JP2708466B2 - Optical splitting method - Google Patents

Description

The present invention relates to a method for efficiently resolving a mixture of optical isomers of myo-inositol by a diastereomer method.

[Prior Art and Problems to be Solved by the Invention] Many studies have been made on a method for efficiently separating a mixture of optical isomers such as amino acids by a chromatography method. However, conventionally, any of the proposed methods has insufficient separation performance,
It was difficult to efficiently separate all optical isomers.

[Means for Solving the Problems] The present inventors have conducted intensive studies on a method for solving the above-mentioned problems, and as a result, have found that diastereomers can be optically resolved by a stationary phase having optical resolution, and the present invention has been achieved. Reached.

That is, the present invention provides a diastereomer by reacting an optically active compound with an optical isomer mixture of myo-inositol, and the diastereomer is subjected to a chromatography method using a stationary phase containing a polysaccharide derivative as an active ingredient. This is an optical resolution method for a myo-inositol optical isomer mixture, which is characterized by optical resolution.

Specific examples of the myo-inositol derivative in the optical isomer mixture of myo-inositol to be subjected to optical resolution include, for example, 5,6-di-O-benzoyl-3,4-O- (tetraisopropyldisiloxane-1,3- Diyl) -myo-inositol and 4,5-di-O-benzoyl-3,6-di-
O-benzyl-myo-inositol and the like.

These optical isomer mixtures need to have at least one functional group capable of reacting with an optically active compound. For example, a hydroxyl group, an amino group, a carboxyl group, or any other group capable of reacting may be used. .

On the other hand, the optically active compound that forms a diastereomer is essentially the same as the above-mentioned optical isomer mixture, a substance having substantially high optical purity, and a functional group capable of reacting with the optical isomer. 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 capable of reacting with the functional group of the optical isomer mixture is selected.

That is, specific examples of the optically active compound include, for example, 1- or d-menthoxyacetyl chloride, l- or d-menthyl chloroformate, camphoric acid chloride,
Examples thereof include 1- or d-menthol, 1- or d-1-phenylethylamine, and the like.

In a reaction for producing a diastereomer by reacting an optically active compound with an optical isomer mixture, generally the following conditions are employed.

The reaction molar ratio between the optical isomer mixture and the optically active compound is usually 1: 1. The reaction is performed in an inert solvent, for example, in the co-presence of a tertiary amine such as triethylamine, and can be optionally performed in pyridine. The reaction temperature is preferably in the range of 0 ° C. to room temperature.
In addition, l- or d-menthol and l- or d-
When 1-phenylethylamine is used, the reaction is preferably performed in the presence of a condensing agent such as dicyclohexylcarbodiimide and 2-chloro-1-methylpyridinium.

As a method of pretreating the reaction product for purification or the like, a method of recrystallization and a method of silica gel chromatography are usually adopted.

In the present invention, examples of the stationary phase used for optical resolution of the diastereomer include polysaccharide derivatives such as cellulose and amylose.

Specifically, a polysaccharide derivative may be any one of a synthetic polysaccharide, a natural polysaccharide, and a natural product-modified polysaccharide, as long as it is optically active, but is preferably a highly regular homoglycan. And the bonding mode is also constant. More preferably, cellulose, amylose, β, from which a high-purity polysaccharide can be easily obtained.
-1,4-chitosan, chitin, β-1,4-mannan, β-1,
4-xylan, inulin, α-1.3-glucan, α-1.3
-Glucan and the like. The polysaccharide derivative is obtained by substituting a part or all of the hydrogen atom of the hydroxyl group or amino group of the polysaccharide, that is, 30% or more, preferably 50% or more, and more preferably 85% or more with another atomic group. Things.

The atomic group here is R is an aliphatic group having 1 to 3 carbon atoms, 3 to 8
A cyclic aliphatic group consisting of an aromatic group consisting of 6 to 20 carbon atoms or a heteroaromatic group consisting of 4 to 20 carbon atoms,
As the atomic group, one kind of these may be used, or two or more kinds may be used. This is preferably selected in terms of separation performance.

Further, any of them may have a substituent. Examples of the substituent include an alkyl group which may have a C _{1 to} C ₅ branch such as a methyl group and a t-butyl group, and a halogen such as chlorine. Various substituents can be used in a range in which is improved. In addition, the number of substituents may be one or more as long as the performance of separation is improved. Also the position of the substituent, for example,
When an aromatic group such as a phenyl group is used, when only one kind of substituent is used, the substituent can be selected within the range of improving the performance of separation such as ortho, meta and para positions. Further, when two kinds of substituents are used, 3,4
Various arrangements can be selected similarly, such as the position and the third and fifth positions.

These derivatives can be easily obtained using various known chemical reactions. For example, when a cellulose derivative containing an aromatic group is shown as an example of synthesis, a part or all of hydrogen of a hydroxyl group of cellulose is substituted with an aromatic group. Examples of the type of bond in this substitution include an ester bond, an ether bond, and a urethane bond.

Examples of the polysaccharide derivatives as described above include cellulose triacetate, cellulose tribenzoate, cellulose tris (p-methylbenzoate), cellulose trisphenylcarbamate, cellulose tris (p-methylphenylcarbamate), and cellulose tris (3,5-dimethylphenylcarbamate). , Cellulose tris (p-chlorophenylcarbamate), cellulose tris (p-
t-butylphenyl carbamate) and cellulose tricinnamate.

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

The filler used for the stationary phase of the present invention is 1 μm to 10 μm, preferably 1 μm, both inorganic and organic.
It can be used as a carrier having a particle size of m to 300 μm. It is preferably porous and has an average pore size of 10
Å-100 μm, preferably 30Å10000Å.

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

As the carrier, an organic carrier may be used, but an inorganic carrier such as silica gel is preferable, and the properties thereof are as described above. Further, as a method for retaining, there are a physical method, a method of chemically bonding and the like, and it is preferable that the carrier is subjected to a surface treatment such as a silane treatment using an organic silane compound.

Means for optically resolving diastereomers using the above-mentioned separating agents include chromatography methods such as gas chromatography, liquid chromatography, and thin layer chromatography. Among them, the liquid chromatography method 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 separating agent is bound to the carrier by a chemical method or insolubilized by crosslinking, there is no restriction except for the reactive liquid. Needless to say, since the separation characteristics of the compound or the optical isomer change depending on the developing solvent, it is desirable to examine various developing solvents.

EXAMPLES Hereinafter, the present invention will be described in detail with reference to Synthesis Examples and Examples, but the present invention is not limited to these Examples. In addition, the definition of the term represented in an Example is as follows.

Synthesis Example 1 (filler) Synthesis of cellulose tris (3,5-dimethylphenyl carbamate): 1 g of microcrystalline cellulose (manufactured by Merck, degree of polymerization 100), pyridine 50 ml, 3,5-dimethylphenyl isocyanate 6.5
After heating the ml at 100 ° C. for 17 hours, the reaction mixture was poured into 500 ml of methanol. The resulting precipitate was separated by filtration and dried to obtain a 3,5-dimethylphenylcarbanate derivative. Substitution degree is almost
100%.

Yield 3.26g Yield 88% One part of the obtained cellulose tris (3,5-dimethylphenylcarbamate) was dissolved in 8 parts of acetone, and diphenylsilane-treated silica gel (Lichrospher manufactured by Merck) was used.
After mixing with 4 parts of Si-1000), acetone was distilled off under reduced pressure to obtain a filler. The filler was packed into a column having an inner diameter of 0.46 cm and a length of 25 cm by a slurry method using methanol.

Examples 1 and 2 and Comparative Examples 1 and 2 l-menthoxyacetyl chloride (l-MntAcCl) was reacted with hydroxyl groups of the optical isomer mixture of inositol derivatives shown in Table 1 in pyridine at 0 ° C. to room temperature. The mixture was separated by silica gel column chromatography to prepare a methanol solution containing a small amount of chloroform.

Next, 1 ml / min was added to the packing column prepared in the above synthesis example.
And the separation factor (α) and the degree of separation (Rs) were measured. The results are shown in Table 1.

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

As a result, it was confirmed that the product obtained by reacting the optically active compound had much higher resolving power than the product not reacted, and that the conventional method was capable of sufficient separation even when the mixture was insufficiently separated. Was. The desired optically active myo-inositol derivative could be obtained by removing the l-menthoxyacetyl group from the diastereomer thus obtained by a conventional method.

[Effects of the Invention] According to the present invention, the separation efficiency can be significantly improved even for an optical isomer mixture for which optical resolution was difficult.

 ──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-58-128366 (JP, A) JP-A-59-190955 (JP, A) JP-A-62-24242 (JP, A) JP-A-1- 132542 (JP, A) JP-A-62-211552 (JP, A) JP-A-62-270602 (JP, A)

Claims (1)

(57) [Claims] 1. An optically active compound is reacted with a mixture of optical isomers of myo-inositol to form a diastereomer, and the diastereomer is optically purified by chromatography using a stationary phase containing a polysaccharide derivative as an active ingredient. An optical resolution method for a mixture of optical isomers of myo-inositol, which comprises resolving the mixture.