JPH0442371B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a separating agent, and particularly to a separating agent containing a halogen-substituted aromatic carbamate derivative of a polysaccharide as an active ingredient. The separating agent of the present invention can be used for separating various chemical substances, especially for optical resolution. As is well known, optical isomers of the same chemical compound usually have different effects on living organisms. Therefore, in fields such as medicine, agrochemicals, and biochemistry-related industries, improvements in medicinal efficacy per unit,
The preparation of optically pure compounds has become an extremely important issue for the purpose of preventing side effects and drug damage. Conventionally, preferential crystallization methods and diastereomer methods have been used to separate optically isomeric mixtures, that is, optically resolve them, but these methods limit the types of compounds that can be optically resolved, and also require long It often takes time and a lot of effort. Therefore, there is a strong need for a technique for easily performing optical resolution using chromatography. [Prior Art and Problems] Research on optical resolution using chromatography has been conducted for some time. However, conventionally developed separation agents have problems such as poor separation efficiency and the need for special functional groups in the target compound.
There are also various problems such as poor stability of the separating agent, making it difficult to perform satisfactory optical resolution on all compounds. [Means for solving the problem] Therefore, it has a chemical structure different from that of existing separating agents, and therefore has different separation properties from them, or has a more advanced optical isomer. It is an object of the present invention to provide a separation agent with discrimination ability. In particular, the physical properties of substituents on aromatic rings,
It seeks to link chemical properties to novel separation properties. The present invention achieves the above object by using a separation agent containing a halogen-substituted aromatic carbamate derivative of polysaccharide as an active ingredient. The separating agent of the present invention preferably exhibits different adsorption powers for optical isomers of some compound. (Polysaccharide) Polysaccharides in the present invention include synthetic polysaccharides, natural polysaccharides,
Any polysaccharide that is optically active may be used, including any modified natural polysaccharide, but preferably one with a highly regular bonding pattern. For example, β−
1,4-glucan (cellulose), α-1,4-
Glucan (amylose, amylopectin), α-
1,6-glucan (dextran), β-1,6
- Glucan (pustulan), β-1,3-glucan (e.g. curdlan, schizophyllan, etc.), α-
1,3-glucan, β-1,2-glucan (CrownGall polysaccharide), 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-xylan, β-1,3-xylan, β-1,4-chitosan, β-1,4-N-acetyl chitosan (chitin), pullulan, agarose, alginic acid etc., and more preferably cellulose, amylose, β-1,4, from which highly purified polysaccharides can be easily obtained.
- Chitosa, chitin, β-1,4-mannan, β-
1,4-xylan, inulin, curdlan, etc. The number average degree of polymerization (average number of pyranose or furanose rings contained in one molecule) of these polysaccharides is 5 or more, preferably 10 or more, and although there is no upper limit, it is preferably 500 or less for ease of handling. . (Carbamate) The halogen-substituted aromatic carbamate of the present invention is a carbamoyl group containing an aromatic group in which one or more than one hydrogen atom of the aromatic group is replaced with a halogen atom, and the alcohol moiety is the above-mentioned polysaccharide. It consists of: The carbamoyl group preferably has a group represented by the following formula. However, X, Y, Z are halogen atoms such as bromine, chlorine, fluorine, etc., l, m indicate the number of X, Y, Z, l is an integer of 1 to 5, and m is an integer of 1 to 7. be. n is an integer from 0 to 5, preferably 0. The aromatic carbamate is one in which an average of 30 to 100%, preferably 85 to 100% of the total number of hydroxyl groups of the polysaccharide forms carbamate bonds. Hydroxyl groups not applicable to the above may exist as free hydroxyl groups, but may also be esterified, etherified, or carbamated to the extent that the separating power of the separating agent is not lost. Among the halogen-substituted aromatic carbamate derivatives of the present invention, those having a halogen at the 4-position are the most stable in terms of solvent resistance. (Synthesis method) As a method for synthesizing the halogen-substituted aromatic carbamate derivative of polysaccharide of the present invention, a conventional reaction method for producing urethane from isocyanate and alcohol can be applied as is. For example, cellulose halogen-substituted phenyl carbamate can be obtained by reacting halogen-substituted phenyl isocyanate with cellulose in the presence of a Lewis base such as a tertiary amine base or a Lewis acid catalyst such as a tin compound. (How to use) In order to use the separation agent of the present invention for the purpose of separating compounds and their optical isomers, chromatography methods such as gas chromatography, liquid chromatography, and thin layer chromatography may be used. is common, but membrane separation can also be performed. In order to apply the separation agent of the present invention to liquid chromatography, there are methods such as filling a column as a powder, coating a capillary column, forming a capillary with the separation agent, and utilizing the inner wall of the separation agent. Methods include spinning the fibers and bundling them into columns, but it is common to form them into powder. In order to make the separating agent into powder, it is preferable to crush it or form it into beads. The size of the particles varies depending on the size of the column used, but is approximately 1 μm.
~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 shrinkage due to solvent substitution, and improve the number of theoretical plates, it is preferable to hold the separating agent on a carrier. The appropriate size of the carrier varies depending on the size of the column and plate used, but is generally 1 μm to 10 mm.
Preferably it is 1 μm to 300 μm. The carrier is preferably porous, with an average pore size of 10 Å to 100 μ
m, preferably 50 Å to 50000 Å.
The amount of the separating agent to be retained is 1 to 100% relative to the carrier.
% by weight, preferably from 5 to 50% by weight. The separating agent may be retained on the carrier by either a chemical method or a physical method. As a physical method,
A method in which the separating agent is dissolved in a soluble solvent, mixed well with the carrier, and the solvent is distilled off by air flow under reduced pressure or heating, or after the separating agent is dissolved in a soluble solvent and mixed well with the carrier. There is also a method in which the solvent is dispersed by stirring and dispersing it in a liquid that is not compatible with the solvent. When crystallizing the separation agent held on the carrier in this manner, a treatment such as heat treatment can be performed. Furthermore, by adding a small amount of solvent to once swell or dissolve the separating agent, and then distilling off the solvent 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 porous organic carriers include polymeric substances such as polystyrene, polyacrylamide, polyacrylate, and the like. Suitable porous inorganic carriers include synthetic or natural materials such as silica, alumina, magnesia, titanium oxide, glass, silicates, and kaolin, which may be surface-treated to improve compatibility with the separation agent. You may also do this. Examples of surface treatment methods include silanization using an organic silane compound and surface treatment using plasma polymerization. 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 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,
Since the separation characteristics of chemical substances or optical isomers change depending on the developing solvent, it is desirable to consider various developing solvents. On the other hand, when performing thin layer chromatography,
The separating agent consists of particles of about 0.1 μm to 0.1 mm,
Thickness 0.1-100 with a small amount of binder if necessary
It is sufficient to form a layer of mm on the support plate. When performing membrane separation, hollow fibers or films are used. [Effects of the Invention] The separating agent containing the halogen-substituted aromatic carbamate of the present invention as an active ingredient is effective in separating various compounds, and is particularly effective in separating optical isomers, which have been extremely difficult to separate in the past. . One of the optical isomers to be separated is more strongly adsorbed by the separating agent. In particular, this separating agent is intended to improve the desired separation effect, especially optical resolution effect, by changing the separation and adsorption properties of the corresponding unsubstituted separating agent with a substituent. Although it is not possible to completely explain the relationship between significant changes in these separation characteristics and substitution, it is important to note that the substituents change the shape of the molecule, and that the physical and chemical properties of the substituents themselves (polarizability, hydrogen bonding, etc.) gender, polarity, etc.),
This is thought to be due to a complex combination of electronic effects of substituents on the π-electron system of the aromatic ring, etc. The present invention has revealed that substituents have an extremely effective effect on modifying the separation characteristics of a separating agent, and it has become possible to develop separating agents having various characteristics. Such effects are naturally expected for various separation agents having polysaccharides other than cellulose in their skeletons. [Examples] The present invention will be described in detail below with reference to Examples, but the present invention is not limited to these Examples.
The definitions of terms used in the Examples are as follows. Capacity ratio (k') = [(Retention time of enantiomer) - (Dead time)] / (Dead time) Separation coefficient (α) = Capacity ratio of enantiomer that is more strongly adsorbed /
Volumetric resolution of the more weakly adsorbed enantiomer (Rs) = 2 x (distance between both peaks of the more strongly adsorbed enantiomer and weaker adsorbed enantiomer)/bandwidth of both peaks Total synthesis example 1 Synthesis of cellulose tris(3,4-dichlorophenyl) carbamate Microcrystalline cellulose (manufactured by Merck & Co., Ltd.) (1 g), pyridine (50 ml), 3,4-dichlorophenyl isocyanate (14.3 g) After heating at 100°C for 17 hours, the reaction mixture was poured into methanol (500ml).
The resulting precipitate was separated and dried. Yield 1.80g Elemental analysis C H N Cl Calculated value 44.66 2.64 5.79 29.29 Measured value 44.39 2.66 5.86 28.46 Example 1 Cellulose tris(3,4-dichlorophenyl) carbamate (0.7g) obtained in Synthesis Example 1 was dissolved in N,
It was dissolved in N-dimethylacetamide (10 ml), and the insoluble portion was removed by centrifugation. This was added in two portions to silica gel treated with 3-aminopropyltriethoxysilane (Merck & Co., LiChrosper SI4000), and each time the solvent was distilled off under reduced pressure to prepare a filler. Synthesis Example 2 Synthesis of cellulose tris(2,6-dichlorophenyl) carbamate A mixture of 0.66 g of microcrystalline cellulose, 5 g of 2,6-dichlorophenyl isocyanate, and 26 ml of pyridine was heated at about 100° C. for 16 hours. Thereafter, the reaction solution was poured into methanol to precipitate a product, which was collected using a glass filter. Elemental analysis (%) C H N Cl Calculated value 44.66 2.64 5.79 29.29 Measured value 43.86 2.63 559 28.54 Example 2 Cellulose tris (2,6-
Dissolve 0.75 g of dichlorophenyl) carbamate in 10 ml of dichloromethane, add this to 3.00 g of silica gel (Merck & Co., LiChropher SI4000) treated with 3-aminopropyltriethoxysilane (divide the solution into two 5 ml portions), The solvent was distilled off to prepare a filler. Application example 1 Cellulose tris (3,4
-Dichlorophenyl) carbamate-supported silica beads were packed into a stainless steel column with a length of 25 cm and an inner diameter of 0.46 cm by a slurry method using hexane-liquid paraffin (2:1). The high-performance liquid chromatography machine used was TRIROTAR- manufactured by JASCO Corporation, and the detector was UVIDEC-. Table 1 shows the results of resolution of various racemates. Table 1 also shows the separation coefficient of a comparative example in which cellulose tris-phenyl carbamate was used instead of cellulose tris-(3,4-dichlorophenyl) carbamate.

[Table] Application Example 2 The filler obtained in Example-2 was also evaluated in the same manner as in Application Example-1. The results are shown in Table 2.

[Table] Synthesis Example 3 Synthesis of cellulose tris(4-chlorophenyl) carbamate A mixture of 1.00 g of microcrystalline cellulose, 5 ml of 4-chlorophenyl isocyanate, and 50 ml of pyridine was heated at about 100° C. for 18 hours. After that, the reaction solution was mixed with water-containing methanol (methanol-water = 500ml: 50ml).
The product was precipitated and collected with a glass filter. Yield 3.39g Elemental analysis (%) C H N Cl
Calculated value 52.07 3.56 6.75
17.08 Measured value 51.89 3.51 7.08 19.23 Example 3 0.75 g of cellulose tris(4-chlorophenyl) carbamate obtained in Synthesis Example 3 was dissolved in 10 ml of tetrahydrofuran, and this was added to the silica gel treated with 3-aminopropyltriethoxysilane (2 The solvent was distilled off and the filler was synthesized. Application Example 3 The filler obtained in Example-3 was also evaluated in the same manner as in Application Example-1. The results are shown in Table 3.

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[Table] Synthesis Example 4 Synthesis of cellulose tris(4-fluorophenyl) carbamate A mixture of 1 g of cellulose, 50 ml of pyridine, and 4 ml of 4-fluorophenyl isocyanate was heated at approximately 110°C.
It was heated for 18 hours. Thereafter, 600 ml of methanol and 100 ml of water were added to the reaction solution to precipitate a polymer, which was collected using a Gusfilter. Yield: 2.90g Elemental analysis C% H% N% Calculated value 56.55 3.87 7.33 Measured value (WO ₃ added) 55.39 3.73 7.01 Example 4 Cellulose tris(4-fluorophenyl) carbamate obtained in Synthesis Example-4 0.75g was dissolved in 10 ml of tetrahydrofuran and adsorbed on 3 g of silica gel in the same manner as in Example-1 to obtain a filler. Application Example 4 The filler obtained in Example-4 was also evaluated in the same manner as in Application Example-1. Table 4 shows the results.
It was shown to.

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[Table] Synthesis Example 5 Synthesis of cellulose tris(4-bromophenyl) carbamate A mixture of 1 g of cellulose, 50 ml of pyridine, and 7.3 g of 4-bromophenyl isocyanate was heated at approximately 110°C.
Heated for 20 hours. The reaction solution was poured into 500 ml of methanol and 50 ml of water to precipitate the polymer, which was collected using a glass filter. Yield: 4.12g Elemental analysis C% H% N% Calculated value 42.89 2.93 5.54 Measured value 42.31 2.84 5.58 Br% Calculated value 31.71 Measured value 31.47 Example 5 Cellulose tris(4-bromophenyl) carbamate obtained in Synthesis Example-5 0.75 g was dissolved in 10 ml of tetrahydrofuran and adsorbed onto 3 g of silica gel in the same manner as in Example-1 to obtain a filler. Application example 5 Regarding the filler obtained in Example-5, application example-
The same evaluation as in 1 was conducted. The results are shown in Table 5.

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[Table] As is clear from Tables 1 to 5, cellulose tris (3,4-dichlorophenyl) carbamate, cellulose tris (2,6-dichlorophenyl) carbamate, cellulose tris (4-chlorophenyl) carbamate, cellulose tris ( Halogen-substituted aromatic carbamate derivatives of polysaccharides such as 4-fluorophenyl) carbamate and cellulose tris(4-bromophenyl) carbamate are
It has been revealed that, compared to cellulose trisphenyl carbamate, it exhibits superior optical resolution in resolving trans-stilbene oxide, Traeger base, Co(acac) ₃ , Cr(acac) ₃ , etc. Furthermore, it was also possible to separate phenyl-2-pyridyl-O-tolylmethyl methacrylate, which was difficult to separate in the past. Synthesis example 6 Synthesis of amylose tris (3,5-dichlorophenyl carbamate) Amylose B (molecular weight 16000) 0.6g (3.70m
mol) in vacuo, and then added to 30 ml of dry pyridine and stirred. Add 3.91 g (20.8 mmol) of 3,5-dichlorophyll isocyanate to this and heat to 100°C.
Heat and stir under a nitrogen stream for 19 hours. The reactants are then collected into LiChropher in methanol. The amount of amylose tris (3,5-dichlorophenyl carbamate) obtained was 2.434 g (yield 90.3%). Synthesis Example 7 Synthesis of amylose tris (3,4-dichlorophenyl carbamate) In the same manner as Synthesis Example-6, isocyanic acid 3,5
-isocyanic acid 3, instead of dichlorophenyl
4.17 g (22.2 mmol) of 4-dichlorophenyl was reacted to obtain 0.91 g (yield 33.8%) of amylose tris (3,4-dichlorophenyl carbamate). The elemental analysis values were as follows. Elemental analysis (%) C H N Calculated value 44.66 2.64 5.79 Measured value 44.52 2.80 5.77 Example 6 and Example 7 Amylosttris (3,5-diclophenyl carbamate) obtained in Synthesis Example 6 and Synthesis Example 7
(Example 6) and amylose tris (3,4-dichlorophenyl carbamate) (Example 7) were supported on silica gel (Merck & Co., LiChrospher SI1000, 10 μm) in the same manner as in Example 1, and used as a filler. did. Application Example 6 and Application Example 7 The filler obtained in Example 6 and Example
cm, packed into a stainless steel column with an inner diameter of 0.46 cm,
The racemic compounds shown in Table 6 were optically resolved by liquid chromatography. When a 9:1 mixed solvent of hexane and 2-propanol was used as the solvent, good results were obtained as shown in Table 6. In the table, k ₁ indicates the retention capacity of the first eluting enantiomer, and the code in parentheses indicates its photochromic property.
Further, α indicates the degree of separation, and Rs indicates the separation coefficient.

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Claims (1)

[Claims] 1. A separation agent containing a halogen-substituted aromatic carbamate derivative of polysaccharide as an active ingredient.