JP5829529B2 - Optically active quaternary ammonium salt and method for producing optically active compound - Google Patents

Description

  The present invention relates to a novel optically active quaternary ammonium salt and a method for producing an optically active compound such as an optically active amino acid derivative using the salt as a catalyst.

In the research and development of pharmaceuticals, optically active compounds such as optically active amino acid derivatives are attracting attention from the viewpoint of enhancing drug efficacy and safety. As methods for synthesizing optically active compounds, an optical resolution method and an asymmetric synthesis method are known. In the optical resolution method, half of the compound synthesized in the previous steps is discarded, so that a great waste is generated from the viewpoint of synthesis of a necessary compound.
On the other hand, the asymmetric synthesis method is such that a necessary compound is preferentially produced using an asymmetric catalyst. Asymmetric reactions are expected to be applied not only to pharmaceuticals but also to fields such as agricultural chemicals and highly functional materials (for example, liquid crystals, nonlinear optical materials, photoreceptors, etc.). However, asymmetric synthesis often involves technical difficulties. Therefore, it is important to develop an asymmetric catalyst capable of synthesizing a target optically active compound with high yield and high optical purity, particularly on an industrial scale.

Various compounds have been proposed as asymmetric catalysts used in the synthesis of optically active amino acid derivatives.
For example, Non-Patent Document 1 describes an optically active quaternary ammonium salt represented by the formula (S-4). Optically active pyrrolidine can be produced through a conjugate addition reaction of an α, β-unsaturated ketone and a glycine ester using the quaternary ammonium salt as a catalyst.

（式（Ｓ−４）中、Ａｒは、３，４，５−トリフルオロフェニル基などを示す。）

(In the formula (S-4), Ar represents a 3,4,5-trifluorophenyl group or the like.)

  Patent Document 1 describes an optically active quaternary ammonium salt represented by the formula (A) and a method for producing an optically active amino acid derivative using the quaternary ammonium salt as a catalyst.

（式（Ａ）中、
Ｒ¹、Ｒ²、Ｒ^1'、Ｒ^2'、Ｒ³およびＲ^3'は、それぞれ独立に水素原子、Ｃ１〜５アルコキシ基などを示す。
Ｒ⁴およびＲ^4'は、３，４，５−トリフルオロフェニル基などを示す。
Ｒ⁷およびＲ⁸はそれぞれ独立にＣ１〜３０アルキル基などを示す。Ｘ^-は、アニオンなどを示す。）

(In the formula (A),
R ¹ , R ² , R ^{1 ′} , R ^{2 ′} , R ³ and R ^{3 ′} each independently represent a hydrogen atom, a C1-5 alkoxy group, or the like.
R ⁴ and R ^{4 ′} represent a 3,4,5-trifluorophenyl group or the like.
R ⁷ and R ⁸ each independently represent a C1-30 alkyl group or the like. X ⁻ represents an anion or the like. )

  Patent Document 2 describes an optically active quaternary ammonium salt represented by the formula (B) and a method for producing an optically active amino acid derivative using the quaternary ammonium salt as a catalyst.

（式（Ｂ）中、
Ｒ²およびＲ^2'は、水素原子、アリール基などを示す。
Ｒ³およびＲ^3'は、Ｃ１〜５アルコキシ基などを示す。
Ｒ⁴およびＲ^4'は、アリール基などを示す。
Ｒ⁷およびＲ⁸はそれぞれ独立にＣ１〜３０アルキル基などを示す。
Ｘ^-は、アニオンなどを示す。）

(In the formula (B),
R ² and R ^{2 ′} represent a hydrogen atom, an aryl group, or the like.
R ³ and R ^{3 ′} represent a C1-5 alkoxy group or the like.
R ⁴ and R ^{4 ′} represent an aryl group or the like.
R ⁷ and R ⁸ each independently represent a C1-30 alkyl group or the like.
X ⁻ represents an anion or the like. )

  Patent Document 3 describes an optically active quaternary ammonium salt represented by the formula (C) and a method for producing an optically active amino acid derivative using the quaternary ammonium salt as a catalyst.

（式（Ｃ）中、
Ｒは、２価の有機基を示す。
Ｒ¹およびＲ²は、水素原子、ハロゲン原子などを示す。
Ｒ^3'およびＲ^4'は、１価の有機基を示す。
Ａｒは、１価の有機基を示す。
Ｘ^-は、カウンターアニオンを示す。＊はビフェニル構造の結合軸が光学活性であることを示す。）

(In the formula (C),
R represents a divalent organic group.
R ¹ and R ² represent a hydrogen atom, a halogen atom or the like.
R ^{3 ′} and R ^{4 ′} represent a monovalent organic group.
Ar represents a monovalent organic group.
X ⁻ represents a counter anion. * Indicates that the bond axis of the biphenyl structure is optically active. )

  The optically active quaternary ammonium salt described in the above prior art document catalyzes a reaction for performing asymmetric alkylation or asymmetric conjugate addition to the α-carbon of the glycine ester shown below. However, when these reactions are carried out on an industrial scale, the target optically active amino acid derivative may not be synthesized with high yield and high optical purity depending on the substrate.

〔式中、Ａｒは、無置換の若しくは置換基を有するアリール基を示す。Ｒは、無置換の若しくは置換基を有するアルキル基を示す。Ｒ^aは、水素原子、無置換の若しくは置換基を有するアルキル基、無置換の若しくは置換基を有するアリール基などを示す。Ｒ^bは、水素原子、無置換の若しくは置換基を有するアルキル基、無置換の若しくは置換基を有するアリール基などを示す。＊は、不斉炭素を示す。〕

[In the formula, Ar represents an unsubstituted or substituted aryl group. R represents an unsubstituted or substituted alkyl group. R ^a represents a hydrogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted aryl group, and the like. R ^b represents a hydrogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted aryl group, and the like. * Indicates an asymmetric carbon. ]

WO2006 / 104226 WO2008 / 038578 WO2009 / 125594

Organic Letters Vol.11, No.9 2027-2029

  An object of the present invention is to provide a novel optically active quaternary ammonium salt. An object of the present invention is to provide an asymmetric catalyst useful for the synthesis of an optically active compound by an asymmetric reaction. Furthermore, this invention makes it a subject to provide the method of manufacturing the optically active amino acid derivative useful in fields, such as a pharmaceutical, an agricultural chemical, and a highly functional material, with a high yield and high optical purity.

  The present inventors diligently studied to solve the above problems. As a result, an optically active quaternary ammonium salt represented by the formula (I) or the formula (V) was obtained. And it discovered that this optically active quaternary ammonium salt has the outstanding catalytic effect in an asymmetric reaction. The present invention has been completed by further studies based on these findings.

  That is, the present invention includes the following aspects.

[1] An optically active quaternary ammonium salt represented by the formula (I).

〔式（I）中、
Ｒ¹は、それぞれ独立に、無置換の若しくは置換基を有するＣ１〜６アルキル基、無置換の若しくは置換基を有するＣ３〜８シクロアルキル基、無置換の若しくは置換基を有するＣ６〜１０アリール基、または無置換の若しくは置換基を有するヘテロアリール基を示す。
Ｒ²は、それぞれ独立に、水酸基、ハロゲン原子、無置換の若しくは置換基を有するＣ１〜６アルキル基、無置換の若しくは置換基を有するＣ２〜６アルケニル基、無置換の若しくは置換基を有するＣ２〜６アルキニル基、または無置換の若しくは置換基を有するＣ１〜６アルコキシ基を示す。
ｎは、それぞれ独立に、Ｒ²の数を示し且つ０〜２のいずれかの整数である。ｎが２のとき、Ｒ²同士は互いに同一であってもよいし、相異なっていてもよい。

Ｒ_a ³およびＲ_b ³は、それぞれ独立に、水酸基、ハロゲン原子、無置換の若しくは置換基を有するＣ１〜６アルキル基、無置換の若しくは置換基を有するＣ２〜６アルケニル基、無置換の若しくは置換基を有するＣ２〜６アルキニル基、または無置換の若しくは置換基を有するＣ１〜６アルコキシ基を示す。
Ｒ_a ³とＲ_b ³は、一緒になって２価の有機基を形成してもよい。

Ｒ⁴およびＲ⁵は、それぞれ独立に、無置換の若しくは置換基を有するＣ１〜６アルキル基、無置換の若しくは置換基を有するＣ２〜６アルケニル基、または無置換の若しくは置換基を有するＣ２〜６アルキニル基を示す。
Ｒ⁴とＲ⁵は、一緒になって２価の有機基を形成してもよい。

＊は、それが付された不斉軸が光学活性であることを示す。
Ｘ^-は、水酸化物イオン、ハロゲン原子系イオン、スルホン酸系イオン、リン酸系イオン、またはカルボン酸系イオンを示す。〕

[In Formula (I),
R ¹ each independently represents an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C3-8 cycloalkyl group, an unsubstituted or substituted C6-10 aryl group. Or an unsubstituted or substituted heteroaryl group.
R ² each independently represents a hydroxyl group, a halogen atom, an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted C 2-6 alkenyl group, an unsubstituted or substituted C 2 A -6 alkynyl group or an unsubstituted or substituted C1-6 alkoxy group is shown.
n represents the number of R < ² > each independently, and is an integer in any one of 0-2. When n is 2, R ² may be the same as or different from each other.

R _a ³ and R _b ³ are each independently a hydroxyl group, a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or A C2-6 alkynyl group having a substituent or an unsubstituted or substituted C1-6 alkoxy group is shown.
R _a ³ and R _b ³ may be combined to form a divalent organic group.

R ⁴ and R ⁵ are each independently an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, or an unsubstituted or substituted C2-6 6 represents an alkynyl group.
R ⁴ and R ⁵ may be combined to form a divalent organic group.

* Indicates that the asymmetric axis to which it is attached is optically active.
X ⁻ represents a hydroxide ion, a halogen atom ion, a sulfonic acid ion, a phosphoric acid ion, or a carboxylic acid ion. ]

[2] In the formula (I),
R _a ³ and R _b ³ are divalent organic groups formed by them together,
The divalent organic group is a C 2-6 alkylene group, —O— (CH ₂ ) _m —O— (m is an integer of 1 to 6), or —O— (CH ₂ CH ₂ The optically active quaternary ammonium salt according to the above [1], which is O) _p − (p is any integer of 2 to 3).

[3] In the formula (I),
R ⁴ and R ⁵ are divalent organic groups formed by them together;
The divalent organic group is a C3-6 alkylene group, or — (CH ₂ ) _q —X— (CH ₂ ) _q — (q is each independently an integer of 1 to 6. X Represents an oxo group, a thio group, or an imino group.) The optically active quaternary ammonium salt according to the above [1] or [2].

[4] An optically active quaternary ammonium salt represented by the formula (V).

〔式（V）中、
Ｒ²は、それぞれ独立に、水酸基、ハロゲン原子、無置換の若しくは置換基を有するＣ１〜６アルキル基、無置換の若しくは置換基を有するＣ２〜６アルケニル基、無置換の若しくは置換基を有するＣ２〜６アルキニル基、または無置換の若しくは置換基を有するＣ１〜６アルコキシ基を示す。
ｎは、それぞれ独立に、Ｒ²の数を示し且つ０〜２のいずれかの整数である。ｎが２のとき、Ｒ²同士は互いに同一であってもよいし、相異なっていてもよい。
Ｒ_a ³およびＲ_b ³は、それぞれ独立に、水酸基、ハロゲン原子、無置換の若しくは置換基を有するＣ１〜６アルキル基、無置換の若しくは置換基を有するＣ２〜６アルケニル基、無置換の若しくは置換基を有するＣ２〜６アルキニル基、または無置換の若しくは置換基を有するＣ１〜６アルコキシ基を示す。
Ｒ_a ³とＲ_b ³は、一緒になって２価の有機基を形成してもよい。
Ｒ⁶は、それぞれ独立に、無置換の若しくは置換基を有するＣ６〜１０アリール基を示す。
ｋは、それぞれ独立に、Ｒ⁶の数を示し且つ２〜５のいずれかの整数である。ｋが２のとき、Ｒ⁶同士は互いに同一であってもよいし、相異なっていてもよい。
＊は、それが付された不斉軸が光学活性であることを示す。
Ｘ^-は、水酸化物イオン、ハロゲン原子系イオン、スルホン酸系イオン、リン酸系イオン、またはカルボン酸系イオンを示す。〕

[In the formula (V),
R ² each independently represents a hydroxyl group, a halogen atom, an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted C 2-6 alkenyl group, an unsubstituted or substituted C 2 A -6 alkynyl group or an unsubstituted or substituted C1-6 alkoxy group is shown.
n represents the number of R < ² > each independently, and is an integer in any one of 0-2. When n is 2, R ² may be the same as or different from each other.
R _a ³ and R _b ³ are each independently a hydroxyl group, a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or A C2-6 alkynyl group having a substituent or an unsubstituted or substituted C1-6 alkoxy group is shown.
R _a ³ and R _b ³ may be combined to form a divalent organic group.
R ⁶ each independently represents an unsubstituted or substituted C 6-10 aryl group.
k shows the number of R < ⁶ > each independently, and is an integer in any one of 2-5. When k is 2, R ⁶ may be the same as or different from each other.
* Indicates that the asymmetric axis to which it is attached is optically active.
X ⁻ represents a hydroxide ion, a halogen atom ion, a sulfonic acid ion, a phosphoric acid ion, or a carboxylic acid ion. ]

[5] In the formula (V),
R _a ³ and R _b ³ are divalent organic groups formed by them together,
The divalent organic group is a C 2-6 alkylene group, —O— (CH ₂ ) _m —O— (m is an integer of 1 to 6), or —O— (CH ₂ CH ₂ The optically active quaternary ammonium salt according to the above [4], which is O) _p − (p is an integer of 2 to 3).

[6] An asymmetric catalyst comprising the optically active quaternary ammonium salt according to any one of [1] to [5].

[7] A method for producing an optically active compound, comprising carrying out an asymmetric reaction in the presence of the optically active quaternary ammonium salt according to any one of [1] to [5].

[8] α, β-unsaturation represented by the formula (III) in the presence of the optically active quaternary ammonium salt according to any one of [1] to [5] in a solvent containing a base A method for producing an optically active amino acid derivative represented by formula (II), comprising reacting an aldehyde derivative with a glycine derivative represented by formula (IV).

（式（III）中、Ｒ^aは、２価の有機基を示す。）

(In formula (III), R ^a represents a divalent organic group.)

（式（IV）中、
Ｒ^bは、水素原子、無置換の若しくは置換基を有するＣ１〜６アルキル基、無置換の若しくは置換基を有するＣ２〜６アルケニル基、無置換の若しくは置換基を有するＣ２〜６アルキニル基、無置換の若しくは置換基を有するＣ７〜１４アラルキル基、無置換の若しくは置換基を有するＣ６〜１０アリール基、または無置換の若しくは置換基を有するヘテロアリール基を示す。
Ｒ^cは、無置換の若しくは置換基を有するＣ１〜６アルキル基、無置換の若しくは置換基を有するＣ２〜６アルケニル基、無置換の若しくは置換基を有するＣ２〜６アルキニル基、無置換の若しくは置換基を有するＣ７〜１４アラルキル基、無置換の若しくは置換基を有するＣ６〜１０アリール基、または無置換の若しくは置換基を有するヘテロアリール基を示す。
Ａｒは、それぞれ独立に、無置換の若しくは置換基を有するＣ６〜１０アリール基を示す。）

(In the formula (IV),
R ^b is a hydrogen atom, an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted C 2-6 alkenyl group, an unsubstituted or substituted C 2-6 alkynyl group, A substituted or substituted C7-14 aralkyl group, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted heteroaryl group is shown.
R ^c is an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, unsubstituted or A C7-14 aralkyl group having a substituent, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted heteroaryl group is shown.
Ar independently represents an unsubstituted or substituted C6-10 aryl group. )

（式（II）中、Ｒ^a、Ｒ^b、Ｒ^c、およびＡｒは、前記と同じ意味を示す。
＊は、それが付された不斉炭素が光学活性であることを示す。）

(In the formula (II), R ^a , R ^b , R ^c , and Ar have the same meaning as described above.
* Indicates that the asymmetric carbon to which it is attached is optically active. )

[9] In a solvent containing a base, in the presence of the optically active quaternary ammonium salt according to any one of the above [1] to [5], α, β-unrepresented by the formula (III) A method for producing an optically active amino acid derivative represented by formula (II-1) or formula (II-2), comprising reacting a saturated aldehyde derivative with a glycine derivative represented by formula (IV).

（式（III）中、Ｒ^aは、２価の有機基を示す。）

(In formula (III), R ^a represents a divalent organic group.)

（式（IV）中、
Ｒ^bは、水素原子、無置換の若しくは置換基を有するＣ１〜６アルキル基、無置換の若しくは置換基を有するＣ２〜６アルケニル基、無置換の若しくは置換基を有するＣ２〜６アルキニル基、無置換の若しくは置換基を有するＣ７〜１４アラルキル基、無置換の若しくは置換基を有するＣ６〜１０アリール基、または無置換の若しくは置換基を有するヘテロアリール基を示す。
Ｒ^cは、無置換の若しくは置換基を有するＣ１〜６アルキル基、無置換の若しくは置換基を有するＣ２〜６アルケニル基、無置換の若しくは置換基を有するＣ２〜６アルキニル基、無置換の若しくは置換基を有するＣ７〜１４アラルキル基、無置換の若しくは置換基を有するＣ６〜１０アリール基、または無置換の若しくは置換基を有するヘテロアリール基を示す。
Ａｒは、それぞれ独立に、無置換の若しくは置換基を有するＣ６〜１０アリール基を示す。）

(In the formula (IV),
R ^b is a hydrogen atom, an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted C 2-6 alkenyl group, an unsubstituted or substituted C 2-6 alkynyl group, A substituted or substituted C7-14 aralkyl group, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted heteroaryl group is shown.
R ^c is an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, unsubstituted or A C7-14 aralkyl group having a substituent, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted heteroaryl group is shown.
Ar independently represents an unsubstituted or substituted C6-10 aryl group. )

（式（II-１）および（II-２）中の、Ｒ^a、Ｒ^b、およびＲ^cは、前記と同じ意味を示す。破線と実線の二重線で表される結合は、単結合または二重結合を示す。）

(In the formulas (II-1) and (II-2), R ^a , R ^b , and R ^c have the same meaning as described above. A bond represented by a broken line and a solid double line is a single bond. Or a double bond.)

[10] An optically active amino acid derivative represented by formula (II-1) or formula (II-2).

（式（II-１）および式（II-２）中、
Ｒ^aは、２価の有機基を示す。
Ｒ^bは、水素原子、無置換の若しくは置換基を有するＣ１〜６アルキル基、無置換の若しくは置換基を有するＣ２〜６アルケニル基、無置換の若しくは置換基を有するＣ２〜６アルキニル基、無置換の若しくは置換基を有するＣ７〜１４アラルキル基、無置換の若しくは置換基を有するＣ６〜１０アリール基、または無置換の若しくは置換基を有するヘテロアリール基を示す。
Ｒ^cは、無置換の若しくは置換基を有するＣ１〜６アルキル基、無置換の若しくは置換基を有するＣ２〜６アルケニル基、無置換の若しくは置換基を有するＣ２〜６アルキニル基、無置換の若しくは置換基を有するＣ７〜１４アラルキル基、無置換の若しくは置換基を有するＣ６〜１０アリール基、または無置換の若しくは置換基を有するヘテロアリール基を示す。
破線と実線の二重線で表される結合は、単結合または二重結合を示す。）

(In formula (II-1) and formula (II-2),
R ^a represents a divalent organic group.
R ^b is a hydrogen atom, an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted C 2-6 alkenyl group, an unsubstituted or substituted C 2-6 alkynyl group, A substituted or substituted C7-14 aralkyl group, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted heteroaryl group is shown.
R ^c is an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, unsubstituted or A C7-14 aralkyl group having a substituent, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted heteroaryl group is shown.
A bond represented by a broken line and a solid double line indicates a single bond or a double bond. )

The optically active quaternary ammonium salt according to the present invention is a novel substance. The optically active quaternary ammonium salt exhibits excellent catalytic action in asymmetric reactions such as asymmetric Michael addition reaction.
When an asymmetric reaction such as an asymmetric Michael addition reaction is performed in the presence of the optically active quaternary ammonium salt, an optically active compound useful in fields such as pharmaceuticals, agricultural chemicals and highly functional materials can be obtained in high yield and high optical purity. Can be synthesized.

1) Optically active quaternary ammonium salt The optically active quaternary ammonium salt according to the present invention is a compound represented by the formula (I) (hereinafter sometimes referred to as the compound (I)) or the formula (V). A compound represented by the following (hereinafter sometimes referred to as compound (V)).

  First, the meanings of “unsubstituted” and “having a substituent” in formula (I) or formula (V) will be described.

The term “unsubstituted” means only the group that is the mother nucleus. In the present specification, when there is no description of “having a substituent” and only the name of the group serving as a mother nucleus is used, it means “unsubstituted” unless otherwise specified.
On the other hand, the term “having a substituent” means that any hydrogen atom of a group serving as a mother nucleus is substituted with a group having the same or different structure as the mother nucleus. Accordingly, the “substituent” is another group bonded to a group serving as a mother nucleus. The number of substituents may be one, or two or more. Two or more substituents may be the same or different.
Terms such as “C1-6” indicate that the number of carbon atoms of the group serving as the mother nucleus is 1-6. This number of carbon atoms does not include the number of carbon atoms present in the substituent. For example, a butyl group having an ethoxy group as a substituent is classified as a C2 alkoxy C4 alkyl group.

The “substituent” is not particularly limited as long as it is chemically acceptable and exhibits the effects of the present invention.
As a group that can be a “substituent”,
Halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom;
C1-6 such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, n-pentyl group and n-hexyl group An alkyl group;
A C3-8 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group;
Vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-pentenyl group 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4 -C2-6 alkenyl groups such as a hexenyl group and a 5-hexenyl group;
Ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 2-methyl-3-butynyl group, 1-pentynyl group 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-2-butynyl group, 2-methyl-3-pentynyl group, 1-hexynyl group, 1,1-dimethyl-2-butynyl group, etc. A C2-6 alkynyl group of
C1-6 alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, s-butoxy group, i-butoxy group, t-butoxy group;
C2-6 alkenyloxy groups such as vinyloxy group, allyloxy group, propenyloxy group, butenyloxy group;
A C2-6 alkynyloxy group such as an ethynyloxy group or a propargyloxy group;
A C6-10 aryl group such as a phenyl group or a naphthyl group;
C6-10 aryloxy groups such as phenoxy group and 1-naphthoxy group;
A C7-11 aralkyl group such as a benzyl group or a phenethyl group;
A C7-11 aralkyloxy group such as a benzyloxy group or a phenethyloxy group;
C1-7 acyl groups such as formyl group, acetyl group, propionyl group, benzoyl group, cyclohexylcarbonyl group;
C1-7 acyloxy groups such as formyloxy group, acetyloxy group, propionyloxy group, benzoyloxy group, cyclohexylcarbonyloxy group;
A C1-6 alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, a t-butoxycarbonyl group;
Carboxyl group;
Hydroxyl group;

C1-6 haloalkyl groups such as chloromethyl group, chloroethyl group, trifluoromethyl group, 1,2-dichloro-n-propyl group, 1-fluoro-n-butyl group, perfluoro-n-pentyl group;
A C2-6 haloalkenyl group such as a 2-chloro-1-propenyl group and a 2-fluoro-1-butenyl group;
A C2-6 haloalkynyl group such as 4,4-dichloro-1-butynyl group, 4-fluoro-1-pentynyl group, 5-bromo-2-pentynyl group;
A C1-6 haloalkoxy group such as a 2-chloro-n-propoxy group and a 2,3-dichlorobutoxy group;
A C2-6 haloalkenyloxy group such as a 2-chloropropenyloxy group and a 3-bromobutenyloxy group;
C6-10 haloaryl groups such as 4-chlorophenyl group, 4-fluorophenyl group, 2,4-dichlorophenyl group;
A C6-10 haloaryloxy group such as a 4-fluorophenyloxy group, a 4-chloro-1-naphthoxy group;
Halogen-substituted C1-7 acyl groups such as chloroacetyl group, trifluoroacetyl group, trichloroacetyl group, 4-chlorobenzoyl group;

Cyano group; nitro group; amino group;
A C1-6 alkylamino group such as a methylamino group, a dimethylamino group, a diethylamino group;
A C6-10 arylamino group such as an anilino group or a naphthylamino group;
A C7-11 aralkylamino group such as a benzylamino group or a phenylethylamino group;
C1-7 acylamino groups such as formylamino group, acetylamino group, propanoylamino group, butyrylamino group, i-propylcarbonylamino group, benzoylamino group;
A C1-6 alkoxycarbonylamino group such as a methoxycarbonylamino group, an ethoxycarbonylamino group, an n-propoxycarbonylamino group, an i-propoxycarbonylamino group;

  An aminocarbonyl group having an unsubstituted or substituted group such as an aminocarbonyl group, a dimethylaminocarbonyl group, a phenylaminocarbonyl group, an N-phenyl-N-methylaminocarbonyl group;

5-membered heteroaryl groups such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl;
A 6-membered heteroaryl group such as a pyridyl group, pyrazinyl group, pyrimidinyl group, pyridanidyl group, triazinyl group;
A tri-C1-6 alkyl-substituted silyl group such as a trimethylsilyl group, a triethylsilyl group, or a t-butyldimethylsilyl group;
A triphenylsilyl group;
And so on.

  Further, in these “substituents”, any hydrogen atom therein may be substituted with a group having the same or different structure as the “substituent”.

[R ^1]
In formula (I), each R ¹ independently represents an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C3-8 cycloalkyl group, an unsubstituted or substituted group. The C6-10 aryl group which has, or the heteroaryl group which is unsubstituted or has a substituent is shown.

  The “C1-6 alkyl group” may be linear or branched. Examples of the C1-6 alkyl group include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, i-propyl group, i-butyl group, s-butyl group, t -Butyl group, i-pentyl group, neopentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, i-hexyl group and the like can be mentioned.

  Examples of the “C3-8 cycloalkyl group” include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.

The “C6-10 aryl group” may be either a single ring or a polycycle in which the rings are bonded to each other. In the polycyclic aryl group, if at least one ring is an aromatic ring, the remaining ring may be a saturated alicyclic ring, an unsaturated alicyclic ring, or an aromatic ring. Examples of the C6-10 aryl group include a phenyl group, a naphthyl group, an azulenyl group, an indenyl group, an indanyl group, and a tetralinyl group. Of these, R ¹ is particularly preferably a phenyl group.

In the “C6-C10 aryl group having a substituent”, a preferable group that can be a substituent is a halogen atom of a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom;
C1-6 such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, n-pentyl group and n-hexyl group An alkyl group;
C1-6 haloalkyl groups such as chloromethyl group, chloroethyl group, trifluoromethyl group, 1,2-dichloro-n-propyl group, 1-fluoro-n-butyl group, perfluoro-n-pentyl group;
And so on.

  The “heteroaryl group” is a 5- to 10-membered aryl group containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms as atoms constituting the ring. In this case, it may be a single ring or a polycyclic ring condensed.

Specific examples of the heteroaryl group include the following groups.
5-membered heteroaryl groups such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl;
A 6-membered heteroaryl group such as a pyridyl group, pyrazinyl group, pyrimidinyl group, pyridanidyl group, triazinyl group;
And so on.

[R ^2]
In formula (I) or formula (V), each R ² independently represents a hydroxyl group, a halogen atom, an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted C 2-6 alkenyl. Or a C2-6 alkynyl group which is unsubstituted or substituted, or a C1-6 alkoxy group which is unsubstituted or substituted.
n represents the number of R < ² > each independently, and is an integer in any one of 0-2. When n is 2, R ² may be the same as or different from each other.

Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
As the “C1-6 alkyl group” in R ^2, the same “C1-6 alkyl group” as mentioned in R ¹ can be exemplified.

  Examples of the “C2-6 alkenyl group” include vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-2-propenyl group, 2-methyl 2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 1-hexenyl group, 2 -A hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, etc. can be mentioned.

  Examples of the “C2-6 alkynyl group” include ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 2-methyl -3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-2-butynyl group, 2-methyl-3-pentynyl group, 1-hexynyl group, 1 , 1-dimethyl-2-butynyl group and the like.

  Examples of the “C1-6 alkoxy group” include methoxy group, ethoxy group, i-propoxy group, n-butoxy group, i-butoxy group, s-butoxy group, t-butoxy group, n-pentyloxy group, i-pentyl. An oxy group, n-hexyloxy group, etc. can be mentioned.

[R _a ³ , R _b ³ ]
In formula (I) or formula (V), R _a ³ and R _b ³ each independently represents a hydroxyl group, a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted group. Or a C2-6 alkynyl group that is unsubstituted or substituted, or a C1-6 alkoxy group that is unsubstituted or substituted. R _a ³ and R _b ³ may be combined to form a divalent organic group.

Examples of the “C1-6 alkyl group” for R _a ³ or R _b ³ include the same “C1-6 alkyl group” as described for R ¹ .
As the “halogen atom”, “C2-6 alkenyl group”, “C2-6 alkynyl group” and “C1-6 alkoxy group” in R _a ³ or R _b ^3, the “halogen atom” mentioned in R ² , The same thing as "C2-6 alkenyl group", "C2-6 alkynyl group", and "C1-6 alkoxy group" can be mentioned.

[Divalent organic group formed by R _a ³ and R _b ³ together]
Examples of the divalent organic group formed by combining R _a ³ and R _b ³ include those represented by any of the following formulas.

In the formula, each X ¹ independently represents an atom or a functional group appropriately selected from the group consisting of a carbon atom, an oxy group, an imino group, a thio group, a carbonyl group, a sulfinyl group, and a sulfonyl group. These atoms or functional groups may each independently have a substituent. The bond between adjacent X ¹ is shown as a single bond in the formula, but may be a double bond.

The carbon atom in the functional group constituting the divalent organic group may have a substituent. Preferred substituents include a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C1-6 alkoxy group, an unsubstituted or substituted C1-6 alkylcarbonyl. Groups, unsubstituted or substituted C6-8 arylcarbonyl groups, unsubstituted or substituted C1-6 alkylsulfonyl groups, unsubstituted or substituted C6-10 arylsulfonyl groups.
The imino group for X ¹ may have a substituent. Preferred substituents are unsubstituted or substituted C1-6 alkyl groups, unsubstituted or substituted C1-6 alkylcarbonyl groups, unsubstituted or substituted C6-8 arylcarbonyl groups, Examples thereof include an unsubstituted or substituted C1-6 alkylsulfonyl group and an unsubstituted or substituted C6-10 arylsulfonyl group.

Preferred divalent organic groups are unsubstituted or substituted C 2-6 alkylene groups, —O— (CH ₂ ) _m —O— (where m is an integer of 1 to 6). And a group represented by —O— (CH ₂ CH ₂ O) _p — (p is any integer of 2 to 3).
Examples of the C2-6 alkylene group include an ethylene group (alias: ethane-1,2-diyl group), a propylene group (alias: propane-1,2-diyl group), and a trimethylene group (alias: propane-1,3-diyl). Group), tetramethylene group, pentamethylene group, hexamethylene group and the like.

  From the viewpoint of the production method, a divalent organic group represented by any one of the following formulas can be exemplified.

In the formula, each X ² independently represents an atom or a functional group appropriately selected from the group consisting of a carbon atom, an oxy group, an imino group, a thio group, a carbonyl group, a sulfinyl group, and a sulfonyl group. These atoms or functional groups may each independently have a substituent. The bond between adjacent X ² is shown as a single bond in the formula, but may be a double bond.

The carbon atom in the functional group constituting the divalent organic group may have a substituent. Examples of the substituent include a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C1-6 alkoxy group, and an unsubstituted or substituted C1-6 alkylcarbonyl group. An unsubstituted or substituted C6-8 arylcarbonyl group, an unsubstituted or substituted C1-6 alkylsulfonyl group, an unsubstituted or substituted C6-10 arylsulfonyl group.
The imino group for X ² may have a substituent. Examples of the substituent include an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C1-6 alkylcarbonyl group, an unsubstituted or substituted C6-8 arylcarbonyl group, an unsubstituted Examples thereof include a substituted or substituted C1-6 alkylsulfonyl group and an unsubstituted or substituted C6-10 arylsulfonyl group.

[R ^4, R ^5]
In formula (I), R ⁴ and R ⁵ are each independently an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted C 2-6 alkenyl group, or an unsubstituted or The C2-6 alkynyl group which has a substituent is shown. R ⁴ and R ⁵ may be combined to form a divalent organic group.

As the “C1-6 alkyl group” for R ⁴ or R ^5, the same “C1-6 alkyl group” as described for R ¹ can be exemplified.
“C2-6 alkenyl group” and “C2-6 alkynyl group” in R ⁴ or R ⁵ are the same as the “C2-6 alkenyl group” and “C2-6 alkynyl group” mentioned in R ² . Can do.

[Divalent organic group formed by combining R ⁴ and R ⁵ ]
Examples of the divalent organic group formed by combining R ⁴ and R ⁵ include those represented by any of the following formulas.

In the formula, each X ¹ independently represents an atom or a functional group appropriately selected from the group consisting of a carbon atom, an oxy group, an imino group, a thio group, a carbonyl group, a sulfinyl group, and a sulfonyl group. These atoms or functional groups may each independently have a substituent. The bond between adjacent X ¹ is shown as a single bond in the formula, but may be a double bond.

As a preferable divalent organic group, a C3-6 alkylene group, — (CH ₂ ) _q —X— (CH ₂ ) _q — (q is each independently an integer of 1 to 6. X is , An oxo group, an imino group, or a thio group).
Examples of C3-6 alkylene groups include propylene groups (also known as propane-1,2-diyl groups), trimethylene groups (also known as propane-1,3-diyl groups), tetramethylene groups, pentamethylene groups, hexamethylene groups, and the like. Can be mentioned.
As the group represented by — (CH ₂ ) _q —X— (CH ₂ ) _q −, — (CH ₂ ) ₂ —O— (CH ₂ ) ₂ —, — (CH ₂ ) ₂ —O— (CH ₂ ) ₃ −, — (CH ₂ ) ₃ —O— (CH ₂ ) ₃ —, — (CH ₂ ) ₂ —NH— (CH ₂ ) ₂ —, — (CH ₂ ) ₂ —NH— (CH ₂ ) _{3 -, - (CH 2)} 3 -NH- (CH 2) 3 -, - (CH 2) 2 -S- (CH 2) 2 -, - (CH 2) 2 -S- (CH 2) 3 - , — (CH ₂ ) ₃ —S— (CH ₂ ) ₃ — and the like.

  From the viewpoint of the production method, a divalent organic group represented by any one of the following formulas can be exemplified.

In the formula, each X ³ independently represents an atom or a functional group appropriately selected from the group consisting of a carbon atom, an oxy group, an imino group, a thio group, a carbonyl group, a sulfinyl group, and a sulfonyl group. These atoms or functional groups may each independently have a substituent. The bonds between adjacent X ^{3 and} between C and X ³ are shown as single bonds in the formula, but may be double bonds.
C in the formula represents a carbon atom. In this case, any of sp carbon, sp2 carbon, and sp3 carbon may be used.
The carbon atom in the functional group constituting the divalent organic group may have a substituent. Examples of the substituent include a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C1-6 alkoxy group, and an unsubstituted or substituted C1-6 alkylcarbonyl group. An unsubstituted or substituted C6-8 arylcarbonyl group, an unsubstituted or substituted C1-6 alkylsulfonyl group, an unsubstituted or substituted C6-10 arylsulfonyl group.
The imino group for X ³ may have a substituent. Examples of the substituent include an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C1-6 alkylcarbonyl group, an unsubstituted or substituted C6-8 arylcarbonyl group, an unsubstituted Examples thereof include a substituted or substituted C1-6 alkylsulfonyl group and an unsubstituted or substituted C6-10 arylsulfonyl group.

[R ^6]
In formula (V), each R ⁶ independently represents an unsubstituted or substituted C 6-10 aryl group. k shows the number of R < ⁶ > each independently, and is an integer in any one of 2-5. When k is 2, R ⁶ may be the same as or different from each other.
As the “C6-10 aryl group” in R ^6, the same “C6-10 aryl group” as mentioned in R ¹ can be exemplified.

[*]
In formula (I) or formula (V), * indicates that the asymmetric axis to which it is attached is optically active. In the present invention, optical activity means that the abundance of a specific optical isomer is greater than 50%. In the present invention, the abundance ratio of the specific optical isomer is preferably 90% or more, more preferably 95% or more, and particularly preferably 98% or more.

[X ^-]
In formula (I) or formula (V), X ⁻ represents a hydroxide ion, a halogen atom ion, a sulfonic acid ion, a phosphoric acid ion, or a carboxylic acid ion.
Examples of the “halogen atom ion” in X ⁻ include fluorine ion, chlorine ion, bromine ion, iodine ion and the like.
Examples of the “sulfonate ion” in X ⁻ include sulfate ion, sulfate ester ion, aryl sulfonate ion, alkyl sulfonate ion and the like.
Examples of “phosphate ions” in X ⁻ include phosphate ions, phosphate ester ions, phosphate diester ions, and the like.
Examples of the “carboxylic acid ion” in X ⁻ include a carbonate ion, a fatty acid ion, and an aryl carboxylate ion.
Of these, preferred X ⁻ is “halogen atom ion”.

2) Method for producing optically active quaternary ammonium salt (Method for producing optically active quaternary ammonium salt represented by formula (I))
The optically active quaternary ammonium salt represented by the formula (I) can be obtained by a known synthesis method.
Here, the production method of the optically active quaternary ammonium salt represented by the formula (6) (the compound in which X ⁻ is a bromocation in the formula (I)) is taken as an example, and the optically active quaternary ammonium salt of the present invention We will contribute to understanding the manufacturing method. The production method described here is one embodiment, and the optically active quaternary ammonium salt according to the present invention may be produced by any other production method.

The optically active quaternary ammonium salt of the present invention can be produced by, for example, a method including each step described below. Here, a compound represented by formula (1) (sometimes referred to as compound (1)), a compound represented by formula (3) (sometimes referred to as compound (3)), and formula (4). R ² , n, R _a ³ , and R in the compound (sometimes referred to as compound (4)) and the compound represented by formula (6) (sometimes referred to as compound (6)) _b ³ has the same meaning as in formula (I). R ¹ in the compound represented by formula (2) (sometimes referred to as compound (2)), compound (3), compound (4), and compound (6) is R in formula (I). the same meaning as ^1. R ⁴ and R ⁵ in the compound represented by formula (5) (sometimes referred to as compound (5)) and compound (6) have the same meaning as those in formula (I).

  Compound (1) is an optically active biphenyl compound. The optically active quaternary ammonium salt of the present invention preferably has a high optical purity. Therefore, the compound (1) used as a starting material is preferably a compound having a high optical purity. Compound (1) is a known substance. Compound (1) having high optical purity can be synthesized by the methods described in International Publication Pamphlet WO 2009/087959 and International Publication Pamphlet WO 2009/125594.

[Step 1]
First, an alkali metal reagent is allowed to act on the compound (1) to cause the compound (2) to react to induce the compound (3).
As an alkali metal reagent,
Simple alkali metals such as lithium, sodium and potassium;
Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride;
Alkali metal organic metals such as methyl lithium, n-butyl lithium, s-butyl lithium, t-butyl lithium, n-butyl magnesium chloride, diethyl zinc, phenyl lithium, phenyl sodium, cyclopentadienyl sodium, cyclopentadienyl potassium Compound;
Alkali metal alkoxides such as lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium glycoxide, lithium phenoxide, sodium phenoxide, potassium phenoxide;
And alkali metal amides such as lithium amide, sodium amide, lithium diisopropylamide (LDA), lithium hexamethyldisilylamide (LHMDS), and sodium hexamethyldisilylamide (NaHMDS).

The amount of the alkali metal reagent to be used is preferably 2.0 mol to 10.0 mol, more preferably 2.1 mol to 5.0 mol, per 1 mol of compound (1).
In step 1, a solvent can be used. Preferable solvents include aromatic solvents such as benzene, toluene and xylene; ether solvents such as ether, isopropyl ether, tetrahydrofuran, tert-butyl methyl ether and CPME.
The volume (L) of the solvent used in the step 1 is volume (L) / weight (kg) with respect to the weight (kg) of the compound (1), preferably 1.0 to 100 L / kg, more preferably. Is 3-30 L / kg.
The reaction in Step 1 is preferably carried out at an appropriate temperature from −80 ° C. to the boiling point of the solvent, more preferably from −80 ° C. to 0 ° C. The reaction can be carried out with stirring. Although reaction time can be suitably set according to reaction rate, Preferably it is 1 to 50 hours, More preferably, it is 2 to 10 hours.

[Step 2]
Next, a halogenating agent (reaction initiator if necessary) is allowed to act on the compound (3) to induce the compound (4) in an appropriate solvent.
Examples of the halogenating agent include iodine, such as chlorine, N-chlorosuccinimide, bromine, N-bromosuccinimide (NBS), and the like. Of these, NBS is preferred.
The amount of the halogenating agent to be used is preferably 2.0 mol to 10.0 mol, more preferably 2.1 mol to 3.0 mol, per 1 mol of compound (3).
Examples of the reaction initiator include radical reaction initiators such as azobisisobutyronitrile (AIBN) and benzoyl peroxide (BPO). The amount of the reaction initiator to be used is preferably 0.05 mol to 1.0 mol, more preferably 0.1 mol to 0.5 mol, per 1 mol of compound (3).

The solvent used in step 2 is not particularly limited as long as it does not inhibit the reaction. For example, hydrocarbon solvents such as hexane, cyclohexane and benzene; chlorine solvents such as methylene chloride, chloroform and chlorobenzene; N, N-dimethylformamide (DMF), N-methylpyrrolidin-2-one (NMP), N Amide solvents such as N, N-dimethylimidazolidin-2-one (DMI).
The volume (L) of the solvent used is a volume (L) / weight (kg) with respect to the weight (kg) of the compound (3), preferably 1.0 to 100 L / kg, more preferably 3 to 3. 30 L / kg.
The reaction in the step 2 is preferably performed at an appropriate temperature from the melting point to the boiling point of the solvent, more preferably from 0 ° C to 100 ° C. The reaction can be carried out with stirring. Although reaction time can be set suitably according to reaction rate, Preferably it is 1 to 50 hours, More preferably, it is 1 to 24 hours.

[Step 3]
Finally, compound (5) is allowed to act on compound (4) in an appropriate solvent in the presence of a base as necessary to obtain compound (6).
The amount of compound (5) is preferably 0.5 mol to 10.0 mol, more preferably 1.0 mol to 3.0 mol, per 1 mol of compound (4).
In step 3, it is not necessary to make the base exist, but it is preferable to make the base exist. Preferred bases include lithium hydroxide, sodium hydroxide, sodium bicarbonate, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium carbonate, potassium methoxide, potassium ethoxide, potassium ter-butoxide, cesium hydroxide And inorganic bases such as cesium carbonate; organic bases such as diazabicycloundecene (DBU), diazabicyclononene (DBN), N, N-diisopropylethylamine (DIEA), and phosphazene bases. The amount of the base to be used is preferably 2 to 30 mol, more preferably 3 to 20 mol, per 1 mol of compound (4).

The solvent used in step 3 is not particularly limited as long as it does not inhibit the reaction. For example, hydrocarbon solvents such as hexane, cyclohexane, benzene and toluene; chlorine solvents such as methylene chloride, chloroform and chlorobenzene; nitrile solvents such as acetonitrile and benzonitrile; N, N-dimethylformamide (DMF), N Examples include amide solvents such as -methylpyrrolidin-2-one (NMP) and N, N'-dimethylimidazolidin-2-one (DMI). The volume (L) of the solvent used is a volume (L) / weight (kg) with respect to the weight (kg) of the compound (4), preferably 1.0 to 100 L / kg, more preferably 3 to 3. 30 L / kg.
The reaction in step 3 can also be performed under phase transfer reaction conditions. In the phase transfer reaction conditions, a general phase transfer catalyst such as tetrabutylammonium bromide, benzyltrimethylammonium bromide, benzyltriethylammonium bromide, 18-crown-6-ether, 15-crown-4-ether may be used. it can. The amount of the phase transfer catalyst to be used is preferably 0.005 mol to 0.2 mol, more preferably 0.01 to 0.05 mol, per 1 mol of compound (4). In the phase transfer reaction conditions, the base can be used as an aqueous solution or solid. The reaction can be performed with stirring. The reaction temperature is preferably an appropriate temperature from the melting point to the boiling point of the solvent, more preferably -20 to 100 ° C. Although reaction time can be set suitably according to reaction rate, Preferably it is 1 to 50 hours, More preferably, it is 1 to 24 hours.

(Method for producing optically active quaternary ammonium salt represented by formula (V))
On the other hand, the optically active quaternary ammonium salt represented by the formula (V) can be produced by a production method similar to the production method of the optically active quaternary ammonium salt represented by the above formula (I). Specifically, it can be produced by replacing the reaction in step 1 in the production method described above with the reaction shown below.

Here, in the compound represented by formula (1 ′) (sometimes referred to as compound (1 ′)) and the compound represented by formula (3 ′) (sometimes referred to as compound (3 ′)). R ² , n, R _a ³ and R _b ³ have the same meaning as in formula (V). Ar in the boron compound represented by formula (2 ′) (sometimes referred to as compound (2 ′)) and compound (3 ′) represents a substituent represented by formula (2′-1), In the formula, R ⁶ and k have the same meaning as in formula (V).

(R ⁶ ) _k Ph (2′-1)

That is, the compound (2 ′) is reacted with the compound (1 ′) in an appropriate solvent in the presence of a palladium catalyst and a base to obtain the compound (3 ′).
Compound (2 ′) is 2.0 mol to 10.0 mol, preferably 2.1 mol to 5.0 mol, more preferably 2.5 mol to 3. mol, per 1 mol of compound (1 ′). 5 moles.
The palladium catalyst is a zero-valent palladium complex such as bis [1,2- (diphenylphosphino) ethane] palladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, or Pd (PPh ₃ ) _4. It can be used suitably. The amount of the palladium catalyst to be used is 0.005 equivalents to 0.2 equivalents, preferably 0.001 equivalents to 0.1 equivalents, more preferably 0.01 equivalents to 0.05 equivalents, relative to the compound (1 ′). It is.
Moreover, a palladium catalyst can also be prepared and used in a reaction system by making a phosphine act on a bivalent palladium compound. Examples of the divalent palladium include palladium halides such as palladium chloride and palladium bromide, palladium acetate, palladium acetoacetate and the like, preferably palladium acetate. Although there is no restriction | limiting in particular in a phosphine, A triaryl phosphine easily available can be used preferably, and a triphenylphosphine is more preferable. The molar ratio of the divalent palladium compound and phosphine is 1: 1 to 1:10, preferably 1: 2 to 1: 5.

Base is lithium hydroxide, sodium hydroxide, sodium bicarbonate, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium carbonate, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, hydroxylated Cesium, cesium carbonate, thallium hydroxide, phosphates, ie, dibasic, tribasic sodium phosphate, hydrates thereof, secondary, tribasic potassium phosphate, hydrates thereof, sodium pyrophosphate, water A hydrate, potassium pyrophosphate, a hydrate thereof, and the like can be used as appropriate, and preferably potassium triphosphate or a hydrate thereof. The amount of the base used is 2.0 mol to 10.0 mol, preferably 2.1 mol to 5.0 mol, more preferably 2.5 mol to 3.5 mol, per 1 mol of compound (1 ′). Is a mole.
Solvents include aromatic solvents such as benzene, toluene, xylene, ether solvents such as ether, isopropyl ether, THF, tert-butyl methyl ether, CPME, DMF, N-methylpyrrolidin-2-one (NMP), N An amide solvent such as N'-dimethylimidazolidin-2-one (DMI) can be preferably used. The volume (L) of the solvent used is a volume (L) / weight (kg) with respect to the weight (kg) of the compound (1 ′), preferably 1.0 to 100 L / kg, more preferably 3 ~ 30 L / kg.
The reaction temperature is an appropriate temperature from the melting point to the boiling point of the solvent, preferably 0 ° C to 120 ° C, more preferably room temperature to 100 ° C.
The reaction can be performed with stirring. Although reaction time can be set suitably according to reaction rate, Preferably it is 3 to 50 hours, More preferably, it is 6 to 24 hours.

3) Asymmetric catalyst The asymmetric catalyst according to the present invention comprises an optically active quaternary ammonium salt represented by the formula (I) or the formula (V). The catalyst is an asymmetric reaction such as asymmetric aldol reaction, asymmetric Mannich addition reaction, asymmetric halogenation reaction, asymmetric aminoxylation reaction, asymmetric hydroxyamination reaction, asymmetric Michael addition reaction, asymmetric conjugate addition reaction, etc. Used for.
The asymmetric catalyst according to the present invention is characterized by having a stable catalytic activity and an extremely high S / C (substrate / catalyst [molar ratio]).

4) Method for Producing Optically Active Compound The method for producing an optically active compound according to the present invention comprises performing an asymmetric reaction in the presence of an optically active quaternary ammonium salt represented by formula (I) or formula (V). Is included. In the method for producing an optically active compound according to the present invention, a solvent can be used.
By bringing the substrate into contact with the catalyst according to the present invention, an asymmetric reaction occurs, and the target optically active amino acid derivative can be produced with high selectivity. Here, the substrate is a compound that is a raw material for the asymmetric reaction. The substrate may be an achiral or prochiral compound, or may be an optically active compound having an asymmetric center or a racemate. In the present invention, the substrate is preferably an achiral or prochiral compound. The substrate may be a single compound or a combination of two or more compounds.

  The method for producing an optically active compound according to the present invention includes a method for producing an optically active amino acid derivative. Examples of the optically active amino acid derivative include a compound represented by the formula (II).

<Optically Active Amino Acid Derivative Represented by Formula (II)>
<R ^a >
In the formula (II), R ^a represents a divalent organic group. Examples of the divalent organic group in R ^a include divalent organic groups represented by any of the following formulas. For example, when R ^a is a trimethylene group (—CH ₂ CH ₂ CH ₂ —), the ring containing R ^a forms a 5-membered ring.

In the formula, each X ¹ independently represents an atom or a functional group appropriately selected from the group consisting of a carbon atom, an oxy group, an imino group, a thio group, a carbonyl group, a sulfinyl group, and a sulfonyl group. These atoms or functional groups may each independently have a substituent. The bond between adjacent X ¹ is shown as a single bond in the formula, but may be a double bond.

  From the viewpoint of the production method, a divalent organic group represented by any one of the following formulas can be exemplified.

In the formula, each X ³ independently represents an atom or a functional group appropriately selected from the group consisting of a carbon atom, an oxy group, an imino group, a thio group, a carbonyl group, a sulfinyl group, and a sulfonyl group. These atoms or functional groups may each independently have a substituent. The bonds between adjacent X ^{3 and} between C and X ³ are shown as single bonds in the formula, but may be double bonds.
C in the formula represents a carbon atom. In this case, any of sp carbon, sp2 carbon, and sp3 carbon may be used.
The carbon atom in the functional group constituting the divalent organic group may have a substituent. Examples of the substituent include a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C1-6 alkoxy group, and an unsubstituted or substituted C1-6 alkylcarbonyl group. An unsubstituted or substituted C6-8 arylcarbonyl group, an unsubstituted or substituted C1-6 alkylsulfonyl group, an unsubstituted or substituted C6-10 arylsulfonyl group.
The imino group for X ³ may have a substituent. Examples of the substituent include an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C1-6 alkylcarbonyl group, an unsubstituted or substituted C6-8 arylcarbonyl group, an unsubstituted Examples thereof include a substituted or substituted C1-6 alkylsulfonyl group and an unsubstituted or substituted C6-10 arylsulfonyl group.

As ^a preferable divalent organic group for R ^a , an unsubstituted or substituted C 2-6 alkylene group, an unsubstituted or substituted C 2-6 alkenylene group, — (CH ₂ ) _q —X— And a group represented by (CH ₂ ) _q − (wherein q is each independently an integer of 1 to 6. X represents an oxo group, an imino group, or a thio group). it can.

Examples of the “C2-6 alkylene group” include an ethylene group (alias: ethane-1,2-diyl group), a propylene group (alias: propane-1,2-diyl group), and a trimethylene group (alias: propane-1,3). -Diyl group), tetramethylene group, pentamethylene group, hexamethylene group and the like.
Examples of the “C2-6 alkenylene group” include a vinylene group (alias: ethene-1,2-diyl group), a propenylene group (also known as prop-1-ene-1,3-diyl group), and a 2-butenylene group (alias). : But-2-ene-1,4-diyl group), 1-methyl-1-butenylene group (also known as penta-3-ene-1,4-diyl group), and the like.
In the alkylene group having a substituent or the alkenylene group having a substituent, preferred groups which can be a substituent include halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methyl group, an ethyl group and an n-propyl group A C1-6 alkyl group such as i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, n-pentyl group, n-hexyl group; cyclopropyl group, cyclobutyl group, C3-6 cycloalkyl groups such as cyclopentyl group and cyclohexyl group; methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, s-butoxy group, i-butoxy group, t-butoxy group, etc. A hydroxyl group; a chloromethyl group, a chloroethyl group, a trifluoromethyl group, 1,2-dichloro- - propyl group, 1-fluoro -n- butyl group, Cl to 6 haloalkyl group such as perfluoro -n- pentyl group; and the like.

Specific examples of the group represented by — (CH ₂ ) _q —X— (CH ₂ ) _q − include —CH ₂ —O—CH ₂ —, —CH ₂ —O— (CH ₂ ) ₂ —, — _{(CH 2) 2 -O- (CH} 2) 2 -, - CH 2 -O- (CH 2) 3 -, - (CH 2) 2 -O- (CH 2) 3 -, - (CH 2) 3 _{-O- (CH 2) 3 -,} - CH 2 -NH-CH 2 -, - CH 2 -NH- (CH 2) 2 -, - (CH 2) 2 -NH- (CH 2) 2 -, - _{CH 2 -NH- (CH 2) 3} -, - (CH 2) 2 -NH- (CH 2) 3 -, - (CH 2) 3 -NH- (CH 2) 3 -, - CH 2 -S- _{CH 2 -, - CH 2 -S-} (CH 2) 2 -, - (CH 2) 2 -S- (CH 2) 2 -, - CH 2 -S- (CH 2) 3 -, - (CH 2 ) ₂ —S— (CH ₂ ) ₃ —, — (CH ₂ ) ₃ —S— (CH ₂ ) ₃ — and the like.

<R ^b >
R ^b is a hydrogen atom, an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted C 2-6 alkenyl group, an unsubstituted or substituted C 2-6 alkynyl group, A substituted or substituted C7-14 aralkyl group, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted heteroaryl group is shown.

As the “C1-6 alkyl group”, “C6-10 aryl group”, and “heteroaryl group” for R ^b, the “C1-6 alkyl group”, “C6-10 aryl group”, and the like mentioned in R ¹ , and The same thing as a "heteroaryl group" can be mentioned.
As "C2~6 alkenyl group" and "C2~6 alkynyl group" in R ^b, it may include the same as those mentioned in R ² 'C2~6 alkenyl group "and" C2~6 alkynyl group ".
Examples of the “C7-14 aralkyl group” for R ^b include a benzyl group, a phenethyl group, a 3-phenylpropyl group, a 1-naphthylmethyl group, and a 2-naphthylmethyl group.

<R ^c >
R ^c is an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, unsubstituted or A C7-14 aralkyl group having a substituent, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted heteroaryl group is shown.

As the “C1-6 alkyl group”, “C6-10 aryl group”, and “heteroaryl group” for R ^c, the “C1-6 alkyl group”, “C6-10 aryl group”, and the like mentioned in R ¹ can be used. The same thing as a "heteroaryl group" can be mentioned.
As "C2~6 alkenyl group" and "C2~6 alkynyl group" in R ^c, it may include the same as those mentioned in R ² 'C2~6 alkenyl group "and" C2~6 alkynyl group ".
The "C7~14 aralkyl group" in R ^c, may include the same as those mentioned in R ^b "C7~14 aralkyl group".

Ar independently represents an unsubstituted or substituted C6-10 aryl group.
Examples of the “C6-10 aryl group” in Ar include the same as the “C6-10 aryl group” mentioned in R ¹ .

  In formula (II), * indicates that the asymmetric carbon to which it is attached is optically active. In the present invention, optical activity means that the abundance of a specific optical isomer is greater than 50%. In the present invention, the abundance ratio of the specific optical isomer is preferably 75% or more, and more preferably 80% or more.

  The optically active amino acid derivative represented by the above formula (II) comprises an α, β-unsaturated aldehyde derivative represented by the following formula (III) and a glycine derivative represented by the following formula (IV): The reaction can be carried out in a solvent containing a base in the presence of the optically active quaternary ammonium salt of the present invention.

（式（III）中、Ｒ^aは、前記と同じ意味を示す。）

(In the formula (III), R ^a has the same meaning as described above.)

（式（IV）中、Ａｒ、Ｒ^b、およびＲ^cは、前記と同じ意味を示す。）

(In the formula (IV), Ar, R ^b and R ^c have the same meaning as described above.)

  The method for producing an optically active amino acid derivative according to the present invention further comprises a method for producing an optically active amino acid derivative represented by the following formula (II-1) or an optically active amino acid derivative represented by the formula (II-2): Include.

（式（II-１）中、Ｒ^a、Ｒ^b、およびＲ^cは、前記と同じ意味を示す。破線と実線の二重線で表される結合は、単結合または二重結合を示す。）

(In Formula (II-1), R ^a , R ^b , and R ^c have the same meaning as described above. The bond represented by a broken line and a solid double line represents a single bond or a double bond. )

（式（II-２）中、Ｒ^a、Ｒ^b、およびＲ^cは、前記と同じ意味を示す。破線と実線の二重線で表される結合は、単結合または二重結合を示す。）

(In Formula (II-2), R ^a , R ^b , and R ^c have the same meaning as described above. The bond represented by a broken line and a solid double line represents a single bond or a double bond. )

<Optically Active Amino Acid Derivatives Represented by Formula (II-1) and Formula (II-2)>
The optically active amino acid derivative represented by the formula (II-1) or the formula (II-2) is obtained by deprotecting the N-diphenylmethylene group in the optically active amino acid derivative represented by the above formula (II). Can be manufactured.
When the asymmetric Michael addition reaction proceeds on the α-position of the glycine derivative, two consecutive solids on the ring structure are simultaneously controlled. As a result of controlling the steric structure, the amino group derived from the glycine derivative and the carbonyl carbon derived from the α, β-unsaturated aldehyde are arranged in close proximity. As a result, the cyclization reaction smoothly proceeds with the deprotection of the substituent on the nitrogen, and the bicyclic optically active amino acid derivative represented by the formula (II-1) or the formula (II-2) is efficiently used. Is obtained.

This reaction can be performed under phase transfer reaction conditions in a two-solution two-phase system of an organic solvent and an aqueous base solution or a one-solution two-phase system in which a single base is dispersed and slurried in an organic solvent.
The molar ratio of glycine derivative represented by formula (IV) (hereinafter referred to as glycine derivative (IV)) / optically active quaternary ammonium salt represented by formula (I) (hereinafter referred to as asymmetric catalyst (I)) is preferably Is 20,000 / 1 to 10/1, more preferably 5,000 / 1 to 20/1, still more preferably 2,000 / 1 to 50/1.
The molar ratio of glycine derivative (IV) / α, β-unsaturated aldehyde derivative of formula (III) (hereinafter referred to as unsaturated aldehyde derivative (III)) is preferably 1 / 0.75 to 1/10, more preferably The ratio is 1/1 to 1/5, more preferably 1 / 1.1-1 / 3.
The molar ratio of glycine derivative (IV) / base is preferably 1/1 to 1/100, more preferably 1/1 to 1/10, and further preferably 1 / 1.1 to 1/5.

  As the base, an inorganic base or an organic base can be used. Inorganic bases include lithium hydroxide, sodium hydroxide, sodium bicarbonate, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium carbonate, potassium methoxide, potassium ethoxide, potassium ter-butoxide, cesium hydroxide, carbonic acid Examples include cesium. Examples of the organic base include diazabicycloundecene (DBU), diazabicyclononene (DBN), N, N-diisopropylethylamine (DIEA), and phosphazene bases. These bases can be used individually by 1 type or in mixture of 2 or more types. When the base is used as an aqueous solution, the concentration (w / w) can be appropriately set in the range from 5% to supersaturation, but is preferably 10% to saturation concentration.

  As the solvent, when the reaction is carried out in a two-solution two-phase system, hydrocarbon solvents such as hexane, cyclohexane, benzene, toluene, xylene, mesitylene, etc .; non-chlorine solvents such as methylene chloride, chloroform, chlorobenzene, etc. A water-soluble solvent etc. can be mentioned. Of these, hydrocarbon solvents such as hexane, cyclohexane, benzene, toluene, xylene and mesitylene are preferred. These solvents can be used alone or in combination of two or more.

  When carrying out the reaction in a one-solution two-phase system, in addition to the above-mentioned solvents, nitrile solvents such as acetonitrile and benzonitrile; N, N-dimethylformamide (DMF), N-methylpyrrolidin-2-one (NMP ), Amide solvents such as N, N′-dimethylimidazolidin-2-one (DMI); ether solvents such as diethyl ether, diisopropyl ether, t-butyl methyl ether, cyclopentyl methyl ether (CPME), and anisole be able to. The volume (L) of the solvent used is volume (L) / weight (kg) with respect to the weight (kg) of the glycine derivative (IV), preferably 1.0 to 100 L / kg, more preferably 5 ~ 30 L / kg. In addition, although it is common to use any of the organic solvents described above, it is also possible to carry out the reaction only with an aqueous base solution without using an organic solvent. The reaction can be performed with stirring. The reaction temperature is preferably an appropriate temperature from the melting point to the boiling point of the solvent, more preferably -20 ° C to 60 ° C. Although reaction time can be suitably set according to reaction rate, Preferably it is 1 to 60 hours, More preferably, it is 1 to 24 hours.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

[Example 1]
Synthesis of optically active quaternary ammonium salt (1-25)

Step 1 Synthesis of Compound (2) 2.73 g (6.40 mmol) of Compound (1) that can be synthesized by a known method was dissolved in 30 mL of tetrahydrofuran. The solution was cooled to −78 ° C. under an argon stream. To this solution, 20 mL of 1.6N n-pentane solution of t-butyllithium was added dropwise over 20 minutes. Then, it stirred for 30 minutes at -78 degreeC. The solution was warmed to −3 ° C. and stirred for 10 minutes. Then, it cooled again to -78 degreeC. To this, a solution prepared by dissolving 2.33 g (12.8 mmol) of benzophenone in 15 mL of tetrahydrofuran was added over 30 minutes. The solution was warmed to room temperature over 2 hours. The reaction was stopped by adding 10 mL of water to the reaction solution. Subsequently, tetrahydrofuran was distilled off with an evaporator. Water was added to the obtained concentrated solution, and extraction was performed using methylene chloride. The methylene chloride phase was dried over magnesium sulfate and filtered. Thereafter, it was concentrated to obtain crude crystals. The crude crystals were washed with a small amount of diethyl ether to obtain 3.17 g (yield 78.3%) of compound (2) as white crystals.
The NMR data of the obtained compound are shown below.
¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.33-7.19 (m, 20H), 6.59 (dd, J = 8.7, 17.1 Hz, 4H), 4.32 (d, J = 11.1Hz, 2H), 3.85 ( m, 2H), 1.95-1.49 (m, 4H), 1.71 (s, 6H).

Step 2 Synthesis of Compound (3) 632.8 mg (1.00 mmol) of Compound (2) and 392.0 mg (2.20 mmol) of NBS were dissolved in 10 ml of benzene. The solution was heated to 80 ° C. and stirred. A solution prepared by dissolving 51.0 mg (0.30 mmol) of AIBN in 2 mL of benzene was added dropwise to this solution. After completion of the addition, the solution was stirred at 80 ° C. for 2 hours. A solution prepared by dissolving 17.0 mg (0.10 mmol) of AIBN in 1 mL of benzene was added dropwise thereto, and after completion of the addition, the mixture was stirred at 80 ° C. for 1 hour. Thereafter, 100.0 mg (0.56 mmol) of NBS was added, and after completion of the addition, the mixture was stirred at 80 ° C. for 1 hour. Subsequently, benzene was distilled off with an evaporator. Thereafter, diethyl ether was added to the residue. Succinimide precipitated. The succinimide was removed by filtration, the filtrate was poured into water and extracted with methylene chloride. The methylene chloride phase was dried over sodium sulfate and filtered. Thereafter, the resultant was concentrated to obtain 1.00 g (quantitative) of a crude product (3).
The NMR data of the obtained compound are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.35-7.17 (m, 20H), 6.87 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 8.8 Hz, 2H), 4.47 (d, J = 10.4 Hz, 2H), 4.38 (d, J = 12.4 Hz, 2H), 4.00 (t, J = 11.2 Hz, 2H), 3.79 (d, J = 10.4 Hz, 2H), 3.57 (s, 2H) , 1.77-1.65 (m, 4H).

Step 3 Synthesis of Compound (1-25) 300.1 mg (0.38 mmol) of Compound (3) was dissolved in 15 mL of acetonitrile. To this solution, 161.6 mg (1.90 mmol) of piperidine was added and stirred at room temperature for 3 hours. Acetonitrile was distilled off with an evaporator. Thereafter, the residue was dissolved in methylene chloride, washed with dilute hydrobromic acid aqueous solution, and then washed with saturated brine. Sodium sulfate was added to the methylene chloride phase to remove water, followed by filtration. Then, it concentrated and obtained the crude product. The crude product was dissolved in a small amount of methylene chloride, and n-hexane was added thereto. Crystals precipitated. The crystals were dried to obtain 162.7 mg (yield 53.7%) of compound (1-25).
The NMR data of the obtained compound are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.45 (d, J = 8.0 Hz, 4H), 6.34 (t, J = 8.0 Hz, 4H), 7.29-7.18 (m, 8H), 7.13 (d, J = 8.0 Hz, 4H), 6.88 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 5.25 (s, 2H), 4.99 (d, J = 13.2 Hz, 2H) , 4.30-4.26 (m, 2H), 4.09-4.05 (m, 2H), 3.42-3.37 (m, 2H), 3.30 (d, J = 13.2 Hz, 2H), 2.73-2.69 (m, 2H), 1.92 -1.25 (m, 10H).

Specific examples of the optically active quaternary ammonium salt represented by the formula (Ia), which can be obtained by the same method as the above synthesis method, are shown in Table 1. Table R ¹ in _{^{1, R a 3, R b}} 3, R 4, R 5, (R a 2) n, (R b 2) n, and X ^- is, R ^1, R in formula (I) _a ³ , R _b ³ , R ⁴ , R ⁵ , (R _a ² ) _n , (R _b ² ) _n , and X ⁻ . Ph is phenyl, Me is methyl, Et is methyl, ^t Bu is t- butyl group, and ⁿ Bu is an abbreviation indicating the, n- butyl group.

A part of the compounds shown in Table 1 was analyzed by ¹ H-NMR (CDCl ₃ , δ ppm). The results were as follows.

Compound 1-11
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.50 (d, J = 7.2 Hz, 4H), 7.35-7.10 (m, 10H), 7.13 (d, J = 7.2 Hz, 4H), 6.91 (d, J = 9.2 Hz, 2H), 6.83 (d, J = 9.2 Hz, 2H), 5.11 (d, J = 14.0 Hz, 2H), 5.04 (s, 2H), 4.36-4.27 (m, 6H), 3.22 (d , J = 14.0 Hz, 2H), 1.98-1.30 (m, 16H).

Compound 1-17
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.47 (d, J = 8.0 Hz, 4H), 7.35 (t, J = 8.0 Hz, 4H), 7.29-7.23 (m, 8H), 7.11 (d, J = 8.0 Hz, 4H), 6.88 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 5.35 (s, 2H), 5.06 (d, J = 13.2 Hz, 2H), 4.28-4.24 (m, 4H), 4.00-3.80 (m, 4H), 3.47-3.40 (m, 2H), 3.37 (d, J = 13.2 Hz, 2H), 2.83-2.75 (m, 2H), 1.92- 1.80 (m, 4H).

Compound 1-31
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.40 (d, J = 6.8 Hz, 4H), 7.31-7.19 (m, 10H), 7.11 (d, J = 7.2 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.8 Hz, 4H), 5.37 (s, 2H), 4.76 (d, J = 12.8 Hz, 2H), 4.28-4.15 (m, 6H), 3.34 (d , J = 12.8 Hz, 2H), 2.88 (m, 2H), 2.16 (m, 2H), 1.89-1.75 (m, 6H).

Compound 1-33
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.46 (d, J = 7.6 Hz, 4H), 7.35-7.20 (m, 10H), 7.11 (d, J = 7.6 Hz, 4H), 6.84 (m, 4H ), 5.57 (s, 2H), 4.91 (d, J = 13.6 Hz, 2H), 4.28-4.18 (m, 4H), 3.83-3.82 (m, 2H), 3.33 (d, J = 13.2 Hz, 2H) , 3.10-2.90 (m, 4H), 2.39-2.37 (m, 2H), 1.90-1.80 (m, 4H).

Compound 1-34
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.46 (d, J = 7.6 Hz, 4H), 7.35-7.20 (m, 10H), 7.11 (d, J = 7.6 Hz, 4H), 6.84 (m, 4H ), 5.57 (s, 2H), 4.91 (d, J = 13.6 Hz, 2H), 4.28-4.18 (m, 4H), 3.83-3.82 (m, 2H), 3.33 (d, J = 13.2 Hz, 2H) , 3.10-2.90 (m, 4H), 2.39-2.37 (m, 2H), 1.90-1.80 (m, 4H).

Compound 1-35
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.16-7.51 (m, 18H), 6.99-7.03 (m, 2H), 6.75-6.90 (m, 4H), 5.94 (br, 1H), 4.94 (br, 1H), 4.93 (d, 2H, J = 14.0 Hz), 4.80 (d, 2H, J = 13.6 Hz), 4.14-4.34 (m, 4H), 3.88 (d, 2H, J = 14.0 Hz), 3.76- 3.90 (m, 1H), 2.80-2.90 (m, 1H), 2.73 (d, 2H, J = 13.6 Hz), 2.54-2.57 (m, 2H), 1.39-2.10 (m, 8H), 0.77 (d, 3H, J = 6.8 Hz), 0.40-0.58 (m, 1H).

[Example 2]
Synthesis example of optically active amino acid derivatives

Step 1 Synthesis of cyclopent-1-enecarbaldehyde (5) 75 mL of diethyl ether was added to 100 mL of an aqueous solution containing 14.2 g (66.4 mmol) of sodium periodate. 25 mL of an aqueous solution containing 6.0 g (50.6 mmol) of 1,2-cyclohexanediol (4) was added dropwise thereto. This was stirred for 30 minutes at room temperature. Thereafter, 20 mL of a 20% aqueous potassium hydroxide solution was added dropwise thereto. The solution was stirred for 1 hour at room temperature and then the reaction was stopped. The diethyl ether phase was taken out by a liquid separation operation. The aqueous layer was extracted with 50 mL of methylene chloride. The diethyl ether phase and the methylene chloride phase were combined and it was dried over magnesium sulfate and filtered. Then, it concentrated and obtained the crude product. The crude product was purified by distillation under reduced pressure (bp 80 ° C./15 mmHg) to obtain 3.21 g (yield 66%) of cyclopent-1-enecarbaldehyde (5) as a transparent liquid.

Step 2 Synthesis of optically active amino acid derivatives (7) and (8) Glycine derivative (6) 88.5 mg (0.30 mmol), cesium carbonate 117.6 mg (0.36 mmol), optically active quaternary ammonium salt (1 -25) is mixed with a solution obtained by dissolving 4 mL of CPME so as to be 2 mol%. This was cooled to 0 ° C. under an argon stream. To this was added a solution prepared by dissolving 58.8 mg (0.6 mmol) of compound (5) in 2 mL of CPME. Stir at 0 ° C. for 3 hours. The reaction solution was then poured into a pH 7 phosphate buffer solution and then extracted with diethyl ether. The diethyl ether phase was dried over magnesium sulfate and filtered. Then, the crude product was obtained by concentrating. This crude product was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1: 12) to give 33.6 mg of optically active amino acid derivative (7) (yield 28.6%, 82.2%). ee) was obtained as white crystals, and 39.7 mg (yield 63.2%, 80.2% ee) of the optically active amino acid derivative (8) was obtained as a yellow oil.
The optical purity of the optically active amino acid derivative (7) is HPLC (Daicel Chiralpak AD-H, hexane / 2-propanol = 98.7 / 1.3, flow rate 0.5 mL / min, λ = 254 nm, retention time: 21.9 min (major ) and 23.2min (minor)).
The NMR data of the obtained compound (7) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ = 9.66 (d, J = 3.2 Hz, 1H), 7.62-7.60 (m, 2H), 7.47-7.43 (m, 3H), 7.38-7.30 (m, 3H ), 7.20-7.18 (m, 2H), 3.90 (d, J = 6.3 Hz, 1H), 3.03-2.99 (m, 1H), 2.86-2.79 (m, 1H), 1.92-1.78 (m, 3H), 1.58-1.55 (m, 2H), 1.43 (m, 9H), 1.34-1.28 (m, 1H).

The optical purity of the optically active amino acid derivative (8) was estimated by determining the optical purity of the compound (10) benzoylated after induction into the compound (9) by HPLC.
The NMR data of the obtained compound (8) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.48 (d, J = 1.6 Hz, 1H), 4.30-4.28 (m, 1H), 3.42-3.39 (m, 1H), 2.80-2.78 (m, 1H ), 1.75-1.44 (m, 5H), 1.48 (m, 9H), 1.28-1.24 (m, 1H).

[Reference Example 1]
Synthesis Step 1 of Compound (10) Synthesis of Compound (9) 40.0 mg of 10% palladium carbon was added to a solution obtained by dissolving 39.7 mg (0.19 mmol) of the compound (8) in 3 mL of ethanol. Thereafter, the reaction system was replaced with hydrogen. Stir at room temperature for 3 hours. Thereafter, palladium carbon was removed by filtration, and the obtained filtrate was concentrated to obtain 45.1 mg (quantitative) of Compound (9) as a yellow oil.
The NMR data of the obtained compound (9) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ = 3.30 (dd, J = 10.7, 7.1 Hz, 1H), 3.18 (d, J = 5.1 Hz, 1H), 2.57-2.54 (m, 2H), 2.47 ( dd, J = 10.7, 5.9 Hz, 1H), 1.94 (br, 1H), 1.74-1.53 (m, 7H), 1.47 (s, 9H).

Step 2 Synthesis of Compound (10) To a solution obtained by dissolving 45.1 mg (0.19 mmol) of Compound (10) in 2 mL of acetonitrile, 42.8 μL of tetramethylethylenediamine and 22.5 μL of 1-methylimidazole were added, and argon was added. Cooled to 0 ° C. under a stream of air. To this solution, 26.2 μL of benzoyl chloride was added and stirred at 0 ° C. for 2 hours. The reaction solution is concentrated, the residue is dissolved in a small amount of methylene chloride, and purified by silica gel column chromatography (ethyl acetate / n-hexane = 1: 2) to give 33.6 mg (yield 56.) of compound (10). 2%, 80.2% ee) was obtained as a clear oil.
The optical purity of the compound (10) was determined by HPLC (Daicel Chiralpak AD-H, hexane / 2-propanol = 90/10, flow rate 0.8 mL / min, λ = 254 nm, retention time: 13.4 min (minor) and 16.2 min ( major)).
The NMR data of the obtained compound (10) are shown below.
¹ H NMR (400 MHz, d-DMSO (140 ° C)): δ = 7.41 (m, 5H), 4.16 (m, 1H), 3.67 (dd, J = 11.5, 7.5 Hz, 1H), 3.35 (m, 1H), 2.80-2.67 (m, 2H), 2.80-1.59 (m, 6H), 1.41 (s, 9H).

[Example 3]
Synthesis example of optically active amino acid derivatives

84.4 mg (0.30 mmol) of glycine derivative (11), 117.6 mg (0.36 mmol) of cesium carbonate, and optically active quaternary ammonium salt (1-25) are dissolved in 4 mL of CPME so as to be 2 mol%. The solution was cooled to 0 ° C. under a stream of argon. To this was added a solution prepared by dissolving 58.8 mg (0.6 mmol) of compound (5) in 2 mL of CPME. This was stirred at 0 ° C. for 3 hours. Thereafter, the reaction solution was poured into ice water and extracted with diethyl ether. The diethyl ether phase was dried over sodium sulfate and filtered. Then, the crude product was obtained by concentrating. This crude product was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1: 10) to give 44.8 mg (yield 39.6%, 77.1% ee) of the optically active amino acid derivative (12). ) As a clear oil, and 29.7 mg (yield 50.7%, 77.7% ee) of the optically active amino acid derivative (13) as white crystals.
The optical purity of the optically active amino acid derivative (12) was determined by HPLC (Daicel Chiralpak AD-H, hexane / 2-propanol = 90/10, flow rate 0.5 mL / min, λ = 254 nm, retention time: 12.0 min (major ) and 14.8min (minor)).
The NMR data of the obtained compound (12) are shown below.
¹ H NMR (400MHz, CDCl ₃ ): δ = 9.66 (d, J = 2.8 Hz, 1H), 7.62-7.60 (m, 2H), 7.46-7.43 (m, 3H), 7.38-7.30 (m, 3H) , 7.20-7.18 (m, 2H), 4.98 (m, 1H), 3.97 (d, J = 6.4 Hz, 1H), 3.04-3.01 (m, 1H), 2.84 (m, 1H), 1.87-1.79 (m , 2H), 1.59-1.50 (m, 2H), 1.35-1.27 (m, 2H), 1.19 (dd, J = 4.8, 6.4 Hz, 6H).

The optical purity of the optically active amino acid derivative (13) was estimated from the optical purity of the compound (15) obtained by derivatizing the compound (14) and then determining the optical purity of the benzoylated compound (15) by HPLC.
The NMR data of the obtained compound (13) are shown below.
¹ H NMR (400MHz, CDCl ₃ ): δ = 7.50 (s, 1H), 5.04 (m, 1H), 4.37-4.34 (m, 1H), 3.43 (m, 1H), 2.81 (m, 1H), 1.74 -1.50 (m, 6H), 1.26 (d, J = 6.8 Hz, 6H).

[Reference Example 2]
Synthesis Step 1 of Compound (15) Synthesis of Compound (14) 29.7 mg of 10% palladium carbon was added to a solution obtained by dissolving 29.7 mg (0.15 mmol) of the compound (13) in 2 mL of ethanol. Next, the reaction system was replaced with hydrogen. This was stirred at room temperature for 2 hours. Then, palladium carbon was removed by filtration, and the obtained filtrate was concentrated to obtain 20.2 mg (yield: 67.3%) of Compound (14) as a transparent oil.
The NMR data of the obtained compound (14) are shown below.
¹ H NMR (400MHz, CDCl ₃ ): δ = 5.02 (m, 1H), 3.29 (dd, J = 7.2, 4.8 Hz, 1H), 3.22 (d, J = 5.6 Hz, 1H), 2.61-2.54 (m , 2H), 2.47 (dd, J = 5.6, 5.2 Hz, 1H), 2.10 (br, 1H), 1.75-1.41 (m, 6H), 1.24 (dd, J = 2.4, 3.2 Hz, 6H).

Step 2 Synthesis of Compound (15) To a solution obtained by dissolving 20.2 mg (0.10 mmol) of Compound (14) in 1 mL of acetonitrile, 17.8 mg of tetramethylethylenediamine and 12.8 mg of 1-methylimidazole were added, and argon was added. Cooled to 0 ° C. under a stream of air. To this solution, 17.3 mg of benzoyl chloride was added and stirred at 0 ° C. for 2 hours. The reaction solution is concentrated, the residue is dissolved in a small amount of methylene chloride, and purified by silica gel column chromatography (ethyl acetate / n-hexane = 1: 2) to give 24.1 mg of compound (15) (yield 78.78). 1%, 77.7% ee) was obtained as a yellow oil.
The optical purity of compound (15) is HPLC (Daicel Chiralpak AD-H, hexane / Ethanol = 80/20, flow rate 0.8 mL / min, λ = 254 nm, retention time: 9.3 min (major) and 10.1 min (minor) ).
The NMR data of the obtained compound (15) are shown below.
¹ H NMR (500 MHz, d-DMSO (140 ° C)): δ = 7.42 (m, 5H), 4.92 (m, 1H), 4.26 (s, 1H), 3.70 (m, 1H), 3.37 (m, 1H ), 2.75-2.69 (m, 2H), 2.03-1.92 (m, 1H), 1.90-1.70 (m, 2H), 1.61-1.59 (m, 2H), 1.45-1.39 (m, 1H), 1.22 (t , 6H).

[Example 4]
The reaction was carried out in the same procedure as in Example 3 except that the solvent used in Step 1 of Example 3 was changed to anisole.
Compound (6) 88.5 mg (0.30 mmol), cesium carbonate 117.6 mg (0.36 mmol), and optically active quaternary ammonium salt (1-25) were dissolved in 5 mL of anisole so as to be 2 mol%. And then cooled to 0 ° C. under a stream of argon. To this was added a solution prepared by dissolving 58.8 mg (0.6 mmol) of compound (5) in 1 mL of anisole. The mixture was stirred at 3 ° C to 8 ° C for 5.5 hours. The reaction solution was then poured into ice water and extracted with diethyl ether. The diethyl ether phase was dried over sodium sulfate and filtered. Then, the crude product was obtained by concentrating. The crude product was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1: 12) to give 29.9 mg (yield 25.5%, 80.6% ee) of compound (7) as white. As a crystal, 40.2 mg (yield 64.0%, 83.9% ee) of compound (8) was obtained as a yellow oil.
The optical purity of compound (7) was determined by HPLC.
The optical purity of the compound (8) was estimated from the optical purity of the compound (10) determined by HPLC in the same manner as in Example 2.

[Example 5]
In Step 1 of Example 3, the same reaction was performed by changing the solvent to diisopropyl ether.
Compound (6) 88.5 mg (0.30 mmol), cesium carbonate 117.6 mg (0.36 mmol), and optically active quaternary ammonium salt (1-25) were dissolved in 5 mL of diisopropyl ether so as to be 2 mol%. And the solution was cooled to 0 ° C. under an argon stream. To this was added a solution prepared by dissolving 58.8 mg (0.6 mmol) of compound (5) in 1 mL of diisopropyl ether. The mixture was stirred at 0 ° C for 40.5 hours. The reaction solution was then poured into ice water and extracted with diethyl ether. The diethyl ether phase was dried over sodium sulfate and filtered. Then, the crude product was obtained by concentrating. The crude product was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1: 12) to give 50.5 mg (yield 43.0%, 82.7% ee) of compound (7) in white. As a crystal, 24.5 mg (yield 39.0%, 86.9% ee) of compound (8) was obtained as a yellow oil.
The optical purity of compound (7) was determined by HPLC.
The optical purity of the compound (8) was estimated from the optical purity of the compound (10) determined by HPLC in the same manner as in Example 2.

  From these results, it is understood that when the optically active quaternary ammonium salt according to the present invention is used as an asymmetric catalyst, the target optically active amino acid derivative can be synthesized with high yield and high optical purity.

[Example 6]
In Example 4, the same reaction was carried out by changing the solvent to toluene.
Compound (8) was obtained in a yield of 73% and 89% ee.
[Example 7]
In Example 4, the same reaction was performed by changing the solvent to trifluoromethylbenzene.
Compound (8) was obtained in a yield of 58% and 90% ee.
[Example 8]
In Example 4, the same reaction was performed by changing cesium carbonate to barium hydroxide.
Compound (8) was obtained in a yield of 46% and 84% ee.
[Example 9]
In Example 4, the same reaction was carried out by changing the optically active quaternary ammonium salt to compound 1-35.
Compound (8) was obtained in a yield of 58% and 90% ee.

[Example 10]
Synthesis of optically active quaternary ammonium salt (2-15)

300 mg (0.55 mmol) of compound (16) and 105 mg (0.25 mol) of compound (1) which can be synthesized by a known method, 5.6 mg (5 mol%) of palladium acetate and 2-Dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl In the presence of a metal catalyst consisting of 20.5 mg (10 mol%), 424 mg (4 equivalents) of tripotassium phosphate was used as a base, heated to 90 ° C. in 5 mL of a toluene solvent, and stirred for 2 days. After completion of the reaction, extraction, drying and concentration operations were performed. Further, the crude product was purified by column chromatography (hexane: ethyl acetate = 20: 1) to obtain 300 mg of compound (17) (yield 94%). The synthesis from the compound (17) to the target optically active quaternary ammonium salt (2-15) is performed by using the same method as the method for synthesizing the above optically active quaternary ammonium salt (1-25). An optically active quaternary ammonium salt (2-15) was synthesized.
The NMR data of the obtained compound are shown below.
¹ H NMR (400MHz, CDCl ₃ ): δ = 8.70 (br, 2H, ArH), 8.45 (br, 4H, ArH), 8.04 (br, 4H, ArH), 7.80-7.90 (m, 10H, ArH), 7.45-7.52 (m, 4H, ArH), 7.35 (br, 2H, ArH), 7.28 (s, 2H, ArH), 7.14-7.19 (m, 2H, ArH), 7.03 (d, 2H, J = 8.8 Hz , Ar-H), 6.41 (d, 2H, J = 8.4 Hz, Ar-H), 4.70-4.78 (m, 4H, ArCH2N), 4.43-4.56 (m, 4H, CH2O), 4.35 (d, 2H, J = 13.6 Hz, ArCH2N), 3.61 (d, 2H, J = 13.2 Hz, ArCH2N), 1.89-2.12 (m, 4H, CH2).

Table 2 shows specific examples of the optically active quaternary ammonium salt represented by the formula (Va), which can be obtained by the same method as the above synthesis method. R _a ³ , R _b ³ , (R _a ² ) _n , (R _b ² ) _n , (R _a ⁶ ) _k , (R _b ⁶ ) _k , and X ⁻ in Table 2 are represented by the formula (Va) R _a ³ , R _b ³ , (R _a ² ) _n , (R _b ² ) _n , (R _a ⁶ ) _k , (R _b ⁶ ) _k , and X ⁻ . Ph is phenyl, Me is methyl, Et is methyl, ^t Bu is t- butyl group, and ⁿ Bu is an abbreviation indicating the, n- butyl group.

[Example 11]
In Example 4, the solvent was changed to diisopropyl ether, and the optically active quaternary ammonium salt was changed to compound (2-15) to carry out the same reaction.
Compound (8) was obtained in a yield of 56% and 87% ee.

  From these results, it is understood that when the optically active quaternary ammonium salt according to the present invention is used as an asymmetric catalyst, the target optically active amino acid derivative can be synthesized with high yield and high optical purity.

Claims (6)

In a solvent containing a base,
In the presence of an optically active quaternary ammonium salt represented by the formula (I) ,
An α, β-unsaturated aldehyde derivative represented by the formula (III);
Reacting with a glycine derivative represented by formula (IV),
A method for producing an optically active amino acid derivative represented by the formula (II).

[In Formula (I),
R ¹ each independently represents an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C3-8 cycloalkyl group, an unsubstituted or substituted C6-10 aryl group. Or an unsubstituted or substituted heteroaryl group.

R ² each independently represents a hydroxyl group, a halogen atom, an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted C 2-6 alkenyl group, an unsubstituted or substituted C 2 A -6 alkynyl group or an unsubstituted or substituted C1-6 alkoxy group is shown.
n represents the number of R < ² > each independently, and is an integer in any one of 0-2. When n is 2, R ² may be the same as or different from each other.

R _a ³ and R _b ³ are each independently a hydroxyl group, a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or A C2-6 alkynyl group having a substituent or an unsubstituted or substituted C1-6 alkoxy group is shown.
R _a ³ and R _b ³ may be combined to form a divalent organic group.

R ⁴ and R ⁵ are each independently an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, or an unsubstituted or substituted C2-6 6 represents an alkynyl group.
R ⁴ and R ⁵ may be combined to form a divalent organic group.

* Indicates that the asymmetric axis to which it is attached is optically active.
X ⁻ represents a hydroxide ion, a halogen atom ion, a sulfonic acid ion, a phosphoric acid ion, or a carboxylic acid ion. ]

(In formula (III), R ^a represents a divalent organic group.)

(In the formula (IV),
R ^b is a hydrogen atom, an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted C 2-6 alkenyl group, an unsubstituted or substituted C 2-6 alkynyl group, A substituted or substituted C7-14 aralkyl group, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted heteroaryl group is shown.
R ^c is an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, unsubstituted or A C7-14 aralkyl group having a substituent, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted heteroaryl group is shown.
Ar independently represents an unsubstituted or substituted C6-10 aryl group. )

(In the formula (II), R ^a , R ^b , R ^c , and Ar have the same meaning as described above.
* Indicates that the asymmetric carbon to which it is attached is optically active. )
In a solvent containing a base,
In the presence of an optically active quaternary ammonium salt represented by the formula (I) ,
An α, β-unsaturated aldehyde derivative represented by the formula (III);
Reacting with a glycine derivative represented by formula (IV),
A process for producing an optically active amino acid derivative represented by formula (II-1) or formula (II-2).

[In Formula (I),
R ¹ each independently represents an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C3-8 cycloalkyl group, an unsubstituted or substituted C6-10 aryl group. Or an unsubstituted or substituted heteroaryl group.

R ² each independently represents a hydroxyl group, a halogen atom, an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted C 2-6 alkenyl group, an unsubstituted or substituted C 2 A -6 alkynyl group or an unsubstituted or substituted C1-6 alkoxy group is shown.
n represents the number of R < ² > each independently, and is an integer in any one of 0-2. When n is 2, R ² may be the same as or different from each other.

R _a ³ and R _b ³ are each independently a hydroxyl group, a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or A C2-6 alkynyl group having a substituent or an unsubstituted or substituted C1-6 alkoxy group is shown.
R _a ³ and R _b ³ may be combined to form a divalent organic group.

R ⁴ and R ⁵ are each independently an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, or an unsubstituted or substituted C2-6 6 represents an alkynyl group.
R ⁴ and R ⁵ may be combined to form a divalent organic group.

* Indicates that the asymmetric axis to which it is attached is optically active.
X ⁻ represents a hydroxide ion, a halogen atom ion, a sulfonic acid ion, a phosphoric acid ion, or a carboxylic acid ion. ]

(In formula (III), R ^a represents a divalent organic group.)

(In the formula (IV),
R ^b is a hydrogen atom, an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted C 2-6 alkenyl group, an unsubstituted or substituted C 2-6 alkynyl group, A substituted or substituted C7-14 aralkyl group, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted heteroaryl group is shown.
R ^c is an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, unsubstituted or A C7-14 aralkyl group having a substituent, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted heteroaryl group is shown.
Ar independently represents an unsubstituted or substituted C6-10 aryl group. )

(In the formulas (II-1) and (II-2), R ^a , R ^b , and R ^c have the same meaning as described above. A bond represented by a broken line and a solid double line is a single bond. Or a double bond.) In formula (I):
R _a ³ and R _b ³ are divalent organic groups formed by them together,
The divalent organic group is a C 2-6 alkylene group, —O— (CH ₂ ) _m —O— (m is an integer of 1 to 6), or —O— (CH ₂ CH ₂ The manufacturing method of Claim 1 or 2 which is O) _p- (p is an integer in any one of 2-3). In formula (I):
R ⁴ and R ⁵ are divalent organic groups formed by them together;
The divalent organic group is a C3-6 alkylene group, or — (CH ₂ ) _q —X— (CH ₂ ) _q — (q is each independently an integer of 1 to 6. X Represents an oxo group, a thio group, or an imino group.) The production method according to any one of claims 1 to 3 . The manufacturing method as described in any one of Claims 1-4 whose optically active quaternary ammonium salt represented by Formula (I) is an optically active quaternary ammonium salt represented by Formula (V).

[In the formula (V),
R ² each independently represents a hydroxyl group, a halogen atom, an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted C 2-6 alkenyl group, an unsubstituted or substituted C 2 A -6 alkynyl group or an unsubstituted or substituted C1-6 alkoxy group is shown.
n represents the number of R < ² > each independently, and is an integer in any one of 0-2. When n is 2, R ² may be the same as or different from each other.
R _a ³ and R _b ³ are each independently a hydroxyl group, a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or A C2-6 alkynyl group having a substituent or an unsubstituted or substituted C1-6 alkoxy group is shown.
R _a ³ and R _b ³ may be combined to form a divalent organic group.
R ⁶ each independently represents an unsubstituted or substituted C 6-10 aryl group.
k shows the number of R < ⁶ > each independently, and is an integer in any one of 2-5. When k is 2, R ⁶ may be the same as or different from each other.
* Indicates that the asymmetric axis to which it is attached is optically active.
X ⁻ represents a hydroxide ion, a halogen atom ion, a sulfonic acid ion, a phosphoric acid ion, or a carboxylic acid ion. ] In formula (V):
R _a ³ and R _b ³ are divalent organic groups formed by them together,
The divalent organic group is a C 2-6 alkylene group, —O— (CH ₂ ) _m —O— (m is an integer of 1 to 6), or —O— (CH ₂ CH ₂ The manufacturing method of Claim 5 which is O) _p- (p is an integer in any one of 2-3).