JP2005206581A - Method for producing optically active cycloalkylidenebisoxazoline compound and intermediate of the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an efficient method for producing an optically active cycloalkylidenebisoxazoline compound. <P>SOLUTION: This method for producing the optically active cycloalkylidenebisoxazoline compound comprises a first process of performing the reaction of an optically active aminoalcohol compound expressed by formula (1) with a cycloalkylidene malonic acid diester compound expressed by formula (2) in the presence of a lithium compound to obtain an optically active cycloalkylidenebisamidealcohol compound expressed by formula (3): and a second process of performing the reaction of the obtained optically active cycloalkylidenebisamidealcohol with a sulfonylation agent in the presence of a basic compound to obtain the optically active cycloalkylidenebisoxazoline compound expressed by formula (4). <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for producing an optically active cycloalkylidenebisoxazoline compound.

  Optically active cycloalkylidene bisoxazoline compounds are important compounds as ligands for asymmetric synthesis catalysts. Specific examples of the asymmetric synthesis catalyst include a copper bisoxazoline catalyst for asymmetric synthesis of intermediates such as agricultural chemicals and pharmaceuticals such as synthetic pyrethroid insecticides. As a method for producing such an optically active cycloalkylidene bisoxazoline compound, for example, a 2,2-methylenebisoxazoline compound obtained by reacting a corresponding optically active amino alcohol with malonoimidate is obtained in the presence of a strong base. -A method of reacting with a dihalogenated alkyl such as dibromoethane is known (for example, see Non-Patent Document 1). However, the total yield was not always satisfactory.

J. et al. Org. Chem. , 65, 5875 (2000)

  Under such circumstances, the present inventors have intensively studied to develop a more efficient method for producing an optically active cycloalkylidene bisoxazoline compound. As a result, in the presence of a lithium compound, an optically active amino alcohol compound and a cyclohexane are present. A method for obtaining an optically active cycloalkylidene bisamide alcohol compound with good yield by reacting with an alkylidene malonic acid diester compound and obtaining an optically active cycloalkylidene bisoxazoline compound efficiently from this was found, leading to the present invention.

（式中、Ｒ^１は炭素数１〜６のアルキル基、置換されていてもよいアラルキル基、置換されていてもよいフェニル基または水素原子を表し、Ｒ^２は炭素数１〜６のアルキル基、置換されていてもよいアラルキル基または置換されていてもよいフェニル基を表す。ここで、Ｒ^１が炭素数１〜６のアルキル基を表す場合は、同じ炭素原子に結合する二つのＲ^１が結合してその結合炭素原子とともに環を形成してもよい。＊は不斉中心を表す。）
で示される光学活性なアミノアルコール化合物と、式（２）

（式中、Ｒ^３は炭素数１〜３のアルキル基を表す。ｎは０〜３の整数を表す。）
で示されるシクロアルキリデンマロン酸ジエステル化合物とを反応させて、式（３）

（式中、Ｒ^１、Ｒ^２、ｎおよび＊は上記と同一の意味を表す。）
で示される光学活性なシクロアルキリデンビスアミドアルコール化合物を得る第１工程；
ならびに、塩基性化合物の存在下、該光学活性なシクロアルキリデンビスアミドアルコール化合物とスルホニル化剤とを反応させることにより、式（４）

（式中、Ｒ^１、Ｒ^２、ｎおよび＊は上記と同一の意味を表す。）
で示される光学活性なシクロアルキリデンビスオキサゾリン化合物を得る第２工程；
からなる光学活性なシクロアルキリデンビスオキサゾリン化合物の製造方法およびその中間体を提供するものである。 That is, the present invention provides a compound of formula (1) in the presence of a lithium compound.

(In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms, an optionally substituted aralkyl group, an optionally substituted phenyl group or a hydrogen atom, and R ² represents an alkyl group having 1 to 6 carbon atoms. Represents an optionally substituted aralkyl group or an optionally substituted phenyl group, and when R ¹ represents an alkyl group having 1 to 6 carbon atoms, two R ¹ bonded to the same carbon atom; May be bonded to form a ring together with the bonded carbon atoms. * Represents an asymmetric center.)
An optically active amino alcohol compound represented by formula (2):

(In the formula, ^{R 3} .n it represents an alkyl group having 1 to 3 carbon atoms is an integer of 0 to 3.)
Is reacted with a cycloalkylidenemalonic acid diester compound represented by formula (3):

(Wherein R ¹ , R ² , n and * represent the same meaning as described above.)
A first step of obtaining an optically active cycloalkylidenebisamide alcohol compound represented by:
And by reacting the optically active cycloalkylidenebisamide alcohol compound with a sulfonylating agent in the presence of a basic compound,

(Wherein R ¹ , R ² , n and * represent the same meaning as described above.)
A second step of obtaining an optically active cycloalkylidenebisoxazoline compound represented by:
The production method of an optically active cycloalkylidene bisoxazoline compound and an intermediate thereof are provided.

  By using the novel production method of the present invention, an optically active cycloalkylidenebisoxazoline compound useful as a ligand for an asymmetric synthesis catalyst can be produced efficiently and inexpensively, which is industrially advantageous.

  First, an optically active amino alcohol compound represented by formula (1) (hereinafter abbreviated as optically active amino alcohol (1)) and a cycloalkylidene malonic acid diester represented by formula (2) in the presence of a lithium compound. A compound (hereinafter abbreviated as cycloalkylidene malonic acid diester (2)) is reacted with an optically active cycloalkylidene bisamide alcohol compound represented by formula (3) (hereinafter referred to as optically active cycloalkylidene bisamide alcohol (3). The first step of abbreviating as) will be described.

In the formula of the optically active amino alcohol (1), R ¹ represents an alkyl group having 1 to 6 carbon atoms, an aralkyl group that may be substituted, a phenyl group that may be substituted, or a hydrogen atom, and R ² represents An alkyl group having 1 to 6 carbon atoms, an optionally substituted aralkyl group, or an optionally substituted phenyl group is represented. When R ¹ represents an alkyl group having 1 to 6 carbon atoms, two R ¹ bonded to the same carbon atom may be bonded to form a ring together with the bonded carbon atom. * Represents an asymmetric center.

  Examples of the alkyl group having 1 to 6 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, and n-hexyl group. A linear or branched alkyl group is exemplified. Examples of the optionally substituted phenyl group include an unsubstituted phenyl group; for example, a phenyl group substituted with the alkyl group having 1 to 6 carbon atoms such as a 3-methylphenyl group and a 4-methylphenyl group; -Phenyl group substituted by C1-C6 alkoxy groups, such as a methoxyphenyl group and 4-methoxyphenyl group; The optionally substituted aralkyl group is composed of a naphthyl group or the above optionally substituted phenyl group and the alkyl group having 1 to 6 carbon atoms, such as benzyl group, 4-methylbenzyl. Group, 4-methoxybenzyl group, 1-naphthylmethyl group, 2-naphthylmethyl group and the like.

R ¹ represents an alkyl group having 1 to 6 carbon atoms, and two R ¹ bonded to the same carbon atom may be bonded to form a ring together with the bonded carbon atom. Examples thereof include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring.

  Examples of the optically active amino alcohol (1) include (R) -2-amino-propanol, (R) -2-amino-1,1-dimethylpropanol, and (R) -2-amino-1,1. -Diethylpropanol, (R) -2-amino-1,1-di (n-propyl) propanol, (R) -2-amino-1,1-diphenylpropanol, (R) -2-amino-1,1 -Di (4-methylphenyl) propanol, (R) -2-amino-1,1-di (2-methoxyphenyl) propanol, (R) -2-amino-1,1-di (4-methoxyphenyl) Propanol, (R) -2-amino-1,1-dibenzylpropanol, 1-((R) -1-aminoethyl) cyclobutanol, 1-((R) -1-aminoethyl) cyclopentanol, 1 -((R 1-aminoethyl) cyclohexanol,

(R) -2-amino-3-methylbutanol, (R) -2-amino-3-methyl-1,1-dimethylbutanol, (R) -2-amino-3-methyl-1,1-diethylbutanol (R) -2-amino-3-methyl-1,1-di (n-propyl) butanol, (R) -2-amino-3-methyl-1,1-diphenylbutanol, (R) -2- Amino-3-methyl-1,1-di (4-methylphenyl) butanol, (R) -2-amino-3-methyl-1,1-di (2-methoxyphenyl) butanol, (R) -2- Amino-3-methyl-1,1-di (4-methoxyphenyl) butanol, (R) -2-amino-3-methyl-1,1-di-benzylbutanol, 1-((R) -1-amino -2-methylpropyl) cyclobutanol, 1-((R) 1-amino-2-methylpropyl) cyclopentanol, 1 - ((R) -1- amino-2-methylpropyl) cyclohexanol,

(R) -2-amino-4-methylpentanol, (R) -2-amino-4-methyl-1,1-dimethylpentanol, (R) -2-amino-4-methyl-1,1- Diethylpentanol, (R) -2-amino-4-methyl-1,1-di (n-propyl) pentanol, (R) -2-amino-4-methyl-1,1-diphenylpentanol, ( R) -2-amino-4-methyl-1,1-di (4-methylphenyl) pentanol, (R) -2-amino-4-methyl-1,1-di (2-methoxyphenyl) pentanol (R) -2-amino-4-methyl-1,1-di (4-methoxyphenyl) pentanol, (R) -2-amino-4-methyl-1,1-dibenzylpentanol, 1- ((R) -1-Amino-3-methylbutyl) cyclobutanol 1 - (((R) -1- amino-3-methylbutyl) cyclopentanol, 1 - ((R) -1- amino-3-methylbutyl) cyclohexanol,

(R) -2-amino-3,3-dimethylbutanol, (R) -2-amino-3,3-dimethyl-1,1-dimethylbutanol, (R) -2-amino-3,3-dimethyl- 1,1-diethylbutanol, (R) -2-amino-3,3-dimethyl-1,1-di (n-propyl) butanol, (R) -2-amino-3,3-dimethyl-1,1 -Diphenylbutanol, (R) -2-amino-3,3-dimethyl-1,1-di (4-methylphenyl) butanol, (R) -2-amino-3,3-dimethyl-1,1-di (2-methoxyphenyl) butanol, (R) -2-amino-3,3-dimethyl-1,1-di (4-methoxyphenyl) butanol, (R) -2-amino-3,3-dimethyl-1 , 1-Dibenzylbutanol, 1-((R) -1-amino 2,2-dimethylpropyl) cyclobutanol, 1-((R) -1-amino-2,2-dimethylpropyl) cyclopentanol, 1-((R) -1-amino-2,2-dimethylpropyl) Cyclohexanol,

(R) -2-amino-2-phenylethanol, (R) -2-amino-2-phenyl-1,1-dimethylethanol, (R) -2-amino-2-phenyl-1,1-diethylethanol (R) -2-amino-2-phenyl-1,1-di (n-propyl) ethanol, (R) -2-amino-2-phenyl-1,1-diphenylethanol, (R) -2- Amino-2-phenyl-1,1-di (4-methylphenyl) ethanol, (R) -2-amino-2-phenyl-1,1-di (2-methoxyphenyl) ethanol, (R) -2- Amino-2-phenyl-1,1-di (4-methoxyphenyl) ethanol, (R) -2-amino-2-phenyl-1,1-dibenzylethanol, 1-((R) -1-amino- 1-phenylmethyl) cyclobutano , 1-(R) -1-amino-1-phenylmethyl) cyclopentanol, 1-(R) -1-amino-1-phenylmethyl) cyclohexanol,

(R) -2-amino-3-phenylpropanol, (R) -2-amino-3-phenyl-1,1-dimethylpropanol, (R) -2-amino-3-phenyl-1,1-diethylpropanol (R) -2-amino-3-phenyl-1,1-di (n-propyl) propanol, (R) -2-amino-3-phenyl-1,1-diphenylpropanol, (R) -2- Amino-3-phenyl-1,1-di (4-methylphenyl) propanol, (R) -2-amino-3-phenyl-1,1-di (2-methoxyphenyl) propanol, (R) -2- Amino-3-phenyl-1,1-di (4-methoxyphenyl) propanol, (R) -2-amino-3-phenyl-1,1-dibenzylpropanol, 1-((R) -1-amino- 2-phenylethyl ) Cyclobutanol, 1-((R) -1-amino-2-phenylethyl) cyclopentanol, 1-((R) -1-amino-2-phenylethyl) cyclohexanol, and the like ( Examples thereof include compounds in which R) is equivalent to (S) and salts such as hydrochlorides, sulfates and acetates thereof.

（式中、Ｒ^２および＊は上記と同一の意味を表し、Ｒ^４は炭素数１〜４のアルキル基または水素原子を表す。）
で示される光学活性なアミノ酸またはそのエステル（以下、光学活性なアミノ酸類（６）と略記する。）を出発原料とする既知の方法により得たものを用いることができる。 Moreover, the manufacturing method of said optically active amino alcohol (1) is not specifically limited, When group shown by R < ¹ > is a hydrogen atom, for example, it is easy to obtain Formula (6)

(In the formula, R ² and * represent the same meaning as described above, and R ⁴ represents an alkyl group having 1 to ⁴ carbon atoms or a hydrogen atom.)
Or an ester thereof (hereinafter abbreviated as “optically active amino acid (6)”) obtained by a known method can be used.

Examples of the alkyl group having 1 to 4 carbon atoms represented by R ⁴ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and a tert-butyl group. Among the optically active amino acids (5), examples of the optically active amino acid ester include (R) -alanine methyl ester, (R) -valine methyl ester, (R) -leucine methyl ester, (R) -tert- Leucine methyl ester, (R) -phenylglycine methyl ester, (R)-(1-naphthyl) glycine methyl ester, (R)-(2-naphthyl) glycine methyl ester, (R) -phenylalanine methyl ester, and these compounds And compounds in which the methyl group of the ester moiety is replaced with an ethyl group, a propyl group, an n-butyl group, and the like, and compounds in which (R) in each of the above compounds is equivalent to (S). Examples of amino acids include (R) -alanine, (R) -valine, (R) -leucine, (R) -tert-leucine, (R) -phenylglycine, (R)-(1-naphthyl) glycine, ( Examples include R)-(2-naphthyl) glycine, (R) -phenylalanine, and compounds in which (R) in each of the above compounds corresponds to (S). Furthermore, examples of the optically active amino acids (6) include salts of the above-mentioned compounds such as hydrochloride, sulfate and acetate.

As a method for producing amino alcohol (1) using such optically active amino acids (6) as a starting material, when R ¹ in formula (1) is a hydrogen atom, for example, optically active amino acids (6) and hydrogen Reaction with boron compounds (for example, Tetrahedron Letters, 33 , 5517 (1992), J. Org. Chem., 58 , 3568 (1993), Turkish Journal of Chemistry, 23 , 123 (1999) and Ang.). Chem. Int. Ed. Engl., 28 , 218 (1989), etc.).

Here, as the borohydride compound, for example, borohydride such as diborane and borane-tetrahydrofuran complex, and a complex of this and a compound having a coordination property; a mixture of a borohydride metal and an acid; a borohydride metal And a mixture of diester of sulfuric acid; metal borohydride; and the like. When an optically active amino acid ester (R ⁴ is an alkyl group having 1 to ⁴ carbon atoms) is used as the optically active amino acid (6), it is preferable to use only a borohydride metal as the borohydride compound. When an optically active amino acid (R ⁴ is a hydrogen atom) is used as the optically active amino acid (6), a boron hydride compound and a complex of borohydride and a compound having a coordination property thereof; It is preferable to use at least one borohydride compound selected from the group consisting of a mixture of a metal borohydride and an acid; a mixture of a metal borohydride and a sulfuric diester; a metal borohydride.

  Examples of the metal borohydride include lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride and the like, and sodium borohydride is preferably used in terms of availability. Examples of the acid mixed with the metal borohydride include inorganic acids such as sulfuric acid and hydrochloric acid; Lewis acids such as boron trifluoride, zinc chloride, aluminum chloride, titanium tetrachloride, and trimethylsilane; halogens such as bromine and iodine. Alkyl halides such as methyl bromide and methyl iodide; and the like. Examples of the sulfuric diester include dimethyl sulfate and diethyl sulfate.

（式中、Ｒ^１は上記と同一の意味を表し、Ｘはハロゲン原子を表す。）
で示されるグリニヤール試剤（以下、グリニヤール試剤（７）と略記する。）Ｘで示されるハロゲン原子としては、例えば塩素原子、臭素原子、ヨウ素原子等が挙げられる。 The base is an alkyl group having 1 to 6 carbon atoms represented by R ^1, a process for preparing optically active amino alcohols of the case have been the aralkyl group or a substituted also be an optionally substituted phenyl group (1) Is, for example, a reaction between an optically active amino acid ester in which R ⁴ in formula (6) is an alkyl group having 1 to ⁴ carbon atoms and a Grignard reagent (see, for example, Tetrahedron Letters, 34 , 1905 (1993)). Is mentioned. As a Grignard reagent, for example, formula (7)

(Wherein R ¹ represents the same meaning as described above, and X represents a halogen atom.)
Examples of the halogen atom represented by X (hereinafter abbreviated as Grignard reagent (7)) X include a chlorine atom, a bromine atom, and an iodine atom.

Examples of the Grignard reagent (7) include methylmagnesium chloride, ethylmagnesium chloride, n-propylmagnesium chloride, isopropylmagnesium chloride, n-butylmagnesium chloride, isobutylmagnesium chloride, tert-butylmagnesium chloride, n-pentylmagnesium chloride, n -Hexylmagnesium chloride, phenylmagnesium chloride, 3-methylphenylmagnesium chloride, 4-methylphenylmagnesium chloride, 2-methoxyphenylmagnesium chloride, 4-methoxyphenylmagnesium chloride, benzylmagnesium chloride, 4-methylbenzylmagnesium chloride, 4- Methoxybenzylmagnesium chlora De, 1-naphthyl methyl magnesium chloride, 2-naphthyl methyl magnesium chloride, and in the above compound "chloride" is "bromide", compounds replaced the "iodide" or the like. Further, as an expression (1), a case where R ¹ represents an alkyl group having 1 to 6 carbon atoms, to form a ring together with the bonded carbon atoms bonded to two R ¹ attached to the same carbon atom When a desired compound is desired, as a Grignard reagent, for example, butane-1,4-dimethylmagnesium dichloride, pentane-1,5-digmagnesium dichloride, hexane-1,6-digmagnesium dichloride, A diglynar reagent such as a compound in which “chloride” is replaced with “bromide” or “iodide” may be used.

  In the optically active amino alcohol (1) thus obtained, the configuration of the asymmetric center indicated by * is the same as the configuration of the optically active amino acid (6) used.

In the cycloalkylidene malonic acid diester (2), R ³ represents an alkyl group having 1 to ³ carbon atoms, and n represents an integer of 0 to 3. For example, when n = 0, the cycloalkylidene malonic acid diester (2) represents a cyclopropylidene malonic acid diester.

  Examples of the cycloalkylidene malonic acid diester (2) include, for example, dimethyl cyclopropane-1,1-dicarboxylate, diethyl cyclopropane-1,1-dicarboxylate, dimethyl cyclobutane-1,1-dicarboxylate, cyclobutane-1,1- Examples include diethyl dicarboxylate, dimethyl cyclopentane-1,1-dicarboxylate, diethyl cyclopentane-1,1-dicarboxylate, dimethyl cyclohexane-1,1-dicarboxylate, diethyl cyclohexane-1,1-dicarboxylate, and the like.

  The amount of the cycloalkylidene malonic acid diester (2) used is usually about 0.2 to 2 mol times, preferably about 0.4 to 1 mol times based on the optically active amino alcohol compound (1).

  Examples of the lithium compound used in the present invention include lithium hydroxide, lithium alkoxides such as lithium methoxide and lithium ethoxide, and lithium halides such as lithium chloride. Although the usage-amount is not specifically limited, Usually, it is about 0.0005-0.5 mol times with respect to diester (2).

  The reaction is usually carried out in the presence of a solvent. Examples of the solvent used include aromatic hydrocarbon solvents such as toluene and xylene, aliphatic hydrocarbon solvents such as hexane, heptane, and octane, halogenated hydrocarbon solvents such as chlorobenzene, such as tetrahydrofuran and dimethoxyethane, and the like. Examples include ether solvents. These are used alone or in admixture of two or more, and the amount used is not particularly limited, but is usually about 2 to 500 times the weight of the optically active amino alcohol compound (1). .

（式中、Ｒ^３は上記と同一の意味を表す。）
で示されるアルコール（以下、アルコール（５）と略記する。）の沸点以上の温度で、アルコール（５）を系外へ除去しながら反応を実施することが好ましい。 The reaction temperature is not particularly limited, and is usually in the range of about 20 to 150 ° C. In addition, the by-product formula (5)

(Wherein R ³ represents the same meaning as described above.)
It is preferable to carry out the reaction while removing the alcohol (5) out of the system at a temperature equal to or higher than the boiling point of the alcohol represented by the formula (hereinafter abbreviated as alcohol (5)).

  This reaction is usually carried out under normal pressure conditions, but may be carried out under pressurized conditions. Moreover, as above-mentioned, it can also implement under pressure reduction conditions in order to remove alcohol (5).

  This reaction is carried out by mixing the lithium compound, the optically active amino alcohol (1) and the cycloalkylidene malonic acid diester (2) in the presence of a solvent, if necessary, and the mixing order is not particularly limited. For example, the reaction temperature may be adjusted after mixing them all together, or a cycloalkylidene malonic acid diester (2) may be added to a mixture of a lithium compound having an adjusted reaction temperature and an optically active amino alcohol (1). You may implement by adding.

  After completion of the reaction, for example, water is added to the reaction mixture, and if necessary, extraction treatment is performed using an organic solvent insoluble in water such as toluene and ethyl acetate, and the obtained organic layer is concentrated to obtain an optically active cycloalkylidenebisamide. Alcohol (3) can be obtained. Alternatively, when the product is precipitated from the reaction mixture, the target product can be obtained by an operation such as filtration. The obtained optically active cycloalkylidenebisamide alcohol (3) can be further purified by a usual method such as a distillation operation or recrystallization.

  In the optically active cycloalkylidenebisamide alcohol (3) thus obtained, the configuration of the asymmetric center indicated by * is the same as that of the optically active amino alcohol (1) used.

  Examples of the optically active cycloalkylidenebisamide alcohol (3) include N, N′-bis [(R) -1-methyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N′-. Bis [(R) -1,2-dimethyl-2-hydroxypropyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-methyl-2-ethyl-2-hydroxybutyl Cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-methyl-2-n-propyl-2-hydroxypentyl] cyclopropane-1,1-dicarboxamide, N, N '-Bis [(R) -1-methyl-2,2-diphenyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [(R) -1-methi -2,2-di (4-methylphenyl) -2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [(R) -1-methyl-2,2-di (2 -Methoxyphenyl) -2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [(R) -1-methyl-2,2-di (4-methoxyphenyl) -2-hydroxy Ethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-methyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1- (1-hydroxycyclobutyl) ethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1- (1-hydroxycyclo Pliers ) Ethyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [(R) -1- (1- hydroxycyclohexyl) ethyl] cyclopropane-1,1-dicarboxamide,

N, N′-bis [(R) -1-isopropyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2-methyl-2 -Hydroxypropyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2-ethyl-2-hydroxybutyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2-n-propyl-2-hydroxypentyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2 , 2-Diphenyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2,2-di (4-methylpheny ) -2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclo Propane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclopropane-1,1-dicarboxamide N, N′-bis [(R) -1-isopropyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) — 2-methyl-1- (1-hydroxycyclobutyl) propyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -2-methyl-1- (1-hydroxy) Cyclopentyl) propyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [(R)-2-methyl-1- (1-hydroxycyclohexyl) propyl] cyclopropane-1,1-dicarboxamide,

N, N′-bis [(R) -1-isobutyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2-methyl-2 -Hydroxypropyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2-ethyl-2-hydroxybutyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2-n-propyl-2-hydroxypentyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2 , 2-Diphenyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2,2-di (4-methylphenyl) -2-hi Roxyethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclopropane-1,1 -Dicarboxamide, N, N'-bis [(R) -1-isobutyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N ' -Bis [(R) -1-isobutyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -3-methyl-1 -(1-Hydroxycyclobutyl) butyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -3-methyl-1- (1-hydroxycyclopentyl) butyl Le] cyclopropane-1,1-dicarboxamide, N, N'-bis [(R)-3-methyl-1- (1-hydroxycyclohexyl) butyl] cyclopropane-1,1-dicarboxamide,

N, N′-bis [(R) -1-tert-butyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2 -Methyl-2-hydroxypropyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2-ethyl-2-hydroxybutyl] cyclopropane-1,1 -Dicarboxamide, N, N'-bis [(R) -1-tert-butyl-2-n-propyl-2-hydroxypentyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [( R) -1-tert-butyl-2,2-diphenyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2, -Di (4-methylphenyl) -2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [(R) -1-tert-butyl-2,2-di (2-methoxy) Phenyl) -2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2,2-di (4-methoxyphenyl) -2-hydroxy Ethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclopropane-1,1-di Carboxamide, N, N′-bis [(R) -2,2-dimethyl-1- (1-hydroxycyclobutyl) propyl] cyclopropane-1,1-dicarboxamide, N, N′-bi [(R) -2,2-dimethyl-1- (1-hydroxycyclopentyl) propyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -2,2-dimethyl-1- (1-hydroxycyclohexyl) propyl] cyclopropane-1,1-dicarboxamide,

N, N′-bis [(R) -1-phenyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2-methyl-2 -Hydroxypropyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2-ethyl-2-hydroxybutyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2-n-propyl-2-hydroxypentyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2 , 2-Diphenyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2,2-di (4-methylphenyl) -2-hydroxy ethyl Cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclopropane-1,1-di Carboxamide, N, N′-bis [(R) -1-phenyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-1- ( 1-hydroxycyclobutyl) methyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [R] -1-phenyl-1- (1-hydroxycyclopentyl) methyl] cyclopropane 1,1-dicarboxamide, N, N'-bis [(R) -1-phenyl-1- (1-hydroxycyclohexyl) methyl] cyclopropane-1,1-dicarboxamide,

N, N′-bis [(R) -1-benzyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2-methyl-2 -Hydroxypropyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2-ethyl-2-hydroxybutyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2-n-propyl-2-hydroxypentyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2 , 2-Diphenyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2,2-di (4-methylphenyl) -2-hydroxy Echi Cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclopropane-1,1- Dicarboxamide, N, N′-bis [(R) -1-benzyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N′- Bis [(R) -1-benzyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -2-phenyl-1- (1-hydroxycyclobutyl) ethyl] cyclopropane-1,1-dicarboxamide, N, N′-bis [(R) -2-phenyl-1- (1-hydroxycyclopentyl) ethyl] cyclopro Down-1,1-dicarboxamide, N, N'-bis [(R)-2-phenyl-1- (1-hydroxycyclohexyl) ethyl] cyclopropane-1,1-dicarboxamide,

N, N′-bis [(R) -1-methyl-2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1,2-dimethyl-2-hydroxypropyl Cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-methyl-2-ethyl-2-hydroxybutyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [ (R) -1-methyl-2-n-propyl-2-hydroxypentyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-methyl-2,2-diphenyl-2 -Hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N'-bis [(R) -1-methyl-2,2-di (4-methylphenyl) -2-hydroxyethyl] cyclobutane-1,1 -Zika Boxamide, N, N′-bis [(R) -1-methyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [ (R) -1-methyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-methyl-2 -Benzyl-2-hydroxy-3-phenylpropyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1- (1-hydroxycyclobutyl) ethyl] cyclobutane-1,1-di Carboxamide, N, N′-bis [(R) -1- (1-hydroxycyclopentyl) ethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1- (1-hydroxy Kurohekishiru) ethyl] cyclobutane-1,1-dicarboxamide,

N, N′-bis [(R) -1-isopropyl-2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2-methyl-2- Hydroxypropyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2-ethyl-2-hydroxybutyl] cyclobutane-1,1-dicarboxamide, N, N′- Bis [(R) -1-isopropyl-2-n-propyl-2-hydroxypentyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2,2-diphenyl -2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2,2-di (4-methylphenyl) -2- Droxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclobutane-1,1-di Carboxamide, N, N′-bis [(R) -1-isopropyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [ (R) -1-isopropyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -2-methyl-1- (1- Hydroxycyclobutyl) propyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -2-methyl-1- (1-hydroxycyclopentyl) propyl Propyl] cyclobutane-1,1-dicarboxamide, N, N'-bis [(R)-2-methyl-1- (1-hydroxycyclohexyl) propyl] cyclobutane-1,1-dicarboxamide,

N, N′-bis [(R) -1-isobutyl-2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2-methyl-2- Hydroxypropyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2-ethyl-2-hydroxybutyl] cyclobutane-1,1-dicarboxamide, N, N′- Bis [(R) -1-isobutyl-2-n-propyl-2-hydroxypentyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2,2-diphenyl -2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2,2-di (4-methylphenyl) -2-hydroxye Lu] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclobutane-1,1-di Carboxamide, N, N′-bis [(R) -1-isobutyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [ (R) -1-isobutyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -3-methyl-1- (1- Hydroxycyclobutyl) butyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -3-methyl-1- (1-hydroxycyclopentyl) butyl] cyclobutane- , 1-dicarboxamide, N, N'-bis [(R)-3-methyl-1- (1-hydroxycyclohexyl) butyl] cyclobutane-1,1-dicarboxamide,

N, N′-bis [(R) -1-tert-butyl-2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2- Methyl-2-hydroxypropyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2-ethyl-2-hydroxybutyl] cyclobutane-1,1-dicarboxamide N, N′-bis [(R) -1-tert-butyl-2-n-propyl-2-hydroxypentyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1 -Tert-butyl-2,2-diphenyl-2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N'-bis [(R) -1-tert-butyl-2,2-di (4 Methylphenyl) -2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2,2-di (2-methoxyphenyl) -2-hydroxy Ethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclobutane-1,1 -Dicarboxamide, N, N'-bis [(R) -1-tert-butyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclobutane-1,1-dicarboxamide, N, N'-bis [ (R) -2,2-dimethyl-1- (1-hydroxycyclobutyl) propyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -2,2- Methyl-1- (1-hydroxycyclopentyl) propyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -2,2-dimethyl-1- (1-hydroxycyclohexyl) propyl] cyclobutane- 1,1-dicarboxamide,

N, N′-bis [(R) -1-phenyl-2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2-methyl-2- Hydroxypropyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2-ethyl-2-hydroxybutyl] cyclobutane-1,1-dicarboxamide, N, N′- Bis [(R) -1-phenyl-2-n-propyl-2-hydroxypentyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2,2-diphenyl -2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2,2-di (4-methylphenyl) -2-hydroxyethyl] cyclobut 1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R ) -1-phenyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-1- (1-hydroxycyclo) Butyl) methyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [R] -1-phenyl-1- (1-hydroxycyclopentyl) methyl] cyclopropane-1,1-dicarboxyl Bromide, N, N'-bis [(R) -1-phenyl-1- (1-hydroxycyclohexyl) methyl] cyclobutane-1,1-dicarboxamide,

N, N′-bis [(R) -1-benzyl-2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2-methyl-2- Hydroxypropyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2-ethyl-2-hydroxybutyl] cyclobutane-1,1-dicarboxamide, N, N′- Bis [(R) -1-benzyl-2-n-propyl-2-hydroxypentyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2,2-diphenyl -2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2,2-di (4-methylphenyl) -2-hydroxyethyl] cyclo Tan-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R ) -1-Benzyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -2-phenyl-1- (1-hydroxycyclo) Butyl) ethyl] cyclobutane-1,1-dicarboxamide, N, N′-bis [(R) -2-phenyl-1- (1-hydroxycyclopentyl) ethyl] cyclobutane-1,1-dicarbox Samido, N, N'-bis [(R)-2-phenyl-1- (1-hydroxycyclohexyl) ethyl] cyclobutane-1,1-dicarboxamide,

N, N′-bis [(R) -1-methyl-2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1,2-dimethyl-2-hydroxy Propyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-methyl-2-ethyl-2-hydroxybutyl] cyclopentane-1,1-dicarboxamide, N, N ′ -Bis [(R) -1-methyl-2-n-propyl-2-hydroxypentyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-methyl-2,2 -Diphenyl-2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N'-bis [(R) -1-methyl-2,2-di (4-methylphenyl) -2-hydroxyethyl] Cyclopentane , 1-dicarboxamide, N, N′-bis [(R) -1-methyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-methyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-methyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1- (1-hydroxycyclobutyl) ethyl] Cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1- (1-hydroxycyclopentyl) ethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R ) 1- (1-hydroxycyclohexyl) ethyl] cyclopentane-1,1-dicarboxamide,

N, N′-bis [(R) -1-isopropyl-2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2-methyl-2 -Hydroxypropyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2-ethyl-2-hydroxybutyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2-n-propyl-2-hydroxypentyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2 , 2-Diphenyl-2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2,2-di (4-methylpheny ) -2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclo Pentane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclopentane-1,1-dicarboxamide N, N'-bis [(R) -1-isopropyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclopentane-1,1-dicarboxamide, N, N'-bis [(R)- 2-methyl-1- (1-hydroxycyclobutyl) propyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -2-methyl-1- (1-hydroxy) Cyclopentyl) propyl] cyclobutane-1,1-dicarboxamide, N, N'-bis [(R)-2-methyl-1- (1-hydroxycyclohexyl) propyl] cyclopentane-1,1-dicarboxamide,

N, N′-bis [(R) -1-isobutyl-2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2-methyl-2 -Hydroxypropyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2-ethyl-2-hydroxybutyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2-n-propyl-2-hydroxypentyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2 , 2-Diphenyl-2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2,2-di (4-methylphenyl) -2-hi Roxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclopentane-1,1 -Dicarboxamide, N, N'-bis [(R) -1-isobutyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N ' -Bis [(R) -1-isobutyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -3-methyl-1 -(1-hydroxycyclobutyl) butyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -3-methyl-1- (1-hydroxycyclopentyl) bu Le] cyclopentane-1,1-dicarboxamide, N, N'-bis [(R)-3-methyl-1- (1-hydroxycyclohexyl) butyl] cyclopentane-1,1-dicarboxamide,

N, N′-bis [(R) -1-tert-butyl-2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2 -Methyl-2-hydroxypropyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2-ethyl-2-hydroxybutyl] cyclopentane-1,1 -Dicarboxamide, N, N'-bis [(R) -1-tert-butyl-2-n-propyl-2-hydroxypentyl] cyclopentane-1,1-dicarboxamide, N, N'-bis [( R) -1-tert-butyl-2,2-diphenyl-2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2, -Di (4-methylphenyl) -2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N'-bis [(R) -1-tert-butyl-2,2-di (2-methoxy) Phenyl) -2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2,2-di (4-methoxyphenyl) -2-hydroxy Ethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclopentane-1,1-di Carboxamide, N, N′-bis [(R) -2,2-dimethyl-1- (1-hydroxycyclobutyl) propyl] cyclopentane-1,1-dicarboxamide, N, N′-bi [(R) -2,2-dimethyl-1- (1-hydroxycyclopentyl) propyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -2,2-dimethyl-1- (1-hydroxycyclohexyl) propyl] cyclopentane-1,1-dicarboxamide,

N, N′-bis [(R) -1-phenyl-2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2-methyl-2 -Hydroxypropyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2-ethyl-2-hydroxybutyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2-n-propyl-2-hydroxypentyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2 , 2-Diphenyl-2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2,2-di (4-methylphenyl) -2-hydroxy ethyl Cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclopentane-1,1-di Carboxamide, N, N′-bis [(R) -1-phenyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-1- ( 1-hydroxycyclobutyl) methyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [R] -1-phenyl-1- (1-hydroxycyclopentyl) methyl] cyclopentane 1,1-dicarboxamide, N, N'-bis [(R) -1-phenyl-1- (1-hydroxycyclohexyl) methyl] cyclopentane-1,1-dicarboxamide,

N, N′-bis [(R) -1-benzyl-2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2-methyl-2 -Hydroxypropyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2-ethyl-2-hydroxybutyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2-n-propyl-2-hydroxypentyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2 , 2-Diphenyl-2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2,2-di (4-methylphenyl) -2-hydroxy Echi Cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclopentane-1,1- Dicarboxamide, N, N′-bis [(R) -1-benzyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′- Bis [(R) -1-benzyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -2-phenyl-1- (1-Hydroxycyclobutyl) ethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -2-phenyl-1- (1-hydroxycyclopentyl) ethyl] cyclopent Down-1,1-dicarboxamide, N, N'-bis [(R)-2-phenyl-1- (1-hydroxycyclohexyl) ethyl] cyclopentane-1,1-dicarboxamide,

N, N′-bis [(R) -1-methyl-2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1,2-dimethyl-2-hydroxypropyl Cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-methyl-2-ethyl-2-hydroxybutyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [ (R) -1-methyl-2-n-propyl-2-hydroxypentyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-methyl-2,2-diphenyl-2 -Hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R) -1-methyl-2,2-di (4-methylphenyl) -2-hydroxyethyl] cyclohexane- , 1-dicarboxamide, N, N′-bis [(R) -1-methyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N '-Bis [(R) -1-methyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R) -1 -Methyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R) -1- (1-hydroxycyclobutyl) ethyl] cyclohexane-1 , 1-dicarboxamide, N, N′-bis [(R) -1- (1-hydroxycyclopentyl) ethyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) 1- (1-hydroxycyclohexyl) ethyl] cyclohexane-1,1-dicarboxamide,

N, N′-bis [(R) -1-isopropyl-2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2-methyl-2- Hydroxypropyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2-ethyl-2-hydroxybutyl] cyclohexane-1,1-dicarboxamide, N, N′- Bis [(R) -1-isopropyl-2-n-propyl-2-hydroxypentyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2,2-diphenyl -2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2,2-di (4-methylpheny ) -2-Hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclohexane 1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-isopropyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -2-methyl- 1- (1-hydroxycyclobutyl) propyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -2-methyl-1- (1-hydroxy Cyclopentyl) propyl] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R)-2-methyl-1- (1-hydroxycyclohexyl) propyl] cyclohexane-1,1-dicarboxamide,

N, N′-bis [(R) -1-isobutyl-2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2-methyl-2 -Hydroxypropyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2-ethyl-2-hydroxybutyl] cyclohexane-1,1-dicarboxamide, N, N ′ -Bis [(R) -1-isobutyl-2-n-propyl-2-hydroxypentyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2,2- Diphenyl-2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2,2-di (4-methylphenyl) -2-hi Roxyethyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-isobutyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclohexane-1,1-di Carboxamide, N, N′-bis [(R) -1-isobutyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [ (R) -1-isobutyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -3-methyl-1- (1- Hydroxycyclobutyl) butyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -3-methyl-1- (1-hydroxycyclopentyl) bu Le] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R)-3-methyl-1- (1-hydroxycyclohexyl) butyl] cyclohexane-1,1-dicarboxamide,

N, N'-bis [(R) -1-tert-butyl-2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R) -1-tert-butyl-2- Methyl-2-hydroxypropyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2-ethyl-2-hydroxybutyl] cyclohexane-1,1-dicarboxamide N, N′-bis [(R) -1-tert-butyl-2-n-propyl-2-hydroxypentyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1 -Tert-butyl-2,2-diphenyl-2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R) -1-tert-butyl-2, -Di (4-methylphenyl) -2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R) -1-tert-butyl-2,2-di (2-methoxyphenyl) ) -2-Hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] Cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-tert-butyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -2,2-dimethyl-1- (1-hydroxycyclobutyl) propyl] cyclohexane-1,1-dicarboxamide, N, N′-bi [(R) -2,2-dimethyl-1- (1-hydroxycyclopentyl) propyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -2,2-dimethyl-1- ( 1-hydroxycyclohexyl) propyl] cyclohexane-1,1-dicarboxamide,

N, N'-bis [(R) -1-phenyl-2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R) -1-phenyl-2-methyl-2- Hydroxypropyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2-ethyl-2-hydroxybutyl] cyclohexane-1,1-dicarboxamide, N, N′- Bis [(R) -1-phenyl-2-n-propyl-2-hydroxypentyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2,2-diphenyl -2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2,2-di (4-methylphenyl) -2-hydroxyethyl Cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R ) -1-phenyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-phenyl-1- (1-hydroxycyclo) Butyl) methyl] cyclopentane-1,1-dicarboxamide, N, N′-bis [R] -1-phenyl-1- (1-hydroxycyclopentyl) methyl] cyclohexane 1,1-dicarboxamide, N, N'-bis [(R) -1-phenyl-1- (1-hydroxycyclohexyl) methyl] cyclohexane-1,1-dicarboxamide,

N, N'-bis [(R) -1-benzyl-2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R) -1-benzyl-2-methyl-2- Hydroxypropyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2-ethyl-2-hydroxybutyl] cyclohexane-1,1-dicarboxamide, N, N′- Bis [(R) -1-benzyl-2-n-propyl-2-hydroxypentyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2,2-diphenyl -2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2,2-di (4-methylphenyl) -2-hydroxyethyl Cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -1-benzyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclohexane-1,1-dicarboxamide N, N′-bis [(R) -1-benzyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [( R) -1-Benzyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -2-phenyl-1- (1-hydroxy) Cyclobutyl) ethyl] cyclohexane-1,1-dicarboxamide, N, N′-bis [(R) -2-phenyl-1- (1-hydroxycyclopentyl) ethyl] cyclohex 1,1-dicarboxamide, N, N′-bis [(R) -2-phenyl-1- (1-hydroxycyclohexyl) ethyl] cyclohexane-1,1-dicarboxamide, etc. Examples include compounds in which (R) is replaced with (S). These optically active cycloalkylidenebisamide alcohols (3) are novel compounds.

  Next, by reacting the optically active cycloalkylidenebisamide alcohol (3) and the sulfonylating agent in the presence of a basic compound, the optically active cycloalkylidenebisoxazoline compound (hereinafter referred to as the formula (4)) The second step of obtaining an optically active cycloalkylidenebisoxazoline (4) will be described.

  Examples of the basic compound include organic amine compounds such as pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine and triethylamine, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, such as sodium methoxide, Examples include alkali metal alkoxides such as potassium tert-butoxide. These basic compounds may be used alone or in combination of two or more arbitrary compounds. The amount of the basic compound to be used is not particularly limited and may be used in a large excess as a solvent, but is usually about 0.0005 to 5 mol times with respect to the optically active cycloalkylidenebisamide alcohol (3). This amount is the total number of moles when two or more basic compounds are used simultaneously.

  The sulfonylating agent represents at least one compound selected from the group consisting of alkylsulfonyl halides, arylsulfonyl halides, alkylsulfonic anhydrides and arylsulfonic anhydrides.

  Examples of the halogenated alkylsulfonyl include C1-C5 compounds having an alkyl group which may be substituted, such as methanesulfonyl chloride, methanesulfonyl bromide, ethanesulfonyl chloride, ethanesulfonyl bromide, and the like. Examples of the arylsulfonyl include compounds having 6 to 10 carbon atoms having an aryl group which may be substituted, such as benzenesulfonyl chloride, benzenesulfonyl bromide, paratoluenesulfonyl chloride, paratoluenesulfonyl bromide and the like. Examples of the alkyl sulfonic acid anhydride include compounds having 2 to 10 carbon atoms having an alkyl group which may be substituted, such as methane sulfonic acid anhydride, ethane sulfonic acid anhydride, and trifluoromethane sulfonic acid anhydride. Examples of the arylsulfonic acid anhydride include compounds having 12 to 20 carbon atoms having an aryl group which may be substituted, such as benzenesulfonic acid anhydride and paratoluenesulfonic acid anhydride. Of these sulfonylating agents, methanesulfonyl chloride or paratoluenesulfonyl chloride is preferably used.

  The usage-amount of a sulfonylating agent is about 1-5 mol times normally with respect to optically active cycloalkylidene bisamide alcohol (3).

  Such a reaction is usually carried out in the presence of a solvent. Examples of the solvent include, but are not limited to, aromatic hydrocarbon solvents such as toluene and xylene, halogenated hydrocarbon solvents such as chlorobenzene, dichloromethane and dichloroethane, ether solvents such as tetrahydrofuran and tert-butyl methyl ether, etc. A mixed solvent is mentioned. The amount used is not particularly limited, but is usually 2 to 200 times by weight with respect to the optically active cycloalkylidenebisamide alcohol (3).

  The reaction temperature is usually in the range of -20 to 150 ° C, preferably about 0 to 100 ° C.

  After completion of the reaction, for example, the obtained reaction solution is concentrated to obtain optically active cycloalkylidenebisoxazoline (4). The obtained optically active cycloalkylidenebisoxazoline (4) can be purified by conventional methods such as column chromatography and recrystallization.

The configuration of the asymmetric center indicated by * in the optically active cycloalkylidene bisoxazoline (4) thus obtained is the same as that of the optically active cycloalkylidene bisamide alcohol (3) used.

  Examples of the optically active cycloalkylidenebisoxazoline (4) include 1,1-bis [2-[(4R) -methyloxazoline]] cyclopropane, 1,1-bis [2-[(4R) -methyl- 5,5-dimethyloxazoline]] cyclopropane, 1,1-bis [2-[(4R) -methyl-5,5-diethyloxazoline]] cyclopropane, 1,1-bis [2-[(4R)- Methyl-5,5-di-n-propyloxazoline]] cyclopropane, 1,1-bis [(4R) -methyl-5,5-diphenyloxazoline]] cyclopropane, 1,1-bis [2-[( 4R) -methyl-5,5-di (4-methylphenyl) oxazoline]] cyclopropane, 1,1-bis [2-[(4R) -methyl-5,5-di (2-methoxyphenyl) oxy] Zoline]] cyclopropane, 1,1-bis [2-[(4R) -methyl-5,5-di (2-methoxyphenyl) oxazoline]] cyclopropane, 1,1-bis [2-[(4R) -Methyl-5,5-di (4-methoxyphenyl) oxazoline]] cyclopropane, 1,1-bis [2-[(4R) -methyl-5,5-dibenzyloxazoline]] cyclopropane, 1,1 -Bis [2- [spiro [(4R) -methyloxazoline-5,1'-cyclobutane]]] cyclopropane, 1,1-bis [2- [spiro [(4R) -methyloxazoline-5,1'- Cyclopentane]]] cyclopropane, 1,1-bis [2- [spiro [(4R) -methyloxazoline-5,1′-cyclohexane]]] cyclopropane,

1,1-bis [2-[(4R) -isopropyloxazoline]] cyclopropane, 1,1-bis [2-[(4R) -isopropyl-5,5-dimethyloxazoline]] cyclopropane, 1,1- Bis [2-[(4R) -isopropyl-5,5-diethyloxazoline]] cyclopropane, 1,1-bis [2-[(4R) -isopropyl-5,5-di-n-propyloxazoline]] cyclo Propane, 1,1-bis [(4R) -isopropyl-5,5-diphenyloxazoline]] cyclopropane, 1,1-bis [2-[(4R) -isopropyl-5,5-di (4-methylphenyl) ) Oxazoline]] cyclopropane, 1,1-bis [2-[(4R) -isopropyl-5,5-di (2-methoxyphenyl) oxazoline]] cyclopropane, 1-bis [2-[(4R) -isopropyl-5,5-di (2-methoxyphenyl) oxazoline]] cyclopropane, 1,1-bis [2-[(4R) -isopropyl-5,5-di (4-methoxyphenyl) oxazoline]] cyclopropane, 1,1-bis [2-[(4R) -isopropyl-5,5-dibenzyloxazoline]] cyclopropane, 1,1-bis [2- [spiro [ (4R) -isopropyloxazoline-5,1′-cyclobutane]]] cyclopropane, 1,1-bis [2- [spiro [(4R) -isopropyloxazoline-5,1′-cyclopentane]]] cyclopropane, 1,1-bis [2- [spiro [(4R) -isopropyloxazoline-5,1′-cyclohexane]]] cyclopropane,

1,1-bis [2-[(4R) -tert-butyloxazoline]] cyclopropane, 1,1-bis [2-[(4R) -tert-butyl-5,5-dimethyloxazoline]] cyclopropane, 1,1-bis [2-[(4R) -tert-butyl-5,5-diethyloxazoline]] cyclopropane, 1,1-bis [2-[(4R) -tert-butyl-5,5-di -N-propyloxazoline]] cyclopropane, 1,1-bis [(4R) -tert-butyl-5,5-diphenyloxazoline]] cyclopropane, 1,1-bis [2-[(4R) -tert- Butyl-5,5-di (4-methylphenyl) oxazoline]] cyclopropane, 1,1-bis [2-[(4R) -tert-butyl-5,5-di (2-methoxyphenyl) oxa Phosphorus]] cyclopropane, 1,1-bis [2-[(4R) -tert-butyl-5,5-di (2-methoxyphenyl) oxazoline]] cyclopropane, 1,1-bis [2-[( 4R) -tert-butyl-5,5-di (4-methoxyphenyl) oxazoline]] cyclopropane, 1,1-bis [2-[(4R) -tert-butyl-5,5-dibenzyloxazoline]] Cyclopropane, 1,1-bis [2- [spiro [(4R) -tert-butyloxazoline-5,1′-cyclobutane]]] cyclopropane, 1,1-bis [2- [spiro [(4R)- tert-Butyloxazoline-5,1′-cyclopentane]]] cyclopropane, 1,1-bis [2- [spiro [(4R) -tert-butyloxazoline-5,1′-cyclohex Down]]] cyclopropane,

1,1-bis [2-[(4R) -phenyloxazoline]] cyclopropane, 1,1-bis [2-[(4R) -phenyl-5,5-dimethyloxazoline]] cyclopropane, 1,1- Bis [2-[(4R) -phenyl-5,5-diethyloxazoline]] cyclopropane, 1,1-bis [2-[(4R) -phenyl-5,5-di-n-propyloxazoline]] cyclo Propane, 1,1-bis [(4R) -phenyl-5,5-diphenyloxazoline]] cyclopropane, 1,1-bis [2-[(4R) -phenyl-5,5-di (4-methylphenyl) ) Oxazoline]] cyclopropane, 1,1-bis [2-[(4R) -phenyl-5,5-di (2-methoxyphenyl) oxazoline]] cyclopropane, 1,1-bis [2-[(4R ) − Enyl-5,5-di (2-methoxyphenyl) oxazoline]] cyclopropane, 1,1-bis [2-[(4R) -phenyl-5,5-di (4-methoxyphenyl) oxazoline]] cyclopropane 1,1-bis [2-[(4R) -phenyl-5,5-dibenzyloxazoline]] cyclopropane, 1,1-bis [2- [spiro [(4R) -phenyloxazoline-5,1 ′] -Cyclobutane]]] cyclopropane, 1,1-bis [2- [spiro [(4R) -phenyloxazoline-5,1'-cyclopentane]]] cyclopropane, 1,1-bis [2- [spiro [ (4R) -phenyloxazoline-5,1′-cyclohexane]]] cyclopropane,

1,1-bis [2-[(4R) -benzyloxazoline]] cyclopropane, 1,1-bis [2-[(4R) -benzyl-5,5-dimethyloxazoline]] cyclopropane, 1,1- Bis [2-[(4R) -benzyl-5,5-diethyloxazoline]] cyclopropane, 1,1-bis [2-[(4R) -benzyl-5,5-di-n-propyloxazoline]] cyclo Propane, 1,1-bis [(4R) -benzyl-5,5-diphenyloxazoline]] cyclopropane, 1,1-bis [2-[(4R) -benzyl-5,5-di (4-methylphenyl) ) Oxazoline]] cyclopropane, 1,1-bis [2-[(4R) -benzyl-5,5-di (2-methoxyphenyl) oxazoline]] cyclopropane, 1,1-bis [2-[(4R ) − Nyl-5,5-di (2-methoxyphenyl) oxazoline]] cyclopropane, 1,1-bis [2-[(4R) -benzyl-5,5-di (4-methoxyphenyl) oxazoline]] cyclopropane 1,1-bis [2-[(4R) -benzyl-5,5-dibenzyloxazoline]] cyclopropane, 1,1-bis [2- [spiro [(4R) -benzyloxazoline-5,1 ′] -Cyclobutane]]] cyclopropane, 1,1-bis [2- [spiro [(4R) -benzyloxazoline-5,1'-cyclopentane]]] cyclopropane, 1,1-bis [2- [spiro [ (4R) -benzyloxazoline-5,1′-cyclohexane]]] cyclopropane, and the bridged ring structure at the 2-position of the oxazoline ring of each compound is a cyclobutane ring, Ropentan ring, or compounds which replaced the cyclohexane ring. In addition, examples include compounds such as 1,1-bis [2-[(4S) -methyloxazoline]] cyclopropane in which the configuration (4R) at the 4-position of the oxazoline ring is replaced with (4S).

  Further, in each of the compounds, the two bisoxazoline skeletons have the same configuration, but one of the two bisoxazoline skeletons is (4R) and the other is (4S). Examples also include compounds such as [2-[(4R) -methyloxazoline]]-1- [2-[(4S) -methyloxazoline]] cyclopropane.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.

Example 1
In a 100 mL Schlenk tube purged with nitrogen, 980 mg (7.14 mmol) of (R) -phenylglycinol, 565 mg (3.57 mmol) of dimethyl 1,1-cyclopropanedicarboxylate, 6.8 mg (0.18 mmol) of lithium methoxide, And 40 mL of normal heptane were mixed and stirred at 100 ° C. for 3 hours. As the reaction progressed, the homogeneous solution turned into a white suspension. Thereafter, the reaction solution is cooled to room temperature, and the obtained powder is dried. When dried, N, N′-bis [(R) -1-phenyl-1- (1-hydroxycyclohexyl) methyl] cyclopropane-1, 1.19 g of a white powder of 1-dicarboxamide was obtained.
Yield: 90%. (Based on dimethyl 1,1-cyclopropanedicarboxylate)
¹ NMR (δ: ppm, CD ₃ S (O) CD ₃ solvent, TMS standard)
8.64 (d, J = 8.60 Hz, 2H), 7.32-7.19 (m, 10H), 5.01 (s, 2H), 4.90 (q, 6.73 Hz, 2H), 3.59 (d, 5.2 Hz, 4H), 1.30 (s, 4H)

Example 2
In Example 1, instead of (R) -phenylglycinol, 980 mg (8.36 mmol) of (S) -tert-leucinol, 661 mg (4.18 mmol) of dimethyl 1,1-cyclopropanedicarboxylate, lithium methoxide Was carried out in the same manner as in Example 1 except that 7.9 mg (0.21 mmol) was used. 1.28 g of a white powder of N, N′-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide was obtained.
Yield: 93%. (Based on dimethyl 1,1-cyclopropanedicarboxylate)
¹ NMR (δ: ppm, CD ₃ S (O) CD ₃ solvent, TMS standard)
7.76 (d, J = 9.56 Hz, 2H), 4.58 (t, J = 5.20 Hz, 2H), 3.72 (dt, J = 9.34 Hz, J = 3.50 Hz, 2H) 3.63-3.57 (m, 2H), 3.41-3.34 (m, 2H), 1.29-1.23 (m, 2H), 1.10-1.05 (m, 2H), 0.82 (s, 18H)

Example 3
In Example 2, 507 mg (4.32 mmol) of (S) -tert-leucinol, 342 mg (2.16 mmol) of dimethyl 1,1-cyclopropanedicarboxylate, lithium hydroxide monohydrate instead of lithium methoxide Was carried out in the same manner as in Example 2 except that 4.5 mg (0.11 mmol) was used. 640 mg of white powder of N, N′-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide was obtained.
Yield: 90%. (Based on dimethyl 1,1-cyclopropanedicarboxylate)

Example 4
The same procedure as in Example 2 was performed except that 954 mg (4.18 mmol) of 1,1-cyclohexanedicarboxylic diethyl was used instead of dimethyl 1,1-cyclopropanedicarboxylate used in Example 2. 1.38 g of white powder of N, N′-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclohexane-1,1-dicarboxamide was obtained.
Yield: 89%. (Based on diethyl 1,1-cyclohexanedicarboxylate)
¹ NMR (δ: ppm, CD ₃ S (O) CD solvent, TMS standard)
6.96 (d, J = 9.49 Hz, 2H), 4.48 (t, J = 5.68 Hz, 2H), 3.77-3.70 (m, 2H), 3.59-3.52 (M, 2H), 3.44-3.35 (m, 2H), 1.98-1.95 (m, 4H), 1.45-1.37 (m, 6H), 0.83 (s , 18H)

Comparative Example 1
The reaction was carried out in the same manner as in Example 2 except that lithium methoxide was not used in Example 2. As a result, the reaction did not proceed and the raw materials (S) -tert-leucinol and dimethyl 1,1-cyclopropanedicarboxylate were recovered. .

Example 5
In a nitrogen-substituted 100 mL Schlenk tube, 490 mg (1.49 mmol) of N, N′-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, 664 mg of triethylamine (6 .56 mmol), 18.2 mg (0.15 mmol) of 4-dimethylaminopyridine and 30 mL of dichloromethane were added to make a homogeneous solution, and then cooled to 0 ° C. Next, 345 mg (3.01 mmol) of methanesulfonyl chloride was added dropwise at the same temperature over 10 minutes, and then the temperature was raised to 20 ° C. and further stirred for 12 hours. Thereafter, 20 mL of a saturated aqueous ammonium chloride solution was added and stirred at room temperature for 10 minutes, followed by liquid separation to obtain an organic layer. The organic layer was washed with 20 mL of a saturated aqueous solution of sodium bicarbonate and then separated. The oil layer was dried by adding 5 g of anhydrous sodium sulfate. The reaction solution was filtered, the obtained filtrate was concentrated, and the residue was purified by column chromatography (alumina neutral, hexane: ethyl acetate = 10: 1 (v / v)). 339 mg of white powder of bis [2-[(4S) -tert-butyloxazoline]] cyclopropane was obtained.
Yield: 77%.
¹ NMR (δ: ppm, CD ₃ Cl ₃ solvent, TMS standard)
4.22-4.10 (m, 4H), 3.85-3.79 (m, 2H), 1.52-1.48 (m, 2H), 1.29-1.24 (m, 2H) ), 0.86 (s, 18H)

Example 6
Instead of 490 mg (1.49 mmol) of N, N′-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide used in Example 5, N, N The same procedure as in Example 5 was performed except that 552 mg (1.49 mmol) of '-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclohexane-1,1-dicarboxamide was used. 458 mg of a white powder of 1,1-bis [2-[(4S) -tert-butyloxazoline]] cyclohexane was obtained.
Yield: 92%.
¹ NMR (δ: ppm, CD ₃ Cl ₃ solvent, TMS standard)
4.16-4.02 (m, 4H), 3.90-3.84 (m, 2H), 2.15-2.07 (m, 2H), 1.98-1.91 (m, 2H) ), 1.69-1.66 (m, 2H), 1.55-1.42 (m, 4H) 0.89 (s, 18H)

Example 7-1 <Synthesis of (S) -t-Leucinol>
To a 100 mL Schlenk tube purged with nitrogen, 2.00 g (15.3 mmol) of (S) -tert-leucine and 10 mL of tetrahydrofuran were added, and the internal temperature was adjusted to 10 ° C. To this suspension, 10.5 borane-tetrahydrofuran solution (30.5 mL, 30.5 mmol) was added dropwise over 30 minutes, and then the internal temperature was raised to 65 ° C., followed by stirring at the same temperature for 5 hours. After cooling the reaction mixture to 10 ° C., 4 mL of methanol was added dropwise over 10 minutes. The reaction mixture was concentrated with an evaporator, 20 mL of 4M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. Next, 30 mL of chloroform was added for extraction, and sodium sulfate was added to the resulting organic layer for dehydration. Sodium sulfate was removed by filtration, and chloroform was distilled off by atmospheric distillation. Next, 1.43 g of (S) -tert-leucinol was obtained as a fraction at 70 to 75 ° C. by distillation under reduced pressure (0.3 kPa).
Yield: 80%.

Example 7-2 <Synthesis of N, N'-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide>
The reaction was performed in the same manner as in Example 2 except that 980 mg (8.36 mmol) of (S) -tert-leucinol obtained in Example 7-1 was used. N, N′-bis [(S) -1-tert -Butyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide 1.28 g of a white powder was obtained.
Yield: 93%. (Based on dimethyl 1,1-cyclopropanedicarboxylate)

Example 7-3 <Synthesis of 1,1-bis [2-[(4S) -tert-butyloxazoline]] cyclopropane>
Except for using 490 mg (1.49 mmol) of N, N′-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide obtained in Example 7-2. When carried out in the same manner as in Example 5, 344 mg of 1,1-bis [2-[(4S) -tert-butyloxazoline]] cyclopropane white powder was obtained.
Yield: 79%.

Example 8-1 <Synthesis of (S) -t-Leucinol>
To a 100 mL Schlenk tube purged with nitrogen, 4.00 g (30.5 mmol) of (S) -tert-leucine and 40 mL of tetrahydrofuran were added, and the internal temperature was adjusted to 10 ° C. To this suspension, 1.46 g (61.0 mmol) of lithium borohydride was added over 5 minutes, and the internal temperature was adjusted to 20 ° C. After dropwise addition of 7.44 g (67.1 mmol) of trimethylsilane chloride over 30 minutes, the internal temperature was raised to 65 ° C., and the mixture was stirred at the same temperature for 3 hours. After cooling the reaction mixture to 10 ° C., 4 mL of methanol was added dropwise over 20 minutes. The reaction mixture was concentrated with an evaporator, 40 mL of 4M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. Next, 40 mL of tert-butyl methyl ether was added for extraction, and sodium sulfate was added to the obtained organic layer for dehydration. Sodium sulfate was removed by filtration, and tert-butyl methyl ether was distilled off by atmospheric distillation. Next, 2.96 g of (S) -tert-leucinol was obtained as a fraction at 70 to 75 ° C. by distillation under reduced pressure (0.3 kPa).
Yield: 83%.

Example 8-2 <Synthesis of N, N'-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide>
2.55 g (21.8 mmol) of (S) -tert-leucinol obtained in Example 8-1; 1.72 g (10.9 mmol) of dimethyl 1,1-cyclopropanedicarboxylate; and 20.20 of lithium methoxide. The reaction was carried out in the same manner as in Example 2 except that 7 mg (0.54 mmol) was used. As a result, N, N′-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclopropane-1,1-di 3.39 g of carboxamide white powder was obtained.
Yield: 95%. (Based on dimethyl 1,1-cyclopropanedicarboxylate)

Example 8-3 <Synthesis of 1,1-bis [2-[(4S) -tert-butyloxazoline]] cyclopropane>
2.70 g (8.22 mmol) of N, N′-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide obtained in Example 8-2. 3.66 g (36.2 mmol) of triethylamine, 100 mg (0.82 mmol) of 4-dimethylaminopyridine and 30 mL of tetrahydrofuran were added to make a homogeneous solution, and then cooled to 10 ° C. Next, 2.07 g (18.1 mmol) of methanesulfonyl chloride was added dropwise at the same temperature over 10 minutes, and then the temperature was raised to 60 ° C. and further stirred for 2 hours. Thereafter, 20 mL of a saturated aqueous ammonium chloride solution was added, and the mixture was stirred at room temperature for 10 minutes, followed by liquid separation to obtain an oil layer. The oil layer was washed with 20 mL of a saturated aqueous sodium hydrogen carbonate solution and then separated to obtain an organic layer. The organic layer was dried by adding 5 g of anhydrous sodium sulfate. The reaction solution was filtered, the obtained filtrate was concentrated, and the residue was purified by column chromatography (alumina neutral, hexane: ethyl acetate = 10: 1 (v / v)). 1.85 g of white powder of bis [2-[(4S) -tert-butyloxazoline]] cyclopropane was obtained.
Yield: 77%.

Reference Example To a nitrogen-substituted 50 mL Schlenk tube, 6.47 mg (0.025 mmol) of copper (I) toluene complex of trifluoromethanesulfonate, 1,1-bis [2-[(4S) -tert-butyloxazoline]] cyclopropane After adding 8.00 mg (0.027 mmol) and 5 mL of dichloroethane, the mixture was stirred at room temperature for 10 minutes to obtain an asymmetric copper complex solution. Thereafter, 8.81 g (50 mmol) of isobutenylmethylbenzyl ether was added and the internal temperature was adjusted to 0 ° C., and then 10 ml of a dichloroethane solution containing 2.85 g (25 mmol) of ethyl diazoacetate was added dropwise over 2 hours. The mixture was stirred and reacted at the same temperature for 30 minutes to obtain a solution containing ethyl 3,3-dimethyl-2- (benzyloxymethyl) cyclopropanecarboxylate.
Yield: 82% (based on ethyl diazoacetate)
Trans isomer / cis isomer ratio: 94/6
(Here, the trans isomer refers to the one in which the ester group at the 1st position and the benzyloxymethyl group at the 2nd position are opposite to the cyclopropane ring plane, and the cis isomer refers to the plane of the cyclopropane ring On the other hand, it means that the ester group at the 1-position and the benzyloxymethyl group at the 2-position are on the same side.)

1 g of the oily substance obtained by concentrating the reaction solution was separated, 4 ml of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at an internal temperature of 100 ° C. for 2 hours, neutralized with 1N hydrochloric acid, extracted with hexane, Concentration operation was performed to obtain 3,3-dimethyl-2-benzyloxymethylcyclopropanecarboxylic acid.
Optical purity: trans isomer 97% e.e. e. (+ Form), cis form 11% e.e. e. (+ Body)

Claims (11)

In the presence of a lithium compound, the formula (1)

(In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms, an optionally substituted aralkyl group, an optionally substituted phenyl group or a hydrogen atom, and R ² represents an alkyl group having 1 to 6 carbon atoms. Represents an optionally substituted aralkyl group or an optionally substituted phenyl group, and when R ¹ represents an alkyl group having 1 to 6 carbon atoms, two R ¹ bonded to the same carbon atom; May be bonded to form a ring together with the bonded carbon atoms. * Represents an asymmetric center.)
An optically active amino alcohol compound represented by formula (2):

(In the formula, ^{R 3} .n it represents an alkyl group having 1 to 3 carbon atoms is an integer of 0 to 3.)
Is reacted with a cycloalkylidenemalonic acid diester compound represented by formula (3):

(Wherein R ¹ , R ² , n and * represent the same meaning as described above.)
A first step of obtaining an optically active cycloalkylidenebisamide alcohol compound represented by:
And by reacting the optically active cycloalkylidenebisamide alcohol compound with a sulfonylating agent in the presence of a basic compound,

(Wherein R ¹ , R ² , n and * represent the same meaning as described above.)
A second step of obtaining an optically active cycloalkylidenebisoxazoline compound represented by:
A process for producing an optically active cycloalkylidenebisoxazoline compound comprising: The process according to claim 1, wherein the sulfonylating agent is paratoluenesulfonyl chloride or methanesulfonyl chloride. In the presence of a lithium compound, the optically active amino alcohol compound represented by the formula (1) and the cycloalkylidene malonic acid diester compound represented by the formula (2) are reacted to form the optically active cyclohexane represented by the formula (3). A method for producing an alkylidene bisamide alcohol compound. The production method according to claim 1 or 3, wherein the lithium compound is at least one lithium compound selected from the group consisting of lithium hydroxide, lithium alkoxide, and lithium halide. The production method according to claim 4, wherein the lithium alkoxide is lithium methoxide or lithium ethoxide. The production method according to claim 4, wherein the lithium halide is lithium chloride. By-product formula (5)

(Wherein R ³ represents the same meaning as described above.)
The production method according to claim 1 or 3, wherein the reaction is carried out while removing the alcohol represented by formula (1). The production method according to claim 1, wherein the group represented by R ¹ is a hydrogen atom. As an optically active amino alcohol compound represented by the formula (1), a compound represented by the formula (6)

(In the formula, R ² and * represent the same meaning as described above, and R ⁴ represents an alkyl group having 1 to ⁴ carbon atoms or a hydrogen atom.)
The manufacturing method of Claim 8 using the optically active amino alcohol compound obtained by reaction of the optically active amino acid shown by these, or its ester, and a borohydride compound. An optically active cycloalkylidenebisamide alcohol compound represented by the formula (3): The compound according to claim 10, wherein the group represented by R ¹ is a hydrogen atom.