JPH0521616B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a polymer film that can efficiently optically resolve amino acids. In particular, the polymer membrane of the present invention is useful in a membrane separation process for optically resolving a D,L-amino acid mixture obtained by chemical synthesis or the like. [Prior Art] A method for separating organic mixtures using a non-porous homogeneous polymer membrane is not only advantageous in terms of continuity, operability, and economy, but is also superior to conventional distillation and recrystallization methods. It is effective for separating mixtures that cannot be separated by conventional methods, such as azeotropic mixtures, near-boiling point mixtures, structural isomers, and mixtures containing substances that are easily denatured by heat. When amino acids are used in medicines, foods, feeds, etc., they are required to be in the natural form, that is, in the L-form. Therefore, when amino acids are synthesized by chemical synthesis, the resulting D, L-amino acids are optically resolved. However, it is necessary to obtain the L-form. Conventionally, crystallization methods, chromatography methods, enzymatic methods, etc. have been used for this optical resolution method, but not only is it extremely difficult to select separation conditions, but the operations are complicated, so they have problems in terms of continuity and stability. There's a problem. Attempts have also been made to use membrane separation methods for the optical resolution of amino acids. Separation membranes include polymer membranes supporting optically active amino acids, membranes in which optically active substances are immobilized on a support membrane by plasma treatment, and optical membranes. Membranes in which a porous membrane is impregnated with a liquid containing an active crown ether compound are known, but the former two have low selectivity and permeability, and the latter has problems with membrane stability, making it difficult to put them into practical use. be. As described above, to date, no polymer membrane has been known that efficiently separates amino acid optical isomers. Further, as in the present invention, a membrane is formed from a polymer having cyclodextrin covalently supported on its side chain,
There have been no known examples of using this membrane for optical resolution of amino acids. [Problems to be Solved by the Invention] The present invention aims to solve the above-mentioned drawbacks of the polymer membrane by providing a polymer membrane with excellent permselectivity that can efficiently separate amino acid optical isomers. That is. [Means for Solving the Problems] It is generally known that cyclodextrins include various organic substances in their intramolecular pores.
This inclusion body formation reflects the size, shape, and even molecular asymmetry of the molecule, so even though the structures are extremely similar, the inclusion ability by cyclodextrin is different even for geometric and optical isomers ( ML Bender, M. Komiyama, ``Chemistry of Cyclodextrin'', Japan Society Publishing Center). Focusing on this point, the present invention has developed an amino acid optical resolution system made of a polymer having cyclodextrin residues in its side chain, which can realize efficient membrane separation by cleverly utilizing the molecular inclusion ability of cyclodextrin. It provides a membrane. Any polymer having a cyclodextrin residue in its side chain may be used as long as it forms a membrane.
Especially from the viewpoint of film formability and permeability, the general formula Repeating unit and general formula represented by A copolymer having a molecular weight of 10,000 or more and consisting of repeating units represented by is preferred. (In the formula, R ¹ and R ² are a hydrogen atom, a halogen atom, or a lower alkyl group, X is a divalent linking group, and Y is an α-, β-, or γ-cyclodextrin residue.) The divalent linking group represented by X above includes an alkylene group, a phenylene group,

[Formula] -COO-, -O-, -S-,

【formula】

The group represented by the formula can be exemplified, and moreover, a plurality of these divalent linking groups can be combined. In addition, an alkylene group means a divalent group formed by removing hydrogen atoms one by one from different carbon atoms of an alkane (however,
methylene group), R ³ and R ⁴ are hydrogen atoms, lower alkyl groups, phenyl groups, or aralkyl groups,
R ⁵ and R ⁶ represent a lower alkyl group, a phenyl group or an aralkyl group. The cyclodextrin residue represented by Y is preferably not substituted with a group other than the group X for binding to the polymer main chain, but may be modified with a group that does not interfere with amino acid inclusion. This copolymer has, for example, the general formula (R ¹ is the same as above.) Acrylonitrile derivative and general formula Copolymer reaction with the cyclodextrin-substituted vinyl monomer represented by (R ² , X and Y are the same as above) or a functional group reactive with the monomer represented by the general formula () It is obtained by reacting a polymer obtained by copolymerizing a vinyl monomer (hereinafter referred to as a reactive monomer) with a cyclodextrin that has been modified in advance with a group that can easily react with the reactive functional group. be able to. The composition of the cyclodextrin-containing repeating unit () in the copolymer is 5 to 90 mol%, preferably 10
~50 mol%. If the number of repeating units exceeds this range, the strength of the polymer membrane will be insufficient, and if there is less, sufficient selectivity cannot be obtained. Further, the molecular weight of the polymer is 10,000 or more, preferably 50,000 or more from the viewpoint of film-forming properties. Reactive monomers include p-nitrophenyl acrylate, m-nitrophenyl methacrylate,
glycidyl methacrylate, 2-mercaptoethyl acrylate, p-mercaptostyrene, p-
Examples include aminostyrene, 2-aminopropyl acrylate, 2-chloroethylmethacrylamide, pentachlorophenyl acrylate, acrylic acid, methacrylic acid, acrylic acid chloride, and p-vinylphenyl isocyanate. The polymer film of the present invention is obtained by forming the above polymer into a film. The film forming method is not particularly limited, and may be any known or well-known method. For example, a polymer solution can be spread on a Teflon plate, metal plate, glass plate, or water surface, and then the solvent can be evaporated to form a durable film. Alternatively, methods such as immersing a porous support in a polymer solution and then pulling it out, or applying the solution to the support and drying it can also be adopted. As the organic solvent for preparing the polymer solution, any organic solvent can be used without particular limitation as long as it dissolves the polymer well. The separation membrane of the present invention has a thickness that allows sufficient amino acid permeation and has practical strength.
It is preferably 0.01 to 200 μm, particularly 0.05 to 100 μm. For thin films with a thickness of 1 μm or less, it is preferable to use them together with a support. As the support, any porous material having sufficient strength to support the membrane can be used, such as a woven or nonwoven support, a microfilter, or an ultrafiltration membrane. It is preferable to use the polymer membrane without crosslinking treatment, but if the polymer membrane significantly swells or dissolves in the liquid mixture to be separated, it can also be used after being insolubilized by crosslinking treatment. In the present invention, the separation membrane is a homogeneous membrane, an asymmetric membrane,
It can also be used in the form of a composite membrane or a laminated membrane in which this separation membrane is laminated with other membranes. Further, the membrane thus obtained can be used in any shape such as a flat membrane, a tubular membrane, or a hollow fiber membrane. The polymer membrane of the present invention has an amino acid optical isomer mixture solution present on one side of the membrane, and utilizes the inclusion specificity of cyclodextrin residues in the membrane to transfer one of the optical isomers to the opposite side of the polymer membrane. It allows for superior penetration. The amino acids that can be optically resolved by the polymer film of the present invention are preferably those having relatively hydrophobic groups such as phenyl groups and alkyl chains, such as phenylalanine, phenylglycine, tyrosine, dopa,
histidine, tryptophan, isoleucine, valine, 3,5-dihydroxyphenylglycine,
Examples include proline. Hereinafter, the present invention will be explained in more detail with reference to Reference Examples and Examples. Reference example 1 20 g of β-cyclodextrin (β-CD) was dissolved in 352 ml of pyridine, 6.36 g of p-toluenesulfonyl chloride was added, and after stirring at room temperature for 1 hour, the pyridine was distilled off. Add water to the residue to make a total volume of 80 ml, and add the white powder obtained after freeze-drying to 550 ml of water.
Recrystallized from ml. Furthermore, recrystallization was repeated from 150 ml of n-butanol (BuOH)-ethanol-water (5:4:3) mixed solvent, and mono-6-p-
Toluenesulfonyl-β-cyclodextrin
Obtained 8.36g (36.3%) as a white powder. Elemental _{analysis (%): Actual value: C, 43.74; H, 6.10; S, 2.71 Calculated value as C49H76O37S ・ 3H2O} : C, _43.82 ; ) (DMSO−d ₆ ): 2.43 (3H), 4.16−4.62 (7H), 4.83 (7H), 5.64 (14H), 7.60 (4H). 1.25 g of the obtained 6-monotosyl-β-cyclodextrin was dissolved in 15 ml of ethylenediamine and heated at 40°C.
After stirring for 22 hours, the reaction solution was concentrated, and the residue was poured into acetone to precipitate it. The obtained pale yellow powder was dissolved in methanol water (3:1) and reprecipitated in acetone. This operation was repeated to obtain 0.49 g (42.9%) of monoethylenediamine as a white powder. Elemental analysis (%): _{C44H76O34N2 ・ 2BuOH} Actual value: C, 46.94; H, 6.84; N, 2.21; _S , 0. Calculated value: C, 47.13; H, 7.30; N, 2, 21; S, 0. NMR (ppm) (DMSO- _d6 ): 2.60-2.94 (2H), 3.31-3.66 (27H), 4,45 (6H), 4.83 (7H), 5.71 (14H). Reference example 2 5.41g of acrylonitrile (AN) and 3.48g of p-nitrophenyl acrylate (PNPA) were charged into a glass polymerization ampoule tube (charged molar ratio
AN/PNPA=0.85/0.15) 0.04g of azobisisobutyronitrile (AIBN) as a polymerization initiator and dimethylformamide (DMF) as a polymerization solvent
After adding 51.1 ml and degassing according to a conventional method, the tube was sealed under high vacuum. A polymerization reaction was carried out by shaking and mixing the mixture at 60°C for 10 hours. By pouring the reaction mixture into a large amount of methanol, the yield was 18.6%.
1.65g of AN-PNPA copolymer was obtained. According to elemental analysis, the mole fraction of PNPA in the copolymer was 0.242. Furthermore, the molecular weight was determined to be 5.8×10 ⁴ in terms of polystyrene by GPC measurement. 1R (cm ^-1 ): 2250 (C≡N), 1730 (C=O), 1540 (NO ₂ ) Reference Examples 3 to 5 Same as Reference Example 2 except that the molar composition ratio of AN and PNPA was changed. AN−PNPA by similar operation
A copolymer was obtained. The results are shown in Table 1.

[Table] Reference Example 6 An AN-PNPM copolymer was obtained in the same manner as in Reference Example 2 except that p-nitrophenyl methacrylate (PNPM) was used instead of PNPA. Yield 19.3%, yield 2.01g. The PNPM mole fraction in the copolymer was 0.131. Furthermore, the molecular weight was found to be 6.00×10 ⁴ by GPC measurement. 0.2 g of the AN-PNPA copolymer obtained in Reference Example 2 was dissolved in 20 ml of dimethyl sulfoxide (DMSO),
Monoaminoethylamino-β- obtained in Reference Example 1
0.594 g of CD was added and stirred at room temperature for 6 days. The reaction mixture was poured into 250 ml of acetone, and the precipitate was filtered off. This was dissolved again in 5.5 ml of DMSO and purified by pouring it into an aqueous methanol solution. yield
0.34g, yield 37.8%. Elemental analysis value (%) C: 48.66, H: 6.14, N: 8.23 IR (cm ^-1 ): 3400 (OH), 2950 (CH ₂ ), 2250 (C≡N), 1650 (NHCO), 1600-1100 (C=O) From the above analysis results, β-CD residue is added to the side chain.
It was confirmed that the copolymer contained 24.2 mol%. Reference Examples 8 to 12 In the same manner as in Reference Example 7, β was added to the side chain by reacting AN-PNPA copolymer or AN-PNPM copolymer with mono-aminoethylamino-β-CD.
A copolymer having -CD residues was obtained. Table 2 shows the results.
Shown below.

[Table] Example 1 0.2 g of the copolymer having a β-CD residue obtained in Reference Example 7 was dissolved in 1 ml of DMF. This solution was cast onto a glass plate and DMF was distilled off at 40°C to obtain a transparent and uniform polymer film with a thickness of 50 μm.
The resulting membrane was inserted into a glass permeation cell, and the membrane permeability of amino acids was measured at 30°C by placing an aqueous amino acid solution on one side of the membrane and pure water on the other side.
The results are shown in Table 3.

[Table] Examples 2 to 8 The copolymers having β-CD residues obtained in Reference Examples 7 to 12 were formed into films in the same manner as in Example 1. The membrane permeability of Phe or Try was measured by inserting the obtained membrane into a glass permeation cell and using a racemic aqueous solution of phenylalanine (Phe) or tryptophan (Try) on one side of the membrane and pure water on the other side. . Furthermore, the abundance ratio of L-form and D-form in the permeate was determined by optical rotation measurement. The results are shown in Table 4.

【table】

Claims (1)

[Scope of Claims] 1. A membrane for optically resolving amino acids comprising a polymer having a cyclodextrin residue in its side chain. 2 A polymer having a cyclodextrin residue has the general formula Repeating unit and general formula represented by The membrane for optical resolution of amino acids according to claim ¹ , which is a copolymer having a molecular weight of 10,000 or ^more and consisting of repeating units represented by , X represents a divalent linking group, and Y represents an α-, β- or γ-cyclodextrin residue). 3. The membrane for optical resolution of amino acids according to claim 2, which uses a copolymer in which the composition ratio of repeating units represented by the general formula () is 5 to 90 mol%.