WO2013058296A1 - Novel method for producing triazol-3-one derivative - Google Patents

Novel method for producing triazol-3-one derivative Download PDF

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WO2013058296A1
WO2013058296A1 PCT/JP2012/076882 JP2012076882W WO2013058296A1 WO 2013058296 A1 WO2013058296 A1 WO 2013058296A1 JP 2012076882 W JP2012076882 W JP 2012076882W WO 2013058296 A1 WO2013058296 A1 WO 2013058296A1
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group
salt
substituent
general formula
represented
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PCT/JP2012/076882
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French (fr)
Japanese (ja)
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節子 新妻
阿部　雅年
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日本化薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

Definitions

  • the present invention relates to a novel production method for efficiently producing a [1,2,4] triazol-3-one derivative or a salt thereof having HSP90 inhibitory activity and useful as an anticancer agent in a short process.
  • Patent Document 1 discloses 5- (2,4-dihydroxyphenyl)-[1,2,4] triazol-3-one that has excellent HSP90 inhibitory activity and also exhibits excellent anticancer activity in animal experiments. Derivatives are described.
  • Patent Documents 2 and 3 and Non-Patent Document 1 5- (2,4-dihydroxyphenyl)-[1,2,4] triazol-3-one derivatives or prodrugs thereof have HSP90 inhibitory activity. Has been reported.
  • Patent Document 1 discloses [1,2,4] triazol-3-thione derivatives (4) as shown in the following reaction formula 1. Has been disclosed, and is then converted into its [1,2,4] triazol-3-one derivative via three steps.
  • the starting material [1,2,4] triazole-3-thione derivative (4) is easy to synthesize, and [1,2,2, 4] There is an advantage that a triazole ring can be constructed.
  • the triazolyl sulfide derivative (2) After the preparation, it was necessary to go through the sulfone derivative (5), and the number of reaction steps was a problem.
  • An object of the present invention is to provide a production method for efficiently producing a [1,2,4] triazol-3-one derivative from a [1,2,4] triazol-3-thione derivative in a short process.
  • a sulfone derivative in the reaction of converting the [1,2,4] triazole-3-thione derivative (4) represented by the reaction formula 1 into the triazol-3-one derivative (1), a sulfone derivative It is an object to provide a method for converting the triazolyl sulfide derivative (2) to the [1,2,4] triazol-3-one derivative (1) in one step without going through (5). To do.
  • reaction formula 2 The triazolyl sulfide derivative represented by the general formula (2) is used in an aprotic solvent in an amount of 1 equivalent or more of water relative to the triazolyl sulfide derivative represented by the general formula (2), and the general formula The following general formula (3) having an excess equivalent to the equivalent of water relative to the triazolyl sulfide derivative represented by (2) MW (3) [Wherein, M represents potassium, sodium or lithium, W represents an alkoxy group represented by O (Q1) or an amino group represented by N (Q2) (Q3), and the Q1 is secondary or 3 A trialkyl group, and Q2 and Q3 may be the same or different from each other and represent an alkyl group or a trialkylsilyl group]. It was found that the triazolyl sulfide derivative (2) can be converted into the triazol-3-one derivative represented by the general formula (1) in one step without going through the zolyl
  • the gist of the present invention is the inventions shown in [1] to [12] below.
  • An alkoxy group which may have a substituent, an aryloxy group which may have a substituent, an aliphatic amino group which may have a substituent, an aromatic which may have a substituent Represents an amino group or a silyl group, R may have a carbocyclic aryl group which may have a substituent, a heterocyclic aryl group which may have a substituent, an alkyl group which may have a substituent, or a substituent.
  • a alkynyl group which may have a good alkenyl group or substituent, Z 1 and Z 2 may be the same or different from each other, and each represents a hydrogen atom or a hydroxyl-protecting group] [1,2,4] triazol-3-one derivative or a salt thereof
  • a manufacturing method The following general formula (2) [Wherein X, Z 1 , Z 2 and R represent the same meaning as X, Z 1 , Z 2 and R in the general formula (1), and Y represents an alkyl group which may have a substituent.
  • the salt is 1 equivalent or more water relative to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof, and the triazolyl represented by the general formula (2).
  • W is an alkoxy group represented by O (Q1)
  • the Q1 group is a tert-butyl group, a sec-butyl group, or an isopropyl group.
  • W is an amino group represented by N (Q2) (Q3), and both Q2 and Q3 are isopropyl groups, or both Q2 and Q3 are trimethylsilyl groups.
  • the amount of water added is 1 to 50 equivalents to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof, and the base represented by the general formula (3) is added.
  • the triazole-3 according to any one of [1] to [4], wherein the amount is 2 to 100 equivalents relative to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof.
  • the addition amount of the water is 1 to 10 equivalents relative to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof, and the addition of the base represented by the general formula (3)
  • the amount is 2 to 20 equivalents relative to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof, and the added amount of the base is 1 to 10 equivalents more than the added amount of water.
  • R is a carbocyclic aryl group having an aliphatic amino group as a substituent, a carbocyclic aryl group having an aliphatic aminoalkyl group as a substituent, or an optionally substituted heterocyclic aryl group.
  • the [1,2,4] triazol-3-one derivative represented by the general formula (1) or a salt thereof is represented by the following general formula (1a) [Wherein, Xa represents an ethyl group, an isopropyl group or a tert-butyl group, m represents 0 to 5, A represents an aliphatic amino group, Za 1 and Za 2 represent an ether type protecting group or an acetal type.
  • the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof is represented by the following general formula (2a) [Wherein, Xa represents an ethyl group, an isopropyl group or a tert-butyl group, Ya represents an optionally substituted alkyl group having 1 to 20 carbon atoms, m represents 0 to 5, and A represents An aliphatic amino group, and Za 1 and Za 2 represent an ether-type protecting group or an acetal-type protecting group] or a salt thereof.
  • the method for producing the triazol-3-one derivative or a salt thereof according to any one of [1] to [9].
  • [12] The [1,2,4] triazol-3-one derivative represented by the general formula (1) or a salt thereof is represented by the following general formula (1a) [Wherein, Xa represents an ethyl group, an isopropyl group or a tert-butyl group, m represents 0 to 5, A represents an aliphatic amino group, Za 1 and Za 2 represent an ether type protecting group or an acetal type protecting group.
  • the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof is represented by the following general formula (2a) [Wherein, Xa represents an ethyl group, an isopropyl group or a tert-butyl group, Ya represents an optionally substituted alkyl group having 1 to 20 carbon atoms, m represents 0 to 5, and A represents An aliphatic amino group, Za 1 and Za 2 represent an ether-type protecting group or an acetal-type protecting group], or a salt thereof, Further, the compound represented by the general formula (7) or a salt thereof is represented by the following general formula (7a): [Wherein Xa represents an ethyl group, an isopropyl group or a tert-butyl group, m represents 0 to 5, and A represents an aliphatic amino group] or a salt thereof [10 ] The manufacturing method of the triazol-3-one derivative or its salt as described in above.
  • the present invention provides an efficient method for producing a [1,2,4] triazol-3-one derivative or a salt thereof.
  • the compound is converted to a 5- (2,4-dihydroxyphenyl)-[1,2,4] triazol-3-one derivative or a salt thereof having excellent HSP90 inhibitory activity, if necessary, through a deprotection step.
  • a 5- (2,4-dihydroxyphenyl)-[1,2,4] triazol-3-one derivative which has excellent HSP90 inhibitory activity and can be used particularly as an active ingredient of a cancer therapeutic agent or
  • the pharmacologically acceptable salt can be conveniently provided in a short process.
  • the halogen atom represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • an alkyl group means a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms.
  • the linear alkyl group include methyl group, ethyl group, n-propyl group, n-butyl group, n-hexyl group, n-dodecyl group, n-tetradecyl group, n-hexadecyl group, and the like. It is done.
  • Examples of the branched alkyl group include isopropyl group, tert-butyl group, 1-methyl-propyl group, 2-methyl-propyl group, 2,2-dimethylpropyl group, and the like.
  • cyclic alkyl group examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an adamantyl group, and the like.
  • the alkenyl group means a linear, branched or cyclic alkenyl group having 2 to 30 carbon atoms having a carbon-carbon double bond at any one or more positions.
  • the linear alkenyl group include 1-alkenyl groups such as ethenyl group, prop-1-enyl group or but-1-enyl group, but-2-enyl group, or penta-2-enyl group, 2-alkenyl groups such as and the like.
  • Examples of the branched alkenyl group include an isopropenyl group, a 3-methylbut-1-enyl group, and a geranyl group.
  • Examples of the cyclic alkenyl group include a cyclohex-2-enyl group, a cyclohexa-2,5-dienyl group, a dicyclopentaenyl group, a dicyclopentadienyl group, and the like.
  • the alkynyl group means an alkynyl group having 2 to 30 carbon atoms having a carbon-carbon triple bond at any one or more positions.
  • a 1-alkynyl group such as an ethynyl group, a prop-1-ynyl group, a 3,3-dimethylbut-1-ynyl group, or a 2-amino group such as a prop-2-ynyl group or a but-2-ynyl group
  • An alkynyl group and the like.
  • the carbocyclic aryl group means a carbocyclic aryl group having 6 to 10 carbon atoms, and examples thereof include a phenyl group and a naphthyl group.
  • the heterocyclic aryl group means a 5-membered or 6-membered monocyclic heterocyclic aryl group, a 5-membered and 6-membered condensed heterocyclic aryl group, or a 6-membered and 6-membered condensed heterocyclic aryl group, for example, , Pyridyl group, pyrimidinyl group, quinolyl group, quinazolinyl group, naphthyridinyl group, furyl group, pyrrolyl group, indolyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, and the like.
  • the alkylthio group means an alkylthio group having 1 to 20 carbon atoms which may have a substituent, and examples thereof include a methylthio group, an isopropylthio group, a benzylthio group, and a dodecylthio group.
  • the arylthio group is a carbocyclic arylthio group having 6 to 10 carbon atoms, a 5-membered or 6-membered monocyclic heterocyclic arylthio group, a 5-membered and 6-membered condensed heterocyclic arylthio group, or a 6-membered and 6-membered condensed group.
  • Type heterocyclic aryl group for example, phenylthio group, naphthylthio group, pyridylthio group, and the like.
  • the alkoxy group means an alkoxy group having 1 to 10 carbon atoms which may have a substituent.
  • substituents include primary alkoxy groups such as methoxy group, ethoxy group, and benzyloxy group, secondary alkoxy groups such as isopropoxy group, sec-butoxy group, and tertiary alkoxy groups such as tert-butoxy group.
  • aryloxy group include a phenoxy group, a naphthyloxy group, and a pyridyloxy group.
  • the aliphatic amino group represents an acyclic primary amino group, an acyclic secondary amino group, or a cyclic secondary amino group.
  • the acyclic aliphatic primary amino group is an amino group in which a linear, branched, or cyclic alkyl group having 1 to 10 carbon atoms is N-monosubstituted. Examples thereof include a methylamino group, isopropylamino group, neopentylamino group, n-hexylamino group, cyclohexylamino group, n-octylamino group, and the like.
  • the acyclic aliphatic secondary amino group may be the same or different, and is an amino group in which a linear, branched, or cyclic alkyl group having 1 to 10 carbon atoms is N, N-disubstituted. It is. For example, dimethylamino group, diisopropylamino group, N-methyl-N-cyclohexylamino group and the like can be mentioned.
  • Examples of the cyclic aliphatic secondary amino group include a morpholino group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group.
  • the aromatic amino group means an amino group in which an aromatic group is bonded to a nitrogen atom.
  • a phenylamino group an N-methyl-N-phenylamino group, an N-methyl-N-pyridylamino group, a diphenylamino group Group, and the like.
  • the silyl group refers to a silyl group substituted with three groups selected from the aforementioned alkyl group and carbocyclic aryl group, such as a trimethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group, and a tert group.
  • -Butyldiphenylsilyl group and the like.
  • examples of the substituent when it is described that it may have a substituent include a mercapto group, a hydroxyl group, a halogen atom, a nitro group, a cyano group, a C 1-8 alkyl group, a carbon number 2 to 10 alkenyl group, 2 to 10 alkynyl group, carbocyclic or heterocyclic aryl group, 1 to 8 alkylthio group, arylthio group, 1 to 8 alkylsulfinyl group, arylsulfinyl group, 1 to carbon atom 8 alkylsulfonyl group, arylsulfonyl group, alkoxy group having 1 to 8 carbon atoms, aryloxy group, aliphatic or aromatic amino group, alkyl group having 1 to 8 carbon atoms substituted with aliphatic amino group, formyl group, acyl group , Carboxyl group, silyl group, and the like.
  • substitution position on the aromatic ring may be ortho, meta, or para.
  • alkylsulfinyl group examples include a methylsulfinyl group, an ethylsulfinyl group, an isopropylsulfinyl group, a cyclohexylsulfinyl group, and the like.
  • the arylsulfinyl group is a carbocyclic arylsulfinyl group having 6 to 10 carbon atoms, a 5-membered or 6-membered monocyclic heterocyclic arylsulfinyl group, a 5-membered and 6-membered condensed heterocyclic arylsulfinyl group, or a 6-membered
  • a 6-membered condensed heterocyclic arylsulfinyl group is exemplified, and examples thereof include a phenylsulfinyl group and a naphthylsulfinyl group.
  • alkyl sulfonyl group examples include a methyl sulfonyl group, an ethyl sulfonyl group, an isopropyl sulfonyl group, a cyclohexyl sulfonyl group, and the like.
  • the arylsulfonyl group is a C6-C10 carbocyclic arylsulfonyl group, a 5-membered or 6-membered monocyclic heterocyclic arylsulfonyl group, a 5-membered and 6-membered condensed heterocyclic arylsulfonyl group, or a 6-membered
  • a 6-membered condensed heterocyclic arylsulfonyl group is exemplified, and examples thereof include a phenylsulfonyl group and a naphthylsulfonyl group.
  • the acyl group means an aliphatic or aromatic acyl group having 2 to 10 carbon atoms, and examples thereof include an acetyl group, a benzoyl group, and a pivaloyl group.
  • the salt refers to a salt produced by adding an acid or a salt produced by adding a base.
  • the salt generated by the addition of acid include sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, hydrofluoride, hydrochloride, hydrobromide, and iodide.
  • Inorganic acid salts such as hydrogenates; Organic carboxylates such as acetate, oxalate, maleate, tartrate, fumarate, citrate; methanesulfonate, trifluoromethanesulfonate, ethanesulfone Organic sulfonates such as acid salts, benzene sulfonates, toluene sulfonates and camphor sulfonates; and amino acid salts such as aspartates and glutamates.
  • Examples of the salt produced by the addition of a base include amine salts such as ammonium salts and amino acid salts; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts.
  • [1,2,4] triazole means that in the general formula (1), the position where the carbonyl group is incorporated in the triazole ring skeleton is the 3-position, and the substitution position of the R group is the 4-position. and then, Z 1 O group in the 4-position, 2-position Z 2 O group is replaced by a further [1,2,4] triazole to position the 5-position of the phenyl group is disposed with a X group.
  • the compound (1) represented by the general formula (1) has a keto-enol tautomer and can have an isomer structure represented by the following general formula (1E). That is, in the present invention, (1) and (1E) are the same compound. Therefore, the present invention also includes the production method of the general formula (1E).
  • the substituent represented by X has a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent.
  • An arylthio group which may have a substituent, an alkoxy group which may have a substituent, an aryloxy group which may have a substituent, an aliphatic amino group which may have a substituent, and a substituent.
  • the alkyl group which may have a substituent represented by X is a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms. Preferably, it is a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent.
  • the alkyl group which may have a substituent in X is preferably a linear or branched alkyl group having 1 to 8 carbon atoms.
  • an ethyl group, an isopropyl group, and a tert-butyl group are preferable, and an isopropyl group is particularly preferable.
  • Examples of the alkenyl group optionally having a substituent represented by X include 1-alkenyl groups and 2-alkenyl groups having 2 to 30 carbon atoms. A 1-alkenyl group or 2-alkenyl group having 2 to 10 carbon atoms which may have a substituent is preferable.
  • Examples of the 1-alkenyl group include ethenyl group, isopropenyl group, 3-hydroxyprop-1-enyl group, 2-acetyl-ethenyl group, 2-phenyl-ethenyl group and the like.
  • Examples of the 2-alkenyl group include an allyl group and a but-2-enyl group.
  • Examples of the alkynyl group which may have a substituent represented by X include a 1-alkynyl group or a 2-alkynyl group having 2 to 30 carbon atoms. A 1-alkynyl group or a 2-alkynyl group having 2 to 10 carbon atoms which may have a substituent is preferable. Examples of the 1-alkynyl group include ethynyl group, 3,3-dimethylbut-1-ynyl group, 2-phenyl-ethynyl group, 2-trimethylsilyl-1-ethynyl group, and the like.
  • Examples of the 2-alkynyl group include prop-2-ynyl group, but-2-ynyl group, 3-phenylprop-2-ynyl group, 4,4-dimethylpent-2-ynyl group, and 3-trimethylsilylprop-2. -Inyl group and the like.
  • a 2-alkynyl group having 2 to 10 carbon atoms is preferable, and a prop-2-ynyl group or a but-2-ynyl group is particularly preferable.
  • Examples of the carbocyclic aryl group that may have a substituent represented by X include a phenyl group, a naphthyl group, a chlorophenyl group, and a methoxyphenyl group.
  • Examples of the heterocyclic aryl group optionally having a substituent represented by X include a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 2-quinolyl group, a 4-quinolyl group, and a 6-quinolyl group. Group, 2-pyrimidinyl group, 4-pyrimidinyl group, 2-furyl group, and the like.
  • the alkylthio group which may have a substituent represented by X represents an alkylthio group having 1 to 20 carbon atoms. Preferably, it is an alkylthio group having 1 to 8 carbon atoms which may have a substituent.
  • methylthio group, isopropylthio group, benzylthio group, phenylethylthio group, and the like can be mentioned.
  • the arylthio group which may have a substituent include a phenylthio group, a naphthylthio group, and a pyridylthio group.
  • the alkoxy group represented by X represents a primary, secondary or tertiary alkoxy group having 1 to 10 carbon atoms.
  • a primary alkoxy group such as a methoxy group, an ethoxy group, and a benzyloxy group
  • a secondary alkoxy group such as an isopropoxy group, a sec-butoxy group, and a tertiary alkoxy group such as a tert-butoxy group. It is done.
  • Examples of the aryloxy group represented by X include a phenoxy group, a naphthyloxy group, and a pyridyloxy group.
  • the aliphatic amino group which may have a substituent represented by X represents an acyclic primary amino group, an acyclic secondary amino group, or a cyclic secondary amino group.
  • the acyclic aliphatic primary amino group is an amino group in which a linear, branched, or cyclic alkyl group having 1 to 10 carbon atoms is N-monosubstituted. Examples thereof include a methylamino group, isopropylamino group, neopentylamino group, n-hexylamino group, cyclohexylamino group, n-octylamino group, and the like.
  • the acyclic aliphatic secondary amino group may be the same or different, and is an amino group in which a linear, branched, or cyclic alkyl group having 1 to 10 carbon atoms is N, N-disubstituted. It is. For example, dimethylamino group, diisopropylamino group, N-methyl-N-cyclohexylamino group and the like can be mentioned.
  • Examples of the cyclic aliphatic secondary amino group include a morpholino group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group.
  • the aromatic amino group optionally having a substituent represented by X represents an amino group in which the aromatic group is bonded to a nitrogen atom, such as a phenylamino group, an N-methyl-N-phenylamino group, N-methyl-N-pyridylamino group, diphenylamino group and the like can be mentioned.
  • Examples of the silyl group represented by X include trimethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, and the like.
  • the position of X on the 2,4-dihydroxyphenyl group may be any of 3, 5, and 6 positions, and may be mono-substituted, di-substituted, or tri-substituted.
  • Preferred substituents represented by X include a halogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or an alkynyl group which may have a substituent. It is. Among these, a linear or branched alkyl group having 1 to 8 carbon atoms or a 2-alkynyl group having 2 to 10 carbon atoms is particularly preferable. Specific examples of the particularly preferred substituent represented by X are an ethyl group, an isopropyl group, a tert-butyl group, a prop-2-ynyl group, and a but-2-ynyl group.
  • the substitution position of X on the 2,4-dihydroxyphenyl group is preferably the 5-position, and more preferably a 5-position mono-substituted product. That is, as a preferable example of the substituent represented by X, one kind selected from an ethyl group, an isopropyl group, a tert-butyl group, a prop-2-ynyl group, and a but-2-ynyl group is located at the 5-position. Examples include mono-substituted embodiments. Among these, an embodiment having an isopropyl group at the 5-position as the X group is particularly preferable.
  • the substituent represented by R is a carbocyclic aryl group that may have a substituent, a heterocyclic aryl group that may have a substituent, or an alkyl that may have a substituent.
  • examples of the carbocyclic aryl group include a phenyl group and a naphthyl group.
  • the carbocyclic aryl group which may have a substituent includes a carbocyclic aryl group having an alkyl group as a substituent, a carbocyclic aryl group having a halogen atom as a substituent, and a carbocyclic aryl having an alkoxy group as a substituent.
  • the carbocyclic aryl group having an alkyl group as the substituent is a carbocyclic aryl group in which at least one linear, branched or cyclic alkyl group having 1 to 30 carbon atoms is substituted.
  • Preferred is a phenyl group substituted by a linear or branched alkyl group having 1 to 8 carbon atoms.
  • the carbocyclic aryl group having a halogen atom as the substituent is a carbocyclic aryl group in which at least one halogen atom is substituted.
  • a monohalogen-substituted phenyl group or a dihalogen-substituted phenyl group is preferable. Examples include 2-chlorophenyl group, 4-chlorophenyl group, 2,4-dichlorophenyl group, 2-bromophenyl group, 4-bromophenyl group, 2,4-dibromophenyl group, and the like.
  • the carbocyclic aryl group having an alkoxy group as the substituent is a carbocyclic aryl group having at least one primary, secondary, or tertiary alkoxy group having 1 to 10 carbon atoms.
  • Examples thereof include a 4-methoxyphenyl group, a 3-methoxyphenyl group, a 3,4-dimethoxyphenyl group, and a 3,4-methylenedioxyphenyl group. Of these, a 4-methoxyphenyl group is preferable.
  • carbocyclic aryl group having an amino group as a substituent represented by R an unsubstituted amino group, an acyclic primary or secondary amino group, or a cyclic secondary amino group is substituted as the amino group.
  • examples thereof include a carbocyclic aryl group provided as a group.
  • examples of the non-cyclic primary amino group include a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, or an amino group substituted with an aryl group.
  • Examples thereof include a methylamino group, an isopropylamino group, a neopentylamino group, an n-hexylamino group, a cyclohexylamino group, an n-octylamino group, and a phenylamino group.
  • the acyclic secondary amino group may be the same or different and is a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, or an amino group in which an aryl group is N, N-disubstituted. It is a group.
  • Examples include dimethylamino group, diisopropylamino group, N-methyl-N-cyclohexylamino group, N-methyl-N-phenylamino group, N-methyl-N-pyridylamino group, diphenylamino group, and the like.
  • Examples of the cyclic secondary amino group include a morpholino group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group.
  • the amino group of the substituent is preferably an acyclic aliphatic primary or acyclic secondary amino group or a cyclic aliphatic secondary amino group. That is, preferred examples of the acyclic aliphatic primary amino group include a methylamino group, an isopropylamino group, a neopentylamino group, an n-hexylamino group, a cyclohexylamino group, and an n-octylamino group. it can.
  • Preferred examples of the acyclic aliphatic secondary amino group include a dimethylamino group, a diisopropylamino group, and an N-methyl-N-cyclohexylamino group.
  • Preferred examples of the cyclic aliphatic secondary amino group include a morpholino group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group. be able to.
  • Examples of the carbocyclic aryl group in the carbocyclic aryl group having an amino group as a substituent include a phenyl group and a naphthyl group.
  • the carbocyclic aryl group is preferably a phenyl group.
  • the substitution position of the amino group on the phenyl group is not particularly limited, and may be any substitution product at the 2-6 position. A substituted amino group at the 3-position or 4-position is preferred.
  • a preferred embodiment is a phenyl group in which an acyclic aliphatic secondary amino group is substituted at the 4-position, or a cyclic aliphatic secondary amino group at the 4-position.
  • Examples include substituted phenyl groups.
  • 4-dimethylaminophenyl group, 4- (morpholino) phenyl group, or 4- (4-methylpiperazin-1-yl) phenyl group is preferable.
  • the carbocyclic aryl group having an aminoalkyl group as a substituent represented by R includes, as the amino group, an unsubstituted amino group, an acyclic primary or acyclic secondary amino group, or a cyclic secondary group. And a carbocyclic aryl group substituted with an alkyl group having 1 to 8 carbon atoms having an amino group as a substituent.
  • Examples of the non-cyclic primary amino group include a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, or an amino group substituted with an aryl group.
  • Examples thereof include a methylamino group, an isopropylamino group, a neopentylamino group, an n-hexylamino group, a cyclohexylamino group, an n-octylamino group, and a phenylamino group.
  • the acyclic secondary amino group may be the same or different and is a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, or an amino group in which an aryl group is N, N-disubstituted. It is a group.
  • Examples include dimethylamino group, diisopropylamino group, N-methyl-N-cyclohexylamino group, N-methyl-N-phenylamino group, N-methyl-N-pyridylamino group, diphenylamino group, and the like.
  • Examples of the cyclic secondary amino group include a morpholino group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group.
  • the amino group of the substituent is preferably an acyclic aliphatic primary or acyclic secondary amino group or a cyclic aliphatic secondary amino group. That is, preferred examples of the acyclic aliphatic primary amino group include a methylamino group, an isopropylamino group, a neopentylamino group, an n-hexylamino group, a cyclohexylamino group, and an n-octylamino group. it can.
  • Preferred examples of the acyclic aliphatic secondary amino group include a dimethylamino group, a diisopropylamino group, and an N-methyl-N-cyclohexylamino group.
  • Preferred examples of the cyclic aliphatic secondary amino group include a morpholino group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group. be able to.
  • Examples of the alkyl group having 1 to 8 carbon atoms having an amino group as a substituent include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and an octyl group.
  • Examples of the carbocyclic aryl group having an aminoalkyl group as a substituent include a phenyl group and a naphthyl group.
  • the carbocyclic aryl group is preferably a phenyl group.
  • the substitution position of the aminoalkyl group on the phenyl group is not particularly limited, and may be any substitution product at the 2-6 position.
  • a substituted amino group at the 3-position or 4-position is preferred.
  • a preferred embodiment is that a cyclic aliphatic secondary amino group is substituted at the terminal position of the alkyl group having 1 to 5 carbon atoms, and the other terminal group is a phenyl group. In which the 4-position is substituted.
  • 4- (morpholinomethyl) phenyl group 4- (4-methylpiperazin-1-ylmethyl) phenyl group, 4- (2-morpholinoethyl) phenyl group, 4- [2- (4-methylpiperazine- 1-yl) ethyl] phenyl group, 4- (4-morpholinobutyl) phenyl group, 4- [5- (4-methylpiperazin-1-yl) pentyl] phenyl group.
  • a more preferred embodiment is 4- (morpholinomethyl) phenyl group or 4- (4-methylpiperazin-1-ylmethyl) phenyl group.
  • the heterocyclic aryl group which may have a substituent represented by R includes a pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, and a substituent.
  • Examples thereof include an oxazolyl group, an isoxazolyl group which may have a substituent, and a triazolyl group which may have a substituent.
  • a pyridyl group which may have a substituent a pyrimidinyl group which may have a substituent, an indolyl group which may have a substituent, an imidazolyl group which may have a substituent
  • a pyridyl group which may have a substituent a pyrimidinyl group which may have a substituent, and an indolyl group which may have a substituent.
  • preferred embodiments of the heterocyclic aryl group optionally having a substituent represented by R include a pyridyl group, a pyridyl group having an alkyl group as a substituent, and an amino group as a substituent.
  • Examples of the pyridyl group having an alkyl group as a substituent include 6-methylpyridin-2-yl group, 2-methylpyridin-4-yl group, 3-methylpyridin-2-yl group, 5-ethylpyridin-2-yl Group, 5-butylpyridin-3-yl group, and the like.
  • Examples of the pyridyl group having an amino group as a substituent include a 4-dimethylaminopyridin-2-yl group.
  • Examples of the pyrimidinyl group having an alkyl group as a substituent include a 2-methylpyrimidin-4-yl group and a 2-methylpyrimidin-3-yl group.
  • Examples of the pyrimidinyl group having an amino group as a substituent include 2-dimethylaminopyrimidin-4-yl group, 2-morpholinopyrimidin-4-yl group, and 2- (4-methylpiperazin-1-yl) pyrimidine-4- Yl group, and the like.
  • Examples of the indolyl group having an alkyl group as a substituent include a 1-methylindol-5-yl group and a 1-ethylindol-5-yl group.
  • the alkyl group which may have a substituent represented by R is a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms which may have a substituent.
  • a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent is preferable.
  • Examples of the linear alkyl group include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-hexyl group, an n-dodecyl group, an n-tetradecyl group, and an n-hexadecyl group.
  • Examples of the branched alkyl group include isopropyl group, tert-butyl group, 1-methyl-propyl group, 2-methyl-propyl group, 2,2-dimethylpropyl group, and the like.
  • Examples of the cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an adamantyl group, and the like.
  • Examples of the substituent in the alkyl group which may have a substituent include a hydroxyl group, a mercapto group, a halogen atom, a nitro group, a cyano group, a carbocyclic aryl group, a heterocyclic aryl group, an aliphatic or aromatic amino group, carbon Examples thereof include an alkylthio group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an aryloxy group, and a carboxyl group.
  • alkyl group which may have a substituent examples include ethyl, isopropyl, 2-methylpropyl, n-hexyl, cyclohexyl, 4-hydroxybutyl, 1,3- Dihydroxy-2-propyl group, 4-bromobutyl group, 2-methoxyethyl group, 1-methoxyethyl group, tetrahydrofuranylmethyl group, 2- (3-pyridyl) ethyl group, 4- (3-pyridyl) butyl group 2-morpholinoethyl group, 3-morpholinopropyl group, and the like.
  • the alkenyl group optionally having a substituent represented by R is an optionally substituted alkenyl group having 2 to 30 carbon atoms having a carbon-carbon double bond at any one or more positions.
  • a chain, branched or cyclic alkenyl group Preferably, it is a linear, branched or cyclic alkenyl group having 2 to 12 carbon atoms.
  • Specific examples of the alkenyl group include a 1-alkenyl group such as an ethenyl group, a prop-1-enyl group, or a but-1-enyl group, a but-2-enyl group, or a penta-2-enyl group, etc. Of 2-alkenyl groups.
  • Examples of the branched alkenyl group include an isopropenyl group, a 3-methylbut-1-enyl group, and a geranyl group.
  • Examples of the cyclic alkenyl group include a cyclohex-2-enyl group, a cyclohexa-2,5-dienyl group, a dicyclopentaenyl group, a dicyclopentadienyl group, and the like.
  • Examples of the substituent in the alkenyl group which may have a substituent include a hydroxyl group, mercapto group, halogen atom, nitro group, cyano group, carbocyclic aryl group, heterocyclic aryl group, aliphatic or aromatic amino group, carbon Examples thereof include an alkylthio group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an aryloxy group, and a carboxyl group. In the alkenyl group, these substituents may optionally be provided.
  • the alkynyl group which may have a substituent represented by R is an alkynyl group having 2 to 30 carbon atoms which may have a substituent and has a carbon-carbon triple bond at any one or more positions. Indicates.
  • An alkynyl group having 2 to 8 carbon atoms is preferable.
  • a 1-alkynyl group such as an ethynyl group, a prop-1-ynyl group, a 3,3-dimethylbut-1-ynyl group, or a 2-amino group such as a prop-2-ynyl group or a but-2-ynyl group
  • An alkynyl group is mentioned.
  • Examples of the substituent in the alkynyl group which may have a substituent include a hydroxyl group, a mercapto group, a halogen atom, a nitro group, a cyano group, a carbocyclic aryl group, a heterocyclic aryl group, an aliphatic or aromatic amino group, carbon Examples thereof include an alkylthio group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an aryloxy group, and a carboxyl group. In the alkynyl group, these substituents may optionally be provided.
  • Z 1 and Z 2 may be the same as or different from each other, and represent a hydrogen atom or a hydroxyl-protecting group.
  • the hydroxyl-protecting group represented by Z 1 and Z 2 is not particularly limited as long as it can later remove the Z 1 group and the Z 2 group to form a corresponding hydroxyl group.
  • Examples of the hydroxyl-protecting group for Z 1 and Z 2 include ether-type protecting groups, acetal-type protecting groups, thioacetal-type protecting groups, silyl-type protecting groups, and acyl-type protecting groups.
  • the ether-type protecting group is a hydroxyl-protecting group that forms an ether structure by bonding of a protecting group, and may be an alkyl group that may have a substituent or an alkenyl that may have a substituent. And an alkynyl group which may have a substituent.
  • ether-type protecting group examples include benzyl group, paramethoxybenzyl group, methyl group, tert-butyl group, allyl group, propargyl group, and the like.
  • a benzyl group, a paramethoxybenzyl group, a methyl group, and an allyl group are preferable.
  • the acetal-type protecting group is a hydroxyl-protecting group that forms an acetal structure or a ketal structure by bonding of a protecting group, and represents an optionally substituted alkoxy group having 1 to 10 carbon atoms.
  • An alkyl group substituted at the 1-position is shown.
  • Examples of the acetal type protecting group include a methoxymethyl group, 2-methoxyethoxymethyl group, 2- (trimethylsilyl) ethoxymethyl group, benzyloxymethyl group, 1-ethoxyethyl group, 1-methyl-1-methoxyethyl group, 1 -Methyl-1-benzyloxyethyl group, tetrahydropyranyl group, 4-methoxytetrahydropyranyl group and the like.
  • the thioacetal-type protecting group is a protecting group for a hydroxyl group that forms a thioacetal structure or a thioketal structure by bonding of a protecting group, and the alkylthio group having 1 to 10 carbon atoms that may have a substituent.
  • An alkyl group for substituting the group at the 1-position or a 1-arylthioalkyl group optionally having a substituent is shown.
  • Examples of the thioacetal type protecting group include a methylthiomethyl group and a phenylthiomethyl group.
  • the silyl-type protecting group is a hydroxyl-protecting group that forms a silyl ether structure by bonding of a protecting group, and has an alkyl group and / or a substituent that may have a substituent. And a silyl group substituted by an aryl group which may be positioned.
  • the silyl-type protecting group include trimethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, and the like.
  • the acyl-type protecting group is a hydroxyl-protecting group that forms an ester structure by bonding of a protecting group, and may have a substituent, an alkylcarbonyl group having 1 to 12 carbon atoms, or a carbon An arylcarbonyl group represented by formulas 7 to 16 is shown.
  • the acyl-type protecting group include acetyl group, trifluoroacetyl group, pivaloyl group, benzoyl group, 2-phenylacetyl group, and the like.
  • the hydroxyl protecting group represented by Z 1 and Z 2 is preferably a hydroxyl protecting group that does not leave under alkaline conditions. Accordingly, preferred protecting groups for hydroxyl groups in Z 1 and Z 2 include ether type protecting groups or acetal type protecting groups. As the hydroxyl-protecting group represented by Z 1 and Z 2 , an acetal-type protecting group is particularly preferable, and a methoxymethyl group and a benzyloxymethyl group are particularly preferable.
  • Y in the general formula (2) is an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a substituent.
  • the aryl group which may have a group is shown.
  • Examples of the alkyl group which may have a substituent represented by Y include linear, branched or cyclic alkyl groups having 1 to 30 carbon atoms. Preferred examples include linear, branched or cyclic alkyl groups having 1 to 20 carbon atoms.
  • Examples of the linear alkyl group include a methyl group, an ethyl group, an n-propyl group, an n-dodecyl group, an n-tetradecyl group, and an n-hexadecyl group.
  • Examples of the branched alkyl group include isopropyl group, tert-butyl group, 2,2-dimethylpropyl group, and the like.
  • Examples of the cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like.
  • alkenyl group which may have a substituent represented by Y examples include a linear, branched or cyclic alkenyl group having 2 to 30 carbon atoms and having a carbon-carbon double bond at any one or more positions. Can be mentioned. Preferably, a linear, branched or cyclic alkenyl group having 2 to 20 carbon atoms is used.
  • linear alkenyl group examples include 1-alkenyl groups such as ethenyl group, 1-propenyl group or 1-butenyl group, or 2-alkenyl groups such as 2-butenyl group or 2-pentenyl group.
  • Examples of the branched alkenyl group include an isopropenyl group, a 3-methyl-1-butenyl group, and a geranyl group.
  • alkynyl group which may have a substituent represented by Y examples include alkynyl groups having 2 to 30 carbon atoms having a carbon-carbon triple bond at any one or more positions.
  • An alkynyl group having 2 to 20 carbon atoms is preferable.
  • Examples thereof include 1-alkynyl groups such as ethynyl group, 1-propynyl group, 3,3-dimethyl-1-butynyl group, and 2-alkynyl groups such as 2-propynyl group and 2-butynyl group.
  • the aryl group which may have a substituent represented by Y represents a carbocyclic aryl group or a heterocyclic aryl group.
  • the carbocyclic aryl group include a phenyl group and a naphthyl group.
  • the heterocyclic aryl group include pyridyl group, pyrimidinyl group, quinolyl group, quinazolinyl group, naphthyridinyl group, furyl group, pyrrolyl group, indolyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, and the like. It is done.
  • Y is preferably a linear or branched alkyl group having 1 to 20 carbon atoms which may have a substituent.
  • substituents methyl group, ethyl group, n-propyl group, n-hexyl group, n-octyl group, n-dodecyl group, n-tetradecyl group, 3-methylbutyl group, 2-cyclohexylethyl group, benzyl group, 2-phenyl Examples thereof include an ethyl group and a 3-phenylpropyl group.
  • a linear alkyl group having 1 to 16 carbon atoms is particularly preferable, and a methyl group, an ethyl group, a propyl group, an n-hexyl group, an n-octyl group, or an n-dodecyl group is particularly preferable.
  • the details of [1,2,4] triazol-3-one in which a phenyl group substituted with an amino group) is substituted at the 4-position will be described.
  • the Xa group in the general formula (1a) is one selected from an ethyl group, an isopropyl group, and a tert-butyl group.
  • the Za 1 and Za 2 groups are hydroxyl protecting groups, and are ether type protecting groups or acetal type protecting groups.
  • the ether-type protecting group or the acetal-type protecting group has the same meaning as the ether-type protecting group and the acetal-type protecting group defined for the Z 1 group and Z 2 group in the general formula (1).
  • the Za 1 and Za 2 groups may be the same hydroxyl protecting group or may be different hydroxyl protecting groups.
  • A represents an aliphatic amino group.
  • the aliphatic amino group represented by A include an aliphatic primary amino group and an aliphatic secondary amino group.
  • Examples of the aliphatic primary amino group include N-alkylamino groups having a linear, branched or cyclic alkyl group having 1 to 8 carbon atoms. Examples thereof include a methylamino group, isopropylamino group, n-butylamino group, cyclohexylamino group, and the like.
  • Examples of the aliphatic secondary amino group include an N, N-dialkylamino group having a linear, branched or cyclic alkyl group having 1 to 8 carbon atoms, or a cyclic secondary amino group.
  • Examples of the N, N-dialkylamino group include dimethylamino group, diisopropylamino group, N-methyl-N-butylamino group, N-methyl-N-cyclohexylamino group, N, N-dicyclohexylamino group, and the like. It is done.
  • cyclic aliphatic secondary amino group examples include a morpholino group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group.
  • the aliphatic amino group represented by A is preferably a cyclic secondary amino group. Of these, a morpholino group or a 4-methylpiperazin-1-yl group is particularly preferable.
  • m represents an integer of 0 to 5. Among these, m is preferably 0 or 1.
  • a linear alkyl group having 1 to 16 carbon atoms is particularly preferable, and a methyl group, an ethyl group, an n-propyl group, an n-hexyl group, an n-octyl group, or an n-dodecyl group is particularly preferable.
  • the general formula (3) MW (3) [Wherein, M represents potassium, sodium or lithium, W represents an alkoxy group represented by O (Q1) or an amino group represented by N (Q2) (Q3), and the Q1 is secondary or 3 A base represented by a secondary alkyl group, wherein Q2 and Q3 may be the same as or different from each other, and represents an alkyl group or a trialkylsilyl group] is used.
  • M in the general formula (3) is an alkali metal and represents potassium, sodium or lithium.
  • W represents an alkoxy group represented by O (Q1) or an amino group represented by N (Q2) (Q3). That is, the base represented by the general formula (3) used in the present invention is an alkali metal alkoxide or an alkali metal amide.
  • the Q1 represents a secondary or tertiary alkyl group. Particularly preferred is a secondary or tertiary alkyl group having 3 to 6 carbon atoms.
  • Q1 include tert-butyl group, sec-butyl group, sec-pentyl group, 1,1-dimethylpropyl group, and isopropyl group. Of these, a tert-butyl group is particularly preferred.
  • the base represented by the general formula (3) is particularly preferably potassium tert-butoxide or sodium tert-butoxide.
  • Q2 and Q3 may be the same or different from each other, and may be an alkyl group or a trialkylsilyl group. Indicates.
  • the alkyl group represented by Q2 and Q3 is preferably a linear, branched or cyclic alkyl group having 1 to 8 carbon atoms. Examples thereof include a methyl group, an ethyl group, an isopropyl group, an n-butyl group, a cyclohexyl group, and the like. Of these, an isopropyl group is particularly preferable.
  • the trialkylsilyl group represented by Q2 and Q3 is preferably a trialkylsilyl group in which a linear or branched alkyl group having 1 to 8 carbon atoms is substituted with three silyl groups. , Trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, and the like. Of these, a trimethylsilyl group is preferable.
  • W is an amino group represented by N (Q2) (Q3)
  • lithium diisopropylamide or potassium hexamethyldisilazide is preferable.
  • the substituent represented by W is preferably an alkoxy group represented by O (Q1), and the base represented by the general formula (3) is potassium tert-butoxide or sodium tert-butoxide. Is particularly preferred.
  • the present invention provides a triazolyl sulfide derivative represented by the general formula (2) or a salt thereof (2) in an aprotic solvent in an amount of 1 equivalent or more of water relative to the triazolyl sulfide derivative or a salt thereof (2). , And the triazolyl sulfide derivative or a salt thereof (2) is mixed with a base represented by the general formula (3) in an excess equivalent to the equivalent of water, and reacted.
  • the mixing mode of the triazolyl sulfide derivative or a salt thereof (2), water and the base (3) is not particularly limited, and each of the triazolyl sulfide derivative or a salt thereof (2)
  • the present invention is achieved by including a step of mixing water and the base (3) in a solution of an aprotic solvent or a suspension thereof, and then a step of reacting.
  • the operation of mixing the triazolyl sulfide derivative or a salt thereof (2), water, and the base represented by the general formula (3) includes a solution of the aprotic solvent of the base (3).
  • the triazolyl sulfide derivative or the salt (2) is added as it is or as a solution or suspension of the aprotic solvent, and finally water is added.
  • the triazolyl sulfide derivative or a salt thereof (2) is used as it is or in an aprotic solvent thereof in a solution or suspension of the base (3) and water.
  • the operation which adds a solution or its suspension can be mentioned.
  • the base and water may be added to a solution of the triazolyl sulfide derivative or its salt (2) in an aprotic solvent, or a suspension thereof.
  • the amount of water added is a stoichiometric equivalent or more with respect to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof (2). It is necessary for that.
  • the amount of water added is 1 to 50 equivalents relative to the triazolyl sulfide derivative of the general formula (2) or a salt thereof.
  • the amount of the base (3) used increases accordingly.
  • a particularly preferable amount of water to be added is 1 to 30 equivalents relative to the triazolyl sulfide derivative or salt (2) thereof. More preferably, it is 1 to 10 equivalents.
  • the amount of the base represented by the general formula (3) to be added in the present invention is an excess equivalent to the addition equivalent of water to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof (2). It is necessary.
  • the addition amount of the base is preferably 1 equivalent or more in excess of the addition equivalent of water as a stoichiometric equivalent with respect to the triazolyl sulfide derivative or a salt thereof (2).
  • the addition amount of the base is 2 to 100 equivalents relative to the triazolyl sulfide derivative or salt thereof (2), and the equivalent amount of water relative to the triazolyl sulfide derivative or salt thereof (2). It is preferable that it is 1 equivalent or more and an excess equivalent.
  • the amount of the base added is particularly preferably 2 to 50 equivalents relative to the triazolyl sulfide derivative or salt (2), and more than the equivalent equivalent of water relative to the triazolyl sulfide derivative or salt (2). Is preferably 1 equivalent or more and excess equivalent.
  • a more preferable addition amount of the base is 2 to 20 equivalents with respect to the triazolyl sulfide derivative or a salt thereof (2), and from the addition equivalent of water to the triazolyl sulfide derivative or a salt thereof (2). Is also an excess equivalent of 1 equivalent or more.
  • the addition amount of water is 1 with respect to the triazolyl sulfide derivative or its salt (2).
  • the amount of the base represented by the general formula (3) is 2 to 100 equivalents relative to the triazolyl sulfide derivative or a salt thereof (2), and the amount of the base (3) added.
  • the combination which is more than the addition equivalent of the said water with respect to a triazolyl sulfide derivative or its salt (2) is preferable.
  • the addition amount of water is 1 to 50 equivalents relative to the triazolyl sulfide derivative or a salt thereof (2), and the addition amount of the base represented by formula (3) is the triazolyl sulfide derivative.
  • the addition amount of the base represented by formula (3) is the triazolyl sulfide derivative.
  • a combination of 2 to 100 equivalents with respect to the salt (2) and the addition equivalent of the base (3) being 1 to 30 equivalents more than the addition equivalent of water is particularly preferable.
  • the addition amount of water may be a triazolyl sulfide derivative or a salt thereof (2).
  • the amount of the base represented by the general formula (3) is 2 to 20 equivalents relative to the triazolyl sulfide derivative or a salt thereof (2), and the base (3 A combination in which the addition equivalent of 1) is 1 to 10 equivalents more than the addition equivalent of water is particularly preferred.
  • the reaction of the present invention uses an aprotic solvent as a reaction solvent.
  • the aprotic solvent used in the reaction of the present invention means a solvent having no proton donating property, and examples thereof include ether solvents, hydrocarbon solvents, halogen solvents and the like.
  • an ether solvent means a solvent having an ether structure, such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether, methylphenyl And ether, tert-butyl methyl ether, and the like.
  • hydrocarbon solvent examples include aliphatic hydrocarbon solvents such as pentane, n-hexane, cyclohexane, heptane, and petroleum ether, or aromatic hydrocarbon solvents such as benzene, toluene, and xylene.
  • halogen solvent examples include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like.
  • the reaction solvent of the present invention is not particularly limited as long as it is an aprotic solvent, but an ether solvent having a boiling point of 60 ° C. or higher is preferable.
  • tetrahydrofuran 1,4-dioxane, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether and the like can be mentioned.
  • an ether solvent having a boiling point of 80 ° C. or higher
  • 1,4-dioxane, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether, etc. can be mentioned as suitable reaction solvents. These may be used alone or as a mixed solvent.
  • the amount of aprotic solvent used is not particularly limited. However, it is preferable to use a solvent amount sufficient to dissolve all of the triazolyl sulfide derivative or a salt thereof (2) under the reaction conditions. That is, the aprotic solvent used in the present invention is preferably 1 to 100 parts by mass with respect to the triazolyl sulfide derivative or a salt thereof (2). More preferably, it is 2 to 50 parts by mass with respect to the triazolyl sulfide derivative or a salt thereof (2).
  • the reaction temperature of the present invention is not particularly limited as long as the reaction proceeds. However, in order to accelerate the reaction, it is preferable to carry out the reaction under heating conditions.
  • the reaction temperature is preferably 60 to 150 ° C. In particular, it is particularly preferable to conduct the reaction at 80 to 120 ° C. because the reaction time can be shortened and a sufficient reaction yield can be achieved.
  • 1,4-dioxane is used as an aprotic solvent, and water is used in an amount of 1 to 10 equivalents relative to the triazolyl sulfide derivative or a salt thereof (2).
  • dimethoxyethane is used as an aprotic solvent
  • water is used in an amount of 1 to 10 equivalents relative to the triazolyl sulfide derivative or a salt thereof (2)
  • potassium tert-butoxide is used as the base.
  • An example is a method in which 2 to 20 equivalents of the derivative or its salt (2) are used, and the potassium tert-butoxide is mixed in an excess of 1 to 10 equivalents with respect to the water.
  • bis (2-methoxyethyl) ether is used as an aprotic solvent
  • water is used in an amount of 1 to 10 equivalents relative to the triazolyl sulfide derivative or a salt thereof (2)
  • potassium tert- An example is a method in which butoxide is used in an amount of 2 to 20 equivalents relative to the triallyl sulfide derivative or a salt thereof (2), and the potassium tert-butoxide is mixed in an excess of 1 to 10 equivalents relative to the water.
  • the present invention easily converts the [1,2,4] triazol-3-one derivative (1) represented by the general formula (1), which is the target product, by simple aqueous post-treatment. Can be separated. That is, the reaction mixture can be treated with water and extracted with an organic solvent to isolate the desired product (1).
  • the isolated target product (1) may be subjected to a purification step such as chromatography or suspension purification, if necessary.
  • the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof is a triazolyl derivative represented by the general formula (2a) in an aprotic solvent also in the general formula (2a). 1 equivalent or more of water with respect to the sulfide derivative or a salt thereof, and the following general formula (3) in excess equivalent to the equivalent of the water with respect to the triazolyl sulfide derivative or a salt thereof represented by the general formula (2a)
  • a base represented by MW By treatment with a base represented by MW, the triazol-3-one derivative represented by the general formula (1a) or a salt thereof (1a) can be converted (Reaction Scheme 3).
  • the [1,2,4] triazol-3-one derivative represented by the general formula (7) or a salt (7) thereof is represented by the following general formula (7E) in the keto / enol tautomer relationship. It is obvious that the isomer structure represented can be taken, and the compound (7) and the compound (7E) are the same compound.
  • the Za 1 and Za 2 groups are hydroxyl protecting groups.
  • a [1,2,4] triazol-3-one derivative having a HSP90 inhibitory activity or a salt thereof (7a) [wherein Xa, A, m is synonymous with the definition in General Formula (1a) described above].
  • the [1,2,4] triazol-3-one derivative represented by the general formula (7a) or a salt (7a) thereof is represented by the following general formula (7aE) in the keto / enol tautomer relationship. It is obvious that the isomer structure represented can be taken, and the compound (7a) and the compound (7aE) are the same compound.
  • Z 1 radicals and Z 2 groups and deprotection reaction of Za 1 group and Za 2 groups, depending on the chemical reactivity of the protective group of the hydroxyl group, such as Z 1 radicals and Z 2 groups
  • Z 1 radicals and Z 2 groups are set as appropriate.
  • the Z 1 group and the Z 2 group are acetal type protecting groups.
  • the deprotection reaction can be performed by treatment under acidic conditions or treatment with trimethylsilyl bromide.
  • a treatment method using acidic conditions is employed.
  • the deprotection reaction when the Z 1 and Z 2 groups are methoxymethyl groups, specific examples of the deprotection reaction include hydrochloric acid-1,4-dioxane solution, hydrochloric acid-ethanol solution, or hydrochloric acid-isopropanol-tetrahydrofuran solution.
  • the deprotection reaction can be carried out by treating with.
  • the produced [1,2,4] triazol-3-one derivative (7) or (7a) is isolated by a known isolation operation, purified as necessary, optionally through a salt formation step, The product can be manufactured.
  • the triazolyl sulfide derivative represented by the general formula (2) which is a raw material compound of the present invention or a salt thereof can be prepared by a known method. For example, it can be synthesized according to the method described in Example 3-1 of Patent Document 1. That is, according to the following reaction formula 6, a substituent Y residue having a suitable leaving group such as a halogen atom in the presence of a base is added to the [1,2,4] triazole-3-thione derivative or its salt (4).
  • a triazolyl sulfide derivative or a salt thereof (2) can be prepared by reacting a reaction reagent having the same.
  • the triazolyl sulfide derivative represented by the general formula (2a) or a salt thereof can also be synthesized by the same method.
  • the [1,2,4] triazole-3-thione derivative or a salt thereof (4) can be prepared by a known method. For example, it can be synthesized according to the method described in Example 1-1 of Patent Document 1. That is, the [1,2,4] triazole-3-thione derivative or its salt (4) can be prepared by heat-treating thiosemicarbazide (8) under basic conditions according to the following reaction formula 7. .
  • Example 1-1 Under stirring at room temperature in an argon atmosphere, 3- (5-isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5- (n-dodecylthio) )-[1,2,4] triazole (2c) (12.74 g, 18.3 mmol) in dry 1,4-dioxane (127 mL) with potassium tert-butoxide (13.56 g, 120.8 mmol). The mixture was further stirred at room temperature for 15 minutes. Next, water (0.725 mL, 40.3 mmol) was added with stirring at room temperature, and the mixture was heated to reflux for 10 hours.
  • the extract (150 mL) was washed with brine (50 mL) and dried over anhydrous sodium sulfate to obtain an ethyl acetate solution (2).
  • the desiccants of the ethyl acetate solution (1) and the ethyl acetate solution (2) were removed by filtration, the filtrates were combined, and the solvent was distilled off under reduced pressure to obtain a pale yellow pasty crude product.
  • the crude product was purified by column chromatography (NH-silica gel, 500 mL) (elution solvent: ethyl acetate-methanol 49: 1 to 19: 1) to obtain 5027 mg of a white solid.
  • HPLC area ratio 99.7% (210 nm)
  • Elution solvent acetonitrile-1% H 3 PO 4 0-20 min: acetonitrile concentration 20 ⁇ 80%; 20-30 min: acetonitrile concentration 80%
  • a 0.5 mg sample was dissolved in acetonitrile (1 mL) -water (1 mL), and 10 ⁇ L was injected.
  • LC / MS retention time 4.403 minutes; Aspect ratio: 100.0% (210 nm); m / z (ESI, POS): 512 [M + H] + .
  • Example 1-2 Example 1-3, Example 1-4 3- (5-Isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5- (n-dodecylthio)-[1,2,4
  • the example which changed the equivalent ratio of water and a base in the hydrolysis reaction of this invention of triazole (2c) is shown.
  • Example 1-2 Under stirring at room temperature in an argon atmosphere, 3- (5-isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5- (n-dodecylthio) )-[1,2,4] triazole (2c)
  • a dry 1,4-dioxane solution of 1 molar equivalent part 10 molar equivalent part of potassium tert-butoxide is added to the compound (2c), Stir for minutes.
  • 7 molar equivalents of water was added to the compound (2c), and the mixture was heated to reflux for 4 hours.
  • the reaction solution was collected, and the raw material (2c) and the product (1bc) were quantitatively analyzed under the following HPLC conditions. The results are shown in Table 1.
  • Example 1-3 The same operation as in Example 1-2 was carried out under the same reaction conditions except that the amount of water added was 4 molar equivalents relative to the compound (2c).
  • Example 1-4 The same operation as in Example 1-2 was carried out under the same reaction conditions except that the amount of water added was 2 molar equivalents relative to the compound (2c).
  • Example 1-2 in which the amount of water added was 7 equivalents relative to the triazolyl sulfide derivative (2c) and potassium tert-butoxide as a base was used in an excess of 3 equivalents relative to the added water was relatively low.
  • the target compound [1,2,4] triazol-3-one (1bc) was produced at a moderate reaction rate.
  • Example 1-3 in which the amount of water added to the compound (2c) was 4 equivalents and potassium tert-butoxide was used in excess of 6 equivalents to the added water, and the amount of water added to the compound (2c) Is 1 equivalent, and potassium tert-butoxide is used in an excess of 8 equivalents with respect to the added water.
  • Example 1-4 has a relatively fast reaction rate and the target compound [1,2,4] triazol-3-one. (1bc) was produced. From the results of this reaction, it has been clarified that the production method of the present invention allows the reaction to proceed at a faster reaction rate as the excess equivalent of the added base increases.
  • Example 2 3- (5-Isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5-methylthio- [1,2,4] triazole (2b).
  • the hydrolysis reaction of the present invention was carried out using various reaction solvents.
  • Example 2-1 Under stirring at room temperature in an argon atmosphere, 3- (5-isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5-methylthio- [1 , 2,4] triazole (2b) (108 mg, 0.20 mmol) in dry 1,4-dioxane (2 mL) in potassium tert-butoxide (148 mg, 1.32 mmol) and water (0.0079 mL, 7 .9 mg, 0.44 mmol) was added, and the mixture was stirred at 100 ° C. for 6 hours.
  • the reaction mixture was added to cold water (13 mL), and 1N aqueous potassium hydrogen sulfate solution and 5% aqueous sodium hydrogen carbonate solution were added to adjust the pH to about 8. Further, an aqueous sodium chloride solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with an aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, solid potassium carbonate was added to the filtrate, and the mixture was stirred at room temperature for 50 minutes. Potassium carbonate was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product (100 mg).
  • Example 2-2 Under stirring at room temperature in an argon atmosphere, 3- (5-isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5-methylthio- [1 , 2,4] triazole (2b) (108 mg, 0.20 mmol) in dry tetrahydrofuran (THF; 2 mL), potassium tert-butoxide (148 mg, 1.32 mmol), and water (0.0079 mL, 7.9 mg). , 0.44 mmol), and stirred at room temperature for 20 hours and 45 minutes, and then heated to reflux for 15.5 hours. The LC / MS surface ratio of the reaction solution was 83.0% of the starting compound (2b) and 15.4% of the desired product (1bc).
  • Example 2-3 Using the reaction solution of Example 2-2, dry bis (2-methoxyethyl) ether (diglyme; 1 mL) and potassium tert-butoxide (148 mg, 1.32 mmol) were then added to the reaction solution, Stir for 5 hours. The LC / MS surface ratio of the reaction solution was 5% or less for the starting compound (2b) and 90% for the target product (1bc). The results of Examples 2-2 and 2-3 are summarized in Table 2 below.
  • Example 2-3 The reaction solution of Example 2-3 was added to cold water (12 mL), and 1N potassium hydrogen sulfate aqueous solution and 5% sodium hydrogen carbonate aqueous solution were added to adjust the pH to about 8. Further, an aqueous sodium chloride solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with an aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a pale yellow oil. N-Hexane (5 mL) was added to the obtained pale yellow oil, and the resulting suspension was stirred at room temperature for 4.5 hours.
  • 1N potassium hydrogen sulfate aqueous solution and 5% sodium hydrogen carbonate aqueous solution were added to adjust the pH to about 8. Further, an aqueous sodium chloride solution was added, and the mixture was extracted with ethyl acetate
  • Example 2-4 Under stirring at room temperature in an argon atmosphere, 3- (5-isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5-methylthio- [1 , 2,4] triazole (2b) (108 mg, 0.20 mmol) in a dry 1,2-dimethoxyethane (DME; 2 mL) solution in potassium tert-butoxide (148 mg, 1.32 mmol) and water (0. 0079 mL, 7.9 mg, 0.44 mmol) was added, and the mixture was heated to reflux for 8 hours.
  • DME 1,2-dimethoxyethane
  • Example 2 the examination of reaction conditions using various ether solvents in the aprotic solvent used as the reaction solvent of the present invention was shown.
  • Example 2-1 (1,4-dioxane / 100 ° C.)
  • Example 2-2 tetrahydrofuran / heated reflux
  • Example 2-3 bis (2-methoxyethyl) ether / 100 ° C.
  • Example 2 As a result of the reaction with -4 (1,2-dimethoxyethane / heated reflux), the reaction proceeded regardless of which reaction ether solvent was used, and the target product (1bc) was obtained. Therefore, an ether solvent is preferable as a suitable aprotic reaction solvent in the present invention.
  • Example 2 when the reaction temperature was 100 ° C.
  • 1,4-dioxane, bis (2-methoxyethyl) ether, and 1,2-dimethoxyethane which can be set at high temperature reaction conditions, are particularly preferred reaction solvents.
  • Comparative Example 1 The production method of Comparative Example 1 is reaction conditions using an aqueous sodium hydroxide solution as the water and base used in the present invention. Under the reaction conditions of Comparative Example 1, formation of the desired product (1bc) was not observed. Based on the results of Examples 1 and 2 and Comparative Example 1, the reaction for converting the triazolyl sulfide derivative (2b or 2c) to the [1,2,4] triazol-3-one derivative (1bc) This was a result that progressed when a strong base of potassium oxide or higher was used in an excess equivalent to the equivalent of added water. Examples according to the present invention are reaction conditions using potassium tert-butoxide as a base together with water.
  • the added water reacts with potassium tert-butoxide, is converted to potassium hydroxide, and is subjected to the reaction. That is, the reaction according to the present invention is characterized in that two types of bases of potassium hydroxide and potassium tert-butoxide are reacted with a triazolyl sulfide derivative (2b or 2c).
  • a triazolyl sulfide derivative (2b or 2c) Such special reaction conditions allow direct conversion of the triazolyl sulfide derivative (2b or 2c) to the [1,2,4] triazol-3-one derivative (1bc), which does not proceed in a normal alkaline hydrolysis reaction. It can be said that the reaction is progressing.
  • 1-iodododecane (8.6 mL, 10.3 g, 34.9 mmol) was added, and the mixture was stirred on an oil bath at a bath temperature of 50 ° C. (inner temperature: 44 to 47 ° C.) for 4 hours.
  • the solvent was evaporated under reduced pressure, water (72 mL) was added to the residue, and the mixture was extracted with ethyl acetate (72 mL, 36 mL).
  • the ethyl acetate extract was washed with 5% aqueous sodium thiosulfate solution (36 mL) and then with saturated brine (36 mL), and dried over anhydrous sodium sulfate.
  • HPLC area ratio 98.6% (254 nm)

Abstract

A triazol-3-one derivative (1) or a salt thereof, which is useful as an antitumor agent, can be produced from a triazolyl sulfide derivative (2) in a single step as shown by the reaction formula by processing the triazolyl sulfide derivative (2), in an aprotic solvent, with one equivalent weight or more of water with respect to the triazolyl sulfide derivative (2) or a salt thereof and a base (3) of a higher equivalent weight than the equivalent weight of water.

Description

トリアゾール－３－オン誘導体の新規な製造法Novel process for the preparation of triazol-3-one derivatives
　本発明は、ＨＳＰ９０阻害活性を有し抗癌剤として有用な［１，２，４］トリアゾール－３－オン誘導体またはその塩を短工程で効率的に製造する新規な製造法に関する。 The present invention relates to a novel production method for efficiently producing a [1,2,4] triazol-3-one derivative or a salt thereof having HSP90 inhibitory activity and useful as an anticancer agent in a short process.
　５－（２，４－ジヒドロキシフェニル）－［１，２，４］トリアゾール－３－オン誘導体がＨＳＰ９０阻害活性を有し、制癌剤として有望であることが報告されている。例えば特許文献１には、優れたＨＳＰ９０阻害活性を有し、動物実験においても優れた制癌活性を示す５－（２，４－ジヒドロキシフェニル）－［１，２，４］トリアゾール－３－オン誘導体が記載されている。また特許文献２及び３、並びに非特許文献１において、５－（２，４－ジヒドロキシフェニル）－［１，２，４］トリアゾール－３－オン誘導体またはそのプロドラッグが、ＨＳＰ９０阻害活性を有することが報告されている。これらの５－（２，４－ジヒドロキシフェニル）－［１，２，４］トリアゾール－３－オン誘導体の有用性に基づき、当該化合物誘導体のＨＳＰ９０阻害活性を利用した医薬品開発が進められている。このため、当該化合物を含有する医薬品の安定供給を可能とする、当該化合物の効率的な合成方法の開発が望まれている。 It has been reported that 5- (2,4-dihydroxyphenyl)-[1,2,4] triazol-3-one derivatives have HSP90 inhibitory activity and are promising as anticancer agents. For example, Patent Document 1 discloses 5- (2,4-dihydroxyphenyl)-[1,2,4] triazol-3-one that has excellent HSP90 inhibitory activity and also exhibits excellent anticancer activity in animal experiments. Derivatives are described. In Patent Documents 2 and 3 and Non-Patent Document 1, 5- (2,4-dihydroxyphenyl)-[1,2,4] triazol-3-one derivatives or prodrugs thereof have HSP90 inhibitory activity. Has been reported. Based on the usefulness of these 5- (2,4-dihydroxyphenyl)-[1,2,4] triazol-3-one derivatives, pharmaceutical development utilizing the HSP90 inhibitory activity of the compound derivatives is underway. For this reason, development of the efficient synthesis | combining method of the said compound which enables the stable supply of the pharmaceutical containing the said compound is desired.
　［１，２，４］トリアゾール－３－オン誘導体の合成法として、特許文献１には、下記反応式１で示されるように、［１，２，４］トリアゾール－３－チオン誘導体（４）を調製し、これから３工程を経由して、その［１，２，４］トリアゾール－３－オン誘導体に変換する合成法が開示されている。 As a method for synthesizing [1,2,4] triazol-3-one derivatives, Patent Document 1 discloses [1,2,4] triazol-3-thione derivatives (4) as shown in the following reaction formula 1. Has been disclosed, and is then converted into its [1,2,4] triazol-3-one derivative via three steps.
反応式１；
Figure JPOXMLDOC01-appb-C000009
 Reaction formula 1;
Figure JPOXMLDOC01-appb-C000009
　上記反応式１に従う製造方法は、出発物質である［１，２，４］トリアゾール－３－チオン誘導体（４）が合成容易であり、穏やかな条件下で、高収率で［１，２，４］トリアゾール環構築ができる利点がある。しかしながら、［１，２，４］トリアゾール－３－チオン誘導体（４）から［１，２，４］トリアゾール－３－オン誘導体（１）へ変換するためには、トリアゾリルスルフィド誘導体（２）を調製した後、該スルフォン誘導体（５）を経由することが必要であり、反応工程数が多いことが課題であった。また、該スルフォン誘導体（５）を製造するにあたり酸化反応を要するため、分子内に酸化され易い部分構造を有している場合、スルフォニル基の生成と同時に、その他の部位の置換基も酸化されることが問題になる。例えば、該トリアゾリルスルフィド誘導体（２）が分子内にアミノ基を有する場合、酸化反応によりスルフォニル基の生成と共に、Ｎ－オキシドの生成を伴う。このため、目的とするスルフォン誘導体（５）を得るためには、Ｎ－オキシド部分の選択的還元が必要になる。結果として、更に反応工程数が増え、操作が煩雑になり、収率にも悪影響を及ぼす課題があった。 In the production method according to the above reaction formula 1, the starting material [1,2,4] triazole-3-thione derivative (4) is easy to synthesize, and [1,2,2, 4] There is an advantage that a triazole ring can be constructed. However, in order to convert the [1,2,4] triazole-3-thione derivative (4) to the [1,2,4] triazol-3-one derivative (1), the triazolyl sulfide derivative (2) After the preparation, it was necessary to go through the sulfone derivative (5), and the number of reaction steps was a problem. In addition, since an oxidation reaction is required to produce the sulfone derivative (5), when the molecule has a partial structure that is easily oxidized, substituents at other sites are oxidized simultaneously with the formation of the sulfonyl group. It becomes a problem. For example, when the triazolyl sulfide derivative (2) has an amino group in the molecule, it is accompanied by generation of an N-oxide along with generation of a sulfonyl group by an oxidation reaction. Therefore, in order to obtain the desired sulfone derivative (5), selective reduction of the N-oxide moiety is necessary. As a result, the number of reaction steps is further increased, the operation becomes complicated, and there is a problem that adversely affects the yield.
国際公開第２００６／０９５７８３号International Publication No. 2006/095783 国際公開第２００９／０２３２１１号International Publication No. 2009/023211 国際公開第２００７／１３４６７８号International Publication No. 2007/134678
　本発明は、［１，２，４］トリアゾール－３－チオン誘導体から、短工程で効率的に［１，２，４］トリアゾール－３－オン誘導体を製造する製造法を提供することを課題とする。具体的には、前記反応式１で示される［１，２，４］トリアゾール－３－チオン誘導体（４）を、該トリアゾール－３－オン誘導体（１）に変換する反応に於いて、スルフォン誘導体（５）を経由することなく、該トリアゾリルスルフィド誘導体（２）から１工程で該［１，２，４］トリアゾール－３－オン誘導体（１）に変換する方法を提供することを課題とする。 An object of the present invention is to provide a production method for efficiently producing a [1,2,4] triazol-3-one derivative from a [1,2,4] triazol-3-thione derivative in a short process. To do. Specifically, in the reaction of converting the [1,2,4] triazole-3-thione derivative (4) represented by the reaction formula 1 into the triazol-3-one derivative (1), a sulfone derivative It is an object to provide a method for converting the triazolyl sulfide derivative (2) to the [1,2,4] triazol-3-one derivative (1) in one step without going through (5). To do.
　上記課題を解決するために本発明者らは鋭意研究を重ねた結果、下記反応式２に示すように、
反応式２；
Figure JPOXMLDOC01-appb-C000010
一般式（２）で表されるトリアゾリルスルフィド誘導体を、非プロトン性溶媒中、前記一般式（２）で表されるトリアゾリルスルフィド誘導体に対して１当量以上の水、及び前記一般式（２）で表されるトリアゾリルスルフィド誘導体に対する前記水の当量よりも過剰当量の下記一般式（３）
Ｍ－Ｗ　　（３）
［式中、Ｍはカリウム、ナトリウムまたはリチウムを示し、ＷはＯ（Ｑ１）で表されるアルコキシ基またはＮ（Ｑ２）（Ｑ３）で表されるアミノ基を示し、前記Ｑ１は２級または３級アルキル基を示し、前記Ｑ２及び前記Ｑ３は、互いに同じであっても異なっていてもよく、アルキル基またはトリアルキルシリル基を示す］で表される塩基を用いて処理することにより、前記トリアゾリルスルフォン誘導体（５）を経由することなく、該トリアゾリルスルフィド誘導体（２）から１工程で一般式（１）で表される該トリアゾール－３－オン誘導体に変換できることを見出し、本発明を完成した。 In order to solve the above problems, the present inventors have conducted extensive research, and as shown in the following reaction formula 2,
Reaction formula 2;
Figure JPOXMLDOC01-appb-C000010
The triazolyl sulfide derivative represented by the general formula (2) is used in an aprotic solvent in an amount of 1 equivalent or more of water relative to the triazolyl sulfide derivative represented by the general formula (2), and the general formula The following general formula (3) having an excess equivalent to the equivalent of water relative to the triazolyl sulfide derivative represented by (2)
MW (3)
[Wherein, M represents potassium, sodium or lithium, W represents an alkoxy group represented by O (Q1) or an amino group represented by N (Q2) (Q3), and the Q1 is secondary or 3 A trialkyl group, and Q2 and Q3 may be the same or different from each other and represent an alkyl group or a trialkylsilyl group]. It was found that the triazolyl sulfide derivative (2) can be converted into the triazol-3-one derivative represented by the general formula (1) in one step without going through the zolyl sulfone derivative (5). Was completed.
　すなわち、本発明は以下［１］乃至［１２］に示す発明を、その要旨とする。
　［１］下記一般式（１）
Figure JPOXMLDOC01-appb-C000011
［式中、Ｘは水素原子、ハロゲン原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、置換基を有していてもよい炭素環アリール基、置換基を有していてもよい複素環アリール基、置換基を有していてもよいアルキルチオ基、置換基を有していてもよいアリールチオ基，置換基を有していてもよいアルコキシ基、置換基を有していてもよいアリールオキシ基、置換基を有していてもよい脂肪族アミノ基、置換基を有していてもよい芳香族アミノ基またはシリル基を示し、
Ｒは置換基を有していてもよい炭素環アリール基、置換基を有していてもよい複素環アリール基、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基または置換基を有していてもよいアルキニル基を示し、
Ｚ１及びＺ２は、互いに同じであっても異なっていてもよく、水素原子または水酸基の保護基を示す］で表される［１，２，４］トリアゾール－３－オン誘導体またはその塩の製造法であって、
下記一般式（２）
Figure JPOXMLDOC01-appb-C000012
［式中Ｘ、Ｚ１、Ｚ２及びＲは、前記一般式（１）のＸ、Ｚ１、Ｚ２及びＲと同じ意味を表し、Ｙは、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基または置換基を有していてもよいアリール基を示す］で表されるトリアゾリルスルフィド誘導体またはその塩を、非プロトン性溶媒中、前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩に対して１当量以上の水、及び前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩に対する前記水の当量よりも過剰当量の下記一般式（３）
Ｍ－Ｗ　　（３）
［式中、Ｍはカリウム、ナトリウムまたはリチウムを示し、ＷはＯ（Ｑ１）で表されるアルコキシ基またはＮ（Ｑ２）（Ｑ３）で表されるアミノ基を示し、前記Ｑ１は２級または３級アルキル基を示し、前記Ｑ２及び前記Ｑ３は、互いに同じであっても異なっていてもよく、アルキル基またはトリアルキルシリル基を示す］で表される塩基で処理し、必要に応じて脱保護工程に付すことを含む、前記一般式（１）
で表されるトリアゾール－３－オン誘導体またはその塩の製造法。 That is, the gist of the present invention is the inventions shown in [1] to [12] below.
[1] The following general formula (1)
Figure JPOXMLDOC01-appb-C000011
[Wherein, X represents a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a substituent. A carbocyclic aryl group which may have a substituent, a heterocyclic aryl group which may have a substituent, an alkylthio group which may have a substituent, an arylthio group which may have a substituent, An alkoxy group which may have a substituent, an aryloxy group which may have a substituent, an aliphatic amino group which may have a substituent, an aromatic which may have a substituent Represents an amino group or a silyl group,
R may have a carbocyclic aryl group which may have a substituent, a heterocyclic aryl group which may have a substituent, an alkyl group which may have a substituent, or a substituent. A alkynyl group which may have a good alkenyl group or substituent,
Z 1 and Z 2 may be the same or different from each other, and each represents a hydrogen atom or a hydroxyl-protecting group] [1,2,4] triazol-3-one derivative or a salt thereof A manufacturing method,
The following general formula (2)
Figure JPOXMLDOC01-appb-C000012
[Wherein X, Z 1 , Z 2 and R represent the same meaning as X, Z 1 , Z 2 and R in the general formula (1), and Y represents an alkyl group which may have a substituent. Represents an alkenyl group which may have a substituent, an alkynyl group which may have a substituent or an aryl group which may have a substituent, or a triazolylsulfide derivative represented by In a non-protic solvent, the salt is 1 equivalent or more water relative to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof, and the triazolyl represented by the general formula (2). The following general formula (3) in excess equivalent to the equivalent of water relative to the sulfide derivative or salt thereof:
MW (3)
[Wherein, M represents potassium, sodium or lithium, W represents an alkoxy group represented by O (Q1) or an amino group represented by N (Q2) (Q3), and the Q1 is secondary or 3 A secondary alkyl group, Q2 and Q3 may be the same or different from each other and represent an alkyl group or a trialkylsilyl group], and deprotection as necessary Including the general formula (1)
A method for producing a triazol-3-one derivative represented by the formula:
　［２］前記一般式（３）において、ＷがＯ（Ｑ１）で表されるアルコキシ基であり、前記Ｑ１基がｔｅｒｔ－ブチル基、ｓｅｃ－ブチル基またはイソプロピル基である前記［１］に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 [2] In the above [1], in the general formula (3), W is an alkoxy group represented by O (Q1), and the Q1 group is a tert-butyl group, a sec-butyl group, or an isopropyl group. A process for producing a triazol-3-one derivative or a salt thereof.
　［３］前記一般式（３）において、ＷがＮ（Ｑ２）（Ｑ３）で表されるアミノ基であり、前記Ｑ２及び前記Ｑ３が共にイソプロピル基、または前記Ｑ２及び前記Ｑ３が共にトリメチルシリル基である前記［１］に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 [3] In the general formula (3), W is an amino group represented by N (Q2) (Q3), and both Q2 and Q3 are isopropyl groups, or both Q2 and Q3 are trimethylsilyl groups. A method for producing a triazol-3-one derivative or a salt thereof according to the above [1].
　［４］前記非プロトン性溶媒が沸点８０℃以上のエーテル溶媒である，前記［１］～［３］のいずれか１項に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 [4] The process for producing a triazol-3-one derivative or a salt thereof according to any one of [1] to [3], wherein the aprotic solvent is an ether solvent having a boiling point of 80 ° C. or higher.
　［５］前記水の添加量が、前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩に対し１～５０当量であり、前記一般式（３）で表される塩基の添加量が、前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩に対し２～１００当量である前記［１］～［４］のいずれか１項に記載に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 [5] The amount of water added is 1 to 50 equivalents to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof, and the base represented by the general formula (3) is added. The triazole-3 according to any one of [1] to [4], wherein the amount is 2 to 100 equivalents relative to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof. -A process for the production of ONE derivatives or their salts.
　［６］反応温度が６０℃から１５０℃である前記［１］～［５］のいずれか１項に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 [6] The process for producing a triazol-3-one derivative or a salt thereof according to any one of [1] to [5] above, wherein the reaction temperature is 60 ° C. to 150 ° C.
　［７］前記水の添加量が、前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩に対し１～１０当量であり、前記一般式（３）で表される塩基の添加量が、前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩に対し２～２０当量であり、且つ前記塩基の添加量が、前記水の添加量よりも１～１０当量過剰である前記［１］～［６］のいずれか１項に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 [7] The addition amount of the water is 1 to 10 equivalents relative to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof, and the addition of the base represented by the general formula (3) The amount is 2 to 20 equivalents relative to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof, and the added amount of the base is 1 to 10 equivalents more than the added amount of water. The method for producing a triazol-3-one derivative or a salt thereof according to any one of [1] to [6] above.
　［８］前記Ｙが、置換基を有していてもよい炭素数１～２０アルキル基である前記［１］～［７］に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 [8] The process for producing a triazol-3-one derivative or a salt thereof according to the above [1] to [7], wherein Y is an optionally substituted alkyl group having 1 to 20 carbon atoms.
　［９］前記Ｒが、置換基として脂肪族アミノ基を有する炭素環アリール基、置換基として脂肪族アミノアルキル基を有する炭素環アリール基、または置換基を有していてもよい複素環アリール基である前記［１］～［８］に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 [9] R is a carbocyclic aryl group having an aliphatic amino group as a substituent, a carbocyclic aryl group having an aliphatic aminoalkyl group as a substituent, or an optionally substituted heterocyclic aryl group The method for producing a triazol-3-one derivative or a salt thereof according to the above [1] to [8].
　［１０］前記［１］～［９］に記載のトリアゾール－３－オン誘導体またはその塩の製造法において、前記Ｚ１及び前記Ｚ２が水酸基の保護基である前記一般式（１）のトリアゾール－３－オン誘導体またはその塩を、更に、脱保護反応により前記Ｚ１及び前記Ｚ２を脱離させ、下記一般式（７）
Figure JPOXMLDOC01-appb-C000013
［式中、Ｘ、Ｒは前記一般式（１）のＸ、Ｒと同じ意味を表す］で表されるトリアゾール－３－オン誘導体またはその塩に変換する脱保護工程を含む、トリアゾール－３－オン誘導体またはその塩の製造法。 [10] In the method for producing a triazol-3-one derivative or a salt thereof according to the above [1] to [9], the triazole of the general formula (1), wherein Z 1 and Z 2 are hydroxyl protecting groups The 3-one derivative or a salt thereof is further desorbed from the Z 1 and Z 2 by a deprotection reaction, and the following general formula (7)
Figure JPOXMLDOC01-appb-C000013
[Wherein, X and R represent the same meaning as X and R in the general formula (1)], and include a deprotection step for converting to a triazol-3-one derivative or a salt thereof. A method for producing an on-derivative or a salt thereof.
　［１１］前記一般式（１）で表される［１，２，４］トリアゾール－３－オン誘導体またはその塩が、下記一般式（１ａ）
Figure JPOXMLDOC01-appb-C000014
［式中、Ｘａはエチル基、イソプロピル基またはｔｅｒｔ－ブチル基を示し、ｍは０乃至５を示し、Ａは脂肪族アミノ基を示し、Ｚａ１及びＺａ２は、エーテル型保護基またはアセタール型保護基を示す］で表わされる化合物またはその塩であり、
前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩が、下記一般式（２ａ）
Figure JPOXMLDOC01-appb-C000015
［式中、Ｘａはエチル基、イソプロピル基またはｔｅｒｔ－ブチル基を示し、Ｙａは置換基を有していてもよい炭素数１～２０アルキル基を示し、ｍは０乃至５を示し、Ａは脂肪族アミノ基を示し、Ｚａ１およびＺａ２はエーテル型保護基またはアセタール型保護基を示す］で表わされる化合物またはその塩である、
前記［１］～［９］のいずれか１項に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 [11] The [1,2,4] triazol-3-one derivative represented by the general formula (1) or a salt thereof is represented by the following general formula (1a)
Figure JPOXMLDOC01-appb-C000014
[Wherein, Xa represents an ethyl group, an isopropyl group or a tert-butyl group, m represents 0 to 5, A represents an aliphatic amino group, Za 1 and Za 2 represent an ether type protecting group or an acetal type. A compound represented by the formula:
The triazolyl sulfide derivative represented by the general formula (2) or a salt thereof is represented by the following general formula (2a)
Figure JPOXMLDOC01-appb-C000015
[Wherein, Xa represents an ethyl group, an isopropyl group or a tert-butyl group, Ya represents an optionally substituted alkyl group having 1 to 20 carbon atoms, m represents 0 to 5, and A represents An aliphatic amino group, and Za 1 and Za 2 represent an ether-type protecting group or an acetal-type protecting group] or a salt thereof.
The method for producing the triazol-3-one derivative or a salt thereof according to any one of [1] to [9].
　[１２]前記一般式（１）で表される［１，２，４］トリアゾール－３－オン誘導体またはその塩が、下記一般式（１ａ）
Figure JPOXMLDOC01-appb-C000016
［式中、Ｘａはエチル基、イソプロピル基またはｔｅｒｔ－ブチル基を示し、ｍは０乃至５を示し、Ａは脂肪族アミノ基を示し、Ｚａ１及びＺａ２はエーテル型保護基またはアセタール型保護基を示す］で表わされる化合物またはその塩であり、
前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩が、下記一般式（２ａ）
Figure JPOXMLDOC01-appb-C000017
［式中、Ｘａはエチル基、イソプロピル基またはｔｅｒｔ－ブチル基を示し、Ｙａは置換基を有していてもよい炭素数１～２０アルキル基を示し、ｍは０乃至５を示し、Ａは脂肪族アミノ基を示し、Ｚａ１及びＺａ２はエーテル型保護基またはアセタール型保護基を示す］で表わされる化合物またはその塩であり、
更に、前記一般式（７）で表される化合物またはその塩が、下記一般式（７ａ）
Figure JPOXMLDOC01-appb-C000018
［式中、Ｘａはエチル基、イソプロピル基またはｔｅｒｔ－ブチル基を示し、ｍは０乃至５を示し、Ａは脂肪族アミノ基を示す］でで表わされる化合物またはその塩である、前記[１０]に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 [12] The [1,2,4] triazol-3-one derivative represented by the general formula (1) or a salt thereof is represented by the following general formula (1a)
Figure JPOXMLDOC01-appb-C000016
[Wherein, Xa represents an ethyl group, an isopropyl group or a tert-butyl group, m represents 0 to 5, A represents an aliphatic amino group, Za 1 and Za 2 represent an ether type protecting group or an acetal type protecting group. Or a salt thereof,
The triazolyl sulfide derivative represented by the general formula (2) or a salt thereof is represented by the following general formula (2a)
Figure JPOXMLDOC01-appb-C000017
[Wherein, Xa represents an ethyl group, an isopropyl group or a tert-butyl group, Ya represents an optionally substituted alkyl group having 1 to 20 carbon atoms, m represents 0 to 5, and A represents An aliphatic amino group, Za 1 and Za 2 represent an ether-type protecting group or an acetal-type protecting group], or a salt thereof,
Further, the compound represented by the general formula (7) or a salt thereof is represented by the following general formula (7a):
Figure JPOXMLDOC01-appb-C000018
[Wherein Xa represents an ethyl group, an isopropyl group or a tert-butyl group, m represents 0 to 5, and A represents an aliphatic amino group] or a salt thereof [10 ] The manufacturing method of the triazol-3-one derivative or its salt as described in above.
　本発明により、［１，２，４］トリアゾール－３－オン誘導体またはその塩の効率的な製造方法が提供される。当該化合物は必要に応じ脱保護工程を経由し、優れたＨＳＰ９０阻害活性を有する５－（２，４－ジヒドロキシフェニル）－［１，２，４］トリアゾール－３－オン誘導体またはその塩に変換される。本発明により、優れたＨＳＰ９０阻害活性を有し、特に癌治療剤の有効成分として用いることができる５－（２，４－ジヒドロキシフェニル）－［１，２，４］トリアゾール－３－オン誘導体またはその薬理学的に許容される塩を、短工程で簡便に提供することが可能となる。 The present invention provides an efficient method for producing a [1,2,4] triazol-3-one derivative or a salt thereof. The compound is converted to a 5- (2,4-dihydroxyphenyl)-[1,2,4] triazol-3-one derivative or a salt thereof having excellent HSP90 inhibitory activity, if necessary, through a deprotection step. The According to the present invention, a 5- (2,4-dihydroxyphenyl)-[1,2,4] triazol-3-one derivative which has excellent HSP90 inhibitory activity and can be used particularly as an active ingredient of a cancer therapeutic agent or The pharmacologically acceptable salt can be conveniently provided in a short process.
　以下に本発明の詳細を述べる。
（用語の説明）
　本発明において、ハロゲン原子とは、フッ素原子、塩素原子、臭素原子、又はヨウ素原子を示す。 Details of the present invention will be described below.
(Explanation of terms)
In the present invention, the halogen atom represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
　本発明において、アルキル基とは特に記載しない場合は炭素数１～３０の直鎖状、分岐状、又は環状アルキル基を示す。直鎖状アルキル基としては、例えば、メチル基、エチル基、ｎ－プロピル基、ｎ－ブチル基、ｎ－へキシル基、ｎ―ドデシル基，ｎ－テトラデシル基，ｎ－ヘキサデシル基、等が挙げられる。分岐状アルキル基としては、例えば、イソプロピル基、ｔｅｒｔ－ブチル基、１－メチル－プロピル基、２－メチル－プロピル基、２，２－ジメチルプロピル基、等が挙げられる。環状アルキル基としては、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、アダマンチル基、等が挙げられる。 In the present invention, unless otherwise specified, an alkyl group means a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms. Examples of the linear alkyl group include methyl group, ethyl group, n-propyl group, n-butyl group, n-hexyl group, n-dodecyl group, n-tetradecyl group, n-hexadecyl group, and the like. It is done. Examples of the branched alkyl group include isopropyl group, tert-butyl group, 1-methyl-propyl group, 2-methyl-propyl group, 2,2-dimethylpropyl group, and the like. Examples of the cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an adamantyl group, and the like.
　本発明において、アルケニル基とはいずれか１カ所以上に炭素－炭素二重結合を有する、炭素数２～３０の直鎖状、分岐状、又は環状アルケニル基を示す。直鎖状アルケニル基としては、例えば、エテニル基、プロパ－１－エニル基又はブタ－1－エニル基、等の１－アルケニル基、若しくはブタ－２－エニル基、又はペンタ－２－エニル基、等の２－アルケニル基、等が挙げられる。分岐状アルケニル基としては、例えばイソプロペニル基、３－メチルブタ－１－エニル基、又はゲラニル基、等が挙げられる。環状アルケニル基としては、シクロヘキサ－２－エニル基、シクロヘキサ－２，５－ジエニル基、ジシクロペンタエニル基、ジシクロペンタジエニル基、等が挙げられる。 In the present invention, the alkenyl group means a linear, branched or cyclic alkenyl group having 2 to 30 carbon atoms having a carbon-carbon double bond at any one or more positions. Examples of the linear alkenyl group include 1-alkenyl groups such as ethenyl group, prop-1-enyl group or but-1-enyl group, but-2-enyl group, or penta-2-enyl group, 2-alkenyl groups such as and the like. Examples of the branched alkenyl group include an isopropenyl group, a 3-methylbut-1-enyl group, and a geranyl group. Examples of the cyclic alkenyl group include a cyclohex-2-enyl group, a cyclohexa-2,5-dienyl group, a dicyclopentaenyl group, a dicyclopentadienyl group, and the like.
　本発明において、アルキニル基とはいずれか１カ所以上に炭素－炭素三重結合を有する、炭素数２～３０のアルキニル基を示す。例えば、エチニル基、プロパ－１－イニル基、３，３－ジメチルブタ－１－イニル基、等の１－アルキニル基、若しくはプロパ－２－イニル基、ブタ－２－イニル基、等の２－アルキニル基、等が挙げられる。 In the present invention, the alkynyl group means an alkynyl group having 2 to 30 carbon atoms having a carbon-carbon triple bond at any one or more positions. For example, a 1-alkynyl group such as an ethynyl group, a prop-1-ynyl group, a 3,3-dimethylbut-1-ynyl group, or a 2-amino group such as a prop-2-ynyl group or a but-2-ynyl group An alkynyl group, and the like.
　本発明において、炭素環アリール基とは炭素数６～１０の炭素環アリール基を示し、例えば、フェニル基、ナフチル基、等が挙げられる。複素環アリール基とは、５員もしくは６員単環型複素環アリール基、５員と６員の縮合型複素環アリール基、または６員と６員の縮合型複素環アリール基を示し、例えば、ピリジル基、ピリミジニル基、キノリル基、キナゾリニル基、ナフチリジニル基、フリル基、ピロリル基、インドリル基、イミダゾリル基、ピラゾリル基、オキサゾリル基、イソキサゾリル基、トリアゾリル基、等が挙げられる。 In the present invention, the carbocyclic aryl group means a carbocyclic aryl group having 6 to 10 carbon atoms, and examples thereof include a phenyl group and a naphthyl group. The heterocyclic aryl group means a 5-membered or 6-membered monocyclic heterocyclic aryl group, a 5-membered and 6-membered condensed heterocyclic aryl group, or a 6-membered and 6-membered condensed heterocyclic aryl group, for example, , Pyridyl group, pyrimidinyl group, quinolyl group, quinazolinyl group, naphthyridinyl group, furyl group, pyrrolyl group, indolyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, and the like.
　本発明において、アルキルチオ基とは置換基を有していてもよい炭素数１～２０のアルキルチオ基を示し、例えば、メチルチオ基、イソプロピルチオ基、ベンジルチオ基，ドデシルチオ基、等が挙げられる。アリールチオ基とは、炭素数６～１０の炭素環アリールチオ基、５員もしくは６員単環型複素環アリールチオ基、５員と６員の縮合型複素環アリールチオ基、または６員と６員の縮合型複素環アリール基を示し、例えば、フェニルチオ基、ナフチルチオ基、ピリジルチオ基、等が挙げられる。 In the present invention, the alkylthio group means an alkylthio group having 1 to 20 carbon atoms which may have a substituent, and examples thereof include a methylthio group, an isopropylthio group, a benzylthio group, and a dodecylthio group. The arylthio group is a carbocyclic arylthio group having 6 to 10 carbon atoms, a 5-membered or 6-membered monocyclic heterocyclic arylthio group, a 5-membered and 6-membered condensed heterocyclic arylthio group, or a 6-membered and 6-membered condensed group. Type heterocyclic aryl group, for example, phenylthio group, naphthylthio group, pyridylthio group, and the like.
　本発明において、アルコキシ基とは置換基を有していてもよい炭素数１～１０のアルコキシ基を示す。例えば、メトキシ基、エトキシ基、ベンジルオキシ基、等の１級アルコキシ基、イソプロポキシ基、ｓｅｃ－ブトキシ基、等の２級アルコキシ基、若しくはｔｅｒｔ－ブトキシ基、等の３級アルコキシ基が挙げられる。アリールオキシ基としては、例えばフェノキシ基、ナフチルオキシ基、ピリジルオキシ基、等が挙げられる。 In the present invention, the alkoxy group means an alkoxy group having 1 to 10 carbon atoms which may have a substituent. Examples thereof include primary alkoxy groups such as methoxy group, ethoxy group, and benzyloxy group, secondary alkoxy groups such as isopropoxy group, sec-butoxy group, and tertiary alkoxy groups such as tert-butoxy group. . Examples of the aryloxy group include a phenoxy group, a naphthyloxy group, and a pyridyloxy group.
　本発明において、脂肪族アミノ基とは非環状の１級アミノ基または非環状の２級アミノ基、若しくは環状の２級アミノ基を示す。非環状の脂肪族１級アミノ基としては、炭素数１～１０の直鎖状、分岐状、または環状アルキル基がＮ－モノ置換したアミノ基である。例えば、メチルアミノ基、イソプロピルアミノ基、ネオペンチルアミノ基、ｎ－ヘキシルアミノ基、シクロヘキシルアミノ基、ｎ－オクチルアミノ基、等が挙げられる。非環状の脂肪族２級アミノ基としては、同一であっても異なっていてもよく、炭素数１～１０の直鎖状、分岐状、または環状アルキル基がＮ，Ｎ－ジ置換したアミノ基である。例えばジメチルアミノ基、ジイソプロピルアミノ基、Ｎ－メチル－Ｎ－シクロヘキシルアミノ基、等が挙げられる。環状の脂肪族２級アミノ基としては、モルフォリノ基、ピペラジン－１－イル基、４－メチルピペラジン－１－イル基、ピペリジン－１－イル基、ピロリジン－１－イル基、等が挙げられる。
　本発明において、芳香族アミノ基とは芳香族基が窒素原子に結合したアミノ基を示し、例えばフェニルアミノ基、Ｎ－メチル－Ｎ－フェニルアミノ基、Ｎ－メチル－Ｎ－ピリジルアミノ基、ジフェニルアミノ基、等が挙げられる。 In the present invention, the aliphatic amino group represents an acyclic primary amino group, an acyclic secondary amino group, or a cyclic secondary amino group. The acyclic aliphatic primary amino group is an amino group in which a linear, branched, or cyclic alkyl group having 1 to 10 carbon atoms is N-monosubstituted. Examples thereof include a methylamino group, isopropylamino group, neopentylamino group, n-hexylamino group, cyclohexylamino group, n-octylamino group, and the like. The acyclic aliphatic secondary amino group may be the same or different, and is an amino group in which a linear, branched, or cyclic alkyl group having 1 to 10 carbon atoms is N, N-disubstituted. It is. For example, dimethylamino group, diisopropylamino group, N-methyl-N-cyclohexylamino group and the like can be mentioned. Examples of the cyclic aliphatic secondary amino group include a morpholino group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group.
In the present invention, the aromatic amino group means an amino group in which an aromatic group is bonded to a nitrogen atom. For example, a phenylamino group, an N-methyl-N-phenylamino group, an N-methyl-N-pyridylamino group, a diphenylamino group Group, and the like.
　本発明において、シリル基とは、前記したアルキル基及び炭素環アリール基から選ばれる３つの基が置換したシリル基を示し、例えば、トリメチルシリル基、トリイソプロピルシリル基、ｔｅｒｔ－ブチルジメチルシリル基、ｔｅｒｔ－ブチルジフェニルシリル基、等が挙げられる。 In the present invention, the silyl group refers to a silyl group substituted with three groups selected from the aforementioned alkyl group and carbocyclic aryl group, such as a trimethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group, and a tert group. -Butyldiphenylsilyl group, and the like.
　本発明において、置換基を有していてもよい、と記載した場合の置換基としては、例えば、メルカプト基、水酸基、ハロゲン原子、ニトロ基、シアノ基、炭素数１～８アルキル基、炭素数２～１０アルケニル基、炭素数２～１０アルキニル基、炭素環または複素環アリール基、炭素数１～８アルキルチオ基、アリールチオ基、炭素数１～８アルキルスルフィニル基、アリールスルフィニル基、炭素数１～８アルキルスルホニル基、アリールスルホニル基、炭素数１～８アルコキシ基、アリールオキシ基、脂肪族又は芳香族アミノ基、脂肪族アミノ基が置換された炭素数１～８アルキル基、ホルミル基、アシル基、カルボキシル基、若しくはシリル基、等を挙げることができる。芳香環上の置換位置は、オルト位でも、メタ位でも、パラ位でもよい。
　本発明において、アルキルスルフィニル基としては、メチルスルフィニル基、エチルスルフィニル基、イソプロピルスルフィニル基、シクロヘキシルスルフィニル基、等が挙げられる。
　アリールスルフィニル基とは、炭素数６～１０の炭素環アリールスルフィニル基、５員もしくは６員単環型複素環アリールスルフィニル基、５員と６員の縮合型複素環アリールスルフィニル基、または６員と６員の縮合型複素環アリールスルフィニル基を示し、例えば、フェニルスルフィニル基、ナフチルスルフィニル基、等が挙げられる。
　アルキルスルフォニル基としては、メチルスルフォニル基、エチルスルフォニル基、イソプロピルスルフォニル基、シクロヘキシルスルフォニル基、等が挙げられる。
　アリールスルフォニル基とは、炭素数６～１０の炭素環アリールスルフォニル基、５員もしくは６員単環型複素環アリールスルフォニル基、５員と６員の縮合型複素環アリールスルフォニル基、または６員と６員の縮合型複素環アリールスルフォニル基を示し、例えば、フェニルスルフォニル基、ナフチルスルフォニル基、等が挙げられる。
　アシル基とは、炭素数２～１０の脂肪族もしくは芳香族アシル基を示し、例えば、アセチル基、ベンゾイル基、ピバロイル基、等が挙げられる。 In the present invention, examples of the substituent when it is described that it may have a substituent include a mercapto group, a hydroxyl group, a halogen atom, a nitro group, a cyano group, a C 1-8 alkyl group, a carbon number 2 to 10 alkenyl group, 2 to 10 alkynyl group, carbocyclic or heterocyclic aryl group, 1 to 8 alkylthio group, arylthio group, 1 to 8 alkylsulfinyl group, arylsulfinyl group, 1 to carbon atom 8 alkylsulfonyl group, arylsulfonyl group, alkoxy group having 1 to 8 carbon atoms, aryloxy group, aliphatic or aromatic amino group, alkyl group having 1 to 8 carbon atoms substituted with aliphatic amino group, formyl group, acyl group , Carboxyl group, silyl group, and the like. The substitution position on the aromatic ring may be ortho, meta, or para.
In the present invention, examples of the alkylsulfinyl group include a methylsulfinyl group, an ethylsulfinyl group, an isopropylsulfinyl group, a cyclohexylsulfinyl group, and the like.
The arylsulfinyl group is a carbocyclic arylsulfinyl group having 6 to 10 carbon atoms, a 5-membered or 6-membered monocyclic heterocyclic arylsulfinyl group, a 5-membered and 6-membered condensed heterocyclic arylsulfinyl group, or a 6-membered A 6-membered condensed heterocyclic arylsulfinyl group is exemplified, and examples thereof include a phenylsulfinyl group and a naphthylsulfinyl group.
Examples of the alkyl sulfonyl group include a methyl sulfonyl group, an ethyl sulfonyl group, an isopropyl sulfonyl group, a cyclohexyl sulfonyl group, and the like.
The arylsulfonyl group is a C6-C10 carbocyclic arylsulfonyl group, a 5-membered or 6-membered monocyclic heterocyclic arylsulfonyl group, a 5-membered and 6-membered condensed heterocyclic arylsulfonyl group, or a 6-membered A 6-membered condensed heterocyclic arylsulfonyl group is exemplified, and examples thereof include a phenylsulfonyl group and a naphthylsulfonyl group.
The acyl group means an aliphatic or aromatic acyl group having 2 to 10 carbon atoms, and examples thereof include an acetyl group, a benzoyl group, and a pivaloyl group.
　本発明において塩とは、酸の添加により生成する塩、または塩基の添加により生成する塩を示す。酸の添加により生成する塩としては、例えば、硫酸塩、硝酸塩、過塩素酸塩、リン酸塩、炭酸塩、重炭酸塩、フッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩などの無機酸塩；酢酸塩、シュウ酸塩、マレイン酸塩、酒石酸塩、フマル酸塩、クエン酸塩などの有機カルボン酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、カンファースルホン酸塩などの有機スルホン酸塩；アスパラギン酸塩、グルタミン酸塩などのアミノ酸塩等が挙げられる。塩基の添加により生成する塩としては、例えばアンモニウム塩、アミノ酸塩などのアミン塩；ナトリウム塩、カリウム塩などのアルカリ金属塩；マグネシウム塩、カルシウム塩などのアルカリ土類金属塩等が挙げられる。 In the present invention, the salt refers to a salt produced by adding an acid or a salt produced by adding a base. Examples of the salt generated by the addition of acid include sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, hydrofluoride, hydrochloride, hydrobromide, and iodide. Inorganic acid salts such as hydrogenates; Organic carboxylates such as acetate, oxalate, maleate, tartrate, fumarate, citrate; methanesulfonate, trifluoromethanesulfonate, ethanesulfone Organic sulfonates such as acid salts, benzene sulfonates, toluene sulfonates and camphor sulfonates; and amino acid salts such as aspartates and glutamates. Examples of the salt produced by the addition of a base include amine salts such as ammonium salts and amino acid salts; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts.
（一般式中の置換基の説明）
　本発明において、［１，２，４］トリアゾールとは、前記一般式（１）において、カルボニル基が該トリアゾール環骨格に組み込まれている位置を３位とし、前記Ｒ基の置換位置を４位とし、４位にＺ１Ｏ基、２位にＺ２Ｏ基が置換し、更にＸ基を備えるフェニル基が配する位置を５位とする［１，２，４］トリアゾールである。
　前記一般式（１）で表される化合物（１）は、ケト－エノール互変異性体が存在し、下記一般式（１Ｅ）で示される異性体構造を取り得る。すなわち本発明において、前記（１）及び（１Ｅ）は同一化合物である。したがって、本発明は、一般式（１Ｅ）の製造法も包含するものである。 (Description of substituents in general formula)
In the present invention, [1,2,4] triazole means that in the general formula (1), the position where the carbonyl group is incorporated in the triazole ring skeleton is the 3-position, and the substitution position of the R group is the 4-position. and then, Z 1 O group in the 4-position, 2-position Z 2 O group is replaced by a further [1,2,4] triazole to position the 5-position of the phenyl group is disposed with a X group.
The compound (1) represented by the general formula (1) has a keto-enol tautomer and can have an isomer structure represented by the following general formula (1E). That is, in the present invention, (1) and (1E) are the same compound. Therefore, the present invention also includes the production method of the general formula (1E).
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
　本発明において、Ｘで表される置換基は、水素原子、ハロゲン原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、置換基を有していてもよい炭素環アリール基、置換基を有していてもよい複素環アリール基、置換基を有していてもよいアルキルチオ基、置換基を有していてもよいアリールチオ基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアリールオキシ基、置換基を有していてもよい脂肪族アミノ基、置換基を有していてもよい芳香族アミノ基、またはシリル基を示す。 In the present invention, the substituent represented by X has a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent. An alkynyl group which may have a substituent, a carbocyclic aryl group which may have a substituent, a heterocyclic aryl group which may have a substituent, an alkylthio group which may have a substituent, and a substituent An arylthio group which may have a substituent, an alkoxy group which may have a substituent, an aryloxy group which may have a substituent, an aliphatic amino group which may have a substituent, and a substituent. An aromatic amino group or a silyl group that may be present.
　Ｘで表される置換基を有していてもよいアルキル基としては、炭素数１～３０の直鎖状、分岐状又は環状アルキル基である。好ましくは置換基を有していてもよい炭素数１～１０の直鎖状、分岐状又は環状アルキル基である。例えばメチル基、エチル基、イソプロピル基、ｔｅｒｔ－ブチル基、２，２－ジメチルプロピル基、シクロプロピル基、Ｎ，Ｎ－ジメチルアミノメチル基、Ｎ，Ｎ－ジメチルアミノエチル基、モルホリニルメチル基、ピペリジニルメチル基、ヒドロキシメチル基、１－ヒドロキシエチル基、２－ヒドロキシエチル基、１－ヒドロキシ－１－メチル－エチル基、メトキシエチル基、メトキシメチル基、ベンジル基、２－フェニルエチル基、ピリジルメチル基、等を挙げることができる。Ｘにおける置換基を有していてもよいアルキル基としては、炭素数１～８の直鎖状または分岐状アルキル基が好ましい。中でもエチル基、イソプロピル基、ｔｅｒｔ－ブチル基が好ましく、イソプロピル基が特に好ましい。 The alkyl group which may have a substituent represented by X is a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms. Preferably, it is a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent. For example, methyl group, ethyl group, isopropyl group, tert-butyl group, 2,2-dimethylpropyl group, cyclopropyl group, N, N-dimethylaminomethyl group, N, N-dimethylaminoethyl group, morpholinylmethyl group Piperidinylmethyl group, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxy-1-methyl-ethyl group, methoxyethyl group, methoxymethyl group, benzyl group, 2-phenylethyl group , Pyridylmethyl group, and the like. The alkyl group which may have a substituent in X is preferably a linear or branched alkyl group having 1 to 8 carbon atoms. Of these, an ethyl group, an isopropyl group, and a tert-butyl group are preferable, and an isopropyl group is particularly preferable.
　Ｘで表される置換基を有していてもよいアルケニル基としては、炭素数２～３０の１－アルケニル基または２－アルケニル基が挙げられる。好ましくは置換基を有していてもよい炭素数２～１０の１－アルケニル基または２－アルケニル基である。１－アルケニル基としては、例えばエテニル基、イソプロペニル基、３－ヒドロキシプロパ－１－エニル基、２－アセチル－エテニル基、２－フェニル－エテニル基、等が挙げられる。２－アルケニル基としては、例えばアリル基、ブタ－２－エニル基、等が挙げられる。 Examples of the alkenyl group optionally having a substituent represented by X include 1-alkenyl groups and 2-alkenyl groups having 2 to 30 carbon atoms. A 1-alkenyl group or 2-alkenyl group having 2 to 10 carbon atoms which may have a substituent is preferable. Examples of the 1-alkenyl group include ethenyl group, isopropenyl group, 3-hydroxyprop-1-enyl group, 2-acetyl-ethenyl group, 2-phenyl-ethenyl group and the like. Examples of the 2-alkenyl group include an allyl group and a but-2-enyl group.
　Ｘで表される置換基を有していてもよいアルキニル基としては、炭素数２～３０の１－アルキニル基または２－アルキニル基が挙げられる。好ましくは置換基を有していてもよい炭素数２～１０の１－アルキニル基または２－アルキニル基である。１－アルキニル基としては、例えばエチニル基、３，３－ジメチルブタ－１－イニル基、２－フェニル－エチニル基、２－トリメチルシリル－１－エチニル基、等が挙げられる。２－アルキニル基としては、例えばプロパ－２－イニル基、ブタ－２－イニル基、３－フェニルプロパ－２－イニル基、４，４－ジメチルペンタ－２－イニル基、３－トリメチルシリルプロパ－２－イニル基、等が挙げられる。炭素数２～１０の２－アルキニル基が好ましく、プロパ－２－イニル基またはブタ－２－イニル基が特に好ましい。 Examples of the alkynyl group which may have a substituent represented by X include a 1-alkynyl group or a 2-alkynyl group having 2 to 30 carbon atoms. A 1-alkynyl group or a 2-alkynyl group having 2 to 10 carbon atoms which may have a substituent is preferable. Examples of the 1-alkynyl group include ethynyl group, 3,3-dimethylbut-1-ynyl group, 2-phenyl-ethynyl group, 2-trimethylsilyl-1-ethynyl group, and the like. Examples of the 2-alkynyl group include prop-2-ynyl group, but-2-ynyl group, 3-phenylprop-2-ynyl group, 4,4-dimethylpent-2-ynyl group, and 3-trimethylsilylprop-2. -Inyl group and the like. A 2-alkynyl group having 2 to 10 carbon atoms is preferable, and a prop-2-ynyl group or a but-2-ynyl group is particularly preferable.
　Ｘで表される置換基を有していてもよい炭素環アリール基としては、例えばフェニル基、ナフチル基、クロロフェニル基、メトキシフェニル基、等が挙げられる。
　Ｘで表される置換基を有していてもよい複素環アリール基としては、例えば２－ピリジル基、３－ピリジル基、４－ピリジル基、２－キノリル基、４－キノリル基、６－キノリル基、２－ピリミジニル基、４－ピリミジニル基、２－フリル基、等が挙げられる。 Examples of the carbocyclic aryl group that may have a substituent represented by X include a phenyl group, a naphthyl group, a chlorophenyl group, and a methoxyphenyl group.
Examples of the heterocyclic aryl group optionally having a substituent represented by X include a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 2-quinolyl group, a 4-quinolyl group, and a 6-quinolyl group. Group, 2-pyrimidinyl group, 4-pyrimidinyl group, 2-furyl group, and the like.
　Ｘで表される置換基を有していてもよいアルキルチオ基としては、炭素数１～２０のアルキルチオ基を示す。好ましくは置換基を有していてもよい炭素数１～８のアルキルチオ基である。例えばメチルチオ基、イソプロピルチオ基、ベンジルチオ基、フェニルエチルチオ基、等が挙げられる。
　置換基を有していてもよいアリールチオ基としては、例えばフェニルチオ基、ナフチルチオ基、ピリジルチオ基、等が挙げられる。 The alkylthio group which may have a substituent represented by X represents an alkylthio group having 1 to 20 carbon atoms. Preferably, it is an alkylthio group having 1 to 8 carbon atoms which may have a substituent. For example, methylthio group, isopropylthio group, benzylthio group, phenylethylthio group, and the like can be mentioned.
Examples of the arylthio group which may have a substituent include a phenylthio group, a naphthylthio group, and a pyridylthio group.
　Ｘで表されるアルコキシ基としては、炭素数１～１０の１級、２級、３級アルコキシ基を示す。例えば、メトキシ基、エトキシ基、ベンジルオキシ基、等の１級アルコキシ基、またはイソプロポキシ基、ｓｅｃ－ブトキシ基、等の２級アルコキシ基、若しくはｔｅｒｔ－ブトキシ基、等の３級アルコキシ基が挙げられる。
　Ｘで表されるアリールオキシ基としては、例えばフェノキシ基、ナフチルオキシ基、ピリジルオキシ基、等が挙げられる。 The alkoxy group represented by X represents a primary, secondary or tertiary alkoxy group having 1 to 10 carbon atoms. For example, a primary alkoxy group such as a methoxy group, an ethoxy group, and a benzyloxy group, or a secondary alkoxy group such as an isopropoxy group, a sec-butoxy group, and a tertiary alkoxy group such as a tert-butoxy group. It is done.
Examples of the aryloxy group represented by X include a phenoxy group, a naphthyloxy group, and a pyridyloxy group.
　Ｘで表される置換基を有していてもよい脂肪族アミノ基とは、非環状の１級アミノ基または非環状の２級アミノ基、若しくは環状の２級アミノ基を示す。非環状の脂肪族１級アミノ基としては、炭素数１～１０の直鎖状、分岐状、または環状アルキル基がＮ－モノ置換したアミノ基である。例えば、メチルアミノ基、イソプロピルアミノ基、ネオペンチルアミノ基、ｎ－ヘキシルアミノ基、シクロヘキシルアミノ基、ｎ－オクチルアミノ基、等が挙げられる。非環状の脂肪族２級アミノ基としては、同一であっても異なっていてもよく、炭素数１～１０の直鎖状、分岐状、または環状アルキル基がＮ，Ｎ－ジ置換したアミノ基である。例えばジメチルアミノ基、ジイソプロピルアミノ基、Ｎ－メチル－Ｎ－シクロヘキシルアミノ基、等が挙げられる。環状の脂肪族２級アミノ基としては、モルフォリノ基、ピペラジン－１－イル基、４－メチルピペラジン－１－イル基、ピペリジン－１－イル基、ピロリジン－１－イル基、等が挙げられる。
　Ｘで表される置換基を有していてもよい芳香族アミノ基としては、芳香族基が窒素原子に結合したアミノ基を示し、例えばフェニルアミノ基、Ｎ－メチル－Ｎ－フェニルアミノ基、Ｎ－メチル－Ｎ－ピリジルアミノ基、ジフェニルアミノ基、等が挙げられる。 The aliphatic amino group which may have a substituent represented by X represents an acyclic primary amino group, an acyclic secondary amino group, or a cyclic secondary amino group. The acyclic aliphatic primary amino group is an amino group in which a linear, branched, or cyclic alkyl group having 1 to 10 carbon atoms is N-monosubstituted. Examples thereof include a methylamino group, isopropylamino group, neopentylamino group, n-hexylamino group, cyclohexylamino group, n-octylamino group, and the like. The acyclic aliphatic secondary amino group may be the same or different, and is an amino group in which a linear, branched, or cyclic alkyl group having 1 to 10 carbon atoms is N, N-disubstituted. It is. For example, dimethylamino group, diisopropylamino group, N-methyl-N-cyclohexylamino group and the like can be mentioned. Examples of the cyclic aliphatic secondary amino group include a morpholino group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group.
The aromatic amino group optionally having a substituent represented by X represents an amino group in which the aromatic group is bonded to a nitrogen atom, such as a phenylamino group, an N-methyl-N-phenylamino group, N-methyl-N-pyridylamino group, diphenylamino group and the like can be mentioned.
　Ｘで表されるシリル基としては、例えば、トリメチルシリル基、トリイソプロピルシリル基、ｔｅｒｔ－ブチルジメチルシリル基，ｔｅｒｔ－ブチルジフェニルシリル基、等が挙げられる。 Examples of the silyl group represented by X include trimethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, and the like.
　２，４－ジヒドロキシフェニル基上のＸの位置は、３、５、６位の何れでもよく、モノ置換、ジ置換、トリ置換のいずれでもよい。 The position of X on the 2,4-dihydroxyphenyl group may be any of 3, 5, and 6 positions, and may be mono-substituted, di-substituted, or tri-substituted.
　Ｘで表される好ましい置換基としては、ハロゲン原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、若しくは置換基を有していてもよいアルキニル基である。中でも、炭素数１～８の直鎖状または分岐状のアルキル基、若しくは炭素数２～１０の２－アルキニル基が特に好ましい。特に好ましいＸで表される置換基の具体例としては、エチル基、イソプロピル基、ｔｅｒｔ－ブチル基、プロパ－２－イニル基またはブタ－２－イニル基である。
　２，４－ジヒドロキシフェニル基上のＸの置換位置は５位が好ましく、５位モノ置換体であることがより好ましい。すなわち、Ｘで表される置換基の好適な例としては、５位にエチル基、イソプロピル基、ｔｅｒｔ－ブチル基、プロパ－２－イニル基またはブタ－２－イニル基から選択される１種がモノ置換された態様が挙げられる。中でもＸ基として、５位にイソプロピル基を備えた態様が特に好ましい。 Preferred substituents represented by X include a halogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or an alkynyl group which may have a substituent. It is. Among these, a linear or branched alkyl group having 1 to 8 carbon atoms or a 2-alkynyl group having 2 to 10 carbon atoms is particularly preferable. Specific examples of the particularly preferred substituent represented by X are an ethyl group, an isopropyl group, a tert-butyl group, a prop-2-ynyl group, and a but-2-ynyl group.
The substitution position of X on the 2,4-dihydroxyphenyl group is preferably the 5-position, and more preferably a 5-position mono-substituted product. That is, as a preferable example of the substituent represented by X, one kind selected from an ethyl group, an isopropyl group, a tert-butyl group, a prop-2-ynyl group, and a but-2-ynyl group is located at the 5-position. Examples include mono-substituted embodiments. Among these, an embodiment having an isopropyl group at the 5-position as the X group is particularly preferable.
　本発明においてＲで表される置換基は、置換基を有していてもよい炭素環アリール基、置換基を有していてもよい複素環アリール基、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、又は置換基を有していてもよいアルキニル基を示す。 In the present invention, the substituent represented by R is a carbocyclic aryl group that may have a substituent, a heterocyclic aryl group that may have a substituent, or an alkyl that may have a substituent. A group, an alkenyl group which may have a substituent, or an alkynyl group which may have a substituent;
　Ｒで表される置換基を有していてもよい炭素環アリール基において、炭素環アリール基としては、フェニル基、ナフチル基が挙げられる。置換基を有していてもよい炭素環アリール基としては、置換基としてアルキル基を有する炭素環アリール基、置換基としてハロゲン原子を有する炭素環アリール基、置換基としてアルコキシ基を有する炭素環アリール基、置換基としてアミノ基を有する炭素環アリール基、または置換基としてアミノアルキル基を有する炭素環アリール基が挙げられる。 In the carbocyclic aryl group optionally having a substituent represented by R, examples of the carbocyclic aryl group include a phenyl group and a naphthyl group. The carbocyclic aryl group which may have a substituent includes a carbocyclic aryl group having an alkyl group as a substituent, a carbocyclic aryl group having a halogen atom as a substituent, and a carbocyclic aryl having an alkoxy group as a substituent. And a carbocyclic aryl group having an amino group as a substituent, or a carbocyclic aryl group having an aminoalkyl group as a substituent.
　前記置換基としてアルキル基を有する炭素環アリール基としては、炭素数１～３０の直鎖状、分岐状、又は環状アルキル基が少なくとも１つ以上を置換する炭素環アリール基である。好ましくは炭素数１～８の直鎖状、又は分岐状アルキル基が置換するフェニル基である。例えば、２－メチルフェニル基、４－メチルフェニル基、３－イソプロピルフェニル基、４－イソプロピルフェニル基、ｎ－ヘキシルフェニル基、ｎ－オクチルフェニル基、１－エチルプロピルフェニル基、２－メチルプロピルフェニル基、等が挙げられる。
　前記置換基としてハロゲン原子を有する炭素環アリール基としては、少なくとも１つ以上のハロゲン原子が置換された炭素環アリール基である。好ましくはモノハロゲン置換フェニル基、またはジハロゲン置換フェニル基である。例えば２－クロロフェニル基、４－クロロフェニル基、２，４－ジクロロフェニル基、２－ブロモフェニル基、４－ブロモフェニル基、２，４－ジブロモフェニル基、等が挙げられる。
　前記置換基としてアルコキシ基を有する炭素環アリール基としては、少なくとも１つ以上の炭素数１～１０の１級、２級、または３級アルコキシ基を有する炭素環アリール基である。例えば、４－メトキシフェニル基、３－メトキシフェニル基、３，４－ジメトキシフェニル基、３，４－メチレンジオキシフェニル基が挙げられる。中でも４－メトキシフェニル基が好ましい。 The carbocyclic aryl group having an alkyl group as the substituent is a carbocyclic aryl group in which at least one linear, branched or cyclic alkyl group having 1 to 30 carbon atoms is substituted. Preferred is a phenyl group substituted by a linear or branched alkyl group having 1 to 8 carbon atoms. For example, 2-methylphenyl group, 4-methylphenyl group, 3-isopropylphenyl group, 4-isopropylphenyl group, n-hexylphenyl group, n-octylphenyl group, 1-ethylpropylphenyl group, 2-methylpropylphenyl Group, and the like.
The carbocyclic aryl group having a halogen atom as the substituent is a carbocyclic aryl group in which at least one halogen atom is substituted. A monohalogen-substituted phenyl group or a dihalogen-substituted phenyl group is preferable. Examples include 2-chlorophenyl group, 4-chlorophenyl group, 2,4-dichlorophenyl group, 2-bromophenyl group, 4-bromophenyl group, 2,4-dibromophenyl group, and the like.
The carbocyclic aryl group having an alkoxy group as the substituent is a carbocyclic aryl group having at least one primary, secondary, or tertiary alkoxy group having 1 to 10 carbon atoms. Examples thereof include a 4-methoxyphenyl group, a 3-methoxyphenyl group, a 3,4-dimethoxyphenyl group, and a 3,4-methylenedioxyphenyl group. Of these, a 4-methoxyphenyl group is preferable.
　Ｒで表される置換基としてアミノ基を有する炭素環アリール基としては、前記アミノ基として、無置換のアミノ基、非環状の１級または２級アミノ基、若しくは環状の２級アミノ基を置換基として備える炭素環アリール基が挙げられる。
　置換基として備わる前記アミノ基において、非環状の１級アミノ基としては、炭素数１～１０の直鎖状、分岐状または環状アルキル基、若しくはアリール基が置換したアミノ基が挙げられる。例えばメチルアミノ基、イソプロピルアミノ基、ネオペンチルアミノ基、ｎ－ヘキシルアミノ基、シクロヘキシルアミノ基、ｎ－オクチルアミノ基、フェニルアミノ基、等が挙げられる。
　非環状の２級アミノ基としては、同一てあっても異なっていてもよく、炭素数１～１０の直鎖状、分岐状または環状アルキル基、若しくはアリール基がＮ，Ｎ－ジ置換したアミノ基である。例えばジメチルアミノ基、ジイソプロピルアミノ基、Ｎ－メチル－Ｎ－シクロヘキシルアミノ基、Ｎ－メチル－Ｎ－フェニルアミノ基、Ｎ－メチル－Ｎ－ピリジルアミノ基、ジフェニルアミノ基、等が挙げられる。
　環状の２級アミノ基としては、モルフォリノ基、ピペラジン－１－イル基、４－メチルピペラジン－１－イル基、ピペリジン－１－イル基、ピロリジン－１－イル基、等が挙げられる。 As the carbocyclic aryl group having an amino group as a substituent represented by R, an unsubstituted amino group, an acyclic primary or secondary amino group, or a cyclic secondary amino group is substituted as the amino group. Examples thereof include a carbocyclic aryl group provided as a group.
In the amino group provided as a substituent, examples of the non-cyclic primary amino group include a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, or an amino group substituted with an aryl group. Examples thereof include a methylamino group, an isopropylamino group, a neopentylamino group, an n-hexylamino group, a cyclohexylamino group, an n-octylamino group, and a phenylamino group.
The acyclic secondary amino group may be the same or different and is a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, or an amino group in which an aryl group is N, N-disubstituted. It is a group. Examples include dimethylamino group, diisopropylamino group, N-methyl-N-cyclohexylamino group, N-methyl-N-phenylamino group, N-methyl-N-pyridylamino group, diphenylamino group, and the like.
Examples of the cyclic secondary amino group include a morpholino group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group.
　前記置換基のアミノ基は、非環状の脂肪族１級または非環状の２級アミノ基、若しくは環状の脂肪族２級アミノ基が好ましい。すなわち、非環状の脂肪族１級アミノ基としては、メチルアミノ基、イソプロピルアミノ基、ネオペンチルアミノ基、ｎ－ヘキシルアミノ基、シクロヘキシルアミノ基、ｎ－オクチルアミノ基、を好ましい例として挙げることができる。非環状の脂肪族２級アミノ基としては、ジメチルアミノ基、ジイソプロピルアミノ基、Ｎ－メチル－Ｎ－シクロヘキシルアミノ基を好ましい例として挙げる事ができる。環状の脂肪族２級アミノ基としては、モルフォリノ基、ピペラジン－１－イル基、４－メチルピペラジン－１－イル基、ピペリジン－１－イル基、ピロリジン－１－イル基、を好ましい例として挙げることができる。
　置換基としてアミノ基を有する炭素環アリール基における、炭素環アリール基としてはフェニル基またはナフチル基が挙げられる。炭素環アリール基としてはフェニル基が好ましい。該フェニル基上のアミノ基の置換位置は特に限定されるものではなく、２～６位の何れの置換体であってよい。３位または４位のアミノ基置換体が好ましい。
　置換基としてアミノ基を有する炭素環アリール基において、好ましい態様としては、４位に非環状の脂肪族２級アミノ基が置換されたフェニル基、または４位に環状の脂肪族２級アミノ基が置換されたフェニル基が挙げられる。特に４－ジメチルアミノフェニル基、４－（モルフォリノ）フェニル基、または４－（４－メチルピペラジン－１－イル）フェニル基が好ましい。 The amino group of the substituent is preferably an acyclic aliphatic primary or acyclic secondary amino group or a cyclic aliphatic secondary amino group. That is, preferred examples of the acyclic aliphatic primary amino group include a methylamino group, an isopropylamino group, a neopentylamino group, an n-hexylamino group, a cyclohexylamino group, and an n-octylamino group. it can. Preferred examples of the acyclic aliphatic secondary amino group include a dimethylamino group, a diisopropylamino group, and an N-methyl-N-cyclohexylamino group. Preferred examples of the cyclic aliphatic secondary amino group include a morpholino group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group. be able to.
Examples of the carbocyclic aryl group in the carbocyclic aryl group having an amino group as a substituent include a phenyl group and a naphthyl group. The carbocyclic aryl group is preferably a phenyl group. The substitution position of the amino group on the phenyl group is not particularly limited, and may be any substitution product at the 2-6 position. A substituted amino group at the 3-position or 4-position is preferred.
In the carbocyclic aryl group having an amino group as a substituent, a preferred embodiment is a phenyl group in which an acyclic aliphatic secondary amino group is substituted at the 4-position, or a cyclic aliphatic secondary amino group at the 4-position. Examples include substituted phenyl groups. In particular, 4-dimethylaminophenyl group, 4- (morpholino) phenyl group, or 4- (4-methylpiperazin-1-yl) phenyl group is preferable.
　Ｒで表される置換基としてアミノアルキル基を有する炭素環アリール基としては、前記アミノ基として、無置換のアミノ基、非環状の１級または非環状の２級アミノ基、若しくは環状の２級アミノ基を置換基として有する炭素数１～８アルキル基が置換した炭素環アリール基が挙げられる。
　非環状の１級アミノ基としては、炭素数１～１０の直鎖状、分岐状または環状アルキル基、若しくはアリール基が置換したアミノ基が挙げられる。例えばメチルアミノ基、イソプロピルアミノ基、ネオペンチルアミノ基、ｎ－ヘキシルアミノ基、シクロヘキシルアミノ基、ｎ－オクチルアミノ基、フェニルアミノ基、等が挙げられる。
　非環状の２級アミノ基としては、同一てあっても異なっていてもよく、炭素数１～１０の直鎖状、分岐状または環状アルキル基、若しくはアリール基がＮ，Ｎ－ジ置換したアミノ基である。例えばジメチルアミノ基、ジイソプロピルアミノ基、Ｎ－メチル－Ｎ－シクロヘキシルアミノ基、Ｎ－メチル－Ｎ－フェニルアミノ基、Ｎ－メチル－Ｎ－ピリジルアミノ基、ジフェニルアミノ基、等が挙げられる。
　環状の２級アミノ基としては、モルフォリノ基、ピペラジン－１－イル基、４－メチルピペラジン－１－イル基、ピペリジン－１－イル基、ピロリジン－１－イル基、等が挙げられる。 The carbocyclic aryl group having an aminoalkyl group as a substituent represented by R includes, as the amino group, an unsubstituted amino group, an acyclic primary or acyclic secondary amino group, or a cyclic secondary group. And a carbocyclic aryl group substituted with an alkyl group having 1 to 8 carbon atoms having an amino group as a substituent.
Examples of the non-cyclic primary amino group include a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, or an amino group substituted with an aryl group. Examples thereof include a methylamino group, an isopropylamino group, a neopentylamino group, an n-hexylamino group, a cyclohexylamino group, an n-octylamino group, and a phenylamino group.
The acyclic secondary amino group may be the same or different and is a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, or an amino group in which an aryl group is N, N-disubstituted. It is a group. Examples include dimethylamino group, diisopropylamino group, N-methyl-N-cyclohexylamino group, N-methyl-N-phenylamino group, N-methyl-N-pyridylamino group, diphenylamino group, and the like.
Examples of the cyclic secondary amino group include a morpholino group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group.
　前記置換基のアミノ基は、非環状の脂肪族１級または非環状の２級アミノ基、若しくは環状の脂肪族２級アミノ基が好ましい。すなわち、非環状の脂肪族１級アミノ基としては、メチルアミノ基、イソプロピルアミノ基、ネオペンチルアミノ基、ｎ－ヘキシルアミノ基、シクロヘキシルアミノ基、ｎ－オクチルアミノ基、を好ましい例として挙げることができる。非環状の脂肪族２級アミノ基としては、ジメチルアミノ基、ジイソプロピルアミノ基、Ｎ－メチル－Ｎ－シクロヘキシルアミノ基を好ましい例として挙げる事ができる。環状の脂肪族２級アミノ基としては、モルフォリノ基、ピペラジン－１－イル基、４－メチルピペラジン－１－イル基、ピペリジン－１－イル基、ピロリジン－１－イル基、を好ましい例として挙げることができる。
　前記アミノ基を置換基として有する炭素数１～８アルキル基としては、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、オクチル基、等を挙げることができる。
　置換基としてアミノアルキル基を有する炭素環アリール基としては、フェニル基またはナフチル基が挙げられる。炭素環アリール基としてはフェニル基が好ましい。該フェニル基上の、アミノアルキル基の置換位置は特に限定されるものではなく、２～６位の何れの置換体であってよい。３位または４位のアミノ基置換体が好ましい。
　置換基としてアミノアルキル基を有する炭素環アリール基において、好ましい態様としては、炭素数１～５アルキル基の末端位に環状の脂肪族２級アミノ基が置換され、もう一方の末端基がフェニル基の４位に置換された態様が挙げられる。特に、４－（モルフォリノメチル）フェニル基、４－（４－メチルピペラジン－１－イルメチル）フェニル基、４－（２－モルフォリノエチル）フェニル基、４－［２－（４－メチルピペラジン－１－イル）エチル］フェニル基、４－（４－モルフォリノブチル）フェニル基、４－［５－（４－メチルピペラジン－１－イル）ペンチル］フェニル基である。更に好ましい態様としては、４－（モルフォリノメチル）フェニル基、または４－（４－メチルピペラジン－１－イルメチル）フェニル基である。 The amino group of the substituent is preferably an acyclic aliphatic primary or acyclic secondary amino group or a cyclic aliphatic secondary amino group. That is, preferred examples of the acyclic aliphatic primary amino group include a methylamino group, an isopropylamino group, a neopentylamino group, an n-hexylamino group, a cyclohexylamino group, and an n-octylamino group. it can. Preferred examples of the acyclic aliphatic secondary amino group include a dimethylamino group, a diisopropylamino group, and an N-methyl-N-cyclohexylamino group. Preferred examples of the cyclic aliphatic secondary amino group include a morpholino group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group. be able to.
Examples of the alkyl group having 1 to 8 carbon atoms having an amino group as a substituent include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and an octyl group.
Examples of the carbocyclic aryl group having an aminoalkyl group as a substituent include a phenyl group and a naphthyl group. The carbocyclic aryl group is preferably a phenyl group. The substitution position of the aminoalkyl group on the phenyl group is not particularly limited, and may be any substitution product at the 2-6 position. A substituted amino group at the 3-position or 4-position is preferred.
In the carbocyclic aryl group having an aminoalkyl group as a substituent, a preferred embodiment is that a cyclic aliphatic secondary amino group is substituted at the terminal position of the alkyl group having 1 to 5 carbon atoms, and the other terminal group is a phenyl group. In which the 4-position is substituted. In particular, 4- (morpholinomethyl) phenyl group, 4- (4-methylpiperazin-1-ylmethyl) phenyl group, 4- (2-morpholinoethyl) phenyl group, 4- [2- (4-methylpiperazine- 1-yl) ethyl] phenyl group, 4- (4-morpholinobutyl) phenyl group, 4- [5- (4-methylpiperazin-1-yl) pentyl] phenyl group. A more preferred embodiment is 4- (morpholinomethyl) phenyl group or 4- (4-methylpiperazin-1-ylmethyl) phenyl group.
　Ｒで表される置換基を有していてもよい複素環アリール基としては、置換基を有していてもよいピリジル基、置換基を有していてもよいピリミジニル基、置換基を有していても良いキノリル基、置換基を有していてもよいキナゾリニル基、置換基を有していてもよいナフチリジニル基、置換基を有していてもよいフリル基、置換基を有していてもよいピロリル基、置換基を有していてもよいインドリル基、置換基を有していてもよいイミダゾリル基、置換基を有していてもよいピラゾリル基、置換基を有していてもよいオキサゾリル基、置換基を有していてもよいイソキサゾリル基、置換基を有していてもよいトリアゾリル基、等が挙げられる。好ましくは、置換基を有していてもよいピリジル基、置換基を有していてもよいピリミジニル基、置換基を有していてもよいインドリル基、置換基を有していてもよいイミダゾリル基を挙げることができる。特に好ましくは置換基を有していてもよいピリジル基、置換基を有していてもよいピリミジニル基、置換基を有していてもよいインドリル基である。 The heterocyclic aryl group which may have a substituent represented by R includes a pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, and a substituent. A quinolyl group which may have a substituent, a quinazolinyl group which may have a substituent, a naphthyridinyl group which may have a substituent, a furyl group which may have a substituent, and a substituent. May have a pyrrolyl group, an indolyl group which may have a substituent, an imidazolyl group which may have a substituent, a pyrazolyl group which may have a substituent, or a substituent. Examples thereof include an oxazolyl group, an isoxazolyl group which may have a substituent, and a triazolyl group which may have a substituent. Preferably, a pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, an indolyl group which may have a substituent, an imidazolyl group which may have a substituent Can be mentioned. Particularly preferred are a pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, and an indolyl group which may have a substituent.
　すなわち、本発明における、Ｒで表される置換基を有していてもよい複素環アリール基の好ましい態様としては、ピリジル基、置換基としてアルキル基を有するピリジル基、置換基としてアミノ基を有するピリジル基、ピリミジニル基、置換基としてアルキル基を有するピリミジニル基、置換基としてアミノ基を有するピリミジニル基、インドリル基、置換基としてアルキル基を有するインドリル基、である。
　置換基としてアルキル基を有するピリジル基としては、６－メチルピリジン－２－イル基、２－メチルピリジン－４－イル基、３－メチルピリジン－２－イル基、５－エチルピリジン－２－イル基、５－ブチルピリジン－３－イル基、等が挙げられる。置換基としてアミノ基を有するピリジル基としては、４－ジメチルアミノピリジン－２－イル基、等が挙げられる。置換基としてアルキル基を有するピリミジニル基としては、２－メチルピリミジン－４－イル基、２－メチルピリミジン－３－イル基、等が挙げられる。置換基としてアミノ基を有するピリミジニル基としては、２－ジメチルアミノピリミジン－４－イル基、２－モルフォリノピリミジン－４－イル基、２－（４－メチルピペラジン－１－イル）ピリミジン－４－イル基、等が挙げられる。置換基としてアルキル基を有するインドリル基としては、１－メチルインドール－５－イル基、１－エチルインドール－５－イル基、等が挙げられる。 That is, in the present invention, preferred embodiments of the heterocyclic aryl group optionally having a substituent represented by R include a pyridyl group, a pyridyl group having an alkyl group as a substituent, and an amino group as a substituent. A pyrimidinyl group having an alkyl group as a substituent, a pyrimidinyl group having an amino group as a substituent, an indolyl group, and an indolyl group having an alkyl group as a substituent.
Examples of the pyridyl group having an alkyl group as a substituent include 6-methylpyridin-2-yl group, 2-methylpyridin-4-yl group, 3-methylpyridin-2-yl group, 5-ethylpyridin-2-yl Group, 5-butylpyridin-3-yl group, and the like. Examples of the pyridyl group having an amino group as a substituent include a 4-dimethylaminopyridin-2-yl group. Examples of the pyrimidinyl group having an alkyl group as a substituent include a 2-methylpyrimidin-4-yl group and a 2-methylpyrimidin-3-yl group. Examples of the pyrimidinyl group having an amino group as a substituent include 2-dimethylaminopyrimidin-4-yl group, 2-morpholinopyrimidin-4-yl group, and 2- (4-methylpiperazin-1-yl) pyrimidine-4- Yl group, and the like. Examples of the indolyl group having an alkyl group as a substituent include a 1-methylindol-5-yl group and a 1-ethylindol-5-yl group.
　Ｒで表される置換基を有していてもよいアルキル基としては、置換基を有していてもよい炭素数１～３０の直鎖状、分岐状または環状アルキル基である。好ましくは、置換基を有していてもよい炭素数１～１０の直鎖状、分岐状または環状アルキル基である。直鎖状アルキル基としては、メチル基、エチル基、ｎ－プロピル基、ｎ－ブチル基、ｎ－へキシル基、ｎ―ドデシル基，ｎ－テトラデシル基，ｎ－ヘキサデシル基、等が挙げられる。分岐状アルキル基としては、イソプロピル基、ｔｅｒｔ－ブチル基、１－メチル－プロピル基、２－メチル－プロピル基、２，２－ジメチルプロピル基、等が挙げられる。環状アルキル基としては、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、アダマンチル基、等が挙げられる。
　置換基を有していてもよいアルキル基における置換基としては、水酸基、メルカプト基、ハロゲン原子、ニトロ基、シアノ基、炭素環アリール基、複素環アリール基、脂肪族若しくは芳香族アミノ基、炭素数１～８アルキルチオ基、炭素数１～８アルコキシ基、アリールオキシ基、カルボキシル基、が挙げられる。
　置換基を有していてもよいアルキル基の具体例としては、エチル基、イソプロピル基、２－メチルプロピル基、ｎ－へキシル基、シクロへキシル基、４－ヒドロキシブチル基、１，３－ジヒドロキシ－２－プロピル基、４－ブロモブチル基、２－メトキシエチル基、１－メトキシエチル基、テトラヒロドフラニルメチル基、２－（３－ピリジル）エチル基、４－（３－ピリジル）ブチル基、２－モルフォリノエチル基、３－モルフォリノプロピル基、等が挙げられる。 The alkyl group which may have a substituent represented by R is a linear, branched or cyclic alkyl group having 1 to 30 carbon atoms which may have a substituent. A linear, branched or cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent is preferable. Examples of the linear alkyl group include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-hexyl group, an n-dodecyl group, an n-tetradecyl group, and an n-hexadecyl group. Examples of the branched alkyl group include isopropyl group, tert-butyl group, 1-methyl-propyl group, 2-methyl-propyl group, 2,2-dimethylpropyl group, and the like. Examples of the cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an adamantyl group, and the like.
Examples of the substituent in the alkyl group which may have a substituent include a hydroxyl group, a mercapto group, a halogen atom, a nitro group, a cyano group, a carbocyclic aryl group, a heterocyclic aryl group, an aliphatic or aromatic amino group, carbon Examples thereof include an alkylthio group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an aryloxy group, and a carboxyl group.
Specific examples of the alkyl group which may have a substituent include ethyl, isopropyl, 2-methylpropyl, n-hexyl, cyclohexyl, 4-hydroxybutyl, 1,3- Dihydroxy-2-propyl group, 4-bromobutyl group, 2-methoxyethyl group, 1-methoxyethyl group, tetrahydrofuranylmethyl group, 2- (3-pyridyl) ethyl group, 4- (3-pyridyl) butyl group 2-morpholinoethyl group, 3-morpholinopropyl group, and the like.
　Ｒで表される置換基を有していてもよいアルケニル基としては、置換基を有していてもよい、いずれか１カ所以上に炭素－炭素二重結合を有する炭素数２～３０の直鎖状、分岐状又は環状アルケニル基である。好ましくは、炭素数２～１２の直鎖状、分岐状又は環状アルケニル基である。アルケニル基の具体例としては、エテニル基、プロパ－１－エニル基、又はブタ－１－エニル基、等の１－アルケニル基、若しくはブタ－２－エニル基、又はペンタ－２－エニル基、等の２－アルケニル基が挙げられる。分岐状アルケニル基としては、例えば、イソプロペニル基、３－メチルブタ－１－エニル基、又はゲラニル基、等が挙げられる。環状アルケニル基としては、シクロヘキサ－２－エニル基、シクロヘキサ－２,５－ジエニル基、ジシクロペンタエニル基、ジシクロペンタジエニル基、等が挙げられる。
　置換基を有していてもよいアルケニル基における置換基としては、水酸基、メルカプト基、ハロゲン原子、ニトロ基、シアノ基、炭素環アリール基、複素環アリール基、脂肪族または芳香族アミノ基、炭素数１～８アルキルチオ基、炭素数１～８アルコキシ基、アリールオキシ基、カルボキシル基、が挙げられる。前記アルケニル基において、これら置換基は任意に備えられていてもよい。 The alkenyl group optionally having a substituent represented by R is an optionally substituted alkenyl group having 2 to 30 carbon atoms having a carbon-carbon double bond at any one or more positions. A chain, branched or cyclic alkenyl group. Preferably, it is a linear, branched or cyclic alkenyl group having 2 to 12 carbon atoms. Specific examples of the alkenyl group include a 1-alkenyl group such as an ethenyl group, a prop-1-enyl group, or a but-1-enyl group, a but-2-enyl group, or a penta-2-enyl group, etc. Of 2-alkenyl groups. Examples of the branched alkenyl group include an isopropenyl group, a 3-methylbut-1-enyl group, and a geranyl group. Examples of the cyclic alkenyl group include a cyclohex-2-enyl group, a cyclohexa-2,5-dienyl group, a dicyclopentaenyl group, a dicyclopentadienyl group, and the like.
Examples of the substituent in the alkenyl group which may have a substituent include a hydroxyl group, mercapto group, halogen atom, nitro group, cyano group, carbocyclic aryl group, heterocyclic aryl group, aliphatic or aromatic amino group, carbon Examples thereof include an alkylthio group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an aryloxy group, and a carboxyl group. In the alkenyl group, these substituents may optionally be provided.
　Ｒで表される置換基を有していてもよいアルキニル基としては、置換基を有していてもよい、いずれか１カ所以上に炭素－炭素三重結合を有する炭素数２～３０のアルキニル基を示す。好ましくは、炭素数２～８のアルキニル基である。例えば、エチニル基、プロパ－１－イニル基、３，３－ジメチルブタ－１－イニル基、等の１－アルキニル基、若しくはプロパ－２－イニル基、ブタ－２－イニル基、等の２－アルキニル基が挙げられる。
　置換基を有していてもよいアルキニル基における置換基としては、水酸基、メルカプト基、ハロゲン原子、ニトロ基、シアノ基、炭素環アリール基、複素環アリール基、脂肪族または芳香族アミノ基、炭素数１～８アルキルチオ基、炭素数１～８アルコキシ基、アリールオキシ基、カルボキシル基、が挙げられる。前記アルキニル基において、これら置換基は任意に備えられていてもよい。 The alkynyl group which may have a substituent represented by R is an alkynyl group having 2 to 30 carbon atoms which may have a substituent and has a carbon-carbon triple bond at any one or more positions. Indicates. An alkynyl group having 2 to 8 carbon atoms is preferable. For example, a 1-alkynyl group such as an ethynyl group, a prop-1-ynyl group, a 3,3-dimethylbut-1-ynyl group, or a 2-amino group such as a prop-2-ynyl group or a but-2-ynyl group An alkynyl group is mentioned.
Examples of the substituent in the alkynyl group which may have a substituent include a hydroxyl group, a mercapto group, a halogen atom, a nitro group, a cyano group, a carbocyclic aryl group, a heterocyclic aryl group, an aliphatic or aromatic amino group, carbon Examples thereof include an alkylthio group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an aryloxy group, and a carboxyl group. In the alkynyl group, these substituents may optionally be provided.
　本発明において、Ｚ１及びＺ２は、互いに同じであっても異なっていてもよく、水素原子または水酸基の保護基を示す。Ｚ１及びＺ２で表される水酸基の保護基としては、後にＺ１基及びＺ２基を脱離させ、相当する水酸基が生成することができるものであれば、特に限定されるものではない。Ｚ１及びＺ２における水酸基の保護基としては、エーテル型保護基、アセタール型保護基、チオアセタール型保護基、シリル型保護基、アシル型保護基、等が挙げられる。 In the present invention, Z 1 and Z 2 may be the same as or different from each other, and represent a hydrogen atom or a hydroxyl-protecting group. The hydroxyl-protecting group represented by Z 1 and Z 2 is not particularly limited as long as it can later remove the Z 1 group and the Z 2 group to form a corresponding hydroxyl group. . Examples of the hydroxyl-protecting group for Z 1 and Z 2 include ether-type protecting groups, acetal-type protecting groups, thioacetal-type protecting groups, silyl-type protecting groups, and acyl-type protecting groups.
　本発明において前記エーテル型保護基とは、保護基の結合によりエーテル構造を形成する水酸基の保護基であって、置換基を有していてもよいアルキル基、置換基を有してもよいアルケニル基、置換基を有してもよいアルキニル基を示す。好ましくは、炭素数１～６の直鎖状、分岐状、または環状アルキル基、炭素数２～８の１－アルケニル基または２－アルケニル基、若しくは置換基を有していてもよいアリール基を置換基とする炭素数１～４の直鎖状アルキル基である。エーテル型保護基としては、例えばベンジル基、パラメトキシベンジル基、メチル基、ｔｅｒｔ－ブチル基、アリル基、プロパルギル基、等が挙げられる。特にベンジル基、パラメトキシベンジル基、メチル基、アリル基、が好ましい。 In the present invention, the ether-type protecting group is a hydroxyl-protecting group that forms an ether structure by bonding of a protecting group, and may be an alkyl group that may have a substituent or an alkenyl that may have a substituent. And an alkynyl group which may have a substituent. Preferably, a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, a 1-alkenyl group or 2-alkenyl group having 2 to 8 carbon atoms, or an aryl group which may have a substituent. It is a linear alkyl group having 1 to 4 carbon atoms as a substituent. Examples of the ether-type protecting group include benzyl group, paramethoxybenzyl group, methyl group, tert-butyl group, allyl group, propargyl group, and the like. In particular, a benzyl group, a paramethoxybenzyl group, a methyl group, and an allyl group are preferable.
　本発明において前記アセタール型保護基とは、保護基の結合によりアセタール構造又はケタール構造を形成する水酸基の保護基であって、置換基を有していてもよい炭素数１～１０のアルコキシ基を１位に置換するアルキル基を示す。アセタール型保護基としては、例えばメトキシメチル基、２－メトキシエトキシメチル基、２－（トリメチルシリル）エトキシメチル基、ベンジルオキシメチル基、１－エトキシエチル基、１－メチル－１－メトキシエチル基、１－メチル－１－ベンジルオキシエチル基、テトラヒドロピラニル基、４－メトキシテトラヒドロピラニル基、等が挙げられる。特にメトキシメチル基、２－メトキシエトキシメチル基、ベンジルオキシメチル基、１－エトキシエチル基、１－メチル－１－メトキシエチル基、１－メチル－１－ベンジルオキシエチル基、テトラヒドロピラニル基、４－メトキシテトラヒドロピラニル基が好ましい。 In the present invention, the acetal-type protecting group is a hydroxyl-protecting group that forms an acetal structure or a ketal structure by bonding of a protecting group, and represents an optionally substituted alkoxy group having 1 to 10 carbon atoms. An alkyl group substituted at the 1-position is shown. Examples of the acetal type protecting group include a methoxymethyl group, 2-methoxyethoxymethyl group, 2- (trimethylsilyl) ethoxymethyl group, benzyloxymethyl group, 1-ethoxyethyl group, 1-methyl-1-methoxyethyl group, 1 -Methyl-1-benzyloxyethyl group, tetrahydropyranyl group, 4-methoxytetrahydropyranyl group and the like. In particular, methoxymethyl group, 2-methoxyethoxymethyl group, benzyloxymethyl group, 1-ethoxyethyl group, 1-methyl-1-methoxyethyl group, 1-methyl-1-benzyloxyethyl group, tetrahydropyranyl group, 4 A -methoxytetrahydropyranyl group is preferred.
　本発明において前記チオアセタール型保護基とは、保護基の結合によりチオアセタール構造、又はチオケタール構造を形成する水酸基の保護基であって、置換基を有していてもよい炭素数１～１０アルキルチオ基を１位に置換するアルキル基、または置換基を有していてもよい１－アリールチオアルキル基を示す。チオアセタール型保護基としては、例えばメチルチオメチル基、フェニルチオメチル基、等が挙げられる。 In the present invention, the thioacetal-type protecting group is a protecting group for a hydroxyl group that forms a thioacetal structure or a thioketal structure by bonding of a protecting group, and the alkylthio group having 1 to 10 carbon atoms that may have a substituent. An alkyl group for substituting the group at the 1-position or a 1-arylthioalkyl group optionally having a substituent is shown. Examples of the thioacetal type protecting group include a methylthiomethyl group and a phenylthiomethyl group.
　本発明において前記シリル型保護基とは、保護基の結合によりシリルエーテル構造を形成する水酸基の保護基であって、置換基を有していてもよいアルキル基及び／または置換基を有して位いてもよいアリール基が置換したシリル基が挙げられる。シリル型保護基としては、トリメチルシリル基、トリイソプロピルシリル基、ｔｅｒｔ－ブチルジメチルシリル基、ｔｅｒｔ－ブチルジフェニルシリル基、等が挙げられる。 In the present invention, the silyl-type protecting group is a hydroxyl-protecting group that forms a silyl ether structure by bonding of a protecting group, and has an alkyl group and / or a substituent that may have a substituent. And a silyl group substituted by an aryl group which may be positioned. Examples of the silyl-type protecting group include trimethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, and the like.
　本発明において前記アシル型保護基とは、保護基の結合によりエステル構造を形成する水酸基の保護基であって、置換基を有していてもよい炭素数１～１２のアルキルカルボニル基、または炭素数７～１６のアリールカルボニル基を示す。アシル型保護基としては、アセチル基、トリフルオロアセチル基、ピバロイル基、ベンゾイル基、２－フェニルアセチル基、等が挙げられる。 In the present invention, the acyl-type protecting group is a hydroxyl-protecting group that forms an ester structure by bonding of a protecting group, and may have a substituent, an alkylcarbonyl group having 1 to 12 carbon atoms, or a carbon An arylcarbonyl group represented by formulas 7 to 16 is shown. Examples of the acyl-type protecting group include acetyl group, trifluoroacetyl group, pivaloyl group, benzoyl group, 2-phenylacetyl group, and the like.
　本発明の反応条件を考慮すると、Ｚ１及びＺ２で示される水酸基の保護基としては、アルカリ条件下で脱離しない水酸基の保護基であることが好ましい。したがって、Ｚ１及びＺ２における好ましい水酸基の保護基として、エーテル型保護基またはアセタール型保護基が挙げられる。Ｚ１及びＺ２で表される水酸基の保護基としては、中でもアセタール型保護基が特に好ましく、中でもメトキシメチル基、ベンジルオキシメチル基が特に好ましい。 In consideration of the reaction conditions of the present invention, the hydroxyl protecting group represented by Z 1 and Z 2 is preferably a hydroxyl protecting group that does not leave under alkaline conditions. Accordingly, preferred protecting groups for hydroxyl groups in Z 1 and Z 2 include ether type protecting groups or acetal type protecting groups. As the hydroxyl-protecting group represented by Z 1 and Z 2 , an acetal-type protecting group is particularly preferable, and a methoxymethyl group and a benzyloxymethyl group are particularly preferable.
　本発明において一般式（２）におけるＹは、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、または置換基を有していてもよいアリール基を示す。
　Ｙで表される置換基を有していても良いアルキル基としては、炭素数１～３０の直鎖状、分岐状又は環状アルキル基が挙げられる。好ましくは炭素数１～２０の直鎖状、分岐状又は環状アルキル基が挙げられる。直鎖状アルキル基としては、例えばメチル基、エチル基、ｎ－プロピル基、ｎ―ドデシル基，ｎ－テトラデシル基，ｎ－ヘキサデシル基、等が挙げられる。分岐状アルキル基としては、例えばイソプロピル基、ｔｅｒｔ－ブチル基、２，２－ジメチルプロピル基、等が挙げられる。環状アルキル基としては、例えばシクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、等が挙げられる。 In the present invention, Y in the general formula (2) is an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a substituent. The aryl group which may have a group is shown.
Examples of the alkyl group which may have a substituent represented by Y include linear, branched or cyclic alkyl groups having 1 to 30 carbon atoms. Preferred examples include linear, branched or cyclic alkyl groups having 1 to 20 carbon atoms. Examples of the linear alkyl group include a methyl group, an ethyl group, an n-propyl group, an n-dodecyl group, an n-tetradecyl group, and an n-hexadecyl group. Examples of the branched alkyl group include isopropyl group, tert-butyl group, 2,2-dimethylpropyl group, and the like. Examples of the cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like.
　Ｙで表される置換基を有していてもよいアルケニル基としては、いずれか１カ所以上に炭素－炭素二重結合を有する炭素数２～３０の直鎖状、分岐状又は環状アルケニル基が挙げられる。好ましくは炭素数２～２０の直鎖状、分岐状又は環状アルケニル基が挙げられる。直鎖状アルケニル基としては、例えばエテニル基、１－プロペニル基又は１－ブテニル基、等の１－アルケニル基、若しくは２－ブテニル基又は２－ペンテニル基、等の２－アルケニル基が挙げられる。分岐状アルケニル基としては、例えばイソプロペニル基、３－メチル－１－ブテニル基、又はゲラニル基、等が挙げられる。 Examples of the alkenyl group which may have a substituent represented by Y include a linear, branched or cyclic alkenyl group having 2 to 30 carbon atoms and having a carbon-carbon double bond at any one or more positions. Can be mentioned. Preferably, a linear, branched or cyclic alkenyl group having 2 to 20 carbon atoms is used. Examples of the linear alkenyl group include 1-alkenyl groups such as ethenyl group, 1-propenyl group or 1-butenyl group, or 2-alkenyl groups such as 2-butenyl group or 2-pentenyl group. Examples of the branched alkenyl group include an isopropenyl group, a 3-methyl-1-butenyl group, and a geranyl group.
　Ｙで表される置換基を有していてもよいアルキニル基としては、いずれか１カ所以上に炭素－炭素三重結合を有する炭素数２～３０のアルキニル基が挙げられる。好ましくは炭素数２～２０のアルキニル基が挙げられる。例えばエチニル基、１－プロピニル基、３，３－ジメチル－１－ブチニル基、等の１－アルキニル基、若しくは２－プロピニル基、２－ブチニル基、等の２－アルキニル基が挙げられる。 Examples of the alkynyl group which may have a substituent represented by Y include alkynyl groups having 2 to 30 carbon atoms having a carbon-carbon triple bond at any one or more positions. An alkynyl group having 2 to 20 carbon atoms is preferable. Examples thereof include 1-alkynyl groups such as ethynyl group, 1-propynyl group, 3,3-dimethyl-1-butynyl group, and 2-alkynyl groups such as 2-propynyl group and 2-butynyl group.
　Ｙで表される置換基を有していてもよいアリール基としては、炭素環アリール基又は複素環アリール基を示す。炭素環アリール基としては、例えばフェニル基、ナフチル基、等が挙げられる。複素環アリール基としては、例えばピリジル基、ピリミジニル基、キノリル基、キナゾリニル基、ナフチリジニル基、フリル基、ピロリル基、インドリル基、イミダゾリル基、ピラゾリル基、オキサゾリル基、イソキサゾリル基、トリアゾリル基、等が挙げられる。 The aryl group which may have a substituent represented by Y represents a carbocyclic aryl group or a heterocyclic aryl group. Examples of the carbocyclic aryl group include a phenyl group and a naphthyl group. Examples of the heterocyclic aryl group include pyridyl group, pyrimidinyl group, quinolyl group, quinazolinyl group, naphthyridinyl group, furyl group, pyrrolyl group, indolyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, and the like. It is done.
　本発明においてＹとしては、置換基を有していてもよい炭素数１～２０の直鎖状または分岐状のアルキル基が好ましい。中でもメチル基、エチル基、ｎ－プロピル基、ｎ－へキシル基、ｎ－オクチル基、ｎ―ドデシル基、ｎ－テトラデシル基、３－メチルブチル基、２－シクロヘキシルエチル基、ベンジル基、２－フェニルエチル基、３－フェニルプロピル基、等が挙げられる。特に好ましくは炭素数１～１６の直鎖状のアルキル基が好ましく、メチル基、エチル基、プロピル基、ｎ－へキシル基、ｎ－オクチル基、またはｎ―ドデシル基が特に好ましい。 In the present invention, Y is preferably a linear or branched alkyl group having 1 to 20 carbon atoms which may have a substituent. Among them, methyl group, ethyl group, n-propyl group, n-hexyl group, n-octyl group, n-dodecyl group, n-tetradecyl group, 3-methylbutyl group, 2-cyclohexylethyl group, benzyl group, 2-phenyl Examples thereof include an ethyl group and a 3-phenylpropyl group. A linear alkyl group having 1 to 16 carbon atoms is particularly preferable, and a methyl group, an ethyl group, a propyl group, an n-hexyl group, an n-octyl group, or an n-dodecyl group is particularly preferable.
　一般式（１）で表される［１，２，４］トリアゾール－３－オン誘導体またはその塩において、下記一般式（１ａ）で表される［１，２，４］トリアゾール－３－オン誘導体またはその塩が、本発明のより好ましい態様として挙げることができる。 [1,2,4] triazol-3-one derivatives represented by the general formula (1) or salts thereof, [1,2,4] triazol-3-one derivatives represented by the following general formula (1a) Or its salt can be mentioned as a more preferable aspect of this invention.
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
　以下に、一般式（１ａ）で表される、Ｘａ基が５位フェニル基の５位に配され、且つ（ＣＨ２）ｍ－Ａ基；（ｍ＝０～５の整数、Ａは脂肪族アミノ基を示す）が置換されたフェニル基が４位に置換された［１，２，４］トリアゾール－３－オンについて、その詳細について述べる。
　一般式（１ａ）におけるＸａ基はエチル基、イソプロピル基またはｔｅｒｔ－ブチル基から選ばれる１種である。Ｚａ１及びＺａ２基は、水酸基の保護基であり、エーテル型保護基またはアセタール型保護基である。エーテル型保護基またはアセタール型保護基としては、前述した一般式（１）におけるＺ１基及びＺ２基について規定したエーテル型保護基、及びアセタール型保護基と同義である。前記Ｚａ１及び前記Ｚａ２基は、同一の水酸基の保護基であってもよく、若しくはそれぞれ異なる水酸基の保護基であってもよい。 In the following, the Xa group represented by the general formula (1a) is arranged at the 5-position of the 5-position phenyl group, and (CH 2 ) mA group; (m = 0 to 5 integer, A is aliphatic The details of [1,2,4] triazol-3-one in which a phenyl group substituted with an amino group) is substituted at the 4-position will be described.
The Xa group in the general formula (1a) is one selected from an ethyl group, an isopropyl group, and a tert-butyl group. The Za 1 and Za 2 groups are hydroxyl protecting groups, and are ether type protecting groups or acetal type protecting groups. The ether-type protecting group or the acetal-type protecting group has the same meaning as the ether-type protecting group and the acetal-type protecting group defined for the Z 1 group and Z 2 group in the general formula (1). The Za 1 and Za 2 groups may be the same hydroxyl protecting group or may be different hydroxyl protecting groups.
　一般式（１ａ）において、前記Ａは脂肪族アミノ基を表す。Ａで表される脂肪族アミノ基としては、脂肪族１級アミノ基または脂肪族２級アミノ基が挙げられる。脂肪族１級アミノ基としては、炭素数１～８の直鎖状、分岐状または環状アルキル基を有するＮ－アルキルアミノ基がある。例えばメチルアミノ基、イソプロピルアミノ基、ｎ－ブチルアミノ基、シクロヘキシルアミノ基、等が挙げられる。脂肪族２級アミノ基としては、炭素数１～８の直鎖状、分岐状または環状アルキル基を有するＮ，Ｎ－ジアルキルアミノ基、若しくは環状の２級アミノ基が挙げられる。Ｎ，Ｎ－ジアルキルアミノ基としては、例えばジメチルアミノ基、ジイソプロピルアミノ基、Ｎ－メチル－Ｎ－ブチルアミノ基、Ｎ－メチル－Ｎ－シクロヘキシルアミノ基、Ｎ，Ｎ－ジシクロヘキシルアミノ基、等が挙げられる。環状の脂肪族２級アミノ基としては、モルフォリノ基、４－メチルピペラジン－１－イル基、ピペリジン－１－イル基、ピロリジン－１－イル基、等が挙げられる。Ａで現される脂肪族アミノ基としては、環状の２級アミノ基が好ましい。中でもモルフォリノ基または４－メチルピペラジン－１－イル基が特に好ましい。
　一般式（１ａ）において、ｍは０乃至５の整数を表す。中でもｍは０または１が好ましい。 In the general formula (1a), A represents an aliphatic amino group. Examples of the aliphatic amino group represented by A include an aliphatic primary amino group and an aliphatic secondary amino group. Examples of the aliphatic primary amino group include N-alkylamino groups having a linear, branched or cyclic alkyl group having 1 to 8 carbon atoms. Examples thereof include a methylamino group, isopropylamino group, n-butylamino group, cyclohexylamino group, and the like. Examples of the aliphatic secondary amino group include an N, N-dialkylamino group having a linear, branched or cyclic alkyl group having 1 to 8 carbon atoms, or a cyclic secondary amino group. Examples of the N, N-dialkylamino group include dimethylamino group, diisopropylamino group, N-methyl-N-butylamino group, N-methyl-N-cyclohexylamino group, N, N-dicyclohexylamino group, and the like. It is done. Examples of the cyclic aliphatic secondary amino group include a morpholino group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group. The aliphatic amino group represented by A is preferably a cyclic secondary amino group. Of these, a morpholino group or a 4-methylpiperazin-1-yl group is particularly preferable.
In general formula (1a), m represents an integer of 0 to 5. Among these, m is preferably 0 or 1.
　一般式（２）で表される［１，２，４］トリアゾリルスルフィド誘導体またはその塩において、下記一般式（２ａ）で表される［１，２，４］トリアゾリルスルフィド誘導体またはその塩が、本発明のより好ましい態様として挙げることができる。 In the [1,2,4] triazolyl sulfide derivative represented by the general formula (2) or a salt thereof, the [1,2,4] triazolyl sulfide derivative represented by the following general formula (2a) or a salt thereof A salt can be mentioned as a more preferable embodiment of the present invention.
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
　一般式（２ａ）で示される［１，２，４］トリアゾリルスルフィド誘導体またはその塩について、その詳細について述べる。一般式（２ａ）において、Ｘａ、Ｚａ１，Ｚａ２、Ａ、ｍについては、前記一般式（１ａ）で規定されたものと同義である。
　一般式（２ａ）において、Ｙａは置換基を有してもよい炭素数１～２０の直鎖状または分岐状のアルキル基である。例えばメチル基、エチル基、ｎ－プロピル基、ｎ－へキシル基、ｎ－オクチル基、ｎ―ドデシル基、ｎ－テトラデシル基、３－メチルブチル基、２－シクロヘキシルエチル基、ベンジル基、２－フェニルエチル基、３－フェニルプロピル基、等が挙げられる。特に好ましくは炭素数１～１６の直鎖状のアルキル基が好ましく、メチル基、エチル基、ｎ－プロピル基、ｎ－へキシル基、ｎ－オクチル基、またはｎ―ドデシル基が特に好ましい。 The [1,2,4] triazolyl sulfide derivative represented by the general formula (2a) or a salt thereof will be described in detail. In the general formula (2a), Xa, Za 1 , Za 2 , A, and m are synonymous with those defined in the general formula (1a).
In the general formula (2a), Ya is a linear or branched alkyl group having 1 to 20 carbon atoms which may have a substituent. For example, methyl group, ethyl group, n-propyl group, n-hexyl group, n-octyl group, n-dodecyl group, n-tetradecyl group, 3-methylbutyl group, 2-cyclohexylethyl group, benzyl group, 2-phenyl Examples thereof include an ethyl group and a 3-phenylpropyl group. A linear alkyl group having 1 to 16 carbon atoms is particularly preferable, and a methyl group, an ethyl group, an n-propyl group, an n-hexyl group, an n-octyl group, or an n-dodecyl group is particularly preferable.
　本発明において一般式（３）
Ｍ－Ｗ　　（３）
［式中、Ｍはカリウム、ナトリウムまたはリチウムを示し、ＷはＯ（Ｑ１）で表されるアルコキシ基またはＮ（Ｑ２）（Ｑ３）で表されるアミノ基を示し、前記Ｑ１は２級または３級アルキル基を示し、前記Ｑ２及び前記Ｑ３は、互いに同じであっても異なっていてもよく、アルキル基またはトリアルキルシリル基を示す］で表される塩基が用いられる。一般式（３）におけるＭはアルカリ金属であり、カリウム、ナトリウムまたはリチウムを示す。ＷはＯ（Ｑ１）で表されるアルコキシ基、またはＮ（Ｑ２）（Ｑ３）で表されるアミノ基を示す。すなわち、本発明で用いる一般式（３）で示す塩基は、アルカリ金属アルコキシドまたはアルカリ金属アミドである。 In the present invention, the general formula (3)
MW (3)
[Wherein, M represents potassium, sodium or lithium, W represents an alkoxy group represented by O (Q1) or an amino group represented by N (Q2) (Q3), and the Q1 is secondary or 3 A base represented by a secondary alkyl group, wherein Q2 and Q3 may be the same as or different from each other, and represents an alkyl group or a trialkylsilyl group] is used. M in the general formula (3) is an alkali metal and represents potassium, sodium or lithium. W represents an alkoxy group represented by O (Q1) or an amino group represented by N (Q2) (Q3). That is, the base represented by the general formula (3) used in the present invention is an alkali metal alkoxide or an alkali metal amide.
　本発明において、一般式（３）のＷがＯ（Ｑ１）で表されるアルコキシ基において、前記Ｑ１は２級または３級アルキル基を示す。特に好ましくは炭素数３～６の２級または３級アルキル基である。Ｑ１としては、例えば、ｔｅｒｔ－ブチル基、ｓｅｃ－ブチル基、ｓｅｃ－ペンチル基、１，１－ジメチルプロピル基またはイソプロピル基が挙げられる。中でも，ｔｅｒｔ－ブチル基が特に好ましい．本発明において、ＷがＯ（Ｑ１）で表されるアルコキシ基の場合、一般式（３）で示される塩基としては、カリウムｔｅｒｔ－ブトキシド、またはナトリウムｔｅｒｔ－ブトキシドが特に好ましい。 In the present invention, in the alkoxy group in which W in the general formula (3) is O (Q1), the Q1 represents a secondary or tertiary alkyl group. Particularly preferred is a secondary or tertiary alkyl group having 3 to 6 carbon atoms. Examples of Q1 include tert-butyl group, sec-butyl group, sec-pentyl group, 1,1-dimethylpropyl group, and isopropyl group. Of these, a tert-butyl group is particularly preferred. In the present invention, when W is an alkoxy group represented by O (Q1), the base represented by the general formula (3) is particularly preferably potassium tert-butoxide or sodium tert-butoxide.
　本発明において、一般式（３）のＷがＮ（Ｑ２）（Ｑ３）で表されるアミノ基において、Ｑ２及びＱ３は互いに同じであっても異なっていてもよく、アルキル基またはトリアルキルシリル基を示す。前記Ｑ２及び前記Ｑ３で表されるアルキル基としては、炭素数１～８の直鎖状、分岐状または環状アルキル基であることが好ましい。例えば、メチル基、エチル基、イソプロピル基、ｎ－ブチル基、シクロヘキシル基、等が挙げられる。中でも、イソプロピル基が特に好ましい。本発明において、前記Ｑ２及び前記Ｑ３で表されるトリアルキルシリル基としては、炭素数１～８の直鎖状または分岐状アルキル基がシリル基に３つ置換したトリアルキルシリル基が好ましく、例えば、トリメチルシリル基、トリエチルシリル基、トリイソプロピルシリル基、等が挙げられる。中でも、トリメチルシリル基が好ましい。本発明において、ＷがＮ（Ｑ２）（Ｑ３）で表されるアミノ基の場合の塩基としては、リチウムジイソプロピルアミド、またはカリウムヘキサメチルジシラジドが好ましい。 In the present invention, in the amino group in which W in the general formula (3) is represented by N (Q2) (Q3), Q2 and Q3 may be the same or different from each other, and may be an alkyl group or a trialkylsilyl group. Indicates. The alkyl group represented by Q2 and Q3 is preferably a linear, branched or cyclic alkyl group having 1 to 8 carbon atoms. Examples thereof include a methyl group, an ethyl group, an isopropyl group, an n-butyl group, a cyclohexyl group, and the like. Of these, an isopropyl group is particularly preferable. In the present invention, the trialkylsilyl group represented by Q2 and Q3 is preferably a trialkylsilyl group in which a linear or branched alkyl group having 1 to 8 carbon atoms is substituted with three silyl groups. , Trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, and the like. Of these, a trimethylsilyl group is preferable. In the present invention, as the base when W is an amino group represented by N (Q2) (Q3), lithium diisopropylamide or potassium hexamethyldisilazide is preferable.
　本発明において、Ｗで表される置換基としては，Ｏ（Ｑ１）で表されるアルコキシ基が好ましく、一般式（３）で表される塩基としては、カリウムｔｅｒｔ－ブトキシド、またはナトリウムｔｅｒｔ－ブトキシドが特に好ましい。 In the present invention, the substituent represented by W is preferably an alkoxy group represented by O (Q1), and the base represented by the general formula (3) is potassium tert-butoxide or sodium tert-butoxide. Is particularly preferred.
（反応の説明）
　次に、下記反応式２に示す一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩（２）を、非プロトン性溶媒中、前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩に対して１当量以上の水、及び前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩に対する前記水の当量よりも過剰当量の下記一般式（３）で表される塩基を用いて処理することにより、一般式（１）で表されるトリアゾール－３－オン誘導体またはその塩（１）に変換する反応について説明する。 (Description of reaction)
Next, the triazolyl sulfide derivative represented by the general formula (2) or the salt (2) represented by the following reaction formula 2 is converted into the triazolyl represented by the general formula (2) in an aprotic solvent. 1 equivalent or more of water with respect to the sulfide derivative or salt thereof, and the following general formula (3) in an excess equivalent to the equivalent of water with respect to the triazolyl sulfide derivative or salt thereof represented by the general formula (2) A reaction for converting to the triazol-3-one derivative represented by the general formula (1) or a salt thereof (1) by treatment with the represented base will be described.
反応式２；
Figure JPOXMLDOC01-appb-C000022
 Reaction formula 2;
Figure JPOXMLDOC01-appb-C000022
　本発明は、一般式（２）で示すトリアゾリルスルフィド誘導体またはその塩（２）を、非プロトン性溶媒中、前記トリアゾリルスルフィド誘導体またはその塩（２）に対して１当量以上の水、及び前記トリアゾリルスルフィド誘導体またはその塩（２）に対する前記水の当量よりも過剰当量の一般式（３）で表される塩基と混合し、反応させることで達成される。前記トリアゾリルスルフィド誘導体またはその塩（２）、水、前記塩基（３）の混合様式は特に限定されるものではなく、前記トリアゾリルスルフィド誘導体またはその塩（２）を、それぞれ所定当量の水及び前記塩基（３）と、非プロトン性溶媒の溶液中、またはその懸濁液中で混合する工程、次いで反応させる工程を含むことにより、本発明は達成される。
　本発明において、前記トリアゾリルスルフィド誘導体またはその塩（２）、水、及び前記一般式（３）で表される塩基を混合する操作としては、前記塩基（３）の非プロトン性溶媒の溶液、またはその懸濁液中に、前記トリアゾリルスルフィド誘導体またはその塩（２）をそのまま、またはその非プロトン性溶媒の溶液、または懸濁液として加え、最後に水を添加する操作が挙げられる。別の態様として、前記塩基（３）及び水の非プロトン性溶媒の溶液、またはその懸濁液中に、前記トリアゾリルスルフィド誘導体またはその塩（２）をそのまま、若しくはその非プロトン性溶媒の溶液、またはその懸濁液を加える操作を挙げることができる。或いは、反対に、前記トリアゾリルスルフィド誘導体またはその塩（２）の非プロトン性溶媒の溶液、またはその懸濁液中に、前記塩基及び水を加える操作であってもよい。
　本発明において、非プロトン性溶媒中で、前記トリアゾリルスルフィド誘導体またはその塩（２）と前記塩基（３）の混合物を予め調製し、これに対し最後に水を添加する操作が好ましい。 The present invention provides a triazolyl sulfide derivative represented by the general formula (2) or a salt thereof (2) in an aprotic solvent in an amount of 1 equivalent or more of water relative to the triazolyl sulfide derivative or a salt thereof (2). , And the triazolyl sulfide derivative or a salt thereof (2) is mixed with a base represented by the general formula (3) in an excess equivalent to the equivalent of water, and reacted. The mixing mode of the triazolyl sulfide derivative or a salt thereof (2), water and the base (3) is not particularly limited, and each of the triazolyl sulfide derivative or a salt thereof (2) The present invention is achieved by including a step of mixing water and the base (3) in a solution of an aprotic solvent or a suspension thereof, and then a step of reacting.
In the present invention, the operation of mixing the triazolyl sulfide derivative or a salt thereof (2), water, and the base represented by the general formula (3) includes a solution of the aprotic solvent of the base (3). In the suspension, the triazolyl sulfide derivative or the salt (2) is added as it is or as a solution or suspension of the aprotic solvent, and finally water is added. . In another embodiment, the triazolyl sulfide derivative or a salt thereof (2) is used as it is or in an aprotic solvent thereof in a solution or suspension of the base (3) and water. The operation which adds a solution or its suspension can be mentioned. Or, conversely, the base and water may be added to a solution of the triazolyl sulfide derivative or its salt (2) in an aprotic solvent, or a suspension thereof.
In the present invention, it is preferable to prepare a mixture of the triazolyl sulfide derivative or its salt (2) and the base (3) in an aprotic solvent in advance, and finally add water.
　本発明の反応において、水の添加量は、一般式（２）で示すトリアゾリルスルフィド誘導体またはその塩（２）に対し化学量論当量以上であることが、満足すべき反応収率を得るためには必要である。好ましくは、水の添加量は一般式（２）のトリアゾリルスルフィド誘導体またはその塩に対し１～５０当量である。水の添加量が、トリアゾリルスルフィド誘導体またはその塩（２）に対し５０当量を超える量用いると、前記塩基（３）の使用量もそれに伴い増加するため、５０当量を超えない量用いるのが好ましい。特に好ましい水の添加量は、トリアゾリルスルフィド誘導体またはその塩（２）に対し１～３０当量である。更に好ましくは１～１０当量である。 In the reaction of the present invention, a satisfactory reaction yield is obtained when the amount of water added is a stoichiometric equivalent or more with respect to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof (2). It is necessary for that. Preferably, the amount of water added is 1 to 50 equivalents relative to the triazolyl sulfide derivative of the general formula (2) or a salt thereof. When the amount of water used exceeds 50 equivalents relative to the triazolyl sulfide derivative or salt thereof (2), the amount of the base (3) used increases accordingly. Is preferred. A particularly preferable amount of water to be added is 1 to 30 equivalents relative to the triazolyl sulfide derivative or salt (2) thereof. More preferably, it is 1 to 10 equivalents.
　本発明において添加する一般式（３）で表される塩基の量は、一般式（２）で示すトリアゾリルスルフィド誘導体またはその塩（２）に対する前記水の添加当量よりも、過剰当量であることが必要である。前記塩基の添加量は、トリアゾリルスルフィド誘導体またはその塩（２）に対する化学量論当量として、前記水の添加当量よりも１当量以上過剰であることが好ましい。具体的な前記塩基の添加量としては、トリアゾリルスルフィド誘導体またはその塩（２）に対し２～１００当量であって、且つトリアゾリルスルフィド誘導体またはその塩（２）に対する前記水の添加当量よりも１当量以上過剰当量であることが好ましい。前記塩基の添加量として、特に好ましくはトリアゾリルスルフィド誘導体またはその塩（２）に対し２～５０当量であって、且つトリアゾリルスルフィド誘導体またはその塩（２）に対する前記水の添加当量よりも１当量以上過剰当量であることが好ましい。更に好ましい前記塩基の添加量は、トリアゾリルスルフィド誘導体またはその塩（２）に対して２～２０等量であって、トリアゾリルスルフィド誘導体またはその塩（２）に対する前記水の添加当量よりも、１当量以上過剰当量である。 The amount of the base represented by the general formula (3) to be added in the present invention is an excess equivalent to the addition equivalent of water to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof (2). It is necessary. The addition amount of the base is preferably 1 equivalent or more in excess of the addition equivalent of water as a stoichiometric equivalent with respect to the triazolyl sulfide derivative or a salt thereof (2). Specifically, the addition amount of the base is 2 to 100 equivalents relative to the triazolyl sulfide derivative or salt thereof (2), and the equivalent amount of water relative to the triazolyl sulfide derivative or salt thereof (2). It is preferable that it is 1 equivalent or more and an excess equivalent. The amount of the base added is particularly preferably 2 to 50 equivalents relative to the triazolyl sulfide derivative or salt (2), and more than the equivalent equivalent of water relative to the triazolyl sulfide derivative or salt (2). Is preferably 1 equivalent or more and excess equivalent. A more preferable addition amount of the base is 2 to 20 equivalents with respect to the triazolyl sulfide derivative or a salt thereof (2), and from the addition equivalent of water to the triazolyl sulfide derivative or a salt thereof (2). Is also an excess equivalent of 1 equivalent or more.
　本発明の反応において、水の添加量、及び一般式（３）で表される塩基の添加量の組み合わせとしては、水の添加量が、トリアゾリルスルフィド誘導体またはその塩（２）に対し１～５０当量であり、一般式（３）で表される塩基の添加量が、トリアゾリルスルフィド誘導体またはその塩（２）に対し２～１００当量であって、前記塩基（３）の添加量が、トリアゾリルスルフィド誘導体またはその塩（２）に対する前記水の添加当量より過剰である組合せが好ましい。更に好ましくは、水の添加量が、トリアゾリルスルフィド誘導体またはその塩（２）に対し１～５０当量であり、一般式（３）で表される塩基の添加量が、トリアゾリルスルフィド誘導体またはその塩（２）に対し２～１００当量であって、且つ該塩基（３）の添加当量が、前記水の添加当量よりも１～３０当量過剰である組み合わせが特に好ましい。 In the reaction of the present invention, as a combination of the addition amount of water and the addition amount of the base represented by the general formula (3), the addition amount of water is 1 with respect to the triazolyl sulfide derivative or its salt (2). The amount of the base represented by the general formula (3) is 2 to 100 equivalents relative to the triazolyl sulfide derivative or a salt thereof (2), and the amount of the base (3) added However, the combination which is more than the addition equivalent of the said water with respect to a triazolyl sulfide derivative or its salt (2) is preferable. More preferably, the addition amount of water is 1 to 50 equivalents relative to the triazolyl sulfide derivative or a salt thereof (2), and the addition amount of the base represented by formula (3) is the triazolyl sulfide derivative. Alternatively, a combination of 2 to 100 equivalents with respect to the salt (2) and the addition equivalent of the base (3) being 1 to 30 equivalents more than the addition equivalent of water is particularly preferable.
　本発明の反応において、水の添加量、及び一般式（３）で表される塩基の添加量のより好適な組み合わせとしては、水の添加量が、トリアゾリルスルフィド誘導体またはその塩（２）に対し１～１０当量であり、一般式（３）で表される塩基の添加量が、トリアゾリルスルフィド誘導体またはその塩（２）に対し２～２０当量であって、且つ該塩基（３）の添加当量が、前記水の添加当量よりも１～１０当量過剰である組み合わせが特に好ましい。 In the reaction of the present invention, as a more preferable combination of the addition amount of water and the addition amount of the base represented by the general formula (3), the addition amount of water may be a triazolyl sulfide derivative or a salt thereof (2). The amount of the base represented by the general formula (3) is 2 to 20 equivalents relative to the triazolyl sulfide derivative or a salt thereof (2), and the base (3 A combination in which the addition equivalent of 1) is 1 to 10 equivalents more than the addition equivalent of water is particularly preferred.
　本発明の反応は、非プロトン性溶媒を反応溶媒として使用する。本発明の反応に用いる非プロトン性溶媒とはプロトン供与性を持たない溶媒を意味し、例えばエーテル溶媒、炭化水素溶媒、ハロゲン溶媒等が挙げられる。
　本発明において、エーテル溶媒とはエーテル構造を有する溶媒を意味し、例えばジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、１，４－ジオキサン、１，２－ジメトキシエタン、ビス（２－メトキシエチル）エーテル、メチルフェニルエーテル、ｔｅｒｔ－ブチルメチルエーテル、等が挙げられる。
　炭化水素溶媒としては、ペンタン、ｎ－ヘキサン、シクロヘキサン、ヘプタン、石油エーテル、等の脂肪族炭化水素系溶媒、若しくはベンゼン、トルエン、キシレン、等の芳香族炭化水素系溶媒が挙げられる。
　ハロゲン溶媒としては、ジクロロメタン、クロロホルム、四塩化炭素、１，２－ジクロロエタン、等が挙げられる。
　本発明の反応溶媒は、非プロトン性溶媒であれば特に限定されるものではないが、中でも沸点６０℃以上のエーテル溶媒が好ましい。例えば、テトラヒドロフラン、１，４－ジオキサン、１，２－ジメトキシエタン、ビス（２－メトキシエチル）エーテル、等が挙げられる。特に好ましくは沸点が８０℃以上のエーテル溶媒であり、１，４－ジオキサン、１，２－ジメトキシエタン、ビス（２－メトキシエチル）エーテル、等が好適な反応溶媒として挙げることができる。これらは単独で用いてもよく、混合溶媒として用いてもよい。 The reaction of the present invention uses an aprotic solvent as a reaction solvent. The aprotic solvent used in the reaction of the present invention means a solvent having no proton donating property, and examples thereof include ether solvents, hydrocarbon solvents, halogen solvents and the like.
In the present invention, an ether solvent means a solvent having an ether structure, such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether, methylphenyl And ether, tert-butyl methyl ether, and the like.
Examples of the hydrocarbon solvent include aliphatic hydrocarbon solvents such as pentane, n-hexane, cyclohexane, heptane, and petroleum ether, or aromatic hydrocarbon solvents such as benzene, toluene, and xylene.
Examples of the halogen solvent include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like.
The reaction solvent of the present invention is not particularly limited as long as it is an aprotic solvent, but an ether solvent having a boiling point of 60 ° C. or higher is preferable. For example, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether and the like can be mentioned. Particularly preferred is an ether solvent having a boiling point of 80 ° C. or higher, and 1,4-dioxane, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether, etc. can be mentioned as suitable reaction solvents. These may be used alone or as a mixed solvent.
　本発明において、非プロトン性溶媒の使用量は特に限定されるものではない。しかしながら、トリアゾリルスルフィド誘導体またはその塩（２）が当該反応条件において、全て溶解するのに十分な溶媒量を用いることが好ましい。すなわち、本発明において用いる非プロトン性溶媒は、トリアゾリルスルフィド誘導体またはその塩（２）に対し１～１００質量部が好ましい。より好ましくは、トリアゾリルスルフィド誘導体またはその塩（２）に対し２～５０質量部である。 In the present invention, the amount of aprotic solvent used is not particularly limited. However, it is preferable to use a solvent amount sufficient to dissolve all of the triazolyl sulfide derivative or a salt thereof (2) under the reaction conditions. That is, the aprotic solvent used in the present invention is preferably 1 to 100 parts by mass with respect to the triazolyl sulfide derivative or a salt thereof (2). More preferably, it is 2 to 50 parts by mass with respect to the triazolyl sulfide derivative or a salt thereof (2).
　本発明の反応温度は、反応が進行する限りにおいて特に限定されるものではない。しかしながら、反応促進のため、加熱条件で反応させることが好ましい。反応温度は，６０℃から１５０℃で行なうことが好ましい。特に８０℃から１２０℃で反応を行なうことで、反応時間の短縮と、十分な反応収率を達成できることから特に好ましい。 The reaction temperature of the present invention is not particularly limited as long as the reaction proceeds. However, in order to accelerate the reaction, it is preferable to carry out the reaction under heating conditions. The reaction temperature is preferably 60 to 150 ° C. In particular, it is particularly preferable to conduct the reaction at 80 to 120 ° C. because the reaction time can be shortened and a sufficient reaction yield can be achieved.
　本発明における好ましい反応条件としては、第１の態様としては、非プロトン性溶媒として１，４－ジオキサンを用い、水を前記トリアゾリルスルフィド誘導体またはその塩（２）に対して１～１０当量用い、塩基としてカリウムｔｅｒｔ－ブトキシドを前記トリアリルスルフィド誘導体またはその塩（２）に対して２～２０当量用い、前記カリウムｔｅｒｔ－ブトキシドは前記水より１～１０当量過剰で混合する製法が挙げられる。第２の態様として、非プロトン性溶媒としてジメトキシエタンを用い、水を前記トリアゾリルスルフィド誘導体またはその塩（２）に対して１～１０当量用い、塩基としてカリウムｔｅｒｔ－ブトキシドを前記トリアリルスルフィド誘導体またはその塩（２）に対して２～２０当量用い、前記カリウムｔｅｒｔ－ブトキシドは前記水より１～１０当量過剰で混合する製法が挙げられる。第３の態様として、非プロトン性溶媒としてビス（２－メトキシエチル）エーテルを用い、水を前記トリアゾリルスルフィド誘導体またはその塩（２）に対して１～１０当量用い、塩基としてカリウムｔｅｒｔ－ブトキシドを前記トリアリルスルフィド誘導体またはその塩（２）に対して２～２０当量用い、前記カリウムｔｅｒｔ－ブトキシドは前記水より１～１０当量過剰で混合する製法が挙げられる。 As preferable reaction conditions in the present invention, as a first aspect, 1,4-dioxane is used as an aprotic solvent, and water is used in an amount of 1 to 10 equivalents relative to the triazolyl sulfide derivative or a salt thereof (2). And a method in which potassium tert-butoxide is used as a base in an amount of 2 to 20 equivalents relative to the triallyl sulfide derivative or a salt thereof (2), and the potassium tert-butoxide is mixed in an excess of 1 to 10 equivalents from the water. . In a second embodiment, dimethoxyethane is used as an aprotic solvent, water is used in an amount of 1 to 10 equivalents relative to the triazolyl sulfide derivative or a salt thereof (2), and potassium tert-butoxide is used as the base. An example is a method in which 2 to 20 equivalents of the derivative or its salt (2) are used, and the potassium tert-butoxide is mixed in an excess of 1 to 10 equivalents with respect to the water. In a third embodiment, bis (2-methoxyethyl) ether is used as an aprotic solvent, water is used in an amount of 1 to 10 equivalents relative to the triazolyl sulfide derivative or a salt thereof (2), and potassium tert- An example is a method in which butoxide is used in an amount of 2 to 20 equivalents relative to the triallyl sulfide derivative or a salt thereof (2), and the potassium tert-butoxide is mixed in an excess of 1 to 10 equivalents relative to the water.
　本発明は、当該反応終了後、通常行なわれる水性後処理により、容易に目的生成物である一般式（１）で示される［１，２，４］トリアゾール－３－オン誘導体（１）を単離することができる。すなわち、当該反応混合物を水性処理し、有機溶媒にて抽出し、目的生成物（１）を単離できる。単離された目的生成物（１）は必要に応じ、クロマトグラフィー又は懸濁精製、等による精製工程を経由してもよい。 After completion of the reaction, the present invention easily converts the [1,2,4] triazol-3-one derivative (1) represented by the general formula (1), which is the target product, by simple aqueous post-treatment. Can be separated. That is, the reaction mixture can be treated with water and extracted with an organic solvent to isolate the desired product (1). The isolated target product (1) may be subjected to a purification step such as chromatography or suspension purification, if necessary.
　本発明において、一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩が、前記一般式（２ａ）においても、非プロトン性溶媒中、前記一般式（２ａ）で表されるトリアゾリルスルフィド誘導体またはその塩に対して１当量以上の水、及び前記一般式（２ａ）で表されるトリアゾリルスルフィド誘導体またはその塩に対する前記水の当量よりも過剰当量の下記一般式（３）Ｍ－Ｗで表される塩基を用いて処理することにより、一般式（１ａ）で表されるトリアゾール－３－オン誘導体またはその塩（１ａ）に変換する事ができる（反応式３）。 In the present invention, the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof is a triazolyl derivative represented by the general formula (2a) in an aprotic solvent also in the general formula (2a). 1 equivalent or more of water with respect to the sulfide derivative or a salt thereof, and the following general formula (3) in excess equivalent to the equivalent of the water with respect to the triazolyl sulfide derivative or a salt thereof represented by the general formula (2a) By treatment with a base represented by MW, the triazol-3-one derivative represented by the general formula (1a) or a salt thereof (1a) can be converted (Reaction Scheme 3).
反応式３；
Figure JPOXMLDOC01-appb-C000023
 Reaction formula 3;
Figure JPOXMLDOC01-appb-C000023
　本発明により得られる一般式（１）で表される［１，２，４］トリアゾール－３－オン誘導体またはその塩（１）は、Ｚ１及びＺ２基が水酸基の保護基である場合、下記反応式４で表されるように脱保護反応により、ＨＳＰ９０阻害活性を有する［１，２，４］トリアゾール－３－オン誘導体またはその塩（７）［式中、Ｘ，Ｒは、前述した一般式（１）における規定と同義である］に変換できる。 In the [1,2,4] triazol-3-one derivative represented by the general formula (1) obtained by the present invention or a salt thereof (1), when Z 1 and Z 2 groups are hydroxyl protecting groups, [1,2,4] triazol-3-one derivative or its salt (7) having HSP90 inhibitory activity by deprotection reaction as represented by the following reaction formula 4, wherein X and R are as defined above It is synonymous with the definition in the general formula (1).
反応式４；
Figure JPOXMLDOC01-appb-C000024
 Reaction formula 4;
Figure JPOXMLDOC01-appb-C000024
　なお、一般式（７）で表される［１，２，４］トリアゾール－３－オン誘導体またはその塩（７）は、ケト／エノール互変異性体の関係にある下記一般式（７Ｅ）で表される異性体構造を取り得る事は自明であって、前記化合物（７）及び前記化合物（７Ｅ）は同じ化合物である。 The [1,2,4] triazol-3-one derivative represented by the general formula (7) or a salt (7) thereof is represented by the following general formula (7E) in the keto / enol tautomer relationship. It is obvious that the isomer structure represented can be taken, and the compound (7) and the compound (7E) are the same compound.
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
　同様に、本発明により得られる一般式（１ａ）で表される［１，２，４］トリアゾール－３－オン誘導体またはその塩（１ａ）は、Ｚａ１及びＺａ２基が水酸基の保護基である場合、下記反応式５で表されるように脱保護反応により、ＨＳＰ９０阻害活性を有する［１，２，４］トリアゾール－３－オン誘導体またはその塩（７ａ）［式中、Ｘａ，Ａ，ｍは、前述した一般式（１ａ）における規定と同義である］に変換できる。 Similarly, in the [1,2,4] triazol-3-one derivative represented by the general formula (1a) obtained by the present invention or a salt thereof (1a), the Za 1 and Za 2 groups are hydroxyl protecting groups. In some cases, a [1,2,4] triazol-3-one derivative having a HSP90 inhibitory activity or a salt thereof (7a) [wherein Xa, A, m is synonymous with the definition in General Formula (1a) described above].
反応式５；
Figure JPOXMLDOC01-appb-C000026
 Reaction formula 5;
Figure JPOXMLDOC01-appb-C000026
　なお、一般式（７ａ）で表される［１，２，４］トリアゾール－３－オン誘導体またはその塩（７ａ）は、ケト／エノール互変異性体の関係にある下記一般式（７ａＥ）で表される異性体構造を取り得る事は自明であって、前記化合物（７ａ）及び前記化合物（７ａＥ）は同じ化合物である。 The [1,2,4] triazol-3-one derivative represented by the general formula (7a) or a salt (7a) thereof is represented by the following general formula (7aE) in the keto / enol tautomer relationship. It is obvious that the isomer structure represented can be taken, and the compound (7a) and the compound (7aE) are the same compound.
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
　反応式４または反応式５によるＺ１基及びＺ２基、並びにＺａ１基及びＺａ２基の脱保護反応は、Ｚ１基及びＺ２基等の該水酸基の保護基の化学反応性に応じ、適宜設定されるものである。例えばＺ１基及びＺ２基がアセタール型保護基であり、例えばメトキシメチル基の場合、酸性条件による処理またはトリメチルシリルブロマイドによる処理、等により脱保護反応をすることができる。好ましくは、酸性条件による処理方法が採用される。
　一般式（１）において、Ｚ１及びＺ２基がメトキシメチル基の場合における脱保護反応の具体例としては、塩酸－１，４－ジオキサン溶液、塩酸－エタノール溶液、または塩酸－イソプロパノール－テトラヒドロフラン溶液、等で処理することにより、脱保護反応を行なうことができる。
　生成した［１，２，４］トリアゾール－３－オン誘導体（７）または（７ａ）は、公知の単離操作により単離され、必要に応じ精製操作、任意に造塩工程を経由し、目的生成物をして製造することができる。 Scheme 4 or Scheme 5 by Z 1 radicals and Z 2 groups, and deprotection reaction of Za 1 group and Za 2 groups, depending on the chemical reactivity of the protective group of the hydroxyl group, such as Z 1 radicals and Z 2 groups Are set as appropriate. For example, the Z 1 group and the Z 2 group are acetal type protecting groups. For example, in the case of a methoxymethyl group, the deprotection reaction can be performed by treatment under acidic conditions or treatment with trimethylsilyl bromide. Preferably, a treatment method using acidic conditions is employed.
In the general formula (1), when the Z 1 and Z 2 groups are methoxymethyl groups, specific examples of the deprotection reaction include hydrochloric acid-1,4-dioxane solution, hydrochloric acid-ethanol solution, or hydrochloric acid-isopropanol-tetrahydrofuran solution. The deprotection reaction can be carried out by treating with.
The produced [1,2,4] triazol-3-one derivative (7) or (7a) is isolated by a known isolation operation, purified as necessary, optionally through a salt formation step, The product can be manufactured.
　本発明の原料化合物である一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩は、公知の方法により調製できる。例えば、特許文献１の実施例３－１等に記載の方法に準じて合成できる。すなわち下記反応式６に従い、［１，２，４］トリアゾール－３－チオン誘導体またはその塩（４）に対し、塩基存在下で、ハロゲン原子等適当な脱離基を有する置換基Ｙ残基を有する反応試薬を反応させることにより、トリアゾリルスルフィド誘導体またはその塩（２）が調製できる。一般式（２ａ）で表されるトリアゾリルスルフィド誘導体またはその塩も、同様の方法により合成することができる。 The triazolyl sulfide derivative represented by the general formula (2) which is a raw material compound of the present invention or a salt thereof can be prepared by a known method. For example, it can be synthesized according to the method described in Example 3-1 of Patent Document 1. That is, according to the following reaction formula 6, a substituent Y residue having a suitable leaving group such as a halogen atom in the presence of a base is added to the [1,2,4] triazole-3-thione derivative or its salt (4). A triazolyl sulfide derivative or a salt thereof (2) can be prepared by reacting a reaction reagent having the same. The triazolyl sulfide derivative represented by the general formula (2a) or a salt thereof can also be synthesized by the same method.
反応式６；
Figure JPOXMLDOC01-appb-C000028
 Reaction formula 6;
Figure JPOXMLDOC01-appb-C000028
　また、前記［１，２，４］トリアゾール－３－チオン誘導体またはその塩（４）は、公知の方法により調製できる。例えば、特許文献１の実施例１－１等に記載の方法に準じて合成できる。すなわち、下記反応式７に従い、チオセミカルバジド（８）を塩基性条件下で加熱処理することにより、［１，２，４］トリアゾール－３－チオン誘導体またはその塩（４）を調製することができる。 The [1,2,4] triazole-3-thione derivative or a salt thereof (4) can be prepared by a known method. For example, it can be synthesized according to the method described in Example 1-1 of Patent Document 1. That is, the [1,2,4] triazole-3-thione derivative or its salt (4) can be prepared by heat-treating thiosemicarbazide (8) under basic conditions according to the following reaction formula 7. .
反応式７；
Figure JPOXMLDOC01-appb-C000029
 Reaction formula 7;
Figure JPOXMLDOC01-appb-C000029
　次に本発明を実施例により更に具体的に説明するが、本発明はこれらの例によって何ら制限されるものではない。
　実施例として、トリアゾリルメチルスルフィド誘導体（２ｂ）またはトリアゾリルｎ－ドデシルスルフィド誘導体（２ｃ）を用いた、本発明による、５－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－２，４－ジヒドロ－［１，２，４］トリアゾール－３－オン（１ｂｃ）の合成について示す（スキーム１）。 EXAMPLES Next, although an Example demonstrates this invention further more concretely, this invention is not restrict | limited at all by these examples.
As an example, 5- (5-isopropyl-2,4-bis-methoxymethoxyphenyl) -4 according to the invention using a triazolylmethyl sulfide derivative (2b) or a triazolyl n-dodecyl sulfide derivative (2c) The synthesis of — [4- (4-methylpiperazin-1-ylmethyl) phenyl] -2,4-dihydro- [1,2,4] triazol-3-one (1bc) is shown (Scheme 1).
スキーム１；
Figure JPOXMLDOC01-appb-C000030
 Scheme 1;
Figure JPOXMLDOC01-appb-C000030
　実施例化合物、及び合成例化合物の検出及び同定、並びに純度測定のためのＬＣ／ＭＳ測定条件は次のとおりである。
機種：島津　ＬＣＭＳ－２０１０Ａ
カラム：Ｉｎｅｒｔｓｉｌ　ＯＤＳ－３、２．１ｍｍ×１００ｍｍ、
移動相Ａ：アセトニトリル／ギ酸　（９９．９／０．１）
移動相Ｂ：水／ギ酸　（９９．９／０．１）
グラジェント：時間（分）　０．０　　５．５　　６．５　　６．５１　　１０．０
　　　　　　　Ａ濃度　　　　５　　　９０　　　９０　　　　　５　　　　　５
流速：０．３ｍＬ／分 LC / MS measurement conditions for detection and identification of Example compounds and synthesis example compounds, and purity measurement are as follows.
Model: Shimadzu LCMS-2010A
Column: Inertsil ODS-3, 2.1 mm × 100 mm,
Mobile phase A: acetonitrile / formic acid (99.9 / 0.1)
Mobile phase B: water / formic acid (99.9 / 0.1)
Gradient: Time (min) 0.0 5.5 6.5 6.51 10.0
A concentration 5 90 90 5 5
Flow rate: 0.3 mL / min
実施例１
３－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－５－（ｎ－ドデシルチオ）－［１，２，４］トリアゾール（２ｃ）の本発明の加水分解反応による、５－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－２，４－ジヒドロ－［１，２，４］トリアゾール－３－オン（１ｂｃ）の製造 Example 1
3- (5-Isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5- (n-dodecylthio)-[1,2,4 ] 5- (5-Isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl]-by the hydrolysis reaction of the present invention for triazole (2c) Preparation of 2,4-dihydro- [1,2,4] triazol-3-one (1bc)
実施例１－１
　アルゴン雰囲気中、室温撹拌下、３－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－５－（ｎ－ドデシルチオ）－［１，２，４］トリアゾール（２ｃ）（１２．７４ｇ，１８．３ｍｍｏｌ）の乾燥１，４－ジオキサン（１２７ｍＬ）溶液中に、カリウムｔｅｒｔ－ブトキシド（１３．５６ｇ，１２０．８ｍｍｏｌ）を加え、室温で１５分撹拌した。次いで、室温撹拌下、水（０．７２５ｍＬ，４０．３ｍｍｏｌ）を加え、１０時間加熱還流した。氷冷撹拌下、反応液に、食塩水（１２７ｍＬ）、及び１Ｎ硫酸水素カリウム（１２１ｍＬ）を加えてｐＨ約７－８とし、酢酸エチル（２００ｍＬ，１００ｍＬ，６０ｍＬ）で抽出した。抽出液を、食塩水（１００ｍＬ，２回）で洗浄し、無水硫酸ナトリウムで乾燥して、酢酸エチル溶液（１）を得た。ｐＨ約７－８の水層に、固形炭酸水素ナトリウム（３．０７５ｇ，３６．６ｍｍｏｌ）を加え、酢酸エチルで抽出した。抽出液（１５０ｍＬ）を食塩水（５０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥して、酢酸エチル溶液（２）を得た。酢酸エチル溶液（１）と酢酸エチル溶液（２）の乾燥剤を濾去し、濾液を合して減圧下溶媒を留去し、淡黄色ペースト状の粗生成物を得た。この粗生成物を、カラムクロマトグラフィー（ＮＨ－シリカゲル，５００ｍＬ）（溶出溶媒：酢酸エチル－メタノール　４９：１～１９：１）により精製し、白色固体５０２７ｍｇを得た。この白色固体に、ジイソプロピルエーテル（４０ｍＬ）及びｎ－ヘキサン（１０ｍＬ）を加え、得られた懸濁液を室温で３時間撹拌した。析出している固体を濾取し、ジイソプロピルエーテル－ｎ－ヘキサン（２：１）（５ｍＬ，１０ｍＬ）で洗浄後、減圧乾燥して５－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－２，４－ジヒドロ－［１，２，４］トリアゾール－３－オン（１ｂｃ）４７６９ｍｇ（５１％）を白色固体として得た。 Example 1-1
Under stirring at room temperature in an argon atmosphere, 3- (5-isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5- (n-dodecylthio) )-[1,2,4] triazole (2c) (12.74 g, 18.3 mmol) in dry 1,4-dioxane (127 mL) with potassium tert-butoxide (13.56 g, 120.8 mmol). The mixture was further stirred at room temperature for 15 minutes. Next, water (0.725 mL, 40.3 mmol) was added with stirring at room temperature, and the mixture was heated to reflux for 10 hours. Under ice-cooling and stirring, brine (127 mL) and 1N potassium hydrogen sulfate (121 mL) were added to the reaction solution to adjust the pH to about 7-8, and the mixture was extracted with ethyl acetate (200 mL, 100 mL, 60 mL). The extract was washed with brine (100 mL, twice) and dried over anhydrous sodium sulfate to obtain an ethyl acetate solution (1). Solid sodium hydrogen carbonate (3.075 g, 36.6 mmol) was added to the aqueous layer having a pH of about 7-8, and the mixture was extracted with ethyl acetate. The extract (150 mL) was washed with brine (50 mL) and dried over anhydrous sodium sulfate to obtain an ethyl acetate solution (2). The desiccants of the ethyl acetate solution (1) and the ethyl acetate solution (2) were removed by filtration, the filtrates were combined, and the solvent was distilled off under reduced pressure to obtain a pale yellow pasty crude product. The crude product was purified by column chromatography (NH-silica gel, 500 mL) (elution solvent: ethyl acetate-methanol 49: 1 to 19: 1) to obtain 5027 mg of a white solid. Diisopropyl ether (40 mL) and n-hexane (10 mL) were added to the white solid, and the resulting suspension was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration, washed with diisopropyl ether-n-hexane (2: 1) (5 mL, 10 mL), and then dried under reduced pressure to give 5- (5-isopropyl-2,4-bis-methoxymethoxyphenyl). ) -4- [4- (4-Methylpiperazin-1-ylmethyl) phenyl] -2,4-dihydro- [1,2,4] triazol-3-one (1bc) 4769 mg (51%) as a white solid Obtained.
　得られた生成物の分析結果を以下に示す。
ＨＰＬＣ面比：９９．７％（２１０ｎｍ）
カラム：Ｉｎｅｒｔｓｉｌ　ＯＤＳ－３；４．６×１５０ｍｍ；　カラム温度：３０℃
溶出溶媒：アセトニトリル－１％Ｈ３ＰＯ４
０－２０ｍｉｎ：アセトニトリル濃度　２０→８０％；　２０－３０ｍｉｎ：アセトニトリル濃度　８０％
試料０．５ｍｇをアセトニトリル（１ｍＬ）－水（１ｍＬ）に溶解し、１０μＬをインジェクトした。
ＬＣ／ＭＳ　保持時間：４．４０３分；　面比：１００．０％（２１０ｎｍ）；
ｍ／ｚ（ＥＳＩ，ＰＯＳ）：５１２［Ｍ＋Ｈ］＋．
ＮＭＲ［４００ＭＨｚ，ＣＤＣｌ３，ＴＭＳ］ｐｐｍ：１．１５８（６Ｈ，ｄ，Ｊ＝７．０Ｈｚ），２．２８５（３Ｈ，ｓ），２．４４９（８Ｈ，ｂｒｓ），３．１７０（３Ｈ，ｓ），３．２３４（１Ｈ，ｓｅｐｔｅｔ，Ｊ＝７．０Ｈｚ），３．４４６（２Ｈ，ｓ），３．４７６（３Ｈ，ｓ），４．６３０（２Ｈ，ｓ），５．１７４（２Ｈ，ｓ），６．８１２（１Ｈ，ｓ），７．１３２（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．２０９（１Ｈ，ｓ），７．２９６（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），１０．０２１（１Ｈ，ｂｒｓ）． The analysis result of the obtained product is shown below.
HPLC area ratio: 99.7% (210 nm)
Column: Inertsil ODS-3; 4.6 × 150 mm; Column temperature: 30 ° C.
Elution solvent: acetonitrile-1% H 3 PO 4
0-20 min: acetonitrile concentration 20 → 80%; 20-30 min: acetonitrile concentration 80%
A 0.5 mg sample was dissolved in acetonitrile (1 mL) -water (1 mL), and 10 μL was injected.
LC / MS retention time: 4.403 minutes; Aspect ratio: 100.0% (210 nm);
m / z (ESI, POS): 512 [M + H] + .
NMR [400 MHz, CDCl 3 , TMS] ppm: 1.158 (6H, d, J = 7.0 Hz), 2.285 (3H, s), 2.449 (8H, brs), 3.170 (3H, s), 3.234 (1H, seppet, J = 7.0 Hz), 3.446 (2H, s), 3.476 (3H, s), 4.630 (2H, s), 5.174 (2H) , S), 6.812 (1H, s), 7.132 (2H, d, J = 8.4 Hz), 7.209 (1H, s), 7.296 (2H, d, J = 8.4 Hz). ), 10.021 (1H, brs).
実施例１－２、実施例１－３、実施例１－４
　３－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－５－（ｎ－ドデシルチオ）－［１，２，４］トリアゾール（２ｃ）の本発明の加水分解反応における、水及び塩基の当量比を変えた例を示す。 Example 1-2, Example 1-3, Example 1-4
3- (5-Isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5- (n-dodecylthio)-[1,2,4 The example which changed the equivalent ratio of water and a base in the hydrolysis reaction of this invention of triazole (2c) is shown.
実施例１－２
　アルゴン雰囲気中、室温撹拌下、３－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－５－（ｎ－ドデシルチオ）－［１，２，４］トリアゾール（２ｃ）１モル当量部の乾燥１，４－ジオキサン溶液中に、カリウムｔｅｒｔ－ブトキシドを該化合物（２ｃ）に対し１０モル当量部を加え、室温で１５分撹拌した。次いで、室温撹拌下、水を該化合物（２ｃ）に対し７モル当量部を加え、４時間加熱還流した。反応溶液を採取し、以下のＨＰＬＣ条件にて原料（２ｃ）、及び生成物（１ｂｃ）の定量分析を行なった。結果を表１に示した。 Example 1-2
Under stirring at room temperature in an argon atmosphere, 3- (5-isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5- (n-dodecylthio) )-[1,2,4] triazole (2c) In a dry 1,4-dioxane solution of 1 molar equivalent part, 10 molar equivalent part of potassium tert-butoxide is added to the compound (2c), Stir for minutes. Next, with stirring at room temperature, 7 molar equivalents of water was added to the compound (2c), and the mixture was heated to reflux for 4 hours. The reaction solution was collected, and the raw material (2c) and the product (1bc) were quantitatively analyzed under the following HPLC conditions. The results are shown in Table 1.
　原料（２ｃ）及び生成物（１ｂｃ）の定量分析に用いたＨＬＰＣ分析条件を示す。
カラム：Ｉｎｅｒｔｓｉｌ　ＯＤＳ－３；４．６×１５０ｍｍ；　カラム温度：室温
溶出溶媒：アセトニトリル－１％Ｈ３ＰＯ４
０－２０ｍｉｎ：アセトニトリル濃度　２０→８０％；　２０－３０ｍｉｎ：アセトニトリル濃度　８０％
試料：１ｍＬのメスフラスコに反応液２０μＬをとり、５０％アセトニトリル水溶液を加えてメスアップして試料溶液とし、２μＬをインジェクトした。
検出波長：２５４ｎｍ The HLPC analysis conditions used for the quantitative analysis of the raw material (2c) and the product (1bc) are shown.
Column: Inertsil ODS-3; 4.6 × 150 mm; Column temperature: Room temperature Elution solvent: Acetonitrile-1% H 3 PO 4
0-20 min: acetonitrile concentration 20 → 80%; 20-30 min: acetonitrile concentration 80%
Sample: Take 20 μL of the reaction solution in a 1 mL volumetric flask, add 50% acetonitrile aqueous solution to make up the sample solution, and inject 2 μL.
Detection wavelength: 254 nm
実施例１－３
　実施例１－２における、水の添加量を該化合物（２ｃ）に対し４モル当量部とした以外は、同様の反応条件にて同様の操作を行なった。反応時間４時間時点での反応系内における原料（２ｃ）、及び生成物（１ｂｃ）の定量分析を行なった。結果を表１に示した。 Example 1-3
The same operation as in Example 1-2 was carried out under the same reaction conditions except that the amount of water added was 4 molar equivalents relative to the compound (2c). The raw material (2c) and the product (1bc) in the reaction system at the reaction time of 4 hours were quantitatively analyzed. The results are shown in Table 1.
実施例１－４
　実施例１－２における、水の添加量を該化合物（２ｃ）に対し２モル当量部とした以外は、同様の反応条件にて同様の操作を行なった。反応時間４時間時点での反応系内における原料（２ｃ）、及び生成物（１ｂｃ）の定量分析を行なった。結果を表１に示した。 Example 1-4
The same operation as in Example 1-2 was carried out under the same reaction conditions except that the amount of water added was 2 molar equivalents relative to the compound (2c). The raw material (2c) and the product (1bc) in the reaction system at the reaction time of 4 hours were quantitatively analyzed. The results are shown in Table 1.
表１：実施例１－２，１－３，１－４の結果一覧
Figure JPOXMLDOC01-appb-T000031
＊１；２ｃに対する当量、　＊２；ＨＰＬＣ面積換算値 Table 1: List of results of Examples 1-2, 1-3, and 1-4
Figure JPOXMLDOC01-appb-T000031
* 1: Equivalent to 2c * 2: HPLC area conversion value
　実施例１－２、１－３、及び１－４の結果から、本発明の製造方法は、水及び塩基の添加当量により、反応速度を制御できることが明らかとなった。すなわち、トリアゾリルスルフィド誘導体（２ｃ）に対し水の添加量を７当量とし、塩基であるカリウムｔｅｒｔ－ブトキシドを、添加水に対して３当量過剰に用いた実施例１－２は、比較的穏やかな反応速度で、目的化合物である［１，２，４］トリアゾール－３－オン（１ｂｃ）を生成した。一方、該化合物（２ｃ）に対する水の添加量が４当量で、カリウムｔｅｒｔ－ブトキシドが添加水に対して６当量過剰に用いた実施例１－３、及び該化合物（２ｃ）に対する水の添加量が２当量で、カリウムｔｅｒｔ－ブトキシドが添加水に対して８当量過剰に用いた実施例１－４は比較的速い反応速度で、目的化合物である［１，２，４］トリアゾール－３－オン（１ｂｃ）を生成した。本反応結果から、本発明の製造方法は、添加する塩基の過剰当量が多いほど、より速い反応速度で当該反応を進行させられる事が明らかとなった。 From the results of Examples 1-2, 1-3, and 1-4, it was revealed that the production method of the present invention can control the reaction rate by the addition equivalent of water and base. That is, Example 1-2 in which the amount of water added was 7 equivalents relative to the triazolyl sulfide derivative (2c) and potassium tert-butoxide as a base was used in an excess of 3 equivalents relative to the added water was relatively low. The target compound [1,2,4] triazol-3-one (1bc) was produced at a moderate reaction rate. On the other hand, Example 1-3 in which the amount of water added to the compound (2c) was 4 equivalents and potassium tert-butoxide was used in excess of 6 equivalents to the added water, and the amount of water added to the compound (2c) Is 1 equivalent, and potassium tert-butoxide is used in an excess of 8 equivalents with respect to the added water. Example 1-4 has a relatively fast reaction rate and the target compound [1,2,4] triazol-3-one. (1bc) was produced. From the results of this reaction, it has been clarified that the production method of the present invention allows the reaction to proceed at a faster reaction rate as the excess equivalent of the added base increases.
実施例２
　３－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－５－メチルチオ－［１，２，４］トリアゾール（２ｂ）の本発明の加水分解反応を、種々の反応溶媒を用いて実施した。 Example 2
3- (5-Isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5-methylthio- [1,2,4] triazole (2b The hydrolysis reaction of the present invention was carried out using various reaction solvents.
実施例２－１
　アルゴン雰囲気中、室温撹拌下、３－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－５－メチルチオ－［１，２，４］トリアゾール（２ｂ）（１０８ｍｇ，０．２０ｍｍｏｌ）の乾燥１，４－ジオキサン（２ｍＬ）溶液中に、カリウムｔｅｒｔ－ブトキシド（１４８ｍｇ，１．３２ｍｍｏｌ）、及び水（０．００７９ｍＬ，７．９ｍｇ，０．４４ｍｍｏｌ）を加え、１００℃で６時間撹拌した。反応液を冷水（１３ｍＬ）中に加え、１Ｎ硫酸水素カリウム水溶液、及び５％炭酸水素ナトリウム水溶液を加えてｐＨ約８とした。更に、塩化ナトリウム水溶液を加え、酢酸エチルで抽出した。酢酸エチル抽出液を合して塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去し、濾液に固形炭酸カリウムを加えて室温で５０分撹拌した。炭酸カリウムを濾去し、減圧下溶媒を留去して、粗生成物（１００ｍｇ）を得た。この粗生成物（９５ｍｇ）を、酢酸エチルーメタノール（２９：１）（２ｍＬ）に溶解し、カラムクロマトグラフィー（ＮＨ－シリカゲル，４５ｍＬ）（溶出溶媒：酢酸エチル－メタノール　２９：１）により精製し、５－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－２，４－ジヒドロ－［１，２，４］トリアゾール－３－オン（１ｂｃ），５９ｍｇ（６１％）を白色固体として得た。
　得られた生成物のＬＣ／ＭＳ分析結果を示す。 
ＬＣ／ＭＳ
保持時間：４．３６８分；　面比：１００．０％（２１０ｎｍ）；
ｍ／ｚ（ＥＳＩ，ＰＯＳ）：５１２［Ｍ＋Ｈ］＋． Example 2-1
Under stirring at room temperature in an argon atmosphere, 3- (5-isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5-methylthio- [1 , 2,4] triazole (2b) (108 mg, 0.20 mmol) in dry 1,4-dioxane (2 mL) in potassium tert-butoxide (148 mg, 1.32 mmol) and water (0.0079 mL, 7 .9 mg, 0.44 mmol) was added, and the mixture was stirred at 100 ° C. for 6 hours. The reaction mixture was added to cold water (13 mL), and 1N aqueous potassium hydrogen sulfate solution and 5% aqueous sodium hydrogen carbonate solution were added to adjust the pH to about 8. Further, an aqueous sodium chloride solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with an aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, solid potassium carbonate was added to the filtrate, and the mixture was stirred at room temperature for 50 minutes. Potassium carbonate was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product (100 mg). This crude product (95 mg) was dissolved in ethyl acetate-methanol (29: 1) (2 mL) and purified by column chromatography (NH-silica gel, 45 mL) (elution solvent: ethyl acetate-methanol 29: 1). , 5- (5-Isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -2,4-dihydro- [1,2,4] Triazol-3-one (1bc), 59 mg (61%) was obtained as a white solid.
The LC / MS analysis result of the obtained product is shown.
LC / MS
Retention time: 4.368 minutes; Area ratio: 100.0% (210 nm);
m / z (ESI, POS): 512 [M + H] + .
実施例２－２
　アルゴン雰囲気中、室温撹拌下、３－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－５－メチルチオ－［１，２，４］トリアゾール（２ｂ）（１０８ｍｇ，０．２０ｍｍｏｌ）の乾燥テトラヒドロフラン（ＴＨＦ；２ｍＬ）溶液中に、カリウムｔｅｒｔ－ブトキシド（１４８ｍｇ，１．３２ｍｍｏｌ）、及び水（０．００７９ｍＬ，７．９ｍｇ，０．４４ｍｍｏｌ）を加え、室温で２０時間４５分撹拌し、次いで、１５．５時間加熱還流した。
　反応液のＬＣ／ＭＳ面比は、原料化合物（２ｂ）８３．０％、目的物（１ｂｃ）１５．４％であった。 Example 2-2
Under stirring at room temperature in an argon atmosphere, 3- (5-isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5-methylthio- [1 , 2,4] triazole (2b) (108 mg, 0.20 mmol) in dry tetrahydrofuran (THF; 2 mL), potassium tert-butoxide (148 mg, 1.32 mmol), and water (0.0079 mL, 7.9 mg). , 0.44 mmol), and stirred at room temperature for 20 hours and 45 minutes, and then heated to reflux for 15.5 hours.
The LC / MS surface ratio of the reaction solution was 83.0% of the starting compound (2b) and 15.4% of the desired product (1bc).
実施例２－３
　実施例２－２の反応溶液を用い、次いで、反応液に乾燥ビス（２－メトキシエチル）エーテル（ジグライム；１ｍＬ）、及びカリウムｔｅｒｔ－ブトキシド（１４８ｍｇ，１．３２ｍｍｏｌ）を加え、１００℃で３．５時間撹拌した。
　反応液のＬＣ／ＭＳ面比は、原料化合物（２ｂ）が５％以下、目的物（１ｂｃ）が９０％であった。
　実施例２－２、２－３の結果を下記表２にまとめた。 Example 2-3
Using the reaction solution of Example 2-2, dry bis (2-methoxyethyl) ether (diglyme; 1 mL) and potassium tert-butoxide (148 mg, 1.32 mmol) were then added to the reaction solution, Stir for 5 hours.
The LC / MS surface ratio of the reaction solution was 5% or less for the starting compound (2b) and 90% for the target product (1bc).
The results of Examples 2-2 and 2-3 are summarized in Table 2 below.
表２；実施例２－２、実施例２－３の反応結果
Figure JPOXMLDOC01-appb-T000032
＊１；ＨＰＬＣ面積換算値 Table 2: Reaction results of Example 2-2 and Example 2-3
Figure JPOXMLDOC01-appb-T000032
* 1: HPLC area conversion value
　実施例２－３の反応液を冷水（１２ｍＬ）中に加え、１Ｎ硫酸水素カリウム水溶液、及び５％炭酸水素ナトリウム水溶液を加えてｐＨ約８とした。更に、塩化ナトリウム水溶液を加え、酢酸エチルで抽出した。酢酸エチル抽出液を合して塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去し、減圧下溶媒を留去して、淡黄色オイルを得た。得られた淡黄色オイルにｎ－ヘキサン（５ｍＬ）を加え、得られた懸濁液を室温で４．５時間撹拌した。析出している固体を濾取し、ｎ－ヘキサン（２ｍＬ）、及びｎ－ヘキサン（２ｍＬ）－ジイソプロピルエーテル（０．５ｍＬ）で洗浄し、白色固体（７３．９ｍｇ）を得た。この粗生成物を、酢酸エチル－メタノール（２９：１）（２．５ｍＬ）、及びジクロロメタン（０．６ｍＬ）に溶解し、カラムクロマトグラフィー（ＮＨ－シリカゲル，４０ｍＬ）（溶出溶媒：酢酸エチル－メタノール　２９：１）により精製し、５－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－２，４－ジヒドロ－［１，２，４］トリアゾール－３－オン（１ｂｃ），５７ｍｇ（５６％）を，白色固体として得た。
　得られた生成物のＬＣ／ＭＳ分析結果を示す。
ＬＣ／ＭＳ
保持時間：４．３８５分；　面比：１００．０％（２１０ｎｍ）；
ｍ／ｚ（ＥＳＩ，ＰＯＳ）：５１２［Ｍ＋Ｈ］＋． The reaction solution of Example 2-3 was added to cold water (12 mL), and 1N potassium hydrogen sulfate aqueous solution and 5% sodium hydrogen carbonate aqueous solution were added to adjust the pH to about 8. Further, an aqueous sodium chloride solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with an aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a pale yellow oil. N-Hexane (5 mL) was added to the obtained pale yellow oil, and the resulting suspension was stirred at room temperature for 4.5 hours. The precipitated solid was collected by filtration and washed with n-hexane (2 mL) and n-hexane (2 mL) -diisopropyl ether (0.5 mL) to obtain a white solid (73.9 mg). This crude product is dissolved in ethyl acetate-methanol (29: 1) (2.5 mL) and dichloromethane (0.6 mL), and column chromatography (NH-silica gel, 40 mL) (elution solvent: ethyl acetate-methanol). 29: 1) and purified by 5- (5-isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -2,4-dihydro- [1,2,4] Triazol-3-one (1bc), 57 mg (56%) was obtained as a white solid.
The LC / MS analysis result of the obtained product is shown.
LC / MS
Retention time: 4.385 minutes; Area ratio: 100.0% (210 nm);
m / z (ESI, POS): 512 [M + H] + .
実施例２－４
　アルゴン雰囲気中、室温撹拌下、３－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－５－メチルチオ－［１，２，４］トリアゾール（２ｂ）（１０８ｍｇ，０．２０ｍｍｏｌ）の乾燥１，２－ジメトキシエタン（ＤＭＥ；２ｍＬ）溶液中に、カリウムｔｅｒｔ－ブトキシド（１４８ｍｇ，１．３２ｍｍｏｌ）、及び水（０．００７９ｍＬ，７．９ｍｇ，０．４４ｍｍｏｌ）を加え、８時間加熱還流した。室温撹拌下、反応液にカリウムｔｅｒｔ－ブトキシド（７４ｍｇ，０．６６ｍｍｏｌ）を追加し、更に７時間加熱還流した。反応液を冷水（１３ｍＬ）中に加え、１Ｎ硫酸水素カリウム水溶液（１．７ｍＬ）を加えてｐＨ７－８とし、更に、塩化ナトリウム水溶液を加えて酢酸エチルで抽出した。酢酸エチル抽出液を合して塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去し、減圧下溶媒を留去して、粗生成物（８７ｍｇ）を得た。この粗生成物（８７ｍｇ）を、酢酸エチルーメタノール（２９：１）（２ｍＬ）に溶解し、カラムクロマトグラフィー（ＮＨ－シリカゲル，４５ｍＬ）（溶出溶媒：酢酸エチル－メタノール　２９：１）により精製して，５－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－２，４－ジヒドロ－［１，２，４］トリアゾール－３－オン（１ｂｃ）、５６ｍｇ（５５％）を白色固体として得た。
　得られた生成物のＬＣ／ＭＳ分析結果を示す。
ＬＣ／ＭＳ
保持時間：４．３６９分；　面比：９９．７％（２１０ｎｍ）；
ｍ／ｚ（ＥＳＩ，ＰＯＳ）：５１２［Ｍ＋Ｈ］＋． Example 2-4
Under stirring at room temperature in an argon atmosphere, 3- (5-isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5-methylthio- [1 , 2,4] triazole (2b) (108 mg, 0.20 mmol) in a dry 1,2-dimethoxyethane (DME; 2 mL) solution in potassium tert-butoxide (148 mg, 1.32 mmol) and water (0. 0079 mL, 7.9 mg, 0.44 mmol) was added, and the mixture was heated to reflux for 8 hours. Under stirring at room temperature, potassium tert-butoxide (74 mg, 0.66 mmol) was added to the reaction mixture, and the mixture was further heated to reflux for 7 hours. The reaction mixture was added to cold water (13 mL), 1N aqueous potassium hydrogen sulfate solution (1.7 mL) was added to adjust pH to 7-8, and further aqueous sodium chloride solution was added, followed by extraction with ethyl acetate. The ethyl acetate extracts were combined, washed with an aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product (87 mg). This crude product (87 mg) was dissolved in ethyl acetate-methanol (29: 1) (2 mL) and purified by column chromatography (NH-silica gel, 45 mL) (elution solvent: ethyl acetate-methanol 29: 1). 5- (5-isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -2,4-dihydro- [1,2,4 Triazol-3-one (1bc), 56 mg (55%) was obtained as a white solid.
The LC / MS analysis result of the obtained product is shown.
LC / MS
Retention time: 4.369 minutes; Aspect ratio: 99.7% (210 nm);
m / z (ESI, POS): 512 [M + H] + .
　実施例２では、本発明の反応溶媒として用いられる非プロトン性溶媒において、種々のエーテル溶媒を用いた反応条件の検討を示した。実施例２－１（１，４－ジオキサン／１００℃）、実施例２－２（テトラヒドロフラン／加熱還流）、実施例２－３（ビス（２－メトキシエチル）エーテル／１００℃）、実施例２－４（１，２－ジメトキシエタン／加熱還流）にて反応を行なった結果、何れの反応エーテル溶媒を用いても反応は進行し、目的物（１ｂｃ）が得られた。したがって、本発明における好適な非プロトン性反応溶媒としては、エーテル溶媒が好ましい。
　実施例２において、反応温度を１００℃以上にすると、本発明の製造方法は反応速度が速くなる傾向が認められた。したがって高温の反応条件に設定できる、１，４－ジオキサン、ビス（２－メトキシエチル）エーテル、１，２－ジメトキシエタンが特に好ましい反応溶媒である。 In Example 2, the examination of reaction conditions using various ether solvents in the aprotic solvent used as the reaction solvent of the present invention was shown. Example 2-1 (1,4-dioxane / 100 ° C.), Example 2-2 (tetrahydrofuran / heated reflux), Example 2-3 (bis (2-methoxyethyl) ether / 100 ° C.), Example 2 As a result of the reaction with -4 (1,2-dimethoxyethane / heated reflux), the reaction proceeded regardless of which reaction ether solvent was used, and the target product (1bc) was obtained. Therefore, an ether solvent is preferable as a suitable aprotic reaction solvent in the present invention.
In Example 2, when the reaction temperature was 100 ° C. or higher, it was recognized that the production method of the present invention tends to increase the reaction rate. Accordingly, 1,4-dioxane, bis (2-methoxyethyl) ether, and 1,2-dimethoxyethane, which can be set at high temperature reaction conditions, are particularly preferred reaction solvents.
比較例１
３－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－５－メチルチオ－［１，２，４］トリアゾール（２ｂ）の水酸化ナトリウム水溶液による加水分解反応の検討
　室温撹拌下、３－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－５－メチルチオ－［１，２，４］トリアゾール（２ｂ）（５４ｍｇ，０．１０ｍｍｏｌ）のビス（２－メトキシエチル）エーテル（ジグライム；０．４ｍＬ）溶液中に、５％水酸化ナトリウム水溶液（０．２ｍＬ，０．２５ｍｍｏｌ）を加え、室温で１７．５時間、次いで９０℃で２時間１５分撹拌した。反応液は原料の（２ｂ）のみで、目的物の（１ｂｃ）は認められなかった（薄層クロマトグラフィーによる検出分析）。 Comparative Example 1
3- (5-Isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5-methylthio- [1,2,4] triazole (2b ) Hydrolysis reaction with aqueous sodium hydroxide solution Under stirring at room temperature, 3- (5-isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl ] -5-Methylthio- [1,2,4] triazole (2b) (54 mg, 0.10 mmol) in bis (2-methoxyethyl) ether (diglyme; 0.4 mL) solution in 5% aqueous sodium hydroxide (0.2 mL, 0.25 mmol) was added, and the mixture was stirred at room temperature for 17.5 hours and then at 90 ° C. for 2 hours and 15 minutes. The reaction solution was only the raw material (2b), and the target product (1bc) was not observed (detection analysis by thin layer chromatography).
　比較例１の製造方法は、本発明において用いる水及び塩基として水酸化ナトリウム水溶液を用いた反応条件である。比較例１の反応条件では、目的物（１ｂｃ）の生成は認められなかった。
　実施例１及び２、並びに比較例１の結果を踏まえると、トリアゾリルスルフィド誘導体（２ｂまたは２ｃ）から［１，２，４］トリアゾール－３－オン誘導体（１ｂｃ）へ変換する反応は、水酸化カリウム以上の強塩基を、添加した水の当量より過剰当量に用いる場合において進行する結果であった。本発明に係る実施例は、塩基としてカリウムｔｅｒｔ－ブトキシドを、水と共に用いた反応条件である。添加した水は、カリウムｔｅｒｔ－ブトキシドと反応し、水酸化カリウムに変換され、反応に供せられる。すなわち、本発明に係る反応は、水酸化カリウムとカリウムｔｅｒｔ－ブトキシドの２種類の塩基を、トリアゾリルスルフィド誘導体（２ｂまたは２ｃ）に対し反応させる事を特徴とするものである。このような特殊な反応条件が、通常のアルカリ加水分解反応では進行しないトリアゾリルスルフィド誘導体（２ｂまたは２ｃ）から［１，２，４］トリアゾール－３－オン誘導体（１ｂｃ）への直接変換の反応を進行させていると言える。 The production method of Comparative Example 1 is reaction conditions using an aqueous sodium hydroxide solution as the water and base used in the present invention. Under the reaction conditions of Comparative Example 1, formation of the desired product (1bc) was not observed.
Based on the results of Examples 1 and 2 and Comparative Example 1, the reaction for converting the triazolyl sulfide derivative (2b or 2c) to the [1,2,4] triazol-3-one derivative (1bc) This was a result that progressed when a strong base of potassium oxide or higher was used in an excess equivalent to the equivalent of added water. Examples according to the present invention are reaction conditions using potassium tert-butoxide as a base together with water. The added water reacts with potassium tert-butoxide, is converted to potassium hydroxide, and is subjected to the reaction. That is, the reaction according to the present invention is characterized in that two types of bases of potassium hydroxide and potassium tert-butoxide are reacted with a triazolyl sulfide derivative (2b or 2c). Such special reaction conditions allow direct conversion of the triazolyl sulfide derivative (2b or 2c) to the [1,2,4] triazol-3-one derivative (1bc), which does not proceed in a normal alkaline hydrolysis reaction. It can be said that the reaction is progressing.
合成例１
５－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－２，４－ジヒドロ－［１，２，４］トリアゾール－３－チオン（４ｃ）のアルキル化反応による、３－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－５－（ｎ－ドデシルチオ）－［１，２，４］トリアゾール（２ｃ）の合成反応（スキーム２） Synthesis example 1
5- (5-Isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -2,4-dihydro- [1,2,4] triazole 3- (5-Isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -5 by alkylation reaction of -3-thione (4c) Synthesis reaction of-(n-dodecylthio)-[1,2,4] triazole (2c) (Scheme 2)
スキーム２；
Figure JPOXMLDOC01-appb-C000033
 Scheme 2;
Figure JPOXMLDOC01-appb-C000033
　５－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－２，４－ジヒドロ－［１，２，４］トリアゾール－３－チオン（４ｃ）は、特許文献１；国際公開ＷＯ２００６／０９５７８３号の実施例２－５の記載に従い合成した。
　５－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－２，４－ジヒドロ－［１，２，４］トリアゾール－３－チオン（４ｃ）（１８ｇ，３４．１ｍｍｏｌ）のエタノール（９０ｍＬ）懸濁液を浴温５０℃（内温４４℃）で加温した後、炭酸セシウム（１２．２３ｇ，３７．５ｍｍｏｌ）を加え、油浴上、浴温５０℃（内温４４℃）で１時間撹拌した。次いで、１－ヨードドデカン（８．６ｍＬ，１０．３ｇ，３４．９ｍｍｏｌ）を加え、油浴上、浴温５０℃（内温４４～４７℃）で４時間撹拌した。減圧下溶媒を留去し、残渣に水（７２ｍＬ）を加え、酢酸エチル（７２ｍＬ，３６ｍＬ）で抽出した。酢酸エチル抽出液を５％チオ硫酸ナトリウム水溶液（３６ｍＬ）、次いで、飽和食塩水（３６ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥した。無水硫酸ナトリウムを濾去、減圧下溶媒を留去し、残渣を減圧乾燥して、３－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－５－（ｎ－ドデシルチオ）－［１，２，４］トリアゾール（２ｃ）（２３．７８ｇ，収率１００％；　ＨＰＬＣ　９６．５％）を得た。このものを精製することなく、本発明に係る加水分解反応の原料として用いた。 5- (5-Isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -2,4-dihydro- [1,2,4] triazole -3-Thion (4c) was synthesized according to the description in Example 2-5 of Patent Document 1; International Publication WO 2006/095783.
5- (5-Isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -2,4-dihydro- [1,2,4] triazole A suspension of -3-thione (4c) (18 g, 34.1 mmol) in ethanol (90 mL) was heated at a bath temperature of 50 ° C. (internal temperature: 44 ° C.), and then cesium carbonate (12.23 g, 37.5 mmol). The mixture was stirred on an oil bath at a bath temperature of 50 ° C. (inner temperature: 44 ° C.) for 1 hour. Next, 1-iodododecane (8.6 mL, 10.3 g, 34.9 mmol) was added, and the mixture was stirred on an oil bath at a bath temperature of 50 ° C. (inner temperature: 44 to 47 ° C.) for 4 hours. The solvent was evaporated under reduced pressure, water (72 mL) was added to the residue, and the mixture was extracted with ethyl acetate (72 mL, 36 mL). The ethyl acetate extract was washed with 5% aqueous sodium thiosulfate solution (36 mL) and then with saturated brine (36 mL), and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was dried under reduced pressure to give 3- (5-isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazine). -1-ylmethyl) phenyl] -5- (n-dodecylthio)-[1,2,4] triazole (2c) (23.78 g, yield 100%; HPLC 96.5%) was obtained. This was used as a raw material for the hydrolysis reaction according to the present invention without purification.
実施例３
５－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－２，４－ジヒドロ－［１，２，４］トリアゾール－３－オン（１ｂｃ）の脱保護反応による、５－（２，４－ジヒドロキシー５－イソプロピルフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－２，４－ジヒドロ－［１，２，４］トリアゾール－３－オン・２塩酸塩（７ｂｃ）の製造（スキーム３） Example 3
5- (5-Isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -2,4-dihydro- [1,2,4] triazole 5- (2,4-dihydroxy-5-isopropylphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -2,4- by deprotection of -3-one (1bc) Preparation of dihydro- [1,2,4] triazol-3-one dihydrochloride (7bc) (Scheme 3)
スキーム３；
Figure JPOXMLDOC01-appb-C000034
 Scheme 3;
Figure JPOXMLDOC01-appb-C000034
　室温下、５－（５－イソプロピル－２，４－ビス－メトキシメトキシフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－２，４－ジヒドロ－［１，２，４］トリアゾール－３－オン（１ｂｃ）（６．０７ｇ，１１．８７ｍｍｏｌ）に２規定塩酸／エタノール溶液（４８．６ｍＬ）を加え、室温で２４時間撹拌した。析出している結晶を濾取、エタノール（４８．６ｍＬ）で洗浄し、減圧乾燥して粗結晶（５．９６ｇ）を得た。反応が完結していなかったため、この粗結晶に再び２規定塩酸／エタノール溶液（４８．６ｍＬ）を加え、５５℃で６．５時間撹拌した。析出している結晶を濾取、エタノール（４８．６ｍＬ）で洗浄し、減圧乾燥して、５－（２，４－ジヒドロキシ－５－イソプロピルフェニル）－４－［４－（４－メチルピペラジン－１－イルメチル）フェニル］－２，４－ジヒドロ－［１，２，４］トリアゾール－３－オン・２塩酸塩（７ｂｃ）（５．７８ｇ，９８．１％）を白色結晶として得た。 At room temperature, 5- (5-isopropyl-2,4-bis-methoxymethoxyphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -2,4-dihydro- [1,2, 4] 2N hydrochloric acid / ethanol solution (48.6 mL) was added to triazol-3-one (1bc) (6.07 g, 11.87 mmol), and the mixture was stirred at room temperature for 24 hours. The precipitated crystals were collected by filtration, washed with ethanol (48.6 mL), and dried under reduced pressure to obtain crude crystals (5.96 g). Since the reaction was not completed, 2N hydrochloric acid / ethanol solution (48.6 mL) was added to the crude crystals again, and the mixture was stirred at 55 ° C. for 6.5 hours. The precipitated crystals were collected by filtration, washed with ethanol (48.6 mL), and dried under reduced pressure to give 5- (2,4-dihydroxy-5-isopropylphenyl) -4- [4- (4-methylpiperazine- 1-ylmethyl) phenyl] -2,4-dihydro- [1,2,4] triazol-3-one dihydrochloride (7bc) (5.78 g, 98.1%) was obtained as white crystals.
　得られた生成物の分析結果を以下に示す。
ＨＰＬＣ面比：９８．６％（２５４ｎｍ）
カラム：Ｉｎｅｒｔｓｉｌ　ＯＤＳ－３；４．６×１５０ｍｍ；　カラム温度：室温
溶出溶媒：アセトニトリル－１％Ｈ３ＰＯ４
０－２０ｍｉｎ：アセトニトリル濃度　１０→３０％；　２０－３０ｍｉｎ：アセトニトリル濃度　３０％
試料２ｍｇをアセトニトリル－水（１：１）を加えて１ｍＬとし、５μＬをインジェクトした。
ＬＣ／ＭＳ
保持時間：３．６５分；　面比：９９．０％（２１０ｎｍ）；
ｍ／ｚ（ＥＳＩ，ＰＯＳ）：４２４［Ｍ－２ＨＣｌ＋Ｈ］＋
融点：＞２３０℃
ＮＭＲ（４００ＭＨｚ，Ｄ２Ｏ）ｐｐｍ：０．９０９（６Ｈ，ｄ，Ｊ＝６．８Ｈｚ），２．９７２（３Ｈ，ｓ），２．９７７（１Ｈ，ｓｅｐｔｅｔ，Ｊ＝６．８Ｈｚ），３．２９５（４Ｈ，ｂｓ），３．４９５（４Ｈ，ｂｓ），４．１５２（２Ｈ，ｓ），６．３８８（１Ｈ，ｓ），６．８８４（１Ｈ，ｓ），７．３２３（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．５２２（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．
  The analysis result of the obtained product is shown below.
HPLC area ratio: 98.6% (254 nm)
Column: Inertsil ODS-3; 4.6 × 150 mm; Column temperature: Room temperature Elution solvent: Acetonitrile-1% H 3 PO 4
0-20 min: acetonitrile concentration 10 → 30%; 20-30 min: acetonitrile concentration 30%
2 mg of a sample was added to acetonitrile-water (1: 1) to make 1 mL, and 5 μL was injected.
LC / MS
Retention time: 3.65 minutes; Aspect ratio: 99.0% (210 nm);
m / z (ESI, POS): 424 [M-2HCl + H] +
Melting point:> 230 ° C
NMR (400 MHz, D 2 O) ppm: 0.909 (6H, d, J = 6.8 Hz), 2.972 (3H, s), 2.977 (1H, septet, J = 6.8 Hz), 3 .295 (4H, bs), 3.495 (4H, bs), 4.152 (2H, s), 6.388 (1H, s), 6.884 (1H, s), 7.323 (2H, d, J = 8.6 Hz), 7.522 (2H, d, J = 8.6 Hz).

Claims (12)

  1. 　下記一般式（１）
    Figure JPOXMLDOC01-appb-C000001
    ［式中、Ｘは、水素原子、ハロゲン原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、置換基を有していてもよい炭素環アリール基、置換基を有していてもよい複素環アリール基、置換基を有していてもよいアルキルチオ基、置換基を有していてもよいアリールチオ基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアリールオキシ基、置換基を有していてもよい脂肪族アミノ基、置換基を有していてもよい芳香族アミノ基、またはシリル基を示し、
    Ｒは、置換基を有していてもよい炭素環アリール基、置換基を有していてもよい複素環アリール基、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、または置換基を有していてもよいアルキニル基を示し、
    Ｚ１及びＺ２は、互いに同じであっても異なっていてもよく、水素原子または水酸基の保護基を示す］で表される［１，２，４］トリアゾール－３－オン誘導体またはその塩の製造法であって、
    下記一般式（２）
    Figure JPOXMLDOC01-appb-C000002
    ［式中、Ｘ、Ｚ１、Ｚ２、及びＲは前記一般式（１）のＸ、Ｚ１、Ｚ２、及びＲと同じ意味を表し、Ｙは、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、または置換基を有していてもよいアリール基を示す］で表されるトリアゾリルスルフィド誘導体またはその塩を、非プロトン性溶媒中、前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩に対して１当量以上の水、及び前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩に対する前記水の当量よりも過剰当量の下記一般式（３）
    Ｍ－Ｗ　　（３）
    ［式中、Ｍはカリウム、ナトリウムまたはリチウムを示し、ＷはＯ（Ｑ１）で表されるアルコキシ基またはＮ（Ｑ２）（Ｑ３）で表されるアミノ基を示し、前記Ｑ１は２級または３級アルキル基を示し、前記Ｑ２及び前記Ｑ３は、互いに同じであっても異なっていてもよく、アルキル基またはトリアルキルシリル基を示す］で表される塩基で処理し、必要に応じて脱保護工程に付すことを含む、前記一般式（１）
    で表されるトリアゾール－３－オン誘導体またはその塩の製造法。     The following general formula (1)
    Figure JPOXMLDOC01-appb-C000001
    [Wherein, X represents a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a substituent. A carbocyclic aryl group which may have a group, a heterocyclic aryl group which may have a substituent, an alkylthio group which may have a substituent, an arylthio group which may have a substituent An alkoxy group which may have a substituent, an aryloxy group which may have a substituent, an aliphatic amino group which may have a substituent, an aromatic which may have a substituent Group amino group or silyl group,
    R has a carbocyclic aryl group which may have a substituent, a heterocyclic aryl group which may have a substituent, an alkyl group which may have a substituent, and a substituent. An alkenyl group that may be substituted or an alkynyl group that may have a substituent,
    Z 1 and Z 2 may be the same or different from each other, and each represents a hydrogen atom or a hydroxyl-protecting group] [1,2,4] triazol-3-one derivative or a salt thereof A manufacturing method,
    The following general formula (2)
    Figure JPOXMLDOC01-appb-C000002
    [Wherein, X, Z 1 , Z 2 and R represent the same meaning as X, Z 1 , Z 2 and R in the general formula (1), and Y may have a substituent. An alkyl group, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or an aryl group which may have a substituent]] The derivative or a salt thereof is represented by one or more equivalents of water relative to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof in an aprotic solvent, and the general formula (2). The following general formula (3) having an excess equivalent to the equivalent of water relative to the triazolyl sulfide derivative or a salt thereof:
    MW (3)
    [Wherein, M represents potassium, sodium or lithium, W represents an alkoxy group represented by O (Q1) or an amino group represented by N (Q2) (Q3), and the Q1 is secondary or 3 A secondary alkyl group, Q2 and Q3 may be the same or different from each other and represent an alkyl group or a trialkylsilyl group], and deprotection as necessary Including the general formula (1)
    A method for producing a triazol-3-one derivative represented by the formula:
  2. 　前記一般式（３）において、ＷがＯ（Ｑ１）で表されるアルコキシ基であり、前記Ｑ１基がｔｅｒｔ－ブチル基、ｓｅｃ－ブチル基またはイソプロピル基である請求項１に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 The triazole-3 according to claim 1, wherein, in the general formula (3), W is an alkoxy group represented by O (Q1), and the Q1 group is a tert-butyl group, a sec-butyl group, or an isopropyl group. -A process for the production of ONE derivatives or their salts.
  3. 　前記一般式（３）において、ＷがＮ（Ｑ２）（Ｑ３）で表されるアミノ基であり、前記Ｑ２及び前記Ｑ３が共にイソプロピル基、または前記Ｑ２及び前記Ｑ３が共にトリメチルシリル基である請求項１に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 In the general formula (3), W is an amino group represented by N (Q2) (Q3), and both Q2 and Q3 are isopropyl groups, or both Q2 and Q3 are trimethylsilyl groups. 2. A process for producing the triazol-3-one derivative or a salt thereof according to 1.
  4. 　前記非プロトン性溶媒が、沸点が８０℃以上のエーテル溶媒である請求項１～３のいずれか１項に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 The process for producing a triazol-3-one derivative or a salt thereof according to any one of claims 1 to 3, wherein the aprotic solvent is an ether solvent having a boiling point of 80 ° C or higher.
  5. 　前記水の添加量が、前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩に対し１～５０当量であり、前記一般式（３）で表される塩基の添加量が、前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩に対し２～１００当量である請求項１～４のいずれか１項に記載に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 The amount of water added is 1 to 50 equivalents to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof, and the amount of base represented by the general formula (3) is The triazol-3-one derivative or a salt thereof according to any one of claims 1 to 4, which is 2 to 100 equivalents relative to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof. Manufacturing method.
  6. 　反応温度が６０℃から１５０℃である請求項１～５のいずれか１項に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 The process for producing a triazol-3-one derivative or a salt thereof according to any one of claims 1 to 5, wherein the reaction temperature is 60 ° C to 150 ° C.
  7. 　前記水の添加量が、前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩に対し１～１０当量であり、前記一般式（３）で表される塩基の添加量が、前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩に対し２～２０当量であり、且つ前記塩基の添加量が、前記水の添加量よりも１～１０当量過剰である請求項１～６のいずれか１項に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 The amount of water added is 1 to 10 equivalents relative to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof, and the amount of base represented by the general formula (3) is 2 to 20 equivalents to the triazolyl sulfide derivative represented by the general formula (2) or a salt thereof, and the addition amount of the base is 1 to 10 equivalents more than the addition amount of water. Item 7. A process for producing a triazol-3-one derivative or a salt thereof according to any one of Items 1 to 6.
  8. 　前記Ｙが、置換基を有していてもよい炭素数１～２０アルキル基である請求項１～７のいずれか１項に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 The method for producing a triazol-3-one derivative or a salt thereof according to any one of claims 1 to 7, wherein Y is an alkyl group having 1 to 20 carbon atoms which may have a substituent.
  9. 　前記Ｒが、置換基として脂肪族アミノ基を有する炭素環アリール基、置換基として脂肪族アミノアルキル基を有する炭素環アリール基、または置換基を有していてもよい複素環アリール基である請求項１～８のいずれか１項に記載のトリアゾール－３－オン誘導体またはその塩の製造法。 The R is a carbocyclic aryl group having an aliphatic amino group as a substituent, a carbocyclic aryl group having an aliphatic aminoalkyl group as a substituent, or an optionally substituted heterocyclic aryl group. Item 9. A process for producing a triazol-3-one derivative or a salt thereof according to any one of Items 1 to 8.
  10. 　前記請求項１～９のいずれか１項に記載のトリアゾール－３－オン誘導体またはその塩の製造法において、前記Ｚ１及び前記Ｚ２が水酸基の保護基である前記一般式（１）のトリアゾール－３－オン誘導体またはその塩を、更に、脱保護反応により前記Ｚ１及び前記Ｚ２を脱離させ、下記一般式（７）
    Figure JPOXMLDOC01-appb-C000003
    ［式中、Ｘ、Ｒは前記一般式（１）のＸ、Ｒと同じ意味を表す］で表されるトリアゾール－３－オン誘導体またはその塩に変換する脱保護工程を含む、トリアゾール－３－オン誘導体またはその塩の製造法。     10. The method for producing a triazol-3-one derivative or a salt thereof according to any one of claims 1 to 9, wherein Z 1 and Z 2 are hydroxyl protecting groups. The 3-one derivative or a salt thereof is further desorbed from the Z 1 and Z 2 by a deprotection reaction, and the following general formula (7)
    Figure JPOXMLDOC01-appb-C000003
    [Wherein, X and R represent the same meaning as X and R in the general formula (1)], and include a deprotection step for converting to a triazol-3-one derivative or a salt thereof. A method for producing an on-derivative or a salt thereof.
  11. 　前記一般式（１）で表される［１，２，４］トリアゾール－３－オン誘導体またはその塩が、下記一般式（１ａ）
    Figure JPOXMLDOC01-appb-C000004
    ［式中、Ｘａはエチル基、イソプロピル基またはｔｅｒｔ－ブチル基を示し、ｍは０乃至５を示し、Ａは脂肪族アミノ基を示し、Ｚａ１及びＺａ２はエーテル型保護基またはアセタール型保護基を示す］で表わされる化合物またはその塩であり、
    前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩が、下記一般式（２ａ）
    Figure JPOXMLDOC01-appb-C000005
    ［式中、Ｘａはエチル基、イソプロピル基またはｔｅｒｔ－ブチル基を示し、Ｙａは置換基を有していてもよい炭素数１～２０アルキル基を示し、ｍは０乃至５を示し、Ａは脂肪族アミノ基を示し、Ｚａ１及びＺａ２はエーテル型保護基またはアセタール型保護基を示す］で表わされる化合物またはその塩である
    請求項１～９のいずれか１項に記載のトリアゾール－３－オン誘導体またはその塩の製造法。     The [1,2,4] triazol-3-one derivative represented by the general formula (1) or a salt thereof is represented by the following general formula (1a)
    Figure JPOXMLDOC01-appb-C000004
    [Wherein, Xa represents an ethyl group, an isopropyl group or a tert-butyl group, m represents 0 to 5, A represents an aliphatic amino group, Za 1 and Za 2 represent an ether type protecting group or an acetal type protecting group. Or a salt thereof,
    The triazolyl sulfide derivative represented by the general formula (2) or a salt thereof is represented by the following general formula (2a)
    Figure JPOXMLDOC01-appb-C000005
    [Wherein, Xa represents an ethyl group, an isopropyl group or a tert-butyl group, Ya represents an optionally substituted alkyl group having 1 to 20 carbon atoms, m represents 0 to 5, and A represents The triazole-3 according to any one of claims 1 to 9, which is an aliphatic amino group, Za 1 and Za 2 each represent an ether-type protecting group or an acetal-type protecting group] or a salt thereof. -A process for the production of ONE derivatives or their salts.
  12. 　前記一般式（１）で表される［１，２，４］トリアゾール－３－オン誘導体またはその塩が、下記一般式（１ａ）
    Figure JPOXMLDOC01-appb-C000006
    ［式中、Ｘａはエチル基、イソプロピル基またはｔｅｒｔ－ブチル基を示し、ｍは０乃至５を示し、Ａは脂肪族アミノ基を示し、Ｚａ１及びＺａ２はエーテル型保護基またはアセタール型保護基を示す］で表わされる化合物またはその塩であり、
    前記一般式（２）で表されるトリアゾリルスルフィド誘導体またはその塩が、下記一般式（２ａ）
    Figure JPOXMLDOC01-appb-C000007
    ［式中、Ｘａはエチル基、イソプロピル基またはｔｅｒｔ－ブチル基を示し、Ｙａは置換基を有していてもよい炭素数１～２０アルキル基を示し、ｍは０乃至５を示し、Ａは脂肪族アミノ基を示し、Ｚａ１及びＺａ２はエーテル型保護基またはアセタール型保護基を示す］で表わされる化合物またはその塩であり、
    更に、前記一般式（７）で表される化合物またはその塩が、下記一般式（７ａ）
    Figure JPOXMLDOC01-appb-C000008
    ［式中、Ｘａはエチル基、イソプロピル基またはｔｅｒｔ－ブチル基を示し、ｍは０乃至５を示し、Ａは脂肪族アミノ基を示す］でで表わされる化合物またはその塩である、請求項１０に記載のトリアゾール－３－オン誘導体またはその塩の製造法。     The [1,2,4] triazol-3-one derivative represented by the general formula (1) or a salt thereof is represented by the following general formula (1a)
    Figure JPOXMLDOC01-appb-C000006
    [Wherein, Xa represents an ethyl group, an isopropyl group or a tert-butyl group, m represents 0 to 5, A represents an aliphatic amino group, Za 1 and Za 2 represent an ether type protecting group or an acetal type protecting group. Or a salt thereof,
    The triazolyl sulfide derivative represented by the general formula (2) or a salt thereof is represented by the following general formula (2a)
    Figure JPOXMLDOC01-appb-C000007
    [Wherein, Xa represents an ethyl group, an isopropyl group or a tert-butyl group, Ya represents an optionally substituted alkyl group having 1 to 20 carbon atoms, m represents 0 to 5, and A represents An aliphatic amino group, Za 1 and Za 2 represent an ether-type protecting group or an acetal-type protecting group], or a salt thereof,
    Further, the compound represented by the general formula (7) or a salt thereof is represented by the following general formula (7a):
    Figure JPOXMLDOC01-appb-C000008
    Wherein Xa represents an ethyl group, an isopropyl group or a tert-butyl group, m represents 0 to 5 and A represents an aliphatic amino group, or a salt thereof. A process for producing a triazol-3-one derivative or a salt thereof as described in 1. above.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006095783A1 (en) * 2005-03-09 2006-09-14 Nippon Kayaku Kabushiki Kaisha Novel hsp90 inhibitor

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WO2006095783A1 (en) * 2005-03-09 2006-09-14 Nippon Kayaku Kabushiki Kaisha Novel hsp90 inhibitor

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