JPH10507192A - Method for separating enantiomers from a racemic mixture - Google Patents

Abstract

(57) Abstract: A method for separating enantiomers from a racemic mixture by countercurrent extraction using at least two substances, one containing a racemic mixture to be separated and the other containing a chiral adjuvant Wherein the chiral adjuvant is associated with or is a part of a gel-forming substance in the form of discrete particles in a liquid, wherein the gel-forming substance comprises a racemic compound to be separated. From the flowing liquid, the gel-forming particles separated as a result of the extraction are separated by a microporous membrane having a pore size such that they can no longer penetrate the pores) and then a mirror image therefrom under the influence of a stimulus One of the isomers is released, after which the particles are optionally reinserted into the extraction process. During the extraction process, the gel-forming substance is preferably in an expanded state, in the form of discrete particles, and flows through a microporous membrane, preferably made of polypropylene.

Description

DETAILED DESCRIPTION OF THE INVENTION         Method for separating enantiomers from a racemic mixture   The present invention relates to at least two substances, one of which contains the racemic mixture to be separated. Liquid, while the other contains a chiral adjuvant). , A process for separating enantiomers from a racemic mixture.   Such a method was early proposed in WO 94/07814. Have been. The method disclosed therein involves the use of a racemic mixture using at least two liquids. Details at least one of which is chiral or chiral. Contains adjuvants, the liquids are completely miscible and the liquids are immiscible The phases separate them from each other. Separable, immiscible phases are porous Or incorporated into a solid support which can be non-porous and preferably in the form of hollow fibers be able to.   Most racemic mixtures can be very efficiently separated by the methods disclosed in the above references. However, the racemate is readily soluble in the extraction liquid. As well as in phases that separate these liquids and are immiscible with them Can be easily dissolved. The separation cannot be performed by the known method or the separation is very difficult. Examples of difficult substances are functional groups such as amino groups, keto groups, esters or hydro- Chiral substances without xyl groups as well as certain aromatic compounds.   Only chiral adjuvants available to separate racemic mixtures are very narrow. A large number of separations to achieve high purity. Separation techniques that give the same result with fewer separation steps when steps are needed There is a demand for surgery.   Therefore, a method for separating a racemic mixture that can be barely separated by known techniques There is a practical demand for it.   The present invention now provides a way in which the above requirements can be largely met.   The present invention relates to a method of the known type described in the first paragraph. The bunt is combined with a gel-forming substance in the form of discrete particles in the liquid or Is part of it (where the gel-forming substance contains the racemate to be separated) The gel-forming particles separated as a result of the extraction from the countercurrent Separated by a microporous membrane with a pore size such that it cannot penetrate) Release one of the enantiomers therefrom under the influence of a stimulus, after which the particles are subjected to an extraction process. Characterized in that it may be re-inserted into the source.   Gel-forming substances in the form of discrete particles to separate the racemic mixture from the liquid Chiral adjuvant used in combination with Masakazu Negawa and Fumihiko Reference by Shoji, J.S. Chromatog. 590 (1992), pages 113-117, as such Note that it is known. It is filled with a chiral stationary phase Light using eight columns Simulated moving bed adsorption (SMB) A) The use of the technique is described. In theory, the authors argue that the stationary phase Is a true countercurrent flow where the racemic liquid moves continuously in the opposite direction Although the process is mentioned, the only practical embodiment used is a simulated moving bed.   The main advantage of the newly proposed method here is that liquids containing racemic mixtures are no longer Must be separated from the chiral adjuvant-containing phase by an immiscible phase Which is much faster than possible using known methods. Enable.   A further advantage of the method proposed here is that the chiral adjuvant is Separated and extracted with it because it is combined with or part of the quality Separation of the enantiomers can be made simple enough. In that case, the chiral adjuvant Can be covalently bound to a protein-forming substance. Another possibility is that chiral adjuvants Molecularly imprinted polymer prepared for one of the enantiomers to be separated (molecularly imprinted polymer) (MIP) It is.   To prevent gel-forming particles from penetrating the pores of the membrane during the extraction process, Is in an expanded state. The enantiomers that are mixed with them during extraction use stimuli Will be released again. This stimulus can be temperature, pH, salt concentration, electric or magnetic Field and / or form of change in solvent composition Possible.   After release from the gel-forming particles, the enantiomer is generally extracted and the desired And further purified by evaporation and / or crystallization of the extractant.   The gel-forming substance exists in the form of discrete particles. These particles are larger Larger particles are also suitable, but can have a size between 50 nm and 300 μm. Wear. When larger particles are used, the gel-forming substance no longer contains all of the particles. Alternatively, the gel-forming substance is provided on a carrier and is physically, preferably covalently, The embodiment where it is coupled to is preferred. In such a process, When the gel-forming substance is provided in the pores of the carrier and on the surface thereof In both cases, favorable results can be achieved. The carrier is an inorganic or organic substance Can be any of Examples of inorganic carriers include α-alumina, γ-alumina, carbon, Ceramic materials or combinations thereof, such as alumina on a porous carbon support is there. Examples of porous organic carriers based on organic polymers are described in U.S. Pat.No. 4,247,498. It is described in detail in the specification and US Pat. No. 4,519,909.   When particles with a relatively high specific weight are used, liquids flowing in the opposite direction Gravity may be used to create a backflow.   The porous membrane to be used in the method of the invention preferably has the largest possible pore Where the largest dimension is The pores are chosen so that the pores are too small for the expanded particles to penetrate.   When a porous membrane is used, it is better to use a membrane with the same polarity as the extraction liquid. preferable. More preferably, when the polarity of the extraction liquid does not correspond to the polarity of the membrane, Depending on whether the flowing liquid is polar or non-polar, the chemical route The membrane can be made hydrophilic or hydrophobic, for example by grafting with an acrylate compound. Preferred methods can be used to achieve favorable results. But that Depending on whether the surrounding liquid is polar or non-polar, To make the membrane hydrophilic or hydrophobic, for example by treatment with a surfactant compound. The method is preferred.   In another embodiment, the liquid flowing around the microporous membrane is made compatible with the membrane. By including a small amount of the compound, it is adapted to the polarity of the membrane. Therefore, polyps When a porous membrane based on propylene is used, the alcoholic extraction liquid is Very favorable results are achieved by including 0.1-5% by weight of the xane .   Non-thermoplastic polymers such as cuprophane, cellulose acetate Tate, cellulose triacetate, cellulose nitrate, polytetraf Fluoroethylene, polyacrylonitrile or (regenerated) cellulose and heat Plastics such as polyolefins, condensation polymers, oxidized polymers and their Can be used when making a membrane to be used in accordance with the present invention . Examples of suitable polymers for making membranes are low and high pressure polyethylene, polypropylene Ren, polystyrene, polyvinyl chloride, polyvinylidene chloride, acrylo Nitrile-butadiene-styrene-terpolymer, styrene-acrylonitrile -Copolymer, styrene-butadiene-copolymer, poly (4-methyl-pentene) -1), polybutene, polyvinyl butyral, chlorinated polyethylene, polyvinyl alcohol Acetate, polyvinyl alcohol, polymethyl methacrylate, polymethyl Relate, polyimide, polyvinyl disulfide, polyphenylene oxide, Polyethylene terephthalate, polybutylene terephthalate, polyaramid, Tylene terephthalate and polyethylene oxide having a molecular weight in the range of 800 to 6000 Copolyetherester based on oxide glycol, polyamide 6, polyamide 6,6, polyamide 11, polyamide 12, polycarbonate, polyether urea, poly Lipiperazine, polypiperazine amide, polyvinylpyrrolidone, polyethers Rufone, polysulfone and polydimethylsiloxane (PDMS).   The production of microporous membranes from thermoplastic polymers is described, inter alia, in US Pat. No. 4,098,901. It is described in the specification. On the production of hollow fiber membranes from thermoplastic polymers See, for example, US Pat. No. 4,564,488. Polypropylene hollow fiber membrane , Very good results can be obtained.   Hollow fiber membranes are usually arranged in hollow fiber modules. Thus, the gel-forming particles generally flow through the hollow fibers, while the racemic mixture It flows around it. Unlike the separation method disclosed in WO 94/07814 Generally, only one chiral adjuvant is used in the method of the invention . Of course, it would still be possible to use a symmetrical system, for example as described in the literature. It is possible. However, in that case, it differs only by the identification by the chiral adjuvant. Whereas two gel-forming substances must be available.   In general, a macroporous membrane with a minimum thickness, usually in the range of 0.1 μm to 1 mm, is selected. The thickness is preferably in the range of 1 μm to 100 μm.   According to the present invention, it is chiral in itself or covalently linked to a chiral adjuvant. Molecules produced for one of the enantiomers to be combined or to be separated At least one gel former which is an optically imprinted polymer (MIP) There is always quality.   The liquid used as a solvent for the racemate to be separated is a gel-forming It can expand a substance. Generally, one skilled in the art will know which solvent or solvent You will know if you should choose a combination of media.   Chiral adjuvants are incorporated into or are part of the gel-forming substance . Cellulose triacetate is a chiral gel-forming substance by itself. Can be Another example is that the polymer chain has, for example, a chiral diol or Gel forming polyester incorporating dicarboxylic acid. Alternatively, gel formation The substance can be combined with a chiral adjuvant. To optically active monomers and polymers A new synthetic route is described in Kevin D. et al. Belfield et al.,TRIP 3, Vol. 6, No. 6 (June 1995), pp. 180-185. The following compounds (Including their salts and derivatives) are incorporated into gel-forming substances as chiral adjuvants. Suitable for inclusion: 1-aminoethylphosphonic acid, 2-bromopropionic acid, milk Acid, epichlorohydrin, serine, 2,3-diaminopropionic acid, propylene oxide Cid, alaninol, 1-amino-2-propanol, aspartic acid, malic acid, Tartaric acid, 5- (hydroxymethyl) -2-pyrrolidinone, proline, cis-3-hydro Xyproline, trans-1,2-cyclopentanediol, 2-methylbutyric acid, α- Droxyisovaleric acid, methyl-3-hydroxybutyrate, methyl β-hydroxy Isobutyrate, arabinose, lyxose, ribose, xylose, prolino , Alanine ethyl ester, norvaline, valine, methionine, penicillium Methionine sulfoxide, 2-pentanol, 2,4-pentanediol, arabic Thor, 2-methyl-1-butylamine, vallinol, 1,2-diaminocyclohexane , Α-methylbenzylamine, 1-amino-2- (methoxymethyl) pyrrolidine, lysine Arginine, 2-hexanol, 2-methyl-2,4-pentanediol, leucino , 2-fluorophenylalanine, 3-fluorophenylalanine, 5-fluoro Tryp Fan, 5-hydroxytryptophan, 2-benzyloxy-1,3,4-butantrio Isopropyl noradrenaline, 1- (1-naphthyl) ethanol, 1- (1-naphthyl) Fthyl) ethylamine, trans-2-phenyl-1-cyclohexanol, Syn, methyl acetate, N- (3,5-dinitrobenzoyl) -α-phenyl-gly Syn, N-methylephedrine, 3,5-dinitro-N- (1-phenylethyl) -benzami And α, α-diphenylprolinol.   The method of the present invention allows for the separation of racemates with the most widely varying properties. You. This racemate is a compound having a pharmacon group, Synthons, aromatic compounds and fragrances or insecticides.   According to the present invention, a very wide variety of chiral gel-forming substances can be broader or even wider. Chiral gel formers suitable for use in the separation of various racemic mixtures The use of certain combinations of quality and the racemic mixture to be separated is highly preferred. Especially Preferred are chiral polymers which interact strongly with the racemate to be separated It is. Such strong interactions may be due to hydrogen bonding or Coulomb forces and / or Can be due to van der Waals forces but also should be separated, for example One of the enantiomers is easily incorporated into the space of a chiral gel-forming substance It can be due to fact. This condition is disclosed in US Pat. No. 5,066,793. -Type polymers such as cellulose esters Not only does it occur with a polymer, but it is also suitable for molecularly imprinted polymers (MIP). Can be used. MIP is based on Nicholls et al.Trends Biochem . Sci.13 (19 95), pp. 47-51, chemical functionality converted to imprint species functionality A monomer or monomer mixture wisely selected to be complementary to It is prepared by mixing with an imprint molecule in the presence of a suitable crosslinker. Built. The complementary interacting functionalities form a predictable solution structure, That is, after polymerization and extraction of the imprint species, longer due to the imprinted enantiomer Always brings residence time. This effect differs from the enantiomer at the MIP recognition site. Is reflected by the binding affinity. As MIP, O.D. Ramstrom OfTetrahedron: Asymmetry 5 (1994), pp. 649-656. Copolymer of methacrylic acid and ethylene glycol dimethacrylate Good results are obtained with the use of a mer.   Average particle size 1 ~ 200μm and specific surface area 10 ~ 300m^Two/ G, substantially spherical Of finely divided aromatic or aromatic-aliphatic carboxylic acids in the form of partially crystalline particles Examples of particulate cellulose esters are disclosed in U.S. Pat.No. 5,066,793. I have. Specifically, cellulose tribenzoate, cellulose tri (paramethi) Lebenzoate), cellulose tri (m-methylbenzoate), cellulose Tricinnamate, o-methylbenzoyl cellulose, p-ethylbenzoyl cellulose Lulose, p-chlorobenzoyl cell Loose and m-chlorobenzoyl cellulose.   Another group of optically active adsorbents is disclosed in U.S. Patent No. 5,347,042. You. They are derived from sulfur-containing amino acids and have specific esters and amides Groups, especially sterically bulky and rigid ester and amide groups, Sorbent. The crosslinked polymer is preferably in the form of small particles. The degree of swelling of the particles can be determined by using a cross-linking agent such as 1,6-hexanediol diacrylate. And the nature and amount of 1,2-ethylene glycol diacrylate, It can be adjusted by the method. This adsorbent contains amino acids, hexahydrocarbazo Derivatives such as 3-γ- (4-fluorophenylsulfonamido) -9- (2-carboxy Ethyl) -1,2,3,4,4a, 9a-hexahydrocarbazole, benzodiazepine e.g. Oxazepam, arylpropionic acid and its amides such as ketoprofen and Particularly suitable for the separation of ibuprofenamide.   For example, the following chiral gel-forming substances are required to separate the following racemic mixtures: Can be used advantageously:   Incorporation of cyclodextrin, more particularly β-cyclodextrin Where gel-forming epoxy resin or polyurethane. Lasse of Used for the separation of mixtures: antihistamines of the diphenylalkylamine type Agents such as bromopheniramine; methyl mandelate; indole alkaloid Chlormezanone, rolip Rum (rolipram), triazoline; succinimide such as methsuximide (methsux imide) and phensuximide; hydantoins such as mefenit In (mephenytoin); aminoglutethimide; ketoprofen; calcium channel Lublocker (calcium channel blocker) e.g. nimodipin and Verapamil; Methylphenidate; Chlorthalidone; Glutethimide; E; etaqualon and metacharone; steroids such as indenest Roll A (indenestrol A), indenestrol B (indenestrol B) and norge Sterols (norgesterol); insecticides such as EPN, salicion and 3-phenoki Cibenzyl chrysanthemate; praziquante l).   Derivatives of microcrystalline cellulose I, for example   a) Cellulose triacetate for the separation of the following racemic mixture:   β-butyrolactone, ketamine, cyanofenfos, dihydro-3-hydroxy 4,4-dimethyl-2 (3H) -furanone, 4-hydroxy-2-cyclo-pentenone, 4- Phenyl-1,3-dioxane, δ-phenyl-δ-valerolactone, quinazo Linone, 1- (9-anthryl) -2,2,2-trifluoroethanol; Madelinamide , Praziquantel, trans-2,3-diphenyloxirane.   b) Cellulose tribenzoate for the separation of the following racemic mixture:   1-acenaphthenol, 2-acetoxy-1-phenylpropane, benzylmethyls Rufoxide, 1-butynyl-3-benzoate, 1-decalone, 1,3-diacetoxybuta , Dibenzoyloxyalkane derivatives, methylphenylsulfoxide, napro Anilide, 4-phenyl-1,3-dioxane, 1-phenylethanol, 1-phenylp Lopanol.   c) For separation of the following racemic mixture, use cellulose trisphenylcarbamate G:   Acephate, alboatrin, benzoin, benzoin ethyl Ether, benzylvinyltolyl sulfoxide, catechin, cholylrubin , Coridarin, 2-cyclopenten-1-one-4-acetic acid ester, 1,3-di (9-anth Ril) butanol, 2,2′-dihydroxy-6,6′-dimethylbiphenyl, DIOP, Guaifenesin, α- (1-hydroxyethyl) naphthalene, isofenphos, Isoprothiolane sulfoxide, β-lactam, laudanosine, oxazepam , 2-phenylcyclohexanone, 2-phenylpropionic acid, phosphinoxide, Sulphilimine, sulfoxide, tetrahydrochrysamine (tetra hydrocrysamine), tetrahydropalmatine, salictravine, Warfarin.   For the subsequent separation of the racemic mixture, biopolymers such as albumin and acid α -Glycoprotein:   β-blockers; local anesthetics such as bupivacaine and prilocaine; Azepines such as oxazepam; Pyramides and tocainides; anticoagulants such as warfarin; NSAID examples For example, ibuprofen, fenoprofen and naproxen; atropine, chestnut Dinium, mepenzolate, oxyphencyclidine; anti-neoplastic Rukyating agents such as cyclophosphamide; verapamil; histamine antagonist Chlorpheniramine, bromodiphenhydramine, Lomethazine, mianserin; doxylamine; cocaine, butorphanol, Tadone, propoxyphen and pentazocine; ephedrine and pseudo- Ephedrine; catecholamines such as dobutamine; terbutaline; phenmet Razine (phenmetrazine).   For the subsequent separation of the racemic mixture, an amylose gel such as amylose carb Mate:   Chlorpheniramine, dihydropyridine, dimethothiazine, NSAIDs such as Flurbiprofen, ketoprofen and ibuprofen, methylsuccinimi Acid (methyl succinimic acid), 5-norbornene, p-cyclophane, 2-phenylbutyric acid, 1-phenyl-1,2-ethanediol, porphyrin, promethazine Sulindac methyl ester, thiaprofenic acid, 1,1,1-trichloro-2-heta Hetanol, 4-acetoxy-2-azetidine, afloquanone, 2-chloro-2-  Butanone, 2-cyano-4-phenylbutyric acid, ethiazide, ofloxazine methyl Steal.   For separation of the following racemic mixture, polymethylmethacrylate Rate-based gels:   Binaphthol and tocopherol.   .BETA.-Sympathicomimetic and .BETA.-Sympathicomimetic Ethanolamines, amino acids and ants such as tic (β-sympathicolytic) Tartaric acid, mandelic acid or amino acid derivatives Gels based on polyurethane modified with.   To separate racemic mixtures of amino acids, D-glucosamine-modified polyacyl Gel based on Lilamide.   The method of the present invention can be performed by a single countercurrent extraction, but is preferably This is performed using a number of extraction units connected in series. Expanded gel with maximum pore size Embodiments using hollow fiber membranes that are smaller than the smallest diameter of the particles are preferred. Good. Best results are obtained with closed shell and closed lumen operation Obtained by convection in a macroporous polymer module.   The present invention is further described by the following examples. Here, among other things, the invention > 99% when separating two enantiomeric mixtures using the method of It is shown that purity is obtained. Further, to further illustrate the present invention, a number of The figure is included. Of course, a non-limiting example is a better understanding of the invention. Only given for solution.   FIG. 1 shows the hollow fiber module assembly used in the experiment described in Example II. Indicates assembly.   FIG. 2 shows the hollow fiber module assembly used in the experiment described in Example V. Indicates assembly.   FIG. 3 shows the hollow fiber module assembly used in the experiment described in Example VI. Indicates assembly.   In FIG. 1, the above-mentioned hollow fiber module has a socket 7 at both ends via a yarn. Or a tubular case 1 connected to an end cap 8. Case 1 is longitudinal The hollow end is partially filled with a hollow fiber 4, the hollow end of which is filled with epoxy potting (p otting) Open to 5 and 6. The hollow cap 8 above the potting , Connections 9 and 10 through which the suspension is pumped through a pump 23. It is kept in a fixed movement. The cap 8 is further connected to the container 11 via a pipe and a pump 12. Combined, the container 11 contains a suspension held in constant motion by a magnetic bar 13.   During the experiment, the suspension was removed from the container 11, pump 12, cap 8, fiber 4, socket 7 To the container 15 via the fiber 4a, the cap 8a, and the pump 14. Solvent in container 16 Is connected to the shell end of the fiber 4a via the pump 17, the side connection 2a, and the pump 18 At the shell end of the fiber 4 and via a pump 19 ends in a container 20. Racemic in container 22 The solution of the mixture is sent to the socket 7 via the pump 21.   FIG. 2 shows the configuration of eight modules. Each module is connected at two ends Consists of a 254 mm long glass tube. The inner diameter of each glass tube is 10 mm, The effective length during the knot is 200mm. Each module is oxyphane Includes hollow fibers 300 of (Oxyphan) Ox-pp5045 / 02.01. The inner diameter of each fiber is 280μm , And the outer diameter is 380 μm. The fibers are bundled in a mat shape. During the experiment, The medium flows from the container 1 to the module case 9a via the pump 5 and the entrance 10a at the lumen end. Proceeding and left the case via the connecting portion 12a. Solvents, in a similar manner, the other seven Passed through the lumen of the module and ended up in the container 2 via the pump 6. In container 3 The suspension is passed through the pump 7 and the shell end connection 13h to the shell end of the module 9h. Proceeding to the connection, it left via the shell end connection 11h. Next, the other seven suspensions Through the shell of the module in a similar manner, ending in the container 4 via the pump 8 Was.   FIG. 3 shows the configuration of eight modules of the same type as FIG. Magnetic in container 1 The stirred suspension is recirculated via pumps 2, 4, 5 and 6 to remove the solvent Regeneration modules 9a and 9b, stripper modules 9c and 9d, extraction module Rules 9e and 9f and wash modules 9g and 9h, respectively. Cleansed The suspended suspension is returned via the pump 8 and ends in the container 1. The cleaned solvent is Leaving the cap 19 and flowing to the solvent supply vessel 10 via the pump 20. Melt in container 22 The dissolved racemic mixture is sent to the system via a pump 21.   The poorly retained solution of the enantiomer was added between metering pumps 16 and 18. Is collected in a container 17 using the flow rate difference at Of the more strongly retained enantiomer The solution is weighed Using the difference in flow rates between pumps 13 and 15, collected in a similar manner to vessel 14 You.Example I   R- and S-ketamine. For racemic HCl, how much more than the R-configuration Many S-configurations form a suspension of expanded cellulose triacetate (CTA-I) particles. First, it was measured at room temperature to determine whether or not it was incorporated. CTA-I (from Fluka) expands It consisted of a sieve fraction of 15-25 μm particles in the unwashed state. 70 ° C Etano After cooling and decanting, the volume at room temperature was 25 ml. A suspension of expanded particles having / 10 g was obtained.   Ten suspensions were prepared, each containing about 250 mg of expanded CTA-I particles and about 1 mg Tamin. HCl / ml alcoholic solution neutralized with sodium carbonate 90, 96 and 100% ethanol, and 90, 96 and 100% 2-propano, respectively 750 mg).   After shaking for about 5 minutes at room temperature, the suspension was allowed to settle. The above liquid The product was filtered through a filter paper having a pore size of 0.5 μm, and the concentration of the ketamine enantiomer was measured. Filtration was measured on the filtrate using Pilarizone electrophoresis. In this analysis, The alcoholic solution used to prepare the suspension was used as an external standard for filtration. The ketamine enantiomer content in the liquor was calculated.   In the table below, ket.HCl is ketamine. HCl, ETOH stands for ethanol and IPA stands for 2-propanol.   The control solution contained 1.17 g of ketamine. HCl / ml ETOH and 1.02 g ketamine. H Each containing Cl / ml IPA. Measured amounts and R- and S-enantiomers in the liquid phase The calculated amounts of R- and S-enantiomers in the CTA and CTA-I phases are shown in Table 2. Example II   R- and S-ketamine. A racemic mixture of HCl is added to two serially connected Separation using empty fiber modules 1 and 1a (having an inner diameter of 23 mm and a length of 155 mm) Released. Each module has 2100 porous polypropylene fibers (240 μm inner diameter) To). Prior to starting the passage of the dispersion, fill the device with solvent and apply Degassed at the shell edge by application. The solvent here is 96% ethanol and 4% 0.01M Na_TwoHPO_FourIt was a mixture consisting of an aqueous solution. The dispersion of gel particles is It consisted of CTA-I particles having the same dimensions as Example I.   The dispersion is subjected to ultrasonic vibration to prevent the hollow fibers from clogging due to particle agglomeration. I did. For the same reason, the modules are arranged vertically and the dispersion is modular from top to bottom. Through the wool. In addition, the dispersion is kept in motion beyond potting Two membrane pumps 23 and 23 to ensure pulsation and create a pulsed flow in the lumen. And 24. After 80 minutes, the amount of solids decreased from about 11.1% to about 8% by weight. The concentration of the feed in the channel connected to the lumens of the two modules is the first 30 minutes The interval was 1 g / 100 ml. After 50 minutes, use feeds of different composition, which also , Containing the salts used to neutralize. This solution contains 1 g / 100 ml of ketamine . It contained NaCl. After 87 minutes, the device was flushed with ethanol. 5 The measurement data collected by minute sampling and analysis is shown in the table below. ee^R% Refers to the percent of enantiomeric excess, which for the (R) -enantiomer When defined, read as: ee^R% = (C^R-c^S) / (C^R+ c^R) X 100% (where c^R Is the concentration of the (R) -enantiomer in mg / ml). Example III   In a manner similar to that disclosed in Example I, racemic 4-phenyl-1,3-dioxane For the mixture, at room temperature, how much more the (-)-configuration than the (+)-configuration expanded It was determined whether it was incorporated into the suspension of cellulose triacetate (CTA-I) particles. The eluent used was 96% ethanol. A sample of the suspension was 1 g of CTA-I And 7 g of 96% ethanol, where 1.16 mg / ml of (±) -4- Nyl-1,3-dioxane had been dissolved. After shaking for 1 hour at room temperature, the suspension is It was in a stable state.   Use an analytical column containing CTA-I for enantiomer identification and concentration determination References by R.M.Wolf and E.FrancotteJ.Chem.So c.Perkin Trans.II (1988), pages 893-901.   After 1 hour, the upper liquid contained 0.43 mg / ml of (+)-4-phenyl-1,3-dioxane and 0 It contained .26 mg / ml of (-)-4-phenyl-1,3-dioxane.Example IV   The experiment of Example III was repeated, except that the gel-forming chiral used was The adjuvant is tribenzoylcellulose, which is available from K.H. boeck)J.of Chromatography, Vol. 351 (1986), pages 346-350. So got. Tribenzoyl cellulose Has the opposite affinity to that of CTA-I and, consequently, in the liquid and gel phases. It was found that the concentrations were distributed in reverse. A sample of the suspension was 1.0 g Of cellulose (CTB) and 7 g of 96% ethanol, wherein 1.16 mg / ml (±) -4-phenyl-1,3-dioxane was dissolved.   After 1 hour, the upper liquid contained 0.37 mg / ml of (+)-4-phenyl-1,3-dioxane and 0 It contained .40 mg / ml of (-)-4-phenyl-1,3-dioxane.Example V   The following example describes a 50/50 mixture of enantiomers of 4-phenyl-1,3-dioxane. Separating the counter-current mixture using the hollow fiber module configuration shown in FIG. It shows that it is possible by subjecting to separation. In that case reference numbers 9a, 9b, The columns labeled 9c, 9d, 9e, 9f, 9g, and 9h have eight columns connected in series. 3 shows an empty fiber module. Hollow fiber module has an inner diameter of 10mm and an effective length of 200m had m. Each glass module has its inner and outer diameters during epoxy potting. 300 porous polypropylene fibers (Oxyphan®) with diameters of 280 and 380 μm, respectively. x-pp5045 / 02.01). Hollow fibers are knitted with one stitch per cm It was bundled with a machine. Fluid flow from vessel 1 (solvent) and vessel 3 (suspension) Through the module shell and lumen, a back pressure valve installed at the end of the separation column Have Supplied by four membrane pumps. A pair of pumps 5 and 6 in the lumen flow A series of pumps to provide simultaneous membrane beating during pumping and to create a pulsed flow in the lumen. Was tied. A pair of pumps 7 and 8 in the shell flow are operated simultaneously in the same manner. I let you. Fluid displacement on the luminal side, together with the displacement of the suspension on the shell side, is 20 minutes per minute. Changed times. Bubbles of air are used to recirculate the solvent through the buffer vessel and the second buffer volume. Discharged by recirculation of the suspension through the vessel. Liquid in each buffer vessel during recirculation Was kept constant. Wherever you need it, The difference in pump discharges was reduced by adjusting the pump stroke volume.   Used to separate racemic (±) -4-phenyl-1,3-dioxane The liquid consisted of 96% ethanol. The separation was performed as described in Example I. This was performed using a suspension of CTA-I in the same proportion as described above. The suspension is 700 g ethanol-water It consisted of a mixture of 100 g of CTA-I in the mixture (96 + 4).   Subject the suspension to ultrasonic vibration and sieve to prevent clogging through particle aggregation. Divided. For the same reason, arrange the modules vertically and pour the suspension from top to bottom Passed through the module. Settling of the suspension will affect movement in the tubes and modules. Blocked by giving Ruth.   1 g of a racemic compound of 4-phenyl-1,3-dioxane is added to a suspension having the above composition. By adding the extraction process Started. Table 4 shows the measurement data collected by sampling and analysis every 5 minutes. Shown in ee⁺% Refers to the percent enantiomeric excess, which is the (+)-enantiomer When defined for, read as: ee⁺% = (C⁺-c^-) / (C⁺+ c^-) X 100% (this Where c⁺Is the concentration of the (+)-enantiomer in mg / ml). Example IV   In the following examples, enantiomeric mixtures have the configuration schematically shown in FIG. It proves that it can be separated into (+) and (-) components. In this configuration , The suspension in the container 1 is recirculated, and Pass through the shells of tools 9a and 9b, where the remainder of one of the enantiomers passes through the lumen It is removed from the solvent flowing through it. Next, the suspension flow is divided into two extraction modules 9c and 9d, stripper modules 9e and 9f, and wash module 9g and 9g And 9h shell. From there, the enantiomer-free suspension is Proceed to 1. Vertically, enantiomer-free solvent is pumped from vessel 10 through pump 11. Pass through the lumen of the washing module 9h and 9g, where it contains one of the enantiomers The suspension contains substantially all of the enantiomers absorbed by the chiral adjuvant. It is washed to be re-released and a portion of it is strippered before ending in container 14. Through the lumens of the modules 9f and 9e countercurrently. Stripper module Between 9e and 9f and the extraction modules 9c and 9d, the racemic mixture in vessel 22 Exposure using pump 21. From 9c, luminal flow passes through pump 16 to vessel 17 From which, due to the difference in pump discharge between pumps 16 and 18, liquid Part is advanced into the lumen of the solvent regeneration modules 9b and 9a.   The equilibrium data of Example III and those of Giuseppe Storti et al. ,Ind.Eng.Chem.Res ., 34 volumes, 28 Extraction module and strip using the design process disclosed on page 8-301 (1995). By setting the flow ratio in the Par module, the complete separation of the racemic mixture Separation is obtained.   The average flow rate of the suspension in the mechanism shown in FIG. It is held constant and equal for each module by a similar changing pump operation. The solids flow can be calculated from the suspension flow.   The average liquid flow rate is set per module part and the difference in liquid flow rate between parts Is compensated by the solvent, raffinate, feed, and extract stream. Net liquid flow Is calculated from the countercurrent suspension flow rate and the liquid flow rate. Net liquid flow and solids The flow rate is a parameter used in the design process described above.   By adjusting the flow ratio within a certain range, the module part It can be used as a stripper, extractor or solvent regenerator.   The systems disclosed in Examples III and V, with an average flow rate of the suspension of 10 ml / min, were as follows: Requires a typical average liquid flow rate: 28 ml / min liquid for the wash module, 13.9 ml / min for the tripper module, 14.1 ml / min for the extraction module, And 4 ml / min for the amount of regeneration solvent. Final streams of raffinate, feed and extract They are 14.1 ml / min, 0.2 ml / min and 10.2 ml / min, respectively.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI // C07M 7:00

Claims (1)

[Claims] 1. One is the liquid in which the racemic mixture to be separated is present and the other is the chiral Using at least two substances containing adjuvant, the countercurrent extraction In a method of separating enantiomers from a mixture, the chiral adjuvant comprises a liquid Or part of a gel-forming substance in the form of discrete particles in it. (Where the gel-forming substance flows countercurrently containing the racemate to be separated) Gel-forming particles separated from the liquid by extraction can no longer penetrate the pores. Are separated by a microporous membrane with a pore size of To release one of the enantiomers therefrom, after which the particles are reinserted into the extraction process. The method characterized in that it may be performed. 2. After being released from the gel-forming particles, the enantiomers can be extracted or not extracted. The process according to claim 1, wherein the purification is carried out by evaporation and / or crystallization of the extractant. 3. 2. The method of claim 1, wherein the chiral adjuvant is covalently bound to the gel-forming substance. Method. 4. A chiral adjuvant is prepared for one of the enantiomers to be separated 2. A gel-forming substance in the form of a molecularly imprinted polymer (MIP). the method of. 5. The method of claim 1, wherein the gel-forming particles are in an expanded state during the extraction. 6. The stimulus that one of the extracted enantiomers is released from the gel-forming particles Changes in temperature, pH, salt concentration, electric or magnetic field and / or solvent composition The method of claim 1 in the form. 7. 2. The gel-forming particles according to claim 1, wherein the gel-forming particles are provided in or on the pores of the carrier. Method. 8. The method of claim 7, wherein the carrier comprises porous polymer particles. 9. The method of claim 1, wherein the microporous membrane comprises microporous polypropylene. Ten. The method of claim 1, wherein the microporous membrane is in the form of a hollow fiber. 11． The liquid flowing around the microporous membrane may contain small amounts of compounds that are compatible with the membrane. 2. The method of claim 1, wherein the method is adapted to the polarity of the membrane. 12． The surrounding liquid may be polarized or non-polar Depending on whether the microporous membrane is hydrophilic or hydrophobic by a chemical route. The method of claim 1 wherein the method is performed. 13. Depending on whether the liquid flowing around is polar or non-polar, Microporous membranes can become hydrophilic or hydrophilic by physical denaturation, including treatment with surface active compounds. The method of claim 1, wherein is made hydrophobic.