JPH0430931B2 - - Google Patents

Description

[Detailed description of the invention]

<Industrial Application Field> The present invention relates to a filler for optical resolution in which an optically active polymer is immobilized on silica gel. <Prior Art> The resolution of racemic mixtures into optical symmetries is important in analytical and synthetic chemistry. A common method consists of converting a racemic mixture into a diastereomeric mixture and separating the diastereomeric mixtures by differences in physical properties such as solubility. In addition to these conventional methods, techniques for resolving racemic mixtures by chromatography have been extensively studied in recent years, and the following techniques are known. (A) Liquid chromatography using as a filler a bead-like polymer obtained from an acrylamide monomer derived from an optically active amine (Japanese Patent Publication No. 7503/1983). (B) Liquid chromatography using an optically active stationary phase obtained by grafting an optically active substance onto an inorganic carrier such as silica gel as a packing material. (a) Ligand exchange method using an optically active proline-grafted filler (J.
Chromatogr.266, p439 (1983). (b) A method using a charge transfer complex using a filler grafted with an optically active compound lacking π electrons (J. Chromatogr. 122, p. 205 (1976)). (c) Method using a filler grafted with optically active N-acylated amino acids (J.
Chromatogr.186, p543 (1979)). (d) A method using a filler grafted with optically active 1-(9-anthryl)trifluoroethanol or 3,5-dinitrobenzoylated optically active phenylglycine (J.
Chromatogr.192, p143 (1980), J.Org.
Chem.46, p4988 (1981)). (e) Method using filler grafted with optically active aromatic amine (J.Chromatogr.265,
p.117 (1983)). <Problems to be solved by the invention> However, in the conventional method (A), the polymer beads are relatively large and uneven, resulting in low column efficiency, as well as weak mechanical strength and inability to achieve high flow rates. have. Furthermore, since polymer beads do not swell in hydrophilic solvents, there is also the drawback 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 carrier such as silica gel has sufficient mechanical strength and can be used at high speeds. It is possible. However, the compounds that can be separated are limited to a narrow range, or the degree of separation is small.
Furthermore, it is difficult to produce a grafted filler and it is difficult to obtain a filler with reproducible performance, so it is difficult to say that any of these fillers is a practical filler. Among these, method (e), which uses a filler grafted with optically active aromatic amines, can resolve a relatively wide range of racemic mixtures such as amines, alcohols, carboxylic acids, amino acids, oxyacids, and amino alcohols, and has high performance. However, the degree of separation is still not sufficient. <Means and effects for solving the problems> Under such circumstances, the present inventors have developed a filler that can be analyzed over a wide range of compounds, is relatively easy to manufacture, and is chemically stable and practical. As a result of continuing intensive studies with the aim of providing the following general formula (I)
The filler for optical resolution, which is made by immobilizing a polymer consisting of an optically active monomer represented by the following general formula () and a monomer represented by the following general formula (), on silica gel not only exhibits excellent effects in separating a wide range of racemic mixtures, but also exhibits excellent optical resolution. It was discovered that by creating an active polymer structure, it not only has performance equivalent to or better than monomer-type fillers with the same structure, but also exhibits excellent separation ability for compounds with irregular surfaces that were previously difficult to separate. , arrived at the present invention. (In the formula, R ₁ is a phenyl group, a 1-naphthyl group, a 2-naphthyl group, or a phenyl group substituted with a lower alkyl group, a 1-naphthyl group, or a 2-naphthyl group.
represents a naphthyl group, R ₂ represents a lower alkyl group, R ₃ represents a hydrogen atom or a methyl group,
* represents an asymmetric carbon atom. ) (In the formula, R ₄ , R ₅ , and R ₆ represent the same or different alkyl groups, alkoxy groups, hydroxyl groups, or halogen atoms, and at least one of R ₄ , R ₅ , and R ₆ is an alkoxy group 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 R ₁ R ₂ C
HNH ₂ (where R ₁ and R ₂ are as described above)
by reacting with acrylic anhydride or methacrylic anhydride at a temperature of about -5°C to 60°C, especially in the presence of a polymerization inhibitor such as 4-tertiary butylpyrocatechol. However, it is preferable to carry out the reaction using an inert organic solvent at room temperature, particularly a hydrocarbon such as benzene or toluene, 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. Further, the optically active monomer represented by the above general formula (I) is an optically active amine R ₁ R ₂ C〓HNH ₂
(Here, R ₁ and R ₂ are as described above) in the presence of acrylic acid chloride or methacrylic acid chloride and a polymerization inhibitor in the above-mentioned inert organic solvent as a neutralizing agent for hydrochloric acid by-produced. It can also be synthesized by reacting at room temperature or below in the presence of Examples of neutralizing agents for hydrochloric acid include tertiary amines such as triethylamine, and alkaline aqueous solutions such as sodium hydroxide and sodium carbonate. Specific examples of the optically active monomer represented by the above general formula (I) 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 acid-1-phenylpropylamide, R- or S-acrylic acid-
1-(1-naphthyl)ethylamide, R- or S-acrylic acid-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 acid-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-phenylpropylamide, R- or S-methacrylic acid-1-(1-naphthyl)ethylamide, R - or S-methacrylic acid-1-
(2-naphthyl)ethylamide, R- or S-
Methacrylic acid-1-(1-naphthyl)propylamide, R- or S-methacrylic acid-1-(6,
7-dimethyl-1-naphthyl)ethylamide, R
- or S-methacrylic acid-1-(6,7-dimethyl-1-naphthyl)isopropylamide. On the other hand, the monomers represented by the general formula () include 3-methacryloxypropyltrimethoxysilane, 3-methacryloxypropylmethyldiethoxysilane, 3-methacryloxypropyldimethylethoxysilane, 3-methacryloxypropyltrichlorosilane, -methacryloxypropylmethyldichlorosilane, 3-methacryloxypropyldimethylchlorosilane, etc. are preferably used. Among these, 3-methacryloxypropyltrimethoxysilane is particularly preferred. The copolymerization of the optically active monomer represented by the above general formula (I) and the monomer represented by the above general formula ( In the presence of a radical polymerization initiator of an azo compound such as azoisobutyronitrile, an inert organic solvent, preferably an aromatic hydrocarbon such as benzene or toluene, or a halogenated polymer such as methylene chloride, chloroform or 1,2-dichloroethane It is carried out in known manner in hydrocarbons. Particularly preferred solvents include benzene,
An example is toluene. The polymer obtained by polymerization is obtained 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-heptane or cyclohexane. Therefore, it can be separated and recovered as a precipitate. Particularly preferred diluting precipitants include methanol and n-hexane. Benzene the precipitate again,
The polymer can be purified by dissolving it in an aromatic hydrocarbon such as toluene or a halogenated hydrocarbon such as chloroform or methylene chloride, and adding it to 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. . A combination of the monomer represented by the above general formula (I) and the monomer represented by the above general formula () in a polymer consisting of an optically active monomer represented by the above general formula (I) and a monomer represented by the above general formula (). The molar ratio of the polymerization composition is preferably 0.5 or more,
More preferably, it is 1 or more. If the molar ratio is 0.5 or more, it has sufficient performance as a filler for optical resolution. When the molar ratio is less than 0.5, the above general formula (I)
As the amount of the optically active monomer represented by is decreased, the optical resolution performance tends to decrease. Also,
If the molar ratio becomes too large, the above general formula ()
The molar ratio is preferably 100 or less, particularly preferably 80 or less, because the amount of the monomer represented by 2 tends to decrease, and the amount immobilized on the silica gel tends to decrease. Next, immobilization of the polymer onto silica gel will be explained. The silica gel used in the present invention may be in any shape, such as spherical or crushed, but in order to obtain a highly efficient chromatography column, the silica gel should be as fine as possible and have an appropriate pore size. is preferred. The fully porous silica gel usually has an average particle diameter of 1 μm to 1 mm, and preferably has an average pore diameter of 100 angstroms or more. More preferably, a thickness of 300 angstroms or more is used. The average pore diameter is
If the pore diameter is less than 100 angstroms, the pore diameter is too small and it tends to be difficult to immobilize the polymer on the silica gel. There is no particular limit to the upper limit of the pore diameter, but it is usually 5000 mm from the mechanical strength of silica gel.
The thickness is preferably angstrom or less. Using such silica gel, the monomer represented by the above general formula () in the polymer can be dissolved in a solvent in which the polymer can be stably dissolved, such as an aromatic hydrocarbon such as benzene or toluene, or a halogenated hydrocarbon such as chloroform. By reacting the units R ₄ , R ₅ , and R ₆ with the hydroxyl groups on the silica gel surface under heating conditions, the polymer can be easily immobilized on the silica gel with strong covalent bonds. Silica gel can immobilize polymers by simply dehydrating it in advance without requiring complicated 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 immobilization, 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 1 to 100 hours. The amount of polymer immobilized on silica gel is usually
The content is 0.1% by weight or more, preferably 1% by weight or more, and more preferably 3% by weight or more. The optical resolution packing material obtained according to the present invention can be packed into a chromatographic column by a conventional method such as a slurry packing method and used as a stationary phase in liquid chromatography. In liquid chromatography using this stationary phase, by selecting appropriate elution conditions, particularly commonly used conditions for normal phase partitioning or reversed phase partitioning, it is possible to optically resolve 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. In particular, -CONH- group, -OH group, -OCO- group, -
Racemic mixtures of compounds having an OCONH- group or a -N--CONH- group can be separated or analyzed with good resolution and in a short time.
Specific examples include α-chloropropionic acid anilide, hexobarbital, 1-(9-anthryl)trifluoroethanol, N-benzoylalanine ethyl ester, N-benzoyl-1-
Examples include (1-naphthyl)ethylamine, mandelic acid amide, N-3,5-dinitrobenzoylphenylalanine ethyl ester, O-3,5-dinitrophenylcarbamoyl-2-pentanol, and the like. Also, 1,1'-bi-2-naphthol,
2'-methoxy-1,1'-binaphthyl-2-ol, 2'-(1-propene-3-yloxy)-1,
It is characterized by excellent separation ability for compounds with irregular surfaces such as 1'-binaphthyl-2-ol. <Example> Examples of the production and optical resolution of a filler according to the present invention will be explained with the following examples. Example 1 3.0 g of methacrylic acid R-1-(1-naphthyl)ethylamide, 0.14 g of 3-methacryloxypropyltrimethoxysilane, 0.04 g of α.α'-azoisobutyronitrile, and 40 ml of dehydrated toluene were placed in a 100 ml flask. The mixture was heated under a nitrogen atmosphere at 50° C. for 1 hour, then at 80° C. for 1 hour, and then heated under reflux for 16 hours while stirring with a stirrer. The reaction solution was concentrated to about 1/3, about 20 ml of n-hexane was added under stirring, and the precipitated polymer was separated by decantation. Dissolve the crude polymer in 15 ml of benzene and add n again.
- Hexane was added to precipitate the polymer.
It was confirmed by thin layer chromatography that this polymer contained no unreacted monomer.
The polymer yield was 1.75 g, methacrylic acid R-
The copolymerization molar ratio of 1-(1-naphthyl)ethylamide and 3-methacryloxypropyltrimethoxysilane was 24 as calculated from the Si content of the polymer. 3 g of porous silica gel (average particle size 10 μm, average pore size 1000 angstroms) was heated at 200℃ for 5 minutes.
After drying under reduced pressure for an hour, it was added to a solution of 0.30 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,
Washed 4 times with 30 ml of benzene, 3 times with 30 ml of acetone, and finally 3 times with 30 ml of methanol. Dry under reduced pressure at 60°C to obtain R-1-(1-naphthyl) methacrylate.
A filler for optical resolution was obtained in which a copolymer of ethylamide and 3-methacryloxypropyltrimethoxysilane was immobilized on silica gel. The carbon content of the filler obtained was 3.8% by weight. Example 2 Methacrylic acid-S-1-phenylethylamide
4.0 g, 0.48 g of 3-methacryloxypropyltrimethoxysilane, 0.05 g of α,α'-azoisobutyronitrile, and 60 ml of dehydrated toluene were placed in a 100 ml flask, and heated under a nitrogen atmosphere at 80°C for 14 hours while stirring with a stirrer. , and then heated under reflux for 9 hours. It was treated in the same manner as in Example 1 to obtain 1.92 g of optically active polymer. Methacrylic acid-S-1 based on Si content
The copolymerization molar ratio of -phenylethylamide and 3-methacryloxypropyltrimethoxysilane was 23. Using 1.86 g of the above polymer, the polymer was immobilized on the same silica gel as in Example 1 according to the same formulation as in Example 1, and methacrylic acid-S
A filler for optical resolution was obtained in which a copolymer of -1-phenylethylamide and 3-methacryloxypropyltrimethoxysilane was immobilized on silica gel. The carbon content of the filler obtained was 5.7% by weight. Example 3 Acrylic acid-S-1-phenylethylamide
4.0 g, 0.28 g of 3-methacryloxypropyltrimethoxysilane, 0.04 g of α,α'-azoisobutyronitrile, and 40 ml of dehydrated benzene were placed in a 100 ml flask, and heated under reflux under a nitrogen atmosphere for 15 hours while stirring with a stirrer. . Leave the reaction solution as is
The mixture was poured into 200 ml of methanol, and the precipitated polymer was separated by decantation. The yield of optically active polymer was 3.79 g, and acrylic acid-S-1
-The copolymerization molar ratio of phenylethylamide and 3-methacryloxypropyltrimethoxysilane is 25
It was hot. In the same manner as in Example 1, 0.50 g of the above polymer was immobilized on 2.5 g of the same silica gel as in Example 1. The carbon content of the obtained silica gel on which the copolymer of acrylic acid-S-1-phenylethylamide and 3-methacryloxypropyltrimethoxysilane was immobilized was 5.8% by weight. Example 4 100 ml of 1.0 g of methacrylic acid R-1-(1-naphthyl)ethylamide, 0.52 g of 3-methacryloxypropyltrimethoxysilane, 0.04 g of α,α'-azoisobutyronitrile and 20 ml of dehydrated toluene
The mixture was placed in a flask and heated under a nitrogen atmosphere at 50°C for 1 hour, then at 80°C for 1 hour while stirring with a stirrer, and then heated under reflux for 16 hours. The optically active polymer obtained was 0.84 g, and methacrylic acid R-1-
The copolymerization molar ratio of (1-naphthyl)ethylamide and 3-methacryloxypropyltrimethoxysilane was 3 based on the Si content of the polymer. Using 0.44 g of this polymer, the polymer was immobilized on the same silica gel with the same formulation as in Example 1, and R-1-(1-naphthyl methacrylate)
A filler for optical resolution was obtained in which a copolymer of ethylamide and 3-methacryloxypropyltrimethoxysilane was immobilized on silica gel. The carbon content of the filler obtained was 3.6% by weight. Example 5 100 ml of 3.0 g of methacrylic acid R-1-(1-naphthyl)ethylamide, 0.06 g of 3-methacryloxypropyltrimethoxysilane, 0.04 g of α,α'-azoisobutyronitrile and 40 ml of dehydrated toluene
The mixture was placed in a flask and reacted in the same manner as in Example 1.
The weight of the obtained polymer was 1.86 g, and the copolymerization molar ratio of methacrylic acid R-1-(1-naphthyl)ethylamide and 3-methacryloxypropyltrimethoxysilane was 86 based on the Si content of the polymer.
Using 0.30 g of this polymer, the polymer was immobilized on the same silica gel as in Example 1 according to the same formulation as in Example 1, and methacrylic acid R-1-(1-
A filler for optical resolution was obtained in which a copolymer of (naphthyl)ethylamide and 3-methacryloxypropyltrimethoxysilane was immobilized on silica gel. The carbon content of the filler obtained was 1.9% by weight. Example 6 0.40 g of the optically active polymer obtained in Example 1 was immobilized on 3.0 g of porous silica gel (average particle diameter 10 μm, average pore diameter 300 angstroms). The resulting filler for optical resolution, in which the copolymer of methacrylic acid R-1-(1-naphthyl)ethylamide and 3-methacryloxypropyltrimethoxysilane was immobilized on silica gel, had a carbon content of 4.8% by weight. . Examples 7 and 8 The fillers obtained in Examples 1 and 2 were slurry-packed into stainless steel columns with an inner diameter of 4 mm and a length of 30 cm to prepare columns for optical resolution. Using these optical resolution columns, various racemic mixtures were analyzed and the results shown in Table 1 were obtained. Measurements were carried out at room temperature, the eluent flow rate was 1 ml/min, and detection was performed using ultraviolet absorption at 254 nm.

【table】

[Table] Also, 1,
The first chromatogram of 1'-bi-2-naphthol
FIG. 2 shows a chromatogram of α-chloropropionic acid anilide obtained using the optical resolution column of Example 8. <Effects of the Invention> The filler for optical resolution of the present invention not only exhibits an excellent effect in separating a wide range of racemic mixtures, but also has an optically active polymer structure, so that it can be used as a monomer-type filler for optical resolution with a similar structure. Not only does it have performance equivalent to or better than that of the conventional method, but it also exhibits excellent separation ability for compounds with irregular surfaces that were previously difficult to separate. In addition, the optical resolution filler of the present invention does not require any special pretreatment of silica gel, and can be immobilized on silica gel by strong covalent bonds by simply heating the optically active polymer in an inert organic solvent. ,
The manufacturing method is simple, and the filler obtained is chemically stable and can be used for a long period of time. Furthermore, since the packing material of the present invention has sufficient mechanical strength, it is easy to speed up chromatography.
It also has the excellent advantage of not being subject to restrictions on the solvent used.

[Brief explanation of drawings]

Figure 1 is a chromatogram of 1,1'-bi-2-naphthol using the optical resolution column of Example 7, and Figure 2 is a chromatogram of α-chloropropionic acid anilide using the optical resolution column of Example 8. Gram. The vertical axis of the figure represents UV absorption intensity, and the horizontal axis represents retention time.

Claims (1)

[Scope of Claims] 1. 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 (). (In the formula, R ₁ is a phenyl group, a 1-naphthyl group, a 2-naphthyl group, or a phenyl group substituted with a lower alkyl group, a 1-naphthyl group, or a 2-naphthyl group.
represents a naphthyl group, R ₂ represents a lower alkyl group, R ₃ represents a hydrogen atom or a methyl group,
* represents an asymmetric carbon atom. ) (In the formula, R ₄ , R ₅ , and R ₆ represent the same or different alkyl groups, alkoxyl groups, hydroxyl groups, or halogen atoms, and at least one of R ₄ , R ₅ , and R ₆ is an alkoxyl group or a halogen atom. be.)