JPH1087536A - Production of optically active alicyclic alcohol derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To make it possible to obtain inexpensively, simply and efficiently an alicyclic alcohol of high optical purity, which is useful as raw material for medicines and agrochemicals, by subjecting an tartaric ester to diastereomer splitting followed by hydrolysis. SOLUTION: A compound of the formula each of R<1> and R<2> are a 1-4C alkyl carbonyl, phenyl, a (1-4C alkyl, halogen-substituted) aryl-carbonyl; R<3> is [1-4C alkyl, alkoxy, (1-4C alkyl, halogen-substituted) phenyl, aralkyl- substituted] alicyclic alkyl; the tartaric skeleton is (R, R) configuration or (S, S) configuration} is subjected to the diastereomer splitting through crystallization, column separation, simulated moving bed separation to obtain an optically active tartaric ester followed by hydrolysis.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active alicyclic alcohol derivative which is important as a raw material for medicines and agricultural chemicals, and more particularly to an ester of a racemic alicyclic alcohol derivative and an optically active tartaric acid. This is a method for producing an optically active alicyclic alcohol derivative, comprising producing an optically active tartaric acid ester by diastereomeric resolution of a certain tartaric acid ester, and then hydrolyzing the optically active tartaric acid ester.

[0002]

2. Description of the Related Art Various processes for producing optically active alicyclic alcohol derivatives have been conventionally known. For example, (1) a method in which a racemic cyclohexanol derivative is reacted with propionic acid to synthesize an ester and then enzymatically resolved with LipazeP (Sy
nthesis 1137 (1990)), (2) A method of reacting racemic alcohol and phthalic anhydride, optically resolving the obtained racemic carboxylic acid with optically active α-phenylethylamine, and hydrolyzing to obtain an optically active alcohol (European Patent No.6563
No. 44) is known. These methods are excellent methods for producing optically active alicyclic alcohol derivatives, but each has its own drawbacks. In the method (1), an expensive enzyme is used, and the optical selectivity of the enzyme varies greatly depending on the target compound, so that it is difficult to obtain an alicyclic alcohol derivative having high optical purity.

[0003] In the method (2), after synthesizing a phthalic acid derivative, the optically active α-phenylethylamine and a diastereomer salt must be formed again to perform optical resolution, which is disadvantageous in that it is complicated.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide an inexpensive and simple industrial method for producing an optically active alicyclic alcohol derivative having a high optical purity.

[0005]

Means for Solving the Problems The present inventors diligently studied a method for producing an optically active alicyclic alcohol derivative, and found that a tartaric acid ester synthesized from an optically active tartaric acid anhydride and a racemic alicyclic alcohol derivative was obtained. The inventors have found that an optically active alicyclic alcohol derivative having a high optical purity can be efficiently produced by diastereomeric resolution followed by hydrolysis, thereby completing the present invention. That is, the present invention obtains an optically active tartaric acid ester by diastereomeric resolution of a tartaric acid ester obtained by reacting a racemic alicyclic alcohol derivative with an optically active tartaric anhydride,
Next, a method for producing an optically active alicyclic alcohol derivative by hydrolyzing the obtained optically active tartaric acid ester.

[0006]

DETAILED DESCRIPTION OF THE INVENTION A tartaric acid ester can be produced from a racemic alicyclic alcohol derivative and an optically active tartaric acid derivative anhydride, for example, as shown in formula (2).

[0007]

Embedded image Here, the racemic alicyclic alcohol derivative means an alkyl-substituted alicyclic alcohol such as 2-methylcyclohexanol or 3-methylcyclooctanol, or a halogen-substituted alicyclic alcohol such as 3-chlorocycloheptanol or 2-chlorohexanol. 2-methoxycyclohexanol, 3
-Alkoxy-substituted alicyclic alcohols such as -ethoxycyclooctanol and the like. The racemic alicyclic alcohol derivative is not limited to a mixture containing an equal amount of the R-form and the S-form, but one of the (S) -form and the (R) -form is more than 50%,
Also includes mixtures of up to 9%.

The stereostructure of the optically active tartaric acid derivative anhydride used here can be an L-structure or D-structure compound depending on the purpose. Natural L-tartaric acid derivative anhydrides are preferred from the viewpoint of industrial availability in large quantities and at low cost, but are not limited thereto, and D-tartaric acid derivative anhydrides can also be used. For example, O, O'-dibenzoyl-L-tartaric acid, O, O'-dibenzoyl-D-tartaric acid,
O, O'-Ditoluoyl-L-tartaric acid, O, O'-Ditoluoyl-D-tartaric acid, O, O'-di (p-chlorobenzoyl) -L-tartaric acid, O, O'-di (p-chlorobenzoyl)- D-tartaric acid, O, O'-di (3,4-dimethylbenzoyl) -L-tartaric acid, O, O'-di (3,4-dimethylbenzoyl) -D-tartaric acid and the like.

The method for producing the tartaric acid ester may be a known method. For example, a method of reacting an alcohol with an acid anhydride in the presence of pyridine and paradimethylaminopyridine (Synthesis 1137 (1990)) or a method of reacting in a solvent (Aust. J. Chem., 32, 65 (1979) ))It has been known. The reaction can also be carried out in the presence of a Lewis acid catalyst.

The tartaric acid ester thus obtained is separated into diastereomers. The diastereomer resolution method uses a difference in solubility of each optical isomer to separate by crystallization, a method to separate each optical isomer by a column, and a simulated moving bed for each optical isomer. A division method can be selected depending on the purpose.

In the case of crystallization separation, the crystallization solvent varies depending on the type of ester, but generally, water, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, ketones,
Ethers or a mixed solvent thereof can be used.

When the column is divided, silica gel, modified silica gel, zeolite, alumina and the like can be used as a column filler. In particular, in the case of industrial production, it is more effective to perform column separation in a simulated moving bed.
The developing solvent varies depending on the type of tartaric acid ester and the column packing, but must be a chemically stable solvent. For example, aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and dichloroethane, alicyclic hydrocarbons such as cyclohexane and cyclooctane, acetonitrile, and water can be used alone or in a mixed solvent. Can also be used as

The optically active tartaric ester is obtained by diastereomeric resolution of the tartaric ester. Here, the optically active tartaric acid ester means a mixture in which one of the (S) -form and the (R) -form of the alicyclic alcohol component is 80% or more.

The desired optically active alicyclic alcohol derivative can be produced by hydrolyzing the diastereomerically resolved optically active tartaric acid ester. The ester group can be hydrolyzed with either an acid or an alkali, but it is essential that the optically active alicyclic alcohol of the target compound does not undergo racemization. For example, aqueous solutions of mineral acids such as sulfuric acid and hydrochloric acid,
Alternatively, the reaction may be carried out with an aqueous alkali solution such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like. At that time, hydrolysis can be performed in the presence of an organic solvent such as methanol, isopropanol, acetone, toluene, and chloroform in addition to water as a solvent. The reaction temperature cannot be specified because the hydrolysis rate differs depending on the compound, but heating may be performed within a range not causing racemization, and room temperature to 100 ° C. is preferable. When hydrolyzed with an aqueous alkali solution, O, O'-diacyltartaric acid is simultaneously hydrolyzed with an acyl group to form tartaric acid. When hydrolyzed with a mineral acid aqueous solution, the hydrolysis of the acyl group of O, O'-diparatoluoyltartaric acid or O, O'-dibenzyltartaric acid is slow, and depending on the hydrolysis conditions, O, O'-diparatoluoyltartaric acid, Alternatively, it can be recovered and reused as O, O'-dibenzyltartaric acid.

In order to recover the thus obtained optically active alicyclic alcohol derivative from the reaction solution, for example, it is separated from the optically active tartaric acid or the optically active tartaric acid derivative by solvent extraction and then distilled to obtain the optically active alicyclic alcohol derivative. An alcohol derivative can be obtained.

[0016]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. still,
Optical purity analysis was performed by liquid chromatography. The analysis conditions vary depending on the target compound, but the basic analysis conditions are as follows.

Liquid chromatography analysis conditions; Column: CAPCELL PAK SG120 (manufactured by Shiseido) 4.6 mmφ × 150 mm, eluent: 0.05% phosphoric acid aqueous solution / acetonitrile = 55/45, flow rate: 1 ml / mi
n. Detection UV 254 nm Example 1 Diparatol oil-L- was placed in a 500 ml four-necked flask equipped with a thermometer, a dropping funnel, a condenser and a stirrer.
47.8 g (0.13 mol) of tartaric anhydride, (RS) -2
-Methoxycyclohexanol 13.0 g (0.1 mol), anhydrous iron trichloride 1.2 g, and toluene 300 ml
And heated to reflux for 10 hours. As a result of analyzing the reaction solution by liquid chromatography, diparatoluoyl-L-
Tartaric acid-mono (2-methoxy) cyclohexyl ester was found to be 92%. Under the liquid chromatography analysis conditions, each peak detection time is (R)-
35mi of 2-methoxycyclohexanol ester
n, the ester of (S) -2-methoxycyclohexanol was 37 min. Unreacted diparatol oil-L
-After filtration of the tartaric anhydride, the filtrate was concentrated and then separated by column. Column packing is silica gel (Merck)
8. Kieselgel 60 60-230 mesh) was used for chromatographic separation by changing the composition of acetonitrile / cyclohexane, and diparatoluoyl-L-tartaric acid-mono (R) -2-methoxycyclohexyl ester was used as a forerunner.
5 g were obtained. When analyzed by liquid chromatography,
The ratio of (R) ester to (S) ester was 99/1. This compound was treated with a 1N aqueous solution of sodium hydroxide 30
The mixture was stirred at 30 ° C. for 5 hours and hydrolyzed. The reaction solution was extracted three times with 100 ml of dichloroethane. The extract was concentrated to obtain 2.8 g of a concentrate containing (R) -2-methoxycyclohexanol. Distillation was performed under a reduced pressure of 2.6 kPa to obtain 2.2 g of a distillate. The optical rotation is −
It was 75 ゜. (C = 2.10 dichloromethane)
The post-column components of the column separation were similarly treated to obtain 2.1 g of (S) -2-methoxycyclohexanol. Optical rotation was + 74 °. (C = 2.00 dichloromethane) Example 2 Dibenzoyl-L-tartaric acid-mono (R) -2-methoxycyclohexyl ester obtained in the same manner as in Example was added to about 2
0 g of concentrated solution containing silica gel (Kieselgel manufactured by Merck)
Using a column packed with 60 to 230 mesh), chromatographic separation was performed by changing the composition of acetonitrile / cyclohexane. The eluate was concentrated to obtain 5.8 g of dibenzoyl-L-tartaric acid-mono (R) -2-methoxycyclohexyl ester. Under the above-mentioned liquid chromatography analysis conditions, (R) -2-methoxycyclohexanol ester was detected in 17 minutes, and (S) -2-methoxycyclohexanol ester was detected in 18 minutes. As a result of analyzing the concentrated solution under these conditions, the ratio of (R) -ester to (S) -ester was 98/2. After treating in the same manner as in Example 1, vacuum distillation was performed to obtain (R) -2-methoxycyclohexanol.

[0018]

According to the present invention, an optically active tartaric acid ester having high optical purity can be produced by diastereomeric resolution of a tartaric acid ester which can be easily synthesized from a racemic alcohol and an optically active tartaric acid derivative acid anhydride. I can do it. Furthermore, by hydrolyzing this optically active tartaric acid ester, an optically active alicyclic alcohol derivative which is important as a pharmaceutical intermediate can be produced.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 69/70 C07C 69/70 // C07M 7:00

Claims (6)

[Claims] 1. A compound represented by the following general formula (I): (Here, R ¹ and R ² are an alkyl group having 1 to 4 carbon atoms, a phenyl group, an alkylcarbonyl group having 1 to 4 carbon atoms, unsubstituted, or substituted by an alkyl group having 1 to 4 carbon atoms or a halogen atom. R ³ represents a substituted or unsubstituted alicyclic alkyl group, wherein the substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, or A phenyl group or an aralkyl group substituted or unsubstituted by an alkyl group having 1 to 4 carbon atoms or a halogen atom, and a tartaric acid skeleton represented by (R,
R) conformation or (S, S) conformation. A) diastereomeric resolution of the tartaric acid ester to produce an optically active tartaric acid ester, and then a step of hydrolyzing the tartaric acid ester. 2. In the general formula (I), R ¹ and R ² are the same,
Alternatively, the process for producing an optically active alicyclic alcohol derivative according to claim 1, wherein the alkylcarbonyl group has a different carbon number from 1 to 4. 3. In the general formula (I), R ¹ and R ² are the same,
2. The method for producing an optically active alicyclic alcohol derivative according to claim 1, wherein the compound is an arylcarbonyl group substituted with a different hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a halogen atom. 4. The optically active alicyclic alcohol derivative according to claim 1, wherein in formula (I), the alicyclic alkyl group of R ³ is a cyclohexyl group. Manufacturing method. 5. The method for producing an optically active alicyclic alcohol derivative according to claim 4, wherein in the general formula (I), R ³ is a 2-methoxycyclohexyl group. 6. The method according to claim 1, wherein the diastereomer of the tartaric acid ester represented by the general formula (I) is separated by crystallization, column separation, or separation using a simulated moving bed. 6. The method for producing the optically active alicyclic alcohol derivative according to any one of 1 to 5.