JPS60216842A - Isolating agent comprising polysaccharide derivative - Google Patents

Abstract

PURPOSE:To obtain an isolating agent having higher function for discriminating an optically active mother compound by using an aralkyl carboxylic acid ester of a polysaccharide as an effective component. CONSTITUTION:An aralkyl carboxylic acid ester of a polysaccharide is used as an effective component. The isolating agent is effective for the isolation of several kinds of compound, particularly extremely effective for the isolation for optically active isomers which have been very difficultly isolated conventionally. One of the optically active isomers being an object of isolation is adsorbed more strongly to the isolating agent than other forms of the isomers.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a separating agent, particularly a separating agent comprising a polysaccharide derivative containing an aralkylcarboxylic acid ester of a polysaccharide as an active ingredient.

[Industrial application field]

The separating agent of the present invention can be used for separation of all chemical substances, especially for dioptric separation.

As is well known, chemical (-) is the same compound, but its optical isomers usually have different effects on living organisms (2). For the purpose of improving drug efficacy per unit and preventing side effects and drug damage, etc. (2. Preparing optically pure compounds has become an extremely important issue. Conventionally, preferential crystallization methods and diastereomer methods have been used for optical resolution, but these methods limit the types of compounds that can be optically resolved and require a long time and a lot of effort. Therefore, there is a strong demand for a technique for easily carrying out optical resolution using chromatography.

[Prior art]

Research on optical resolution using chromatography methods has been carried out for some time. However, conventionally developed separation agents have various problems, such as poor separation efficiency, the need for special functional groups in the target compound, and poor stability of the separation agent. , it was difficult to perform satisfactory optical resolution for all compounds (two pairs).

[Purpose of the invention]

Therefore, it is an object of the present invention to provide a separating agent that has a chemical structure different from that of existing separating agents, and thereby has different separation properties or higher optical isomer discrimination ability. It is a purpose.

In particular, by modifying a polysaccharide with a sufficiently long substituent group, the asymmetric structure of the polysaccharide can be increased and the ability to discriminate between optical isomers can be increased.

[Structure of the invention]

That is, the present invention uses a separation agent containing an aralkylcarboxylic acid ester of polysaccharide as an active ingredient.

It achieves the target.

The separating agent of the present invention preferably exhibits different adsorption powers for optical isomers of any compound.

[Polysaccharide]

The polysaccharide in the present invention includes synthetic polysaccharides, natural polysaccharides, and natural polysaccharides, and may be any optically active polysaccharide, but preferably one with a highly regular bonding pattern. Examples include 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 (crownG
all polysaccharides), 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-containing pullulan, agarose, alginic acid, etc., and more preferably cellulose, amylose, β-1, 4-chitosan, chitin, β-1,4-mannan, β-1°4-xylan,
These include inulin and curdlan.

The number average degree of polymerization (-average number of pyranose or furanose rings contained in the 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. .

[Aralkyl carboxylic acid ester]

In the present invention, the acid is considered to be a substituted derivative of acetic acid, and includes arifati, cucarboxylic acid and its famous substituted products having an aromatic group as a substituent in the molecule, preferably arylacetic acid, It is a gamma sulfuroxyacetic acid derivative. Even if they have an aromatic ring, acrylic acid derivatives, benzoic tl/derivatives, and propionic acid derivatives are excluded. Examples of the aromatic ring include phenyl, naphthyl, phenanthryl, anthryl, etc., and any form in which these may be bonded to the acetic acid skeleton may be used.

To give an example, phenylacetic acid Phenoquine acetic acid Naphthalene acetic acid (α, /1 bottle) 0-CH-COOH etc.

Further, the aromatic ring 2 may be provided with various substituents within the range that does not impair the effects of the present invention.

The polysaccharide aralkyl carboxylic acid ester of the present invention is one in which an average of 30 to 100%, preferably 85 to 100%, of the hydroxyl groups of the polysaccharide form an ester with the carboxylic acid. Hydroxyl groups that do not fall under this category may be free hydroxyl groups, or may be esterified, etherified, or carbamated as long as the separation ability of the separating agent is not impaired.

(Synthesis method) The esterification method for obtaining the substance of the present invention can be carried out in accordance with the conventionally known method (2) used for cellulose, amylose, etc. (For example, Asakura Shoten "Big Organic Chemistry 19. Natural polymer chemistry is acid halides, the most common of which is acid chloride.

It is desirable to use a tertiary amine base or a Lewis acid as a catalyst, and any reaction solvent may be used as long as it does not inhibit the esterification reaction; for example, pyridine or quinoline is often used as the base. Oftentimes mediated reactions such as 4-(N,N-dimethylamino)pyridine are effective in promoting the reaction.

Abuse.

It is also possible to combine the corresponding calginic acid with a suitable dehydrating agent to form a polysaccharide (double action).

The polysaccharide used as a raw material for the reaction often has poor reactivity (=poor reactivity), and in such cases it is activated by treatments such as dissolution-reprecipitation, dissolution-freeze-drying, etc. Alternatively, it is better to select a solvent for the reaction that dissolves the polysaccharide.

〔how to use〕

In order to use the separation agent of the present invention for the purpose of separating compounds and their optical isomers, it is common to use chromatography methods such as gas chromatography, liquid chromatography, and thin layer chromatography. Membrane separation can also be carried out.

In order to apply the separation agent of the present invention to a liquid chromatography method, methods include filling a column as a powder, coating a capillary column, forming a capillary with the separation agent and utilizing its inner wall, spinning,
Methods such as bundling these into columns are used, but it is common to form them into powder.

To make the separation agent into powder, it can be crushed or bead-shaped (
It is preferable to The size of the particles varies depending on the size of the column or plate used, but is generally 1 μm or more.
The particle size is preferably 1 μm to 300 μm, and the particles are preferably porous. Preferably, the agent is retained in a carrier. The appropriate size of the carrier varies depending on the size of the column or plate used (although it varies, generally 1 μm-IQsm, preferably 1 μm) to 30
It is 0 μm. The carrier is preferably porous, and has an average pore diameter of IOA to 100. The amount of the separating agent retained is 1 to 100% by weight, preferably 5 to 50% by weight, based on the carrier.
It is.

The separating agent may be retained on the carrier by either a chemical method or a physical method. Physical methods include dissolving the separating agent in a soluble solvent, mixing well with the carrier, and distilling off the solvent with an air stream under reduced pressure or heating, or dissolving the separating agent in a soluble solvent, There is also a method of thoroughly mixing with a carrier and then stirring and dispersing in a liquid that is incompatible with the solvent to diffuse the solvent. When crystallizing the separating agent held on the carrier in this way (- means heat treatment or other treatment can be performed.Also, add a small amount of solvent to once swell or dissolve the separating agent, and then add the solvent again. By distilling off, it is possible to change the retention state and thus the separation 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 substances such as silica, alumina, magnesia, titanium oxide, glass, silicates, and kaolin. Processing may be performed.

Examples of surface treatment methods include silanization using an organic silane compound and surface treatment using plasma polymerization.

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, and it is desirable to consider various developing solvents.

On the other hand, when performing thin layer chromatography (second is O1μ
It may be formed on a support plate having a thickness of 11 to 100 fins and made of the separation agent consisting of particles of about m to Q, l mm and, if necessary, a small amount of a binder.

When performing membrane separation, it is used as a hollow fiber or film.

(Effects of the Invention) The separating agent containing polysaccharide aralkylcarboxylic acid ester as an active ingredient of the present invention is effective in separating various compounds, and is particularly effective in separating optical isomers, which were extremely difficult to separate in the past. Among the optical isomers to be separated, one of them is more strongly adsorbed by the separating agent.

EXAMPLES The present invention will be explained 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.

Synthesis Example 1 Human silica beads (Ltchloapher manufactured by Merck)
Put SI 1000 ) 10f into a 200 mL 8-captured round bottom flask and add oil.

After vacuum drying in a bath at 120°C for 3 hours, NQ was added.

Two 100 mt of silica beads were added to toluene distilled with CaH2. Next, 3n+ of Nidiphenyldimethoxysilane (Shin-Etsu Chemical KBM 202) was added and stirred, and then reacted at 120°C for 1 hour. Furthermore, 3 to 5 mt of toluene was distilled off and reacted at 1120°C for 2 hours.

It was filtered through a glass filter for 11 minutes, washed three times with 50 mt of toluene and three times with 50 mt of methanol, and vacuum-dried at 40°C for 1 hour.

Next, about 10 f of the silica beads were placed in a 200 mA round bottom flask, and after drying under IJJ vacuum at 100°C for 3 hours, the pressure was returned to normal pressure, and after the temperature reached room temperature, N2 was introduced. 100 ml of distilled toluene was added to a mixture of dry silica beads.Next, 1 mt of trimethylsilyl agent N, 0-BiS-()limethylsilyl)acetamide was added and stirred.
The reaction was carried out at 15°C for 3 hours. Next, it was passed through a Nigelas filter, washed with toluene, and dried under vacuum for about 4 hours.

Synthesis Example 2 Cellulose triacetate (manufactured by Daicel Kagaku KK) with a number average degree of modification of 110 and a degree of substitution of 297 was dissolved in 1 t of acetic acid (Kanto Kagaku KK), 5.2 ml of water and 5 ml of concentrated sulfuric acid were added, and the mixture was heated at 80°C for 30 minutes. Allowed time to react. The reaction solution was cooled, and the sulfuric acid was neutralized with an excess aqueous magnesium acetate solution. The solution was poured into 3 tons of water to precipitate cellulose triacetate having a lower molecular weight. Glass filter (G3
) by CP, further dispersed in 1 t of water and separated,
Vacuum dried. The product is dissolved in methylene chloride (=dissolved, 2
- Propatol (purified by repeating the reprecipitation procedure twice and then bar-dried. The product was found to be cellulose triacetate according to the I'R spectrum and NNR spectrum, and the number average molecular weight determined by the vapor pressure osmotic method was 7900. When converted to number average degree of polymerization, it was 27.The vapor pressure osmotic pressure method was performed using a paper pressure osmometer C0RONA, 11.
7, using a mixed solvent of chloroform and 1% ethanol as the solvent.

The cellulose triacetate 602 thus obtained was
- Dispersed in propatool at 200 mA, and slowly dripped with 60 mt of 100% hydrazine hydrogen hydride (Dochu Kagaku) without stirring. After the suspension was withdrawn and washed, it was vacuum dried at 60°C. In the TR spectrum of the product, no absorption based on carbonyl groups near 1720 cr was detected, which coincided with that of cellulose.

Synthesis Example 3 Cellulose obtained in Synthesis Example-2 1.51F+ = Dehydrated Pyri 9 Fufu 0 mA, Dehydrated Triethylamine 7,7
rnL, 50 mf of 4-dimethylaminopyridine was added, and while stirring, 12.9 mf of phenylacetyl chloride was added.
9 was added and reacted at 100°C for 5 hours. After cooling, add 400 ml of ethanol to the product. The mixture was added with stirring to precipitate it, and the mixture was filtered through a glass filter and thoroughly washed with ethanol. After vacuum drying, the residue was dissolved in 30 mtf of methylene chloride, and after removing insoluble matter, it was reprecipitated in 400 mtf of ethanol. The precipitate was filtered, washed with ethanol, dehydrated and dried. 432 cellulose phenylacetate was obtained.

The characteristic absorption bands of the infrared absorption spectrum obtained after dissolving in methylene chloride, coating on common salt, and drying are as follows.

1 30506n Post-aromatic C-H stretching vibration 1 1750 crn C-0 stretching vibration of carboxylic acid salt 16106 n-', 1500 crn, 1460 crn Stretching between carbons in benzene ring (skeletal vibration due to 2 1250 (7)-1 ester C-O stretching vibration 1030
~1160cm-' C-0-C stretching vibration of cellulose 690-900crn-' Out-of-plane bending vibration of benzene ring Around 3450cm-' based on OH of cellulose
□Almost no yield was observed, and it was a 3-substituted product.

Further, the characteristic absorption of the proton NMR spectrum measured in CDC68 is as follows.

60-7.8ppm Benzene ring proton 3-, . 4
ppm Methylene proton of phenylacetic acid 3-5.4p
pm ``t! Proton of rulose ring and methylene at position 6 Example 1 The product 1.27 obtained in Synthesis Example 3 was dissolved in dichloromethane' 7
．． 5 mt, 7.5 mA of the solution was absorbed into the silica gel particles obtained in Synthesis Example 1, and the solvent was distilled off under reduced pressure to obtain a powdered support.

Application Example The silica beads supporting trisphenylacetate obtained in Example 1 were packed in a stainless steel column with a length of 25 cm and an inner diameter of 0.46 cm by a slurry method. The high-performance liquid chromatography machine is TRIROT manufactured by JASCO Corporation.
AR-8R was used, and UVIDEO-V was used as a detector.

Table 1 shows the results of dividing the Traeger base.

Table 1 Optical resolution of various racemates

Claims (1)

[Claims] A separation agent consisting of a polysaccharide derivative whose active ingredient is aralkylcarboxylic acid ester of polysaccharide.