JPH01290635A - Optical resolution process - Google Patents

Abstract

PURPOSE:To perform optical resolution of even a mixture of optical isomers which has been difficult to be separated by conventional optical resolution process, in high efficiency, by converting a mixture of optical isomers into diastereomer and subjecting to chromatography using a stationary phase having optical resolution capability. CONSTITUTION:A mixture of optical isomers having functional group such as hydroxyl group, amino group and carboxyl group (e.g. myoinositol derivative) is made to react with an optically active compound (e.g. l- or d-methoxyacetyl chloride or l- or d-menthol) having a functional group reactive with the fnctional group of said mixture. The resultant diastereomer is subjected to optical resolution by chromatography using a stationary phase having optical resolution capability. The stationary phase is e.g. a metal complex of an optically active amino acid derivative, a polyamino acid, a polysaccaride such as cellulose or amylose, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for efficiently optically resolving a mixture of optical isomers by a diastereomer method.

[Prior Art and Problems to be Solved by the Invention] Many studies have been conducted on methods for efficiently separating mixtures of optical isomers such as amino acids by chromatography. However, all of the conventionally proposed methods have been insufficient in separation performance, and it has been difficult to efficiently separate all optical isomers.

[Means for Solving the Problems] As a result of intensive studies on methods for solving the above-mentioned problems, the present inventors discovered that diastereomers can be optically resolved using a stationary phase capable of optical resolution. reached.

That is, the present invention is characterized in that after a mixture of optical isomers is reacted with an optically active compound to form a diastereomer, the diastereomer is optically resolved by a chromatography method using a stationary phase capable of optical resolution. This is a method for optical resolution of a mixture of optical isomers.

In the present invention, the optical isomer mixture may be any optical isomer, but it is particularly effective to apply to optical isomer mixtures that are difficult to optically resolve.

Typical examples of optical isomers include optically active amino acids, and optical isomers have recently attracted attention in the agricultural and pharmaceutical fields, and examples thereof include natural products or synthetic products. Further, optical isomers such as myo-inositol derivatives can also be exemplified.

Specific examples of myo-inositol derivatives to be subjected to optical resolution include 5,6-di-0-benzoyl-3,4
Examples include -0-(tetraisopropyldisiloxane-1,3-diyl)-myo-inositol and 4,5-di-0-benzoyl-3,6-di-0-benzyl-myo-inositol.

These optical isomer mixtures must have one or more functional groups that can react with optically active compounds, such as hydroxyl groups, amino groups, carboxyl groups,
Any other group that can react may be used.

On the other hand, the optically active compound that forms the diastereomer is the same wood as the optical isomer mixture mentioned above, has substantially high optical purity, and has a functional group that can react with the optical isomer. It is something that you have. Examples of such functional groups include those substantially the same as the functional groups of the optical isomers described above. However, it goes without saying that an optically active compound having a functional group that can react with the functional group of the optical isomer mixture is selected.

That is, specific examples of optically active compounds include 2- or d-menthoxyacetyl chloride, 1- or d-menthyl chloroformate, camphoric acid chloride, 1
- or d-menthol, l or d-1-phenylethylamine, and the like.

The following general conditions are employed in the reaction for producing a diastereomer by reacting an optically active compound with an optical isomer mixture.

The reaction molar ratio between the optical isomer mixture and the optically active compound is usually 1:1. The reaction is carried out in an inert solvent, for example in the presence of a tertiary amine such as triethylamine, and optionally in pyridine. The reaction temperature is preferably in the range of 0°C to room temperature.

In addition, 2- or d-menthol and 2- or d-
When using 1-phenylethylamine, it is preferable to cause the reaction in the presence of a condensing agent such as dicyclohexylcarbodiimide and 2-chloro-1-methylpyridinium.

Recrystallization and silica gel chromatography are usually employed as methods for pre-treating the reaction product for purification and the like.

In the present invention, a stationary phase capable of optical resolution is a packing material containing a compound having an asymmetric center or a molecularly asymmetric compound as an active ingredient.

Examples of fillers containing a compound having an asymmetric center, that is, an asymmetric carbon, as an active ingredient include those using optically active amino acids. Specific examples include those using metal complexes of optically active amino acid derivatives as asymmetric identification, as described in Japanese Patent Publication No. 52-18151, etc., and polymer types such as polyamino acids and cellulose. , polysaccharides such as amylose, or derivatives thereof.

Specifically referring to the polysaccharide or its derivative, the polysaccharide here may be any optically active polysaccharide, regardless of whether it is a synthetic polysaccharide, a natural polysaccharide, or a modified natural polysaccharide.
Preferably, it is a homoglycan with a high degree of regularity, and the binding mode is also constant. More preferably, cellulose, amylose, β-1,4-chitosan, chitin, β-1,4-mannan, β-1,4-xylan, inulin, α-1, 3-
glucan, β-1,3-glucan, etc. A polysaccharide derivative is one in which some or all of the hydrogen atoms of the hydroxyl group or amino group of the polysaccharide, that is, 30% or more, preferably 50% or more, more preferably 85% or more, are replaced with other atomic groups. It is something.

aliphatic group consisting of 3 to 8 carbon atoms, cycloaliphatic group consisting of 3 to 8 carbon atoms
It is an aromatic group consisting of ~20 or a heteroaromatic group consisting of 4 to 20 monomers, and one type of these may be used as the atomic group, but two or more types may be used. This is preferably selected from the viewpoint of separation performance.

Moreover, all may have a substituent. The substituents mentioned here include C3 to Cs such as methyl group and t-butyl group.
Examples include an alkyl group that may have a branch, a halogen such as chlorine, and various other substituents can be used as long as they improve the separation performance. Further, the number of substituents can be selected to be one or more within a range that improves the separation performance. In addition, the position of the substituent may be, for example,
When an aromatic group such as a phenyl group is used, if there is only one type of substituent, it can be selected from the ortho, meta, and rose positions within a range that improves the separation performance. Furthermore, when there are two types of substituents, 3.
Similarly, various placements such as 4th place, 3.5th place, etc. can be selected.

These derivatives can be easily obtained using various known chemical reactions. For example, as an example of synthesis of a cellulose derivative containing an aromatic group, some or all of the hydrogen atoms in the hydroxyl groups of cellulose are replaced with aromatic groups. Examples of the type of bond in this substitution include ester bonds, ether bonds, and urethane bonds.

Examples of the above polysaccharides or derivatives thereof include microcrystalline cellulose, and examples of the polysaccharide derivatives include cellulose triacetate, cellulose tribenzoate, cellulose tris(p-methylbenzoate), cellulose tris phenyl carbamate, Cellulose tris (p-methylphenyl carbamate), cellulose tris (3,5-dimethylphenyl carbamate), cellulose tris (P-chlorophenyl carbamate), cellulose tris (p-t-butylphenyl carbamate), cellulose tricinnamate, etc. .

Further, the above-mentioned derivatives of polysaccharides other than cellulose such as amylose, chitosan, xylan, chitin, and dextran can also be used.

Furthermore, examples of the polymer type include those having an asymmetric carbon in the main chain or those having an asymmetric carbon in the side chain, and synthesized products of either of these can be used.

An example of the former is exemplified in JP-A-53-1350, in which an optically active low-molecular-weight compound supported on silica gel is used for asymmetric identification, and an example of the latter is JP-A-53-1350. Showa 63-1446. Japanese Patent Publication No. 61-16005
4. Japanese Patent Publication No. 61-162750. Japanese Patent Publication No. 61-1627
Examples include those using a polymer having an optically active group in the main chain or side chain, as disclosed in Japanese Patent No. 51, et al.

Furthermore, examples of molecularly asymmetric compounds include optically active polymers whose main component is a polymeric compound represented by the following formula.

〇R, -〇 -R3 In the formula, R,, R2 and R3 are an alkyl group, a halogen or an amino group which may be the same or different, and 11. ta indicates the number of substituents and is an integer from 1 to 5.

The filler used in the present invention, whether inorganic or organic, can be used as a carrier with a particle size of 1 to 10 scales, preferably 1 to 300 scales. Preferably, it is porous, and its average pore diameter is IOλ~1100.
p, preferably 30 to 100 people.

In addition, as for the organic type, it is preferable that the carrier retains 1 to 100% by weight, preferably 5 to 50% by weight.

Although organic carriers can be used, inorganic carriers such as silica gel are preferred, and their properties are as described above. In addition, methods for retaining include physical methods and chemical bonding methods, and it is preferable to subject the carrier to surface treatment such as silane treatment using an organic silane compound.

Chromatography methods such as gas chromatography, liquid chromatography, and thin layer chromatography are available as means for optically resolving diastereomers using an aerated separation agent. Among these, liquid chromatography is most suitable for the optical resolution of the present invention.

The developing solvent used in liquid chromatography or thin layer chromatography is not particularly limited, except for a liquid that dissolves or reacts with the separating agent. When the separation agent is bonded to a carrier by a chemical method or made insolubilized by crosslinking, there are no restrictions except for the reactive liquid. Needless to say, the separation characteristics of compounds or optical isomers change depending on the developing solvent, so it is desirable to consider various developing solvents.

[Examples] Hereinafter, the present invention will be explained in detail with reference to synthesis examples and examples, but the present invention is not limited to these examples.

The definitions of terms used in the examples are as follows.

Separation coefficient (α) = Separation degree (Rs) = Synthesis example 1 (filler) Synthesis of cellulose tris (3,5-dimethylphenyl carbamate): Microcrystalline cellulose (manufactured by Merck & Co., degree of polymerization 1100) 1,
After heating 50 o+fL of pyridine and 6.5 m+1 of 3.5-dimethylphenylisocyanate at 100°C for 17 hours, the reaction mixture was poured into 500 mL of methanol.

The resulting precipitate was filtered and dried to obtain a 3.5-dimethylphenylcarbanate derivative. The degree of substitution was approximately 100%.

Yield: 3.26g Yield: 88% Elemental Analysis One part of the obtained cellulose tris(3,5-dimethylphenylcarbamate) was dissolved in 8 parts of acetone, and silica gel treated with diphenylsilane (Merck Lic) was dissolved in 8 parts of acetone.
After mixing with 4 parts of Hrospher 5i-1000), acetone was distilled off under reduced pressure to obtain a filler.

The filler was made into an inner diameter of 0 by a slurry method using methanol.
．． A column of 4 δ cm and length of 25 cll+ was packed.

Examples 1-2 and Comparative Examples 1-2 The hydroxyl group of the optical isomer mixture, which is an inositol derivative shown in Table 1, was reacted with 1-menthoxyacetyl chloride (1-MntAcCj!) in pyridine at 0°C to room temperature. and separated by silica gel column chromatography to prepare a methanol solution containing a small amount of chloroform.

Next, Isj/w was added to the packing column prepared in the above synthesis example.
The separation coefficient (α) and degree of separation (R
s) was measured and the results are shown in Table 1.

As a comparative example, the results of optical resolution performed using the same fixed layer without inducing diastereomers are also shown.

As a result, the separation ability of the reaction with an optically active compound was significantly improved compared to that of a reaction without reaction, and it was confirmed that even in the case of mixtures for which separation was insufficient using conventional methods, sufficient separation was possible. Ta. By removing the 2-menthoxyacetyl group from the diastereomer thus obtained by a conventional method, the desired optically active myo-inositol derivative could be obtained.

[Effects of the Invention] According to the present invention, the separation efficiency can be significantly improved even for optical isomer mixtures that are difficult to optically resolve.

Claims (1)

[Claims] 1. An optical method characterized by reacting an optically active compound with an optical isomer mixture to form a diastereomer, and then optically resolving the diastereomer by a chromatography method using a stationary phase capable of optical resolution. Method for optical resolution of isomer mixtures.