JP3202824B2 - Process for producing optically active hydroxynitrile and novel synthetic intermediate used in this process - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION This invention relates to novel synthetic intermediates used in the preparation process and the preparation of optically active hydroxy nitrile, its purpose is eating pests grass and crops Japanese beetle (Popillia japonica Newman) and Anomala cuprea ( Anomala cuprea Hope) is an optically active hydroxynitrile that is useful as a synthetic pheromone synthetic intermediate or as a synthetic intermediate for various pharmaceuticals, agricultural chemicals, and biologically active substances. An object of the present invention is to provide a production method capable of selectively obtaining a high-purity optically active substance and a novel synthetic intermediate used in the production method.

[0002]

BACKGROUND OF THE INVENTION Hitherto, optically active hydroxynitrile has received attention as a synthetic intermediate for various pharmaceuticals, agricultural chemicals, physiologically active substances and the like. That is, optically active hydroxynitrile can be easily derived into an optically active hydroxycarboxylic acid or an optically active lactone by hydrolysis, and thus is positioned as a synthetic intermediate having extremely wide application. In particular, optically active (R) -4-hydroxy-5-tetradecinonitrile represented by the general formula 25 (Chemical Formula 25), which is one of the optically active (R) -hydroxynitrile, is a turf vermin beetle (Popillia japonica New
man) as one of the sex pheromone synthetic intermediates.
(Pirkle, WH et al, J. Org. Chem., 44 , 2169 (19
79). The (R) -4-hydroxy-5-tetradecinonitrile was used as a turf insect pest (Popillia japonica).
(R) -5- (1-decynyl) oxacyclopentan-2-one represented by the general formula 26, which is one of synthetic intermediates of the sex pheromone of Newman). It is regarded as an important substance (Shuji Senda
et al; Agrical. Biological. Chem., 47 , 2595-2598 (1
983)).

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Further, (R) represented by the general formula 27 (Chemical Formula 27), which is also one of (R) -hydroxynitrile.
-4-Hydroxy-5-dodecinonitrile is (R) -5 represented by the general formula 28 (Chemical Formula 28), which is one of synthetic intermediates of the turf vermin Anomala cuprea Hope.
It is an important substance that can be easily derived into (1-octenyl) oxacyclopentan-2-one (Leal,
WS; Naturwissenschafen, 78 , 521-523 (1991)).

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[0004] Bean beetle (Popillia japonica Newman) is a beetle belonging to the order Scarabaeidae and was originally a pest in Japan. It is called the Japanese beetle and is positioned as a major pest that damages fruit trees, agricultural crops, etc., and its total damage is enormous. In addition, in Japan, the damage to the turf in golf courses has been serious in recent years, and intensive studies have been made on such countermeasures against such damage. On the other hand, Douganebuibu (Anomala cuprea Hope) is also a beetle belonging to the order Scarabaeidae, distributed throughout Japan,
Adult insects damage the leaves of various trees such as legumes, plums, apricots, grapes, chestnuts, and pears in a mesh-like manner, and are a kind of pests that are particularly severely damaged in vineyards.

[0005] Such a beetle (Popillia japonica)
Newman) and Doganebuibu (Anomala cuprea Hope) and other pests have been mainly used for chemical control methods using pesticides and pesticides. In recent years, problems such as residual toxicity, danger to living organisms, environmental protection, and undesired biological activity on crops and soil due to the use of insecticides have been regarded as problems. Control methods using pheromones instead of simple chemical control methods have come to attract attention, and research and development thereof have been actively conducted.

[0006]

2. Description of the Related Art Conventionally, as a method for synthesizing an optically active hydroxynitrile, as shown in the scheme of FIG.
The corresponding racemate (1) is reacted with optically active naphthylethyl isocyanate (2) to give diastereocarbamates (3a) and (3b), and then separated by high performance liquid chromatography (hereinafter abbreviated as HPLC). (Pirkle, WH et al, J. Org. Chem.,
44 , 2169 (1979). Alternatively, as shown in the scheme of FIG. 2, a method of asymmetric reduction of the corresponding ketonitrile using yeast has also been reported (Gopalan, A. et al., Synt.
h. Commun., 21 , 1321 (1991)).

[0007]

However, the above-mentioned method of synthesizing the racemate by reacting it with optically active naphthylethyl isocyanate requires an expensive resolving agent, naphthylethyl isocyanate, and therefore can be used for general purposes. In addition, there is a problem that it is not a production method suitable for industrial production, for example, it is difficult to perform large-scale processing by HPLC fractionation. In addition, in the method of asymmetric reduction using yeast, the productivity is low because the concentration of the substrate during the reaction cannot be increased, and the absolute stereochemistry of one of the optically active hydroxynitrile enantiomers is also required. There was a problem that only the optically active substance in the arrangement could be obtained. Therefore, in view of the above-mentioned circumstances, there has been a demand in the industry to create a production method capable of obtaining both enantiomers of optically active hydroxynitrile simply and in good yield by a method suitable for versatility.

[0008]

According to the present invention, at least optically active (R) -hydroxynitrile and optically active (S) are used.
A carboxylic acid or a carboxylic acid derivative in an organic solvent in the presence of a lipase to act on a mixture containing -hydroxynitrile to preferentially acylate the (R) -optically active form to obtain an optically active (R ) -Cyanoester, and the optically active (R) -cyanoester and the optically active (S) -hydroxynitrile are separated.
A method for producing an optically active hydroxynitrile characterized by obtaining an optically active (R) -hydroxynitrile by hydrolyzing a cyanoester and containing at least an optically active (R) -cyanoester and an optically active (S) -cyanoester. the mixture, by the action of lipase (R) - optically active form preferentially hydrolyzing optically active (R) - and hydroxy nitrile, then the optically active (R) - hydroxy nitrile with optically active (S) - Separating the cyanoester,
Furthermore, the above-mentioned conventional problems are completely eliminated by providing a process for producing optically active hydroxynitrile, which is characterized in that optically active (S) -cyanoester is hydrolyzed to obtain optically active (S) -hydroxynitrile.

[0009]

The construction of the optically active hydroxynitrile according to the present invention and the construction of the novel synthetic intermediate used in this production method will be described below in detail. First, the method for producing the optically active hydroxynitrile according to the present invention will be described in detail. The present invention discloses three methods of producing an optically active hydroxynitrile, a first production method, a second production method, and a third production method. The first process is to use hydroxynitrile which is not optically pure, ie, a compound represented by the general formula 29
In this method, a mixture containing an optically active (R) -hydroxynitrile represented by the formula (1) and an optically active (S) -hydroxynitrile represented by the general formula 30 is used as a starting material.

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Embedded image (Wherein, R ₁ is a group represented by the general formula 31 or the general formula 3)
2 shows a compound represented by the formula (2). * Indicates asymmetric carbon. )

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Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)

This mixture may be any mixture containing optically active (R) -hydroxynitrile and optically active (S) -hydroxynitrile, and is represented by the general formula 33 containing both in equal amounts. Racemic hydroxynitrile can be suitably used.

Embedded image (Where R ₁ is a group represented by the general formula 34 (formula 34) or the general formula 3)
The compound represented by Formula 5 (Formula 35) is shown. * Indicates asymmetric carbon. )

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Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)

Specific examples of the racemic hydroxynitrile include 4-hydroxy-5-tetradecinonitrile,
4-hydroxy-5-tridecinonitrile, 4-hydroxy-5-dodecinonitrile, 4-hydroxy-5-undecinonitrile, 4-hydroxy-5-decinonitrile, 4-hydroxy-5-noninonitrile, 4-hydroxy-5- Tetradecenonitrile, 4-hydroxy-5
-Tridecenonitrile, 4-hydroxy-5-dodecenonitrile, 4-hydroxy-5-undecenonitrile,
4-hydroxy-5-decenonitrile, 4-hydroxy-5-nonenonitrile and the like are exemplified. In particular, general formula 36
By using 4-hydroxy-5-tetradecinonitrile represented by Chemical formula 36 as a starting material, it is possible to synthesize a sex pheromone synthesis intermediate of the turf vermin (Popillia japonica Newman). Similarly, when 4-hydroxy-5-dodecinonitrile represented by the general formula 37 (Formula 37) is used as a starting material, the crop pest Douganebuui ( Anom
ala cuprea Hope) can be synthesized.

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[0012] Such a racemic hydroxynitrile is a substance that can be easily produced. As a specific example, taking an example of the synthesis of 4-hydroxy-5-dodecinonitrile, the compound can be easily synthesized by reacting 3-formylpropiononitrile with 1-octylmagnesium bromide at room temperature ( Pirkle, WHet al, J. O
rg. Chem., 43 , 2091 (1978).

[0013] In the first production method of the present invention, the above-mentioned racemic hydroxamic nitrile ((R) - hydroxy nitrile with (S) - equal mixture of hydroxynitrile) to Li
In the presence of a pase , a carboxylic acid or a carboxylic acid derivative is allowed to act as an acyl group donor in an organic solvent, and a stereoselective acylation reaction is performed. To an optically active (R) -cyanoester represented by the general formula 38.

Embedded image (Where R ₁ is a group represented by the general formula 39 or the general formula 4)
0 (Chemical formula 40), wherein R ₃ has 1 to 1 carbon atoms
12 represents any of an alkyl group, an aralkyl group and a haloalkyl group. * Indicates asymmetric carbon. )

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Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)

Examples of the lipase used in this reaction include lipase derived from pig pancreas, lipase derived from bacteria, lipase derived from yeast, and lipase derived from mold. These enzymes may be purified or crude products, and the form is not particularly limited. Powdered, granular, or dried microbial cells containing the enzyme (treated cells, resting cells) Etc. can be used as appropriate. These enzymes can be used as they are, or they can be used after being immobilized on an immobilization carrier. It is also possible to reuse the enzyme recovered after completion of the reaction.

The organic solvent used in this reaction may be any non-aqueous organic solvent, and specific examples thereof include linear aliphatic hydrocarbons such as n-hexane, n-heptane, n-octane and isooctane, and cyclopentane. , Cycloaliphatic hydrocarbons such as cyclohexane, dichloromethane, trichloromethane, halogen-containing hydrocarbons such as carbon tetrachloride, benzene,
Any non-aqueous solvent that dissolves hydroxynitrile, such as aromatic hydrocarbons such as toluene and xylene, ethers such as diethyl ether, isopropyl ether and n-butyl ether, may be used without limitation.

The carboxylic acid or carboxylic acid derivative used in this reaction may be in a range that can be used as a substrate for lipase , and a carboxylic acid or carboxylic acid derivative having about 2 to 20 carbon atoms can be suitably used. Specifically, carboxylic acids include acetic acid, propionic acid, butyric acid,
Preferred examples include valeric acid, caproic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, lauric acid, myristic acid, and stearic acid. As the carboxylic acid derivative, esters of the above carboxylic acids, particularly enol esters such as vinyl ester and isopropenyl ester are preferably presented. Alternatively, anhydrides of the carboxylic acids can also be exemplified. Examples of the linear carboxylic acid anhydride include anhydrides such as acetic acid, propionic acid, butyric acid, valeric acid, and caproic acid, and examples of the cyclic carboxylic acid anhydride include succinic anhydride. And glutaric anhydride are preferably exemplified.

The mixing ratio of racemic hydroxynitrile and carboxylic acid or carboxylic acid derivative in this reaction is not particularly limited. The reaction temperature of this reaction may be within the activity temperature of the enzyme, and is usually in the range of 0 ° C to 70 ° C, more preferably 15 to 50 ° C.

After completion of the stereoselective acylation reaction, the optically active (R) -cyanoester represented by the general formula 41 (Chemical formula 41) obtained by this reaction is combined with the general formula 42 (Chemical formula 42)
Is separated from the optically active (S) -hydroxynitrile.

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Embedded image (Where R ₁ is a group represented by the general formula 43 (Formula 43) or the general formula 4)
Wherein R ₃ is a compound having 1 to 4 carbon atoms
12 represents any of an alkyl group, an aralkyl group and a haloalkyl group. * Indicates asymmetric carbon. )

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Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)

The separation method is not particularly limited, but is a separation method by extraction using a poorly water-soluble organic solvent or a two-phase solvent composed of a water-insoluble organic solvent and water, a separation method using a column, a separation method by distillation. And the like. The optically active (R) -cyanoester thus obtained is then treated with an alkali such as potassium carbonate to easily obtain the compound of the general formula 45 having the same optical purity.
(R) -hydroxynitrile shown in 5).

Embedded image (Where R ₁ is a group represented by the general formula 46 (Formula 46) or the general formula 4)
7 shows a compound represented by the formula (7). * Indicates asymmetric carbon. )

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Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)

Next, the second method of producing the optically active hydroxynitrile according to the present invention will be described in detail.
In this second production method, an optically pure cyanoester, that is, an optically active (R) -cyanoester represented by the general formula 48 (Chemical Formula 48) and an optically active (S) represented by the general formula 49 (Chemical Formula 49) are used. Mixture containing a cyanoester is used as starting material.

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Embedded image (Where R ₁ is a group represented by the general formula 50 or the general formula 5)
Wherein R ₃ is a compound represented by the formula (1)
12 represents any of an alkyl group, an aralkyl group and a haloalkyl group. * Indicates asymmetric carbon. )

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Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)

The mixture may be any mixture containing an optically active (R) -cyanoester and an optically active (S) -cyanoester. For example, the mixture may be represented by the following general formula 52 in which both are contained in an equal amount. The racemic cyanoester shown can be suitably used.

Embedded image (Where R ₁ is a group represented by the general formula 53 or the general formula 5)
Wherein R ₃ is a compound having 1 to 4 carbon atoms
12 represents any of an alkyl group, an aralkyl group and a haloalkyl group. * Indicates asymmetric carbon. )

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Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)

Specific examples of the racemic cyano ester include 4-acyloxy-5-tetradecinonitrile,
Acyloxy-5-tridecinonitrile, 4-acyloxy-5-dodecinonitrile, 4-acyloxy-5-undecinonitrile, 4-acyloxy-5-decinonitrile,
4-acyloxy-5-nonononitrile, 4-acyloxy-5-tetradecenonitrile, 4-acyloxy-5-tridecenonitrile, 4-acyloxy-5-dodecenonitrile, 4-acyloxy-5-undesenonitrile, 4-
Acyloxy-5-decenonitrile, 4-acyloxy-5
-Nonenonitrile and the like are preferably exemplified. In particular, general formula 5
Using 4-acyloxy-5-tetradecinonitrile represented by Chemical Formula 5 as a starting material, it is possible to synthesize an important optically active substance as a synthetic intermediate of a sex pheromone of a lawn insect, Popillia japonica Newman. Can be. In addition, when 4-acyloxy-5-dodecinonitrile represented by the general formula 56 is used as a starting material, the crop pest Doganebuibu ( Anomala cuprea Hope) can be obtained.
An important optically active compound can be synthesized as an intermediate for the synthesis of

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Such a racemic cyano ester is a substance which can be easily produced by acylating the racemic hydroxy nitrile described in the first production method with a carboxylic anhydride or a carboxylic acid halide.

In this second production method, a lipase is allowed to act on a racemic cyano ester to perform stereoselective hydrolysis, and the (R) -optically active compound is preferentially hydrolyzed to give a compound of the general formula 57 To obtain an optically active (R) -hydroxynitrile.

Embedded image (Where R ₁ is a group represented by the general formula 58 or the general formula 5)
The compound represented by Formula 9 (Formula 59) is shown. * Indicates asymmetric carbon. )

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Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)

The solvent used in this reaction is not particularly limited, whether it is aqueous or non-aqueous. Specific examples include water or a buffer such as a phosphate buffer, n-hexane, n-heptane, n-octane, isooctane. Chain hydrocarbons such as cyclopentane and cyclohexane, halogen-containing hydrocarbons such as dichloromethane, trichloromethane and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether and isopropyl Preferred examples include organic solvents such as ethers such as ether and n-butyl ether, or solvents obtained by saturating the organic solvent with water or a buffer, and two-phase solvents of the organic solvent and water or a buffer.

As the lipase used in this reaction, the same lipase as in the first production method can be suitably used without any particular limitation. Further, the reaction temperature may be within the activity temperature of the enzyme, and is usually used in the range of 0 to 70 ° C, preferably 10 to 40 ° C. After the completion of the stereoselective hydrolysis reaction, a large amount of the solvent described above is added to extract a reaction product. Next, the optically active (R) -hydroxynitrile represented by the general formula 60 (Formula 60) and the optically active (S) -cyanoester represented by the general formula 61 (Formula 61) obtained by this reaction are separated.

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Embedded image (Wherein, R ₁ is a group represented by the general formula 62 or the general formula 6)
Wherein R ₃ is a compound having 1 to ₃ carbon atoms.
12 represents any of an alkyl group, an aralkyl group and a haloalkyl group. * Indicates asymmetric carbon. )

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Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)

As the separation method, the same separation method by extraction, separation method by column, and separation method by distillation as in the first production method can be suitably used without limitation.

The optically active (S) -cyanoester obtained by this reaction can be obtained by converting the (R) -cyanoester into (R) -hydroxynitrile in the first production method, such as calcium carbonate. By hydrolyzing with an alkali, an optically active (S) -hydroxynitrile represented by the general formula 64 can be obtained.

Embedded image (Where R ₁ is a group represented by the general formula 65 or the general formula 6)
The compound represented by Formula 6 (Formula 66) is shown. * Indicates asymmetric carbon. )

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Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)

Next, the third production method of the present invention will be described in detail. In the third production method, as in the first production method, a mixture containing optically active (R) -hydroxynitrile and optically active (S) -hydroxynitrile (for example, racemic hydroxynitrile) is added to an organic solvent in the presence of lipase. A carboxylic acid or a carboxylic acid derivative is allowed to act as an acyl group donor in the reaction, a stereoselective acylation reaction is performed, and the (R) -optically active form is preferentially acylated to give a compound of the general formula 67
Is used as a starting material, and a lipase is allowed to act in the same manner as in the second production method.

Embedded image (Where R ₁ is a group represented by the general formula 68 or the general formula 6)
Wherein R ₃ is a compound represented by the formula:
12 represents any of an alkyl group, an aralkyl group and a haloalkyl group. * Indicates asymmetric carbon. )

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Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)

In this starting material, the optically active (R) -cyanoester produced by the acylation reaction is represented by the general formula 7
Optically active (S) -cyanoester represented by Formula 0 (Formula 70) and optically active (S) represented by Formula 71 (Formula 71)
-Hydroxynitrile is mixed.

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Embedded image (Where R ₁ is a group represented by the general formula 72 (Chemical Formula 72) or the general formula 7)
Wherein R ₃ is a compound represented by the formula:
12 represents any of an alkyl group, an aralkyl group and a haloalkyl group. * Indicates asymmetric carbon. )

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Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)

Using such a mixture as a starting material, the same treatment as in the second production method, that is, the lipase is allowed to act, stereoselective hydrolysis is performed, and the optically active (R) -cyanoester is preferentially hydrolyzed. Decompose to general formula 74
4) to give an optically active (R) -hydroxynitrile, then separating the optically active (R) -hydroxynitrile from the optically active (S) -cyanoester, and further converting this optically active (S) -cyanoester to An alkali treatment is performed to obtain an optically active (S) -hydroxynitrile represented by the general formula 75 (Formula 75), and an optically active (R)-having a high optical purity.
Hydroxynitrile and optically active (S) -hydroxynitrile are obtained.

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Embedded image (Wherein, R ₁ is a group represented by the general formula 76 (formula 76) or the general formula 7)
The compound represented by Formula 7 (Formula 77) is shown. * Indicates asymmetric carbon. )

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Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)

The solvent to be used in this third method, Li
Pase , reaction temperature, and the like can be substantially the same as those in the first and second production methods.

The present invention is not limited to the third production method, and if the first and second production methods are appropriately combined with each other, it becomes possible to obtain optically active hydroxynitrile having higher optical purity.

Next, the novel synthetic intermediate used in the process for producing the optically active hydroxynitrile according to the present invention will be described in detail. Optical activity (R)-represented by the general formula 78 (Chemical Formula 78) used in the first production method of the present invention.
Cyanoester is a novel synthetic intermediate according to the present invention.

Embedded image (Where R ₁ is a group represented by the general formula 79 or the general formula 8)
0 (Chemical Formula 80), wherein R ₃ has 1 to 1 carbon atoms
12 represents any of an alkyl group, an aralkyl group and a haloalkyl group. * Indicates asymmetric carbon. )

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Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)

This intermediate varies depending on the type of the starting material and the substrate used. For example, (R) -4-acetoxy-
5-dodecinonitrile, (R) -4-propionyloxy-5-dodecinonitrile, (R) -4-butanoyloxy-5-dodecinonitrile, (R) -4-succinoyloxy-5-dodecinonitrile, (R)- 4-acetoxy-5-tetradecinonitrile, (R) -4-propionyloxy-5-tetradecinonitrile, (R) -4
-Butanoyloxy-5-tetradecinonitrile,
(R) -4-succinoyloxy-5-tetradecinonitrile and the like are exemplified, but not particularly limited. Such optically active (R) -cyanoesters are commercially available from bean bugs (Pop
illia japonica Newman) and Douganebuoyui ( Anomala
cuprea Hope) is an important intermediate that can be easily derived into optically active hydroxynitrile, which is useful as an intermediate for the synthesis of sex pheromones.

The optical activity (S) represented by the general formula 81 (Chemical Formula 81) used in the second production method of the present invention.
-Cyanoester is a novel synthetic intermediate according to the present invention.

Embedded image (Where R ₁ is a group represented by the general formula 82 (formula 82) or the general formula 8)
Wherein R ₃ is a compound having 1 to ₃ carbon atoms
12 represents any of an alkyl group, an aralkyl group and a haloalkyl group. * Indicates asymmetric carbon. )

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Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)

This intermediate varies depending on the type of the starting material and the substrate to be used. For example, (S) -4-acetoxy-
5-Dodecinonitrile, (S) -4-propionyloxy-5-dodecinonitrile, (S) -4-butanoyloxy-5-dodecinonitrile, (S) -4-succinoyloxy-5-dodecinonitrile, (S)- 4-acetoxy-5-tetradecinonitrile, (S) -4-propionyloxy-5-tetradecinonitrile, (S) -4
-Butanoyloxy-5-tetradecinonitrile,
(S) -4-succinoyloxy-5-tetradecinonitrile and the like are exemplified, but not particularly limited. Such an optically active (S) -cyanoester can be used for bean pods (Pop
illia japonica Newman) and Douganebuoyui ( Anomala
cuprea Hope) is an important intermediate that can be easily derived into optically active hydroxynitrile, which is useful as an intermediate for the synthesis of sex pheromones.

[0038]

The production method of the optically active hydroxynitrile according to the present invention and the novel intermediate in this production method will be described in more detail with reference to examples. The present invention is not limited by the following embodiments.

(Example 1) Isopropyl ether (20 ml), racemic 4-hydroxy-5-dodecinonitrile (1 g), acetic anhydride (2
60 mg), lipase (trade name: Amano PS) (1 g)
Was added and mixed to prepare a suspension. 25 of this suspension
After stirring at 16 ° C. for 16 hours, the reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure, and then the solvent was removed. The obtained oily substance was purified by hexane / ethyl acetate-based silica gel chromatography, and 500 mg of (R) -4-acetoxy-5-dodecinonitrile (85% optical purity) and 520 mg
mg of (S) -4-hydroxy-5-dodecinonitrile (optical purity 75%) was obtained. The obtained (R) -4-acetoxy-5-dodecinonitrile has an absorption wave number (cm ^-1 ) of an infrared absorption spectrum of 2900, 2830 and 221.
0, 1740, 1430, 1370, 1230, 115
0, 1030, and the σ value of the proton magnetic resonance spectrum ( ¹ H-NMR) (400 MHz) analysis was 0.88 (3H, t, J = 7.1 Hz), 1.24 to
1.38 (6H, m), 1.45 to 1.58 (2H,
m), 2.06 to 2.10 (2H, m), 2.08 (3
H, S), 2.19 (2H, td, J = 7.3, 2.0
Hz), 2.52 (2H, t, J = 7.7 Hz), 5.
It was identified from the fact that it was 44-5.47 (1H, m) (see FIGS. 3 and 4). Also, the absorption wave number (cm ^-1 ) of the infrared absorption spectrum of (S) -4-hydroxy-5-dodecinonitrile is 3400, 2900, 283.
0, 2220, 1430, 1330, 1140, 105
0 and the proton magnetic resonance spectrum ( ¹
H-NMR) (400 MHz) has a σ value of 0.88.
(3H, t, J = 7.1 Hz), 1.22-1.39
(6H, m), 1.45 to 1.51 (2H, m), 2.
19 (2H, td, J = 6.8, 2.0 Hz), 2.5
3 (2H, td, J = 7.3, 3.9 Hz), 4.48
４4.53 (1H, m) (see FIGS. 5 and 6). The above optical purity can be determined by a known method (E. Fukusaki et al.) After hydrolyzing each with ethanol / sodium hydroxide, distilling as the corresponding hydroxycarboxylic acid, and deriving the corresponding lactone.
al., Tetrahedron, 47 , 6223, (1991)).
Was determined. Also, the (R) -4- obtained above
Acetoxy-5-dodecinonitrile (85% optical purity)
Was dissolved in methanol, and 1.2 equivalents of potassium carbonate was added thereto, followed by stirring at room temperature for one day to obtain (R) -4-hydroxy-5-dodecinonitrile in a yield of 90%. This (R) -4-hydroxy-5-dodecinonitrile has an absorption wave number (cm ^-1 ) of an infrared absorption spectrum and a proton magnetic resonance spectrum ( ¹ H-NMR) (400
The σ value of the (MHz) analysis was identified because it was similar to that of the (S) -optically active substance (see FIGS. 5 and 6).

Example 2 In a 100 ml Meyer flask, isopropyl ether (20 ml), racemic 4-hydroxy-5-dodecinonitrile (1 g), propionic anhydride (300 mg), lipase (trade name: Amano PS)
(1 g) was added and mixed to prepare a suspension. After the suspension was stirred at 25 ° C. for 16 hours, the reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure to remove the solvent. The obtained oil was purified by hexane / ethyl acetate silica gel column chromatography to obtain 520 mg of (R) -4.
-Propionyloxy-5-dodecinonitrile (optical purity 86%) and 500 mg of (S) -4-hydroxy-5
-Dodecinonitrile (optical purity 76%) was obtained. Incidentally, the optical purity is determined by hydrolyzing each with ethanol / sodium hydroxide, distilling as the corresponding hydroxycarboxylic acid, and deriving to the corresponding lactone, followed by a known method (E. Fukusaki et al., Tetrahedron, 47 , 6223,
(1991)) using HPLC. The (R) -4-pyropionyloxy-5-dodecinonitrile (optical purity 86%) obtained above was dissolved in methanol, 1.2 equivalents of potassium carbonate was added, and the mixture was stirred at room temperature for 24 hours. , 90% yield of (R) -4-hydroxy-5-dodecinonitrile. This (R) -4-hydroxy-5-dodecinonitrile had the same absorption wave number (cm ^-1 ) of infrared absorption spectrum and σ value of proton magnetic resonance spectrum ( ¹ H-NMR) (400 MHz) analysis as in Example 1. Was identified.

(Example 3) Isopropyl ether (20 ml), racemic 4-hydroxy-5-dodecinonitrile (1 g), butyric anhydride (3
50 mg), lipase (trade name: Amano PS) (1 g)
Was added and mixed to prepare a suspension. 25 of this suspension
After stirring at 16 ° C. for 16 hours, the reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure, and then the solvent was removed. The obtained oily substance was purified by silica gel column chromatography using a hexane / ethyl acetate system, and 550 mg of (R) -4-butanoyloxy-5-dodecinonitrile (optical purity 90%) was obtained.
%) And 500 mg of (S) -4-hydroxy-5-dodecinonitrile (76% optical purity). The obtained (R) -4-butanoyloxy-5-dodecinonitrile had an absorption wave number (cm ^-1 ) of an infrared absorption spectrum of 29.
30, 2900, 2840, 2220, 1740, 14
60, 1430, 1380, 1250, 1040 and the proton magnetic resonance spectrum ( ¹ H-NM
R) (400 MHz) analysis has a σ value of 0.88 (3H,
t, J = 7.1 Hz), 0.94 (3H, t, J = 7.
3 Hz), 1.23 to 1.38 (6H, m), 1.45
~ 1.52 (2H, m), 1.57-1.70 (2H,
m), 2.06-2.12 (2H, m), 2.19 (2
H, td, J = 6.8, 2.0 Hz), 2.53 (2
H, td, J = 7.3, 3.9 Hz), 4.48-4.
53 (1H, m) (see FIGS. 7 and 8). For (S) -4-hydroxy-5-dodecinonitrile, the absorption wave number (cm ^-1 ) of the infrared absorption spectrum and the proton magnetic resonance spectrum ( ¹ H)
-NMR) (400 MHz) was identified because the σ value of the analysis was the same as in Example 1. In addition, the said optical purity can be hydrolyzed with ethanol / sodium hydroxide, distilled as the corresponding hydroxycarboxylic acid, and then derivatized to the corresponding lactone.
Fukusaki et al., Tetrahedron, 47 , 6223, (1991)). Further, the (R) -4-butanoyloxy-5-dodecinonitrile (optical purity 90%) obtained above was dissolved in methanol, 1.2 equivalents of potassium carbonate was added, and the mixture was stirred at room temperature for 24 hours. (R) -4-Hydroxy-5-dodecinonitrile was obtained in 90% yield. The obtained (R) -4-hydroxy-5-dodecinonitrile has an absorption wave number (cm ^-1 ) of an infrared absorption spectrum and a proton magnetic resonance spectrum ( ¹ H).
-NMR) (400 MHz) was identified because the σ value of the analysis was the same as in Example 1.

Example 4 In a 100 ml Meyer flask, isopropyl ether (20 ml), racemic 4-hydroxy-5-dodecinonitrile (1 g), succinic anhydride (330 mg), lipase (trade name: Amano PS) (1)
g) was added and mixed to prepare a suspension. 25 suspensions
After stirring at 16 ° C. for 16 hours, the reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure, and then the solvent was removed. The obtained oily substance was purified by hexane / ethyl acetate silica gel column chromatography, and 530 mg of (R) -4-succinoyloxy-5-dodecinonitrile (optical purity: 92
%) And 500 mg of (S) -4-hydroxy-5-dodecinonitrile (79% optical purity). In addition, the optical purity was determined by hydrolyzing each with ethanol / sodium hydroxide to form the corresponding hydroxycarboxylic acid, and then distilling to the corresponding lactone, followed by a known method (E.
Fukusaki et al., Tetrahedron, 47 , 6223, (1991)). Further, the (R) -4-succinoyloxy-5-dodecinonitrile (optical purity 92%) obtained above was dissolved in methanol, 1.2 equivalents of potassium carbonate was added, and the mixture was stirred at room temperature for 24 hours. (R) -4-Hydroxy-5-dodecinonitrile was obtained in 90% yield. The obtained (R) -4-hydroxy-5-dodecinonitrile has an absorption wave number (cm ^-1 ) of an infrared absorption spectrum and a proton magnetic resonance spectrum ( ¹ H).
-NMR) (400 MHz) was identified because the σ value of the analysis was the same as in Example 1.

Example 5 In a 100 ml Meyer flask, isopropyl ether (20 ml), racemic 4-hydroxy-5-tetradecinonitrile (1 g), acetic anhydride (240 mg), lipase (trade name: Amano PS) (1)
g) was added and mixed to prepare a suspension. After the suspension was stirred at 25 ° C. for 16 hours, the reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure to remove the solvent. The obtained oil was purified by hexane / ethyl acetate silica gel column chromatography, and 510 mg of (R) -4-acetoxy-5-tetradecinonitrile (88% optical purity).
And 520 mg of (S) -4-hydroxy-5-tetradecinonitrile (optical purity 76%). Incidentally, the optical purity is determined by hydrolyzing each with ethanol / sodium hydroxide, distilling as the corresponding hydroxycarboxylic acid, and deriving to the corresponding lactone, followed by a known method (E. Fukusaki et al., Tetrahedron, 47 , 6223, (199
Determined using HPLC according to 1)). Further, (R) -4-acetoxy-5-dodecinonitrile (optical purity: 88%) obtained above was dissolved in methanol, and 1.2 equivalents of potassium carbonate was added thereto. (R) -4-Hydroxy-5-tetradecinonitrile was obtained in a yield.

Example 6 Isopropyl ether (20 ml), racemic 4-hydroxy-5-tetradecinonitrile (1 g), propionic anhydride (290 mg), lipase (trade name: Amano P) were placed in a 100 ml Mayer flask.
S) (1 g) was added and mixed to prepare a suspension. This suspension was stirred at 25 ° C. for 16 hours. After filtering the reaction solution,
The obtained filtrate was concentrated under reduced pressure to remove the solvent. The obtained oily substance was purified by hexane / ethyl acetate silica gel column chromatography, and 530 mg of (R)-
4-propionyloxy-5-tetradecinonitrile (optical purity 88%) and 500 mg of (S) -4-hydroxy-5-tetradecinonitrile (optical purity 77%) were obtained. The above optical purity can be determined by a known method (E. Fukusaki et al., Tetrahedro) after hydrolyzing each with ethanol / sodium hydroxide, distilling as the corresponding hydroxycarboxylic acid, and deriving the corresponding lactone.
n, 47 , 6223, (1991)). Also, the (R) -4-propionyloxy-5-tetradecinonitrile (optical purity 88%) obtained above is dissolved in methanol, 1.2 equivalents of potassium carbonate is added, and the mixture is stirred at room temperature for 24 hours. Yielded (R) -4-hydroxy-5-tetradecinonitrile in 90% yield.

Example 7 In a 100 ml Meyer flask, isopropyl ether (20 ml), racemic 4-hydroxy-5-tetradecinonitrile (1 g), butyric anhydride (340 mg), lipase (trade name: Amano PS) (1)
g) was added and mixed to prepare a suspension. After the suspension was stirred at 25 ° C. for 16 hours, the reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure to remove the solvent. The obtained oily substance was purified by silica gel column chromatography using a hexane / ethyl acetate system, and 560 mg of (R) -4-butanoyloxy-5-tetradecinonitrile (optical purity 9) was obtained.
0%) and 500 mg of (S) -4-hydroxy-5-tetradecinonitrile (76% optical purity). Incidentally, the optical purity is determined by hydrolyzing each with ethanol / sodium hydroxide, distilling as the corresponding hydroxycarboxylic acid, and deriving to the corresponding lactone, followed by a known method (E. Fukusaki et al., Tetrahedron, 47 , 6223,
(1991)) using HPLC. The (R) -4-butanoyloxy-5-tetradecinonitrile (optical purity 90%) obtained above was dissolved in methanol, 1.2 equivalents of potassium carbonate was added, and the mixture was stirred at room temperature for 24 hours. Yielded (R) -4-hydroxy-5-tetradecinonitrile in 90% yield.

Example 8 Isopropyl ether (20 ml), racemic 4-hydroxy-5-tetradecinonitrile (1 g), succinic anhydride (310 mg), and lipase (trade name: Amano PS) were placed in a 100 ml Mayer flask.
(1 g) was added and mixed to prepare a suspension. After the suspension was stirred at 25 ° C. for 16 hours, the reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure to remove the solvent. The obtained oil was purified by hexane / ethyl acetate silica gel column chromatography, and 540 mg of (R) -4-
Succinoyloxy-5-tetradecinonitrile (optical purity 92%) and 500 mg of (S) -4-hydroxy-
5-Tetradecinonitrile (79% optical purity) was obtained.
Incidentally, the optical purity is determined by hydrolyzing each with ethanol / sodium hydroxide, distilling as the corresponding hydroxycarboxylic acid, and deriving to the corresponding lactone, followed by a known method (E. Fukusaki et al., Tetrahedron, 47 ,
6223, (1991)). Further, the (R) -4-succinoyloxy- obtained above is obtained.
Dissolve 5-tetradecinonitrile (optical purity 92%) in methanol, add 1.2 equivalents of potassium carbonate, and stir at room temperature for 24 hours to obtain (R) -4 at a yield of 90%.
-Hydroxy-5-dodecinonitrile was obtained.

(Example 9) 50 mM phosphate buffer (pH 7) (50 ml), racemic 4-acetoxy-5-dodecinonitrile (1 g) and lipase (trade name: Amano PS) (1 g) were placed in a 100 ml Mayer flask and mixed. To prepare a suspension. After the suspension was stirred at 25 ° C. for 16 hours, diethyl ether was added to the reaction solution for extraction. The obtained extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The obtained oil was purified by hexane / ethyl acetate silica gel column chromatography to obtain 400 mg of (R) -4.
-Hydroxy-5-dodecinonitrile (optical purity 80
%) And 500 mg of (S) -4-acetoxy-5-dodecinonitrile (optical purity 70%). The obtained (R) -4-hydroxy-5-dodecinonitrile had the absorption wave number (cm ^-1 ) of the infrared absorption spectrum and the σ value of the proton magnetic resonance spectrum ( ¹ H-NMR) (400 MHz) analysis which were the same as those of Example 1 above. It was identified because it was similar. In addition, the absorption wave number (cm) of the infrared absorption spectrum of (S) -4-acetoxy-5-dodecinonitrile was also determined.
^-1) and proton magnetic resonance spectrum ⁽¹ H-NMR)
It was identified because the σ value of the (400 MHz) analysis was similar to that of the (R) -optically active substance of Example 1. Incidentally, the optical purity is determined by hydrolyzing each with ethanol / sodium hydroxide, distilling as the corresponding hydroxycarboxylic acid, and deriving to the corresponding lactone, followed by a known method (E. Fukusaki et al., Tetrahedron, 47 , 6223, (199
Determined using HPLC according to 1)). The (S) -4-acetoxy-5-dodecinonitrile (optical purity 70%) obtained above was dissolved in methanol, 1.2 equivalents of potassium carbonate was added, and the mixture was stirred at room temperature for one day and 90% to obtain 90%. (S) -4-hydroxy-5-dodecinonitrile was obtained in a yield of With respect to the obtained (S) -4-hydroxy-5-dodecinonitrile, the absorption wave number (cm ^-1 ) of the infrared absorption spectrum and the σ value of the proton magnetic resonance spectrum ( ¹ H-NMR) (400 MHz) analysis were as described in Example 1 above. It was identified because it was similar to.

Example 10 A 50 ml phosphate buffer (pH 7) (50 ml), racemic 4-propionyloxy-5-dodecinonitrile (1) was placed in a 100 ml Mayer flask.
g) and lipase (trade name: Amano PS) (1 g) were added and mixed to prepare a suspension. After the suspension was stirred at 25 ° C. for 16 hours, diethyl ether was added to the reaction solution for extraction. The obtained extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent.
The obtained oily substance was purified by hexane / ethyl acetate silica gel column chromatography to obtain 380 mg.
(R) -4-hydroxy-5-dodecinonitrile (optical purity 82%) and 500 mg of (S) -4-propionyloxy-5-dodecinonitrile (optical purity 70%) were obtained. The above optical purity can be determined by a known method (E. Fukusaki et al., Tetrahedro) after hydrolyzing each with ethanol / sodium hydroxide, distilling as the corresponding hydroxycarboxylic acid, and deriving the corresponding lactone.
n, 47 , 6223, (1991)). The (S) -4-propionyloxy-5-dodecinonitrile (optical purity 70%) obtained above was dissolved in methanol, 1.2 equivalents of potassium carbonate was added, and the mixture was stirred at room temperature for 24 hours to obtain 90%. (S) -4 in the yield of
-Hydroxy-5-dodecinonitrile was obtained.

Example 11 In a 100 ml Meyer flask, 50 mM phosphate buffer (pH 7) (50 ml), racemic 4-butanoyloxy-5-dodecinonitrile (1
g) and lipase (trade name: Amano PS) (1 g) were added and mixed to prepare a suspension. After the suspension was stirred at 25 ° C. for 16 hours, diethyl ether was added to the reaction solution for extraction. The obtained extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent.
The obtained oil was purified by hexane / ethyl acetate silica gel column chromatography to give 350 mg.
(R) -4-hydroxy-5-dodecinonitrile (optical purity 84%) and 500 mg of (S) -4-butanoyloxy-5-dodecinonitrile (optical purity 70%). The obtained (R) -4-hydroxy-5-dodecinonitrile has an absorption wave number (cm ^-1 ) of an infrared absorption spectrum.
And proton magnetic resonance spectra ⁽¹ H-NMR) (4
00MH ₂ ) was identified because the σ value in the analysis was the same as in Example 1. (S) -4-butanoyloxy-5-dodecinonitrile has an absorption wave number (cm ^-1 ) of an infrared absorption spectrum and a proton magnetic resonance spectrum ( ¹ H).
-NMR) (400 MH ₂ ) was identified because the σ value was the same as that of the (R) -optically active substance of Example 3. Incidentally, the optical purity is determined by hydrolyzing each with ethanol / sodium hydroxide, distilling as the corresponding hydroxycarboxylic acid, and deriving to the corresponding lactone, followed by a known method (E. Fukusaki et al., Tetrahedron,
47 , 6223, (1991)) using HPLC.
Further, the (S) -4-butanoyloxy-
5-Dodecinonitrile (84% optical purity) is dissolved in methanol, 1.2 equivalents of potassium carbonate is added, and the mixture is stirred at room temperature for 24 hours to obtain (S) -4-hydroxy-5-dodecinonitrile at a yield of 90%. I got The obtained (S) -4-hydroxy-5-dodecinonitrile has an absorption wave number (cm ^-1 ) of an infrared absorption spectrum and a proton magnetic resonance spectrum ( ¹ H-NMR) (400 MH ₂ ).
It was identified because the σ value of the analysis was the same as in Example 1.

(Example 12) In a 100 ml Meyer flask, 50 mM phosphate buffer (pH 7) (50 ml), racemic 4-succinoyloxy-5-dodecinonitrile (1
g) and lipase (trade name: Amano PS) (1 g) were added and mixed to prepare a suspension. After the suspension was stirred at 25 ° C. for 16 hours, diethyl ether was added to the reaction solution for extraction. The obtained extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent.
The obtained oil was purified by hexane / ethyl acetate silica gel column chromatography to give 330 mg
(R) -4-hydroxy-5-dodecinonitrile (optical purity 86%) and 500 mg of (S) -4-succinoyloxy-5-dodecinonitrile (optical purity 70%). The above optical purity can be determined by a known method (E. Fukusaki et al., Tetrahedro) after hydrolyzing each with ethanol / sodium hydroxide, distilling as the corresponding hydroxycarboxylic acid, and deriving the corresponding lactone.
n, 47 , 6223, (1991)). (S) -4-succinoyloxy- obtained above
5-Dodecinonitrile (optical purity 70%) was dissolved in methanol, 1.2 equivalents of potassium carbonate was added, and the mixture was stirred at room temperature for 24 hours to obtain (S) -4-hydroxy-5-dodecinonitrile at a yield of 90%. I got

(Example 13) 50 mM phosphate buffer (pH 7) (50 ml), racemic 4-acetoxy-5-tetradecinonitrile (1
g) and lipase (trade name: Amano PS) (1 g) were added and mixed to prepare a suspension. After the suspension was stirred at 25 ° C. for 16 hours, diethyl ether was added to the reaction solution for extraction. The obtained extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent.
The resulting oils were purified by hexane / ethyl acetate silica gel column chromatography, and 390 mg
(R) -4-hydroxy-5-tetradecinonitrile (optical purity 80%) and 500 mg of (S) -4-acetoxy-5-tetradecinonitrile (optical purity 70%). The above optical purity can be determined by a known method (E. Fukusaki et al., Tetrahedro) after hydrolyzing each with ethanol / sodium hydroxide, distilling as the corresponding hydroxycarboxylic acid, and deriving the corresponding lactone.
n, 47 , 6223, (1991)). Further, the (S) -4-acetoxy-5- obtained above.
Tetradecinonitrile (70% optical purity) is dissolved in methanol, 1.2 equivalents of potassium carbonate is added, and the mixture is stirred at room temperature all day and night to obtain (S) -4-hydroxy-5-yl with a yield of 90%. Tetradecinonitrile was obtained.

Example 14 In a 100 ml Meyer flask, 50 mM phosphate buffer (pH 7) (50 ml), racemic 4-propionyloxy-5-tetradecinonitrile (1 g), lipase (trade name: Amano PS) (1 g) Was added and mixed to prepare a suspension. 25 ° C
After stirring for 16 hours, diethyl ether was added to the reaction solution, followed by extraction. The obtained extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The obtained oily substance was purified by hexane / ethyl acetate silica gel column chromatography to obtain 380
mg of (R) -4-hydroxy-5-tetradecinonitrile (optical purity 82%) and 510 mg of (S) -4-propionyloxy-5-tetradecinonitrile (optical purity 70%) were obtained. Incidentally, the above optical purity can be determined by a known method (E. Fukusaki et al.,
Tetrahedron, 47 , 6223, (1991)). The (S) -4-propionyloxy-5-tetradecinonitrile obtained above (optical purity 7
(0%) was dissolved in methanol, 1.2 equivalents of potassium carbonate was added, and the mixture was stirred at room temperature for 24 hours to obtain (S) -4-hydroxy-5-tetradecinonitrile at a yield of 90%. .

Example 15 In a 100 ml Meyer flask, 50 mM phosphate buffer (pH 7) (50 ml), racemic 4-butanoyloxy-5-tetradecinonitrile (1 g), lipase (trade name: Amano PS) (1 g) ) Was added and mixed to prepare a suspension. 25 ° C
After stirring for 16 hours, diethyl ether was added to the reaction solution, followed by extraction. The obtained extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The obtained oily substance was purified by hexane / ethyl acetate silica gel column chromatography to give 330
mg (R) -4-hydroxy-5-tetradecinonitrile (optical purity 84%) and 500 mg (S) -4-butanoyloxy-5-tetradecinonitrile (optical purity 70%) were obtained. . The above optical purity can be determined by a known method (E. Fukusaki et al., T.) after hydrolyzing each with ethanol / sodium hydroxide, distilling as the corresponding hydroxycarboxylic acid, and deriving the corresponding lactone.
etrahedron, 47 , 6223, (1991)). The (S) -4-butanoyloxy-5-tetradecinonitrile obtained above (with an optical purity of 70)
%) Was dissolved in methanol, 1.2 equivalents of potassium carbonate was added, and the mixture was stirred at room temperature for 24 hours to obtain (S) -4-hydroxy-5-tetradecinonitrile at a yield of 90%.

Example 16 In a 100 ml Meyer flask, 50 mM phosphate buffer (pH 7) (50 ml), racemic 4-succinoyloxy-5-tetradecinonitrile (1 g), lipase (trade name: Amano PS) ( 1g) was added and mixed to prepare a suspension. 25 ° C
After stirring for 16 hours, diethyl ether was added to the reaction solution, followed by extraction. The obtained extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The obtained oily substance was purified by hexane / ethyl acetate silica gel column chromatography to give 320
mg of (R) -4-hydroxy-5-tetradecinonitrile (optical purity 86%) and 500 mg of (S) -4-succinoyloxy-5-tetradecinonitrile (optical purity 70%) were obtained. Was. Incidentally, the above optical purity can be determined by a known method (E. Fukusaki et al.,
Tetrahedron, 47 , 6223, (1991)). The (S) -4-succinoyl-5-tetradecinonitrile obtained above (with an optical purity of 70)
%) Was dissolved in methanol, 1.2 equivalents of potassium carbonate was added, and the mixture was stirred at room temperature for 24 hours to obtain (S) -4-hydroxy-5-tetradecinonitrile at a yield of 90%.

[0055]

As described in detail above, the present invention relates to a method for preparing a mixture containing at least optically active (R) -hydroxynitrile and optically active (S) -hydroxynitrile in an organic solvent in the presence of a hydrolase. An acid or carboxylic acid derivative is acted on to preferentially acylate the (R) -optically active compound to obtain an optically active (R) -cyanoester,
Next, the optically active (R) -cyanoester and the optically active (S) -hydroxynitrile are separated, and the optically active optically active (R) -cyanoester is hydrolyzed to obtain an optically active (R) -hydroxynitrile. A method for producing an optically active hydroxynitrile, characterized in that a hydrolyzing enzyme is allowed to act on a mixture containing at least an optically active (R) -cyanoester and an optically active (S) -cyanoester, and the (R) -optically active substance is obtained. Is preferentially hydrolyzed to optically active (R) -hydroxynitrile, then the optically active (R) -hydroxynitrile and the optically active (S) -cyanoester are separated, and the optically active (S) -cyanoester is further separated. A process for producing optically active hydroxynitrile, characterized in that an ester is hydrolyzed to obtain optically active (S) -hydroxynitrile. Al, as is apparent from the examples, Japanese beetle (Popillia japonica Newman) and cupreous chafer (Anomala cuprea Hope) as sex pheromone a synthetic intermediate for crop pests such, or various medicines,
An optically active hydroxynitrile useful as a pesticide or a physiologically active substance has an excellent effect that it is extremely easy at room temperature, has high production safety, and can selectively obtain a high-purity optically active substance. .

[Brief description of the drawings]

FIG. 1 is a scheme showing an example of a conventional synthesis method of optically active hydroxynitrile.

FIG. 2 is a scheme showing one example of a conventional synthesis method of optically active hydroxynitrile.

FIG. 3 shows (R) -4-acetoxy- obtained in Example 1.
It is an infrared-absorption spectrum figure of 5-dodecinonitrile.

FIG. 4 is a proton magnetic resonance spectrum chart of the above.

FIG. 5 shows (S) -4-hydroxy- obtained in Example 1.
It is an infrared-absorption spectrum figure of 5-dodecinonitrile.

FIG. 6 is a proton magnetic resonance spectrum diagram of the above.

FIG. 7 is an infrared absorption spectrum of (R) -4-butanoyloxy-5-dodecinonitrile obtained in Example 3.

FIG. 8 is a proton magnetic resonance spectrum diagram of the above.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Hozumi Tanaka 1-1-2 Shimohozumi, Ibaraki-shi, Osaka Nippon Denko Corporation (72) Inventor Tetsuo Omata 1-2-1, Shimohozumi, Ibaraki-shi, Osaka Issue No. TOKYO DENKO CORPORATION (58) Field surveyed (Int. Cl. ⁷ , DB name) C12P 41/00 C07C 255/19 BIOSIS (DIALOG) CA (STN) REGISTRY (STN)

Claims (11)

(57) [Claims] 1. A mixture containing at least an optically active (R) -hydroxynitrile represented by the general formula 1 (formula 1) and an optically active (S) -hydroxynitrile represented by the general formula 2 (formula 2): A carboxylic acid or a carboxylic acid derivative is allowed to act in an organic solvent in the presence of a lipase , and
The optically active form is preferentially acylated to give an optically active (R) -cyanoester represented by the general formula 3 (formula 3), and then this optically active (R) -cyanoester and the optically active (S)
-Hydroxynitrile, and further hydrolyzing the optically active (R) -cyanoester to obtain an optically active (R) -hydroxynitrile represented by the general formula (4). Nitrile manufacturing method. Embedded image Embedded image Embedded image Embedded image (Wherein, R ₁ is a compound represented by the general formula 5 or 6), and R ₃ is any one of an alkyl group, an aralkyl group, and a haloalkyl group having 1 to 12 carbon atoms. * Indicates an asymmetric carbon.) Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.) Wherein said optically active (R) - hydroxy nitrile with optically active (S) - claims, wherein the mixture containing the hydroxy nitrile is racemic hydroxynitrile represented by formula 7 (of 7) Item 6. The method for producing an optically active hydroxynitrile according to Item 1 . Embedded image (Wherein, R ₁ represents a compound represented by the general formula 8 (chemical formula 8) or the general formula 9 (chemical formula 9). * Represents an asymmetric carbon.) Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.) 3. The method for producing an optically active hydroxynitrile according to claim 2, wherein said racemic hydroxynitrile is 4-hydroxy-5-tetradecinonitrile. 4. The method for producing an optically active hydroxynitrile according to claim 2, wherein said racemic hydroxynitrile is 4-hydroxy-5-dodecinonitrile. 5. The method according to claim 1, wherein the carboxylic acid derivative is a carboxylic anhydride. 6. A mixture containing at least an optically active (R) -cyanoester represented by the general formula 10 (formula 10) and an optically active (S) -cyanoester represented by the general formula 11 (formula 11): The lipase is allowed to act to preferentially hydrolyze the (R) -optically active compound to obtain an optically active (R) -hydroxynitrile represented by the general formula 12 (formula 12). The optically active (S) -cyanoester is separated, and the optically active (S) -cyanoester is further hydrolyzed to obtain an optically active (S) -hydroxynitrile represented by the general formula 13 (Formula 13). Production method of optically active hydroxy nitrile. Embedded image Embedded image Embedded image Embedded image (Wherein, R ₁ is a group represented by the general formula 14 (formula 14) or the general formula 1)
Wherein R ₃ is a compound represented by the formula:
12 represents any of an alkyl group, an aralkyl group and a haloalkyl group. * Indicates asymmetric carbon. ) Embedded image (In the formula, R ₂ represents a linear or branched alkyl group having 1 to 10 carbon atoms.) 7. The optically active (R) -cyanoester and
A mixture containing an optically active (S) -cyanoester;
Racemic cyanoester represented by the general formula 16
The optically active hide according to claim 6, wherein
Roxynitrile manufacturing method. Embedded image (Where R ₁ is a group represented by the general formula 17 or the general formula 1)
A compound represented by the formula (8), wherein R ₃ has 1 to 1 carbon atoms
12 alkyl groups, aralkyl groups and haloalkyl groups
Indicates whether there is any deviation. * Indicates asymmetric carbon. ) [Of 17] Embedded image (However, in the formula, R ₂ is a linear or branched alkyl having 1 to 10 carbon atoms.
Represents a kill group. ) 8. The method according to claim 8, wherein the racemic cyanoester is 4-acylo.
Xy-5-tetradecinonitrile
The production of the optically active hydroxynitrile according to claim 7.
Law. 9. The method according to claim 9, wherein the racemic cyanoester is 4-acylo.
Xy-5-dodecinonitrile
8. The method for producing an optically active hydroxynitrile according to claim 7. 10. The preparation of the optically active hydroxynitrile.
General formula 19 used in the method and purification method
Novel synthetic intermediate optically active (R) -sia represented by 9)
Noester. Embedded image (Where R ₁ is a group represented by the general formula 20 or the general formula 2)
A compound represented by the formula (1), wherein R ₃ has 1 to 1 carbon atoms
12 alkyl groups, aralkyl groups and haloalkyl groups
Indicates whether there is any deviation. * Indicates asymmetric carbon. ) [Of 20] Embedded image (However, in the formula, R ₂ is a linear or branched alkyl having 1 to 10 carbon atoms.
Represents a kill group. ) 11. Production of said optically active hydroxynitrile
New compound represented by the general formula 22
Regular synthetic intermediate optically active (S) -cyanoester. Embedded image (Where R ₁ is a group represented by the general formula 23 or the general formula 2)
Wherein R ₃ is a compound represented by the formula:
12 alkyl groups, aralkyl groups, haloalkyl groups
Indicates whether there is any deviation. * Indicates asymmetric carbon. ) [Of 23] Embedded image (However, in the formula, R ₂ is a linear or branched alkyl having 1 to 10 carbon atoms.
Represents a kill group. )