JPH0710822A - Separation of optical isomer of amino acid ester - Google Patents

Abstract

PURPOSE:To easily and efficiently obtain an optical isomer of an amino acid ester having substituted phenyl group or naphthyl group in high optical purity by taking advantage of the formation of a clathrate compound with an optically active host compound. CONSTITUTION:A mixture of optical isomers of an amino acid ester having substituted phenyl group or naphthyl group, e.g. a compound of the formula I (Ar is substituted phenyl or naphthyl; R is a 1-6C alkyl) is dissolved together with a proper amount of an optically active host compound in a solvent and a clathrate compound is precipitated e.g. by temperature change, evaporation of solvent, addition of poor solvent, etc. The objective optical isomer is separated and recovered from the clathrate compound. The optically active host compound is e.g. an acetylene compound of the formula II ((n) is 1-3; X is H, group of the formula III or formula IV; Ar and Ar' are aryl) and a trans-1,2- disubstituted cyclic compound of the formula V [R is group of the formula III or CO-NR<1>2 (R<1> is methyl or two R<1> groups form a group of the formula VI together with N)], especially preferably a benzoic acid derivative of the formula VII or the formula VIII ((m') is 4 or 5).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for separating optical isomers of amino acid esters having a substituted phenyl group or a naphthyl group, and the method for separating optical isomers of amino acid esters of the present invention is mainly used for medicines and agricultural chemicals. It can be used in the field of fine chemistry.

[0002]

2. Description of the Related Art Amino acid esters having a substituted phenyl group or a naphthyl group represented by the following formula (I) are important as intermediates for various fine chemicals, mainly pharmaceuticals and agricultural chemicals. Occupy a position.

[0003]

[Chemical 2]

(In the formula, Ar represents a substituted phenyl group or a naphthyl group, and R represents an alkyl group having 1 to 6 carbon atoms.) Particularly, a substituted phenyl group or a naphthyl group represented by the above formula (I) is contained. The optical isomers of amino acid esters may have remarkably different physiological activities among the optical isomers, and a means for easily obtaining a specific optical isomer has been required.
Conventionally, as a method for obtaining an optically active amino acid ester, (1) a method for separating an amino acid ester using an enzyme (Journal of Organic Chemistry, 3
8 , 457 (1973)) (2) Method of using clathrate compounds (Journal
Of Chemical Society Perkin Transfer, 2, 1971 (1991)) and the like are known. However, in the method of separating using the enzyme of (1), operating conditions such as pH are considerably limited. Further, the method of using the clathrate compound of (2) is efficiently carried out in the resolution of an amino acid ester having no substituted phenyl group or naphthyl group, but for the amino acid ester having a substituted phenyl group or naphthyl group, a host compound Is difficult to predict. That is, when a compound having a similar molecular structure, such as 2-methylcyclohexanone and 3-methylcyclohexanone, is optically resolved using chiral host ace, only 3-methylcyclohexanone is efficiently resolved. (Synthetic organic chemistry,
745 (1987)). As is clear from such an example, it is difficult to predict the host compound by optical resolution using a clathrate compound. Therefore, a means for efficiently obtaining a specific optical isomer has been demanded.

[0005]

The present inventors have searched for a method for separating optical isomers of amino acid esters having a substituted phenyl group or a naphthyl group, and as a result, have utilized clathrate compound formation with an optically active host compound. By doing so, a simple and highly separable method for separating optical isomers of amino acid ester having a substituted phenyl group or a naphthyl group was found, and the present invention was completed.

That is, the present invention forms a clathrate compound of an optical isomer mixture of an amino acid ester having a substituted phenyl group or a naphthyl group and an optically active host compound, and from this clathrate compound, an optical isomer of an amino acid ester. The present invention provides a method for separating optical isomers of amino acid esters, which comprises separating one of the two.

An amino acid ester having a substituted phenyl group or a naphthyl group gives a racemate in a usual chemical synthesis, but a specific optical isomer is industrially required,
By the method of the present invention, an optical isomer having a high optical purity of an amino acid ester having a substituted phenyl group or a naphthyl group can be obtained easily and efficiently.

In the present invention, examples of the amino acid ester having a substituted phenyl group or a naphthyl group include compounds represented by the above formula (I). Ar in formula (I)
Examples of the substituted phenyl group represented by include tolyl, chlorophenyl, bromophenyl, fluorophenyl and the like, and examples of the alkyl group having 1 to 6 carbon atoms represented by R 1 include methyl, ethyl, propyl, butyl and the like. Groups.

The optically active host compound used in the present invention includes an acetylene compound represented by the following formula (II), a trans-1,2-disubstituted cyclic compound represented by the following formula (III), or the following: Examples thereof include biphenyl derivatives represented by the formula (IV), (V) or (VI).

[0010]

[Chemical 3]

[0011]

[Chemical 4]

[0012] In addition, the cyclic structure in the formula has 3 to 7 atoms, any structure atom other than the two carbon atoms may be present, and the cyclic structure may have a substituent. As a specific example of this cyclic structure,

[0013]

[Chemical 5]

[0014]

[Chemical 6]

Among these host compounds, tartaric acid derivatives represented by the following formula (VII) or (VIII) are particularly preferable.

[0016]

[Chemical 7]

Any method may be used for producing the clathrate compound in the method of the present invention. The most common method is to dissolve a mixture of optical isomers of an amino acid ester having a substituted phenyl group or a naphthyl group and an appropriate amount of an optically active host compound in a solvent, and then change the temperature, evaporate the solvent, add a poor solvent, etc. Precipitate the late compound. In some cases, the clathrate compound may be produced simply by mixing. Further, both components can be crystallized by applying ultrahigh pressure in the absence of solvent or in the presence of solvent, and in such a case, crystals different from those under normal pressure may be produced. The solid thus obtained is a clathrate compound and exhibits physical properties (melting point, crystal form, etc.) different from those of the starting material. However, in practice, it is sufficient to achieve the desired separation, and it is not necessary to confirm the presence of the clathrate compound. The method for recovering the optical isomer to be separated from the clathrate compound may be any method, but the simplest method is to separate only the component having a low boiling point into another container by vacuum distillation. By such an operation, the content of the specific optical isomer of the target amino acid ester having a substituted phenyl group or naphthyl group can be increased. In order to further increase the purity, recrystallization may be performed at the stage of clathrate compound.

[0018]

Although the reason why the method of the present invention is suitable for separating optical isomers of amino acid esters having a substituted phenyl group or a naphthyl group is not clear, the optically active host compound used in the present invention is a substituted phenyl group or It has a size and polarity that easily interact with an amino acid ester having a naphthyl group, and is considered to easily form a clathrate compound.

[0019]

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

Example 1 (−) form of a compound represented by the following formula (IX) (2.97 g, 5.
87 mmol) and the racemic amino acid ester represented by the following formula (X) (1.51 g, 5.87 mmol) were dissolved in benzene (3 ml), hexane (6 ml) was added, and the mixture was allowed to stand at room temperature for 24 hours to precipitate crystals. (2.39 g, colorless prism shape). This crystal was recrystallized once from benzene and hexane. The crystals thus obtained were collected by filtration, dried and then heated at 250 ° C. under reduced pressure (1 mmHg) to obtain the (+) form (0.40 g) of the amino acid ester represented by the following formula (X). It was The specific rotation was [α] _D = + 25.9 ° (c 0.59, methanol), and the optical purity was 100% ee.

[0021]

[Chemical 8]

Examples 2 to 8 Optically active amino acid esters were produced in the same manner as in Example 1 by using the racemic amino acid esters shown in Table 1 and the optically active host compounds. The results are shown in Table 1.

[0023]

[Table 1]

[0024]

The host compound used in the present invention can be repeatedly used. Especially tartaric acid derivative host,
Since tartaric acid is used as a raw material, it can be produced in large quantities and at relatively low cost. Therefore, the present invention makes it possible to supply a large amount of an optically active substance of an amino acid ester having a substituted phenyl group or a naphthyl group which is industrially important with high purity.

Claims (2)

[Claims] 1. A clathrate compound of an optical isomer mixture of an amino acid ester having a substituted phenyl group or a naphthyl group and an optically active host compound is formed, and one of the optical isomers of the amino acid ester is formed from the clathrate compound. A method for separating an optical isomer of an amino acid ester, which is characterized by separation. 2. The method for separating optical isomers of an amino acid ester according to claim 1, wherein the amino acid ester having a substituted phenyl group or a naphthyl group is represented by the following formula (I). [Chemical 1] (In the formula, Ar represents a substituted phenyl group or a naphthyl group, R
Represents an alkyl group having 1 to 6 carbon atoms. )