KR20060136404A - Method for producing optically active cycloalkylidene bisoxazoline compound and intermediate thereof - Google Patents

Abstract

The present invention provides an optically active cycloalkylidenebisamide alcohol compound represented by the formula (3), a method for producing the same, and a method for producing the optically active cycloalkylidenebisoxazoline compound represented by the formula (4) using the same.

<Formula 3>

Wherein R ¹ represents an alkyl group of C 1-6, a phenyl group which may be substituted, an aralkyl group which may be substituted, or a hydrogen atom, or two R ¹ bonded to the same carbon atom to which they are bonded A ring is formed together with an atom, R ² represents an alkyl group of C 1-6, an aralkyl group which may be substituted, or a phenyl group which may be substituted, and * represents a subtitle center.

<Formula 4>

In formula, R <^1> , R <^2> , n and * are as above-mentioned.

Optical activity, cycloalkylidenebisamide alcohol compound, cycloalkylidenebisoxazoline compound

Description

METHOD FOR PRODUCING OPTICALLY ACTIVE CYCLOALKYLIDENE BISOXAZOLINE COMPOUND AND INTERMEDIATE THEREOF}

The present invention relates to a method for producing an optically active cycloalkylidenebisoxazoline compound, which is an important compound as a ligand for a subsidiary synthesis catalyst.

The optically active cycloalkylidenebisoxazoline compound is known as a component of, for example, a copper bisoxazoline catalyst for synthesizing intermediates such as pesticides such as synthetic pyrethroid insecticides and pharmaceuticals, and such optical activity As a manufacturing method of a phosphorus cycloalkylidene bisoxazoline compound, the 2, 2-methylene bisoxazoline compound obtained by reaction of the corresponding optically active amino alcohol and malonimidate, for example is 1, Methods such as reacting with dihalogenated alkyl such as 2-dibromoethane and the like are known (see, for example, J. Org. Chem., 65, 5875 (2000)). However, his overall yield is not necessarily satisfactory.

[Non-Patent Document 1] J. Org. Chem., 65, 5875 (2000)

According to the present invention, an optically active cycloalkylidenebisoxazoline compound can be efficiently produced.

That is, one aspect of the present invention,

The present invention relates to an optically active cycloalkylidenebisamide alcohol compound represented by the formula (3), and another embodiment of the present invention provides a cycloalkyl represented by the formula (2) in which an optically active aminoalcohol compound represented by the formula (1) is present in the presence of a lithium compound. It relates to a method for producing an optically active cycloalkylidene bisamide alcohol compound of the formula (3) characterized by reacting with a diene malonic acid diester compound,

Another embodiment is an optically active cycloalkylidenebisoxa represented by the formula (4), wherein an optically active cycloalkylidenebisamide alcohol compound of the formula (3) is reacted with a sulfonylating agent in the presence of a basic compound. It relates to a method for producing a sleepy compound.

Wherein R ¹ represents an alkyl group of C 1-6, a phenyl group which may be substituted, an aralkyl group which may be substituted, or a hydrogen atom, or

Two R ¹ bonded to the same carbon atom combine to form a ring with the carbon atom to which they are attached,

R ² represents an alkyl group of C 1-6, a phenyl group which may be substituted, or an aralkyl group which may be substituted, n represents an integer of 0 to 3, and * represents a subtitle center.

Wherein R ¹ , R ² And * are as described above.

In formula, R <^3> represents a C1-3 alkyl group. n represents the integer of 0-3.

In the formula, R ¹ , R ² , n and * are as defined in the formula (3).

Best Mode for Carrying Out the Invention

The optically active aminoalcohol compound (hereinafter abbreviated as optically active aminoalcohol (1)) represented by the formula (1) will be described.

In the optically active aminoalcohol (1), examples of the C1-6 alkyl group represented by R ¹ or R ² include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, Linear or branched C1-6 alkyl groups, such as a tert- butyl group, n-pentyl group, and n-hexyl group, are illustrated.

As a substituted phenyl group represented by R <^1> or R <^2> , For example, Unsubstituted phenyl group; For example, the phenyl group substituted by the above-mentioned C1-6 alkyl group, such as 3-methylphenyl group and 4-methylphenyl group; Phenyl group substituted with C1-6 alkoxy groups (for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy groups), such as 2-methoxyphenyl group and 4-methoxyphenyl group, for example. The phenyl group which may be substituted by 1 or more selected from the group containing C1-6 alkyl groups and C1-6 alkoxy groups, such as these is illustrated.

Examples of the aralkyl group which may be substituted represented by R ¹ or R ² include, for example, a C7-16 aralkyl group which may be substituted (more specifically, for example, a naphthyl group or a phenyl group which may be substituted). C1-6 alkyl group) is exemplified. As a substituent of the C7-16 aralkyl group which may be substituted, the 1 or more substituent chosen from the group containing the C1-6 alkyl group and C1-6 alkoxy group is illustrated, for example. Specific examples of the aralkyl group which may be substituted include, for example, an alkyl group of C1-6 or C1, such as a benzyl group, 4-methylbenzyl group, 4-methoxybenzyl group, 1-naphthylmethyl group and 2-naphthylmethyl group C1-6 alkyl group substituted with a phenyl group which may be substituted with a -6 alkoxy group and C1-6 alkyl group with naphthyl substitution are exemplified.

Examples of the ring formed by bonding two R ¹ 's bonded to the same carbon atom together with the carbon atom to which they are bonded include C3-6 such as cyclopropane ring, cyclobutane ring, cyclopentane ring and cyclohexane ring. Cycloalkanes of are exemplified.

Specific examples of the aminoalcohol (1) which is optically active here include, for example, (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-diethyl Butanol, (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) cyclohexane All,

(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-diethyl Ethanol, (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) cyclobutanol, 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-diethyl Propanol, (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 compounds in which (R) in each compound described above corresponds to (S), and salts such as hydrochloride, sulfate and acetate thereof.

In addition, the manufacturing method of the above-mentioned optically active aminoalcohol (1) is not specifically limited, For example, the optically active amino acid type compound or its ester which are represented by General formula (6) which is easy to obtain (hereinafter, optically active amino acid ( It is possible to use those obtained by a known method using the starting material 6).

In the formula, R ² And * represent the same meaning as described above, and R ⁴ represents an alkyl group or a hydrogen atom of C 1-4.

As a C1-4 alkyl group represented by R < ⁴ >, a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, tert- butyl group, etc. are illustrated, for example. As optically active amino acid ester in optically active amino acid (6), it is (R) -alanine methyl ester, (R)-valine methyl ester, (R)-leucine methyl ester, (R) -tert- leucine, for example. 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 The compound in which the methyl group of the ester part of is substituted by ethyl group, a propyl group, n-butyl group, etc., the compound whose (R) in each said compound corresponds to (S), etc. are illustrated. As amino acids, for example, (R) -alanine, (R) -valine, (R) -leucine, (R) -tert-leucine, (R) -phenylglycine, (R)-(1-naphthyl) glycine , (R)-(2-naphthyl) glycine, (R) -phenylalanine, the compound in which (R) in each said compound corresponds to (S), etc. are illustrated. Moreover, as optically active amino acid (6), salt, such as hydrochloride, sulfate, and acetate of each said compound, is also illustrated.

As a method for producing aminoalcohol (1) using such an optically active amino acid (6) as a starting material, when R ¹ in the general formula (1) is a hydrogen atom, for example, an optically active amino acid (6) and a boron hydride compound Reactions are exemplified (see, eg, Tetrahedron Letters, 33, 5517 (1992), J. Org. Chem., 58, 3568 (1993) and Angew. Chem. Int. Ed. Engl., 28, 218). (1989) et al.

Examples of the boron hydride compound include, for example, a complex of boron hydride such as diborane and borane-tetrahydrofuran complex and a compound having coordination with this; A mixture comprising boron hydride metal and an acid; A mixture comprising a boron hydride metal and a diester sulfate; Boron hydride metal etc. are illustrated.

As an optically active amino acid (6), when using optically active amino acid ester (R <^4> is a C1-C4 alkyl group), it is preferable to use only a borohydride metal as a boron hydride compound. Further, the optically active amino acid (6) as an optically active amino acid complexes of compounds having a fold satellite and borohydride, and it has a borohydride compound When using the (R ⁴ is a hydrogen atom); A mixture comprising a boron hydride metal and an acid; A mixture comprising a boron hydride metal and a diester sulfate; Preference is given to using at least one boron hydride compound selected from the group comprising boron hydride metals.

Examples of the borohydride metal include lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride and the like, but sodium borohydride is preferably used in view of availability. As an acid mixed with a boron hydride metal, For example, inorganic acids, such as a sulfuric acid and hydrochloric acid; For example, Lewis acids, such as boron trifluoride, zinc chloride, aluminum chloride, titanium tetrachloride, trimethylsilyl chloride, and iodine, etc. are illustrated. As diester sulfate, dimethyl sulfate, diethyl sulfate, etc. are illustrated, for example.

In addition, as the manufacturing method of the amino alcohol (1) in the case where R ¹ is an aralkyl group or a phenyl group which may be substituted with an optionally substituted C1-6 alkyl group, in the formula (1), for example, the R ⁴ in the formula (6) The reaction of the optically active amino acid ester which is an alkyl group of C1-4 with Grignard reagent is illustrated. As the Grignard reagent, for example, Grignard reagent (hereinafter abbreviated as Grignard reagent (7)) represented by the formula (7), and halogen atoms represented by X, for example, chlorine atom, bromine atom and iodine atom, etc. This is illustrated.

R ¹ MgX

In the formula, R ¹ represents the same meaning as described above, and X represents a halogen atom.

As Grignard reagent (7), for example, methyl magnesium chloride, ethyl magnesium chloride, n-propyl magnesium chloride, isopropyl magnesium chloride, n-butyl magnesium chloride, isobutyl magnesium chloride, tert-butyl magnesium chloride, n-pentyl Magnesium chloride, n-hexyl magnesium chloride, phenylmagnesium chloride, 3-methylphenylmagnesium chloride, 4-methylphenylmagnesium chloride, 2-methoxyphenylmagnesium chloride, 4-methoxyphenylmagnesium chloride, benzylmagnesium chloride, 4-methylbenzyl magnesium Chloride, 4-methoxybenzylmagnesium chloride, 1-naphthylmethylmagnesium chloride, 2-naphthylmethylmagnesium chloride and compounds in which "chloride" is substituted with "bromide" and "iodide" in the above compounds do. As formula (1), and when the R ¹ represents an alkyl group having 1 to 6 carbon atoms, if the two R ¹ bonded to the same carbon atom to which the desired compound, which forms a ring together with their bonded carbon atom, the Grignard As a reagent, for example, butane-1,4-dimagnesium dichloride, pentane-1,5-dimagnesium dichloride, hexane-1,6-dimagnesium dichloride and "chloride" in each of said compounds are "bromide" and Grignard reagents such as compounds substituted with "iodide" can be used.

In the optically active aminoalcohol (1) obtained in this way, the stereoscopic configuration of the subtitle center represented by * is the same as that of the optically active amino acid (6) used.

In the cycloalkylidene malonic acid diester compound represented by the formula (2) (hereinafter abbreviated as cycloalkylidene malonic acid diester (2)), for example, when n = 0, the cycloalkylidene malonic acid diester (2) is cyclo A propylidene malonic acid diester is shown.

As the cycloalkylidene malonic acid diester (2), for example, cyclopropane-1,1-dicarboxylic acid dimethyl, cyclopropane-1,1-dicarboxylic acid diethyl, cyclobutane-1,1-dicarboxyl Dimethyl acid, cyclobutane-1,1-dicarboxylic acid diethyl, cyclopentane-1,1-dicarboxylic acid dimethyl, cyclopentane-1,1-dicarboxylic acid diethyl, cyclohexane-1,1-dica Dimethyl carboxylate, cyclohexane-1,1-dicarboxylic acid diethyl, etc. are illustrated, and the cycloalkylidene malonic acid diester (2) which has a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, respectively, is illustrated. Any of the methyl ester or ethyl ester exemplified above can be obtained as a commercial item.

An optically active cycloalkylidenebisamide alcohol compound represented by formula (3) by reacting a cycloalkylidene malonic acid diester (2) with an optically active aminoalcohol compound (1) (hereinafter referred to as an optically active cycloalkylidenebisamide alcohol ( The process of obtaining abbreviation 3) is demonstrated.

The reaction of the optically active aminoalcohol (1) and the cycloalkylidene malonic acid diester (2) is usually carried out in the presence of a lithium compound.

The amount of the cycloalkylidene malonic acid diester (2) to be used is usually 0.2 to 2 mol, preferably 0.4 to 1 mol with respect to 1 mol of the optically active aminoalcohol compound (1).

As a lithium compound used for this invention, lithium alkoxides, such as lithium hydroxide, for example, lithium methoxide, and lithium ethoxide, for example, lithium halides, such as lithium chloride, etc. are illustrated. The amount of use thereof is not particularly limited and may be a catalytic amount, but is usually about 0.0005 to 0.5 mol per mol of diester (2).

The reaction is usually carried out in the presence of a solvent. As the solvent used, for example, aromatic hydrocarbon solvents such as toluene and xylene, aliphatic hydrocarbon solvents such as hexane, heptane and octane, for example halogenated hydrocarbon solvents such as chlorobenzene, for example tetrahydrofuran and dimeth Ether solvents, such as methoxyethane, etc. are illustrated. These are each used individually or in mixture of 2 or more types, Although the usage-amount is not specifically limited, Usually, it is about 2-500 weight part with respect to 1 weight part of optically active amino alcohol compounds (1).

The reaction temperature is not particularly limited and is usually in the range of about 20 to 150 ° C. Moreover, it is preferable to perform reaction, removing alcohol (5) out of system at the temperature more than the boiling point of the alcohol represented by Formula (5) (hereinafter abbreviated as alcohol (5)) by-product during reaction.

R ³ OH

In formula, R <^3> represents the same meaning as the above.

Although this reaction is normally performed under atmospheric pressure conditions, it can also be performed under pressurized conditions. Moreover, as above-mentioned, it can also carry out under reduced pressure conditions for the purpose of removing alcohol (5).

The present reaction is carried out by mixing a lithium compound, an optically active aminoalcohol (1) and a cycloalkylidene malonic acid diester (2) in the presence of a solvent as necessary, and the mixing order thereof is not particularly limited. For example, it can also carry out by adjusting reaction temperature after mixing these collectively, and adding cycloalkylidene malonic acid diester (2) to the mixture of the lithium compound and optically active amino alcohol (1) which adjusted reaction temperature. You can also carry out.

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 which is not dissolved in water such as toluene and ethyl acetate, and the obtained organic layer is concentrated to thereby provide optically active cycloalkylidene. Bisamide alcohol (3) can be obtained. Moreover, when a product precipitates from a reaction mixture, a target object can be obtained by operation, such as filtration. The obtained optically active cycloalkylidenebisamide alcohol (3) can be further purified by a conventional method such as distillation operation and recrystallization.

In the optically active cycloalkylidenebisamide alcohol (3) obtained in this way, the stereoscopic configuration of the subsidiary center represented by * is the same as that of the optically active aminoalcohol (1).

As such optically active cycloalkylidenebisamide alcohol (3), for example, 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-dicarbox Mead, N, N'-bis [(R) -1-methyl-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-hydroxyethyl] 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-hydroxycyclopentyl) 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-methylphenyl) -2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [(R) -1-iso Propyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclopropane-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-fe Propyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [(R) -2-methyl-1- (1-hydroxycyclobutyl) propyl] cyclopropane-1,1-dicar Copyamide, N, N'-bis [(R) -2-methyl-1- (1-hydroxycyclopentyl) 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-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [(R) -1-iso Butyl-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] cycloprop Plate-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] 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-dica Leboxamide, N, N'-bis [(R) -1-tert-butyl-2,2-diphenyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N ' -Bis [(R) -1-tert-butyl-2,2-di (4-methylphenyl) -2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [( R) -1-tert-butyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [(R) -1-tert-butyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [(R) -1 -tert-butyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclopropane-1,1- Carboxamide, N, N'-bis [(R) -2,2-dimethyl-1- (1-hydroxycyclobutyl) propyl] cyclopropane-1,1-dicarboxamide, N, N'- Bis [(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-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [(R) -1-phenyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [(R) -1-phenyl-2,2-di (4-meth 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-dicar Replica,

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-hydroxyethyl] 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-meth 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-fe -1- (1-hydroxycyclobutyl) ethyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [(R) -2-phenyl-1- (1-hydroxycyclopentyl) Ethyl] cyclopropane-1,1-dicarboxamide, N, N'-bis [(R) -2-phenyl-1- (1-hydroxycyclohexyl) ethyl] cyclopropane-1,1-dicar Replica,

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-dicarboxamide, 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] cyclo Butane-1,1-dicarboxamide, N, N'-bis [(R) -1- (1-hydroxycyclobutyl) ethyl ] Cyclobutane-1,1-dicarboxamide, N, N'-bis [(R) -1- (1-hydroxycyclopentyl) ethyl] cyclobutane-1,1-dicarboxamide, N, N'-bis [(R) -1- (1-hydroxycyclohexyl) 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] cyclo Butane-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-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N'-bis [(R) -1- Isopropyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, 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] cyclo part Tan-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] 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-hydroxyethyl] cyclobutane-1,1-dicarboxamide, N, N'-bis [(R) -1-iso Butyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclobutane-1,1-dicarboxamide, 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-dicarboxami , 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-1,1-dicarboxamide, N, N'-bis [(R) -3-methyl-1- (1-hydr Oxycyclohexyl) 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-dica Leboxamide, 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-hydroxyethyl] 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'- S [(R) -2,2-dimethyl-1- (1-hydroxycyclobutyl) propyl] cyclobutane-1,1-dicarboxamide, N, N'-bis [(R) -2,2 -Dimethyl-1- (1-hydroxycyclopentyl) propyl] cyclobutane-1,1-dicarboxamide, N, N'-bis [(R) -2,2-dimethyl-1- (1-hydrate Oxycyclohexyl) 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] cyclobutane-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-meth 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- Dicarboxamide, 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] cyclobutane-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-meth 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-hydroxycycle) Butyl) ethyl] cyclobutane-1,1-dicarboxamide, N, N'-bis [(R) -2-phenyl-1- (1-hydroxycyclopentyl) ethyl] cyclobutane-1,1- Dicarboxamide, 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-hydroxypropyl] 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-1,1-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] cyclo Pentane-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-methylphenyl) -2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N'-bis [(R) -1-iso Propyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclopentane-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] cyclophene -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-hydroxycyclopentyl) 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-hydroxyethyl] 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-dicarboxami , N, N'-bis [(R) -3-methyl-1- (1-hydroxycyclobutyl) butyl] cyclopentane-1,1-dicarboxamide, N, N'-bis [(R) -3-methyl-1- (1-hydroxycyclopentyl) butyl] cyclopentane-1,1-dicarboxamide, N, N'-bis [(R) -3-methyl-1- (1-hydr Oxycyclohexyl) 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-dica Leboxamide, N, N'-bis [(R) -1-tert-butyl-2,2-diphenyl-2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N.N ' -Bis [(R) -1-tert-butyl-2,2-di (4-methylphenyl) -2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N.N'-bis [( R) -1-tert-butyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N'-bis [(R) -1-tert-butyl-2,2-di (4-methoxyphenyl) -2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N'-bis [(R) -1 -tert-butyl-2-benzyl-2-hydroxy-3-phenylpropyl] cyclopentane-1,1-dicarboxamide, N, N'- S [(R) -2,2-dimethyl-1- (1-hydroxycyclobutyl) propyl] cyclopentane-1,1-dicarboxamide, N, N'-bis [(R) -2,2 -Dimethyl-1- (1-hydroxycyclopentyl) propyl] cyclopentane-1,1-dicarboxamide, N, N'-bis [(R) -2,2-dimethyl-1- (1-hydrate Oxycyclohexyl) 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-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N'-bis [(R) -1-phenyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclopentane-1,1-dicarboxamide, N, N'-bis [(R) -1-phenyl-2,2-di (4-meth 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-hydroxycyclo Butyl) 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-hydroxyethyl] 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-meth 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-hydroxycycle) Butyl) ethyl] cyclopentane-1,1-dicarboxamide, N, N'-bis [(R) -2-phenyl-1- (1-hydroxycyclopentyl) ethyl] cyclopentane-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-1,1-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] cyclo Hexane-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-methylphenyl) -2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R) -1-iso Propyl-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] cyclohex -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-hydroxycyclopentyl) 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-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R) -1-iso Butyl-2,2-di (2-methoxyphenyl) -2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, 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-dicarboxami , N, N'-bis [(R) -3-methyl-1- (1-hydroxycyclobutyl) butyl] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R) -3-methyl-1- (1-hydroxycyclopentyl) butyl] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R) -3-methyl-1- (1-hydr Oxycyclohexyl) 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-dica Leboxamide, N, N'-bis [(R) -1-tert-butyl-2,2-diphenyl-2-hydroxyethyl] cyclohexane-1,1-dicarboxamide, N, N ' -Bis [(R) -1-tert-butyl-2,2-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'- S [(R) -2,2-dimethyl-1- (1-hydroxycyclobutyl) propyl] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R) -2,2 -Dimethyl-1- (1-hydroxycyclopentyl) propyl] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R) -2,2-dimethyl-1- (1-hydrate Oxycyclohexyl) 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-meth 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-meth 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-hydroxycycle) Butyl) ethyl] cyclohexane-1,1-dicarboxamide, N, N'-bis [(R) -2-phenyl-1- (1-hydroxycyclopentyl) ethyl] cyclohexane-1,1- Dicarboxamide, N, N'-bis [(R) -2-phenyl-1- (1-hydroxycyclohexyl) ethyl] cyclohexane-1,1-dicarboxamide and the like The compound etc. which batch (R) substituted by (S) are illustrated.

Subsequently, by reacting the optically active cycloalkylidenebisamide alcohol (3) with a sulfonylating agent in the presence of a basic compound, an optically active cycloalkylidenebisoxazoline compound represented by the formula (4) (hereinafter, optically active The process of obtaining cycloalkylidene bisoxazoline (it shows by 4) is demonstrated.

Examples of the basic compound include organic amine compounds such as pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine and triethylamine, for example alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, for example sodium methoxide. Seed and alkali metal alkoxides, such as potassium-tert-butoxide, etc. are illustrated. These basic compounds may be used alone or in combination of two or more arbitrary compounds. Although the quantity of the basic compound to be used is not specifically limited, Although it can use very much as a solvent, it is about 0.0005-5 mol normally with respect to 1 mol of cycloalkylidene bisamide alcohol (3) optically active normally. This quantity is the number-of-moles of the sum total, when using 2 or more types of basic compounds simultaneously.

The sulfonylating agent represents one or more compounds selected from the group consisting of halogenated alkylsulfonyl, halogenated arylsulfonyl, alkylsulfonic anhydride and arylsulfonic anhydride.

As the halogenated alkylsulfonyl, for example, compounds having 1 to 5 carbon atoms having an alkyl group which may be substituted, such as methanesulfonyl chloride, methanesulfonyl bromide, ethanesulfonyl chloride and ethanesulfonyl bromide, are exemplified. Examples of the polyyl include compounds having an optionally substituted aryl group of C6-10, such as benzenesulfonyl chloride, benzenesulfonyl bromide, paratoluenesulfonyl chloride, and paratoluenesulfonyl bromide. Moreover, as alkylsulfonic anhydride, the compound which has a C2-10 substituted alkyl group, such as methanesulfonic anhydride, an ethanesulfonic anhydride, and a trifluoromethanesulfonic anhydride, is illustrated, for example, As aryl sulfonic anhydride, for example, benzene Examples include compounds having a C12-20 optionally substituted aryl group, such as sulfonic anhydride and paratoluenesulfonic anhydride. Of these sulfonylating agents, preferably methanesulfonyl chloride or paratoluenesulfonyl chloride is used.

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

This reaction is usually carried out in the presence of a solvent. Although it does not specifically limit as a solvent, For example, aromatic hydrocarbon solvents, such as toluene and xylene, For example, halogenated hydrocarbon solvents, such as chlorobenzene, dichloromethane, and dichloroethane, ether solvents, such as tetrahydrofuran and tert- butylmethyl ether, etc. Single or mixed solvent of Although the usage-amount in particular is not specifically limited, Usually, it is 2-200 weight part with respect to 1 weight part of optically active cycloalkylidene bisamide alcohol (3).

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

After completion | finish of reaction, for example, the obtained reaction liquid is concentrated, and optically active cycloalkylidenebisoxazoline (4) is obtained. The obtained optically active cycloalkylidenebisoxazoline (4) can be refine | purified by a conventional method, such as column chromatography and recrystallization, as needed.

In the thus-obtained optically active cycloalkylidenebisoxazoline (4), the stereoscopic configuration of the subsidiary center represented by * is the same as that of the optically active cycloalkylidenebisamide alcohol (3) used.

As such optically active cycloalkylidenebisoxazoline (4), for example, 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) oxazoline]] 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) -methyloxazole -5,1'- cyclopentane]]] cyclopropane, 1,1-bis [2- [spiro [(4R) - methyl oxazoline -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]] cyclopropane, 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, 1,1-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) Isopro Oxazoline -5,1'- cyclopentane]]] cyclopropane, 1,1-bis [2-spiro [(4R) - isopropyl-oxazoline -5,1'- cyclohexane]]] cyclopropane,

1,1-bis [2-[(4R) -tert-butyloxazoline]] cyclopropane, 1,1-bis [2-[(4R) -tert-butyl-5,5-dimethyloxazoline]] cyclo Propane, 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) oxazoline]] 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]]] cyclo Ropan, 1,1-bis [2-spiro [(4R) -tert- butyl oxazoline -5,1'- cyclohexane]]] 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-propyl Oxazoline]] cyclopropane, 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) -phenyl-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'-cyclo Pentane]]] cyclopropane, 1,1-bis [2- [spiro [(4R) -phenyloxazoline-5,1 '-Cyclohexane]]] cyclopropane,

1,1-bis [2-[(4R) -benzyloxazoline]] cyclopropane, 1,1-bis [2 一 [(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-propyl Oxazoline]] cyclopropane, 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) -benzyl-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 a compound in which the cross-linked ring structure of the oxazoline ring of each compound is substituted with a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, etc. are illustrated. Moreover, compounds, such as 1,1-bis [2-[(4S) -methyloxazoline]] cyclopropane, in which the stereoposition (4R) of the 4-position of an oxazoline ring was substituted by (4S) is also illustrated.

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

Example 1

980 mg (7.14 mmol) of (R) -phenylglycinol, 565 mg (3.57 mmol) of dimethyl 1,1-cyclopropanedicarboxylic acid, 6.8 mg (0.18 mmol) of lithium methoxide in a nitrogen-substituted 100 ml Schlenk tube And 40 ml of normal heptane and stirred at 100 ° C. for 3 hours. The reaction proceeded to a white suspension from a homogeneous solution. Thereafter, the reaction mixture was cooled to room temperature, the reaction solution was filtered, and the powder obtained was dried to obtain N, N'-bis [(R) -1-phenyl-1- (1-hydroxycyclohexyl) methyl] cyclopropane-1, 1.19 g of white powder of 1-dicarboxamide were obtained.

Yield: 90% (based on dimethyl 1,1-cyclopropanedicarboxylic acid).

Example 2

In Example 1, 980 mg (8.36 mmol) of (S) -tert-roysinol, 655 mg (4.14 mmol) of 1,1-cyclopropanedicarboxylic acid dimethyl, and 7.9 mg of lithium methoxide (0.21) were used as reaction reagents, respectively. It carried out similarly to Example 1 except having used mmol). 1.28 g of white powders of N, N'-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide were obtained.

Yield: 94% (based on dimethyl 1,1-cyclopropanedicarboxylic acid).

Example 3

In Example 2, 507 mg (4.32 mmol) of (S) -tert-roysinol, 342 mg (2.16 mmol) of 1,1-cyclopropanedicarboxylic acid dimethyl, lithium hydroxide-hydrate 4.5, respectively, as reaction reagents It carried out similarly to Example 2 except having used mg (0.11 mmol). 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-cyclopropanedicarboxylic acid).

Example 4

The same procedure as in Example 2 was repeated except that 945 mg (4.14 mmol) of 1,1-cyclohexanedicarboniethyl was used in place of the dimethyl dimethyl carbonate used in Example 2. 1.38 g of white powders of N, N'-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclohexane-1,1-dicarboxamide were obtained.

Yield: 90% (based on diethyl 1,1-cyclohexanedicarboxylic acid).

Comparative Example 1

Except not using lithium methoxide in Example 3, the reaction was carried out in the same manner as in Example 3, and the reaction did not proceed, so that (S) -tert-roysinol and 1,1-cyclopropanedicarboxylic acid dimethyl as raw materials were used. Was recovered.

Example 5

490 mg (1.49 mmol) of N, N'-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide in a 100 ml Schlenk tube substituted with nitrogen 664 mg (6.56 mmol) of ethylamine, 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. Subsequently, 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 saturated aqueous ammonium chloride solution was added and stirred at room temperature for 10 minutes, followed by separating an oil layer. The oil layer was washed with 20 ml of saturated aqueous sodium hydrogen carbonate solution and then separated, and 5 g of sodium sulfate anhydride was added to the oil layer and dried. The reaction solution was filtrated, and the filtrate obtained was concentrated, and the residue was purified by column chromatography (alumina neutral, hexane: ethyl acetate = 10: 1 (v / v)) to give 1,1-bis [2- 339 mg of white powder of [(4S) -tert-butyloxazoline]] cyclopropane was obtained.

Yield 77%.

Example 6

N, N'-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide 490 mg (1.49 mmol) used in Example 5, N, The procedure was carried out as in Example 5, except that 552 mg (1.49 mmol) of N'-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclohexane-1,1-dicarboxamide was used. It was. 458 mg of white powder of 1,1-bis [2-[(4S) -tert-butyloxazoline]] cyclohexane was obtained.

Yield 92%.

Example 7-1 <Synthesis of (S) -t-roysinol>

2.00 g (15.3 mmol) of (S) -tert-leucine and 10 ml of tetrahydrofuran were added to a 100 ml Schlenk tube substituted with nitrogen, and internal temperature was 10 degreeC. 30.5 mL (30.5 mmol) of 1 M borane-tetrahydrofuran solution was added dropwise to the suspension over 30 minutes, and then the internal temperature was raised to 65 ° C and stirred 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. After the reaction mixture was concentrated by an evaporator, 20 ml of 4 M aqueous sodium hydroxide solution was added and stirred at room temperature for 1 hour. Subsequently, 30 ml of chloroform was added and extracted, and sodium sulfate was added to the obtained organic layer, and it dehydrated. Sodium sulfate was removed by filtration, and chloroform was removed by atmospheric distillation. Subsequently, 1.43 g of (S) -tert-roysinol was obtained by distillation at 70-75 degreeC 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>

N, N'-bis [(S) -1-tert- was obtained in the same manner as in Example 2 except that 980 mg (8.36 mmol) of (S) -tert-roysinol obtained in Example 7-1 was used. 1.28 g of white powders of butyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide were obtained.

Yield: 93% (based on dimethyl 1,1-cyclopropanedicarboxylic acid).

Example 7-3 <Synthesis of 1,1-bis [2-[(4S) -tert-butyloxazoline]] cyclopropane>

490 mg (1.49 mmol) of N, N'-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide obtained in Example 7-2 A white powder of 1,1-bis [2-[(4S) -tert-butyloxazoline] cyclopropane was obtained in the same manner as in Example 5, except that 344 mg was obtained.

Yield: 79%.

Example 8-1 <Synthesis of (S) -t-roysinol>

4.00 g (30.5 mmol) of (S) -tert-leucine and 40 ml of tetrahydrofuran were added to the 100 ml Schlenk tube substituted with nitrogen, and internal temperature was 10 degreeC. 1.46 g (61.0 mmol) of lithium borohydride was added to this suspension over 5 minutes, and internal temperature was 20 degreeC. 7.44 g (67.1 mmol) of trimethylsilane chloride was added dropwise over 30 minutes, and then the internal temperature was raised to 65 ° C and stirred for 3 hours at the same temperature. After cooling the reaction mixture to 10 ° C, 4 ml of methanol was added dropwise over 20 minutes. After the reaction mixture was concentrated by an evaporator, 40 ml of 4 M aqueous sodium hydroxide solution was added and stirred at room temperature for 1 hour. Subsequently, 40 ml of tert-butyl methyl ether was added and extracted, sodium sulfate was added to the obtained organic layer, and it dehydrated. Sodium sulfate was filtered off, and tert-butylmethyl ether was distilled off by atmospheric distillation. Then, 2.96 g of (S) -tert-roysinol was obtained by distillation at 70-75 degreeC 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-roysinol obtained in Example 8-1, 1.72 g (10.9 mmol) of 1,1-cyclopropanedicarboxylic acid dimethyl, and 20.7 mg of lithium methoxide ( 0.54 mmol) was carried out in the same manner as in Example 2 except that N, N'-bis [(S) -1-tert-butyl-2-hydroxyethyl] cyclopropane-1,1-dicarboxamide was used. 3.39 g of white powder were obtained.

Yield: 95% (based on dimethyl 1,1-cyclopropanedicarboxylic acid).

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 ethylamine, 100 mg (0.82 mmol) of 4-dimethylaminopyridine and 30 ml of tetrahydrofuran were added to make a uniform solution, followed by cooling to 10 ° C. Subsequently, 2.07 g (18.1 mmol) of methanesulfonyl chloride was added dropwise over 10 minutes at the same temperature, and then the temperature was raised to 60 ° C and stirred for further 2 hours. Thereafter, 20 ml of saturated aqueous ammonium chloride solution was added and stirred at room temperature for 10 minutes, followed by separating an oil layer. The oil layer was washed with 20 ml of saturated aqueous sodium hydrogen carbonate solution, and then separated to obtain an organic layer. To the organic layer was added 5 g of sodium sulfate anhydride and dried. The reaction solution was filtrated, the filtrate obtained was concentrated, and the residue was purified by column chromatography (alumina neutral, hexane: ethyl acetate-10: 1 (v / v)) to obtain 1,1-bis [2-. 1.85 g of white powder of [(4S) -tert-butyloxazoline]] cyclopropane was obtained.

Yield 77%.

Reference Example

6.47 mg (0.025 mmol) of trifluoromethanesulfonic acid copper (I) toluene complex and 8.00 mg of 1,1-bis [2-[(4S) -tert-butyloxazoline]] cyclopropane in a 50 ml Schlenk tube substituted with nitrogen. (0.027 mmol) and 5 ml of dichloroethane were added, followed by stirring at room temperature for 10 minutes to obtain a solution of the subtitle copper complex. 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 diazotate was added over 2 hours. It was dripped, and also it stirred and reacted at the same temperature for 30 minutes, and obtained the solution containing ethyl 3, 3- dimethyl- 2- (benzyloxymethyl) cyclopropane carboxylate.

Yield: 82% (based on ethyl diazot acetate)

Trans body / sheath ratio: 94/6

(In this case, transmer refers to an ester group at 1 position and a benzyloxymethyl group at 2 positions on the opposite side to the cyclopropane ring plane, and cischer is an ester group at 1 position and a benzyl at 2 positions relative to the cyclopropane ring plane. Oxymethyl groups on the same side)

1 g of the oily substance obtained by concentrating a reaction liquid was fractionated, 4 ml of 2N sodium hydroxide aqueous solution was added, it stirred at internal temperature 100 degreeC for 2 hours, neutralized with 1N hydrochloric acid, extraction with hexane, and The concentration operation was performed to obtain 3,3-dimethyl-2-benzyloxymethylcyclopropanecarboxylic acid.

Optical purity: 97% e.e. (+ body) of trans body, 11% e.e.

According to the present invention, an optically active cycloalkylidenebisoxazoline compound which is an important compound as a ligand of a subsidiary synthesis catalyst can be efficiently produced.

Claims (14)

An optically active cycloalkylidenebisamide alcohol compound represented by the formula (3). <Formula 3>

Wherein R ¹ represents an alkyl group of C 1-6, a phenyl group which may be substituted, an aralkyl group which may be substituted, or a hydrogen atom, or Two R ¹ bonded to the same carbon atom combine to form a ring with the carbon atom to which they are attached, R ² represents an alkyl group of C 1-6, a phenyl group which may be substituted, or an aralkyl group which may be substituted, n represents an integer of 0 to 3, and * represents a subtitle center. The phenyl group, C1-6 alkyl group and C1-, wherein R ¹ may be substituted with one or more selected from the group consisting of C1-6 alkyl group, C1-6 alkyl group and C1-6 alkoxy group. Or represent a C7-16 aralkyl group or hydrogen atom which may be substituted with one or more substituents selected from the group consisting of alkoxy groups of 6, Or two R ¹ bonded to the same carbon atom combine to represent a cycloalkane of C 3-6 together with the carbon atom to which they are bonded; R ² is a phenyl group which may be substituted with one or more selected from the group consisting of an alkyl group of C1-6, an alkyl group of C1-6 and an alkoxy group of C1-6, an alkyl group of C1-6 and an alkoxy group of C1-6 An optically active cycloalkylidenebisamide alcohol compound which is an aralkyl group of C7-16 which may be substituted with one or more substituents selected from. The optically active cycloalkylidenebisamide alcohol compound according to claim 1 or 2, wherein R ² is a phenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group or 4-methoxyphenyl group. An optically active aminoalcohol compound represented by the general formula (1) and a cycloalkylidene malonic acid diester compound represented by the general formula (2) are reacted in the presence of a lithium compound. Method for producing an alkylidene bisamide alcohol compound. <Formula 1>

Wherein R ¹ , R ² And * are as described in claim 1. <Formula 2>

In formula, R <^3> represents a C1-3 alkyl group. n represents the integer of 0-3. The process according to claim 4, wherein the cycloalkylidenebisamide alcohol compound of formula (3) which is optically active is reacted with a sulfonylating agent in the presence of a basic compound to obtain an optically active cycloalkylidenebisoxazoline compound represented by formula (4). The manufacturing method which consists of. <Formula 4>

Wherein R ¹ represents an alkyl group of C 1-6, a phenyl group which may be substituted, an aralkyl group which may be substituted, or a hydrogen atom, or Two R ¹ bonded to the same carbon atom combine to form a ring with the carbon atom to which they are attached, R ² represents an alkyl group of C 1-6, an optionally substituted aralkyl group or a optionally substituted phenyl group, n represents an integer of 0 to 3, and * represents a subtitle center. An optically active cycloalkylidenebisoxazoline compound represented by formula (4), wherein the cycloalkylidenebisamide alcohol compound of formula (3) which is the optically active according to claim 1 is reacted with a sulfonylating agent in the presence of a basic compound. Method of preparation. <Formula 4>

Wherein R ¹ represents an alkyl group of C 1-6, a phenyl group which may be substituted, an aralkyl group which may be substituted, or a hydrogen atom, or Two R ¹ bonded to the same carbon atom combine to form a ring with the carbon atom to which they are attached, R ² represents an alkyl group of C 1-6, an optionally substituted aralkyl group or a optionally substituted phenyl group, n represents an integer of 0 to 3, and * represents a subtitle center. The production method according to claim 2 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 7, wherein the lithium alkoxide is lithium methoxide or lithium ethoxide. The production method according to claim 7, wherein the lithium halide is lithium chloride. The production method according to claim 4 or 5, wherein the reaction is carried out while removing the alcohol represented by the general formula (5). <Formula 5> R ³ OH In formula, R <^3> represents a C1-3 alkyl group. The production method according to claim 2, wherein the optically active aminoalcohol compound of the formula (1) is an optically active aminoalcohol compound obtained by the reaction of an optically active amino acid represented by the formula (6) or an ester thereof with a boron hydride compound. <Formula 6>

In the formula, R ² represents an alkyl group of C 1-6, an aralkyl group which may be substituted, or a phenyl group which may be substituted, R ⁴ represents an alkyl group or a hydrogen atom of C 1-4, and * represents a subtitle center. The production process according to claim 5 or 6, wherein the sulfonylating agent is paratoluenesulfonyl chloride or methanesulfonyl chloride. The phenyl group according to claim 4 or 5, wherein R ¹ is a phenyl group which may be substituted with one or more selected from the group consisting of an alkyl group of C1-6, an alkyl group of C1-6, and an alkoxy group of C1-6, Or represent a C7-16 aralkyl group or hydrogen atom which may be substituted with one or more substituents selected from the group consisting of an alkyl group and a C1-6 alkoxy group, Or two R ¹ bonded to the same carbon atom combine to represent a cycloalkane of C 3-6 together with the carbon atom to which they are bonded; R ² is at least one selected from the group consisting of a C1-6 alkyl group, a C1-6 alkyl group and a C1-6 alkoxy group which may be substituted with at least one selected from the group consisting of The manufacturing method which is a C7-16 aralkyl group which may be substituted by the substituent. The production method according to claim 13, wherein R ² is a phenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group or 4-methoxyphenyl group.