JPH0430376B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to the use of cellulose phenyl carbamate, a cellulose derivative, as a material separation agent. 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, and 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 Traditionally, the preferential crystallization method and diastereomer method 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 in optical resolution as separation agents for column chromatography. Examples of cellulose derivatives include microcrystalline cellulose triacetate and carboxymethyl cellulose, which belong to crystalline types. However, these celluloses or some cellulose derivatives have a narrow range of targets for separation and do not have sufficient separation ability. As a result of extensive research, the present inventors surprisingly discovered that cellulose phenyl carbamate has excellent compound separation ability and isomer separation ability, particularly optical isomer separation ability. The exact reason why cellulose phenyl carbamate exhibits excellent optical isomer separation is not clear, but it is due to the regular asymmetry of cellulose, the ability of the carbamate group to form hydrogen bonds, and the aromaticity and rigidity of the phenyl group. It is thought that this has a great influence on the separation of optical isomers. The cellulose phenyl carbamate of the present invention has a number average degree of polymerization of 5 to 5,000, preferably 10 to 1,000.
and more preferably 10 to 500. The average degree of substitution of cellulose phenyl carbamate is defined by the following formula. Average degree of substitution = number average degree of polymerization of phenyl carbamate groups per molecule The average degree of substitution of the cellulose phenyl carbamate of the present invention is 1 to 3.4, preferably 1.8 to 3.2.
The unreacted hydroxyl group of the cellulose phenyl carbamate can be further esterified, carbamate-formed, or etherified within a range that does not impair the isomer separation ability of the cellulose phenyl carbamate of the present invention. For the synthesis of cellulose phenyl carbamate of the present invention, a conventional reaction method for producing urethane from isocyanate and alcohol can be applied as is. For example, it can be obtained by reacting phenyl isocyanate and cellulose in the presence of a Lewis base such as a tertiary amine base or a Lewis acid catalyst such as a tin compound. Since the separating agent for chromatography is preferably in the form of particles, in order to use cellulose phenyl carbamate as a separating agent for compounds, it is preferable to crush the cellulose phenyl carbamate or form it into beads. The size of the particles varies depending on the size of the column and plate used, but is between 1 μm and 10 μm.
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,
Preferably, cellulose phenyl carbamate is retained on a carrier. The appropriate size of the carrier varies depending on the size of the column or plate used, but is generally 1 μm to 10 mm, preferably 1 μm to 300 μm.
It is m. Preferably, the carrier is porous;
The average pore size is 10〓~100μm, preferably,
50〓～50000〓. The amount of cellulose phenyl carbamate retained is 1 to 100% of the carrier.
% by weight, preferably from 5 to 50% by weight. A method for retaining cellulose phenyl carbamate on a carrier may be a chemical method or a physical method. Physical methods include dissolving cellulose phenyl carbamate in a soluble solvent, mixing well with the carrier, and distilling off the solvent with an air stream under reduced pressure or heating, and dissolving cellulose phenyl carbamate in a soluble solvent. There is also a method in which the solvent is thoroughly mixed with a carrier and then stirred and dispersed in a liquid that is incompatible with the solvent. When the cellulose phenyl carbamate held on the carrier in this manner is crystallized, a treatment such as heat treatment can be performed. In addition, by adding a small amount of solvent to once swell or dissolve cellulose phenyl carbamate, and then distilling off the solvent again,
It is possible to change the retention state and thus the separation power. 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; You may also process it. Examples of surface treatment methods include silanization using an organic silane compound and surface treatment using plasma polymerization. In order to use the separation agent containing cellulose phenyl carbamate as a main component of the present invention for the purpose of separating compounds, chromatography is suitable. A solvent that dissolves cellulose phenyl carbamate cannot be used as a developing solvent when used in chromatography, but when cellulose phenyl carbamate is bonded to a carrier by a chemical method or when cellulose phenyl carbamate is crosslinked, There are no particular restrictions. The separating agent containing cellulose phenyl carbamate as a main component of the present invention is effective in separating compounds, and is particularly effective in resolving optical isomers, which have conventionally been very difficult to separate. 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 phenyl carbamate. 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 Cellulose (Merck Co., Ltd., for column chromatography) 1
g was dispersed in 50 mg of dry pyridine, 8 ml of phenyl isocyanate was added thereto, and the temperature was maintained at 110°C with stirring. After 16 hours, the reaction mixture was poured into 1 methanol.
Separate the white solid that forms and store at room temperature for 2 hours at 60°C.
It was dried under reduced pressure at ℃ for 3 hours. The yield was 1.45g. The product was almost completely dissolved in chloroform, methylene chloride, dioxane, etc. Infrared and NMR
The spectrum confirmed that it was cellulose itris phenyl carbamate, and the degree of polymerization determined by GPC was 200. Elemental analysis Measured value C, 60.93%; H, 4.68%; N, 7.93% Theoretical value C, 62.42%; H, 4.85%; N, 8.09% [as (C ₂₇ H ₂₅ N ₃ O ₈ ) _o ] Synthesis example 2 Silica gel (Lichrospher SI4000, Merck & Co.)
After drying 102g at 180℃ for 2 hours, dry benzene 600g
ml, 6 ml of pyridine and 20 ml of 3-aminopropyltriethoxysilane, and reacted under heating under reflux for 16 hours. After the reaction was completed, the reaction mixture was poured into 2 methanol, and the modified silica gel was separated. 0.76 g of cellulose trisphenyl carbamate obtained in Synthesis Example 1 was dissolved in a mixed solvent of 10 ml of dioxane and 5 ml of ethanol. After removing a trace amount of insoluble matter, 3.0 g of modified silica gel was mixed with 5 ml of the solution, and the solvent was distilled off under reduced pressure. This loading operation was repeated twice to prepare cellulose trisphenyl carbamate-supported silica gel. Example 1 The supported silica gel prepared in Synthesis Example 2 was 25 cm long.
A stainless steel column with an inner diameter of 0.46 cm was packed using the slurry method. The high-performance liquid chromatograph is TRIROTAR- manufactured by JASCO Corporation, and the detector is
UVIDEC- and DIP-181 polarimeters were used.
The solvents include (1) hexane-2-propanol (mixing weight ratio 90/10), (2) hexane-2-propanol (80:20), (3) hexane-2-propanol-diethylamine (80:20:0.001). ), (4) ethanol-water (50:50), (5) ethanol-water (70:30),
Flow rate is 0.5ml/min in both cases, column temperature is 25℃
And so. Table 1 shows the resolution results of various racemates, and Table 2 shows the separation results of various achiral compounds. Molecular weight measurement Molecular weight was determined by GPC method using a calibration curve for standard polystyrene. GPC column is
Shodex A80M was used, and tetrahydrofuran was used as the solvent.

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[Table] Synthesis Example 3 100 g of cellulose triacetate with a number average degree of polymerization of 110 and a degree of acetylation of 2.49 was dissolved in 1 part of acetic acid, 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 magnesium aqueous solution. The solution was placed in water in Step 3 to precipitate cellulose triacetate having a lower molecular weight. Glass filter (G3)
After dispersion in water, the mixture was separated and dried under vacuum. Dissolve the product in methylene chloride,
The procedure of reprecipitation in 2-propanol was repeated twice for purification and then drying. The product is cellulose triacetate according to the IR spectrum and NMR spectrum, and the number average molecular weight determined by vapor pressure osmotic pressure method is 7900, which is 27 when converted to number average degree of polymerization.
It was hot. The vapor pressure osmotic pressure method was measured using a paper pressure osmometer CORONA117 using a mixed solvent of chloroform and 1% ethanol as the solvent. Obtained low molecular weight cellulose triacetate
Dissolve 10.0g in 100ml of pyridine, then add 8.0ml of
100% hydrated hydrazine was added. After being left at room temperature for 1 hour, it was heated to 90-100°C. The generated precipitate was separated using a glass filter and then washed with pyridine. The obtained product was confirmed to be cellulose by IR spectrum. 100 ml of dry pyridine was added to 5 g of the obtained low molecular weight cellulose and some pyridine to disperse it, and 100 ml of benzene was added to remove water, which was then distilled off through a rectification tube. The remaining pyridine suspension of low molecular weight cellulose was heated to 60-70°C and stirred.
Drop 16.3 ml of phenyl isocyanate and add 100 ml of phenyl isocyanate.
It was kept at ~105°C for 3 hours and 35 minutes. Pyridine and phenyl isocyanate were distilled off under reduced pressure, and the reaction product was dissolved in methylene chloride. After the by-produced methylene chloride insoluble matter was separated using a glass filter (G3), the soluble portion was fractionated using 2-propanol. 5.67 g of the 2-propanol-insoluble product was obtained as a light brown solid. IR spectrum, NMR
From the spectrum, it was confirmed that it was cellulose trisphenyl carbamate. IR spectrum: 3500cm ^-1 ν _NH , 3300cm ^-1 ν _NH , 1700
cm ^-1 ν _C=0 , 1530cm ^-1 ν _NH , NMR spectrum: 18H Broad singlet centered
at δ 7 7H multiplets δ 6.0 to 3.0 Synthesis Example 4 Silica gel (Lichrospher SI1000, manufactured by Merck & Co.) was heated to 120 to 150° C. for 2 to 10 hours in a stream of dry nitrogen and dried. 20 g of dried silica gel was suspended in 100 ml of anhydrous benzene, 6 g of 3-aminopropyltrimethoxysilane was added thereto, and the mixture was heated to reflux under a stream of dry nitrogen. The reaction was continued for 5 to 10 hours while the methanol produced at this time was removed from the system. After the reaction was completed, the mixture was cooled to room temperature and filtered through a glass filter. The obtained modified silica gel was washed with anhydrous benzene and then dried in vacuo at 40°C. 6g of aminopropylsilane-treated silica gel
After drying under reduced pressure at 80℃ for 1 hour, it was dispersed in 50 ml of dry methylene chloride, and then triethylamine 2
ml and phenyl isocyanate (1 ml) were added, mixed well, and left to stand for one day. Thereafter, the mixture was heated to 40°C for 1 hour. Decant the solvent, methylene chloride,
After washing with ethanol and acetone, it was dried. 0.9 g of cellulose trisphenyl carbamate obtained in Synthesis Example 1 was dissolved in 4.5 ml of methylene chloride, mixed with 3.5 g of modified silica gel, and the solvent was distilled off under reduced pressure. Example 2 The silica beads supporting cellulose trisphenyl carbamate obtained in Synthesis Example 4 were
A 25 cm stainless steel column with an inner diameter of 0.46 cm was packed using the slurry method. The high-performance liquid chromatograph used was TRIROTARSR manufactured by JASCO Corporation, and the detector used was UVIDEC-. The flow rate was 0.2 ml/min, and the solvent was hexane-2-propanol (9:1).
It was used. Table 3 shows the results of resolution of various racemates.

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Claims (1)

[Claims] 1. A separation agent whose main component is cellulose phenyl carbamate.