WO2017006929A1 - Production method for optically active compound, and triazolium salt used as catalyst in same - Google Patents

Production method for optically active compound, and triazolium salt used as catalyst in same Download PDF

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WO2017006929A1
WO2017006929A1 PCT/JP2016/069888 JP2016069888W WO2017006929A1 WO 2017006929 A1 WO2017006929 A1 WO 2017006929A1 JP 2016069888 W JP2016069888 W JP 2016069888W WO 2017006929 A1 WO2017006929 A1 WO 2017006929A1
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group
optionally substituted
alkyl group
general formula
optically active
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PCT/JP2016/069888
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French (fr)
Japanese (ja)
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貴史 大井
亨介 大松
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国立大学法人名古屋大学
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • 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
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • 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 method for producing an optically active compound and a triazolium salt used as a catalyst therefor.
  • Optically active ⁇ -tetrasubstituted ⁇ -amino nitrile derivatives and optically active ⁇ -tetrasubstituted ⁇ -amino acids are widely used as intermediates for the synthesis of medicines and agricultural chemicals.
  • a method for synthesizing an ⁇ -tetrasubstituted ⁇ -amino nitrile derivative and an optically active ⁇ -tetrasubstituted ⁇ -amino acid for example, a method using a step of performing a cyanation reaction (Strecker reaction) using ketimine is known.
  • ketoimine has low reactivity, and it is difficult to catalytically control stereochemistry in the cyanation reaction (Strecker reaction), and it is difficult to synthesize with good yield and stereoselectivity.
  • a method for synthesizing such ⁇ -tetrasubstituted ⁇ -amino nitrile derivatives and optically active ⁇ -tetrasubstituted ⁇ -amino acids there is also known a method using a step of proceeding the reaction using hydrogen cyanide or silyl cyanide in the presence of an optically active catalyst. (For example, Non-Patent Documents 1 and 2).
  • hydrogen cyanide is volatile and difficult to handle, and silyl cyanide is expensive.
  • An object of the present invention is to provide a production method capable of easily obtaining an optically active ⁇ -tetrasubstituted ⁇ -amino nitrile derivative or an intermediate for the synthesis thereof with good yield and stereoselectivity.
  • the present inventors have conducted intensive research to solve the above problems.
  • direct cyanation of the ketoimine derivative is achieved by reacting with a specific ketoimine derivative using an inexpensive and easy-to-handle metal cyanide as the cyano source. It has been found that a Strecker reaction can be caused.
  • the optically active compound obtained by this method the desired ⁇ -tetrasubstituted ⁇ -amino nitrile derivative can be easily obtained with good yield and stereoselectivity.
  • the present inventors have further studied and completed the present invention. That is, the present invention includes the following configurations.
  • R 1 and R 2 are different and each represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group.
  • R 5 and R 8 to R 10 are the same or different and each represents an optionally substituted alkyl group or an optionally substituted aryl group.
  • R 6 represents an optionally substituted primary alkyl group.
  • R 7 represents an optionally substituted aliphatic alkyl group or an optionally substituted cycloalkyl group.
  • X 1 represents a halogen atom or a monovalent anion.
  • a compound represented by A production method comprising a reaction step of reacting with a metal cyanide.
  • R 1 and R 2 are both an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted aryl group.
  • Item 2 The production method according to Item 1.
  • Item 3. The production method according to Item 1 or 2, wherein R 1 and R 2 in the general formulas (1) and (3) are both an optionally substituted alkyl group or an optionally substituted cycloalkyl group. .
  • Item 4. The production method according to any one of Items 1 to 3, wherein the metal cyanide is potassium cyanide.
  • Item 5 The production method according to any one of Items 1 to 4, wherein R 5 and R 8 to R 10 in the general formula (2) are all optionally substituted aryl groups.
  • Item 6. The production method according to any one of Items 1 to 5, wherein R 6 in the general formula (2) is a primary alkyl group substituted with an alkoxy group.
  • Item 7. The production method according to any one of Items 1 to 6, wherein R 10 in the general formula (2) is an aryl group substituted with a halogenated alkyl group.
  • a production method comprising a step of neutralizing an optically active compound obtained by the production method according to Item 8.
  • R 5 and R 8 to R 10 are the same or different and each represents an optionally substituted alkyl group or an optionally substituted aryl group.
  • R 6 represents an optionally substituted primary alkyl group.
  • R 7 represents an optionally substituted aliphatic alkyl group or an optionally substituted cycloalkyl group.
  • X 1 represents a halogen atom or a monovalent anion.
  • Item 11 The catalyst according to Item 10, wherein R 5 and R 8 to R 10 in the general formula (2) are all optionally substituted aryl groups.
  • R 1 and R 2 are different and each represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group.
  • R 3 represents an organic group.
  • R 1 and R 2 are both an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted aryl group.
  • Item 13 The catalyst according to Item 12.
  • R 5 and R 8 to R 10 are the same or different and each represents an optionally substituted alkyl group or an optionally substituted aryl group.
  • R 6A represents a primary alkyl group substituted with an alkoxy group.
  • R 7 represents an optionally substituted aliphatic alkyl group.
  • X 1 represents a halogen atom or a monovalent anion.
  • Item 15 The triazolium salt according to Item 14, wherein R 5 and R 8 to R 10 in the general formula (2) are all optionally substituted aryl groups.
  • Item 16 The triazolium salt according to Item 14 or 15, wherein R 10 is an aryl group substituted with a halogenated alkyl group.
  • R 1 and R 2 are different and each represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group.
  • R 3A represents a dialkylphenyl group.
  • R 1 and R 2 in the general formula (1A) are both an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted aryl group.
  • an inexpensive and easy-to-handle metal cyanide is used as a cyano source to react with a specific ketoimine derivative, thereby reducing the ketoimine derivative.
  • a Strecker reaction that causes direct cyanation can occur.
  • an optically active compound can be obtained by effectively reacting a specific ketoimine derivative with a metal cyanide in the presence of a specific triazolium salt.
  • various optically active compounds can be usually obtained by reacting a specific ketoimine derivative with a metal cyanide in a solvent in the presence of a specific triazolium salt.
  • Substrate Compound The compound used as a substrate to be subjected to the reaction is not particularly limited.
  • R 1 and R 2 are different and each represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group.
  • the alkyl group represented by R 1 and R 2 is not particularly limited, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, sec And acyclic aliphatic alkyl groups such as a butyl group and a tert-butyl group (preferably an acyclic aliphatic alkyl group having 1 to 10 carbon atoms, particularly 3 to 6 carbon atoms).
  • a linear acyclic aliphatic alkyl group can also be employ
  • alkyl groups include halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.), alkoxy groups described below, alkenyl groups described below, aryl groups described below, alkoxycarbonyl groups described below, aryloxy groups described below, etc. It may have about 1 to 6 (particularly 1 to 3) substituents.
  • the alkyl group having such a substituent is an aralkyl group (preferably having 7 to 20 carbon atoms, particularly carbon atoms) such as a benzyl group, a methylbenzyl group, a phenethyl group, a methylphenethyl group, a naphthylmethyl group, and a methylnaphthylmethyl group.
  • an aralkyl group of 7 to 14 is an aralkyl group (preferably having 7 to 20 carbon atoms, particularly carbon atoms) such as a benzyl group, a methylbenzyl group, a phenethyl group, a methylphenethyl group, a naphthylmethyl group, and a methylnaphthylmethyl group.
  • an aralkyl group of 7 to 14 such as a benzyl group, a methylbenzyl group, a phenethyl group, a methylphenethy
  • the cycloalkyl group represented by R 1 and R 2 is not particularly limited, and examples thereof include a cyclopropyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclobutylmethyl group, a cyclopentyl group, and a cyclopentylmethyl.
  • a cycloalkyl group such as a group, a cyclohexyl group, a cyclohexylmethyl group, a cyclohexylethyl group, an adamantyl group (preferably a cycloalkyl group having 3 to 10 carbon atoms, particularly 5 to 8 carbon atoms, etc.).
  • Substituents such as halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.), alkoxy groups described below, alkenyl groups described below, aryl groups described below, alkoxycarbonyl groups described below, aryloxy groups described below, etc. It can also have about 3 (especially 1 to 3).
  • the alkenyl group represented by R 1 and R 2 is not particularly limited, and examples thereof include alkenyl groups such as vinyl groups and allyl groups (preferably having 2 to 11 carbon atoms, particularly 4 to 4 carbon atoms). 7 alkenyl group) and the like.
  • alkenyl groups include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), the above alkyl group, an alkoxy group described below, the above alkenyl group, an aryl group described below, an alkoxycarbonyl group described below, It may have about 1 to 6 (especially 1 to 3) substituents such as an aryloxy group.
  • the aryl group represented by R 1 and R 2 is not particularly limited, and examples thereof include a phenyl group, a tolyl group (o-tolyl group, m-tolyl group, p-tolyl group), xylyl Group (o-xylyl group, m-xylyl group, p-xylyl group), naphthyl group and the like.
  • aryl groups include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), the above alkyl group, an alkoxy group described below, an alkenyl group described below, an aryl group described above, an alkoxycarbonyl group described below, It may have about 1 to 6 (especially 1 to 3) substituents such as an aryloxy group.
  • halogen atom fluorine atom, chlorine atom, bromine atom, iodine atom, etc.
  • an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, etc. are preferable, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, and the like are more preferable, and an unsubstituted acyclic aliphatic alkyl group, an unsubstituted cycloalkyl group, and the like are more preferable.
  • R 1 and R 2 are different.
  • the organic group represented by R 3 is not particularly limited, and is a hydrocarbon group (alkyl group, cycloalkyl group, alkenyl group, aryl group), alkoxy group, alkoxycarbonyl group, aryloxy group. Etc.
  • the alkoxy group represented by R 3 is not particularly limited, and examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, and a sec-butoxy group.
  • an acyclic aliphatic alkoxy group such as a tert-butoxy group (preferably an acyclic aliphatic alkoxy group having 1 to 10 carbon atoms, particularly 3 to 6 carbon atoms).
  • an acyclic linear aliphatic alkoxy group can also be employ
  • These alkoxy groups include a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), the alkyl group, the cycloalkyl group, the alkoxy group, the alkenyl group, the aryl group, which will be described later. It may have about 1 to 6 (especially 1 to 3) substituents such as an alkoxycarbonyl group and an aryloxy group described later.
  • the alkoxycarbonyl group as the organic group represented by R 3 is not particularly limited, and examples thereof include a methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n- Aliphatic alkoxycarbonyl groups such as butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group (preferably an aliphatic alkoxycarbonyl group having 2 to 11 carbon atoms, particularly 4 to 7 carbon atoms), etc. Is mentioned.
  • a linear aliphatic alkoxycarbonyl group can also be employ
  • These alkoxycarbonyl groups include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), the alkyl group, the alkoxy group, the alkenyl group, the aryl group, the alkoxycarbonyl group, which will be described later. 1-6 (especially 1 to 3) of substituents such as aryloxy groups may be included.
  • the aryloxy group as the organic group represented by R 3 is not particularly limited, and examples thereof include phenoxy group, tolyloxy group (o-tolyloxy group, m-tolyloxy group, p-tolyloxy group). And xylyloxy group (o-xylyloxy group, m-xylyloxy group, p-xylyloxy group), naphthyloxy group and the like.
  • aryloxy groups include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), the alkyl group, the alkoxy group, the alkenyl group, the aryl group, the alkoxycarbonyl group, 1-6 (especially 1 to 3) of substituents such as aryloxy groups may be included.
  • an aryl group which may be substituted is preferable from the viewpoint of yield, stereoselectivity, and the like, a substituted aryl group is more preferable, and an aryl group substituted with 1 to 3 alkyl groups Is more preferable.
  • Etc. are more preferable.
  • a metal cyanide is used in order to introduce a cyano group into the substrate compound (compound (3)).
  • the metal cyanide include alkali metal cyanides such as potassium cyanide and sodium cyanide; alkaline earth metal cyanides such as calcium cyanide and magnesium cyanide. Of these, alkali metal cyanide is preferable and potassium cyanide is more preferable from the viewpoint of yield, stereoselectivity, and the like.
  • the cyanation reaction can proceed without using a cyanating agent that is difficult to handle, such as hydrogen cyanide.
  • the amount of metal cyanide used is not particularly limited, and from the viewpoint of yield, stereoselectivity, etc., for example, it is usually preferably about 0.5 to 20 moles, preferably about 1 to 10 moles per mole of compound (3). Is more preferable.
  • R 5 and R 8 to R 10 are the same or different and each represents an optionally substituted alkyl group or an optionally substituted aryl group.
  • R 6 represents an optionally substituted primary alkyl group.
  • R 7 represents an optionally substituted aliphatic alkyl group or an optionally substituted cycloalkyl group.
  • X 1 represents a halogen atom or a monovalent anion. ] (Hereinafter also referred to as “triazolium salt (2)”).
  • alkyl group and aryl group represented by R 5 those described above can be employed.
  • the kind and number of substituents are the same.
  • an aryl group which may be substituted is preferable, a substituted aryl group is more preferable, and 1 to 6, particularly 1 to 3 halogen atoms (fluorine atom, chlorine) are preferable.
  • Atom, bromine atom, iodine atom, etc.) an aryl group substituted with the aryl group or the like is more preferred.
  • aryl group substituted with the aryl group or the like is more preferred.
  • the primary alkyl group represented by R 6 is not particularly limited, and examples thereof include acyclic groups such as a methyl group, an ethyl group, an n-propyl group, an n-butyl group, and an isobutyl group. And an aliphatic primary alkyl group (preferably an acyclic aliphatic primary alkyl group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms).
  • These primary alkyl groups include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), the alkoxy group, the alkenyl group, the aryl group, the alkoxycarbonyl group, the aryloxy group. It may have about 1 to 6 (especially 1 to 3) substituents such as groups.
  • the primary alkyl group having such a substituent is an aromatic primary alkyl group such as an aralkyl group such as a benzyl group, a methylbenzyl group, a phenethyl group, a methylphenethyl group, a naphthylmethyl group, or a methylnaphthylmethyl group.
  • a group preferably an aromatic primary alkyl group such as an aralkyl group having 7 to 20 carbon atoms, particularly 7 to 14 carbon atoms).
  • an acyclic aliphatic primary alkyl group When an acyclic aliphatic primary alkyl group is used, a linear acyclic aliphatic primary alkyl group can also be used, and a branched acyclic primary aliphatic alkyl group is also used. You can also Among them, from the viewpoint of yield, stereoselectivity, etc., an aromatic primary alkyl group which may be substituted is preferable, an optionally substituted aralkyl group is more preferable, a substituted aralkyl group is more preferable, and 1 Aralkyl groups substituted with up to 3 alkoxy groups and the like are particularly preferred.
  • the aliphatic alkyl group represented by R 7 is not particularly limited, and examples thereof include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec- And acyclic aliphatic alkyl groups such as a butyl group and a tert-butyl group (preferably an acyclic aliphatic alkyl group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms).
  • a linear acyclic aliphatic alkyl group can also be employ
  • These aliphatic alkyl groups include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), the alkoxy group, the alkenyl group, the aryl group, the alkoxycarbonyl group, and the aryloxy group. It can also have about 1 to 6 (especially 1 to 3) substituents such as.
  • R 8 and R 9 as the alkyl group and aryl group represented by R 8 and R 9 , those described above can be adopted.
  • the kind and number of substituents are the same. Among these, from the viewpoints of yield, stereoselectivity, etc., an aryl group which may be substituted is preferable, an unsubstituted aryl group or an aryl group substituted with one halogen atom is more preferable, a phenyl group or chlorophenyl Groups are more preferred.
  • R 8 and R 9 may be the same or different.
  • alkyl group and aryl group represented by R 10 those described above can be employed.
  • the kind and number of substituents are the same.
  • an aryl group which may be substituted is preferable from the viewpoints of yield, stereoselectivity, etc., an unsubstituted aryl group or two alkyl groups (preferably a halogenated alkyl group, particularly a perfluoroalkyl group).
  • An aryl group substituted with the alkoxy group or the like is more preferable, and a phenyl group, a dimethoxyphenyl group, or a bis (trifluoromethyl) phenyl group is more preferable.
  • a chlorine atom, a bromine atom, an iodine atom or the like can be adopted as the halogen atom represented by X 1 .
  • X 1 is preferably a halogen atom, more preferably a chlorine atom, a bromine atom, or the like, and further preferably a bromine atom, from the viewpoints of yield, stereoselectivity, and the like.
  • triazolium salts (2) may be known or commercially available compounds, and may be synthesized according to the methods described in the previous reports (J. Am. Chem. Soc. 2011, 133, 1307-1309., Etc.). You can also
  • the amount of the triazolium salt (2) to be used is not particularly limited, and from the viewpoint of yield, stereoselectivity, etc., for example, usually about 0.002 to 0.1 mol is preferable with respect to 1 mol of compound (3), and 0.005 to 0.05 A molar degree is more preferable.
  • Such a triazolium salt (2) is not limited to the production method of the present invention, and can be used as a catalyst for Strecker reaction.
  • R 5 , R 7 to R 10 and X 1 are the same as defined above.
  • R 6A represents the primary alkyl group substituted with the alkoxy group. ] Is a novel compound not described in any literature.
  • solvent examples include water; aromatic hydrocarbons such as toluene, xylene, benzene and mesitylene; aliphatic halogenated carbonization such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane.
  • chain ethers such as diethyl ether, dimethoxyethane, diisopropyl ether, and tert-butyl methyl ether
  • esters such as ethyl acetate and ethyl propionate
  • ketones such as acetone and methyl ethyl ketone.
  • a mixed solvent of water and aromatic hydrocarbons is preferable from the viewpoint of yield, stereoselectivity, and the like.
  • the content ratio is not particularly limited, and from the viewpoint of yield, stereoselectivity, etc., the volume ratio is water: aromatic. It is preferable to adjust the hydrocarbons to 1: 5 to 100, particularly 1:10 to 50.
  • the reaction can proceed without using a base.
  • the present invention is preferably carried out under an inert gas atmosphere (nitrogen gas, argon gas, etc.), and the reaction temperature is usually about ⁇ 78 ° C. to room temperature (25 ° C.), preferably about ⁇ 70 to 20 ° C.
  • the temperature is preferably about ⁇ 60 to 0 ° C., more preferably about ⁇ 50 to ⁇ 20 ° C.
  • the reaction time may be a time for which the reaction proceeds sufficiently, and is usually about 10 minutes to 72 hours, preferably about 1 to 48 hours.
  • the target compound After completion of the reaction, the target compound can be obtained through normal isolation and purification steps as necessary.
  • R 3A represents a dialkylphenyl group (a dimethylphenyl group such as a 3,5-dimethylphenyl group or a 2,5-dimethylphenyl group; a diethylphenyl group).
  • R 3A represents a dialkylphenyl group (a dimethylphenyl group such as a 3,5-dimethylphenyl group or a 2,5-dimethylphenyl group; a diethylphenyl group).
  • any of the optically active compounds obtained in Examples described later is a novel compound not described in any literature, and is useful as an intermediate for the synthesis of medical and agricultural chemicals.
  • optically active compound (1) is obtained by the production method of the present invention described above, a cyano group is converted to a carboxy group and a —SO 2 R 3 group is converted according to a conventional method.
  • a desired amino acid can also be obtained by conversion to an amino group or —NH 3 X group (X is a halogen atom such as chlorine, bromine, iodine, etc.). For example, removal of a sulfonyl group described in J. Am. Chem. Soc., 2006, 128, 2548., etc., hydrolysis of a nitrile group described in Org. Proc. Res. Dev., 2008, 12, 298.
  • the amino acid can be obtained from the optically active compound (1) according to the above.
  • the amino acid thus obtained has the general formula (4):
  • R 1 and R 2 are the same as defined above.
  • X represents a halogen atom.
  • It is an optically active compound represented by these.
  • the desired amino acid can also be obtained by neutralization according to a conventional method.
  • the amino acid thus obtained has the general formula (5):
  • Me represents a methyl group.
  • t-Bu represents a tert-butyl group.
  • Et represents an ethyl group.
  • Ar represents a 3,5-dimethylphenyl group. The same applies hereinafter.
  • 4-OMeC 6 H 4 represents a 4-methoxyphenyl group.
  • 3,5-CF 3 C 6 H 3 represents a 3,5-di (trifluoromethyl) phenyl group.
  • the same applies hereinafter. was synthesized according to the synthesis method described in the previous report (J. Am. Chem. Soc. 2011, 133, 1307-1309.) (In the same manner except that the substituents of the raw materials were changed).
  • Example 1-2 The same treatment as in Example 1-1 was performed, except that various compounds were used as substrate compounds and any of the triazolium salts obtained in Synthesis Examples 2-1 and 2-2 was used as a catalyst. As a result, it was confirmed that an optically active compound having a substituent shown in Table 1 below was obtained. The results are shown in Table 1.
  • entry 4 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.55 (2H, s), 7.22 (1H, s), 4.86 (1H, brs), 2.39 (6H, s), 2.09 (3H, br), 1.74 -1.61 (12H, m), 1.56 (3H, s).
  • TFA trifluoroacetic acid.
  • BzCl represents benzoyl chloride.
  • DCM dichloromethane.
  • a test tube was charged with compound 3 (29.4 mg, 0.1 mmol) obtained in Example 1-1, trifluoroacetic acid (0.9 mL), thioanisole (0.1 mL) and methanesulfonic acid (10 ⁇ L), and the mixture was stirred at room temperature for 10 hours. Stir. After the reaction, concentrate in an evaporator, add dichloromethane (0.5 mL), water (0.5 mL) and potassium carbonate (55.3 mg, 0.4 mmol) to the test tube containing the crude product, and benzoyl chloride (20 ⁇ L, 0.15 mmol).

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Abstract

The present invention makes it easy to obtain, with good yield and stereoselectivity, an optically active α-tetrasubstituted α-amino nitrile derivative, or an intermediate for the synthesis of said derivative, by reacting a cyanometalate with a compound represented by formula (3), in which R1-R3 are as described, under the presence of a triazolium salt represented by formula (2), in which R5 and R8-R10 are the same or different and represent an aryl group which may be substituted, R6 represents a primary alkyl group which may be substituted, R7 represents a fatty alkyl group which may be substituted, or a cycloalkyl group which may be substituted, and X1 represents a halogen atom or a monovalent anion.

Description

光学活性化合物の製造方法及びそれに触媒として用いられるトリアゾリウム塩Process for producing optically active compound and triazolium salt used as catalyst for the same
　本発明は、光学活性化合物の製造方法及びそれに触媒として用いられるトリアゾリウム塩に関する。 The present invention relates to a method for producing an optically active compound and a triazolium salt used as a catalyst therefor.
　光学活性α四置換αアミノニトリル誘導体及び光学活性α四置換αアミノ酸は、医農薬品合成の中間体に広く使用されている。α四置換αアミノニトリル誘導体及び光学活性α四置換αアミノ酸の合成方法としては、例えば、ケトイミンを用いたシアノ化反応（ストレッカー反応）を行う工程を使用した方法が知られている。しかしながら、ケトイミンは反応性が低く、また、シアノ化反応（ストレッカー反応）における立体化学の触媒的な制御が困難であり、収率及び立体選択率よく合成することは困難であった。このようなα四置換αアミノニトリル誘導体及び光学活性α四置換αアミノ酸の合成方法としては、光学活性な触媒の存在下、シアン化水素又はシリルシアニドを用いて反応を進行させる工程を使用した方法も知られている（例えば、非特許文献１～２等）。しかしながら、シアン化水素は揮発性が高く取扱いが困難であり、シリルシアニドは高価であった。 Optically active α-tetrasubstituted α-amino nitrile derivatives and optically active α-tetrasubstituted α-amino acids are widely used as intermediates for the synthesis of medicines and agricultural chemicals. As a method for synthesizing an α-tetrasubstituted α-amino nitrile derivative and an optically active α-tetrasubstituted α-amino acid, for example, a method using a step of performing a cyanation reaction (Strecker reaction) using ketimine is known. However, ketoimine has low reactivity, and it is difficult to catalytically control stereochemistry in the cyanation reaction (Strecker reaction), and it is difficult to synthesize with good yield and stereoselectivity. As a method for synthesizing such α-tetrasubstituted α-amino nitrile derivatives and optically active α-tetrasubstituted α-amino acids, there is also known a method using a step of proceeding the reaction using hydrogen cyanide or silyl cyanide in the presence of an optically active catalyst. (For example, Non-Patent Documents 1 and 2). However, hydrogen cyanide is volatile and difficult to handle, and silyl cyanide is expensive.
　本発明は、光学活性α四置換αアミノニトリル誘導体又はその合成のための中間体を、簡便に、収率及び立体選択性よく得ることができる製造方法を提供することを目的とする。 An object of the present invention is to provide a production method capable of easily obtaining an optically active α-tetrasubstituted α-amino nitrile derivative or an intermediate for the synthesis thereof with good yield and stereoselectivity.
　本発明者らは上記の課題を解決するために鋭意研究を行った。その結果、特定の1,2,3－トリアゾリウム塩触媒の存在下、安価で取扱いの容易なシアン化金属をシアノ源とし、特定のケトイミン誘導体と反応させることで、ケトイミン誘導体に対して直接シアノ化を引き起こすストレッカー反応を起こさせることができることを見出した。この方法により得られる光学活性化合物を使用することで、所望のα四置換αアミノニトリル誘導体を簡便に、且つ収率及び立体選択性よく得ることができる。本発明者らは、このような知見に基づき、さらに研究を重ね、本発明を完成した。すなわち、本発明は以下の構成を包含する。 The present inventors have conducted intensive research to solve the above problems. As a result, in the presence of a specific 1,2,3-triazolium salt catalyst, direct cyanation of the ketoimine derivative is achieved by reacting with a specific ketoimine derivative using an inexpensive and easy-to-handle metal cyanide as the cyano source. It has been found that a Strecker reaction can be caused. By using the optically active compound obtained by this method, the desired α-tetrasubstituted α-amino nitrile derivative can be easily obtained with good yield and stereoselectivity. Based on such knowledge, the present inventors have further studied and completed the present invention. That is, the present invention includes the following configurations.
　項１．一般式（1）： Item 1. General formula (1):
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
［式中、R1及びR2は異なり、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、置換されていてもよいアルケニル基、又は置換されていてもよいアリール基を示す。R3は有機基を示す。］
で表される光学活性化合物の製造方法であって、
一般式（2）： [Wherein, R 1 and R 2 are different and each represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group. Show. R 3 represents an organic group. ]
A process for producing an optically active compound represented by:
General formula (2):
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
［式中、R5及びR8～R10は同一又は異なって、置換されていてもよいアルキル基、又は置換されていてもよいアリール基を示す。R6は置換されていてもよい第一級アルキル基を示す。R7は置換されていてもよい脂肪族アルキル基、又は置換されていてもよいシクロアルキル基を示す。X1はハロゲン原子又は1価のアニオンを示す。］
で表されるトリアゾリウム塩の存在下に、
一般式（3）： [Wherein, R 5 and R 8 to R 10 are the same or different and each represents an optionally substituted alkyl group or an optionally substituted aryl group. R 6 represents an optionally substituted primary alkyl group. R 7 represents an optionally substituted aliphatic alkyl group or an optionally substituted cycloalkyl group. X 1 represents a halogen atom or a monovalent anion. ]
In the presence of a triazolium salt represented by
General formula (3):
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
［式中、R1～R3は前記に同じである。］
で表される化合物と、
シアン化金属とを反応させる反応工程
を備える、製造方法。 [Wherein R 1 to R 3 are the same as defined above. ]
A compound represented by
A production method comprising a reaction step of reacting with a metal cyanide.
　項２．前記一般式（1）及び（3）におけるR1及びR2がいずれも、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、又は置換されていてもよいアリール基である、項１に記載の製造方法。 Item 2. In the general formulas (1) and (3), R 1 and R 2 are both an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted aryl group. Item 2. The production method according to Item 1.
　項３．前記一般式（1）及び（3）におけるR1及びR2がいずれも、置換されていてもよいアルキル基又は置換されていてもよいシクロアルキル基である、項１又は２に記載の製造方法。 Item 3. Item 3. The production method according to Item 1 or 2, wherein R 1 and R 2 in the general formulas (1) and (3) are both an optionally substituted alkyl group or an optionally substituted cycloalkyl group. .
　項４．前記シアン化金属がシアン化カリウムである、項１～３のいずれかに記載の製造方法。 Item 4. Item 4. The production method according to any one of Items 1 to 3, wherein the metal cyanide is potassium cyanide.
　項５．前記一般式（2）におけるR5及びR8～R10がいずれも、置換されていてもよいアリール基である、項１～４のいずれかに記載の製造方法。 Item 5. Item 5. The production method according to any one of Items 1 to 4, wherein R 5 and R 8 to R 10 in the general formula (2) are all optionally substituted aryl groups.
　項６．前記一般式（2）におけるR6が、アルコキシ基で置換された第一級アルキル基である、項１～５のいずれかに記載の製造方法。 Item 6. Item 6. The production method according to any one of Items 1 to 5, wherein R 6 in the general formula (2) is a primary alkyl group substituted with an alkoxy group.
　項７．前記一般式（2）におけるR10が、ハロゲン化アルキル基で置換されたアリール基である、項１～６のいずれかに記載の製造方法。 Item 7. Item 7. The production method according to any one of Items 1 to 6, wherein R 10 in the general formula (2) is an aryl group substituted with a halogenated alkyl group.
　項８．一般式（4）： Item 8. General formula (4):
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
［式中、R1～R2は前記に同じである。Xはハロゲン原子を示す。］
で表される光学活性化合物の製造方法であって、
項１～７のいずれかに記載の製造方法で得られた光学活性化合物における－SO2R3基をアラルキル基に置換した後に、該アラルキル基を－NH3X基に置換する工程
を備える、製造方法。 [Wherein R 1 and R 2 are the same as defined above. X represents a halogen atom. ]
A process for producing an optically active compound represented by:
A step of substituting the aralkyl group for the -SO 2 R 3 group in the optically active compound obtained by the production method according to any one of Items 1 to 7, and then substituting the aralkyl group with a -NH 3 X group. Production method.
　項９．一般式（5）： Item 9. General formula (5):
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
［式中、R1～R2は前記に同じである。］
で表される光学活性化合物の製造方法であって、
項８に記載の製造方法で得られた光学活性化合物を中和する工程
を備える、製造方法。 [Wherein R 1 and R 2 are the same as defined above. ]
A process for producing an optically active compound represented by:
Item 9. A production method comprising a step of neutralizing an optically active compound obtained by the production method according to Item 8.
　項１０．一般式（2）： Item 10. General formula (2):
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
［式中、R5及びR8～R10は同一又は異なって、置換されていてもよいアルキル基、又は置換されていてもよいアリール基を示す。R6は置換されていてもよい第一級アルキル基を示す。R7は置換されていてもよい脂肪族アルキル基、又は置換されていてもよいシクロアルキル基を示す。X1はハロゲン原子又は1価のアニオンを示す。］
で表されるトリアゾリウム塩からなるストレッカー反応用触媒。 [Wherein, R 5 and R 8 to R 10 are the same or different and each represents an optionally substituted alkyl group or an optionally substituted aryl group. R 6 represents an optionally substituted primary alkyl group. R 7 represents an optionally substituted aliphatic alkyl group or an optionally substituted cycloalkyl group. X 1 represents a halogen atom or a monovalent anion. ]
A Strecker reaction catalyst comprising a triazolium salt represented by the formula:
　項１１．前記一般式（2）におけるR5及びR8～R10がいずれも、置換されていてもよいアリール基である、項１０に記載の触媒。 Item 11. Item 11. The catalyst according to Item 10, wherein R 5 and R 8 to R 10 in the general formula (2) are all optionally substituted aryl groups.
　項１２．前記ストレッカー反応は、
一般式（3）： Item 12. The Strecker reaction is
General formula (3):
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
［式中、R1及びR2は異なり、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、置換されていてもよいアルケニル基、又は置換されていてもよいアリール基を示す。R3は有機基を示す。］
で表される化合物と、
シアン化金属とを反応させて、
一般式（1）： [Wherein, R 1 and R 2 are different and each represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group. Show. R 3 represents an organic group. ]
A compound represented by
React with metal cyanide,
General formula (1):
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
［式中、R1～R3は前記に同じである。］
で表される光学活性化合物を得る反応である、項１０又は１１に記載の触媒。 [Wherein R 1 to R 3 are the same as defined above. ]
Item 12. The catalyst according to Item 10 or 11, which is a reaction for obtaining an optically active compound represented by the formula:
　項１３．前記一般式（1）及び（3）におけるR1及びR2がいずれも、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、又は置換されていてもよいアリール基である、項１２に記載の触媒。 Item 13. In the general formulas (1) and (3), R 1 and R 2 are both an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted aryl group. Item 13. The catalyst according to Item 12.
　項１４．一般式（2A）： Item 14. General formula (2A):
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
［式中、R5及びR8～R10は同一又は異なって、置換されていてもよいアルキル基、又は置換されていてもよいアリール基を示す。R6Aはアルコキシ基で置換された第一級アルキル基を示す。R7は置換されていてもよい脂肪族アルキル基を示す。X1はハロゲン原子又は1価のアニオンを示す。］
で表されるトリアゾリウム塩。 [Wherein, R 5 and R 8 to R 10 are the same or different and each represents an optionally substituted alkyl group or an optionally substituted aryl group. R 6A represents a primary alkyl group substituted with an alkoxy group. R 7 represents an optionally substituted aliphatic alkyl group. X 1 represents a halogen atom or a monovalent anion. ]
A triazolium salt represented by
　項１５．前記一般式（2）におけるR5及びR8～R10がいずれも、置換されていてもよいアリール基である、項１４に記載のトリアゾリウム塩。 Item 15. Item 15. The triazolium salt according to Item 14, wherein R 5 and R 8 to R 10 in the general formula (2) are all optionally substituted aryl groups.
　項１６．前記R10が、ハロゲン化アルキル基で置換されたアリール基である、項１４又は１５に記載のトリアゾリウム塩。 Item 16. Item 16. The triazolium salt according to Item 14 or 15, wherein R 10 is an aryl group substituted with a halogenated alkyl group.
　項１７．一般式（1A）： Item 17. General formula (1A):
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
［式中、R1及びR2は異なり、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、置換されていてもよいアルケニル基、又は置換されていてもよいアリール基を示す。R3Aはジアルキルフェニル基を示す。］
で表される光学活性化合物。 [Wherein, R 1 and R 2 are different and each represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group. Show. R 3A represents a dialkylphenyl group. ]
An optically active compound represented by
　項１８．前記一般式（1A）におけるR1及びR2がいずれも、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、又は置換されていてもよいアリール基である、項１７に記載の光学活性化合物。 Item 18. In item 17, R 1 and R 2 in the general formula (1A) are both an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted aryl group. The optically active compound described.
　本発明によれば、特定の1,2,3－トリアゾリウム塩触媒の存在下、安価で取扱いの容易なシアン化金属をシアノ源とし、特定のケトイミン誘導体と反応させることで、ケトイミン誘導体に対して直接シアノ化を引き起こすストレッカー反応を起こさせることができる。 According to the present invention, in the presence of a specific 1,2,3-triazolium salt catalyst, an inexpensive and easy-to-handle metal cyanide is used as a cyano source to react with a specific ketoimine derivative, thereby reducing the ketoimine derivative. A Strecker reaction that causes direct cyanation can occur.
　この反応は、効率よく進行し、様々な光学活性化合物を、一段階で立体選択的に合成することができる。 This reaction proceeds efficiently, and various optically active compounds can be stereoselectively synthesized in one step.
　また、この反応により得られる光学活性化合物を中間体として、医薬中間体として有用な所望のα四置換αアミノニトリル誘導体及びα四置換αアミノ酸を簡便に合成することも可能である。 It is also possible to easily synthesize desired α-tetrasubstituted α-amino nitrile derivatives and α-tetrasubstituted α-amino acids useful as pharmaceutical intermediates using the optically active compound obtained by this reaction as an intermediate.
　このようにして得られるα四置換αアミノニトリル誘導体のうち一部の化合物は新規化合物である。 Some of the α-tetrasubstituted α-amino nitrile derivatives thus obtained are novel compounds.
　１．光学活性化合物の製造方法
　本発明においては、特定のトリアゾリウム塩の存在下に、特定のケトイミン誘導体と、シアン化金属とを効果的に反応させて、光学活性化合物を得ることができる。 1. Production Method of Optically Active Compound In the present invention, an optically active compound can be obtained by effectively reacting a specific ketoimine derivative with a metal cyanide in the presence of a specific triazolium salt.
　本発明においては、種々の基質化合物（ケトイミン誘導体）に対して、基質選択性広く、シアノ基を導入することができるため、様々な光学活性化合物を得ることも可能である。 In the present invention, since a cyano group can be introduced with a wide substrate selectivity with respect to various substrate compounds (ketoimine derivatives), various optically active compounds can be obtained.
　本発明においては、通常、溶媒中、特定のトリアゾリウム塩の存在下に、特定のケトイミン誘導体と、シアン化金属とを反応させて様々な光学活性化合物を得ることができる。 In the present invention, various optically active compounds can be usually obtained by reacting a specific ketoimine derivative with a metal cyanide in a solvent in the presence of a specific triazolium salt.
　（1－1）基質化合物
　反応に供される基質としての化合物としては、特に制限されないが、例えば、一般式（3）： (1-1) Substrate Compound The compound used as a substrate to be subjected to the reaction is not particularly limited. For example, the general formula (3):
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
［式中、R1及びR2は異なり、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、置換されていてもよいアルケニル基、又は置換されていてもよいアリール基を示す。R3は有機基を示す。］
で表される化合物（以下、「化合物（3）と言うこともある」）を採用できる。 [Wherein, R 1 and R 2 are different and each represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group. Show. R 3 represents an organic group. ]
(Hereinafter, also referred to as “compound (3)”).
　一般式（3）において、R1及びR2で示されるアルキル基としては、特に制限はなく、例えば、メチル基、エチル基、n－プロピル基、イソプロピル基、n－ブチル基、イソブチル基、sec－ブチル基、tert－ブチル基等の非環式脂肪族アルキル基（好ましくは炭素数1～10、特に炭素数3～6の非環式脂肪族アルキル基）等が挙げられる。なお、非環式脂肪族アルキル基を採用する場合、直鎖非環式脂肪族アルキル基を採用することもでき、分岐鎖非環式脂肪族アルキル基を採用することもできる。これらアルキル基は、ハロゲン原子（フッ素原子、塩素原子、臭素原子、ヨウ素原子等）、後述のアルコキシ基、後述のアルケニル基、後述のアリール基、後述のアルコキシカルボニル基、後述のアリールオキシ基等の置換基を1～6個（特に1～3個）程度有することもできる。つまり、このような置換基を有するアルキル基は、ベンジル基、メチルベンジル基、フェネチル基、メチルフェネチル基、ナフチルメチル基、メチルナフチルメチル基等のアラルキル基（好ましくは炭素数7～20、特に炭素数7～14のアラルキル基）等であってもよい。 In the general formula (3), the alkyl group represented by R 1 and R 2 is not particularly limited, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, sec And acyclic aliphatic alkyl groups such as a butyl group and a tert-butyl group (preferably an acyclic aliphatic alkyl group having 1 to 10 carbon atoms, particularly 3 to 6 carbon atoms). In addition, when employ | adopting an acyclic aliphatic alkyl group, a linear acyclic aliphatic alkyl group can also be employ | adopted and a branched acyclic aliphatic alkyl group can also be employ | adopted. These alkyl groups include halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.), alkoxy groups described below, alkenyl groups described below, aryl groups described below, alkoxycarbonyl groups described below, aryloxy groups described below, etc. It may have about 1 to 6 (particularly 1 to 3) substituents. That is, the alkyl group having such a substituent is an aralkyl group (preferably having 7 to 20 carbon atoms, particularly carbon atoms) such as a benzyl group, a methylbenzyl group, a phenethyl group, a methylphenethyl group, a naphthylmethyl group, and a methylnaphthylmethyl group. And an aralkyl group of 7 to 14).
　一般式（3）において、R1及びR2で示されるシクロアルキル基としては、特に制限はなく、例えば、シクロプロピル基、シクロプロピルメチル基、シクロブチル基、シクロブチルメチル基、シクロペンチル基、シクロペンチルメチル基、シクロヘキシル基、シクロヘキシルメチル基、シクロヘキシルエチル基、アダマンチル基等のシクロアルキル基（好ましくは炭素数3～10、特に炭素数5～8のシクロアルキル基等が挙げられる。これらシクロアルキル基は、ハロゲン原子（フッ素原子、塩素原子、臭素原子、ヨウ素原子等）、後述のアルコキシ基、後述のアルケニル基、後述のアリール基、後述のアルコキシカルボニル基、後述のアリールオキシ基等の置換基を０～３個（特に１～３個）程度有することもできる。 In the general formula (3), the cycloalkyl group represented by R 1 and R 2 is not particularly limited, and examples thereof include a cyclopropyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclobutylmethyl group, a cyclopentyl group, and a cyclopentylmethyl. A cycloalkyl group such as a group, a cyclohexyl group, a cyclohexylmethyl group, a cyclohexylethyl group, an adamantyl group (preferably a cycloalkyl group having 3 to 10 carbon atoms, particularly 5 to 8 carbon atoms, etc.). Substituents such as halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.), alkoxy groups described below, alkenyl groups described below, aryl groups described below, alkoxycarbonyl groups described below, aryloxy groups described below, etc. It can also have about 3 (especially 1 to 3).
　一般式（3）において、R1及びR2で示されるアルケニル基としては、特に制限はなく、例えば、ビニル基、アリル基等のアルケニル基（好ましくは炭素数2～11、特に炭素数4～7のアルケニル基）等が挙げられる。これらアルケニル基は、ハロゲン原子（フッ素原子、塩素原子、臭素原子、ヨウ素原子等）、前記のアルキル基、後述のアルコキシ基、前記のアルケニル基、後述のアリール基、後述のアルコキシカルボニル基、後述のアリールオキシ基等の置換基を1～6個（特に1～3個）程度有することもできる。 In the general formula (3), the alkenyl group represented by R 1 and R 2 is not particularly limited, and examples thereof include alkenyl groups such as vinyl groups and allyl groups (preferably having 2 to 11 carbon atoms, particularly 4 to 4 carbon atoms). 7 alkenyl group) and the like. These alkenyl groups include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), the above alkyl group, an alkoxy group described below, the above alkenyl group, an aryl group described below, an alkoxycarbonyl group described below, It may have about 1 to 6 (especially 1 to 3) substituents such as an aryloxy group.
　一般式（3）において、R1及びR2で示されるアリール基としては、特に制限はなく、例えば、フェニル基、トリル基（o－トリル基、m－トリル基、p－トリル基）、キシリル基（o－キシリル基、m－キシリル基、p－キシリル基）、ナフチル基等が挙げられる。これらアリール基は、ハロゲン原子（フッ素原子、塩素原子、臭素原子、ヨウ素原子等）、前記のアルキル基、後述のアルコキシ基、後述のアルケニル基、前記のアリール基、後述のアルコキシカルボニル基、後述のアリールオキシ基等の置換基を1～6個（特に1～3個）程度有することもできる。 In the general formula (3), the aryl group represented by R 1 and R 2 is not particularly limited, and examples thereof include a phenyl group, a tolyl group (o-tolyl group, m-tolyl group, p-tolyl group), xylyl Group (o-xylyl group, m-xylyl group, p-xylyl group), naphthyl group and the like. These aryl groups include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), the above alkyl group, an alkoxy group described below, an alkenyl group described below, an aryl group described above, an alkoxycarbonyl group described below, It may have about 1 to 6 (especially 1 to 3) substituents such as an aryloxy group.
　これらのR1及びR2のなかでも、収率、立体選択性等の観点から、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基等が好ましく、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基等がより好ましく、非置換非環式脂肪族アルキル基、非置換シクロアルキル基等がさらに好ましい。また、一般式（3）において、R1及びR2は異なるものとする。 Among these R 1 and R 2 , from the viewpoint of yield, stereoselectivity, etc., an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, etc. Are preferable, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, and the like are more preferable, and an unsubstituted acyclic aliphatic alkyl group, an unsubstituted cycloalkyl group, and the like are more preferable. In the general formula (3), R 1 and R 2 are different.
　一般式（3）において、R3で示される有機基としては、特に制限されず、炭化水素基（アルキル基、シクロアルキル基、アルケニル基、アリール基）、アルコキシ基、アルコキシカルボニル基、アリールオキシ基等が挙げられる。 In the general formula (3), the organic group represented by R 3 is not particularly limited, and is a hydrocarbon group (alkyl group, cycloalkyl group, alkenyl group, aryl group), alkoxy group, alkoxycarbonyl group, aryloxy group. Etc.
　一般式（3）において、R3で示される有機基としてのアルキル基、シクロアルキル基、アルケニル基及びアリール基としては、上記説明したものを採用できる。好ましい具体例も同様である。 In the general formula (3), as the alkyl group, cycloalkyl group, alkenyl group and aryl group as the organic group represented by R 3 , those described above can be adopted. The same applies to preferred embodiments.
　一般式（3）において、R3で示されるアルコキシ基としては、特に制限はなく、例えば、メトキシ基、エトキシ基、n－プロポキシ基、イソプロポキシ基、n－ブトキシ基、イソブトキシ基、sec－ブトキシ基、tert－ブトキシ基等の非環式脂肪族アルコキシ基（好ましくは炭素数1～10、特に炭素数3～6の非環式脂肪族アルコキシ基）等が挙げられる。なお、非環式脂肪族アルコキシ基を採用する場合、非環式直鎖脂肪族アルコキシ基を採用することもでき、非環式分岐鎖脂肪族アルコキシ基を採用することもできる。これらアルコキシ基は、ハロゲン原子（フッ素原子、塩素原子、臭素原子、ヨウ素原子等）、前記のアルキル基、前記のシクロアルキル基、前記のアルコキシ基、前記のアルケニル基、前記のアリール基、後述のアルコキシカルボニル基、後述のアリールオキシ基等の置換基を1～6個（特に1～3個）程度有することもできる。 In the general formula (3), the alkoxy group represented by R 3 is not particularly limited, and examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, and a sec-butoxy group. And an acyclic aliphatic alkoxy group such as a tert-butoxy group (preferably an acyclic aliphatic alkoxy group having 1 to 10 carbon atoms, particularly 3 to 6 carbon atoms). In addition, when employ | adopting an acyclic aliphatic alkoxy group, an acyclic linear aliphatic alkoxy group can also be employ | adopted and an acyclic branched aliphatic alkoxy group can also be employ | adopted. These alkoxy groups include a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), the alkyl group, the cycloalkyl group, the alkoxy group, the alkenyl group, the aryl group, which will be described later. It may have about 1 to 6 (especially 1 to 3) substituents such as an alkoxycarbonyl group and an aryloxy group described later.
　一般式（3）において、R3で示される有機基としてのアルコキシカルボニル基としては、特に制限はなく、例えば、メトキシカルボニル基、エトキシカルボニル基、n－プロポキシカルボニル基、イソプロポキシカルボニル基、n－ブトキシカルボニル基、イソブトキシカルボニル基、sec－ブトキシカルボニル基、tert－ブトキシカルボニル基等の脂肪族アルコキシカルボニル基（好ましくは炭素数2～11、特に炭素数4～7の脂肪族アルコキシカルボニル基）等が挙げられる。なお、脂肪族アルコキシカルボニル基を採用する場合、直鎖脂肪族アルコキシカルボニル基を採用することもでき、分岐鎖脂肪族アルコキシカルボニル基を採用することもできる。これらアルコキシカルボニル基は、ハロゲン原子（フッ素原子、塩素原子、臭素原子、ヨウ素原子等）、前記のアルキル基、前記のアルコキシ基、前記のアルケニル基、前記のアリール基、前記のアルコキシカルボニル基、後述のアリールオキシ基等の置換基を1～6個（特に1～3個）程度有することもできる。 In the general formula (3), the alkoxycarbonyl group as the organic group represented by R 3 is not particularly limited, and examples thereof include a methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n- Aliphatic alkoxycarbonyl groups such as butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group (preferably an aliphatic alkoxycarbonyl group having 2 to 11 carbon atoms, particularly 4 to 7 carbon atoms), etc. Is mentioned. In addition, when employ | adopting an aliphatic alkoxycarbonyl group, a linear aliphatic alkoxycarbonyl group can also be employ | adopted and a branched aliphatic alkoxycarbonyl group can also be employ | adopted. These alkoxycarbonyl groups include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), the alkyl group, the alkoxy group, the alkenyl group, the aryl group, the alkoxycarbonyl group, which will be described later. 1-6 (especially 1 to 3) of substituents such as aryloxy groups may be included.
　一般式（3）において、R3で示される有機基としてのアリールオキシ基としては、特に制限はなく、例えば、フェノキシ基、トリルオキシ基（o－トリルオキシ基、m－トリルオキシ基、p－トリルオキシ基）、キシリルオキシ基（o－キシリルオキシ基、m－キシリルオキシ基、p－キシリルオキシ基）、ナフチルオキシ基等が挙げられる。これらアリールオキシ基は、ハロゲン原子（フッ素原子、塩素原子、臭素原子、ヨウ素原子等）、前記のアルキル基、前記のアルコキシ基、前記のアルケニル基、前記のアリール基、前記のアルコキシカルボニル基、前記のアリールオキシ基等の置換基を1～6個（特に1～3個）程度有することもできる。 In the general formula (3), the aryloxy group as the organic group represented by R 3 is not particularly limited, and examples thereof include phenoxy group, tolyloxy group (o-tolyloxy group, m-tolyloxy group, p-tolyloxy group). And xylyloxy group (o-xylyloxy group, m-xylyloxy group, p-xylyloxy group), naphthyloxy group and the like. These aryloxy groups include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), the alkyl group, the alkoxy group, the alkenyl group, the aryl group, the alkoxycarbonyl group, 1-6 (especially 1 to 3) of substituents such as aryloxy groups may be included.
　これらのR3のなかでも、収率、立体選択性等の観点から、置換されていてもよいアリール基が好ましく、置換アリール基がより好ましく、1～3個のアルキル基で置換されたアリール基がさらに好ましい。 Among these R 3, an aryl group which may be substituted is preferable from the viewpoint of yield, stereoselectivity, and the like, a substituted aryl group is more preferable, and an aryl group substituted with 1 to 3 alkyl groups Is more preferable.
　このような条件を満たす基質としての化合物（3）としては、例えば、 As a compound (3) as a substrate that satisfies such conditions, for example,
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
等を使用することができ、 Etc. can be used
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
等が好ましく、 Etc. are preferred,
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
等がより好ましい。 Etc. are more preferable.
　（1－2）シアン化金属
　本発明においては、上記した基質化合物（化合物（3））にシアノ基を導入するため、シアン化金属を使用する。シアン化金属としては、シアン化カリウム、シアン化ナトリウム等のシアン化アルカリ金属；シアン化カルシウム、シアン化マグネシウム等のシアン化アルカリ土類金属等が挙げられる。なかでも、収率、立体選択性等の観点から、シアン化アルカリ金属が好ましく、シアン化カリウムがより好ましい。本発明においては、シアン化水素のような取扱いが困難なシアノ化剤を使用せずともシアノ化反応を進行させることができる。 (1-2) Metal Cyanide In the present invention, a metal cyanide is used in order to introduce a cyano group into the substrate compound (compound (3)). Examples of the metal cyanide include alkali metal cyanides such as potassium cyanide and sodium cyanide; alkaline earth metal cyanides such as calcium cyanide and magnesium cyanide. Of these, alkali metal cyanide is preferable and potassium cyanide is more preferable from the viewpoint of yield, stereoselectivity, and the like. In the present invention, the cyanation reaction can proceed without using a cyanating agent that is difficult to handle, such as hydrogen cyanide.
　シアン化金属の使用量は、特に制限されず、収率、立体選択性等の観点から、例えば、化合物（3）1モルに対し、通常、0.5～20モル程度が好ましく、1～10モル程度がより好ましい。 The amount of metal cyanide used is not particularly limited, and from the viewpoint of yield, stereoselectivity, etc., for example, it is usually preferably about 0.5 to 20 moles, preferably about 1 to 10 moles per mole of compound (3). Is more preferable.
　（1－3）トリアゾリウム塩
　本発明において、触媒として使用されるトリアゾリウム塩は、一般式（2）： (1-3) Triazolium salt In the present invention, the triazolium salt used as a catalyst is represented by the general formula (2):
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
［式中、R5及びR8～R10は同一又は異なって、置換されていてもよいアルキル基、又は置換されていてもよいアリール基を示す。R6は置換されていてもよい第一級アルキル基を示す。R7は置換されていてもよい脂肪族アルキル基、又は置換されていてもよいシクロアルキル基を示す。X1はハロゲン原子又は1価のアニオンを示す。］
で表されるトリアゾリウム塩である（以下、「トリアゾリウム塩（2）」と言うこともある）。 [Wherein, R 5 and R 8 to R 10 are the same or different and each represents an optionally substituted alkyl group or an optionally substituted aryl group. R 6 represents an optionally substituted primary alkyl group. R 7 represents an optionally substituted aliphatic alkyl group or an optionally substituted cycloalkyl group. X 1 represents a halogen atom or a monovalent anion. ]
(Hereinafter also referred to as “triazolium salt (2)”).
　一般式（2）において、R5で示されるアルキル基及びアリール基としては、上記したものを採用することができる。置換基の種類及び数も同様である。なかでも、収率、立体選択性等の観点から、置換されていてもよいアリール基が好ましく、置換アリール基がより好ましく、1～6個、特に1～3個のハロゲン原子（フッ素原子、塩素原子、臭素原子、ヨウ素原子等）、前記アリール基等で置換されたアリール基がさらに好ましい。具体的には、収率、立体選択性等の観点から、 In the general formula (2), as the alkyl group and aryl group represented by R 5 , those described above can be employed. The kind and number of substituents are the same. Among these, from the viewpoint of yield, stereoselectivity, etc., an aryl group which may be substituted is preferable, a substituted aryl group is more preferable, and 1 to 6, particularly 1 to 3 halogen atoms (fluorine atom, chlorine) are preferable. Atom, bromine atom, iodine atom, etc.), an aryl group substituted with the aryl group or the like is more preferred. Specifically, from the viewpoint of yield, stereoselectivity, etc.
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
［式中、Phはフェニル基を示す。以下同様である。］
等が好ましい。 [Wherein, Ph represents a phenyl group. The same applies hereinafter. ]
Etc. are preferred.
　一般式（2）において、R6で示される第一級アルキル基としては、特に制限されず、例えば、メチル基、エチル基、n－プロピル基、n－ブチル基、イソブチル基等の非環式脂肪族第一級アルキル基（好ましくは炭素数1～6、特に炭素数1～4の非環式脂肪族第一級アルキル基）等が挙げられる。これら第一級アルキル基は、ハロゲン原子（フッ素原子、塩素原子、臭素原子、ヨウ素原子等）、前記のアルコキシ基、前記のアルケニル基、前記のアリール基、前記のアルコキシカルボニル基、前記のアリールオキシ基等の置換基を1～6個（特に1～3個）程度有することもできる。つまり、このような置換基を有する第一級アルキル基は、ベンジル基、メチルベンジル基、フェネチル基、メチルフェネチル基、ナフチルメチル基、メチルナフチルメチル基等のアラルキル基等の芳香族第一級アルキル基（好ましくは炭素数7～20、特に炭素数7～14のアラルキル基等の芳香族第一級アルキル基）等も挙げられる。なお、非環式脂肪族第一級アルキル基を採用する場合、直鎖非環式脂肪族第一級アルキル基を採用することもでき、分岐鎖非環式第一級脂肪族アルキル基を採用することもできる。なかでも、収率、立体選択性等の観点から、置換されていてもよい芳香族第一級アルキル基が好ましく、置換されていてもよいアラルキル基がより好ましく、置換アラルキル基がさらに好ましく、1～3個のアルコキシ基等で置換されたアラルキル基が特に好ましい。 In the general formula (2), the primary alkyl group represented by R 6 is not particularly limited, and examples thereof include acyclic groups such as a methyl group, an ethyl group, an n-propyl group, an n-butyl group, and an isobutyl group. And an aliphatic primary alkyl group (preferably an acyclic aliphatic primary alkyl group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms). These primary alkyl groups include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), the alkoxy group, the alkenyl group, the aryl group, the alkoxycarbonyl group, the aryloxy group. It may have about 1 to 6 (especially 1 to 3) substituents such as groups. That is, the primary alkyl group having such a substituent is an aromatic primary alkyl group such as an aralkyl group such as a benzyl group, a methylbenzyl group, a phenethyl group, a methylphenethyl group, a naphthylmethyl group, or a methylnaphthylmethyl group. And a group (preferably an aromatic primary alkyl group such as an aralkyl group having 7 to 20 carbon atoms, particularly 7 to 14 carbon atoms). When an acyclic aliphatic primary alkyl group is used, a linear acyclic aliphatic primary alkyl group can also be used, and a branched acyclic primary aliphatic alkyl group is also used. You can also Among them, from the viewpoint of yield, stereoselectivity, etc., an aromatic primary alkyl group which may be substituted is preferable, an optionally substituted aralkyl group is more preferable, a substituted aralkyl group is more preferable, and 1 Aralkyl groups substituted with up to 3 alkoxy groups and the like are particularly preferred.
　一般式（2）において、R7で示されるシクロアルキル基としては、上記したものを採用することができる。置換基の種類及び数も同様である。 In the general formula (2), as the cycloalkyl group represented by R 7 , those described above can be employed. The kind and number of substituents are the same.
　一般式（2）において、R7で示される脂肪族アルキル基としては、特に制限されず、例えば、メチル基、エチル基、n－プロピル基、イソプロピル基、n－ブチル基、イソブチル基、sec－ブチル基、tert－ブチル基等の非環式脂肪族アルキル基（好ましくは炭素数1～6、特に炭素数1～4の非環式脂肪族アルキル基）等が挙げられる。なお、非環式脂肪族アルキル基を採用する場合、直鎖非環式脂肪族アルキル基を採用することもでき、分岐鎖非環式脂肪族アルキル基を採用することもできる。これら脂肪族アルキル基は、ハロゲン原子（フッ素原子、塩素原子、臭素原子、ヨウ素原子等）、前記のアルコキシ基、前記のアルケニル基、前記のアリール基、前記のアルコキシカルボニル基、前記のアリールオキシ基等の置換基を1～6個（特に1～3個）程度有することもできる。 In the general formula (2), the aliphatic alkyl group represented by R 7 is not particularly limited, and examples thereof include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec- And acyclic aliphatic alkyl groups such as a butyl group and a tert-butyl group (preferably an acyclic aliphatic alkyl group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms). In addition, when employ | adopting an acyclic aliphatic alkyl group, a linear acyclic aliphatic alkyl group can also be employ | adopted and a branched acyclic aliphatic alkyl group can also be employ | adopted. These aliphatic alkyl groups include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), the alkoxy group, the alkenyl group, the aryl group, the alkoxycarbonyl group, and the aryloxy group. It can also have about 1 to 6 (especially 1 to 3) substituents such as.
　一般式（2）において、R8及びR9で示されるアルキル基及びアリール基としては、上記したものを採用することができる。置換基の種類及び数も同様である。なかでも、収率、立体選択性等の観点から、置換されていてもよいアリール基が好ましく、非置換アリール基又は1個の前記ハロゲン原子で置換されたアリール基がより好ましく、フェニル基又はクロロフェニル基がさらに好ましい。R8とR9は同一でもよいし、異なっていてもよい。 In the general formula (2), as the alkyl group and aryl group represented by R 8 and R 9 , those described above can be adopted. The kind and number of substituents are the same. Among these, from the viewpoints of yield, stereoselectivity, etc., an aryl group which may be substituted is preferable, an unsubstituted aryl group or an aryl group substituted with one halogen atom is more preferable, a phenyl group or chlorophenyl Groups are more preferred. R 8 and R 9 may be the same or different.
　一般式（2）において、R10で示されるアルキル基及びアリール基としては、上記したものを採用することができる。置換基の種類及び数も同様である。なかでも、収率、立体選択性等の観点から、置換されていてもよいアリール基が好ましく、非置換アリール基又は2個の前記アルキル基（好ましくはハロゲン化アルキル基、特にパーフルオロアルキル基）、前記アルコキシ基等で置換されたアリール基がより好ましく、フェニル基、ジメトキシフェニル基、ビス（トリフルオロメチル）フェニル基がさらに好ましい。 In the general formula (2), as the alkyl group and aryl group represented by R 10 , those described above can be employed. The kind and number of substituents are the same. Among these, an aryl group which may be substituted is preferable from the viewpoints of yield, stereoselectivity, etc., an unsubstituted aryl group or two alkyl groups (preferably a halogenated alkyl group, particularly a perfluoroalkyl group). An aryl group substituted with the alkoxy group or the like is more preferable, and a phenyl group, a dimethoxyphenyl group, or a bis (trifluoromethyl) phenyl group is more preferable.
　一般式（2）において、X1で示されるハロゲン原子としては、塩素原子、臭素原子、ヨウ素原子等を採用し得る。 In the general formula (2), a chlorine atom, a bromine atom, an iodine atom or the like can be adopted as the halogen atom represented by X 1 .
　一般式（2）において、X1で示される1価のアニオンとしては、フェノキシド、カルボキシラート、テトラフルオロホウ酸イオン等を採用し得る。 In the general formula (2), as the monovalent anion represented by X 1 , phenoxide, carboxylate, tetrafluoroborate ion, or the like can be employed.
　なかでも、X1としては、収率、立体選択性等の観点から、ハロゲン原子が好ましく、塩素原子、臭素原子等がより好ましく、臭素原子がさらに好ましい。 Among these, X 1 is preferably a halogen atom, more preferably a chlorine atom, a bromine atom, or the like, and further preferably a bromine atom, from the viewpoints of yield, stereoselectivity, and the like.
　このような条件を満たすトリアゾリウム塩（2）としては、具体的には、 As a triazolium salt (2) that satisfies such conditions, specifically,
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
［式中、Bnはベンジル基を示す。以下同様である。］
等が挙げられる。 [Wherein, Bn represents a benzyl group. The same applies hereinafter. ]
Etc.
　これらトリアゾリウム塩（2）は、公知又は市販の化合物を使用することもできるし、既報（J. Am. Chem. Soc. 2011, 133, 1307-1309.等）に記載の方法に準じて合成することもできる。 These triazolium salts (2) may be known or commercially available compounds, and may be synthesized according to the methods described in the previous reports (J. Am. Chem. Soc. 2011, 133, 1307-1309., Etc.). You can also
　トリアゾリウム塩（2）の使用量は、特に制限されず、収率、立体選択性等の観点から、例えば、化合物（3）1モルに対し、通常、0.002～0.1モル程度が好ましく、0.005～0.05モル程度がより好ましい。 The amount of the triazolium salt (2) to be used is not particularly limited, and from the viewpoint of yield, stereoselectivity, etc., for example, usually about 0.002 to 0.1 mol is preferable with respect to 1 mol of compound (3), and 0.005 to 0.05 A molar degree is more preferable.
　このようなトリアゾリウム塩（2）は、本発明の製造方法のみに限られず、ストレッカー反応用触媒として使用することができる。また、トリアゾリウム塩（2）のうち、一般式（2A）： Such a triazolium salt (2) is not limited to the production method of the present invention, and can be used as a catalyst for Strecker reaction. Of the triazolium salts (2), the general formula (2A):
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
［式中、R5、R7～R10及びX1は前記に同じである。R6Aは前記アルコキシ基で置換された前記第一級アルキル基を示す。］
で表される化合物は文献未記載の新規化合物である。 [Wherein R 5 , R 7 to R 10 and X 1 are the same as defined above. R 6A represents the primary alkyl group substituted with the alkoxy group. ]
Is a novel compound not described in any literature.
　（1－4）他の添加物及び反応条件
　溶媒としては、例えば、水；トルエン、キシレン、ベンゼン、メシチレン等の芳香族炭化水素；ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン等の脂肪族ハロゲン化炭化水素；ジエチルエーテル、ジメトキシエタン、ジイソプロピルエーテル、tert－ブチルメチルエーテル等の鎖状エーテル；酢酸エチル、プロピオン酸エチル等のエステル；アセトン、メチルエチルケトン等のケトン等が挙げられる。これらは、1種のみを用いることもでき、2種以上を組合せて用いることもできる。なかでも、収率、立体選択性等の観点から、水と芳香族炭化水素類との混合溶媒が好ましい。 (1-4) Other additives and reaction conditions Examples of the solvent include water; aromatic hydrocarbons such as toluene, xylene, benzene and mesitylene; aliphatic halogenated carbonization such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane. Examples include hydrogen; chain ethers such as diethyl ether, dimethoxyethane, diisopropyl ether, and tert-butyl methyl ether; esters such as ethyl acetate and ethyl propionate; ketones such as acetone and methyl ethyl ketone. These can be used alone or in combination of two or more. Of these, a mixed solvent of water and aromatic hydrocarbons is preferable from the viewpoint of yield, stereoselectivity, and the like.
　本発明において、水と芳香族炭化水素類との混合溶媒を採用する場合、その含有量比は、特に制限されず、収率、立体選択性等の観点から、体積比で、水：芳香族炭化水素類が1：5～100、特に1：10～50となるように調整することが好ましい。 In the present invention, when a mixed solvent of water and aromatic hydrocarbons is employed, the content ratio is not particularly limited, and from the viewpoint of yield, stereoselectivity, etc., the volume ratio is water: aromatic. It is preferable to adjust the hydrocarbons to 1: 5 to 100, particularly 1:10 to 50.
　なお、本発明においては、塩基を使用せずとも反応を進行させることが可能である。 In the present invention, the reaction can proceed without using a base.
　本発明は、不活性ガス雰囲気（窒素ガス、アルゴンガス等）下で行うことが好ましく、反応温度は、通常、－78℃～室温（25℃）程度、好ましくは－70～20℃程度、より好ましくは－60～0℃程度、さらに好ましくは－50～－20℃程度である。反応時間は、反応が十分に進行する時間とすればよく、通常、10分～72時間程度、好ましくは1～48時間程度である。 The present invention is preferably carried out under an inert gas atmosphere (nitrogen gas, argon gas, etc.), and the reaction temperature is usually about −78 ° C. to room temperature (25 ° C.), preferably about −70 to 20 ° C. The temperature is preferably about −60 to 0 ° C., more preferably about −50 to −20 ° C. The reaction time may be a time for which the reaction proceeds sufficiently, and is usually about 10 minutes to 72 hours, preferably about 1 to 48 hours.
　反応終了後は、必要に応じて通常の単離及び精製工程を経て、目的化合物を得ることができる。 After completion of the reaction, the target compound can be obtained through normal isolation and purification steps as necessary.
　（1－5）生成物
　このようにして得られる光学活性化合物は、一般式（1）： (1-5) Product The optically active compound thus obtained has the general formula (1):
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
［式中、R1～R3は前記に同じである。］
で表される化合物である。このうち、一般式（1A）： [Wherein R 1 to R 3 are the same as defined above. ]
It is a compound represented by these. Of these, general formula (1A):
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
［式中、R1～R2は前記に同じである。R3Aはジアルキルフェニル基（3,5－ジメチルフェニル基、2,5－ジメチルフェニル基等のジメチルフェニル基；ジエチルフェニル基等）を示す。］
で表される化合物はいずれも文献未記載の新規化合物である。特に、後述の実施例で得られる光学活性化合物は、いずれも文献未記載の新規化合物であり、医農薬品合成の中間体に有用である。 [Wherein R 1 and R 2 are the same as defined above. R 3A represents a dialkylphenyl group (a dimethylphenyl group such as a 3,5-dimethylphenyl group or a 2,5-dimethylphenyl group; a diethylphenyl group). ]
Are all novel compounds not described in any literature. In particular, any of the optically active compounds obtained in Examples described later is a novel compound not described in any literature, and is useful as an intermediate for the synthesis of medical and agricultural chemicals.
　２．光学活性化合物を用いた製造方法
　上記した本発明の製造方法により、光学活性化合物（1）を得た後、常法にしたがって、シアノ基をカルボキシ基に変換するとともに、－SO2R3基をアミノ基又は－NH3X基（Xは塩素、臭素、ヨウ素等のハロゲン原子）に変換することで、所望のアミノ酸を得ることもできる。例えば、J. Am. Chem. Soc., 2006, 128, 2548.等に記載のスルホニル基の除去、Org. Proc. Res. Dev., 2008, 12, 298.等に記載のニトリル基の加水分解等にしたがって、光学活性化合物（1）からアミノ酸を得ることができる。 2. Production method using optically active compound After the optically active compound (1) is obtained by the production method of the present invention described above, a cyano group is converted to a carboxy group and a —SO 2 R 3 group is converted according to a conventional method. A desired amino acid can also be obtained by conversion to an amino group or —NH 3 X group (X is a halogen atom such as chlorine, bromine, iodine, etc.). For example, removal of a sulfonyl group described in J. Am. Chem. Soc., 2006, 128, 2548., etc., hydrolysis of a nitrile group described in Org. Proc. Res. Dev., 2008, 12, 298. The amino acid can be obtained from the optically active compound (1) according to the above.
　このようにして得られるアミノ酸は、一般式（4）： The amino acid thus obtained has the general formula (4):
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
［式中、R1～R2は前記に同じである。Xはハロゲン原子を示す。］
で表される光学活性化合物である。 [Wherein R 1 and R 2 are the same as defined above. X represents a halogen atom. ]
It is an optically active compound represented by these.
　このようにして光学活性化合物（4）を得た後、常法にしたがって、中和することで、所望のアミノ酸を得ることもできる。 After obtaining the optically active compound (4) in this way, the desired amino acid can also be obtained by neutralization according to a conventional method.
　このようにして得られるアミノ酸は、一般式（5）： The amino acid thus obtained has the general formula (5):
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
［式中、R1～R2は前記に同じである。］
で表される光学活性化合物である。 [Wherein R 1 and R 2 are the same as defined above. ]
It is an optically active compound represented by these.
　以下、本発明について、実施例を挙げて具体的に説明するが、本発明は、これらの実施例に何ら制約されるものではない。 Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.
　［合成例1：ケトイミン誘導体の合成］ [Synthesis Example 1: Synthesis of ketoimine derivative]
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
［式中、Meはメチル基を示す。t-Buはtert－ブチル基を示す。Etはエチル基を示す。Arは3,5－ジメチルフェニル基を示す。以下同様である。］
　3,3-ジメチルブタン-2-オン（1.5 g, 15 mmol）及び3,5-ジメチルベンゼンスルホンアミド（1.4 g, 7.5 mmol）のトルエン（75 mL）溶液に、テトラエトキシチタン（Ti(OEt)4; 4.7 mL, 22.5 mmol）を、攪拌しながら添加した。反応混合物を還流下に加熱した。20時間還流した後、黄色混合物を室温まで冷却し、NaOH水溶液（0.5 M, 75 mL）をゆっくりと添加した。チタン酸化物の白色ゲルをセライトパッドでろ過して二層のろ液を得た。有機層を分離し、水層をジエチルエーテル（Et2O）で抽出した。合わせた有機抽出物をかん水で洗浄し、Na2SO4で乾燥した。減圧下にろ過及び濃縮を行い、目的物を黄色固体として得た（706 mg, 3.5 mmol, 47 %収率）。
1H NMR (400 MHz, CDCl3) δ 7.58 (2H, s), 7.20 (1 H, s), 2.55 (3H, s), 2.39 (6H, s), 1.17 (9H, s)。 [Wherein, Me represents a methyl group. t-Bu represents a tert-butyl group. Et represents an ethyl group. Ar represents a 3,5-dimethylphenyl group. The same applies hereinafter. ]
To a solution of 3,3-dimethylbutan-2-one (1.5 g, 15 mmol) and 3,5-dimethylbenzenesulfonamide (1.4 g, 7.5 mmol) in toluene (75 mL) was added tetraethoxytitanium (Ti (OEt) 4 ; 4.7 mL, 22.5 mmol) was added with stirring. The reaction mixture was heated under reflux. After refluxing for 20 hours, the yellow mixture was cooled to room temperature and aqueous NaOH (0.5 M, 75 mL) was added slowly. A white gel of titanium oxide was filtered through a celite pad to obtain a two-layer filtrate. The organic layer was separated and the aqueous layer was extracted with diethyl ether (Et 2 O). The combined organic extracts were washed with brine and dried over Na 2 SO 4 . Filtration and concentration were performed under reduced pressure to obtain the desired product as a yellow solid (706 mg, 3.5 mmol, 47% yield).
1 H NMR (400 MHz, CDCl 3 ) δ 7.58 (2H, s), 7.20 (1 H, s), 2.55 (3H, s), 2.39 (6H, s), 1.17 (9H, s).
　［合成例2：トリアゾリウム塩の合成］
　合成例2－1：トリアゾリウム塩1a・Brの合成
　トリアゾリウム塩1a・Br： [Synthesis Example 2: Synthesis of triazolium salt]
Synthesis Example 2-1: Synthesis of triazolium salt 1a · Br Triazolium salt 1a · Br:
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
［式中、4－OMeC6H4は4－メトキシフェニル基を示す。3,5－CF3C6H3は3,5－ジ（トリフルオロメチル）フェニル基を示す。以下同様である。］
を、既報（J. Am. Chem. Soc. 2011, 133, 1307-1309.）に記載の合成方法に準じて（原料の置換基等を変更すること等以外は同様の方法で）合成した。
1H NMR (400 MHz, CDCl3) δ 10.4 (1H, brs), 9.88 (1H, brs), 8.77 (2H, s), 7.95-7.89 (4H, m), 7.71 (1H, t, J = 7.3 Hz), 7.53-7.50 (2H, m), 7.39 (2H, t, J = 7.8 Hz), 7.31-7.25 (3H, m), 7.11-7.08 (3H, m), 7.03 (2H, t, J = 7.3 Hz), 6.93 (2H, d, J = 6.8 Hz), 6.94-6.85 (2H, m), 6.70 (2H, d, J = 8.7 Hz), 6.51 (2H, d, J = 8.7 Hz), 4.85 (1H, d, J = 14.6 Hz), 4.79 (1H , d, J = 14.6 Hz), 3.77 (3H, s), 1.64 (3H, d, J = 7.2 Hz); 13C NMR (101 MHz, CDCl3) δ 165.0, 160.8, 142.9, 140.4, 139.2, 138.7, 135.8, 134.5, 132.7, 132.6, 131.7, 131.7 (q, JC-F = 33.9 Hz), 131.4, 130.6, 129.7, 129.4, 128.9, 128.8, 128.8, 128.5, 128.5, 128.3, 128.1, 127.6, 127.2, 125.2, 123.2 (q, JC-F = 277 Hz), 121.8, 120.3, 114.6, 69.9, 65.7, 55.5, 54.9, 15.7; 19F NMR δ -62.3 ppm; HRMS (ESI) Calcd for C46H37F6N4O2 ([M]+) 791.2815. Found 791.2806。 [Wherein 4-OMeC 6 H 4 represents a 4-methoxyphenyl group. 3,5-CF 3 C 6 H 3 represents a 3,5-di (trifluoromethyl) phenyl group. The same applies hereinafter. ]
Was synthesized according to the synthesis method described in the previous report (J. Am. Chem. Soc. 2011, 133, 1307-1309.) (In the same manner except that the substituents of the raw materials were changed).
1 H NMR (400 MHz, CDCl 3 ) δ 10.4 (1H, brs), 9.88 (1H, brs), 8.77 (2H, s), 7.95-7.89 (4H, m), 7.71 (1H, t, J = 7.3 Hz), 7.53-7.50 (2H, m), 7.39 (2H, t, J = 7.8 Hz), 7.31-7.25 (3H, m), 7.11-7.08 (3H, m), 7.03 (2H, t, J = 7.3 Hz), 6.93 (2H, d, J = 6.8 Hz), 6.94-6.85 (2H, m), 6.70 (2H, d, J = 8.7 Hz), 6.51 (2H, d, J = 8.7 Hz), 4.85 (1H, d, J = 14.6 Hz), 4.79 (1H, d, J = 14.6 Hz), 3.77 (3H, s), 1.64 (3H, d, J = 7.2 Hz); 13 C NMR (101 MHz, CDCl 3 ) δ 165.0, 160.8, 142.9, 140.4, 139.2, 138.7, 135.8, 134.5, 132.7, 132.6, 131.7, 131.7 (q, J CF = 33.9 Hz), 131.4, 130.6, 129.7, 129.4, 128.9, 128.8, 128.8, 128.5, 128.5, 128.3, 128.1, 127.6, 127.2, 125.2, 123.2 (q, J CF = 277 Hz), 121.8, 120.3, 114.6, 69.9, 65.7, 55.5, 54.9, 15.7; 19 F NMR δ -62.3 ppm; HRMS (ESI) Calcd for C 46 H 37 F 6 N 4 O 2 ([M] + ) 791.2815. Found 791.2806.
　合成例2－2：トリアゾリウム塩1b・Brの合成
　トリアゾリウム塩1b・Br： Synthesis Example 2-2: Synthesis of triazolium salt 1b · Br Triazolium salt 1b · Br:
Figure JPOXMLDOC01-appb-C000035
  
Figure JPOXMLDOC01-appb-C000035
  
を、既報（J. Am. Chem. Soc. 2011, 133, 1307-1309.）に記載の合成方法に準じて（原料の置換基等を変更すること等以外は同様の方法で）合成した。
1H NMR (400 MHz, CDCl3) δ 8.47 (1H, s), 8.27 (2H, s), 8.08 (1H, dd, J = 7.8, 1.4 Hz), 8.01 (1H, s), 7.56 (2H, d, J = 7.3 Hz), 7.43 (1H, td, J = 7.3, 1.4 Hz), 7.39-7.32 (5H, m), 7.28-7.24 (3H, m), 7.19-7.17 (3H, m), 7.04-7.01 (2H, m), 6.97 (2H, d, J = 7.8 Hz), 5.79 (1H, q, J = 7.3 Hz), 5.54 (1H, s), 1.30 (3H, d, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3) δ 162.7, 146.0, 141.7, 140.4, 139.3, 136.6, 134.5, 132.4 (q, JC-F = 34.2 Hz), 130.3, 129.1, 128.9, 128.9, 128.6, 128.4, 128.4, 128.3, 128.3, 128.2, 128.2, 127.9, 127.6 (q, JC-F = 4.2 Hz), 127.2, 125.4 (sept, JC-F = 3.7 Hz), 123.0 (q, JC-F = 272 Hz), 122.3, 68.4, 63.0, 15.9, one peak for aromatic carbon was not found probably due to overlapping; 19F NMR δ -62.8 ppm; HRMS (ESI) Calcd for C38H28F6N4O ([M+H]+) 671.2240. Found 671.2233。 Was synthesized according to the synthesis method described in the previous report (J. Am. Chem. Soc. 2011, 133, 1307-1309.) (In the same manner except that the substituents of the raw materials were changed).
1 H NMR (400 MHz, CDCl 3 ) δ 8.47 (1H, s), 8.27 (2H, s), 8.08 (1H, dd, J = 7.8, 1.4 Hz), 8.01 (1H, s), 7.56 (2H, d, J = 7.3 Hz), 7.43 (1H, td, J = 7.3, 1.4 Hz), 7.39-7.32 (5H, m), 7.28-7.24 (3H, m), 7.19-7.17 (3H, m), 7.04 -7.01 (2H, m), 6.97 (2H, d, J = 7.8 Hz), 5.79 (1H, q, J = 7.3 Hz), 5.54 (1H, s), 1.30 (3H, d, J = 7.3 Hz) ; 13 C NMR (125 MHz, CDCl 3 ) δ 162.7, 146.0, 141.7, 140.4, 139.3, 136.6, 134.5, 132.4 (q, J CF = 34.2 Hz), 130.3, 129.1, 128.9, 128.9, 128.6, 128.4, 128.4 , 128.3, 128.3, 128.2, 128.2, 127.9, 127.6 (q, J CF = 4.2 Hz), 127.2, 125.4 (sept, J CF = 3.7 Hz), 123.0 (q, J CF = 272 Hz), 122.3, 68.4, 63.0, 15.9, one peak for aromatic carbon was not found probably due to overlapping; 19 F NMR δ -62.8 ppm; HRMS (ESI) Calcd for C 38 H 28 F 6 N 4 O ([M + H] + ) 671.2240. Found 671.2233.
　［実施例1：ケトイミン誘導体の不斉シアノ化］
　実施例1－1 [Example 1: Asymmetric cyanation of ketoimine derivative]
Example 1-1
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
　試験管に合成例1で得たケトイミン誘導体2（267 mg, 1 mmol）及び合成例2－1で得たトリアゾリウム塩1a・Br（0.01 mmol, 8.7 mg）を入れ、トルエン（5 mL）に溶解させ、-40℃に冷却した。続いて、シアン化カリウム（130 mg, 2 mmol）と水（250μL）とを順次投入した後、-40℃のまま9時間激しく攪拌した。水（10 mL）を入れ、分液漏斗に移した後、酢酸エチル（10 mL×3）で抽出した。乾燥後、エバポレーターで溶媒を留去し、粗生成物をシリカゲルカラムクロマトグラフィー（展開溶媒：ヘキサン／酢酸エチル（EtOAc）= 4: 1）で精製し、生成物3を得た（274 mg, 0.93 mmol, 99 %収率, 93 %エナンチオ選択率）。この結果は、後述の表１のentry 2に相当する。
1H NMR (400 MHz, CDCl3) δ 7.55 (2H, s), 7.23 (1H, s), 4.85 (1H, brs), 2.39 (6H, s), 1.59 (3H, s), 1.08 (9H, s)。 Put the ketoimine derivative 2 (267 mg, 1 mmol) obtained in Synthesis Example 1 and the triazolium salt 1a · Br (0.01 mmol, 8.7 mg) obtained in Synthesis Example 2-1 into a test tube and dissolve in toluene (5 mL). And cooled to -40 ° C. Subsequently, potassium cyanide (130 mg, 2 mmol) and water (250 μL) were sequentially added, and the mixture was vigorously stirred at −40 ° C. for 9 hours. Water (10 mL) was added, transferred to a separatory funnel, and extracted with ethyl acetate (10 mL × 3). After drying, the solvent was distilled off with an evaporator, and the crude product was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate (EtOAc) = 4: 1) to obtain product 3 (274 mg, 0.93). mmol, 99% yield, 93% enantioselectivity). This result corresponds to entry 2 in Table 1 described later.
1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (2H, s), 7.23 (1H, s), 4.85 (1H, brs), 2.39 (6H, s), 1.59 (3H, s), 1.08 (9H, s).
　実施例1－2
　基質化合物として種々の化合物を用い、触媒として合成例2－1～2－2で得たいずれかのトリアゾリウム塩を用いたこと以外は上記実施例1－1と同様の処理を行った。その結果、以下の表１に示す置換基を有する光学活性化合物が得られたことを確認した。結果を表１に示す。 Example 1-2
The same treatment as in Example 1-1 was performed, except that various compounds were used as substrate compounds and any of the triazolium salts obtained in Synthesis Examples 2-1 and 2-2 was used as a catalyst. As a result, it was confirmed that an optically active compound having a substituent shown in Table 1 below was obtained. The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
entry 1: 1H NMR (400 MHz, CDCl3) δ 7.54 (2H, s), 7.22 (1H, s), 4.85 (1H, brs), 2.39 (6H, s), 1.93-1.81 (4H, m), 1.73-1.65 (2H, m), 1.60-1.56 (1H, m), 1.58 (3H, s), 1.29-1.04 (5H, m)。
entry 3: 1H NMR (400 MHz, CDCl3) δ 7.55 (2H, s), 7.23 (1H, s), 4.98 (1H, brs), 2.39 (6H, s), 1.68-1.61 (1H, m), 1.58 (3H, s), 1.56-1.50 (1H, m), 1.39-1.25 (3H, m), 1.00 (3H, t, J = 7.3 Hz), 0.97 (3H, t, J = 7.3 Hz)。
entry 4: 1H NMR (400 MHz, CDCl3) δ 7.55 (2H, s), 7.22 (1H, s), 4.86 (1H, brs), 2.39 (6H, s), 2.09 (3H, br), 1.74-1.61 (12H, m), 1.56 (3H, s)。
entry 5: 1H NMR (400 MHz, CDCl3) δ 7.55 (2H, s), 7.23 (1H, s), 4.89 (1H, brs), 2.40 (6H, s), 1.93 (1H, dq, J = 14.1, 7.3 Hz), 1.87 (1H, dq, J = 14.1, 7.3 Hz), 1.63 (3H, s), 1.06 (3H, t, J = 7.3 Hz)。
entry 6: 1H NMR (400 MHz, CDCl3) δ 7.56 (2H, s), 7.21 (1H, s), 4.84 (1H, brs), 2.38 (6H, s), 2.06-1.98 (1H, m), 1.92-1.84 (1H, m), 1.83-1.76 (5H, m), 1.69-1.64 (1H, m), 1.25-1.08 (5H, m), 0.94 (3H, t, J = 7.3 Hz)。
entry 7: 1H NMR (400 MHz, CDCl3) δ 7.40 (2H, d, J = 7.3 Hz), 7.32 (1H, s), 7.28-7.24 (2H, m), 7.21 (2H, t, J = 7.8 Hz), 7.15 (1H, d, J = 7.8 Hz), 5.19 (1H, brs), 2.60 (3H, s), 2.21 (3H, s), 1.93 (3H, s)。
entry 8: 1H NMR (400 MHz, CDCl3) δ 7.65 (1H, dd, J = 5.5, 3.4 Hz), 7.24-7.21 (4H, m), 7.15 (1H, d, J = 7.8 Hz), 6.93 (1H, dd, J = 5.5, 3.4 Hz), 5.08 (1H, brs), 2.58 (3H, s), 2.25 (3H, s), 2.21 (3H, s), 2.14 (3H, s)。 entry 1: 1 H NMR (400 MHz, CDCl 3 ) δ 7.54 (2H, s), 7.22 (1H, s), 4.85 (1H, brs), 2.39 (6H, s), 1.93-1.81 (4H, m) , 1.73-1.65 (2H, m), 1.60-1.56 (1H, m), 1.58 (3H, s), 1.29-1.04 (5H, m).
entry 3: 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (2H, s), 7.23 (1H, s), 4.98 (1H, brs), 2.39 (6H, s), 1.68-1.61 (1H, m) , 1.58 (3H, s), 1.56-1.50 (1H, m), 1.39-1.25 (3H, m), 1.00 (3H, t, J = 7.3 Hz), 0.97 (3H, t, J = 7.3 Hz).
entry 4: 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (2H, s), 7.22 (1H, s), 4.86 (1H, brs), 2.39 (6H, s), 2.09 (3H, br), 1.74 -1.61 (12H, m), 1.56 (3H, s).
entry 5: 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (2H, s), 7.23 (1H, s), 4.89 (1H, brs), 2.40 (6H, s), 1.93 (1H, dq, J = 14.1, 7.3 Hz), 1.87 (1H, dq, J = 14.1, 7.3 Hz), 1.63 (3H, s), 1.06 (3H, t, J = 7.3 Hz).
entry 6: 1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (2H, s), 7.21 (1H, s), 4.84 (1H, brs), 2.38 (6H, s), 2.06-1.98 (1H, m) , 1.92-1.84 (1H, m), 1.83-1.76 (5H, m), 1.69-1.64 (1H, m), 1.25-1.08 (5H, m), 0.94 (3H, t, J = 7.3 Hz).
entry 7: 1 H NMR (400 MHz, CDCl 3 ) δ 7.40 (2H, d, J = 7.3 Hz), 7.32 (1H, s), 7.28-7.24 (2H, m), 7.21 (2H, t, J = 7.8 Hz), 7.15 (1H, d, J = 7.8 Hz), 5.19 (1H, brs), 2.60 (3H, s), 2.21 (3H, s), 1.93 (3H, s).
entry 8: 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (1H, dd, J = 5.5, 3.4 Hz), 7.24-7.21 (4H, m), 7.15 (1H, d, J = 7.8 Hz), 6.93 (1H, dd, J = 5.5, 3.4 Hz), 5.08 (1H, brs), 2.58 (3H, s), 2.25 (3H, s), 2.21 (3H, s), 2.14 (3H, s).
　［実施例2：ケトイミン誘導体の不斉シアノ化］ [Example 2: Asymmetric cyanation of ketoimine derivative]
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
［式中、TFAはトリフルオロ酢酸を示す。BzClは塩化ベンゾイルを示す。DCMはジクロロメタンを示す。］
　試験管に実施例1－1で得た化合物3（29.4 mg, 0.1 mmol）、トリフルオロ酢酸（0.9 mL）、チオアニソール（0.1 mL）及びメタンスルホン酸（10μL）を投入し、室温で10時間攪拌した。反応後、エバポレーターで濃縮し、粗生成物が入った試験管にジクロロメタン（0.5 mL）、水（0.5 mL）及び炭酸カリウム（55.3 mg, 0.4 mmol）を投入し、塩化ベンゾイル（20μL, 0.15 mmol）を滴下した。室温で18時間攪拌した後、水（10 mL）を加え、酢酸エチル（10 mL×3）で抽出した。乾燥後、エバポレーターで溶媒を留去し、粗生成物をシリカゲルカラムクロマトグラフィー（展開溶媒：ヘキサン／酢酸エチル（EtOAc）= 4: 1）で精製し、生成物4を得た（16.4 mg, 0.071 mmol）。 [In the formula, TFA represents trifluoroacetic acid. BzCl represents benzoyl chloride. DCM represents dichloromethane. ]
A test tube was charged with compound 3 (29.4 mg, 0.1 mmol) obtained in Example 1-1, trifluoroacetic acid (0.9 mL), thioanisole (0.1 mL) and methanesulfonic acid (10 μL), and the mixture was stirred at room temperature for 10 hours. Stir. After the reaction, concentrate in an evaporator, add dichloromethane (0.5 mL), water (0.5 mL) and potassium carbonate (55.3 mg, 0.4 mmol) to the test tube containing the crude product, and benzoyl chloride (20 μL, 0.15 mmol). Was dripped. After stirring at room temperature for 18 hours, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). After drying, the solvent was distilled off with an evaporator, and the crude product was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate (EtOAc) = 4: 1) to obtain the product 4 (16.4 mg, 0.071). mmol).
　ナスフラスコに得られた化合物4（16.4 mg, 0.071 mmol）及び6 N塩酸（1 mL）を入れ、還流管を接続し、120℃のオイルバスで24時間加熱した。室温まで冷却した後、ジエチルエーテル（5 mL×2）を用いて分液し、有機化合物を水相から除去した。その後、水溶液をエバポレーターで濃縮し、生成物5を得た（12.9 mg, 0.071 mmol）。
1H NMR (400 MHz, D2O) δ 1.53 (3H, s), 1.08 (9H, s); 13C NMR (125 MHz, D2O) δ 174.8, 67.4, 36.0, 25.4, 18.5; HRMS (ESI) Calcd for C7H16NO2 ([M-Cl]+) 146.1175. Found 146.1176。 The obtained compound 4 (16.4 mg, 0.071 mmol) and 6 N hydrochloric acid (1 mL) were placed in an eggplant flask, connected to a reflux tube, and heated in an oil bath at 120 ° C. for 24 hours. After cooling to room temperature, liquid separation was performed using diethyl ether (5 mL × 2), and the organic compound was removed from the aqueous phase. Thereafter, the aqueous solution was concentrated by an evaporator to obtain a product 5 (12.9 mg, 0.071 mmol).
1 H NMR (400 MHz, D 2 O) δ 1.53 (3H, s), 1.08 (9H, s); 13 C NMR (125 MHz, D 2 O) δ 174.8, 67.4, 36.0, 25.4, 18.5; HRMS ( ESI) Calcd for C 7 H 16 NO 2 ([M-Cl] + ) 146.1175. Found 146.1176.

Claims (18)

  1. 一般式（1）：
    Figure JPOXMLDOC01-appb-C000001
     ［式中、R1及びR2は異なり、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、置換されていてもよいアルケニル基、又は置換されていてもよいアリール基を示す。R3は有機基を示す。］
    で表される光学活性化合物の製造方法であって、
    一般式（2）：
    Figure JPOXMLDOC01-appb-C000002
     ［式中、R5及びR8～R10は同一又は異なって、置換されていてもよいアルキル基、又は置換されていてもよいアリール基を示す。R6は置換されていてもよい第一級アルキル基を示す。R7は置換されていてもよい脂肪族アルキル基、又は置換されていてもよいシクロアルキル基を示す。X1はハロゲン原子又は1価のアニオンを示す。］
    で表されるトリアゾリウム塩の存在下に、
    一般式（3）：
    Figure JPOXMLDOC01-appb-C000003
     ［式中、R1～R3は前記に同じである。］
    で表される化合物と、
    シアン化金属とを反応させる反応工程
    を備える、製造方法。     General formula (1):
    Figure JPOXMLDOC01-appb-C000001
     [Wherein, R 1 and R 2 are different and each represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group. Show. R 3 represents an organic group. ]
    A process for producing an optically active compound represented by:
    General formula (2):
    Figure JPOXMLDOC01-appb-C000002
     [Wherein, R 5 and R 8 to R 10 are the same or different and each represents an optionally substituted alkyl group or an optionally substituted aryl group. R 6 represents an optionally substituted primary alkyl group. R 7 represents an optionally substituted aliphatic alkyl group or an optionally substituted cycloalkyl group. X 1 represents a halogen atom or a monovalent anion. ]
    In the presence of a triazolium salt represented by
    General formula (3):
    Figure JPOXMLDOC01-appb-C000003
     [Wherein R 1 to R 3 are the same as defined above. ]
    A compound represented by
    A production method comprising a reaction step of reacting with a metal cyanide.
  2. 前記一般式（1）及び（3）におけるR1及びR2がいずれも、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、又は置換されていてもよいアリール基である、請求項１に記載の製造方法。 In the general formulas (1) and (3), R 1 and R 2 are both an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted aryl group. The manufacturing method according to claim 1.
  3. 前記一般式（1）及び（3）におけるR1及びR2がいずれも、置換されていてもよいアルキル基又は置換されていてもよいシクロアルキル基である、請求項１又は２に記載の製造方法。 The production according to claim 1 or 2, wherein R 1 and R 2 in the general formulas (1) and (3) are both an optionally substituted alkyl group or an optionally substituted cycloalkyl group. Method.
  4. 前記シアン化金属がシアン化カリウムである、請求項１～３のいずれかに記載の製造方法。 The production method according to any of claims 1 to 3, wherein the metal cyanide is potassium cyanide.
  5. 前記一般式（2）におけるR5及びR8～R10がいずれも、置換されていてもよいアリール基である、請求項１～４のいずれかに記載の製造方法。 5. The production method according to claim 1, wherein R 5 and R 8 to R 10 in the general formula (2) are all optionally substituted aryl groups.
  6. 前記一般式（2）におけるR6が、アルコキシ基で置換された第一級アルキル基である、請求項１～５のいずれかに記載の製造方法。 6. The production method according to claim 1, wherein R 6 in the general formula (2) is a primary alkyl group substituted with an alkoxy group.
  7. 前記一般式（2）におけるR10が、ハロゲン化アルキル基で置換されたアリール基である、請求項１～６のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 6, wherein R 10 in the general formula (2) is an aryl group substituted with a halogenated alkyl group.
  8. 一般式（4）：
    Figure JPOXMLDOC01-appb-C000004
     ［式中、R1～R2は前記に同じである。Xはハロゲン原子を示す。］
    で表される光学活性化合物の製造方法であって、
    請求項１～７のいずれかに記載の製造方法で得られた光学活性化合物における－SO2R3基をアラルキル基に置換した後に、該アラルキル基を－NH3X基に置換する工程
    を備える、製造方法。     General formula (4):
    Figure JPOXMLDOC01-appb-C000004
     [Wherein R 1 and R 2 are the same as defined above. X represents a halogen atom. ]
    A process for producing an optically active compound represented by:
    A step of substituting the aralkyl group with an —NH 3 X group after substituting the —SO 2 R 3 group with an aralkyl group in the optically active compound obtained by the production method according to claim 1. ,Production method.
  9. 一般式（5）：
    Figure JPOXMLDOC01-appb-C000005
     ［式中、R1～R2は前記に同じである。］
    で表される光学活性化合物の製造方法であって、
    請求項８に記載の製造方法で得られた光学活性化合物を中和する工程
    を備える、製造方法。     General formula (5):
    Figure JPOXMLDOC01-appb-C000005
     [Wherein R 1 and R 2 are the same as defined above. ]
    A process for producing an optically active compound represented by:
    The manufacturing method provided with the process of neutralizing the optically active compound obtained with the manufacturing method of Claim 8.
  10. 一般式（2）：
    Figure JPOXMLDOC01-appb-C000006
     ［式中、R5及びR8～R10は同一又は異なって、置換されていてもよいアルキル基、又は置換されていてもよいアリール基を示す。R6は置換されていてもよい第一級アルキル基を示す。R7は置換されていてもよい脂肪族アルキル基、又は置換されていてもよいシクロアルキル基を示す。X1はハロゲン原子又は1価のアニオンを示す。］
    で表されるトリアゾリウム塩からなるストレッカー反応用触媒。     General formula (2):
    Figure JPOXMLDOC01-appb-C000006
     [Wherein, R 5 and R 8 to R 10 are the same or different and each represents an optionally substituted alkyl group or an optionally substituted aryl group. R 6 represents an optionally substituted primary alkyl group. R 7 represents an optionally substituted aliphatic alkyl group or an optionally substituted cycloalkyl group. X 1 represents a halogen atom or a monovalent anion. ]
    A Strecker reaction catalyst comprising a triazolium salt represented by the formula:
  11. 前記一般式（2）におけるR5及びR8～R10がいずれも、置換されていてもよいアリール基である、請求項１０に記載の触媒。 The catalyst according to claim 10, wherein R 5 and R 8 to R 10 in the general formula (2) are all optionally substituted aryl groups.
  12. 前記ストレッカー反応は、
    一般式（3）：
    Figure JPOXMLDOC01-appb-C000007
     ［式中、R1及びR2は異なり、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、置換されていてもよいアルケニル基、又は置換されていてもよいアリール基を示す。R3は有機基を示す。］
    で表される化合物と、
    シアン化金属とを反応させて、
    一般式（1）：
    Figure JPOXMLDOC01-appb-C000008
     ［式中、R1～R3は前記に同じである。］
    で表される光学活性化合物を得る反応である、請求項１０又は１１に記載の触媒。     The Strecker reaction is
    General formula (3):
    Figure JPOXMLDOC01-appb-C000007
     [Wherein, R 1 and R 2 are different and each represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group. Show. R 3 represents an organic group. ]
    A compound represented by
    React with metal cyanide,
    General formula (1):
    Figure JPOXMLDOC01-appb-C000008
     [Wherein R 1 to R 3 are the same as defined above. ]
    The catalyst of Claim 10 or 11 which is reaction which obtains the optically active compound represented by these.
  13. 前記一般式（1）及び（3）におけるR1及びR2がいずれも、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、又は置換されていてもよいアリール基である、請求項１２に記載の触媒。 In the general formulas (1) and (3), R 1 and R 2 are both an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted aryl group. The catalyst according to claim 12.
  14. 一般式（2A）：
    Figure JPOXMLDOC01-appb-C000009
     ［式中、R5及びR8～R10は同一又は異なって、置換されていてもよいアルキル基、又は置換されていてもよいアリール基を示す。R6Aはアルコキシ基で置換された第一級アルキル基を示す。R7は置換されていてもよい脂肪族アルキル基を示す。X1はハロゲン原子又は1価のアニオンを示す。］
    で表されるトリアゾリウム塩。     General formula (2A):
    Figure JPOXMLDOC01-appb-C000009
     [Wherein, R 5 and R 8 to R 10 are the same or different and each represents an optionally substituted alkyl group or an optionally substituted aryl group. R 6A represents a primary alkyl group substituted with an alkoxy group. R 7 represents an optionally substituted aliphatic alkyl group. X 1 represents a halogen atom or a monovalent anion. ]
    A triazolium salt represented by
  15. 前記一般式（2）におけるR5及びR8～R10がいずれも、置換されていてもよいアリール基である、請求項１４に記載のトリアゾリウム塩。 The triazolium salt according to claim 14, wherein R 5 and R 8 to R 10 in the general formula (2) are all optionally substituted aryl groups.
  16. 前記R10が、ハロゲン化アルキル基で置換されたアリール基である、請求項１４又は１５に記載のトリアゾリウム塩。 The triazolium salt according to claim 14 or 15, wherein R 10 is an aryl group substituted with a halogenated alkyl group.
  17. 一般式（1A）：
    Figure JPOXMLDOC01-appb-C000010
     ［式中、R1及びR2は異なり、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、置換されていてもよいアルケニル基、又は置換されていてもよいアリール基を示す。R3Aはジアルキルフェニル基を示す。］
    で表される光学活性化合物。     General formula (1A):
    Figure JPOXMLDOC01-appb-C000010
     [Wherein, R 1 and R 2 are different and each represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group. Show. R 3A represents a dialkylphenyl group. ]
    An optically active compound represented by
  18. 前記一般式（1A）におけるR1及びR2がいずれも、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、又は置換されていてもよいアリール基である、請求項１７に記載の光学活性化合物。 The R 1 and R 2 in the general formula (1A) are both an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted aryl group. The optically active compound described in 1.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012082155A (en) * 2010-10-08 2012-04-26 Nagoya Univ Triazolium salt and method for producing the same, and method for producing alkylated oxindol using azide alcohol and asymmetric reaction

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012082155A (en) * 2010-10-08 2012-04-26 Nagoya Univ Triazolium salt and method for producing the same, and method for producing alkylated oxindol using azide alcohol and asymmetric reaction

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Title
HUANG,X. ET AL.: "Asymmetric Strecker reaction of keto imines catalyzed by a novel chiral bifunctional N,N'-dioxide", ADVANCED SYNTHESIS & CATALYSIS, vol. 348, no. 18, 2006, pages 2579 - 2584, XP055345314, ISSN: 1615-4150 *
OHMATSU, K. ET AL.: "Catalytic asymmetric Mannich- type reactions of a-cyano a-sulfonyl carbanions", CHEMICAL COMMUNICATIONS, vol. 48, no. 64, 2012, pages 7913 - 7915, ISSN: 1359-7345 *
OHMATSU,K. ET AL.: "Chiral 1,2,3-Triazoliums as New Cationic Organic Catalysts with Anion- Recognition Ability: Application to Asymmetric Alkylation of Oxindoles", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 133, no. 5, 2011, pages 1307 - 1309, XP055345317, ISSN: 0002-7863 *
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WANG,H. ET AL.: "Solvent-controlled asymmetric Strecker reaction: stereoselective synthesis of a-trifluoromethylated a-amino acids", ORGANIC LETTERS, vol. 8, no. 7, 2006, pages 1379 - 1381, XP055345311, ISSN: 1523-7060 *

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