JP5963140B2 - Asymmetric dehydration condensation agent - Google Patents

Description

  The present invention relates to a novel chiral optically active quaternary ammonium compound prepared from a chiral optically active tertiary amine and a triazine derivative, and an asymmetric dehydrating condensing agent comprising the compound. The present invention also relates to a novel kinetic optical resolution method for racemic chiral organic acids using the asymmetric dehydrating condensing agent.

  In recent years, the demand for optically active compounds has increased dramatically. In particular, the demand for pharmaceutical intermediates in the pharmaceutical industry has increased. For this reason, development research on methods for efficiently obtaining optically active compounds has been actively conducted all over the world. One of the methods for obtaining an optically active compound is an optical resolution method. As the optical resolution method, a preferred crystal method, a diastereomer resolution method, a kinetic resolution method and the like are known. Since the preferential crystal method has a narrow range of application, there are significant limitations on the resulting compounds. The diastereomeric resolution method requires a stoichiometric amount of a resolving agent, requires many steps, and has problems such as complicated operation. On the other hand, the kinetic resolution method uses a reaction rate difference between a racemate and an enantiomer by carrying out a reaction using an optically active catalyst, so that only a specific enantiomer reacts preferentially and optically reacts. This is a technique for splitting, and a splitting method mainly using an enzyme has been put into practical use, and is an effective means for obtaining optically active amino acids, alcohols and the like. However, in general, kinetic resolution using an enzyme requires a long time for the reaction, and in order to obtain a high optical yield, it is necessary to dilute the substrate concentration. There was a problem left.

  Several research examples of chemical kinetic resolution methods have been reported. As a method of chemically optically resolving a racemic isomer of a chiral carboxylic acid derivative such as an α-amino acid, an optical resolution method by alcoholysis of a urethane-protected amino acid-N-carboxy anhydride using a cinchona alkaloid derivative as a catalyst has been reported. (Non-Patent Document 1). Although this method can perform optical resolution with high efficiency by selecting a catalyst, the synthesis of cinchona alkaloid derivatives is generally difficult and expensive and difficult to obtain. It is unsuitable. In addition, the above method has a problem that enantiomeric selectivity is lowered when optical resolution is carried out at a high substrate concentration.

  Catalytic asymmetric acylation represented by the following formula (1) (Non-patent document 2) and formula (2) (Non-patent document 3) is a method for chemically optically resolving racemic isomers of chiral amines. An optical resolution method by reaction has been reported.

  However, all of these must be carried out at a very low temperature in an aprotic organic solvent after using a fat-soluble acid anhydride or ester as an acylating agent rather than a carboxylic acid itself. As an amidation reaction, the method was poor in practicality.

  Recently, Kaminski et al., An enantioselective peptide comprising a reaction of a racemic N-protected amino acid with an L-form C-protected amino acid in the presence of a stoichiometric amount of an asymmetric dehydrating condensing agent and 0.1 equivalent of a base. A synthesis reaction (formula (3)) was reported (Non-patent Document 4). However, the reaction requires a stoichiometric amount or more of an optically active chiral tertiary amine, and it is necessary to use an asymmetric dehydrating condensation agent prepared in advance. Further, high selectivity is not obtained in a protic solvent (THF-tert-BuOH). Furthermore, since strychnine, which is an optically active chiral tertiary amine used in the reaction, is a toxic compound, it is not a practical method.

Deng, L. et al., J. Am. Chem. Soc., 2001, 123, 12696-12697. Fu, G. C. et al., Angew. Chem. Int. Ed., 2001, 40, 234-236. Seidel, D. et al., J. Am. Chem. Soc., 2009, 131, 17060-17061. Kolesinska, B. et al., Tetrahedron Lett., 2010, 51, 20-22.

  In order to synthesize an amide from a carboxylic acid and an amine, a dehydrating condensing agent is generally used. The dehydration condensation reaction is a two-stage reaction consisting of activation of a carboxylic acid followed by acylation of an amine, but the active intermediate of the carboxylic acid produced in the first stage is usually a nucleophilic substance such as water or alcohol. The amidation reaction does not proceed efficiently because it is unstable in a protic solvent and is decomposed by solvent molecules. On the other hand, since a compound having a carboxy group or an amino group is generally highly polar, it is often insoluble or hardly soluble in an organic solvent. Due to such a trade-off problem, there have been no successful examples of a catalytic asymmetric amidation reaction between an amine and a carboxylic acid using an optically active chiral dehydration condensing agent in a protic solvent.

  An object of the present invention is to provide a novel compound that can be stably used in a wide range of solvents including protic solvents such as water and alcohol, and is useful as a practical asymmetric dehydration condensing agent, and a chiral compound using the same, particularly It is to provide a kinetic optical resolution method for chiral organic acids.

  As a result of intensive studies under such circumstances, the present inventors have obtained the following formula (I):

[Where
R ¹ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted aromatic ring group;
R ² represents an optionally substituted C _1-6 alkyl group,
Y is a single bond, an oxygen atom, a sulfur atom, NR ⁷ (where R ⁷ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted aromatic group). Represents a cyclic group), PR ⁸ (wherein R ⁸ represents an optionally substituted alkyl group or an optionally substituted aromatic ring group), Si (R ⁹ ) (R ¹⁰ ) ( Here, R ⁹ and R ¹⁰ each independently represent an optionally substituted alkyl group or an optionally substituted aromatic ring group.) Or C (R ¹¹ ) (R ¹² ) (here , R ¹¹ and R ¹² each independently represent an optionally substituted alkyl group or an optionally substituted aromatic ring group, or R ¹¹ and R ¹² together with the carbon atom to which they are attached. Cyclic carbonization which may be substituted Containing groups may be formed.) Indicates,
R ³ represents a hydrogen atom, a halogen atom, an alkyl group that may be substituted, an alkenyl group that may be substituted, an alkynyl group that may be substituted, or a cyclic group that may be substituted;
R ⁴ , R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or a substituted group. Optionally substituted alkyl-carbonyl group, optionally substituted alkoxy-carbonyl group, carbamoyl group, mono- or di-C _1-6 alkylamino-carbonyl group, formyl group, cyano group, optionally substituted alkoxy group Or R ³ —Y and R ⁴ , and / or R ⁵ and R ⁶ may form a condensed ring together with the benzene ring to which they are bonded, and X ⁻ Represents a counter anion which is not nucleophilic or has low nucleophilicity. ] [The compound (I) may be called hereafter.) Moreover, it may be referred to as “compound (I) of the present invention” as a broad abbreviation including compound (I ′) or compound (I ″) described later. It was found for the first time that it can be isolated stably. The present inventors also have a compound (I ′) which is an optical isomer of compound (I) in the presence of a protic solvent:

[Each symbol in the formula is as defined above. Or compound (I ″):

[Each symbol in the formula is as defined above. A compound (II ') which is a catalytic amount of optically pure chiral tertiary amine in the reaction system:

[Each symbol in the formula is as defined above. Or compound (II "):

[Each symbol in the formula is as defined above. ] And triazine compound (III):

[Wherein, X ¹ represents a halogen atom, an optionally substituted alkylsulfonyloxy group or an optionally substituted arylsulfonyloxy group, and R ¹ has the same meaning as described above. ]
It was also found that the compound (I ′) or the compound (I ″) can be used as it is for the kinetic optical resolution of a chiral organic acid without being isolated, by preparing it at the time of use by reaction with As a result, it was found that the compound (I) of the present invention is useful as a novel and practical asymmetric dehydration condensing agent, and the present invention was completed.

That is, the present invention is as follows.
[1] Formula (I):

[Where
R ¹ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted aromatic ring group;
R ² represents an optionally substituted C _1-6 alkyl group,
Y is a single bond, an oxygen atom, a sulfur atom, NR ⁷ (where R ⁷ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted aromatic group). Represents a cyclic group), PR ⁸ (wherein R ⁸ represents an optionally substituted alkyl group or an optionally substituted aromatic ring group), Si (R ⁹ ) (R ¹⁰ ) ( Here, R ⁹ and R ¹⁰ each independently represent an optionally substituted alkyl group or an optionally substituted aromatic ring group.) Or C (R ¹¹ ) (R ¹² ) (here , R ¹¹ and R ¹² each independently represent an optionally substituted alkyl group or an optionally substituted aromatic ring group, or R ¹¹ and R ¹² together with the carbon atom to which they are attached. Cyclic carbonization which may be substituted Containing groups may be formed.) Indicates,
R ³ represents a hydrogen atom, a halogen atom, an alkyl group that may be substituted, an alkenyl group that may be substituted, an alkynyl group that may be substituted, or a cyclic group that may be substituted;
R ⁴ , R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or a substituted group. Optionally substituted alkyl-carbonyl group, optionally substituted alkoxy-carbonyl group, carbamoyl group, mono- or di-C _1-6 alkylamino-carbonyl group, formyl group, cyano group, optionally substituted alkoxy group Or R ³ —Y and R ⁴ , and / or R ⁵ and R ⁶ may form a condensed ring together with the benzene ring to which they are bonded, and X ⁻ Represents a counter anion which is not nucleophilic or has low nucleophilicity. ]
A compound represented by
[2] The compound represented by the formula (I) is represented by the formula (I ′):

[Each symbol in the formula is as defined above. A compound represented by formula (I ″):

[Each symbol in the formula is as defined above. The compound of the said [1] description which is a compound represented by these, or those mixtures.
[3] The compound according to the above [1] or [2], wherein R ¹ is an optionally substituted C _1-3 alkyl group.
[4] The compound according to any one of the above [1] to [3], wherein R ² is a C _1-3 alkyl group _optionally substituted by 1 to 3 halogen atoms.
[5] The compound according to any one of [1] to [4] above, wherein Y is a single bond.
[6] The compound according to any one of [1] to [5] above, wherein R ³ is an optionally substituted alkynyl group or an optionally substituted aryl group.
[7] The above [6], wherein R ³ is a C _2-6 alkynyl group optionally substituted with an aryl group or a C _6-10 aryl group _optionally substituted with 1 to 3 halogen atoms. The described compound.
[8] The compound according to any one of [1] to [7] above, wherein R ⁵ and R ⁶ form a naphthalene ring together with a benzene ring to which they are bonded.
[9] X ^- is fluoride, chloride, bromide, iodide, optionally substituted alkyl sulfonate, optionally substituted aryl sulfonate, perchlorate, tetrafluoroborate, hexafluorophosphate, hexafluoroantimonate , A compound according to any one of [1] to [8] above, which is a counter anion selected from the group consisting of tetraphenylborate and arsenate.
[10] The compound according to [9] above, wherein X ⁻ is chloride or trifluoromethanesulfonate.
[11] R ¹ is an optionally substituted C _1-3 alkyl group,
R ² is a C _1-3 alkyl group which may be substituted with 1 to 3 halogen atoms,
Y is a single bond,
R ³ is a C _6-10 aryl group _optionally substituted by 1 to 3 halogen atoms,
R ⁴ is a hydrogen atom,
The compound according to the above [1], wherein R ⁵ and R ⁶ form a naphthalene ring together with a benzene ring to which they are bonded, and X ⁻ is chloride or trifluoromethanesulfonate.
[12] R ¹ is an optionally substituted C _1-3 alkyl group,
R ² is a C _1-3 alkyl group which may be substituted with 1 to 3 halogen atoms,
Y is a single bond,
R ³ is an ethynyl group optionally substituted by an aryl group,
R ⁴ is a hydrogen atom,
The compound according to the above [1], wherein R ⁵ and R ⁶ form a naphthalene ring together with a benzene ring to which they are bonded, and X ⁻ is chloride or trifluoromethanesulfonate.
[13] The following formula:

Or an optical isomer thereof.
[14] A dehydrating condensing agent comprising the compound according to any one of [1] to [13].
[15] An asymmetric dehydrating condensing agent comprising the compound according to any one of [2] to [13] above or an optical isomer thereof.
[16] The asymmetric dehydrating condensing agent according to the above [15], wherein the asymmetric dehydrating condensing agent is an asymmetric amidation catalyst.
[17] The asymmetric dehydrating condensing agent according to the above [15], wherein the asymmetric dehydrating condensing agent is an asymmetric esterification catalyst.
[18] Formula (I):

[Where
R ¹ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted aromatic ring group;
R ² represents an optionally substituted C _1-6 alkyl group,
Y is a single bond, an oxygen atom, a sulfur atom, NR ⁷ (where R ⁷ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted aromatic group). A ring group), PR ⁸ (wherein R ⁸ represents an optionally substituted alkyl group or an optionally substituted aromatic ring group), Si (R ⁹ ) (R ¹⁰ ) ( Here, R ⁹ and R ¹⁰ each independently represent an optionally substituted alkyl group or an optionally substituted aromatic ring group.) Or C (R ¹¹ ) (R ¹² ) (here , R ¹¹ and R ¹² each independently represent an optionally substituted alkyl group or an optionally substituted aromatic ring group, or R ¹¹ and R ¹² together with the carbon atom to which they are attached. Cyclic hydrocarbon which may be substituted May be formed.) Indicates,
R ³ represents a hydrogen atom, a halogen atom, an alkyl group that may be substituted, an alkenyl group that may be substituted, an alkynyl group that may be substituted, or a cyclic group that may be substituted;
R ⁴ , R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or a substituted group. Optionally substituted alkyl-carbonyl group, optionally substituted alkoxy-carbonyl group, carbamoyl group, mono- or di-C _1-6 alkylamino-carbonyl group, formyl group, cyano group, optionally substituted alkoxy group Or R ³ —Y and R ⁴ , and / or R ⁵ and R ⁶ may form a condensed ring together with the benzene ring to which they are bonded, and X ⁻ Represents a counter anion which is not nucleophilic or has low nucleophilicity. ]
A process for producing a compound represented by
Formula (II):

[Each symbol in the formula is as defined above. ]
A compound represented by formula (III):

[Wherein, X ¹ represents a halogen atom, an optionally substituted alkylsulfonyloxy group or an optionally substituted arylsulfonyloxy group, and R ¹ has the same meaning as described above. ]
The manufacturing method including the process with which the compound represented by these is made to react in a reaction solvent.
[19] The compound represented by the formula (I) is represented by the formula (I ′):

[Each symbol in the formula is as defined above. A compound represented by formula (I ″):

[Each symbol in the formula is as defined above. Or a mixture thereof, and the compound represented by the formula (II) is represented by the formula (II ′):

[Each symbol in the formula is as defined above. ]
A compound of formula (II ″):

[Each symbol in the formula is as defined above. ]
The method of said [18] description which is a compound represented by these, or those mixtures.
[20] R ² is a C _1-3 alkyl group _optionally substituted by 1 to 3 halogen atoms,
Y is a single bond,
R ³ is a C _6-10 aryl group _optionally substituted by 1 to 3 halogen atoms,
The method according to [18] or [19] above, wherein R ⁴ is a hydrogen atom, and R ⁵ and R ⁶ form a naphthalene ring together with a benzene ring to which they are bonded.
[21] R ² is a C _1-3 alkyl group which may be substituted with 1 to 3 halogen atoms,
Y is a single bond,
R ³ is an ethynyl group optionally substituted by an aryl group,
The method according to [18] or [19] above, wherein R ⁴ is a hydrogen atom, and R ⁵ and R ⁶ form a naphthalene ring together with a benzene ring to which they are bonded.
[22] The reaction solvent is THF, water, alcohol, N, N-dimethylformamide, dimethyl sulfoxide, diethyl ether, dibutyl ether, DME, diglyme, tert-butyl methyl ether, dioxane, ethyl acetate, hexane, methylene chloride, chloroform. , Dichloroethane, acetonitrile, acetone, or a mixed solvent of two or more thereof, [18] to [21].
[23] A racemic isomer of a chiral organic acid is converted into an asymmetric dehydrating condensing agent and the formula (III):

[Wherein, X ¹ represents a halogen atom or an optionally substituted alkylsulfonoxy group, and R ¹ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or An aromatic ring group which may be substituted. In the presence of a compound represented by the following formula, a kinetic optical resolution is obtained by reacting with a nucleophile in a reaction solvent to obtain a stereoisomerically enriched chiral organic acid-nucleophile condensate. A method comprising using the compound according to any one of the above [2] to [13] as the asymmetric dehydrating condensing agent.
[24] The method described in [23] above, wherein the chiral organic acid is an N-protected α-amino acid.
[25] The method described in [24] above, wherein the N-protected α-amino acid is N-protected α-phenylalanine.
[26] The method according to any one of [23] to [25] above, wherein the nucleophile is an alcohol or an amine, and the corresponding chiral organic acid-nucleophile condensate is an ester or an amide.
[27] The method described in [26] above, wherein the amine is a primary amine.
[28] The method described in [27] above, wherein the primary amine is C _7-14 aralkylamine.
[29] The method according to any one of [23] to [28] above, wherein the reaction solvent contains a lower alcohol.
[30] The method described in [29] above, comprising a lower alcohol as the nucleophile and reaction solvent.
[31] The asymmetric dehydrating condensing agent is a catalytic amount of the formula (II ′):

[Each symbol in the formula is as defined above. ]
A compound of formula (II ″):

[Each symbol in the formula is as defined above. ]
A compound represented by formula (III):

[Each symbol in the formula is as defined above. ]
The method according to any one of [23] to [30] above, which is formed in the reaction system by a reaction with a compound represented by the formula:
[32] R ² is a C _1-3 alkyl group _optionally substituted by 1 to 3 halogen atoms,
Y is a single bond,
R ³ is a C _6-10 aryl group _optionally substituted by 1 to 3 halogen atoms,
The method according to [31] above, wherein R ⁴ is a hydrogen atom, and R ⁵ and R ⁶ form a naphthalene ring together with a benzene ring to which they are bonded.
[33] R ² is a C _1-3 alkyl group _optionally substituted by 1 to 3 halogen atoms,
Y is a single bond,
R ³ is an ethynyl group optionally substituted by an aryl group,
The method according to [31] above, wherein R ⁴ is a hydrogen atom, and R ⁵ and R ⁶ form a naphthalene ring together with a benzene ring to which they are bonded.
[34] The method according to any one of [31] to [33] above, wherein the catalyst amount is 0.1 mol% to 50 mol% with respect to the racemic form of the chiral organic acid.
[35] The following formula:

A compound represented by or an optical isomer thereof,
Etc.

  According to the present invention, optically pure compound (I) can be synthesized easily and with high yield, and can be stably used in a wide range of solvents including protic solvents (water, alcohol, etc.). Therefore, a novel asymmetric dehydration condensing agent suitable for kinetic optical resolution of various chiral compounds, particularly chiral organic acids (for example, α-amino acid derivatives) can be provided. Also according to the invention, optically pure compound (I) is prepared in the reaction system by reaction of a catalytic amount of optically pure chiral tertiary amine (II) with triazine compound (III). Since the compound (I) is not required to be isolated and can be easily recovered and reused, a simple and practical kinetic optical resolution method for various chiral compounds can be provided. .

  Hereinafter, the present invention will be described in detail.

(Definition)

  In the present specification, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present specification, the “alkyl group” in the “optionally substituted alkyl group” means a linear or branched alkyl group having 1 or more carbon atoms, and the carbon number range is particularly limited. When not present, a C _1-20 alkyl group is preferred, among which a C _1-12 alkyl group is more preferred, a C _1-6 alkyl group is further preferred, and a C _1-3 alkyl group is particularly preferred.

In the present specification, the “C _1-20 alkyl group” means a linear or branched alkyl group having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. -Butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl , Nonyl, decyl, undecyl, dodecyl, tridecyl, eicosyl and the like.

In the present specification, the “C _1-12 alkyl group” means a linear or branched alkyl group having 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. -Butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl , Nonyl, decyl, undecyl, dodecyl and the like.

In the present specification, the “C _1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. -Butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc. .

In the present specification, the “C _1-3 alkyl group” means a linear or branched alkyl group having 1 to 3 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl and the like.

In the present specification, the “aryl group” means a monocyclic or polycyclic (condensed) hydrocarbon group exhibiting aromaticity, and specifically includes, for example, phenyl, 1-naphthyl, 2-naphthyl. , C _6-22 aryl groups such as biphenylyl, terphenyl, diphenylnaphthyl, 2-anthryl, phenanthryl and the like. Among them, a C _6-14 aryl group is preferable, and a C _6-10 aryl group is particularly preferable.

In the present specification, examples of the “C _6-10 aryl group” include phenyl, 1-naphthyl, and 2-naphthyl, and phenyl is particularly preferable.

In the present specification, “C _6-10 aryloxy group” means a group in which “C _6-10 aryl group” is bonded to an oxygen atom, such as phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like. Is mentioned. Of these, a phenoxy group is preferable.

In the present specification, the “aromatic ring” in the “optionally substituted aromatic ring group” represents a C _6-22 aromatic hydrocarbon or an aromatic heterocyclic ring.
In the present specification, “C _6-22 aromatic hydrocarbon” indicates a ring corresponding to “C _6-22 aryl group”. As the C _6-22 aromatic hydrocarbon, a ring corresponding to “C _6-14 aryl group” is preferable, and a ring corresponding to “C _6-10 aryl group” (eg, benzene or naphthalene) is particularly preferable.
In the present specification, the “aromatic heterocyclic ring” refers to a ring corresponding to the “aromatic heterocyclic group”. Among these, monocyclic aromatic heterocycles are preferable, and 5- or 6-membered monocyclic aromatic heterocycles are particularly preferable.
In the present specification, the “aromatic ring” may have a substituent at a substitutable position. The number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different.

  In the present specification, the “aromatic heterocyclic group” means an aromaticity containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom. Means a monocyclic or polycyclic (fused) heterocyclic group shown.

  In the present specification, examples of the “monocyclic aromatic heterocyclic group” include furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl (1, 2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (1,2,4-triazolyl, 1,2,3- Triazolyl), tetrazolyl, triazinyl and the like. Among them, a 5- or 6-membered monocyclic aromatic heterocyclic group is preferable, and pyridyl is particularly preferable. .

  In the present specification, the “polycyclic (fused) aromatic heterocyclic group” means that the monocyclic aromatic heterocyclic group is a monocyclic aromatic ring (preferably a benzene ring or a monocyclic aromatic group). Heterocycle), such as quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, benzotriazolyl , Indolyl, indazolyl, pyrrolopyridyl, pyrazolopyridyl, imidazopyridyl, thienopyridyl, pyrrolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, thienopyrazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, thienopyrimidinyl, etc. .

  Examples of the “heterocycle (group)” in the present specification include an aromatic heterocyclic group and a non-aromatic heterocyclic group.

  Examples of the “aromatic heterocyclic group” in the present specification include the groups described above.

  Examples of the “non-aromatic heterocyclic group” in the present specification include 4 to 7 members containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom. (Preferably 5 or 6-membered) monocyclic non-aromatic heterocyclic group and condensed non-aromatic heterocyclic group are mentioned. Examples of the condensed non-aromatic heterocyclic group include a ring corresponding to the 4- to 7-membered monocyclic non-aromatic heterocyclic group, and a 5- or 6-membered aromatic containing 1 or 2 nitrogen atoms. 1 or 2 rings selected from a heterocycle (eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocycle containing one sulfur atom (eg, thiophene) and a benzene ring Examples thereof include a group derived from a condensed ring and a group obtained by partial saturation of the group.

  Preferred examples of the non-aromatic heterocyclic group include azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxazolinyl, thiazolinyl, imidazolinyl, dioxolanyl, dioxolanyl, , Monocyclic non-aromatic heterocyclic groups such as pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrothiopyranyl, tetrahydrofuryl, pyrazolidinyl, pyrazolinyl, tetrahydropyrimidinyl, dihydrotriazolyl, tetrahydrotriazolyl, dihydroindolyl, dihydro Isoindolyl, dihydrobenzofuranyl, dihydrobenzodioxinyl, dihydrobenzodioxepinyl, tetrahydrobenzo Ranil, chromenyl, dihydrochloride Mesnil, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, and the like condensed non-aromatic heterocyclic group such as dihydrophthalazinyl the like.

In the present specification, the “aralkyl” in the “optionally substituted aralkyl group” means a group in which an “aryl group” is substituted on an “alkyl group”, preferably “C _7-14 aralkyl”. is there.

In the present specification, “C _7-14 aralkyl” means a group in which “C _1-4 alkyl group” is replaced by “C _6-10 aryl group”, and examples thereof include benzyl, 1-phenylethyl, 2 -Phenylethyl, (naphthyl-1-yl) methyl, (naphthyl-2-yl) methyl, 1- (naphthyl-1-yl) ethyl, 1- (naphthyl-2-yl) ethyl, 2- (naphthyl-1) -Yl) ethyl, 2- (naphthyl-2-yl) ethyl, biphenylylmethyl and the like.

In the present specification, “C _7-14 aralkyloxy” means a group in which “C _7-14 aralkyl group” is bonded to an oxygen atom, and examples thereof include benzyloxy, 1-naphthylmethyloxy, 2-naphthylmethyloxy. Etc. Of these, a benzyloxy group is preferable.

In the present specification, the “alkenyl group” in the “optionally substituted alkenyl group” means a linear or branched alkenyl group having 2 or more carbon atoms, and the carbon number range is not particularly limited. Preferably, it is a _C2-6 alkenyl group.

In the present specification, the “C _2-6 alkenyl group” means a linear or branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl. -1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1 -Hexenyl, 3-hexenyl, 5-hexenyl and the like. Among these, a C _2-4 alkenyl group is particularly preferable.

In the present specification, the “alkynyl group” in the “optionally substituted alkynyl group” means a linear or branched alkynyl group having 2 or more carbon atoms, and the carbon number range is not particularly limited. Preferably, it is a C _2-6 alkynyl group.

In the present specification, the “C _2-6 alkynyl group” means a linear or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl. 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like. Among them, a C _2-4 alkynyl group is preferable, and an ethynyl group is particularly preferable.

In the present specification, the “C _3-8 cycloalkyl group” means a cyclic alkyl group having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. It is done. Among these, a C _3-6 cycloalkyl group is preferable.

In the present specification, the “alkoxy group” in the “optionally substituted alkoxy group” means a linear or branched alkoxy group having 1 or more carbon atoms, and the carbon number range is not particularly limited, Preferably, it is a C _1-6 alkoxy group.

In the present specification, the “C _1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, Examples include sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like. Among these, a C _1-4 alkoxy group is preferable.

In the present specification, the “C _1-6 alkylthio group” means a linear or branched alkylthio group having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio. , Sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio and the like. Among these, a C _1-4 alkylthio group is preferable.

In the present specification, the “C _6-10 arylthio group” means a group in which a “C _6-10 aryl group” is bonded to a sulfur atom, and examples thereof include phenylthio, 1-naphthylthio, 2-naphthylthio and the like. . Of these, a phenylthio group is preferable.

In the present specification, the “alkyl-carbonyl group” in the “optionally substituted alkyl-carbonyl group” means a group in which an “alkyl group” is bonded to —C═O—, and in particular, the carbon number range is but not limited to, _{preferably, C 1-6} alkyl - is a carbonyl group.

“C _1-6 alkyl-carbonyl group” means a group in which “C _1-6 alkyl group” is bonded to —C═O—, for example, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butyl Examples include carbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, hexylcarbonyl and the like. Among these, a C _1-4 alkyl-carbonyl group is preferable.

“C _1-6 alkyl-carbonyloxy group” means a group in which “C _1-6 alkyl-carbonyl group” is bonded to an oxygen atom. For example, acetoxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy Butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy, tert-butylcarbonyloxy, pentylcarbonyloxy, isopentylcarbonyloxy, neopentylcarbonyloxy, hexylcarbonyloxy and the like. Among these, a C _1-4 alkyl-carbonyloxy group is preferable.

In the present specification, “C _6-10 aryl-carbonyl group” means a group in which “C _6-10 aryl group” is bonded to —C═O—, and examples thereof include benzoyl, 1-naphthoyl, 2- Naphthoyl etc. are mentioned. Of these, a benzoyl group is preferable.

Herein, - the term "C _6-10 arylcarbonyl group", an oxygen atom - means "C _6-10 arylcarbonyl group" attached group, e.g., benzoyloxy, 1-naphthoyloxy , 2-naphthoyloxy and the like. Of these, a benzoyloxy group is preferable.

In the present specification, “C _1-6 alkoxy-carbonyl group” means a group in which “C _1-6 alkoxy group” is bonded to —C═O—, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl. , Isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl and the like. Among these, a C _1-4 alkoxy-carbonyl group is preferable.

In the present specification, “C _2-6 alkenyloxy-carbonyl group” means a group in which “C _2-6 alkenyloxy group” is bonded to —C═O—, for example, vinyloxycarbonyl, allyloxy. Examples include carbonyl, 2-methyl-1-propenyloxycarbonyl, 1-butenyloxycarbonyl, 2-butenyloxycarbonyl, 3-butenyloxycarbonyl, 1-pentenyloxycarbonyl, 1-hexenyloxycarbonyl and the like. Of these, an allyloxycarbonyl group is particularly preferable.

In the present specification, “C _6-10 aryloxy-carbonyl group” means a group in which “C _6-10 aryloxy group” is bonded to —C═O—, such as phenoxycarbonyl, 1-naphthyl. Examples include oxycarbonyl and 2-naphthyloxycarbonyl. Of these, a phenoxycarbonyl group is preferable.

In the present specification, “C _7-14 aralkyloxy-carbonyl group” means a group in which “C _7-14 aralkyloxy group” is bonded to —C═O—, and examples thereof include benzyloxycarbonyl, 1- Naphthylmethyloxycarbonyl, 2-naphthylmethyloxycarbonyl, etc. are mentioned. Of these, a benzyloxycarbonyl group is preferred.

In the present specification, the "C _1-6 alkylsulfonyl group", -S (O) 2 _- means the "C _1-6 alkyl group" is bonded to groups such as methylsulfonyl, ethylsulfonyl, propyl Examples include sulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, hexylsulfonyl and the like. Among these, a C _1-4 alkylsulfonyl group is preferable.

In the present specification, the _{"C 6-10} arylsulfonyl group", -S _{(O) 2} - means the _{"C 6-10} aryl group" is bonded group, e.g., phenylsulfonyl, 1-naphthylsulfonyl , 2-naphthylsulfonyl and the like. Of these, a phenylsulfonyl group is preferred.

In the present specification, the “alkylsulfonoxy group” in the “optionally substituted alkylsulfonoxy group” means a group in which an “alkyl group” is bonded to the sulfur atom of —S (O) ₂ —O—. Meaning, for example, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonoxy, tert-butylsulfonoxy, C _1-6 alkyl sulfonoxy groups such as pentyl sulfonoxy, isopentyl sulfoniloxy, neopentyl sulfonoxy, hexyl sulfonoxy and the like can be mentioned. Among these, a C _1-4 alkylsulfonoxy group is preferable. The “optionally substituted alkylsulfonoxy group” is particularly preferably a methylsulfonoxy group (eg, trifluoromethanesulfonoxy group) which may be substituted with a halogen atom.

In the present specification, the “optionally substituted arylsulfonoxy group” means a group in which an “aryl group” is bonded to the sulfur atom of —S (O) ₂ —O—. Nyloxy, 1-naphthylsulfonyloxy, 2-naphthylsulfonyloxy and the like can be mentioned. Of these, a phenylsulfonoxy group is preferable. The “optionally substituted arylsulfonoxy group” is particularly preferably a phenylsulfonoxy group (eg, benzenesulfonoxy group, p-toluenesulfonoxy group) which may be substituted with a methyl group. .

In the present specification, “alkyl sulfonate” in “optionally substituted alkyl sulfonate” means a group in which an “alkyl group” is bonded to —SO ₃ ^— , such as methyl sulfonate, ethyl sulfo Nert, propyl sulfonate, isopropyl sulfonate, butyl sulfonate, isobutyl sulfonate, sec-butyl sulfonate, tert-butyl sulfonate, pentyl sulfonate, isopentyl sulfonate, neopentyl sulfonate, hexyl sulfonate, etc. It is done. Among these, C _1-4 alkyl sulfonate is preferable. As the “optionally substituted alkyl sulfonate”, methyl sulfonate optionally substituted with a halogen atom (eg, trifluoromethane sulfonate) is particularly preferable.

In the present specification, “aryl sulfonate” in “optionally substituted aryl sulfonate” means a group in which an “aryl group” is bonded to —SO ₃ ^— , such as phenyl sulfonate, 1- Examples thereof include C _6-10 aryl sulfonates such as naphthyl sulfonate and 2-naphthyl sulfonate. Of these, phenylsulfonate is preferred. As the “aryl sulfonate” in the “optionally substituted aryl sulfonate”, phenyl sulfonate (eg, benzene sulfonate, p-toluene sulfonate) optionally substituted with a methyl group is particularly preferable.

In the present specification, the “mono- or di-C _1-6 alkylamino-carbonyl group” means a carbonyl group on a mono- or di-substituted amino group with a linear or branched alkyl group having 1 to 6 carbon atoms. Means a bonded group, for example, methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group, isopropylaminocarbonyl group, dimethylaminocarbonyl group, diethylaminocarbonyl group, dipropylaminocarbonyl group, diisopropylaminocarbonyl group, etc. Can be mentioned.

In the present specification, the “tri-substituted silyl group” means a silyl group substituted by three identical or different substituents (eg, C _1-6 alkyl group, C _6-10 aryl group), As the group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a triphenylsilyl group, and the like are preferable.

In the present specification, the “protected amino group” means an amino group protected by the same or different one or two “protecting groups”. As the “protecting group”, for example, a protecting group for an amino group described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980) can be used, and a C _1-6 alkyl group, a C _2-6 alkenyl group can be used. C _6-10 aryl group, C _7-14 aralkyl group, formyl group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group, C _2-6 alkenyloxy-carbonyl group, C _6-10 Aryl-carbonyl group, C _7-14 aralkyl-carbonyl group, C _6-10 aryloxy-carbonyl group, C _7-14 aralkyloxy-carbonyl group, C _6-10 arylsulfonyl group, benzhydryl group, trityl group, tri-C Protecting groups such as _1-6 alkylsilyl group, 9-fluorenylmethyloxycarbonyl group, phthaloyl group and the like can be mentioned. The protecting group may be substituted with a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a nitro group. Specific examples of the protective group for the amino group include acetyl, trifluoroacetyl, pivaloyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzhydryl, Examples include trityl, phthaloyl, allyloxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, trimethylsilylethoxycarbonyl and the like.

In the present specification, “optionally substituted” means that it may have one or more substituents unless otherwise specified. As the “substituent”, ( 1) halogen atom, (2) nitro group, (3) cyano group, (4) hydroxy group, (5) amino group, (6) oxo group, (7) thioxo group, (8) mercapto group, (9) Carbamoyl group, (10) C _1-6 alkyl group, (11) carboxy group, (12) C _3-8 cycloalkyl group, (13) C _3-8 cycloalkenyl group, (14) C _2-6 alkenyl group (15) C _2-6 alkynyl group, (16) C _1-6 alkoxy group, (17) C _1-6 alkoxy-C _1-6 alkoxy group, (18) C _1-6 alkylenedioxy group, _{19) C 6-10} aryl group, _{(20) C 6-10} Ariruoki Group, _{(21) C 7 - 14} aralkyl group, _{(22) C 7 - 14} aralkyloxy group, _{(23) C 1-6} alkoxy - carbonyl group, _{(24) C 7 - 14} aralkyloxy - carbonyl group, (25 ) C _1-6 alkyl-carbonyl group, (26) C _6-10 aryl-carbonyl group, (27) C _1-6 alkyl-carbonyloxy group, (28) C _6-10 aryl-carbonyloxy group, (29 ) C _6-10 aryloxy-carbonyl group, (30) C _1-6 alkylsulfonyl group, (31) C _6-10 arylsulfonyl group, (32) formyl group, (33) azide group, (34) C _{1 -6} alkylthio group, _{(35) C 6-10} arylthio group, (36) mono- or di _{-C 1-6} alkylamino - carbonyl group, (37) an aromatic heterocyclic group (38) trisubstituted silyl group, and amino group protected (39). Among them, halogen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, methylenedioxy, C _1-6 alkoxy-carbonyl, benzyloxycarbonyl, acetyl, benzoyl, formyl, carbamoyl, benzyl, trityl, phenyl, Phenoxy, naphthyl, pyridyl, thienyl, furyl, pyrrolyl, indolyl, quinolyl, azide, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triphenylsilyl, dimethylamino, acetylamino, benzyl Oxycarbonylamino and tert-butoxycarbonylamino are preferred. When a plurality of substituents are present, each substituent may be the same or different.

The above substituent may be further substituted with the above substituent. The number of substituents is not particularly limited as long as it is a substitutable number, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different. The substituent may further include a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a C _3-8 cycloalkenyl group, a C _6-14 aryl group, It may be substituted with a C _7-14 aralkyl group, a heterocyclic group, a halogen atom, a hydroxy group, a carboxy group, an amino group, a carbamoyl group, a cyano group, a nitro group, an oxo group or the like. The number of substituents is not particularly limited as long as it is a substitutable number, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different.

In the present specification, examples of the “cyclic group” of the “optionally substituted cyclic group” include cyclic groups such as C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, C _6-10 aryl group and the like. A hydrocarbon group, a heterocyclic group, etc. are mentioned. Among them, a C _3-8 cycloalkyl group or a C _6-10 aryl group is preferable, and a C _6-10 aryl group is particularly preferable.

  In the present specification, the “fused ring” means a saturated or unsaturated carbocyclic or heterocyclic structure sharing a one-to-one side with an adjacent benzene ring, and examples thereof include indane, tetralin, naphthalene, quinoline, Examples include benzothiophene, benzofuran, indole, and indoline. Among them, a saturated or unsaturated carbocycle is preferable, and naphthalene is particularly preferable.

  In the present specification, the “chiral compound” means a compound having central chirality, axial chirality or planar chirality, for example, central chirality (asymmetric center, ie, asymmetric carbon atom). ).

  In the present specification, the “chiral organic acid” means a carboxylic acid or sulfonic acid having central chirality, axial chirality or planar chirality, and among them, central chirality (asymmetric carbon atom) A carboxylic acid having an asymmetric carbon atom at the α-position of the carboxy group is more preferable, and an α-amino acid is particularly preferable.

  In the present specification, the “nucleophile” may be any chemical species having a reactive lone electron pair, and may be any of an electrically neutral one, an organic anion, and an inorganic anion. Examples of these nucleophiles include nitrogen nucleophiles (amines, amides, imides, ammonia, hydrazine, azides, etc.), oxygen nucleophiles (water, alcohol, hydroxide ions, alkoxides, siloxanes, carboxylates). , Peroxides, etc.), sulfur nucleophiles (mercaptan, thiolate, bisulphite, thiocyanate, etc.), carbon nucleophiles (cyanide, malonate, acetylide, enolate, inolate, Grignard reagent, organic copper reagent, organozinc reagent, Organolithium reagents, etc.), hydride anions and the like. Among them, amine, water, alcohol or thiol are preferable, and amine or alcohol is particularly preferable because of easy handling. Among these, from the viewpoint of reaction rate, a primary amine is preferable as the amine, and specifically, allylamine, benzylamine, phenethylamine, phenylpropylamine and the like can be suitably used, and primary alcohol is preferable as the alcohol. , Methanol, ethanol, n-propanol, n-butanol, benzyl alcohol, allyl alcohol, trifluoroethanol, cinnamyl alcohol and the like can be suitably used. In addition, if a nucleophilic moiety is contained in a part of a reaction substrate (eg, a chiral organic acid), kinetic resolution by intramolecular reaction can also be performed. A reactive gas (eg, HCN gas) can also be used as the nucleophile. The gas partial pressure at that time is preferably in the range of 0.1 to 1000 atm, more preferably 0.5 to 100 atm, and still more preferably 1 to 10 atm.

  In the present specification, the “chiral organic acid-nucleophile condensate” means a compound in which a chiral organic acid and a nucleophile are formed by a dehydration condensation reaction or the like. The “chiral organic acid-nucleophile condensate” in the case where a chiral carboxylic acid is used as the nucleophile and an alcohol or amine is used as the nucleophile is a chiral ester or a chiral amide, respectively.

  In this specification, “catalytic amount” means a substoichiometric amount of the catalyst based on the amount of the reaction substrate. Specifically, the catalyst amount is 0.01 mol% to 90 mol%, more preferably 0.1 mol% to 50 mol%, particularly preferably relative to the amount of the reaction substrate (100 mol%). , 0.1 mol% to 10 mol% of catalyst.

  As used herein, “stereoisomerically enriched” means an enantiomerically enriched or diastereoselectively enriched state, specifically, It produces a specific stereoisomer of the reaction product in preference to other possible stereoisomers. “Enantiomerically enriched” means that the production of one of the two possible enantiomers in the reaction product takes precedence over the production of the other.

  When a racemate is used as the chiral organic acid, one reactant enantiomer of the chiral organic acid reacts more slowly than the other in the presence of the asymmetric dehydrating condensing agent of the present invention, and is resolved according to the reaction rate. This results in an enantiomerically enriched chiral organic acid-nucleophile condensate. Such a process is called "kinetic optical resolution". The stereoisomers that can be resolved by the kinetic optical resolution method of the present invention may have two or more asymmetric centers and may be in a diastereomeric relationship with each other.

  In the present specification, “ee” is an abbreviation for enantiomeric excess and represents the optical purity of a chiral compound. “Ee” is calculated by subtracting the amount of the smaller enantiomer from the amount of the larger enantiomer and dividing by the total amount of material and multiplying by 100 and expressed as “% ee”. The

  In this specification, “optically pure” represents a state showing an optical purity of 99% ee or more.

  In the present specification, “optically active” means a state of rotating the plane polarized light of light, that is, a state having an optical rotation ability. Preferably, it is in an optically pure state.

  In the present specification, the “enantiomer” means an optical enantiomer in which the configuration of all asymmetric carbon atoms in the optically active chiral compound is different, and the optically active chiral compound and the right hand of each other. And a pair of optical isomers in the relationship with the left hand. Specifically, for example, when the optically active chiral compound is (L) -N-benzoylphenylalanine, the enantiomer is (D) -N-benzoylphenylalanine.

(Compound of the present invention)
The compound of the present invention is a compound (compound (I)) represented by the following formula (I).

  Formula (I):

[Where
R ¹ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted aromatic ring group;
R ² represents an optionally substituted C _1-6 alkyl group,
Y is a single bond, an oxygen atom, a sulfur atom, NR ⁷ (where R ⁷ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted aromatic group). Represents a cyclic group), PR ⁸ (wherein R ⁸ represents an optionally substituted alkyl group or an optionally substituted aromatic ring group), Si (R ⁹ ) (R ¹⁰ ) ( Here, R ⁹ and R ¹⁰ each independently represent an optionally substituted alkyl group or an optionally substituted aromatic ring group.) Or C (R ¹¹ ) (R ¹² ) (here , R ¹¹ and R ¹² each independently represent an optionally substituted alkyl group or an optionally substituted aromatic ring group, or R ¹¹ and R ¹² together with the carbon atom to which they are attached. Cyclic carbonization which may be substituted Containing groups may be formed.) Indicates,
R ³ represents a hydrogen atom, a halogen atom, an alkyl group that may be substituted, an alkenyl group that may be substituted, an alkynyl group that may be substituted, or a cyclic group that may be substituted;
R ⁴ , R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or a substituted group. Optionally substituted alkyl-carbonyl group, optionally substituted alkoxy-carbonyl group, carbamoyl group, mono- or di-C _1-6 alkylamino-carbonyl group, formyl group, cyano group, optionally substituted alkoxy group Or R ³ —Y and R ⁴ , and / or R ⁵ and R ⁶ may form a condensed ring together with the benzene ring to which they are bonded, and X ⁻ Represents a counter anion which is not nucleophilic or has low nucleophilicity. It is a compound represented by.

  Hereinafter, each group of the compound (I) of the present invention will be described.

R ¹ represents a group selected from the group consisting of a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group, and an optionally substituted aromatic ring group, and depending on the selection of R ¹ The solubility and reactivity of the compound (I) of the present invention can be controlled.

R ¹ is preferably a C _1-20 alkyl group or a C _6-22 aryl group, more preferably a C _1-12 alkyl group or a C _6-14 aryl group, and a C _1-6 alkyl group, or A C _6-10 aryl group (eg, phenyl group, naphthyl group) is more preferable, and a C _1-3 alkyl group is particularly preferable. Each group may be substituted by the above-described substituent, and when having a plurality of substituents, they may be the same or different.

R ² represents an optionally substituted C _1-6 alkyl group.

R ² is preferably a C _1-3 alkyl group. The group may be substituted with the substituent described above, and when it has a plurality of substituents, they may be the same or different. As the substituent, a halogen atom is preferable.

R ² is particularly preferably a methyl group or an ethyl group which may be substituted by 1 to 3 halogen atoms (eg, fluorine atom).

Y is a single bond, an oxygen atom, a sulfur atom, NR ⁷ (where R ⁷ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted aromatic group). Represents a cyclic group), PR ⁸ (wherein R ⁸ represents an optionally substituted alkyl group or an optionally substituted aromatic ring group), Si (R ⁹ ) (R ¹⁰ ) ( Here, R ⁹ and R ¹⁰ each independently represent an optionally substituted alkyl group or an optionally substituted aromatic ring group.) Or C (R ¹¹ ) (R ¹² ) (here , R ¹¹ and R ¹² each independently represents an optionally substituted alkyl group or an optionally substituted aromatic ring group, or R ³ is a hydrogen atom, and R ¹¹ and R ^12. Are placed together with the carbon atom to which they are attached. Which may be a cyclic hydrocarbon group (e.g., C _3-8 cycloalkyl group) may be formed.) Represents the.

  Y is preferably a single bond.

R ³ represents a hydrogen atom, a halogen atom, an alkyl group that may be substituted, an alkenyl group that may be substituted, an alkynyl group that may be substituted, or a cyclic group that may be substituted.

R ³ is preferably an optionally substituted alkynyl group or an optionally substituted cyclic group, and more preferably an optionally substituted C _2-6 alkynyl group or optionally substituted. An aryl group, more preferably an _optionally substituted ethynyl group or an optionally substituted C _6-22 aryl group, and particularly preferably an optionally substituted ethynyl group or substituted. _{Or a} C _6-10 aryl group (eg, phenyl group, naphthyl group). Each group may be substituted by the above-described substituent, and when it has a plurality of substituents, they may be the same or different. As the substituent of the alkynyl group, an aryl group which may be substituted is preferable, and as the substituent of the cyclic group, a halogen atom, a cyano group, a nitro group, an aryl group, or 1 to 3 halogen atoms. optionally substituted C _1-6 alkyl group or 1 to 3 of a C _1-6 alkoxy group optionally substituted by a halogen atom, is preferred. Among them, an ethynyl group substituted with a phenyl group, or a C _6-10 aryl group (eg, phenyl group, naphthyl group) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom) is R ^3. As the most preferred.

R ⁴ , R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or a substituted group. An optionally substituted alkyl-carbonyl group, an optionally substituted alkoxy-carbonyl group, an optionally substituted carbamoyl group, a formyl group, a cyano group, an optionally substituted alkoxy group or an optionally substituted group. R ³ —Y and R ⁴ , and / or R ⁵ and R ⁶ together with the benzene ring to which they are attached form a condensed ring.

R ⁴ is preferably a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkyl-carbonyl group, a C _1-6 alkoxy-carbonyl group, a carbamoyl group, a formyl group, a cyano group, C _{1- 6} alkoxy groups. Each group may be substituted by the above-described substituent, and when having a plurality of substituents, they may be the same or different. As the substituent, a halogen atom, an aryl group, an aralkyl group, a C _1-6 alkyl group, or a C _1-6 alkoxy group is preferable.

R ⁴ is more preferably a hydrogen atom or a halogen atom.

R ⁵ and R ⁶ preferably form a fused ring with the benzene ring to which they are attached. The fused ring may be substituted with the above-described substituents, and when it has a plurality of substituents, they may be the same or different. Examples of the substituent include a halogen atom, a cyano group, a nitro group, an aryl group, a C _1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, or a substituent of 1 to 3 halogen atoms. An optionally substituted C _1-6 alkoxy group is preferred.

R ⁵ and R ⁶ more preferably form a naphthalene ring together with a benzene ring to which they are bonded.

X ⁻ represents a counter anion having no nucleophilicity or low nucleophilicity, and preferably, for example, fluoride, chloride, bromide, iodide, optionally substituted alkyl sulfonate, or substituted A good aryl sulfonate, perchlorate, tetrafluoroborate, hexafluorophosphate, hexafluoroantimonate, tetraphenylborate, and counter-anion selected from the group consisting of arsenates.

X ⁻ is more preferably chloride, trifluoromethanesulfonate, perchlorate, or tetrafluoroborate, and particularly preferably chloride or trifluoromethanesulfonate.

  As compound (I), formula (I ′):

[Each symbol in the formula is as defined above. ] An optically pure compound represented by the following (hereinafter also referred to as “compound (I ′)”), formula (I ″):

[Each symbol in the formula is as defined above. Or a non-equivalent mixture thereof is preferable, and the following compounds are more preferable among them: an optically pure compound represented by formula (hereinafter also referred to as “compound (I ″)”). is there.

[Compound (IA)]
R ¹ is an optionally substituted C _1-3 alkyl group;
R ² is an optionally substituted C _1-3 alkyl group;
Y is a single bond;
R ³ is an optionally substituted aryl group;
R ⁴ is a hydrogen atom;
R ⁵ and R ⁶ together with the benzene ring to which they are attached form a naphthalene ring; and X ⁻ is fluoride, chloride, bromide, iodide, optionally substituted alkyl sulfonate, optionally substituted aryl Compound (I ′), Compound (I ″) or an unequal mixture thereof which is sulfonate, perchlorate, tetrafluoroborate, hexafluorophosphate, hexafluoroantimonate, tetraphenylborate or arsenate.

[Compound (IB)]
R ¹ is a C _1-3 alkyl group;
R ² is an optionally substituted C _1-3 alkyl group which may be substituted by 1 to 3 halogen atoms;
Y is a single bond;
R ³ is a C _6-10 aryl group _optionally substituted by 1 to 3 halogen atoms;
R ⁴ is a hydrogen atom;
Compound (I ′), Compound (I) wherein R ⁵ and R ⁶ together with the benzene ring to which they are attached form a naphthalene ring; and X ⁻ is chloride, trifluoromethanesulfonate, perchlorate, or tetrafluoroborate I ″) or non-equal mixtures thereof.

[Compound (IC)]
R ¹ is a methyl group, an ethyl group or an isopropyl group;
R ² is an optionally substituted methyl group which may be substituted with 1 to 3 fluorine atoms;
Y is a single bond;
R ³ is a phenyl group or a naphthyl group optionally substituted by 1 to 3 halogen atoms;
R ⁴ is a hydrogen atom;
R ⁵ and R ⁶ together with the benzene ring to which they are attached form a naphthalene ring; and X ⁻ is chloride or trifluoromethanesulfonate, compound (I ′), compound (I ″) or their non- Equal volume mixture.

[Compound (ID)]
R ¹ is a methyl group, an ethyl group or an isopropyl group;
R ² is an optionally substituted methyl group which may be substituted with 1 to 3 fluorine atoms;
Y is a single bond;
R ³ is an ethynyl group optionally substituted by a phenyl group;
R ⁴ is a hydrogen atom;
R ⁵ and R ⁶ together with the benzene ring to which they are attached form a naphthalene ring; and X ⁻ is chloride or trifluoromethanesulfonate, compound (I ′), compound (I ″) or their non- Equal volume mixture.

Particularly preferred compounds (I) are specifically the following compounds or optical isomers thereof.

The present invention also includes the following chiral tertiary amine compound (II), which is a synthetic intermediate of the above compound (I), or an optical isomer thereof.

(Synthesis of Compound (I) of the Present Invention)
Although it does not specifically limit as a manufacturing method of compound (I) of this invention, For example, it can synthesize | combine through the following reactions.

  The raw material compounds can be easily obtained as commercial products unless otherwise specified, or by a method known per se (Ooi, T. et al., J. Am. Chem. Soc., 2003, 125, 5139-5151. ) Or a method according to these methods.

[Production Method 1]
Compound (I) of the present invention can be produced, for example, by the following steps.

[Each symbol in the formula is as defined above. ]

Step (1-1)
This step is a step of producing compound (1b) by trifluoromethanesulfonylation of two hydroxy groups of compound (1a).
The reaction is carried out using a trifluoromethanesulfonylating agent in the presence of a base in a solvent that does not affect the reaction.

As the trifluoromethanesulfonylating agent, for example, trifluoromethanesulfonic acid anhydride, trifluoromethanesulfonic acid halide and the like can be used, and among them, trifluoromethanesulfonic acid anhydride is preferable.
The amount of the trifluoromethanesulfonylating agent to be used is generally 2 to 8 equivalents relative to 1 equivalent of compound (1a).

Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkaline earth metals such as magnesium hydroxide and calcium hydroxide; alkali metals such as sodium carbonate and potassium carbonate Alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, N, N-dimethylaniline, 1,5-diazabicyclo [4; .3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), and organic such as tetramethylguanidine Bases, etc., among which triethylamine, diisopropyl Pills ethylamine and the like are preferable.
The amount of the base to be used is generally 2 to 8 equivalents relative to 1 equivalent of compound (1a).

  Examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and trichloroethylene; dioxane, tetrahydrofuran (THF), diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol-dimethyl ether (DME), Ethers such as diethylene glycol dimethyl ether (diglyme); hydrocarbons such as hexane, benzene, toluene and the like. Among them, dichloromethane, chloroform, DME and the like are particularly preferable.

The reaction temperature is generally −78 ° C. to 120 ° C., preferably −78 ° C. to room temperature.
The reaction time is usually 0.1 to 30 hours.

Step (1-2)
This step is a step of producing compound (1c) by converting two trifluoromethanesulfonoxy groups of compound (1b) into methyl groups.
The reaction is performed using a Grignard reagent (methyl magnesium iodide) in the presence of a nickel (II) catalyst in a solvent that does not affect the reaction.

Examples of the nickel (II) catalyst include bis (triphenylphosphine) nickel (II) dichloride, [1,3-bis (diphenylphosphino) propane] nickel (II) dichloride, [1,2-bis (diphenylphosphine). (Fino) ethane] nickel (II) dichloride and the like. Among them, bis (triphenylphosphine) nickel (II) dichloride is preferable.
The usage-amount of this nickel (II) catalyst is 0.0001-0.2 equivalent normally with respect to 1 equivalent of compounds (1b), Preferably, it is 0.01-0.1 equivalent.

  The amount of the Grignard reagent to be used is generally 2 to 8 equivalents relative to 1 equivalent of compound (1b).

  Examples of the solvent include ethers such as THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, diglyme, and among them, diethyl ether is particularly preferable.

The reaction temperature is generally 0 ° C. to 120 ° C., preferably room temperature to 60 ° C.
The reaction time is usually 0.1 to 30 hours.

Step (1-3)
This step is a step of producing compound (1d) by brominating two methyl groups (benzyl position) of compound (1c).

  As a brominating agent that can be used in this step, N-bromosuccinimide (NBS) is suitable. The brominating agent is used with a catalytic amount of azoisobutyronitrile (AIBN).

  The usage-amount of AIBN is 0.001-0.5 equivalent normally with respect to 1 equivalent of compounds (1c), Preferably, it is 0.01-0.1 equivalent.

  The usage-amount of NBS is 2-4 equivalent normally with respect to 1 equivalent of compounds (1c), Preferably, it is 2-2.4 equivalent.

  Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene, and among them, benzene is particularly preferable.

The reaction temperature is generally 0 ° C to 120 ° C, preferably room temperature to 80 ° C.
The reaction time is usually 0.1 to 30 hours.

Step (1-4)
The process is the reaction of the compound (1d) with a primary amine (R 2 ^NH _2), a step for preparing chiral tertiary amine compound (II).
The reaction is performed in a solvent that does not affect the reaction.

Examples of the primary amine include methylamine and the like. When the primary amine is available as an aqueous solution, the aqueous solution can be used for the reaction as it is.
The usage-amount of a primary amine is 2-20 equivalent normally with respect to 1 equivalent of compounds (1d).

  Examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and trichloroethylene; ethers such as dioxane, THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, and diglyme; hexane, benzene And hydrocarbons such as toluene; and nitriles such as acetonitrile. Among them, dichloromethane, chloroform, THF, acetonitrile and the like are particularly preferable.

The reaction temperature is generally −78 ° C. to 120 ° C., preferably 0 ° C. to 60 ° C.
The reaction time is usually 0.1 to 30 hours.

Step (1-5)
The said process is a process of manufacturing a compound (I) by reaction with a chiral tertiary amine compound (II) and a triazine compound (1f).
The reaction is performed in a solvent that does not affect the reaction.

  The amount of compound (1f) to be used is generally 1 to 4 equivalents relative to 1 equivalent of compound (II).

  Examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and trichloroethylene; ethers such as dioxane, THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, and diglyme; hexane, benzene And hydrocarbons such as toluene; nitriles such as acetonitrile; and alcohols such as methanol and ethanol. Among them, dichloromethane, chloroform, THF, acetonitrile and the like are particularly preferable.

The reaction temperature is generally 0 ° C to 120 ° C, preferably room temperature to 80 ° C.
The reaction time is usually 0.1 to 6 hours.

The compound (I) obtained by the reaction is mixed with MX ′ in a solvent that does not affect the reaction, if necessary, to convert the counter anion X ⁻ into another counter anion X ′ ⁻ . Because it can be converted, other salts of compound (I) can be readily prepared.

  M in the reactant represented by MX ′ represents a metal atom or a quaternary ammonium group. Specifically, for example, an alkali metal such as lithium, potassium, sodium or cesium; an alkaline earth such as magnesium or calcium Examples include metals, noble metals such as gold and silver, heavy metals such as thallium, and tetramethylammonium groups. Among these, lithium, sodium, and silver are preferable.

X ′ in the reactant represented by MX ′ is a group other than a chlorine atom, an optionally substituted alkylsulfonyloxy group or an optionally substituted arylsulfonyloxy group among the groups corresponding to X ^−. The group is non-nuclear or has a low nucleophilicity. Specific examples include perchlorate, tetrafluoroborate, hexafluorophosphate, hexafluoroantimonate, tetraphenylborate, and arsenate.

  The amount of MX ′ to be used is generally 1-10 equivalents, preferably 1-3 equivalents, relative to 1 equivalent of compound (I).

  Examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and trichloroethylene; ethers such as dioxane, THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, and diglyme; hexane, benzene And hydrocarbons such as toluene; mixed solvents thereof and the like. Among them, dichloromethane is particularly preferable.

The reaction temperature is generally −30 to 100 ° C., preferably 0 to 40 ° C.
The reaction time is usually 0.1 to 30 hours.

[Production Method 2]
In compound (I), Y is a single bond, and R ³ is an optionally substituted aryl group (in this specification, sometimes abbreviated as compound (I-1)), for example, It can be produced by the following production method 2 or a method analogous thereto.

(Each symbol in the formula is as defined above.)

Step (2-1)
This step is a step of producing compound (2b) by methoxymethylating two hydroxy groups of compound (2a).
The reaction is performed using methoxymethyl chloride in the presence of a base in a solvent that does not affect the reaction.
The starting compound (2a) is commercially available, or a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (Richard C. Larock) The method described in “Brunel, JM, Chem. Rev., 2005, 105, 857-897”] or a method analogous thereto.

  The amount of methoxymethyl chloride to be used is generally 2 to 8 equivalents relative to 1 equivalent of compound (2a).

Examples of the base include hydride bases such as sodium hydride; alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth metals such as magnesium hydroxide and calcium hydroxide; Alkali metal carbonates such as sodium and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, N, N-dimethyl Aniline, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene ( DBU), organic bases such as tetramethylguanidine, etc. , Among them sodium hydride are preferred.
The amount of the base to be used is generally 2 to 8 equivalents relative to 1 equivalent of compound (2a).

  Examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and trichloroethylene; ethers such as dioxane, THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, and diglyme; hexane, benzene And hydrocarbons such as toluene; nitriles such as acetonitrile; and alcohols such as methanol and ethanol. Among them, THF is particularly preferable.

The reaction temperature is generally 0 ° C to 120 ° C, preferably room temperature to 80 ° C.
The reaction time is usually 0.1 to 6 hours.

Step (2-2)
This step is a step of producing a compound (2c) by introducing a bromine atom into the ortho position of two methoxymethoxy groups of the compound (2b).
The reaction is performed electrophilically using a brominating agent after lithiation of the ortho position of the two methoxymethoxy groups of compound (2b) in a solvent that does not affect the reaction.

As the organolithium reagent used for lithiation of the ortho position of the two methoxymethoxy groups of the compound (2b), n-butyllithium is preferably used.
The usage-amount of n-butyllithium is 2-8 equivalent normally with respect to 1 equivalent of compounds (2b).

As an electrophilic brominating agent, bromine is preferably used.
The amount of the brominating agent to be used is generally 2-8 equivalents relative to 1 equivalent of compound (2b).

  Examples of the solvent include ethers such as dioxane, THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, and diglyme; hydrocarbons such as hexane, benzene, and toluene, among which THF is particularly preferable.

The reaction temperature is generally −78 ° C. to 100 ° C., preferably −78 ° C. to room temperature.
The reaction time is usually 0.1 to 6 hours.

Step (2-3)
This step is a step of producing compound (2d) by removing two methoxymethyl groups of compound (2c).
The reaction is carried out by acid-treating compound (2c) in a solvent that does not affect the reaction.

Examples of the acid include those that can be used for deprotection of the methoxymethyl group described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980), but other substituents on the compound (2c) include There is no particular limitation as long as it does not affect. Preferred acids include hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like, and hydrochloric acid is particularly preferred.
The amount of the acid to be used is generally 0.1 to 10 equivalents relative to 1 equivalent of compound (2c).

  Examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and trichloroethylene; ethers such as dioxane, THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, and diglyme; hexane, benzene And hydrocarbons such as toluene; alcohols such as methanol and ethanol; esters such as ethyl acetate; and dioxane is particularly preferable.

The reaction temperature is generally 0 ° C to 120 ° C, preferably room temperature to 80 ° C.
The reaction time is usually 0.1 to 6 hours.

Step (2-4)
This step is a step of producing a compound (2e) by trifluoromethanesulfonylation of two hydroxy groups of the compound (2d).
This step can be performed under the same reaction conditions as in step (1-1) of production method 1.

Step (2-5)
This step is a step for producing compound (1b) by substituting two bromo groups of compound (2e) with a desired aryl group.
This step can be performed in a solvent that does not affect the reaction, for example, in the presence of a palladium catalyst and a base, by a cross-coupling reaction with an aryl boronic acid (Suzuki coupling reaction) or the like.

Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium, and palladium acetate in the presence of triphenylphosphine. A system using palladium acetate in the presence of phosphine is preferred.
The usage-amount of a palladium catalyst is 0.001-0.5 equivalent normally with respect to 1 equivalent of compounds (2e), Preferably, it is 0.05-0.2 equivalent.

As the desired aryl boronic acid, a commercially available product or one synthesized from a commercially available raw material by a method known per se can be used.
The amount of the aryl boronic acid to be used is generally 2 to 4 equivalents relative to 1 equivalent of compound (2e).

  Examples of the base include tripotassium phosphate, trisodium phosphate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, and the like, among which tripotassium phosphate is preferable.

  Examples of the solvent include ethers such as THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, and diglyme, dioxane, and DMF, and THF is particularly preferable.

The reaction temperature is usually 50 ° C to 150 ° C, preferably 60 ° C to 110 ° C.
The reaction time is usually 0.1 to 12 hours.

Step (2-6)
This step can be carried out under the same reaction conditions as in step (1-2) to step (1-5) of production method 1 from compound (2f).

[Production Method 3]
In compound (I), compound (I-1) wherein Y is a single bond and R ³ is an optionally substituted aryl group (eg, 3,4,5-trifluorophenyl group) is, for example, Also, it can be produced by the following production method 3 or a method analogous thereto.

(Each symbol in the formula is as defined above.)

Step (3-1)
This step is a step for producing a compound (3a) by introducing a hydroxy group into the ortho position of two methoxymethoxy groups of the compound (2b).
The reaction is carried out by lithiation of the ortho position of two methoxymethoxy groups of compound (2b) in a solvent that does not affect the reaction, followed by oxidation following boronation.

As the organolithium reagent used for lithiation of the ortho position of the two methoxymethoxy groups of the compound (2b), n-butyllithium is preferably used.
The usage-amount of n-butyllithium is 2-8 equivalent normally with respect to 1 equivalent of compounds (2b).

Trimethoxyborane is used for boronation.
The amount of trimethoxyborane to be used is generally 2 to 8 equivalents relative to 1 equivalent of compound (2b).

Hydrogen peroxide is preferably used as the oxidizing agent used in the oxidation reaction following boronation.
The usage-amount of an oxidizing agent is 2-8 equivalent normally with respect to 1 equivalent of compounds (2b).

  Examples of the solvent include ethers such as dioxane, THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME and diglyme; hydrocarbons such as hexane, benzene and toluene, and benzene is particularly preferable.

The reaction temperature is generally 0 ° C to 120 ° C, preferably room temperature to 80 ° C.
The reaction time is usually 0.1 to 6 hours.

Step (3-2)
The said process is a process of manufacturing a compound (3b) by methylating two hydroxy groups of a compound (3a).
The reaction is performed using a methylating agent in the presence of a base in a solvent that does not affect the reaction.

  The methylating agent is not particularly limited, but methyl iodide is preferably used.

  The usage-amount of a methylating agent is 2-8 equivalent normally with respect to 1 equivalent of compounds (3a).

Examples of the base include hydride bases such as sodium hydride; alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth metals such as magnesium hydroxide and calcium hydroxide; Alkali metal carbonates such as sodium and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, N, N-dimethyl Aniline, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene ( DBU), organic bases such as tetramethylguanidine, etc. , Among which potassium carbonate is preferred.
The amount of the base to be used is generally 2-8 equivalents relative to 1 equivalent of compound (3a).

  Examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and trichloroethylene; ethers such as dioxane, THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, and diglyme; hexane, benzene , Hydrocarbons such as toluene; nitriles such as acetonitrile; alcohols such as methanol and ethanol; ketones such as acetone, among which acetone is particularly preferable.

The reaction temperature is generally 0 ° C to 120 ° C, preferably room temperature to 80 ° C.
The reaction time is usually 0.1 to 24 hours.

Step (3-3)
This step is a step of producing compound (3c) by removing two methoxymethyl groups of compound (3b).
This step can be performed under the same reaction conditions as in step (2-3) of production method 2.

Step (3-4)
This step is a step of producing compound (3d) by trifluoromethanesulfonylation of two hydroxy groups of compound (3c).
This step can be performed under the same reaction conditions as in step (1-1) of production method 1.

Step (3-5)
This step is a step for producing a compound (3e) by converting two trifluoromethanesulfonyloxy groups of the compound (3d) into a methyl group.
This step can be performed under the same reaction conditions as in step (1-2) of production method 1.

Step (3-6)
This step is a step of producing compound (3f) by demethylating two methoxy groups of compound (3e).
The reaction is performed using a Lewis acid in a solvent that does not affect the reaction.

Examples of the Lewis acid include those which can be used for deprotection of a methoxy group described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980), but other substituents on the compound (3e) include There is no particular limitation as long as it does not affect. Preferred Lewis acids include aluminum chloride, boron tribromide and the like, with boron tribromide being particularly preferred.
The amount of the Lewis acid to be used is generally 2 to 10 equivalents, preferably 2 to 3 equivalents, relative to 1 equivalent of compound (3e).

  Examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and trichloroethylene; hydrocarbons such as hexane, benzene, and toluene. Among them, dichloromethane is particularly preferable.

The reaction temperature is usually 0 ° C. to room temperature.
The reaction time is usually 0.1 to 24 hours.

Step (3-7)
This step is a step of producing the compound (3g) by trifluoromethanesulfonylating two hydroxy groups of the compound (3f).
This step can be performed under the same reaction conditions as in step (1-1) of production method 1.

Step (3-8)
This step is a step for producing a compound (3h) by substituting two trifluoromethanesulfonyloxy groups of the compound (3g) with a desired aryl group.
This step can be performed under the same reaction conditions as in step (2-5) of production method 2.

Step (3-9)
This step can be carried out under the same reaction conditions as in step (1-3) to step (1-5) of production method 1 from compound (3h).

[Production Method 4]
In compound (I), a compound in which Y is an oxygen atom (in this specification, sometimes abbreviated as compound (I-2)) can be produced, for example, by the following production method 4 or a method analogous thereto. it can.

(Wherein X ¹ represents a leaving group, and other symbols are as defined above.)

Step (4-1)
This step is a step of producing the compound (4a) by alkylating or aralkylating two hydroxy groups of the compound (3a) with R ³ X ¹ .
The reaction is carried out using a desired alkylating agent or aralkylating agent in the presence of a base in a solvent that does not affect the reaction.

The alkylating agent or aralkylating agent represented by R ³ X ¹ is not particularly limited, and examples of the leaving group X ¹ include a halogen atom (preferably an iodine atom, a bromine atom, etc.), trifluoromethanesulfonyl, and the like. Examples include oxy. Specific examples of R ³ X ¹ include tert-butyl chloride and trityl chloride.

The amount of the alkylating agent or aralkylating agent represented by R ³ X ¹ is usually 2 to 8 equivalents relative to 1 equivalent of compound (3a).

Examples of the base include hydride bases such as sodium hydride; alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth metals such as magnesium hydroxide and calcium hydroxide; Alkali metal carbonates such as sodium and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, N, N-dimethyl Aniline, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene ( DBU), organic bases such as tetramethylguanidine, etc. , Among them sodium hydride are preferred.
The amount of the base to be used is generally 2-8 equivalents relative to 1 equivalent of compound (3a).

  Examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and trichloroethylene; ethers such as dioxane, THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, and diglyme; hexane, benzene And hydrocarbons such as toluene; nitriles such as acetonitrile; and alcohols such as methanol and ethanol. Among them, THF is particularly preferable.

The reaction temperature is generally 0 ° C to 120 ° C, preferably room temperature to 80 ° C.
The reaction time is usually 0.1 to 6 hours.

Step (4-2)
This step is a step of producing compound (4b) by removing two methoxymethyl groups of compound (4a).
This step can be performed under the same reaction conditions as in step (2-3) of production method 2.

Step (4-3)
This step can be carried out under the same reaction conditions as in step (1-1) to step (1-5) of production method 1 from compound (4b).

[Production Method 5]
In compound (I), Y is Si (R ⁹ ) (R ¹⁰ ) or C (R ¹¹ ) (R ¹² ) (wherein each symbol is as defined above) (in the present specification, Compound (I-3) may be produced by, for example, the following production method 5 or a method analogous thereto.

(Wherein X ² represents a leaving group, and other symbols are as defined above.)

Step (5-1)
This step is a step for producing a compound (5a) by substituting two bromo groups of the compound (2c) with Y—R ³ groups.
This step is carried out by reaction with R ³ YX ² after lithiation of the ortho position of the two methoxymethoxy groups of compound (2c) in a solvent that does not affect the reaction.

As the organic lithium reagent used for lithiation of the ortho position of the two methoxymethoxy groups of the compound (2c), n-butyllithium, tert-butyllithium and the like are preferably used.
The usage-amount of an organolithium reagent is 2-8 equivalent normally with respect to 1 equivalent of compounds (2c).

The silylating agent or alkylating agent represented by R ³ YX ² is not particularly limited, and examples of the leaving group X ² include a halogen atom (preferably an iodine atom, a bromine atom, etc.), trifluoromethanesulfonyl, and the like. Examples include oxy. Specific examples of R ³ YX ² include silyl halides such as tert-butyldimethylsilyl chloride, tert-butyldiphenylsilyl chloride, and triphenyl chloride; alkyl halides such as tert-butyl chloride and trityl chloride.
The amount of the base to be used is generally 2 to 8 equivalents relative to 1 equivalent of compound (2c).

  Examples of the solvent include ethers such as dioxane, THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, and diglyme; hydrocarbons such as hexane, benzene, and toluene, among which THF is particularly preferable.

The reaction temperature is generally 0 ° C to 120 ° C, preferably room temperature to 80 ° C.
The reaction time is usually 0.1 to 6 hours.

Step (5-2)
This step is a step of producing compound (5b) by removing two methoxymethyl groups of compound (5a).
This step can be performed under the same reaction conditions as in step (2-3) of production method 2.

Step (5-3)
This step can be carried out under the same reaction conditions as in step (1-1) to step (1-5) of production method 1 from compound (5b).

[Production Method 6]
In the compound (I), a compound in which Y is NR ⁷ (wherein R ⁷ has the same meaning as described above) (may be abbreviated as compound (I-4) in the present specification) is, for example, It can be produced by the following production method 6 or a method analogous thereto.

(Each symbol in the formula is as defined above.)

Step (6-1)
This step is a step for producing the compound (6a) by substituting two bromo groups of the compound (2c) with N (R ³ ) (R ⁷ ) groups.
This step is performed in a solvent that does not affect the reaction, for example, in the presence of a palladium catalyst, by a cross-coupling reaction (Buchwald-Hartwig coupling reaction) with an amine ((R ³ ) (R ⁷ ) NH). Can do.

Examples of the palladium catalyst include a system using tris (dibenzylideneacetone) dipalladium or palladium acetate in the presence of a phosphorus ligand. A system using benzylideneacetone) dipalladium is preferred.
Examples of bidentate chelate organophosphorus compounds that can be used as phosphorus ligands include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP) and 1,1′-bis (diphenyl). Examples include phosphino) ferrocene (DPPF), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos), and among these, BINAP is preferable.
The usage-amount of a palladium catalyst is 0.01-0.2 equivalent normally with respect to 1 equivalent of compounds (2c).
The usage-amount of an organophosphorus compound is 0.01-0.2 equivalent normally with respect to 1 equivalent of compounds (2c).

(R ³ ) (R ⁷ ) NH is not particularly limited, and R ³ and R ^{7 of} (R ³ ) (R ⁷ ) NH may form a cyclic group together with the nitrogen atom to which they are bonded. .
The amount of (R ³ ) (R ⁷ ) NH used is usually 2 to 8 equivalents relative to 1 equivalent of compound (2c).

  Examples of the solvent include ethers such as dioxane, THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, and diglyme; hydrocarbons such as hexane, benzene, and toluene, among which toluene is particularly preferable.

The reaction temperature is usually room temperature to 150 ° C, preferably 60 ° C to 110 ° C.
The reaction time is usually 0.1 to 6 hours.

Step (6-2)
This step is a step for producing compound (6b) by removing two methoxymethyl groups of compound (6a).
This step can be performed under the same reaction conditions as in step (2-3) of production method 2.

Step (6-3)
This step can be carried out under the same reaction conditions as in step (1-1) to step (1-5) of production method 1 from compound (6b).

[Production Method 7]
In compound (I), Y is a single bond and R ³ is an optionally substituted alkynyl group (in this specification, sometimes abbreviated as compound (I-5)), for example, It can be produced by the following production method 7 or a method analogous thereto.

(Each symbol in the formula is as defined above.)

Step (7-1)
This step is a step of producing compound (7a) by substituting two trifluoromethanesulfonoxy groups of compound (3g) with a desired alkynyl group.
This step is performed in a solvent that does not affect the reaction, for example, in the presence of a palladium catalyst, a copper catalyst, and a base, by a cross-coupling reaction with a terminal alkyne (for example, arylacetylene) (Sonogashira cross-coupling reaction) or the like. It can be carried out.

Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium dichloride, and palladium acetate in the presence of triphenylphosphine. Among them, palladium acetate is used in the presence of triphenylphosphine. The system is preferred.
The usage-amount of a palladium catalyst is 0.001-0.5 equivalent normally with respect to 1 equivalent of compounds (3g), Preferably, it is 0.05-0.2 equivalent.

Examples of the copper catalyst include copper (I) bromide and copper (I) iodide, and copper (I) bromide is particularly preferable.
The usage-amount of a copper catalyst is 0.001-0.5 equivalent normally with respect to 1 equivalent of compounds (3g), Preferably, it is 0.05-0.2 equivalent.

  Examples of the base include organic amines such as diethylamine, triethylamine, dicyclohexylamine, diisopropylethylamine, and among them, diethylamine is preferable.

The type of terminal alkyne is not particularly limited, but arylacetylene (eg, phenylacetylene) is preferable.
As the terminal alkyne, a commercially available product or one synthesized from a commercially available raw material by a method known per se can be used.
The usage-amount of terminal alkyne is 2-4 equivalent normally with respect to 1 equivalent of compounds (3g).

  Examples of the solvent include ethers such as THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, diglyme, dioxane, DMF, ethyl acetate, benzene, etc. Among them, DMF is particularly preferable.

The reaction temperature is usually room temperature to 150 ° C, preferably room temperature to 110 ° C.
The reaction time is usually 0.1 to 12 hours.

Step (7-2)
This step can be carried out under the same reaction conditions as in step (1-3) to step (1-5) of production method 1 from compound (7a).

  When compound (I) has an isomer such as an optical isomer, a stereoisomer, or a positional isomer, any isomer and a mixture thereof are encompassed in compound (I) of the present invention. For example, when compound (I) has an optical isomer, the optical isomer resolved from the racemate is also encompassed in compound (I). Each of these isomers can be obtained as an optically pure compound by a synthesis method known per se, a separation method (eg, concentration, solvent extraction, column chromatography, recrystallization) or the like.

  Compound (I) may be a solvate or a solvate.

Compound (I) may also be labeled with an isotope (eg, ³ H, ¹⁴ C, etc.).
Further, compound (I) may be a deuterium converter.

  The compound (I) of the present invention can be stably isolated, is easy to handle, and does not deactivate even in a reaction system containing a protic solvent such as alcohol, and can be used as an asymmetric dehydrating condensing agent. Can be used. In addition, the compound (I) of the present invention can be easily prepared at the time of use by a reaction between a catalytic amount of an optically active chiral tertiary amine compound (II) and the compound (III), and can be used as it is without isolation. Since it can be used as a simultaneous dehydration condensation agent (asymmetric dehydration condensation catalyst), a practical kinetic optical resolution method for chiral compounds can be provided as shown below.

(Method of optical resolution of racemic α-amino acid using optically pure compound (I))
The optically pure compound (I) of the present invention, that is, the compound (I ′) or the compound (I ″) is asymmetric dehydration condensation without being deactivated even in a reaction system containing a protic solvent such as alcohol. It can be used as an agent. In addition, since it can be easily prepared in a reaction system, practically, a catalytic amount of an optically active chiral tertiary amine compound (II) (compound (II ′) or compound (II ″)), It is preferably used for the kinetic optical resolution of the racemic chiral organic acid in the presence of the triazine compound (III) and various nucleophiles. That is, a small amount of optically active chiral tertiary amine compound (II) may be used as a catalyst to repeatedly generate a dehydrating condensing agent. For example, kinetic optical resolution of N-protected-α-amino acids that are chiral organic acids can be performed as follows.

(Each symbol in the formula is as defined above.)

  The “N-protected-α-amino acid” used in the present invention is not particularly limited as long as the amino group is protected, and N-protected-phenylalanine, N-protected-leucine and the like are preferable. As the protecting group for the amino group of the N-protected-α-amino acid, for example, the protecting group for the amino group described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980) can be used. Specific examples of the amino-protecting group include benzoyl, benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, and the like, and preferably benzoyl or benzyloxycarbonyl.

  Examples of the “nucleophilic agent” used in the present invention include those described above, and among them, amines or alcohols can be preferably used. Specifically, the amine is preferably a primary amine (eg, allylamine, benzylamine, phenethylamine, phenylpropylamine, etc.), and the alcohol is a primary alcohol (eg, methanol, ethanol, n-propanol). N-butanol, benzyl alcohol, allyl alcohol, trifluoroethanol, cinnamyl alcohol, etc.).

  The amount of the nucleophile used in the present invention is preferably 0.1 to 10 equivalents, more preferably 0.25 to 5 equivalents, particularly preferably 1 equivalent of N-protected-α-amino acid. Is in the range of 0.4 to 2 equivalents.

  The amount of the chiral tertiary amine compound (II) used in the present invention may be a catalytic amount, and is preferably 0.001 to 0.5 with respect to 1 equivalent of N-protected-α-amino acid. Equivalent, more preferably 0.01 to 0.3 equivalent, particularly preferably 0.05 to 0.2 equivalent.

  The amount of compound (III) used in the present invention is 1.0 to 5 equivalents, more preferably 1.0 to 3 equivalents, particularly preferably 0.5 equivalents of N-protected-α-amino acid. Is in the range of 1 to 2 equivalents.

  The kinetic resolution method in the present invention is preferably carried out in a solvent. The solvent is not particularly limited as long as it does not affect the reaction. The reaction solution may be either a homogeneous system or a heterogeneous system, but the homogeneous system has an advantage that the reaction rate is excellent. Suitable solvents include ether solvents (diethyl ether, dibutyl ether, 1,2-dimethoxyethane, diglyme, tert-butyl methyl ether (MTBE), THF, dioxane, cyclopropyl methyl ether, etc.), halogenated hydrocarbons Solvent (carbon tetrachloride, chloroform, dichloromethane, dichloroethane, etc.), hydrocarbon solvent (hexane, pentane, etc.), aromatic solvent (benzene, toluene, xylene, ethylbenzene, styrene, anisole, N, N-dimethylaniline, chlorobenzene) , Dichlorobenzene, methyl benzoate, etc.), ester solvents (ethyl acetate, etc.), ketone solvents (acetone, methyl ethyl ketone, etc.), protic solvents (methanol, ethanol, 2-propanol, butanol, etc.) Alcohol, water), aprotic polar solvents (acetonitrile, N, N- dimethylformamide, dimethyl sulfoxide, etc.) and the like, may be used in combination of two or more of these.

  Since the compound (I) of the present invention tends to show high enantioselectivity without being deactivated even when a protic solvent such as alcohol or water is used, it is highly polar and various solvents such as amino acids. It can be particularly preferably used for optical resolution of a compound having low solubility in azobenzene.

  In the kinetic resolution method of the present invention, an ionic liquid, a supercritical fluid, or the like can be used as a solvent. In addition, a two-phase solvent such as an emulsion or suspension and a lipid biphase can be used as the solvent. Furthermore, the reaction can also be performed in a solid phase.

  When the kinetic optical resolution method of the present invention is performed in an alcohol-containing solvent in the absence of a nucleophile such as a primary amine, the alcohol used as the solvent also acts as a nucleophile, and N-protection The corresponding optically active N-protected α-amino acid ester is obtained as the α-amino acid-nucleophile condensate.

  The kinetic resolution method of the present invention does not require special temperature adjustment and can be performed efficiently at room temperature. In addition, according to the present invention, the compound (II ′) or compound (II ″), which is a chiral tertiary amine compound, can be easily recovered and reused after completion of the reaction. An excellent method can be provided.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to synthesis examples, reference examples, examples and test examples. However, the present invention is not limited thereto and does not depart from the scope of the present invention. It may be changed with.
The reaction was monitored by thin layer chromatography using Merck 60 F254 silica gel plates (thickness 0.25 mm).
¹ H and ¹³ C-NMR spectra were measured using JEOL ECS400 or ECS600 using deuterated chloroform or deuterated methanol as a solvent. The data for ¹ H-NMR are chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet, dt = double triplet, brs. = Broad singlet, sep = septet), coupling constant (Hz), integration and assignment.
High resolution mass spectral analysis (HRMS) was performed using JEOL JMS-SX102A.
The melting point (mp) was measured using a Yanagimoto trace melting point measuring device.
Elemental analysis was performed using a Yanaco CHN Corder MT-5.
The optical purity of the prepared compounds (I) and (II) of the present invention was measured by JASCO high performance liquid chromatography pump PU-2080, JASCO UV-visible detector MD-910, JASCO optical rotation detector OR -990 was used. As a chiral column, Daicel CHIRALPAK IB-3 or CHIRALPAK AD was used.
Preparative thin layer chromatography was performed using Merck 60 F254 silica gel plates (thickness 0.5 mm). Flash chromatography was performed using silica gel 60N from Kanto Chemical Co., Inc. (Tokyo, Japan).
“Room temperature” in the following examples usually indicates about 10 ° C. to about 30 ° C. The ratio shown in the mixed solvent is a volume ratio unless otherwise specified. Unless otherwise indicated, “%” indicates “% by weight”.

  In the following examples, 4,6-dimethoxy-2-trifluoromethanesulfonyloxy-1,3,5-triazine used as compound (III) was prepared by a method known per se (Kunishima, M. et al., Tetrahedron Lett., 2002, 43, 3323-3326.) Was used. Further, (R) -2,2′-bis (bromomethyl) -3,3′-diphenyl-1,1′-binaphthyl, which is a raw material compound used for the synthesis of the chiral tertiary amine compound (II), (R ) -2,2′-bis (bromomethyl) -3,3′-bis (2-naphthyl) -1,1′-binaphthyl, and (R) -2,2′-bis (bromomethyl) -3,3 ′ -Bis (3,4,5-trifluorophenyl) -1,1'-binaphthyl is a commercially available product or a method known per se (Ooi, T. et al., J. Am. Chem. Soc., 2003, 125, 5139-5151.) Or a method analogous thereto.

(Synthesis Example 1)
2-chloro-4,6-diisopropoxy-1,3,5-triazine

60% sodium hydride (1.80 g, 45.0 mmol) and tetrahydrofuran (30 mL) were added to a 100 mL eggplant flask. To this solution, 2-propanol (2.29 mL, 30.0 mmol) was added dropwise at 0 ° C. in a nitrogen atmosphere, and reacted for 30 minutes after completion of the addition to obtain an alkoxide solution. Cyanuric chloride (2.77 g, 15.0 mmol) and tetrahydrofuran (30 mL) were added to another 100 mL eggplant flask. To this solution, the alkoxide solution was added dropwise at −78 ° C. under a nitrogen atmosphere. Then, it heated up to 0 degreeC and made it react for 12 hours. After completion of the reaction, the reaction mixture was diluted with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extracted organic layer was washed with saturated brine and dried over sodium sulfate. The residue was separated and purified by column chromatography (hexane / ethyl acetate = 10: 1) to obtain the desired product (2.10 g, yield 61%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 5.37 (sep, 2H), 1.40 (d, 12H);
ESI-MS: m / z = 232 ((M + H) ^<+> ).

(Reference Example 1)
Synthesis of (R) -4,5-dihydro-4-methyl-2,6-diphenyl-3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepine (compound (II-1a))

(R) -2,2′-bis (bromomethyl) -3,3′-diphenyl-1,1′-binaphthyl (2.72 g, 4.60 mmol) in THF (18 mL) was added to a 40% aqueous methylamine solution (18 mL). (4.6 mL, 55.2 mmol) was added and allowed to react at room temperature for 8 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with distilled water, saturated aqueous sodium hydrogen carbonate solution and saturated brine. Sodium sulfate was added to the obtained organic layer and dried. After filtration, the solvent was removed, and the residue was recrystallized from a dichloromethane-hexane solution to obtain Compound (II-1a) (1.94 g, yield 92%). Obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.95 (d, 2H, J = 9.2 Hz), 7.94 (s, 2H), 7.59-7.57 (m, 4H), 7 50-7.37 (m, 10H), 7.29 (d, 2H, 7.3 Hz), 3.82 (d, 2H, J = 12.4 Hz), 3.07 (d, 2H, J = 12.8 Hz), 1.85 (s, 3H);
¹³ C-NMR (100 MHz, CDCl ₃ ): δ 141.38, 140.43, 136.07, 132.51, 131.70, 130.82, 130.05, 128.99, 128.27, 128. 10, 127.54, 127.05, 125.77, 125.68, 52.69, 42.90;
IR (KBr): 3037, 3020, 3005, 2976, 2931, 1589, 1494, 1448, 1194, 1047, 895, 752, 725, 687 cm ⁻¹ ;
HRMS (FAB): calculated ^{_{(C 35 H 38 N (M}} + H) +): 462.2222; Found: 462.2218;
Elemental analysis _{(C 35 H} 27 N): Calculated: C, 91.07; H, 5.90 ; N, 3.03. Found: C, 91.01; H, 5.98; N, 3.15;
Melting point: 234-238 ° C.

(Reference Example 2)
(R) -4,5-dihydro-4-methyl-2,6-bis (2-naphthyl) -3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepine (compound (II-1b ))

(R) -2,2′-bis (bromomethyl) -3,3′-bis (2-naphthyl) -1,1′-binaphthyl (21 mg, 0.0303 mmol) in THF (0.120 mL) % Methylamine aqueous solution (0.03 mL, 0.364 mmol) was added and reacted at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was concentrated, and the residue was separated and purified by thin layer chromatography (hexane / ethyl acetate = 5: 1) to obtain compound (II-1b) (11 mg, yield 65%). .
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.06-8.04 (d, 2H), 8.04 (s, 2H), 8.00-7.98 (m, 2H), 7.93 -7.89 (m, 6H), 7.74-7.73 (m, 2H), 7.54-7.50 (m, 8H), 7.34-7.30 (m, 2H), 3 91-3.89 (d, 2H), 3.18-3.14 (d, 2H), 1.84 (s, 3H);
ESI-MS: m / z = 562 ((M + H) ⁺ ).

(Reference Example 3)
(R) -2,6-bis [3,5-bis (trifluoromethyl) phenyl] -4,5-dihydro-4-methyl-3H-dinaphth [2,1-c: 1 ′, 2′-e Synthesis of azepine (compound (II-1c))

Of (R) -3,3′-bis [3,5-bis (trifluoromethyl) phenyl] -2,2′-bis (bromomethyl) -1,1′-binaphthyl (4.0 mg, 4.6 μmol) A 40% methylamine aqueous solution (5 μL, 55 μmol) was added to a THF solution (46 μL) and reacted at room temperature for 4 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with distilled water, saturated aqueous sodium hydrogen carbonate solution and saturated brine. Sodium sulfate was added to the obtained organic layer, followed by drying. After filtration, the solvent was removed, and the residue was purified by preparative thin layer chromatography (hexane / ethyl acetate = 5: 1) to give compound (II- 1c) (3.0 mg, 89% yield) was obtained.
¹ H-NMR (600 MHz, CDCl ₃ ): δ 8.13 (brs, 4H), 8.00 (d, 2H, J = 8.3 Hz), 7.98 (s, 2H), 7.57-7 .54 (m, 2H), 7.47 (d, 2H, J = 8.3 Hz), 7.37-7.34 (m, 2H), 3.59 (d, 2H, J = 12.7 Hz) 3.13 (d, 2H, J = 12.7 Hz), 1.93 (s, 3H);
¹³ C-NMR (100 MHz, CDCl ₃ ): δ 143.32, 137.21, 136.31, 132.49, 131.70, 131.48, 131.24, 130.86, 130.19, 129. 62, 128.52, 127.46, 126.78, 126.53, 124.26, 122.45, 121.04, 52.74, 42.47;
ESI-MS: m / z = 734 ((M + H) ⁺ ).

(Reference Example 4)
(R) -4,5-dihydro-4-methyl-2,6-bis (3,4,5, -trifluorophenyl) -3H-dinaphtho [2,1-c: 1 ′, 2′-e] Synthesis of azepine (compound (II-1d))

(R) -2,2′-bis (bromomethyl) -3,3′-bis (3,4,5-trifluorophenyl) -1,1′-binaphthyl (78.8 mg, 0.113 mmol) in THF 40% methylamine aqueous solution (0.113 mL, 1.35 mmol) was added to (0.45 mL) and reacted at room temperature for 8 hours. After completion of the reaction, the reaction solution was concentrated. The residue was dissolved in methanol, and water was added to precipitate a solid, which was collected by filtration to obtain compound (II-1d) (61.2 mg, yield 95%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.96 (d, 2H, J = 8.2 Hz), 7.90 (s, 2H), 7.54-7.50 (m, 2H), 7 .41 (d, 2H, J = 8.2 Hz), 7.33-7.29 (m, 2H), 3.71 (d, 2H, J = 12.4 Hz), 3.04 (d, 2H, J = 12.4 Hz), 1.95 (s, 3H);
¹³ C-NMR (100 MHz, CDCl ₃ ): δ 150.81 (ddd, J = 251, 4.6, 4.6 Hz), 139.27 (d, J = 252 Hz), 137.38, 137.17, 136.22, 132.41, 131.04, 130.74, 129.32, 128.40, 127.40, 126.51, 126.37, 114.18 (dd), 52.54, 42.81 ;
ESI-MS: m / z = 570 ((M + H) ^<+> ).

(Reference Example 5)
(R) -4,5-dihydro-4-methyl-2,6-bis (phenylethynyl) -3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepine (compound (II-1e) )

To a THF solution (0.25 mL) of (R) -2,2′-bis (bromomethyl) -3,3′-bis (phenylethynyl) -1,1′-binaphthyl (16.3 mg, 25.4 μmol), A 40% methylamine aqueous solution (25 μL, 305 μmol) was added and reacted at room temperature for 5 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with distilled water, saturated aqueous sodium hydrogen carbonate solution and saturated brine. Sodium sulfate was added to the obtained organic layer for drying, and after filtration, the solvent was removed. The residue was purified by preparative thin layer chromatography (hexane / ethyl acetate = 5: 1) to give compound (II-1e) (11.0 mg, 85% yield) was obtained.
¹ H-NMR (600 MHz, CDCl ₃ ): δ 8.27 (s, 2H), 7.93 (d, 2H, J = 8.2 Hz), 7.61-7.60 (m, 4H), 7 .48 (dd, 2H, J = 7.9, 6.9 Hz), 7.39-7.35 (m, 8H), 7.29-7.26 (m, 2H), 4.46 (d, 2H, J = 12.4 Hz), 3.13 (d, 2H, J = 12.4 Hz), 2.57 (s, 3H);
ESI-MS: m / z = 510 ((M + H) ⁺ ).

Example 1
(R) -4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4,5-dihydro-4-methyl-2,6-diphenyl-3H-dinaphtho [2,1- c: 1 ′, 2′-e] azepinium synthesis of trifluoromethanesulfonate (compound (I-1a))

To a THF solution (0.3 mL) of the compound (II-1a) (25.0 mg, 54.2 μmol) obtained in Reference Example 1, was added 4,6-dimethoxy-1,3,5-triazinyl-2-trifluoro. L-methanesulfonic acid (23.5 μL, 81.2 μmol) was added and reacted at room temperature for 5 minutes in a nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated, and anhydrous diethyl ether was added to the resulting residue to remove the supernatant. This operation was repeated 5 times, and the remaining solid was dried to obtain compound (I-1a) (35.9 mg, yield 88%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.15 (s, 1H), 8.09 (d, 1H, J = 8.2 Hz), 7.99 (d, 1H, J = 7.8 Hz) , 7.87 (s, 1H), 7.71-7.63 (m, 2H), 7.52-7.38 (m, 14H), 5.65 (d, 1H, J = 13.3 Hz) , 5.12 (d, 1H, J = 13.3 Hz), 4.66 (d, 1H, J = 13.3 Hz), 4.19 (d, 1H, J = 13.3 Hz), 3.91 ( s, 6H), 3.09 (s, 3H).

  (Example 2) to (Example 4) were prepared in the same manner as in (Example 1) above, and any of the compounds of Reference Examples 2 to 4 (compounds (II-1c) to (II-1e)) Then, compounds (I-1c) to (I-1e) were synthesized by the reaction of 4,6-dimethoxy-1,3,5-triazinyl-2-trifluoromethanesulfonic acid. The chemical yield and physical property data of the compounds (I-1c) to (I-1e) are shown below.

(Example 2)
(R) -2,6-bis [3,5-bis (trifluoromethyl) phenyl] -4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4,5-dihydro -4-Methyl-3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepinium trifluoromethanesulfonate (compound (I-1c))

Yield 43%, white solid;
¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.16 (s, 1H), 8.13 (d, 1H, J = 8.2 Hz), 8.05 (d, 1H, J = 8.2 Hz) , 7.99 (s, 1H), 7.96-7.29 (br, 3H) 7.92 (s, 1H), 7.91 (s, 1H), 7.78-7.70 (m, 3H), 7.54-7.46 (m, 4H), 5.37 (d, 1H, J = 13.5 Hz), 5.14 (d, 1H, J = 13.5 Hz), 4.68 ( d, 1H, J = 13.5 Hz), 4.40 (d, 1H, J = 13.5 Hz), 3.95 (s, 6H), 3.20 (s, 3H);
ESI-MS: m / z = 873 ((M) +).

(Example 3)
(R) -4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4,5-dihydro-4-methyl-2,6-bis (3,4,5-trifluoro Phenyl) -3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepinium trifluoromethanesulfonate (compound (I-1d))

Yield 60%, white solid;
¹ H-NMR (400 MHz, CDCl ₃ ): δ; 8.12 (s, 1H), 8.09 (d, 1H, J = 8.2 Hz), 8.00 (d, 1H, J = 8.2 Hz) ), 7.84 (s, 1H), 7.72 (d, 1H, J = 8.2 Hz), 7.68 (d, 1H, J = 8.7 Hz), 7.49-7.41 (m , 4H), 7.11 (brs, 4H), 5.43 (d, 1H, J = 13.7 Hz), 5.09 (d, 1H, J = 13.7 Hz), 4.84 (d, 1H) , J = 13.7 Hz), 4.21 (d, 1H, J = 13.7 Hz), 4.06 (s, 6H), 3.22 (s, 3H);
ESI-MS: m / z = 709 ((M) +).

Example 4
(R) -4,5-dihydro-4-methyl-2,6-bis (phenylethynyl) -3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepinium trifluoromethanesulfonate (compound ( I-1e))

Yield 34%, white solid;
ESI-MS: m / z = 649 ((M) ⁺ ).

(Test Example 1)
Kinetic optical resolution of racemic N-benzyloxycarbonyl-phenylalanine using compound (II-1a) and compound (III-1)

  In a 10 mL eggplant flask, 2-propanol (0.65 mL), N-benzyloxycarbonylphenylalanine (19.5 mg, 65.0 μmol), chiral tertiary amine compound (II-1a) (3.00 mg, 6.50 μmol, 10 mol%), 2-phenethylamine (8 μL, 65.0 μmol) was added. 2-Chloro-4,6-diisopropoxy-1,3,5-triazine (Compound (III-1)) (16.6 mg, 71.5 μmol) was added, and the mixture was reacted at room temperature for 1.5 hours. N, N-dimethylethylenediamine (8 μL, 71.5 μmol) was added and the reaction was terminated by stirring for 30 minutes. Ethyl acetate was added to this solution for dilution, and the solution was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The obtained organic layer was dried over sodium sulfate. The residue was separated and purified by silica gel column chromatography to obtain the desired amide compound (8.4 mg, yield 32%,> 99% ee). HPLC analysis conditions of optical isomer of target amide compound: Daicel Chiral Pack IB-3, hexane / 2-propanol = 9: 1, flow rate = 1.0 mL / min, retention time 12 minutes (S form) and 17 minutes ( R-form). 2-propanol

  This reaction is considered to proceed through the catalyst cycle as shown above. That is, the compound (I-1e), which is a dehydration condensing agent generated by the reaction between the compound (II-1a) and the compound (III-1), preferentially reacts with one optical isomer of N-Cbz-phenylalanine. Then, after forming a chiral intermediate, condensation with an amine yields one chiral amide with high enantioselectivity, and the other optical isomer of N-Cbz-phenylalanine remains unreacted with high optical purity. Collected.

  In this amidation reaction, high enantioselectivity was achieved because the compound (I-1e), which is an asymmetric dehydration condensing agent, and a chiral intermediate have sufficient stability even in a protic solvent. This is considered to be caused, and this point is one of the features of the present invention not found in the prior art.

  The compound (I) of the present invention can be stably isolated, is easy to handle, and does not deactivate even in a reaction system containing a protic solvent such as alcohol, and can be used as an asymmetric dehydrating condensing agent. Can be used. Further, according to the present invention, the compound (I) of the present invention can be easily prepared at the time of use and isolated by reaction of a catalytic amount of the optically active compound (II) with the triazine compound (III). In addition, since it can be used as a catalyst as it is, a practical kinetic optical resolution method for chiral compounds can be provided.

Claims (35)

Formula (I):
[Where
R ¹ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted aromatic ring group;
R ² represents an optionally substituted C _1-6 alkyl group,
Y is a single bond, an oxygen atom, a sulfur atom, NR ⁷ (where R ⁷ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted aromatic group). Represents a cyclic group), PR ⁸ (wherein R ⁸ represents an optionally substituted alkyl group or an optionally substituted aromatic ring group), Si (R ⁹ ) (R ¹⁰ ) ( Here, R ⁹ and R ¹⁰ each independently represent an optionally substituted alkyl group or an optionally substituted aromatic ring group.) Or C (R ¹¹ ) (R ¹² ) (here , R ¹¹ and R ¹² each independently represent an optionally substituted alkyl group or an optionally substituted aromatic ring group, or R ¹¹ and R ¹² together with the carbon atom to which they are attached. Cyclic carbonization which may be substituted Containing groups may be formed.) Indicates,
R ³ represents a hydrogen atom, a halogen atom, an alkyl group that may be substituted, an alkenyl group that may be substituted, an alkynyl group that may be substituted, or a cyclic group that may be substituted;
R ⁴ , R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or a substituted group. Optionally substituted alkyl-carbonyl group, optionally substituted alkoxy-carbonyl group, carbamoyl group, mono- or di-C _1-6 alkylamino-carbonyl group, formyl group, cyano group, optionally substituted alkoxy group Or R ³ —Y and R ⁴ , and / or R ⁵ and R ⁶ may form a condensed ring together with the benzene ring to which they are bonded, and X ⁻ Represents a counter anion which is not nucleophilic or has low nucleophilicity. ]
A compound represented by The compound represented by the formula (I) is represented by the formula (I ′):
[Each symbol in the formula is as defined above. A compound represented by formula (I ″):
[Each symbol in the formula is as defined above. The compound of Claim 1 which is a compound represented by these, or those mixtures. The compound according to claim 1 or 2, wherein R ¹ is an optionally substituted C _1-3 alkyl group. The compound according to any one of claims 1 to 3, wherein R ² is a C _1-3 alkyl group which may be substituted with 1 to 3 halogen atoms.   The compound according to any one of claims 1 to 4, wherein Y is a single bond. The compound according to any one of claims 1 to 5, wherein R ³ is an optionally substituted alkynyl group or an optionally substituted aryl group. The compound according to claim 6, wherein R ³ is a C _2-6 alkynyl group which may be substituted with an aryl group or a C _6-10 aryl group which may be substituted with 1 to 3 halogen atoms. The compound according to any one of claims 1 to 7, wherein R ⁵ and R ⁶ form a naphthalene ring together with a benzene ring to which they are bonded. X ⁻ is fluoride, chloride, bromide, iodide, optionally substituted alkyl sulfonate, optionally substituted aryl sulfonate, perchlorate, tetrafluoroborate, hexafluorophosphate, hexafluoroantimonate, tetraphenyl The compound according to any one of claims 1 to 8, which is a counter anion selected from the group consisting of borates and arsenates. 10. A compound according to claim 9, wherein X < ^- > is chloride or trifluoromethanesulfonate. R ¹ is an optionally substituted C _1-3 alkyl group,
R ² is a C _1-3 alkyl group which may be substituted with 1 to 3 halogen atoms,
Y is a single bond,
R ³ is a C _6-10 aryl group _optionally substituted by 1 to 3 halogen atoms,
R ⁴ is a hydrogen atom,
The compound of claim 1, wherein R ⁵ and R ⁶ together with the benzene ring to which they are attached form a naphthalene ring, and X ^- is chloride or trifluoromethanesulfonate. R ¹ is an optionally substituted C _1-3 alkyl group,
R ² is a C _1-3 alkyl group which may be substituted with 1 to 3 halogen atoms,
Y is a single bond,
R ³ is an ethynyl group optionally substituted by an aryl group,
R ⁴ is a hydrogen atom,
The compound of claim 1, wherein R ⁵ and R ⁶ together with the benzene ring to which they are attached form a naphthalene ring, and X ^- is chloride or trifluoromethanesulfonate. Following formula:
Or an optical isomer thereof.   A dehydrating condensing agent comprising the compound according to claim 1.   An asymmetric dehydration condensing agent comprising the compound according to any one of claims 2 to 13 or an optical isomer thereof.   The asymmetric dehydration condensing agent according to claim 15, wherein the asymmetric dehydration condensing agent is an asymmetric amidation catalyst.   The asymmetric dehydration condensing agent according to claim 15, wherein the asymmetric dehydration condensing agent is an asymmetric esterification catalyst. Formula (I):
[Where
R ¹ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted aromatic ring group;
R ² represents an optionally substituted C _1-6 alkyl group,
Y is a single bond, an oxygen atom, a sulfur atom, NR ⁷ (where R ⁷ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted aromatic group). A ring group), PR ⁸ (wherein R ⁸ represents an optionally substituted alkyl group or an optionally substituted aromatic ring group), Si (R ⁹ ) (R ¹⁰ ) ( Here, R ⁹ and R ¹⁰ each independently represent an optionally substituted alkyl group or an optionally substituted aromatic ring group.) Or C (R ¹¹ ) (R ¹² ) (here , R ¹¹ and R ¹² each independently represent an optionally substituted alkyl group or an optionally substituted aromatic ring group, or R ¹¹ and R ¹² together with the carbon atom to which they are attached. Cyclic hydrocarbon which may be substituted May be formed.) Indicates,
R ³ represents a hydrogen atom, a halogen atom, an alkyl group that may be substituted, an alkenyl group that may be substituted, an alkynyl group that may be substituted, or a cyclic group that may be substituted;
R ⁴ , R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or a substituted group. Optionally substituted alkyl-carbonyl group, optionally substituted alkoxy-carbonyl group, carbamoyl group, mono- or di-C _1-6 alkylamino-carbonyl group, formyl group, cyano group, optionally substituted alkoxy group Or R ³ —Y and R ⁴ , and / or R ⁵ and R ⁶ may form a condensed ring together with the benzene ring to which they are bonded, and X ⁻ Represents a counter anion which is not nucleophilic or has low nucleophilicity. ]
A process for producing a compound represented by
Formula (II):
[Each symbol in the formula is as defined above. ]
A compound represented by formula (III):
[Wherein, X ¹ represents a halogen atom, an optionally substituted alkylsulfonyloxy group or an optionally substituted arylsulfonyloxy group, and R ¹ has the same meaning as described above. ]
The manufacturing method including the process with which the compound represented by these is made to react in a reaction solvent. The compound represented by the formula (I) is represented by the formula (I ′):
[Each symbol in the formula is as defined above. A compound represented by formula (I ″):
[Each symbol in the formula is as defined above. Or a mixture thereof, and the compound represented by the formula (II) is represented by the formula (II ′):
[Each symbol in the formula is as defined above. ]
A compound of formula (II ″):
[Each symbol in the formula is as defined above. ]
The method of Claim 18 which is a compound represented by these, or those mixtures. R ² is a C _1-3 alkyl group which may be substituted with 1 to 3 halogen atoms,
Y is a single bond,
R ³ is a C _6-10 aryl group _optionally substituted by 1 to 3 halogen atoms,
The method according to claim 18 or 19, wherein R ⁴ is a hydrogen atom, and R ⁵ and R ⁶ together with the benzene ring to which they are bonded form a naphthalene ring. R ² is a C _1-3 alkyl group which may be substituted with 1 to 3 halogen atoms,
Y is a single bond,
R ³ is an ethynyl group optionally substituted by an aryl group,
The method according to claim 18 or 19, wherein R ⁴ is a hydrogen atom, and R ⁵ and R ⁶ together with the benzene ring to which they are bonded form a naphthalene ring.   The reaction solvent is THF, water, alcohol, N, N-dimethylformamide, dimethyl sulfoxide, diethyl ether, dibutyl ether, DME, diglyme, tert-butyl methyl ether, dioxane, ethyl acetate, hexane, methylene chloride, chloroform, dichloroethane, The method according to any one of claims 18 to 21, which is acetonitrile, acetone or a mixed solvent of two or more thereof. A racemic form of a chiral organic acid is converted into an asymmetric dehydration condensing agent and the formula (III):
[Wherein, X ¹ represents a halogen atom or an optionally substituted alkylsulfonoxy group, and R ¹ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or An aromatic ring group which may be substituted. In the presence of a compound represented by the following formula, a kinetic optical resolution is obtained by reacting with a nucleophile in a reaction solvent to obtain a stereoisomerically enriched chiral organic acid-nucleophile condensate. It is a method, Comprising: The method of using the compound of any one of Claims 2-13 as this asymmetric dehydration condensation agent.   24. The method of claim 23, wherein the chiral organic acid is an N-protected α-amino acid.   25. The method of claim 24, wherein the N-protected [alpha] -amino acid is N-protected [alpha] -phenylalanine.   26. A method according to any one of claims 23 to 25, wherein the nucleophile is an alcohol or an amine and the corresponding chiral organic acid-nucleophile condensate is an ester or amide.   27. The method of claim 26, wherein the amine is a primary amine. 28. The method of claim 27, wherein the primary amine is a _C7-14 aralkylamine.   The method according to any one of claims 23 to 28, wherein the reaction solvent comprises a lower alcohol.   30. The method of claim 29, comprising a lower alcohol as the nucleophile and reaction solvent. The asymmetric dehydrating condensing agent is a catalytic amount of formula (II ′):
[Each symbol in the formula is as defined above. ]
A compound of formula (II ″):
[Each symbol in the formula is as defined above. ]
A compound represented by formula (III):
[Each symbol in the formula is as defined above. ]
The method according to any one of claims 23 to 30, wherein the method is formed in a reaction system by a reaction with a compound represented by the formula: R ² is a C _1-3 alkyl group which may be substituted with 1 to 3 halogen atoms,
Y is a single bond,
R ³ is a C _6-10 aryl group _optionally substituted by 1 to 3 halogen atoms,
R ⁴ is hydrogen atom, and R ⁵ and R ⁶ is to form a naphthalene ring with the benzene ring to which they are attached, The method of claim 31, wherein. R ² is a C _1-3 alkyl group which may be substituted with 1 to 3 halogen atoms,
Y is a single bond,
R ³ is an ethynyl group optionally substituted by an aryl group,
R ⁴ is hydrogen atom, and R ⁵ and R ⁶ is to form a naphthalene ring with the benzene ring to which they are attached, The method of claim 31, wherein.   The method according to any one of claims 31 to 33, wherein the catalyst amount is 0.1 mol% to 50 mol% with respect to the racemic chiral organic acid. Following formula:
Or an optical isomer thereof.