JP2013023483A - Crown ether-like cyclic structure, novel compound having binaphthyl group and manufacturing method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel compound including a crown ether-like structure and an optically active binaphthyl group which is expected in the application as an asymmetry recognizing agent and in various applications as various functional materials and to provide a manufacturing method thereof.SOLUTION: The novel compound having a crown ether-like structure and a binaphthyl structure is provided by further derivatizing a binaphthyl derivative in which the 6,6'-positions are replaced with bromines and the 3,3'-positions are replaced with specific substituents, by a specific reaction.

Description

  The present invention relates to a novel compound and a production method thereof, and more particularly to a novel compound having a crown ether-like cyclic structure and a binaphthyl group and a production method thereof.

Compounds having a crown ether-like cyclic structure and a binaphthyl group have hitherto been used as raw materials for chromatographic separation agents. For example, a separating agent for optical isomers is known in which a binaphthyl derivative in which a crown ether-like cyclic structure is bridged on each naphthyl ring of a binaphthyl group is adsorbed on a carrier (see, for example, Patent Document 1). . This optical isomer separating agent is suitable for optical resolution of a compound having an amino group such as an amino acid.
Binaphthol derivatives, which are raw materials for compounds having the above-mentioned crown ether-like cyclic structure and binaphthyl group, have been attracting attention as useful asymmetric ligands in asymmetric synthesis, and are derivatives for improving their functionality. There are researches on composting.

  Among such derivatizations, research on halogenation is in progress, and 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP) is converted to trifluoromethanesulfonic acid (hereinafter “TfOH”). In the presence of BINAP and N, N′-diiodo-5,5-dimethylhydantoin (hereinafter also referred to as “DIH”), iodine was introduced into the 5,5 ′ position of binaphthyl. In addition, a method for efficiently obtaining diiodo BINAP is known (for example, see Non-Patent Document 1).

（式中、Ａｒは、フェニル基、４−メチルフェニル基または４−メトキシフェニル基を示す） Also, synthesis of a binaphthol derivative in which the 6,6′-position of 2,2′-dimethoxy-1,1′-binaphthyl is selectively iodinated using the above DIH and a catalytic amount of Lewis acid as an iodinating agent. Examples have been reported (for example, Non-Patent Document 2).
Furthermore, a tetraiodo binaphthol derivative in which the 3,3 ′, 6,6 ′ position of 2,2′-dimethoxy-1,1′-binaphthyl is selectively iodinated has also been reported, and according to the report, 2,2′-dimethoxy- selectively brominated at the 6,6′-position using N, N′-dibromo-5,5-dimethylhydantoin (hereinafter also referred to as “DBH”) as a brominating agent First, a derivative of 1,1′-binaphthyl was obtained, and then the brominated binaphthol derivative was subjected to selective iodination at the 3,3 ′ position using DIH, whereby 3,3′-diiodo- It has been reported that 6,6′-dibromo-2,2′-dimethoxy-1,1′-binaphthyl was obtained. The resulting 3,3′-diiodo-6,6′-dibromo-2,2′-dimethoxy-1,1′-binaphthyl is subjected to a selective Suzuki-Miyaura cross-coupling reaction to produce 3,3 It has been reported that a compound represented by the following formula in which an aryl group (phenyl group, 4-methylphenyl group or 4-methoxyphenyl group) is introduced only at the 3 ′ position was obtained (for example, Non-Patent Document 3). reference).

(In the formula, Ar represents a phenyl group, a 4-methylphenyl group or a 4-methoxyphenyl group)

  As described above, in the derivatization of the binaphthyl group, an attempt is made to introduce a desired substituent into the binaphthyl group by selectively halogenating a predetermined position of the binaphthyl group and then performing a cross-coupling reaction. . In addition, as described above, further development of binaphthyl derivatives having an asymmetric structure brings about improvement and probability of technology by asymmetric identification. Therefore, a new binaphthyl derivative is synthesized. For example, the synthesis of a novel compound having a crown ether-like cyclic structure and a binaphthyl group as described above is also expected.

Japanese Examined Patent Publication No. 3-57816

Toyoji Shimada and five others, “Simplified synthesis of 5-monoiodo BINAP and its derivatization”, The 88th Annual Meeting of the Chemical Society of Japan, 4PB-086 (2008) Toyoji Shimada and three others, “Regioselective iodination catalyzed by Lewis acid”, The 90th Annual Meeting of the Chemical Society of Japan, 2F-34 (2010) Toyoji Shimada and two others, "A new synthesis method of 3,3 ', 6,6'-tetrasubstituted binaphthol", The 91st Annual Meeting of the Chemical Society of Japan, 2C4-44 (2011)

  The present invention provides a novel compound containing a crown ether-like cyclic structure and a binaphthyl group, and a method for producing the same.

  The present inventor used as a starting material a binaphthyl derivative in which the 6,6′-position of the binaphthyl group was substituted with bromine and the 3,3′-position was substituted with a specific substituent, which was further derivatized by a specific reaction. As a result, it was found that a novel compound having a crown ether-like cyclic structure and a binaphthyl group was obtained, and the present invention was completed.

［式中、Ｒ₁及びＲ₂は、それぞれ、置換基を有していてもよいアリール基を表し、Ｒ₃及びＲ₄は、それぞれ、置換基を有していてもよいアルキル基、アルケニル基、アルキニル基、アリール基、または−（ＣＨ₂）₃−Ａを表し、Ａは、下記式（ｉ）で示される構造であり、ｎは４〜６の整数を表す。］

［式中、Ｒ₅、Ｒ₆及びＲ₇はそれぞれ独立して置換基を有していてもよいアルキル基、アルケニル基、アルキニル基、アリール基またはアルコキシ基を表す。］ That is, the present invention provides a compound represented by the following formula (I).

[Wherein, R ₁ and R ₂ each represents an aryl group which may have a substituent, and R ₃ and R ₄ each represent an alkyl group or an alkenyl group which may have a substituent. , An alkynyl group, an aryl group, or — (CH ₂ ) ₃ —A, wherein A is a structure represented by the following formula (i), and n represents an integer of 4 to 6. ]

[Wherein R ₅ , R ₆ and R ₇ each independently represents an optionally substituted alkyl group, alkenyl group, alkynyl group, aryl group or alkoxy group. ]

The present invention also provides the above compound wherein n is 4, and R ₁ and R ₂ are each a phenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, a 3,5-dimethylphenyl group, a 3,5-dimethoxy group. The above-mentioned compound, which is a phenyl group, 4-methoxynaphthyl group or 4-fluorophenyl group, R ₃ and R ₄ are 2-propenyl group, phenyl group or — (CH ₂ ) ₃ —Si (C ₃ H ₅ ) Wherein said compound is ₃ .

In addition, the present invention provides a B step for obtaining a binaphthyl derivative B in which the bromo groups at the 6 and 6 ′ positions of the binaphthyl derivative A represented by the following formula (II) are respectively replaced by R ₃ and R _{4 represented} by the following formula (III) And C step of obtaining a binaphthyl derivative C in which the methoxy group becomes a hydroxyl group by hydrolyzing the 2,2′-position methoxy group of the binaphthyl derivative B, and cross-linking each of the hydroxyl groups of the binaphthyl derivative C with a polyethylene glycol derivative. And a D step for obtaining a compound represented by the following formula (I) having a crown ether-like cyclic structure and a binaphthyl group, and a method for producing the compound represented by the above formula (I).

［式中、Ｒ₁及びＲ₂は、それぞれ、上記式（Ｉ）のＲ₁及びＲ₂と同じである。］

［式中、Ｒ₁及びＲ₂は、それぞれ、上記式（Ｉ）のＲ₁及びＲ₂と同じであり、Ｒ₃及びＲ₄は、それぞれ、それぞれ、置換基を有していてもよいアルキル基、アルケニル基、アルキニル基またはアリール基を表す。］

[Wherein, R ₁ and R ₂ are the same as R ₁ and R _{2 in} the formula (I), respectively. ]

[Wherein, R ₁ and R ₂ are the same as R ₁ and R _{2 in} the formula (I), respectively, and R ₃ and R ₄ are alkyls each optionally having a substituent. Represents a group, an alkenyl group, an alkynyl group or an aryl group. ]

In addition, the present invention provides 6,6′-dibromo-2,2′-dimethoxy-1,1′-binaphthyl by brominating 6,6′-position of 2,2′-dimethoxy-1,1′-binaphthyl, respectively. And obtaining 6,6′-dibromo-3,3′-diiodo- by iodination at 3,3′-position of the 6,6′-dibromo-2,2′-dimethoxy-1,1′-binaphthyl, respectively. A step of obtaining 2,2′-dimethoxy-1,1′-binaphthyl, and 3,3 of 6,6′-dibromo-3,3′-diiodo-2,2′-dimethoxy-1,1′-binaphthyl There is provided the above production method further comprising a step A including a step of obtaining a binaphthyl derivative A by substituting the i-position at the 'position with R ₁ and R ₂ , respectively.

［式中、Ｒは置換基を有していてもよいアルキル基、アルケニル基、アルキニル基またはアリール基を表し、Ｍｇはマグネシウムを表し、Ｘは塩素、臭素又はヨウ素を表す。］ Moreover, this invention provides the said manufacturing method which makes binaphthyl derivative B and the compound shown by following formula (IV) react in presence of a transition metal catalyst in B process, and obtains binaphthyl derivative B.

[Wherein, R represents an optionally substituted alkyl group, alkenyl group, alkynyl group or aryl group, Mg represents magnesium, and X represents chlorine, bromine or iodine. ]

［式中、Ｙは置換基を有していてもよいアリール基を表す。］ Moreover, this invention provides the said manufacturing method which makes binaphthyl derivative A and the compound shown by following formula (V) react in presence of a palladium catalyst and a base in B process, and obtains binaphthyl derivative B.

[Wherein Y represents an aryl group which may have a substituent. ]

  In the step D, the polyoxyethylene glycol ditosylate having 5 to 7 repeating oxyethylene groups is reacted under alkaline conditions to crosslink between the hydroxyl groups of the binaphthyl derivative C in the step D. Provided is the process described above for obtaining the indicated compound.

［式中、Ｒ₁及びＲ₂は、それぞれ、置換基を有していてもよいフェニル基又は置換基を有していてもよいナフチル基を表す。］

［式中、Ｒ₁及びＲ₂は、それぞれ、上記式（ＩＩ）のＲ₁及びＲ₂と同じである。］

［式中、Ｒ₁及びＲ₂は、それぞれ、上記式（ＩＩ）のＲ₁及びＲ₂と同じである。］

［式中、Ｒ₁及びＲ₂は、それぞれ、上記式（ＩＩ）のＲ₁及びＲ₂と同じであり、Ｒ₈、Ｒ₉及びＲ₁₀は、それぞれ、独立して置換基を有していてもよいアルキル基、アルケニル基、アルキニル基、アリール基またはアルコキシ基を表す。］ The present invention also includes a B ′ step in which a binaphthyl derivative A represented by the following formula (II) and allylmagnesium bromide are reacted in the presence of a catalyst containing palladium to obtain a compound represented by the following formula (VI): Hydrolyzing the 2,2′-position methoxy group of the compound to obtain a compound in which the methoxy group becomes a hydroxyl group, and crosslinking each of the hydroxyl groups of the compound with a polyethylene glycol derivative to form a crown ether Hydrosilylation is performed on the D ′ step for obtaining a compound represented by the following formula (VII) having a ring-like cyclic structure and a binaphthyl group, and the 2-propenyl group at the 6,6 ′ position of the compound represented by the following formula (VII) And the following formula (VII) including the E step and the F step in which the 6,6′-position subjected to hydrosilylation is further replaced with R ₅ and R _{6 represented} by the following formula (VIII): A process for producing the compound represented by I) is provided.

[Wherein, R ₁ and R ₂ each represents a phenyl group which may have a substituent or a naphthyl group which may have a substituent. ]

[Wherein, R ₁ and R ₂ are the same as R ₁ and R _{2 in} the formula (II), respectively. ]

[Wherein, R ₁ and R ₂ are the same as R ₁ and R _{2 in} the formula (II), respectively. ]

[Wherein, R ₁ and R ₂ are the same as R ₁ and R _{2 in} the formula (II), respectively, and R ₈ , R ₉ and R ₁₀ each independently have a substituent. And may represent an alkyl group, an alkenyl group, an alkynyl group, an aryl group or an alkoxy group. ]

According to the present invention, a novel compound having a crown ether-like cyclic structure and a binaphthyl group, which is expected to be used as an asymmetric identifier and is expected to be used as a raw material for various functional materials, and production thereof A method can be provided.
In particular, the present invention employs a starting material in which iodine is introduced at the 3,3′-position and bromine is introduced at the 6,6′-position, and the reactivity of the Suzuki-Miyaura cross-coupling reaction is superior to the iodide. Is used to regioselectively couple only the 3,3 ′ position and then to the already introduced 6,6 ′ position bromine. And many combinations of 6 and 6 'positions can be synthesized.

2 is a diagram illustrating a ¹ H NMR spectrum of a compound (b) obtained in Synthesis Example 1. FIG. 4 is a diagram illustrating a ¹ H NMR spectrum of a compound (c) obtained in Synthesis Example 2. FIG. Is a diagram illustrating the ¹ H NMR spectrum of the compound obtained in Synthesis Example 3 (d-1). It is a figure which expands and shows a part of < ¹ > H NMR spectrum of the compound (d-1) obtained by the synthesis example 3. FIG. It is a figure showing the spectrum of < ¹³ > C NMR of the compound (d-1) obtained by the synthesis example 3. FIG. It is a figure showing the ¹ H NMR spectrum of the compound (d-2) obtained by the synthesis example 4. It is a figure which expands and shows a part of < ¹ > H NMR spectrum of the compound (d-2) obtained by the synthesis example 4. FIG. It is a figure showing the spectrum of < ¹³ > C NMR of the compound (d-2) obtained by the synthesis example 4. FIG. 6 is a diagram illustrating a ¹ H NMR spectrum of a compound (d-3) obtained in Synthesis Example 5. FIG. It is a figure which expands and shows a part of < ¹ > H NMR spectrum of the compound (d-3) obtained by the synthesis example 5. FIG. 6 is a diagram showing a ¹³ C NMR spectrum of a compound (d-3) obtained in Synthesis Example 5. FIG. 6 is a diagram illustrating a ¹ H NMR spectrum of a compound (d-4) obtained in Synthesis Example 6. FIG. It is an enlarged view showing a part of the ¹ H NMR spectrum of the compound obtained in Synthesis Example 6 (d-4). 6 is a diagram illustrating a ¹³ C NMR spectrum of a compound (d-4) obtained in Synthesis Example 6. FIG. 6 is a diagram illustrating a ¹ H NMR spectrum of a compound (d-5) obtained in Synthesis Example 7. FIG. It is a figure which expands and shows a part of < ¹ > H NMR spectrum of the compound (d-5) obtained by the synthesis example 7. FIG. 6 is a diagram showing a ¹³ C NMR spectrum of a compound (d-5) obtained in Synthesis Example 7. FIG. 6 is a diagram illustrating a ¹ H NMR spectrum of a compound (d-6) obtained in Synthesis Example 8. FIG. It is a figure which expands and shows a part of < ¹ > H NMR spectrum of the compound (d-6) obtained by the synthesis example 8. FIG. 6 is a diagram showing a ¹³ C NMR spectrum of a compound (d-6) obtained in Synthesis Example 8. FIG. 6 is a diagram illustrating a ¹ H NMR spectrum of a compound (d-7) obtained in Synthesis Example 9. FIG. It is an enlarged view showing a part of the ¹ H NMR spectrum of the compound obtained in Synthesis Example 9 (d-7). 6 is a diagram showing a ¹³ C NMR spectrum of a compound (d-7) obtained in Synthesis Example 9. FIG. It is a figure showing the spectrum of ¹⁹ F NMR of the compound (d-7) obtained by the synthesis example 9. 4 is a diagram illustrating a ¹ H NMR spectrum of a compound (e) obtained in Synthesis Example 10. FIG. It is a figure which expands and shows a part of < ¹ > H NMR spectrum of the compound (e) obtained by the synthesis example 10. FIG. It is an enlarged view showing another part of the ¹ H NMR spectrum of the compound obtained in Synthesis Example 10 (e). ¹ is a diagram showing a ¹ H NMR spectrum of a compound (f) obtained in Synthesis Example 11. FIG. Is an enlarged view showing a part of the ¹ H NMR spectrum of the compound obtained in Synthesis Example 11 (f). Is an enlarged view showing another part of the ¹ H NMR spectrum of the compound obtained in Synthesis Example 11 (f). Is a diagram illustrating the ¹ H NMR spectrum of the compound obtained in Synthesis Example 12 (g). It is a figure which expands and shows a part of < ¹ > H NMR spectrum of the compound (g) obtained by the synthesis example 12. FIG. Is a diagram illustrating the ¹ H NMR spectrum of the compound obtained in Synthesis Example 13 (h). It is an enlarged view showing a part of the ¹ H NMR spectrum of the compound obtained in Synthesis Example 13 (h). It is an enlarged view showing another part of the ¹ H NMR spectrum of the compound obtained in Synthesis Example 13 (h). 14 is a diagram illustrating a ¹³ C NMR spectrum of a compound (h) obtained in Synthesis Example 13. FIG. Is a diagram illustrating the ¹ H NMR spectrum of the compound obtained in Synthesis Example 14 (i). It is an enlarged view showing a part of the ¹ H NMR spectrum of the compound obtained in Synthesis Example 14 (i). It is an enlarged view showing another part of the ¹ H NMR spectrum of the compound obtained in Synthesis Example 14 (i). It shows still expanding another portion of the ¹ H NMR spectrum of the compound obtained in Synthesis Example 14 (i).

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

［式中、Ｒ₁及びＲ₂は、それぞれ、置換基を有していてもよいアリール基を表し、Ｒ₃及びＲ₄は、それぞれ、置換基を有していてもよいアルキル基、アルケニル基、アルキニル基、アリール基、または−（ＣＨ₂）₃−Ａを表し、Ａは、下記式（ｉ）で示される構造であり、ｎは４〜６の整数を表す。］

［式中、Ｒ₅、Ｒ₆及びＲ₇はそれぞれ独立して置換基を有していてもよいアルキル基、アルケニル基、アルキニル基、アリール基またはアルコキシ基を表す。］

[Wherein, R ₁ and R ₂ each represents an aryl group which may have a substituent, and R ₃ and R ₄ each represent an alkyl group or an alkenyl group which may have a substituent. , An alkynyl group, an aryl group, or — (CH ₂ ) ₃ —A, wherein A is a structure represented by the following formula (i), and n represents an integer of 4 to 6. ]

[Wherein R ₅ , R ₆ and R ₇ each independently represents an optionally substituted alkyl group, alkenyl group, alkynyl group, aryl group or alkoxy group. ]

In the above formula (I), R ₁ and R ₂ each represents an aryl group which may have a substituent, and examples of the aryl group include a phenyl group, a naphthyl group, an anthranyl group, and a pyrenyl group. For example, when the final synthesized product is used as a separating agent for optical isomers, a phenyl group or a naphthyl group can be preferably exemplified from the viewpoint of improving the separation performance of optical isomers. The aryl group may have one or more substituents such as a fluorine atom, a methoxy group, an ethoxy group, a methyl group, an ethyl group, an isopropyl group, a t-butyl group, an isobutyl group, and a phenyl group. , Allyl group, alkyl silyl group having 1 to 3 carbon atoms, aryl silyl group, allyl silyl group, diallyl ethoxy silyl group, triallyl silyl group, methallyl silyl group, carboxyl group, -COOC ₂ H ₅ , -CONH ₂ , -CONH _{(C 2 H 5), -} CONH (Ph) can be preferably exemplified.
Of the above arylsilyl groups, preferred are a triphenylsilyl group and a t-butyldiphenylsilyl group.

Specific examples of R ₁ and R ₂ include phenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 3,5-dimethylphenyl group, 3,5-dimethoxyphenyl group, 4-methoxynaphthyl group or 4-fluoro. Preferred is a phenyl group.

In the above formula (I), the alkyl group of R ₃ and R ₄ can be exemplified by those having 1 to 22 carbon atoms, and particularly preferably those having 1 to 8, 10, 12, 16, 20, and 22. Specific examples of the alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, pentyl group, hexyl group, octyl group and dodecyl group. And hexadecyl group.

In the above formula (I), the alkenyl group of R ₃ and R ₄ is a monovalent unsaturated hydrocarbon group obtained by removing one hydrogen atom from any carbon atom of a branched or unbranched alkene. And those having 2 to 22 carbon atoms, particularly 2 to 8, 18, 20, and 22 are preferable. The free valence may be on an unsaturated carbon atom such as a vinyl group (CH ₂ ═CH—) or on a saturated carbon atom such as an allyl group (CH ₂ ═CHCH ₂ —). May be. A particularly preferred example of the alkenyl group is a 2-propenyl group.

An alkynyl group is a monovalent unsaturated hydrocarbon group obtained by removing one hydrogen atom from any carbon atom of a branched or unbranched alkyne, and has 2 to 6 carbon atoms, particularly 2 to 3 carbon atoms. Is preferred. The free valence may be on an unsaturated carbon atom, for example an ethynyl group (CH≡C—), or on a saturated carbon atom, for example a propargyl group (CH≡CCH ₂ —). Also good.

In the above formula (I), the aryl group of R ₃ and R ₄ is a monovalent group obtained by removing one hydrogen atom from the ring-constituting carbon atom of a monocyclic or polycyclic aromatic hydrocarbon, The thing of Formula 6-16 can illustrate preferably. Specific examples of the aryl group include a phenyl group, a naphthyl group, an anthranyl group, a pyrenyl group, and the like. Is particularly preferable.

The alkyl group, alkenyl group, alkynyl group or aryl group of R ₃ and R ₄ may have one or more substituents.
Examples of such a substituent include a fluorine atom, a methoxy group, an ethoxy group, an ethyl group, a trimethylsilyl group, a carboxyl group, —COOC ₂ H ₅ , —CONH ₂ , —CONH (C ₂ H ₅ ), and —CONH (Ph). Can be mentioned.

When R ₃ and R ₄ are — (CH ₂ ) ₃ —A, A is a structure represented by the following formula (i).

In the above formula, R ₅ , R ₆ and R ₇ each independently represents an optionally substituted alkyl group, alkenyl group, alkynyl group, aryl group or alkoxy group, an alkyl group, an alkenyl group, Examples of the alkynyl group and aryl group are preferably the same as those described above for R ₃ and R ₄ , more preferably examples of the alkyl group include a methyl group and an ethyl group, and examples of the alkenyl group include an allyl group and a methallyl group. Further preferable examples can be given. Preferred examples of the alkoxy group include those having 1 to 3 carbon atoms such as a methoxy group, an ethoxy group, and a propoxy group.
Among the silyl groups represented by the above formula (i), particularly preferred are triallylsilyl group, diallylmethylsilyl group, allyldimethylsilyl group, methoxysilyl group and ethoxysilyl group.

［式中、Ｒ₁及びＲ₂は、それぞれ、上記式（Ｉ）のＲ₁及びＲ₂と同じである。］

［式中、Ｒ₁及びＲ₂は、それぞれ、上記式（Ｉ）のＲ₁及びＲ₂と同じであり、Ｒ₃及びＲ₄は、それぞれ、上記式（Ｉ）のＲ₃及びＲ₄と同じである。］

［式中、Ｒ₁及びＲ₂は、それぞれ、上記式（ＩＩ）のＲ₁及びＲ₂と同じであり、Ｒ₃及びＲ₄は、それぞれ、上記式（ＩＩＩ）のＲ₃及びＲ₄と同じであり、ｎは４〜６の整数を表す。］ The compound of the present invention provides a binaphthyl derivative B obtained by substituting the bromo group at the 6,6′-position of the binaphthyl derivative A represented by the following formula (II) with R ₃ and R _{4 represented} by the following formula (III), respectively. A step of hydrolyzing the 2,2′-position methoxy group of the binaphthyl derivative B to obtain a binaphthyl derivative C in which the methoxy group is converted to a hydroxyl group, and each of the hydroxyl groups of the binaphthyl derivative C with a polyethylene glycol derivative. And D step of obtaining a compound represented by the following formula (I) having a crown ether-like cyclic structure by crosslinking.

[Wherein, R ₁ and R ₂ are the same as R ₁ and R _{2 in} the formula (I), respectively. ]

Wherein, R ₁ and R ₂ are each the same as R ₁ and R ₂ in the formula (I), R ₃ and R _4, respectively, and R ₃ and R ₄ in the formula (I) The same. ]

Wherein, R ₁ and R ₂ are each the same as R ₁ and R ₂ in the formula (II), R ₃ and R _4, respectively, and R ₃ and R ₄ in the formula (III) It is the same and n represents the integer of 4-6. ]

  In the present invention, the binaphthyl derivative A represented by the formula (II) can be synthesized, for example, through the step A including the following steps (1) to (3), but is not limited to this production method. Absent.

(1) 2,6′-dibromo-1,2′-dimethoxy-1,1′-binaphthyl (manufactured by Tokyo Chemical Industry Co., Ltd.) (a) is brominated at 6,6′-dibromo- 2,2′-Dimethoxy-1,1′-binaphthyl (b) is obtained.

In this case, selective bromination at the 6,6′-position, for example, dissolved N, N′-dibromo-5,5′-dimethylhydantoin (hereinafter also referred to as DBH) in the absence of Lewis acid. In a solvent such as dichloroethane, chloroform and dichloromethane, 0 to 100 ° C., preferably 20 to 30 ° C. from the viewpoint of suppressing the formation of by-products, 10 to 30 hours, more preferably 20 to 30 hours. it can.
In the step (1), the amount of DBH used is 2 to 3 molar equivalents with respect to 1 molar equivalent of the substrate represented by the formula (a) from the viewpoint of yield and peaking of the effect. Preferably, it is 2.1-2.2 molar equivalent. N, N′-dibromo-5,5′-dimethylhydantoin can be prepared by adding bromine and sodium hydroxide to 5,5′-dimethylhydantoin, and can also be obtained as a commercial product.

(2) Next, the 3,3′-position of the compound represented by (b) is iodinated to produce 6,6′-dibromo-3,3′-diiodo-2,2′-dimethoxy-1,1′-binaphthyl. (C) is obtained.

In this case, the selective iodination at the 3,3′-position is performed by, for example, converting the compound represented by the formula (b) into N, N′-diiodo-5,5′-dimethylhydantoin (DIH) and Bi (OTf). _In a solvent such as dichloroethane, chloroform or dichloromethane in which a Lewis acid such as ₃ is dissolved, 0 to 100 ° C., preferably 20 to 30 ° C., more preferably 10 to 30 hours from the viewpoint of suppressing the formation of by-products. Can be made to react for 20 to 30 hours.
In the step (2), the amount of DIH used is 1.2 to 2.2 molar equivalents relative to 1 molar equivalent of the substrate represented by the formula (a) from the viewpoint of yield and peaking of the effect. It is preferable that it is 1.5-1.6 molar equivalent.
In the step (2), the amount of the Lewis acid such as Bi (OTf) ₃ used is 0.05 to 1 mol equivalent of the substrate represented by the formula (b) from the viewpoint of the yield and the peak of the effect. It is preferably ˜0.20 molar equivalent, and more preferably 0.10 molar equivalent. In addition, the amount of Lewis acid such as Bi (OTf) ₃ used is preferably 10 to 20 and more preferably 15 in terms of molar ratio to DIH from the viewpoint of yield and peaking of the effect. A Lewis acid such as Bi (OTf) ₃ can be obtained as a commercial product.

(3) Further, the iodo group at the 3,3 ′ position of 6,6′-dibromo-2,2′-dimethoxy-1,1′-binaphthyl represented by the above formula (c) is substituted with R ₁ and R ₂ , respectively. By replacement, the binaphthyl derivative A represented by the formula (II) is obtained.
In this case, replacing only the 3,3′-position of the compound represented by the formula (c) with the R ₁ and R ₂ can be performed, for example, by a Suzuki-Miyaura cross-coupling reaction.
In this step, the Suzuki-Miyaura cross-coupling reaction is carried out in the presence of a compound represented by the formula (c), a catalyst containing palladium such as tetrakis (triphenylphosphine) palladium, palladium acetate, and a base such as potassium carbonate. It is a reaction that occurs by reacting with boronic acid.
The reaction temperature in this step is preferably 80 to 120 ° C., and more preferably 100 ° C. in order to reliably replace only the 3,3 ′ position with the above R ₁ and R ₂ .
Examples of the solvent that can be used in this step include N, N-dimethylformamide (hereinafter also referred to as DMF) and toluene.
In this step, the amount of the catalyst containing palladium is 0.05 to 0.20 molar equivalents relative to 1 molar equivalent of the substrate represented by the formula (c) from the viewpoint of yield and peaking of the effect. It is preferable that it is 0.08 to 0.12 molar equivalent.

Examples of the aryl group of the arylboronic acid used in the step (3) include a phenyl group, a naphthyl group, an anthranyl group, and a pyrenyl group. For example, when the final product is used as a separating agent for optical isomers, From the viewpoint of improving the separation performance of the body, a phenyl group or a naphthyl group can be preferably exemplified. The aryl group may have one or more substituents such as a fluorine atom, a methoxy group, an ethoxy group, a methyl group, an ethyl group, an isopropyl group, a t-butyl group, an isobutyl group, and a phenyl group. , Allyl group, alkyl silyl group having 1 to 3 carbon atoms, aryl silyl group, allyl silyl group, diallyl ethoxy silyl group, triallyl silyl group, methallyl silyl group, carboxyl group, -COOC ₂ H ₅ , -CONH ₂ , -CONH _{(C 2 H 5), -} CONH (Ph) can be preferably exemplified.
Of the above arylsilyl groups, preferred are a triphenylsilyl group and a t-butyldiphenylsilyl group.
In the case where R ₁ and R ₂ are aryl groups having a substituent and the substituent includes a silyl group, for example, diallyl [4- (4,4,4] described in Tetrahedron vol.63 (2007) 11467-11474 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] ethoxysilane, commercially available 4-triallylsilylphenylboronic acid, 4- (triphenylsilyl) phenylboronic acid It can be produced by reacting such an aryl boronic acid.

Among these, the aryl group is phenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 3,5-dimethylphenyl group, 3,5-dimethoxyphenyl group, p-methylphenyl group, 4-fluorophenyl group, etc. As the aryl boronic acid, a commercially available one can be used, and can be preferably exemplified. For example, those described in the catalog of Suzuki Coupling Reagents published by Sigma-Ardrich can also be used.
Binaphthyl derivative (c) can be easily synthesized in high yield by using a reaction using Lewis acid such as Sc (OTf) ₃ or Bi (OTf) ₃ and DIH to obtain binaphthyl derivative (c) as described above. Is possible.

In the step B, a binaphthyl derivative B is obtained by replacing the bromo groups at the 6 and 6 ′ positions of the binaphthyl derivative A represented by the formula (II) with R ₃ and R ₄ represented by the formula (III), respectively. is there.

［式中、Ｒは置換基を有していてもよいアルキル基、アルケニル基、アルキニル基またはアリール基を表し、Ｍｇはマグネシウムを表し、Ｘは塩素、臭素又はヨウ素を表す。］ In the first aspect of the step B, the binaphthyl derivative A represented by the above formula (II) and the compound represented by the following formula (IV) are reacted in the presence of a transition metal catalyst to produce the above formula (III). It is preferable to obtain the binaphthyl derivative B shown by these.

[Wherein, R represents an optionally substituted alkyl group, alkenyl group, alkynyl group or aryl group, Mg represents magnesium, and X represents chlorine, bromine or iodine. ]

The compound represented by the above formula (IV) is an organomagnesium halide known as a Grignard reagent.
Examples of the alkyl group for R include those having 1 to 22 carbon atoms, and those having 1 to 8, 10, 12, 16, 20, and 22 are particularly preferable. Specific examples of the alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, pentyl group, hexyl group, octyl group and dodecyl group. And hexadecyl group.
The alkenyl group of R is a monovalent unsaturated hydrocarbon group obtained by removing one hydrogen atom from any carbon atom of a branched or unbranched alkene, and has 2 to 22 carbon atoms, particularly 2 to 8 carbon atoms. , 18, 20, and 22 are preferable. The free valence may be on an unsaturated carbon atom such as a vinyl group (CH ₂ ═CH—) or on a saturated carbon atom such as an allyl group (CH ₂ ═CHCH ₂ —). May be. A particularly preferred example of the alkenyl group is a 2-propenyl group.
The alkynyl group of R is a monovalent unsaturated hydrocarbon group obtained by removing one hydrogen atom from any carbon atom of a branched or unbranched alkyne, and has 2 to 6 carbon atoms, particularly 2 to 3 carbon atoms. Are preferred. The free valence may be on an unsaturated carbon atom, for example an ethynyl group (CH≡C—), or on a saturated carbon atom, for example a propargyl group (CH≡CCH ₂ —). Also good.
Examples of the aryl group for R include a phenyl group, a naphthyl group, an anthranyl group, and a pyrenyl group.
The above alkyl group, alkenyl group, alkynyl group or aryl group may have one or more substituents. Examples of such a substituent include a fluorine atom, a methoxy group, an ethoxy group, an ethyl group, a trimethylsilyl group, a carboxyl group, —COOC ₂ H ₅ , —CONH ₂ , —CONH (C ₂ H ₅ ), and —CONH (Ph). Can be mentioned.

  X in the above formula (IV) is chlorine, bromine or iodine, and bromine is preferably used.

The above organic magnesium halide can be synthesized by reacting a raw material organic halide with metallic magnesium mainly in an ether or tetrahydrofuran (THF) solvent under an inert gas atmosphere. Moreover, you may use what is marketed. Examples of commercially available Grignard reagents include methyl Grignard reagents, ethyl Grignard reagents, propyl Grignard reagents, cyclopentyl Grignard reagents, cyclohexyl Grignard reagents, and other alkyl Grignard reagents, vinyl Grignard reagents, allyl Grignard reagents, crotyl Grignard reagents, Alkyl Grignard reagents, such as ril Grignard reagents, cinnamyl Grignard reagents, phenyl Grignard reagents, naphthyl Grignard reagents, aryl phenyl Grignard reagents such as biphenyl Grignard reagents, benzyl Grignard reagents, phenyl ethyl Grignard reagents, naphthyl methyl Grignard reagents, naphthyl ethyl Grignard reagents, etc. And aralkyl Grignard reagents.
Of the above organic magnesium halides, it is practically preferable to use allylmagnesium bromide.

  The transition metal catalyst used in the first aspect of the step B is preferably one containing palladium, and dichloro [1,1′-bis (diphenylphosphine) ferrocene] palladium is preferably used.

  As the solvent used in the first aspect of Step B, an ether solvent is preferably used, and examples thereof include diethyl ether and tetrahydrofuran. Among these, diethyl ether is particularly preferable.

  In the first aspect of the step B, the reaction is carried out in a system in which the solvent is refluxed, and the temperature of the constant temperature oil tank used for the reflux is set to be about 30 to 40 ° C. higher than the boiling point of the solvent to be used. The time is preferably set to 15 to 24 hours, more preferably 20 to 22 hours, from the viewpoint of surely substituting R at the 6 and 6 'positions.

［式中、Ｙは置換基を有していてもよいアリール基を表す。］ In the second embodiment of the step B, the binaphthyl derivative A represented by the above formula (II) and the compound represented by the following formula (V) are reacted in the presence of a palladium catalyst and a base to produce the above formula (III). It is preferable to obtain a binaphthyl derivative B represented by This reaction is known as the Suzuki-Miyaura cross-coupling reaction.

[Wherein Y represents an aryl group which may have a substituent. ]

The aryl group of the above formula (V) is a monovalent group obtained by removing one hydrogen atom from a ring-constituting carbon atom of a monocyclic or polycyclic aromatic hydrocarbon, and has 6 to 16 carbon atoms. Preferred examples can be given. Specific examples of the aryl group include a phenyl group, a naphthyl group, an anthranyl group, and a pyrenyl group. For example, when the final product is used as a separating agent for an optical isomer, the phenyl group is used from the viewpoint of separation performance of the optical isomer. Is particularly preferable.
Examples of the substituent that the aryl group of the above formula (V) may have include a fluorine atom, a methoxy group, an ethoxy group, an ethyl group, a trimethylsilyl group, a carboxyl group, —COOC ₂ H ₅ , —CONH ₂ , _{-CONH (C 2 H 5),} - CONH (Ph) and the like.
As the compound (arylboronic acid) represented by the above formula (V), for example, those commercially available from the above-mentioned Sigma-Ardorich and the like can be used, and it is preferable to use phenylboronic acid.

  In the second aspect of the step B, tetrakis (triphenylphosphine) is used as a catalyst containing palladium when the binaphthyl derivative A represented by the above formula (II) is reacted with the compound represented by the above formula (V). It is preferable to use palladium (0). Moreover, it is preferable to use potassium carbonate as a base to be present during the above reaction.

  As the solvent used in the second aspect of the step B, an ether solvent is preferably used, for example, tetrahydrofuran is preferably used.

  In the second aspect of the step B, the reaction temperature is 60 to 100 ° C., preferably 75 to 85 ° C., and the reaction time is 16 to 30 hours, more preferably 20 to 24 hours. From the viewpoint of surely substituting the above position with Y.

The C step can be performed by a reaction under mild conditions because the 2,2 ′ position of binaphthyl is highly reactive among the binaphthyl derivative B. Examples of such reaction conditions include dealkylation reaction with boron tribromide under ice cooling to room temperature.
As more specific conditions, the reaction is usually carried out at 10 to 5 ° C. for 1.5 to 2 hours. This reaction is usually carried out in a solvent such as dichloromethane or dichloroethane.
It is preferable to perform the C step under such conditions from the viewpoint of suppressing the influence on the other structure of the binaphthyl derivative B and obtaining the binaphthyl derivative C with higher yield.

Said D process can be performed on the conditions on which polyoxyethylene can be bridge | crosslinked to the 2,2'-position hydroxyl group of binaphthyl derivative C. Such crosslinking can be performed using hydrolysis. For example, by reacting polyoxyethylene glycol ditosylate having 5 to 7 repeating oxyethylene groups under alkaline conditions, It can be carried out by crosslinking between 2, 2 ′ hydroxyl groups.
This reaction is usually performed at 60 to 80 ° C. for 15 to 24 hours. In addition, this reaction is usually carried out in a solvent such as tetrahydrofuran, dichloromethane or dichloroethane.

［式中、Ｒ₁及びＲ₂は、それぞれ、置換基を有していてもよいアリール基を表す。］

［式中、Ｒ₁及びＲ₂は、それぞれ、上記式（ＩＩ）のＲ₁及びＲ₂と同じである。］

［式中、Ｒ₁及びＲ₂は、それぞれ、上記式（ＩＩ）のＲ₁及びＲ₂と同じである。］

［式中、Ｒ₁及びＲ₂は、それぞれ、上記式（ＩＩ）のＲ₁及びＲ₂と同じであり、Ｒ₈、Ｒ₉及びＲ₁₀は、それぞれ、独立して置換基を有していてもよいアルキル基、アルケニル基、アルキニル基、アリール基またはアルコキシ基を表す。］ In the present invention, a B ′ step in which a binaphthyl derivative A represented by the following formula (II) and allylmagnesium bromide are reacted in the presence of a catalyst containing palladium to obtain a compound represented by the following formula (VI); A C ′ step in which the methoxy group at the 2,2 ′ position of the compound is hydrolyzed to obtain a compound in which the methoxy group becomes a hydroxyl group, and each of the hydroxyl groups of the compound is crosslinked with a polyethylene glycol derivative to form a crown ether-like compound. A D ′ step for obtaining a compound represented by the following formula (VII) having a cyclic structure and a binaphthyl group, an E step for hydrosilylating the 6,6 ′ position of the compound represented by the following formula (VII), and hydrosilylation: Provided is a method for producing a compound represented by the following formula (VIII), which comprises the F step of derivatizing the performed 6,6′-position as represented by the following formula (VIII). .

[Wherein, R ₁ and R ₂ each represents an aryl group which may have a substituent. ]

[Wherein, R ₁ and R ₂ are the same as R ₁ and R _{2 in} the formula (II), respectively. ]

[Wherein, R ₁ and R ₂ are the same as R ₁ and R _{2 in} the formula (II), respectively. ]

[Wherein, R ₁ and R ₂ are the same as R ₁ and R _{2 in} the formula (II), respectively, and R ₈ , R ₉ and R ₁₀ each independently have a substituent. And may represent an alkyl group, an alkenyl group, an alkynyl group, an aryl group or an alkoxy group. ]

  Said B 'process is the same process as the above-mentioned B process except restrict | limiting so that allyl magnesium bromide may be used as R-MgX shown by Formula (IV) used at the above-mentioned B process. Through this step, the compound represented by the above formula (VI) is obtained.

  The compound represented by the above formula (VI) is subjected to the same C ′ step and D ′ step as the above-described C step and D step, thereby giving the formula (VII) having the above crown ether-like cyclic structure and binaphthyl group. Is obtained. In addition, the same conditions as the above-mentioned C process and D process can be used for each condition of C 'process and D' process.

  For the 2-propenyl group at the 6,6′-position of the compound represented by the formula (VII), the E step for hydrosilylation includes the compound represented by the formula (VII), tetrabutylammonium hexachloroplatinate (IV), After dissolving in a mixed solvent such as dichloromethane and diethyl ether in the presence of di-μ-chlorodichlorobis (ethylene) diplatinum (II) and cooling, for example, trichlorosilane, dichloromethylsilane, chlorodimethylsilane, etc. In this step, 20 to 30 ° C., preferably 25 ° C., and 24 to 48 hours, preferably 36 to 48 hours are added.

In the F step, with respect to the compound obtained through the E step, halogen atoms such as a chlorine atom introduced into the 6,6′-position silyl group are substituted with R ₈ , R ₉ and R represented by the above formula (VIII). _This is the process of replacing with ₁₀ . In the F step, the following two embodiments are preferably exemplified.

In the first aspect of Step F, the reaction is performed using the Grignard reagent described in the first aspect of Step B above. The same Grignard reagent as that described above can be used. Among these, an allyl Grignard reagent and a methallyl Grignard reagent can be preferably used.
The reaction at this time is preferably carried out using an ether solvent such as diethyl ether or tetrahydrofuran at a temperature of 20 to 30 ° C., more preferably 25 ° C., for 8 to 12 hours, more preferably 10 to 12 hours. .

On the other hand, in the second aspect of the F step, a halogen atom such as a chlorine atom introduced into the 6,6′-position silyl group is substituted with 1 to 3 carbon atoms in the presence of a base such as triethylamine or pyridine. In this step, a lower alcohol is allowed to act to replace the halogen atom introduced into the silyl group with a lower alkoxy group.
Among lower alcohols having 1 to 3 carbon atoms, preferred are methanol and ethanol.
The temperature at this time is preferably 20-30 ° C., and the reaction time is more preferably 12-15 hours.

  The binaphthyl derivative obtained in each step may be purified, or the product may be used as a raw material for the next step as it is.

  Since the compound having a crown ether structure and a binaphthyl group produced by the present invention is expected to introduce various substituents while maintaining the asymmetric structure, it has high performance in asymmetric synthesis and optical resolution. Expected to be used as a simultaneous identification agent. Therefore, the present invention greatly contributes to the development of useful asymmetric synthesis catalysts and separation agents for optical isomers, and the development of new materials in various fields such as pharmaceuticals, chemical products, cosmetics, and electronic materials using them. Is expected to do.

In this example, all moisture sensitive operations were performed in a nitrogen atmosphere dried over phosphorus pentoxide. The NMR spectrum was measured with a Fourier transform nuclear magnetic resonance apparatus (JNM-ECX400) (400 MHz for ¹ H NMR, 400 MHz for ¹³ C NMR, 400 MHz for ¹⁹ F NMR). The chemical shift was δ ppm, tetramethylsilane was reported as ¹ H NMR, and deuterated chloroform (δ 77.0) as ¹³ C NMR.

窒素雰囲気下、化合物（ａ）（１０００ｍｇ，３．１８１ｍｍｏｌ）およびＮ，Ｎ’−ジブロモ−５，５−ジメチルヒダントイン（ＤＢＨ） （１９０９．９ｍｇ，６．６８０ｍｍｏｌ）をｄｉｓｔ. ＣＨ₂Ｃｌ₂ （４０ ｍＬ）に溶解させ、室温で２４時間攪拌した。反応終了後、反応混合物は５重量％硫酸ナトリウム水溶液でクエンチし、水層をＣＨ₂Ｃｌ₂で抽出した。集めた有機層は飽和塩化ナトリウム水溶液で洗浄し、ＭｇＳＯ₄で乾燥させた後、ろ過・濃縮し、目的の化合物（ｂ）を得た（１５０１ｍｇ，１００％）。 <Synthesis Example 1>
Bromination of 6,6′-position of 2,2′-dimethoxy-1,1′-binaphthyl (a)

Under a nitrogen atmosphere, compound (a) (1000 mg, 3.181 mmol) and N, N′-dibromo-5,5-dimethylhydantoin (DBH) (1909.9 mg, 6.680 mmol) were added to dist. CH ₂ Cl ₂ (40 mL) and stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was quenched with 5 wt% aqueous sodium sulfate and the aqueous layer was extracted with CH ₂ Cl ₂ . The collected organic layer was washed with a saturated aqueous sodium chloride solution, dried over MgSO ₄ , filtered and concentrated to obtain the target compound (b) (1501 mg, 100%).

The measurement result of NMR of the obtained (b) is shown below. The ¹ H NMR spectrum is shown in FIG.
¹ H NMR (CDCl ₃ ) δ 3.762 (s, 6H), 6.930 (d, J = 9.2)
Hz, 2H), 7.271 (d, J = 8.8 Hz, 2H), 7.461 (d, J = 8.8 Hz, 2H), 7.888 (d, J = 9.2 Hz, 2H), 8.020 (s, 2H).

窒素雰囲気下、化合物（ｂ）（１４１９．１ｍｇ, ３．００５ｍｍｏｌ）、Ｎ，Ｎ’−ジヨード−５、５’ジメチルヒダントイン（ＤＩＨ）（１７１２．８ｍｇ, ４．５０８ｍｍｏｌ）およびビスマス（ＩＩＩ）トリフラート（１９７．２ｍｇ, ０．３００５ｍｍｏｌ）をｄｉｓｔ. ＣＨ₂Ｃｌ₂（４０ｍＬ）に溶解させ、室温で１０時間攪拌した。反応終了後、反応混合物は５重量％硫酸ナトリウムス水溶液でクエンチし、水層をＣＨ₂Ｃｌ₂で抽出した。集めた有機層は飽和炭酸ナトリウム水溶液と飽和塩化ナトリウム水溶液で洗浄し、ＭｇＳＯ₄で乾燥させた後、ろ過・濃縮し、粗生成物を得た。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ＣＨＣｌ₃）により原点抜きをし、目的の化合物（ｃ）を得た（２１７５．９ｍｇ,９３％）。 <Synthesis Example 2>
Iodination of 3,3′-position of 6,6′-dibromo-2,2′-dimethoxy-1,1′-binaphthyl (b)

Under a nitrogen atmosphere, compound (b) (1419.1 mg, 3.005 mmol), N, N′-diiodo-5,5′dimethylhydantoin (DIH) (1712.8 mg, 4.508 mmol) and bismuth (III) triflate ( 197.2 mg, 0.3005 mmol) was dissolved in dist. CH ₂ Cl ₂ (40 mL) and stirred at room temperature for 10 hours. After completion of the reaction, the reaction mixture was quenched with 5% by weight aqueous sodium sulfate solution, and the aqueous layer was extracted with CH ₂ Cl ₂ . The collected organic layer was washed with a saturated aqueous sodium carbonate solution and a saturated aqueous sodium chloride solution, dried over MgSO ₄ , filtered and concentrated to obtain a crude product. The obtained crude product was subjected to silica gel column chromatography (CHCl ₃ ) to remove the origin to obtain the desired compound (c) (2175.9 mg, 93%).

The NMR measurement results of the obtained (c) are shown below. The ¹ H NMR spectrum is shown in FIG.
¹ H NMR (CDCl ₃ ) δ 3.751 (s, 6H), 6.877 (d, J = 9.2)
Hz, 2H), 7.283 (d, J = 9.2 Hz, 2H), 8.010 (s, 2H), 8.279 (s, 2H).

窒素雰囲気下、化合物（Ｃ）（１００ｍｇ, ０．１３８１ｍｍｏｌ）、フェニルボロン酸（３３．６８ｍｇ, ０．２７６３ ｍｍｏｌ）、炭酸カリウム（７６．３６ｍｇ, ０．５５２５ ｍｍｏｌ）およびテトラキス（トリフェニルホスフィン）パラジウム（０）（１５．９６ｍｇ, ０．０１３８１ｍｍｏｌ）をｄｉｓｔ. ＤＭＦ（５ｍＬ）に溶解させ、１００℃で２４時間攪拌した。反応終了後、反応混合物を室温まで冷却し、ＤＭＦを除去した後、ヘキサン／酢酸エチル＝１／５の混合溶媒に溶解させた。続いて、飽和塩化アンモニウム水溶液により二回洗浄し、水層をヘキサン／酢酸エチル＝１／５の混合溶媒で抽出した。集めた有機層は飽和塩化ナトリウム水溶液で二回洗浄し、ＭｇＳＯ₄で乾燥させた後、ろ過・濃縮し、粗生成物を得た。得られた粗生成物をプレパラＴＬＣ（ヘキサン／酢酸エチル＝６／１）により精製し、目的の化合物（ｄ−１）を得た（６４．３ｍｇ, ７８％）。 <Synthesis Example 3>

Under nitrogen atmosphere, Compound (C) (100 mg, 0.1381 mmol), phenylboronic acid (33.68 mg, 0.2763 mmol), potassium carbonate (76.36 mg, 0.5525 mmol) and tetrakis (triphenylphosphine) palladium (0) (15.96 mg, 0.01381 mmol) was dissolved in dist. DMF (5 mL) and stirred at 100 ° C. for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, DMF was removed, and the mixture was dissolved in a mixed solvent of hexane / ethyl acetate = 1/5. Subsequently, the mixture was washed twice with a saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with a mixed solvent of hexane / ethyl acetate = 1/5. The collected organic layer was washed twice with a saturated aqueous sodium chloride solution, dried over MgSO ₄ , filtered and concentrated to obtain a crude product. The obtained crude product was purified by prepara TLC (hexane / ethyl acetate = 6/1) to obtain the target compound (d-1) (64.3 mg, 78%).

The NMR measurement results of the obtained (d-1) are shown below. The ¹ H NMR spectrum is shown in FIGS. 3 and 4, and the ¹³ C NMR spectrum is shown in FIG.
¹ H NMR (CDCl ₃ ) δ 3.793 (s, 6H), 7.100 (d, J = 9.2 Hz, 2H), 7.303 (d, J = 9.2 Hz, 2H), 7.404 (S, 2H), 7.492-7.612 (m, 10H), 8.038 (s, 2H).
¹³ C NMR (CDCl ₃ ) δ 6.682, 115.892, 117.865, 118.294, 127.276, 127.781, 128.258, 128.544, 129.707, 129.993, 132. 806, 140.005, 141.282, 154.497.

窒素雰囲気下、化合物（ｃ）（１０００ｍｇ, １．３８２ｍｍｏｌ）、４−メチルフェニルボロン酸（３７５．６ｍｇ, ２．６３ｍｍｏｌ）、炭酸カリウム（７６３．６ｍｇ, ５．５２５ｍｍｏｌ）およびテトラキス（トリフェニルホスフィン）パラジウム（０） （１５９．６ｍｇ,０．１３８１ ｍｍｏｌ）をｄｉｓｔ. ＤＭＦ （５０ｍＬ）に溶解させ、１００℃で２７時間攪拌した。反応終了後、反応混合物を室温まで冷却し、ＤＭＦを除去した後、ヘキサン／酢酸エチル＝１／５の混合溶媒に溶解させた。続いて、飽和塩化アンモニウム水溶液により二回洗浄し、水層をヘキサン／酢酸エチル＝１／５の混合溶媒で抽出した。集めた有機層は飽和塩化ナトリウム水溶液で二回洗浄し、ＭｇＳＯ₄で乾燥させた後、ろ過・濃縮し、粗生成物を得た。得られた粗生成物をシリカゲルフラッシュカラムクロマトグラフィーにより精製し、目的の化合物（ｄ−２）を得た（６４５．８ ｍｇ, ７２％）。 <Synthesis Example 4>

Under nitrogen atmosphere, compound (c) (1000 mg, 1.382 mmol), 4-methylphenylboronic acid (375.6 mg, 2.63 mmol), potassium carbonate (763.6 mg, 5.525 mmol) and tetrakis (triphenylphosphine) Palladium (0) (159.6 mg, 0.1381 mmol) was dissolved in dist. DMF (50 mL) and stirred at 100 ° C. for 27 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, DMF was removed, and the mixture was dissolved in a mixed solvent of hexane / ethyl acetate = 1/5. Subsequently, the mixture was washed twice with a saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with a mixed solvent of hexane / ethyl acetate = 1/5. The collected organic layer was washed twice with a saturated aqueous sodium chloride solution, dried over MgSO ₄ , filtered and concentrated to obtain a crude product. The obtained crude product was purified by silica gel flash column chromatography to obtain the target compound (d-2) (645.8 mg, 72%).

The NMR measurement results of the obtained (d-2) are shown below. The ¹ H NMR spectrum is shown in FIGS. 6 and 7, and the ¹³ C NMR spectrum is shown in FIG. 8, respectively.
¹ H NMR (CDCl ₃ ) δ 2.510 (s, 6H), 3.802 (s, 6H), 7.082 (d, J = 9.2 Hz, 2H), 7.301 (d, J = 9. 2Hz, 2H), 7.389 (d, J = 8Hz, 4H), 7.392 (s, 2H), 7.507 (d, J = 8Hz, 4H), 8.053 (s, 2H).
¹³ C NMR (CDCl ₃ ) δ 21.309, 56.720, 115.872, 117.779, 118.161, 127.295, 128.344, 128.716, 129.269, 129.640, 129.888 , 132.835, 137.116, 137.583, 141.301, 154.535.

窒素雰囲気下、化合物（ｃ）（１００ｍｇ, ０．１３８１ｍｍｏｌ）、４−メトキシフェニルボロン酸（４１．９８ｍｇ, ０．２７６３ｍｍｏｌ）、炭酸カリウム（７６．３６ｍｇ, ０．５５２５ｍｍｏｌ）およびテトラキス（トリフェニルホスフィン）パラジウム（０）（１５．９６ｍｇ, ０．０１３８１ ｍｍｏｌ）をｄｉｓｔ. ＤＭＦ（５ ｍＬ）に溶解させ、１００℃で２４時間攪拌した。反応終了後、反応混合物を室温まで冷却し、ＤＭＦを除去した後、ヘキサン／酢酸エチル＝１／５の混合溶媒に溶解させた。続いて、飽和塩化アンモニウム水溶液により二回洗浄し、水層をヘキサン／酢酸エチル＝１／５の混合溶媒で抽出した。集めた有機層は飽和塩化ナトリウム水溶液で二回洗浄し、ＭｇＳＯ₄で乾燥させた後、ろ過・濃縮し、粗生成物を得た。得られた粗生成物をプレパラＴＬＣ（ヘキサン／酢酸エチル＝１／１）により精製し、目的の化合物ｄ−３を得た（５８．６ｍｇ, ６２％）。 <Synthesis Example 5>

Under nitrogen atmosphere, compound (c) (100 mg, 0.1381 mmol), 4-methoxyphenylboronic acid (41.98 mg, 0.2763 mmol), potassium carbonate (76.36 mg, 0.5525 mmol) and tetrakis (triphenylphosphine) Palladium (0) (15.96 mg, 0.01381 mmol) was dissolved in dist. DMF (5 mL) and stirred at 100 ° C. for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, DMF was removed, and the mixture was dissolved in a mixed solvent of hexane / ethyl acetate = 1/5. Subsequently, the mixture was washed twice with a saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with a mixed solvent of hexane / ethyl acetate = 1/5. The collected organic layer was washed twice with a saturated aqueous sodium chloride solution, dried over MgSO ₄ , filtered and concentrated to obtain a crude product. The obtained crude product was purified by prepara TLC (hexane / ethyl acetate = 1/1) to obtain the target compound d-3 (58.6 mg, 62%).

The NMR measurement results of the obtained (d-3) are shown below. The ¹ H NMR spectrum is shown in FIGS. 9 and 10, and the ¹³ C NMR spectrum is shown in FIG. 11, respectively.
¹ H NMR (CDCl ₃ ) δ 3.805 (s, 6H), 3.945 (s, 6H), 7
. 080 (d, J = 9.2 Hz, 2H), 7.113 (d, J = 8.8 Hz, 4H), 7.300 (d, J = 8.8 Hz, 2H), 7.384 (s , 2H), 7.539 (d, J = 8.4 Hz, 4H), 8.052 (s, 2H).
¹³ C NMR (CDCl ₃ ) δ 55.395, 56.701, 113.966, 115.872, 117.751, 118.046, 127.295, 128.334, 128.830, 129.6612, 131.099 , 132.339, 132.844, 140.967, 154.535, 159.264.

窒素雰囲気下、化合物（ｃ）（８０ｍｇ， ０．１１０５ ｍｍｏｌ）、３，５−ジメチルフェニルボロン酸（３３．１５ｍｇ, ０．２２１０ｍｍｏｌ）、炭酸カリウム（６１．０９ ｍｇ, ０．４４２０ｍｍｏｌ）およびテトラキス（トリフェニルホスフィン）パラジウム（０） （１２．７７ｍｇ, ０．０１１０５ｍｍｏｌ）をｄｉｓｔ. ＤＭＦ（４ ｍＬ）に溶解させ、１００℃で２４時間攪拌した。反応終了後、反応混合物を室温まで冷却し、ＤＭＦを除去した後、ヘキサン／酢酸エチル＝１／５の混合溶媒に溶解させた。続いて、飽和塩化アンモニウム水溶液により二回洗浄し、水層をヘキサン／酢酸エチル＝１／５の混合溶媒で抽出した。集めた有機層は飽和塩化ナトリウム水溶液で二回洗浄し、ＭｇＳＯ₄で乾燥させた後、ろ過・濃縮し、粗生成物を得た。得られた粗生成物をプレパラＴＬＣ（ヘキサン／酢酸エチル＝７／１）により精製し、目的の化合物（ｄ−４）を得た（５６．０ｍｇ, ７４％）。
得られた（ｄ−４）のＮＭＲの測定結果を以下に示す。また前記¹Ｈ ＮＭＲのスペクトルを図１２及び図１３に、¹³Ｃ ＮＭＲのスペクトルを図１４に、それぞれ示す。
¹Ｈ ＮＭＲ （ＣＤＣｌ₃） δ２．４６１ （ｓ, １２Ｈ）, ３．７９４ （ｓ, ６Ｈ）, ７．０７２（ｄ, Ｊ＝９．２ Ｈｚ, ２Ｈ）, ７．１４９（ｓ, ２Ｈ）, ７．２２０（ｓ,
４H）, ７．２９０ （ｄ, Ｊ＝９．２ Ｈｚ, ２Ｈ）, ７．３８３（ｓ, ２Ｈ）, ８．０４１（ｓ, ２Ｈ）.
¹³Ｃ ＮＭＲ （ＣＤＣｌ₃） δ２１．４４２, ５６．６７２, １１５．７２９, １１７．６８４, １１８．１２３, １２７．２２８, １２７．７６２, １２８．３９１, １２８．６９６, １２９.３７３, １２９．５９３, １３２．７６８, １３８．０５０, １３９．９９５, １４１．５５９, １５４．４５９. <Synthesis Example 6>

Under a nitrogen atmosphere, compound (c) (80 mg, 0.1105 mmol), 3,5-dimethylphenylboronic acid (33.15 mg, 0.2210 mmol), potassium carbonate (61.09 mg, 0.4420 mmol) and tetrakis ( Triphenylphosphine) palladium (0) (12.77 mg, 0.01105 mmol) was dissolved in dist. DMF (4 mL) and stirred at 100 ° C. for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, DMF was removed, and the mixture was dissolved in a mixed solvent of hexane / ethyl acetate = 1/5. Subsequently, the mixture was washed twice with a saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with a mixed solvent of hexane / ethyl acetate = 1/5. The collected organic layer was washed twice with a saturated aqueous sodium chloride solution, dried over MgSO ₄ , filtered and concentrated to obtain a crude product. The obtained crude product was purified by prepara TLC (hexane / ethyl acetate = 7/1) to obtain the target compound (d-4) (56.0 mg, 74%).
The NMR measurement results of the obtained (d-4) are shown below. The ¹ H NMR spectrum is shown in FIGS. 12 and 13, and the ¹³ C NMR spectrum is shown in FIG. 14, respectively.
¹ H NMR (CDCl ₃ ) δ 2.461 (s, 12H), 3.794 (s, 6H), 7.072 (d, J = 9.2 Hz, 2H), 7.149 (s, 2H), 7.220 (s,
4H), 7.290 (d, J = 9.2 Hz, 2H), 7.383 (s, 2H), 8.041 (s, 2H).
¹³ C NMR (CDCl ₃ ) δ 21.442, 56.672, 115.729, 117.684, 118.123, 127.228, 127.762, 128.391, 128.696, 129.373, 129.593 , 132.768, 138.050, 139.995, 141.559, 154.459.

窒素雰囲気下、化合物（ｃ）（８０ｍｇ,０．１１０５ ｍｍｏｌ）、３，５−ジメトキシフェニルボロン酸（４０．２２ｍｇ, ０．２２１０ｍｍｏｌ）、炭酸カリウム（６１．０９ ｍｇ, ０．４４２０ｍｍｏｌ）およびテトラキス（トリフェニルホスフィン）パラジウム（０）（１２．７７ｍｇ, ０．０１１０５ｍｍｏｌ）をｄｉｓｔ.ＤＭＦ（４ｍＬ）に溶解させ、１００℃で２４時間攪拌した。反応終了後、反応混合物を室温まで冷却し、ＤＭＦを除去した後、ヘキサン／酢酸エチル＝１／５の混合溶媒に溶解させた。続いて、飽和塩化アンモニウム水溶液により二回洗浄し、水層をヘキサン／酢酸エチル＝１／５の混合溶媒で抽出した。集めた有機層は飽和塩化ナトリウム水溶液で二回洗浄し、ＭｇＳＯ₄で乾燥させた後、ろ過・濃縮し、粗生成物を得た。得られた粗生成物をプレパラＴＬＣ（ヘキサン／酢酸エチル＝ ２／１）により精製し、目的の化合物（ｄ−５）を得た（５３ｍｇ, ６４％）。 <Synthesis Example 7>

Under a nitrogen atmosphere, compound (c) (80 mg, 0.1105 mmol), 3,5-dimethoxyphenylboronic acid (40.22 mg, 0.2210 mmol), potassium carbonate (61.09 mg, 0.4420 mmol) and tetrakis ( Triphenylphosphine) palladium (0) (12.77 mg, 0.01105 mmol) was dissolved in dist.DMF (4 mL) and stirred at 100 ° C. for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, DMF was removed, and the mixture was dissolved in a mixed solvent of hexane / ethyl acetate = 1/5. Subsequently, the mixture was washed twice with a saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with a mixed solvent of hexane / ethyl acetate = 1/5. The collected organic layer was washed twice with a saturated aqueous sodium chloride solution, dried over MgSO ₄ , filtered and concentrated to obtain a crude product. The obtained crude product was purified by preparatory TLC (hexane / ethyl acetate = 2/1) to obtain the target compound (d-5) (53 mg, 64%).

The NMR measurement results of the obtained (d-5) are shown below. The ¹ H NMR spectrum is shown in FIGS. 15 and 16, and the ¹³ C NMR spectrum is shown in FIG. 17, respectively.
¹ H NMR (CDCl ₃ ) δ 3.806 (s, 6H), 3.892 (s, 12H), 6.615 (s, 2H), 6.749 (s, 4H), 7078 (d, J = 8.8 Hz, 2H), 7.303 (d, J = 9.2 Hz, 2H), 7.417 (s, 2H),
8.082 (s, 2H).
¹³ C NMR (CDCl ₃ ) δ 55.528, 56.710, 99.788, 108.130, 115.510, 117.846, 118.323, 127.209, 128.344, 128.487, 129. 726, 132.701, 141.196, 141.997, 154.383, 160.675.

窒素雰囲気下、化合物（ｃ）（８０ｍｇ, ０．１１０５ ｍｍｏｌ）、６−メトキシ−２−ナフチルボロン酸（４４．６５ｍｇ, ０．２２１０ ｍｍｏｌ）、炭酸カリウム（６１．０９ｍｇ, ０．４４２０ｍｍｏｌ）およびテトラキス（トリフェニルホスフィン）パラジウム（０）（１２．７７ｍｇ, ０．０１１０５ ｍｍｏｌ）をｄｉｓｔ. ＤＭＦ（４ｍ
Ｌ）に溶解させ、１００℃で２４時間攪拌した。反応終了後、反応混合物を室温まで冷却し、ＤＭＦを除去した後、ヘキサン／酢酸エチル＝１／５の混合溶媒に溶解させた。続いて、飽和塩化アンモニウム水溶液により二回洗浄し、水層をヘキサン／酢酸エチル＝１／５の混合溶媒で抽出した。集めた有機層は飽和塩化ナトリウム水溶液で二回洗浄し、ＭｇＳＯ₄で乾燥させた後、ろ過・濃縮し、粗生成物を得た。得られた粗生成物をプレパラＴＬＣ（ヘキサン／酢酸エチル＝３／１）により精製し、目的の化合物（ｄ−６）を得た（５０．４ｍｇ, ５９％）。 <Synthesis Example 8>

Under nitrogen atmosphere, compound (c) (80 mg, 0.1105 mmol), 6-methoxy-2-naphthylboronic acid (44.65 mg, 0.2210 mmol), potassium carbonate (61.09 mg, 0.4420 mmol) and tetrakis (Triphenylphosphine) palladium (0) (12.77 mg, 0.01105 mmol) was added to dist. DMF (4 m
L) and stirred at 100 ° C. for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, DMF was removed, and the mixture was dissolved in a mixed solvent of hexane / ethyl acetate = 1/5. Subsequently, the mixture was washed twice with a saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with a mixed solvent of hexane / ethyl acetate = 1/5. The collected organic layer was washed twice with a saturated aqueous sodium chloride solution, dried over MgSO ₄ , filtered and concentrated to obtain a crude product. The resulting crude product was purified by preparatory TLC (hexane / ethyl acetate = 3/1) to obtain the target compound (d-6) (50.4 mg, 59%).

The NMR measurement results of the obtained (d-6) are shown below. The ¹ H NMR spectrum is shown in FIGS. 18 and 19, and the ¹³ C NMR spectrum is shown in FIG. 20, respectively.
¹ H NMR (CDCl ₃ ) δ3.821 (s, 6H), 3.981 (s, 6H), 7.147 (d, J = 9.2 Hz, 2H), 7.253 (d, J = 8 .8 Hz, 2H), 7.265 (s, 2H), 7.324 (d, J = 9.2 Hz, 2H), 7.498 (s, 2H), 7.698 (d, J = 8 .4 Hz, 2H), 7.848 (d, J = 8.8 Hz, 2H), 7.919 (d, J = 8.4 Hz, 2H), 8.000 (s, 2H), 8. 087 (s, 2H).
¹³ C NMR (CDCl ₃ ) δ 55.395, 56.720, 105.613, 116.149, 117.844, 118.304, 119.448, 126.856, 127.343, 128.410, 128. 630, 128.840, 129.650, 129.717, 132.882, 133.921, 135.294, 141.358, 154.573, 158.044.

窒素雰囲気下、化合物（ｃ）（８０ｍｇ, ０．１１０５ｍｍｏｌ）、４−フルオロフェニルボロン酸（３０．９２ｍｇ, ０．２２１０ｍｍｏｌ）、炭酸カリウム（６１．０９ｍｇ, ０．４４２０ｍｍｏｌ）およびテトラキス（トリフェニルホスフィン）パラジウム（０）（１２．７７ｍｇ, ０．０１１０５ｍｍｏｌ）をｄｉｓｔ. ＤＭＦ（４ｍＬ）に溶解させ、１００℃で２４時間攪拌した。反応終了後、反応混合物を室温まで冷却し、ＤＭＦを除去した後、ヘキサン／酢酸エチル＝１／５の混合溶媒に溶解させた。続いて、飽和塩化アンモニウム水溶液により二回洗浄し、水層をヘキサン／酢酸エチル＝１／５の混合溶媒で抽出した。集めた有機層は飽和塩化ナトリウム水溶液で二回洗浄し、ＭｇＳＯ₄で乾燥させた後、ろ過・濃縮し、粗生成物を得た。得られた粗生成物をプレパラＴＬＣ（ヘキサン／酢酸エチル＝６／１）により精製し、目的の化合物（ｄ−７）を得た（５４ ｍｇ, ７４％）。 <Synthesis Example 9>

Under nitrogen atmosphere, compound (c) (80 mg, 0.1105 mmol), 4-fluorophenylboronic acid (30.92 mg, 0.2210 mmol), potassium carbonate (61.09 mg, 0.4420 mmol) and tetrakis (triphenylphosphine) Palladium (0) (12.77 mg, 0.01105 mmol) was dissolved in dist. DMF (4 mL) and stirred at 100 ° C. for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, DMF was removed, and the mixture was dissolved in a mixed solvent of hexane / ethyl acetate = 1/5. Subsequently, the mixture was washed twice with a saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with a mixed solvent of hexane / ethyl acetate = 1/5. The collected organic layer was washed twice with a saturated aqueous sodium chloride solution, dried over MgSO ₄ , filtered and concentrated to obtain a crude product. The obtained crude product was purified by prepara TLC (hexane / ethyl acetate = 6/1) to obtain the target compound (d-7) (54 mg, 74%).

The NMR measurement results of the obtained (d-7) are shown below. 21 and 22 show the ¹ H NMR spectrum, FIG. 23 shows the ¹³ C NMR spectrum, and FIG. 24 shows the ¹⁹ F NMR spectrum, respectively.
¹ H NMR (CDCl ₃ ) δ 3.813 (s, 6H), 7.080 (d, J = 9.2)
Hz, 2H), 7.275 (t, J = 8.8 Hz, 4H), 7.318 (d, J = 9.2)
Hz, 2H), 7.376 (s, 2H), 7.576 (dd, J = 8.8 Hz, 5.2 Hz, 4H), 7.967 (s, 2H).
¹³ C NMR (CDCl ₃ ) δ 56.720, 115.567 (J _CF = 21 Hz),
115.949, 118.008, 118.390, 127.285, 128.077,
_{128.630, 129.812, 131.586 (J CF} = 7.7 Hz), 132.777, 135.905, 140.214, 154.440, 162.506 (J CF = 246 Hz).
¹⁹ F NMR (CDCl ₃ ) δ-114.223.

窒素雰囲気下、化合物（ｄ−２）（１５０４ｍｇ, ２．３０５ｍｍｏｌ）とジクロロ［１，１’−ビス（ジフェニルホスフィノ）フェロセン］パラジウム（３５．７２ｍｇ, ０．０４６１１ｍｍｏｌ）の混合物にｄｉｓｔ.ジエチルエーテル （７５．２ ｍＬ）を加え、０℃まで冷却した。この時、化合物（ｄ−２）は溶媒に完璧に溶解していない。そこへ、アリルマグネシウムブロミド（７．６０７ ｍＬ,ジエチルエーテル中で１Ｍ ７．６０７ ｍｍｏｌ）を滴下し、反応温度を６０℃まで上昇させ、２２時間還流下で攪拌した。反応終了後、反応混合物は０℃まで冷却し、水でクエンチした後１０％ＨＣｌを塩がなくなるまで加えた。有機層を分離し、水層はジエチルエーテルで抽出を行い、集めた有機層は飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で洗浄し、ＭａＳＯ₄で乾燥させた後、ろ過・濃縮し、粗生成物を得た。粗生成物はショートカラム (酢酸エチル＝１００％)に通し、目的の化合物（ｅ）を定量的に得た。 <Example>
(Synthesis Example 10: Implementation of Step B-1)

Under a nitrogen atmosphere, a mixture of compound (d-2) (1504 mg, 2.305 mmol) and dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (35.72 mg, 0.04611 mmol) was added to dist. Diethyl ether. (75.2 mL) was added and cooled to 0 ° C. At this time, the compound (d-2) is not completely dissolved in the solvent. To this, allylmagnesium bromide (7.607 mL, 1M 7.607 mmol in diethyl ether) was added dropwise, the reaction temperature was raised to 60 ° C., and the mixture was stirred under reflux for 22 hours. After completion of the reaction, the reaction mixture was cooled to 0 ° C., quenched with water and then 10% HCl was added until free of salt. The organic layer is separated, the aqueous layer is extracted with diethyl ether, and the collected organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over MaSO ₄ , filtered and concentrated to produce a crude product. I got a thing. The crude product was passed through a short column (ethyl acetate = 100%) to quantitatively obtain the target compound (e).

The NMR measurement results of the obtained (e) are shown below. The ¹ H NMR spectra are shown in FIGS. 25, 26 and 27, respectively.
¹ H NMR (CDCl ₃ ) δ 2.504 (s, 6H), 3.401 (d, J = 6.4 Hz, 2H), 3.787 (s, 6H), 4.981-5.052 (m, 4H), 5.883-5.984 (m, 2H) 7.088 (d, J = 8.4 Hz, 2H), 7.191 (d, J = 8.4 Hz, 2H), 7.359. (S, 2H), 7.371 (d, J = 9.2 Hz, 4H), 7.540 (d, J = 8 Hz, 4H), 7.709 (s, 2H).

窒素雰囲気下、化合物（ｅ）（２６４．３ｍｇ, ０．４５９９ｍｍｏｌ）をｄｉｓｔ. ＣＨ₂Ｃｌ₂（９ｍＬ）に溶解させ、−７８℃に冷却した。そこへ、１Ｍの三臭化ホウ素ジクロロメタン溶液１．０１２ｍＬ （１．０１２ｍｍｏｌ）をゆっくり滴下した。滴下終了後、反応温度を０℃で２時間攪拌した。反応終了後、反応混合物を０℃のまま、水でクエンチし、水層をＣＨ₂Ｃｌ₂で抽出した。集めた有機層は飽和塩化ナトリウム水溶液で洗浄し、ＭｇＳＯ₄で乾燥させた後、ろ過・濃縮し、粗生成物を得た。得られた粗生成物をシリカゲルカラムクロマトグラフィー （ヘキサン／酢酸エチル＝４／１）により精製し、目的の化合物（ｆ）を得た（２２１ｍｇ, ８８％）。 <Synthesis Example 11: Implementation of Step C>

Under a nitrogen atmosphere, compound (e) (264.3 mg, 0.4599 mmol) was dissolved in dist. CH ₂ Cl ₂ (9 mL) and cooled to −78 ° C. Thereto, 1.012 mL (1.012 mmol) of a 1M boron tribromide dichloromethane solution was slowly added dropwise. After completion of the dropwise addition, the reaction temperature was stirred at 0 ° C. for 2 hours. After completion of the reaction, the reaction mixture was quenched with water at 0 ° C., and the aqueous layer was extracted with CH ₂ Cl ₂ . The collected organic layer was washed with a saturated aqueous sodium chloride solution, dried over MgSO ₄ , filtered and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to obtain the target compound (f) (221 mg, 88%).

The NMR measurement results of the obtained (f) are shown below. The ¹ H NMR spectra are shown in FIG. 28, FIG. 29 and FIG. 30, respectively.
¹ H NMR (CDCl ₃ ) δ 2.498 (s, 6H), 3.418 (d, J = 6.4 Hz, 2H), 4.999-5.058 (m, 4H), 5.165 (br, 2H), 5.881-5.966 (m, 2H) 7.183 (d, J = 8.4 Hz, 2H), 7.255 (d, J = 8 Hz, 2H), 7.320 (s, 2H) ), 7.365 (d, J = 8 Hz, 4H), 7.499 (d, J = 8 Hz, 4H), 7.760 (s, 2H).

化合物（ｄ−２）（８１ｍｇ, ０．１２４２ｍｍｏｌ）、フェニルボロン酸（４５．４１ｍｇ, ０．３７２５ｍｍｏｌ）およびテトラキス（トリフェニルホスフィン）パラジウム（０）（１２．７７ｍｇ, ０．０１１０５ｍｍｏｌ）を封管に入れ、窒素を吹き込みながらｄｉｓｔ. ＴＨＦ （２．９９ｍＬ）に溶解させ、さらに１Ｍ炭酸カリウム水溶液（０．６２０８ｍＬ, ０．６２０８ｍｍｏｌ）を加え、蓋をした。反応は８０℃で２４時間攪拌した。反応終了後、反応混合物を室温まで冷却し、少量のクロロホルムに溶解させた。続いて飽和塩化アンモニウム水溶液により洗浄し、水層をクロロホルムで抽出した。集めた有機層は飽和塩化ナトリウム水溶液で洗浄し、ＭｇＳＯ₄で乾燥させた後、ろ過・濃縮し、粗生成物を得た。得られた粗生成物をプレパラＴＬＣ（ヘキサン／酢酸エチル＝７／１）により精製し、目的の化合物（ｇ）を得た（３７．４ｍｇ, ４７％）。 (Synthesis Example 12: Implementation of Step B-2)

Compound (d-2) (81 mg, 0.1242 mmol), phenylboronic acid (45.41 mg, 0.3725 mmol) and tetrakis (triphenylphosphine) palladium (0) (12.77 mg, 0.01105 mmol) in a sealed tube The solution was dissolved in dist. THF (2.99 mL) while blowing nitrogen, and further 1M potassium carbonate aqueous solution (0.6208 mL, 0.6208 mmol) was added and the lid was capped. The reaction was stirred at 80 ° C. for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and dissolved in a small amount of chloroform. Subsequently, the mixture was washed with a saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with chloroform. The collected organic layer was washed with a saturated aqueous sodium chloride solution, dried over MgSO ₄ , filtered and concentrated to obtain a crude product. The obtained crude product was purified by preparatory TLC (hexane / ethyl acetate = 7/1) to obtain the desired compound (g) (37.4 mg, 47%).

The NMR measurement results of the obtained (d-1) are shown below. The ¹ H NMR spectrum is shown in FIGS. 32 and 32, respectively.
¹ H NMR (CDCl ₃ ) δ 2.506 (s, 6H), 3.848 (s, 6H), 7.289 (t, J = 7.4 Hz, 2H), 7.372-7.408 ( m, 10H), 7.441 (s, 2H), 7.517-7.606 (m, 10H), 8.165 (s, 2H).

窒素雰囲気下、化合物（ｆ）（８６ｍｇ, ０．１５７３ｍｍｏｌ）およびカリウムｔｅｒｔ−ブトキシド（３５．３０ｍｇ, ０．３１４６ｍｍｏｌ）をｄｉｓｔ. ＴＨＦ（２．７６ ｍＬ）に溶解させ、７０℃で４０分攪拌した。その後、ペンタエチレングリコールジ−ｐ−トルエンスルホン酸（８６ｍｇ, ０．１５７３ｍｍｏｌ）をｄｉｓｔ. ＴＨＦ（４．６３ｍＬ）に溶解させた溶液を３０分かけて滴下した。滴下終了後、さらに７０℃で１８時間加熱攪拌した。反応終了後、反応混合物を濃縮した後、ＣＨ₂Ｃｌ₂に溶かし、水で洗浄し、水層をＣＨ₂Ｃｌ₂で抽出した。集めた有機層は飽和塩化ナトリウム水溶液で洗浄し、Ｎａ₂ＳＯ₄で乾燥させた後、ろ過・濃縮し、粗生成物を得た。得られた粗生成物をプレパラＴＬＣ（ヘキサン／酢酸エチル＝３／２)により精製し、目的の化合物（ｈ）を得た（１９．７ｍｇ １６％）。 (Synthesis Example 13: Implementation of Step D)

Under a nitrogen atmosphere, compound (f) (86 mg, 0.1573 mmol) and potassium tert-butoxide (35.30 mg, 0.3146 mmol) were dissolved in dist. THF (2.76 mL) and stirred at 70 ° C. for 40 minutes. . Thereafter, a solution of pentaethylene glycol di-p-toluenesulfonic acid (86 mg, 0.1573 mmol) dissolved in dist. THF (4.63 mL) was added dropwise over 30 minutes. After completion of dropping, the mixture was further heated and stirred at 70 ° C. for 18 hours. After completion of the reaction, the reaction mixture was concentrated, dissolved in CH ₂ Cl ₂ , washed with water, and the aqueous layer was extracted with CH ₂ Cl ₂ . The collected organic layer was washed with saturated aqueous sodium chloride solution, dried over Na ₂ SO ₄ , filtered and concentrated to obtain a crude product. The obtained crude product was purified by prepara TLC (hexane / ethyl acetate = 3/2) to obtain the target compound (h) (19.7 mg 16%).

The measurement result of NMR of (h) obtained is shown below. 33, 34 and 35 show the ¹ H NMR spectrum, and FIG. 36 shows the ¹³ C NMR spectrum. ¹ H NMR (CDCl ₃ ) δ 2.502 (s, 6H), 3.348-3.670 (m, 20H), 4.045-4.094 (m, 2H), 4.196-4.251 ( m, 2H), 4.984-5.506 (m, 4H), 5.887-5.987 (m, 2H), 7.087 (d, J = 8.6 Hz, 2H), 7.224. (D, J = 8.8 Hz, 2H), 7.367 (d, J = 8 Hz, 4H), 7.384 (s, 2H), 7.528 (d, J = 7.6 Hz, 4H) ), 7.724 (s, 2H).
¹³ C NMR (CDCl ₃ ) δ 21.299, 40.349, 69.830, 70.516, 70.555, 70.841, 115.586, 117.398, 119.896, 124.835, 126.132 , 127.505, 127.791, 129.030, 130.050, 133.283, 135.170, 137.001, 133.573, 137.964, 140.987, 153.544.

窒素雰囲気下、化合物ｈ（７６．３ ｍｇ， ０．１０１９ ｍｍｏｌ）とテトラブチルアンモニウムヘキサクロロプラチネート（ＩＶ）（０．３６ｍｇ，０．０００４０７５ｍｍｏｌ）の混合物をｄｉｓｔ.ジクロロメタン（１ｍＬ）とｄｉｓｔ.ジエチルエーテル（０．５ｍＬ）の混合溶媒に溶解させ、０℃まで冷却した。トリクロロシラン（４１．１９μＬ, ０．４７０５ｍｍｏｌ）を加え、室温で４８時間攪拌した。攪拌終了後、反応混合物を濃縮し、窒素雰囲気下で０℃に冷却後、アリルマグネシウムブロミド（０．８１５ ｍＬ,ジエチルエーテル中 １Ｍ，０．８１５ｍｍｏｌ）を滴下し、室温で１２時間攪拌した。反応終了後、反応混合物を０℃まで冷却し、水でクエンチした後１０％塩酸を塩がなくなるまで加えた。有機層を分離し、水層はジクロロメタンで抽出を行い、集めた有機層は飽和炭酸水素ナトリウム水溶液及び飽和塩化ナトリウム水溶液で洗浄し、Ｎａ₂ＳＯ₄で乾燥させた後、ろ過・濃縮し、粗生成物を得た。粗生成物はプレパラＴＬＣ（ヘキサン／酢酸エチル＝３／２）により精製し、目的の化合物ｉを得た（６．７ｍｇ,６％）。 (Synthesis Example 14: Synthesis of Compound i)

Under a nitrogen atmosphere, a mixture of compound h (76.3 mg, 0.1019 mmol) and tetrabutylammonium hexachloroplatinate (IV) (0.36 mg, 0.0004075 mmol) was mixed with dist. Dichloromethane (1 mL) and dist. Diethyl ether. (0.5 mL) was dissolved in a mixed solvent and cooled to 0 ° C. Trichlorosilane (41.19 μL, 0.4705 mmol) was added and stirred at room temperature for 48 hours. After completion of the stirring, the reaction mixture was concentrated, cooled to 0 ° C. under a nitrogen atmosphere, allylmagnesium bromide (0.815 mL, 1M in diethyl ether, 0.815 mmol) was added dropwise, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was cooled to 0 ° C., quenched with water, and 10% hydrochloric acid was added until there was no salt. The organic layer is separated, the aqueous layer is extracted with dichloromethane, and the collected organic layer is washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over Na ₂ SO ₄ , filtered and concentrated, and crude. The product was obtained. The crude product was purified by preparatory TLC (hexane / ethyl acetate = 3/2) to obtain the target compound i (6.7 mg, 6%).

The measurement result of NMR of (i) obtained is shown below. The ¹ H NMR spectra are shown in FIGS. 37, 38, 39 and 40, respectively.
¹ H NMR (CDCl ₃ ) δ 0.595-0.637 (m, 4H), 1.541 (d, J = 8.4 Hz, 12H), 1.587-1.633 (m, 4H), 2 .506 (s, 6H), 2.628 (t, J = 7.4 Hz, 4H), 3.381-3.672 (m, 16H), 4.053-4.102 (m, 2H), 4 198-4.253 (m, 2H), 4.793-4845 (m, 12H), 5.674-5.781 (m, 6H), 7.064 (d, J = 8.8 Hz, 2H), 7.223 (d, J = 8.4 Hz, 2H), 7.373 (d, J = 8.8 Hz, 4H), 7.384 (s, 2H), 7.534 (d, J = 8Hz, 4H), 7.684 (s, 2H).

  When a compound having a binaphthyl derivative and a crown ether-like cyclic structure is used as a separating agent for optical isomers, depending on factors such as the type of substituent introduced into binaphthyl and the size of the crown ether-like cyclic structure, There is a possibility that the separation characteristics can be adjusted. According to the present invention, the development of a new material having desired characteristics can be greatly expected by introducing a substituent at a desired position of a binaphthyl group in a compound having a binaphthyl derivative and a crown ether-like cyclic structure. The

Claims (10)

A compound represented by the following formula (I).

[Wherein, R ₁ and R ₂ each represents an aryl group which may have a substituent, and R ₃ and R ₄ each represent an alkyl group or an alkenyl group which may have a substituent. , An alkynyl group, an aryl group, or — (CH ₂ ) ₃ —A, A is a silyl group represented by the following formula (i), and n represents an integer of 4 to 6. ]

[Wherein R ₅ , R ₆ and R ₇ each independently represents an optionally substituted alkyl group, alkenyl group, alkynyl group, aryl group or alkoxy group. ]   2. The compound according to claim 1, wherein n is 4. R ₁ and R ₂ are each a phenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 3,5-dimethylphenyl group, 3,5-dimethoxyphenyl group, 4-methoxynaphthyl group or 4-fluorophenyl. The compound according to claim 1 or 2, wherein the compound is a group. R ₃ and R ₄ are each a 2-propenyl group, a phenyl group, or — (CH ₂ ) ₃ —Si (C ₃ H ₅ ) _3. Compound described in 1. B step for obtaining a binaphthyl derivative B in which the bromo group at the 6,6′-position of the binaphthyl derivative A represented by the following formula (II) is respectively replaced with R ₃ and R _{4 represented} by the following formula (III);
C step of obtaining a binaphthyl derivative C in which the methoxy group is converted into a hydroxyl group by hydrolyzing the methoxy group at the 2,2 ′ position of the binaphthyl derivative B;
A step D in which each of the hydroxyl groups of the binaphthyl derivative C is crosslinked with a polyethylene glycol derivative to obtain a compound represented by the following formula (I) having a crown ether-like cyclic structure and a binaphthyl group;
A process for producing a compound represented by the following formula (I):

[Wherein, R ₁ and R ₂ each represents an aryl group which may have a substituent. ]

[Wherein, R ₁ and R ₂ are the same as R ₁ and R ₂ in formula (II), respectively, and R ₃ and R ₄ are each an optionally substituted alkyl group, alkenyl. Represents a group, an alkynyl group or an aryl group. ]

Wherein, R ₁ and R ₂ are each the same as R ₁ and R ₂ of formula (II), R ₃ and R ₄ are each the same as R ₃ and R ₄ of formula (III) Yes, n represents an integer of 4-6. ] (1) Step of brominating 6,6′-position of 2,2′-dimethoxy-1,1′-binaphthyl to obtain 6,6′-dibromo-2,2′-dimethoxy-1,1′-binaphthyl When,
(2) The 6,3′-position of 6,6′-dibromo-2,2′-dimethoxy-1,1′-binaphthyl is iodinated to form 6,6′-dibromo-3,3′-diiodo-2. , 2′-dimethoxy-1,1′-binaphthyl;
(3) The iodo group at the 3,3 ′ position of the 6,6′-dibromo-3,3′-diiodo-2,2′-dimethoxy-1,1′-binaphthyl is replaced with R ₁ and R ₂ , respectively. Obtaining binaphthyl derivative A;
The manufacturing method according to claim 5, further comprising an A step including The process according to claim 5 or 6, wherein in step B, the binaphthyl derivative A is reacted with a compound represented by the following formula (IV) in the presence of a transition metal catalyst to obtain the binaphthyl derivative B. .

[Wherein, R represents an optionally substituted alkyl group, alkenyl group, alkynyl group or aryl group, Mg represents magnesium, and X represents chlorine, bromine or iodine. ] The process according to claim 5 or 6, wherein in step B, the binaphthyl derivative A is reacted with a compound represented by the following formula (V) in the presence of a palladium catalyst and a base to obtain a binaphthyl derivative B. Method.

[Wherein Y represents an aryl group which may have a substituent. ]   In step D, polyoxyethylene glycol ditosylate having 5 to 7 repeating oxyethylene groups is reacted under alkaline conditions to crosslink between the hydroxyl groups of binaphthyl derivative C to have a crown ether-like cyclic structure and a binaphthyl group The production method according to any one of claims 5 to 8, wherein the compound represented by the formula (I) is obtained. A B ′ step in which a binaphthyl derivative A represented by the following formula (II) and allylmagnesium bromide are reacted in the presence of a catalyst containing palladium to obtain a compound represented by the following formula (VI); And a C ′ step for obtaining a compound in which the methoxy group becomes a hydroxyl group by hydrolyzing the methoxy group at the 2,2′-position of the compound represented by (2), and cross-linking each of the hydroxyl groups of the compound with a polyethylene glycol derivative. A step D ′ for obtaining a compound represented by the following formula (VII) having a crown ether-like cyclic structure and a binaphthyl group; a step E for hydrosilylating the 6,6 ′ position of the compound represented by the following formula (VII); A process for producing a compound represented by the following formula (VIII), comprising an F step of derivatizing the 6,6′-position subjected to hydrosilylation as represented by the following formula (VIII) To provide.

[Wherein, R ₁ and R ₂ each represents an aryl group which may have a substituent. ]

[Wherein, R ₁ and R ₂ are the same as R ₁ and R _{2 in} the formula (II), respectively. ]

[Wherein, R ₁ and R ₂ are the same as R ₁ and R _{2 in} the formula (II), respectively. ]

[Wherein, R ₁ and R ₂ are the same as R ₁ and R _{2 in} the formula (II), respectively, and R ₈ , R ₉ and R ₁₀ each independently have a substituent. And may represent an alkyl group, an alkenyl group, an alkynyl group, an aryl group or an alkoxy group. ]

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