JPH06211902A - Substituted aromatic carbamate derivative of polysaccharide, and separating agent - Google Patents

Abstract

PURPOSE:To obtain a compd. useful as the active ingredient of a separating agent usable in separation of various chemical substances, particularly in optical resolution, by choosing a substd. arom. carbamate deriv. of a polysaccharide having a predetermined amt. of the OH groups thereof substd. with specific groups. CONSTITUTION:Choice is made of a substd. arom. carbamate deriv. of a polysaccharide (e.g. cellulose) having 80-100% of the OH groups thereof substd. with groups of the formula (wherein R1 to R4 are each H, 1-8C alkyl, or a halogen atom, provided that at least two of R1 to R4 are each 1-8C alkyl or a halogen atom, and are different from each other).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel polysaccharide derivative which is extremely useful as a functional material, and a separating agent containing this polysaccharide derivative as an active ingredient. The separating agent of the present invention is
It can be used for the separation of various chemical substances, especially for optical resolution.

[0002]

BACKGROUND OF THE INVENTION As is well known, even if the compounds are chemically the same,
The optical isomers normally have different effects on the living body. Therefore, in the fields of medicine, agricultural chemicals, biochemistry related industries, etc., it is a very important task to prepare an optically pure compound in order to improve the drug efficacy per unit, prevent side effects and phytotoxicity, etc. ing. To date, a large number of polysaccharide derivatives have been investigated for their optical resolution in order to separate, ie, optically resolve a mixture of optical isomers. For example, cellulose trisphenyl carbamate (J. Am. Che
Soc., 106, 5357 , 1984), alkyl-substituted phenylcarbamate derivatives of polysaccharides (JP-A-63-178101, JP-A-1-203402, etc.), and halogen-substituted aromatic carbamate derivatives of polysaccharides (JP-A-Sho. It is already known that a packing material for liquid chromatography having 61-233633) as a stationary phase has an excellent optical resolution. However, it is a fact that some compounds cannot be optically resolved even by using these polysaccharide derivatives, and the development of a separating agent that can optically resolve such compounds is desired.

[0003]

Means for Solving the Problems As a result of intensive studies to solve these problems, the present inventors have found that a carbamate derivative of a polysaccharide having an aromatic group having two or more kinds of different substituents is excellent. They have found that they have the ability of simultaneous discrimination, and have completed the present invention. That is, the present invention provides a substituted aromatic carbamate derivative of a polysaccharide in which 80% to 100% of the hydroxyl groups of the polysaccharide are substituted with a group represented by the following general formula (1), and a substituted aromatic carbamate derivative of this polysaccharide. It provides a separating agent as a component.

[0004]

[Chemical 2]

(Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each a hydroxyl atom, an alkyl group having 1 to 8 carbon atoms or a halogen atom, and at least R _{1 to} R ₅ Two of them are alkyl groups having 1 to 8 carbon atoms or halogen atoms and different substituents.) The polysaccharide in the present invention means an optically active substance regardless of whether it is a synthetic polysaccharide, a natural polysaccharide or a naturally-modified polysaccharide. Any one may be used as long as it is preferable, but a highly regular binding mode is preferable. For example, β-1,4-glucan (cellulose), α-1,4-glucan (amylose, amylopectin), α-1,6-glucan, β-1,4-galactan, β-1,6- Glucan (Bustulan), α-1,6-glucan, β-1,3-glucan (eg curdlan, sizofiran, etc.), α-1,3
-Glucan, β-1,4-galactan, β-1,4-mannan, α-1,6-mannan, β-1,2-fructan (inulin), β-2,6-fructan (levan), β -1,4-
Examples include xylan, β-1,4-chitosan, β-1,4-N-acetylchitosan (chitin), pullulan, agarose, and alginic acid, and also include starch containing amylose. Particularly preferred are β-1,4-glucan (cellulose), α-1,4, from which high-purity polysaccharide can be easily obtained.
-Glucan (amylose, amylopectin), β-1,4
-Chitosan, β-1,4-N-acetylchitosan (chitin), β-1,4-mannan, β-1,4-xylan, inulin, curdlan and the like.

The number average degree of polymerization of these polysaccharides (the average number of pyranose rings or furanose rings contained in one molecule) is 5 or more, preferably 10 or more, and there is no particular upper limit, but it is 500 or less. It is preferable in terms of easiness.

The carbamoyl group forming the carbamate derivative of the polysaccharide of the present invention is represented by the above general formula (1), and 80% to 100% of all the hydroxyl groups of the corresponding polysaccharide form a urethane bond with the carbamoyl group. Is what
The remaining 20% to 0% generally remain hydroxyl groups,
It can be partially converted to other substituents.

In the group represented by the general formula (1), R ₁
R ₂ , R ₃ , R ₄ and R ₅ are each a hydroxyl atom, an alkyl group having 1 to 8 carbon atoms or a halogen atom, and R ₁
To R ₅ are at least two alkyl groups having 1 to 8 carbon atoms or halogen atoms and different substituents, and particularly preferably at least one of R _{1 to} R ₅ is an alkyl group having 1 to 8 carbon atoms. And at least one is a halogen atom. Examples of the alkyl group having 1 to 8 carbon atoms include a methyl group, an ethyl group, a propyl group, a butyl group, a hexyl group and an octyl group, and examples of the halogen atom include a chlorine atom, a bromine atom and an iodine atom. To be

For the synthesis of the carbamate derivative according to the present invention, the usual reaction for producing urethane from alcohol and isocyanate can be applied as it is. For example, it can be obtained by reacting a corresponding isocyanate with a polysaccharide in a suitable solvent using a Lewis base such as a tertiary amine or a Lewis acid such as a tin compound as a catalyst. The isocyanate can be easily synthesized, for example, by reacting phosgene with the amino group of the corresponding aniline derivative.

The polysaccharide carbamate derivative of the present invention is an extremely useful substance as a functional material, and is particularly useful as a separating agent for optical resolution. When the polysaccharide carbamate derivative of the present invention is used as a separating agent for the purpose of separating compounds and optical isomers, chromatographic methods such as gas chromatography, liquid chromatography, thin layer chromatography and supercritical chromatography are used. In general, it is also possible to carry it on a membrane for membrane separation.

In order to apply the polysaccharide carbamate derivative of the present invention to a liquid chromatography method as a separating agent, a method of packing it in a column as a powder, a method of coating a capillary column, forming a capillary with the separating agent, and forming an inner wall thereof The method of use may be selected, but powder is generally used. In order to make the separating agent into powder, it is preferable to grind it or make it into a bead form.
The size of the particles varies depending on the size of the column used, but is 1 μm to 10 mm, preferably 1 μm to 300 μm
Then, 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 hold the separating agent on a carrier. The size of the carrier depends on the size of the column or plate used,
Generally 1 μm to 10 mm, preferably 1 μm to 300 μ
m, the carrier is preferably porous and has an average pore size of
It is 10Å to 100 μm, preferably 50Å to 50000Å. 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 supporting the polysaccharide derivative on the carrier may be a chemical method or a physical method. As a chemical method, there is a method in which some hydroxyl groups are protected when derivatizing a polysaccharide, and after derivatization, deprotection is performed and this is chemically bonded to silica gel (Y. Okamoto et al. al.,
J. Liq. Chromatogr., 10 (8 & 9), 1613, 1987).
As a physical method, there is a method in which the polysaccharide derivative is dissolved in a soluble solvent, well mixed with the carrier, and the solvent is distilled off under reduced pressure, under heating or under an air stream.

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 polymeric 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, in order to improve the affinity with the polysaccharide derivative. The surface treatment may be carried out. Examples of the surface treatment method include a silanization treatment using an organic silane compound and a surface treatment method by plasma polymerization.

The eluent for liquid chromatography is not particularly limited except for a liquid which dissolves or reacts with the separating agent, and when the separating agent is bound to a carrier by a chemical method. There is no limitation except for the reactive liquid, but a mixed solution of n-hexane, various alcohols, tetrahydrofuran and the like is preferably used. Further, since the separation characteristics of the compound or the optical isomer may change depending on the eluent, it is preferable to study the separation characteristics depending on the mixing ratio of various solvents.

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

[0017]

EFFECT OF THE INVENTION The separating agent of the present invention containing a polysaccharide carbamate derivative having an aromatic group having two or more different substituents as an active ingredient is effective for separating various compounds, and particularly conventional separation is very difficult. It is extremely effective in separating the existing optical isomers. One of the optical isomers to be separated is strongly adsorbed by the present separating agent. In particular, the present separating agent changes the separation and adsorption characteristics of the separating agent consisting of the corresponding non-substituted product, mono-substituted product or derivative having two same substituents depending on the substituents, particularly the desired separation effect, particularly optical resolution. It is intended to be effective.

Although it is not possible to completely explain the relationship between such a significant change in the separation characteristics and the substituent, the fact that the substituent changes the shape of the molecule, the physical property of the substituent itself,
It is considered that the chemical properties (polarizability, hydrogen bondability, polarity, etc.) and the electronic influence of the substituent on the π-electron system of the aromatic ring are intricately combined. According to the present invention, it has been clarified that the substituent has a very effective influence in modifying the separation characteristics of the separating agent, and it has become possible to develop a separating agent having various characteristics.

[0019]

EXAMPLES The present invention will be specifically described below with reference to examples, but it goes without saying that the present invention is not limited to these. Parameters used in the examples
k ′ and α are defined as follows.

[0020]

[Equation 1]

Synthesis Example-1 Cellulose Tris (3-methyl-4-chlorophenylcarboxyl)
Lubamate) synthetic microcrystalline cellulose (Merck) 1.0 g, pyridine 50
ml, 3-methyl-4-chlorophenyl isocyanate
After heating 9.3 g at 100 ° C. for 17 hours, the reaction mixture was poured into methanol (500 ml). The precipitate formed is filtered, dried,
Cellulose tris (3-methyl-4-chlorophenylcarbamate) was obtained. Yield 3.48 g The elemental analysis values of the obtained cellulose tris (3-methyl-4-chlorophenylcarbamate) are shown below. Calculated C, 54.33%; H, 3.92%; N, 6.34%; Cl, 1
6.08% Found C, 53.27%; H, 4.24%; N, 6.28%; Cl, 1
5.65% Example-1 Cellulose tris (3-methyl-4-) obtained in Synthesis Example-1
Chlorophenyl carbamate) 1.0 g was dissolved in N, N-dimethylacetamide (10 ml), and this was divided into 4.0 g of silica gel (Daiso Co., Ltd., Daiso gel (pore size 1000 μm)) treated with 3-aminopropylethoxysilane, divided into two portions. In each case, the solvent was distilled off under reduced pressure to prepare a filler.

Application Example-1 Cellulose tris (3-methyl-) obtained in Example-1
Silica beads carrying 4-chlorophenyl carbamate) were packed in a stainless steel column having a length of 25 cm and an inner diameter of 0.46 cm by a slurry method using hexane-liquid paraffin (2: 1). Gulliver PU980 manufactured by JASCO Corporation for high-performance liquid chromatograph, Gulliver UV9 for detector
70 was used. The results of dividing various racemates are shown in Table 1.

Synthesis Example-2 Cellulose Tris (3-chloro-4-methylphenylcarboxyl)
Lubamate) synthetic microcrystalline cellulose (Merck) 1.0 g, pyridine 50
ml, 3-chloro-4-methylphenyl isocyanate
After heating 9.3 g at 100 ° C. for 17 hours, the reaction mixture was poured into methanol (500 ml). The precipitate formed is filtered, dried,
Cellulose tris (3-chloro-4-methylphenylcarbamate) was obtained. Yield 3.42 g The elemental analysis values of the obtained cellulose tris (3-chloro-4-methylphenylcarbamate) are shown below. Calculated C, 54.33%; H, 3.92%; N, 6.34%; Cl, 1
6.08% Found C, 53.14%; H, 4.23%; N, 6.22%; Cl, 1
5.96% Example-2 Cellulose tris (3-chloro-4-) obtained in Synthesis Example-2
1.0 g of methylphenylcarbamate) was dissolved in N, N-dimethylacetamide (10 ml), and this was added to 4.0 g of silica gel (LiChrosper S14000 manufactured by Merck & Co., Inc.) treated with 3-aminopropylethoxysilane in two portions. In each case, the solvent was distilled off under reduced pressure to prepare a filler.

Application Example-2 Cellulose tris (3-chloro-) obtained in Example-2
Silica beads carrying 4-methylphenylcarbamate) were packed in a stainless steel column having a length of 25 cm and an inner diameter of 0.46 cm by a slurry method using hexane-liquid paraffin (2: 1). Gulliver PU980 manufactured by JASCO Corporation for high-performance liquid chromatograph, Gulliver UV9 for detector
70 was used. The results of dividing various racemates are shown in Table 1.

Comparative Example-1 In order to clarify the effect of the present invention, a separating agent containing a cellulose tris (3,5-dimethylphenylcarbamate) derivative as an active ingredient was prepared as a comparative product, and its optical resolution was performed on various racemates. The results are shown in Table 1.

[0026]

[Table 1]

Claims (3)

[Claims] 1. 80% to 100% of the hydroxyl groups of the polysaccharide
Is a substituted aromatic carbamate derivative of a polysaccharide substituted with a group represented by the following general formula (1). [Chemical 1] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each a hydroxyl atom or an alkyl group having 1 to 8 carbon atoms or a halogen atom, and at least two of R _{1 to} R ₅ are It is an alkyl group having 1 to 8 carbon atoms or a halogen atom and different substituents.) 2. The substituted aroma of the polysaccharide according to claim 1, wherein in the general formula (1), at least one of R _{1 to} R ₅ is an alkyl group having 1 to 8 carbon atoms, and at least one is a halogen atom. Group carbamate derivatives. 3. A separating agent containing the substituted aromatic carbamate derivative of the polysaccharide according to claim 1 as an active ingredient.