JP7141632B2 - Sample preparation method for crystal structure analysis for structural analysis of hydrophilic organic compounds having polar groups by the crystal sponge method - Google Patents

Description

TECHNICAL FIELD The present invention relates to a crystal structure analysis sample preparation method for structural analysis of a hydrophilic organic compound having a polar group by the crystal sponge method.

BACKGROUND ART In recent years, trace amounts of physiologically active substances derived from marine organisms and the like have been expected as agricultural and pharmaceutical resources. Therefore, it is extremely important to accurately and efficiently determine the molecular structure of these trace amounts of organic compounds in the development of new agrochemicals and the like. In addition, when agrochemicals are manufactured, it is required to accurately identify minute amounts of impurities contained in the agrochemicals and their raw materials in order to improve safety. Similarly, with regard to raw materials used in the manufacture of electronic parts, it is desired to identify trace amounts of impurities and reduce them as the performance of electronic parts has improved in recent years. Thus, in recent years, there has been a demand in many fields to accurately and efficiently determine the molecular structure of trace amounts of organic compounds.

Single-crystal X-ray structural analysis is conventionally known as a method for determining the molecular structure of organic compounds. Single-crystal X-ray structure analysis is a very useful method because the molecular structure of an organic compound can be accurately determined if a single crystal of good quality can be produced. However, when the amount of the organic compound is very small, a sufficient amount of single crystals cannot be obtained, making it difficult to employ single crystal X-ray structural analysis as a method for determining the molecular structure. In addition, when the organic compound that determines the molecular structure is liquid at around room temperature (that is, when the melting point is below room temperature), it is difficult to produce a single crystal.

A crystalline sponge method is known as a method for solving the above problems of the single crystal X-ray structural analysis method (Patent Document 1). The crystal sponge method is a crystal formed by encapsulating an organic compound whose structure is to be determined in the voids of a polymer metal complex having a three-dimensional network structure and voids that are regularly arranged three-dimensionally within the three-dimensional network structure. This is a method of determining the molecular structure of the organic compound by preparing a sample for structural analysis and conducting structural analysis of the sample for crystal structure analysis.

Patent No. 5969616

However, the crystal sponge method has a problem that it is impossible to determine the structure of compounds that cannot be put into the pores of the polymer metal complex. For example, a compound that is larger than the voids cannot be put into the voids, and a highly hydrophilic compound cannot be put into the voids because the constituent components of the polymer metal complex are lipophilic.

An object of the present invention is to provide a sample preparation method for analyzing the molecular structure of a hydrophilic organic compound by the crystal sponge method.

As a result of intensive studies aimed at solving the above problems, the present inventors have found that by introducing a hydrophobic substituent into the polar group of a hydrophilic organic compound, the organic compound can be included in the voids of the polymer metal complex. We have found that it is possible to achieve this, and have completed the present invention. That is, the present invention includes the following aspects.

（式中、Ａｒは、置換基を有していてもよい３価の芳香族基を表し、Ｘ¹～Ｘ³は、それぞれ独立に、２価の有機基、またはＡｒとＹ¹～Ｙ³とを直接結ぶ単結合を表し、Ｙ¹～Ｙ³は、それぞれ独立に、配位性部位を有する１価の有機基を表す）で示される三座配位子を表し、ｎは任意の自然数を表す〕で示される高分子金属錯体の結晶であって、
前記三座配位子が、前記金属イオンに配位して三次元ネットワーク構造を形成し、かつ、該三次元ネットワーク構造が、その内部に空隙を有し、前記空隙に、脂肪族炭化水素；脂環式炭化水素；エーテル類；エステル類；ベンゼン、トルエン、キシレン、メシチレン、ナフタレン、アントラセン及びフェナントレンからなる群から選ばれる芳香族炭化水素；ハロゲン化炭化水素、並びにニトリル類からなる群から選ばれる少なくとも一種が、ゲスト化合物（Ａ）として内包されており、
前記空隙における、前記ゲスト化合物（Ａ）の存在量が、前記空隙に内包されているすべてのゲスト化合物に対して６０モル％以上である、工程、
（２）前記有機化合物を含む溶媒溶液に前記ゲスト化合物内包高分子金属錯体結晶を浸漬させて、前記三次元ネットワーク構造内の空隙に、前記有機化合物の分子が内包されてなる結晶構造解析用試料を得る工程、並びに
（３）前記結晶構造解析用試料の結晶構造解析を行って、前記三次元ネットワーク構造内の空隙に内包されている有機化合物の分子構造を決定する工程、
を含む、方法であり、
前記結晶構造解析用試料調製方法が、以下の工程（ａ）及び（ｂ）、
（ａ）前記親水性有機化合物の極性基に疎水性置換基を導入して、疎水性置換基を導入した有機化合物を得る工程、及び
（ｂ）前記疎水性置換基を導入した有機化合物を含む溶媒溶液に前記ゲスト化合物内包高分子金属錯体結晶を浸漬させて、前記三次元ネットワーク構造内の空隙に、前記疎水性置換基を導入した有機化合物の分子が内包されてなる前記結晶構造解析用試料を得る工程、
を含むことを特徴とする、結晶構造解析用試料調製方法。 [1] A method for preparing a sample for crystal structure analysis for structural analysis by the crystal sponge method of a hydrophilic organic compound having a polar group, comprising:
The crystal sponge method is a method for determining the molecular structure of an organic compound, and comprises the following steps (1) to (3),
(1) A step of providing a polymer metal complex crystal containing a guest compound,
The guest compound-encapsulating polymer metal complex crystal has the formula: [[M(X) ₂ ] ₃ (L) ₂ ] _n [wherein M represents a metal ion, X represents a monovalent anion, L is the following formula (1)

(In the formula, Ar represents a trivalent aromatic group which may have a substituent, and X ¹ to X ³ are each independently a divalent organic group, or Ar and Y ¹ to Y ³ Y ¹ to Y ³ each independently represent a monovalent organic group having a coordinating site), n is any natural number A crystal of a polymer metal complex represented by
The tridentate ligand coordinates to the metal ion to form a three-dimensional network structure, and the three-dimensional network structure has voids therein, and the voids contain an aliphatic hydrocarbon; Ethers; Esters; Aromatic hydrocarbons selected from the group consisting of benzene, toluene, xylene, mesitylene, naphthalene, anthracene and phenanthrene; Halogenated hydrocarbons, and Nitriles. At least one is included as a guest compound (A),
a step in which the abundance of the guest compound (A) in the voids is 60 mol% or more with respect to all guest compounds contained in the voids;
(2) A sample for crystal structure analysis in which the polymer metal complex crystal containing the guest compound is immersed in a solvent solution containing the organic compound, and the molecules of the organic compound are included in the voids in the three-dimensional network structure. and (3) performing crystal structure analysis of the sample for crystal structure analysis to determine the molecular structure of the organic compound contained in the voids in the three-dimensional network structure;
a method comprising
The method for preparing a sample for crystal structure analysis includes the following steps (a) and (b),
(a) introducing a hydrophobic substituent to the polar group of the hydrophilic organic compound to obtain an organic compound having a hydrophobic substituent; and (b) comprising the organic compound having the hydrophobic substituent. The sample for crystal structure analysis, in which the polymer metal complex crystal encapsulating the guest compound is immersed in a solvent solution, and molecules of the organic compound introduced with the hydrophobic substituent are included in the voids in the three-dimensional network structure. a step of obtaining
A sample preparation method for crystal structure analysis, comprising:

[2] The sample preparation method according to [1] above, wherein the hydrophobic substituent has at least one aromatic ring.

[3] The sample preparation method according to [2] above, wherein the hydrophobic substituent has two benzene rings, one benzene ring and one tert-butyl group, one indole ring, or one naphthalene ring.

[4] The sample preparation according to any one of [1] to [3], wherein the hydrophobic substituent is a group that improves the lipophilicity of the hydrophilic organic compound by introduction into the polar group. Method.

[5] The sample preparation method according to any one of [1] to [4] above, wherein the hydrophobic substituent is a group that interacts with the polymer metal complex.

[6] The sample preparation method according to any one of [1] to [5] above, wherein the polar group is an amino group, hydroxyl group, thiol group or carboxy group.

[7] The sample preparation method according to [6] above, wherein the polar group is an amino group or a carboxy group.

[8] The above [7], wherein the polar group is an amino group, and the hydrophobic substituent is introduced into the polar group by an amide bond, a urethane bond, a urea bond or a thiourea bond in the step (a). Sample preparation method as described.

[9] The sample according to [8] above, wherein the hydrophobic substituent is a 1-naphthylcarbamothioyl group, a 1,1-diphenylacetyl group, a 4-tert-butylbenzoyl group, or a 2-indolecarbonyl group. Method of preparation.

[10] The sample preparation method according to [7] above, wherein the polar group is a carboxy group, and the hydrophobic substituent is introduced into the polar group by an ester bond or an amide bond in the step (a).

[11] The sample preparation method according to [10] above, wherein the hydrophobic substituent is a diphenylmethyl group.

[12] The sample preparation method according to any one of [1] to [11] above, wherein the hydrophilic organic compound is an amino acid or a nucleic acid.

[13] A method for structural analysis of a hydrophilic organic compound by a crystal sponge method, comprising the step of analyzing the crystal structure of the sample obtained by the sample preparation method according to any one of [1] to [12] above. .

[14] A reagent for introducing a substituent, for use in the sample preparation method according to any one of [1] to [12] above, and containing the compound that provides the hydrophobic substituent.

The present invention provides a sample preparation method for analyzing the molecular structure of a hydrophilic organic compound by the crystal sponge method.

FIG. 1 shows the direction in which the pores of the polymer-metal complex extend. FIG. 2 shows the three-dimensional network structure of the polymer metal complex 1. FIG. FIG. 3 shows the three-dimensional network structure of the polymer metal complex 3. FIG. FIG. 4 shows the three-dimensional network structure of the polymer metal complex 5. As shown in FIG. FIG. 5 shows an example of an apparatus used in concentrating the solvent solution. FIG. 6 shows a conceptual diagram of preparing a sample for crystal structure analysis by dropping a liquid organic compound that determines the molecular structure from a dropper onto a single crystal of a polymer metal complex containing a guest compound. 7 shows the crystal structure of the polymer metal complex containing methyl (2S)-2-(1-naphthylcarbamothioylamino)propanoate obtained in Example 1. FIG. FIG. 8 shows interactions assumed from the crystal structure of FIG. 9 shows the crystal structure of the polymer metal complex containing methyl (2S)-2-[(2,2-diphenylacetyl)amino]propanoate obtained in Example 2. FIG. FIG. 10 shows interactions assumed from the crystal structure of FIG. 11 shows the crystal structure of the polymer metal complex containing methyl (2S)-2-[(2,2-diphenylacetyl)amino]-3-phenyl-propanoate obtained in Example 3. FIG. 12 shows the crystal structure of the polymer metal complex including methyl (2S)-2-[(2,2-diphenylacetyl)amino]-3-methyl-butanoate obtained in Example 4. FIG. 13 shows the crystal structure of the polymer metal complex containing methyl (2S)-2-[(2,2-diphenylacetyl)amino]-3-hydroxy-propanoate obtained in Example 5. FIG. 14 shows the crystal structure of the dimethyl(2S)-2-[(2,2-diphenylacetyl)amino]pentanedioate-containing polymer metal complex obtained in Example 6. FIG. 15 shows the crystal structure of the N-[(1S)-1-benzyl-2-hydroxy-ethyl]-2,2-diphenyl-acetamide encapsulating polymer metal complex obtained in Example 7. FIG. 16 shows the crystal structure of the polymer metal complex including methyl (2S)-2-[(4-tert-butylbenzoyl)amino]propanoate obtained in Example 8. FIG. FIG. 17 shows interactions assumed from the crystal structure of FIG. 18 shows the crystal structure of the polymer metal complex including methyl (2S)-2-[(4-tert-butylbenzoyl)amino]-3-(4-hydroxyphenyl)propanoate obtained in Example 9. FIG. . 19 shows the crystal structure of the polymer metal complex containing methyl (2S)-2-[(4-tert-butylbenzoyl)amino]-3-hydroxy-propanoate obtained in Example 10. FIG. 20 shows the crystal structure of the polymer metal complex containing methyl (2S)-1-(1H-indole-2-carbonyl)pyrrolidine-2-carboxylate obtained in Example 11. FIG. FIG. 21 shows interactions assumed from the crystal structure of FIG. 22 shows the crystal structure of the polymer metal complex including methyl (2S)-2-(1H-indole-2-carbonylamino)-3-phenyl-propanoate obtained in Example 12. FIG. 23 shows the crystal structure of the benzhydryl (2R)-2-hydroxy-2-phenyl-acetate-encapsulating polymer metal complex obtained in Example 13. FIG. FIG. 24 shows interactions assumed from the crystal structure of FIG.

（式中、Ａｒは、置換基を有していてもよい３価の芳香族基を表し、Ｘ¹～Ｘ³は、それぞれ独立に、２価の有機基、またはＡｒとＹ¹～Ｙ³とを直接結ぶ単結合を表し、Ｙ¹～Ｙ³は、それぞれ独立に、配位性部位を有する１価の有機基を表す）で示される三座配位子を表し、ｎは任意の自然数を表す〕で示される高分子金属錯体の結晶であって、
前記三座配位子が、前記金属イオンに配位して三次元ネットワーク構造を形成し、かつ、該三次元ネットワーク構造が、その内部に空隙を有し、前記空隙に、脂肪族炭化水素；脂環式炭化水素；エーテル類；エステル類；ベンゼン、トルエン、キシレン、メシチレン、ナフタレン、アントラセン及びフェナントレンからなる群から選ばれる芳香族炭化水素；ハロゲン化炭化水素、並びにニトリル類からなる群から選ばれる少なくとも一種が、ゲスト化合物（Ａ）として内包されており、
前記空隙における、前記ゲスト化合物（Ａ）の存在量が、前記空隙に内包されているすべてのゲスト化合物に対して６０モル％以上である、工程、
（２）前記有機化合物を含む溶媒溶液に前記ゲスト化合物内包高分子金属錯体結晶を浸漬させて、前記三次元ネットワーク構造内の空隙に、前記有機化合物の分子が内包されてなる結晶構造解析用試料を得る工程、並びに
（３）前記結晶構造解析用試料の結晶構造解析を行って、前記三次元ネットワーク構造内の空隙に内包されている有機化合物の分子構造を決定する工程、
を含む、方法であり、
前記結晶構造解析用試料調製方法が、以下の工程（ａ）及び（ｂ）、
（ａ）前記親水性有機化合物の極性基に疎水性置換基を導入して、疎水性置換基を導入した有機化合物を得る工程、及び
（ｂ）前記疎水性置換基を導入した有機化合物を含む溶媒溶液に前記ゲスト化合物内包高分子金属錯体結晶を浸漬させて、前記三次元ネットワーク構造内の空隙に、前記疎水性置換基を導入した有機化合物の分子が内包されてなる前記結晶構造解析用試料を得る工程、
を含むことを特徴とする、試料調製方法に関する。 The present invention is a crystal structure analysis sample preparation method for structural analysis by the crystal sponge method of a hydrophilic organic compound having a polar group,
The crystal sponge method is a method for determining the molecular structure of an organic compound, and comprises the following steps (1) to (3),
(1) A step of providing a polymer metal complex crystal containing a guest compound,
The guest compound-encapsulating polymer metal complex crystal has the formula: [[M(X) ₂ ] ₃ (L) ₂ ] _n [wherein M represents a metal ion, X represents a monovalent anion, L is the following formula (1)

(In the formula, Ar represents a trivalent aromatic group which may have a substituent, and X ¹ to X ³ are each independently a divalent organic group, or Ar and Y ¹ to Y ³ Y ¹ to Y ³ each independently represent a monovalent organic group having a coordinating site), n is any natural number A crystal of a polymer metal complex represented by
The tridentate ligand coordinates to the metal ion to form a three-dimensional network structure, and the three-dimensional network structure has voids therein, and the voids contain an aliphatic hydrocarbon; Ethers; Esters; Aromatic hydrocarbons selected from the group consisting of benzene, toluene, xylene, mesitylene, naphthalene, anthracene and phenanthrene; Halogenated hydrocarbons, and Nitriles. At least one is included as a guest compound (A),
a step in which the abundance of the guest compound (A) in the voids is 60 mol% or more with respect to all guest compounds contained in the voids;
(2) A sample for crystal structure analysis in which the polymer metal complex crystal containing the guest compound is immersed in a solvent solution containing the organic compound, and the molecules of the organic compound are included in the voids in the three-dimensional network structure. and (3) performing crystal structure analysis of the sample for crystal structure analysis to determine the molecular structure of the organic compound contained in the voids in the three-dimensional network structure;
a method comprising
The method for preparing a sample for crystal structure analysis includes the following steps (a) and (b),
(a) introducing a hydrophobic substituent to the polar group of the hydrophilic organic compound to obtain an organic compound having a hydrophobic substituent; and (b) comprising the organic compound having the hydrophobic substituent. The sample for crystal structure analysis, in which the polymer metal complex crystal encapsulating the guest compound is immersed in a solvent solution, and molecules of the organic compound introduced with the hydrophobic substituent are included in the voids in the three-dimensional network structure. a step of obtaining
It relates to a sample preparation method, comprising:

step (a)
The sample preparation method of the present invention includes a step of introducing a hydrophobic substituent into the polar group of the hydrophilic organic compound to obtain an organic compound having a hydrophobic substituent (step (a)).

In the present invention, the term "hydrophilic organic compound" refers to an organic compound that is readily soluble or miscible with water and is insoluble in non-polar solvents. “Hydrophobic substituent” refers to a substituent that has low affinity for water and high affinity for nonpolar solvents. A "polar group" refers to a polar atomic group.

The hydrophobic substituent preferably has at least one aromatic ring, more preferably two benzene rings, one benzene ring and one tert-butyl group, one indole ring or one naphthalene ring. Preferred hydrophobic substituents include 1-naphthylcarbamothioyl group, 1,1-diphenylacetyl group, 4-tert-butylbenzoyl group, 2-indolecarbonyl group, diphenylmethyl group, [4-(dimethylamino)- 1-naphthyl]carbamothioyl group, naphthalene-1-carbonyl group, ferrocenecarbonyl group, benzoyl group, 3-bromo-4-tert-butylbenzoyl group, benzyl group and the like. As the hydrophobic substituent, those having no aromatic ring may be used, and examples thereof include methyl group, ethyl group, isopropyl group, tert-butyl group and the like.

By introducing a hydrophobic substituent into the polar group of a hydrophilic organic compound, the lipid solubility of the hydrophilic organic compound is improved. It can be dissolved in a solvent and put into the pores of the polymer metal complex crystal. Lipid solubility can be evaluated, for example, by measuring the octanol-water partition coefficient by a conventionally known method, or by calculation based on the structural formula. Hydrophobic substituents can also interact with polymeric metal complexes used in the crystalline sponge method. Interactions may include pi-pi interactions, CH-pi interactions, halogen-pi interactions, charge transfer type interactions, and the like. The interaction is detected by displaying the atomic coordinate data after X-ray crystal structure analysis with drawing software and comparing it with a standard or database, for example, by confirming that the interatomic distance is smaller than the van der Waals radius. can do. Furthermore, when the polar group of the hydrophilic compound has nucleophilicity, the polar group of the hydrophilic compound impairs the structure of the polymer metal complex crystal formed by the coordinate bond between the metal and the ligand. However, by introducing a hydrophobic substituent to the polar group, the nucleophilicity of the polar group can be reduced and the structure of the polymer metal complex crystal can be maintained. Due to these actions of the hydrophobic substituent, the organic compound into which the hydrophobic substituent is introduced can be included in the voids of the polymer metal complex.

The polar group of the hydrophilic organic compound is not particularly limited, but is preferably an amino group, a hydroxyl group, a thiol group or a carboxy group, more preferably an amino group or a carboxy group.

When the polar group is an amino group, a hydrophobic substituent may be introduced into the polar group in step (a), for example via an amide bond, a urethane bond, a urea bond or a thiourea bond. When the polar group is an amino group, the hydrophobic substituent is preferably a 1-naphthylcarbamothioyl group, a 1,1-diphenylacetyl group, a 4-tert-butylbenzoyl group or a 2-indolecarbonyl group.

When the polar group is a carboxy group, the hydrophobic substituent may be introduced into the polar group in the step (a) by, for example, an ester bond or an amide bond. When the polar group is a carboxy group, the hydrophobic substituent is preferably a methyl group, ethyl group, isopropyl group, tert-butyl group, benzyl group or diphenylmethyl group.

When the polar group is a hydroxyl group, in the step (a), the hydrophobic substituent may be introduced into the polar group by, for example, an ether bond or an ester bond. When the polar group is a hydroxyl group, the hydrophobic substituent is preferably a methyl group, ethyl group, isopropyl group, tert-butyl group, benzyl group, diphenylmethyl group, benzoyl group or diphenylacetyl group.

When the polar group is a thiol group, in step (a), the hydrophobic substituent may be introduced into the polar group by, for example, a thioether bond. When the polar group is a hydroxyl group, the hydrophobic substituent is preferably a methyl group, ethyl group, isopropyl group, tert-butyl group, benzyl group or diphenylmethyl group.

The hydrophilic organic compound is not particularly limited as long as it has a size that allows it to enter the pores of the polymer metal complex used in the crystal sponge method after the introduction of the hydrophobic substituent. Hydrophilic organic compounds are preferably amino acids, nucleic acids, or organic acids. Amino acids and nucleic acids may include salts or derivatives thereof.

The method for introducing the hydrophobic substituent into the polar group is not particularly limited, and conventionally known methods for bonding the polar group and the hydrophobic substituent can be used depending on the type.

step (b)
In the method of preparing a sample for crystal structure analysis of the present invention, the guest compound-encapsulating polymer metal complex crystal is immersed in a solvent solution containing an organic compound to which a hydrophobic substituent is introduced, and hydrophobic a step of obtaining a sample for crystal structure analysis in which the molecule of the organic compound into which the sexual substituent is introduced is included (step (b)). In the step (b), except for using the solvent solution containing the organic compound into which the hydrophobic substituent is introduced obtained in the step (a) as the solvent solution containing the organic compound, a sample for crystal structure analysis in the crystal sponge method described later is used. It can be carried out in the same manner as the manufacturing method.

The present invention also relates to a method for structural analysis of a hydrophilic organic compound by the crystalline sponge method, which comprises the step of analyzing the crystal structure of the sample for crystal structure analysis obtained in step (b). In the present invention, the crystal structure analysis of the sample is carried out in the same manner as the method for determining the molecular structure of an organic compound in the crystal sponge method described below, except that the sample for crystal structure analysis obtained in step (b) is used as the sample. can be done. In the present invention, since a hydrophobic substituent with a known structure is introduced into the polar group of the hydrophilic organic compound that is the target of structural analysis, the electron density derived from the introduced hydrophobic substituent is used as a clue to determine the unknown structure. analysis of hydrophilic organic compounds can be facilitated.

The present invention further relates to a substituent-introducing reagent containing a compound that provides a hydrophobic substituent for use in the above sample preparation method.

Examples of compounds that provide hydrophobic substituents include 1-naphthyl isothiocyanate, diphenylacetyl chloride, 4-tert-butylbenzoic acid, indole-2-carboxylic acid, diphenylmethyltrichloroacetimidate, iodomethane, trimethylsilyldiazomethane, and the like. can be mentioned.

Substituent introducing reagents may optionally include acid chlorides, N-hydroxysuccinimide esters, carboxylic acids, isothiocyanates, alcohols, alkyl halides, trichloroacetimidates, and the like.

The crystalline sponge method is described in detail in US Pat. No. 5,969,616, which is incorporated herein by reference in its entirety.

Hereinafter, the crystal sponge method used in the present invention will be described as A) a polymer metal complex crystal containing a guest compound, B) a method for producing a polymer metal complex crystal containing a guest compound, C) a method for preparing a sample for crystal structure analysis, and D) Method for Determining Molecular Structure of Organic Compounds.

A) Guest compound-encapsulating polymer metal complex crystal The guest compound-encapsulating polymer metal complex crystal is a polymer metal complex containing a ligand having two or more coordinating sites and a metal ion as a central metal, The voids of the polymer-metal complex, which has a three-dimensional network structure formed by the coordination of the ligand to the metal ion, and voids that are arranged three-dimensionally and regularly within the three-dimensional network structure. At least one selected from the group consisting of aliphatic hydrocarbons, alicyclic hydrocarbons, ethers, esters, aromatic hydrocarbons, halogenated hydrocarbons, and nitriles is included as a guest compound (A). The amount of the guest compound (A) present in the voids is 60 mol % or more of all the guest compounds contained in the voids.

(i) Polymer metal complex A polymer metal complex has a three-dimensional network structure including a ligand having two or more coordinating sites and a metal ion as a central metal.
Here, the term "three-dimensional network structure" refers to a structural unit formed by binding a ligand (a ligand having two or more coordinating sites and other monodentate ligands) and a metal ion, It refers to a network structure that is repeated three-dimensionally.

[Ligand]
A ligand having two or more coordinating sites (hereinafter sometimes referred to as a "polydentate ligand") is capable of forming the three-dimensional network structure by coordinating with a metal ion. It is not particularly limited as long as it is used, and known polydentate ligands can be used.
Here, the term "coordination site" refers to an atom or atomic group in a ligand having a lone pair of electrons capable of coordinative bonding. Examples thereof include heteroatoms such as a nitrogen atom, an oxygen atom, a sulfur atom and a phosphorus atom; atomic groups such as a nitro group, an amino group, a cyano group and a carboxyl group; and the like. Among them, a nitrogen atom or an atomic group containing a nitrogen atom is preferable.

Moreover, as the multidentate ligand, those having an aromatic ring are preferable because the ligand has high planarity and is likely to form a strong three-dimensional network structure.
Furthermore, from the viewpoint of easily obtaining a polymer metal complex having relatively large voids, the multidentate ligand is preferably a ligand having two or more coordinating sites. A ligand having three (hereinafter sometimes referred to as a "tridentate ligand") is more preferable, and the lone pairs of electrons (orbitals) of the three coordinating sites are present on the quasi-coplanar plane, and , three coordinating sites are evenly spaced radially with respect to the center of the tridentate ligand.

Here, "existing on the quasi-coplanar plane" means that each lone pair exists on the same plane, or is slightly deviated from the plane, for example, 20° or less with respect to the reference plane. This also includes states existing on planes that intersect with .
Further, "the three coordinating sites are arranged radially at equal intervals with respect to the central part of the tridentate ligand" means that on a line radially extending from the central part of the ligand at equal intervals, It refers to a state in which three coordinating sites are arranged at substantially equal distances from the center.

（式中、Ａｒは、置換基を有していてもよい３価の芳香族基を表す。Ｘ¹～Ｘ³は、それぞれ独立に、２価の有機基、又はＡｒとＹ¹～Ｙ³とを直接結ぶ単結合を表す。Ｙ¹～Ｙ³は、それぞれ独立に、配位性部位を有する１価の有機基を表す。）で示される配位子が挙げられる。 Examples of tridentate ligands include formula (1)

(In the formula, Ar represents a trivalent aromatic group which may have a substituent. X ¹ to X ³ are each independently a divalent organic group, or Ar and Y ¹ to Y ³ Y ¹ to Y ³ each independently represent a monovalent organic group having a coordinating site.).

In formula (1), Ar represents a trivalent aromatic group.
The number of carbon atoms constituting Ar is usually 3-22, preferably 3-13, more preferably 3-6.

Ar is a trivalent aromatic group having a monocyclic structure consisting of one six-membered aromatic ring, or a trivalent aromatic group having a condensed ring structure consisting of three condensed six-membered aromatic rings. groups.

Examples of the trivalent aromatic group having a monocyclic structure consisting of one six-membered aromatic ring include groups represented by the following formulas (2a) to (2d). Examples of the trivalent aromatic group having a condensed ring structure in which three six-membered aromatic rings are condensed include groups represented by the following formula (2e). In formulas (2a) to (2e), "*" represents the bonding position with X ¹ to X ³ respectively.

Ar may have a substituent at any position of the aromatic group represented by formulas (2a) and (2c) to (2e). Such substituents include alkyl groups such as methyl group, ethyl group, isopropyl group, n-propyl group and t-butyl group; alkoxy groups such as methoxy group, ethoxy group, n-propoxy group and n-butoxy group; fluorine halogen atoms such as atoms, chlorine atoms, bromine atoms; Among these, the aromatic group represented by formula (2a) or (2b) is preferred, and the aromatic group represented by formula (2b) is particularly preferred.

X ¹ to X ³ each independently represent a divalent organic group or a single bond directly connecting Ar and Y ¹ to Y ³ .

As the divalent organic group, those capable of forming a π-electron conjugated system together with Ar are preferable. The divalent organic groups represented by X ¹ to X ³ form a π-electron conjugated system, thereby improving the planarity of the tridentate ligand represented by formula (1) and forming a stronger three-dimensional network. structure is easier to form.
The number of carbon atoms constituting the divalent organic group is preferably 2-18, more preferably 2-12, even more preferably 2-6.

The divalent organic group includes a divalent unsaturated aliphatic group having 2 to 10 carbon atoms, a divalent organic group having a monocyclic structure consisting of one 6-membered aromatic ring, and 2 to 4 6-membered aromatic rings. A divalent organic group having a condensed ring structure formed by individual condensation, an amide group [-C(=O)-NH-], an ester group [-C(=O)-O-], these divalent organic A combination of two or more groups and the like can be mentioned.

Examples of the divalent unsaturated aliphatic group having 2 to 10 carbon atoms include a vinylene group and an acetylene group (ethynylene group).
Examples of the divalent organic group having a monocyclic structure consisting of one 6-membered aromatic ring include a 1,4-phenylene group.
The divalent organic group having a condensed ring structure in which 2 to 4 six-membered aromatic rings are condensed includes a 1,4-naphthylene group, a 1,5-naphthylene group, a 2,6-naphthylene group and anthracene. -1,4-diyl group and the like.
Combinations of two or more of these divalent organic groups include the following.

These aromatic rings may contain heteroatoms such as nitrogen, oxygen and sulfur atoms in the ring.
Moreover, the divalent organic group may have a substituent. Examples of such substituents include the same substituents as those described above for Ar.
Among these, the following are preferred as the divalent organic groups represented by X ¹ to X ³ .

Y ¹ to Y ³ each independently represent a monovalent organic group having a coordinating site.
As the organic groups represented by Y ¹ to Y ³ , those capable of forming a π-electron conjugated system together with Ar and X ¹ to X ³ are preferred.
When the organic groups represented by Y ¹ to Y ³ form a π-electron conjugated system, the planarity of the tridentate ligand represented by formula (1) is improved and a strong three-dimensional network structure is formed. becomes easier.
The number of carbon atoms constituting Y ¹ to Y ³ is preferably 5-11, more preferably 5-7.

Y ¹ to Y ³ include organic groups represented by the following formulas (3a) to (3f). In formulas (3a) to (3f), "*" represents the bonding position with X ¹ to X ³ .

Y ¹ to Y ³ may have a substituent at any position of the organic groups represented by formulas (3a) to (3f). Examples of such substituents include those exemplified above as the substituents of Ar.
Among these, the group represented by formula (3a) is particularly preferred.

By appropriately selecting Ar, X ¹ to X ³ , and Y ¹ to Y ³ in the tridentate ligand represented by formula (1), the pore size of the polymer metal complex can be adjusted. . By using this method, it is possible to efficiently obtain a single crystal of a polymer-metal complex having voids large enough to clathrate an organic compound that determines the molecular structure.

As a tridentate ligand represented by formula (1), a strong three-dimensional network structure is likely to be formed, so it has high planarity and symmetry, and a π-conjugated system spreads over the entire ligand. things are preferred. Examples of such a tridentate ligand include ligands represented by the following formulas (4a) to (4f).

Among these, the tridentate ligand represented by formula (1) includes 2,4,6-tris(4-pyridyl)-1,3,5-triazine (TPT) represented by formula (4a) above. is particularly preferred.

〔Metal ions〕
The metal ion as the central metal is not particularly limited as long as it can form a coordinate bond with the multidentate ligand to form a three-dimensional network structure, and includes known metal ions. Among them, metal ions of groups 8 to 12 of the periodic table such as iron ions, cobalt ions, nickel ions, copper ions, zinc ions, and silver ions are preferable, and divalent metal ions of groups 8 to 12 of the periodic table. is more preferred. Among them, zinc (II) ions and cobalt (II) ions are particularly preferred, since a polymer metal complex having large voids can be easily obtained.

[Other Components Constituting Polymer Metal Complex]
Polymer metal complexes are usually stabilized by the coordination of a neutral multidentate ligand and a monodentate ligand that serves as a counterion.
Such monodentate ligands include monovalent anions such as chloride ion (Cl ^- ), bromide ion (Br ^- ), iodide ion (I ^- ) and thiocyanate ion (SCN ^- ).

Further, the polymer metal complex contains a solvent; an electrically neutral coordinating compound such as ammonia, monoalkylamine, dialkylamine, trialkylamine, ethylenediamine; and a skeleton-forming aromatic compound described later. There may be.

A “skeleton-forming aromatic compound” is constrained in a three-dimensional network structure by bonds or interactions other than coordinate bonds, and constitutes part of the skeleton of a host molecule (compound that can incorporate a guest compound). An aromatic compound that When the polymer metal complex contains the skeleton-forming aromatic compound, the three-dimensional network structure tends to become stronger, and the three-dimensional network can be formed even after inclusion of the molecules of the organic compound that determine the molecular structure. The structure may become more stable.

Skeleton-forming aromatic compounds include condensed polycyclic aromatic compounds. Examples thereof include those represented by the following formulas (5a) to (5i).

[Three-dimensional network structure of polymer metal complex]
The three-dimensional network structure of the polymer metal complex is formed by coordinating the multidentate ligands to the metal ions, and has voids that are three-dimensionally and regularly arranged therein.

Here, "voids that are three-dimensionally regularly aligned" refer to voids that are regularly aligned without disorder to the extent that the voids can be confirmed by single crystal X-ray structural analysis. Voids include pores and hollows defined below.
The "pores" refer to the spaces A and B formed between the three-dimensional network structures as shown in FIGS. It means a space formed between three-dimensional network structures of a polymer metal complex, such as a space formed between repeating units. The term “hollow” refers to the internal space of the spherical complex structure in the repeating unit of the spherical complex structure shown in FIG. 4(a) (the part surrounded by lines, see FIG. 4(b)).
In this specification, "pores in the three-dimensional network structure", "pores in the polymer-metal complex", and "pores in the single crystal" all have the same meaning.

The three-dimensional network structure is not particularly limited as long as it has the above structural characteristics and the voids are of a size capable of enclosing the molecules of the organic compound that determine the molecular structure.
In general, when a multidentate ligand with a long distance from the center of the ligand to the coordinating site is used, a polymer metal complex with relatively large voids can be obtained. The use of polydentate ligands with short distances to coordinating sites yields polymer metal complexes with relatively small voids.

The size of the pore is the inscribed circle of the pore (hereinafter simply It is sometimes called "the inscribed circle of the pore").

The "direction in which the pores extend" can be determined by the following method.
That is, first, an appropriately oriented crystal plane X (A plane, B plane, C plane, or a diagonal of each, etc.) is selected across the pore of interest. Then, by representing atoms existing on the crystal plane X and constituting the host molecule using van der Waals radii, a cross-sectional view of the pore with the crystal plane X as the cross section is drawn. Similarly, a cross-sectional view of a pore is drawn with a crystal plane Y, which is shifted by one unit cell from the crystal plane X, as a cutting plane. Next, the centers of the cross-sectional shapes of the pores on the respective crystal planes are connected by straight lines (one-dot chain lines) in a three-dimensional view (see FIG. 1). The direction of the straight line obtained at this time is the direction in which the pores extend.

Also, the "diameter of the inscribed circle of the pore" can be obtained by the following method.
That is, first, a cross-sectional view of the pore with the parallel plane as the cross-section is drawn by the same method as described above. Next, draw an inscribed circle of the pore in the cross-sectional view, measure the diameter, and then convert the obtained measured value to an actual scale to obtain the actual diameter of the inscribed circle of the pore. be able to.
Furthermore, the diameter of the inscribed circle of the narrowest part and the widest part are measured by measuring the diameter of the inscribed circle of the pore in each parallel plane while gradually moving the parallel plane by one unit cell. The diameter of the inscribed circle of the part is determined.

The diameter of the inscribed circle of the pores of the polymer metal complex is preferably 2 to 30 Å, more preferably 3 to 10 Å.

In addition, when the shape of the pore is greatly different from a perfect circle, it is preferable to predict the guest molecule inclusion ability of the polymer metal complex from the minor axis and the major axis of the inscribed ellipse of the pore in the parallel plane.
The length of the inscribed ellipse of the pore of the polymer metal complex is preferably 2 to 30 Å, more preferably 3 to 10 Å. The minor axis of the inscribed ellipse of the pores of the polymer metal complex is preferably 2 to 30 Å, more preferably 3 to 10 Å.

The pore volume of polymeric metal complexes is determined in the article Acta Crystallogr. A46, 194-201 (1990). That is, it can be calculated using "single crystal volume×void ratio in unit cell" based on Solvent Accessible Void (void volume in unit cell) calculated by a calculation program (PLATON SQUEEZE PROGRAM).
The pore volume of the polymer metal complex (the volume of all pores in one single crystal) is preferably 1×10 ⁻⁷ to 0.1 mm ³ , more preferably 1×10 ⁻⁵ to 1×10 ⁻³ mm. ³ is more preferred.

Moreover, as described above, when the polymer metal complex is composed of repeating units of spherical complex structures, each spherical complex structure has an internal space (hollow). Hollow size, as well as pore volume, is also determined in the article Acta Crystallogr. A46, 194-201 (1990).

The polymer metal complex preferably does not lose its crystallinity even after the guest compound is incorporated into the pores and has relatively large pores.

These polymer metal complexes contain the organic solvent (hereinafter, sometimes referred to as "crystallization solvent") used during the synthesis of the polymer metal complex in the voids thereof.
If the crystallization solvent is the guest compound (A), the obtained polymer metal complex corresponds to a guest compound-encapsulating polymer metal complex.
When the crystallization solvent is not the guest compound (A), it can be suitably used for preparing a sample for crystal structure analysis by substituting the guest compound (A) for the crystallization solvent as a guest, as described later. It can be a guest compound-encapsulating polymer metal complex.

A polymer metal complex is generally prepared by combining a first solvent solution of a ligand having two or more coordinating sites and a second solvent solution containing a metal salt with the ligand and a metal ion. can be obtained by mixing so as to have a predetermined ratio. For example, as a ligand, a tridentate ligand represented by the formula (1) is used, and as a metal salt, zinc (II) salts such as zinc iodide and zinc bromide; cobalt thiocyanate and the like ( II) salts and the like can be used. The details of the method for synthesizing the polymer metal complex will be described later.

As a specific example of the polymer metal complex, TPT (2,4,6-tris(4-pyridyl)-1,3,5-triazine) represented by the formula (4a) is used as the tridentate ligand. Polymer metal complexes represented by the following formulas (6a) to (6d) obtained by These polymeric metal complexes are particularly suitable as polymeric metal complexes.

In the above formulas (6a) to (6d), "solv" represents the crystallization solvent contained in the voids, "SA" represents the skeleton-forming aromatic compound, and a and b represent any natural number. show.
These polymer metal complexes will be described in detail below. In the following explanation, ligands and solvent molecules may be omitted as follows.

PhNO ₂ : nitrobenzene TPH: triphenylene PER: perylene MeOH: methanol DCB: 1,2-dichlorobenzene

(1) [(ZnI2) ₃ (TPT) ₂ (solv) _a ] _{b (} 6a)
As the polymer metal complex represented by the formula (6a), JP-A-2008-214584, J. Am. Am. Chem. Soc. 2004, v. 126, pp. 16292-16293, [(ZnI ₂ ) ₃ (TPT) ₂ (PhNO ₂ ) _5.5 ] _n (polymer metal complex 1).

The three-dimensional network structure of polymer metal complex 1 is shown in FIGS. 2(a) to 2(d).
The three-dimensional network structure of polymer-metal complex 1 is composed of two three-dimensional network structures 5 and 6 . In the three-dimensional network structures 5, 6, each zinc(II) ion is coordinated by two TPT pyridyl groups and two iodide ions in a tetracoordinated tetrahedral fashion. Then, by TPT, these structures containing zinc (II) ions are three-dimensionally connected to form respective three-dimensional network structures [Fig. 2(a)].

The three-dimensional network structures 5 and 6 each have a closed cyclic chain structure composed of 10 TPT molecules and 10 Zn atoms as the shortest closed cyclic chain structure [FIG. 2(b)].
These three-dimensional network structures 5 and 6 can be regarded as spiral hexagonal three-dimensional network structures with a pitch of 15 Å along the (010) axis [Fig. 2(c)].

The three-dimensional network structures 5, 6 do not share the same zinc(II) ions and are independent of each other. A composite three-dimensional network structure is constructed by interpenetrating each other in a nested manner so as to share the same space.
The polymer-metal complex 1 having this composite three-dimensional network structure has one type of regularly aligned pores [Fig. 2(d)].

The porosity of the polymer metal complex 1 is 50%.
The diameter of the inscribed circle of the pores of the polymer metal complex 1 is 5 to 8 Å.

(2) [( _ZnBr2 ) ₃ (TPT) ₂ (solv) _a ] _b (6b)
Examples of the polymer metal complex represented by formula (6b) include [(ZnBr ₂ ) ₃ (TPT) ₂ (PhNO ₂ ) ₅ (H ₂ O)] _n (polymer metal Complex 2) can be mentioned.

Polymer metal complex 2 has a structure similar to the three-dimensional network structure of polymer metal complex 1, except that (ZnI ₂ ) is replaced with (ZnBr ₂ ).
The shape, size and porosity of the pores of polymer metal complex 2 are almost the same as those of polymer metal complex 1 .

(3) [(ZnI2) ₃ (TPT) _{2 (} SA)(solv) _a )] _b (6c)
Examples of the polymer metal complex represented by formula (6c) include [(ZnI ₂ ) ₃ (TPT) ₂ (TPH)(PhNO ₂ ) _3.9 (MeOH) _1.8 ] _n (high molecular metal complex 3) and [(ZnI ₂ ) ₃ (TPT) ₂ (PER)(PhNO ₂ ) ₄ ] _n (polymer metal complex 4).

The three-dimensional network structure of polymer metal complex 3 is shown in FIGS. 3(a) to 3(c).
The three-dimensional network structure of the polymer metal complex 3 is composed of two three-dimensional network structures 7 and 8. In the three-dimensional network structures 7, 8, each zinc(II) ion is coordinated in a tetracoordinated tetrahedral fashion by two iodide ions and two pyridyl groups of TPT. Then, by TPT, the structures containing these zinc (II) ions are three-dimensionally connected to each other, thereby forming respective three-dimensional network structures.
The three-dimensional network structures 7, 8 do not share the same zinc(II) ions and are independent of each other. A composite three-dimensional network structure is constructed by interpenetrating each other in a nested manner so as to share the same space.

In the polymer metal complex 3, the triphenylene molecule (11) is composed of the π plane of tris(4-pyridyl)triazine [TPT(9)] of the three-dimensional network structure 7 and the tris(4-pyridyl ) is firmly intercalated between the π-planes of the triazine [TPT(10)] [Fig. 3(b)]. At this time, the triphenylene molecule is stabilized by the π-π interaction between TPT(9) and TPT(10) and functions as part of the main skeleton of the polymer metal complex 3. In addition, FIG.3(b) is a figure when the part enclosed with the line in Fig.3 (a) is seen from the side.

The polymer metal complex 3 has two kinds of pores (pores A and B) arranged regularly in its three-dimensional network structure [Fig. 3(c)]. The pores A and B are regularly formed between stacked structures in which TPT and TPH are alternately stacked.
The pore A is approximately cylindrical and is substantially surrounded by hydrogen atoms present on the side edges of the π-planes of the numerous stacked TPTs and TPHs.
On the other hand, the pore B has a substantially triangular prism shape, and of the three faces forming the triangular prism, two are surrounded by the π plane of TPT, and the other is a stack of countless TPT and TPH. It is surrounded by hydrogen atoms that lie on the side edges of the pi-plane.
These pores A and B have a slightly meandering elongated shape.

The porosity of the pores of the polymer metal complex 3 is 28%.
The diameter of the inscribed circle of the pore A of the polymer metal complex 3 is 5 to 8 Å.
The diameter of the inscribed circle of the pore B of the polymer metal complex 3 is 5 to 8 Å.

Polymer metal complex 4 has the same skeletal structure as polymer metal complex 3 except that perylene molecules are inserted between two TPTs instead of the triphenylene molecules of polymer metal complex 3 .
The shape, size and porosity of the pores of the polymer metal complex 4 are almost the same as those of the polymer metal complex 3 .

(4) [(Co(NCS) ₂ ) ₃ (TPT) ₄ (solv) _a ] _b (6d)
Examples of the polymer metal complex represented by formula (6d) include [(Co(NCS) ₂ ) ₃ (TPT) ₄ (DCB) ₂₅ (MeOH) ₅ ] _n (polymer metal complex 5).

The three-dimensional network structure of the polymer metal complex 5 is shown in FIG. 4(a).
The polymer metal complex 5 has a [Co ₆ (TPT) ₄ ] structure composed of 6 cobalt ions and 4 TPTs as structural units. This structural unit has an octahedral three-dimensional shape, and cobalt ions are arranged at the six vertices of the octahedron [FIG. 4(b)]. Each cobalt(II) ion is coordinated in a hexacoordinated octahedral fashion by four TPT pyridyl groups and two thiocyanate ions. In addition, FIG.4(b) is the figure which expanded the part enclosed with the line in Fig.4 (a).
Then, the [Co ₆ (TPT) ₄ ] structure is three-dimensionally linked while sharing the cobalt ions located at the respective vertices of the [Co ₆ (TPT) ₄ ] structure, thereby forming the [Co ₆ (TPT) ₄ ] Pores are formed between the structures [Fig. 4(c)].
Moreover, the structural unit has a hollow inside.
The porosity of the polymer metal complex 5 is 78%. This value is a value calculated by combining the volume of pores and hollows.
The diameter of the inscribed circle of the pores of the polymer metal complex 5 is 10 to 18 Å.

As the guest compound-encapsulating polymer metal complex crystal, the guest compound (A) encapsulated in the pores does not hinder the uptake of the organic compound that is desired to be finally incorporated into the pores, and the guest compound (A) encapsulated in the pores undergoes guest exchange with the organic compound to form an organic compound. It is preferable to form an encapsulated polymer metal complex crystal.

From this point of view, the guest compound (A) is at least one selected from the group consisting of aliphatic hydrocarbons, alicyclic hydrocarbons, ethers, esters, aromatic hydrocarbons, halogenated hydrocarbons, and nitriles. is preferred.

The aliphatic hydrocarbon as the guest compound (A) is not particularly limited as long as it can enter the voids. Examples include methane, ethane, propane, butane, pentane, hexane, heptane, octane, decane, tetradecane, Chain or branched saturated aliphatic hydrocarbons having 1 to 20 carbon atoms such as octadecane; chain or branched carbon atoms having 1 or 2 or more double bonds or triple bonds in the molecule 2 to 20 unsaturated aliphatic hydrocarbons;

The alicyclic hydrocarbon is not particularly limited as long as it can enter the voids. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclododecane, Saturated alicyclic hydrocarbons having 3 to 20 carbon atoms such as cycloundecane and decalin; unsaturated alicyclic hydrocarbons having 3 to 20 carbon atoms and having one or more double bonds or triple bonds in their molecules. hydrogen; and the like.

Ethers are not particularly limited as long as they can enter the voids. dimethoxyethane, 1,4-dioxane and the like.

Esters are not particularly limited as long as they can enter the voids. Examples include ethyl formate, methyl acetate, ethyl acetate, propyl acetate, pentyl acetate, octyl acetate, ethyl lactate, ethyl propionate, methyl butanoate, Examples include ethyl butanoate, pentyl butanoate, pentyl valerate and the like.

The aromatic hydrocarbon is not particularly limited as long as it can enter the voids, and examples thereof include benzene, toluene, xylene, mesitylene, naphthalene, anthracene, and phenanthrene.

The halogenated hydrocarbon is not particularly limited as long as it can enter the voids. For example, the compounds exemplified as the aliphatic hydrocarbons, alicyclic hydrocarbons, and aromatic hydrocarbons, Compounds in which one or more of the carbon atoms are substituted with halogen atoms such as fluorine, chlorine, bromine and iodine atoms can be exemplified. Specific examples include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, trifluoromethane, chlorobenzene, bromobenzene, 1,2-dichlorobenzene and the like.

Nitriles are not particularly limited as long as they can enter the voids, and include acetonitrile, benzonitrile and the like.
These can be used singly or in combination of two or more.

Among these, alicyclic hydrocarbons with 3 to 20 carbon atoms and carbonized aromatic hydrocarbons with 6 to 10 carbon atoms are preferred from the viewpoint of easy guest exchange with organic compounds and easy preparation of high-quality crystal structure analysis samples. Hydrogen is preferred, alicyclic hydrocarbons having 5 to 10 carbon atoms and aromatic hydrocarbons having 6 to 10 carbon atoms are more preferred, cyclohexane and toluene are further preferred, and cyclohexane is particularly preferred.

The amount of the guest compound (A) present in the polymer metal complex is 60 mol% or more, preferably 75 mol% or more, more preferably 90 mol% of all the guest compounds contained in the voids. That's it.
It is preferable that the guest compound (A) exists in an amount of 60 mol % or more with respect to all the guest compounds contained in the voids, since the target sample for crystal structure analysis can be easily prepared.

In the guest compound-encapsulating polymer metal complex crystal, the occupancy rate of all the guest compounds included in the voids of the polymer metal complex is preferably 10% or more, more preferably 30% or more. is more preferable, and 50% or more is even more preferable.
When the occupancy is 10% or more, it becomes easy to determine the structure of the guest compound in X-ray single crystal structure analysis, and the structural data obtained from this also has high chemical reliability.

The occupancy is a value obtained by single crystal structure analysis, and represents the amount of the guest compound actually present in the single crystal when the amount of the guest compound in the ideal clathrate state is taken as 100%. be.

B) Method for Producing Guest Compound-encapsulating Polymer Metal Complex Crystal A method for producing a guest compound-encapsulating polymer metal complex crystal comprises a polymer containing a ligand having two or more coordinating sites and a metal ion as a central metal. In the voids of the polymer metal complex, which is a metal complex and has a three-dimensional network structure formed by the coordination of the ligand to the metal ion, and voids within the three-dimensional network structure , a crystallization solvent-encapsulating polymer metal complex crystal encapsulating a crystallization solvent (excluding the guest compound (A); the same shall apply hereinafter) is added to the liquid guest compound (A) or the guest compound (A ) is immersed in an inert solvent solution containing.

That is, the above production method comprises (i) synthesizing a polymer metal complex crystal in a crystallization solvent to obtain a polymer metal complex crystal containing a crystallization solvent, and then (ii) obtaining a crystallization solvent containing polymer. A step of immersing the metal complex crystal in a liquid guest compound (A) or an inert solvent solution containing the guest compound (A) to replace the crystallization solvent in the voids with the guest compound (A). have.

(i) Synthesis of polymer metal complex crystal containing crystallization solvent The polymer metal complex containing crystallization solvent can be synthesized by a known method of reacting a polydentate ligand, a metal ion-containing compound, and the like. For example, a method of adding a solvent solution of a metal ion-containing compound in a second solvent to a solvent solution of a polydentate ligand in a first solvent and allowing the mixture to stand at 0 to 70° C. for several hours to several days. is mentioned.

A metal ion-containing compound is not particularly limited. Examples include compounds represented by the formula: _MXn . Here, M represents a metal ion, X represents a counterion, and n represents the valence of M.

Specific examples of X include F ⁻ , Cl ⁻ , Br ⁻ , I ⁻ , SCN ⁻ , NO ₃ ⁻ , ClO ₄ ⁻ , BF ₄ ⁻ , SbF ₄ ⁻ , PF ₆ ⁻ , AsF ₆ ⁻ , CH ₃ CO ₂ ^{- and} so on.

As the first and second solvents, those capable of dissolving the polydentate ligand and the like are preferable.
Specific examples include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene and nitrobenzene; aliphatic hydrocarbons such as n-pentane, n-hexane and n-heptane; cyclopentane , cyclohexane, alicyclic hydrocarbons such as cycloheptane; nitriles such as acetonitrile and benzonitrile; sulfoxides such as dimethylsulfoxide (DMSO); amides such as N,N-dimethylformamide and n-methylpyrrolidone; diethyl ethers such as ether, tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane; alcohols such as methanol, ethanol and isopropyl alcohol; ketones such as acetone, methyl ethyl ketone and cyclohexanone; cellosolves such as ethyl cellosolve; , chloroform, carbon tetrachloride, 1,2-dichloroethane and other halogenated hydrocarbons; methyl acetate, ethyl acetate, ethyl lactate, ethyl propionate and other esters; water; These solvents can be used singly or in combination of two or more.

When it is desired to obtain a relatively large single crystal of a polymer metal complex, it is possible to use solvents that are not compatible with each other (that is, separate into two layers) as the first solvent and the second solvent. preferable. Specifically, nitrobenzene, dichlorobenzene, nitrobenzene, or a mixed solvent of these and methanol is preferably used as the first solvent, and alcohols such as methanol, ethanol, and isopropyl alcohol are preferably used as the second solvent.
As described above, each of the polymer metal complexes 1 to 5 can be synthesized according to the method described in the above literature.

(ii) Substitution with Guest Compound The obtained polymer-metal complex has a three-dimensional network structure, and voids are regularly arranged three-dimensionally within the three-dimensional network structure. Contains a solvent.
This crystallization solvent-encapsulating polymer metal complex crystal is immersed in a liquid guest compound (A) or an inert solvent solution containing the guest compound (A) and allowed to stand, and the crystallization solvent in the voids is removed. , the desired guest compound-encapsulating polymer metal complex crystal can be obtained by substituting with the guest compound (A).

As the guest compound (A), those similar to those described above can be mentioned.
The inert solvent to be used is compatible with the guest compound (A) and inactive with respect to the polymer metal complex, that is, it is less likely to be substituted into the voids of the polymer metal complex than the guest compound (A). There are no particular restrictions. Examples of inert solvents include alcohols such as methanol, ethanol, and isopropyl alcohol.
If the guest compound (A) is liquid, it can be used as it is.

The amount of the liquid guest compound (A) to be used or the inert solvent solution containing the guest compound (A) (hereinafter sometimes abbreviated as "solution of guest compound (A)") is determined by the polymer It is usually 1-100 ml, preferably 5-30 ml, per 100 mg of the metal complex crystal.

The immersion temperature is not particularly limited, but is usually 0 to 70°C, preferably 10 to 70°C, more preferably 20 to 60°C.
The immersion time is the time until the guest compound (A) occupies 60% or more of the voids, and is usually 6 hours or more, preferably 12 hours to 10 days, more preferably 1 to 8 days. .
During this period, in order to promote replacement, the supernatant liquid of the immersion liquid (guest compound (A) solution) is removed by a decanting method every other day, and a new immersion liquid is added for the amount removed. is preferred.

Substitution inclusion of the guest compound (A) in the voids can be confirmed by elemental analysis, X-ray crystal structure analysis, or the like.

In the guest compound-encapsulating polymer metal complex crystal obtained as described above, the guest compound (A) in the voids easily replaces a small amount of the organic compound sample with the guest. It is useful as a production material.
The guest compound-encapsulating polymer metal complex crystal obtained as described above enables efficient incorporation without inhibiting guest exchange when other various guest compounds are clathrated. The sample in guest exchange does not have to be a crystalline solid, and any liquid, gas, amorphous solid, or the like can be applied. The weight of the guest compound required for clathration may be 5 µg or less, and even an amount of several tens of ng can provide sufficiently good single crystal X-ray structure analysis data. Single-crystal X-ray structure analysis by the crystal sponge method can accurately determine the three-dimensional structure including the absolute configuration of molecules. In addition, even for unstable compounds that are prone to thermal decomposition or solvolysis, stereostructures (absolute structures) can be obtained without heating or dissolving them in various solvents or buffer solutions. rice field.

The guest compound polymer metal complex crystal is preferably a single crystal having a cubic or rectangular parallelepiped shape with one side of 10 to 1000 μm, preferably 60 to 200 μm. By using a single crystal of a polymer-metal complex having such a shape, it becomes easier to obtain a high-quality sample for crystal structure analysis.

A single crystal of the guest compound-encapsulating polymer-metal complex is exposed to MoKα rays (wavelength: 0.71 Å) generated at a tube voltage of 24 kV and a tube current of 50 mA, Cu rays, synchrotron radiation (e.g., wavelength of 0.75 Å), etc. Preferably, the molecular structure can be determined with a resolution of at least 1.5 Å when irradiated and diffracted X-rays are detected by a semiconductor detector, CCD detector, imaging plate detector, or the like. A high-quality sample for crystal structure analysis can be obtained from a single crystal of the guest compound-encapsulating polymer metal complex having such properties.

C) Method for producing a sample for crystal structure analysis The method for producing a sample for crystal structure analysis is a crystal in which organic compound molecules for determining the molecular structure are arranged with regularity in the pores of the polymer metal complex crystal. A method for preparing a sample for structural analysis, characterized by comprising a step of immersing a guest compound-encapsulating polymer metal complex crystal in a solvent solution containing the organic compound.

[Organic compound that determines molecular structure]
The organic compound that determines the molecular structure in the crystal sponge method (hereinafter sometimes referred to as "organic compound (α)") is not particularly limited as long as it has a size that allows it to enter the pores of the polymer metal complex. . In the present invention, the organic compound that determines the molecular structure is a hydrophilic compound having a polar group.
When the organic compound (α) is a low molecular compound, its molecular weight is usually 20-3000, preferably 50-1000, more preferably 100-500.
When the organic compound (α) is a chain polymer compound having repeating units such as polyethylene, its molecular weight is usually 10 ³ to 10 ⁶ , preferably 10 ⁴ to 10 ⁵ . Furthermore, the organic compound (α) may be solid or liquid at around room temperature (25° C.±5° C.).

The size of the organic compound (α) is previously determined to some extent by nuclear magnetic resonance spectroscopy, mass spectrometry, elemental analysis, etc., and the guest compound-encapsulating polymer metal complex crystal to be used is appropriately selected according to the size. is preferred.

If the organic compound (α) is an impurity contained in a synthetic compound (compounds derived from natural products, agricultural drugs, synthetic polymers, etc.), the purity of the organic compound (α) is increased by a known purification method such as liquid chromatography. After that, it is preferable to prepare a sample for crystal structure analysis. When liquid chromatography is used, the eluent containing the target substance can be used as it is as the "solvent solution of the organic compound" described later.

The method of preparing a sample for crystal structure analysis does not require a large amount of organic compounds (α), and organic compounds (α) are originally only trace amounts such as compounds derived from natural products and impurities in agrochemicals. It is a useful method when it is not available. Moreover, the organic compound (α) may be solid or liquid at room temperature (20° C.).

The content of the organic compound (α) in the solvent solution is not particularly limited, but may be 100 μg or less. The lower limit of the content of the organic compound (α) is usually 0.5 µg or more.

A method for preparing a sample for crystal structure analysis is to add a solvent solution containing 100 μg or less of an organic compound (α) to an A value calculated from the following formula (2) of 100 or less, preferably 0.1 to 30, more preferably It is preferable to have a step of immersing the single crystal of the guest compound-encapsulating polymer metal complex in an amount of 1 to 5.

In the formula, b represents the amount of the organic compound in the solvent solution, and a represents the amount of the substance with a specific gravity of 1 required when it is assumed that all the voids in the polymer metal complex crystal are filled with the substance with a specific gravity of 1. represents

When the A value is 0.1 to 30, the organic compound (α) is sufficiently incorporated into the pores of the single crystal of the polymer-metal complex, making it easy to obtain a good quality sample for crystal structure analysis. On the other hand, even if the A value is large, the desired sample for crystal structure analysis can be obtained, but the corresponding effect cannot be obtained, and the organic compound (α) tends to be wasted. In other words, this method is a useful method for preparing a sample for crystal structure analysis for determining the structure of organic compounds that are originally only available in trace amounts, such as compounds derived from natural products and impurities in agricultural drugs. .

Note that it is not necessary that the organic compound (α) is incorporated into all the pores of the polymer metal complex, and even if the A value is less than 1, a good quality sample for crystal structure analysis is required. can be made.

In addition, the concentration of the organic compound (α) in the solvent solution is not particularly limited, but from the viewpoint of efficiently preparing a good quality sample for crystal structure analysis, it is usually 0.001 to 50 µg/µL, preferably 0.01. ~5 μg/μL, more preferably 0.1-1 μg/μL.

The solvent used for preparing the solvent solution does not dissolve the crystals of the polymer metal complex, but dissolves the organic compound (α). There are no particular limitations as long as the solvent solution of compound (α) can be concentrated.
From this point of view, the solvent to be used preferably has a boiling point of 0 to 250°C, more preferably 0 to 185°C, and even more preferably 30 to 150°C at normal pressure (1 x 10 ⁵ Pa). preferable.

Specific examples of solvents to be used include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and 1,2-dichlorobenzene; aliphatic hydrocarbons such as n-pentane, n-hexane and n-heptane; alicyclic hydrocarbons such as pentane, cyclohexane, cycloheptane; nitriles such as acetonitrile and benzonitrile; sulfoxides such as dimethylsulfoxide; amides such as N,N-dimethylformamide and N-methylpyrrolidone; Ethers such as tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane; Alcohols such as methanol, ethanol and isopropyl alcohol; Ketones such as acetone, methyl ethyl ketone and cyclohexanone; Cellosolves such as ethyl cellosolve; , carbon tetrachloride, 1,2-dichloroethane and other halogenated hydrocarbons; methyl acetate, ethyl acetate, ethyl lactate, ethyl propionate and other esters; water; These solvents can be used singly or in combination of two or more.
Among these, the guest compound (A) used above is preferably used from the viewpoint of obtaining a high-quality sample for crystal structure analysis.

In the above method, the guest compound-encapsulating polymer metal complex crystal is immersed in a solvent solution containing the organic compound (α).

The number of single crystals of the guest compound-encapsulating polymer metal complex to be immersed is not particularly limited as long as the above requirements for the A value are satisfied. When the amount of the organic compound (α) is extremely small, a desired sample for crystal structure analysis can be obtained by immersing one single crystal. When the amount of the organic compound (α) is sufficient, two or more single crystals of the same type of guest compound-encapsulating polymer metal complex are immersed, or different single crystals of guest compound-encapsulating polymer metal complexes are immersed at the same time. You may make it immerse.

The solvent solution can be concentrated by evaporating the solvent under mild conditions after the single crystal of the guest compound-encapsulating polymer metal complex is immersed. By performing this treatment, it is possible to efficiently incorporate a small amount of the organic compound (α) into the voids in the single crystal.

The immersion conditions (concentration conditions) at this time are not particularly limited, but the temperature of the solvent is preferably 0 to 180°C, more preferably 0 to 80°C, and still more preferably 20 to 60°C.
The immersion time (concentration time) is usually 6 hours or more, preferably 12 to 168 hours, more preferably 24 to 78 hours.

The volatilization rate of the solvent is preferably 0.1 to 1000 μL/24 hours, more preferably 1 to 100 μL/24 hours, still more preferably 5 to 50 μL/24 hours.
If the volatilization rate of the solvent is too fast, a good quality sample for crystal structure analysis may not be obtained. On the other hand, if the volatilization rate of the solvent is too slow, it is not preferable from the viewpoint of work efficiency.

The temperature at which the solvent is volatilized is usually 0 to 180°C, preferably 0 to 120°C, more preferably 15 to 60°C, although it depends on the boiling point of the organic solvent used.

Further, the operation of immersing the single crystal of the guest compound-encapsulating polymer metal complex in the solvent solution of the organic compound (α), evaporating the solvent, and concentrating the solvent solution may be performed under normal pressure or under reduced pressure. or under pressure.
The pressure during the operation of evaporating the solvent and concentrating the solvent solution is usually 1 to 1×10 ⁶ Pa, preferably 1×10 to 1×10 ⁶ Pa.
As described above, the volatilization rate of the solvent can be appropriately adjusted by adjusting the temperature and pressure during the operation of concentrating the solvent solution.

Further, the above method comprises a step (I) of separating a mixture containing the organic compound (α) by liquid chromatography to obtain a solvent solution of the organic compound (α); is immersed in a solvent solution containing an organic compound that determines the molecular structure obtained in step (I), and then the solvent is volatilized under mild conditions to concentrate the solvent solution (II). can be anything.

That is, a mixture containing the organic compound (α) is separated using a liquid chromatography device to obtain a solvent solution of the organic compound (α) (a solution in which the organic compound other than the solvent is the organic compound (α)). Then, a single crystal of the guest compound-encapsulating polymer metal complex is immersed in this fraction A, the solvent is volatilized under mild conditions, and the solvent solution is concentrated to obtain a sample for crystal structure analysis can be obtained.
In this case, after replacing the solvent of the solvent solution with another solvent, the polymer complex crystals may be immersed in the obtained solution.

In this method, a mixture of multiple compounds with similar structures is separated by liquid chromatography, and a polymer complex crystal is immersed in each solvent solution containing the separated compounds to prepare a sample for crystal structure analysis. can do. This method is also useful for separating a mixture of compounds with similar structures, for which it is difficult to determine the structure of a compound only from measurement data such as NMR spectra, and determining the molecular structure.

Moreover, the above method for preparing a sample for crystal structure analysis can also be applied when the organic compound (α) is a liquid substance at around room temperature (around 25° C.). That is, after immersing a single crystal of the guest compound-encapsulating polymer metal complex in a solvent solution of the organic compound (α), which is a liquid, the solvent is evaporated under mild conditions to concentrate the solvent solution. Then, a sample for crystal structure analysis can be produced.

Furthermore, as shown in FIG. 6, an extremely small amount of liquid organic compound (α) was added dropwise to the single crystal of the guest compound-encapsulating polymer metal complex using a dropper or the like, and the mixture was kept at room temperature of 25° C. for several hours. A desired sample for crystal structure analysis can also be produced by leaving it for several days. If the organic compound (α) is a volatile substance at around room temperature (25°C), a sample obtained by dropping the organic compound (α) onto a single crystal of the polymer metal complex containing the guest compound is placed in a sealed vial bottle or the like. It is preferably placed in a container.

The obtained sample for crystal structure analysis, which is a single crystal of the polymer metal complex containing an organic compound, is MoKα ray (wavelength: 0.71 Å) generated at a tube voltage of 24 kV and a tube current of 50 mA, or a tube voltage of 40 kV and a tube current of 40 kV. Preferably, the molecular structure can be determined with a resolution of at least 1.5 Å when irradiated with CuKα rays generated at 30 mA and the diffracted X-rays are detected with a CCD detector.

The sample for crystal structure analysis is composed of regularly arranged molecules of the organic compound (α) substituted with the guest compound (A) in the voids in the single crystal of the polymer metal complex.
Here, "the molecules of the organic compound are arranged with regularity" means that the molecules of the organic compound are not disordered to the extent that the structure can be determined by single-crystal X-ray structure analysis, and the pores of the polymer metal complex It means that it is regularly accommodated within.

If the structure of the organic compound (α) can be determined in the crystal structure analysis sample, the organic compound (α) must be incorporated into all the pores in the single crystal of the polymer metal complex. no. For example, the solvent used for the solvent solution of the organic compound (α) may be incorporated into part of the voids in the single crystal of the polymer metal complex.

It is preferable that the sample for crystal structure analysis has a molecular occupancy of the organic compound of 10% or more. The occupancy rate of the molecule of the organic compound is a value obtained by single crystal structure analysis. It represents the amount of guest molecules actually present in the

A single crystal of a high-quality polymer-metal complex is obtained by selecting a polymer-metal complex crystal that satisfies the above requirements for the A value and has voids that match the molecular size of the organic compound (α) as described above. A sample for crystal structure analysis can be efficiently produced by clathrating the organic compound (α) in the voids of the single crystal.

In order to concentrate the polymer metal complex by evaporating the solvent after immersing the single crystal of the polymer metal complex containing the guest compound in the solvent solution of the organic compound (α), for example, the preparation shown in FIG. Apparatus A or fabrication apparatus B can be used.

5A is a side view of the manufacturing apparatus A, and FIG. 5B is a top view of the manufacturing apparatus A. FIG.
12 is a lid, 13 is an opening through which gas molecules can pass, 14 is a container body, 15 is a solvent solution of an organic compound (α), and 16 is a single crystal of a polymer metal complex.
As the lid (12), anything that can seal the container can be used. For example, a lid made of rubber such as a septum can be used. The opening (13) can be formed, for example, by inserting a gas venting hollow needle into the lid (12). As the container body (14), for example, a glass container such as a test tube or a pressure-resistant glass bottle can be used. The bottom of the container body (14) may be flat, but if it has a sharp tip as shown in FIG. excellent and desirable. When a transparent container body (14) is used, the volatilization state of the solvent and the color change of the crystal (the color of the crystal changes when guest molecules are taken into the voids of the polymer metal complex). ) can be easily observed from the outside.

In the apparatus shown in FIGS. 5(a) and 5(b) , the solvent of the solvent solution (15) of the organic compound (α) gradually volatilizes from the narrow hole of the opening (hollow needle for gas venting) (13), As a result, the solvent is completely removed from the organic compound (α). Next, the lid (sealing stopper) (12) is opened, the sample for crystal structure analysis is taken out from the container body (vial) (14), and crystal structure analysis can be performed using this sample.

5(c) is a side view of the manufacturing apparatus B, and FIG. 5(d) is a top view of the manufacturing apparatus B. FIG.
As shown in FIGS. 5(c) and 5(d), the device B comprises a sealable container having a lid (12), a container body (14), and an opening (13) through which gas molecules can pass; a crystal support (17) fixed to the lid, wherein the tip of the crystal support (17) contains a ligand having two or more coordinating sites and a metal ion as a central metal. A single crystal (16) of a polymer metal complex having a three-dimensional network structure can be fixed, and when the container is closed, the tip of the crystal support (17) faces downward into the container. It is to be accommodated.

In the fabrication apparatus B shown in FIG. 5(c), the single crystal (16) of the polymer metal complex is fixed at the tip of the single crystal support (17) by a cryoloop (not shown).
In apparatus B, after the organic compound (α) is clathrated in the voids of the polymer metal complex to obtain a sample for crystal analysis, the sample is directly placed on a crystal structure analysis apparatus such as an X-ray crystal analysis apparatus, It is preferable that the measurement can be performed.

D) Method for Determining Molecular Structure of Organic Compound In the method for determining the molecular structure of an organic compound, the molecular structure of the organic compound contained within the pores of the sample for crystal structure analysis is determined by analyzing the crystal structure of the sample for crystal structure analysis. is characterized by determining
In the above method, either X-ray diffraction or neutron diffraction can be used.
When determining the molecular structure of an organic compound by the above method, the same method as in the conventional method can be used, except that the sample for crystal structure analysis obtained by the above method is mounted instead of the conventional single crystal.

According to the molecular structure determination method described above, it is possible to efficiently perform crystal structure analysis and determine the molecular structure of even a very small amount of an organic compound.
Moreover, even if the organic compound is liquid at room temperature, the molecular structure can be determined by using a sample for crystal structure analysis that includes the organic compound.
The organic compound used for sample preparation can be introduced into the single crystal of the polymer-metal complex, regardless of whether it is gas, liquid or solid, as long as it can be dissolved in an organic solvent.
The amount of the organic compound required for one single crystal of the polymer metal complex is at most 5 μg, and in the case of a small amount, even 50 ng can provide a single crystal structure.
The crystalline sponge method enables rapid and accurate structure determination of trace impurities in pharmaceuticals, flavoring agents, food additives, trace components in animals and plants, and the like. Moreover, even for unstable compounds that are prone to thermal decomposition or solvolysis, stereostructures (absolute structures) can be obtained without heating or dissolution in various solvents, buffer solutions, or the like.

(equipment)
(1) NMR
¹ H-NMR of the product was measured using AVANCE III 400 manufactured by Brucker.
(2) LC/MS
The m/z of the product was measured using a Waters ACQUITY UPLC system (SQD system).
(3) Single crystal X-ray structure analysis The X-ray crystal structure analysis of Examples 1, 2, 3, 4, 5, 8, 9, 10, and 12 was performed by Rigaku XtaLAB pro P200 MM007 (radiation source: Mo-Kα The line wavelength was 0.71 Å, the output was 50 mA, 24 kV, and the measurement temperature was 93 K).
The X-ray crystal structure analysis of Example 7 was performed using R-AXIS RAPID 191R manufactured by Rigaku Corporation (radiation source: Cu-Kα ray wavelength 1.54 Å, output: 30 mA, 40 kV, measurement temperature 98 K).
The X-ray crystal structure analysis of Examples 6, 11, and 13 was performed at Inter-University Research Institute Corporation High Energy Accelerator Research Organization Synchrotron Radiation Research Facility Beamline 5A (wavelength 0.75 Å, measurement temperature 95 K).

(Reference example 1)
<Synthesis of cyclohexane-encapsulating polymer metal complex crystal>
A cyclohexane-containing polymer metal complex crystal was synthesized in the same manner as in Example 8 of Japanese Patent No. 5,969,616.

(Reference example 2)
<Synthesis of normal heptane-encapsulating polymer metal complex crystals>
A cyclohexane-encapsulating polymer metal complex crystal was synthesized in the same manner as in Example 8 of Japanese Patent No. 5969616, except that the solvent was changed from cyclohexane to normal heptane.

Ｌ－アラニンメチルエステル塩酸塩（１００ｍｇ、０．７１６ｍｍｏｌ）をアセトニトリル（１ｍＬ）に溶解した。この溶液に氷冷下トリエチルアミン（１１０μＬ、０．７８８ ｍｍｏｌ）、イソチオシアンサン酸１－ナフチル（１４６ｍｇ、０．７８８ｍｍｏｌ）を加え１時間撹拌した。この反応液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ－ヘキサン＝１／４～１／１）にて精製することで白色固体として表題化合物を得た。
¹Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）δ ９．７６（ｓ，１Ｈ），８．０６-７．７５（ｍ，４Ｈ），７．６６-７．４４（ｍ，４Ｈ），４．９７（ｐ，Ｊ＝７．３Ｈｚ，１Ｈ），３．６５（ｓ，３Ｈ），１．３６（ｄ，Ｊ＝７．３Ｈｚ，３Ｈ）． (Example 1)
(Step a) Synthesis of methyl (2S)-2-(1-naphthylcarbamothioylamino)propanoate (compound 1) by introducing a 1-naphthylcarbamothioyl group into the amino group of L-alanine methyl ester hydrochloride

L-alanine methyl ester hydrochloride (100 mg, 0.716 mmol) was dissolved in acetonitrile (1 mL). To this solution, under ice-cooling, triethylamine (110 μL, 0.788 mmol) and 1-naphthyl isothiocyanoate (146 mg, 0.788 mmol) were added and stirred for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/4-1/1) to obtain the title compound as a white solid.
¹ H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.06-7.75 (m, 4H), 7.66-7.44 (m, 4H), 4.97 ( p, J=7.3 Hz, 1 H), 3.65 (s, 3 H), 1.36 (d, J=7.3 Hz, 3 H).

(Step b) Synthesis of polymer metal complex crystal encapsulating methyl (2S)-2-(1-naphthylcarbamothioylamino)propanoate (compound 1) Single crystal 1 of cyclohexane-encapsulating polymer metal complex crystal obtained in Reference Example 1 The granules were placed in a septum-capped micro vial bottle with 100 μL of cyclohexane, and 10 μL of a 1 mg/mL dichloromethane solution of compound 1 obtained in step a was added thereto. The cap of this microvial bottle was closed, the septum portion was pierced with an injection needle (21G: inner diameter 0.57 mm), and left at 50°C for 2 days to concentrate the solution in the microvial bottle.

The obtained single crystal was subjected to X-ray crystal structure analysis to confirm the molecules included in the crystal. The crystallographic data are shown in Table 1 and the crystal structure is shown in FIG. FIG. 8 shows interactions assumed from the obtained crystal structure.

Ｌ－アラニンメチルエステル塩酸塩（１００ｍｇ、０．７１６ｍｍｏｌ）をジクロロメタン（２ｍＬ）に溶解した。この溶液に氷冷下トリエチルアミン（２２０μＬ、１．５８ｍｍｏｌ）を加え５分間撹拌した。この溶液に氷冷下ジフェニルアセチルクロリド（１６５ｍｇ、０．７１６ｍｍｏｌ）を加え、９０分間撹拌した。この反応液を水（２ｍＬ）にて希釈し、ジクロロメタン（２ｍＬ）で３回抽出した。抽出液を合わせ濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ－ヘキサン＝１／９～１／１）にて精製することで白色固体として表題化合物（１７８ ｍｇ）を得た。
¹Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ ８．７４（ｄ，Ｊ＝７．１Ｈｚ，１Ｈ），７．３５-７．１８（ｍ，１１Ｈ），５．０１（ｓ，１Ｈ），４．２７（ｐ，Ｊ＝７．２Ｈｚ，１Ｈ），３．６１（ｓ，３Ｈ），１．２８（ｄ，Ｊ＝７．１Ｈｚ，３Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ２９８（Ｍ＋Ｈ）⁺． (Example 2)
(Step a) Introduction of a 1,1-diphenylacetyl group to the amino group of L-alanine methyl ester hydrochloride to produce methyl (2S)-2-[(2,2-diphenylacetyl)amino]propanoate (compound 2) synthesis

L-alanine methyl ester hydrochloride (100 mg, 0.716 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (220 μL, 1.58 mmol) was added to this solution under ice-cooling, and the mixture was stirred for 5 minutes. Diphenylacetyl chloride (165 mg, 0.716 mmol) was added to this solution under ice-cooling, and the mixture was stirred for 90 minutes. The reaction was diluted with water (2 mL) and extracted with dichloromethane (2 mL) three times. The extracts were combined and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/9-1/1) to give the title compound (178 mg) as a white solid.
¹ H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J=7.1 Hz, 1 H), 7.35-7.18 (m, 11 H), 5.01 (s, 1 H), 4. 27 (p, J=7.2 Hz, 1 H), 3.61 (s, 3 H), 1.28 (d, J=7.1 Hz, 3 H); MS (ESI) m/z 298 (M+H) ⁺ .

(Step b) Synthesis of polymer metal complex crystal encapsulating methyl (2S)-2-[(2,2-diphenylacetyl)amino]propanoate (compound 2) One crystal was placed in a micro vial bottle with a septum cap along with 100 μL of cyclohexane, and 5 μL of a 0.20 mg/mL dichloromethane solution of compound 2 obtained in step a was added thereto. The cap of this microvial bottle was closed, the septum portion was pierced with an injection needle (21G: inner diameter 0.57 mm), and left at 50°C for 2 days to concentrate the solution in the microvial bottle.

The obtained single crystal was subjected to X-ray crystal structure analysis to confirm the molecules included in the crystal. The crystallographic data are shown in Table 2 and the crystal structure is shown in FIG. FIG. 10 shows interactions assumed from the obtained crystal structure.

Ｌ－フェニルアラニンメチルエステル塩酸塩（１０３ｍｇ、０．４７８ｍｍｏｌ）をジクロロメタン（２ｍＬ）に溶解した。この溶液に氷冷下トリエチルアミン（１４７μＬ、 １．０５ｍｍｏｌ）、ジフェニルアセチルクロリド（１１０ｍｇ、０．４７８ｍｍｏｌ）を加え、一晩撹拌した。この反応液を水（２ｍＬ）にて希釈し、ジクロロメタン（３ｍＬ）で３回抽出した。抽出液を合わせ濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ－ヘキサン＝５～３５％）にて精製することで白色固体として表題化合物（１６６ｍｇ）を得た。
¹Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ ８．７３（ｄ，Ｊ＝７．７Ｈｚ，１Ｈ），７．３５-７．２１（ｍ，６Ｈ），７．２６-７．１４（ｍ，６Ｈ），７．１７-７．０９（ｍ，２Ｈ），７．１０-７．０３（ｍ，２Ｈ），４．９９（ｓ，１Ｈ），４．５２（ｔｄ，Ｊ＝９．４，７．７，５．４Ｈｚ，１Ｈ），３．５９（ｓ，３Ｈ），３．０４（ｄｄ，Ｊ＝１３．８，５．４Ｈｚ，１Ｈ），２．９１（ｄｄ，Ｊ＝１３．８，９．４Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ３７４（Ｍ＋Ｈ）⁺． (Example 3)
(Step a) Methyl (2S)-2-[(2,2-diphenylacetyl)amino]-3-phenyl-propanoate by introduction of a 1,1-diphenylacetyl group to the amino group of L-phenylalanine methyl ester hydrochloride Synthesis of (compound 3)

L-Phenylalanine methyl ester hydrochloride (103 mg, 0.478 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (147 μL, 1.05 mmol) and diphenylacetyl chloride (110 mg, 0.478 mmol) were added to this solution under ice-cooling, and the mixture was stirred overnight. The reaction was diluted with water (2 mL) and extracted three times with dichloromethane (3 mL). The extracts were combined and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=5-35%) to give the title compound (166 mg) as a white solid.
¹ H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J=7.7 Hz, 1 H), 7.35-7.21 (m, 6 H), 7.26-7.14 (m, 6 H ), 7.17-7.09 (m, 2H), 7.10-7.03 (m, 2H), 4.99 (s, 1H), 4.52 (td, J = 9.4, 7 .7, 5.4 Hz, 1H), 3.59 (s, 3H), 3.04 (dd, J = 13.8, 5.4 Hz, 1H), 2.91 (dd, J = 13.8, 9.4 Hz, 1 H); MS (ESI) m/z 374 (M+H) ⁺ .

(Step b) Synthesis of polymer metal complex crystals encapsulating methyl (2S)-2-[(2,2-diphenylacetyl)amino]-3-phenyl-propanoate (compound 3) Cyclohexane-encapsulating polymer obtained in Reference Example 1 One metal complex crystal single crystal was placed in a micro vial bottle with a septum cap along with 45 μL of cyclohexane, and 5 μL of a 1 mg/mL 1,2-dichloroethane solution of compound 3 obtained in step a was added thereto. After closing the cap of the microvial bottle and leaving it overnight at 50°C, the septum portion was pierced with an injection needle (21G: inner diameter 0.57 mm) and left at 26°C for one day to concentrate the solution in the microvial bottle. .

The obtained single crystal was subjected to X-ray crystal structure analysis to confirm the molecules included in the crystal. The crystallographic data are shown in Table 3 and the crystal structure is shown in FIG.

Ｌ－バリンメチルエステル塩酸塩（１００ｍｇ、０．５９７ｍｍｏｌ）をジクロロメタン（３ ｍＬ）に溶解した。この溶液に室温にてトリエチルアミン（１８３μＬ、１．３１ｍｍｏｌ）、ジフェニルアセチルクロリド（１３８ｍｇ、０．５９７ｍｍｏｌ）を加え、１時間撹拌した。この反応液を水（３ｍＬ）にて希釈し、ジクロロメタン（２ｍＬ）で３回抽出した。抽出液を合わせ濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ－ヘキサン＝１／８～１／６）にて精製することで白色固体として表題化合物（１８８ ｍｇ）を得た。
¹Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ ８．５９（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．３５-７．１７（ｍ，１０Ｈ），５．１８（ｓ，１Ｈ），４．２１（ｄｄ，Ｊ＝８．１，６．３Ｈｚ，１Ｈ），３．６２（ｓ，３Ｈ），２．０３（ｍ，１Ｈ），０．８５（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），０．８２（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ３２６（Ｍ＋Ｈ）⁺． (Example 4)
(Step a) Methyl (2S)-2-[(2,2-diphenylacetyl)amino]-3-methyl-butanoate by introduction of a 1,1-diphenylacetyl group to the amino group of L-valine methyl ester hydrochloride Synthesis of (compound 4)

L-valine methyl ester hydrochloride (100 mg, 0.597 mmol) was dissolved in dichloromethane (3 mL). Triethylamine (183 μL, 1.31 mmol) and diphenylacetyl chloride (138 mg, 0.597 mmol) were added to this solution at room temperature and stirred for 1 hour. The reaction was diluted with water (3 mL) and extracted with dichloromethane (2 mL) three times. The extracts were combined and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/8-1/6) to give the title compound (188 mg) as a white solid.
¹ H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J=8.2 Hz, 1 H), 7.35-7.17 (m, 10 H), 5.18 (s, 1 H), 4. 21 (dd, J = 8.1, 6.3Hz, 1H), 3.62 (s, 3H), 2.03 (m, 1H), 0.85 (d, J = 6.8Hz, 3H), 0.82 (d, J=6.8 Hz, 3H); MS (ESI) m/z 326 (M+H) ⁺ .

(Step b) Synthesis of polymer metal complex crystal containing methyl (2S)-2-[(2,2-diphenylacetyl)amino]-3-methyl-butanoate (compound 4) Cyclohexane-containing polymer obtained in Reference Example 1 One metal complex crystal single crystal was placed in a micro vial bottle with a septum cap along with 45 μL of cyclohexane, and 5 μL of a 1 mg/mL 1,2-dichloroethane solution of compound 4 obtained in step a was added thereto. After closing the cap of the microvial bottle and leaving it overnight at 50° C., the septum portion was pierced with an injection needle (21G: inner diameter 0.57 mm) and left at 26° C. for 10 days to concentrate the solution in the microvial bottle.

The obtained single crystal was subjected to X-ray crystal structure analysis to confirm the molecules included in the crystal. The crystallographic data are shown in Table 4 and the crystal structure is shown in FIG.

Ｌ－セリンメチルエステル塩酸塩（１１８ｍｇ、０．７５８ｍｍｏｌ）をジクロロメタン（３ｍＬ）に溶解した。この溶液に０℃にてトリエチルアミン（１０６μＬ、０．７５８ｍｍｏｌ）、ジフェニルアセチルクロリド（２２７ｍｇ、０．９８５ｍｍｏｌ）を加え、室温まで昇温し１００分間撹拌した。この反応液に更にトリエチルアミン（１０６μＬ、０．７５８ｍｍｏｌ）を加え、室温にて８０分間撹拌した。この反応液を水（３ｍＬ）にて希釈し、ジクロロメタン（３ｍＬ）で３回抽出した。抽出液を合わせ濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ－ヘキサン＝１／２～１／１）にて精製することで白色固体として表題化合物（１０１ｍｇ）を得た。
¹Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ ８．６１（ｄ，Ｊ＝７．５Ｈｚ，１Ｈ），７．３５-７．２４（ｍ，８Ｈ），７．２８-７．１７（ｍ，２Ｈ），５．１７（ｓ，１Ｈ），５．０８（ｔ，Ｊ＝５．５Ｈｚ，１Ｈ），４．３７（ｄｔ，Ｊ＝７．５，４．８Ｈｚ，１Ｈ），３．７１（ｍ，１Ｈ），３．６１（ｓ，３Ｈ），３．６１（ｍ，１Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ３１４（Ｍ＋Ｈ）⁺． (Example 5)
(Step a) Methyl (2S)-2-[(2,2-diphenylacetyl)amino]-3-hydroxy-propanoate by introduction of a 1,1-diphenylacetyl group to the amino group of L-serine methyl ester hydrochloride Synthesis of (compound 5)

L-serine methyl ester hydrochloride (118 mg, 0.758 mmol) was dissolved in dichloromethane (3 mL). Triethylamine (106 μL, 0.758 mmol) and diphenylacetyl chloride (227 mg, 0.985 mmol) were added to this solution at 0° C., the temperature was raised to room temperature, and the mixture was stirred for 100 minutes. Additional triethylamine (106 μL, 0.758 mmol) was added to the reaction and stirred at room temperature for 80 minutes. The reaction was diluted with water (3 mL) and extracted three times with dichloromethane (3 mL). The extracts were combined and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2-1/1) to obtain the title compound (101 mg) as a white solid.
¹ H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J=7.5 Hz, 1 H), 7.35-7.24 (m, 8 H), 7.28-7.17 (m, 2 H ), 5.17 (s, 1H), 5.08 (t, J = 5.5Hz, 1H), 4.37 (dt, J = 7.5, 4.8Hz, 1H), 3.71 (m , 1H), 3.61 (s, 3H), 3.61 (m, 1H); MS (ESI) m/z 314 (M+H) ⁺ .

(Step b) Synthesis of polymer metal complex crystal containing methyl (2S)-2-[(2,2-diphenylacetyl)amino]-3-hydroxy-propanoate (compound 5) Cyclohexane-containing polymer obtained in Reference Example 1 One metal complex crystal single crystal was placed in a micro vial bottle with a septum cap along with 45 μL of cyclohexane, and 5 μL of a 1 mg/mL 1,2-dichloroethane solution of compound 5 obtained in step a was added thereto. The cap of the microvial bottle was closed, the septum portion was pierced with an injection needle (21G: inner diameter 0.57 mm), and the solution in the microvial bottle was concentrated by standing at 26°C for 3 days.

The obtained single crystal was subjected to X-ray crystal structure analysis to confirm the molecules included in the crystal. The crystallographic data are shown in Table 5 and the crystal structure is shown in FIG.

Ｌ－グルタミン酸ジメチルエステル塩酸塩（５１ｍｇ、０．２４ｍｍｏｌ）をジクロロメタン（２ｍＬ）に溶解した。この溶液に０℃にてトリエチルアミン（６７μＬ、０．４８ｍｍｏｌ）、ジフェニルアセチルクロリド（５０ｍｇ、０．２２ｍｍｏｌ）を加え、室温まで昇温し２時間撹拌した。この反応液を濃縮し、残渣を逆相ＨＰＣＬ（０．１％ＴＦＡアセトニトリル／０．１％ＴＦＡ水＝１５～９０％）にて精製後、凍結乾燥することで白色固体として表題化合物（５８ｍｇ）を得た。
¹Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ ８．７２（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ），７．３５-７．１８（ｍ，１０Ｈ），５．０３（ｓ，１Ｈ），４．２９（ｄｄｄ，Ｊ＝９．０，７．４，５．５Ｈｚ，１Ｈ），３．６０（ｓ，３Ｈ），３．５６（ｓ，３Ｈ），２．３９-２．２６（ｍ，２Ｈ），２．００（ｍ，１Ｈ），１．８４（ｍ，１Ｈ）；ＭＳ（ＥＳＩ） ｍ／ｚ３７０（Ｍ＋Ｈ）⁺． (Example 6)
(Step a) Dimethyl (2S)-2-[(2,2-diphenylacetyl)amino]pentanedioate (compound 6) by introducing a 1,1-diphenylacetyl group into the amino group of L-glutamic acid dimethyl ester hydrochloride ) synthesis

L-glutamic acid dimethyl ester hydrochloride (51 mg, 0.24 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (67 μL, 0.48 mmol) and diphenylacetyl chloride (50 mg, 0.22 mmol) were added to this solution at 0° C., and the mixture was warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated, and the residue was purified by reverse-phase HPLC (0.1% TFA acetonitrile/0.1% TFA water = 15-90%), and then lyophilized to obtain the title compound (58 mg) as a white solid. got
¹ H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J=7.4 Hz, 1 H), 7.35-7.18 (m, 10 H), 5.03 (s, 1 H), 4. 29 (ddd, J = 9.0, 7.4, 5.5Hz, 1H), 3.60 (s, 3H), 3.56 (s, 3H), 2.39-2.26 (m, 2H ), 2.00 (m, 1H), 1.84 (m, 1H); MS (ESI) m/z 370 (M+H) ⁺ .

(Step b) Synthesis of polymer metal complex crystal encapsulating dimethyl (2S)-2-[(2,2-diphenylacetyl)amino]pentanedioate (compound 6) Cyclohexane encapsulating polymer metal complex crystal obtained in Reference Example 1 A single crystal of was placed in a micro vial with a septum cap along with 50 μL of cyclohexane, and 5 μL of a 5 mM ethyl acetate solution of compound 6 obtained in step a was added thereto. The microvial was capped and left at 50° C. for 1 day, then the septum was pierced with an injection needle (21G: inner diameter 0.57 mm) and left at 6° C. for 5 days to concentrate the solution in the micro vial. .

The obtained single crystal was subjected to X-ray crystal structure analysis to confirm the molecules included in the crystal. The crystallographic data are shown in Table 6 and the crystal structure is shown in FIG.

Ｌ－フェニルアラニノール（３７ｍｇ、０．２４ｍｍｏｌ）をジクロロメタン（２ｍＬ）に溶解した。この溶液に０℃にてトリエチルアミン（３４μＬ、０．２４ｍｍｏｌ）、ジフェニルアセチルクロリド（５０ｍｇ、０．２２ｍｍｏｌ）を加え、室温まで昇温し３時間撹拌した。この反応液を濃縮し、残渣を逆相ＨＰＣＬ（０．１％ＴＦＡアセトニトリル／０．１％ＴＦＡ水＝５～９５％）にて精製後、凍結乾燥することで白色固体として表題化合物（７４ ｍｇ）を得た。
¹Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ ８．１２（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．３４-７．０９（ｍ，１３Ｈ），７．０９-７．０１（ｍ，２Ｈ），４．９２（ｓ， １Ｈ），４．８１（ｓ，１Ｈ），３．９５（ｍ，１Ｈ），２．８４（ｄｄ，Ｊ＝１３．７，５．３Ｈｚ，１Ｈ），２．６１（ｄｄ，Ｊ＝１３．７，８．７Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ３４６（Ｍ＋Ｈ）⁺． (Example 7)
(Step a) N-[(1S)-1-benzyl-2-hydroxy-ethyl]-2,2-diphenyl-acetamide ( Synthesis of compound 7)

L-Phenylalaninol (37 mg, 0.24 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (34 μL, 0.24 mmol) and diphenylacetyl chloride (50 mg, 0.22 mmol) were added to this solution at 0° C., and the mixture was warmed to room temperature and stirred for 3 hours. The reaction solution was concentrated, and the residue was purified by reverse-phase HPLC (0.1% TFA acetonitrile/0.1% TFA water = 5-95%), and then lyophilized to give the title compound (74 mg) as a white solid. ).
¹ H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J=8.4 Hz, 1 H), 7.34-7.09 (m, 13 H), 7.09-7.01 (m, 2 H ), 4.92 (s, 1H), 4.81 (s, 1H), 3.95 (m, 1H), 2.84 (dd, J=13.7, 5.3 Hz, 1H), 2. 61 (dd, J=13.7, 8.7 Hz, 1 H); MS (ESI) m/z 346 (M+H) ⁺ .

(Step b) Synthesis of N-[(1S)-1-benzyl-2-hydroxy-ethyl]-2,2-diphenyl-acetamide (compound 7) encapsulating polymer metal complex crystal Normal heptane obtained in Reference Example 2 One single crystal of the encapsulated polymer metal complex crystal was placed in a micro vial bottle with a septum cap along with 50 μL of cyclohexane, and 5 μL of a 5 mM acetic acid 1,2-dichloroethane solution of compound 7 obtained in step a was added. . The cap of this micro vial bottle was closed and the septum was pierced with an injection needle (24G: inner diameter 0.37 mm) and left at 50°C for one day. The solution in the microvial bottle was concentrated by placing.

The obtained single crystal was subjected to X-ray crystal structure analysis to confirm the molecules included in the crystal. The crystallographic data are shown in Table 7 and the crystal structure is shown in FIG.

Ｌ－アラニンメチルエステル塩酸塩（６０ｍｇ、０．４３ｍｍｏｌ）、Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ′，Ｎ′－テトラメチルウロニウムヘキサフルオロりん酸塩（１８０ｍｇ、０．４７ｍｍｏｌ）、４－ｔｅｒｔ－ブチル安息香酸（７７ｍｇ、０．４３ｍｍｏｌ）をジクロロメタン（２ｍＬ）に溶解した。この溶液に室温にてトリエチルアミン（１３０μＬ、０．９５ｍｍｏｌ）を加え７０分間撹拌した。この反応液を水（２ｍＬ）にて希釈し、ジクロロメタン（２ｍＬ）で３回抽出した。抽出液を合わせ濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ－ヘキサン１５～４０％）にて精製することで無色シロップとして表題化合物（９０ ｍｇ）を得た。
¹Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ ８．７０（ｄ，Ｊ＝７．０Ｈｚ，１Ｈ），７．８１（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），７．４９（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），４．４７（ｍ，１Ｈ），３．６４（ｓ，３Ｈ），１．４０（ｄ，Ｊ＝７．３Ｈｚ，３Ｈ），１．３０（ｓ，９Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ２６４（Ｍ＋Ｈ）⁺． (Example 8)
(Step a) introduction of a 4-tert-butylbenzoyl group to the amino group of L-alanine methyl ester hydrochloride to produce methyl (2S)-2-[(4-tert-butylbenzoyl)amino]propanoate (Compound 8) synthesis

L-alanine methyl ester hydrochloride (60 mg, 0.43 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (180 mg , 0.47 mmol), 4-tert-butylbenzoic acid (77 mg, 0.43 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (130 μL, 0.95 mmol) was added to this solution at room temperature and stirred for 70 minutes. The reaction was diluted with water (2 mL) and extracted with dichloromethane (2 mL) three times. The extracts were combined and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane 15-40%) to give the title compound (90 mg) as a colorless syrup.
¹ H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 7.0 Hz, 1 H), 7.81 (d, J = 8.5 Hz, 2 H), 7.49 (d, J = 8 .5 Hz, 2 H), 4.47 (m, 1 H), 3.64 (s, 3 H), 1.40 (d, J = 7.3 Hz, 3 H), 1.30 (s, 9 H); ESI) m/z 264 (M+H) ⁺ .

(Step b) Synthesis of polymer metal complex crystal encapsulating methyl (2S)-2-[(4-tert-butylbenzoyl)amino]propanoate (compound 8) One crystal was placed in a micro vial bottle with a septum cap along with 45 μL of cyclohexane, and 5 μL of a 1 mg/mL 1,2-dichloroethane solution of compound 8 obtained in step a was added thereto. After closing the cap of the microvial bottle and leaving it at 50°C for one day, the septum was pierced with an injection needle (21G: inner diameter 0.57 mm) and left at 50°C for one day to concentrate the solution in the microvial bottle. .

The obtained single crystal was subjected to X-ray crystal structure analysis to confirm the molecules included in the crystal. The crystallographic data are shown in Table 8 and the crystal structure is shown in FIG. FIG. 17 shows interactions assumed from the obtained crystal structure.

４－ｔｅｒｔ－ブチル安息香酸（１０２ ｍｇ、０．５７２ ｍｍｏｌ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（１１０ ｍｇ、０．５７２ｍｍｏｌ）をジクロロメタン（２ ｍＬ）に溶解した。この溶液に室温にてトリエチルアミン（１５９ μＬ、１．１４ ｍｍｏｌ、，Ｌ－チロシンメチルエステル（１１２ ｍｇ、０．５７２ ｍｍｏｌ）を加え３時間撹拌した。この反応液を水（１０ ｍＬ）にて希釈し、ジクロロメタン（１０ ｍＬ）で３回抽出した。抽出液を合わせ濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ－ヘキサン２５～５０％）にて精製することで無色シロップとして表題化合物（１６５ ｍｇ）を得た。
¹Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ ９．１９（ｓ，１Ｈ），８．６７（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．７４（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ），７．４７（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ），７．０７（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），６．６４（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），４．５５（ｄｄｄ，Ｊ＝９．９，７．８，５．３Ｈｚ，１Ｈ），３．６２（ｓ，３Ｈ），３．０３（ｄｄ，Ｊ＝１３．８，５．３Ｈｚ，１Ｈ），２．９６（ｄｄ，Ｊ＝１３．８，９．９Ｈｚ，１Ｈ），１．２９（ｓ，９Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ３５６（Ｍ＋Ｈ）⁺． (Example 9)
(Step a) Methyl (2S)-2-[(4-tert-butylbenzoyl)amino]-3-(4-hydroxyphenyl)propanoate by introduction of 4-tert-butylbenzoyl group to amino group of tyrosine methyl ester Synthesis of (compound 9)

4-tert-butylbenzoic acid (102 mg, 0.572 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (110 mg, 0.572 mmol) were dissolved in dichloromethane (2 mL). . Triethylamine (159 μL, 1.14 mmol, ,L-tyrosine methyl ester (112 mg, 0.572 mmol) was added to this solution at room temperature and stirred for 3 hours. The reaction solution was diluted with water (10 mL). The extracts were combined and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane 25-50%) to give the title compound ( 165 mg).
¹ H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1 H), 8.67 (d, J = 7.8 Hz, 1 H), 7.74 (d, J = 8.7 Hz, 2 H), 7.47 (d, J = 8.7Hz, 2H), 7.07 (d, J = 8.3Hz, 2H), 6.64 (d, J = 8.3Hz, 2H), 4.55 (ddd , J = 9.9, 7.8, 5.3 Hz, 1H), 3.62 (s, 3H), 3.03 (dd, J = 13.8, 5.3 Hz, 1H), 2.96 ( dd, J=13.8, 9.9 Hz, 1 H), 1.29 (s, 9 H); MS (ESI) m/z 356 (M+H) ⁺ .

(Step b) Synthesis of Polymer Metal Complex Crystal Encapsulating Methyl (2S)-2-[(4-tert-butylbenzoyl)amino]-3-(4-hydroxyphenyl)propanoate (Compound 9) Obtained in Reference Example 1 One single crystal of the cyclohexane-encapsulating polymer metal complex crystal was placed in a micro vial bottle with a septum cap along with 45 μL of cyclohexane, and 5 μL of the 1 mg/mL ethyl acetate solution of compound 9 obtained in step a was added thereto. The cap of this microvial bottle was closed and left at 50°C overnight, and then the septum was pierced with an injection needle (24G: inner diameter 0.37 mm) and left at 50°C for 2 days to concentrate the solution in the microvial bottle. .

The obtained single crystal was subjected to X-ray crystal structure analysis to confirm the molecules included in the crystal. The crystallographic data are shown in Table 9 and the crystal structure is shown in FIG.

４－ｔｅｒｔ－ブチル安息香酸（５０ｍｇ、０．２８ｍｍｏｌ）、Ｎ，Ｎ，Ｎ′，Ｎ′－テトラメチルウロニウムヘキサフルオロりん酸塩（１２０ｍｇ、０．３１ｍｍｏｌ）をジクロロメタン（２ｍＬ）に溶解した。この溶液に室温にてトリエチルアミン（３４μＬ、０．２４ｍｍｏｌ）、Ｌ－セリンメチルエステル塩酸塩（４８ｍｇ、０．３１ｍｍｏｌ）を加え一晩撹拌した。この反応液を濃縮し、残渣を逆相ＨＰＣＬ（０．１％ＴＦＡアセトニトリル／０．１％ＴＦＡ水＝５～９５％）にて精製し後凍結乾燥することで白色固体として表題化合物（８５ｍｇ）を得た。
¹Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ ８．４６（ｄ，Ｊ＝７．５Ｈｚ，１Ｈ），７．８５-７．８０（ｍ，２Ｈ），７．５２-７．４６（ｍ，２Ｈ），４．５３（ｄｔ，Ｊ＝７．５，５．４Ｈｚ，１Ｈ），３．７９（ｄ，Ｊ＝５．４Ｈｚ，２Ｈ），３．６４（ｓ，３Ｈ），１．３０（ｓ，９Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ２８０（Ｍ＋Ｈ）⁺． (Example 10)
(Step a) Methyl (2S)-2-[(4-tert-butylbenzoyl)amino]-3-hydroxy-propanoate by introduction of a 4-tert-butylbenzoyl group to the amino group of L-serine methyl ester hydrochloride Synthesis of (compound 10)

4-tert-butylbenzoic acid (50 mg, 0.28 mmol), N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 0.31 mmol) were dissolved in dichloromethane (2 mL). Triethylamine (34 μL, 0.24 mmol) and L-serine methyl ester hydrochloride (48 mg, 0.31 mmol) were added to this solution at room temperature and stirred overnight. The reaction solution was concentrated, and the residue was purified by reverse-phase HPLC (0.1% TFA acetonitrile/0.1% TFA water = 5-95%), and then lyophilized to give the title compound (85 mg) as a white solid. got
¹ H NMR (400MHz, DMSO-d6) δ 8.46 (d, J = 7.5Hz, 1H), 7.85-7.80 (m, 2H), 7.52-7.46 (m, 2H) ), 4.53 (dt, J = 7.5, 5.4 Hz, 1H), 3.79 (d, J = 5.4 Hz, 2H), 3.64 (s, 3H), 1.30 (s , 9H); MS (ESI) m/z 280 (M+H) ⁺ .

(Step b) Synthesis of polymer metal complex crystals encapsulating methyl (2S)-2-[(4-tert-butylbenzoyl)amino]-3-hydroxy-propanoate (compound 10) Cyclohexane-encapsulating polymer obtained in Reference Example 1 One metal complex crystal single crystal was placed in a micro vial with a septum cap along with 50 μL of cyclohexane, and 5 μL of a 5 mM ethyl acetate solution of compound 10 obtained in step a was added thereto. The cap of this microvial bottle was closed, and the 5 septum was pierced with an injection needle (24G: inner diameter 0.37 mm) and left at 50°C for 3 days to concentrate the solution in the microvial bottle.

The obtained single crystal was subjected to X-ray crystal structure analysis to confirm the molecules included in the crystal. The crystallographic data are shown in Table 10 and the crystal structure is shown in FIG.

Ｌ－プロリンメチルエステル塩酸塩（８３．５ｍｇ、０．５０４ｍｍｏｌ）、インドール－２－カルボン酸（８１．２ｍｇ、０．６０５ ｍｍｏｌ）、Ｎ，Ｎ，Ｎ′，Ｎ′－テトラメチルウロニウムヘキサフルオロりん酸塩（２３０ｍｇ、１．１１ ｍｍｏｌ）をジクロロメタン（２ｍＬ）に溶解した。この溶液に室温にてトリエチルアミン（１５５μＬ、１．１１ｍｍｏｌ）を加え、一晩撹拌した。この反応液を水（２０ｍＬ）にて希釈し、ジクロロメタン（１０ｍＬ）で３回抽出した。抽出液を合わせ濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ－ヘキサン＝３０～５０％）にて精製し、更に残渣を逆相ＨＰＣＬ（０．１％ＴＦＡアセトニトリル／０．１％ＴＦＡ水＝１５～８０％）にて精製後、凍結乾燥することで白色固体として表題化合物（８８．３ｍｇ）を得た。
¹Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ １１．５９（ｓ，１Ｈ），７．６５（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），７．４４（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），７．２１（ｍ，１Ｈ），７．１０-７．０１（ｍ，２Ｈ），４．５７（ｄｄ，Ｊ＝８．５，４．７Ｈｚ，１Ｈ），３．９６（ｔ，Ｊ＝６．８Ｈｚ，２Ｈ），３．６５（ｓ，３Ｈ），２．２７（ｍ，１Ｈ），２．１０-１．９８（ｍ，２Ｈ），１．９３（ｍ，１Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ２７３（Ｍ＋Ｈ）⁺． (Example 11)
(Step a) Methyl (2S)-1-(1H-indole-2-carbonyl)pyrrolidine-2-carboxylate (compound 11) by introduction of a 2-indolecarbonyl group to the amino group of L-proline methyl ester hydrochloride Synthesis of

L-proline methyl ester hydrochloride (83.5 mg, 0.504 mmol), indole-2-carboxylic acid (81.2 mg, 0.605 mmol), N,N,N',N'-tetramethyluronium hexafluoro Phosphate (230 mg, 1.11 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (155 μL, 1.11 mmol) was added to the solution at room temperature and stirred overnight. The reaction was diluted with water (20 mL) and extracted three times with dichloromethane (10 mL). The extracts were combined and concentrated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30-50%). After purification with 1% TFA water (15-80%), it was freeze-dried to obtain the title compound (88.3 mg) as a white solid.
¹ H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.44 (d, J = 8.5 Hz, 1 H), 7.21 (m, 1H), 7.10-7.01 (m, 2H), 4.57 (dd, J=8.5, 4.7Hz, 1H), 3.96 (t, J=6 .8 Hz, 2H), 3.65 (s, 3H), 2.27 (m, 1H), 2.10-1.98 (m, 2H), 1.93 (m, 1H); MS (ESI) m/z 273 (M+H) ⁺ .

(Step b) Synthesis of polymer metal complex crystal encapsulating methyl (2S)-1-(1H-indole-2-carbonyl)pyrrolidine-2-carboxylate (compound 11) Cyclohexane-encapsulating polymer metal complex obtained in Reference Example 1 One single crystal of the crystal was placed in a micro vial bottle with a septum cap along with 50 μL of cyclohexane, and 1 μL of a 1 mg/mL ethyl acetate solution of compound 11 obtained in step a was added thereto. After closing the cap of the microvial bottle and leaving it at 50° C. for one day, the septum was pierced with an injection needle (21G: inner diameter 0.57 mm) and left at 50° C. for 3 days to concentrate the solution in the microvial bottle.

The obtained single crystal was subjected to X-ray crystal structure analysis to confirm the molecules included in the crystal. The crystallographic data are shown in Table 11 and the crystal structure is shown in FIG. FIG. 21 shows interactions assumed from the obtained crystal structure.

インドール－２－カルボン酸（５０ｍｇ、０．３１ｍｍｏｌ）、Ｎ，Ｎ，Ｎ′，Ｎ′－テトラメチルウロニウムヘキサフルオロりん酸塩（１３０ｍｇ、０．３４ｍｍｏｌ）をジクロロメタン（２ｍＬ）に溶解した。この溶液に室温にてトリエチルアミン（９５μＬ、０．６８ｍｍｏｌ）、Ｌ－フェニルアラニンメチルエステル塩酸塩（７４ｍｇ、０．３４ｍｍｏｌ）を加え、１時間撹拌した。この反応液を濃縮し、残渣を逆相ＨＰＣＬ（０．１％ＴＦＡアセトニトリル／０．１％ＴＦＡ水＝１５～９０％）にて精製後、凍結乾燥することで白色固体として表題化合物（８８ｍｇ）を得た。
¹Ｈ ＮＭＲ（４００ ＭＨｚ，ＤＭＳＯ－ｄ６）δ １１．５２（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ），８．８４（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），７．６３（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．４０（ｄｄ，Ｊ＝８．３，１．１Ｈｚ，１Ｈ），７．３５-７．２３（ｍ，４Ｈ），７．２２-７．１５（ｍ，３Ｈ），７．０３（ｍ，１Ｈ），４．７１（ｄｄｄ，Ｊ＝１０．１，８．０，５．２Ｈｚ，１Ｈ），３．６５（ｓ，３Ｈ），３．１９（ｄｄ，Ｊ＝１３．８，５．２Ｈｚ，１Ｈ），３．１０（ｄｄ，Ｊ＝１３．８，１０．１Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ ｍ／ｚ３２３（Ｍ＋Ｈ）⁺． (Example 12)
(Step a) Methyl (2S)-2-(1H-indole-2-carbonylamino)-3-phenyl-propanoate (compound 12) by introducing a 2-indolecarbonyl group to the amino group of L-phenylalanine methyl ester hydrochloride ) synthesis

Indole-2-carboxylic acid (50 mg, 0.31 mmol), N,N,N',N'-tetramethyluronium hexafluorophosphate (130 mg, 0.34 mmol) were dissolved in dichloromethane (2 mL). Triethylamine (95 μL, 0.68 mmol) and L-phenylalanine methyl ester hydrochloride (74 mg, 0.34 mmol) were added to this solution at room temperature and stirred for 1 hour. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC (0.1% TFA acetonitrile/0.1% TFA water = 15-90%), and then lyophilized to give the title compound (88 mg) as a white solid. got
¹ H NMR (400 MHz, DMSO-d6) δ 11.52 (d, J = 2.2 Hz, 1 H), 8.84 (d, J = 8.0 Hz, 1 H), 7.63 (d, J = 7.8Hz, 1H), 7.40 (dd, J = 8.3, 1.1Hz, 1H), 7.35-7.23 (m, 4H), 7.22-7.15 (m, 3H) ), 7.03 (m, 1H), 4.71 (ddd, J = 10.1, 8.0, 5.2 Hz, 1H), 3.65 (s, 3H), 3.19 (dd, J = 13.8, 5.2 Hz, 1 H), 3.10 (dd, J = 13.8, 10.1 Hz, 1 H); MS (ESI) m/z m/z 323 (M+H) ⁺ .

(Step b) Synthesis of polymer metal complex crystal encapsulating methyl (2S)-2-(1H-indole-2-carbonylamino)-3-phenyl-propanoate (compound 12) Cyclohexane-encapsulating metal polymer obtained in Reference Example 1 One single crystal of the complex crystal was placed in a micro vial bottle with a septum cap along with 50 μL of cyclohexane, and 5 μL of a 5 mM ethyl acetate solution of compound 12 obtained in step a was added thereto. The microvial was capped and left at 50° C. for 3 days, and then the septum was pierced with an injection needle (21G: inner diameter 0.57 mm) and left at 50° C. for 1 day to concentrate the solution in the micro vial. .

The obtained single crystal was subjected to X-ray crystal structure analysis to confirm the molecules included in the crystal. The crystallographic data are shown in Table 12 and the crystal structure is shown in FIG.

Ｄ－マンデル酸（５１．５ ｍｇ， ０．３３８ ｍｍｏｌ）をジクロロエメタン（２ ｍＬ）に溶解し、ＳＹＮＬＥＴＴ ２０１４， ２５， ０２８３-０２８７．記載の方法で合成したジフェニルメチルトリクロロアセトイミダート（１１４ｍｇ、０．４３９ｍｍｏｌ）を加え、室温にて一晩撹拌した。この反応液を濃縮し残渣をシリカゲルカラムクロマトグラフィーにて精製することで、表題化合物（９６．９ｍｇ）を得た。
¹Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ ７．４９-７．４２（ｍ，２Ｈ），７．４０-７．３０（ｍ，７Ｈ），７．２７（ｍ，１Ｈ），７．２３-７．１７（ｍ，３Ｈ），７．１４-７．０７（ｍ，２Ｈ），６．７７（ｓ，１Ｈ），６．１７（ｓ，１Ｈ），５．３０（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ１６７（Ｍ－Ｃ８Ｈ７Ｏ３）⁺． (Example 13)
(Step a) Synthesis of benzhydryl (2R)-2-hydroxy-2-phenyl-acetate (compound 13) by introduction of a diphenylmethyl group to the carboxy group of D-mandelic acid

D-mandelic acid (51.5 mg, 0.338 mmol) was dissolved in dichloroethane (2 mL), SYNLETT 2014, 25, 0283-0287. Diphenylmethyltrichloroacetimidate (114 mg, 0.439 mmol) synthesized by the method described was added and stirred overnight at room temperature. The reaction solution was concentrated and the residue was purified by silica gel column chromatography to give the title compound (96.9 mg).
¹ H NMR (400 MHz, DMSO-d6) δ 7.49-7.42 (m, 2H), 7.40-7.30 (m, 7H), 7.27 (m, 1H), 7.23- 7.17 (m, 3H), 7.14-7.07 (m, 2H), 6.77 (s, 1H), 6.17 (s, 1H), 5.30 (s, 1H); (ESI) m/z 167 (M-C8H7O3) ⁺ .

(Step b) Synthesis of benzhydryl (2R)-2-hydroxy-2-phenyl-acetate (compound 13)-encapsulating polymer metal complex crystal 45 μL of one single crystal of the cyclohexane-encapsulating polymer metal complex crystal obtained in Reference Example 1. of cyclohexane into a micro vial bottle with a septum cap, and 5 μL of a 1 mg/mL ethyl acetate solution of compound 13 obtained in step a was added thereto. After closing the cap of this microvial bottle and leaving it at 50° C. for one day, the septum portion was pierced with an injection needle (21G: inner diameter 0.57 mm) and left at 50° C. for one day to concentrate the solution in the microvial bottle.

The obtained single crystal was subjected to X-ray crystal structure analysis to confirm the molecules included in the crystal. The crystallographic data are shown in Table 13 and the crystal structure is shown in FIG. FIG. 24 shows interactions assumed from the obtained crystal structure.

The present invention relates to structural analysis of hydrophilic organic compounds, particularly trace amounts of physiologically active substances derived from marine organisms, trace substances contained in agricultural drugs and their raw materials, or trace substances contained in raw materials used in the production of electronic parts. It is useful for identifying the molecular structure of hydrophilic organic compounds as

1 crystal plane X
2 Crystal plane Y
3 pores
4 Direction in which pores extend
5 Three-dimensional network structure
6 Three-dimensional network structure
7 Three-dimensional network structure
8 Three-dimensional network structure
9 Tris(4-pyridyl)triazine
10 Tris(4-pyridyl)triazine
11 triphenylene molecule
12 Lid (lid with septum)
12a Septum
12b plastic part
13 Opening (hollow needle for degassing)
14 Container body (vial bottle)
15 Solvent solutions of organic compounds (α)
16 Single crystals of polymer metal complexes
17 crystal supports
A pore
B pore

Claims (14)

A sample preparation method for crystal structure analysis for structural analysis by the crystal sponge method of a hydrophilic organic compound having a polar group, comprising:
The crystal sponge method is a method for determining the molecular structure of an organic compound, and comprises the following steps (1) to (3),
(1) A step of providing a polymer metal complex crystal containing a guest compound,
The guest compound-encapsulating polymer metal complex crystal has the formula: [[M(X) ₂ ] ₃ (L) ₂ ] _n [wherein M represents a metal ion, X represents a monovalent anion, L is the following formula (1)

(In the formula, Ar represents a trivalent aromatic group which may have a substituent, and X ¹ to X ³ are each independently a divalent organic group, or Ar and Y ¹ to Y ³ Y ¹ to Y ³ each independently represent a monovalent organic group having a coordinating site), n is any natural number A crystal of a polymer metal complex represented by
The tridentate ligand coordinates to the metal ion to form a three-dimensional network structure, and the three-dimensional network structure has voids therein, and the voids contain an aliphatic hydrocarbon; Ethers; Esters; Aromatic hydrocarbons selected from the group consisting of benzene, toluene, xylene, mesitylene, naphthalene, anthracene and phenanthrene; Halogenated hydrocarbons, and Nitriles. At least one is included as a guest compound (A),
a step in which the abundance of the guest compound (A) in the voids is 60 mol% or more with respect to all guest compounds contained in the voids;
(2) A sample for crystal structure analysis in which the polymer metal complex crystal containing the guest compound is immersed in a solvent solution containing the organic compound, and the molecules of the organic compound are included in the voids in the three-dimensional network structure. and (3) performing crystal structure analysis of the sample for crystal structure analysis to determine the molecular structure of the organic compound contained in the voids in the three-dimensional network structure;
a method comprising
The method for preparing a sample for crystal structure analysis includes the following steps (a) and (b),
(a) introducing a hydrophobic substituent to the polar group of the hydrophilic organic compound to obtain an organic compound having a hydrophobic substituent; and (b) comprising the organic compound having the hydrophobic substituent. The sample for crystal structure analysis, in which the polymer metal complex crystal encapsulating the guest compound is immersed in a solvent solution, and molecules of the organic compound introduced with the hydrophobic substituent are included in the voids in the three-dimensional network structure. a step of obtaining
A sample preparation method for crystal structure analysis, comprising: 2. The sample preparation method of claim 1, wherein said hydrophobic substituent has at least one aromatic ring. 3. The sample preparation method of claim 2, wherein the hydrophobic substituent has two benzene rings, one benzene ring and one tert-butyl group, one indole ring or one naphthalene ring. The sample preparation method according to any one of claims 1 to 3, wherein the hydrophobic substituent is a group that improves the fat-solubility of the hydrophilic organic compound when introduced into the polar group. The sample preparation method according to any one of claims 1 to 4, wherein the hydrophobic substituent is a group that interacts with the polymer metal complex. The sample preparation method according to any one of claims 1 to 5, wherein the polar group is an amino group, hydroxyl group, thiol group or carboxy group. 7. The sample preparation method according to claim 6, wherein the polar group is an amino group or a carboxy group. The sample preparation according to claim 7, wherein the polar group is an amino group, and the hydrophobic substituent is introduced into the polar group by an amide bond, a urethane bond, a urea bond, or a thiourea bond in the step (a). Method. The sample preparation method according to claim 8, wherein the hydrophobic substituent is a 1-naphthylcarbamothioyl group, a 1,1-diphenylacetyl group, a 4-tert-butylbenzoyl group or a 2-indolecarbonyl group. 8. The sample preparation method according to claim 7, wherein said polar group is a carboxy group, and said hydrophobic substituent is introduced into said polar group by an ester bond or an amide bond in said step (a). 11. The sample preparation method of claim 10, wherein said hydrophobic substituent is a diphenylmethyl group. The sample preparation method according to any one of claims 1 to 11, wherein the hydrophilic organic compound is an amino acid, a nucleic acid, or an organic acid. A method for structural analysis of a hydrophilic organic compound by a crystal sponge method, comprising the step of analyzing the crystal structure of the sample obtained by the sample preparation method according to any one of claims 1 to 12. A reagent for introducing a substituent, which is used in the sample preparation method according to any one of claims 1 to 12 and contains a compound that provides the hydrophobic substituent.

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