JP2018039757A - Method for producing imidazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel method for producing an optically active imidazole compound useful as a pharmaceutical.SOLUTION: A production method includes the steps for making a compound represented by formula (3) react with hydrogen gas in the presence of an optically active metal complex catalyst, to obtain a compound represented by formula (4) with high yield and high selectivity (in the formula, Ris an amino protecting group, and * is an asymmetric carbon atom).SELECTED DRAWING: None

Description

  The present invention relates to a method for producing an optically active imidazole compound and an intermediate thereof.

  The optically active imidazole compound represented by formula (1) (compound (1)) is a selective α2 adrenergic receptor agonist and is useful as a sedative / analgesic agent (Patent Document 1). In addition, the optically active imidazole compound represented by the formula (2) (compound (2)) is useful for prevention or treatment of a condition associated with overexpression or hypersensitivity of α2 adrenergic receptor (Patent Document 2). ).

  Conventionally, as a method for producing compounds (1) and (2), their racemates are chlorinated using an optically active acid (such as L-(+)-tartaric acid or D-(-)-tartaric acid). And the method of dividing | segmenting by recrystallization is known (patent documents 1 thru | or 3).

Japanese Patent Publication No. 6-25138 Special table 2000-503298 U.S. Pat. No. 8,877,941

  The present invention provides a novel method for producing an optically active imidazole compound. The present invention also provides a novel optically active imidazole compound that is an intermediate for the production.

In the above-mentioned method, since the racemic acid salt is first synthesized, and then the compound (1) or (2) is divided by repeating recrystallization, the operation is complicated and the yield is low. Have. Moreover, although the method of reducing the frequency | count of recrystallization by selecting an appropriate optically active acid is known, the yield has not been improved (US Pat. No. 8,877,941: Patent Document 3).
As a result of intensive studies, the present inventors conducted an asymmetric reduction reaction on the olefin compound represented by the formula (3) (compound (3)), whereby the compound (1) was produced in a high yield and with a simple operation. The compound (1) or (2) can be produced through the deprotection reaction of the intermediate, and the present invention was completed. That is, the present invention relates to the following.

［式中、Ｒ^１はアミノ保護基を表し、＊は不斉炭素原子を表す。］で表される光学活性なイミダゾール化合物を製造する方法であって、
式（３）

［式中、Ｒ^１は前記と同じ意味を表す。］で表されるオレフィン化合物に、光学活性金属錯体触媒（該光学活性金属錯体触媒は、光学活性ロジウム錯体触媒、光学活性イリジウム錯体触媒及び光学活性コバルト触媒からなる群より選ばれる化合物である。）の存在下、水素ガスを反応させることを特徴とする製造方法。
［２］
Ｒ^１が、スルファモイル保護基、スルホニル保護基、アルコキシカルボニル保護基、アルキル保護基、シリル保護基、エーテル保護基、アシル保護基又はカルバモイル保護基である、上記［１］に記載の製造方法。
［３］
Ｒ^１が、Ｎ，Ｎ−ジメチルスルファモイル基、メタンスルホニル基、ｐ−トルエンスルホニル基、ベンジルオキシカルボニル基、ｔ−ブトキシカルボニル基、トリフェニルメチル基、ベンジル基、［２−（トリメチルシリル）エトキシ］メチル基、２−メトキシメチル基又はアセチル基である、上記［２］に記載の製造方法。
［４］
光学活性金属錯体触媒が、光学活性ロジウム錯体触媒である、上記［１］乃至［３］の何れか１つに記載の製造方法。
［５］
光学活性金属錯体触媒が、Ａ、Ｂ及びＣからなる群より選ばれる化合物であり、ここにおいて、Ａは式（７−１）、Ｂは式（７−２）、Ｃは式（７−３）

［式中、Ｌ^３は、エチレン、１，５−シクロオクタジエン及びノルボルナ−２，５−ジエンからなる群より単独に選ばれる有機配位子であり、
Ｑ^２は、塩化物イオン、テトラフルオロホウ酸イオン、ヘキサフルオロリン酸イオン、ヘキサフルオロアンチモン酸イオン、トリフルオロメタンスルホン酸イオンからなる群より単独に選ばれるアニオンである。］で表されるロジウム錯体触媒の前駆体と、Ｊｏｓｉｐｈｏｓ配位子、ＭｅＯＢＩＰＨＥＰ配位子及びＭｏｎｏＰｈｏｓ配位子からなる群より選ばれる光学活性配位子Ｌ^４より、反応系中で生成させた化合物である、上記［４］に記載の製造方法。
［６］
ロジウム錯体触媒の前駆体が、式（７−１）

［式中、Ｌ^３はノルボルナ−２，５−ジエン及び１，５−シクロオクタジエンであり、Ｑ^２はテトラフルオロホウ酸イオン及びトリフルオロメタンスルホン酸イオンである。］で表される化合物である、上記［５］に記載の製造方法。
［７］
Ｌ^４が、式（ａ−１）から式（ａ−８）

の何れかで表される化合物である、上記［５］又は［６］に記載の製造方法。
［８］
有機溶媒中で反応を実施することを特徴とする、上記［１］乃至［７］の何れか１つに記載の製造方法。
［９］
有機溶媒が、芳香族炭化水素溶媒、アルコール溶媒及び含ハロゲン炭化水素溶媒からなる群より選択される少なくとも一種の溶媒を含む、上記［８］に記載の製造方法。
［１０］
下記工程（ａ）及び（ｂ）を含む、式（８）で表される光学活性なイミダゾール化合物の製造方法。
（ａ）
上記［１］乃至［９］の何れか１つに記載の方法により、
式（４）

［式中、Ｒ^１はアミノ保護基を表し、＊は不斉炭素原子を表す。］で表される光学活性なイミダゾール化合物を得る工程。
（ｂ）
式（４）で表される光学活性なイミダゾール化合物を脱保護して、式（８）

［式中、＊は前期と同じ意味を表す。］で表される光学活性なイミダゾール化合物を得る工程。
［１１］
式（４）

［式中、Ｒ^１が、スルファモイル保護基、スルホニル保護基、アルコキシカルボニル保護基、アルキル保護基、シリル保護基、エーテル保護基、アシル保護基又はカルバモイル保護基を表し、＊は不斉炭素原子を表す。］で表される光学活性なイミダゾール化合物。
［１２］
式（５）

［式中、Ｒ^１は前記と同じ意味を表す。］で表される、上記［１１］に記載の化合物。
［１３］
Ｒ^１が、Ｎ，Ｎ−ジメチルスルファモイル基、メタンスルホニル基、ｐ−トルエンスルホニル基、ベンジルオキシカルボニル基、ｔ−ブトキシカルボニル基、トリフェニルメチル基、ベンジル基、［２−（トリメチルシリル）エトキシ］メチル基、２−メトキシメチル基又はアセチル基である、上記［１２］に記載の化合物。
［１４］
式（６）

［式中、Ｒ^１は前記と同じ意味を表す。］で表される、上記［１１］に記載の化合物。
［１５］
Ｒ^１が、Ｎ，Ｎ−ジメチルスルファモイル基、メタンスルホニル基、ｐ−トルエンスルホニル基、ベンジルオキシカルボニル基、ｔ−ブトキシカルボニル基、トリフェニルメチル基、ベンジル基、［２−（トリメチルシリル）エトキシ］メチル基、２−メトキシメチル基又はアセチル基である、上記［１４］に記載の化合物。 [1]
Formula (4)

[Wherein R ¹ represents an amino protecting group, and * represents an asymmetric carbon atom. A method for producing an optically active imidazole compound represented by the formula:
Formula (3)

[Wherein R ¹ represents the same meaning as described above. And an optically active metal complex catalyst (the optically active metal complex catalyst is a compound selected from the group consisting of an optically active rhodium complex catalyst, an optically active iridium complex catalyst, and an optically active cobalt catalyst). A production method comprising reacting hydrogen gas in the presence of
[2]
The production method according to the above [1], wherein R ¹ is a sulfamoyl protecting group, a sulfonyl protecting group, an alkoxycarbonyl protecting group, an alkyl protecting group, a silyl protecting group, an ether protecting group, an acyl protecting group or a carbamoyl protecting group.
[3]
R ¹ is N, N-dimethylsulfamoyl group, methanesulfonyl group, p-toluenesulfonyl group, benzyloxycarbonyl group, t-butoxycarbonyl group, triphenylmethyl group, benzyl group, [2- (trimethylsilyl) ethoxy ] The production method according to the above [2], which is a methyl group, a 2-methoxymethyl group or an acetyl group.
[4]
The production method according to any one of [1] to [3], wherein the optically active metal complex catalyst is an optically active rhodium complex catalyst.
[5]
The optically active metal complex catalyst is a compound selected from the group consisting of A, B and C, wherein A is the formula (7-1), B is the formula (7-2), and C is the formula (7-3). )

[Wherein L ³ is an organic ligand independently selected from the group consisting of ethylene, 1,5-cyclooctadiene and norborna-2,5-diene;
Q ² is an anion independently selected from the group consisting of chloride ion, tetrafluoroborate ion, hexafluorophosphate ion, hexafluoroantimonate ion, and trifluoromethanesulfonate ion. A compound formed in a reaction system from a precursor of a rhodium complex catalyst represented by the following formula and an optically active ligand L ⁴ selected from the group consisting of a Josiphos ligand, a MeOBIPHEP ligand, and a MonoPhos ligand The production method according to [4] above.
[6]
The precursor of the rhodium complex catalyst has the formula (7-1)

[Wherein L ³ is norborna-2,5-diene and 1,5-cyclooctadiene, and Q ² is a tetrafluoroborate ion and a trifluoromethanesulfonate ion. ] The manufacturing method as described in said [5] which is a compound represented by this.
[7]
L ⁴ represents the formula (a-1) to the formula (a-8).

The production method according to [5] or [6] above, which is a compound represented by any of the above:
[8]
The production method according to any one of [1] to [7], wherein the reaction is carried out in an organic solvent.
[9]
The production method according to [8] above, wherein the organic solvent contains at least one solvent selected from the group consisting of an aromatic hydrocarbon solvent, an alcohol solvent, and a halogen-containing hydrocarbon solvent.
[10]
The manufacturing method of the optically active imidazole compound represented by Formula (8) including the following process (a) and (b).
(A)
By the method according to any one of [1] to [9] above,
Formula (4)

[Wherein R ¹ represents an amino protecting group, and * represents an asymmetric carbon atom. The process of obtaining the optically active imidazole compound represented by this.
(B)
The optically active imidazole compound represented by formula (4) is deprotected to give formula (8)

[In the formula, * represents the same meaning as in the previous term. The process of obtaining the optically active imidazole compound represented by this.
[11]
Formula (4)

[Wherein R ¹ represents a sulfamoyl protecting group, a sulfonyl protecting group, an alkoxycarbonyl protecting group, an alkyl protecting group, a silyl protecting group, an ether protecting group, an acyl protecting group or a carbamoyl protecting group, and * represents an asymmetric carbon atom. Represent. ] The optically active imidazole compound represented by this.
[12]
Formula (5)

[Wherein R ¹ represents the same meaning as described above. ] The compound as described in said [11] represented by.
[13]
R ¹ is N, N-dimethylsulfamoyl group, methanesulfonyl group, p-toluenesulfonyl group, benzyloxycarbonyl group, t-butoxycarbonyl group, triphenylmethyl group, benzyl group, [2- (trimethylsilyl) ethoxy The compound according to [12] above, which is a methyl group, a 2-methoxymethyl group or an acetyl group.
[14]
Formula (6)

[Wherein R ¹ represents the same meaning as described above. ] The compound as described in said [11] represented by.
[15]
R ¹ is N, N-dimethylsulfamoyl group, methanesulfonyl group, p-toluenesulfonyl group, benzyloxycarbonyl group, t-butoxycarbonyl group, triphenylmethyl group, benzyl group, [2- (trimethylsilyl) ethoxy The compound according to [14] above, which is a methyl group, a 2-methoxymethyl group or an acetyl group.

  According to the present invention, a novel method for producing an optically active imidazole compound useful in the pharmaceutical field can be provided. In addition, according to the present invention, a novel optically active imidazole compound which is a production intermediate can be provided.

  Hereinafter, the present invention will be described in detail.

  As used herein, “n-” is normal, “s-” is secondary, “t-” and “tert-” are tertiary, “i-” is iso, “o-” is ortho, “m-” is Meta, “p-” means para, “E” means trans, “Z” means cis, “Bu” means butyl, “Pr” means propyl, “Ph” means phenyl. Further, the addition of “*” to the asymmetric carbon atom in the structural formula means that the carbon atom (and the molecule containing the carbon atom) is chiral.

  Terms used for describing the chemical structure in this specification will be explained. In the present specification, (R) and (S) represent the configuration of a chiral molecule in which central chirality or axial chirality exists.

  Terms used for describing the chemical structure in this specification will be explained. In the present specification, (+) and (-) represent the dextrorotatory and levorotatory chirality of a chiral molecule in which central chirality or axial chirality exists.

  In the present specification, the amino protecting group means a protecting group for an amino group used in a normal organic synthesis reaction. Amino protecting groups can be removed by performing a deprotection reaction (eg, Protective Groups in Organic Synthesis, Fourth edition), Green (T. W. Greene), John Wiley & Sons Inc. (2006), etc.). Specific examples of the amino protecting group include a sulfamoyl protecting group (N, N-dimethylsulfamoyl group and the like), a sulfonyl protecting group (methanesulfonyl group, mesitylenesulfonyl group, p-methoxyphenylsulfonyl group, benzenesulfonyl group, p- Toluenesulfonyl group etc.), alkoxycarbonyl protecting group (benzyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, 2- (trimethylsilyl) ethoxycarbonyl group, 2- (4-trifluoromethylphenylsulfonyl) ethoxyoxycarbonyl Group, t-butoxycarbonyl group, 1-adamantyloxycarbonyl group, 2-adamantyloxycarbonyl group, 2,4-dimethylpent-3-yloxycarbonyl group, cyclohexyloxycarbonyl group, 1,1-dimethyl-2, , 2-trichloroethoxycarbonyl group, 1-chloroethoxycarbonyl group, etc.), alkyl protecting group (vinyl group, 2-chloroethyl group, hydroxymethyl group, 2-methoxyethoxymethyl group, 1-ethoxyethyl group, 2- (2 '-Pyridyl) ethyl group, 2- (4'-pyridyl) ethyl group, 2- (4-nitrophenyl) ethyl group, 2-phenylsulfonylethyl group, allyl group, benzyl group, p-methoxybenzyl group, 3, 4-dimethoxybenzyl group, 3-methoxybenzyl group, 3,5-dimethoxybenzyl group, 2-nitrobenzyl group, 2,4-dinitrobenzyl group, phenacyl group, triphenylmethyl group, diphenylmethyl group, diphenyl-4- Pyridylmethyl group, 2- (2′-pyridyl) ethyl group, 2- (4′-pyridyl) ethyl group, 2- ( -Nitrophenyl) ethyl group, etc.), silyl protecting groups (t-butyldimethylsilyl group, triisopropylsilyl group, etc.), ether protecting groups (methoxymethyl group, diethoxymethyl group, 2-chloroethoxymethyl group, [2- (Trimethylsilyl) ethoxy] methyl group, t-butoxymethyl group, t-butyldimethylsiloxymethyl group, pivaloyloxymethyl group, benzyloxymethyl group, dimethylaminomethyl group, 2-tetrahydropyranyl group, etc.), acyl protection Groups (formyl group, acetyl group, dichloromethylcarbonyl group, pivalloyl group, etc.), carbamoyl protecting groups (N, N-diethylcarbamoyl group, etc.) and the like. Preferably, a sulfamoyl protecting group, a sulfonyl protecting group, an alkoxycarbonyl protecting group, an alkyl protecting group, a silyl protecting group, an ether protecting group, an acyl protecting group or a carbamoyl protecting group, more preferably N, N-dimethylsulfamoyl. Group, methanesulfonyl group, p-toluenesulfonyl group, t-butoxycarbonyl group, benzyloxycarbonyl group, triphenylmethyl group, benzyl group, [2- (trimethylsilyl) ethoxy] methyl group, 2-methoxymethyl group or acetyl group It is.

  The structure of the compound used in the present invention will be described below.

［式中、Ｒ^１及び＊は前記と同じ意味を表す。］
そのため、保護基Ｒ^１を導入することにより、化合物（３）に対応する位置異性体として、化合物（３’）が生成する場合がある。同様に、次工程において、化合物（４）に対応する位置異性体として、化合物（４’）が生成する場合がある。 Compound (9), which is a precursor of compound (3), has a tautomer (compound (9 ′)) produced by changing the bonding position of the hydrogen atom bonded to the imidazole ring.

[Wherein, R ¹ and * represent the same meaning as described above. ]
Therefore, introduction of the protecting group R ¹ may produce the compound (3 ′) as a regioisomer corresponding to the compound (3). Similarly, in the next step, compound (4 ′) may be produced as a positional isomer corresponding to compound (4).

  In carrying out the production method of the present invention, it goes without saying that there is no problem even if the raw material compound contains impurities that do not interfere with the reaction. However, to explain just in case, in the production method of the present invention, the compound (3 ) May be used alone or as a mixture with compound (3 ′). Further, in the subsequent deprotection reaction, the compound (4) may be used alone or as a mixture with the compound (4 ′).

  Hereinafter, the reaction of the present invention will be described in detail.

First, the starting compound (3) used in the present invention will be described.

  Compound (3) can be synthesized from the above compound (9) as a raw material by a protecting group introduction reaction well known to those skilled in the art. As the specific reaction, for example, it can be synthesized by the methods described in Reference Synthesis Examples 1 to 10.

［式中、Ｒ^１及び＊は前記と同じ意味を表す。］
本発明は、化合物（３）と水素ガスを反応させる工程を含むものであって、該反応の工程において、光学活性金属錯体触媒（該光学活性金属錯体触媒は、光学活性ロジウム錯体触媒、光学活性イリジウム錯体触媒及び光学活性コバルト触媒からなる群より選ばれる化合物である）を共存させることを特徴とするものである。なお以下に示す溶媒、反応試剤の添加順序については限定されず、順序を変更しても実施できる。化合物（４）は脱保護（Ｒ^１の除去）により、化合物（８）へと誘導可能である。 Next, a method for producing the compounds (4) and (8) of the present invention will be described. The outline of this production method is shown in the following scheme.

[Wherein, R ¹ and * represent the same meaning as described above. ]
The present invention includes a step of reacting compound (3) with hydrogen gas, and in the reaction step, an optically active metal complex catalyst (the optically active metal complex catalyst is an optically active rhodium complex catalyst, an optically active catalyst). A compound selected from the group consisting of an iridium complex catalyst and an optically active cobalt catalyst). The order of addition of the solvent and reaction reagent shown below is not limited and can be carried out even if the order is changed. Compound (4) can be derived to compound (8) by deprotection (removal of R ¹ ).

  The optically active metal complex catalyst that can be used in the production method of the present invention is a compound selected from the group consisting of an optically active rhodium complex catalyst, an optically active iridium complex catalyst, and an optically active cobalt catalyst, preferably an optically active rhodium complex catalyst. It is.

Optically active rhodium complex catalyst can be prepared by using a precursor and an optically active ligand L ⁴ of the rhodium complex catalyst, to produce in the reaction system. In the present invention, an isolated optically active rhodium complex catalyst can also be used.

で表される化合物等が挙げられる。好ましいロジウム錯体触媒の前駆体は、式（７−１）で表される化合物である。
Ｌ^３は、有機配位子を意味し、例えば、エチレン、１，５−シクロオクタジエン、及びノルボルナ−２，５−ジエン等が挙げられる。好ましいＬ^３は、ノルボルナ−２，５−ジエン及び１，５−シクロオクタジエンである。Ｑ^２は、アニオンを意味し、例えば、塩化物イオン、テトラフルオロホウ酸イオン、ヘキサフルオロリン酸イオン、ヘキサフルオロアンチモン酸イオン、トリフルオロメタンスルホン酸イオン等が挙げられる。好ましいＱ^２は、テトラフルオロホウ酸イオン及びトリフルオロメタンスルホン酸イオンである。 The precursor of the rhodium complex catalyst is, for example, the formula (7-1), the formula (7-2), or the formula (7-3).

The compound etc. which are represented by these are mentioned. A preferred precursor of the rhodium complex catalyst is a compound represented by the formula (7-1).
L ³ means an organic ligand, and examples thereof include ethylene, 1,5-cyclooctadiene, and norborna-2,5-diene. Preferred L ³ is norborna-2,5-diene and 1,5-cyclooctadiene. Q ² means an anion, and examples thereof include chloride ion, tetrafluoroborate ion, hexafluorophosphate ion, hexafluoroantimonate ion, trifluoromethanesulfonate ion and the like. Preferred Q ² is tetrafluoroborate ion and trifluoromethanesulfonate ion.

L ⁴ means an optically active ligand, for example, BINAP ligand, SEGPHOS ligand, Josiphos ligand, MeOBIPHEP ligand, Walphos ligand, Taniaphos ligand, Mandyphos ligand, DuPhos ligand, catASium ligand, P-Phos ligand, PhanePhos ligand, BoPhoz ligand, BPE ligand, MonoPhos ligand, Reetz ligand, BINOL ligand, BOX Ligand, PYBOX ligand, PHOX ligand, Salen ligand, Cinchona alkaloid ligand, QuinoxP ^* ligand, DIPAMP ligand, DIOP ligand, Trost ligand, Landis coordination Child, Aminophosphine ligand.

The Josiphos ligand is a chiral phosphorus ligand having a chiral ferrocene structure (see, for example, asymmetric reduction reaction Asymmetric Catalyst (Chemfiles vol. 8, No. 2) of SIGMA-ALDLICH). Specific examples include the following compounds.

The MeOBIPHEP ligand is a chiral phosphorus ligand having a dimethoxybiphenyl structure (see, for example, Asymmetric Reduction Reaction Asymmetric Catalysis (Chemfiles vol. 8, No. 2) manufactured by SIGMA-ALDLICH). Specific examples include the following compounds.

The MonoPhos ligand is a monodentate chiral phosphorus ligand having a phosphoramidite structure (see, for example, asymmetric reduction reaction Asymmetric Catalysis (Chemfiles vol. 8, No. 2) of SIGMA-ALDLICH). Specific examples include the following compounds.

The BINAP ligand is a ligand having a 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl structure (Asymmetric Reduction Reaction (Asymmetric Metallization, Chemfiles vol. 8 of SIGMA-ALDLICH). , No. 2)). Specific examples include the following compounds.

The SEGPHOS ligand is a ligand having a 5,5′-bis (diphenylphosphino) -4,4′-bi-1,3-benzodioxole structure (asymmetric of SIGMA-ALDLICH) Reduction reaction Asymmetric Catalysis (Chemfiles vol. 8, No. 2) etc.). Specific examples include the following compounds.

The Walphos ligand is a chiral phosphorus ligand having a chiral ferrocene structure (see, for example, asymmetric reduction reaction Asymmetric Catalyst (Chemfiles vol. 8, No. 2) of SIGMA-ALDLICH). Specific examples include the following compounds.

The Taniaphos ligand is a chiral phosphorus ligand having a chiral ferrocene structure (see, for example, Asymmetric Reduction Reaction Asymmetric Catalyst (Chemfiles vol. 8, No. 2) manufactured by SIGMA-ALDLICH). Specific examples include the following compounds.

The Mandyphos ligand is a chiral phosphorus ligand having a chiral ferrocene structure (see, for example, asymmetric reduction reaction Asymmetric Catalysis (Chemfiles vol. 8, No. 2) manufactured by SIGMA-ALDLICH). Specific examples include the following compounds.

The DuPhos ligand is a ligand having a phospholane structure developed by DuPont (see, for example, asymmetric reduction reaction Asymmetric Catalysis (Chemfiles vol. 8, No. 2) of SIGMA-ALDLICH). Specific examples include the following compounds.

The BPE ligand is a ligand having a phospholane structure (see, for example, asymmetric reduction reaction Asymmetric Catalysis (Chemfiles vol. 8, No. 2) of SIGMA-ALDLICH). Specific examples include the following compounds.

The catASium ligand is a ligand developed by Evonik Degussa and marketed under the registered trademark of catASium (Asymmetric Reduction Reaction Asymmetric Catalysis (Chemfiles vol. 8, No. 2) of SIGMA-ALDLICH). Etc.) Specific examples include the following compounds.

The P-Phos ligand is a ligand having a biarylbisphosphine structure (see, for example, asymmetric reduction reaction Asymmetric Catalyst (Chemfiles vol. 8, No. 2) of SIGMA-ALDLICH). Specific examples include the following compounds.

The PhanePhos ligand is a phosphorus ligand having a cyclophane structure (see, for example, asymmetric reduction reaction Asymmetric Catalyst (Chemfiles vol. 8, No. 2) of SIGMA-ALDLICH). Specific examples include the following compounds.

The BoPhoz ligand is any of the following compounds.

The Reetz ligand is a phosphorus ligand having a diphosphonite structure derived from 1,1′-bi-2-naphthol (Asymmetric Reduction Reaction Asymmetric Catalysis (Chemfiles vol. 8, No. 2 of SIGMA-ALDLICH). )). Specific examples include the following compounds.

The BINOL ligand is a phosphorus ligand having a structure of 1,1′-bi-2-naphthol or a derivative thereof (Asymmetric Reduction Reaction Asymmetric Catalysis (Chemfiles vol. 8, No. 1 of SIGMA-ALDLICH). 2) etc.). Specific examples include the following compounds.

The BOX ligand is a ligand having a C2 symmetric chiral bisoxazoline structure (see, for example, asymmetric reduction reaction Asymmetric Catalyst (Chemfiles vol. 8, No. 2) of SIGMA-ALDLICH). Specific examples include the following compounds.

The PYBOX ligand is a ligand having a structure having two oxazoline groups on the pyridine ring (see, for example, asymmetric reduction reaction Asymmetric Catalysis (Chemfiles vol. 8, No. 2) of SIGMA-ALDLICH). . Specific examples include the following compounds.

The PHOX ligand is a ligand having a phosphinooxazoline structure (see, for example, asymmetric reduction reaction Asymmetric Catalyst (Chemfiles vol. 8, No. 2) of SIGMA-ALDLICH). Specific examples include the following compounds.

A Salen ligand is a ligand having an N, N′-bis (2-hydroxybenzylidene) ethylenediamine structure (Asymmetric Reduction Reaction Asymmetric Catalysis (Chemfiles vol. 8, No. 2) manufactured by SIGMA-ALDLICH). Etc.) Specific examples include the following compounds.

The cinchona alkaloid ligand is a ligand having a cinchona alkaloid structure (see, for example, asymmetric reduction reaction Asymmetric Catalyst (Chemfiles vol. 8, No. 2) of SIGMA-ALDLICH). Specific examples include the following compounds.

The QuinoxP ^* ligand is a ligand having an electron-withdrawing quinoxaline structure (see, for example, Asymmetric Reduction Reaction Asymmetric Catalyst (Chemfiles vol. 8, No. 2) manufactured by SIGMA-ALDLICH). Specific examples include the following compounds.

The DIPAMP ligand is a ligand having a chiral diphosphine (see, for example, asymmetric reduction reaction Asymmetric Catalyst (Chemfiles vol. 8, No. 2) of SIGMA-ALDLICH). Specific examples include the following compounds.

The DIOP ligand is any of the following compounds.

The Trost ligand is a ligand having diaminocyclohexyl (see, for example, Asymmetric Reduction Reaction Asymmetric Catalyst (Chemfiles vol. 8, No. 2) of SIGMA-ALDLICH). Specific examples include the following compounds.

The Landis ligand is a ligand having a chiral 3,4-diazaborophoran structure (see, for example, asymmetric reduction reaction Asymmetric Catalysis (Chemfiles vol. 8, No. 2) manufactured by SIGMA-ALDLICH). Specific examples include the following compounds.

The Aminophosphine ligand is a ligand having an aminophosphine structure (see, for example, asymmetric reduction reaction Asymmetric Catalyst (Chemfiles vol. 8, No. 2) of SIGMA-ALDLICH). Specific examples include the following compounds.

で表される化合物の何れかである。なお、それぞれの化合物名は、以下の通りである。
（ａ−１）：（Ｒ）−（６，６’−ジメトキシビフェニル−２，２’−ジイル）ビス［ビス（３，５−ジ−ｔ−ブチルフェニル）ホスフィン］
（ａ−２）：（Ｓ）−（６，６’−ジメトキシビフェニル−２，２’−ジイル）ビス［ビス（３，５−ジ−ｔ−ブチルフェニル）ホスフィン］
（ａ−３）：（２Ｒ）−１−［（１Ｒ）−１−［ビス（１，１−ジメチルエチル）ホスフィノ］エチル］−２−（ジフェニルホスフィノ）フェロセン
（ａ−４）：（２Ｓ）−１−［（１Ｓ）−１−［ビス（１，１−ジメチルエチル）ホスフィノ］エチル］−２−（ジフェニルホスフィノ）フェロセン
（ａ−５）：（２Ｒ）−１−［（１Ｒ）−１−［ビス（１，１−ジメチルエチル）ホスフィノ］エチル］−２−［ビス［４−（トリフルオロメチル）フェニル］ホスフィノ］フェロセン
（ａ−６）：（２Ｓ）−１−［（１Ｓ）−１−［ビス（１，１−ジメチルエチル）ホスフィノ］エチル］−２−［ビス［４−（トリフルオロメチル）フェニル］ホスフィノ］フェロセン
（ａ−７）：（Ｓ，Ｓ，Ｓ）−（＋）−（３，５−ジオキサ−４−ホスファシクロヘプタ［２，１−ａ：３，４−ａ’］ジナフタレン−４−イル）ビス（１−フェニルエチル）アミン
（ａ−８）：（Ｒ，Ｒ，Ｒ）−（＋）−（３，５−ジオキサ−４−ホスファシクロヘプタ［２，１−ａ：３，４−ａ’］ジナフタレン−４−イル）ビス（１−フェニルエチル）アミン L ⁴ used in the production method of the present invention is preferably a BINAP ligand, a SEGPHOS ligand, a Josiphos ligand, a MeOBIPHEP ligand, a Walphos ligand, a Taniaphos ligand, a Mandyphos derivative, or a DuPhos coordination. Ligand, P-Phos ligand, PhanePhos ligand, BoPhoz ligand, MonoPhos ligand, Reetz ligand, BOX ligand, PYBOX ligand, PHOX ligand, QuinoxP ^* ligand , A DIPAMP ligand or a DIOP ligand, more preferably a Josiphos ligand, a MeOBIPHEP ligand or a MonoPhos ligand, and more preferably a formula (a-1) to a formula (a-8).

It is either of the compounds represented by these. In addition, each compound name is as follows.
(A-1): (R)-(6,6′-dimethoxybiphenyl-2,2′-diyl) bis [bis (3,5-di-t-butylphenyl) phosphine]
(A-2): (S)-(6,6′-dimethoxybiphenyl-2,2′-diyl) bis [bis (3,5-di-t-butylphenyl) phosphine]
(A-3): (2R) -1-[(1R) -1- [bis (1,1-dimethylethyl) phosphino] ethyl] -2- (diphenylphosphino) ferrocene (a-4): (2S ) -1-[(1S) -1- [Bis (1,1-dimethylethyl) phosphino] ethyl] -2- (diphenylphosphino) ferrocene (a-5): (2R) -1-[(1R) -1- [Bis (1,1-dimethylethyl) phosphino] ethyl] -2- [bis [4- (trifluoromethyl) phenyl] phosphino] ferrocene (a-6): (2S) -1-[(1S ) -1- [Bis (1,1-dimethylethyl) phosphino] ethyl] -2- [bis [4- (trifluoromethyl) phenyl] phosphino] ferrocene (a-7): (S, S, S)- (+)-(3,5-dioxa-4-phosphine Cyclohepta [2,1-a: 3,4-a ′] dinaphthalen-4-yl) bis (1-phenylethyl) amine (a-8): (R, R, R)-(+)-(3 , 5-Dioxa-4-phosphacyclohepta [2,1-a: 3,4-a ′] dinaphthalen-4-yl) bis (1-phenylethyl) amine

  The amount of the rhodium complex catalyst used can be 0.00001 equivalent to 1 equivalent with respect to 1 equivalent of compound (3). A preferable usage amount is 0.001 equivalent to 0.5 equivalent, and a more preferable usage amount is 0.01 equivalent to 0.1 equivalent.

  As the optically active ligand, 1 equivalent to 3 equivalents can be used with respect to 1 equivalent of the compound (3). A preferred usage amount is 1 equivalent to 2 equivalents, and a more preferred usage amount is 1 equivalent to 1.2 equivalents.

The solvent used for the reaction is not particularly limited as long as it does not inhibit the progress of the reaction. For example, an alcohol solvent (for example, methanol, ethanol, 2-propanol, ethylene glycol, benzyl alcohol, 2,2,2- Trifluoroethanol, 1,1,1,3,3,3-hexafluoroisopropanol, etc.), halogen-containing hydrocarbon solvents (for example, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1 -Trichloroethane, trichloroethylene, tetrachloroethylene, etc.), halogen-containing aromatic hydrocarbon solvents (eg, chlorobenzene, dichlorobenzene, etc.), aromatic hydrocarbon solvents (eg, benzene, toluene, xylene, etc.), aliphatic hydrocarbon solvents (eg, Hexane, heptane, etc.), pyridine solvents (eg , Pyridine, picoline, etc.), ether solvents (eg, dimethyl ether, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, cyclopentylmethyl ether, 1-methoxy-2- (2-methoxyethoxy) ethane, etc. ), Dimethyl sulfoxide, sulfolane, 1,3-dimethyl-2-imidazolidinone, water and the like. These solvents may be used alone or in combination of two or more. Preferably, it is an aromatic hydrocarbon solvent, an alcohol solvent, a halogen-containing hydrocarbon solvent, or a mixed solvent of an alcohol solvent and a halogen-containing hydrocarbon solvent, more preferably toluene, ethanol, methylene chloride, chloroform or ethanol and methylene chloride. It is a mixed solvent, more preferably methylene chloride or a mixed solvent of ethanol and methylene chloride.

  The amount of the solvent to be used is preferably 0.1 to 1000 times by mass, more preferably 1 to 100 times by mass with respect to the mass of compound (3).

  The reaction temperature is not particularly limited, but is preferably −10 ° C. to 90 ° C., more preferably 0 ° C. to 30 ° C.

  The pressure of the hydrogen gas is not particularly limited, but is preferably 0.1 MPa to 10 MPa, more preferably 0.2 MPa to 1.0 MPa.

Compound (4) is a deprotection reaction (e.g., Protective Groups in Organic Synthesis, Fourth edition), John (TW Greens), John Wiley. and Sons, Inc. (John Wiley & Sons Inc.) by performing (2006) refer to the like) to remove the ^{R 1,} can be derived to the compound (8).

  Isolation and purification of the resulting compound (8) can be carried out by conventional methods. For example, the compound (8) can be isolated and purified by a known method such as extraction with a solvent, silica gel column chromatography, high performance liquid chromatography, or crystallization.

  Reference Synthesis Examples and Synthesis Examples are shown below to describe the present invention in more detail, but the present invention is not limited to these examples.

The proton nuclear magnetic resonance ( ¹ H NMR) of the examples was measured in a heavy solvent using JNM-ECP300 manufactured by JEOL or JNM-ECX300 manufactured by JEOL. The chemical shift is indicated by a δ value (ppm) when tetramethylsilane is used as an internal standard (0.0 ppm).

In the description of NMR spectra, “s” is a singlet, “d” is a doublet, “t” is a triplet, “q” is a quartet, “m” is a multiplet, “br” is broad, and “J” is a coupling constant. , “Hz” means Hertz and “CDCl ₃ ” means deuterated chloroform.

  4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole used in the reference synthesis example was synthesized according to the method described in European Patent Application Publication No. 1918282.

反応容器の内部を窒素ガスで置換した後、４−（１−（２，３−ジメチルフェニル）ビニル）−１Ｈ−イミダゾール（１．００ｇ、５．０４ｍｍｏｌ）、クロロホルム（３０．２１ｇ）、トリエチルアミン（１．０４、１０．３ｍｍｏｌ）を順次、反応容器に加えた。その後、反応溶液に、トリフェニルメチルクロリド（２．１１ｇ、７．５７ｍｍｏｌ）のクロロホルム（１０．００ｇ）溶液を、２１℃から２６℃の範囲で５分かけて滴下した。室温下２時間撹拌後、反応容器に１ｍｏｌ／Ｌ塩酸を加えた。３０分撹拌後分液し、有機層を飽和炭酸水素ナトリウム水溶液、水で洗浄した。得られた有機層を無水硫酸マグネシウムで乾燥後、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ−ヘキサン）で精製し、表題化合物（２．２２ｇ、１００％）を白色固体として得た。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．４４（ｄ，１Ｈ，Ｊ＝１．１Ｈｚ）、７．３２−７．２５（ｍ，９Ｈ）、７．１４−７．０９（ｍ，６Ｈ）、７．０７−７．００（ｍ，３Ｈ）、６．２５（ｄ，１Ｈ，Ｊ＝１．５Ｈｚ）、６．０９（ｄ，１Ｈ，Ｊ＝２．２Ｈｚ）、４．９９（ｄ，１Ｈ，Ｊ＝２．２Ｈｚ）、２．１９（ｓ，３Ｈ）、１．９７（ｓ，３Ｈ） Reference synthesis example 1
Synthesis of 4- (1- (2,3-dimethylphenyl) vinyl) -1-trityl-1H-imidazole (Compound 10)

After the inside of the reaction vessel was replaced with nitrogen gas, 4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole (1.00 g, 5.04 mmol), chloroform (30.21 g), triethylamine ( 1.04, 10.3 mmol) was added sequentially to the reaction vessel. Thereafter, a solution of triphenylmethyl chloride (2.11 g, 7.57 mmol) in chloroform (10.00 g) was added dropwise to the reaction solution over 5 minutes in the range of 21 ° C. to 26 ° C. After stirring at room temperature for 2 hours, 1 mol / L hydrochloric acid was added to the reaction vessel. After stirring for 30 minutes, the layers were separated, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and water. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (2.22 g, 100%) as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.44 (d, 1H, J = 1.1 Hz), 7.32-7.25 (m, 9H), 7.14-7.09 (m, 6H), 7.07-7.00 (m, 3H), 6.25 (d, 1H, J = 1.5 Hz), 6.09 (d, 1H, J = 2.2 Hz), 4.99 (d, 1H) , J = 2.2 Hz), 2.19 (s, 3H), 1.97 (s, 3H)

反応容器の内部を窒素ガスで置換した後、４−（１−（２，３−ジメチルフェニル）ビニル）−１Ｈ−イミダゾール（５１．５ｍｇ、０．２６ｍｍｏｌ）、クロロホルム（１ｍＬ）、トリエチルアミン（７２．５μＬ、０．５２ｍｍｏｌ）、ジメチルスルファモイルクロリド（４１．５μＬ、０．３９ｍｍｏｌ）を順次、反応容器に加えた。室温下２３時間撹拌後、酢酸エチル、１ｍｏｌ／Ｌ塩酸を順次、反応容器に加えた。３０分撹拌後分液し、有機層を５％炭酸水素ナトリウム水溶液、５％塩化ナトリウム水溶液で洗浄した。得られた有機層を無水硫酸マグネシウムで乾燥後、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ−ヘキサン）で精製し、表題化合物（５３．３ｍｇ、６７．２％）を淡桃色固体として得た。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．９０（ｄ，１Ｈ，Ｊ＝１．２Ｈｚ）、７．１９−７．０４（ｍ，３Ｈ）、６．６３（ｄ，１Ｈ，Ｊ＝１．２Ｈｚ）、６．２３（ｄ，１Ｈ，Ｊ＝２．０Ｈｚ）、５．１６（ｄ，１Ｈ，Ｊ＝２．０Ｈｚ）、２．８２（ｓ，６Ｈ）、２．３３（ｓ，３Ｈ）、２．１２（ｓ，３Ｈ） Reference synthesis example 2
Synthesis of 4- (1- (2,3-dimethylphenyl) vinyl) -N, N-dimethyl-1H-imidazole-1-sulfonamide (Compound 11)

After the inside of the reaction vessel was replaced with nitrogen gas, 4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole (51.5 mg, 0.26 mmol), chloroform (1 mL), triethylamine (72. 5 μL, 0.52 mmol) and dimethylsulfamoyl chloride (41.5 μL, 0.39 mmol) were sequentially added to the reaction vessel. After stirring at room temperature for 23 hours, ethyl acetate and 1 mol / L hydrochloric acid were sequentially added to the reaction vessel. After stirring for 30 minutes, liquid separation was performed, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and 5% aqueous sodium chloride solution. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (53.3 mg, 67.2%) as a pale pink solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.90 (d, 1H, J = 1.2 Hz), 7.19-7.04 (m, 3H), 6.63 (d, 1H, J = 1.2 Hz) ), 6.23 (d, 1H, J = 2.0 Hz), 5.16 (d, 1H, J = 2.0 Hz), 2.82 (s, 6H), 2.33 (s, 3H), 2.12 (s, 3H)

反応容器の内部を窒素ガスで置換した後、４−（１−（２，３−ジメチルフェニル）ビニル）−１Ｈ−イミダゾール（２５７．３ｍｇ、１．３０ｍｍｏｌ）、塩化メチレン（３ｍＬ）、トリエチルアミン（３９４．０ｍｇ、３．８９ｍｍｏｌ）を順次、反応容器に加えた。反応液を０℃まで冷却後、メタンスルホニルクロリド（１５１μＬ、１．９５ｍｍｏｌ）を反応容器に加えた。室温下２時間撹拌後、酢酸エチル、飽和塩化アンモニウム水溶液を順次、反応容器に加えた。３０分撹拌後分液し、有機層を飽和塩化ナトリウム水溶液で洗浄した。得られた有機層を無水硫酸マグネシウムで乾燥後、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ−ヘキサン）で精製し、表題化合物（３１５．８ｍｇ、８７．７％）を白色固体として得た。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．９６（ｓ，１Ｈ）、７．１８−７．０４（ｍ，３Ｈ）、６．６８（ｓ，１Ｈ）、６．２６（ｓ，１Ｈ）、５．１９（ｓ，１Ｈ）、３．２２（ｓ，３Ｈ）、２．３２（ｓ，３Ｈ）、２，１１（ｓ，３Ｈ） Reference synthesis example 3
Synthesis of 4- (1- (2,3-dimethylphenyl) vinyl) -1- (methanesulfonyl) -1H-imidazole (Compound 12)

After replacing the inside of the reaction vessel with nitrogen gas, 4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole (257.3 mg, 1.30 mmol), methylene chloride (3 mL), triethylamine (394) 0.03 mg, 3.89 mmol) was added sequentially to the reaction vessel. After cooling the reaction solution to 0 ° C., methanesulfonyl chloride (151 μL, 1.95 mmol) was added to the reaction vessel. After stirring at room temperature for 2 hours, ethyl acetate and a saturated aqueous ammonium chloride solution were sequentially added to the reaction vessel. After stirring for 30 minutes, the layers were separated, and the organic layer was washed with a saturated aqueous sodium chloride solution. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (315.8 mg, 87.7%) as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.18-7.04 (m, 3H), 6.68 (s, 1H), 6.26 (s, 1H), 5 .19 (s, 1H), 3.22 (s, 3H), 2.32 (s, 3H), 2, 11 (s, 3H)

反応容器の内部を窒素ガスで置換した後、４−（１−（２，３−ジメチルフェニル）ビニル）−１Ｈ−イミダゾール（２５２．０ｍｇ、１．２７ｍｍｏｌ）、１、２−ジクロロエタン（３ｍＬ）、トリエチルアミン（３８５．８ｍｇ、３．８１ｍｍｏｌ）、４−ジメチルアミノピリジン（１５．６ｍｇ、０．１３ｍｍｏｌ）、ｐ−トルエンスルホニルクロリド（３６３．５ｍｇ、１．９１ｍｍｏｌ）を順次、反応容器に加えた。室温下２時間撹拌後、酢酸エチル、飽和塩化アンモニウム水溶液を順次、反応容器に加えた。３０分撹拌後分液し、有機層を飽和塩化ナトリウム水溶液で洗浄した。得られた有機層を無水硫酸マグネシウムで乾燥後、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ−ヘキサン）で精製し、表題化合物（４３８．０ｍｇ、９７．６％）を白色固体として得た。
^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ７．９８（ｄ，１Ｈ，Ｊ＝１．５Ｈｚ）、７．７４（ｄ，２Ｈ，Ｊ＝８．５Ｈｚ）、７．３３（ｄ，２Ｈ，Ｊ＝８．１Ｈｚ）、７．１７−６．９８（ｍ，３Ｈ）、６．６６（ｄ，１Ｈ，Ｊ＝１．１Ｈｚ）、６．１７（ｄ，１Ｈ，Ｊ＝１．５Ｈｚ）、５．１１（ｄ，１Ｈ，Ｊ＝１．８Ｈｚ）、２．４３（ｓ，３Ｈ）、２．３１（ｓ，３Ｈ）、２．０３（Ｓ，３Ｈ） Reference synthesis example 4
Synthesis of 4- (1- (2,3-dimethylphenyl) vinyl) -1-tosyl-1H-imidazole (Compound 13)

After replacing the inside of the reaction vessel with nitrogen gas, 4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole (252.0 mg, 1.27 mmol), 1,2-dichloroethane (3 mL), Triethylamine (385.8 mg, 3.81 mmol), 4-dimethylaminopyridine (15.6 mg, 0.13 mmol) and p-toluenesulfonyl chloride (363.5 mg, 1.91 mmol) were sequentially added to the reaction vessel. After stirring at room temperature for 2 hours, ethyl acetate and a saturated aqueous ammonium chloride solution were sequentially added to the reaction vessel. After stirring for 30 minutes, the layers were separated, and the organic layer was washed with a saturated aqueous sodium chloride solution. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (438.0 mg, 97.6%) as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (d, 1 H, J = 1.5 Hz), 7.74 (d, 2 H, J = 8.5 Hz), 7.33 (d, 2 H, J = 8) .1 Hz), 7.17-6.98 (m, 3H), 6.66 (d, 1 H, J = 1.1 Hz), 6.17 (d, 1 H, J = 1.5 Hz), 5.11 (D, 1H, J = 1.8 Hz), 2.43 (s, 3H), 2.31 (s, 3H), 2.03 (S, 3H)

反応容器の内部を窒素ガスで置換した後、４−（１−（２，３−ジメチルフェニル）ビニル）−１Ｈ−イミダゾール（２５１．７ｍｇ、１．２７ｍｍｏｌ）、テトラヒドロフラン（３．２１ｇ）、トリエチルアミン（３８５．６ｍｇ、３．８１ｍｍｏｌ）、ジ−ｔｅｒｔ−ブチル−ジカルボネート（４１５．６ｍｇ、１．９０ｍｍｏｌ）を順次、反応容器に加えた。室温下１９時間撹拌後、酢酸エチル、飽和塩化アンモニウム水溶液を順次、反応容器に加えた。３０分撹拌後分液し、有機層を水で洗浄した。得られた有機層を無水硫酸マグネシウムで乾燥後、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ−ヘキサン）で精製し、表題化合物（３６８．０ｍｇ、９６．９％）を白色固体として得た。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ８．０５（ｄ，１Ｈ，Ｊ＝０．７Ｈｚ）、７．１６−７．０４（ｍ，３Ｈ）、６．７４（ｓ，１Ｈ）、６．１９（ｄ，１Ｈ、Ｊ＝１．８Ｈｚ）、５．１１（ｄ，１Ｈ，Ｊ＝１．８Ｈｚ）、２．３１（ｓ，３Ｈ）、２．１２（ｓ，３Ｈ）、１．５８（ｓ，９Ｈ） Reference synthesis example 5
Synthesis of tert-butyl-4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole-1-carboxylate (Compound 14)

After replacing the inside of the reaction vessel with nitrogen gas, 4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole (251.7 mg, 1.27 mmol), tetrahydrofuran (3.21 g), triethylamine ( 385.6 mg, 3.81 mmol) and di-tert-butyl-dicarbonate (415.6 mg, 1.90 mmol) were sequentially added to the reaction vessel. After stirring at room temperature for 19 hours, ethyl acetate and a saturated aqueous ammonium chloride solution were sequentially added to the reaction vessel. After stirring for 30 minutes, liquid separation was performed, and the organic layer was washed with water. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (368.0 mg, 96.9%) as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.05 (d, 1H, J = 0.7 Hz), 7.16-7.04 (m, 3H), 6.74 (s, 1H), 6.19 ( d, 1H, J = 1.8 Hz), 5.11 (d, 1H, J = 1.8 Hz), 2.31 (s, 3H), 2.12 (s, 3H), 1.58 (s, 9H)

反応容器の内部を窒素ガスで置換した後、４−（１−（２，３−ジメチルフェニル）ビニル）−１Ｈ−イミダゾール（２５０．６ｍｇ、１．２６ｍｍｏｌ）、塩化メチレン（６．０１ｇ）、トリエチルアミン（３８６．１ｍｇ、３．８２ｍｍｏｌ）、クロロギ酸ベンジル（３２２．６ｍｇ、１．８９ｍｍｏｌ）を順次、反応容器に加えた。室温下２５時間撹拌後、酢酸エチル、飽和塩化アンモニウム水溶液を順次、反応容器に加えた。３０分撹拌後分液し、有機層を水で洗浄した。得られた有機層を無水硫酸マグネシウムで乾燥後、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ−ヘキサン）で精製し、表題化合物（４１４．５ｍｇ、９９．２％）を無色油状物として得た。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ８．１３（ｄ，１Ｈ，Ｊ＝１．１Ｈｚ）、７．４２−７．３７（ｍ，５Ｈ）、７．１６−７．０２（ｍ，３Ｈ）、６．７９（ｄ，１Ｈ，Ｊ＝１．１Ｈｚ）、６．２１（ｄ，１Ｈ，Ｊ＝２．２Ｈｚ）、５．３６（ｓ，２Ｈ）、５．１３（ｄ，１Ｈ，Ｊ＝２．２Ｈｚ）、２．３１（ｓ，３Ｈ）、２．１０（ｓ，３Ｈ） Reference synthesis example 6
Synthesis of benzyl-4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole-1-carboxylate (Compound 15)

After replacing the inside of the reaction vessel with nitrogen gas, 4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole (250.6 mg, 1.26 mmol), methylene chloride (6.01 g), triethylamine (386.1 mg, 3.82 mmol) and benzyl chloroformate (322.6 mg, 1.89 mmol) were sequentially added to the reaction vessel. After stirring at room temperature for 25 hours, ethyl acetate and a saturated aqueous ammonium chloride solution were sequentially added to the reaction vessel. After stirring for 30 minutes, liquid separation was performed, and the organic layer was washed with water. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (414.5 mg, 99.2%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.13 (d, 1H, J = 1.1 Hz), 7.42-7.37 (m, 5H), 7.16-7.02 (m, 3H), 6.79 (d, 1H, J = 1.1 Hz), 6.21 (d, 1H, J = 2.2 Hz), 5.36 (s, 2H), 5.13 (d, 1H, J = 2) .2 Hz), 2.31 (s, 3H), 2.10 (s, 3H)

反応容器の内部を窒素ガスで置換した後、４−（１−（２，３−ジメチルフェニル）ビニル）−１Ｈ−イミダゾール（１０１．４ｍｇ、０．５１１ｍｍｏｌ）、Ｎ，Ｎ−ジメチルホルムアミド（２．０２ｇ）を順次、反応容器に加えた。反応液を０℃に冷却後、水素化ナトリウム（７４．５ｍｇ、純度５０％、１．５５ｍｍｏｌ）を反応容器に加えた。反応液を室温まで昇温し、室温下２時間撹拌した。その後、室温下ベンジルブロミド（９１μＬ、０．７７ｍｍｏｌ）を反応容器に加えた。室温下２時間３０分撹拌後、酢酸エチル、飽和塩化アンモニウム水溶液を順次、反応容器に加えた。３０分撹拌後分液し、有機層を飽和食塩水で洗浄した。得られた有機層を無水硫酸マグネシウムで乾燥後、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ−ヘキサン）で精製し、表題化合物（１１２．１ｍｇ、７６．１％）を白色固体として得た。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．５２（ｄ，１Ｈ，Ｊ＝１．１Ｈｚ）、７．３６−７．２９（ｍ，３Ｈ）、７．１３−７．０４（ｍ，５Ｈ）、６．３４（ｄ，１Ｈ，Ｊ＝１．１Ｈｚ）、６．１２（ｄ，１Ｈ，Ｊ＝２．２Ｈｚ）、５．０１（ｓ，２Ｈ）、４．９８（ｄ，１Ｈ，Ｊ＝１．８Ｈｚ）、２．２８（ｓ，３Ｈ）、２．１１（ｓ，３Ｈ） Reference synthesis example 7
Synthesis of 1-benzyl-4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole (Compound 16)

After the inside of the reaction vessel was replaced with nitrogen gas, 4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole (101.4 mg, 0.511 mmol), N, N-dimethylformamide (2. 02g) was sequentially added to the reaction vessel. After cooling the reaction solution to 0 ° C., sodium hydride (74.5 mg, purity 50%, 1.55 mmol) was added to the reaction vessel. The reaction was warmed to room temperature and stirred at room temperature for 2 hours. Thereafter, benzyl bromide (91 μL, 0.77 mmol) was added to the reaction vessel at room temperature. After stirring at room temperature for 2 hours and 30 minutes, ethyl acetate and a saturated aqueous ammonium chloride solution were sequentially added to the reaction vessel. After stirring for 30 minutes, the mixture was separated, and the organic layer was washed with saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (112.1 mg, 76.1%) as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.52 (d, 1H, J = 1.1 Hz), 7.36-7.29 (m, 3H), 7.13-7.04 (m, 5H), 6.34 (d, 1H, J = 1.1 Hz), 6.12 (d, 1H, J = 2.2 Hz), 5.01 (s, 2H), 4.98 (d, 1H, J = 1) .8 Hz), 2.28 (s, 3H), 2.11 (s, 3H)

反応容器の内部を窒素ガスで置換した後、４−（１−（２，３−ジメチルフェニル）ビニル）−１Ｈ−イミダゾール（５０１．８ｍｇ、２．５３ｍｍｏｌ）、Ｎ，Ｎ−ジメチルホルムアミド（５ｍＬ）を順次、反応容器に加えた。反応液を４℃に冷却後、水素化ナトリウム（３６６．０ｍｇ、純度５０％、７．６３ｍｍｏｌ）を反応容器に加えた。反応液を室温まで昇温し、室温下１時間撹拌した。その後、室温下メトキシメチルクロリド（３８１μＬ、５．０６ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１ｍＬ）溶液を、２２℃から２８℃の範囲で８分かけて反応液に滴下した。室温下１時間撹拌後、酢酸エチル、１４％塩化アンモニウム水溶液を順次、反応容器に加えた。３０分程撹拌後分液し、有機層を５％食塩水で洗浄した。得られた有機層を無水硫酸マグネシウムで乾燥後、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ−ヘキサン）で精製し、表題化合物（３８９．１ｍｇ、６３．６％）を黄色油状物として得た。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．６０（ｄ，１Ｈ，Ｊ＝１．６Ｈｚ）、７．１６−７．０８（ｍ，３Ｈ）、６．４６（ｄ，１Ｈ，Ｊ＝１．２Ｈｚ）、６．１５（ｄ，１Ｈ，Ｊ＝２．０Ｈｚ）、５．１２（ｓ，２Ｈ）、５．０３（ｄ，１Ｈ，Ｊ＝２．０Ｈｚ）、３．２５（ｓ，３Ｈ）、２．３２（ｓ，３Ｈ）、２．１４（ｓ，３Ｈ） Reference synthesis example 8
Synthesis of 4- (1- (2,3-dimethylphenyl) vinyl) -1- (methoxymethyl) 1H-imidazole (Compound 17)

After replacing the inside of the reaction vessel with nitrogen gas, 4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole (501.8 mg, 2.53 mmol), N, N-dimethylformamide (5 mL) Were sequentially added to the reaction vessel. After cooling the reaction solution to 4 ° C., sodium hydride (366.0 mg, purity 50%, 7.63 mmol) was added to the reaction vessel. The reaction solution was warmed to room temperature and stirred at room temperature for 1 hour. Thereafter, a solution of methoxymethyl chloride (381 μL, 5.06 mmol) in N, N-dimethylformamide (1 mL) at room temperature was added dropwise to the reaction solution over a period of 8 minutes in the range of 22 ° C. to 28 ° C. After stirring at room temperature for 1 hour, ethyl acetate and a 14% aqueous ammonium chloride solution were sequentially added to the reaction vessel. After stirring for about 30 minutes, the mixture was separated, and the organic layer was washed with 5% brine. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (389.1 mg, 63.6%) as a yellow oil.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.60 (d, 1H, J = 1.6 Hz), 7.16-7.08 (m, 3H), 6.46 (d, 1H, J = 1.2 Hz) ), 6.15 (d, 1H, J = 2.0 Hz), 5.12 (s, 2H), 5.03 (d, 1H, J = 2.0 Hz), 3.25 (s, 3H), 2.32 (s, 3H), 2.14 (s, 3H)

反応容器の内部を窒素ガスで置換した後、４−（１−（２，３−ジメチルフェニル）ビニル）−１Ｈ−イミダゾール（２５７．１ｍｇ、１．３０ｍｍｏｌ）、塩化メチレン（４ｍＬ）、トリエチルアミン（１３１．２ｍｇ、１．３０ｍｍｏｌ）を順次、反応容器に加えた。反応液を０℃に冷却後、塩化アセチル（９２μＬ、１．３０ｍｍｏｌ）を反応容器に加えた。反応液を室温まで昇温し、室温下３時間撹拌した。析出した固体をろ過し、塩化メチレン（１０ｍＬ）で洗浄した。得られたろ液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ−ヘキサン）で精製し、表題化合物（１９７．１ｍｇ、６３．１％）を白色固体として得た。
^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ８．１４（ｄ，１Ｈ，Ｊ＝１．１Ｈｚ）、７．１７−７．０３（ｍ，３Ｈ）、６．８１（ｄ，１Ｈ，Ｊ＝１．１Ｈｚ）、６．２４（ｄ，１Ｈ，Ｊ＝１．８Ｈｚ）、５．１６（ｄ，１Ｈ，Ｊ＝１．８Ｈｚ）、２．５１（ｓ，３Ｈ）、２．３２（ｓ，３Ｈ）、２．１１（ｓ，３Ｈ） Reference synthesis example 9
Synthesis of 1- (4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazol-1-yl) ethane-1-one (Compound 18)

After the inside of the reaction vessel was replaced with nitrogen gas, 4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole (257.1 mg, 1.30 mmol), methylene chloride (4 mL), triethylamine (131 .2 mg, 1.30 mmol) was added sequentially to the reaction vessel. After cooling the reaction solution to 0 ° C., acetyl chloride (92 μL, 1.30 mmol) was added to the reaction vessel. The reaction was warmed to room temperature and stirred at room temperature for 3 hours. The precipitated solid was filtered and washed with methylene chloride (10 mL). The resulting filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (197.1 mg, 63.1%) as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.14 (d, 1H, J = 1.1 Hz), 7.17-7.03 (m, 3H), 6.81 (d, 1H, J = 1.1 Hz) ), 6.24 (d, 1H, J = 1.8 Hz), 5.16 (d, 1H, J = 1.8 Hz), 2.51 (s, 3H), 2.32 (s, 3H), 2.11 (s, 3H)

反応容器の内部を窒素ガスで置換した後、４−（１−（２，３−ジメチルフェニル）ビニル）−１Ｈ−イミダゾール（２０７．５ｍｇ、１．０５ｍｍｏｌ）、Ｎ，Ｎ−ジメチルホルムアミド（３ｍＬ）を順次、反応容器に加えた。反応液を０℃に冷却後、水素化ナトリウム（１５０．１ｍｇ、純度５０％、３．１３ｍｍｏｌ）を反応容器に加えた。反応液を室温まで昇温し、室温下１時間３０分撹拌した。その後、室温下２−（トリメチルシリル）エトキシメチルクロリド（２７５μＬ、１．５７ｍｍｏｌ）を反応容器に加えた。室温下１時間撹拌後、クロロホルム、飽和塩化アンモニウム水溶液を順次、反応容器に加えた。３０分程撹拌後分液し、有機層を水で洗浄した。得られた有機層を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ｎ−ヘキサン）で精製し、表題化合物（１８５．９ｍｇ、５３．９％）を黄色油状物として得た。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．８５（ｄ，１Ｈ，Ｊ＝１．１Ｈｚ）、７．１５−７．０７（ｍ，３Ｈ）、６．４３（ｄ，１Ｈ，Ｊ＝１．１Ｈｚ）、６．１３（ｄ，１Ｈ，Ｊ＝１．８Ｈｚ）、５．１４（ｓ，２Ｈ）、５．０１（ｄ，１Ｈ，Ｊ＝２．２Ｈｚ）、３．４６−３．４０（ｍ，２Ｈ）、２．３１（ｓ，３Ｈ）、２．１２（ｓ，３Ｈ）、０．８９−０．８４（ｍ，２Ｈ）、−０．０４（ｓ，９Ｈ） Reference synthesis example 10
Synthesis of 4- (1- (2,3-dimethylphenyl) vinyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole (Compound 19)

After replacing the inside of the reaction vessel with nitrogen gas, 4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole (207.5 mg, 1.05 mmol), N, N-dimethylformamide (3 mL) Were sequentially added to the reaction vessel. After cooling the reaction solution to 0 ° C., sodium hydride (150.1 mg, purity 50%, 3.13 mmol) was added to the reaction vessel. The reaction solution was warmed to room temperature and stirred at room temperature for 1 hour and 30 minutes. Thereafter, 2- (trimethylsilyl) ethoxymethyl chloride (275 μL, 1.57 mmol) was added to the reaction vessel at room temperature. After stirring at room temperature for 1 hour, chloroform and a saturated aqueous ammonium chloride solution were sequentially added to the reaction vessel. After stirring for about 30 minutes, liquid separation was performed, and the organic layer was washed with water. The obtained organic layer was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (185.9 mg, 53.9%) as a yellow oil.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.85 (d, 1H, J = 1.1 Hz), 7.15-7.07 (m, 3H), 6.43 (d, 1H, J = 1.1 Hz) ), 6.13 (d, 1H, J = 1.8 Hz), 5.14 (s, 2H), 5.01 (d, 1H, J = 2.2 Hz), 3.46-3.40 (m , 2H), 2.31 (s, 3H), 2.12 (s, 3H), 0.89-0.84 (m, 2H), -0.04 (s, 9H)

耐圧用の反応容器に、４−（１−（２，３−ジメチルフェニル）ビニル）１−トリチル−１Ｈ−イミダゾール（化合物（１０））（６６．２ｍｇ、０．１５ｍｍｏｌ）、（Ｒ）−（６，６’−ジメトキシビフェニル−２，２’−ジイル）ビス［ビス（３，５−ジ−ｔ−ブチルフェニル）ホスフィン］（１８．５ｍｇ、０．０１８ｍｍｏｌ）及びビス（２，５−ノルボルナジエン）ロジウム（Ｉ）テトラフルオロボレート（５．６ｍｇ、０．０１５ｍｍｏｌ）を順次加え、反応容器の内部をアルゴンガスで置換した。反応容器に塩化メチレン（１．５ｍＬ）を加え、水素雰囲気下（０．８ＭＰａ）、２５℃で２４時間撹拌した。得られた溶液をＨＰＬＣ分析条件［１］で分析したところ、転化率は１００％、表題化合物の光学純度は７２．７％ｅｅ（Ｒ）であった。 Synthesis example 1
Synthesis of (R) -4- (1- (2,3-dimethylphenyl) ethyl) -1-trityl-1H-imidazole (Compound 20)

In a pressure-resistant reaction vessel, 4- (1- (2,3-dimethylphenyl) vinyl) 1-trityl-1H-imidazole (compound (10)) (66.2 mg, 0.15 mmol), (R)-( 6,6′-dimethoxybiphenyl-2,2′-diyl) bis [bis (3,5-di-tert-butylphenyl) phosphine] (18.5 mg, 0.018 mmol) and bis (2,5-norbornadiene) Rhodium (I) tetrafluoroborate (5.6 mg, 0.015 mmol) was sequentially added, and the inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 25 ° C. for 24 hours under a hydrogen atmosphere (0.8 MPa). When the obtained solution was analyzed under HPLC analysis conditions [1], the conversion was 100%, and the optical purity of the title compound was 72.7% ee (R).

HPLC analysis conditions [1]
Column: YMC-Pack SIL (250 × 4.6 mm, 5 μm)
→ Daicel CHIRALPAK IB (250mm × 4.6mm, 5μm)
Mobile phase: n-hexane / isopropanol = 97/3 (0-25 minutes) (v / v)
Temperature: 40 ° C
Flow rate: 2.0 mL / min Detection wavelength: 230 nm
Retention time: (S) 11.2 minutes, (R) 7.6 minutes

Synthesis example 2
Synthesis of (R) -4- (1- (2,3-dimethylphenyl) ethyl) -1-trityl-1H-imidazole (Compound 20) 4- (1- (2,3-dimethyl) was added to a pressure-resistant reaction vessel. Phenyl) vinyl) 1-trityl-1H-imidazole (compound (10)) (65.8 mg, 0.15 mmol), (R)-(6,6′-dimethoxybiphenyl-2,2′-diyl) bis [bis (3,5-di-t-butylphenyl) phosphine] (18.5 mg, 0.018 mmol) and bis (2,5-norbornadiene) rhodium (I) tetrafluoroborate (5.6 mg, 0.015 mmol) sequentially In addition, the inside of the reaction vessel was replaced with argon gas. Toluene (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 25 ° C. for 24 hours under a hydrogen atmosphere (0.8 MPa). When the obtained solution was analyzed under HPLC analysis conditions [1], the conversion was 99.9% and the optical purity of the title compound was 73.4% ee (R).

Synthesis example 3
Synthesis of (R) -4- (1- (2,3-dimethylphenyl) ethyl) -1-trityl-1H-imidazole (Compound 20) 4- (1- (2,3-dimethyl) was added to a pressure-resistant reaction vessel. Phenyl) vinyl) 1-trityl-1H-imidazole (compound (10)) (66.1 mg, 0.15 mmol), (R)-(6,6′-dimethoxybiphenyl-2,2′-diyl) bis [bis (3,5-di-t-butylphenyl) phosphine] (18.8 mg, 0.018 mmol) and bis (2,5-norbornadiene) rhodium (I) tetrafluoroborate (5.6 mg, 0.015 mmol) sequentially In addition, the inside of the reaction vessel was replaced with argon gas. Chloroform (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 25 ° C. for 24 hours under a hydrogen atmosphere (0.8 MPa). When the obtained solution was analyzed under HPLC analysis conditions [1], the conversion was 99.6% and the optical purity of the title compound was 75.8% ee (R).

Synthesis Example 4 Synthesis of (R) -4- (1- (2,3-dimethylphenyl) ethyl) -1-trityl-1H-imidazole (Compound 20) 4- (1- (2, 3-Dimethylphenyl) vinyl) 1-trityl-1H-imidazole (compound (10)) (66.1 mg, 0.15 mmol), (2R) -1-[(1R) -1- [bis (1,1- Dimethylethyl) phosphino] ethyl] -2- (diphenylphosphino) ferrocene (9.7 mg, 0.018 mmol) and bis (2,5-norbornadiene) rhodium (I) tetrafluoroborate (5.6 mg, 0.015 mmol) Were sequentially added, and the inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 25 ° C. for 24 hours under a hydrogen atmosphere (0.8 MPa). When the obtained solution was analyzed under HPLC analysis conditions [1], the conversion was 99.9% and the optical purity of the title compound was 92.0% ee (R).

Synthesis example 5
Synthesis of (R) -4- (1- (2,3-dimethylphenyl) ethyl) -1-trityl-1H-imidazole (Compound 20) 4- (1- (2,3-dimethyl) was added to a pressure-resistant reaction vessel. Phenyl) vinyl) 1-trityl-1H-imidazole (compound (10)) (66.0 mg, 0.15 mmol), (2R) -1-[(1R) -1- [bis (1,1-dimethylethyl) Phosphino] ethyl] -2- [bis [4- (trifluoromethyl) phenyl] phosphino] ferrocene (12.2 mg, 0.018 mmol) and bis (2,5-norbornadiene) rhodium (I) tetrafluoroborate (5. 5 mg, 0.015 mmol) was sequentially added, and the inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 25 ° C. for 24 hours under a hydrogen atmosphere (0.8 MPa). When the obtained solution was analyzed under HPLC analysis conditions [1], the conversion was 100% and the optical purity of the title compound was 87.9% ee (R).

耐圧用の反応容器に４−（１−（２，３−ジメチルフェニル）ビニル）１−トリチル−１Ｈ−イミダゾール（化合物（１０））（６６．５ｍｇ、０．１５ｍｍｏｌ）、（Ｓ，Ｓ，Ｓ）−（＋）−（３，５−ジオキサ−４−ホスファシクロヘプタ［２，１−ａ：３，４−ａ’］ジナフタレン−４−イル）ビス（１−フェニルエチル）アミン（９．８ｍｇ、０．０１８ｍｍｏｌ）及びビス（２，５−ノルボルナジエン）ロジウム（Ｉ）テトラフルオロボレート（５．６ｍｇ、０．０１５ｍｍｏｌ）を順次加え、反応容器の内部をアルゴンガスで置換した。反応容器に塩化メチレン（１．５ｍＬ）を加え、水素雰囲気下（０．８ＭＰａ）、２５℃で２４時間撹拌した。得られた溶液をＨＰＬＣ分析条件［１］で分析したところ、転化率は８８．８％、表題化合物の光学純度は８９．２％ｅｅ（Ｓ）であった。 Synthesis Example 6
Synthesis of (S) -4- (1- (2,3-dimethylphenyl) ethyl) -1-trityl-1H-imidazole (Compound 21)

4- (1- (2,3-dimethylphenyl) vinyl) 1-trityl-1H-imidazole (compound (10)) (66.5 mg, 0.15 mmol), (S, S, S) )-(+)-(3,5-dioxa-4-phosphacyclohepta [2,1-a: 3,4-a ′] dinaphthalen-4-yl) bis (1-phenylethyl) amine (9 .8 mg, 0.018 mmol) and bis (2,5-norbornadiene) rhodium (I) tetrafluoroborate (5.6 mg, 0.015 mmol) were sequentially added, and the inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 25 ° C. for 24 hours under a hydrogen atmosphere (0.8 MPa). When the obtained solution was analyzed under HPLC analysis conditions [1], the conversion was 88.8%, and the optical purity of the title compound was 89.2% ee (S).

Synthesis example 7
Synthesis of (S) -4- (1- (2,3-dimethylphenyl) ethyl) -1-trityl-1H-imidazole (Compound 21) 4- (1- (2,3-dimethyl) was added to a pressure-resistant reaction vessel. Phenyl) vinyl) 1-trityl-1H-imidazole (compound (10)) (66.2 mg, 0.15 mmol), (2S) -1-[(1S) -1- [bis (1,1-dimethylethyl) Phosphino] ethyl] -2- (diphenylphosphino) ferrocene (1.0 mg, 0.0018 mmol) and bis (2,5-norbornadiene) rhodium (I) tetrafluoroborate (0.6 mg, 0.0016 mmol) were added sequentially. The inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 25 ° C. for 3 hours under a hydrogen atmosphere (0.8 MPa). The obtained solution was analyzed under HPLC analysis conditions [1]. As a result, the conversion was 99.9% and the optical purity of the title compound was 91.7% ee (S).

Synthesis example 8
Synthesis of (S) -4- (1- (2,3-dimethylphenyl) ethyl) -1-trityl-1H-imidazole (Compound 21) 4- (1- (2,3-dimethyl) was added to a pressure-resistant reaction vessel. Phenyl) vinyl) 1-trityl-1H-imidazole (compound (10)) (3.00 g, 6.81 mmol), (2S) -1-[(1S) -1- [bis (1,1-dimethylethyl) Phosphino] ethyl] -2- (diphenylphosphino) ferrocene (44.5 mg, 0.082 mmol) and bis (2,5-norbornadiene) rhodium (I) tetrafluoroborate (25.4 mg, 0.068 mmol) were added sequentially. The inside of the reaction vessel was replaced with argon gas. Methylene chloride (23 mL) and ethanol (45 mL) were added to the reaction vessel, and the mixture was stirred under a hydrogen atmosphere (0.8 MPa) in the range of 0 ° C. to 2 ° C. for 18 hours. The resulting reaction solution was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (2.79 g, 92.7%) as a white solid. When the obtained title compound was analyzed under HPLC analysis conditions [1], the optical purity was 94.8% ee (S).
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.37 (d, 1H, J = 1.2 Hz), 7.34-7.30 (m, 9H), 7.17-7.11 (m, 6H), 7.05-6.95 (m, 3H), 6.44 (s, 1H), 4.36 (q, 1H, J = 7.0 Hz), 2.26 (s, 3H), 2.21 ( s, 3H), 1.53 (d, 3H, J = 7.0 Hz)

Synthesis Example 9
Synthesis of (S) -4- (1- (2,3-dimethylphenyl) ethyl) -1-trityl-1H-imidazole (Compound 21) 4- (1- (2,3-dimethyl) was added to a pressure-resistant reaction vessel. Phenyl) vinyl) 1-trityl-1H-imidazole (compound (10)) (66.2 mg, 0.15 mmol), (2S) -1-[(1S) -1- [bis (1,1-dimethylethyl) Phosphino] ethyl] -2- (diphenylphosphino) ferrocene (1.0 mg, 0.0018 mmol) and bis (2,5-norbornadiene) rhodium (I) trifluoromethanesulfonate (0.7 mg, 0.0016 mmol) sequentially In addition, the inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 10 ° C. for 3 hours under a hydrogen atmosphere (0.8 MPa). When the obtained solution was analyzed under HPLC analysis conditions [1], the conversion was 99.0%, and the optical purity of the title compound was 93.7% ee (S).

Synthesis Example 10
Synthesis of (S) -4- (1- (2,3-dimethylphenyl) ethyl) -1-trityl-1H-imidazole (Compound 21) 4- (1- (2,3-dimethyl) was added to a pressure-resistant reaction vessel. Phenyl) vinyl) 1-trityl-1H-imidazole (compound (10)) (66.0 mg, 0.15 mmol), (2S) -1-[(1S) -1- [bis (1,1-dimethylethyl) Phosphino] ethyl] -2- (diphenylphosphino) ferrocene (1.0 mg, 0.0018 mmol) and bis (1,5-cyclooctadiene) rhodium (I) tetrafluoroborate (0.6 mg, 0.0016 mmol). Sequentially added, the inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 30 ° C. for 19 hours under a hydrogen atmosphere (0.8 MPa). The obtained solution was analyzed under HPLC analysis conditions [1]. As a result, the conversion rate was 100% and the optical purity of the title compound was 90.9% ee (S).

耐圧用の反応容器に４−（１−（２，３−ジメチルフェニル）ビニル）−Ｎ，Ｎ−ジメチル−１Ｈ−イミダゾール−１−スルホンアミド（化合物（１１））（４５．７ｍｇ、０．１５ｍｍｏｌ）、（Ｒ）−（６，６’−ジメトキシビフェニル−２，２’−ジイル）ビス［ビス（３．５−ジ−ｔ−ブチルフェニル）ホスフィン］（１８．７ｍｇ、０．０１８ｍｍｏｌ）及びビス（２，５−ノルボルナジエン）ロジウム（Ｉ）テトラフルオロボレート（５．７ｍｇ、０．０１５ｍｍｏｌ）を順次加え、反応容器の内部をアルゴンガスで置換した。反応容器に塩化メチレン（１．５ｍＬ）を加え、水素雰囲気下（０．８ＭＰａ）、２５℃で２４時間撹拌した。得られた溶液をＨＰＬＣ分析条件［２］で分析したところ、転化率は１００％、表題化合物の光学純度は８５．７％ｅｅ（Ｒ）であった。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．８４（ｄ，１Ｈ，Ｊ＝１．２Ｈｚ）、７．１１−７．０１（ｍ，３Ｈ）、６．８１（ｓ，１Ｈ）、４．４０（ｑ，１Ｈ，Ｊ＝７．０Ｈｚ）、２．８３（ｓ，６Ｈ）、２．３１（ｓ，３Ｈ）、２．２６（ｓ，３Ｈ）、１．６１（ｄ，３Ｈ，７．０Ｈｚ） Synthesis Example 11
Synthesis of (R) -4- (1- (2,3-dimethylphenyl) ethyl) -N, N-dimethyl-1H-imidazole-1-sulfonamide (Compound 22)

In a pressure-resistant reaction vessel, 4- (1- (2,3-dimethylphenyl) vinyl) -N, N-dimethyl-1H-imidazole-1-sulfonamide (compound (11)) (45.7 mg, 0.15 mmol) ), (R)-(6,6′-dimethoxybiphenyl-2,2′-diyl) bis [bis (3.5-di-t-butylphenyl) phosphine] (18.7 mg, 0.018 mmol) and bis (2,5-Norbornadiene) rhodium (I) tetrafluoroborate (5.7 mg, 0.015 mmol) was sequentially added, and the inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 25 ° C. for 24 hours under a hydrogen atmosphere (0.8 MPa). The obtained solution was analyzed under HPLC analysis conditions [2]. As a result, the conversion rate was 100% and the optical purity of the title compound was 85.7% ee (R).
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.84 (d, 1H, J = 1.2 Hz), 7.11-7.01 (m, 3H), 6.81 (s, 1H), 4.40 ( q, 1H, J = 7.0 Hz), 2.83 (s, 6H), 2.31 (s, 3H), 2.26 (s, 3H), 1.61 (d, 3H, 7.0 Hz)

HPLC analysis conditions [2]
Column: Daicel CHIRALPAK IA (250 mm × 4.6 mm, 5 μm)
Mobile phase: n-hexane / isopropanol = 97/3 (0-15 minutes) (v / v)
Temperature: 40 ° C
Flow rate: 2.0 mL / min Detection wavelength: 230 nm
Retention time: (S) body 8.0 minutes, (R) body 9.3 minutes

Synthesis Example 12
Synthesis of (R) -4- (1- (2,3-dimethylphenyl) ethyl) -N, N-dimethyl-1H-imidazole-1-sulfonamide (Compound 22) 4- (1 -(2,3-Dimethylphenyl) vinyl) -N, N-dimethyl-1H-imidazole-1-sulfonamide (Compound (11)) (45.8 mg, 0.15 mmol), (2R) -1-[( 1R) -1- [Bis (1,1-dimethylethyl) phosphino] ethyl] -2- (diphenylphosphino) ferrocene (9.8 mg, 0.018 mmol) and bis (2,5-norbornadiene) rhodium (I) Tetrafluoroborate (5.6 mg, 0.015 mmol) was sequentially added, and the inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 25 ° C. for 24 hours under a hydrogen atmosphere (0.8 MPa). When the obtained solution was analyzed under HPLC analysis conditions [2], the conversion was 100% and the optical purity of the title compound was 90.8% ee (R).

耐圧用の反応容器に４−（１−（２，３−ジメチルフェニル）ビニル）−１−（メタンスルホニル）−１Ｈ−イミダゾール（化合物（１２））（４１．３ｍｇ、０．１５ｍｍｏｌ）、（２Ｓ）−１−［（１Ｓ）−１−［ビス（１，１−ジメチルエチル）ホスフィノ］エチル］−２−（ジフェニルホスフィノ）フェロセン（１．０ｍｇ、０．００１８ｍｍｏｌ）及びビス（２，５−ノルボルナジエン）ロジウム（Ｉ）テトラフルオロボレート（０．６ｍｇ、０．００１６ｍｍｏｌ）を順次加え、反応容器の内部をアルゴンガスで置換した。反応容器に塩化メチレン（１．５ｍＬ）を加え、水素雰囲気下（０．８ＭＰａ）、１０℃で２０時間撹拌した。得られた溶液をＨＰＬＣ分析条件［３］で分析したところ、転化率は１００％、表題化合物の光学純度は９６．７％ｅｅであった（不斉中心の絶対配置は未決定）。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．８９（ｓ，１Ｈ）、７．１０−７．０１（ｍ，３Ｈ）、６．８４（ｓ，１Ｈ）、４．３８（ｑ，１Ｈ，Ｊ＝７．０Ｈｚ）、３．２２（ｓ，３Ｈ）、２．３０（ｓ，３Ｈ）、２．２４（ｓ，３Ｈ）、１．６０（ｄ，３Ｈ，Ｊ＝７．０Ｈｚ） Synthesis Example 13
Synthesis of optically active substance (compound 23) of 4- (1- (2,3-dimethylphenyl) ethyl) -1-methanesulfonyl-1H-imidazole

4- (1- (2,3-dimethylphenyl) vinyl) -1- (methanesulfonyl) -1H-imidazole (compound (12)) (41.3 mg, 0.15 mmol), (2S ) -1-[(1S) -1- [Bis (1,1-dimethylethyl) phosphino] ethyl] -2- (diphenylphosphino) ferrocene (1.0 mg, 0.0018 mmol) and bis (2,5- Norbornadiene) rhodium (I) tetrafluoroborate (0.6 mg, 0.0016 mmol) was sequentially added, and the inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 10 ° C. for 20 hours under a hydrogen atmosphere (0.8 MPa). The obtained solution was analyzed under HPLC analysis conditions [3]. As a result, the conversion was 100% and the optical purity of the title compound was 96.7% ee (the absolute configuration of the asymmetric center was not determined).
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.89 (s, 1H), 7.10-7.01 (m, 3H), 6.84 (s, 1H), 4.38 (q, 1H, J = 7.0 Hz), 3.22 (s, 3H), 2.30 (s, 3H), 2.24 (s, 3H), 1.60 (d, 3H, J = 7.0 Hz)

HPLC analysis conditions [3]
Column: Daicel CHIRALPAK AD-H (250 mm × 4.6 mm, 5 μm)
Mobile phase: n-hexane / ethanol = 90/10 (0-20 minutes) (v / v)
Temperature: 40 ° C
Flow rate: 2.0 mL / min Detection wavelength: 230 nm
Retention time: 5.6 minutes, 6.2 minutes (respectively (R) form or (S) form)

耐圧用の反応容器に４−（１−（２，３−ジメチルフェニル）ビニル）−１−トシル−１Ｈ−イミダゾール（化合物（１３））（５２．９ｍｇ、０．１５ｍｍｏｌ）、（２Ｓ）−１−［（１Ｓ）−１−［ビス（１，１−ジメチルエチル）ホスフィノ］エチル］−２−（ジフェニルホスフィノ）フェロセン（１．０ｍｇ、０．００１８ｍｍｏｌ）及びビス（２，５−ノルボルナジエン）ロジウム（Ｉ）テトラフルオロボレート（０．６ｍｇ、０．００１６ｍｍｏｌ）を順次加え、反応容器の内部をアルゴンガスで置換した。反応容器に塩化メチレン（１．５ｍＬ）を加え、水素雰囲気下（０．８ＭＰａ）、１０℃で２０時間撹拌した。得られた溶液をＨＰＬＣ分析条件［３］で分析したところ、転化率は９８．４％、表題化合物の光学純度は９５．３％ｅｅであった（不斉中心の絶対配置は未決定）。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．９３（ｄ，１Ｈ，Ｊ＝０．８Ｈｚ）、７．７９（ｄ，２Ｈ，Ｊ＝８．６Ｈｚ）、７．３５（ｄ，２Ｈ，Ｊ＝８．６Ｈｚ）、７．０７−６．９４（ｍ，３Ｈ）、６．８６（ｓ，１Ｈ）４．３２（ｑ，１Ｈ，Ｊ＝７．０Ｈｚ）、２．４６（ｓ，３Ｈ）、２．２９（ｓ，３Ｈ）、２．１９（ｓ，３Ｈ）、１．５４（ｄ，３Ｈ，Ｊ＝７．０Ｈｚ） Synthesis Example 14
Synthesis of optically active compound (compound 24) of 4- (1- (2,3-dimethylphenyl) ethyl) -1-tosyl-1H-imidazole

In a pressure-resistant reaction vessel, 4- (1- (2,3-dimethylphenyl) vinyl) -1-tosyl-1H-imidazole (compound (13)) (52.9 mg, 0.15 mmol), (2S) -1 -[(1S) -1- [Bis (1,1-dimethylethyl) phosphino] ethyl] -2- (diphenylphosphino) ferrocene (1.0 mg, 0.0018 mmol) and bis (2,5-norbornadiene) rhodium (I) Tetrafluoroborate (0.6 mg, 0.0016 mmol) was sequentially added, and the inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 10 ° C. for 20 hours under a hydrogen atmosphere (0.8 MPa). When the obtained solution was analyzed under HPLC analysis conditions [3], the conversion was 98.4%, and the optical purity of the title compound was 95.3% ee (the absolute configuration of the asymmetric center was not determined).
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93 (d, 1 H, J = 0.8 Hz), 7.79 (d, 2 H, J = 8.6 Hz), 7.35 (d, 2 H, J = 8) .6 Hz), 7.07-6.94 (m, 3H), 6.86 (s, 1H) 4.32 (q, 1H, J = 7.0 Hz), 2.46 (s, 3H), 2 .29 (s, 3H), 2.19 (s, 3H), 1.54 (d, 3H, J = 7.0 Hz)

HPLC analysis conditions [3]
Retention time: 4.5 minutes, 5.4 minutes (Either (R) body or (S) body)

耐圧用の反応容器にｔｅｒｔ−ブチル−４−（１−（２，３−ジメチルフェニル）ビニル）−１Ｈ−イミダゾール−１−カルボキシレート（化合物（１４））（４４．７ｍｇ、０．１５ｍｍｏｌ）、（２Ｓ）−１−［（１Ｓ）−１−［ビス（１，１−ジメチルエチル）ホスフィノ］エチル］−２−（ジフェニルホスフィノ）フェロセン（１．０ｍｇ、０．００１８ｍｍｏｌ）及びビス（２，５−ノルボルナジエン）ロジウム（Ｉ）テトラフルオロボレート（０．６ｍｇ、０．００１６ｍｍｏｌ）を順次加え、反応容器の内部をアルゴンガスで置換した。反応容器に塩化メチレン（１．５ｍＬ）を加え、水素雰囲気下（０．８ＭＰａ）、１０℃で１８時間撹拌した。得られた溶液をＨＰＬＣ分析条件［４］で分析したところ、転化率は５３．６％、表題化合物の光学純度は９４．２％ｅｅあった（不斉中心の絶対配置は未決定）。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．９７（ｄ，１Ｈ，Ｊ＝１．２Ｈｚ）、７．０６−６．９９（ｍ，３Ｈ）、６．９３（ｄ，１Ｈ，Ｊ＝１．２Ｈｚ）、４．３９−４．３２（ｍ，１Ｈ）、２．２９（ｓ，３Ｈ）、２．２５（ｓ，３Ｈ）、１．５９（ｓ，９Ｈ）１．５７（ｄ，３Ｈ，Ｊ＝７．４Ｈｚ） Synthesis Example 15
Synthesis of optically active compound (compound 25) of tert-butyl-4- (1- (2,3-dimethylphenyl) ethyl) -1H-imidazole-1-carboxylate

To a pressure-resistant reaction vessel, tert-butyl-4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole-1-carboxylate (compound (14)) (44.7 mg, 0.15 mmol), (2S) -1-[(1S) -1- [Bis (1,1-dimethylethyl) phosphino] ethyl] -2- (diphenylphosphino) ferrocene (1.0 mg, 0.0018 mmol) and bis (2, 5-Norbornadiene) rhodium (I) tetrafluoroborate (0.6 mg, 0.0016 mmol) was sequentially added, and the inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 10 ° C. for 18 hours under a hydrogen atmosphere (0.8 MPa). The obtained solution was analyzed under HPLC analysis conditions [4]. As a result, the conversion was 53.6%, and the optical purity of the title compound was 94.2% ee (the absolute configuration of the asymmetric center has not been determined).
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97 (d, 1 H, J = 1.2 Hz), 7.06 to 6.99 (m, 3 H), 6.93 (d, 1 H, J = 1.2 Hz) ), 4.39-4.32 (m, 1H), 2.29 (s, 3H), 2.25 (s, 3H), 1.59 (s, 9H) 1.57 (d, 3H, J) = 7.4Hz)

HPLC analysis conditions [4]
Column: Daicel CHIRALPAK IB (250 mm × 4.6 mm, 5 μm)
→ Daicel CHIRALPAK IB (250mm × 4.6mm, 5μm)
Mobile phase: n-hexane / isopropanol = 98.5 / 1.5 (0-10 minutes) (v / v)
Temperature: 40 ° C
Flow rate: 2.0 mL / min Detection wavelength: 230 nm
Retention time: 5.5 minutes, 6.0 minutes (each of (R) and (S) bodies)

耐圧用の反応容器にベンジル−４−（１−（２，３−ジメチルフェニル）ビニル）−１Ｈ−イミダゾール−１−カルボキシレート（化合物（１５））（４９．９ｍｇ、０．１５ｍｍｏｌ）、（２Ｓ）−１−［（１Ｓ）−１−［ビス（１，１−ジメチルエチル）ホスフィノ］エチル］−２−（ジフェニルホスフィノ）フェロセン（１．０ｍｇ、０．００１８ｍｍｏｌ）及びビス（２，５−ノルボルナジエン）ロジウム（Ｉ）テトラフルオロボレート（０．６ｍｇ、０．００１６ｍｍｏｌ）を順次加え、反応容器の内部をアルゴンガスで置換した。反応容器に塩化メチレン（１．５ｍＬ）を加え、水素雰囲気下（０．８ＭＰａ）、１０℃で１８時間撹拌した。得られた溶液をＨＰＬＣ分析条件［１］で分析したところ、転化率は９９．３％、表題化合物の光学純度は９５．６％ｅｅであった（不斉中心の絶対配置は未決定）。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ８．０８（ｄ，１Ｈ，Ｊ＝１．２Ｈｚ）、７．４５−７．３７（ｍ，５Ｈ）、７．０９−６．９９（ｍ，４Ｈ）、５．３８（ｓ，２Ｈ）、４．４０−４．３３（ｍ，１Ｈ）、２．３０（ｓ，３Ｈ）、２．２５（ｓ，３Ｈ）、１．５８（ｄ，３Ｈ，Ｊ＝７．０Ｈｚ） Synthesis Example 16
Synthesis of optically active compound (compound 26) of benzyl-4- (1- (2,3-dimethylphenyl) ethyl) -1H-imidazole-1-carboxylate

In a pressure-resistant reaction vessel, benzyl-4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole-1-carboxylate (compound (15)) (49.9 mg, 0.15 mmol), (2S ) -1-[(1S) -1- [Bis (1,1-dimethylethyl) phosphino] ethyl] -2- (diphenylphosphino) ferrocene (1.0 mg, 0.0018 mmol) and bis (2,5- Norbornadiene) rhodium (I) tetrafluoroborate (0.6 mg, 0.0016 mmol) was sequentially added, and the inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 10 ° C. for 18 hours under a hydrogen atmosphere (0.8 MPa). The obtained solution was analyzed under HPLC analysis conditions [1]. As a result, the conversion was 99.3%, and the optical purity of the title compound was 95.6% ee (the absolute configuration of the asymmetric center was not determined).
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.08 (d, 1H, J = 1.2 Hz), 7.45-7.37 (m, 5H), 7.09-6.99 (m, 4H), 5.38 (s, 2H), 4.40-4.33 (m, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 1.58 (d, 3H, J = 7.0Hz)

HPLC analysis conditions [1]
Retention time: 8.8 minutes, 9.4 minutes (each of (R) and (S) bodies)

耐圧用の反応容器に１−ベンジル−４−（１−（２，３−ジメチルフェニル）ビニル）−１Ｈ−イミダゾール（化合物（１６））（４３．３ｍｇ、０．１５ｍｍｏｌ）、（２Ｓ）−１−［（１Ｓ）−１−［ビス（１，１−ジメチルエチル）ホスフィノ］エチル］−２−（ジフェニルホスフィノ）フェロセン（１．０ｍｇ、０．００１８ｍｍｏｌ）及びビス（２，５−ノルボルナジエン）ロジウム（Ｉ）テトラフルオロボレート（０．７ｍｇ、０．００１６ｍｍｏｌ）を順次加え、反応容器の内部をアルゴンガスで置換した。反応容器に塩化メチレン（１．５ｍＬ）を加え、水素雰囲気下（０．８ＭＰａ）、１０℃で１８時間撹拌した。得られた溶液をＨＰＬＣ分析条件［３］で分析したところ、転化率は９９．２％、表題化合物の光学純度は９２．３％ｅｅあった（不斉中心の絶対配置は未決定）。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．４６（ｄ，１Ｈ，Ｊ＝１．２Ｈｚ）、７．３８−７．２８（ｍ，３Ｈ）、７．１４−６．９９（ｍ，５Ｈ）、６．４６（ｓ，１Ｈ）、５．０２（ｓ，２Ｈ）、４．３９（ｑ，１Ｈ，Ｊ＝７．０Ｈｚ）、２．２９（ｓ，３Ｈ）、２．２５（ｓ，３Ｈ）、１．５８（ｄ，３Ｈ，Ｊ＝７．０Ｈｚ） Synthesis Example 17
Synthesis of 1-benzyl-4- (1- (2,3-dimethylphenyl) ethyl) -1H-imidazole optically active compound (compound 27)

In a pressure-resistant reaction vessel, 1-benzyl-4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazole (compound (16)) (43.3 mg, 0.15 mmol), (2S) -1 -[(1S) -1- [Bis (1,1-dimethylethyl) phosphino] ethyl] -2- (diphenylphosphino) ferrocene (1.0 mg, 0.0018 mmol) and bis (2,5-norbornadiene) rhodium (I) Tetrafluoroborate (0.7 mg, 0.0016 mmol) was sequentially added, and the inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 10 ° C. for 18 hours under a hydrogen atmosphere (0.8 MPa). The obtained solution was analyzed under HPLC analysis conditions [3]. As a result, the conversion was 99.2% and the optical purity of the title compound was 92.3% ee (the absolute configuration of the asymmetric center was not determined).
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.46 (d, 1H, J = 1.2 Hz), 7.38-7.28 (m, 3H), 7.14-6.99 (m, 5H), 6.46 (s, 1H), 5.02 (s, 2H), 4.39 (q, 1H, J = 7.0 Hz), 2.29 (s, 3H), 2.25 (s, 3H) , 1.58 (d, 3H, J = 7.0Hz)

HPLC analysis conditions [3]
Retention time: 4.3 minutes, 7.3 minutes (each of (R) and (S) bodies)

耐圧用の反応容器に４−（１−（２，３−ジメチルフェニル）ビニル）−１−（メトキシメチル）１Ｈ−イミダゾール（化合物（１７））（３６．３ｍｇ、０．１５ｍｍｏｌ）、（２Ｓ）−１−［（１Ｓ）−１−［ビス（１，１−ジメチルエチル）ホスフィノ］エチル］−２−（ジフェニルホスフィノ）フェロセン（１．０ｍｇ、０．００１８ｍｍｏｌ）及びビス（２，５−ノルボルナジエン）ロジウム（Ｉ）テトラフルオロボレート（０．６ｍｇ、０．００１６ｍｍｏｌ）を順次加え、反応容器の内部をアルゴンガスで置換した。反応容器に塩化メチレン（１．５ｍＬ）を加え、水素雰囲気下（０．８ＭＰａ）、２５℃で１９時間撹拌した。得られた溶液をＨＰＬＣ分析条件［５］で分析したところ、転化率は９９．３％、表題化合物の光学純度は８７．１％ｅｅあった（不斉中心の絶対配置は未決定）。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．５１（ｄ，１Ｈ，Ｊ＝０．８Ｈｚ）、７．０９−６．９９（ｍ，３Ｈ）６．５７（ｓ，１Ｈ）、５．１２（ｓ，２Ｈ）、４．３８（ｑ，１Ｈ，Ｊ＝７．０Ｈｚ）、３．２４（ｓ，３Ｈ）、２．２９（ｓ，３Ｈ）、２．２４（ｓ，３Ｈ）、１．５９（ｄ，３Ｈ，Ｊ＝７．４Ｈｚ） Synthesis Example 18
Synthesis of optically active substance (compound 28) of 4- (1- (2,3-dimethylphenyl) ethyl) -1- (methoxymethyl) 1H-imidazole

In a pressure-resistant reaction vessel, 4- (1- (2,3-dimethylphenyl) vinyl) -1- (methoxymethyl) 1H-imidazole (compound (17)) (36.3 mg, 0.15 mmol), (2S) -1-[(1S) -1- [Bis (1,1-dimethylethyl) phosphino] ethyl] -2- (diphenylphosphino) ferrocene (1.0 mg, 0.0018 mmol) and bis (2,5-norbornadiene) ) Rhodium (I) tetrafluoroborate (0.6 mg, 0.0016 mmol) was sequentially added, and the inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 25 ° C. for 19 hours under a hydrogen atmosphere (0.8 MPa). The obtained solution was analyzed under HPLC analysis conditions [5]. As a result, the conversion was 99.3%, and the optical purity of the title compound was 87.1% ee (the absolute configuration of the asymmetric center was not determined).
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.51 (d, 1H, J = 0.8 Hz), 7.09-6.99 (m, 3H) 6.57 (s, 1H), 5.12 (s , 2H), 4.38 (q, 1H, J = 7.0 Hz), 3.24 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H), 1.59 ( d, 3H, J = 7.4 Hz)

HPLC analysis conditions [5]
Column: Daicel CHIRALPAK AD-H (250 mm × 4.6 mm, 5 μm)
Mobile phase: n-hexane / ethanol = 95/5 (0-15 minutes) (v / v)
Temperature: 40 ° C
Flow rate: 2.0 mL / min Detection wavelength: 230 nm
Retention time: 5.0 minutes, 6.3 minutes (respectively, either (R) body or (S) body)

耐圧用の反応容器に１−（４−（１−（２，３−ジメチルフェニル）ビニル）−１Ｈ−イミダゾール−１−イル）エタン−１−オン（化合物（１８））（３５．９ｍｇ、０．１５ｍｍｏｌ）、（２Ｓ）−１−［（１Ｓ）−１−［ビス（１，１−ジメチルエチル）ホスフィノ］エチル］−２−（ジフェニルホスフィノ）フェロセン（１．０ｍｇ、０．００１８ｍｍｏｌ）及びビス（２，５−ノルボルナジエン）ロジウム（Ｉ）テトラフルオロボレート（０．６ｍｇ、０．００１６ｍｍｏｌ）を順次加え、反応容器の内部をアルゴンガスで置換した。反応容器に塩化メチレン（１．５ｍＬ）を加え、水素雰囲気下（０．８ＭＰａ）、２５℃で１９時間撹拌した。得られた溶液をＨＰＬＣ分析条件［６］で分析したところ、転化率は９８．１％、表題化合物の光学純度は９０．６％ｅｅであった（不斉中心の絶対配置は未決定）。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ８．０４（ｄ，１Ｈ，Ｊ＝１．２Ｈｚ）、７．０６−７．００（ｍ，４Ｈ）、４．４０−４．３３（ｍ，１Ｈ）、２．５２（ｓ，３Ｈ）、２．２９（ｓ，３Ｈ）、２．２４（ｓ，３Ｈ）、１．５９（ｄ，３Ｈ、Ｊ＝７．０Ｈｚ） Synthesis Example 19
Synthesis of optically active substance (compound 29) of 1- (4- (1- (2,3-dimethylphenyl) ethyl) -1H-imidazol-1-yl) ethane-1-one

In a pressure-resistant reaction vessel, 1- (4- (1- (2,3-dimethylphenyl) vinyl) -1H-imidazol-1-yl) ethane-1-one (compound (18)) (35.9 mg, 0 .15 mmol), (2S) -1-[(1S) -1- [bis (1,1-dimethylethyl) phosphino] ethyl] -2- (diphenylphosphino) ferrocene (1.0 mg, 0.0018 mmol) and Bis (2,5-norbornadiene) rhodium (I) tetrafluoroborate (0.6 mg, 0.0016 mmol) was sequentially added, and the inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 25 ° C. for 19 hours under a hydrogen atmosphere (0.8 MPa). The obtained solution was analyzed under HPLC analysis conditions [6]. As a result, the conversion was 98.1%, and the optical purity of the title compound was 90.6% ee (the absolute configuration of the asymmetric center was not determined).
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.04 (d, 1H, J = 1.2 Hz), 7.06 to 7.00 (m, 4H), 4.40-4.33 (m, 1H), 2.52 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H), 1.59 (d, 3H, J = 7.0 Hz)

HPLC analysis conditions [6]
Column: Daicel CHIRALPAK IA (250 mm × 4.6 mm, 5 μm)
→ Daicel CHIRALPAK IA (250 mm × 4.6 mm, 5 μm)
Mobile phase: n-hexane / ethanol = 97/3 (0-20 minutes) (v / v)
Temperature: 40 ° C
Flow rate: 2.0 mL / min Detection wavelength: 230 nm
Retention time: 17.2 minutes, 18.0 minutes (each of (R) and (S) bodies)

耐圧用の反応容器に４−（１−（２，３−ジメチルフェニル）ビニル）−１−（（２−（トリメチルシリル）エトキシ）メチル）−１Ｈ−イミダゾール（化合物（１９））（４９．２ｍｇ、０．１５ｍｍｏｌ）、（２Ｓ）−１−［（１Ｓ）−１−［ビス（１，１−ジメチルエチル）ホスフィノ］エチル］−２−（ジフェニルホスフィノ）フェロセン（１．０ｍｇ、０．００１８ｍｍｏｌ）及びビス（２，５−ノルボルナジエン）ロジウム（Ｉ）テトラフルオロボレート（０．６ｍｇ、０．００１６ｍｍｏｌ）を順次加え、反応容器の内部をアルゴンガスで置換した。反応容器に塩化メチレン（１．５ｍＬ）を加え、水素雰囲気下（０．８ＭＰａ）、４０℃で２４時間撹拌した。得られた溶液をＨＰＬＣ分析条件［７］で分析したところ、転化率は１００％、表題化合物の光学純度は７０．８％ｅｅであった（不斉中心の絶対配置は未決定）。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．５１（ｄ，１Ｈ，Ｊ＝１．２Ｈｚ）、７．０９−６．９９（ｍ，３Ｈ）、６．５７（ｓ，１Ｈ）、５．１６（ｓ，２Ｈ）、４．３９（ｑ，１Ｈ，Ｊ＝７．０Ｈｚ）、３．４７−３．４２（ｍ，２Ｈ）、２．２９（ｓ，３Ｈ）、２．２５（ｓ，３Ｈ）、１．５９（ｄ，３Ｈ，Ｊ＝７．０Ｈｚ）、０．９２−０．８４（ｍ，２Ｈ）、−０．０２（ｓ，９Ｈ） Synthesis Example 20
Synthesis of optically active compound (compound 30) of 4- (1- (2,3-dimethylphenyl) ethyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1-imidazole

In a pressure-resistant reaction vessel, 4- (1- (2,3-dimethylphenyl) vinyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole (compound (19)) (49.2 mg, 0.15 mmol), (2S) -1-[(1S) -1- [bis (1,1-dimethylethyl) phosphino] ethyl] -2- (diphenylphosphino) ferrocene (1.0 mg, 0.0018 mmol) And bis (2,5-norbornadiene) rhodium (I) tetrafluoroborate (0.6 mg, 0.0016 mmol) were sequentially added, and the inside of the reaction vessel was replaced with argon gas. Methylene chloride (1.5 mL) was added to the reaction vessel, and the mixture was stirred at 40 ° C. for 24 hours under a hydrogen atmosphere (0.8 MPa). The obtained solution was analyzed under HPLC analysis conditions [7]. The conversion rate was 100% and the optical purity of the title compound was 70.8% ee (the absolute configuration of the asymmetric center was not determined).
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.51 (d, 1H, J = 1.2 Hz), 7.09-6.99 (m, 3H), 6.57 (s, 1H), 5.16 ( s, 2H), 4.39 (q, 1H, J = 7.0 Hz), 3.47-3.42 (m, 2H), 2.29 (s, 3H), 2.25 (s, 3H) 1.59 (d, 3H, J = 7.0 Hz), 0.92-0.84 (m, 2H), -0.02 (s, 9H)

HPLC analysis conditions [7]
Column: Daicel CHIRALPAK AD-H (250 mm × 4.6 mm, 5 μm)
Mobile phase: n-hexane / ethanol = 98/2 (0-15 minutes) (v / v)
Temperature: 40 ° C
Flow rate: 2.0 mL / min Detection wavelength: 230 nm
Retention time: 4.0 minutes, 4.7 minutes (each of which is either (R) or (S))

反応容器の内部を窒素ガスで置換した後、（Ｓ）−４−（１−（２，３−ジメチルフェニル）エチル）−１−トリチル−１Ｈ−イミダゾール（化合物（２１））（１６９．１ｍｇ、０．３８２ｍｍｏｌ、光学純度９４．８％ｅｅ（Ｓ））、トルエン（１．７０ｇ）、１０％塩酸（１．７０ｇ）を順次、反応容器に加えた。反応液を８４℃に昇温後、８０℃から８４℃の範囲で４時間撹拌した。室温まで冷却後、分液した。得られた水層をトルエン（５．０１ｇ）で洗浄した。得られた水層に、酢酸エチル（１０．２１ｇ）、１０％水酸化ナトリウム水溶液（２．２０ｇ）を順次加えた。３０分撹拌後分液し、得られた有機層を水で洗浄後、濃縮した。得られた残渣に酢酸エチル（１．３６ｇ）、ｎ−ヘプタン（３．４０ｇ）を順次加え、析出した固体をろ過した。得られた固体を減圧乾燥して、表題化合物（６０．１ｍｇ、７８．６％）を白色固体として得た。得られた表題化合物をＨＰＬＣ分析条件［８］で分析したところ、光学純度は９９．２％ｅｅ（Ｓ）であった。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．５０（ｂｒ，１Ｈ）、７．０８−６．９７（ｍ，３Ｈ）、６．７７（ｂｒ，１Ｈ）、４．４１（ｑ，１Ｈ，Ｊ＝７．２Ｈｚ）、２．３０（ｓ，３Ｈ）、２．２４（ｓ，３Ｈ）、１．６０（ｄ，３Ｈ，Ｊ＝７．２Ｈｚ） Synthesis Example 21
Synthesis of (S) -4- (1- (2,3-dimethylphenyl) ethyl) -1H-imidazole (Compound 31)

After replacing the inside of the reaction vessel with nitrogen gas, (S) -4- (1- (2,3-dimethylphenyl) ethyl) -1-trityl-1H-imidazole (compound (21)) (169.1 mg, 0.382 mmol, optical purity 94.8% ee (S)), toluene (1.70 g), 10% hydrochloric acid (1.70 g) were sequentially added to the reaction vessel. The temperature of the reaction solution was raised to 84 ° C. and then stirred in the range of 80 ° C. to 84 ° C. for 4 hours. Liquid separation was carried out after cooling to room temperature. The obtained aqueous layer was washed with toluene (5.01 g). Ethyl acetate (10.21 g) and 10% aqueous sodium hydroxide solution (2.20 g) were sequentially added to the obtained aqueous layer. After stirring for 30 minutes, liquid separation was performed, and the obtained organic layer was washed with water and concentrated. Ethyl acetate (1.36 g) and n-heptane (3.40 g) were sequentially added to the obtained residue, and the precipitated solid was filtered. The obtained solid was dried under reduced pressure to give the title compound (60.1 mg, 78.6%) as a white solid. When the obtained title compound was analyzed under HPLC analysis conditions [8], the optical purity was 99.2% ee (S).
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.50 (br, 1H), 7.08-6.97 (m, 3H), 6.77 (br, 1H), 4.41 (q, 1H, J = 7.2 Hz), 2.30 (s, 3H), 2.24 (s, 3H), 1.60 (d, 3H, J = 7.2 Hz)

HPLC analysis conditions [8]
Column: Daicel CHIRALCEL OD-H (250 mm × 4.6 mm, 5 μm)
→ Daicel CHIRALCEL OD-H (250 mm × 4.6 mm, 5 μm)
Mobile phase: n-hexane / (methanol / ethanol = 1/1 (V / V)) = 95/5 (0-20 minutes) (v / v)
Temperature: 40 ° C
Flow rate: 1.5 mL / min Detection wavelength: 230 nm
Retention time: (S) body 11.4 minutes, (R) body 14.2 minutes

  The present invention can provide a novel method for producing an optically active imidazole compound useful as a pharmaceutical product. The present invention can also provide a novel optically active imidazole compound that is a production intermediate.

Claims (15)

Formula (4)

[Wherein R ¹ represents an amino protecting group, and * represents an asymmetric carbon atom. A method for producing an optically active imidazole compound represented by the formula:
Formula (3)

[Wherein R ¹ represents the same meaning as described above. And an optically active metal complex catalyst (the optically active metal complex catalyst is a compound selected from the group consisting of an optically active rhodium complex catalyst, an optically active iridium complex catalyst, and an optically active cobalt catalyst). A production method comprising reacting hydrogen gas in the presence of The production method according to claim 1, wherein R ¹ is a sulfamoyl protecting group, a sulfonyl protecting group, an alkoxycarbonyl protecting group, an alkyl protecting group, a silyl protecting group, an ether protecting group, an acyl protecting group or a carbamoyl protecting group. R ¹ is N, N-dimethylsulfamoyl group, methanesulfonyl group, p-toluenesulfonyl group, benzyloxycarbonyl group, t-butoxycarbonyl group, triphenylmethyl group, benzyl group, [2- (trimethylsilyl) ethoxy The production method according to claim 2, which is a methyl group, a 2-methoxymethyl group or an acetyl group. The production method according to any one of claims 1 to 3, wherein the optically active metal complex catalyst is an optically active rhodium complex catalyst. The optically active metal complex catalyst is a compound selected from the group consisting of A, B and C, wherein A is the formula (7-1), B is the formula (7-2), and C is the formula (7-3). )

[Wherein L ³ is an organic ligand independently selected from the group consisting of ethylene, 1,5-cyclooctadiene and norborna-2,5-diene;
Q ² is an anion independently selected from the group consisting of chloride ion, tetrafluoroborate ion, hexafluorophosphate ion, hexafluoroantimonate ion, and trifluoromethanesulfonate ion. A compound formed in a reaction system from a precursor of a rhodium complex catalyst represented by the following formula and an optically active ligand L ⁴ selected from the group consisting of a Josiphos ligand, a MeOBIPHEP ligand, and a MonoPhos ligand The manufacturing method according to claim 4, wherein The precursor of the rhodium complex catalyst has the formula (7-1)

[Wherein L ³ is norborna-2,5-diene and 1,5-cyclooctadiene, and Q ² is a tetrafluoroborate ion and a trifluoromethanesulfonate ion. The manufacturing method of Claim 5 which is a compound represented by this. L ⁴ represents the formula (a-1) to the formula (a-8).

The manufacturing method of Claim 5 or 6 which is a compound represented by either. The production method according to claim 1, wherein the reaction is carried out in an organic solvent.   The production method according to claim 8, wherein the organic solvent contains at least one solvent selected from the group consisting of an aromatic hydrocarbon solvent, an alcohol solvent, and a halogen-containing hydrocarbon solvent. The manufacturing method of the optically active imidazole compound represented by Formula (8) including the following process (a) and (b).
(A)
A method according to any one of claims 1 to 9,
Formula (4)

[Wherein R ¹ represents an amino protecting group, and * represents an asymmetric carbon atom. The process of obtaining the optically active imidazole compound represented by this.
(B)
The optically active imidazole compound represented by formula (4) is deprotected to give formula (8)

[In the formula, * represents the same meaning as in the previous term. The process of obtaining the optically active imidazole compound represented by this. Formula (4)

[Wherein R ¹ represents a sulfamoyl protecting group, a sulfonyl protecting group, an alkoxycarbonyl protecting group, an alkyl protecting group, a silyl protecting group, an ether protecting group, an acyl protecting group or a carbamoyl protecting group, and * represents an asymmetric carbon atom. Represent. ] The optically active imidazole compound represented by this. Formula (5)

[Wherein R ¹ represents the same meaning as described above. The compound of Claim 11 represented by these. R ¹ is N, N-dimethylsulfamoyl group, methanesulfonyl group, p-toluenesulfonyl group, benzyloxycarbonyl group, t-butoxycarbonyl group, triphenylmethyl group, benzyl group, [2- (trimethylsilyl) ethoxy The compound according to claim 12, which is a methyl group, a 2-methoxymethyl group or an acetyl group. Formula (6)

[Wherein R ¹ represents the same meaning as described above. The compound of Claim 11 represented by these. R ¹ is N, N-dimethylsulfamoyl group, methanesulfonyl group, p-toluenesulfonyl group, benzyloxycarbonyl group, t-butoxycarbonyl group, triphenylmethyl group, benzyl group, [2- (trimethylsilyl) ethoxy The compound according to claim 14, which is a methyl group, a 2-methoxymethyl group or an acetyl group.