JP2000290201A - Division of optical isomer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for dividing optical isomers. SOLUTION: This method is based on an adsorption, distillation, absorption or membrane-aided separation to divide optical isomers by bringing a mixture containing optical isomers counter-currently with a classificating solution composed of a classificating agent and diluent, and to recover the classificating solution containing the isomers at 5 wt.% or less, wherein at least one of the following conditions is satisfied: (a) the diluent has a relative dielectric constant of 30 or less, and classificating solution has a viscosity of 0.2 Pa.s or less at division operating temperature, (b) the classificating solution is composed of the classificating agent having an effect of splitting 1H- or 13C-NMR spectral peak, and diluent whose relative dielectric constant is the same as, or lower than, that of the solvent used for measuring 1H- or 13C-NMR spectral pattern, (c) the classificating agent has a lower boiling point than the diluent at division operating pressure, (d) the diluent has at least 10 deg.C higher boiling point than any of the optical isomers at division operating pressure, and (e) the classificating solution contains the classificating agent at 10 wt.% or more.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for resolving optical isomers.

Optical enantiomers obtained by the optical resolution method are widely used as various chemical products, for example, agricultural chemicals, pharmaceuticals, food additives and intermediates thereof.

Specific examples of optical enantiomers include optically active halogen-containing compounds, amino acids, amino acid derivatives, carboxylic acids, carboxylic acid derivatives, amine-containing compounds, alcohol compounds, hydroxycarboxylic acids, hydroxycarboxylic acid derivatives and the like. .

[0004]

2. Description of the Related Art As a method for obtaining an optical enantiomer from an optical isomer by optical resolution, a preferential crystallization method, a diastereo salt crystallization method, and the like have been known for a long time (see Quarterly Review of Chemistry, Optical Isomerism). Body Separation, No. 6, 1989, Academic Publishing Center).

In addition to the above, various optical division methods have been proposed. For example, liquid chromatography (adsorption separation)
And optical separation using an optical splitting separation film, which is a film in which an optically active source is fixed to a film.

[0006] In the adsorption separation of optical isomers, adsorption separation using an adsorbent having an optically active source immobilized thereon is widely known. For example, as an adsorbent for adsorption and separation of optical isomers, a polysaccharide derivative (ester or carbamate, such as cellulose or amylose) or a polysaccharide derivative supported on silica gel, a cyclodextrin derivative, a cyclodextrin derivative supported on silica gel, or the like. , A polyacrylate derivative, and a polyacrylate derivative supported on silica gel or the like are known. Adsorption separation of optical isomers using polysaccharide derivatives was reported by Yashima and Okamoto (Baltein Chemical Society Japan (Bull. Chem. Soc. Jp.).
n. ), 68, 3289-3307 (1995). Also, a method of resolving an optical isomer using a mobile phase to which an optical isomer having a structure similar to the optical isomer to be resolved is added and an adsorbent is disclosed in French Patent Publication No. 259.
No. 3409.

[0007] For the distillation separation of optical isomers, a method of resolution by extractive distillation is described in French Patent Publication No. 217662.
No. 1. Further, Hungarian Patent Publication No. 212256 discloses a method for resolving amphetamine enantiomers by fractional distillation.

A compound similar or identical to a cyclodextrin derivative, which is one of the discriminating agents used in the present invention, is disclosed in European Patent Publication No. 407412 and US Pat.
No. 8395 discloses a stationary phase composition for resolving optical isomers.

[0009]

When one kind of compound (optical enantiomer) is to be taken out of optical isomers,
There are various methods described above. However, for the need to resolve optical isomers, a method known so far is not always perfect, so a new resolution method is desired. The preferential crystallization method and the diastereo salt crystallization method require a solid-liquid separation step, so that they are batch-type processes, and have a problem of low productivity and operational complexity.

In the conventional adsorption separation method for optical isomers, the mechanical strength of the adsorbent is generally low, as represented by the adsorption separation agent in which a polysaccharide derivative or the like is supported on silica gel. It was difficult. Further, these adsorbents are very expensive due to the long production process, and have a problem that the polysaccharide derivative is eluted in a long-term use because the polysaccharide derivative is only supported. Further, in the case of a separation method in which an optical antipode is added to a mobile phase disclosed in FR2593409 or the like,
No mention is made of a device for recycling the mobile phase, which is a problem in industrial separation, or a requirement for an efficient industrial production process.

As a conventional distillation separation method of optical isomers, a separation method by extractive distillation separation method is disclosed in French Patent Publication No. 2176621. Although the present invention shows the concept of resolution of optical isomers using an extractant, it has many problems such as a step of recycling the extractant and selection of an optimal extractant. Also, H
U212256B discloses a method for resolving amphetamine enantiomers by fractional distillation. The present invention relates to a method for isolating an amphetamine isomer to be resolved with a specific resolving agent and then obtaining a specific optical enantiomer by fractional distillation. However, the above homogenization step (for example, diastereomeric However, there is a problem that a continuous high productivity process cannot be constructed.

Further, since there is no adsorbent / separating agent capable of separating all of a large number of optical isomers, development of various new adsorbing / separating agents and separation systems is desired.

There has been a demand for a novel optical splitting method which can solve such various problems.

[0014]

Means for Solving the Problems The present inventors have made a mixture containing an optical isomer countercurrently contact an identification liquid comprising an identification agent capable of identifying the optical isomer and a diluent, and perform adsorption separation, An optical isomer is separated by distillation separation, absorption separation or membrane separation, and thereafter, the discriminating liquid is recovered at a content of the optical isomer of 5% by weight or less and is recycled for use. The relative permittivity of the diluent is 30 or less, and the viscosity of the identification liquid is 0.2 Pa · s or less at the temperature under the dividing operation. (B) By adding the identification agent, ¹ H
Or a discriminating agent having an effect of splitting a ¹³ C-NMR spectrum peak, and a diluent having a dielectric constant equal to or lower than the relative dielectric constant of a measurement solvent at the time of measuring the ¹ H or ¹³ C-NMR spectrum. (C) the boiling point of the at least one compound of the discriminating agent at the pressure under the splitting operation is higher than the boiling point of the at least one compound of the diluent at the pressure under the splitting operation; (d) at least one compound of the diluent That the boiling point at the pressure under the separation operation is higher than the boiling point at the pressure under the separation operation of the optical isomer to be separated by 10 ° C. or more. (E) When the concentration of the discriminating agent in the discrimination liquid is 10% by weight or more. Among them, the present inventors have found that the optical isomer can be efficiently separated by a method for resolving an optical isomer characterized by satisfying one or more conditions.

If none of these conditions (a) to (e) is satisfied, a continuous high-productivity process cannot be constructed when dividing the optically active substance.
The division of the optically active substance cannot be performed efficiently.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.

In the text, the term "optical isomer" refers to a mixture of isomers comprising a plurality of enantiomers, and the term "optical enantiomer" refers to one optically active compound. .

As the optical isomer in the present invention, amino acids, amines, carboxylic acids, hydroxycarboxylic acids, hydrocarbons, halogenated hydrocarbons, ketones, alcohols, ethers and derivatives thereof are preferred. Amine derivatives, carboxylic acid derivatives, halogenated hydrocarbons, ketones,
Alcohols and ethers are more preferable, and carboxylic acid derivatives, halogenated hydrocarbons, ketones, alcohols and ethers are particularly preferable.

The carboxylic acid derivative of the optical isomer in the present invention includes, for example, 2-chloropropionic acid methyl ester, 2-chloropropionic acid ethyl ester, 2-chloropropionic acid ethyl ester and 2-chloropropionic acid ethyl ester.
Methyl bromopropionate, ethyl 2-bromopropionate, pentyl 2-bromopropionate, sec-butyl 2-bromopropionate, sec-hexyl 2-bromopropionate, α-acetyl-α-methyl- γ-butyrolactone, β-butyrolactone and the like.

Examples of the halogenated hydrocarbon include 3-bromo-1-butene, 1-chloro-2-bromopropane,
Examples of 3-dichlorobutane, 1,2-dichloropropane, and the like, and examples of ketones include 3-chloro-2-butanone, 2-chloro-cyclopentanone, and 2-chloro-cyclohexanone.

As the alcohol derivative, 2-acetoxybutane, 2-acetoxypentane, 2-acetoxyhexane, 2-acetoxyheptane, 2-acetoxy-4
-Methylpentane, glycidyl acetate, glycidyl formate, methyl 3-acetoxybutanoate, ethyl 3-acetoxybutanoate, methyl 3-acetoxy-4-chlorobutanoate, methyl 2-acetoxypropionate,
3-acetoxytetrahydrofuran and the like.

As the ether, 2-bromomethyl-tetrahydropyran, butadiene-monoepoxide, 2-
Examples include, but are not limited to, chloromethyl-tetrahydropyran, 3,4-dihydro-2-methoxypyran, trans 2,5-dimethoxytetrahydrofuran, epichlorohydrin, epibromohydrin, and the like. .

The discriminating liquid in the present invention is a liquid obtained by diluting a discriminating agent with a diluent. In an industrial process for performing optical resolution, separation of optical isomers by adsorption separation, distillation separation, absorption separation or membrane separation is particularly preferred. It is used for.

The discriminating liquid in the present invention is used for separation by adsorption separation, distillation separation, absorption separation, or membrane separation. The separation is preferably performed by adsorption separation or distillation separation, and particularly preferably performed by distillation separation.

In the present invention, the countercurrent contact is a contact in which the flow of the discriminating liquid and the flow of the optical isomer to be split face each other in the process system. A moving bed or a simulated moving bed process is known for adsorption separation, and an extractive distillation process and a normal absorption separation process are known for distillation separation.

The division by adsorption separation in the present invention is as follows.
This is a separation using solid-liquid equilibrium, and preferentially adsorbs the enantiomer, which is difficult to discriminate by the discriminating agent, from the discrimination liquid in which the optical isomer is dissolved, that is, the mobile phase, by adsorption separation operation etc. This is a method of dividing the optical enantiomer remaining on the mobile phase side and being easily identified (the optical enantiomer captured on the identification liquid side). As a method of the separation by the adsorption separation method, any method can be used as long as there is a solid-liquid contact operation, but the separation by the simulated moving bed method involving countercurrent contact is particularly preferable in terms of process.

The separation by distillation separation or absorption separation in the present invention is a separation utilizing vapor-liquid equilibrium, in which an enantiomer which is difficult to be identified by an identification agent is distilled from an identification liquid in which an optical isomer is dissolved. This is a method of preferentially taking out by absorption and dividing it into optical enantiomers that are easily identified (optical enantiomers captured on the identification liquid side). As a dividing method by distillation separation, any method can be used as long as it has a gas-liquid contact operation, but an extractive distillation separation method involving countercurrent contact is particularly preferable.

The separation of optical isomers by membrane separation in the present invention means that an optical antipode which is hard to be identified by an identification agent is preferentially removed by membrane separation from an identification liquid in which optical isomers are dissolved, and the optical isomers are separated. This is a method of dividing the optical enantiomer (the optical enantiomer captured by the discrimination liquid). In the method of performing membrane separation, a method comprising a multilayered membrane, wherein the discriminating liquid and the optical isomer to be separated are brought into countercurrent contact is particularly preferable.

The discriminating agent in the present invention refers to a compound that discriminates at least one specific optical enantiomer among optical isomers to be resolved. The discriminating agent may be any as long as it is an optically active compound that discriminates a specific enantiomer. Among them, a discriminating agent comprising an optically active compound having at least two asymmetric atoms is preferable. Specifically, cyclic host compounds such as saccharides, saccharide derivatives (cyclodextrin, cyclodextrin derivatives, polysaccharides, polysaccharide derivatives, etc.), tartaric acid, tartaric acid derivatives, optically active crown ethers, natural optically active compounds, natural optics Derivatives of the active compound, host compounds having a host-guest compound relationship, and the like can be given. Further, an optically active compound having one or more axial asymmetries such as binaphthol is also included in the optically active compound having two asymmetric atoms in the present invention.

Further, as the discriminating agent in the present invention,
Compounds in which asymmetric atoms are bonded adjacently are preferred. In this case, since an optical isomer discrimination field is formed between adjacent asymmetric atoms, it functions as a discriminating agent having high separation performance. Further, a derivative obtained by chemically modifying a substituent around an adjacent asymmetric atom can further enhance the optical isomer discrimination ability, and thus is more preferable.

When the discriminating agent in the discriminating liquid discriminates optical isomers as in the present invention, the resolution performance is improved as described above by using an optically active compound having at least two asymmetric atoms. In addition, by performing the division by the countercurrent contact method, the division with higher productivity can be performed.

As the discriminating agent having an asymmetric atom adjacent thereto in the present invention, for example, a saccharide, a hydroxycarboxylic acid, a saccharide derivative, a hydroxycarboxylic acid derivative and the like are preferable. Saccharides or saccharide derivatives are more preferred, and cyclodextrins or cyclodextrin derivatives are particularly preferred.

The saccharide in the present invention is a disaccharide, a trisaccharide, an oligosaccharide, a cyclodextrin, a polysaccharide and the like.

As the cyclodextrin derivative in the present invention, any one may be used as long as the hydroxyl group of cyclodextrin is modified, but it may be acylated, etherified, or partially etherified. Partially acylated are particularly preferred.
Among the partially etherified and partially acylated derivatives, the 2- and 6-positions of the hydroxyl group of the glucose unit
Those having an ether group at the 3-position and an ether group or acyl group at the 3-position are preferred. In particular, 2,6-O-dialkyl-3-O
-Acyl-cyclodextrin, 2,3,6-O-trialkyl-cyclodextrin (the alkyl group and the acyl group have 1 to 15 carbon atoms).

Further, among the cyclodextrin derivatives, heptakis (2,6-O-dipentyl-3-O-trifluoroacetyl) -β-cyclodextrin and heptakis (2,6-O-dipentyl-3-O-trichloro) Acetyl) -β-cyclodextrin, heptakis (2,6-O-dipentyl-3-O-butyryl) -β-
Cyclodextrin, heptakis (2,6-O-dipentyl-3-O-acetyl) -β-cyclodextrin,
Heptakis (2,6-O-dipentyl-3-O-propanoyl) -β-cyclodextrin, hexakis (2
6-O-dipentyl-3-O-trifluoroacetyl)
-Α-cyclodextrin, hexakis (2,6-O-
Dipentyl-3-O-trichloroacetyl) -α-cyclodextrin, hexakis (2,6-O-dipentyl-3-O-butyryl) -α-cyclodextrin, hexakis (2,6-O-dipentyl-3-O) -Acetyl)
-Α-cyclodextrin, hexakis (2,6-O-
Dipentyl-3-O-propanoyl) -α-cyclodextrin, octakis (2,6-O-dipentyl-3-
O-trifluoroacetyl) -γ-cyclodextrin, octakis (2,6-O-dipentyl-3-O-trichloroacetyl) -γ-cyclodextrin, octakis (2,6-O-dipentyl-3-O-butyryl) )-
γ-cyclodextrin, octakis (2,6-O-dipentyl-3-O-acetyl) -γ-cyclodextrin, octakis (2,6-O-dipentyl-3-O-propanoyl) -γ-cyclodextrin, heptakis (2,6-O-dihexyl-3-O-trifluoroacetyl) -β-cyclodextrin, heptakis (2,6
-O-dioctyl-3-O-trifluoroacetyl)-
β-cyclodextrin, heptakis (2,6-O-dioctyl-3-O-acetyl) -β-cyclodextrin, heptakis (2,6-O-dioctyl-3-O-propionyl) -β-cyclodextrin, heptakis (2,6-O-dioctyl-3-O-butyryl) -β-
Cyclodextrin, heptakis (2,6-O-dioctyl-3-O-valeryl) -β-cyclodextrin,
Heptakis (2,6-O-dioctyl-3-O-hexanoyl) -β-cyclodextrin, Heptakis (2,
6-O-didecyl-3-O-trifluoroacetyl)-
β-cyclodextrin, heptakis (2,6-O-dibutyl-3-O-propionyl) -β-cyclodextrin, heptakis (2,6-O-dibutyl-3-O-trifluoroacetyl) -β-cyclodextrin Octakis (2,6-O-dihexyl-3-O-trifluoroacetyl) -γ-cyclodextrin, octakis (2,6-O-dioctyl-3-O-trifluoroacetyl) -γ-cyclodextrin, octakis (2,6
-O-dioctyl-3-O-acetyl) -γ-cyclodextrin, octakis (2,6-O-dioctyl-3)
-O-propionyl) -γ-cyclodextrin, octakis (2,6-O-dioctyl-3-O-butyryl)
-Γ-cyclodextrin, octakis (2,6-O-
Dioctyl-3-O-valeryl) -γ-cyclodextrin, octakis (2,6-O-dioctyl-3-O-
Hexanoyl) -γ-cyclodextrin, octakis (2,6-O-didecyl-3-O-trifluoroacetyl) -γ-cyclodextrin, octakis (2,6-
O-dibutyl-3-O-propionyl) -γ-cyclodextrin, octakis (2,6-O-dibutyl-3-
O-trifluoroacetyl) -γ-cyclodextrin, hexakis (2,6-O-dihexyl-3-O-trifluoroacetyl) -α-cyclodextrin, hexakis (2,6-O-dioctyl-3-O-) Trifluoroacetyl) -α-cyclodextrin, hexakis (2,6-O-dioctyl-3-O-acetyl) -α-
Cyclodextrin, hexakis (2,6-O-dioctyl-3-O-propionyl) -α-cyclodextrin, hexakis (2,6-O-dioctyl-3-O-butyryl) -α-cyclodextrin, hexakis (2 ,
6-O-dioctyl-3-O-valeryl) -α-cyclodextrin, hexakis (2,6-O-dioctyl-
3-O-hexanoyl) -α-cyclodextrin, hexakis (2,6-O-didecyl-3-O-trifluoroacetyl) -α-cyclodextrin, hexakis (2,6-O-dibutyl-3-O-) Propionyl) -α
-Cyclodextrin, hexakis (2,6-O-dibutyl-3-O-trifluoroacetyl) -α-cyclodextrin as a main component are preferable, and heptakis (2,6-O-dipentyl-3-O- Trifluoroacetyl) -β-cyclodextrin, heptakis (2,6
-O-dipentyl-3-O-trichloroacetyl) -β
-Cyclodextrin, heptakis (2,6-O-dipentyl-3-O-butyryl)-[beta] -cyclodextrin, heptakis (2,6-O-dipentyl-3-O-acetyl)-[beta] -cyclodextrin, heptakis ( 2,
6-O-dipentyl-3-O-propanoyl) -β-cyclodextrin, heptakis (2,6-O-dihexyl-3-O-trifluoroacetyl) -β-cyclodextrin, heptakis (2,6-O- Dioctyl-3-
O-trifluoroacetyl) -β-cyclodextrin, heptakis (2,6-O-dioctyl-3-O-acetyl) -β-cyclodextrin, heptakis (2,
6-O-dioctyl-3-O-propionyl) -β-cyclodextrin, heptakis (2,6-O-dioctyl-3-O-butyryl) -β-cyclodextrin, heptakis (2,6-O-dioctyl- 3-O-valeryl) -β-cyclodextrin, heptakis (2,6-
O-dioctyl-3-O-hexanoyl) -β-cyclodextrin, heptakis (2,6-O-didecyl-3)
-O-trifluoroacetyl) -β-cyclodextrin, heptakis (2,6-O-dibutyl-3-O-propionyl) -β-cyclodextrin, heptakis (2,6-O-dibutyl-3-O-tri Fluoroacetyl) -β-cyclodextrin, octakis (2,6-
O-dihexyl-3-O-trifluoroacetyl) -γ
-Hexakis (2,6-O-dipentyl-3-O-trifluoroacetyl) -β-cyclodextrin, heptakis (2,6-O-dipentyl-3-O) -Trichloroacetyl) -β-cyclodextrin, heptakis (2,6-O-dipentyl-3-O-butyryl) -β-
Cyclodextrin, heptakis (2,6-O-dipentyl-3-O-acetyl) -β-cyclodextrin,
Heptakis (2,6-O-dipentyl-3-O-propanoyl) -β-cyclodextrin, heptakis (2,6-O-dihexyl-3-O-trifluoroacetyl) -β-cyclodextrin, heptakis (2 6
-O-dioctyl-3-O-trifluoroacetyl)-
β-cyclodextrin, heptakis (2,6-O-dioctyl-3-O-acetyl) -β-cyclodextrin, heptakis (2,6-O-dioctyl-3-O-propionyl) -β-cyclodextrin, heptakis (2,6-O-dioctyl-3-O-butyryl) -β-
Cyclodextrin, heptakis (2,6-O-dioctyl-3-O-valeryl) -β-cyclodextrin,
Heptakis (2,6-O-dioctyl-3-O-hexanoyl) -β-cyclodextrin, Heptakis (2,
6-O-didecyl-3-O-trifluoroacetyl)-
β-cyclodextrin, heptakis (2,6-O-dibutyl-3-O-propionyl) -β-cyclodextrin, heptakis (2,6-O-dibutyl-3-O-trifluoroacetyl) -β-cyclodextrin And octakis (2,6-O-dihexyl-3-O-trifluoroacetyl) -γ-cyclodextrin as a main component. The particularly preferred cyclodextrin derivative contains a compound represented by the following formula (I) as a main component.

[0036]

Embedded image (When R1 = pentyl, R2 = trifluoroacetyl, acetyl, propionyl, butyryl, valeryl or hexanoyl, when R1 = n-hexyl, R2 = trifluoroacetyl, when R1 = n-octyl, R2
= Trifluoroacetyl, acetyl, propionyl, butyryl, valeryl or hexanoyl, R1 = n-decyl, R2 = trifluoroacetyl, R1 = n-butyl, R2 = propionyl or trifluoroacetyl) cyclodextrin derivatives as described above Is synthesized by dissolving cyclodextrin in a dimethylsulfoxide (hereinafter abbreviated as DMSO) solvent, and then mixing granular or powdered sodium hydroxide. Then, while controlling the exothermic reaction, the alkyl halide is added dropwise at a rate of 5 g / min or less, more preferably 1 g / min or less, to 1 g of cyclodextrin. ° C range, more preferably 40 ° C
The reaction is carried out at a temperature in the range of -100 ° C for 1 hour or more to effect etherification. The resulting ether form is esterified with an esterifying agent to produce a cyclodextrin derivative composition. As the halogen of the alkyl halide, chlorine, bromine and iodine are preferable, and bromine is more preferable.

Preferably, carboxylic anhydride is used as the esterifying agent. In that case, it is preferable to remove by-produced carboxylic acid by distillation. The removed carboxylic acid may be reused in the reaction after being converted into carboxylic anhydride by a dehydration treatment or the like. In addition, since the carboxylic acid is removed before performing the neutralization and water washing treatment, it is possible to reduce the amount of wastewater generated in the treatment.

The discriminating liquid in the present invention contains a discriminating agent and a diluent. The diluent is a liquid which can sufficiently dissolve the discriminating agent and has a dielectric constant low enough not to impair the discriminating ability of the discriminating agent. It is preferable to use a material having low viscosity.

When a compound having a large polarity is used as the diluent in the present invention, the intermolecular interaction between the discriminating agent and the optical isomer is inhibited, and the discriminating ability, that is, the optical resolving ability is deteriorated. Therefore, the relative permittivity of the diluent is preferably 30 or less, more preferably 10 or less. Relative permittivity 30
Examples of the following diluents include dichloromethane, chloroform, 1,1,1-trichloroethane, α-pinene,
d-limonene, benzene, toluene, anisole, methylanisole, veratrol, cymene, diethylbenzene, tetralin, dichlorotoluene, chloro-P-xylene, benzotrichloride, n-hexane, petroleum ether, n-decane, n-paraffin, min Branched paraffin,
Examples thereof include aliphatic hydrocarbon compounds such as olefins, ether compounds such as diethyl ether and diisopropyl ether, and the like, but are not limited thereto.

The relative permittivity in the present invention refers to a value obtained by dividing the capacitance when a solvent is inserted between the plates of a capacitor of a dielectric constant measuring apparatus by the capacitance when a vacuum is applied, and is generally used. The relative permittivity increases as the polarity of the solvent increases. The method for measuring the relative dielectric constant is described in detail in "New Edition Electrochemical Handbook" (edited by The Electrochemical Society, page 269 of Maruzen Co., Ltd.). Also,
As the relative dielectric constant of the desorbing agent in the present invention, "Revised 3rd Edition Chemical Handbook Basic Edition II" (edited by The Chemical Society of Japan, Maruzen Co., Ltd., page 501) and "New Edition Solvent Pocket Book" (edited by The Synthetic Organic Chemistry Association, Ohmsha) The stated values can be used.

The diluent in the present invention has an effect of diluting the discriminating agent and lowering the viscosity of the discriminating liquid. Generally, the discriminating agent is often a solid or a viscous liquid. By adding the diluent, the viscosity of the identification liquid is reduced, so that the identification liquid can be used without suffering pressure loss in the process system. Also,
After resolving the optical isomer, when the discriminating agent and the diluent are recycled, the operability is improved by lowering the viscosity of the discriminating liquid. In the resolution method of the present invention, after the optical isomer is resolved, the content of the optical isomer to be resolved is recovered as a discrimination liquid of 5% by weight or less. Thus, it is possible to suppress a decrease in division performance. The preferred optical isomer content at the time of recovery of the identification liquid in the present invention is 5% by weight or less, more preferably 3% by weight or less, more preferably 1% or less, and particularly preferably 0.1% or less.
5% by weight or less.

According to the present invention, an identification separation liquid comprising an identification agent capable of identifying an optical isomer and a diluent is brought into countercurrent contact with a mixture containing the optical isomer, and the mixture is subjected to adsorption separation, distillation separation, absorption separation or membrane separation. The method relates to a method for resolving optical isomers in which the discriminating liquid is recovered at a content of the optical isomer of 5% by weight or less and recycled for use. It is necessary to meet at least one. (A) The relative permittivity of the diluent is 30 or less, and the viscosity of the identification liquid is 0.2 Pa · s or less at the temperature under the dividing operation. (B) By adding the identification agent, the optical isomer ¹ H of
Or a discriminating agent having an effect of splitting a ¹³ C-NMR spectrum peak, and a diluent having a dielectric constant equal to or lower than the relative dielectric constant of a measurement solvent at the time of measuring the ¹ H or ¹³ C-NMR spectrum. (C) the boiling point of the at least one compound of the discriminating agent at the pressure under the splitting operation is higher than the boiling point of the at least one compound of the diluent at the pressure under the splitting operation; (d) at least one compound of the diluent That the boiling point at the pressure under the separation operation is higher than the boiling point at the pressure under the separation operation of the optical isomer to be separated by 10 ° C. or more. (E) When the concentration of the discriminating agent in the discrimination liquid is 10% by weight or more. Hereinafter, the respective conditions (a) to (e) will be described. (A) The relative permittivity of the diluent is 30 or less, and the viscosity of the discriminating liquid is 0.2 Pa · s or less at the temperature under the dividing operation. The discriminating liquid has a discriminating ability for separating optical isomers. An important factor is the fluidity for retaining and circulating through the process as a liquid for recovery.

It has been found that when a compound having a large polarity is used as the diluent, the intermolecular interaction between the discriminating agent and the optical isomer is inhibited, and the discriminating ability, that is, the optical resolving ability is deteriorated. Therefore, the relative permittivity of the diluent is preferably 30 or less, more preferably 10 or less.

It has also been found that controlling the viscosity of the identification liquid facilitates handling of the identification liquid in the process system and recovery (purification) by distillation, evaporation, or the like. That is, the viscosity of the identification liquid at the temperature under the dividing operation is preferably 0.2 Pa · s (200 cp) or less, more preferably 0.1 Pa · s (100 cp) or less, and 0.05 Pa · s (50 cp) or less. Is particularly preferred.

In this case, since the discriminating agent discriminates the optical isomer in the solution state, there is a great merit in the case of including the separation and recycling as in the process of the present invention. This is because optical resolution can be performed as a solution, and (1) continuity can be achieved and a highly productive process can be constructed. Further, since the viscosity of the identification liquid is relatively small,
(2) The identification liquid can be collected and recycled by a simple method such as distillation or evaporation. In the resolution method of the present invention, after separating the optical isomer, the content of the optical isomer mixture is recovered as a discrimination liquid having a content of 5% by weight or less, thereby suppressing the deterioration of purity due to contamination during recycling. There is. It has been found that by satisfying the conditions of the present invention, the collection and purification of the identification liquid can be facilitated.

The viscosity of the discriminating liquid is measured by an ordinary method, for example, a measuring method using a Ubbelohde viscometer. (B) By adding a discriminating agent, ¹ H of the optical isomer can be obtained.
Or a discriminating agent having an effect of splitting a ¹³ C-NMR spectrum peak, and a diluent having a dielectric constant equal to or lower than the relative dielectric constant of a measurement solvent at the time of measuring the ¹ H or ¹³ C-NMR spectrum. in the present invention, by adding a discriminating agent, it is preferable to have the effect ^{of 1} H or ^{1 3} C-NMR spectra peaks of the optical isomers divide. Usually, the ¹ H or ¹³ C-NMR spectrum peak of the optical isomer is exactly the same whether it is in the R-form, the S-form, or the racemic form. The splitting of the peak in the present invention is caused by the difference in the strength of the intermolecular interaction between the discriminating agent and the optical isomer. That is, ¹ H or ¹³
The effect of splitting the C-NMR spectrum peak by adding the discriminating agent indicates that the discriminating agent essentially discriminates the optical isomer. In the present invention, since the molecules remain in a solution state, the mutual interaction between the molecules is relatively weak, but the difference in the relative discriminating ability between the discriminating agent and the optical isomer is large. Becomes possible.

In this case, since the discriminating agent discriminates the optical isomer in the solution state, there is a great merit in the case of including the separation and recycling as in the process of the present invention. This is because (1) optical resolution can be performed in the form of a solution, so that continuity can be achieved and a highly productive process can be constructed. This is because the identification liquid can be collected by a simple method such as distillation or evaporation and recycled. In the resolution method of the present invention, unless the optical isomer is separated and the content of the optical isomer mixture is not recovered as a discrimination liquid having a content of 5% by weight or less, the purity may be deteriorated due to contamination when recycled. However, it has been found that, according to the method of the present invention, the identification liquid can be easily recovered and purified for the above-mentioned reason.

The ¹ H or ¹³ C-NMR spectrum in the present invention is preferably measured using a measuring device having an observation frequency of 200 MHz or more, and most preferably 500 MHz or more. This is because if the observation frequency is small, the resolution of the spectrum is deteriorated, and there is a possibility that the peak splitting that should be observed is overlooked. The measurement of the ¹ H or ¹³ C-NMR spectrum in the present invention is carried out according to a standard method.

The measuring solvent in the present invention is usually NM
R solvents such as deuterated chloroform (CDCl ₃ ) and deuterated dichloromethane (CD ₂ C
l ₂ ), heavy benzene (C ₆ D ₆ ), heavy DMSO, heavy water, heavy toluene (CD ₃ C ₆ D ₅ ), heavy methanol (CD ₃ OD,
CD ₃ OH).

The diluent of the present invention, the ¹ H or
^It is preferable to use a solvent having the same or lower relative dielectric constant than the measuring solvent used when the splitting of the peak was confirmed in the ¹³ C-NMR spectrum.

This is because a diluent whose relative dielectric constant satisfies the above requirements is considered to have a small interaction with the discriminating agent, so that the discriminating ability of the discriminating agent is sufficiently exhibited. (C) the boiling point of the at least one compound of the discriminating agent at the pressure under the splitting operation is higher than the boiling point of the at least one compound of the diluent at the pressure under the splitting operation. It is preferred that the boiling point at the pressure under the splitting operation of one compound be higher than the boiling point at the pressure under the splitting operation of at least one compound of the diluent components. This boiling point difference is preferably higher by 10 ° C. or higher, more preferably higher by 20 ° C. or higher, and particularly preferably higher by 30 ° C. or higher. When the boiling point of the discriminating agent is higher than the boiling point of the diluent, the discriminating agent can be easily purified and separated by distillation and / or evaporation when recycled. However, when the diluent is composed of a plurality of components, at least one compound may satisfy the above conditions. (D) The boiling point of the at least one compound of the diluent at the pressure under the resolution operation is higher than the boiling point at the pressure under the resolution operation of the optical isomer to be resolved by 10 ° C. or more. It is preferred that the boiling point of the at least one compound of the components at the pressure under the resolution operation is higher by 10 ° C. or more than the boiling point at the pressure under the resolution operation of the optical isomer to be optically resolved. This boiling point difference is more preferably higher by 20 ° C. or higher, particularly preferably higher by 30 ° C. or higher. Diluent is optical isomer to be resolved and 10 ° C
This is because such a difference in boiling point facilitates purification and separation by distillation and / or evaporation when the discriminating agent is recycled.

In the present invention, the relationship between the respective boiling points (° C.) is more preferably such that the discriminating agent component boiling point> the diluent component boiling point> the optical isomer boiling point + 10 under the dividing operation. When this condition is satisfied, it becomes easier to continuously and efficiently produce optical isomers separated by the identification liquid.

That is, the optical isomer is separated into an optical antipode held on the discrimination liquid side after coming into contact with the discrimination liquid and an optical antipode which escapes out of the discrimination liquid without being discriminated by the discriminating agent in the discrimination liquid. . Each enantiomer can be obtained as having an increased optical purity. If the process is performed in multiple stages (repeating the contact operation a plurality of times), a higher purity optical antipode can be obtained. At this time, if the above conditions are satisfied, the optical enantiomer held on the identification liquid side can be easily separated by distillation and / or evaporation. Further, even if the diluent slightly flows out together with the optical antipode, there is an advantage that the discriminating agent is not lost. The diluent that has slightly flowed out can be purified by further performing distillation and / or evaporation. (E) The concentration of the discriminating agent in the discriminating liquid is 10% by weight or more In the present invention, the concentration of the discriminating agent in the discriminating liquid is preferably 10% by weight or more, since discrimination performance is improved. It is more preferably at least 20% by weight, even more preferably 3% by weight.
0% by weight or more, and particularly preferably 40% by weight or more.

The discriminating liquid in the present invention includes the above (a) to
More preferably, two or more of the conditions (e) are satisfied. Among them, (a) and (b), (a) and (c),
(A) and (d), (a) and (e), (b) and (c),
(B) and (d), (b) and (e) or (c) and (d)
Is preferably satisfied.

It is particularly preferable that three or more conditions are satisfied, and in particular, (a), (b) and (c), and (a) and (b)
And (d), (a) and (b) and (e), (a) and (c) and (d), (a) and (b), (c) and (d), and (b) and ( c) and (d), (c) and (d) and (e), (a) and (c) and (d) and (e), or (b) and (e) and (c).
And (d) are preferably satisfied.

[0056] Among them, <br/> Ri preferably yo satisfy (c) and the (d), satisfies the (c) and (d), further (a),
It is particularly preferable to satisfy at least one of (b) and (e). Most preferably, all of (a) to (e) are satisfied.

In the case of using adsorption separation in the present invention,
(A) and (c), (a) and (d), (a) and (e),
(A) and (b) and (c), (a) and (b) and (d),
(A) and (b) and (e), (a) and (c) and (d),
(A), (b), (c) and (d), (b) and (c),
(B) and (d), (b) and (e), (b) and (c) and (d), (c) and (d), (c) and (d) and (e),
(A), (c), (d), and (e), (b), (c), (d), and (e) or (a), (b), (c), and (d)
And (e) are preferably satisfied. It is more preferable that (c) and (d) are satisfied, and it is particularly preferable that (c) and (d) are satisfied, and further that at least one of (a), (b), and (e) is satisfied.

When distillation separation, absorption separation or membrane separation is used in the present invention, (a) and (b), (a) and (c), (a) and (d), (a) and (e) , (A) and (b) and (c), (a) and (b) and (d), (a) and (b) and (e), (a) and (c) and (d), ( a), (b), (c) and (d), (b) and (c), (b) and (d), (b) and (e), (b) and (c) and (d) ,
(C) and (d), (c) and (d) and (e), (a) and (c) and (d) and (e), (b) and (c), (d), and (e) ) Or (a), (b), (c), (d) and (e)
Is preferably satisfied, (c) and (d) are more preferably satisfied, and (c) and (d) are satisfied.
It is particularly preferable to satisfy at least one of (b) and (e).

In the present invention, after the optical isomer contacts the discriminating liquid, it is discriminated by the discriminating agent in the discriminating liquid and held on the discriminating liquid side. It splits into optical antipodes that escape from the identification liquid. Each enantiomer can be obtained as having an increased optical purity. It is preferable to multi-step the process (repeating the contact operation a plurality of times) in order to obtain an optical antipode with higher purity.

Whatever the process in the present invention, the optical enantiomer dissolved in the discriminating liquid is:
Need to be separated. It is preferable that the separated optical antipodes and the discrimination liquid are recycled into the process system as required. As a method for separating the enantiomer and the discriminating liquid, it is preferable to separate the liquid by distillation and / or evaporation. In the case of the present process, the identification liquid needs to be continuously collected and recycled, and a combination with a process in which continuous separation is easily performed such as distillation and / or evaporation is very effective.

Since the optical enantiomer and the discriminating agent are easily deteriorated or racemized by heat, a method capable of separating at a low temperature is preferable, and distillation under reduced pressure and / or evaporation under reduced pressure are particularly preferable.

It is preferred that one of the optically resolved optical isomers is racemized and recycled.

The technique of the present invention can be used in the following forms in the distillation separation represented by extractive distillation separation or the absorption separation process. It is preferable to carry out distillation separation or absorption separation under conditions that do not precipitate crystals in the process system. Crystals precipitated in the process system of the present invention,
There are three main types.

The first type is a crystal in which a part of the discriminating agent, the mixture of optical isomers and the diluent is precipitated in the tower due to the change in the concentration of the diluent in the process system.

The second is a crystal in which a part of the discriminating agent, the mixture of optical isomers and the diluent is precipitated due to a temperature change in the process system.

The third refers to a crystal which forms a diastereo or clathrate compound (clathrate compound) by mixing the discriminating liquid and the optical isomer to be separated, or which precipitates due to solubility. . When diastereo salts or clathrates are formed, the optical purity of the enantiomer on the crystal side which is formed is drastically increased, but is disadvantageous in consideration of handling in a process such as solid-liquid separation.

In the present invention, an advantage of performing the process under the condition that no crystal is precipitated is that it is possible to prevent complication and complexity in a continuous process such as countercurrent contact. That is, by being able to handle the solution as a uniform solution, it is possible to purify the optical antipode by continuous production or a multi-stage process, and to smoothly carry out the production.

The condition under which no crystal is precipitated in the present invention means that the following condition is satisfied. (1) In the process system, the discriminating agent, the optical isomer mixture, and the diluent do not precipitate due to a concentration change within the concentration range used. (2) In the process system, the discriminating agent, the optical isomer mixture, and the diluent do not precipitate. (3) In the process system, if the concentration distribution of the discriminating agent and the optical isomer to be resolved is such that a diastereo salt or an inclusion compound is formed by the reaction between the two. Also, if the concentration is such that no crystals are generated, or the discriminating agent and the optical isomer to be resolved do not form crystals at all, (3), sampling should be performed at each part in the column and concentration analysis should be performed. It can be verified by doing

The discrimination liquid in the distillation separation or the absorption separation in the present invention has the following effects. The effect is that when the optical isomer to be split is mixed with the discriminating liquid, a solution is prepared under conditions that do not precipitate crystals, and the gas-liquid equilibrium composition is measured, the component ratio of the optical isomer of the gas phase component is determined. Is different from the component ratio of the optical isomer mixed first. That is, under the above conditions, the effect is obtained that the relative volatility between the gas and liquid of the optical isomer does not become 1. In this case, the gas-liquid component ratio of the optical isomer is, for example, the ratio of the R-form component to the S-form component. This component ratio can be easily measured by a generally well-known liquid chromatography method for optical isomer analysis or a gas chromatography method.

The component ratio between the discriminating agent and the diluent in the discriminating liquid is as follows:
The weight ratio of the discriminating agent is preferably 1% or more, more preferably 5% or more, more preferably 10% or more,
It is more preferably at least 30%, particularly preferably from 30 to 80%. Further, in the present invention, it is preferable that each component of the identification liquid has a boiling point higher than that of the optical isomer to be separated or does not volatilize.
Further, it is preferable that the discrimination liquid sufficiently dissolves the mixture containing the optical isomer to be resolved.

The method for resolving the above optical isomers is basically based on a distillation separation method or an absorption separation method. All the advantages of the so-called extractive distillation and absorption separation processes known so far can be exploited in this process. In the present invention, the so-called countercurrent contact type separation, in which the discriminating liquid and the optical isomer to be split are brought into contact in opposite directions, is preferable. As the distillation separation or absorption separation process, a method of continuously injecting the identification liquid from the upper stage of the distillation column or the absorption column and the mixture containing the optical isomer to be separated from the middle stage of the distillation column or the absorption column, respectively, is particularly preferable. . Figure 1 shows a preferred device.
Alternatively, it is preferable to use the apparatus shown in FIG.

That is, the present invention provides a separation apparatus for continuously injecting a discriminating liquid from the upper part of a distillation tower or an absorption tower and a mixture containing an optical isomer to be split from the middle part of the distillation tower or an absorption tower, respectively. It is preferable to carry out.
The separation can also be preferably performed by a separation device in which the mixture containing the optical isomer to be split and the identification liquid are continuously injected from the middle stage of the distillation tower or the absorption tower, respectively. Further, a separation device for continuously injecting the identification liquid from the upper stage of the distillation column or the absorption column and the mixture containing the optical isomer to be split from the middle stage of the distillation column and the identification liquid, respectively, is similarly preferable.

As a more preferable separation method in the present invention, a solution containing the identification liquid and the optical enantiomer is extracted from the lower part of the distillation tower or the absorption tower, and the optical liquid is separated from the identification liquid. Is returned to a distillation tower or an absorption tower, whereby an efficient and economical separation method can be achieved.

Further, among the enantiomer components extracted from the upper or lower part of the distillation column or the absorption column, unnecessary optical enantiomer components are optical isomers to be separated after isomerization (racemization). Returning to the process as is a more preferable separation method.

In the present invention, the method of distillation separation or absorption separation of optical isomers is preferably carried out at a temperature as low as possible because the discriminating agent and the separated optical enantiomer are liable to isomerization or structural change by heat. As a method of performing the process at a low temperature, a method of dividing the process system by reducing the pressure inside the process system is preferable. Accordingly, the bottom temperature of the distillation column is 40 to 30.
The temperature is preferably set to 0 ° C, more preferably 40 to 200 ° C. Particularly preferably, the bottom temperature of the distillation column is 40 to 200.
C. and distillation or absorption separation under reduced pressure is particularly preferred.

The technique of the present invention can be used in the following manner in the adsorption separation process.

In the adsorptive separation process of the present invention, since the discriminating liquid comprising the discriminating agent and the diluent functions as a mobile phase, the discriminating liquid must also have the ability to desorb the optical isomer adsorbed on the adsorbent.

In the adsorption separation process, in order for the discriminating liquid to exhibit a sufficient desorbing force and to be an efficient process, any one of the optical antipode A and the diluent B in the mixture containing the optical isomers is required. _{A / B} between 0.1 and 1
It is preferably 0.0, and more preferably 0.2 to 5.0.

In the present invention, the characteristics of the adsorbent are represented by the following adsorption selection coefficient α _{A / B.}

Α _{A / B} = ([adsorption phase A] / [adsorption phase B])
/ ([Liquid phase A] / [liquid phase B]) The adsorption selection coefficient is determined by the concentration of each component in the liquid phase [adsorbed phase A], [adsorbed phase B], [liquid phase A], [liquid phase B] Is calculated by analyzing by liquid chromatography or gas chromatography. The concentration of each component is preferably determined by an internal standard method. Preferred internal standards include n-nonane.If the mobile phase is water-soluble or polar solvent, and n-nonane does not dissolve, an appropriate non-adsorbed component is selected and used as an internal standard. There is a need to.

When α _{A / B} is larger than 1, the component A is adsorbed, and when α _{A / B} is smaller than 1, the component B is adsorbed. On the other hand, if this value is too large, the optical isomer adsorbed on the adsorbent is difficult to be desorbed into the diluent, so that the adsorption separation efficiency is deteriorated.If this value is too small, the optical antipode is hardly adsorbed on the adsorbent. Adsorption and separation efficiency will deteriorate.

In the present invention, a specific enantiomer is obtained from a mixture containing optical isomers using an optically active discriminating agent, a diluent and an adsorbent. The discriminating liquid, that is, the discriminating agent in the mobile phase, discriminates a specific optical enantiomer in a mixture containing optical isomers by complex formation, intermolecular interaction such as hydrogen bond or π-π interaction. The specific optical enantiomer that is hard to be identified is easily adsorbed to the adsorbent, and the specific optical enantiomer that is easily identified is hard to be adsorbed to the adsorbent. By utilizing this principle, optical isomers can be adsorbed and separated.

As a technique for adsorption separation using the method of the present invention, an adsorption separation method using a moving bed or a simulated moving bed is preferable. In particular, a continuous adsorption separation technique using a simulated moving bed is preferable as an industrial process, and the advantages of the present invention can be fully utilized.

As the basic operation of the adsorption separation by the simulated moving bed system, the following adsorption operation, concentration operation and desorption operation are continuously circulated and carried out. (1) Adsorption operation: The mixture containing the optical isomer comes into contact with the adsorbent, and the strongly adsorbed component is adsorbed while leaving the weakly adsorbed component selectively. The strongly adsorbed component is recovered together with a mobile phase containing an optically active discriminating agent as an extract component. (2) Concentration operation: The raffinate containing a large amount of weakly adsorbed components is further contacted with an adsorbent, and the strongly adsorbed components are selectively adsorbed, whereby the weakly adsorbed components in the raffinate are highly purified. (3) Desorption operation: The highly purified weakly adsorbed component is recovered as a raffinate, while the strongly adsorbed component is expelled from the adsorbent by the discriminating liquid containing the optically active compound and recovered as an extract component with the discriminating liquid. You.

In this method, components obtained from the extract can be highly purified. In addition, after recovering an undesired optical enantiomer, it can be isomerized and returned to the process.

In the adsorption / separation process of the present invention, the identification liquid and the optical enantiomer are separated to obtain a high-purity optical enantiomer product, and the mobile phase component is recovered and returned, or the unnecessary isomer is separated and identified. When the liquid component is recovered and returned, (c) the boiling point of the at least one compound of the discriminating agent at the pressure under the splitting operation, which is a feature of the present invention, is the pressure at the pressure of the at least one compound of the diluent under the splitting operation. And / or (d) the boiling point of the at least one compound of the diluent at the pressure under the resolution operation is higher than the boiling point at the pressure under the resolution operation of the optical isomer to be resolved. It is important that the temperature is higher than 10 ° C.

[0087]

Next, the effects of the present invention will be described with reference to examples. 1. Preparation of identification liquid <Preparation of heptakis (2,6-O-dipentyl) -β-cyclodextrin> Heptakis (2,6-O-dipentyl) -β-cyclodextrin (DP-B-CD)
G. Wenz, Carbohydrate Res
The compound was prepared in the following manner with reference to "earth, 214, 257-265p (1991)".

2144.6 g of β-cyclodextrin (manufactured by Japan Food Processing Co., Ltd.) was dissolved in 10.18 l of DMSO (manufactured by Toray Fine Chemical Co., Ltd.). 4794.4 g of 1-bromopentane (manufactured by Tosoh Corporation) was added thereto, and then granular NaOH (manufactured by Katayama Chemical Industry Co., Ltd.) 1322.0
g was added slowly and stirred at room temperature for about 4 days. Thereafter, excess n-hexane was added and stirred, and the supernatant phase was extracted. This operation was repeated three times. The organic phase was washed three times with a saturated saline solution, and dried by adding sodium sulfate. Thereafter, n-hexane was removed at room temperature under a reduced pressure of about 1 mmHg. Further, the mixture was gradually heated to 100 ° C., and low-boiling compounds were distilled off to obtain DP-B-CD.

<Heptakis (2,6-O-dipentyl-
Preparation of 3-O-trifluoroacetyl) -β-cyclodextrin (DPTFA-B-CD)> Heptakis (2,6-O-dipentyl-3-O-trifluoroacetyl) -β-cyclodextrin (DPTFA-B) -C
D). Y. Li, H .; L. Jin, D.A. W. Ar
Mstrong, J .; Chromatogr. , 50
9, 303-324p (1990) was prepared as follows.

Heptakis (2,6-O-dipentyl)-
1000 g of β-cyclodextrin is added to 50 parts of n-hexane.
Was dissolved in 00 g. While stirring, 4000 g of trifluoroacetic anhydride (manufactured by Asahi Glass Co., Ltd.) was gradually added dropwise thereto. Then, after stirring overnight, after washing three times with water,
The mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and further washed with water.

Further, the mixture was concentrated with an evaporator to remove n-hexane to obtain DPTFA-B-CD as a discriminating agent.

<Heptakis (2,6-O-dihexyl)
Preparation of -β-cyclodextrin> Heptakis (2,6
—O-dihexyl) -β-cyclodextrin (DHx
-B-CD), Wentz, Carbohydrate Research (G. Wenz, Carbohydrate)
Research), 214, 257-265p (1
991) and prepared as follows.

25.0 g of β-cyclodextrin (manufactured by Japan Food Processing Co., Ltd.) was dissolved in 150 ml of DMSO (manufactured by Toray Fine Chemical Co., Ltd.). Then 0.7mm
15.1 g of granular NaOH (manufactured by Kishida Chemical Co., Ltd.) was added and stirred. There, 1-bromohexane (Tokyo Chemical Co., Ltd.)
Was added over 1 hour, and the mixture was heated to 70 ° C. and stirred for about 8 hours. Then, n-hexane 100m
After adding and stirring, 20% saline was added to extract an organic phase. 100 ml of 20% saline was added to the organic phase, and the mixture was stirred, and the organic phase was extracted. Organic phase is 20% saline 100
After washing with 20 ml, 20 ml of n-paraffin SL (manufactured by Nippon Petrochemical Co., Ltd.) was added to the organic phase, and the mixture was heated at 60 ° C./50 mm.
The n-hexane was removed under reduced pressure of Hg,
Under reduced pressure of 20 ° C./20 mmHg, n-paraffin and unreacted 1-bromohexane and 1-hexanol were distilled off.
Hx-B-CD was obtained.

<Heptakis (2,6-O-dihexyl-
Preparation of 3-O-trifluoroacetyl) -β-cyclodextrin (DHxTFA-B-CD)> Heptakis (2,6-O-dihexyl-3-O-trifluoroacetyl) -β-cyclodextrin (DHxTFA-B) −
CD), Y. Lee, H. L. Gin, D. W. By Armstrong Journal Chromatography (WY Li, HL Jin, DW Armst)
Rong, J .; Chromatogr. ), 509, 3
03-324 (1990) was prepared as follows.

Heptakis (2,6-O-dihexyl)-
43.3 g of β-cyclodextrin was dissolved in 65 ml of diisopropyl ether (Nippon Petrochemical Co., Ltd.). While stirring, 35.7 g of trifluoroacetic anhydride (manufactured by Asahi Glass Co., Ltd.) was gradually added dropwise thereto. 25 ° C 12
After stirring for an hour, the solvent was distilled off under reduced pressure of 50 ° C./60 mmHg. 150 ml of diisopropyl ether for residue
Was added to the mixture, and the mixture was neutralized with a 10% aqueous sodium carbonate solution, and the organic phase was washed with 100 ml of 20% saline. Wash again with 100 ml of 20% saline, add 50 ml of n-paraffin SL to the organic phase, and add 60 ° C./50 mm
Diisopropyl ether was removed under a reduced pressure of Hg, and then n-paraffin was distilled off under a reduced pressure of 120 ° C / 20 mmHg to obtain 48.0 g of DHxTFA-B-CD.

<Heptakis (2,6-O-dioctyl)
Preparation of -β-cyclodextrin> 100.0 g of β-cyclodextrin (manufactured by Japan Food Processing Co., Ltd.) was added to DMSO
(Manufactured by Toray Fine Chemical Co., Ltd.) in 600 ml. Next, 0.7 mm granular NaOH (Kishida Chemical Co., Ltd.)
Was added and stirred. 286.0 g of 1-bromooctane (manufactured by Tokyo Chemical Industry Co., Ltd.) was added thereto over 1 hour, and the mixture was heated to 70 ° C. and stirred for about 8 hours. Then, after adding 500 ml of n-hexane and stirring, 20%
The organic phase was extracted by adding saline. 400 ml for organic phase
Was added and stirred, and the organic phase was extracted. After the organic phase was washed with 500 ml of a 20% saline solution, 100 m of n-paraffin SL (manufactured by Nippon Petrochemical Co., Ltd.) was added to the organic phase.
n-hexane was removed under reduced pressure of 60 ° C./50 mmHg, and then n-paraffin and unreacted 1-bromooctane,
-Octanol was distilled off to obtain DO-B-CD. When this was developed on a silica gel 60F254 TLC plate (manufactured by Merck) with a developing solvent (hexane: ethyl acetate = 3: 1 by volume), Rf = 0.65.

<Heptakis (2,6-O-dioctyl-
Preparation of 3-O-trifluoroacetyl) -β-cyclodextrin (DOTFA-B-CD)> 238 g of heptakis (2,6-O-dioctyl) -β-cyclodextrin was added to diisopropyl ether (Nippon Petrochemical Co., Ltd.). ) Dissolved in 400 ml. While stirring, 160 g of trifluoroacetic anhydride (produced by Asahi Glass Co., Ltd.)
Was gradually added dropwise. After stirring at 25 ° C for 12 hours, the solvent was distilled off under reduced pressure of 50 ° C / 60 mmHg. Add 500 ml of diisopropyl ether to the residue and dissolve it.
An aqueous sodium carbonate solution was added for neutralization, and the organic phase was further washed with 200 ml of 20% saline. After washing with 200 ml of 20% saline again, the organic phase was n-paraffin SL20.
0 ml, and diisopropyl ether was removed under reduced pressure of 60 ° C./50 mmHg.
The n-paraffin was distilled off under reduced pressure of mHg, and DO-TF was removed.
28-0.0 g of AB-CD was obtained. When this was developed on a silica gel 60F254 TLC plate (manufactured by Merck) with a developing solvent (hexane: ethyl acetate = 3: 1 by volume), Rf = 0.83.

<Heptakis (2,6-O-dioctyl-
3-O-acetyl) -β-cyclodextrin (DOA
Preparation of c-B-CD) Heptakis (2,6-O-dioctyl) -β-cyclodextrin (7.1 g) and 4-dimethylaminopyridine (2.2 g) are dissolved in triethylamine (Katayama Chemical Co., Ltd.) (40 ml). Was. While stirring
2.3 g of acetic anhydride (manufactured by Nacalai Tesque, Inc.) was gradually added dropwise thereto. After stirring at 25 ° C for 7 hours, the solvent was
The solvent was distilled off under a reduced pressure of 60 ° C./60 mmHg. The residue was dissolved by adding 50 ml of diisopropyl ether, and neutralized by adding 10% hydrochloric acid. The organic phase was washed with 200 ml of water, 20 ml of n-paraffin SL was added to the organic phase, and the mixture was heated at 60 ° C./50.
Diisopropyl ether was removed under a reduced pressure of mmHg, and then n-paraffin was distilled off at a reduced pressure of 120 ° C./20 mmHg to obtain 8.1 g of DOAc-B-CD. This was developed on a silica gel 60F254 TLC plate (manufactured by Merck) with a developing solvent (hexane: t-butyl methyl ether = 1: 1 by volume), and Rf = 0.
52.

<Heptakis (2,6-O-dioctyl-
3-O-propionyl) -β-cyclodextrin (D
Preparation of OPr-B-CD> Heptakis (2,6-O-
Dioctyl) -β-cyclodextrin (7.0 g)
1.1 g of dimethylaminopyridine was dissolved in 40 ml of triethylamine (manufactured by Katayama Chemical Co., Ltd.). While stirring, add propionic anhydride (Nacalai Tesque Co., Ltd.)
2.9 g). After stirring at 25 ° C for 6 hours, the solvent was distilled off under reduced pressure of 50 ° C / 60 mmHg.
The residue was dissolved by adding 50 ml of diisopropyl ether, and neutralized by adding 10% hydrochloric acid. The organic phase was washed with 200 ml of water, 20 ml of n-paraffin SL was added to the organic phase, diisopropyl ether was removed under reduced pressure of 60 ° C./50 mmHg, and then n-paraffin was distilled off under reduced pressure of 120 ° C./20 mmHg. 8.5 g of -B-CD was obtained. This is silica gel 60F254TLC
Using a plate (manufactured by Merck), a developing solvent (hexane: t-
When developed with butyl methyl ether (1: 1 volume ratio), Rf was 0.56.

<Heptakis (2,6-O-dioctyl-
3-O-butyryl) -β-cyclodextrin (DOB
Preparation of u-B-CD) 8.7 g of heptakis (2,6-O-dioctyl) -β-cyclodextrin and 1.4 g of 4-dimethylaminopyridine are dissolved in 40 ml of triethylamine (manufactured by Katayama Chemical Co., Ltd.). Was. While stirring
4.3 g of butyric anhydride (manufactured by Tokyo Chemical Industry Co., Ltd.) was gradually added dropwise thereto. After stirring at 25 ° C for 6 hours, the solvent was removed at 50 ° C / 6.
The solvent was distilled off under reduced pressure of 0 mmHg. The residue was dissolved by adding 50 ml of diisopropyl ether, and neutralized by adding 10% hydrochloric acid. Wash the organic phase with 200 ml of water and add n
-Add paraffin SL 20ml, 60 ℃ / 50mmH
The diisopropyl ether was removed under a reduced pressure of 10 g, and then n-paraffin was distilled off under a reduced pressure of 120 ° C./20 mmHg to obtain 9.6 g of DOBu-B-CD. This is silica gel 60F254 TLC plate (Merck)
And developing solvent (hexane: t-butyl methyl ether =
(1: 1 volume ratio), Rf = 0.57.

<Heptakis (2,6-O-dioctyl-
3-O-valeryl) -β-cyclodextrin (DOV
Preparation of a-B-CD) Heptakis (2,6-O-dioctyl) -β-cyclodextrin (9.0 g) and 4-dimethylaminopyridine (1.4 g) are dissolved in triethylamine (Katayama Chemical Co., Ltd.) (40 ml). Was. While stirring
To this, 5.2 g of valeric anhydride (manufactured by Tokyo Chemical Industry Co., Ltd.) was gradually added dropwise. After stirring at 25 ° C for 6 hours, the solvent was removed at 50 ° C /
The solvent was distilled off under reduced pressure of 60 mmHg. The residue was dissolved by adding 50 ml of diisopropyl ether, and neutralized by adding 10% hydrochloric acid. The organic phase is washed with 200 ml of water, 20 ml of n-paraffin SL is added to the organic phase, and the temperature is 60 ° C./50 mm.
Diisopropyl ether was removed under reduced pressure of Hg, and then n-paraffin was distilled off under reduced pressure of 120 ° C./20 mmHg to obtain 11.3 g of DOVa-B-CD. This was developed on a silica gel 60F254 TLC plate (manufactured by Merck) with a developing solvent (hexane: t-butyl methyl ether = 1: 1 by volume), and Rf = 0.60.

<Heptakis (2,6-O-dioctyl-
3-O-hexanoyl) -β-cyclodextrin (D
Preparation of OHx-B-CD)> Heptakis (2,6-O-
5.5 g of dioctyl) -β-cyclodextrin and 4-
0.8 g of dimethylaminopyridine was dissolved in 20 ml of triethylamine (manufactured by Katayama Chemical Co., Ltd.). 2. While stirring, add hexanoic anhydride (manufactured by Tokyo Chemical Industry Co., Ltd.)
7 g was gradually added dropwise. After stirring at 25 ° C for 6 hours, the solvent was distilled off under reduced pressure of 50 ° C / 60 mmHg. Add 50 ml of diisopropyl ether to the residue and dissolve
Hydrochloric acid was added for neutralization. The organic phase was washed with 200 ml of water, and 20 ml of n-paraffin SL was added to the organic phase.
The diisopropyl ether was removed under reduced pressure of 50 ° C / 50 mmHg, and then n was reduced under reduced pressure of 120 ° C / 20 mmHg.
-Paraffin is distilled off and DOHx-B-CD
g was obtained. This was developed on a silica gel 60F254 TLC plate (manufactured by Merck) with a developing solvent (hexane: t-butyl methyl ether = 1: 1 by volume) to obtain Rf.
= 0.64.

<Heptakis (2,6-O-didecyl)-
Preparation of β-cyclodextrin> 6.1 g of β-cyclodextrin (manufactured by Nippon Food Processing Co., Ltd.) was dissolved in 50 ml of DMSO (manufactured by Toray Fine Chemical Co., Ltd.). Next, powdered NaOH (manufactured by Katayama Chemical Industry Co., Ltd.) 4.
0 g was added and stirred. 20.0 g of 1-bromodecane (manufactured by Tokyo Chemical Industry Co., Ltd.) was added thereto over 5 minutes, and then 70 ° C.
And stirred for about 12 hours. Thereafter, 100 ml of n-hexane was added and the mixture was stirred, and 20% saline was added to extract an organic phase. 100 ml of 20% saline was added to the organic phase, and the mixture was stirred, and the organic phase was extracted. After the organic phase was washed with 100 ml of 20% saline, n-paraffin S was added to the organic phase.
L (manufactured by Nippon Petrochemical Co., Ltd.) at 20 ° C /
N-Hexane was removed under a reduced pressure of 50 mmHg, and then n-paraffin, unreacted 1-bromodecane and 1-decanol were distilled off under a reduced pressure of 120 ° C / 20 mmHg to obtain DD-B-CD. This is silica gel 60F2
When developed with a developing solvent (hexane: ethyl acetate = 3: 1 by volume) on a 54 TLC plate (manufactured by Merck), R
f = 0.68.

<Heptakis (2,6-O-didecyl-3)
Preparation of —O-trifluoroacetyl) -β-cyclodextrin (DDTFA-B-CD)> Heptakis (2,
6-O-didecyl) -β-cyclodextrin 15.0
g to diisopropyl ether (Nippon Petrochemical Co., Ltd.)
Dissolved in 50 ml. While stirring, 14 g of trifluoroacetic anhydride (manufactured by Asahi Glass Co., Ltd.) was gradually added dropwise thereto. After stirring at 25 ° C for 20 hours, the solvent was removed at 50 ° C / 60m
Distilled off under reduced pressure of mHg. The residue was dissolved by adding 50 ml of diisopropyl ether, neutralized by adding a 10% aqueous sodium carbonate solution, and the organic phase was washed with 50 ml of 20% saline solution. Wash again with 50 ml of 20% saline,
Add 20 ml of n-paraffin SL to the organic phase,
Diisopropyl ether was removed under reduced pressure of 50 mmHg, and then n-paraffin was distilled off under reduced pressure of 120 ° C./20 mmHg to obtain 15.9 g of DDTFA-B-CD.
I got This was applied to a silica gel 60F254 TLC plate (manufactured by Merck) using a developing solvent (hexane: ethyl acetate =
(3: 1 volume ratio), Rf = 0.84.

<Heptakis (2,6-O-butyl) -β
-Preparation of cyclodextrin> 6.1 g of β-cyclodextrin (manufactured by Nippon Shokuhin Kako Co., Ltd.) was dissolved in 50 ml of DMSO (manufactured by Toray Fine Chemical Co., Ltd.). Next, powdered NaOH (manufactured by Katayama Chemical Industry Co., Ltd.) 4.0
g was added and stirred. After adding 12.4 g of 1-bromodecane (manufactured by Tokyo Chemical Industry Co., Ltd.) over 5 minutes, the mixture was heated to 70 ° C. and stirred for about 12 hours. Then, n-hexane 1
After adding and stirring 00 ml, 20% saline was added to extract an organic phase. 100 ml of 20% saline was added to the organic phase, and the mixture was stirred, and the organic phase was extracted. After the organic phase was washed with 100 ml of 20% saline, n-paraffin SL was added to the organic phase.
(Manufactured by Nippon Petrochemical Co., Ltd.)
N-Hexane was removed under a reduced pressure of 0 mmHg, and then n-paraffin and unreacted 1-bromobutane and 1-butanol were distilled off under a reduced pressure of 120 ° C / 20 mmHg.
DBu-B-CD was obtained.

<Heptakis (2,6-O-dibutyl-3)
—O-propionyl) -β-cyclodextrin (DB
Preparation of uPr-B-CD)> Heptakis (2,6-O-
7.3 g of (dibutyl) -β-cyclodextrin and 1.6 g of 4-dimethylaminopyridine were dissolved in 40 ml of triethylamine (manufactured by Katayama Chemical Co., Ltd.). While stirring, add propionic anhydride (Nacalai Tesque Co., Ltd.)
4.1 g) was gradually added dropwise. After stirring at 25 ° C for 8 hours, the solvent was distilled off under reduced pressure of 50 ° C / 60 mmHg.
The residue was dissolved by adding 50 ml of diisopropyl ether, and neutralized by adding 10% hydrochloric acid. The organic phase was washed with 200 ml of water, 20 ml of n-paraffin SL was added to the organic phase, diisopropyl ether was removed under reduced pressure of 60 ° C./50 mmHg, and then n-paraffin was distilled off under reduced pressure of 120 ° C./20 mmHg. -B-CD
8.3 g was obtained. This is silica gel 60F254TL
When developed with a developing solvent (hexane: ethyl acetate = 3: 1 by volume) on a C plate (manufactured by Merck), Rf =
0.52.

<1.11. Preparation of Heptakis (2,6-O-butyl-3-O-trifluoroacetyl) -β-cyclodextrin (DBuTFA-B-CD)> Heptakis (2,6-O-dibutyl) -β-cyclodextrin 0 g was dissolved in 50 ml of diisopropyl ether (Nippon Petrochemical Co., Ltd.). While stirring, 12 g of trifluoroacetic anhydride (manufactured by Asahi Glass Co., Ltd.) was gradually added dropwise thereto. After stirring at 25 ° C for 20 hours, the solvent was
The solvent was distilled off under a reduced pressure of 60 ° C./60 mmHg. The residue is dissolved by adding 50 ml of diisopropyl ether, neutralized by adding a 10% aqueous sodium carbonate solution, and further added with 20% saline 5
The organic phase was washed with 0 ml of water. Again 50 ml of 20% saline
, And 20 ml of n-paraffin SL was added to the organic phase, diisopropyl ether was removed under reduced pressure of 60 ° C / 50 mmHg, then n-paraffin was distilled off under reduced pressure of 120 ° C / 20 mmHg, and DBuTFA-BC was removed.
D was obtained in an amount of 14.5 g. This is silica gel 60F254
When developed on a TLC plate (manufactured by Merck) with a developing solvent (hexane: ethyl acetate = 3: 1 by volume), R
f = 0.79.

2. Separation of Optical Isomers by Distillation Separation Example 1 An experiment was performed using a distillation apparatus having an inner diameter of 40 mm and an oldershaw-type tray having 40 stages. A mixture of the identification liquid and the optical isomer to be separated (DPTFA-B-CD: n-nonane (Tokyo Kasei) Co., Ltd.): Methyl RS-2-chloropropionate (manufactured by Tokyo Chemical Industry Co., Ltd.) = Solution having a composition of 62: 33: 5 (weight ratio), optical purity of methyl RS-2-chloropropionate 50%) Was continuously introduced into the column at about 20 g / min. The bottom temperature was maintained at 85 ° C., the bottom liquid was continuously withdrawn at about 14.5 g / min from the bottom, and the distillate was continuously withdrawn from the top at a reflux ratio of 0.20.

After the operation was stabilized for several hours, the bottom liquid and the distillate were obtained in a container. When the components were analyzed, the optical purity of methyl R-2-chloropropionate in the distillate was 54%, and S-2-
The optical purity of methyl chloropropionate was 87%. The analysis of the R-form and the S-form was performed by using
Component analysis was performed by gas chromatography using a capillary column (manufactured by ASTEC). After separating and recovering n-nonane and methyl 2-chloropropionate from the bottom liquid by an evaporator, n-nonane is added thereto to add a discrimination liquid having the above composition (DPTFA-B-CD: n-nonane (Tokyo Chemical Industry Co., Ltd.) ) = 62: 33 (weight ratio)). As a result of analyzing the reconstituted identification liquid, it was confirmed that the concentration of the optical isomer methyl RS-2-chloropropionate was 1% by weight or less. Similar distillation experiment results were obtained when the reconstituted identification liquid was used. An evaporating fraction and a distillate of the bottom liquid were separated by a distillation column, and the obtained n-nonane was recycled. It was confirmed that the process of the present invention can be continuously performed by recycling the identification liquid satisfying the requirements of the present invention.

From the above examples, it was shown that the optical isomers can be efficiently resolved if the conditions of the present invention are satisfied.

Example 2 An experiment was carried out using a distillation apparatus having an inner diameter of 40 mm and an oldershaw type tray having 20 stages. A mixture of the identification liquid and the optical isomer to be separated (DPTFA-B-CD: n-paraffin SL (Nippon Oil) A solution having a composition of 2: 1 (weight ratio) was continuously introduced into the column at a rate of about 10.5 g / min, and 250 g of methyl RS-2-chloropropionate was previously introduced into the bottom of the column. The bottom temperature was maintained at 67 ° C. The distillate was continuously withdrawn at 0.36 g / min from the top of the tower.

The distillate after one hour of operation was collected in a container.
When the components were analyzed, the R-
The optical purity of methyl 2-chloropropionate was 72%.

The discriminating agent (DPTFA-BC) was obtained from the bottom liquid.
An identification liquid composed of D) and a diluent (n-paraffin SL) and an optical isomer (methyl RS-2-chloropropionate) were separated by an evaporator. Separation with an evaporator was performed at a bath temperature of 95 ° C. and 5 mmHg to obtain a diluent and an optical isomer, and a mixture of a diluent and a discriminating agent, respectively. Thereafter, the optical isomer and the diluent were separated using a packed distillation column. Since the difference in boiling point between the discriminating agent and the diluent, and between the diluent and the optical isomer, was 10 ° C. or more, they could be easily separated by using an evaporator and a distillation apparatus.

The separated diluent and the mixture of the diluent and the discriminating agent are mixed, and the diluent is added to the discrimination liquid having the above-mentioned composition (DPTFA-B-CD: n-paraffin SL = 2: 1).
(Weight ratio)) was prepared again. As a result of analyzing the reconstituted identification liquid by gas chromatography, it was confirmed that the concentration of the optical isomer methyl RS-2-chloropropionate was 1% by weight or less. The reconstituted identification liquid was recycled.

It was confirmed that the process of the present invention can be continuously performed by recycling the identification liquid satisfying the requirements of the present invention.

The physical properties of the identification liquid and the like of this embodiment are shown below. Viscosity of identification liquid 0.09 Pa · s (80 ° C) Dielectric constant of diluent (n-paraffin SL) 1.99 to 2.02 Identification agent boiling point 150 ° C or higher / 30mmHg Diluent boiling point 80 to 90 ° C / 30mmHg Separation Object boiling point Approx. 50 ° C./30 mmHg Identification agent concentration 66.7% by weight n-paraffin S having a low viscosity and a low dielectric constant as a diluent
By selecting L, the discriminating ability of the discriminating liquid was maintained and the effect of lowering the viscosity was obtained. The discriminating agent DPTFA-B-CD itself has a very high viscosity and is not easy to circulate or recycle in a process, but in this example, it could be carried out smoothly without any problem. It was measured ¹ H-NMR spectrum in ⁽¹ H-NMR measurement of the spectrum) the following analysis conditions.

Apparatus UNITYINOVA600 type (manufactured by Varian) Observation frequency 599.8 MHz Solvent CDCl ₃ reference substance TMS Number of points 64 K Observation width 8 KHz Pulse width 45 degree Repetition time 7 sec Integration times 32 times CDCl ₃ 900 mg to methyl RS-2-chloropropionate Sample 1 with 20 mg added and CDCl ₃ 900
Sample 2 in which 20 mg of methyl S-2-chloropropionate was added to mg, and DPTFA-B-CD: CDCl ₃ =
Sample 3 was prepared by adding 20 mg of methyl RS-2-chloropropionate to 900 mg of a 1: 1 (weight ratio) solution, and measured under the above measurement conditions. The peak (quadruple) of the α-position proton of methyl 2-chloropropionate is shown in FIG.
(Sample 1), FIG. 4 (Sample 2), and FIG. 5 (Sample 3).

In the case of samples 1 and 2 containing only methyl RS-2-chloropropionate, quadruples were obtained, but DP
In the case of Sample 3 to which TFA-B-CD was added, splitting of a quadruplex was observed.

From the above results, DPTFA-B-CD showed that R-form and S-form
Confirmed to identify the body.

The relative permittivity of CDCl ₃ is 4.81.
The relative dielectric constant of the n- paraffins SL is in the range of 1.99 to 2.02, it can be seen that a CDCl ₃ smaller value.

(Measurement of Specific Volatility) DPTFA-BC
D: n-paraffin SL (manufactured by Nippon Oil Co., Ltd.): RS-
Methyl 2-chloropropionate (Tokyo Kasei Co., Ltd.) =
A solution having a composition of 2: 1: 0.2 (weight ratio) was prepared. In addition, n-paraffin SL has a boiling range of 182 to 212.
° C. n-paraffin. The gas-liquid equilibrium of methyl RS-2-chloropropionate in this solution was measured according to a conventional method. The heating of the liquid phase was performed at 80 ° C. under a reduced pressure of 30 mmHg. The mixture was allowed to stand in a stable state for several hours, the R-form / S-form ratio of methyl RS-2-chloropropionate of the liquid phase component and the gas phase component was measured, and the relative volatility α _{R / S} was calculated based on the following equation. . When the relative volatility is 1, it is impossible to separate both components by simple distillation. When the relative volatility is greater than 1, both components can be separated by distillation or absorption, and the larger the value, the easier the separation.

Α _{R / S} = (ratio of R-isomer / S-isomer in gas phase) / (ratio of R-isomer / S-isomer in liquid phase) Analysis of R-isomer and S-isomer was carried out using a chiraldex B-TA capillary column (ASTEC Co., Ltd.). Was analyzed by gas chromatography. The specific volatility α _{R / S} was 1.33. As the gas component, a liquid rich in R-form was obtained (boiling point: 45 ° C.), and a liquid rich in S-form was obtained as the bottom liquid. In other words, it was confirmed that the optical isomer methyl RS-2-chloropropionate could be resolved by using the discriminating liquid composed of the discriminating agent DPTFA-B-CD and the diluent n-paraffin SL. The same result was obtained when an experiment was performed using the above-described recycled identification liquid as the identification liquid.

From the above examples, it was shown that the optical isomers can be efficiently resolved if the conditions of the present invention are satisfied.

Example 3 Inside diameter 25 filled with SULZER type experimental packing EX
The experiment was carried out using a distillation apparatus in which two packed towers having a height of 800 mm and a height of 800 mm and 20 stages of an Aldershaw type tray having an inner diameter of 35 mm were directly connected vertically. A mixture of the identification liquid and the optical isomer to be separated (DOTFA-B-CD: Mentane (Nippon Terpene Co., Ltd.), which was depressurized to 11 mmHg by a vacuum pump from the top of the condenser at the top of the distillation column and kept at 50 ° C. 5) Methyl RS-2-chloropropionate (manufactured by Tokyo Chemical Industry Co., Ltd.) = 64: 32: 4 (weight ratio), 50% optical purity of methyl RS-2-chloropropionate) It was continuously introduced into the tower at 9.9 g / min. The tower bottom temperature was maintained at 85 ° C., and 4.5 g / min was continuously withdrawn from the bottom of the tower, and a distillate was continuously withdrawn at a reflux ratio of 0.56 from the top of the tower. After being stabilized for several hours, the bottom liquid and the distillate were collected in a container. Analysis of each component revealed that R-2 in the distillate was
The optical purity of methyl-chloropropionate was 63%, and the optical purity of methyl S-2-chloropropionate in the bottom liquid was 96%. The analysis of the R-form and the S-form was carried out by using a chiraldex B-TA capillary column (Astec (AS
Component analysis was performed by gas chromatography using TEC). Mentane and methyl 2-chloropropionate were recovered from the bottom liquid by an evaporator. By adding menthan, an identification liquid having the above composition (DOTFA-BC)
D: Mentan (manufactured by Nippon Terpene Co., Ltd.) = 64:32:
(Weight ratio)) was prepared again. As a result of the analysis, the optical isomer R
The concentration of methyl S-2-chloropropionate is 1% by weight.
It was confirmed that: The evaporating fraction and the distillate of the bottom liquid by an evaporator are separated in a distillation column, respectively.
The obtained menthan was recycled. The same effects as in Examples 1 and 2 were confirmed.

Example 4 DOTFA-B-CD: n-paraffin SL (manufactured by Nippon Oil Co., Ltd.): Methyl RS-2-chloropropionate (manufactured by Tokyo Chemical Industry Co., Ltd.) = 2: 1: 0.2 ( (Weight ratio), and a gas-liquid equilibrium contact was performed in the same manner as in Example 2.

The specific volatility α _{R / S} was 1.52. As the gas component, a liquid rich in R-form was obtained (boiling point: 45 ° C.), and a liquid rich in S-form was obtained as the bottom liquid. That is, it was confirmed that the use of the discriminating liquid consisting of DO-TFA-B-CD as the discriminating agent and n-paraffin SL as the diluent can separate methyl RS-2-chloropropionate as an optical isomer. .

Since the difference in boiling point between the discriminating agent (DOTFA-B-CD) and the diluent (n-paraffin SL), and between the diluent and the optical isomer (methyl RS-2-chloropropionate) is 10 ° C. or more, DOTFA-B-CD and n
-Paraffin SL and the enantiomer could be easily separated by using an evaporator and a distillation apparatus, and the separated one could be reused to obtain the same result. From the above, the same effects as in Example 2 were confirmed.

Example 5 DOTFA-B-CD: n-paraffin SL (manufactured by Nippon Oil Co., Ltd.): Methyl RS-2-chloropropionate (manufactured by Tokyo Chemical Industry Co., Ltd.) = 6: 3: 0.2 ( (Weight ratio), and a gas-liquid equilibrium contact was performed in the same manner as in Example 2.

The specific volatility α _{R / S} was 1.94. As the gas component, a liquid rich in R-form was obtained (boiling point: 45 ° C.), and a liquid rich in S-form was obtained as the bottom liquid. That is, it was confirmed that the use of the discriminating liquid including DOTFA-B-CD as the discriminating agent and n-paraffin SL as the diluent can resolve methyl RS-2-chloropropionate as an optical isomer.

Since the difference in boiling point between the discriminating agent (DOTFA-B-CD) and the diluent (n-paraffin SL), and between the diluent and the optical isomer (methyl RS-2-chloropropionate) is 10 ° C. or more, DOTFA-B-CD and n
-Paraffin SL and the enantiomer could be easily separated by using an evaporator and a distillation apparatus, and the separated one could be reused to obtain the same result. From the above, the same effects as in Example 2 were confirmed.

Example 6 DPTFA-B-CD: n-paraffin SL (manufactured by Nippon Oil Co., Ltd.): Methyl RS-2-chloropropionate (manufactured by Tokyo Chemical Industry Co., Ltd.) = 62.4: 31.2: A solution having a composition of 6.4 (weight ratio) was prepared, and gas-liquid equilibrium contact was performed in the same manner as in Example 2 except that the temperature of the liquid phase was set to 85 ° C.

The relative volatility α _{R / S} was 1.21. A liquid rich in R-form is obtained by distillation, and the bottom liquid is S-form.
A rich liquid was obtained. That is, DPT which is an identification agent
By using a discriminating liquid consisting of FA-B-CD and n-paraffin SL as a diluent, the optical isomer RS-2 is obtained.
-It was confirmed that methyl chloropropionate could be separated.

From the above, the same effects as in Example 2 were confirmed.

Example 7 The composition of the solution to be prepared was DPTFA-B-CD: n-paraffin SL (manufactured by Nippon Oil Co., Ltd.): RS-epichlorohydrin (manufactured by Tokyo Chemical Industry Co., Ltd.) = 63.1: 31.5:
At 5.4 (weight ratio), the temperature of the liquid phase was 60 ° C., the pressure in the system was 15 mmHg, and the gas-liquid equilibrium contact was carried out on the outside in the same manner as in Example 2. The specific volatility α _{R / S} was 1.06. That is, it was confirmed that the optical isomer RS-epichlorohydrin could be separated by using the discriminating liquid composed of the discriminating agent DPTFA-B-CD and the diluent n-paraffin SL.

From the above, the same effects as in Example 2 were confirmed.

Example 8 The same experiment as in Example 6 was performed using the solution obtained by further heating the bottom liquid used in Example 6 and extracting the optical isomer. Crystals did not precipitate in the bottom liquid, and continuous repeated experiments were possible. Solution DPTFA-B-
The CD / 2-methyl methyl chloropropionate ratio is 14.37.
Meanwhile, the ratio of R-form / S-form of methyl 2-chloropropionate is 0.73, and in this case, the specific volatility is 1.62.
It became. By the multi-step process, an enantiomer enriched in the S-form could be obtained. According to this example, the same effect as that of Example 11 was confirmed.

Example 9 The same experiment as in Example 11 was performed using the solution obtained by further heating the bottom liquid used in Example 8 and extracting the optical isomer. The DPTFA-B-CD / 2-methyl methyl 2-chloropropionate ratio of the solution was 24.47, and the R-form / S-form ratio of methyl 2-chloropropionate was 0.53.
In this case, the specific volatility was 1.83. By the multi-stage process, an optical antipode enriched in S-form could be obtained. According to this example, the same effect as that of Example 11 was confirmed.

Comparative Example 1 An experiment similar to that of Example 1 was performed using only the solution of methyl RS-2-chloropropionate. The specific volatility was 1.00. From this, the optical isomer R
It can be seen that methyl S-chloropropionate cannot be separated by distillation unless a discriminating liquid containing an optically active discriminating agent is used.

Comparative Example 2 Example 2 was repeated except that the solution was RS-epichlorohydrin.
When the same experiment as described above was performed, the relative volatility was 1.00. This shows that RS-epichlorohydrin, which is an optical isomer, cannot be separated by distillation unless a discriminating liquid containing an optically active discriminating agent is used. 3. Resolution of optical isomers by adsorption separation Example 10 (Evaluation of adsorption separation performance) DPTFA-B-CD: diisopropyl ether: methyl RS-2-chloropropionate (manufactured by AH Marks) = 46.59: 46. .7
A solution having a composition of 7: 6.63 (weight ratio) was prepared, and 3.0 was prepared.
0 g was placed in an Erlenmeyer flask with a file. There, 200
1.0 g of silica gel 4B (manufactured by Fuji Silysia Ltd.) dried at 10 ° C. for 10 hours was added. After leaving for 1 hour at room temperature, the mixture was stirred well and left for another hour. Thereafter, the supernatant was collected and subjected to component analysis by gas chromatography using a Chiraldex B-TA capillary column (manufactured by ASTEC). The calculated adsorption selectivity coefficient αR-form / S-form was 1.31, and αR-form / diisopropyl ether was 0.960. From this result, it was found that the R-form and the S-form can be adsorbed and separated by using DPTFA-B-CD as an optically active discriminating agent and using silica gel as an adsorbent. Since the adsorption selectivity coefficient between diisopropyl ether and the R-form is about 1, it has been found that it has a sufficient desorbing power and can be used as a diluent.

(Preparation of identification liquid) As the mobile phase, DP was used.
TFA-B-CD, n-paraffin SL (manufactured by Nippon Petrochemical Co., Ltd .: boiling point at normal pressure: n-paraffin at 182 to 212 ° C.) and diisopropyl ether (manufactured by Nippon Petrochemical Co., Ltd .: boiling point at normal pressure) 77 ° C.) in a weight ratio of 2: 1: 2.
Was used (identifying agent concentration 40% by weight). DPTFA-B-CD functions as an optically active discriminating agent, n-paraffin SL functions as a diluent, and diisopropyl ether functions as a diluent having desorbing power.

(Pseudo moving bed method / adsorption separation process) Twelve stainless steel columns having a length of 1 m and an inner diameter of 4.75 mm were connected as adsorption column towers, and silica gel 4B was connected to each column.
(30-80 mesh, manufactured by Fuji Silysia Ltd.). It confirmed by the following method using the simulated moving bed process as shown in FIG. The fluid outlet and inlet were controlled by rotary valves. All experiments were performed at room temperature. From the inlet DPTFA-B-CD: n-paraffin S
L: Methyl RS-2-chloropropionate (AHM
2.32 ml of a liquid having a composition of 2: 1: 1
/ H. The discriminating liquid was supplied at 180.90 ml / hour. The extract was extracted at 28.69 ml / hour and the raffinate at 26.80 ml / hour. The rotary valve was switched every 380 seconds. After 12 hours of operation under these conditions until a steady state was reached, 78 mg of methyl S-2-chloropropionate was obtained from the extract.
And the raffinate contained 8100 ppm of methyl R-2-chloropropionate, each having an optical purity of 1 ppm.
Eluted at 00% ee. Component analysis was performed by Chiraldex B-
Gas chromatography was performed using a TA capillary column (manufactured by ASTEC).

The solution containing methyl S-2-chloropropionate extracted from the raffinate was distilled under reduced pressure with an evaporator at 30 mmHg to obtain a liquid containing isopropyl ether and methyl S-2-chloropropionate. (Boiling point of methyl S-2-chloropropionate at 30 mmHg: about 50 to 60 ° C, boiling point of n-paraffin SL at 30 mmHg: 80 ° C or more) Further, isopropyl ether (boiling point at normal pressure: 77 ° C) was constantly used. 96% of chemical purity (optical purity 100
% Ee) of methyl S-2-chloropropionate (boiling point 133 ° C. at normal pressure).

The bottom liquid of the evaporator is almost 2-
After further concentration until methyl chloropropionate is no longer contained, isopropyl ether and n-paraffin S
L was added to prepare a solution having a mobile phase composition, and the solution was returned to the mobile phase.

It was confirmed that the optical isomer was efficiently adsorbed and separated as a continuous process, and that the discrimination liquid could be returned into the process system.

(Evaluation of Performance of Cyclodextrin Derivative Composition) The following examples show the results of evaluation using identification liquids composed of several cyclodextrin derivatives and a diluent.

The evaluation results of the batch system in each of the following examples were measured under static conditions, but the evaluation of the batch system was performed separately for the simulated moving bed system shown in the tenth embodiment. It can be considered that the adsorptive separation ability obtained by the above evaluation method is simply evaluated. In other words, a material having the adsorption selectivity obtained under a static condition can find a large difference by the simulated moving bed method. For this reason, what obtained the difference under static conditions can be easily separated by a chromatography method using a substantially batch system or a moving bed system.

Example 11 1.0 g of faujasite-type zeolite KY calcined at 500 ° C. for 3 hours was weighed, and the discriminating agent DHxTFA-B-
4.0 g of CD and p-diethylbenzene (manufactured by Toray Industries, Inc.)
3.5 g of a uniform solution consisting of 6.0 g and 1.0 g of methyl RS-2-chloropropionate (manufactured by Tokyo Chemical Industry Co., Ltd.)
In addition, after adsorbing at room temperature for 24 hours, the supernatant RS-2
-R / S ratio of methyl chloropropionate was analyzed. R
The / S analysis was carried out by gas chromatography using a Chiraldex B-TA (manufactured by Astec) column.
The results are shown in Table 1.

Example 12 In the same manner as in Example 11, the discriminating agent was replaced with DOTFA-BC.
Instead of D, the adsorptive separation ability was evaluated. The results are shown in Table 1.

Example 13 In the same manner as in Example 11, the discriminating agent was replaced with DOAc-B-CD.
And the adsorptive separation ability was evaluated. The results are shown in Table 1.

Example 14 In the same manner as in Example 11, the discriminating agent was replaced with DOPr-B-CD.
And the adsorptive separation ability was evaluated. The results are shown in Table 1.

Example 15 In the same manner as in Example 11, the discriminating agent was DOBu-B-CD.
And the adsorptive separation ability was evaluated. The results are shown in Table 1.

Example 16 In the same manner as in Example 11, the discriminating agent was DOVa-B-CD
And the adsorptive separation ability was evaluated. The results are shown in Table 1.

Example 17 In the same manner as in Example 11, the discriminating agent was replaced with DOHx-B-CD.
And the adsorptive separation ability was evaluated. The results are shown in Table 1.

Example 18 In the same manner as in Example 11, the discriminating agent was replaced with DDTFA-BC.
Instead of D, the adsorptive separation ability was evaluated. The results are shown in Table 1.

Example 19 In the same manner as in Example 11, DBuPr-BC was used as the discriminating agent.
Instead of D, the adsorptive separation ability was evaluated. The results are shown in Table 1.

Example 20 In the same manner as in Example 11, the discriminating agent was used as DBuTFA-B-
Instead of CD, the adsorptive separation ability was evaluated. The results are shown in Table 1.

[0157]

[Table 1]

[0158]

The optical isomers can be efficiently separated by using the method for resolving optical isomers of the present invention.

[Brief description of the drawings]

FIG. 1 is a diagram showing a distillation separation device of the present invention.

FIG. 2 is a diagram showing an absorption separation device of the present invention.

FIG. 3 shows ¹ H- of sample 1 (methyl RS-2-chloropropionate only, solvent CDCl ₃ ) in Example 2.
It is a figure which shows an NMR spectrum.

FIG. 4 shows sample 2 (methyl S-2-chloropropionate + DPTFA-B-CD, solvent C) in Example 2.
FIG. ₃ shows a ¹ H-NMR spectrum of DCl ₃ ).

FIG. 5 shows sample 3 (methyl RS-2-chloropropionate + DPTFA-B-CD, solvent) in Example 2.
FIG. ₃ is a diagram showing a ¹ H-NMR spectrum of CDCl ₃ ).

FIG. 6 is a view showing a simulated moving bed system used in Embodiment 10.

 ──────────────────────────────────────────────────続 き Continued on front page (31) Priority claim number Japanese Patent Application No. 11-28194 (32) Priority date February 5, 1999 (1999.2.5) (33) Priority claim country Japan (JP) (72) Inventor Katsuhiro Shibayama, 1-9 Toe, Nagoya Office, Minato-ku, Nagoya, Aichi Prefecture (72) Inventor Tomoyuki Aoki 1-9, Oe-cho, Minato-ku, Nagoya, Aichi Nagoya, Ltd. In-plant (72) Inventor Shinobu Yamakawa 1-9-9 Oe-cho, Minato-ku, Nagoya-shi, Aichi F-term (reference) in Nagoya Plant in Toray 4D017 AA03 BA04 CA11 DA02 EA01 4D076 AA16 GA10 HA14 HA20 JA03 4H006 AA02 AC83 AD11 BC10 BC11 BC51 BC52

Claims (18)

[Claims] 1. A discrimination liquid comprising a discriminating agent and a diluent capable of discriminating the optical isomer is brought into countercurrent contact with a mixture containing the optical isomer, and the mixture is optically separated by adsorption separation, distillation separation, absorption separation or membrane separation. A method for resolving optical isomers in which an isomer is separated and the discriminating liquid is recovered at a content of the optical isomer of 5% by weight or less and recycled for use. (A) When the relative permittivity of the diluent is 30 or less, And the viscosity of the discriminating liquid is 0.2 Pa · s or less at the temperature under the dividing operation. (B) By adding the discriminating agent, the ¹ H
Or a discriminating agent having an effect of splitting a ¹³ C-NMR spectrum peak, and a diluent having a dielectric constant equal to or lower than the relative dielectric constant of a measurement solvent at the time of measuring the ¹ H or ¹³ C-NMR spectrum. (C) the boiling point of the at least one compound of the discriminant at the pressure under the splitting operation is higher than the boiling point of the at least one compound of the diluent at the pressure under the splitting operation; (d) at least one compound of the diluent That the boiling point at the pressure under the splitting operation is higher than the boiling point at the pressure under the splitting operation of the optical isomer to be split by 10 ° C. or more (e) When the concentration of the discriminating agent in the discriminating liquid is 10% by weight or more A method for resolving optical isomers, characterized by satisfying one or more conditions. 2. The method for resolving optical isomers according to claim 1, wherein the discriminating agent has at least two or more asymmetric atoms. 3. The method for resolving optical isomers according to claim 1, wherein the discriminating agent is at least one selected from saccharides, hydroxycarboxylic acids, saccharide derivatives and hydroxycarboxylic acid derivatives. 4. The method for resolving optical isomers according to claim 3, wherein the discriminating agent is a cyclodextrin derivative. 5. The method for resolving optical isomers according to claim 4, wherein the cyclodextrin derivative has an ether group and / or an ester group. 6. A cyclodextrin derivative represented by the following formula (I): (When R1 = pentyl, R2 = trifluoroacetyl, acetyl, propionyl, butyryl, valeryl or hexanoyl, when R1 = n-hexyl, R2 = trifluoroacetyl, when R1 = n-octyl, R2
= Trifluoroacetyl, acetyl, propionyl, butyryl, valeryl or hexanoyl, R1 = n-decyl, R2 = trifluoroacetyl, R1 = n-butyl, R2 = propionyl or trifluoroacetyl) The method for resolving an optical isomer according to claim 5, wherein the method comprises: 7. The method for resolving an optical isomer according to claim 1, wherein the optically active substance having an increased optical purity is separated from the identification liquid by distillation and / or evaporation. 8. The method for resolving optical isomers according to claim 7, wherein the enantiomer having an increased optical purity is separated from the discriminating liquid by distillation under reduced pressure and / or evaporation under reduced pressure. 9. The method for resolving optical isomers according to claim 1, wherein one of the optically resolved optical isomers is racemized and recycled as an optical isomer mixture. 10. The method for resolving optical isomers according to claim 1, wherein the optical isomer mixture is subjected to distillation separation or absorption separation under conditions that do not precipitate crystals. 11. The separation of optical isomers according to claim 10, wherein the discriminating liquid is injected from the upper part of the distillation tower or the absorption tower, and the optical isomer mixture is injected from the middle part of the distillation tower or the absorption tower. Method. 12. The method for separating optical isomers according to claim 10, wherein the optical isomer mixture and the discriminating liquid are injected from the middle part of the distillation tower or the absorption tower. 13. A method comprising extracting a solution containing an identification liquid and an optical enantiomer from a lower portion of a distillation column, separating the optical enantiomer and the identification liquid, and returning the collected identification liquid to the distillation column. The method for resolving an optical isomer according to claim 10. 14. A method comprising extracting a solution containing an enantiomer from the upper or lower part of a distillation tower or an absorption tower, racemizing the recovered enantiomer component, and returning the racemic component to the distillation column. A method for resolving an optical isomer according to any one of claims 10 to 13. 15. The method for resolving optical isomers according to claim 10, wherein the method is performed under reduced pressure. 16. The method for resolving optical isomers according to claim 10, wherein the bottom temperature of the distillation column is 40 to 200 ° C. 17. The adsorption selectivity α _{A / B} between any of the optical isomers A and the diluent B in the optical isomers is 0.2 to 5.
2. The method for resolving optical isomers according to claim 1, wherein the value is 0. 18. The method for separating optical isomers according to claim 1, wherein the separation is performed using a simulated moving bed.