JP2003286255A - Method for producing high-purity optically active cyclic alcohol - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To produce a high-purity optically active alcohol from a nitrogen- containing cyclic olefin. <P>SOLUTION: The method for producing the high purity optically active cyclic alcohol comprises refining an optically active cyclic alcohol obtained by a production method comprising (1) a step for reacting a mixed liquid of an α-pinene with sodium borohydride and an activating agent with a nitrogen- containing cyclic olefin and (2) a step for reacting the reaction liquid obtained in the step (1) with an oxidizing agent by using an optically active carboxylic acid. An optically active amino acid, etc. is preferably used as the optically active carboxylic acid. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active nitrogen-containing cyclic alcohol. The optically active nitrogen-containing cyclic alcohol is a compound useful as a pharmaceutical intermediate, an agricultural chemical intermediate, a liquid crystal material, a fragrance, and the like.

[0002]

2. Description of the Related Art As a method for synthesizing an optically active nitrogen-containing cyclic alcohol characterized by converting a carbon-carbon double bond into a hydroxyl group, a method via a hydroboration reaction is known. For example, α-pinene and diborane or BH ₃
-Synthesis of optically active N-substituted-3-pyrrolidinol by asymmetric hydroboration-oxidation using diisopinocamphenylborane synthesized from SMe ₂ etc. (Journal of Organic Chemistry.,
51, 4296, (1986), Journal of American Chemical Society. , 108, 204
9 (1986), Heterocycles, 28, 1, 283.
(1989)).

However, in the method described in the literature, BH3.SMe2 is used as the borane source, which is very expensive as an industrial raw material and economically economical except when the target product is considerably expensive. It doesn't match. Also, BH3 ・ S
1 diisopinocampheylborane synthesized from Me2
-Benzyl-3-pyrroline is used in a two-fold molar amount and is carried out under severe conditions of -25 ° C, but there is a description suggesting that the optical purity is lowered when the reaction temperature is 0 ° C. However, nothing is mentioned about the influence of the amount and temperature of diisopinocampheylborane used on the chemical yield and the optical purity.

As a method of generating diborane in the system, a method of reacting sodium borohydride with an activator such as boron trifluoride is known (Journal
Of American Chemical Society. , 86,
No. 393 (1964)) examined the synthesis of an optically active nitrogen-containing cyclic alcohol using borane generated by this method.

Further, in the method described in the literature, since the reaction temperature is as low as -25 ° C., it is necessary to install special cooling equipment, it is difficult to carry out with general equipment, and it is hard to say that it is a practical method. .

Certainly, at a laboratory level, 99% ee. When the above α-pinene is used, 99% ee. Although an optically active alcohol of 99% ee. The method of synthesizing the high-purity α-pinene of H. et al. C. The method of Brown et al. Is only known (Journal of Organic Chemistry., 47, 4583, (1982)), and it is not suitable for an industrial production method in terms of price and has a high purity. No example of industrially using α-pinene has been reported.

Further, as a method for highly purifying a racemic nitrogen-containing cyclic alcohol, a diastereomer salt resolution method using an acidic compound (JP-A-11-246522, JP-A-9-263578, JP-A-402166).
No. 2, Japanese Patent No. 2830364, etc.) and enzyme resolution methods (Japanese Patent No. 3024361, Japanese Patent No. 2703768, etc.) are known, but a low-purity optically active alcohol synthesized from a nitrogen-containing cyclic olefin is highly purified. No examples have been reported.

Therefore, at present, there has been no report on a method for industrially producing a high-purity optically active cyclic alcohol from a nitrogen-containing cyclic olefin.

Therefore, H. C. Even when an attempt is made to obtain a high-purity optically active alcohol by purifying a low-purity optically active alcohol synthesized from low-purity α-pinene using the method of Brown et al., H. C. Α-as reported by Brown et al.
An optically active alcohol corresponding to the optical purity of pinene was not obtained, and industrial use was impossible.

Therefore, it has been strongly desired to create a safe and convenient industrial process for producing a highly pure optically active cyclic alcohol.

[0011]

DISCLOSURE OF THE INVENTION The present invention is an industrial process for producing a high-purity optically active cyclic alcohol using inexpensive raw materials, using a safe and simple process when producing a high-purity optically active cyclic alcohol. To provide a manufacturing method.

[0012]

Means for Solving the Problems The inventors of the present invention have earnestly studied a method for producing a high-purity optically active cyclic alcohol by a safe and simple method using inexpensive raw materials, and completed the present invention. That is, (1) a step of reacting a mixed solution of α-pinene, sodium borohydride and an activator with a nitrogen-containing cyclic olefin, (2) the reaction solution obtained in the step (1) as an oxidant. A method for producing a highly pure optically active cyclic alcohol, which comprises purifying an optically active cyclic alcohol obtained by a production method comprising a step of reacting with an optically active carboxylic acid.

[0013]

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

The specific method of this reaction is illustrated, but not limited thereto.

An activator is added to a mixed solution containing α-pinene, sodium borohydride, and optionally a solvent.
Here, the amount of sodium borohydride used is usually α
-It is 0.1 to 1.0 mol times, preferably 0.2 to 0.8 mol times, and more preferably, to pinene.
It is 0.2 to 0.6 mol times. On the other hand, the amount of the activator to be used varies depending on the kind of the activator, but it is usually 0.1 to 1.0 mol times with respect to α-pinene, and preferably 0.
2 to 0.8 mole times, and more preferably 0.2 to
It is 0.6 mol times. The order of charging the raw materials is not limited, and α-pinene may be added last, but it is preferable to add the activator last, and the nitrogen-containing cyclic olefin is added in the next step. To do.

First, the α-pinene used means one that is industrially available. In the present invention, since there is a purification step with an optically active carboxylic acid, even if a low-purity α-pinene is used, a high purity is obtained. A pure optically active cyclic alcohol can be obtained. In this case, the optical purity is 70 to 95% ee. Are preferred. The chemical purity is also not particularly limited, and a mixture of other terpenes and a solution state with a solvent can be used as long as α-pinene is the main component, but generally 90% or more. , Preferably 9
It is 5% or more. Regarding the optical rotatory power, either a (+) body or a (-) body may be used depending on the purpose.

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, dimethylsulfate, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, methyl iodide and iodine, and more preferably boron halide.

When boron halides are used, they may be used alone or as a mixture, and may be used as a complex with a solvent or the like. For example, boron trifluoride / dimethyl ether complex, boron trifluoride / diethyl ether complex, boron trifluoride / tetrahydrofuran complex, boron trifluoride / 1,4-dioxane complex, boron trifluoride / methanol complex, trifluoride Examples thereof include boron / pyridine complex and boron trifluoride / triethylamine complex.

As an example of the nitrogen-containing cyclic olefin,
1,2-dihydroazeto, azeto derivatives such as 2-methyl-1,2-dihydroazeto, 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-
Pyrroline derivatives such as benzyl-2-ethylpyrroline and 4-phenyl-2-pyrroline can also be used as
-Tetrahydropyridine, N-methyl-1,2,3,4
-Tetrahydropyridine, N-benzyl-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,
Examples thereof include a tetrahydropyridine derivative such as 3,4-tetrahydropyridine, and the like, preferably a pyrroline derivative or a tetrahydropyridine derivative, more preferably represented by any of the general formulas (I) to (IV). 2-pyrroline derivative, 3-pyrroline derivative 1,2,3,6-tetrahydropyridine derivative or 1,2,3,4-tetrahydropyridine derivative.

[0021]

[Chemical 2]

(Wherein X is a) an alkyl group having 1 to 10 carbon atoms, and b) an aromatic ring is substituted with an unsubstituted, alkyl group having 1 to 10 carbon atoms or an alkoxy group having 1 to 10 carbon atoms. Aryl group, c) the aromatic ring is unsubstituted, and has 1 to 10 carbon atoms
Or an aralkyl group substituted with an alkoxy group having 1 to 10 carbon atoms, d) an alkyl or aryloxycarbonyl group, and R is e) an alkyl group or alkoxy group having 1 to 10 carbon atoms. , F) an aryl group in which the aromatic ring is unsubstituted or substituted with an alkyl group having 1 to 10 carbon atoms or an alkoxy group having 1 to 10 carbon atoms, g) an aromatic group is unsubstituted, alkyl having 1 to 10 carbon atoms Group, or an aralkyl group substituted with an alkoxy group having 1 to 10 carbon atoms, h) an alkyl or aryloxycarbonyl group, and n is 0 to 4. ) Further, the structure of the optically active cyclic alcohol obtained is such that at least one of the elements constituting the ring is a nitrogen atom,
Specific examples thereof include, but are not limited to, 2-azetidinol, 3-azetidinol, and 2-methyl-3-.
Azetidinol, 3-methoxy-2-azetidinol,
Azetidinol derivatives such as N-benzyl-2-azetidinol, 2-pyrrolidinol, 3-pyrrolidinol,
2-methyl-3-pyrrolidinol, 3-ethoxy-2-
Pyrrolidinol, N-benzyl-3-pyrrolidinol,
Pyrrolidinol derivatives such as 2-piperidinol, 3
-Piperidinol, 4-piperidinol, 2-methyl-
3-piperidinol, N-benzyl-3-piperidinol, and other piperidinol derivatives, 2-azepanol,
3-azepanol, 4-azepanol, 2-methyl-3
-Azepanol derivatives such as azepanol and N-benzyl-3-azepanol can be mentioned, and five-membered cyclic pyrrolidinol derivatives and six-membered cyclic piperidinol derivatives are preferable.

The optically active carboxylic acid used for purification is
Although not particularly limited, examples thereof include an optically active amino acid derivative, an optically active tartaric acid derivative, an optically active mandelic acid derivative, etc., preferably an optically active amino acid derivative, more preferably an optically active phenylalanine derivative, an optically active phenylglycine derivative. is there.

Specific examples of the oxidizing agent used in the present invention include:
Examples thereof include hydrogen peroxide, perbenzoic acid, peracetic acid, oxygen, etc., preferably hydrogen peroxide, perbenzoic acid, peracetic acid, and more preferably hydrogen peroxide.

It is preferable to use a solvent in the step (1), and specific examples of the solvent include tetrahydrofuran, tetrahydropyran, monoglyme, diglyme, dimethoxymethane, dimethoxyethane, diethoxymethane, diethoxyethane, diethyl ether, isopropyl ether. , Aliphatic ethers such as dibutyl ether, methyl tert-butyl ether, 1,4-dioxane and 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 solvent used here is a water concentration,
It is not necessary to perform a treatment for reducing the dissolved oxygen concentration in advance.
Since diborane and borane complex decompose immediately due to the influence of water and dissolved oxygen, pretreatment of the solvent is essential, but in this system, a commercially available solvent can be used without pretreatment. The same result as in the case of pretreatment is obtained. This means that the step of drying the solvent is unnecessary, and the result of the present study found that the result is very significant when considering the industrial process.
However, it is preferable to carry out the nitrogen substitution in the reaction system as it is carried out in a usual industrial process.

The amount of the reaction solvent used is preferably such that the total concentration of α-pinene, sodium borohydride and the activator is in the range of 5 to 80% by weight. It is preferably 10 to 60% by weight, and more preferably 20 to 50% by weight. Within this range,
Whether the reaction liquid is a solution or a slurry, there is no problem in operation and it can be applied to industrial production.

The reaction temperature in the step of mixing α-pinene, sodium borohydride and the activator is not particularly limited, but is preferably -80 to 80 ° C,
More preferably -20 to 20 ° C, particularly preferably -1.
It is 0-10 degreeC. Within this range, it can be applied to industrial production using general-purpose equipment.

On the other hand, the temperature of the step of reacting the nitrogen-containing cyclic olefin is -10 to 10 when the industrial production method is assumed.
It is preferably in the range of 10 ° C. That is, when the method described in the above-mentioned document is carried out at -25 ° C, BH ₃ (complex system, which is difficult to use industrially, rapidly reacts, and the optically active -3 with an isolated yield of 89%. -Pyrrolidinol was obtained, but it was found that the method for generating borane in the system shown in the present study significantly reduced the yield. In the literature, optically active N-carbobenzyloxy-3-
In the pyrrolidinol synthesis, the optical purity of the obtained optically active alcohol is lower than that of the raw material α-pinene (1
00% ee. → 89% ee. ) And nothing about the synthesis of optically active N-benzyl-3-pyrrolidinol which basically differs in reaction conditions such as the amount of reagent used.

Further, the amount of BH ₃ reagent used is different in both compounds, and the optical purity of the produced optically active alcohol is also an estimated value from the optical rotation, which is generally more accurate than the method using GC or HPLC. Can be said to be low.

On the other hand, in general, the higher the temperature is, the lower the optical purity of the optically active-3-pyrrolidinol produced is. Therefore, the temperature of the step is preferably within the range of -10 to 10 ° C.

When boron halide is used as the activator, the amount of the nitrogen-containing cyclic olefin used in the reaction is preferably 0.5 mol times or less of the boron halide used. That is, when the amount used is more than this value, the nitrogen-containing cyclic olefin does not react quantitatively, the raw material remains, and the optical purity of the obtained high-purity optically active cyclic alcohol is 0.5 times mol. It was confirmed that it was lower than the case.

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 that the reaction solution obtained by adding the cyclic olefin is made alkaline and then the oxidizing agent is added. Specifically, the pH value is 7
It is larger, and 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 in the range of -25 to 80 ° C.

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

The optical purity of the low-purity optically active alcohol obtained in the step (2) has a great influence on the chemical yield and optical purity of the high-purity optically active alcohol obtained in the subsequent purification step.

Since the production efficiency greatly changes depending on the optical purity of the low-purity optically active alcohol, a low-purity optically active alcohol having an optical purity equivalent to that of low-purity α-pinene is used in the purification step from the viewpoint of manufacturing cost. There is a need.

As a method for purifying the low-purity optically active alcohol thus obtained, any method using an optically active carboxylic acid can be adopted. Although the amount of the optically active carboxylic acid used varies depending on the type to be used, it is usually used in an amount of 0.5 to 1.5 mol times, and preferably 0.6 to 1.2 mol, with respect to the low purity optically active alcohol. Times, and more preferably 0.7 to 1.2 times by mole.

In addition, during purification, a mineral acid such as sulfuric acid or hydrochloric acid may be allowed to coexist in the charged liquid. In this case, the mineral acid forms a soluble salt with the low-purity optically active alcohol instead of the optically active carboxylic acid to dissolve the unwanted optical isomers, which promotes purification and reduces the amount of optically active carboxylic acid used. It is effective when you want to.

As a general operation method, a known method may be adopted. In the presence of a solvent, an acidic compound is added to a mixed solution of N-benzyl-3-pyrrolidinol and a solvent, and the temperature is raised with stirring. Dissolve completely. After that, preferably, a method is employed in which seed crystals are added to precipitate a diastereomeric salt, the mixture is sufficiently aged, and then gradually cooled.

The temperature range adopted in this operation varies depending on the purpose and the type of solvent, but is generally 0 to 100 ° C.

As the optically active carboxylic acid used here, various ones such as an optically active tartaric acid derivative, an optically active mandelic acid derivative and an optically active amino acid derivative are used, but preferably an optically active amino acid derivative,
More preferably, it is an optically active phenylalanine derivative or an optically active phenylglycine derivative.

The solvent used here is N-benzyl-3.
-Pyrrolidinol and an optically active carboxylic acid are both dissolved, and a diastereomeric salt can be precipitated without chemically deteriorating. For example, water, alcohols such as methanol, ethanol, n-propanol and isopropanol, and ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone can be used.

The crystals thus obtained can be isolated by a method such as filtration. This crystal is N-benzyl-3
-A salt of pyrrolidinol and an acidic compound, and the method of decomposing the salt is arbitrary. For example, a method of treating with an acid or an alkali in an aqueous solvent can be applied.

As described above, as the industrial production method of high-purity optically active alcohol, the production conditions which regulated the amount of the nitrogen-containing cyclic olefin raw material and the reaction temperature were found, whereby the optical purity of low-purity α-pinene was determined. By establishing a method for producing a low-purity optically active alcohol maintaining the above condition, and further purifying using an acidic compound, a safe and simple industrial process with cost competitiveness has been established. A conceptual diagram of the process is shown below in comparison with the method described in the known literature.

<Methods described in publicly known documents> Low-purity α-pinene → (purification) → high-purity α-pinene → (reaction) → high-purity optically active alcohol <Method described in this case> low-purity α-pinene → (reaction) → Low-purity optically active alcohol → (Purification) → High-purity optically active alcohol

[0049]

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited thereto.
However, all the reactions exemplified below were carried out under a nitrogen atmosphere.

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 3.2mm × 1.0m Carrier helium Injection pressure 70kPa / cm2 Column temperature 50 ° C (2min)-(20 ° C / min Temperature rise) -140 ° C (2 minutes)-(20 ° C / min) -220 ° C (2.5 minutes) Injection temperature 230 ° C Detector temperature 230 ° C Detection method FID sample preparation method The reaction solution before oxidation is oxidized. Used for analysis after processing.

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 (adjusted to pH 4.5 with acetic acid) / acetonitrile = 48/52 (v / v) Flow rate 1 0.0 ml / min Temperature 40 ° C. Detector UV (243 nm) Sample preparation The optically active alcohol is derivatized to diastereomer with di-o-toluoyl-D-tartaric anhydride and then used for analysis. Example 1 72 g of undried tetrahydrofuran and (+)-α-pinene (optical purity 84% ee.) In a 300 mL round-bottomed flask equipped with a dropping funnel, a condenser, and a stirrer, which had been previously degassed in vacuum and purged with nitrogen, 28 0.0 g (= 0.206 m
ol) was added and mixed. To this, 2.91 g (= 0.0769 mol) of sodium borohydride was added and cooled to 0 ° C. To the slurry, 14.6 g of boron trifluoride / diethyl ether complex (boron trifluoride / diethyl ether complex (= 0.102 mol) was added over 0.5 hours, and then at a temperature of 0 to 15 ° C for 12 hours. The reaction solution was aged and then N-benzyl-3-pyrroline 8.21 was added to the reaction solution.
g (= 0.0516 mol), the temperature of the reaction solution is -5
The mixture was added dropwise while adjusting to 0 ° C. and reacted for 7 hours.

The thus obtained (S) -N-benzyl-3-
To the reaction solution of pyrrolidinol, 40.0 g (= 0.300 mol) of 30% sodium hydroxide aqueous solution and 34.0 (= 0.300 mol) of 30% hydrogen peroxide solution were added in this order, and then the upper layer was extracted and 30% sulfuric acid water was added. The pH was adjusted to 1.0 with and the THF was distilled off under reduced pressure with an evaporator and then extracted twice with toluene. The extraction residual water layer was adjusted to pH 11 or higher with a 30% aqueous sodium hydroxide solution and extracted twice with toluene. After mixing the toluene layers, concentrate to concentrate 8.69 g of 83
% Ee. (S) -N-benzyl-3-pyrrolidinol was isolated (chemical purity 95.0%, optical purity 83% e
e. , Isolation yield 90.0% / vs. N-benzylpyrroline).

7.47 g of N-benzyl-3-pyrrolidinol thus obtained (N-benzylpyrroline pure content = 7.1)
0 g, 0.0400 mol) thermometer, condenser,
Place in a 100 ml round bottom flask with stirrer, 19.
8 ml ethanol / isopropanol = 85/15 and p-toluenesulfonyl-L-phenylalanine 12.
7 g (= 0.0400 mol) was added and stirred. 70 ° C
After the temperature was raised to dissolve, a seed crystal was added and aged, and then cooled to 20 ° C. The precipitated crystals were filtered, 48% aqueous sodium hydroxide solution was added, and the mixture was extracted with toluene. After toluene was concentrated, it was distilled to obtain yellow oily N-benzyl-3-
6.2 g of pyrrolidinol was obtained. As a result of analysis by HPLC, the optical purity was 97.5% ee. (Isolated yield 87.3%, charged (S) -body standard 94.2%).

Example 2 An experiment was conducted in the same manner as in Example 1 except that the amount of N-benzyl-3-pyrroline added was changed to 9.52 g (= 0.0598 mol).

As a result of analyzing the reaction solution, (S) -N-
Benzyl-3-pyrrolidinol yield was 69% (vs. N-benzylpyrroline), chemical purity was 95%, optical purity was 77.
% Ee. Met.

Of the N-benzyl-3-pyrrolidinol thus obtained, 7.50 g (N-benzylpyrroline pure content =
7.12 g, 0.0402 mol)
Purification with p-toluenesulfonyl-L-phenylalanine was carried out in the same manner as in.

As a result, 6.16 g of N-benzyl-3-pyrrolidinol was obtained. As a result of analysis by HPLC,
The optical purity is 97.0% ee. (Isolated yield 86.
5%, preparation (S) -body standard 96.3%).

Comparative Example An experiment was carried out under the same conditions except that N-benzyl-3-pyrrolidinol used in Example 1 was changed to a racemate.

As a result, 3.1 g (= 0.017 mol) of N-benzyl-3-pyrrolidinol was obtained. The optical purity is 81.8% ee. (Isolated yield 42.4%, charged (S) -form basis 79.4%).

[0063]

According to the present invention, an optically active cyclic alcohol obtained by adding a nitrogen-containing cyclic olefin to a mixed solution of α-pinene, sodium borohydride and an activator and then treating the resulting mixture with an oxidant, By purifying using an optically active carboxylic acid, a highly pure optically active cyclic alcohol can be produced in high yield, safely, simply and efficiently.

Claims (7)

[Claims] 1. A step (1) of reacting a mixed solution of α-pinene, sodium borohydride and an activator with a nitrogen-containing cyclic olefin, (2) a reaction solution obtained in the step (1) above. A method for producing a highly pure optically active cyclic alcohol, characterized in that the optically active cyclic alcohol obtained by the method comprising the step of reacting with an oxidizing agent is purified using an optically active carboxylic acid. 2. A nitrogen-containing cyclic olefin represented by the general formula (I):
(IV) [Chemical formula 1] (In the formula, X is a) an alkyl group having 1 to 10 carbon atoms, and b) an aromatic ring in which the aromatic ring is substituted with an unsubstituted alkyl group having 1 to 10 carbon atoms or an alkoxy group having 1 to 10 carbon atoms. , C) an aromatic ring is unsubstituted, an aralkyl group substituted by an alkyl group having 1 to 10 carbon atoms or an alkoxy group having 1 to 10 carbon atoms, d) an alkyl or aryloxycarbonyl group, and R is , E) 1 to 1 carbon atoms
0 alkyl group or alkoxy group, f) aromatic ring is unsubstituted, alkyl group having 1 to 10 carbon atoms, or 1 carbon atom
An aryl group substituted with an alkoxy group having 10 to 10 g) an aromatic ring having no substituent, an alkyl group having 1 to 10 carbon atoms, or an aralkyl group substituted with an alkoxy group having 1 to 10 carbon atoms, h) alkyl or aryl It represents any of oxycarbonyl groups, and n is any of 0 to 4. The method for producing a highly pure optically active cyclic alcohol according to claim 1, which is a pyrroline derivative or a tetrahydropyridine derivative represented by any one of (1) to (4). 3. The method for producing a highly pure optically active cyclic alcohol according to claim 1, wherein the activator is a boron halide. 4. The highly pure optically active cyclic alcohol according to claim 1, wherein the amount of the nitrogen-containing cyclic olefin used is 0.5 times or less the molar amount of the boron halide. Manufacturing method. 5. The method for producing a highly pure optically active cyclic alcohol according to claim 1, wherein the reaction temperature in step (2) is −10 to 10 ° C. 6. The optical purity of α-pinene is 70 to 95% e.
e. It is any one of Claims 1-5 characterized by these.
Item 6. A method for producing a highly pure optically active cyclic alcohol according to Item. 7. The optically active carboxylic acid is an optically active amino acid derivative, according to any one of claims 1 to 6.
Item 6. A method for producing a highly pure optically active cyclic alcohol according to Item.