmaceuticals and agricultural chemicals
  • 2--2-mouth phenylaceton as an intermediate in the production method.
  • Examples of the synthesis of 1-hydroxy-2-alkylindole, a reduction intermediate, include the synthesis of 1-hydroxy-2-methylindole by reducing 2-nitrophenylacetone with zinc and ammonium chloride (Brutin de La Rob Societe Chimike * de * France (Bu i 1. Soc. Chim. Fr.), 1 296 (1967)) and electrochemical a— (o-hydroxyaminophenyl) ) There is a synthesis from propene (Bulchin de la Rob, Society, Cimique, France) (Bu 11 1. Soc. Chim. Fr.), 121 (1974)).
  • 1-hydroxy-2-phenylindole or 1-benzoyloxy-2-phenylindole is synthesized from 1-hydroxy-2-phenylindole with acetic anhydride or benzoyl chloride.
  • Examples ((Journal of the Chemical Society (J. Chem. Soc.), 3466 (I960)) and 1-Acetoxy 2 _methylindole (Burctin de la ⁇ ob)
  • Sosaikote "Chimike” and “De” France
  • Bull. Soc. Chim. Fr. 3040 (1973).
  • 1-benzoyloxy-2-phenylindole or 1-acetoxy-3-cyano-2-phenylindole is reduced in ethanol with a palladium catalyst supported on activated carbon.
  • Examples of obtaining 2-phenylindole or 3-cyano-2-phenylindole Journal of the Chemical Society (J. Chem. Soc.), 34 66 (1960
  • this method requires multiple steps to obtain the target indole compound from the starting 2-nitrobenzyl carbonyl compound, and is not an efficient method.
  • 2-Ditrophenyl-2-acetone compounds are important intermediates in the production of various heterocyclic compounds due to having two kinds of functional groups, ie, di- and carbonyl groups in the molecule.
  • Luaceton Tetrahedron Letters, 42, 1387 (2001)
  • 4-chloro-2-nitrophenylacetone Chem. Pharm. Bull.
  • 4-fluoro-2-nitrophenylacetone Japanese Patent Laid-Open No. 47947/1987.
  • An object of the present invention is to provide a method for producing an industrially advantageous indole compound and an intermediate thereof. Disclosure of the invention
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, in the step of reducing a 2-2 trobenzyl carbonyl compound with a hydrogen donor in the presence of a reduction catalyst, the coexistence of an acylating agent and a base Indole compounds are found to be able to be produced in a single step with good yield, and at the same time, they are important raw materials for the production of 6-fluoro-2-methylindole, one of the indole compounds.
  • acetone As a result of studying various methods for producing acetone, a novel 2--2-toluene phenylacetone compound as a key intermediate and 3_ (4-fluoro-2-nitrophenyl) via the compound were investigated.
  • R 2 each independently represent a hydrogen atom, an optionally substituted alkyl group or a phenyl group
  • R 3 represents an optionally substituted alkyl group, a phenyl group, an alkoxy group Represents an alkoxycarbonyl group or a halogen atom
  • n represents an integer of 0 to 4.
  • the indole compound represented by the formula is converted into an alkali metal salt, and then reacted with 1- (N, N-dimethylsulfamoyl) -3-chlorosulfonyl-1,2,4-triazole to obtain the formula (3 )
  • R 3 represents an alkyl group, a phenyl group, an alkoxy group, an alkoxycarbonyl group, or a halogen atom which may be substituted; n represents an integer of 0 to 4;
  • the step of reducing the 2-nitrobenzylcarbonyl compound represented by the above formula (1) with a hydrogen donor in the presence of a reducing catalyst is characterized by coexisting an acylating agent and a base.
  • the indole compound is 2-methyl-6-fluoroindole [11] The production method according to [1].
  • X represents a fluorine atom, a chlorine atom or a bromine atom.
  • a 2-nitrophenylacetone compound represented by the above formula (I) produced by reacting the compound with a dicalponyl compound represented by the following formula: The method according to [18], [19] or [20].
  • a method for producing a 2-nitrophenylacetone compound represented by the formula (I) by reacting a nitrobenzene represented by the formula (II) with a dicarbonyl compound represented by the formula (III) .
  • R 4 represents an acyl group of the above-mentioned acylating agent.
  • an indole compound can be produced at a high yield with almost no by-product of an indoline compound as a reduction by-product.
  • Examples of the compound to which the present invention is applied include a 2-nitrobenzyl carbonyl compound represented by the formula (1) and an indole compound represented by the formula (2), and R 2 are each independently a hydrogen atom, R 3 represents an optionally substituted alkyl group, a phenyl group, an alkoxy group, an alkoxycarbonyl group or a halogen atom, and n represents 0 to 4.
  • R 2 each independently represents a hydrogen atom or an optionally substituted alkyl group; R 3 represents a halogen atom; and n represents an integer of 0 or 1.
  • R 2 represents a hydrogen atom
  • R 3 represents a fluorine atom
  • n represents an integer of 0 or 1.
  • the 2-nitrobenzylcarbonyl compound represented by the formula (1) which is a starting material of the present invention, is produced by a known method.
  • 2-nitrophenylacetone Tetrahedrone's Letters, 42, 1387 (2001)
  • 4-chloro-2-nitrophenylacetone chemical's) Pharmaceutical Burtin
  • 4-fluoro-2-nitrophenylacetone JP-A-47-38947.
  • the reagents and reaction conditions used in the step of reducing the 12-trobenzylcarbonyl compound are as follows, but are not limited thereto.
  • an organic acid anhydride having a reactive active acyl group is effective, and acetic anhydride, trifluoroacetic anhydride, propionic anhydride, butyric anhydride, cabronic anhydride, crotonic anhydride, maleic anhydride, and benzoic anhydride.
  • An acid, succinic anhydride, or a mixed acid anhydride synthesized from acetic anhydride and formic acid is preferred, and a mixture of these can also be used.
  • acetic anhydride is particularly preferred in terms of economy.
  • the amount of the acylating agent to be used is preferably 0.01 to 10 mol, more preferably 1 to 5 mol, per 1 mol of the 2-nitrobenzylcarbonyl compound.
  • Examples of the base include organic bases such as amine pyridine and organic acid salts, carbonates, bicarbonates, phosphates, sulfites, and hydroxides of metals such as alkali metals and alkaline earth metals. And inorganic bases such as oxides, but preferably reacts with an organic acid salt of an alkali metal or an organic acid anhydride or an organic acid generated therefrom in a reaction solution to form an organic acid salt of an alkali metal. Bases such as carbonates, bicarbonates, and hydroxides of alkali metals are exemplified.
  • sodium formate, potassium formate, sodium acetate, potassium acetate, sodium propionate, potassium propionate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and the like are particularly preferable. Mixed use of these bases is also possible.
  • the amount of the base used is preferably from 0.01 to 5 mol, more preferably from 0.1 to 2 mol, per 1 mol of the 2-nitrobenzylcarbonyl compound.
  • a metal catalyst such as a nickel catalyst, a palladium catalyst, a platinum catalyst, a rhodium catalyst, and a ruthenium catalyst, which are usually used for hydrogenation, are preferable.
  • a supported noble metal catalyst is particularly preferable, and palladium on activated carbon is more preferable in terms of economy.
  • the amount of the reduction catalyst to be used is preferably 0.01% to 50%, more preferably 1% to 10%.
  • hydrogen donor examples include, in addition to hydrogen gas, sodium formate, potassium formate, ammonium formate, sodium phosphite, potassium phosphite, potassium diphosphite, sodium diphosphite, etc. which can be a hydrogen donor in the reaction system.
  • hydrogen gas is particularly preferred in terms of economy.
  • the amount of the hydrogen donor to be used is 2 to 5 mol, preferably 3 to 4 mol, per 1 mol of the 2-nitrobenzylcarbonyl compound.
  • the solvent is not particularly limited as long as it is inert to the reaction.
  • aromatics such as benzene, toluene, xylene, getyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane Ethers such as tan, diethylene diol glycol dimethyl ether, esters such as methyl formate, ethyl formate, methyl acetate, ethyl acetate, butyl acetate, ethyl propionate, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone , Hydrocarbons such as hexane, heptane, octane, and nonane; organic acids such as formic acid, acetic acid, and propionic acid; N, N-dimethylformamide; N, N-dimethylacetate
  • the amount of the solvent to be used is preferably 1 to 20 times, more preferably 3 to 10 times the amount of the 2-nitropentylcarbonyl compound.
  • the reaction is carried out by reacting a mixture of a 2-nitrobenzylcarbonyl compound, an acylating agent, a base, a reduction catalyst and a solvent with a hydrogen donor.
  • the reaction can be carried out at a temperature ranging from a low temperature of room temperature or lower to several hundred degrees, preferably from room temperature to a boiling point of the reaction solvent or lower.
  • the reaction can be carried out under normal pressure to a high pressure of 100 kg / cm 2 or the like, but it is preferably in the range of normal pressure to 10 kg / cm 2 , and preferably as a hydrogen partial pressure. Is in the range of 0.01 to 10 kg / cm 2 , and the higher the pressure, the faster the reaction.
  • the reaction time is affected by the stirring speed, and the reaction is completed within 4 to 50 hours under normal pressure under normal stirring conditions and within several hours under pressurized conditions.
  • a solution of the indole compound can be obtained by removing the reduction catalyst by filtration and then washing the reaction solution with water.
  • the reagents and by-products used in the reaction can be removed by washing the reaction solution with an alkaline aqueous solution such as sulfuric acid and hydrochloric acid.
  • the recovered reduction catalyst can be used over and over again without being poisoned.
  • novel 2-nitofene phenylaceton compound provided by the present invention has the formula (I)
  • R represents a methyl group, a methoxy group, or an ethoxy group.
  • the novel 2-nitrophenylacetone compound has a keto-enol tautomer, which can be observed in a mixed form by ordinary 1 H-NMR.
  • the structure of the formula (I) is unified as including the enol form.
  • the compound of the formula (III) can also be produced by a novel method by reacting a dikarponyl compound represented by the formula: The reaction described in the same manner as above is usually performed in the presence of a base.
  • bases can be used for the reaction, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, Various substances such as potassium bicarbonate, lithium hydride, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium isopropoxide, and potassium tert-butoxide are included, but the operability of the reaction and the economical efficiency For example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like are preferable. These bases can be used alone or in combination.
  • the amount of the base to be used is generally 0.3 to 10 mol, particularly preferably 0.5 to 5 mol, per 1 mol of the dicarbonyl compound of the formula (III).
  • Additives include tetramethylammonium chloride, tetramethylammonium chloride, tetramethylammonium chloride, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium bromide, tetraethylammonium chloride Zide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, cetyltrimethylammonium chloride, cetyltrimethylammonium bromide, benzyltriethylammonium chloride, benzyltolylchloride Quaternary ammonium salts such as thiammonium bromide, triphenylmethylphosphonium chloride, triphenylmethylphosphonium chloride, triphenylmethylphosphon
  • the amount of these additives is usually 0.001 to 1 mol, preferably 0.001 to 0.5 mol, per 1 mol of the dicarbonyl compound of the formula (III).
  • the reaction is preferably performed by diluting with a solvent in order to smoothly carry out the reaction including the dispersion and mixing of the reagents used in the reaction.
  • the solvent used in the reaction is not particularly limited as long as it is an inactive solvent in the reaction.
  • dimethyl ether, methyl tert-butyl ether, tetrahydrofuran, dimethoxymethane, diethoxymethane, and ethylene glycol dimethyl ester Ethers such as ethylene glycol dimethyl ether, ethylene glycol dibutyl ether, diethylene diol glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol dibutyl ether, triethylene glycol dimethyl ether, 1,4-dioxane, and methanol , Ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, 2-methyl-2-propanol, methyl-solvent, ethy
  • a preferable temperature range is usually 0 to 150, particularly preferably 10 to 100.
  • the reaction time varies depending on the amount, concentration, reaction temperature, etc. of the reagent used, but conditions are usually set so that the reaction is completed within a range of 0.1 to 200 hours, preferably 1 to 70 hours. preferable.
  • the solvent is distilled off if necessary, and then the crude reaction product is extracted by adding water and a solvent immiscible with water, and then subjected to ordinary methods such as distillation, recrystallization, and column chromatography from the organic layer.
  • ordinary methods such as distillation, recrystallization, and column chromatography from the organic layer.
  • the 2-nitrophenylacetone compound of the formula (I) obtained by the above reaction can be treated in the presence of an acid or a base to give an important intermediate such as indole production.
  • 2--2-trophenyl Can be easily derived into acetone.
  • Various bases can be used for the reaction, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate , Potassium bicarbonate, etc., but from the viewpoint of reaction operability, economical efficiency, etc. Lium and potassium hydroxide are preferred.
  • Examples of the acid that can be used in this reaction include mineral acids such as sulfuric acid, nitric acid, and hydrochloric acid, aliphatic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, and propionic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and benzenesulfonic acid.
  • Examples thereof include acids and organic sulfonic acids such as toluenesulfonic acid. From the viewpoint of practicality and economy, it is preferable to use sulfuric acid and hydrochloric acid alone or in combination with other acids based on these.
  • the base or acid is usually used in an amount of 0.01 to 50 mol, preferably 0.1 to 20 mol, per 1 mol of 2-nitrophenylacetone of the formula (I).
  • the reaction is preferably performed by diluting with a solvent from the viewpoint of operability.
  • the solvent used for the reaction is not particularly limited as long as it is an inert solvent for this reaction.
  • examples include getyl ether, methyl-t-butyl ether, tetrahydrofuran, dimethoxymethane, ethoxymethane, ethylene glycol dimethyl ether, and ethylene.
  • Ethers such as glycol getyl ether, ethylene glycol dibutyl ether, diethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol dibutyl ether, triethylene glycol dimethyl ether, 1,4-dioxane, methanol, ethanol, 1- Propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, 2-methyl-12-propanol, methylaceto-solve, ethylsil-solve, i- Ropyrcellosolve, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, cyclohexanol, alcohols such as benzyl alcohol, acetone, methyl ethyl ketone, diethyl ketone, 2-pentanone, methyl isobutyl ketone, cyclohexane Ketones such as xan
  • a preferable temperature range is usually 20 to 200: particularly preferably 50 to 150. .
  • the reaction time varies depending on the amount, concentration, reaction temperature, etc. of the reagents used, but conditions are usually set so that the reaction is completed within a range of 0.1 to 50 hours, preferably 1 to 30 hours. preferable.
  • the solvent is distilled off, if necessary, and then the desired product is directly obtained by distillation, or water and a solvent that is immiscible with water are added to the crude reaction product, washed thoroughly, and distilled from the organic layer. It is possible to purify and isolate the target 3- (4-fluoro-2-nitrophenyl) acetone by performing a conventional method such as chromatography.
  • reaction of the above two steps of the present invention can be continually operated, and there is a great merit such as an improvement in productivity.
  • the solvent is distilled off and replaced with a solvent that does not mix with water. Then, water is added to extract the new intermediate 2-nitrophenylacetone compound into an organic solvent. If further purification is required here, the compound is transferred from the organic solvent solution containing the 2-nitrophenylacetone compound to the aqueous solution with the required amount and concentration of an alkaline aqueous solution, then acidified, and then the organic solvent is newly added. And the compound is again dissolved in an organic solvent.
  • the desired 3- (4-fluoro-2-nitrophenyl) acetone can be obtained in good yield by directly reacting the solution containing the 2-nitrophenylacetone compound or by concentrating the solution and adding an appropriate acid or base.
  • the two-step reaction can be carried out by a continuous operation substantially in a solution state without using a technique such as recrystallization or chromatography.
  • the compound represented by the formula (3) is a fungicide described in International Patent Application Publication No. WO99Z21851 Panfret.
  • Examples of the solvent at that stage include cyclic or non-cyclic solvents such as getyl ether, dipropyl ether, diglyme, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol getyl ether, tetrahydrofuran, tetrahydropyran, and 1,4-dioxane. Cyclic ether solvents are mentioned.
  • Alkali metal compounds include sodium hydroxide, sodium hydroxide hydroxide and other alkali metal hydroxides, sodium carbonate and potassium carbonate metal such as lithium carbonate, sodium methoxide, potassium—t— Alkoxides such as butoxide, sodium hydride and the like.
  • the alkali metal compound is preferably an alkoxide, for example, sodium methoxide is particularly preferable.
  • the amount of the alkali metal compound to be used is 0.5 to 1 mol of the indole compound. Although it is 20 mol, 1-2 mol is particularly preferred.
  • the reaction temperature depends on the kind of the indole compound and the reaction material to be used, but is usually selected from the range of 0 to 10 and is preferably 20 to 5 Ot.
  • reaction conditions for example, reflux under reduced pressure is preferable.
  • the reaction time varies depending on the substrate used, but is usually 5 minutes to 24 hours, preferably 1 hour to 3 hours. However, if the reaction is not performed until the salt is sufficiently formed in the reaction system, the subsequent condensation reaction may not proceed well.
  • phase transfer catalyst can be used for the reaction.
  • the phase transfer catalyst at this stage include quaternary ammonium salts such as tetrabutylammonium chloride and the like, and 18 crown 6 and the like.
  • Examples of the solvent used in the step of reacting the obtained alkali metal salt with 1- (N, N-dimethylsulfamoyl)-3-clothrosulfonyl-1,2,4-triazole include, for example, dimethyl ether, dipropyl ether And cyclic or acyclic ether solvents such as diglyme, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol getyl ether, tetrahydrofuran, tetrahydropyran, and 1,4-dioxane.
  • an alkali metal salt is formed in the system, and then the reaction solution is mixed in a system containing 1 _ (N, N-dimethylsulfamoyl) -3 -chlorosulfonyl-1,2,4-triazole compound. It is preferable that the reaction is performed while dropping the solution.
  • the reaction temperature is preferably from 0 to 100, particularly preferably from 0 to 20.
  • 1_ (N, N-dimethylsulfamoyl) —3 —Chlorosulfonyl— can be produced by reacting with 1,2,4-triazole.
  • Examples of the solvent in the halogenation step include halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloromethane, ethers such as dimethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, acetone, Ketones such as methylethyl ketone and methyl isobutyl ketone; nitriles such as acetonitrile and propionitrile; N, N-dimethylformamide; Solvents that are not affected by halogenating agents such as acid amides such as N and N, N-dimethylacetamide can be used, but aromatic hydrocarbon solvents such as benzene, toluene, and xylene that are subject to halogenation can also be used.
  • toluene is a preferable solvent from the viewpoint of industrial handling.
  • halogenating agent examples include chlorine, bromine, iodine, N-chloro succinimide, N-bromosuccinimide, N-odosuccinimide, sodium hypobromite and the like.
  • the halogenation is preferably performed under alkaline conditions in the presence of an alkali metal compound.
  • an alkali metal compound for example, sodium hydroxide is preferable.
  • the amount of the halogenating agent to be used is, for example, preferably 1 mol or around 1 mol of the indole compound.
  • the amount of sodium hydroxide is preferably, for example, 1.1 mol or about 1 mol per 1 mol of the indole compound.
  • sodium hypobromite When sodium hypobromite is used as the halogenating agent, it is preferable that sodium hydroxide and bromine coexist in the reaction system, and that sodium hypobromite be generated in the system before the reaction. .
  • the reaction temperature depends on the kind of the indole compound and the reaction material to be used, but is usually selected from the range of 0 to 100, preferably 0 to 10.
  • the reaction time varies depending on the substrate used, but is usually 5 minutes to 24 hours, preferably 1 hour to 3 hours.
  • the obtained halide can be used in the form of a solution, if necessary, washed with an aqueous solution of sodium hydrogen sulfite or the like, and then subjected to the next reaction for producing an alkali metal salt.
  • an aqueous solution of sodium hydrogen sulfite or the like washed with an aqueous solution of sodium hydrogen sulfite or the like, and then subjected to the next reaction for producing an alkali metal salt.
  • the reaction mixture was washed sequentially with 35 g of water, 10 g of water, 14 g of a 5% aqueous sodium hydroxide solution, 10 g of water and 10 g of water. After separation, a toluene solution of 6-fluoro-2-methylindole was obtained.
  • a toluene solution of 6-fluoro-2-methylindole was obtained.
  • a mixed suspension of 7.65 g of powdered potassium carbonate, 4.00 g of 2,5-difluoronitrobenzene and 2 OmL of N, N-dimethylformamide was heated at 40 to 40, and 2.90 g of acetylacetone was added.
  • the reaction solution was heated to 80 and stirred overnight under a nitrogen atmosphere. After cooling, 2 OmL of toluene was added to the reaction mixture, and the mixture was stirred, and then added to 5 OmL (10) of cold water.
  • the toluene phase was separated, and then an extraction operation was performed three times by adding 3 OmL of toluene to the aqueous phase.
  • the obtained toluene phases were combined, washed three times with 15 OmL of water, and then extracted with an aqueous phase by adding 15 OmL of a 5% sodium hydroxide solution (twice). To the obtained aqueous phase, 35 mL of 35% hydrochloric acid was added to adjust the pH to 3, and extraction was performed twice with 15 OmL of toluene.
  • the obtained toluene phases were combined, and an extraction operation into an aqueous phase by adding 10 OmL of a 1 N aqueous potassium hydroxide solution was performed twice.
  • an extraction operation into an aqueous phase by adding 10 OmL of a 1 N aqueous potassium hydroxide solution was performed twice.
  • 25 mL of 35% hydrochloric acid was added to adjust the pH to 2, and extraction was performed twice with 15 OmL of toluene.
  • the obtained toluene phase was washed with 15 OmL of water three times, then with 10 OmL of saturated saline, and dried over anhydrous sodium sulfate.
  • 1- (4-fluoro-2-nitrophenyl) acetone which is a useful intermediate for indole production and the like, which has been conventionally difficult to produce, can be easily used as an intermediate with novel 2_nitrophenylacetones.
  • Indole compounds can be produced from 2-nitrobenzylcarbonyl compounds in very high yields, and sulfamoyltriazole compounds useful as fungicides can be produced from indole compounds in high yields. Can be obtained at

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

Abstract

La présente invention concerne un procédé de production d'un composé indole repésenté par la formule (2) par réduction d'un composé représenté par la formule (1) où R1 et R2 sont chacun indépendamment hydrogène, alkyle éventuellement substitué ou phényle, R3 est alkyle, halogène, etc., et n est un entier de 0 à 4. La réduction, qui utilise un donneur d'hydrogène en présence d'un catalyseur de réduction, est caractérisée en ce qu'on fait coexister pendant l'opération de réduction un agent d'acylation et une base. L'invention concerne également un procédé permettant d'utiliser le 4-fluoro-2-nitrophénylacétone produit à partir de 2-chloro-4-fluoronitrobenzene. L'invention concerne enfin un procédé de production d'un composé sulfamoyltriazole par réaction du composé indole avec le 1-(N,N-diméthylsulfamoyl)-3-chlorosulfonyl-1,2,4-triazole.
PCT/JP2003/003963 2002-04-01 2003-03-28 Procedes de production de compose indole WO2003082860A1 (fr)

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JP2006176500A (ja) * 2004-11-25 2006-07-06 Nissan Chem Ind Ltd インドール化合物の製造方法

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CN104304290A (zh) * 2014-11-04 2015-01-28 崔淑华 一种含吲唑磺菌胺与异丙菌胺的杀菌组合物及应用
CN108203385B (zh) * 2016-12-20 2021-03-09 青岛恒宁生物科技有限公司 一种制备3-(4-氟-2-硝基苯基)丙酮的方法
CN109734616B (zh) * 2019-02-16 2022-05-13 安徽诺全药业有限公司 两步法合成(z)-3-氨基-2-(2-氟-3-甲氧基苯基)-2-丁烯酸乙酯的方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2121394A1 (fr) * 1971-01-08 1972-08-25 Anvar Procédé d'obtention de dérivés d'acides indole carboxyliques et produits préparables par ce procédé.
JPS5728045A (en) * 1980-07-28 1982-02-15 Nissan Chem Ind Ltd Preparation of 4-hydroxyindole
JPS6431760A (en) * 1987-07-28 1989-02-02 Nippon Kayaku Kk Production of indoles
WO1999021851A1 (fr) * 1997-10-24 1999-05-06 Nissan Chemical Industries, Ltd. Composes de sulfamyle et bactericide agricole ou horticole
JP2000302781A (ja) * 1999-04-22 2000-10-31 Nissan Chem Ind Ltd インドール化合物並びに農園芸用殺菌剤
JP2001192381A (ja) * 2000-01-11 2001-07-17 Nissan Chem Ind Ltd インドール化合物及び農園芸用殺菌剤

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2121394A1 (fr) * 1971-01-08 1972-08-25 Anvar Procédé d'obtention de dérivés d'acides indole carboxyliques et produits préparables par ce procédé.
JPS5728045A (en) * 1980-07-28 1982-02-15 Nissan Chem Ind Ltd Preparation of 4-hydroxyindole
JPS6431760A (en) * 1987-07-28 1989-02-02 Nippon Kayaku Kk Production of indoles
WO1999021851A1 (fr) * 1997-10-24 1999-05-06 Nissan Chemical Industries, Ltd. Composes de sulfamyle et bactericide agricole ou horticole
JP2000302781A (ja) * 1999-04-22 2000-10-31 Nissan Chem Ind Ltd インドール化合物並びに農園芸用殺菌剤
JP2001192381A (ja) * 2000-01-11 2001-07-17 Nissan Chem Ind Ltd インドール化合物及び農園芸用殺菌剤

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEM. PHARM. BULL., vol. 29, no. 3, 1981, pages 726 - 738, XP000992810 *
J. CHEM. SOC., PERKIN TRANS., no. 10, 1978, pages 1117 - 1125, XP002970216 *
J. ORG. CHEM., vol. 48, no. 12, 1983, pages 2066 - 2069, XP002970217 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006176500A (ja) * 2004-11-25 2006-07-06 Nissan Chem Ind Ltd インドール化合物の製造方法

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