JPH06263653A - Production of organic porous particle for separation of optical isomer - Google Patents

Abstract

(57) [Summary] [Structure] After impregnating an organic polymer particle with a vinyl monomer containing 1% by weight to 100% by weight of a crosslinkable polyvinyl monomer, a radical polymerization initiator and a porosifying solvent, The organic porous material for separating optical isomers, characterized in that the particles are suspended in an aqueous medium, the temperature of the suspension is raised, and an optically active vinyl monomer is added to the suspension during the polymerization reaction. EFFECT OF THE INVENTION According to the present invention, since the packing material for liquid chromatography for optical isomer separation is produced by using the seed polymerization method, the optical isomer can be produced more easily and reproducibly than conventional methods. A filler for body separation can be manufactured. Further, since the organic porous particles obtained by the method of the present invention are monodisperse particle diameters,
The column efficiency as a packing material is good, the stability is also good, and the optical isomer discrimination ability is higher than that of the particles for optical isomer separation produced by the conventional method.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing organic porous particles suitable for liquid chromatographic separation of optical isomers.

[0002]

2. Description of the Related Art Optical resolution, that is, a method of splitting a racemic mixture, which is a mixture of optical antipodes, into respective optical antipodes is used in the pharmaceutical, agrochemical and food industries. Particularly in recent years, a method for separating a racemic mixture by liquid chromatography has been actively studied. The separation method by liquid chromatography uses an optically active adsorbent such as a porous silica gel coated with a cellulose derivative such as cellulose triacetate or an optically active poly (triphenylmethyl) methacrylate as a stationary phase. A method and a method of using a copolymer of an optically active vinyl monomer and a small amount of a crosslinkable monomer as an adsorbent are known (for example, JP-B-59-7503 and JP-A-62-67056). Gazette).

Furthermore, the cross-linking agent is 1 in the total amount of the monomers used.
An adsorbent for optical resolution obtained by copolymerizing a polymer carrier having a content of 5% by weight or more (a degree of crosslinking of 15% or more), an optically active vinyl monomer, and a crosslinking monomer (JP-A-1-199643). ) Or an optically active vinyl monomer is graft-polymerized on a cross-linked polymer carrier having a group capable of graft-polymerizing the monomer (Japanese Patent Application Laid-Open No. 2-212242).

However, an adsorbent for optical resolution obtained by coating a porous silica gel with a cellulose derivative such as cellulose triacetate or an optically active poly (triphenylmethyl) methacrylate does not go beyond the means of analysis and is used for industrial purposes. However, there is a problem in terms of durability and ease of manufacturing. In addition, the adsorbent for optical resolution obtained by copolymerizing an optically active vinyl monomer and a small amount of a crosslinkable monomer has a low degree of crosslinking, and thus is easily consolidated,
It has a drawback that it is difficult to pass the liquid at high pressure and high flow rate.

Further, an optical resolution adsorbent obtained by polymerizing a polymer carrier having a degree of crosslinking of 15% or more, an optically active vinyl monomer and a crosslinking monomer, and an optically active vinyl. All of the adsorbents for optical resolution obtained by graft-polymerizing a monomer on a cross-linked polymer carrier having a group capable of graft-polymerizing the monomer, first produce a polymer carrier, and then produce an optically active vinyl monomer in the presence of the carrier. Although it can be obtained by polymerization, the operation is complicated and it is difficult to reproducibly produce an adsorbent having a desired separation performance.

[0006]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a method for easily producing organic porous particles for optical isomer separation having excellent separation performance.

[0007]

Means for Solving the Problems In the so-called seed polymerization method in which seed particles composed of organic polymer particles are impregnated with a vinyl monomer for polymerization, the inventor has found that an optically active vinyl monomer is used during the polymerization. It has been found that the addition of the isomer can easily and reproducibly obtain organic porous particles suitable for separation of optical isomers, and thus the present invention has been completed.
Further, the organic porous particles produced by the method of the present invention,
Since the particle size distribution is narrow, the column efficiency is high, the stability is good, and the optical isomer discrimination ability is higher than that of the particles synthesized by the conventional method.

That is, according to the present invention, organic polymer particles are impregnated with a vinyl monomer containing 1% by weight to 100% by weight of a crosslinkable polyvinyl monomer, a radical polymerization initiator and a porosifying solvent, The organic porous material for separating optical isomers, characterized in that the particles are suspended in an aqueous medium, the temperature of the suspension is raised, and an optically active vinyl monomer is added to the suspension during the polymerization reaction. The gist of the present invention is a method for producing a hydrophilic particle.

The present invention will be described in detail below. The organic polymer particles (seed particles) used in the present invention can be produced by generally well-known ball-forming polymerization such as emulsion polymerization, soap-free emulsion polymerization, dispersion polymerization and suspension polymerization. Among them, emulsion polymerization,
Polymer particles obtained by soap-free emulsion polymerization, dispersion polymerization and the like are particles having a narrow particle size distribution as compared with those produced by suspension polymerization, which is preferable.

The composition of the seed particles is preferably a polymer composed of an aromatic monovinyl monomer and / or an aliphatic monovinyl monomer. These may be either homopolymers or copolymers of two or more kinds of monomers, and may be copolymers with 1% by weight or less of a crosslinkable polyvinyl monomer. Particles made of polystyrene or polymethacrylic acid ester are typically preferred. The size of the seed particles can be arbitrarily selected according to the purpose within the range of 0.1 to 1000 μm.

In the production method of the present invention, 1 to 100 crosslinkable polyvinyl monomers are added to the seed particles composed of the organic polymer particles.
A so-called seed polymerization is carried out in which the vinyl monomer is contained in an amount of 1% by weight and then polymerized. As this seed polymerization method, a known method can be applied, but regarding the seed polymerization method using 0.1 to 1.5 μm polymer particles produced by an emulsion polymerization method or a soap-free emulsion polymerization method as seed particles, First, after primary swelling with a swelling aid, seed polymerization is performed to obtain 10
A method capable of producing porous particles having a uniform particle size of up to about 0 μm (J. Ugelstad et al., Makromole.
curare Chemie, 80, 737, 1
979) is preferred.

Further, 1 to 10 produced by dispersion polymerization
A method in which polymer particles of μm are used as seed particles and seed polymerization is performed (for example, JP-A-64-26617) is also suitable. As the crosslinkable polyvinyl monomer used during seed polymerization, aromatic polyvinyl monomers and aliphatic polyvinyl monomers are preferable, and as the aromatic polyvinyl monomer, divinylbenzene and aliphatic polyvinyl monomers are used. As the polyvinyl monomer, poly (meth) acrylate of polyhydric alcohol and alkylene poly (meth) acrylamide are preferable.
Examples thereof include ethylene glycol di (meth) acrylate, polyethylene glycol di (meth) acrylate, glycerol di (meth) acrylate, trimethylolpropane tri (meth) acrylate, tetrahydroxybutane di (meth) acrylate, and methylenebisacrylamide. Can be mentioned. The other vinyl monomer is a monovinyl monomer, preferably an aromatic monovinyl monomer and an aliphatic monovinyl monomer. The aromatic monovinyl monomer is preferably a styrene derivative such as styrene, t-butoxycarbonylstyrene, ethylstyrene or haloalkylstyrene, or a vinyl ester of a carboxylic acid such as vinyl benzoate or vinyl p-t-butylbenzoate. Further, the aliphatic monovinyl monomer is preferably a monounsaturated carboxylic acid, a monounsaturated carboxylic acid ester, an acrylamide derivative or the like, and examples thereof include (substituted) alkyl such as methyl (meth) acrylate and benzyl (meth) acrylate. Examples thereof include (meth) acrylate, glycidyl (meth) acrylate, glycerol mono (meth) acrylate, 2-hydroxyethyl (meth) acrylate, vinyl cyclohexanecarboxylate, vinyl butanoate, and N-isopropylacrylamide.

The amount of these vinyl monomers is appropriately determined in consideration of the size of seed particles to be used and the target particle size. The amount of the crosslinkable polyvinyl monomer in the vinyl monomer with which the polymer particles are impregnated is 1 to 100% by weight, preferably 25 to 100% by weight. Further, at the time of seed polymerization, as a porosifying solvent to be impregnated in the seed particles, an aliphatic or aromatic hydrocarbon which is an organic solvent that acts as a phase separation agent and promotes porosity of the produced particles,
Examples thereof include esters, ketones, ethers, and alcohols. Examples of such an organic solvent include toluene, xylene, cyclohexane, octane, butyl acetate, dimethyl phthalate, dibutyl phthalate, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ether, 1-hexanol, 2-octanol, decanol, cyclohexanol and the like. And these are used alone or as a mixture.

Radical polymerization initiators at the time of seed polymerization include peroxide type initiators such as benzoyl peroxide and butyl peroxyhexanoate, and azo type initiators such as azobisisobutyronitrile and azobisisovaleronitrile. preferable. These polymerization initiators are impregnated in the seed particles before the temperature is raised to the polymerization temperature and the seed polymerization is started. Impregnation of the polymerization initiator is carried out at the same time as or before or after the impregnation of the vinyl monomer by dissolving it in the vinyl monomer or the porosifying solvent.

When the seed particles are impregnated with the vinyl monomer, the porosifying solvent and the radical polymerization initiator, it may be preferable to dilute the seed particles with a solvent having a high affinity for the seed particles and impregnate them, if necessary. The polymerization initiator may be dissolved in this solvent and added. Examples of such a solvent include water-miscible low boiling point solvents such as alcohol, acetone, tetrahydrofuran and dioxane, and halogenated hydrocarbons such as dichloroethane and methylene chloride. It is also preferable that these solvents that promote impregnation are distilled off under reduced pressure before the start of seed polymerization.

In the present invention, the seed particles are swelled using the vinyl monomer, the porosifying solvent, the radical polymerization initiator and the like as described above, and then the suspension polymerization is carried out in an aqueous medium. The aqueous medium contains a dispersion stabilizer in order to prevent the water and the swollen seed particles from aggregating, deforming or fusing during the seed polymerization and increasing the dispersion stability thereof. As the dispersion stabilizer, known anionic and nonionic surfactants and synthetic polymers such as polyvinylpyrrolidone, polyethyleneimine and vinyl alcohol-vinyl acetate copolymer are preferable, and vinyl alcohol-vinyl acetate copolymer is particularly preferable. . Among them, a relatively low molecular weight vinyl alcohol-vinyl acetate copolymer having a degree of polymerization of about 500 is particularly preferable.

In the present invention, examples of the optically active vinyl monomer added after the initiation of the seed polymerization include monovinyl monomers having a substituent containing an asymmetric carbon atom, and one example thereof is an optically active vinyl monomer. Examples thereof include (meth) acrylamide derivatives, optically active (meth) acrylate derivatives, and optically active vinyl benzoic acid amide derivatives. Specifically, (R) or (S) -N- (1-phenylethyl)
(Meth) acrylamide, (R) or (S) -N-
(1-toluylethyl) (meth) acrylamide,
(R) or (S) -N- (1-cyclohexylethyl) (meth) acrylamide, (R) or (S) -N
-(1-naphthylethyl) (meth) acrylamide,
(L) or (D) -N- (meth) acryloyl-phenylalanine ethyl ester, (L) or (D) -N
-(Meth) acryloyl-phenylalaninol,
(L) or (D) -N- (meth) acryloyl-phenylglycinol, (R) or (S) -1-phenylethyl (meth) acrylic acid ester, (1R, 2S, 5
R) -menthyl (meth) acrylic acid ester, (R) or (S) -1-phenylethyl-N-vinylcarbamic acid ester, (1R, 2S, 5R) -menthyl-N-
Vinyl carbamate, (R) or (S) -1
Examples include -phenylethyl-N-isopropenylcarbamic acid ester and (1R, 2S, 5R) -menthyl-N-isopropenylcarbamic acid ester.

It is also possible to mix and use a crosslinkable polyvinyl monomer in a part of the optically active vinyl monomer, and the amount of the crosslinkable polyvinyl monomer used is that of the optically active vinyl monomer. It is preferably 1% or less. The addition amount of the optically active vinyl monomer is 5 to 70% by weight, preferably 10 to 50% by weight based on the vinyl monomer to be impregnated.

The addition timing of the optically active vinyl monomer is 0.5 after the seed polymerization is started by raising the temperature to a predetermined polymerization temperature.
It is added at once or dividedly in a period of -12 hours, preferably 1-8 hours. When dividedly added, for example, a method of adding every 10 to 60 minutes is preferable. The optically active vinyl monomer is added as it is, or diluted or dissolved with a solvent and added. When the optically active vinyl monomer is a solid, it may be added as a lump, but a method of finely pulverizing and adding is more preferable, and a method of dividing and adding the pulverized solid is particularly preferable. When diluted with a solvent and added, water-miscible solvents such as acetone and methanol, and halogenated hydrocarbons such as dichloroethane and methylene chloride are preferable as the solvent.

Seed polymerization is initiated by raising the temperature to the polymerization temperature. The polymerization temperature is preferably 50 ° C to 80 ° C, though it depends on the kind of the polymerization initiator used. The polymerization time of the seed polymerization is preferably around the half-life of the polymerization initiator or longer, and for example, 3 hours to 48 hours is preferable.
It is also preferable to add a polymerization initiator, particularly a water-soluble polymerization initiator such as potassium peroxodisulfate, at the same time when the optically active vinyl monomer is added after starting the seed polymerization. When this water-soluble polymerization initiator is not added, it is preferable to add an underwater polymerization inhibitor such as sodium nitrite to the aqueous medium prior to seed polymerization.

In the present invention, after completion of the polymerization, the organic polymer particles used as seed particles may be washed with a good solvent to remove a part or all of the polymer derived from the seed particles. A resin with the desired porosity is obtained.
The preferred pore physical properties of the porous polymer particles obtained by the method of the present invention vary depending on the application, but the average pore radius is 10 to 6000 angstroms, preferably 20 to 2000 angstroms, and the pore volume is 0.2-1.8 ml / g, preferably 0.4-1.
2 ml / g, and as the pore surface area, a value measured by the BET method is 1 to 2000 m ² / g, preferably 5
~1500m is a ² / g.

In the method of the present invention, the fact that the optically active vinyl monomer added at the time of seed polymerization was incorporated into the particles and the surface of the particles and / or the surface of the pores was functionalized was easily increased in weight or apparently. It can be verified by changes in various physical properties, and further analytically, it can be confirmed by elemental analysis or measurement of infrared absorption spectrum.

[0023]

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples. Example 1

(1) Preparation of polystyrene seed particles 0.27 g of sodium chloride was dissolved in 300 ml of water (ultra-pure water which was boiled while bubbling argon and then cooled), and 0.27 g of sodium chloride was dissolved, and styrene 5 was purified by distillation.
ml was added. While gently stirring these with a mechanical stirrer at room temperature, argon was bubbled for another 20 minutes to replace the inside of the reaction vessel, and then the vessel was sealed. Raise the temperature of the vessel to 75 ° C, and simultaneously increase the stirring speed to 35
Raised to 0 rpm. After keeping this state for 30 minutes, water 2
Potassium peroxodisulfate dissolved in 7.8 ml.
21 g was added to initiate polymerization. The initially clear solution started to become milky in about 20 minutes. After 30 minutes from the start of polymerization, 5 ml of styrene was further added, and then 5 ml of styrene was added every hour until the total amount of styrene finally added reached 40 ml. The polymerization time was 22.5 hours after the addition of the initiator. After the solidification is roughly removed from the emulsion after polymerization, the mixture is centrifuged (4500 rpm for 30 minutes), the supernatant is discarded, water is added to disperse the particles again, and then the supernatant is similarly removed to remove the supernatant. did. This operation was repeated until the supernatant became completely transparent. The particles were again dispersed in water, and the particles were observed with an optical microscope. As a result, it was confirmed that polystyrene particles having a particle size of approximately 1 μm and having extremely high monodispersity were obtained. The yield based on the weight of polystyrene particles was 65%, and the concentration of the finally prepared aqueous dispersion of polystyrene particles was 9.5% by weight. The resulting aqueous dispersion of monodisperse polystyrene particles was directly used for seed polymerization.

(2) Primary swelling with swelling aid 0.95 ml of dibutyl phthalate was mixed with benzoyl peroxide of 0.95 ml.
085 g was dissolved, 0.04 g of sodium dodecyl sulfate and 10 ml of water were added thereto, and a fine dispersion liquid was prepared under ice cooling using an ultrasonic generator. 1.4 ml of the aqueous dispersion of polystyrene seed particles (9.5% by weight) prepared in (1) above was added to the fine dispersion thus prepared, and gently stirred at room temperature (magnetic stirrer, 125r).
The seed particles were impregnated with the fine dispersion while pm). The completion of swelling was confirmed by an optical microscope, but it was completely completed within 2 to 4 hours. The particles whose swelling was completed were designated as primary swollen particles.

(3) Preparation of particles for separating optical isomers 10 ml of toluene and 4 ml (4.24 g) of ethylene glycol dimethacrylate, 5 methyl methacrylate
ml (4.72 g) of polyvinyl alcohol (polymerization degree 5
00, saponification degree 89%) 1.92 g was added to a solution prepared by dissolving 90 ml of water. A fine dispersion was prepared using an ultrasonic generator under ice cooling, added to the primary swollen particles prepared in (2), and similarly stirred gently at room temperature (1
(25 rpm) The finely dispersed liquid was impregnated into the swollen particles (finished in 1 hour, this operation is called secondary swelling). Transfer the suspension after the secondary swelling to a 200 ml separable flask,
After adding 0.01 g of sodium sulfite, argon was bubbled for 20 minutes at room temperature with gentle stirring. After sealing the container, the temperature was raised to 80 ° C. to start seed polymerization. Every 30 to 30 minutes after the initiation of polymerization, 0.2 g of (S) -N- (1-phenylethyl) methacrylamide was finely ground in a mortar and 1 g in total was added. The polymerization was carried out for 23 hours after the initiation. In this process, formation of secondary particles due to polymerization of the monomer used for impregnation was not observed.
After the polymerization was completed, the suspension was poured into 200 ml of water, shaken with an ultrasonic generator until the particles were uniformly dispersed, and then left standing overnight at room temperature. After discarding the supernatant liquid, methanol 20
After 0 ml was added and the particles were dispersed again with an ultrasonic generator in the same manner, the particles were allowed to settle by allowing them to settle, and the supernatant was discarded. This operation was repeated twice with methanol and twice with tetrahydrofuran, and then the particles were filtered with a micro filter (Fluoropore, FP-200 manufactured by Sumitomo Electric Co., Ltd.) and dried at room temperature, and then the weight was obtained. 91% yield
Met. The content rate of each element by elemental analysis is carbon: 6
0.12%, Hydrogen: 7.29%, Nitrogen: 0.91%, Oxygen: 31.68%, and since secondary particles are not produced, it is almost quantitatively an optically active vinyl monomer. Are considered to have been incorporated into the particles.

The obtained particles have an inner diameter of 4.6 mm and a length of 15
Packed in a 0 mm liquid chromatography column and mixed with hexane / tetrahydrofuran (volume ratio = 4: 1).
Was used as an eluent to separate racemic paranitrobenzoyl-1-phenylethylamine. The result is the first
Shown in the table. The separation coefficient α indicating the separation performance is represented by the ratio of the holding capacity ratios, and when α = 1, there is no separation performance, and the separation performance increases as the difference from 1 increases.

Further, using the same column, n-hexane /
Using ethyl acetate (volume ratio = 1: 1) as the eluent, 1.0m
FIG. 1 shows a chromatogram as a result of separation of racemic 1,1′-bi-2-naphthol at a flow rate of 1 / min and analysis by an ultraviolet photodetector (250 nm). The separation coefficient α at this time was 1.29.

Comparative Example 1 (S) -N- (1-phenylethyl) methacrylamide was not added after initiation of seed polymerization but was used as a mixture with a monomer and a porosifying solvent at the time of secondary swelling. Seed polymerization was carried out in the same manner as in 1. After the polymerization, the particles were washed and dried in the same manner as in (3) of Example 1. The obtained particles were packed in a column in the same manner as in Example 1, and a hexane / tetrahydrofuran mixed solution (4: 1) was used as an eluent to separate racemic paranitrobenzoyl-1-phenylethylamine. The results are shown in Table 1. The separation coefficient α indicating the separation performance is as low as 1.05, and it can be seen that only inefficient separation is performed.

[0030]

[Table 1] k ′ = (T1−T0) / T0 T1: Time (retention time) required from injection to elution of the sample (here, D-form or L-form of paranitrobenzoyl-1-phenylethylamine) injected into the column T0: The time required from injection to elution when a substance in which the packing material does not interact with the column was injected into the column. In Example 1 and Comparative Example 1, benzene was used for measurement. Separation coefficient (α) = (k ′ of D body) / (k ′ of L body)

[0031]

Industrial Applicability According to the present invention, since a packing material for liquid chromatography for optical isomer separation is produced by using a seed polymerization method, it is easier and more reproducible than the conventional method for the optical isomer separation. Fillers can be manufactured. Further, since the organic porous particles obtained by the method of the present invention have a narrow particle size distribution, column efficiency as a packing material is good, stability is also good, and particles for optical isomer separation produced by a conventional method are further used. It has a higher ability to discriminate optical isomers.

[Brief description of drawings]

1 is a chromatogram showing the result of separating racemic 1,1′-bi-2-naphthol using the organic porous particles produced in Example 1. FIG.

Claims (1)

[Claims] 1. An organic polymer particle is impregnated with a vinyl monomer containing 1% by weight to 100% by weight of a crosslinkable polyvinyl monomer, a radical polymerization initiator and a porosifying solvent,
The organic porous material for separating optical isomers, characterized in that the particles are suspended in an aqueous medium, the temperature of the suspension is raised, and an optically active vinyl monomer is added to the suspension during the polymerization reaction. Of producing hydrophilic particles