JP2003040863A - Method for producing optically active alcohol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce an optically active alcohol in high yield from the corresponding racemic raw material. SOLUTION: This optically active alcohol is produced safely, efficiently and in high yield from the corresponding cyclic olefin by blending an optically active olefin, sodium borohydride and an activator therefor together followed by adding the cyclic olefin to the system; wherein as to the optically active olefin, an olefin having a cyclic structure containing N, O, S or the like can preferably be used, while as to the activator, a boron halide an preferably be used.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active alcohol. Optically active alcohols are compounds useful as pharmaceutical intermediates, agricultural chemical intermediates, liquid crystal materials, fragrances, and the like.

[0002]

2. Description of the Related Art As a method of synthesizing an optically active alcohol characterized by using a boron compound, a method via a hydroboration reaction is known. For example, α-
Pinene and diborane or borane complex (BH ₃ · SMe ₂ ,
BH ₃ · THF, etc.) asymmetric hydroboration using a synthesized di iso Pinot camphenyl borane from -. The synthesis of optically active alcohols by oxidation (Journal of Organic Nick Chemistry, 47, 50
75, (1982), Heterochemistry, 25, 64.
1 (1987), Journal of Organic Chemistry. , 51, 4296 (1986), Journal of American Chemistry. , 108, 20
49 (1986), Journal of Organics.
chemistry. , 50, 1582, (1985)).

However, diborane has a strong toxicity, and it is difficult to handle diborane including the borane complex in a safe and stable state for a long period while considering the environment, and it is not suitable for an industrial production method.

Therefore, it has been strongly desired to create a safe and convenient industrial production method of an optically active alcohol.

[0005]

DISCLOSURE OF THE INVENTION The present invention is to provide an industrial production method of an optically active alcohol having a high versatility as a substrate which uses an inexpensive raw material when producing an optically active alcohol.

[0006]

[Means for Solving the Problems] The inventors of the present invention have earnestly studied a method for producing an optically active alcohol having a high versatility of a substrate using an inexpensive raw material, and completed the present invention. That is, the present invention includes (1) a step of mixing an optically active olefin, sodium borohydride and an activator, (2) a reaction mixture obtained by adding a cyclic olefin to the mixture obtained in the step (1) and then reacting the mixture. And a step of treating with an agent.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.

A specific method of this reaction will be illustrated.

First, in the step (1), an activator is added to a mixed liquid containing an optically active olefin, sodium borohydride, and a solvent in some cases. Here, the order of charging the raw materials is not limited, and the optically active olefin may be added last, but preferably, the activator is added last, and the cyclic olefin is added in the next step. Added.

The optically active olefin which can be used in the present invention is not particularly limited and may be a natural product or a synthetic product, and either (+)-form or (-)-form may be used. Among them, terpenes are preferably used. As an example, (+)-α-pinene, (−)-α-pinene, (+)
-Β- pinene, (-) - beta-pinene, (+) - Δ ² - Cullen, (-) - Δ ² - Cullen, (+) - Δ ³ - Cullen,
(−)-Δ ³ -carene, longifolene, (+)-citronellol, (+)-linarool, (+)-citronellal, (+)-α-ferrandrene, (−)-β-
Ferrandrene, (-)-1-p-menthene, (+)-
3-p-menthene, (+)-limonene, (+)-cis-
Carveol, (+)-carveol, (+)-dihydrocarbeol, (+)-α-terpineol, trans
-Β-terpineol, γ-terpineol, (+)-
1-p-menthen-4-ol, pinol hydrate,
(+)-Trans-sobrerol, (-)-isopulegone, carbenone, (+)-carbotanaceton, (+)-
Carvone, (-)-dihydrocarvone, (-)-piperidone, (+)-pulegone, diosphenol, pinol, ascaridol, (+)-sabinene, (+)-2-
Borne, (-)-camphene, 3- (hydroxymethylene) -d-camphor, (-)-α-fenken, α
-Camphoramine, (+)-nerolidol, (-)-
β-cadinene, (−)-β-caryophyllene, (−)-
β-santalen, (−)-α-sedrene, (+)-β-
Serinene, (−)-β-bisaborene, α-humulene, longifolene, guaiol, eremophilene, α-santonin, phytol, kaurene, α-camphorene, sembrane, phylloden, limene, cafestol,
Totarol, ferguinol, mannol, abietic acid, levopimaric acid, amblein, α-onoserine,
Agnosterol, euphor, cycloartenol,
Examples include tilcarol, lanosterol, α-amylin, β-amylin, ursolic acid, oleanolic acid, glycyrrhetinic acid, hederagenin, betulin, lupeol, gibberellin A ₃ , malbiin and limonin.

Preferably, (+)-α-pinene, (-)
-Α-pinene, (+)-Δ ² -carene, (-)-Δ ² -carene, (+)-Δ ³ -carene, (-)-Δ ³ -carene, longifolene, (+)-α- Ferrandrene, (-)
-1-p-menthene, (+)-3-p-menthene,
(+)-Α-terpineol, (+)-1-p-menthen-4-ol, pinol hydrate, (+)-trans
-Sobrerol, carbenone, (+)-carbotanacetone, (+)-carvone, (-)-piperidone, diosphenol, pinol, ascaridol, (+)-2-bornene, α-camphoramine, (-)-β -Cadinene, (-)-β-caryophyllene, (-)-α-sedrene, (-)-β-bisaborene, α-humulene, guaiol, elemophylene, α-santonin, 1-α-terpineol, α-camphorene, sembrene Is an optically active cyclic olefin.

Particularly preferably, (+)-α-pinene,
(-)-Α-pinene, (+)-Δ ² -carene, (-)-
Delta ² - Cullen, (+) - delta ³ - Cullen, (-) - delta ³ - Karen, Longhi Faure down, (+) - alpha-phellandrene, (-) - 1-p-menthene, (+) - 3 -P-menthene, (+)-2-bornene, (-)-β-cadinene,
It is an optically active cyclic olefin composed of carbon and hydrogen, such as (−)-β-caryophyllene and (−)-α-cedrene.

The shape of sodium borohydride used in the present invention is not particularly limited, and various particle sizes from fine powder to granular can be used. The addition method of sodium borohydride is not limited, and may be added after being diluted with a solvent, or may be added as it is without being diluted.

As the activator used in the present invention, various ones can be used as long as they activate sodium borohydride. It preferably contains at least one selected from boron halides, mineral acids, sulfonic acids, alkylsulfuric acids, carboxylic acids, metal halides and iodine. Examples include boron halides such as boron trifluoride, boron trichloride, boron tribromide and boron triiodide, aluminum halides such as aluminum trifluoride, aluminum trichloride, aluminum tribromide and aluminum triiodide. Gallium trifluoride, gallium trichloride, gallium tribromide, gallium triiodide and other gallium halides, zinc fluoride, dimethyl zinc, diethyl zinc, zinc fluoride, zinc chloride, zinc bromide, zinc iodide, etc. Zinc halide, iron fluoride, iron chloride, iron bromide, iron iodide and other iron halides, titanium chloride, titanium bromide, sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and other mineral acids, Benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid and other sulfonic acids, dimethylsulfate, diethylsulfate, etc. Examples thereof include carboxylic acid such as alkyl sulfate, trifluoroacetic acid, acetic acid, propionic acid and butyric acid, methyl iodide and iodine, and preferably boron halide, aluminum halide, iron halide, sulfuric acid, hydrochloric acid and odor. Hydrofluoric acid, dimethylsulfuric acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, methyl iodide and iodine, more preferably boron trifluoride and boron trichloride. , Sulfuric acid, hydrochloric acid, iodine, dimethyl sulfuric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid.

The cyclic olefin added in the step (2) after mixing the optically active olefin, sodium borohydride and the activator thereof is not particularly limited as long as it is a cyclic compound having a double bond. Not a thing. The double bond may be present in the skeleton forming the ring structure, or may be present in the substituent. Further, the cyclic olefin may have asymmetric carbon, and in that case, it may be an optically active substance. Examples of cyclic olefins are 2H-oxet, 2H-oxet derivatives such as 2-methyl-2H-oxet, 2,3-dihydrofuran, 2,5-dihydrofuran, 2-methyl-2,3-dihydrofuran, 3 -Methyl-2,3-dihydrofuran, 5-methyl-2,3-
Dihydrofuran, 2,3-dimethyl-2,5-dihydrofuran, 2-hydroxy-2,3-dihydrofuran, 2
-Methoxy-2,3-dihydrofuran, 2-phenyl-
2,3-dihydrofuran, 2-ethoxy-5-methyl-
Dihydrofuran derivatives such as 2,3-dihydrofuran, 2-benzyl-3,4-dimethyl-2,5-dihydrofuran, 2-methyl-3,4-dihydro-2H-pyran,
2-methoxy-3,4-dihydro-2H-pyran, 2-
Acetyl-3,4-dihydro-2H-pyran, 2-methoxy-3,4-dihydro-2H-pyran, 2-ethyl-
3,6-dihydro-2H-pyran, 2-ethoxy-3,
6-dihydro-2H-pyran, 3-hydroxy-3,6
-Dihydropyran derivatives such as dihydro-2H-pyran, 2,3,4,5-tetrahydrooxepin, 2,
3,4,7-tetrahydrooxepin, 2,3,6,7
-Tetrahydrooxepin, 2-methyl-2,3,4
Examples thereof include tetrahydrooxepin derivatives such as 5-tetrahydrooxepin, and oxygen-containing cyclic olefins represented by 3,4,5,6-tetrahydro-2H-oxocine.

Furthermore, 1,2-dihydroazate, 2-
Methyl-1,2-dihydroazate, 2-pyrroline (2,3-dihydro-1H-pyrrole), 3-pyrroline (2,5-dihydro-1H-pyrrole), 2-methyl-
2-pyrroline, 2-ethyl-3-pyrroline, N-benzyl-2-pyrroline, N-benzyl-3-pyrroline, N-
Benzyl-2-ethylpyrroline, 4-phenyl-2-pyrroline, N-tert-butoxycarbonyl-2-pyrroline, N-tert-butoxycarbonyl-3-pyrroline, N
Pyrroline derivatives such as -benzyloxycarbonyl-2-pyrroline and N-benzyloxycarbonyl-3-pyrroline can be mentioned.

1,2,3,6-tetrahydropyridine,
N-methyl-1,2,3,4-tetrahydropyridine,
N-benzyl-1,2,3,6-tetrahydropyridine, N-tert-butoxycarbonyl-1,2,3,6-
Tetrahydropyridine, 2-acetyl-1,2,3,6
-Tetrahydropyridine, 1,2,3,4-tetrahydropyridine, 2-methyl-3-ethyl 1,2,3,4-
Tetrahydropyridine, 2-methoxy-1,2,3,4
-Tetrahydropyridine, N-benzyl-1,2,3
Tetrahydropyridine derivatives such as 4-tetrahydropyridine, N-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine, 2,3,4,5-tetrahydro-1H-azepine, 2,3,4,7- Tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1
Examples thereof include a 7-membered or 8-membered oxygen-containing cyclic olefin represented by H-azepine, 1,2,3,4,5,6-hexahydroazocine and the like.

2H-thiate, 2-benzyl-2H-thiate, 2,3-dihydrothiophene, 2,5-dihydrothiophene, 2-methyl-2,3-dihydrothiophene, 2,3-dimethyl-2,3-dihydro Thiophene,
2-Acetyl-2,5-dihydrothiophene, dihydrothiophene derivatives such as 2-hydroxy-3-methyl-2,5-dihydrothiophene, 3,4-dihydro-2H
-Thiapyran, 2-methyl-3,4-dihydro-2H-
Thiapyran, 2-acetyl-3,4-dihydro-2H-
Thiapyran, 3-ethoxy-3,6-dihydro-2H-
Dihydrothiapyran derivatives such as thiapyran, 3,6-dihydro-2H-thiapyran, 2,3,4,5-tetrahydrothiepine, 2,3,4,7-tetrahydrothiepine, 2,3,6,7- Tetrahydrothiepine, 3,4
Examples thereof include a 7-membered or 8-membered sulfur-containing cyclic olefin represented by 5,6-tetrahydro-2H-thiocin.

2-methylcyclobutene, 2-methylcyclopentene, 2-methylcyclohexene, 2-methylcycloheptene, 2-methylcyclooctene, 2-methylcyclopentadiene, 2-methyl-1,3-cyclohexadiene, 2 -Methyl-1,4-cyclohexadiene,
2-methyl-1,3-cyclooctadiene, 2-methyl-1,4-cyclooctadiene, 2-methyl-1,5-
Cyclooctadiene, 1-phenylcyclohexene,
Aromatic hydrocarbon olefins such as 2,3-dimethyl-2-butene can be mentioned.

Preferred are cyclic compounds having the following structures, and those having nitrogen, oxygen, or sulfur as atoms constituting the ring.

[0021]

[Chemical 2]

(Wherein X is N, O or S. When X is N, N is unsubstituted or a) to e) shown below.
It may be substituted with the substituent.

A) an alkyl group having 1 to 10 carbon atoms, b) an alkyl group having 1 to 10 carbon atoms substituted with a hydroxyl group, a carboxyl group or a carbamoyl group, c) an unsubstituted alkoxy group having 1 to 10 carbon atoms, or An aryl group substituted by a hydroxyl group, d) an aromatic ring which is unsubstituted, or an alkyl group having 1 to 10 carbon atoms, an aralkyl group which is substituted by an alkoxy group having 1 to 10 carbon atoms or a hydroxyl group, e) an alkyl or aryloxycarbonyl group Represents a group. R represents any of the following f) to j).

F) an alkyl group having 1 to 10 carbon atoms, an alkoxy group or a hydroxyl group, g) an unsubstituted or an aryl group substituted with an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms or a hydroxyl group. H) an aralkyl group in which an aromatic ring is unsubstituted or substituted with an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms or a hydroxyl group, i) an alkyl or aryloxycarbonyl group, j) an acyl group, Further, m, n and p are all 0 to 10 and m +
The relational expressions of n ≧ 1 and m + n + 2 ≧ p ≧ 0 are satisfied. ) Where X is N, p = 0, m = n =
1 and N is unsubstituted or substituted by any of the above a), d) and e).

For example, the above-mentioned 2H-oxet derivative, dihydrofuran derivative, dihydropyran derivative, tetrahydrooxepin derivative, hexahydroazocine derivative, dihydroazeto derivative, pyrroline derivative, tetrahydropyridine derivative, tetrahydroazepine derivative, hexahydro. A nitrogen-containing, oxygen-containing or sulfur-containing heterocyclic olefin such as an azocin derivative, a 2H-thiate derivative, a dihydrothiophene derivative, a dihydrothiopyran derivative, a tetrahydrothiepine derivative and a tetrahydrothiocin derivative, and more preferably dihydrofuran. It is a nitrogen-containing, oxygen-containing or sulfur-containing heterocyclic olefin having 5 or 6 ring members such as a derivative, a pyrroline derivative and a dihydrothiophene derivative.

These cyclic olefins are added to the mixture of the optically active olefin, sodium borohydride and the activator in the step (1), reacted and then treated with an oxidant to give the corresponding optically active alcohol. To generate.

The following can be mentioned as examples of the optically active alcohol obtained. Oxetanol derivatives such as 2-oxetanol, 3-oxetanol, 3-methyl-2-oxetanol, 2-hydroxytetrahydrofuran, 3-hydroxytetrahydrofuran, 3-methyl-2-hydroxytetrahydrofuran,
2-methyl-3-hydroxytetrahydrofuran, 5-
Ethoxy-2-hydroxytetrahydrofuran, 2,5
A hydroxytetrahydrofuran derivative such as dihydroxytetrahydrofuran.

2-hydroxytetrahydropyran, 3-
Hydroxytetrahydropyran derivatives such as hydroxytetrahydropyran, 4-hydroxytetrahydropyran, 3-methyl-2-hydroxytetrahydropyran, 4-ethoxy-2-hydroxytetrahydropyran.

Oxepanol derivatives such as 2-oxepanol, 3-oxepanol, 4-oxepanol and 2-methyl-3-oxepanol, 2-azetidinol, 3-azetidinol, 2-methyl-3-azetidinol, 3-methoxy-2-azetidinol. , N-benzyl-2-azetidinol and other azetidinol derivatives.

2-pyrrolidinol, 3-pyrrolidinol, 2-methyl-3-pyrrolidinol, 3-ethoxy-
Pyrrolidinol derivatives such as 2-pyrrolidinol, N-benzyl-3-pyrrolidinol, N-tert-butoxy-2-pyrrolidinol, N-benzyloxycarbonyl-3-pyrrolidinol, N-acetyl-2-pyrrolidinol, 2-piperidinol, 3- Piperidinol, 4-piperidinol, 2-methyl-3-piperidinol, N-
Benzyl-3-piperidinol, N-tert-butoxy-
2-piperidinol, N-benzyloxycarbonyl-
Piperidinol derivatives such as 3-piperidinol and N-acetyl-2-piperidinol.

2-azepanol, 3-azepanol, 4
-Azepanol, 2-methyl-3-azepanol, N-
Benzyl-3-azepanol, N-tert-butoxy-2
-Azepanol, N-benzyloxycarbonyl-3-
Azepanol derivatives such as azepanol and N-acetyl-2-azepanol, 2-thiethanol, 2-methyl-
Thioethanol derivatives such as 3-thiethanol.

2-hydroxytetrahydrothiophene,
3-hydroxytetrahydrothiophene, 2-methyl-
Hydroxytetrahydrothiophene derivative such as 3-hydroxytetrahydrothiophene, 2-hydroxytetrahydrothiopyran, 3-hydroxytetrahydrothiopyran, tetrahydrothiopyran derivative such as 2-methyl-4-hydroxytetrahydrothiopyran, 2-thiepanol, 3-thiepanol Cyclic alcohols whose ring structure is hydrocarbon, such as thipropanol derivatives such as 4-thiepanol, 2-methyl-3-ethylcyclobutanol, 2-acetylcyclopentanol, and 3-benzylcyclopentanol.

Preferred are optically active alcohols containing nitrogen, oxygen or sulfur as ring-constituting atoms, represented by the following structures.

[0034]

[Chemical 3]

For example, an oxygen-containing heterocyclic alcohol such as a hydroxy-2H-oxet derivative, a hydroxydihydrofuran derivative, a hydroxydihydropyran derivative, a hydroxytetrahydrooxepin derivative or a hydroxytetrahydrooxocin derivative, a hydroxydihydroazate derivative, Nitrogen-containing heterocyclic alcohols such as hydroxypyrrolidine derivatives, hydroxytetrahydropyridine derivatives, hydroxytetrahydroazepine derivatives, hydroxytetrahydroazocine derivatives, hydroxythiate derivatives, hydroxydihydrothiophene derivatives, hydroxydihydrothiopyran derivatives, hydroxytetrahydrothiepine derivatives, Examples thereof include sulfur-containing heterocyclic alcohols such as hydroxytetrahydrothiocin derivatives, and more preferable ones are: Number is oxygen-containing heterocyclic alcohols 5 or 6, nitrogen-containing heterocyclic alcohol, a sulfur-containing heterocyclic alcohol.

Specific examples of the oxidizing agent used in the step (2) of the present invention include hydrogen peroxide, perbenzoic acid, peracetic acid, oxygen and the like, preferably hydrogen peroxide, perbenzoic acid and peroxybenzoic acid. Acetic acid, more preferably hydrogen peroxide.

The present invention includes (1) a step of mixing an optically active olefin, sodium borohydride and an activator,
(2) The method is characterized by including a step of adding a cyclic olefin to the mixture obtained in the step (1), reacting the mixture, and then treating the mixture with an oxidizing agent.

When a solvent is used in the step (1), specific examples of the solvent include tetrahydrofuran, tetrahydropyran, monoglyme, diglyme, dimethoxymethane, dimethoxyethane, diethoxymethane, diethoxyethane, diethyl ether, isopropyl ether, diether. Butyl ether, methyl tert-butyl ether, aliphatic ether such as 1,4-dioxane, 1,3-dioxane, anisole, ethoxybenzene, 1,4
-Aromatic ethers such as dimethoxybenzene, hydrocarbons such as benzene, toluene, o-xylene, m-xylene, p-xylene, 1,3,5-trimethylbenzene, ethylbenzene and cyclohexane, chloroform, dichloromethane, carbon tetrachloride, etc. And halogenated hydrocarbons thereof. Aliphatic ethers and aromatic ethers are preferable, and aliphatic ethers are more preferable.

The amount of the optically active olefin used in the step (1) depends on the kind of the optically active olefin to be used, but is generally 1 to 1 with respect to sodium borohydride.
The molar ratio is preferably 0 times, more preferably 1 to 5 times, and particularly preferably 1 to 3 times. Within this range, an optically active dialkylborane, which is a precursor of alcohol, can be efficiently produced, and the optical purity of the target optically active alcohol can be increased.

The amount of activator used in step (1) is
Depending on the type of activator used, it is preferably 0.05 to 10 mole times with respect to sodium borohydride,
The molar ratio is more preferably 0.1 to 5.0, and particularly preferably 0.3 to 2.0. Within this range, optically active dialkylborane can be efficiently generated, which is economical.

For example, when the activator is boron trifluoride, the amount used is 1.
The molar ratio is preferably 0 to 1.5, and when the activator is sulfuric acid, the molar ratio is preferably 0.5 to 1.0.

The amount of the reaction solvent used in the step (1) does not have to be used when the optically active olefin is a liquid, but in general, the total amount of the optically active olefin, sodium borohydride and its activator is used. The concentration of 5-8
It is preferable to set it in the range of 0% by weight. It is preferably 10 to 60% by weight, and more preferably 20 to
It is 50% by weight. Within this range, the reaction solution is a solution,
In the case of either slurry, there is no operational problem and it can be applied to industrial production.

The range of the reaction temperature in the step (1) is not particularly limited, but it is preferably -80 to 80 ° C, more preferably -50 to 50 ° C, particularly preferably -25 to 25 ° C.
It is 30 ° C. Within this range, industrial production is easy.

The amount of the cyclic olefin added in the step (2) is preferably 0.01 to 5 times the molar amount of the sodium borohydride used in the step (1), and more preferably 0.1 to 5.
It is 3 times by mole, and more preferably 0.3 to 2 times by mole. Within this range, the cyclic olefin can be efficiently converted and high productivity can be expected.

When the solvent is used in the step (2), it is preferable to use the solvent used in the step (1) as it is, but a reaction solvent may be added or another reaction solvent may be added. .

The reaction temperature in step (2) is -80 to 80 ° C.
Is good, preferably -50 to 25 ° C, and more preferably -25 to 20 ° C. Within this range, the optical purity of the produced optically active alcohol can be increased, and a good quality product can be obtained.

Further, if the mixture is agitated for a long time with the cyclic olefin added, racemization may occur, and the optical purity tends to decrease, so long-term storage in this state is not preferable.

In the present invention, the timing of addition of the cyclic olefin is very important. In order to obtain an optically active alcohol, the active species generated from sodium borohydride and its activator are first converted to the optically active olefin. It is necessary to add to the cyclic olefin after the addition. That is, the optically active olefin plays the role of a chiral template, and it is essential that the active species generated in the system first be added to the optically active olefin which is the chiral template.

A typical example will be described below. In the reaction in which (+)-α-pinene is used as the optically active olefin, boron trifluoride / ethyl ether complex is used as the activator, and N-benzyl-3-pyrroline is used as the cyclic olefin, in the present invention, α-pinene → Sodium borohydride-> boron trifluoride-> N-benzyl-3-pyrroline are added in this order. Here, if the order is changed and α-pinene → sodium borohydride → N-benzyl-3-pyrroline → boron trifluoride is added in this order, addition of the active species to N-benzyl-3-pyrroline is α Since it occurs competitively with addition to -pinene, the optical purity of the target product, N-benzyl-3-pyrrolidinol, is low. It is considered that this is because the active species is added to N-benzyl-3-pyrroline before being added to the chiral template α-pinene.

In addition, addition of α-pinene → sodium borohydride → boron trifluoride → (mixture of N-benzyl-3-pyrroline and boron trifluoride) gives N--
Benzyl-3-pyrroline forms a complex with boron trifluoride to reduce the activity against addition of active species, and an optically active alcohol can be obtained only in a very low yield.

That is, as shown in the present invention, it is very important to add a cyclic olefin to a system in which an optically active olefin and sodium borohydride and its activator are present in order to obtain an optically active alcohol. Is.

The step of treating with an oxidizing agent can be carried out according to a generally known method (Journal of Organic Chemistry., 47, 5074 (1982)). That is, it is a method in which the reaction solution is made alkaline with an alkaline solution such as an aqueous sodium hydroxide solution, and then an oxidizing agent such as hydrogen peroxide solution is added. As the oxidant used here, perbenzoic acid, peracetic acid, oxygen and the like can be used in addition to hydrogen peroxide solution.

In the step of treating with an oxidizing agent, it is preferable to add the oxidizing agent after making the reaction solution obtained by adding the cyclic olefin of the step (2) alkaline, and specifically, to adjust the pH value. It is larger than 7, more preferably 8 or more.

Further, the amount of the oxidizing agent used in the step of treating with the oxidizing agent is 1 with respect to sodium borohydride.
The range of 10 to 10 times by mole is preferable, the range of 2 to 7 times by mole is preferable, and the range of 3 to 5 times by mole is more preferable. Within this range, the optically active olefin can be economically and efficiently obtained.

The reaction temperature of the step of treating with an oxidizing agent is not particularly limited, and it is generally preferable to carry out the reaction within the range of -25 to 80 ° C.

The reaction system can be carried out in air, in an atmosphere of an inert gas such as nitrogen, helium or argon, but is preferably an inert atmosphere.

[0057]

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited thereto.

The reaction yield of the produced optically active alcohol was calculated using gas chromatography under the analytical conditions described below.

Model Shimadzu GC-14B column Unisole 10T + KOH (10 + 3)% / Uniport HP
3.2 mm × 1.0 m Carrier helium injection pressure 70 kPa / cm ² Column temperature 50 ° C. (2 minutes)-(20 ° C./minute temperature increase) -1
40 ° C (2 minutes)-(20 ° C / minute) -220 ° C (2.5
Min) Injection temperature 230 ° C Detector temperature 230 ° C Detection method FID sample preparation method The reaction solution before oxidation is used for analysis after performing oxidation treatment.

The optical purity of the obtained optically active alcohol is measured by liquid chromatography and R
It was calculated from the area ratio of the-body peak and the S-body peak. When the R body is selectively generated, it is calculated according to the following equation.

Optical purity (% ee.) = (Area value of R-body peak-Area value of S-body peak) / (Area value of R-body peak +
Area value of S-body peak) × 100 The analysis conditions are as follows.

Model Shimadzu LC-10Vp column CAPCELLPAK C18, 4.6 mm × 25 cm (Shiseido) Mobile phase 0.03% ammonia water (pH 4.5 with acetic acid)
Preparation) / acetonitrile = 48/52 (v / v) Flow rate 1.0 ml / min Temperature 40 ° C. Detector UV (243 nm) Sample preparation Optically active alcohol was diastereos with di-o-toluoyl-D-tartaric anhydride. After derivatization into mer, it is used for analysis.

Example 1 250 g of tetrahydrofuran and 100.0 g (= 0.734) of α-pinene (optical purity 91% ee.) In a 1 L round bottom flask equipped with a dropping funnel, a condenser and a stirrer.
mol) and mixed. To this, 10.4 g (= 0.275 mol) of sodium borohydride was added and cooled to 0 ° C. To the slurry, 102 g of a tetrahydrofuran solution of boron trifluoride / diethyl ether complex (boron trifluoride / diethyl ether complex content 52.0 g =
0.366 mol) was added over 0.5 hours, and then 1
Aged for 2 hours. Next, N-benzyl-
58.69 g of a solution of 3-pyrroline in tetrahydrofuran
(N-benzyl-3-pyrroline content 29.2 g = 0.1
(83 mol) was added dropwise while adjusting the temperature of the reaction solution to -3 to 3 ° C, and the reaction was carried out for 9 hours.

As a result of analyzing the reaction solution, the yield of N-benzyl-3-pyrrolidinol was 93.1% (vs. N-benzylpyrroline) and the optical purity was 83.6% ee. Met.

Example 2 An experiment was conducted in the same manner as in Example 1 except that the reaction temperature after adding N-benzyl-3-pyrroline was changed to 6 to 8 ° C.

As a result of analyzing the reaction solution, the yield of N-benzyl-3-pyrrolidinol was 89.1% (vs. N-benzylpyrroline) and the optical purity was 74.4% ee. Met.

Example 3 The amount of N-benzyl-3-pyrroline added was 23.4 g (=
The experiment was conducted in the same manner as in Example 1 except that the amount was changed to 0.146 mol).

As a result of analyzing the reaction solution, the yield of N-benzyl-3-pyrrolidinol was 92.2% (vs. N-benzylpyrroline) and the optical purity was 81.6% ee. Met.

Example 4 The amount of N-benzyl-3-pyrroline added was 35.0 g (=
The experiment was performed in the same manner as in Example 1 except that the content was changed to 0.220 mol).

As a result of analyzing the reaction solution, the yield of N-benzyl-3-pyrrolidinol was 68.5% (vs. N-benzylpyrroline) and the optical purity was 77.4% ee. Met.

Example 5 250 g of tetrahydrofuran and 100.0 g (= 0.734) of α-pinene (optical purity 91% ee.) In a 1 L round bottom flask equipped with a dropping funnel, a condenser and a stirrer.
mol) and mixed. Sodium borohydride (13.9 g, = 0.367 mol) was added thereto, and the mixture was cooled to 0 ° C. 18.4 g of 98% sulfuric acid (=
0.184 mol) was added over 0.5 hours and then 1
Aged for 2 hours. Next, N-benzyl-
58.69 g of a solution of 3-pyrroline in tetrahydrofuran
(N-benzyl-3-pyrroline content 29.2 g = 0.1
(83 mol) was added dropwise while adjusting the temperature of the reaction solution to -3 to 3 ° C, and the reaction was carried out for 9 hours.

As a result of analyzing the reaction solution, the yield of N-benzyl-3-pyrrolidinol was 66.3% (vs. N-benzyl-3-pyrroline) and the optical purity was 75.3% ee. Met.

Comparative Example 1 In Example 1, an experiment was conducted in which the charged amount was the same and the addition order was changed. That is, an experiment was performed by the same operation as in Example 1 except that N-benzyl-3-pyrroline was added before the addition of boron trifluoride.

As a result of analysis of the reaction solution, N-benzyl-3-pyrrolidinol yield was 17.5% (vs. N-benzyl-3-pyrroline), optical purity was 10.5% ee. Met.

Comparative Example 2 In Example 1, an experiment was conducted in which the charged amount was the same and the addition order was changed. That is, boron trifluoride / diethyl ether complex was added to a tetrahydrofuran solution of N-benzyl-3-pyrroline in advance, and the mixture was stirred and cooled to 0 ° C. to obtain a slurry, which was mixed with tetrahydrofuran, α-pinene and sodium borohydride. Was added dropwise at the same temperature and time as in Example 1.

As a result of analysis of the reaction solution, N-benzyl-3-pyrrolidinol yield was 10.6% (vs. N-benzylpyrroline) and optical purity was 7.2% ee. Met.

Comparative Example 3 An experiment was conducted in the same manner as in Example 5 except that N-benzyl-3-pyrroline was added before adding sulfuric acid.

As a result of analyzing the reaction solution, the yield of N-benzyl-3-pyrrolidinol was 10.3% (vs. N-benzyl-3-pyrroline) and the optical purity was 6.5% ee. Met.

[0079]

According to the present invention, an optically active olefin,
By adding the cyclic olefin to the mixed solution of sodium borohydride and its activator, the optically active alcohol can be produced safely and in high yield.

Claims (7)

[Claims] 1. A step of (1) mixing an optically active olefin, sodium borohydride and an activator, (2) adding a cyclic olefin to the mixture obtained in the step (1), and then treating with an oxidizing agent. The process for producing an optically active alcohol, which comprises: 2. The method for producing an optically active alcohol according to claim 1, wherein the optically active olefin has a ring structure. 3. The activator contains at least one selected from boron halides, mineral acids, sulfonic acids, alkylsulfates, carboxylic acids, metal halides, and iodine. 2. The method for producing an optically active alcohol according to 2. 4. An element constituting a ring of a cyclic olefin is
The method for producing an optically active alcohol according to any one of claims 1 to 3, which contains nitrogen, oxygen, or sulfur. 5. The cyclic olefin has the general formula (I), and the optically active alcohol obtained has the general formula (II) or (II).
The method for producing an optically active alcohol according to claim 4, which is I). [Chemical 1] (In the formula, X is N, O or S. When X is N, N may be unsubstituted or may be substituted with the following substituents a) to e). a) an alkyl group having 1 to 10 carbon atoms, b) an alkyl group having 1 to 10 carbon atoms substituted with a hydroxyl group, a carboxyl group or a carbamoyl group, and c) an aromatic ring which is unsubstituted or has 1 to 10 carbon atoms. An aryl group substituted with a group or a hydroxyl group, d) an aromatic ring is unsubstituted, or an alkyl group having 1 to 10 carbon atoms, an aralkyl group substituted with an alkoxy group having 1 to 10 carbon atoms or a hydroxyl group, e) an alkyl group or an aryl group Represents an oxycarbonyl group. R represents any of the following f) to j). f) an alkyl group having 1 to 10 carbon atoms, an alkoxy group or a hydroxyl group, g) an unsubstituted or an alkyl group having 1 to 10 carbon atoms, an aryl group substituted with an alkoxy group having 1 to 10 carbon atoms or a hydroxyl group, h) An aralkyl group whose aromatic ring is unsubstituted or substituted with an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms or a hydroxyl group, i) an alkyl or aryloxycarbonyl group, j) an acyl group, and m , N and p are all 0 to 10 and m +
The relational expressions of n ≧ 1 and m + n + 2 ≧ p ≧ 0 are satisfied. ) 6. The optically active alcohol according to any one of claims 1 to 5, wherein the oxidizing agent is at least one selected from hydrogen peroxide, perbenzoic acid, peracetic acid, and oxygen. Manufacturing method. 7. The method according to claim 5, wherein p = 0, X = N, m =
n = 1 is satisfied and N is unsubstituted, or
A method for producing an optically active alcohol, characterized in that it is substituted with any of a), d) and e).