JPS61160054A - Packing material for optical splitting - Google Patents

Abstract

PURPOSE:To obtain a packing agent having not only good separation efficiency but also sufficient mechanical strength and easily adaptable to high performance chromatography and having excellent separation capacity even to a roughened plane compound, by fixing a copolymer consisting of a specific optically active monomer and a vinyl silane compound to a silica gel. CONSTITUTION:A copolymer, which consists of an optically active monomer represented by formula I (wherein R1 is phenyl, 1-naphthyl, 2-naphthyl or lower alkyl and phenyl and 1- or 2-naphthyl may have a substituent. R2 is lower alkyl, R3 is H or CH3 and * is asymmetric carbon) and a compound represented by formula II (wherein R4, R5 and R6 are alkyl, alkoxy, OH or halogen and one or more of R4, R5, R6 is alkoxy and halogen), is obtained so that the mol ratio of the compound represented by the formula I and the compound represented by the formula II is 0.5-80. This copolymer is fixed to a silica gel particle pref. having a uniform particle size and an average fine pore size of 100Angstrom or more. By this method, a packing agent excellent in the optical separation capacity of a wide range of a racemic mixture.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a filler for optical resolution immobilized on an optically active polymer-containing silica gel.

<Prior Art> The separation of maggot a compound into optically symmetric bodies is important in analytical and synthetic chemistry.

A common method consists of converting the mixture into diastereomeric mixtures and separating the diastereomeric mixtures by differences in physical properties such as solubility. In addition to these conventional methods, the technique of separating the Ugimi mixture by chromatography has been extensively researched in recent years, and the following techniques are known.

(A) Liquid chromatography using as a filler a doze-like polymer derived from an acrylic 7-midomo/mer derived from an optically active amine (Japanese Patent Publication No. 59-7503
Publication No.).

(B) Liquid chromatography using an optically active stationary phase obtained by grafting an optically active substance onto a free carrier such as silica gel as a packing material.

(a) Ligand exchange method using an optically active proline-grafted filler (J.

Chromatoar, 266, 0439 (19
83)).

(b) Removal by a charge transfer complex using a filler grafted with an optically active compound lacking π electrons (J,
ChrOn+atOgr, 1 2 2
．． p 205 (1976)).

(C) Method using a filler grafted with optically active N-acylated amino acids <J, ChrOmatOLJr
, 186, ρ543 (1979)).

(d) A method using a filler grafted with optically active 1-(9-anthryl)trifluoroethanol or 3,5-dinitrobenzoylated optically active phenylglycine (J, Cbromatogr, 1)
92, p143 (1980), J. Ora, Chell.
, 46. o 4988 (1981))).

<e> Method using a filler grafted with an optically active aromatic amine (J, (:, chromatogr
.

265, p. 117 (1983)).

<Problems to be solved by the invention> However, in the prior art (△) method, the polymer beads are relatively large and uneven, resulting in low column efficiency, as well as weak mechanical strength and high It has the disadvantage of not being able to increase the flow rate. Furthermore, since polymer beads do not swell in hydrophilic solvents, they have the disadvantage that the solvents that can be used are limited. On the other hand, in the conventional method (B), the optically active stationary phase obtained by grafting an optically active substance onto an inorganic jH body such as silica gel has sufficient mechanical strength and is suitable for speeding up. It is possible. However, the compounds that can be separated are limited to a narrow range, the degree of separation is small, and it is difficult to produce grafted fillers, making it difficult to obtain fillers with reproducible performance. Therefore, it is difficult to say that any of them are practical fillers.

Among these, method (e), which uses a filler grafted with optically active aromatic amines, separates a relatively wide range of racemic mixtures such as amines, alcohols, carboxylic acids, amino acids, oxyacids, and amino alcohols, and provides high performance. In Although,
The degree of separation is still not sufficient.

Under these circumstances, the present inventors have developed a method that expands the range of compounds that can be analyzed, is relatively easy to construct with WIJ, is chemically stable, and is practical. As a result of our continued investigation with the aim of providing fillers, we have found that a polymer consisting of an optically active monomer represented by the following general formula (1) and a monomer represented by the following general formula (II) is immobilized on silica gel. The filler for optical resolution not only shows a wide range of effects in separating racemic mixtures, but by creating an optically active polymer structure, it not only has performance equivalent to or better than monomer-type fillers with the same structure. discovered that it exhibits excellent separation ability for compounds with irregular surfaces, which were difficult to separate in the past, and developed the present invention.
Reached.

(In the formula, R1 is a phenyl group, a 1-naphthyl group, or a 2-
Represents a phenyl group, 1-naphthyl group or 2-naphthyl group substituted with a naphthyl group or a lower alkyl group,
R2 represents a lower alkyl group, R3 represents a hydrogen atom or a methyl group, and * represents an asymmetric carbon atom. ) Normal CF+2 -CH-8i -Rs ・
... (II) (wherein R4, R5, and Rs represent the same or different alkyl groups, alkoxyl groups, hydroxyl groups, or halogen atoms, and at least one of R4, R5, and R6 is an alkoxyl filler or a halogen atom) ) The filler of the present invention is an extremely useful filler because it can be easily produced by ordinary chemical reactions and is also chemically stable.

The optically active monomer represented by the above general formula (I) is, for example, an optically active amine RIR2♂HNH2 (where R1 and R2 are as described above), an acrylic lS
! Anhydrous or methacrylic 5! Anhydrous and especially 4-tertiary
It can be obtained by reacting at a temperature of about -5°C to 60°C in the presence of a polymerization inhibitor such as F&, butylpyrocatechol, etc., but it can be obtained by reacting with an organic solvent that is inert at air temperature, especially benzene, toluene, etc. It is preferable to carry out the reaction using a hydrocarbon or a halogenated hydrocarbon such as methylene chloride or chloroform. The reaction time depends on the applied reaction temperature, but is usually about 30 minutes to 4 hours.

The optically active monomer represented by the above general formula (1) is an optically active amine RI R2CHNH2 (where R1 and R2 are the above-mentioned and J5) and acrylic acid chloride or methacrylic acid chloride. It can also be synthesized by reacting J5 in the presence of a reaction inhibitor in the above-mentioned inert organic solvent at a temperature below the mold temperature in the presence of a neutralizing agent for hydrochloric acid produced as a by-product. As a neutralizing agent for hydrochloric acid, tertiary amines such as triethylamine, sodium hydroxide, sodium carbonate/
Examples of alkaline aqueous solutions include:

Examples of the optical monomer represented by the above general formula (r) include the following compounds.

R- or S-acrylic acid-1-phenylethylamide, R- or S-acrylic acid-1-(2-methylphenyl)ethylamide, R- or S-acrylic acid 1-(4
-methylphenyl)ethylamide, R- or S-acrylic alcohol-1-phenylpropylamide, R- or S-
Acrylic acid-1-(1-naphthyl)ethylamide, R-
Or S-Acrylic! ! ! -1-(2-naphthyl)ethylamide, R- or S-acrylic acid-1-(1-naphthyl)propylamide, R- or S-acrylic acid-1
-(6,7-dimethyl-1-naphthyl)ethylamide,
R- or S-acrylic acid-1-(6,7-dimethyl-
1-naphthyl) isopropylamide, R- or S-methacrylic M-1-phenylethylamide, R- or S
-methacrylic acid-1-(2-methylphenyl)ethylamide, R- or S-methacrylic acid-1-(4-methylphenyl)ethylamide, R- or S-methacrylic acid
! 1-1-phenylprotolylamide, R- or S-methacrylic 1-(1-naphthyl)ethylamide, R- or S-methacrylic 1-(2-naphthyl)ethylamide, R- or S-methacrylic M -1-(
1-naphthyl)propylamide, R- or S-methacrylic! l! -1-<6.7-dimethyl-1-naphthyl)
Ethylamide, R- or S-methacrylic lS! l-1
-<6.7-dimethyl-1-naphthyl)isopropylamide.

On the other hand, the monomers represented by the above general formula <ff) include vinyldiethylethoxysilane, vinylmethyldichlorosilane, vinylmethyldichlorosilane, vinylmethyljethoxysilane, vinyltrichlorosilane, vinyltriethoxysilane, and vinyltriisopropoxysilane. , vinyltrimethoxysilane, etc. are preferably used. Among these, vinyltrimethoxysilane, vinyltriethoxysilane 1, and vinylmethyljethoxysilane are particularly preferred.

Copolymerization of the optically active monomer represented by the above general formula (1) and the monomer represented by the above general formula (Ir) can be carried out using radicals such as peroxides such as dibenzoyl peroxy)nide and dilauroyl peroxide. In the presence of a radical initiation initiator of the forming compound or an azo compound such as azoisobutyronitrile, an inert organic solvent, preferably an aromatic hydrocarbon such as benzene, toluene or methylene chloride, chloroform, 1°2-dichloroethane, etc. in a known manner in halogenated hydrocarbons.

Particularly preferred solvents include benzene and toluene.

The polymer obtained by polymerization can be precipitated by pouring the reaction solution as it is or by concentrating it into a large excess of a polymer-insoluble solvent, such as a lower alcohol such as methanol or ethanol, or an aliphatic alkane such as n-hebutane or cyclohexane. [Can be separated and recovered as 1. Particularly preferred diluent precipitants include methanol, n-
Examples include hexane. The polymer can be purified by dissolving the precipitate again in an aromatic hydrocarbon such as benzene or toluene or a halogenated hydrocarbon such as chloroform or methylene chloride, and introducing the solution into a diluted precipitant. Alternatively, it is also possible to use the reaction solution as it is without separating the polymer from the reaction solution and react with pre-dried silica gel to immobilize the polymer. According to this method, the filler can be manufactured more easily. .

In a polymer consisting of an optically active monomer represented by the above general formula (+>) and a monomer represented by the general formula (IF), a 7mer represented by the above general formula <1) and the above general formula (If> The molar ratio of the copolymerization composition of the monomers represented by is preferably 0.5 or more, more preferably 1 or more.

If the molar ratio is 0.51J or above, it has sufficient performance as a filler for optical resolution. If the molar ratio is less than 0.5, the number of optically active molecules represented by the above general formula (I) decreases, and the optical resolution performance tends to deteriorate. Furthermore, if the molar ratio becomes too large, the amount of the monomer represented by the above general formula (IF) tends to decrease, and the amount immobilized on the silica gel tends to decrease, so the molar ratio is preferably 100 or less. , particularly preferably 80 or less.

Next, we will discuss the immobilization of polymers onto silica gel.

The shape of the silica gel used in the present invention may be any shape, such as spherical or crushed, but in order to obtain a highly efficient adhesive column, it is necessary to use fine particles with uniform particle size and an appropriate pore size. It is preferable to have The fully porous silica gel usually has an average particle diameter of 1 μm to 11 μl, and preferably has an average pore diameter of 100 angstroms or more. More preferably, the thickness is 300 angstroms or more. If the average pore diameter is less than 100 angstroms, the pore diameter is too small, and the polymer tends to be strongly immobilized on the silica gel.

The upper limit of the pore diameter is not particularly limited, but it is usually preferably 5000 angstroms or less in view of the mechanical strength of the silica gel. R4, R5゜R6 of the seven-mer unit represented by the above general formula (I [) in the polymer and the hydroxyl group on the surface of the silica gel are reacted in a halogenated hydrocarbon such as group hydrocarbon or chloroform under heating conditions. This allows polymers to be easily immobilized on silica gel with strong covalent bonds. Can silica gel be simply dehydrated in advance? Polymers can be immobilized without the need for extensive pretreatment. This is one feature of the present invention. Furthermore, the obtained packing material has sufficient mechanical strength, making it easy to speed up chromatography.
Moreover, because it is chemically stable, it can be used for a long period of time.

In order to suppress hydrolysis of the polymer during the immobilization process, it is preferable to use the solvent after dehydrating it in advance. The reaction time of the immobilization treatment depends on the heating temperature, but is usually between 1 and ioog. The amount of immobilized polymer is usually 0.1% by weight or more, preferably 1 m2, based on the silica gel.
It is at least 3%, preferably at least 3%.

The optical resolution packing material obtained according to the present invention can be packed into a chromatographic column according to a conventional method such as a slurry packing method and used as a stationary phase in liquid O-chromatography. In liquid chromatography using this stationary phase, by selecting appropriate elution conditions, especially commonly used normal phase distribution or reversed phase distribution conditions, it is possible to determine the optical fraction 1j of optical isomers of a wide range of compounds. .

Examples of optically resolvable compounds include aromatic hydrocarbons, halides, alcohols, aldehydes, ketones, carboxylic acids, amines, ethers, esters, amides, nitriles, amino acids, oxycarboxylic acids, and the like. especially,
100NH- group bonded to an asymmetric carbon atom, -08 base, -
oco-m, -0CONH-W, Matahar N-CONH
Separation or analysis of racemic mixtures of compounds having - groups can be carried out efficiently and in a short time. Specific examples include α-chlorbu O pionic acid anilide, hexobarbicur, 1-(9-anthryl)
Trifluoroethanol, N-benzoylalanine ethyl ester, N-benzoyl-1-(1-fufudyl)ethylamine, Mandel amide, N-3,5-dinitrobenzoylphenylalanine ethyl ester, ○-3,
Examples include 5-dinito[1-phenylcarbamoyl-2-pentanol. Also, 1.1-bi-2-naphthol, 2'-methoxy-1,1'- and naphthyl-2-ol, 2-(1-propene-3-yloxy)-1,1
--It is characterized by excellent separation ability for compounds with irregular surfaces such as binaphthyl-2-ol.

<Example> Examples of the production and optical resolution of a filler according to the present invention will be explained with reference to the following examples.

Example 1 Methacrylic IR-1-(1-naphthyl)ethylamide 3
．． ○Put 0.11 g of Q, vinyltriethoxysilane, 0.04 g of jj, α, α'-7 zoisobutyronitrile, and 40...1 of dehydrated toluene into a 1QQml flask, and stir under a nitrogen atmosphere for 50 minutes while using a stirrer. C for 1 hour, then heated at 80°C for 1 hour, and then heated under reflux for 16 hours.The reaction solution was concentrated to about 1/3, and about 2011 ml of n-hexylene was added with stirring, and precipitated by decantation. The polymer was separated.The crude polymer was mixed with 15ml of benzene.
and n-hexane was added again to precipitate the polymer. It was confirmed by thin layer chromatography that this polymer contained no unreacted monomer.

Polymer yield was 1.65g, methacryl BR-1
- The copolymerization molar ratio of (1-naphthyl)ethylamide and vinyltriethoxysilane is determined from the S1 content of the polymer to fI.
Ae was 26.

Porous silica gel (average particle size 10 μm, average pore size 1
After drying 39 under reduced pressure at 200°C for 5 hours, it was added to a solution of 0.50 g of the above polymer dissolved in 30 ml of dehydrated toluene, and the mixture was heated under reflux for 20 hours.

Collect the polymer-immobilized silica gel and add 3Qml of benzene.
4 times, 3 times with 30Il11 of acetone, and finally 3 times with 3Qml of methanol. The column was dried under reduced pressure at 60° C. to obtain an optical resolution column in which a co-merge of methacryl IR-1-(1-pufthyrunethylamide and vinyltriethoxysilane) was immobilized on silica gel.The obtained packing material The carbon content was 4°0!Jfft%.

A column made of stainless steel with an inner diameter of 4 mm and a length of 30 cm was slurry filled with the obtained filler to prepare a column for optical resolution. Using this optical resolution column, various racemic mixtures were analyzed and the results shown in Table 1 were obtained. The measurement was carried out at air temperature, the eluent flow rate was 1 m1/min, and the detection rate was 254
nm ultraviolet absorption was used.

Table 1 *Transfer + n silk composition: n-hexane/isopropanol (98:2) Can-hexane/dichloromethane/ethanol (90:2)
:10:2) D20-hexane/dichloromethane/ethanol (70
:30:2) E:n-hexane/1.2-ethane/ethanol <20:6:1) Also, (1, 1' by an optical resolution column packed with a packing material) The chromatograms of - and -2-naphthol are shown in Figure 1.

Example 2 Methacrylic acid-3-1-phenylethylamide 4.0 (
1, vinyltriethoxysilane 0.37 (+ and α,
0.059 .alpha.'-azoisobutyronitrile and 601 w1 of dehydrated toluene were placed in a 100 ml flask, and heated under υΩ reflux at 80° C. for 14 hours and then 9 hours under a nitrogen atmosphere while stirring with a stirrer. Treated in the same manner as in Example 1, 1
．． An optically active polymer of No. 859 was obtained.

From the stirring containing $1, the copolymerization molar ratio of methacrylic 5-s-i-phenylethylamide and vinyltriethoxysilane is 2.
It was 5. Using 1.80 g of the above polymer, the polymer was immobilized on the same silica gel as in Example 1 with the same formulation as in Example 1. Common 1
An optical resolution filler in which the coalescence is immobilized on silica gel (η
is. The carbon content of 1q filler was 5.9%.

Real IafI143 Acrylic a-si-phenylethylamide 4, OQ,
Vinyltriethoxysilane 0.219 and α, α--
Azoisobutyronitrile 0.04g and dehydrated benzene 4Q
10 ml was placed in a flask and heated under reflux for 15 hours under a nitrogen atmosphere while stirring with a stirrer. The reaction solution was directly poured into 200111 methanol, and the precipitated polymer was separated by decantation. Optically active polymer The effort is 3.659, and acrylic acid-8
The copolymerization ratio of -1-phenylethylamide and nyltriethoxysilane was 24. In the same manner as in Example 1, 1.50 g of the above polymer was immobilized on 2.5 g of the same silica gel as in Example 1. The resulting acrylic 5-s
A copolymer of -i-phenylethylamide and vinyltriethoxysilane was immobilized, and the carbon content of the silica gel was 5.8 mm%.

<Effects of the Invention> The filler for optical resolution of the present invention not only exhibits excellent fA performance for the separation of a wide range of racemic compounds, but also has an optically active polymer structure, so that it can be used for monomer types with similar structures. It not only has performance equivalent to or better than optical resolution fillers, but also exhibits excellent separation ability for compounds with irregular surfaces, which were difficult to separate in the past.

Furthermore, the filler for optical resolution of the present invention does not require any special pretreatment of silica gel, and the optically active polymer can be treated with an inert compound.
The manufacturing method is simple, as it can be immobilized on silica gel by strong covalent bonds simply by heating in a solvent.Furthermore, the filler is chemically stable and can be used for a long period of time. Since the packing material of the present invention has sufficient mechanical strength, it is easy to speed up chromatography, and it also has the excellent advantage of not being limited by the solvents that can be used.

[Brief explanation of the drawing]

FIG. 1 (1) The light of the present invention
i゛Divided charge 1! This is a chromatogram of 1,1--bi-2-]phthol obtained by a column packed with IPIl+, in which the vertical axis represents the UV absorption intensity and the horizontal axis represents the retention))0) question. Special; 1 applicant: Toshi Co., Ltd.

Claims (1)

[Scope of Claims] A filler for optical resolution, which is obtained by immobilizing on silica gel a polymer consisting of an optically active monomer represented by the following general formula (I) and a monomer represented by the following general formula (II). ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(I) (In the formula, R_1 is a phenyl group, 1-naphthyl group, or 2
- Represents a phenyl group, 1-naphthyl group, or 2-naphthyl group substituted with a naphthyl group or a lower alkyl group, R_2 represents a lower alkyl group, R_3 represents a hydrogen atom or a methyl group, and * represents an asymmetric carbon atom. represent. ) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(II) (In the formula, R_4, R_5, R_6 represent the same or different alkyl groups, alkoxyl groups, hydroxyl groups, or halogen atoms, and R_4, R_5, R_6 At least one of them is an alkoxyl group or a halogen atom.)