WO2002100850A1 - Procedes de preparation de composes heterocycliques - Google Patents

Procedes de preparation de composes heterocycliques Download PDF

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Publication number
WO2002100850A1
WO2002100850A1 PCT/JP2002/005594 JP0205594W WO02100850A1 WO 2002100850 A1 WO2002100850 A1 WO 2002100850A1 JP 0205594 W JP0205594 W JP 0205594W WO 02100850 A1 WO02100850 A1 WO 02100850A1
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group
substituent
general formula
optionally substituted
represented
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PCT/JP2002/005594
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English (en)
Japanese (ja)
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Hideki Matsuda
Masahiro Torihara
Yoshin Tamai
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Kuraray Co., Ltd.
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Publication of WO2002100850A1 publication Critical patent/WO2002100850A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • 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

Definitions

  • the present invention relates to a method for producing a heterocyclic compound, particularly a benzofuran, a benzothiophene or a monosubstituted indole.
  • benzofurans, benzothiophenes, and mono-substituted mono-indoles obtained by the present invention are all useful compounds as raw materials for pharmaceuticals and agricultural chemicals.
  • benzofurans are useful, for example, as synthetic intermediates of 2-piperazinobenzofuran-5-carbamides, which are useful as antidepressants (see, for example, German Patent No. 195 14567), and benzothiophenes are, for example, Alzheimer's It is useful as an intermediate for synthesizing 5-substituted benzothiophenes, which are useful as disease drugs (see Japanese Patent No. 383281). Background art
  • Method (3) above requires high-temperature conditions to obtain benzothiophenes: with high yield (80% or more). There is a problem that the reaction must be carried out at a temperature below 200 ° C.
  • the above method has a problem that a highly corrosive boron trifluoride getyl ether complex is used.
  • polyphosphoric acid which has high viscosity and is difficult to handle, is used about 2 times the mass of the raw material, so that a large amount of waste liquid containing a phosphorus compound that requires complicated processing steps is generated. Has problems.
  • the above-mentioned method (2) has a problem that the arylthioacetaldehyde used as a raw material is decomposed under the reaction conditions to generate the corresponding arylthiol, and the selectivity is reduced, so that the yield is low. Therefore, none of these methods is an industrially advantageous method for producing benzothiophenes.
  • the above methods (1) and (2) have a problem that it is difficult to obtain indole and N-substituted phenylhydrazine as raw materials, respectively.
  • the above method (2) has a problem that the reaction must be performed under high temperature conditions (350 ° C). Further, the above method has a problem that an expensive ruthenium catalyst must be used. Therefore, none of these methods can be said to be industrially advantageous methods for producing mono-substituted indoles.
  • an object of the present invention is to provide a method for industrially and advantageously producing heterocyclic compounds, particularly benzofurans, benzothiophenes and monosubstituted indoles, under mild conditions with good yield. Is to provide. Disclosure of the invention
  • RR 2 , R 3 and R 4 each have a hydrogen atom, a halogen atom, and a substituent
  • aldehyde (III) is cyclized in the presence of less than an equimolar amount of a phosphoric acid-based compound with respect to the acetal (II) or the aldehyde (III).
  • heterocyclic compound (I) For producing a heterocyclic compound represented by the formula [hereinafter referred to as heterocyclic compound (I)]
  • R 1 R 2 , R 3 and R 4 are as defined above.
  • aryl thiol (hereinafter referred to as aryl thiol (IV)) represented by the general formula (V)
  • chloroacetaldehyde acetal (V) By reacting with chloroacetaldehyde acetal [hereinafter referred to as chloroacetaldehyde acetal (V)] represented by the general formula (II-1)
  • R 1 R 2 , R 3 , R 4 , R 8 and R 9 are as defined above.
  • aryl thioacetate acetal [hereinafter, aryl thioacetate] Aldehyde acetal (II-1)), and the obtained arylthioacetaldehyde (II-1) was less than equimolar to the arylthioacetaldehyde acetal (II-1).
  • benzothiophenes (1-1) A method for producing benzothiophenes [hereinafter referred to as benzothiophenes (1-1)] represented by:
  • Arylthioacetaldehyde (IV) is reacted with chloroacetaldehyde acetal (V) in the presence of a base to give arylthioacetaldehyde acetal (II-1).
  • Acetaldehyde acetal (I1-1) is hydrolyzed under acidic conditions to give the general formula (III-11)
  • R 1 R 2 , R 3 and R 4 are as defined above.
  • arylthioacetaldehyde (II1-1)) is converted to a phosphoric acid-based compound having an equimolar amount to the arylthioacetaldehyde (III-1).
  • arylthiol (IV) is converted to chloroacetaldehyde acetate in the presence of a base. (V) to give arylthioacetaldehyde acetal (II-1), and the resulting arylthioacetaldehyde acetal (II-11) is hydrolyzed under acidic conditions.
  • R 10 is an alkyl group which may have a substituent, and which may have a substituent. Represents an alkenyl group, an aryl group which may have a substituent or an aralkyl group which may have a substituent.
  • N-substituted anilinoacetaldehyde acetal (VI)] is cyclized in the presence of an acid.
  • R 1 (3 is as defined above, and Y represents a halogen atom.
  • halogen compound (IX) to obtain N-substituted anilinoacetaldehyde acetal (VI), and the resulting N monosubstituted aurynoacetaldehyde acetal (
  • examples of the halogen atom represented by R 1 R 2 , R 3 , R 4, and Y include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the alkyl group represented by R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 1 ° is a chain alkyl group having 1 to 8 carbon atoms or A cycloalkyl group having 3 to 6 carbon atoms is preferable.
  • Examples include a neopentyl group, a hexyl group, a heptyl group, an octyl group, a cyclopropynole group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • These alkyl groups may have a substituent. Examples of the substituent include fluorine.
  • a halogen atom such as an atom, a chlorine atom, a bromine atom and an iodine atom; an alkoxyl group having preferably 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group; a methoxycarbyl group and an ethoxycarbyl group; A alkenyl group such as a propoxycarbonyl group, an isopropoxycarbonyl group or a butoxycarbonyl group, preferably an alkoxycarbonyl group having an alkyl group having 1 to 4 carbon atoms as an alkyl moiety; a nitro group.
  • the alkenyl group represented by R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 10 is preferably an alkenyl group having 2 to 8 carbon atoms, for example, a vinyl group, a propenyl group Group, a ptenyl group, an otathenyl group and the like.
  • These alkenyl groups may have a substituent.
  • the strong substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methoxy group, an ethoxy group and a propoxy group.
  • a butoxy group preferably an alkoxyl group having 1 to 4 carbon atoms; a nitro group.
  • the aryl group represented by each of RR 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 10 is preferably an aryl group having 6 to 10 carbon atoms, such as a phenyl group and a naphthyl group.
  • the aralkyl group is preferably an aralkyl group having an alkyl group having 1 to 6 carbon atoms and having an aryl group having 6 to 10 carbon atoms, such as a benzyl group and a naphthylmethyl group. Is mentioned.
  • aryl and aralkyl groups may have a substituent, and examples of the substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methyl group, an ethyl group and a propynole group.
  • a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom
  • a methyl group an ethyl group and a propynole group.
  • an alkyl group having 1 to 8 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, such as an isopropyl group, an isopropyl group, a butyl group, an isobutyl group, a sec butyl group, and a tert-butyl group.
  • the alkoxyl group represented by R ⁇ R 2 , R 3 and R 4 is preferably a linear alkoxyl group having 1 to 8 carbon atoms or a cycloalkyloxy group having 3 to 6 carbon atoms, for example, a methoxy group, Ethoxy group, propoxy group, isopropoxy group, butoxy group, hexinole group, octinole group, cyclopentyl / reoxy group, cyclohexinoleoxy And the like.
  • These alkoxyl groups may have a substituent.
  • substituents examples include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methoxy group, an ethoxy group, a propoxy group and a butoxy group. And the like, preferably an alkoxyl group having 1 to 4 carbon atoms; a nitro group.
  • the aryloxy group represented by each of R 1 , R 2 , R 3 and R 4 is preferably an aryloxy group having an aryl group having 6 to 10 carbon atoms, such as a phenyloxy group and a naphthyloxy group, and an aralkyloxy group.
  • the alkyl moiety has an alkyl group having 1 to 6 carbon atoms and the aryl moiety has an aryl group having 6 to 10 carbon atoms, such as a benzyloxy group and a naphthylmethyloxy group. Is mentioned.
  • These aryloxy and aralkyloxy groups may have a substituent.
  • substituents examples include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methyl group, an ethyl group, a propyl group; Alkyl groups having 1 to 8 carbon atoms, such as isopropyl, butyl, isobutyl, sec_butyl, tert-butyl, etc .; methoxy, ethoxy, propoxy, butoxy, etc.
  • Preferable examples include an alkoxyl group having 1 to 4 carbon atoms; a nitro group.
  • R 3 and R 4 each preferably has an alkyl group with carbon number 1-8 as alkyl moiety, for example Asechiru group and propionyl group.
  • These alkylcarbyl groups may have a substituent.
  • substituents include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methoxy group, an ethoxy group and a propoxy group.
  • a butoxy group preferably an alkoxyl group having 1 to 4 carbon atoms; a nitro group.
  • the arylcarbonyl group represented by R 1 , RR 3 and R 4 is preferably an arylaryl group having an aryl group having 6 to 10 carbon atoms, such as a benzoyl group.
  • the alkylcarbonyl group and the aralkylcarbonyl group may have a substituent.
  • substituents examples include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methyl group and an ethyl group
  • a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom
  • An alkyl group preferably having 1 to 8 carbon atoms, such as propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; methoxy, ethoxy, propoxy, butoxy, etc.
  • an alkoxyl group having 1 to 4 carbon atoms; a nitro group and the like.
  • the alkoxycarbonyl group R ⁇ R 2, R 3 and R 4 represent each, preferably has an alkyl group having 1 to 8 carbon atoms as alkyl le moiety, for example main Tokishika Ruponiru group, ethoxy Cal Poni group, propoxycarbonyl group And an isopropoxycarbonyl group, a butoxycarbonyl group, a hexyloxycarbonyl group, and an octyloxycarbonyl group. These alkoxycarbonyl groups may have a substituent.
  • substituents examples include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methoxy group, an ethoxy group and a propoxy group. And a butoxy group, preferably an alkoxyl group having 1 to 4 carbon atoms; a nitro group.
  • the aryloxycarbonyl group represented by each of RR 2 , R 3 and R 4 is preferably an aryloxy group having an aryl group having 6 to 10 carbon atoms, such as a phenoxycarbonyl group and a naphthyloxycarbonyl group.
  • the aralkyloxycarbonyl group is preferably a group having an alkyl group having 1 to 6 carbon atoms as an alkyl moiety and having an aryl group having 6 to 10 carbon atoms as a motive group. And a carboxycarbonyl group and a naphthylmethyloxycarbonyl group.
  • These aryloxycarbyl groups and aralkyloxycarbol groups may have a substituent.
  • Examples of such a substituent include a fluorine atom, a chlorine atom, a bromine atom, A halogen atom such as an iodine atom; an alkyl group preferably having 1 to 8 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group; Preferable examples include an alkoxyl group having 1 to 4 carbon atoms such as a ethoxy group, an ethoxy group, a propoxy group and a butoxy group; a nitro group.
  • the alkylene group represented by R 8 and R 9 together is preferably a linear alkylene group having 2 to 6 carbon atoms, for example, an ethylene group, a trimethylene group, a 2-methylpropylene group, a 2-ethylpropylene group. And the like.
  • These alkylene groups may have a substituent, and examples of the substituent include a phenyl group and the like, preferably a C 6-10 aryl group.
  • reaction 1 an acetal (II) or an aldehyde (III) is reacted with the acetal (II) or the aldehyde (III) in the presence of a less than equimolar amount of a phosphoric acid compound to form a heterocyclic compound.
  • reaction 1 The reaction for obtaining (I) (hereinafter referred to as reaction 1) will be described.
  • Examples of the phosphoric acid compound include orthophosphoric acid, pyrophosphoric acid, metaphosphoric acid, phosphonic acid, and phosphinic acid. Of these, orthophosphoric acid is preferable. reaction
  • the amount of the phosphoric acid compound used in 1 is an amount less than equimolar to acetal (II) or aldehyde (III).
  • the molar amount is preferably in the range of 0.01 to 0.3 times mol.
  • Reaction 1 is preferably performed in the presence of a solvent.
  • the solvent is not particularly limited as long as it does not adversely affect the reaction.
  • aliphatic hydrocarbons such as hexane, cyclohexane and heptane; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; dichloroethane, chloroform Halogenated hydrocarbons, such as benzene and dichlorobenzene, are used.
  • One type of solvent may be used alone, or two or more types may be used in combination. Among them, aromatic hydrocarbons are preferable.
  • the amount of the solvent to be used is not particularly limited, but is preferably from 1 to 100 times by mass, more preferably from 2 to 20 times by mass, with respect to acetal (II) or aldehyde (III).
  • reaction temperature in reaction 1 varies depending on the type of solvent used, but is preferably in the range of 0 ° C to the reflux temperature of the reaction system. Reaction 1 can be carried out under increased or reduced pressure.
  • reaction time varies depending on the reaction temperature, but is in the range of 30 minutes to 24 hours. Is preferred.
  • Reaction 1 can be carried out, for example, by mixing acetal (II) or aldehyde (III), a phosphoric acid compound and, if necessary, a solvent, and stirring the mixture at a predetermined temperature.
  • alcohol is used when acetal (II) is used, and water is generated when aldehyde (III) is used.
  • the alcohol or water is removed from the reaction system.
  • the method for removing the alcohol from the reaction system is not particularly limited.
  • a solvent having a higher boiling point than the alcohol generated during the reaction is used, and the solvent is heated to a temperature higher than the boiling point of the alcohol.
  • a method of performing reaction 1 while distilling off the alcohol is not particularly limited.
  • the method for removing water from the reaction system is not particularly limited.
  • a solvent azeotropic with water is used, and water generated in the reaction is not distilled off by azeotropic distillation with the solvent.
  • a method of performing reaction 1 and the like can be mentioned.
  • a dehydrating agent that does not adversely affect the reaction such as molecular sieves, may be present in the reaction system of reaction 1.
  • Isolation and purification of the heterocyclic compound (I) obtained in Reaction 1 from the reaction mixture can be carried out in the same manner as the method generally used in the isolation and purification of an organic compound.
  • the reaction mixture is cooled to room temperature, washed with water, an aqueous solution of sodium hydrogencarbonate, saline, and the like, concentrated, and the obtained residue is purified by distillation, column chromatography, or the like.
  • step 1 a step of reacting aryl thiol (IV) with chloroacetaldehyde acetal (V) in the presence of a base to obtain aryl thioacetaldehyde acetal (I1-1) Is referred to as step 1).
  • the amount of chloroacetaldehyde acetal (V) used is preferably in the range of 0.1 to 10 mol, more preferably 0.8 to 5 mol, per 1 mol of arylthiol (IV).
  • the base include alkali metal hydroxides such as sodium hydroxide and hydroxylated lime; alkali metal bicarbonates such as sodium bicarbonate and hydrogen hydride; alkaline metals such as sodium carbonate and carbonized lime.
  • Metal carbonates Alkali metal hydrides such as sodium hydride and hydrogenating power; Alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide; Trimethylamine, triethylamine, tripropyla Tertiary amines such as amine and tributylamine; and pyridines such as pyridine, picoline and lutidine.
  • Alkali metal hydrides such as sodium hydride and hydrogenating power
  • Alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide
  • Trimethylamine, triethylamine, tripropyla Tertiary amines such as amine and tributylamine
  • pyridines such as pyridine, picoline and lutidine.
  • sodium hydroxide, sodium hydride, and sodium methoxide are preferred.
  • the amount of the base to be used is preferably in the range of
  • step 1 if necessary, from the viewpoint of shortening the reaction time, for example, quaternary ammonium salts such as tetrabutylammonium bromide and tetrabutylammonium iodide; You can do it in the presence.
  • the amount used is preferably in the range of 0.001 to 1 mol, and more preferably in the range of 0.05 to 0.3 mol, per 1 mol of arylthiol (IV). More preferred.
  • Step 1 is preferably performed in the presence of a solvent.
  • the solvent is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include aliphatic hydrocarbons such as hexane, cyclohexane, heptane, and octane; aromatic hydrocarbons such as benzene, toluene, xylene, and mesitylene; dichloroethane, Halogenated hydrocarbons such as benzene, dichlorobenzene, etc .; N, N-dimethylacetamide, N, N-getylacetamide, N, N-dimethinoleformamide, N-methinolepyrrolidone, dimethylsulfoxide , Sulfolane, 1,
  • Aprotic polar solvents such as 3-dimethylimidazolidin-2-one; ethers such as diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, diglyme, and triglyme;
  • One type of solvent may be used alone, or two or more types may be used in combination.
  • aromatic hydrocarbons are preferable.
  • the use amount of the solvent is not particularly limited, but is 1 to 100 times by mass relative to arylthiol (IV). The range is preferable, and the range of 3 to 20 times by mass is more preferable.
  • the reaction temperature in step 1 varies depending on the type of the solvent used, but is preferably in the range of 0 ° C to the reflux temperature of the reaction system.
  • the reaction can be carried out under pressure or under reduced pressure.
  • the reaction time varies depending on the reaction temperature, but is preferably in the range of 30 minutes to 24 hours.
  • step 1 There is no particular limitation on the operation method in step 1.
  • a base is added at a predetermined temperature to a solution of arylthiol (IV) dissolved in a solvent, and then chloroacetaldehyde acetal (V) is added thereto. It can be performed by stirring at a temperature.
  • the isolation and purification of the arylthioacetaldehyde acetal (I1-1) obtained in Step 1 from the reaction mixture is performed in the same manner as that used for the isolation and purification of organic compounds. Can be done.
  • the reaction mixture is cooled to room temperature, washed with water, saline, and the like, concentrated, and the obtained residue is purified by distillation, column chromatography, or the like. Further, the obtained residue may be subjected to the above-mentioned reaction 1 or the reaction of the next step (step 2) described later without purification.
  • step 2 a step of hydrolyzing the arylthioacetaldehyde acetal (I1-1) obtained in Step 1 under acidic conditions to obtain arylthioacetaldehyde (II1-1) (Hereinafter, this is referred to as step 2) will be described.
  • examples of the acid used to make the acidic condition include sulfuric acid, hydrochloric acid, phosphoric acid, p-tonoleenesulfonic acid, pyridium-p-toluenesulfonate, trifluoroacetic acid and the like.
  • the amount of the acid used is preferably in the range of 0.01 to 1 mol, more preferably 0.01 to 0.5 mol, per 1 mol of arylthioacetaldehyde acetal (II-1). Is more preferable.
  • the amount of water to be used is not particularly limited, but is preferably in the range of 0.1 to L00 mass times based on arylthioacetaldehyde acetal (I1-1), and 0.3 to L0. The range of mass times is more preferable.
  • Step 2 may be performed in the presence of a solvent.
  • a solvent do not adversely affect the reaction.
  • aliphatic hydrocarbons such as hexane, cyclohexane, heptane, and octane
  • aromatic hydrocarbons such as benzene, toluene, xylene, and mesitylene
  • Aprotic polar solvents such as diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, diglyme and triglyme;
  • One type of solvent may be used alone, or two or more types may be used in combination. Among them, aromatic hydrocarbons are preferable.
  • the amount of the solvent to be used is not particularly limited, but is preferably in the range of 0.1 to 100 times by mass, and more preferably in the range of 0.3 to 10 times by mass relative to arylthioacetaldehyde acetal (I1-1). Is more preferred.
  • the reaction temperature in step 2 varies depending on the type of the solvent used, but is preferably in the range of 0 ° C to the reflux temperature of the reaction system.
  • the reaction can be carried out under pressure or under reduced pressure.
  • the reaction time varies depending on the reaction temperature, but is preferably in the range of 30 minutes to 24 hours.
  • the method of operation in step 2 is not particularly limited.
  • the method is carried out by mixing arylthioacetaldehyde acetal (I1-1), water, an acid, and a solvent as necessary, and stirring the mixture at a predetermined temperature.
  • arylthioacetaldehyde acetal I1-1
  • water an acid
  • a solvent as necessary
  • Isolation and purification of the arylthioacetaldehyde (II1-1) obtained in step 2 from the reaction mixture should be carried out in the same manner as is generally used for the isolation and purification of organic compounds.
  • the reaction mixture is cooled to room temperature, washed with water, an aqueous solution of sodium hydrogen carbonate, saline, and the like, concentrated, and the obtained residue is purified by distillation, column chromatography, or the like. Further, the obtained residue may be subjected to the above-mentioned reaction 1 without purification.
  • anilinoacetaldehyde acetal (D) Then, the anilinoacetaldehyde acetal (VIII) is The step of obtaining an N-substituted anilinoacetaldehyde acetal (VI) by reacting with a halogen compound (II) (hereinafter referred to as step i) will be described.
  • halogen compound (IX) examples include, for example, methyl fluoride, butyl fluoride, propyl fluoride, butyl fluoride, methyl fluoroacetate, ethyl fluoroacetate, methyl chloride, chlorinated tinole, propyl chloride, butyl chloride, Methyl acetate, methyl ethyl acetate, methyl bromide, methyl bromide, propyl bromide, butyl bromide, methyl bromoacetate, ethyl bromoacetate, methyl iodide, methyl iodide, propyl iodide, propyl iodide Butyl chloride, methyl iodoacetate, ethyl iodoacetate, 1-fluoro-2-propene, 1-fluoro-2-butene, 1-chloro-2-propene, 1-chloro-2-butene, 1-ch
  • the amount of the halogenated compound (IX) to be used is preferably in the range of 0.1 to 10 mol, more preferably in the range of 0.8 to 5 mol, per 1 mol of the anilinoacetaldehyde acetal (VIII).
  • Examples of the base include alkali metal hydroxides such as sodium hydroxide and hydroxylated lime; alkali metal bicarbonates such as sodium hydrogencarbonate and hydrogenated lime; alkali metal carbonates such as sodium carbonate and carbonated lime; Alkali metal hydrides such as sodium hydride and hydrogenation power; alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide; trimethylamine, triethynoleamine, tripropylamine, tributylamine Tertiary amines such as amines; pyridines such as pyridine, picoline and lutidine.
  • the amount of the base used is preferably in the range of 0.1 to 10 mol, more preferably in the range of 0.8 to 5 mol, per 1 mol of anilinoacetaldehyde acetal (VIII).
  • Step i is preferably performed in the presence of a solvent.
  • the solvent is not particularly limited as long as it does not adversely affect the reaction.
  • aliphatic hydrocarbons such as hexane, cyclohexane, heptane and octane; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene Hydrogen; alcohols such as methanol, ethanol, propanol and isopropanol; halogenated hydrocarbons such as dichloroethane, chlorobenzene and dichlorobenzene; nitriles such as acetonitrile, propionitrile and benzonitrile; N, N-dimethylacetamide, N , N- GETS chill ⁇ Seto Ami de, N, N- dimethylformamidine de, N- Mechirupirori pyrrolidone, dimethyl sulfoxide, sulfolane, 1, 3-Jimechiruimi
  • nitrile and alcohol are preferable.
  • the amount of the solvent to be used is not particularly limited, but is preferably from 1 to 100 times by mass, more preferably from 3 to 20 times by mass, based on anilinoacetaldehyde acetanol (VIII).
  • the reaction temperature in step i varies depending on the type of the solvent used, but is preferably in the range of 0 ° C to the reflux temperature of the reaction system.
  • the reaction can be carried out under pressure or under reduced pressure.
  • the reaction time varies depending on the reaction temperature, but is preferably in the range of 30 minutes to 24 hours.
  • Step i can be performed, for example, by mixing anilinoacetaldehyde acetal (VIII), a halogen compound (IX), a base, and a solvent and stirring the mixture at a predetermined temperature.
  • Isolation and purification of the N-substituted arinoacetoaldehyde acetal (VI) obtained in step i from the reaction mixture are carried out in the same manner as those generally used for the isolation and purification of organic compounds. It can be carried out. For example, after cooling the reaction mixture to room temperature, water is added to separate an organic layer and an aqueous layer, and the aqueous layer is extracted with an organic solvent such as toluene, hexane, getyl ether, or ethyl acetate. After combining and concentrating the above organic layers, the residue is further purified by distillation, recrystallization, column chromatography and the like.
  • step ii a step of cyclizing the N-substituted anilinoacetaldehyde acetal (VI) obtained in the step i in the presence of an acid to obtain 1-substituted indoles (VII) (hereinafter, referred to as This will be referred to as step ii).
  • the acid examples include hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, acetic acid, and trifluoroacetic acid. Of these, sulfuric acid is preferred.
  • the amount of the acid used is preferably in the range of 0.01 to 5 mol, and more preferably in the range of 0.05 to 0.5 mol, per 1 mol of N-substituted anilinoacetaldehyde acetal (VI). More preferred.
  • Step ii is preferably performed in the presence of a solvent.
  • the solvent is not particularly limited as long as it does not adversely affect the reaction.
  • water aliphatic hydrocarbons such as hexane, cyclohexane and heptane; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; dichloroethane And halogenated hydrocarbons such as benzene and dichlorobenzene.
  • the solvent may be used alone or as a mixture of two or more. Among them, water or a mixed solvent of water and an aromatic hydrocarbon is preferable. There is no particular limitation on the mixing ratio when two or more solvents are used in combination.
  • the amount of the solvent to be used is not particularly limited, but is preferably from 1 to 100 times by mass, more preferably from 2 to 20 times by mass, with respect to the N-substituted anilinoacetaldehyde acetal (VI). More preferred.
  • the reaction temperature in step ii varies depending on the type of solvent used, but is preferably in the range of 0 ° C to the reflux temperature of the reaction system.
  • the reaction can be carried out under increased or reduced pressure.
  • the reaction time varies depending on the reaction temperature, but is preferably in the range of 30 minutes to 24 hours.
  • Step ii can be performed, for example, by mixing an N-substituted aerinoacetaldehyde acetal (VI), an acid and a solvent and stirring the mixture at a predetermined temperature.
  • Alcohol is generated with the progress of the reaction, and preferably the mono-substituted indole (VII) can be obtained in good yield by performing the reaction while removing the alcohol outside the reaction system.
  • the method of removing the alcohol outside the reaction system is not particularly limited.
  • a solvent having a higher boiling point than the alcohol generated during the reaction is used, and A method in which the reaction is carried out while heating to the above temperature and distilling off the alcohol.
  • Isolation of the mono-substituted indoles (VI I) obtained in X @ ii from the reaction mixture 'Purification can be carried out in the same manner as is commonly used in the isolation and purification of organic compounds. it can.
  • the reaction mixture is cooled to room temperature, the acid remaining in the reaction system is neutralized with an aqueous solution of sodium hydrogen carbonate, etc., then the organic layer and the aqueous layer are separated, and the aqueous layer is diluted with toluene.
  • an organic solvent such as xan, getyl ether or ethyl acetate, the extract and the previous organic layer are combined and concentrated.
  • the residue is further purified by distillation, recrystallization, column chromatography and the like.
  • the aryloxyacetaldehyde acetal [compound in which X is an oxygen atom in acetal (II)] used as a raw material in the method of the present invention may be, for example, a compound obtained by converting a phenol to a halogeno compound in the presence of a base. It can be easily and inexpensively synthesized by reacting with acetaldehyde dialkyl acetal. [See Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 28, p. 347 (1985)] .
  • the aryloxyacetaldehydes [compounds in which X is an oxygen atom in the aldehyde (III)] used as a raw material in the method of the present invention include, for example, halogenoacetaldehyde dialkyl acetals obtained by converting phenols in the presence of a base. Can be easily and inexpensively synthesized by hydrolysis after the reaction [see Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 28, p. 347 (1980)]. ].
  • the arylthiol (IV) used as a raw material in the method of the present invention for example,! 1) Toluenethiol is industrially produced, commercially available, and easily available.
  • anilinoacetaldehyde acetal (VIII) used as a raw material in the method of the present invention can be easily synthesized, for example, by reacting an aniline with a halogenoacetaldehyde acetal in the presence of a base.
  • the resulting methanol was heated to reflux for another 1 hour while distilling off the generated methanol outside the reaction system, and the conversion of 4-methylphenoxyacetaldehyde dimethyl acetal was 99.9% or more. .
  • the resulting reaction mixture was cooled to 20 ° C., added with 5 Om 1 of water, and extracted with toluene (50 m IX 2).
  • the obtained extract was washed with 50 ml of a 2% by mass aqueous sodium hydrogen carbonate solution and concentrated to obtain 6.60 g of a crude product.
  • the obtained crude product was analyzed by gas chromatography to find that 5.48 g (yield: 83.0% based on 4-methylphenoxyacetaldehyde dimethyl acetal) of 5-methylenbenzobenzofuran was formed. .
  • Distillation apparatus a dropping funnel, a three-necked flask having an inner volume of 200 ml equipped with a thermometer and magnetic stirrer, was placed a 85 mass 0/0 orthophosphoric acid 0. 47 g (4. Ommo l) and toluene 70 g The mixture was heated to 110 ° C. and refluxed. A solution prepared by dissolving 8.48 g (40.Ommo1) of m-methoxyphenyloxyacetaldehyde dimethyl acetal in 6.3 g of toluene was added dropwise to the mixture over 5 hours. The formed methanol was distilled out of the reaction system.
  • the resulting methanol was distilled off to the outside of the reaction system and heated under reflux for an additional hour to obtain m-methoxyphenyloxyacetaldehyde.
  • the conversion of the hydrodimethyl acetal was above 99.9%.
  • the resulting reaction mixture was cooled to 20 ° C., added with 4 Om 1 of water, and extracted with toluene (4 Om 1 X 2).
  • the obtained extract was washed with 4% of a 2% by mass aqueous solution of sodium hydrogen carbonate and concentrated to obtain 5.82 g of a crude product.
  • the resulting water was further heated and refluxed for 1 hour while distilling off the generated water out of the reaction system.
  • the conversion of 4-methylphenoxyacetaldehyde was 99.9% or more.
  • the obtained reaction mixture was cooled to 20 ° C., added with 5 Oml of water, and extracted with toluene (50 ml ⁇ 2).
  • the obtained extract was washed with a 2% by mass aqueous solution of sodium bicarbonate (5 Om1) and concentrated to obtain 6.58 g of a crude product.
  • the resulting crude product was analyzed by gas chromatography to find that 5.13 g of 5-methylbenzofuran was obtained (77.7% yield based on 4-methylphenoxyacetaldehyde, 77.7% selectivity).
  • Example 3 the corresponding benzofurans were prepared in the same manner as in Example 3 except that 4-methylphenoxyacetoaldehyde was replaced with aryloxyacetaldehyde having a different substituent on the benzene ring.
  • Example 3 the corresponding benzofurans were prepared in the same manner as in Example 3 except that 4-methylphenoxyacetoaldehyde was replaced with aryloxyacetaldehyde having a different substituent on the benzene ring. was synthesized. The results are shown in Table 1.
  • the obtained reaction mixture was cooled to 20 ° C, and 2 Oml of water was added to separate an organic layer and an aqueous layer.
  • the obtained organic layer was washed with brine (2 Om1) and concentrated to obtain 16.Olg of a crude product.
  • Analysis of the resulting crude product by gas chromatography revealed that 14.31 g of 4-methylphenylthioacetaldehyde dimethyl acetal was produced (96% yield based on p-toluenethiol). That is, the purity of 4-methylphenylthioacetaldehyde dimethyl acetal in the crude product is 89.4%.
  • the obtained reaction mixture was cooled to 20 ° C., and 20 ml of water was added to separate an organic layer and an aqueous layer.
  • the obtained organic layer was washed with 20 ml of saline and concentrated to obtain 16.01 g of a crude product.
  • the obtained crude product was analyzed by gas chromatography to find that 14.31 g (96% yield based on p-toluenethiol) of 4-methylphenylthioacetaldehyde dimethyl acetal was formed. That is, the purity of 4-methylphenylthioacetaldehyde dimethyl acetate in the crude product is 89.4%.
  • the extract was washed with 25% by weight of a 2% by weight aqueous sodium hydrogen carbonate solution and concentrated to obtain 12.17 g of a crude product.
  • the obtained crude product was analyzed by gas chromatography to find that 10.38 g of 4-methylphenylthioacetaldehyde (92% yield based on 4-methylphenylthioacetaldehyde dimethyl acetal) was formed.
  • 10.38 g of 4-methylphenylthioacetaldehyde 92% yield based on 4-methylphenylthioacetaldehyde dimethyl acetal
  • Example 8 the corresponding benzothiophenes (1-1) were prepared in the same manner as in Example 8, except that p-toluenethiol was replaced with arylthiol (IV) having a different substituent on the benzene ring. ) was synthesized. The results are shown in Table 2.
  • step (c) of Example 11 a mixture of 6-methoxybenzothiophene and 4-methoxybenzothiophene in a ratio of 3 to 1 (mass ratio) was obtained (a yield of 52% is the total yield of both). Represents the rate).
  • Table 2
  • N-benzyl-p-toluidinoacetaldehyde dimethyl acetal obtained in (a) above was placed in a 3-liter flask with an internal volume of 5 Om1 equipped with a cooling pipe, a thermometer and a magnetic stirrer. g (13. Ommol), 127 mg (1.3 mmol) sulfuric acid and 13 g of water were added and heated at 90 ° C for 7 hours.
  • the obtained reaction mixture was cooled to 20 ° C., and after adding 13 ml of a 2% aqueous sodium hydrogen carbonate solution, an organic layer and an aqueous layer were separated, and the aqueous layer was extracted with toluene (13 ml ⁇ 2).
  • the organic layer at the top of the extract was combined and concentrated, and 3.14 g of the obtained crude product was purified by silica gel column chromatography to obtain 1.93 g of 1-benzyl-5-methylindole. (8.7 mmO1, 67% yield).
  • N- ⁇ -benzyl-p-toluidinoacetaldehyde methyl dimethyla obtained by the method of Example 1 (a) acetal 2.
  • the obtained reaction mixture was cooled to 20 ° C., and 10 ml of a 2% by mass aqueous sodium hydrogen carbonate solution was added.
  • N-methylaniline 16.1 g (15 Ommo 1), promoacetoaldehyde dimethyl acetal 27.9 g (165 mmo 1) were placed in a 300 ml three-necked flask equipped with a condenser, thermometer and magnetic stirrer.
  • Example 16 A 100 ml 3-necked flask equipped with a cooling tube, thermometer and magnetic stirrer was charged with 4.88 g of the N-methylanilinoacetaldehyde dimethyl acetal obtained by the method of Reference Example 1 above (25.Ommol). ), 245 mg (2.5 mmol) of sulfuric acid, 19 g of toluene and 25 g of water, and the mixture was heated under reflux at 83 ° C for 8 hours. The obtained reaction mixture was cooled to 20 ° C., and 25 ml of a 2% aqueous sodium hydrogen carbonate solution was added.
  • the obtained reaction mixture was cooled to 20 ° C., and after adding 20 ml of a 2% by mass aqueous sodium hydrogen carbonate solution, an organic layer and an aqueous layer were separated, and the aqueous layer was extracted with toluene 2 Oml. Extract The organic layer and the organic layer were combined and concentrated.
  • the obtained crude product (3.89 g) was purified by silica gel column chromatography to obtain 1.75 g of 1-methyl- 5- chloroindole. (10.6 mmo1, yield 53%).
  • the organic layer and the aqueous layer were separated by adding 31 ml and 3 ml of toluene to the residue, and the aqueous layer was extracted with 31 ml of toluene.
  • the extract and the organic layer were combined, concentrated, and the crude product obtained was purified by silica gel column chromatography to obtain N- (2-propene-1-yl) -p-toluene. 6.86 g of Louisinoacetaldehyde dimethyl acetal was obtained (29.2 mmol 1, yield 94%).
  • the obtained reaction mixture was cooled to 20 ° C., and after adding 17% of a 2% by mass aqueous solution of sodium hydrogencarbonate, an organic layer and an aqueous layer were separated, and the aqueous layer was extracted with 17 ml of toluene.
  • the organic layer at the top of the extract was combined and concentrated, and 3.45 g of the obtained crude product was purified by silica gel column chromatography to obtain 1- (2-propene-1-inole) -1-5- 1.60 g of methylindole was obtained (9.4 mmol, yield 55%).
  • Example 19 (a) 3 loflasks with a volume of 20 Om 1 equipped with a cooling pipe, thermometer and magnetic stirrer, p-toluidinoacetaldehyde dimethyl acetal 6.31 g (32.Ommo 1) Then, 7.42 g (48. Ommo 1), methyl bromoacetate, 3.60 g (33.6 mmo 1) of sodium carbonate and 5 Om1 of methanol were added, and the mixture was heated under reflux at 60 ° C. for 8 hours. After cooling the obtained reaction mixture to 20 ° C., a solid substance was filtered, and methanol was distilled off from the obtained filtrate.
  • heterocyclic compounds particularly benzofurans, benzothiophenes and 1-substituted indoles, can be industrially advantageously produced under mild conditions with good yield.

Abstract

L'invention concerne un procédé de préparation de composés hétérocycliques représentés par la formule générale (I), consistant à cycliser un acétal (II) ou un aldéhyde (III) en présence d'un composé d'acide phosphorique dans une quantité molaire inférieure à la quantité molaire d'acétal ou d'aldéhyde. L'invention concerne en outre un procédé de préparation d'indoles substitués en 1 représentés par la formule générale (VII), consistant à cycliser un anilinoacétaldéhyde acétal substitué en N (VI) en présence d'un acide. Dans les formules, R?1, R2, R3, R4, R8, R9, R10¿ et X ont les significations spécifiées dans la description.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2210884A2 (fr) 2005-03-28 2010-07-28 Toyama Chemical Co., Ltd. Procédé de fabrication de l'acide propionique 1-(3-(2-(1-benzothiophén-5-yl)-éthoxy) et de l'azétidin-3-ol 1-(3-(2-(1-benzothiophén-5-yl)-éthoxy)propyl) et de leurs sels
EP2248809A1 (fr) 2005-03-28 2010-11-10 Toyama Chemical Co., Ltd. Alkyl-3-[2-(benzo[b]thiophèn-5-yl)-éthoxy]-propanoates en tant qu'intermediaires dans la production de dérivés d'azétidin-3-ol
US7951963B2 (en) 2005-03-28 2011-05-31 Toyama Chemical Co., Ltd. Process for production of 1-(3-(2-(1-benzothiophen-5-yl)-ethoxy)propyl)azetidin-3-ol or salts thereof
EP2348022A1 (fr) 2005-03-28 2011-07-27 Toyama Chemical Co., Ltd. Procédé de fabrication de l'azétidin-3-ol 1-(3-(2-(1-benzothiophén-5-yl)-éthoxy)propyl) et de leurs sels
US8273902B2 (en) 2005-03-28 2012-09-25 Toyama Chemical Co., Ltd. Process for production of 1-(3-(2-(1-benzothiophen-5-yl)-ethoxy)propyl)azetidin-3-ol or salts thereof

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