JP2016011275A - PRODUCTION METHOD OF OPTICALLY ACTIVE β-HYDROXYKETONE COMPOUND - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new method for producing an optically active β-hydroxyketone compound.SOLUTION: A production method of an optically active compound represented by formula (4) is provided, which comprises allowing a compound represented by formula (2) to react with a compound represented by formula (3) in the presence of an optically active compound represented by formula (1). In the formulae, Ar represents a phenyl group which may have a substituent, or the like; Arrepresents a phenyl group which may have a substituent; Rrepresents a hydrocarbon group which may have a substituent, or the like; Y represents a sulfur atom or the like; Rrepresents one group selected from a set (A) of groups; and * represents an asymmetric carbon atom.

Description

  The present invention relates to a method for producing an optically active β-hydroxyketone compound.

例えば、特許文献１に示されるように、医薬、農薬、動物薬等の製造中間体として有用であることが知られている。
特許文献１には、ラセミ体の式（４）で示される化合物の製造方法として、アルドール反応による製造方法が記載されている。
一方、非特許文献１には、化合物（Ａ）を触媒とする不斉アルドール反応が記載されている。

The compound represented by the formula (4) (in the formula, each symbol is as described below):

For example, as shown in Patent Document 1, it is known to be useful as an intermediate for producing pharmaceuticals, agricultural chemicals, animal drugs and the like.
Patent Document 1 describes a production method by an aldol reaction as a production method of a compound represented by the racemic formula (4).
On the other hand, Non-Patent Document 1 describes an asymmetric aldol reaction using the compound (A) as a catalyst.

JP2013-10739A

Angelwandte Chemie, International Edition (2010), 49 (49), 9460-9464

  An object of the present invention is to provide a novel method capable of producing an optically active β-hydroxyketone compound.

  As a result of intensive studies to solve the above problems, the present inventors have found that in the presence of an optically active compound represented by the formula (1), a compound represented by the formula (2) and a formula (3) It was found that an optically active compound represented by the formula (4) can be produced by reacting the compound shown.

[式中、Ａｒは、置換基を有していてもよいフェニル基、置換基を有していてもよいナフチル基、置換基を有していてもよいインダニル基または置換基を有していてもよいインドリジニル基を表し、
Ａｒ¹は置換基を有していてもよいフェニル基を表し、
Ｒ^１は、置換基を有していてもよい炭化水素基、または置換基を有していてもよい複素環基を表し、
Ｙは、酸素原子、硫黄原子またはＮＲ^２（式中、Ｒ^２は、水素原子、置換基を有していてもよい炭化水素基、または置換基を有していてもよい複素環基を表すか、
Ｒ^１が結合する窒素原子、Ｒ^２が結合する窒素原子、ＮＲ^２が結合している炭素原子、Ｒ^１、およびＲ^２が一緒になって、置換基を有していてもよい含窒素複素環を形成してもよく、
Ｒ^３は、群Ａより選ばれるいずれか１つの基を表し、
＊は、不斉炭素原子を表す。
群A：置換基を有していてもよいキヌクリジニル基および下式（５）〜（８）で示される基からなる群

（式中、Ｒ^４及びＲ^５は同一または相異なり、置換基を有していてもよい炭化水素基または置換基を有していてもよい複素環基を表すか、
Ｒ^４とＲ^５とが一緒になって−（ＣＨ_２）_ｐ−を表し、ｐは３または４を表し、
Ｒ^６及びＲ^７は同一または相異なり、置換基を有していてもよい炭化水素基を表すか、
Ｒ^６とＲ^７とが一緒になって−（ＣＨ_２）_ｑ−を表し、ｑは２〜５のいずれか１つの整数を表し、
Ｒ^８及びＲ^９は同一または相異なり、置換基を有していてもよい炭化水素基を表し、
Ｒ^１０は、置換基を有していてもよいキヌクリジニル基を表し、
ｍは３または４を表す）]。
［２］光学活性な式（１）で示される化合物がグループ1中に記載された化合物より選ばれるいずれか1つであることを特徴とする、［１］記載の製造方法
グループ1

（式中、Ａｒ^２は１個以上のトリフルオロメチル基を有していてもよいフェニル基を表し、Ａｒ^３はＣ１−Ｃ４アルコキシ基を有していてもよいキノリル基を表し、Ｒ^１1及びＲ^１２はフェニル基を表すか、Ｒ^１１とＲ^１２とが一緒になって−（ＣＨ_２）_４−を表し、Ｒ^１３及びＲ^１４は同一または相異なり、Ｃ１−Ｃ３アルキル基を表すか、Ｒ^１３とＲ^１４とが一緒になって、−（ＣＨ_２）_４−を表し、Ｒ^１５は、Ｃ２炭化水素基を表す）。
［３］光学活性な式（１）で示される化合物がグループ２中に記載された化合物より選ばれるいずれか１つであることを特徴とする、［１］記載の製造方法
グループ２

（式中、Ｐｈはフェニル基を表し、Ｍｅはメチル基を表す）。
［４］光学活性な式（１）で示される化合物がグループ３中に記載された化合物より選ばれるいずれか１つであることを特徴とする、［１］記載の製造方法
グループ３

（式中、Ｍｅはメチル基を表す）。
［５］Ａｒが、群Ａより選ばれる１個以上基を有していてもよいフェニル基または群Ａより選ばれる１個以上の基を有していてもよいナフチル基である、［１］〜［４］いずれか一項記載の製造方法（群Ａ：１個以上のハロゲン原子を有していてもよいＣ１−Ｃ１２アルコキシ基）。
［６］Ａｒ^１が、１個以上のハロゲン原子を有していてもよいフェニル基である、［１］〜［５］いずれか一項記載の製造方法。 That is, the present invention is as follows.
[1] An optically active formula characterized by reacting a compound represented by formula (2) with a compound represented by formula (3) in the presence of an optically active compound represented by formula (1) Method for producing compound represented by (4)

[In the formula, Ar has a phenyl group which may have a substituent, a naphthyl group which may have a substituent, an indanyl group which may have a substituent, or a substituent. Represents a good indolizinyl group,
Ar ¹ represents an optionally substituted phenyl group,
R ¹ represents a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent,
Y represents an oxygen atom, a sulfur atom or NR ² (wherein R ² represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent). Sure,
A nitrogen atom to which R ¹ is bonded, a nitrogen atom to which R ² is bonded, a carbon atom to which NR ² is bonded, R ¹ and R ² may be combined to form a nitrogen-containing complex which may have a substituent May form a ring,
R ³ represents any one group selected from group A;
* Represents an asymmetric carbon atom.
Group A: a group consisting of an optionally substituted quinuclidinyl group and groups represented by the following formulas (5) to (8)

(Wherein R ⁴ and R ⁵ are the same or different and each represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent,
R ⁴ and R ⁵ together represent — (CH ₂ ) _p —, p represents 3 or 4,
R ⁶ and R ⁷ are the same or different and each represents an optionally substituted hydrocarbon group,
R ⁶ and R ⁷ together represent — (CH ₂ ) _q —, q represents any one integer of 2 to 5,
R ⁸ and R ⁹ are the same or different and each represents a hydrocarbon group which may have a substituent,
R ¹⁰ represents a quinuclidinyl group which may have a substituent,
m represents 3 or 4)].
[2] The production method group 1 according to [1], wherein the optically active compound represented by formula (1) is any one selected from the compounds described in group 1

(In the formula, Ar ² represents a phenyl group optionally having one or more trifluoromethyl groups, Ar ³ represents a quinolyl group optionally having a C1-C4 alkoxy group, R ¹¹ and R ¹² represents a phenyl group, or R ¹¹ and R ¹² together represent — (CH ₂ ) ₄ —, and R ¹³ and R ¹⁴ are the same or different and represent a C1-C3 alkyl group, R ¹³ and R ¹⁴ together represent — (CH ₂ ) ₄ —, and R ¹⁵ represents a C2 hydrocarbon group).
[3] The production method group 2 according to [1], wherein the optically active compound represented by formula (1) is any one selected from the compounds described in group 2

(In the formula, Ph represents a phenyl group, and Me represents a methyl group).
[4] The production method group 3 according to [1], wherein the optically active compound represented by formula (1) is any one selected from the compounds described in group 3.

(In the formula, Me represents a methyl group).
[5] Ar is a phenyl group which may have one or more groups selected from group A or a naphthyl group which may have one or more groups selected from group A. [1] -[4] The manufacturing method as described in any one (Group A: C1-C12 alkoxy group which may have one or more halogen atoms).
[6] The production method according to any one of [1] to [5], wherein Ar ¹ is a phenyl group which may have one or more halogen atoms.

  According to the production method of the present invention, a new method capable of producing an optically active compound represented by the formula (4) can be provided.

  Hereinafter, the present invention will be described in detail.

  In the present specification, examples of the hydrocarbon group in the “hydrocarbon group which may have a substituent” include, for example, methyl group, ethyl group, propyl group, isopropyl group, phenyl group, benzyl group, 4-fluorophenyl. Group, 3,5- (bistrifluoromethyl) phenyl group, 3,4-dichlorophenyl group, 4-nitrophenyl group.

  In the present specification, examples of the heterocyclic group in the “optionally substituted heterocyclic group” include a pyridyl group, a quinolyl group, an isoquinolyl group, a furanyl group, and a thienyl group.

  In the present specification, examples of the nitrogen-containing heterocycle in the “nitrogen-containing heterocycle optionally having a substituent” include benzothiadiazine-1,1-dioxide, quinazolinone, and benzimidazole.

In the present specification, “an optionally substituted phenyl group, naphthyl group, indanyl group or indolizinyl group”, “an optionally substituted phenyl group”, “having a substituent May be a hydrocarbon group "," optionally substituted heterocyclic group "," optionally substituted nitrogen-containing heterocyclic ring "," optionally substituted quinuclidinyl group As the “substituent” of “,” the following substituent A can be mentioned.
[Substituent A]
C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkenyl group, C4-C8 cycloalkadienyl group, C6-C14 aryl group, C7-C16 An aralkyl group, a heterocyclic group;
Hydroxy group, C1-C6 alkoxy group, C2-C6 alkenyloxy group, C2-C6 alkynyloxy group, C3-C8 cycloalkyloxy group, C3-C8 cycloalkenyloxy group, C4-C8 cycloalkadienyloxy group, C6 -C14 aryloxy group, C7-C16 aralkyloxy group, heterocyclic oxy group;
Formyl group, C1-C6 alkylcarbonyl group, C2-C6 alkenylcarbonyl group, C2-C6 alkynylcarbonyl group, C3-C8 cycloalkylcarbonyl group, C3-C8 cycloalkenylcarbonyl group, C4-C8 cycloalkadienylcarbonyl group, A C6-C14 arylcarbonyl group, a C7-C16 aralkylcarbonyl group, a heterocyclic carbonyl group;
Carboxy group, C1-C6 alkoxy C1-C6 alkoxycarbonyl group, C2-C6 alkenyloxycarbonyl group, C2-C6 alkynyloxycarbonyl group, C3-C8 cycloalkoxycarbonyl group, C3-C8 cycloalkenyloxycarbonyl group, C4-C8 A cycloalkadienyloxycarbonyl group, a C6-C14 aryloxycarbonyl group, a C7-C16 aralkyloxycarbonyl group, a heterocyclic oxycarbonyl group;
C1-C6 alkylcarbonyloxy group, C2-C6 alkenylcarbonyloxy group, C2-C6 alkynylcarbonyloxy group, C3-C8 cycloalkylcarbonyloxy group, C3-C8 cycloalkenylcarbonyloxy group, C4-C8 cycloalkadienylcarbonyl An oxy group, a C6-C14 arylcarbonyloxy group, a C7-C16 aralkylcarbonyloxy group, a heterocyclic carbonyloxy group;
Sulfanyl group, C1-C6 alkylsulfanyl group, C2-C6 alkenylsulfanyl group, C2-C6 alkynylsulfanyl group, C3-C8 cycloalkylsulfanyl group, C3-C8 cycloalkenylsulfanyl group, C4-C8 cycloalkadienylsulfanyl group, A C6-C14 arylsulfanyl group, a C7-C16 aralkylsulfanyl group, a heterocyclic sulfanyl group;
Sulfinyl group, C1-C6 alkylsulfinyl group, C2-C6 alkenylsulfinyl group, C2-C6 alkynylsulfinyl group, C3-C8 cycloalkylsulfinyl group, C3-C8 cycloalkenylsulfinyl group, C4-C8 cycloalkadienylsulfinyl group, A C6-C14 arylsulfinyl group, a C7-C16 aralkylsulfinyl group, a heterocyclic sulfinyl group;
Sulfonyl group (sulfo group), C1-C6 alkylsulfonyl group, C2-C6 alkenylsulfonyl group, C2-C6 alkynylsulfonyl group, C3-C8 cycloalkylsulfonyl group, C3-C8 cycloalkenylsulfonyl group, C4-C8 cycloalkadi An enylsulfonyl group, a C6-C14 arylsulfonyl group, a C7-C16 aralkylsulfonyl group, a heterocyclic sulfonyl group;
C1-C6 alkylsulfonyloxy group, C2-C6 alkenylsulfonyloxy group, C2-C6 alkynylsulfonyloxy group, C3-C8 cycloalkylsulfonyloxy group, C3-C8 cycloalkenylsulfonyloxy group, C4-C8 cycloalkadienylsulfonyl An oxy group, a C6-C14 arylsulfonyloxy group, a C7-C16 aralkylsulfonyloxy group, a heterocyclic sulfonyloxy group;
Amino group, mono- or di-C1-C6 alkylamino group, mono- or di-C2-C6 alkenylamino group, mono- or di-C2-C6 alkynylamino group, mono- or di-C3-C8 cycloalkylamino group, mono- or Di-C3-C8 cycloalkenylamino group, mono- or di-C4-C8 cycloalkadienylamino group, mono- or di-C6-C14 arylamino group, mono- or di-C7-C16 aralkylamino group, mono- or di- A heterocyclic amino group;
Carbamoyl group, mono- or di-C1-C6 alkylcarbamoyl group, mono- or di-C2-C6 alkenylcarbamoyl group, mono- or di-C2-C6 alkynylcarbamoyl group, mono- or di-C3-C8 cycloalkylcarbamoyl group, mono- or Di-C3-C8 cycloalkenylcarbamoyl group, mono- or di-C4-C8 cycloalkadienylcarbamoyl group, mono- or di-C6-C14 arylcarbamoyl group, mono- or di-C7-C16 aralkylcarbamoyl group, mono- or di- A heterocyclic carbamoyl group;
Thiocarbamoyl group, mono- or di-C1-C6 alkylthiocarbamoyl group, mono- or di-C2-C6 alkenylthiocarbamoyl group, mono- or di-C2-C6 alkynylthiocarbamoyl group, mono- or di-C3-C8 cycloalkylthiocarbamoyl group Mono- or di-C3-C8 cycloalkenylthiocarbamoyl group, mono- or di-C4-C8 cycloalkadienylthiocarbamoyl group, mono- or di-C6-C14 arylthiocarbamoyl group, mono- or di-C7-C16 aralkylthio A carbamoyl group, a mono- or di-heterocyclic thiocarbamoyl group;
A halogen atom;
A cyano group;
A nitro group;
An oxo group;
A thioxo group;
Etc. Although the number of substituents is not particularly limited as long as it is a substitutable number, it is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different. The above substituent may further have a substituent A.

In the present specification, examples of the “C1-C3 alkyl group” include a methyl group, an ethyl group, a propyl group, and an isopropyl group. Of these, a methyl group is preferable.

In the present specification, examples of the “C2 hydrocarbon group” include an ethyl group, a vinyl group, and an ethynyl group. Of these, a vinyl group is preferable.

In the present specification, examples of the “C1-C12 alkoxy group optionally having one or more halogen atoms” include a methoxy group, a trifluoromethoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group. , T-butoxy group, 1-chlorobutoxy group, pentyloxy group, octyloxy group, perfluorooctyloxy group, decyloxy group, dodecyloxy group and the like. Of these, a C1-C4 alkoxy group which may have one or more halogen atoms is preferable.

In the present specification, examples of the “C1-C4 alkoxy group optionally having one or more halogen atoms” include a methoxy group, an ethoxy group, an isopropoxy group, and a t-butoxy group.

In the present specification, examples of the “quinolyl group optionally having a C1-C4 alkoxy group” include a 4-quinolyl group and a 6-methoxy-4-quinolyl group.

In the present specification, examples of the “phenyl group optionally having one or more halogen atoms” include a phenyl group, a 3,5-dichlorophenyl group, a 3,5-dichloro-4-fluorophenyl group, and the like. Can be mentioned.

In the present specification, Ar may have a phenyl group which may have one or more atoms or groups selected from group A, or one or more atoms or groups selected from group A. A naphthyl group is preferred.

In the present specification, examples of the “phenyl group optionally having one or more groups selected from group A” include phenyl group, 2-methoxy group, 3-methoxy group, 4-methoxy group, 3 , 4,5-trimethoxyphenyl group and the like.

In the present specification, examples of the “naphthyl group optionally having one or more groups selected from group A” include 1-naphthyl group, 2-naphthyl group, 2-methoxy-1-naphthyl group, 3-methoxy-2-naphthyl group, 6-methoxy-1-naphthyl group, 8-methoxy-2-naphthyl group, 2,4-dimethoxy-1-naphthyl group, 6,8-dimethoxy-2-naphthyl group, 2 , 5-dimethoxy-1-naphthyl group and the like.

In the present specification, Ar ¹ is preferably a phenyl group which may have one or more halogen atoms.

In the present specification, examples of the “phenyl group optionally having one or more trifluoromethyl groups” include 4- (trifluoromethyl) phenyl group and 3,5-bis (trifluoromethyl) phenyl. Groups and the like.

  In the production method of the present invention, an optically active compound is produced by reacting a compound represented by the formula (2) with a compound represented by the formula (3) in the presence of an optically active compound represented by the formula (1). A compound represented by the formula (4) can be produced. (Asymmetric aldol reaction).

  In this specification, “optical activity” means that a compound having an asymmetric carbon contains one enantiomer in excess relative to the other enantiomer or only one enantiomer. It represents the state that has been.

等が挙げられる。 As an optically active compound represented by the formula (1),

Etc.

（式中、Ａｒ^２は１個以上のトリフルオロメチル基を有していてもよいフェニル基を表し、Ａｒ^３はＣ１−Ｃ４アルコキシ基を有していてもよいキノリル基を表し、Ｒ^１1及びＲ^１２はフェニル基を表すか、Ｒ^１１とＲ^１２とが一緒になって−（ＣＨ_２）_４−を表し、Ｒ^１３及びＲ^１４は同一または相異なり、Ｃ１−Ｃ３アルキル基を表すか、Ｒ^１３とＲ^１４とが一緒になって、−（ＣＨ_２）_４−を表し、Ｒ^１５は、Ｃ２炭化水素基を表す）、

グループ２中に記載された化合物がより好ましく、
グループ２

グループ３中に記載された化合物がさらに好ましい。
グループ３

As the optically active compound represented by the formula (1), compounds described in Group 2 are preferable from the viewpoint of optical purity.

(In the formula, Ar ² represents a phenyl group optionally having one or more trifluoromethyl groups, Ar ³ represents a quinolyl group optionally having a C1-C4 alkoxy group, R ¹¹ and R ¹² represents a phenyl group, or R ¹¹ and R ¹² together represent — (CH ₂ ) ₄ —, and R ¹³ and R ¹⁴ are the same or different and represent a C1-C3 alkyl group, R ¹³ and R ¹⁴ together represent — (CH ₂ ) ₄ —, R ¹⁵ represents a C2 hydrocarbon group),

More preferred are the compounds described in group 2,
Group 2

Even more preferred are the compounds described in Group 3.
Group 3

The optically active compound represented by the formula (1) may be a commercially available product, or may be produced according to a known method. For example, it can be produced according to the methods described in Japanese Patent No. 4384635 and Organic Letters 14 (2012) 3296-3299.

  In the asymmetric aldol reaction, the amount of the optically active compound represented by the formula (1) is usually 1 to 50 mol% with respect to the compound represented by the formula (2) from the viewpoint of yield and economy. It is preferably 3 to 25 mol%.

  The compound represented by the formula (2) used as a raw material may be a commercially available product, or may be produced from a known compound according to a known method.

As the compound represented by the formula (3), a commercially available product may be used, or it may be produced from a known compound according to a known method.
The amount of the compound represented by the formula (3) is usually 0.5 to 2 moles, preferably 0.8 to 1 with respect to the compound represented by the formula (2) from the viewpoint of yield and economy. .2 mole times.

The asymmetric aldol reaction is usually performed in the presence of a solvent. Solvents include aromatic hydrocarbon solvents (eg, toluene, xylene, mesitylene), aliphatic hydrocarbon solvents (eg, hexane, heptane, cyclohexane), aliphatic halogenated hydrocarbon solvents (eg, chloroform, butane chloride); Aromatic halogenated hydrocarbon solvents (eg, chlorobenzene, dichlorobenzene, trifluoromethylbenzene); ether solvents (eg, tert-butyl methyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, ethylene Glycol dimethyl ether); and a mixed solvent thereof. Among these, from the viewpoint of reactivity and selectivity, ether solvents and aromatic hydrocarbon solvents are preferable, and toluene and dibutyl ether are more preferable.
The usage-amount of a solvent is 1-50 weight times normally with respect to the compound shown by Formula (2), and 5-20 weight times is preferable.

The asymmetric aldol reaction is preferably in the range of 0 to 60 ° C, more preferably in the range of 10 to 40 ° C.
The reaction time for the asymmetric aldol reaction is preferably 1 to 72 hours, and more preferably 12 to 50 hours.

  The progress of the asymmetric aldol reaction can be confirmed by analytical means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

  The post-treatment of the asymmetric aldol reaction can be carried out by subjecting the reaction mixture to conventional methods (for example, neutralization, extraction, washing with water, distillation, crystallization, etc.). Further, the purification is performed by subjecting the optically active compound represented by the formula (4) to chromatographic treatment such as adsorption treatment using activated carbon, silica gel, alumina, etc., recrystallization treatment, extraction purification treatment, distillation treatment, silica gel column chromatography and the like. Can be done.

Hereinafter, the present invention will be described in more detail with reference to examples.

化合物２ａ（アセトフェノン）（116.9μL, 1.0mmol）、化合物３ａ（3’,5’-ジクロロ-2,2,2-トリフルオロアセトフェノン）(164μL, 1.0mmol)、表２に記載の触媒（0.2mmol）およびトルエン（1mL）を混合した。25℃で48時間撹拌後、HPLC内部標準分析により化合物４ａａの収率と光学純度を分析した。結果を表１に示す。

＜HPLC分析条件＞
収率分析条件
カラム：CAPCELLPAK C8 DD (150mm x 4.6mm, 5μL)
カラム温度：30℃
移動相：A = イオン交換水、B = アセトニトリル
グラジエント条件： Examples 1-5
Compound 4aa Synthesis of 3- (3,5-dichlorophenyl) -4,4,4-trifluoro-3-hydroxy-1-phenylbutan-1-one

Compound 2a (acetophenone) (116.9 μL, 1.0 mmol), Compound 3a (3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone) (164 μL, 1.0 mmol), the catalyst described in Table 2 (0.2 mmol ) And toluene (1 mL). After stirring at 25 ° C. for 48 hours, the yield and optical purity of compound 4aa were analyzed by HPLC internal standard analysis. The results are shown in Table 1.

<HPLC analysis conditions>
Yield analysis condition column: CAPCELLPAK C8 DD (150mm x 4.6mm, 5μL)
Column temperature: 30 ° C
Mobile phase: A = ion-exchanged water, B = acetonitrile gradient conditions:

流速：1.0mL/min
検出波長：210nm
保持時間(RT)：化合物3aa 25.7min

光学純度分析条件
カラム：CHIRALCEL AD-H (250mm x 4.6mm, 5μm)
カラム温度：30℃
移動相：A = ｎ−ヘキサン、B = イソプロパノール
A/B = 99/1 (v/v)
流速：1.0mL/min
検出波長：254nm
保持時間(RT)：化合物４ａａ 鏡像体1 12.9min、鏡像体2 13.6min

Flow rate: 1.0mL / min
Detection wavelength: 210nm
Retention time (RT): Compound 3aa 25.7min

Optical purity analysis condition column: CHIRALCEL AD-H (250mm x 4.6mm, 5μm)
Column temperature: 30 ° C
Mobile phase: A = n-hexane, B = isopropanol
A / B = 99/1 (v / v)
Flow rate: 1.0mL / min
Detection wavelength: 254nm
Retention time (RT): Compound 4aa Enantiomer 1 12.9 min, Enantiomer 2 13.6 min

化合物２ａ（アセトフェノン）（116.9μL, 1.0mmol）、化合物３ａ（3’,5’-ジクロロ-2,2,2-トリフルオロアセトフェノン）(164μL, 1.0mmol)、触媒C-２（82.7mg, 0.2mmol）および表３に記載の溶媒（1mL）を混合した。25℃で48時間撹拌後、実施例１と同様のHPLC分析により化合物４aaの収率と光学純度を分析した。結果を表３に示す。
Examples 6-15
Compound 4aa Synthesis of 3- (3,5-dichlorophenyl) -4,4,4-trifluoro-3-hydroxy-1-phenylbutan-1-one

Compound 2a (acetophenone) (116.9 μL, 1.0 mmol), Compound 3a (3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone) (164 μL, 1.0 mmol), catalyst C-2 (82.7 mg, 0.2 mmol) mmol) and the solvent described in Table 3 (1 mL). After stirring at 25 ° C. for 48 hours, the yield and optical purity of compound 4aa were analyzed by the same HPLC analysis as in Example 1. The results are shown in Table 3.

化合物２ａ（アセトフェノン）（234μL, 2.0mmol）、化合物３ｂ（2,2,2-トリフルオロアセトフェノン）(348mg, 2.0mmol)、触媒C-２（165mg, 0.4mmol）およびジブチルエーテル（2mL）を混合した。25℃で6日間撹拌後、混合物を濃縮し、残渣をシリカゲルクロマトグラフィーで精製して化合物４ａｂを得た。（341.3mg、単離収率58%）また、HPLC分析により化合物４ａｂの光学純度を分析した。光学純度75%ee。
＜HPLC分析条件＞
光学純度分析条件
カラム：CHIRALCEL AD-H (250mm x 4.6mm, 5μm)
カラム温度：30℃
移動相：A = ｎ−ヘキサン、B = イソプロパノール
A/B = 99/1 (v/v)
流速：1.0mL/min
検出波長：254nm
保持時間(RT)：化合物４ａｂ 鏡像体1 19min、鏡像体2 22min
Example 16
Synthesis of Compound 4ab 4,4,4-trifluoro-3-hydroxy-1,3-diphenylbutan-1-one

Compound 2a (acetophenone) (234 μL, 2.0 mmol), compound 3b (2,2,2-trifluoroacetophenone) (348 mg, 2.0 mmol), catalyst C-2 (165 mg, 0.4 mmol) and dibutyl ether (2 mL) are mixed did. After stirring at 25 ° C. for 6 days, the mixture was concentrated and the residue was purified by silica gel chromatography to give compound 4ab. (341.3 mg, isolated yield 58%) The optical purity of compound 4ab was also analyzed by HPLC analysis. Optical purity 75% ee.
<HPLC analysis conditions>
Optical purity analysis condition column: CHIRALCEL AD-H (250mm x 4.6mm, 5μm)
Column temperature: 30 ° C
Mobile phase: A = n-hexane, B = isopropanol
A / B = 99/1 (v / v)
Flow rate: 1.0mL / min
Detection wavelength: 254nm
Retention time (RT): Compound 4ab Enantiomer 1 19 min, Enantiomer 2 22 min

化合物２ｄ（4’-メトキシアセトフェノン）（300.3mg, 2.0mmol）、化合物３ａ（3’,5’-ジクロロ-2,2,2-トリフルオロアセトフェノン）(486.0mg, 2.0mmol)、触媒C-２（165mg, 0.4mmol）およびジブチルエーテル（2mL）を混合した。25℃で48時間撹拌後、混合物を濃縮し、残渣をシリカゲルクロマトグラフィーで精製して化合物４ｄａを得た。（730mg、単離収率93%）。また、HPLC分析により化合物４ｄａの光学純度を分析した。光学純度79%ee。
＜HPLC分析条件＞
光学純度分析条件
カラム：CHIRALCEL AD-H (250mm x 4.6mm, 5μm)
カラム温度：30℃
移動相：A = ｎ−ヘキサン、B = イソプロパノール
A/B = 99/1 (v/v)
流速：1.0mL/min
検出波長：254nm
保持時間(RT)：化合物４ｄａ 鏡像体1 21min、鏡像体2 27min Example 17
Synthesis of compound 3da 3- (3,5-dichlorophenyl) -4,4,4-trifluoro-3-hydroxy-1- (4-methoxyphenyl) butan-1-one

Compound 2d (4′-methoxyacetophenone) (300.3 mg, 2.0 mmol), Compound 3a (3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone) (486.0 mg, 2.0 mmol), catalyst C-2 (165 mg, 0.4 mmol) and dibutyl ether (2 mL) were mixed. After stirring at 25 ° C. for 48 hours, the mixture was concentrated, and the residue was purified by silica gel chromatography to give compound 4da. (730 mg, 93% isolated yield). Further, the optical purity of the compound 4da was analyzed by HPLC analysis. Optical purity 79% ee.
<HPLC analysis conditions>
Optical purity analysis condition column: CHIRALCEL AD-H (250mm x 4.6mm, 5μm)
Column temperature: 30 ° C
Mobile phase: A = n-hexane, B = isopropanol
A / B = 99/1 (v / v)
Flow rate: 1.0mL / min
Detection wavelength: 254nm
Retention time (RT): Compound 4da Enantiomer 1 21 min, Enantiomer 2 27 min

化合物２ｅ（2’-アセトナフトン）（340.4mg, 2.0mmol）、化合物３ａ（3’,5’-ジクロロ-2,2,2-トリフルオロアセトフェノン）(486.0mg, 2.0mmol)、触媒C-２（165mg, 0.4mmol）およびジブチルエーテル（2mL）を混合した。25℃で48時間撹拌後、混合物を濃縮し、残渣をシリカゲルクロマトグラフィーで精製して化合物４ｅａを得た。（815mg、単離収率99%）また、HPLC分析により化合物４ｅａの光学純度を分析した。光学純度75%ee。
＜HPLC分析条件＞
光学純度分析条件
カラム：CHIRALCEL AD-H (250mm x 4.6mm, 5μm)
カラム温度：30℃
移動相：A = ｎ−ヘキサン、B = イソプロパノール
A/B = 97/3 (v/v)
流速：1.0mL/min
検出波長：254nm
保持時間(RT)：化合物４ｅａ 鏡像体1 10min、鏡像体2 13min Example 18
Compound 4ea Synthesis of 3- (3,5-dichlorophenyl) -4,4,4-trifluoro-3-hydroxy-1- (naphthalen-2-yl) butan-1-one

Compound 2e (2′-acetonaphthone) (340.4 mg, 2.0 mmol), Compound 3a (3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone) (486.0 mg, 2.0 mmol), catalyst C-2 ( 165 mg, 0.4 mmol) and dibutyl ether (2 mL) were mixed. After stirring at 25 ° C. for 48 hours, the mixture was concentrated, and the residue was purified by silica gel chromatography to give compound 4ea. (815 mg, isolated yield 99%) The optical purity of compound 4ea was also analyzed by HPLC analysis. Optical purity 75% ee.
<HPLC analysis conditions>
Optical purity analysis condition column: CHIRALCEL AD-H (250mm x 4.6mm, 5μm)
Column temperature: 30 ° C
Mobile phase: A = n-hexane, B = isopropanol
A / B = 97/3 (v / v)
Flow rate: 1.0mL / min
Detection wavelength: 254nm
Retention time (RT): Compound 4ea Enantiomer 1 10 min, Enantiomer 2 13 min

化合物２ｆ（3’,4’,5’-トリメトキシアセトフェノン）（420.5mg, 2.0mmol）、化合物３ａ（3’,5’-ジクロロ-2,2,2-トリフルオロアセトフェノン）(486.0mg, 2.0mmol)、触媒C-２（165mg, 0.4mmol）およびジブチルエーテル（2mL）を混合した。25℃で48時間撹拌後、混合物を濃縮し、残渣をシリカゲルクロマトグラフィーで精製して化合物４ｆａを得た。（630mg、単離収率70%）また、HPLC分析により化合物４ｆａの光学純度を分析した。光学純度89%ee。
＜HPLC分析条件＞
光学純度分析条件
カラム：CHIRALCEL AD-H (250mm x 4.6mm, 5μm)
カラム温度：30℃
移動相：A = ｎ−ヘキサン、B = イソプロパノール
A/B = 98/2 (v/v)
流速：1.0mL/min
検出波長：254nm
保持時間(RT)：化合物４ｆａ 鏡像体1 18min、鏡像体2 26min
Example 19
Compound 4fa Synthesis of 3- (3,5-dichlorophenyl) -4,4,4-trifluoro-3-hydroxy-1- (3,4,5-trimethoxyphenyl) butan-1-one

Compound 2f (3 ′, 4 ′, 5′-trimethoxyacetophenone) (420.5 mg, 2.0 mmol), Compound 3a (3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone) (486.0 mg, 2.0 mmol), catalyst C-2 (165 mg, 0.4 mmol) and dibutyl ether (2 mL). After stirring at 25 ° C. for 48 hours, the mixture was concentrated, and the residue was purified by silica gel chromatography to give compound 4fa. (630 mg, isolated yield 70%) The optical purity of compound 4fa was also analyzed by HPLC analysis. Optical purity 89% ee.
<HPLC analysis conditions>
Optical purity analysis condition column: CHIRALCEL AD-H (250mm x 4.6mm, 5μm)
Column temperature: 30 ° C
Mobile phase: A = n-hexane, B = isopropanol
A / B = 98/2 (v / v)
Flow rate: 1.0mL / min
Detection wavelength: 254nm
Retention time (RT): Compound 4fa Enantiomer 1 18 min, Enantiomer 2 26 min

  According to the production method of the present invention, an optically active β-hydroxyketone compound can be produced.

Claims (6)

An optically active formula (4) characterized by reacting a compound represented by formula (2) with a compound represented by formula (3) in the presence of an optically active compound represented by formula (1) Process for producing a compound represented by

[In the formula, Ar has a phenyl group which may have a substituent, a naphthyl group which may have a substituent, an indanyl group which may have a substituent, or a substituent. Represents a good indolizinyl group,
Ar ¹ represents an optionally substituted phenyl group,
R ¹ represents a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent,
Y represents an oxygen atom, a sulfur atom or NR ² (wherein R ² represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent). Sure,
A nitrogen atom to which R ¹ is bonded, a nitrogen atom to which R ² is bonded, a carbon atom to which NR ² is bonded, R ¹ and R ² may be combined to form a nitrogen-containing complex which may have a substituent May form a ring,
R ³ represents any one group selected from group A;
* Represents an asymmetric carbon atom.
Group A: a group consisting of an optionally substituted quinuclidinyl group and groups represented by the following formulas (5) to (8)

(Wherein R ⁴ and R ⁵ are the same or different and each represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent,
R ⁴ and R ⁵ together represent — (CH ₂ ) _p —, p represents 3 or 4,
R ⁶ and R ⁷ are the same or different and each represents an optionally substituted hydrocarbon group,
R ⁶ and R ⁷ together represent — (CH ₂ ) _q —, q represents any one integer of 2 to 5,
R ⁸ and R ⁹ are the same or different and each represents a hydrocarbon group which may have a substituent,
R ¹⁰ represents a quinuclidinyl group which may have a substituent,
m represents 3 or 4)]. The production method group 1 according to claim 1, wherein the optically active compound represented by the formula (1) is any one selected from the compounds described in group 1.

(In the formula, Ar ² represents a phenyl group optionally having one or more trifluoromethyl groups, Ar ³ represents a quinolyl group optionally having a C1-C4 alkoxy group, R ¹¹ and R ¹² represents a phenyl group, or R ¹¹ and R ¹² together represent — (CH ₂ ) ₄ —, and R ¹³ and R ¹⁴ are the same or different and represent a C1-C3 alkyl group, R ¹³ and R ¹⁴ together represent — (CH ₂ ) ₄ —, and R ¹⁵ represents a C2 hydrocarbon group). 2. The production method group 2 according to claim 1, wherein the optically active compound represented by the formula (1) is any one selected from the compounds described in group 2. 3.

(In the formula, Ph represents a phenyl group, and Me represents a methyl group). 2. The production method group 3 according to claim 1, wherein the optically active compound represented by the formula (1) is any one selected from the compounds described in group 3. 3.

(In the formula, Me represents a methyl group). Ar is a phenyl group optionally having one or more groups selected from group A or a naphthyl group optionally having one or more groups selected from group A. Any one manufacturing method (Group A: C1-C12 alkoxy group which may have one or more halogen atoms). The manufacturing method as described in any one of Claims 1-5 whose Ar < ¹ > is the phenyl group which may have a 1 or more halogen atom.