JPH10139732A - Optically active tartaric ester and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as a raw material to prepare an optically active secondary alcohol used as an important raw material for medicines and agrochemicals by a highly selective and commercially simple method using a tartaric acid derivative anhydride and a racemic secondary alcohol as the feedstocks. SOLUTION: This tartaric ester shown by formula III is produced by reacting a tartaric acid derivative anhydride of formula I (R<1> and R<2> are each a 1-4C alkyl, phenyl, etc.) with a racemic secondary alcohol of formula II (R<3> and R<4> are each a 1-4C alkyl, phenyl, etc.) in the presence of a Lewis acid catalyst. The Lewis acid to be used is preferably iron chloride in terms of operability, wherein its quantity to be used is 0.01-20mol%, preferably 0.1-10mol% based on the compound of formula II. The reaction temperature is 0-150 deg.C, preferably room temperature to 120 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active tartrate ester useful as a raw material for an optically active secondary alcohol which is important as a raw material for pharmaceuticals and agricultural chemicals. A tartrate ester by reacting an active tartaric anhydride in the presence of a Lewis acid catalyst and a method for producing the same; and an optically active tartaric ester by diastereomeric resolution of the tartrate ester, and a method for producing the same.

[0002]

2. Description of the Related Art Various reactions between carboxylic anhydrides and alcohols have been known. For example, (1) a method of reacting an alcohol with propionic anhydride in the presence of pyridine and paradimethylaminopyridine (Synthesis 1137 (1
990)), (2) A method of reacting O, O'-diacetyltartaric anhydride with a pyridine solvent (Aust. J. Chem., 32, 65 (197)
9)) is known. However, when the tartaric acid derivative acid anhydride is reacted in the presence of a base such as pyridine, there is a disadvantage that the amount of by-product impurities increases. Various methods for producing optically active secondary alcohols are also known. For example
(3) A method in which a racemic cyclohexanol derivative is reacted with propionic anhydride to synthesize an ester, and then enzymatically resolved with Lipaze P (Synthesis 1137 (1990)). (4) A racemic cycloaliphatic alcohol and phthalic anhydride are A method is known in which a reaction is carried out in the presence of a base, and the obtained racemic carboxylic acid is optically resolved with optically active α-phenylethylamine (EP656344). These methods are excellent methods for producing optically active secondary alcohols, but each has its own drawbacks.
In the method (3), it is difficult to use an expensive enzyme, and it is difficult to obtain a secondary alcohol having high optical purity since the optical selectivity of the enzyme greatly differs depending on the target compound. In the case of (4), after producing a phthalic acid derivative, a diastereomer salt is formed again by using an optically active amine, and optical resolution must be performed, which is disadvantageous in that it is complicated.

[0003]

SUMMARY OF THE INVENTION The present invention provides a highly selective and simple method for producing tartaric acid esters from tartaric acid derivative anhydrides and racemic secondary alcohols, and an inexpensive and simple method for producing optically active tartaric acid esters having high optical purity. It is to provide a simple industrial manufacturing method.

[0004]

Means for Solving the Problems As a result of intensive studies on a method for producing an optically active tartaric acid ester, the present inventors have found that (1) when reacting an optically active tartaric acid derivative anhydride with a racemic secondary alcohol, a Lewis acid catalyst is used. By making it exist,
It has been found that there are few by-products and that tartrate esters can be produced efficiently, and that (2) further diastereomeric resolution of the esters enables efficient production of optically active tartrate esters with high optical purity, and completed the present invention. I let it. That is, the present invention provides a tartaric acid ester by reacting an optically active tartaric acid derivative anhydride and a racemic secondary alcohol in the presence of a Lewis acid catalyst, a method for producing the same, and an optical method by diastereomeric resolution of the resulting tartaric acid ester. Activated tartaric acid esters and a method for producing the same.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION As the stereostructure of the optically active tartaric acid derivative anhydride used as a raw material, an L-structure or D-structure compound can be used according to 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'-diacetyl-L-tartaric acid, O, O'-diacetyl-D-tartaric acid, O, O'-dibenzyl-L-tartaric acid, O, O'-dibenzyl-D-tartaric acid O, O'- Dibenzoyl-L-tartaric acid, O, O'-dibenzoyl-D-tartaric acid, O, O'-
Dittle oil-L-tartaric acid, O, O'-Dittle oil-
D-tartaric acid, O, O'-di (parachlorobenzoyl)-
L-tartaric acid, O, O'-di (parachlorobenzoyl) -D
-Tartaric acid, O, O'-di (3,4-dimethylbenzoyl) -L-tartaric acid, O, O'-di (3,4-dimethylbenzoyl) -D-tartaric acid, O, O'-di (methoxybenzoyl) ) -L-tartaric acid, O, O'-di (methoxybenzoyl) -D-tartaric acid and the like.

Racemic secondary alcohols as the other raw materials include alkyl secondary alcohols such as methyl ethyl alcohol, aralkyl alcohols such as α-phenylethyl alcohol, and alicyclic alcohols such as 2-methoxycyclohexanol. No. Racemic alcohol is not only a mixture containing equal amounts of R-form and S-form,
A mixture of 50% or more and 99% or less of one of the (S) form and the (R) form is also included.

An optically active tartaric acid derivative anhydride and a racemic secondary alcohol are reacted in a solvent or without a solvent in the presence of a Lewis acid. Aluminum chloride as the Lewis acid,
Zinc chloride, iron chloride and the like can be mentioned, but iron chloride is preferred from the viewpoint of operability. The amount used is from 0.01 to 20 mol%, preferably from 0.1 to 20 mol%, based on the racemic alicyclic alcohol derivative.
10 mol%.

When a solvent is used, any solvent can be used as long as it does not substantially participate in the reaction. Preferably, aromatic solvents such as benzene, toluene and xylene, and alkyl halides such as dichloromethane and chloroform are used. Is preferred.

The reaction temperature is from 0 ° C. to 150 ° C., preferably from room temperature to 120 ° C., but when the temperature is low, the reaction time is prolonged, and when the temperature is too high, impurities are produced as by-products.

[0010] The tartaric acid ester thus prepared is separated into diastereomers. The method of optical resolution is a method of performing crystallization separation using the solubility difference of each optical isomer,
A method of separating each optical isomer by a column, a method of using a simulated moving bed for each optical isomer, and the like can be mentioned, and a resolution method can be selected according to the purpose. In the case of crystallization separation, the crystallization solvent differs depending on each ester, but generally, water, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, ketones, ethers, or a mixed solvent thereof is used. Can be used. For column separation, silica gel, modified silica gel,
Zeolite, alumina and the like can be used. 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 it is an essential condition that the developing solvent be a chemically stable solvent. For example, benzene, aromatic hydrocarbons such as toluene, dichloromethane, halogenated hydrocarbons such as chloroform, cyclohexane, alicyclic hydrocarbons such as cyclooctane, acetonitrile, water and the like can be used. Alternatively, it can be used as a mixed solvent.

Thus, an optically active tartaric acid ester is produced. Here, the optically active tartaric acid ester means a mixture in which one of the (S) form and the (R) form of the secondary alcohol is 80% or more.

[0012]

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,
In the optical purity analysis by HPLC, the eluent composition differs depending on the target compound, but the basic analysis conditions are as follows.

Column: CAPCELL PAK SG1
20 (manufactured by Shiseido) 4.6 mmφ × 150 mm, eluent: 0.05
% Phosphoric acid aqueous solution / acetonitrile = 55/45, flow rate: 1
ml / min. Detection UV254 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%. The peak detection time in liquid chromatography analysis of each product was (R) -2
-Methoxycyclohexanol ester for 35 min,
The ester of (S) -2-methoxycyclohexanol was 37 minutes. From the analytical data, the ratio of (R) -ester to (S) -ester of the produced tartaric acid ester was almost 1/1. Next, after unreacted diparatoluoyl-L-tartaric anhydride was filtered, the filtrate was concentrated and then subjected to column separation. The column packing is silica gel (Kieselgel 60 60-230 mesh manufactured by Merck), chromatographed by changing the composition of acetonitrile / cyclohexane, and diparatoluoyl-L-tartaric acid-mono (R).
9.5 g of 2-methoxycyclohexyl ester was obtained. Analysis by liquid chromatography showed that (R)
-The optical purity of the ester was 98% ee. ¹ H-NMR chart of this compound (CDCl 3 was used as a solvent)
And MS spectrum are shown in FIGS.

EXAMPLE 2 51.0 g (0.15 mol) of dibenzoyl-L-tartaric anhydride, (RS) -2-methoxycyclohexane was placed in a 500 ml four-necked flask equipped with a thermometer, a dropping funnel, a condenser and a stirrer. 13.0 g (0.1 mol) of hexanol,
1.2 g of anhydrous iron trichloride and 300 ml of toluene were charged and heated under reflux for 10 hours. As a result of analyzing the reaction solution by liquid chromatography, 95% of dibenzoyl-L-tartaric acid-mono (2-methoxy) cyclohexyl ester was produced. The peak detection time of each product in liquid chromatography analysis was 17 minutes for (R) -2-methoxycyclohexanol ester and 17 minutes for (S) -2-
The ester of methoxycyclohexanol was 18 minutes. From the analytical data, the ratio of (R) -ester to (S) -ester of the produced tartaric acid ester was almost 1/1.
Met. After filtration of the insoluble matter, the filtrate was concentrated, and chromatographed by changing the composition of acetonitrile / cyclohexane using a column filled with silica gel (Kieselgel 60 60 to 230 mesh manufactured by Merck) to change the composition. 10.8 g of tartaric acid-mono (R) -2-methoxycyclohexyl ester was obtained. When analyzed by liquid chromatography, the optical purity of the (R) -ester was 96.
% Ee. FIG. 3 shows the ¹ H-NMR chart of this compound (CDCl 3 was used as a solvent).

Example 3 In the same apparatus as in Example 1, 2.5 g (0.02 mol) of α-phenylethyl alcohol, diparatoluoyl-L-
Tartaric anhydride (14.7 g, 0.04 mol), anhydrous iron trichloride (37 mg), and toluene (60 g) were charged and heated under reflux for 5 hours. As a result of analyzing the reaction solution by liquid chromatography, diparatoluoyl-L-tartaric acid-mono (RS) -α
-Phenylethyl ester was 88% produced. still,
The peak detection time in liquid chromatography analysis of each product was (R) -α-phenylethyl alcohol ester for 37 min and (S) -α-phenylethyl alcohol ester for 43 min. From this analytical data, the ratio of (R) -ester to (S) -ester of the produced tartaric acid ester was approximately 1.2 / 1. After filtering the insoluble matter, the filtrate was concentrated, and chromatographically separated by changing the composition of acetonitrile / cyclohexane using a column filled with silica gel (Kieselgel 60 60 to 230 mesh manufactured by Merck) to change diparatol oil-. 3.1 g of L-tartaric acid-mono (R) -α-phenylethyl ester
g was obtained. When analyzed by liquid chromatography,
The optical purity of (R) -ester was 96% ee.

[0016]

According to the present invention, a tartaric acid ester can be easily synthesized from a racemic alcohol and an optically active tartaric acid derivative anhydride. Further, by diastereomeric resolution of the ester, an optically active tartaric ester having high optical purity can be easily produced. This optically active tartaric acid ester is a compound useful as a raw material for producing an optically active alcohol.

[Brief description of the drawings]

FIG. 1 is a chart showing a ¹ H-NMR chart of a compound obtained in Example 1.

FIG. 2 is a view showing an MS spectrum of the compound obtained in Example 1.

FIG. 3 is a chart showing a ¹ H-NMR chart of a compound obtained in Example 2.

Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // C07B 61/00 300 C07B 61/00 300 C07M 7:00

Claims (11)

[Claims] 1. A compound represented by the following general formula (I): (Where 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, an unsubstituted or an alkyl group having 1 to 4 carbon atoms,
Represents an alkoxy group or an arylcarbonyl group substituted with a halogen atom, and may be the same or different. The tartaric acid skeleton has an (R, R) conformation or an (S, S) conformation. ) And an optically active tartaric acid derivative anhydride represented by the following general formula (II): (Where R ³ and R ⁴ are a substituted or unsubstituted C 1 -C 1)
R ³ and R ⁴ are different from each other in an alkyl group of 4, an unsubstituted or C1-C4 alkyl group, a phenyl group and an aralkyl group substituted with a halogen atom. Alternatively, R ³ and R ⁴ are an alicyclic alkyl group bonded thereto, and the alicyclic alkyl group is substituted with an alkyl group having 1 to 4 carbon atoms or an alkoxyl group. ) To react with a racemic secondary alcohol represented by the following general formula (III): (Wherein R ¹ , R ² , R ³ , and R ⁴ are the same as described above). A method for producing a tartaric acid ester, which comprises the presence of a Lewis acid in producing the tartaric acid ester. 2. An anhydride of an optically active tartaric acid derivative represented by the general formula (I)
V) embedded image (Here, R ⁵ and R ⁶ represent an alkylcarbonyl group having 1 to 4 carbon atoms and may be the same or different. Further, the tartaric acid skeleton has an (R, R) conformation or an (S, S) conformation. The method for producing a tartaric acid ester according to claim 1, which is at least one selected from optically active O, O-diacyltartaric anhydrides represented by the following formula: 3. An optically active tartaric acid derivative anhydride having the following general formula (V): (Here, R ⁷ and R ⁸ are unsubstituted or an alkylcarbonyl group having 1 to 4 carbon atoms or an arylcarbonyl group substituted with a halogen atom, and may be the same or different. In addition, the tartaric acid skeleton is represented by (R, The method for producing a tartaric acid ester according to claim 1, wherein the tartaric acid ester is an optically active tartaric anhydride represented by (R) conformation or (S, S) conformation). 4. The method for producing a tartaric acid ester according to claim 1, wherein the racemic secondary alcohol is a racemic alicyclic alcohol derivative. 5. The method according to claim 4, wherein the racemic alicyclic alcohol derivative is 2-methoxycyclohexanol. 6. The method for producing a tartaric acid ester according to claim 1, wherein the Lewis acid is iron chloride. 7. A compound of the general formula (III) (Where 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, an unsubstituted or an alkyl group having 1 to 4 carbon atoms,
Represents an alkoxy group or an arylcarbonyl group substituted with a halogen atom, and may be the same or different. R
^3, R ⁴ is a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, an unsubstituted or alkyl group having 1 to 4 carbon atoms, a phenyl group substituted by a halogen atom, an aralkyl group, R ³
And R ⁴ are different. Alternatively, R ³ and R ⁴ are an alicyclic alkyl group bonded thereto, and the alicyclic alkyl group has 1 to 1 carbon atoms.
4 is substituted with an alkyl group or an alkoxyl group. )) A method for producing an optically active tartaric ester, wherein the tartaric ester represented by the formula (1) is diastereomerically resolved. 8. A method for producing an optically active tartaric acid ester, which comprises separating the tartaric acid ester produced by the method according to claim 1 into diastereomers. 9. The optically active tartaric acid ester according to claim 7 or 8, wherein the diastereomer resolution is carried out by any one of crystallization separation, column separation, and separation using a simulated moving bed. Manufacturing method. 10. A compound of the general formula (VI) (Wherein R ⁷ and R ⁸ represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an arylcarbonyl group substituted with a halogen atom, and may be the same or different). 11. A compound of the general formula (VI) (Where R ⁷ and R ⁸ represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an arylcarbonyl group substituted with a halogen atom, and may be the same or different), and have an optical purity of 80%. Optically active tartaric ester of ee or higher.