JPH0475208B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to the use of cellulose ethers containing aromatic rings, which are cellulose derivatives, as separation agents for substances. The substances to be separated are not only ordinary low-molecular compounds, but also optical isomers, which have traditionally been very difficult to separate directly. In general, racemic forms and optically active forms often exhibit different physiological activities. For example, in the fields of medicine and agrochemicals, it is necessary to separate optical isomers in order to prevent drug damage and improve drug efficacy per unit amount used. There are cases where Conventionally, preferential crystallization and diastereomer methods have been used to separate optical isomers, but these methods limit the types of optical isomers that can be separated and often require a long time. . Therefore, there is a strong desire to develop a simple separation method using chromatography. Research on the separation of optical isomers by chromatography has been conducted for some time. For example, cellulose or some cellulose derivatives are used for optical resolution as separation agents for column chromatography. Examples of cellulose derivatives include microcrystalline cellulose triacetate and carboxymethyl cellulose, which belong to type I crystalline system. However, these celluloses or some cellulose derivatives have a narrow range of objects to be separated and do not have sufficient separation ability. As a result of intensive research, the present inventors surprisingly discovered that cellulose ether containing an aromatic ring has excellent compound separation ability and isomer separation ability, particularly optical isomer separation ability. That is, the present invention relates to a separating agent whose main constituent is cellulose ether having a substituent represented by the following general formula (1).

[Formula] However, in the formula, X is an alkyl group, a nitro group, a halogen, an amino group, an alkyl-substituted amino group, a cyano group, a hydroxyl group, or a carboxyl group,
indicates the number of X, and is an integer from 0 to 5. n
is an integer from 1 to 5, preferably 1. Although it is not clear why the cellulose ether containing an aromatic ring as described above used in the present invention exhibits excellent optical isomer separation ability, the reason is that the regular asymmetry of cellulose and the aromatic properties that form ether bonds It is thought that the aromaticity and rigidity of the group derivatives have a great influence on the separation of optical isomers. The cellulose ether containing an aromatic ring of the present invention has a number average degree of polymerization of 5 to 5,000, preferably 10
-1000, more preferably 10-500.
The average degree of substitution of cellulose ether containing an aromatic ring is defined by the following formula. Average degree of substitution=number of ether bonds per molecule/number average degree of polymerization The average degree of substitution of the cellulose ether containing an aromatic ring of the present invention is 1 to 3.4, preferably 1.8 to 3.2. The unreacted hydroxyl group of the cellulose ether containing an aromatic ring can be further esterified, carbamate-formed, or etherified as long as the isomer separation ability of the cellulose ether containing an aromatic ring of the present invention is not impaired. A conventionally known cellulose etherification method can be applied to the method of synthesizing the cellulose ether containing an aromatic ring of the present invention. That is, it can generally be obtained by a method of reacting cellulose with an aromatic derivative having a leaving group in the presence of a base. For example, NM
Bikales, L. Segel, “Cellulose and Cellulose
Derivatives” p.807 and Asakura Shoten “Large Organic Chemistry”
19, p.93. Furthermore, as a method for obtaining cellulose ethers containing highly substituted aromatic rings, there is a method by Huseman et al. (Makromol.
Chem, 176 3269 (1975)) and Nakano et al.
Proceedings of ISWPC 1983, vol.1, 33). Since the separation agent for chromatography is preferably in the form of particles, in order to use cellulose ether containing an aromatic ring as a separation agent for compounds, it is preferable to crush the cellulose ether containing an aromatic ring or make it into beads. . The particle size varies depending on the column and plate size used, but is approximately 1 μm.
~10 mm, preferably 1 μm to 300 μm, and the particles are preferably porous. Furthermore, in order to improve the pressure resistance of the separation agent, prevent swelling and shrinkage due to solvent substitution, and increase the number of theoretical plates,
The cellulose ether containing an aromatic ring is preferably supported on a carrier. The appropriate carrier size is
Although it varies depending on the size of the column and plate used, it is generally 1 μm to 10 mm, preferably 1 μm to 10 mm.
It is 300 μm. The carrier is preferably porous, with an average pore size of 10 Å to 100 μm, preferably
It is 50 Å to 50000 Å. The amount of cellulose ether containing an aromatic ring to be retained is 1 to 1 to the carrier.
100% by weight, preferably 5-50% by weight. The cellulose ether containing an aromatic ring may be retained on a carrier by either a chemical method or a physical method. Physical methods include dissolving cellulose ether containing aromatic rings in a soluble solvent, mixing well with a carrier, and distilling off the solvent with an air stream under reduced pressure or heating; There is also a method of dissolving the compound in a soluble solvent, thoroughly mixing it with a carrier, and then stirring and dispersing it in a liquid that is incompatible with the solvent to diffuse the solvent. When crystallizing the cellulose derivative 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 cellulose ether containing an aromatic ring, and then distilling off the solvent again, 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 inorganic 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 have good compatibility with cellulose ethers containing aromatic rings. Surface treatment may be performed for this purpose. Examples of surface treatment methods include silanization using an organic silane compound and surface treatment using plasma polymerization. A chromatographic method is suitable for using the separating agent of the present invention whose main constituent is cellulose ether containing an aromatic ring for the purpose of separating compounds. As the chromatographic method, column chromatography and thin layer chromatography are preferred. Solvents that dissolve cellulose ether containing aromatic rings cannot be used as a developing solvent when used in chromatography, but when cellulose ether containing aromatic rings is bonded to a carrier by a chemical method, or There are no particular restrictions when the cellulose ether containing is crosslinked. The separating agent of the present invention whose main component is cellulose ether containing an aromatic ring is effective in separating compounds, and is particularly effective in resolving optical isomers, which have been extremely difficult to separate in the past. The optical isomers to be separated are compounds with an asymmetric center or molecularly asymmetric compounds, and one of the optical isomers is more strongly retained by cellulose ether containing an aromatic ring. 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 more strongly adsorbed enantiomer / weaker adsorbed enantiomer Volume ratio of the bodies Separation degree (R _S ) = 2 × (distance between the two peaks of the more strongly adsorbed enantiomer and the more weakly adsorbed enantiomer) / sum of the band widths of both peaks Synthesis example 1 Cellulose Acetate [substitution degree 2.43, viscosity average polymerization degree 170 (dichloromethane-methanol 9:1 mixed solvent is used as solvent, approximated as [η] with reduced viscosity of 0.2% solution, Km = 8.73 × 10 ^-4 is used) (calculated from DP=[η]/Km), manufactured by Daicel Chemical Industries), was poured into 41.3 parts of 1,4-dioxane, heated externally with stirring, and refluxed for about 10 minutes (100 ℃) and dissolved. Thereafter, while stirring, 36.0 parts of powdered potassium hydroxide was added, and then 51.7 parts of benzyl chloride were gradually added. After the addition of benzyl chloride, the mixture was stirred and reacted at 100°C for 8 hours. After the reaction was completed, the reaction solution was allowed to cool to room temperature, and then the product was extracted from the reaction solution with chloroform. The chloroform solution was washed with about 1N aqueous hydrochloric acid and water, and then poured into methanol to precipitate a yellowish white product. The reaction product was washed with methanol and then dried. The product was benzyl cellulose ether with a degree of substitution of 2.9 [elemental analysis values, C74.75%, H6.54%], and the yield was 91%. The infrared absorption spectrum of the obtained benzyl cellulose ether is shown in FIG. 1, and the wave numbers and assignments of the main absorption bands are described below. (Wave number) [cm ^-1 ] (Attribution) 3100, 3070, 3040 CH stretching vibration of phenyl around 2900 benzyl group and glycose skeleton C ₆ position
CH ₂ stretching vibrations 1960, 1870, 1810, 1750 Overtones and bond tones of mono-substituted phenyl 1610 (1585), 1500 (1460) Skeletal vibration of phenyl around 1100 Skeletal vibration of pyranose ring 740, 700 CH out-of-plane variation of mono-substituted phenyl Angular vibration synthesis example 2 Silica beads (Merck LiChrospher SI
1000) was placed in a 200 ml round bottom flask with arms, vacuum dried in an oil bath at 120°C for 3 hours, and then filled with N ₂ . 100 ml of toluene distilled with CaH ₂ was added to the silica beads. Next, 3 ml of diphenyldimethoxysilane (Shin-Etsu Chemical KBM202) was added, stirred, and reacted at 120°C for 1 hour. 3-5 more
After distilling off ml of toluene, the mixture was reacted at 120°C for 2 hours.
Pass through a glass filter and add 50ml of toluene.
The sample was washed three times with 50 ml of methanol and vacuum dried at 40°C for 1 hour. Next, approximately 10 g of silica beads were placed in a 200 ml round bottom flask with side arms, and after vacuum drying at 100° C. for 3 hours, the pressure was returned to normal pressure and after the temperature reached room temperature, N ₂ was added. 100ml of distilled toluene was added to the dried silica beads. Next, 1 ml of trimethylsilyl agent N,O-Bis-(trimethylsilyl)acetamide was added, stirred, and reacted at 115°C for 3 hours. Next, it was filtered through a glass filter, washed with toluene, and vacuum dried for about 4 hours. Tribenzylcellulose ether obtained in Synthesis Example 1 was dissolved in chloroform, and methanol in an amount four times that of chloroform was added to separate the solution into a soluble portion and an insoluble portion. 1.2 g of the soluble portion was dissolved in a mixed solvent of methylene chloride and benzene (5 ml - 2.5 ml), 6 ml of this solution was mixed with 3.2 g of silane-treated silica gel, and the solvent was distilled off under reduced pressure. These silica beads were used as a filler for optical resolution. Example 1 Silica beads supporting tribenzyl cellulose ether obtained in Synthesis Example 2 were prepared with a length of 25 cm and an inner diameter of 25 cm.
It was packed into a 0.46 cm stainless steel column using the slurry method. The high-performance liquid chromatography machine is manufactured by JASCO Corporation.
The detector is TRIROTAR-SR manufactured by
UVIDEC-V was used. The flow rate was 0.2ml/min.
Ethanol was used as the solvent. Table 1 shows the results of resolution of various racemates.

【table】 [Brief explanation of the drawing]

FIG. 1 is an infrared absorption spectrum of benzyl cellulose ether obtained in Synthesis Example 1.

Claims (1)

[Scope of Claims] 1. A separating agent whose main component is cellulose ether having a substituent represented by the following general formula (1). However, in the formula, X is an alkyl group, nitro group, halogen, amino group, alkyl-substituted amino group, cyano group, hydroxyl group or carboxyl group,
represents the number of X, is an integer from 0 to 5,
n is an integer from 1 to 5.