JP3246760B2 - Optical splitting film and optical splitting method using the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a film for separating optical isomers and an optical resolution method using the film. In particular, a novel membrane that enables efficient resolution of the optical resolution of β-blockers, which are currently used as anti-arrhythmia, anti-angina pectoris, antihypertensive drugs, and glaucoma treatments, and uses the membrane. The optical splitting method used.

[0002]

2. Description of the Related Art With the progress of research and development in the fields of medicines and agrochemicals, flavors, seasonings, liquid crystals and the like, the importance of optically active substances is increasing more and more. In particular, the optically active substance plays a unique role in biological phenomena, and one of the optically active substances (D-form or L-form or + -form or-
It is known that obtaining body) is often very useful. The Ministry of Health and Welfare states in the 1985 edition of the Pharmaceutical Manufacturing Guidelines that "if the drug is racemic, it is desirable to consider the absorption, distribution, metabolism, and excretion kinetics of each isomer."

As an industrial method for obtaining an optically active substance from a racemate, there are presently a diastereomer method, a preferential crystallization method, an enzymatic method, a chromatography method and the like. In the diastereomer method, an optically active acid or base (resolving agent) is allowed to act on a racemate, fractional crystallization is performed using the difference in solubility of the generated diastereomeric salt, and purification is performed by recrystallization. This is a method of obtaining an optically active substance by decomposing it by a chemical treatment. This method involves the difficulty of selecting a resolving agent because the resolving agent must readily form a salt or derivative with the racemate. Further, when the difference in solubility is small or absent, optical resolution is impossible. In addition, there is a problem that it is difficult to obtain a high-purity optically active substance.

The preferential crystallization method is a method in which a pure crystal of one enantiomer is added as a seed to a racemic supersaturated solution, and only the enantiomer crystal of the same type is selectively grown and precipitated. Although it is a very good method, it is difficult to say that it is widely used because of the following problems. That is, in order to resolve a racemic body by the preferential crystallization method, first, the solubility of the racemic body and both active forms is measured, and it is determined that racemic form> active form. It is necessary to confirm in advance that the activity is higher and that the active substance does not dissolve in the saturated solution of the racemic form (Hiro Yamanaka, Yasuhisa Tashiro, Review of Quarterly Chemistry, No.
6, 1989, pp. 4-5).

[0005] The optical resolution method using an enzyme can be classified into a "fermentation method" and an "enzymatic method". However, the enzyme is a kind of asymmetric molecule formed by peptide bond of L-amino acid, and in many cases, the reaction is not possible. Proceeds as a simultaneous reaction. That is, since the enzyme itself has a high selectivity as a catalyst, it is used in the production of optically active substances and is suitable as a method for obtaining a large amount of optically active substances, for example, a hydantoinase reaction and a chemical decarbamylation reaction. An industrial production technology for D-amino acids by an enzymatic method combining S.TAKAHASHI,
“Biotechnology of Aminoacid Production”, H.YAMADA
et al (eds), Kodansha Ltd. (1986) p269]. U.S. Pat. No. 4,800,162 describes a method for obtaining an optically active substance by immobilizing an enzyme in a polyacrylonitrile-based hollow fiber membrane. However, a problem with the enzymatic method is that it is very difficult to find an enzyme that matches the racemate to be resolved.

The chromatographic method is a method in which a chiral compound is used as a filler to form a stationary phase, and separation is performed by utilizing a difference in distribution of a mobile phase due to interaction with an optical isomer in the mobile phase. The development of packing materials for HPLC (high-performance liquid chromatography) has been remarkable in recent years, and many optical separation columns have been launched on the market and a large amount of fractionation has been performed. It is a step now in the area where it takes place.

On the other hand, in the membrane separation method, the microfiltration membrane and the ultrafiltration membrane are almost in parallel with the development of the technology of reverse osmosis membrane for seawater desalination about 30 years ago. Technology development has been promoted, so-called artificial membranes have become established as practical technologies, and are used in various industrial fields such as medicine, electronics industry, and automobiles. These membranes are basically separated based on the principle of molecular sieve utilizing the relative difference between the molecular size and the pore size of the membrane, and have the same molecular weight as chemical isomers like optical isomers. It is well-known that the characteristics are not different but are completely unsuitable for separation.

The features of the membrane separation method are that they are suitable for large-scale processing and that the separation cost is low. Therefore, there is a great demand for the development of a film suitable for optical division and the development of a technique for successfully using the film. In particular, if the racemate to be resolved can be resolved into the optically active substance by a direct membrane method without chemical modification, the industrial value of the technique is excellent. That is, the method of separating an optically active substance using such a membrane is a novel method that overcomes the inherent disadvantages of the above-described diastereomer method, preferential crystallization method, enzymatic method, chromatography method, and the like. It is a technology and it can be expected that a large amount of optically active substances can be obtained economically.

Regarding the separation of an optically active substance using a membrane,
Already, a separation method using a membrane obtained by introducing an optically active substance into a membrane material (Japanese Patent Application No. 2-229743), or a membrane made of a polymer containing a polyamino acid having an α-helical structure as a constituent component A technique such as a separation method (Japanese Patent Application No. 2-334352) and a separation method using a liquid membrane in which a crown compound is retained on a polypropylene microfiltration membrane (Japanese Patent Publication No. 63-57083)
No.) etc. are known. However, these are all membranes for amino acids, and are not applied to separation of drugs or the like having a complicated chemical formula. Therefore, an object of the present invention is to provide a membrane capable of efficiently optically resolving a drug or the like, and a separation method using the membrane.

[0010]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, polysaccharide derivatives and the like which are already frequently used as column packings for liquid chromatography in the analysis and fractionation of optical isomers have been obtained. Attention was paid to a substance having an optical resolving power, and it was found that an optical splitting film having a good resolving power could be obtained by fixing the substance on the inside and both sides of the substrate film, and completed the present invention. That is, the present invention provides an optical splitting film obtained by fixing a substance having an optical splitting ability such as a polysaccharide derivative to the inside and both sides of a substrate film, and a method of bringing a racemic stock solution into contact with one side of the optical splitting film. Another object of the present invention is to provide an optical splitting method characterized in that an optically active substance is obtained by washing the other surface with a washing liquid.

In the present invention, as a method of fixing a substance having an optical resolution to the inside and both surfaces of a base material film, a substance having an optical resolution is dissolved in an organic solvent (referred to as dope), and then the solution is coated on one side of the film. Alternatively, there are a method of coating on both surfaces, a method of dipping a film in a solution dope, and the like. In the case of the present invention, the effect is not changed by either method.

The substance having optical resolving power used in the present invention is an ester derivative of cellulose or amylose,
It is a rubamate derivative or an ether derivative.

The substrate membrane used in the present invention may be an ultrafiltration membrane, a microfiltration membrane, or a microporous membrane. The material is cellulose acetate, cellulose nitrate, regenerated cellulose, Teflon, polypropylene, polyethylene, polysulfone, polyethersulfone, polystyrene, polyamide, polyimide, polyacrylonitrile, etc. A film made of any material can be applied.

In order to fix the polysaccharide derivative on the membrane, the polysaccharide derivative is dissolved in an organic solvent to form a dope. The solvent used for the dope is dimethylformamide (DMF),
Dimethyl sulfoxide (DMSO), tetrahydrofuran (TH
F), pyridine, dimethylacetamide, mesityl oxide, acetone, methylene chloride, chloroform, phenol, 2-pyrrolizone, hexamethylphosphamide, tetramethylurea and the like. Since these solvents have different solubility depending on the kind of the polysaccharide derivative to be used, a solvent having good solubility is appropriately selected and used.

In the optical resolution method according to the present invention, a racemic undiluted solution of the compound to be resolved is brought into contact with one side of the optical resolution film obtained as described above, the other side of the film is left as a space, and the inside of the film is selected. This is a method of intermittently washing the optically active substance adsorbed intermittently with a washing liquid to recover the optically active substance in the washing liquid.

The racemic stock solution optically resolved by the method of the present invention is, for example, ethyl-4- dissolved in a mixed solution of 90% normal hexane and 10% 2-propanol.
(2,2-paracyclophanyl) acrylate, oxprenolol, alprenolol, pindolol, athenol, trans-stilbene oxide, tregger base and the like. As the cleaning liquid used in the present invention, for example, normal hexane-2-propanol mixed solvent,
Examples include a normal hexane-ethanol mixed solvent, ethanol water, and the like.

[0017] The present invention has been found in the preliminary experiments described below and has been a hint of the invention. In the previous experiment, 300 mg of cellulose tris (3,5-dimethylphenylcarbamate) was dissolved in 10 ml of THF to prepare a dope. A 30 mm diameter Teflon microfiltration membrane was immersed in the dope for 1 hour, pulled up, and dried in a nitrogen stream for 1 hour to obtain a polysaccharide derivative-fixed membrane. The selective adsorption of the optically active substance of the obtained film was examined by the following method. The selective adsorptivity of the optically active substance is ethyl-4 represented by the following formula collectively referred to as cyclophane.
A racemic form of-(2,2-paracyclophanyl) acrylate was prepared by adding 90% of normal grade normal hexane and 2-propanol 10
%, Dissolved in a mixed solution at a concentration of 0.88 mg / ml, immersed in the film obtained at room temperature for 4 hours, lifted up, and adsorbed on the film with a mixed solvent of normal hexane 80% and 2-propanol 20%. The obtained optically active substance of ethyl-4- (2,2-paracyclophanyl) acrylate was extracted and measured by liquid chromatography.

[0018]

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The column used for the analysis was a chiral cell OD manufactured by Daicel Chemical Co., Ltd. at a flow rate of 1.0 ml / min, eluent composition: normal hexane 90%, 2-propanol 10%, detector UV (λ = 254 n
m). As a result, the + body has an optical purity of 72% ee
In addition, when the eluent was replaced with 95% normal hexane and 5% 2-propanol, the + form was found to have an optical purity of 68% ee.
It turned out to be.

[0020]

EXAMPLES The findings of the preceding experiments show that it is possible to obtain optically active substances sufficiently and selectively with a film to which a polysaccharide derivative is fixed, and the following Examples 1 to 3 show more details. A newly invented optical splitting film and an optical splitting method using the film will be described. Although the films in Examples 1 and 2 were formed using a film obtained by combining two base films, the present invention is not limited to the case where the films are bonded to two films, and the film is divided into two or more films. Improvements in effects are expected. As shown in the third embodiment, it is of course possible to perform the process with a single film. The present invention is not limited only by these examples.

Example 1 Cellulose tris (3,5-dimethylphenylcarbamate) was used as a polysaccharide derivative, and 200 mg of this was dissolved in 15 cc of a special grade solvent of dimethylacetamide to form a dope.
In this dope, Fluororepore (registered trademark, TYPE FP-045, manufactured by Sumitomo Electric Industries, Ltd., pore size 0.45 μm, diameter 25 m)
m) Two pieces were immersed at room temperature for about 1 hour. After the film pulled out of the immersion dope is dried in a nitrogen stream at room temperature for 1 hour,
It was dried for 34 hours in a desiccator reduced to about 1/10 atm. Further, for the purpose of removing impurities in the film, the film was immersed in a mixed solvent of 90% special grade normal hexane and 10% special grade reagent 2-propanol at room temperature for 12 hours, and then placed in a desiccator reduced to about 1/10 atm for 4 hours. Dried. The two films are bonded together using the dope used above as an adhesive to form one film,
In order to evaluate the optical resolution, it was mounted in a liquid-tight manner at the center of a glass evaluation device as shown in FIG. Both the stock solution chamber 4 and the permeation chamber 5 were filled with a mixed solution of 90% reagent-grade normal hexane and 10% reagent-grade 2-propanol, and the membrane 3 and the inside of the glass cell 1 were thoroughly washed. A solution prepared by dissolving racemic ethyl-4- (2,2-paracyclophanyl) acrylate at a concentration of 0.96 mg / ml in a reagent grade normal hexane solvent.
ml and 1 ml of reagent grade 2-propanol were placed in the stock solution chamber 4. The stock solution was kept stirred by the magnetic stirrer 6.

After several hours, 0.2 ml of a mixture of a reagent grade normal hexane and a reagent grade 2-propanol 8: 2 in a ratio of 8: 2 is added to the permeation chamber 5 as a washing solvent, and the membrane surface on the permeation chamber side is used with this washing solution. After carefully washing for about 10 seconds, they were collected. The measurement of the optically active substance in the recovered washing solution was performed by the HPLC method under the following conditions. Column name: Daicel Chemical Industries Chiral Cell OD Eluent: Reagent grade normal hexane 80%, Reagent grade 2-
20% propanol flow rate; 1.0 ml / min temperature; room temperature detector; UV (λ = 254 nm) The result is ethyl-4- (2,2-paracyclophanyl)
The optical purity of the + form of acrylate was 24% ee, and the recovered amount was 0.03 mg. After several hours, 0.2 ml of a washing solvent was added to the permeation chamber side and washed in the same manner as in the previous method.

Comparative Example 1 Using the membrane used in Example 1, a racemic mixture of ethyl-4- (2,2-paracyclophanyl) acrylate having exactly the same composition as in Example 1 was placed on the stock solution chamber 4 side of the apparatus shown in FIG. A solution prepared by dissolving the compound in normal hexane-2-propanol (90:10) was added. On the other hand, 8 ml of a cleaning liquid having the same composition as that used for cleaning in Example 1 was simultaneously placed in the permeation chamber 5 side, and left at room temperature for several hours while the membrane surface on the permeation chamber side was constantly in contact with the cleaning liquid. .
When the liquid in the permeation chamber was measured by HPLC under the same conditions as in Example 1, the optical purity was almost 0% ee, and no optically active substance was recovered.

Example 2 Cellulose tris (3,5-dimethylphenylcarbamate) was used as a polysaccharide derivative, and 1 g of the polysaccharide derivative was used as a reagent-grade THF.
The dope was dissolved in 9 g. Example 1 in this dope
The two Teflon-based substrate films used in the above were superimposed and immersed for 1 hour. The film was taken out, dried in a nitrogen stream for 1 hour at room temperature, and then dried in a desiccator reduced to about 1/10 atm for 4 hours. The dried membrane is placed in a mixed solution of 90% reagent grade normal hexane and 10% reagent grade 2-propanol.
After immersion for an hour, it was dried for 4 hours in a desiccator reduced to 1/10 atm.

Using the dope used above as an adhesive, the two films were bonded together and mounted on the apparatus shown in FIG. At this time, the amount of cellulose tris (3,5-dimethylphenylcarbamate) fixed in the membrane (effective membrane area: 3.14 cm ² ) was 50 mg. The equipment is placed in a thermostat at 30 ° C, and the stock solution chamber 4 and permeation chamber 5
90% reagent grade normal hexane, reagent grade 2-
The membrane and the inside of the apparatus were thoroughly washed with a mixed solution of 10% propanol. A racemic oxprenolol represented by the following formula, which is used as a β-blocker in medicine, is dissolved at a concentration of 1 mg / ml in a mixed solution of 90% reagent-grade normal hexane and 10% reagent-grade 2-propanol to give a concentration of 1 mg / ml. 8 ml of the solution was put in a stock solution chamber, and kept for several hours while stirring with a magnetic stirrer 6.

[0026]

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0.2 ml of a mixed solution of 80% of reagent grade normal hexane and 20% of reagent grade 2-propanol is put into the permeation chamber, and the membrane surface on the permeation chamber side is thoroughly washed with this washing solution at 30 ° C. for 10 seconds. Repeated 5 times at second intervals. The optically active form of the washing solution was measured by the HPLC method under the following operating conditions. Column name: Chiral Cell OD, manufactured by Daicel Chemical Industries, Ltd. Eluent: 80% special grade normal hexane, 2 grade special reagent
20% propanol, 0.1% diethylamine Flow rate; 1.0 ml / min Temperature; room temperature Detector; UV (λ = 254 nm) The measurement result shows that oxprenolol is an optical purity of 12.2
30 μg was obtained in% ee. Further, when the cleaning is performed in the same manner at intervals of several hours, the optical purity is 25.6% ee, 20.6% ee,
27.5% ee, 23.6% ee with 47.5% of oxprenolol
μg, 55 μg, 37.5 μg and 35 μg were obtained. Approximately similar results were obtained when the conditions were slightly changed, such as a slight change in the cleaning solution composition and a 12-hour interval between cleanings. As a result of performing the washing operation 63 times in total, the results of optical division as the final total are as shown in Table 1.

[0028]

[Table 1]

Example 3 Cellulose tris (3,5-dimethylphenylcarbamate) was used as a polysaccharide derivative, and 100 mg of the polysaccharide derivative was dissolved in 2 g of a reagent grade acetone to form a dope. One PO-200 ultrafiltration membrane (material: aromatic polyamide, nominal molecular weight cut-off 20,000) manufactured by Toyo Roshi Kaisha Ltd. having a diameter of 25 mm was immersed in this dope for 3 hours at room temperature. This film was dried in air for 1 hour, and then dried in a desiccator reduced to 1/10 atm for 6 hours. The amount of cellulose tris (3,5-dimethylphenylcarbamate) in the membrane was 6 mg.

The membrane thus obtained was set in the evaluation apparatus shown in FIG. 1 (effective membrane area: 1.77 cm ² ) and placed in a thermostat.
While keeping the temperature at 30 ° C., 90% of reagent grade normal hexane and reagent grade 2-propanol were placed in both the undiluted solution chamber 4 and the permeation chamber 5.
Each 10 ml of a 10% mixed solvent was filled. The membrane and the entire evaluation apparatus were thoroughly washed for 12 hours. In order to evaluate the optical resolution, 10 mg of oxprenolol (β-blocker) was placed in the stock solution chamber 4 of the apparatus after washing, and the reagent was graded normal hexane.
It was dissolved in 10 ml of a mixed solvent of 90% and a special grade of reagent 2-propanol 10% and put. The temperature was kept at 30 ° C. 0.5 ml of a mixed solvent of 80% reagent grade normal hexane and 20% reagent grade 2-propanol was placed in the permeation chamber 5 side, and the permeate side of the membrane 3 was washed for 1 minute to recover the washing solution. Exactly the same washing operation was repeated 33 times at regular intervals, and the results in Table 2 were obtained.

[0031]

[Table 2]

The optical purity was measured by the HPLC method under the following conditions. Column name; Chiral cell OD eluent manufactured by Daicel Chemical Industries, Ltd. Eluent of reagent grade normal hexane: reagent grade 2-propanol: reagent grade diethylamine (80: 20: 0.1) Flow rate: 1.0 ml / min Temperature: room temperature Detector: UV ( λ = 254nm)

[0033]

The separation of the optically active substance by the membrane separation method as in the present invention is an economical industrial technique because it is easy to operate and suitable for large-volume processing. The present invention relates to a technique in which an optically active substance is directly separated from a racemate using a film formed by a method in which a substance having optical resolution ability such as a polysaccharide derivative is fixed to a substrate film. This is a unique new technology that can easily obtain optically active substances.
Even for medicines and agricultural chemicals such as β-blockers having a complicated chemical structural formula, the technology of obtaining an optically active substance by direct separation by the membrane separation method according to the present invention is epoch-making and has great industrial merit.

[Brief description of the drawings]

FIG. 1 is a cross-sectional view of an optical resolving power evaluation device used in experiments of Examples and Comparative Examples.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Glass cell 2 Laminated stopper 3 Membrane 4 Stock solution room 5 Permeation room 6 Magnetic stirrer

Claims (2)

(57) [Claims] An optical resolution is provided inside and on both sides of a substrate film.
Cellulose or amylose ester derivatives,
An optical resolution film formed by fixing a rubamate derivative or an ether derivative . 2. An optical splitting method, wherein an optically active substance is obtained by bringing a racemic stock solution into contact with one surface of the optical splitting film according to claim 1 , and then washing the other surface with a washing liquid.