JP2898723B2 - Optical splitting separation membrane - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel separation membrane having an asymmetric discrimination ability.

[Problems to be solved by conventional technology and invention]

Many of the compounds used for medicines, agricultural chemicals, and the like have a three-dimensional structure that is a mirror image of each other. These are called optical isomers and are indicated as D / L form or R / S form. When an optical isomer is synthesized by a usual chemical reaction, a mixture of two optical isomers is obtained, which is called a racemate.

Racemic D-forms and L-forms may have a delicate effect on the medicinal properties and toxicity of pharmaceuticals due to differences in their tertiary structures. If it is a racemate, it is desirable to study the absorption, distribution, metabolism, and excretion kinetics for each isomer. "

It is also said that the S-isomer exhibits sweetness, but the R-isomer exhibits bitterness even in a sweet-tasting aspartame comprising optical isomers.

As described above, since the chemical properties of the D-form and the L-form may greatly differ depending on the difference in their steric structures, various methods have been devised for the optical resolution of the racemic body.

Examples of a method for obtaining an optically active substance from a racemate include a preferential crystallization method, a diastereomer method, a chromatography method, a method using an enzyme, and a method using a separation membrane.

The priority crystallization method has a small track record despite the excellent optical resolution method for the following reasons. That is, in order to resolve a racemic body by the preferential crystallization method, first, the solubility of the racemic body and both the active forms is measured, and it is determined that the racemic form is greater than the active form. It is necessary to confirm that the active substance does not dissolve in a racemic saturated solution, and that the infrared absorption spectra of the racemic form and the active form match, etc. (Hiro Yamanaka, Yasuhisa Tashiro, quarterly) Chemical Review No. 6, 1989, pp. 4-5). Also, since the timing of the solid-liquid separation and the reduction of the filtration time are technically important issues, the preferential crystallization method can be applied only to special crystals.

The diastereomer method is a method in which a compound to be optically resolved is allowed to act on a chiral compound to form a diastereomer, which is separated by fractional crystallization. Although considerable application has been found for amine and carboxylic acid compounds, the most difficult part of this method is finding a good resolving agent. It is well known that it is very difficult to obtain a high-purity optically active substance.

Chromatography using a chiral compound as a stationary phase has been rapidly developed with the progress of HPLC (high performance liquid chromatography). Efficient columns have been developed that have a large discriminating ability with respect to the three-dimensional structure of the molecule, and the quantitative processing ability has been improved as well as the resolving power. However, it is considered that satisfactory results have not yet been obtained for economical mass division.

The optical resolution method using an enzyme utilizes the stereospecificity of the enzyme for a substrate. This method is suitable as a method for obtaining a large amount of an optically active substance. For example, a production technique on an industrial scale has already been established for D-amino acids by an enzymatic method combining a hydantoinase reaction and a chemical decarbamylation reaction. [S. Takahasih “Biotechnolo
gy of Amino Acid Production "H. Yamada et al (eds),
Kodansha Ltd., p269 (1986)]. Also, U.S. Pat.
No. 0,162 describes a method for obtaining an optically active substance by immobilizing an enzyme on a capillary type membrane. However, in the case of the enzymatic method, it is extremely difficult to find an enzyme compatible with the target racemate to be resolved.
Therefore, it has the disadvantage that it can only be applied to a very limited number of racemates.

Examples of separating optical isomers by introducing asymmetric discrimination ability into a separation membrane are disclosed in JP-B-63-57083 by Yamaguchi et al.
There are respective publications of 2-180701. These all function as a liquid film by a method in which a crown compound is impregnated into the inside of a porous material, but there is also a concept regarding chemical purity by mixing a crown compound as a carrier into a divided optically active substance.

As described above, each of the above-mentioned various optical resolution methods has its own weak points, and it must be said that the technique is inconvenient as a technique for economically obtaining a large amount of optically active substances.

[Means for solving the problem]

In order to solve the above-mentioned problems, the present inventors have made intensive studies on an optical resolution method using a membrane separation method. The membrane separation method using pressure as a driving force has been recognized as being superior in terms of energy saving, economic efficiency, operability, and the like, and has been established and used in the industrial field and the pharmaceutical field. However, in the conventional membrane separation method, separation of a high molecular substance and a low molecular substance has been performed mainly based on the principle of sieving based on the size of pores present in the active phase of the membrane. Therefore, it was impossible to separate those having the same molecular weight such as optical isomers. However, we have:
By introducing an optically active substance into the separation membrane, the discriminating ability of the optical isomer is imparted to the membrane, and it has been found that the optically active substance can be selectively obtained from the racemic form by a membrane separation method in the same manner as before, The present invention has been completed.

That is, the present invention provides a separation membrane characterized by having an asymmetric discrimination ability, in particular, an optically active substance such as an optically active amino acid condensate by blending the membrane material with an optically active substance. The present invention provides an optical splitting separation membrane characterized by the introduction of

In the present invention, a polymer material soluble in various organic solvents can be used as the film material. Specifically, polysulfone, polyether sulfone, polyacrylonitrile, polyacrylonitrile copolymer, polyvinyl chloride,
Examples include polyimide, cellulose acetate, and cellulose nitrate. Among them, the most preferable is a polysulfone-based resin represented by the following chemical formula (I), (II) or (III).

The optically active substance used in the present invention may be any substance having an asymmetric discrimination ability,
Examples thereof include polysaccharide derivatives, crown ethers, polyacrylic acid derivatives, polyamides, polyamino acid derivatives, and the like, and optically active amino acid condensates are particularly preferable. The amino acids constituting the optically active amino acid condensate include azaserine, asparagine, aspartic acid, amine butyric acid, alanine, arginine, alloisoleucine, allothreonine, isoleucine, ethionine, ornithine, canavanine, carboxymethylcysteine, kynurenine, glutamine, glutamic acid, and cystathionine. , Cysteine, cysteic acid, cystine, citrulline, dihydroxyphenylalanine, serine, thyroxine, tyrosine, tryptophan, threonine, norvaline, norleucine, valine, histidine, hydroxyline, phenylalanine, phenylglycine, methionine, homoserine, lanthionine, lysine, leucine and the like Optically active forms of amino acids may be mentioned. Of these, L-phenylalanine is particularly preferred.

The optically active amino acid condensate used in the present invention can be obtained by condensing the above optically active amino acids by a crosslinking method. In the case of L-phenylalanine, it is converted to a condensate of L-phenylalanine by reacting with glutaraldehyde. In that case, the mixing weight ratio of L-phenylalanine and glutaraldehyde is preferably 1: 0.5 to 1: 4. Most preferably, it is 1: 1 to 1: 3.

In the present invention, as a method of introducing an optically active substance into the film material, a method of blending the film material and the optically active substance is preferable.

A specific example of the production of the optical division separation membrane of the present invention is as follows.

That is, a condensate is formed by a cross-linking method using an optically active amino acid such as L-phenylalanine, and the condensate is blended with a polysulfone resin. A dope is formed and a film is formed.

Mixing of the polysulfone resin and the optically active amino acid condensate can be carried out by any mixing ratio, but in order to make the film suitable for selectively transmitting the optically active substance, the optically active amino acid condensate must be mixed. 5-60% by weight of polysulfone resin
Is preferred. Most preferred is in the range of 10-30% by weight.

In the present invention, the measurement of the optically active capacity of the separation membrane is performed in the second step.
The measurement was performed using the electromagnetic stirring type flat membrane tester shown in the figure. Racemic amino acid concentration to be supplied to the test machine is 2 to 20 mol / m ³ , and pressure is 0.
The measurement was performed at 05 to 2 MPa (megapascal) and at a temperature of 37 ° C., and the separation membrane of the present invention showed a good D / L dividing ability.

〔Example〕

Hereinafter, the present invention will be described in more detail by examples,
The present invention is not limited to these examples.

 The parts in the examples are on a weight basis unless otherwise specified.

Example 1 100 cc of a 2% by weight aqueous solution of glutaraldehyde is added to 100 cc of a 1% by weight aqueous solution of L-phenylalanine, and the mixture is stirred at room temperature for 24 hours to effect cross-linking condensation. The resulting insoluble is an L-phenylalanine condensate.

Union Polycarbonate Polysulfone Resin P-
1700 1 part, reagent grade N-methylpyrrolidone 5 parts, reagent grade lithium nitrate 0.2 parts, L-phenylalanine condensate
Put 0.1 part in a polyethylene container and keep it sealed at room temperature.
Shake for 4 hours to obtain a completely dissolved dope.

 The dope is left as it is to remove bubbles.

As shown in FIG. 1, a defoamed dope 3 is poured onto a glass plate 1 on which a vinyl tape 2 is attached on four sides and placed horizontally, and cast using a cylindrical glass rod 4 with the vinyl tape 2 as a guide. , Remove excess dope.

Immediately, the entire glass plate is transferred to a hot-air dryer kept at 80 ° C. and dried for 2 hours. Then immerse it in a 4 ° C water bath,
After desolvation gelation, L-phenylalanine-immobilized polysulfonic acid was obtained.

The thickness of the obtained film was 158 μm, and the deposited moisture content was 0.63.

The measurement of the membrane performance was performed using an electromagnetic stirring type flat membrane tester (cell volume: 300 ml) shown in FIG. In FIG. 2, 5 is a test solution inlet, 6 is a pressure gauge, 7 is a nitrogen gas inlet, 8 is a cell, 9 is a temperature control water inlet, 10 is an electromagnetic stirrer, 11
Is a valve, 12 is a stirring rod, 13 is a test membrane, 14 is a membrane permeate, 15
Is a permeate bottle.

The flat membrane obtained above is 75 mm in diameter (effective membrane area 28.3 cm
² ) and set in an electromagnetic flat membrane tester shown in FIG. 2 to measure the permeation performance with pure water. For the measurement, ion-exchanged pure water was put into the cell, and the pressurization with N ₂ gas from a nitrogen cylinder was controlled at 0.6 MPa (megapascal). Water temperature
37 ° C. As a result, the pure water permeability coefficient of this membrane was 6.92 ×
It was 10 ^-7 m ³ / m ² · MPa · sec.

For the optical activity resolving power, the electromagnetic stirring type flat membrane tester shown in FIG. 2 was used. Filled in the cell racemic phenylalanine 2 mol / m ³ water solution as a stock solution, the pressure by the N ₂ pressure is 0.5M
The solution temperature was maintained at 37 ° C. while maintaining the pressure at Pa. As a result, the concentration C _PD of the permeate of D- phenylalanine in an amount Jv is ^{2.68 × 10 -7 m 3 / m} 2 · sec for solution passing through the membrane is 0.33 mol /
m ^3, L-concentration C _PL phenylalanine was 0.079 mol / m ^3.

Measurement of optically active substance concentration is made by Daicel Chemical Industries, Ltd.
An LC column was used using Crown Pack CR (+), and operating conditions at that time were as follows.

Column temperature; room temperature Mobile phase: adjusted to pH = 1.5 with perchloric acid aqueous solution Flow rate: 0.6 ml / min Detector; UV (λ = 210 nm) D and L separation coefficients were calculated according to the following equation.

From the feed stock L- phenylalanine concentration above results; permeate of D- phenylalanine concentration C _PL;; permeate of L- phenylalanine concentration C _bD; in the feed stock D- phenylalanine concentration C _bl C _PD here The optical resolution was as shown in Table 1.

Example 2 The mixing ratio of L-phenylalanine and glutaraldehyde and the method for obtaining a condensate therefrom were the same as in Example 1.

The same polysulfone resin as in Example 1 was used, and the compounding ratio of the dope was 1/5 / 0.2 / 0.1 by weight ratio of polysulfone resin / solvent N-methylpyrrolidone / additive lithium nitrate / L-phenylalanine condensate. And

The dope adjusting method and the film forming method were performed in the same manner as in Example 1 to obtain a separation membrane.

Using the obtained membrane, the membrane performance was measured for phenylglycine, a racemic amino acid, under the conditions of a feed solution of racemic phenylglycine at a concentration of 2 mol / m ³ , a pressure of 0.5 MPa, and a temperature of 37 ° C. in the same manner as in Example 1. , permeate speed J _v = 3.16
× 10 ^-7 m ³ / m ² · sec, concentration of D-form in permeate 0.373 mol /
m ³ , the concentration of the same L-form was 0.08 mol / m ³ .

For the measurement of the concentration of the optically active substance, the same Crown Pack CR (+) analysis column as in Example 1 was used.

From the above results, the optical resolution as shown in Table 2 was shown.

Example 3 Using the membrane described in Example 1, optical resolution of racemic methionine was performed.

The concentration of the racemic methionine in the feed solution was 2 mol / m ³ , the pressure was 0.5 MPa, and the liquid temperature was 37 ° C. Permeate velocity J _{v in} this case
Is 3.29 × 10 ⁻⁷ m ³ / m ² · sec, the concentration of D-form methionine in the permeate is 0.079 mol / m ³ , and the concentration of L-form methionine is 0.059 mol
l / m ³ .

The optical resolution is as shown in Table-3. Example 4 To 100 cc of a 0.75% by weight aqueous solution of L-phenylalanine was added 100 cc of a 2.25% by weight aqueous solution of glutaraldehyde, followed by stirring at room temperature for 24 hours, followed by standing and defoaming to obtain an L-phenylalanine condensate.

Using the polysulfone resin of Example 1, dope was adjusted at the following weight mixing ratio. Polysulfone resin / N-methylpyrrolidone / lithium nitrate / L-phenylalanine condensate = 1 /
5 / 0.2 / 0.2. Using this dope, casting was performed on a glass plate in the same manner as in Example 1. Hot air drying and gelation in 4 ° C. water were carried out under the same conditions as in Example 1 to obtain a film.

The obtained film had a thickness of 97 μm and a volume water content of 0.40. The pure water permeation coefficient of this membrane was measured using an electromagnetic stirring type flat membrane tester shown in FIG. 2 using ion-exchanged water having a liquid pressure of 0.6 MPa and a liquid temperature of 37 ° C. and found to be 4.75 × 10 ⁻⁷ m ³ / m ² · MPa · sec. Met.

Using the membrane thus obtained, the resolution of phenylalanine was measured in the same manner as in Example 1. The concentration of the feed racemate phenylalanine was carried out 4 mol / m ^3, the pressure 2 MPa, at a liquid temperature of 37 ° C., the permeate rate J _v is ^{5.60 × 10 -7 m 3 / m} 2 · sec,
The concentration of D-phenylalanine in the permeate was 0.101 mol /
The concentration of m ³ and L-phenylalanine was 0.045 mol / m ³ .

 From the above results, the resolving power as shown in Table-4 was shown.

Example 5 An L-phenylalanine condensate was obtained in the same manner as in Example 1 from 100 cc of a 0.2 wt% aqueous solution of L-phenylalanine and 100 cc of a 0.2 wt% aqueous solution of glutaraldehyde.

Polysulfone resin (P-170)
0) / N-methylpyrrolidone / lithium nitrate / L-phenylalanine condensate = 1/5 / 0.2 / 0.2
A dope was prepared as in Example 1 and cast on a glass plate. 60
The resultant was placed in a hot air drier at 50 ° C. for 50 minutes, and then immediately immersed in water at 4 ° C. to perform gelling and desolvation.

The pure water permeation coefficient of the obtained membrane was measured at a pressure of 0.6 MPa and a water temperature of 37 ° C. using a tester shown in FIG. 2, and was 3.80 × 10 ⁻⁷ m ³ / m
^{It was 2} · MPa · sec.

The optical resolving power of this film was measured in the same manner as in Example 1 with respect to racemic phenylalanine, at a supply racemic concentration of 2 mol / mol.
m ^3, the pressure 1 MPa, the result of measurement under the conditions of a liquid temperature 37 ° C., the permeate rate J _v is ^{2.00 × 10 -7 m 3 / m} 2 · sec, the concentration of D-phenylalanine in the permeate 0.221 mol / The concentration of m ³ and L-form phenylalanine was 0.064 mol / m ³ .

From the above results, the optical resolving power as shown in Table-5 was shown.

[Effect of the Invention] The advantage of the membrane separation is that the operation is easy and the scale-up is simple, so that it is suitable for large-capacity processing. By using the separation membrane of the present invention, optical resolution of a racemate has become possible.

In particular, optically active amino acids are in great demand for use in foods and pharmaceuticals, and the merit of economically obtaining optically active amino acids from racemic amino acids obtained by chemical synthesis using the separation membrane of the present invention is great.

[Brief description of the drawings]

FIG. 1 is a perspective view showing the procedure for casting a dope on a glass plate, and FIG. 2 is an electromagnetic stirring type flat membrane for measuring the pure water permeation rate of a membrane and the optical resolution of a racemic amino acid solution. It is sectional drawing of a test machine. 1: glass plate, 2: vinyl tape 3: dope, 4: cylindrical glass rod 5: test solution inlet, 6: pressure gauge 7: nitrogen gas inlet, 8: cell 8: temperature control water inlet, 10: electromagnetic stirring Equipment 11: Valve, 12: Stir bar 13: Test membrane, 14: Membrane permeate 15: Permeate bottle

Claims (5)

(57) [Claims] An optical splitting membrane characterized in that an optically active substance is introduced into a film material by blending the film material and an optically active substance. 2. The separation membrane according to claim 1, wherein the optically active substance introduced into the membrane material is an optically active amino acid condensate. 3. The separation membrane according to claim 2, wherein the optically active amino acid condensate is an L-phenylalanine condensate. 4. The separation membrane according to claim 1, wherein the membrane material is a polymer substance soluble in an organic solvent. 5. The separation membrane according to claim 4, wherein the polymer substance soluble in the organic solvent is a polysulfone resin.