JPS597503B2 - Adsorbent for optical separation - Google Patents

Description

[Detailed description of the invention] The present invention relates to an adsorbent for optical resolution.

The resolution of racemic mixtures into their optical antipodes is an important task in preparative chemistry.

A common method consists of converting a racemic mixture into a mixture of diastereomers and separating the diastereomer mixtures according to their differences in physical properties. In addition to these conventional methods, techniques for resolving racemic mixtures by chromatography have been extensively studied in recent years. Although in this case optically active adsorbents are used as stationary phases, the results of these studies are not satisfactory. In particular, the optical yields, ie the degrees of resolution, obtained with known optically active polymers are low. Therefore, it is technically difficult to apply such a method to the resolution of racemates. Therefore, an object of the present invention is to provide a novel adsorbent that can resolve racemic mixtures having a wide variety of chemical structures and has high efficiency.

Surprisingly, the inventor has discovered that the general formula I■CH2■
CRI-Co-NR2R3 (wherein R1 is a hydrogen atom or methyl, R2 is 5-1-phenylethyl, 5
-1-naphthylethyl, 5-1-cyclohexylethyl, S1-cyclohexyl-1-phenylmethyl or 1S,2R-2-phenylcyclopropyl, and R3 is a hydrogen atom or methyl.

), or its enantiomer, in the presence of about 1 to 12 mole percent of a crosslinking agent to resolve racemic mixtures. It was found that it was possible to obtain Therefore,
This invention provides a compound of formula 1 or its enantiomer which is crosslinked using a conventional polymerizable compound having at least two vinyl groups in an amount of 1 to 12 mole percent based on the monomer of general formula 1. The present invention relates to crosslinked polymers based on optically active polymerized acrylamides or methacrylamides consisting essentially of polymers.

Additionally, the present invention provides compounds of formula 1 in combination with about 1 to 1 of the crosslinking agents.
Adsorbent for resolving racemic mixtures based on optically active crosslinked poly(meth)acrylic acid amides obtained by polymerization in the presence of 2 mole percent into their optical antipodes. Regarding.

The optically active crosslinked polymer used in this invention has the formula 1
by copolymerizing the compound with a crosslinking agent containing at least two vinyl groups in an amount of 1 to 12 mole percent, preferably 4 to 10 mole percent, especially 5 to 6 mole percent, based on the monomer. Manufacture.

This production method is preferred when the copolymerization is carried out by suspension polymerization using an inert organic phase or an aqueous solution of a protective colloid.

In particular, it is preferable to carry out the suspension polymerization using benzene or chloroform as the inert organic phase, or using an aqueous polyvinyl alcohol solution as the aqueous phase. A further aspect of the invention consists in the use of the crosslinked polymers according to the invention for chromatographically resolving racemic mixtures into their optical antipodes.

The monomers and crosslinking agents which can be used in the above-mentioned copolymerization according to the invention are known or can be obtained by methods known per se.

The compounds used as crosslinking agents are those containing at least and preferably two polymerizable vinyl groups. Preferred crosslinking agents include 1fC. alkanediols diacrylates having 8 or 10 carbon atoms, such as ethylene glycol diacrylate, alkanediols dimethacrylates having a total number of 10 to 14 carbon atoms, especially 1t-12 to 14 carbon atoms; For example, dimethacrylic acid 1,4
-Ptanediol, divinylbenzene, total number of carbon atoms 8
Alkanedicarboxylic acid divinyl esters having from 7 to 10 carbon atoms, especially adipic acid divinyl ester, or benzenedicarboxylic acid divinyl esters, especially terephthalic acid divinyl ester, or N,N''- with a total number of 7 to 9 carbon atoms. Alkylene pisacrylic acid amide, especially N
, N'-methylenebisacrylic acid amide, and the like. The monomer of formula 1 can be, for example, an optically active amine R2R
3NH with acrylic anhydride or methacrylic anhydride,
In particular, it can be obtained by reaction at a temperature of about -5 to 60°C in the presence of a polymerization inhibitor such as VC4-tert-butylpyrocatechol, but at room temperature and with an inert organic It is also advantageous to carry out the reaction using solvents, in particular hydrocarbons such as benzene or toluene or mono-logenated hydrocarbons such as methylene chloride or chloroform.

The reaction time is approximately 30 minutes to 4 hours, depending in particular on the reaction temperature applied. Suspension polymerization of compounds of formula 1 can be carried out using a crosslinking agent and a radical-forming compound such as a peroxide such as dibenzoyl peroxide, dilauroyl peroxide or di-tolyl peroxide or an azo such as azoisobutyronitrile. It can be carried out analogously to known methods in the presence of a compound.

The reactants are dissolved in an inert organic solvent, preferably an aromatic hydrocarbon such as benzene or toluene or a halogenated hydrocarbon such as methylene chloride, chloroform or 1,2-dichloroethane. Particularly preferred solvents include benzene or chloroform. What is very important is to use as little organic solvent as possible. The lower limit of the amount of solvent is determined by the solubility of the monomer, but if the monomer can be completely dissolved, it is especially preferable to use 1 part by weight of solvent for 1 part by weight of monomer. It is advantageous for This organic solution is prepared by using an aqueous protective colloid solution, in particular an aqueous polyvinyl alcohol solution, and for example 2 to 25 parts by weight of the aqueous solution per 1 part by weight of this organic solution.
Mix well with an efficient stirrer. This stirred mixture is heated under an atmosphere of non-reactive gas, especially nitrogen.
About 40°C to 100°C, preferably about 60°C to 90°C
Heat to temperature. Polymerization time is about 4 hours to about 10 hours! Preferably it is about 6 hours. The polymer thus obtained is separated from the reaction solution by filtration and purified by thorough washing with hot water, ethanol, and benzene or chloroform. It is then dried under reduced pressure at a temperature of about 40°C to 80°C. The polymer according to the present invention not only enables the separation of racemic mixtures with high separation efficiency, but also enables high-velocity flow when used as an adsorbent in column chromatography. do.

Therefore, this polymer has important behaviors that make it suitable for its practical applications. For the chromatographic resolution of racemic mixtures, it is particularly advantageous to use particle polymers classified by particle size.

Such granular polymers classified according to particle size can be obtained by known methods, for example by sieving the polymer obtained by polymerization. Using acrylic acid S-1-phenylethylamide, acrylic acid S-1-d-naphthylethylamide or methacrylic acid S-1-d-naphthylethylamide or the enantiomer of these compounds as a monomer Particularly preferred are polymers obtained by the methods described above.

Racemic mixture using the polymer according to this invention. Preparative separation of a substance into its optically active enantiomers is advantageously carried out by column chromatography.

This method is known to chemists skilled in the art. Typically, the adsorbent is suspended in the solvent used for elution, and the suspension is transferred to the column. The racemate is dissolved in as little solvent as possible, this solution is transferred to the top of the column, and finally the column is treated with an eluent and the eluate is divided into each fraction in the usual manner. to be collected. The efficiency of resolving racemates is determined by chromatography of isotopically labeled racemic mandelic acid or racemic mandelic acid amide for the adsorbents described in the examples below. was measured and confirmed.
For this purpose, the radioactivity of each fraction was measured and R
The amounts of each of the - and S-enantiomers were determined. Details of this method can be found in G-Blaschke, Chem. Ber., No. 107.
Vol., p. 203 (1974) IIC. Preference is given to using mixtures of hydrocarbons, especially aromatic hydrocarbons, and ethers as eluents. Particularly suitable are mixtures of benzene and dioxane. Further, the ratio of benzene to dioxane is, for example, 1:1 to 6 by volume.
The ratio is 1 to 1. Using the polymers according to the invention it is possible to resolve racemates of a large number of different types of compounds. Hydroxycarboxylic acids, especially aromatic d
It is particularly advantageous for resolving racemic forms of -hydroxycarboxylic acids and amino acids as well as derivatives of these compounds. The following examples illustrate the preparation of some of the polymers of this invention.

Example 1 Acrylic acid S-1-Phenylethylamide 60y1 Ethylene glycol diacrylate 5.8t and D, d'-
A solution of 0.57 f of azoisobutyronitrile (=AIBN) and 60 f of benzene was added to 13 f of polyvinyl alcohol dissolved in 488 f of water.

The mixture was stirred at about 400 rpm for 6 hours at 80° C. under nitrogen. The obtained polymer was separated and washed with hot water, ethanol, and benzene. The obtained polymer was dried at 60° C. and under reduced pressure to a constant weight, and relatively large particles were separated using a sieve. Nitrogen content: calculated value 7.29%, measured value 7.20% Example 2 Acrylic acid S-1-phenylethylamide 6t1 Dimethacrylic acid 1,4-butanediol 0.77r1 AIBN0.05
A mixture of 100g of alcohol and 6f of benzene was added to a solution of 5t of polyvinyl alcohol and 195y of water.

This reaction solution was heated under nitrogen at 80V:. The mixture was stirred at about 400 rpm for 6 hours under VC. Thereafter, the polymer was separated by filtering, washed with hot water, ethanol and benzene, and dried under reduced pressure to a constant weight. IR: 175 (amide) Example 3 In the same manner as in Example 2, a polymer was obtained from acrylic acid S-1-phenylethylamide 6r and dimethacrylic acid 1,4-butanediol 0.38V.

Example 4 Acrylic acid S-1-phenylethylamide 2
51, divinylbenzene 3.7r and AIBNQ. 2
A mixture of a solution of 3t dissolved in 25r of benzene and a solution of 5.0f polyvinyl alcohol dissolved in 195f1fC of water was stirred at 85° C. for 6 hours under nitrogen.

The resulting polymer was isolated in the same manner as in Example 1. Nitrogen content: calculated value 7.33%, measured value 7.33% Example 5 6t of acrylic acid S-1-phenylethylamide and 0.68f of adipic acid divinyl ester were polymerized in the same manner as in Example 2. A polymer was obtained.

Example 6 R-1-cyclohexyl-1-methacrylate
Phenylmethylamide 57, ethylene glycol diacrylate 0.17f and AIBNO. A solution of O4f dissolved in chloroform JMoVVC and 5t of polyvinyl alcohol
A mixture of the above and a solution prepared by dissolving it in 195 tons of water was stirred under nitrogen at 80 V for 6 hours, and the resulting polymer was isolated in the same manner as in Example 1.

Nitrogen content: calculated value 5.26 (16, measured value 5.26%
Example 7 In the same manner as in Example 2, acrylic acid S-1-
Cyclohexylethylamide 6.0r1 methacrylic acid 1
, 4-butanediol 0.25f and AIBNO. O
55f was polymerized in the presence of benzene 6y1 water 195y} and polyvinyl alcohol 5f to reduce the nitrogen content to 6.
52% (calculated value: 6.50%) of polymer was obtained.

Example 8 In the same manner as in Example 2, acrylic acid (1S,2R-2-
Phenylcyclopropylamide 5f1 ethylene glycol diacrylate 0.45t and AlBNO. 5f is benzene 57, polyvinyl alcohol 5f hexagram and water 195
Polymerization was carried out in the presence of V to obtain a polymer with a nitrogen content of 6.64% (calculated value 6.64(f)).

Example 9 Methacrylic acid S-1-d-naphthylethylamide 6f1
Ethylene glycol diacrylate 0.43f and AI
BNO. A mixture of a solution of O47 dissolved in 12f of chloroform and a solution of polyvinyl alcohol 5r dissolved in 195f11C of water was stirred at 80° C. for 6 hours under nitrogen.

The obtained polymer was isolated by filtration, washed with hot water, ethanol, and chloroform, and then dried at 60° C. under reduced pressure to a constant weight. In the same manner as in Example 1, large particles were removed by sieving. Nitrogen content: Calculated value 5.
46%, measured value 5.48% Example 10 Acrylic acid N-
Methyl-S-1-phenylethylamide 51, ethylene glycol diacrylate 0.44t and AIBNO.
A mixture of a solution of O4t dissolved in benzene 5f and a solution of polyvinyl alcohol 5y dissolved in 1957 VC of water was stirred at 80-85°C for 6 hours under nitrogen, and the resulting polymer was isolated in the same manner as in Example 1. did.

Nitrogen content: calculated value 6.02 (f), measured value 6.02%
Example 11 Methacrylic acid S-1-phenylethylamide 6.0t11,4-butanediol bismethacrylate 0.78r,. A mixture of 0.05f AIBN and 9.0f chloroform was mixed with 55.0f polyvinyl alcohol.
A solution of V dissolved in 195 y of water was stirred at 80-85° C. for 6 hours under nitrogen.

The resulting polymer was isolated in the same manner as in Example 1. Nitrogen content: calculated value 6.33%, measured value 6.33% The polymers obtained in Examples 1 to 11 above were used for chromatographic resolution of racemic compounds. The table below shows the results of the experiments, especially regarding optical yield.
In the table, the column for racemic compounds! IC}, A means a racemic form of mandelic acid, and B means a racemic form of mandelic acid amide. A 4:1 benzene-dioxane mixture was used as the eluent. Although this invention has been described in detail above, a summary of aspects of this invention will be listed below.

All of these aspects are included in the practice of the invention as defined in Article 65-3 of the Patent Law. (1) General formula 1: (wherein, R1 is a hydrogen atom or methyl, and R2 is S-
1-phenylethyl, S-1-naphthylethyl, S-1
-cyclohexylethyl, S-1-cyclohexyl-1
-phenylmethyl or 1S,2R-2-phenylcyclopropyl, and R3 is a hydrogen atom or methyl.

) or a polymer of its enantiomer in an amount of 1 to 12 to the amide monomer of general formula 1 above.
Optically active acrylic acid amide polymer or methacrylic acid amide crosslinked with a mole percent, preferably 4 to 10 mole percent, especially 5 to 6 mole percent, of a polymerizable compound having at least two vinyl groups. An adsorbent for resolving racemic mixtures based on optically active polyacrylamide or polymethacrylamide into their optical antipodes, characterized in that they contain a crosslinked polymer based polymer. . (3) General formula 1: (wherein, R1 is a hydrogen atom or methyl, and R2 is S-
1-phenylethyl, S-1-naphthylethyl-S-1
-cyclohexylethyl, S-1-cyclohexyl-1
-phenylmethyl or 1S,2R-2-phenylcyclopropyl, and R3 is a hydrogen atom or methyl.

) or its enantiomer as an acrylic acid or methacrylic acid derivative, preferably from 1 to 12 mole percent of the crosslinking agent having at least two vinyl groups. A process for producing a crosslinked optically active polymer by copolymerization with 4 to 10 mole percent, especially 5 to 6 mole percent. (4) The method for producing a crosslinked optically active polymer according to item 3 above, which comprises carrying out the polymerization as suspension polymerization using an aqueous polyvinyl alcohol solution as the aqueous phase.

(2) A method of separating a racemic compound into its optically active enantiomers by chromatography, which comprises using polymers classified by particle size as described in item 1 above.

Claims (1)

[Claims] 1 General formula: CH_2=CR^1-CO-NR^2R^3 (in the formula, R
^1 is a hydrogen atom or methyl, R^2 is S-1
-Phenylethyl, S-1-naphthylethyl, S-1-
Cyclohexylethyl, S-1-cyclohexyl-1-
An optically active polymer consisting essentially of a polymer of a compound represented by phenylmethyl or 1S,2R-2-phenylcyclopropyl, and R^3 is a hydrogen atom or methyl, or its enantiomer. A crosslinked polymer based on acrylic acid amide or polymerized methacrylic acid amide, cross-linked with 1 to 12 mole percent of a polymerizable compound having at least two vinyl groups relative to the monomer of the general formula above. 1. An adsorbent for optical resolution for separating a racemic mixture into its optical antipodes, the adsorbent comprising a crosslinked polymer.