JPH0680018B2 - Separation agent - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a separating agent containing a carbamate derivative of polysaccharide as an active ingredient. The separating agent of the present invention can be used for separation of all chemical substances, particularly for optical resolution.

[0002]

2. Description of the Related Art As is well known, the optical isomers of different compounds, which are chemically the same, usually have different effects on the living body. Therefore, in the fields of medicine / agrochemicals, biochemistry related industries, etc.
For the purpose of preventing chemical damage and the like, preparation of an optically pure compound has become a very important issue. Conventionally, a preferential crystallization method or a diastereomer method has been used for separating a mixture of optical isomers, that is, for optical resolution. However, in these methods, the kinds of compounds optically resolved are limited and long. It often takes a lot of time and effort. Therefore, a technique for easily performing optical resolution by a chromatographic method is strongly desired.

Studies on optical resolution by chromatographic methods have been conducted for a long time. However, the conventionally developed separating agents have various problems such as poor separation efficiency, the compound to be resolved requires a special functional group, and the separating agent has poor stability. However, it was difficult to perform satisfactory optical resolution for all compounds.

[0004]

Therefore, a separation agent having a different chemical structure from that of the existing separation agent, and thereby having a different separation characteristic from them or having a higher ability to discriminate optical isomers. It is an object of the present invention to provide an agent.

[0005]

The present invention achieves the above object by a separating agent containing a carbamate derivative of a specific type of polysaccharide as an active ingredient. The separating agent preferably exhibits different adsorptive powers for some optical isomers.

The polysaccharide in the present invention is selected from the group consisting of chitosan, dextran and inulin.

The number average degree of polymerization of these polysaccharides (the average number of pyranose or furanose rings contained in one molecule) is 5
Or more, preferably 10 or more, but there is no particular upper limit, but 500
The following is preferable in terms of easy handling.

The carbamoyl group forming the carbamate derivative of the polysaccharide of the present invention has N 2 to 30 carbon atoms, preferably 2 to 20 carbon atoms.
A substituted carbamoyl group, and examples of the substituent on the nitrogen atom include phenyl, α or β-naphthyl, 4-
Examples thereof include aromatic and heteroaromatic groups containing nitrophenyl and the like, and substitution products thereof, and aliphatic (including alicyclic) groups containing methyl and the like, and substitution products thereof.

The carbamate derivative has an average of 30 to 100%, preferably 8% of all the hydroxyl groups of the corresponding polysaccharide.
5 to 100% form a urethane bond with the carbamoyl group. The hydroxyl group which does not correspond to this may be a free hydroxyl group, but may be further esterified, carbamated or etherified as long as the isomer separation ability of the carbamate derivative is not impaired.

For the synthesis of the carbamate derivative, a usual reaction for producing urethane from an alcohol and an isocyanate can be applied as it is. For example, it can be obtained by reacting a corresponding isocyanate with a polysaccharide using a Lewis base such as a tertiary amine or a Lewis acid such as a tin compound as a catalyst.

When the separating agent of the present invention is used for the purpose of separating a compound or its optical isomer, it is common to use a chromatographic method such as gas chromatography, liquid chromatography or thin layer chromatography. However, membrane separation can also be performed.

In order to apply the separating agent of the present invention to a liquid chromatography method, a method of filling a column as a powder,
A method of coating on a capillary column, a method of forming a capillary with the separating agent and utilizing the inner wall thereof, a method of spinning and bundling the same to form a column, etc., but a powder is generally used. is there.

In order to make the separating agent into powder, it is preferable to crush it or make it into a bead form. The size of the particles depends on the size of the column or plate used, but it is 1μ
m to 10 mm, preferably 1 μm to 300 μm, and the particles are preferably porous.

Further, in order to improve the pressure resistance of the separating agent, prevent swelling and contraction due to solvent substitution, and improve the theoretical plate number, it is preferable to retain the separating agent on a carrier. The size of the suitable carrier varies depending on the size of the column or plate used, but is generally 1 μm to 10 mm, preferably 1 μm to
It is 300 μm. The carrier is preferably porous,
The average pore size is 10Å ~ 100 μm, preferably 50Å ~
It is 50,000Å. The amount of the separating agent retained is 1 to 100% by weight, preferably 5 to 50% by weight, based on the carrier.

The method of holding the separating agent on the carrier may be a chemical method or a physical method. As a physical method, the separating agent is dissolved in a soluble solvent and mixed well with a carrier,
A method of distilling off the solvent by air flow under reduced pressure or heating, or after dissolving the separating agent in a soluble solvent and thoroughly mixing with a carrier, stirring and dispersing in a liquid which is incompatible with the solvent, There is also a method of diffusing the solvent. When the separating agent held on the carrier is crystallized in this manner, a treatment such as heat treatment can be performed. Further, by adding a small amount of a solvent to temporarily swell or dissolve the separating agent, and then distilling the solvent off again, it is possible to change the retention state, and thus the separating ability.

The carrier may be a porous organic carrier or a porous inorganic carrier, preferably a porous inorganic carrier. Suitable examples of the porous organic carrier include polymer substances made of polystyrene, polyacrylamide, polyacrylate and the like. Suitable porous inorganic carriers include synthetic or natural substances such as silica, alumina, magnesia, titanium oxide, glass, silicates and kaolin, and surface treatment for improving the affinity with the separating agent. You may go. Examples of the surface treatment method include a silanization treatment using an organic silane compound and a surface treatment method by plasma polymerization.

When the separating agent is used for separating a compound or an optical isomer, even if the separating agents are chemically the same, the separating characteristics are changed depending on the physical states such as molecular weight, crystallinity and orientation. There is a case. Therefore, when the separating agent is used by any of the methods described so far, depending on the purpose, the solvent used in the step is selected, and the physical treatment such as heat treatment or etching after the step or swelling with a liquid is performed. It is possible to change the separation characteristics.

The developing solvent for 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 is insolubilized by crosslinking, there is no limitation except the reactive liquid. Needless to say, since the separation characteristics of chemicals or optical isomers change depending on the developing solvent, it is desirable to study various developing solvents.

On the other hand, when performing thin layer chromatography, the separating agent composed of particles of about 0.1 μm to 0.1 mm,
If necessary, a layer of a small amount of binder having a thickness of 0.1 to 100 mm may be formed on the support plate. When performing membrane separation, it is used as a hollow system or a film.

The separating agent containing the polysaccharide carbamate derivative of the present invention as an active ingredient is effective for separating various compounds,
Particularly, it is effective for the resolution of optical isomers, which has been extremely difficult to separate in the past. The optical isomers to be separated are those having some difference in the adsorptive power of the separating agent.

[0021]

EXAMPLES The present invention will be described in detail below with reference to 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.

[0022]

[Equation 1]

Synthesis Example 1 (chitosan triphenylcarbame
Synthesis of the salt) 1 g of chitosan and 8 ml of phenylisocyanate were added to 50 ml of pyridine, and the temperature was kept at about 110 ° C. to complete the reaction. The precipitate was precipitated in a large amount of methanol, filtered through a glass filter, washed with methanol, and dried in vacuum.

[0024] Synthetic Examples 2 and 3 In the same manner as in Synthetic Example 1, dextran and inulin were reacted.・ Elemental analysis results of dextran triphenylcarbamate (Synthesis example 2) ・ Elemental analysis results of inulin triphenylcarbamate (Synthesis example 3) Examples 1 to 3 Silica gel trade name LiChrospher SI-4000 (Merck) and a mixture of benzene, pyridine and γ-aminopropyltriethoxysilane dried with sodium metal (10 g: 50
g: 1 g: 2 g) was reacted at 80 ° C. for 16 hours under a nitrogen stream. The reaction solution was poured into methanol, filtered, washed with methanol and dried.

Elemental analysis values C: 0.23%, H: 0.07%, N: 0.09% 750 mg of each of the polysaccharide derivatives obtained in Synthesis Examples 1 to 3 is shown in Table 1.
Was dissolved in 10 ml of the above solvent and mixed with silanized silica gel, and the solvent was distilled off to prepare a separating agent supported on a carrier.

[0026]

[Table 1]

Application Example 1 25 cm × 0.46 of each separating agent obtained in Examples 1 and 2
A (id) cm stainless steel column was packed by a slurry packing method. The theoretical plate number was 4000-7000 for compounds with low adsorption. TRIROTAR-II made by JASCO Corporation for high-performance liquid chromatography, UVIDEC-100-III made by JASCO Corporation as a detector, and DIP-181 made by JASCO Corporation as a polarimeter (cell: 5 cm × 0.3 ( id) cm),
The flow rate was 0.5 ml / min and the temperature was 25 ° C. The division results are summarized in Tables 2 and 3.

[0028]

[Table 2]

[0029]

[Table 3]

Claims (1)

[Claims] 1. A separating agent comprising a carbamate derivative of a polysaccharide selected from the group consisting of chitosan, dextran and inulin as an active ingredient.