GB2233248A

GB2233248A - Enantiomer enrichment by membrane processes

Info

Publication number: GB2233248A
Application number: GB8913065A
Authority: GB
Inventors: Charles Linder; Mara Nemas; Mordechai Perry; Reuven Ketraro
Original assignee: Aligena AG
Current assignee: Aligena AG
Priority date: 1989-06-07
Filing date: 1989-06-07
Publication date: 1991-01-09
Also published as: GB8913065D0

Abstract

A continuous membrane adsorption/desorption or permeation process is provided which involves the enrichment/ separation of enantiomers from racemic mixtures. Suitable membranes used are of essentially chiral polymers, such as optionally chemically modified chiral polysaccharides or chiral acrylic polymers. The process is effected by the selective interaction between the chirality centers of the polymer membrane and the enantiomers, and further by transmembrane concentration and pressure differences. The process can be used for the treatment of any racemic mixtures and leads to high rates of enrichment/separation of the optical isomers. <IMAGE>

Description

Enantiomer Enrichment by Membrane Processes The present invention relates to the field of separation of optical isomers, and more specifically, to a continuous membrane adsorption or permeation process for enriching enantiomers from a racemate.

Pairs of chemical molecules that are nonsuperimposable and are the mirror images of each other are called enantiomers. A mixture of two enantiomers in equal molar proportions possesses no optical activity, since the rotations exactly cancel each other. Such a mixture is called a racemate, and is also referred to as a d,l-mixture.

Enantiomer enrichment is important from an economic point of view as it reduces the quantity of material needed. It is also of health and environmental benefit as less non-active or even slightly active but non-beneficial enantiomer is incorporated in or spread through the environment.

For separating an optical isomer various methods are known in the art including a crystallisation process, an enzyme process or a chromatographic process. The preferred methods for separating said isomers are usually based on chromatography. Such methods, however, are not very efficient in that they suffer e.g. from being non-continuous and not easily upscalable Further, most of the chromatographic processes for optical resolution of racemates which have been proposed, utilize a ligand-exchange process.

Accordingly, it is required to use an eluent containing a metal ion or another optically active compound.

In order to overcome the problems of chromatography and to provide a continuously driven, easily upscalable process with good resolution capacity it was found that these advantages can be achieved by the inventive process for enantiomer enrichment in which membranes essentially consisting of chiral active polymers are used.

Accordingly, it is one object of the present invention to provide a continuous membrane adsorption or permeation process for enriching enantiomers from a racemate which comprises - passing a feed solution containing the racemate in contact with at least one side of a membrane of essentially chiral polymers, - maintaining the feed solution in contact with a dense membrane for sufficient time to effect selective permeation of a quantity of the feed solution through the membrane, optionally to a sweep solution which is simultaneously passed in contact with the other side of the membrane, or to have selective adsorption of a quantity of the feed solution onto the surface of the dense membrane or within the pores of a porous membrane through which the feed solution passes, - effecting removal of the permeate or of the sweep solution containing the permeated portion of the feed solution from the contact with the membrane or desorption of the adsorbed portion of the feed solution from the membrane, the permeated or adsorbed portion of the feed solution being enriched in at least one enantiomer, and - optionally recovering the enriched enantiomer.

Another object of the present invention is the use of the inventive process for separating/enriching active enantiomers from racemic mixtures of e.g.

technical application products or pharmaceutically or agrochemically useful chemical compounds.

The modes of performance of the inventive process will become apparent more fully from the following description.

In one mode the racemic mixture is contacted with a membrane which through (selective adsorption and) selective permeation enriches the material (feed) passing through the membrane in one enantiomer. This may be effected e.g. by transmembrane concentration (transport through the membrane by a kind of dialysis/diffusion process) and/or pressure differences and of course the interactions of the chirality centers of the polymer membranes and the enantiomer.

Another mode relates to a selective adsorption of a feed onto the membrane or within the pores of a porous membrane and its desorption for enriching the enantiomer.

The inventive process utilizes membrane material based on chiral active polymers wherein the monomer unit of the polymers is chirally active itself and the membrane is formed from these polymers. The chiral activity may be contained within the monomer as a portion of the polymer backbone or as a pendant. The polymer should be soluble so as to form the membrane, but it may be crosslinked and made insoluble afterwards.

The membrane may be prepared from a single chiral polymer, a mixture of chiral polymers, or a chiral polymer combined with non-chiral polymers.

Preferred are membranes of a single chiral polymer or of mixtures thereof.

In order to be effective, the membrane must only contain selective transport pathways. This generally requires a minimization of non-selective transport by, for example, convective flow through pores without solutemembrane interactions. Enantiomeric resolution requires, however, a diffusion transport mechanism with membrane-solute interactions.

If the membrane does not have convective transport of the chiral solute then enantiomeric enrichment will be possible. Diffusion with chiral selective interactions between chirality centers of the polymer membrane and an enatiomer are important for achieving good separation and enrichment.

In one alternative of the permeation mode the inventive process comprises - passing, optionally by recycling, a feed solution containing the race mate in contact with one side of a dense membrane of essentially chiral polymers, - simultaneously passing a sweep solution in contact with the other side of the membrane, - maintaining, optionally by recycling, the feed and the sweep solution in contact with the membrane for sufficient time to effect selective permeation of a quantity of the feed solution through the membrane to the sweep solution, - removing the sweep solution which is enriched in at least one enantiomer, and - optionally recovering the enriched enantiomer therefrom.

In this permeation mode an aqueous or organic solution (feed) containing the racemate is passed over the surface of a dense membrane which is in the form of a flat sheet, tubular, tubelet, sprial would, or hollow fiber.

On the second side of the membrane, a solvent not containing enantiomer, is passed. The enantiomer that permeates through the membrane is taken up by this solvent (sweep solution) and the so-called permeate (solution) is formed. The feed and permeate solutions may be cycled once over their respective membrane surface or they may be recycled. The permeate is collected and enriched in the enantiomer which preferentially passes through the membrane. The feed solution, on the other hand, is enriched with the other enantiomer. The feed and permeate solutions are of the same solvent or when different solvents are used, they should be nonmiscible to prevent mixing.

It is found that the enrichment is greater at the beginning of the permeation process, e.g. within the period of the first two hours, and decreases as the sweep solution (permeate) increases in concentration.

The permeate can still be less than for example 10% of the feed in concentration and in most cases less than 1% of the feed, but nevertheless the enrichment factor drops. It appears that this decrease in enrichment is not only a simple function of the difference in concentrations across the membrane, as the concentration difference across the membrane remains large for both enantiomers. It is nevertheless found that if the permeate is removed after a given period and a fresh solvent not containing enantiomer is put in its place, and if the feed is left unchanged, the enrichment of the permeate begins again at the same high value and declines as before. This process of permeate removal, putting in fresh solvents and enantiomer enrichment can be repeated any number of times until the feed is depleted.It is found that the sweep solution which is enriched in at least one enantiomer can continuously or periodically be removed from the contact with the membrane. The periodic removal is governed by the rate of enrichment which decreases as the sweep solution (permeate) increases in concentration.

It is further found in many adsorption experiments that the enriched enantiomer is the one preferentially taken up. The process of continuous renewal of the enrichment by replacing the permeate indicates a continuous membrane process wherein - apart from the difference in chemical concentrations between feed and sweep solutions - only the interactions of the chiral sites (chirality centers) of the membrane as mediator for enantiomer recognition effect the selective mode of transport, and where there are no other nonselective pathways in the membrane. The fact that the membranes operate in a continuous mode is one basis of the inventive process.

Thus a process for enantiomer enrichment can be designed wherein a feed solution is passed over one side of the membrane and a sweep solution (which takes up the permeate enantiomer and becomes the permeate solution) over the other side. After a period of time (e.g. 1 to 120 minutes, preferably 1 to 10 minutes), the permeate is pumped out and fresh solvent is put in. The time before an unacceptable drop in permeate enrichment occurs must be determined experimentally and may vary from minute(s) to hours or days. In the process of sweeping fresh permeate over the downstream side, rapid replacement of the permeate in the order of minutes (1 to 5 minutes) is desirable if the concentration in the permeate is high enough (economically) to collect as much enriched material in the shortest period of time.

The permeate solution with the enriched enatiomer may be handled in several ways: It may be used as the feed of a second permeation unit. Because the membrane process works by having a selective adsorption of the enantiomer that is preferentially transported, the second permeation process will be even more efficient and a further enrichment will occur. This can be repeated with any number of units.

It should be appreciated that if the material which is preferentially transported is not selectively taken up but only selectively diffused across the membrane, its enrichment in subsequent stages will not be as great as when it is selectively taken up.

The problem in this scheme is that the permeate solution is significantly more dilute than the feed. Thus the driving force of permeation, which is a concentration difference, is less and the time of separation longer.

This loss of driving force can be overcome by placing a concentration step (for example solvent evaporation or membrane concentration of the solute) between the permeate and feed of different permeation units.

Secondly, the permeates can be processed to remove the enriched enantiomer and the purified permeates (solvents) can be cycled back to the permeation unit as a replacement for the permeate being used. In the permeation process the membranes must be dense so as not to contain nonselective convective pathways.

The permeation mode of the inventive process can be carried out as a pressure driven process (like a reverse osmosis process) too, wherein a feed solution flows, under pressure, over the upstream side of the membrane. There is then no sweep solution on the downstream side of the membrane. The permeate is collected enriched in one enantiomer. Since the membranes are dense, high pressures of 5 to 300 bars, preferably 10 to 100, and most preferably 10 to 60 bars, have to be applied to achieve practical fluxes.

These dense membranes may be composite membranes having a thickness of about 0.01 to 20 jim which are cast on a microporous support having a thickness of about 10 to 5000 Xm.

In the selective adsorption/desorption mode the inventive process comprises - passing a feed solution containing the racemate in contact with at least one side of a membrane of essentially chiral polymers, - maintaining, optionally by recycling, the feed solution in contact with the dense membrane for sufficient time to effect selective adsorption of a quantity of the feed solution on the surface of the dense membrane or within the pores of a porous membrane through which the solution passes, - effecting desorption of the absorbed portion of the feed solution from the membrane by a solvent capable to remove, optionally by recycling, the adsorbed portion of the feed solution, which portion being enriched in at least one enantiomer, and - optionally recovering the enriched enantiomer therefrom.

In this selective adsorption/desorption mode of the inventive process one or both sides of the membrane can be subjected to a flow of the same solution of racemate, preferably by recycling. After a given period of time, the solutions are removed and a desorbing solvent is passed over the same membrane surface(s). This solvent is designed to remove the adsorbed enantiomeric compounds. Since the membranes have a preferential adsorption, the desorption solution will be enriched by one enantiomer while the original feed solutions will be enriched by the other enantiomer. The desorbing solvent may be different from the solvent of the original feed solution but is preferably the solvent used in the feed solution.

In this approach the membranes may be dense or porous. In porous membranes the feed flows through the membrane and the selective absorption is on the chiral polymers -that form the pore walls.

The solvent may be non-polar or polar and should be capable of dissolving the racemates. Mixtures of solvents (organic/organic or organic/aqueous systems for example) can be used likewise and also pure aqueous systems are suitable.

The preferred solvents or mixtures can be taken in part from chromatography experiments. The solvents giving the best resolution or selectivity for the given polymer in chromatographic separations can be used in the membrane process using the same polymer in a membrane configuration. Besides allowing for selective adsorption the solvents must allow for swelling.

Too much swelling however will reduce selectivity while too little may not allow solute passage.

As indicated the membranes used for the adsorption process may be either dense or microporous. For dense membranes more time for diffusion through the bulk of the membrane must be allowed. In addition the rate is also determined by the concentration of solute in solution. Adsorption rates are well known to be a diffusion limited process in both the membrane and through the bulk of the solution. Dilute solutions are known to have low adsorption rates.

If, however, solution is pumped (1 to 50 bars) through the pores (0.01 to 10 pin) of a microporous membrane constructed of selective enantiomeric polymers, then dilute racemic solutions may be used as the enantiomers are forced through micron sized pores and selectively taken up by the chiral polymers of the pore walls. In addition the time for selective diffusion through the thickness of the membrane and for reaching saturation in the bulk of the polymeric membrane material is reduced. Thus a rapid adsorption/desorption process can be designed for microporous membranes rather than with dense membranes.

The use of microporous membranes in the adsorption/desorption mode would also be beneficial over particles in that rates of adsorption are limited by the unstirred diffusion layer around the particles. Microporous membranes would thus have faster adsorption/desorption rates because the solute is forced through pores smaller than the diffusion layers around particles. Membranes would also be more easily handled and pumping through their large area surfaces would be faster and require less pressure than particle beds which are usually thicker.

Depending on the solvents used in the feed and permeate solutions the inventive process can be carried out at temperatures in the range of from -200C to +800C, and preferably from +150C to +300C.

Preferred polymeric materials that are useful for preparing the inventively used membranes are chiral polysaccharides, which are optionally chemically modified, or chiral acrylic polymers.

Suitable polymers are polysaccharides, especially cellulosic derivatives, such as cellulose di- or -triacetate (G. Hesse et al. Chromatographia 6, 277 (1973)), cellulose tribenzoate, cellulose triphenylcarbamate, cellulose tribenzoylether and cellulose tricinnamate (A. Ichiada et al.

Chromatographia 12, 280 (1984)); phenylcarbamates of cellulose, xylan, amylose, amylopection, chitosan, chitin and other polysaccharides; pullulans, agarose and alginic acid (Y. Okamoto et al, JACS 106, 5357-5359 (1984)); further cellulose nitrates; polytriphenylmethylmethacrylates (Y. Okamoto, JACS 103, 6971 (1981)); polymers of optically active acryl and methacryl amides (Angew. Chem. 92, 14 (1980)); acyl (RCO-, R is e.g. alkyl and aryl) or carbamoyl (RHNCO-) substituted celluloses are the preferred polymers used for preparing the inventively used membranes.

Crystallinity of the polymers is not necessary for chiral resolution.

Experiments have indicated that at least higher order structures are required, at least for polysaccharides and their derivatives, to achieve chiral resolution (JACS, 106, 5357-5359 (1984)).

As chiral acrylic polymers there can be mentioned polymerised esters of methacrylic acid (such as methyl, tert.-butyl or benzyl esters); polymers obtained from (S)-(-)-a-methylbenzylmethacrylate and maleic anhydride; helical poly- (tritylmethacrylates).

Further suitable polymers for preparing membranes that can be used in the inventive process are e.g. helical polyisocyanides; helical polychlorals; polyamides, obtained by free-radical polymerisation of 2,4-pentadienonic acid in the presence of (S)-(-)-2-phenylethylamine; polydienes obtained by polymerisation of optically active (R)-2,3-pentadiene using -allyl- nickel iodide; or polyacids obtained by photopolymerisation of unsaturated dicarboxylic acids in the crystalline phase; or optically active homopolymers based on vinyl carbazole or m-tolylvinylsulfone (G. Wulff, Angewandte Chemie, Int. Ed. Engl. 28, 21-37 (1989)).

The formation of membranes may be made by casting a polymer solution into a membrane form and evaporating the solvent. As previously mentioned, these forms may be: flat sheets, tubulars,tubelets, spiral wound or hollow fibers.Alternatively, but less preferred, the polymer may be extruded as a hot melt. This last step process requires a heat stable polymer at the temperature of extrusion. In solvent casting of membranes, the solvent is expected to have an effect on the trial membrane structure after drying and hence, on the membrane selectivity and strength. In chromatography, for example, resolution is known to be a function of the solvent used to coat the polysaccharides on silica particles (T. Shibata et al, Chromatographia, 24, 552-554 (1987)). Depending on the polymer, different solvents alone, or in combination, may be used to give membranes with the optimum results.Examples of solvents (suitable for cellulosic derivatives) are: the halohydrocarbons such as dichloromethane, chloroform, dibromomethane, dichloroethane; toluene, tetrahydrofuran, benzene, N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, etc. and solvent combinations containing solvents and non-solvents. Examples of solvent combinations are: dichloromethane-trifluoroacetic acid and dichloromethane-phenol. The membranes may be cast alone without support or may be cast on a support. The supports may be of woven or non-woven materials, and of the microporous or ultrafiltration type. The most preferred are microporous membranes.Porous woven or non-woven or microporous substrates include: cellulosics, polyethylenes, polypropylenes, polyamides (nylon), vinyl chloride homo- and copolymers, polystyrenes, polyesters, such as polyethylene terephthalate; polyfluoro materials, such as polyvinylidene fluoride, polytetrafluoroethylene; glass fibers, porous carbon, graphite, inorganic membranes based on alumina and/or silica (optionally coated with zirconium oxides).

Any of the membrane-forming materials may be used for the microfilter or ultrafilter membranes. For example: olefin homo- and copolymers, acrylonitrile homo- and copolymers, polyamides, polyvinyl chloride homo and copolymers, cellulosics, epoxy resins, polyarylene oxides, poly carbonates, polyether ketones, polyetherether ketones, polyheterocyclics, copolymers containing heterocyclic rings, polyvinylidene fluoride, polytetrafluorethylene, polyhexafluorpropylene, polyesters, polyimides, aromatic polysulfones and polyelectrolyte complexes. It is, of course, to be understood that homo- and copolymers may be used even where not specifically mentioned. The term "copolymers" includes not only copoly mers of two monomers but also terpolymers, quadripolymers and those made from five or -more different monomers. Porous metals and ceramic sub strates (e.g., those made from silica, alumina, titanium oxide, zirconium oxide, etc. or glass), may be used as an alternative to those made from synthetic or artificial polymers. Preferred substrate membrane forming materials are: cellulosics, polyacrylonitriles, aromatic poly sulfones, polyamides, polyvinylidene fluoride, polytetrafluorethylene and polyether ketones, as well as metal, ceramics and glass.

The microfilter (MF) membranes are defined as membranes with pores in the range of 0.05 to 10 um. UF membranes have pores of 0.001 to 0.1 pin.

Both MF- and UF-membranes may be symmetric, asymmetric, unsupported, or on a non-woven support. The dense enantiomeric selective coating may be on one or-both surfaces of the MF, UF or non-woven support.

If coated on both surfaces, the two coatings may be separated from each other by the support material. Both surfaces may be connected to each other by the coating materials which can penetrate from one side to the other through the pores.

One of the preferred embodiments of the inventively used membranes is for the coating of selective materials to be coated on either side of an MF-support with the coating material penetrating the pores, thus connecting both coating surfaces. Quite often, a supported dense layer is necessary because the unsupported membrane of the selective materials are mechanically weak.

If the polymeric material is sufficiently strong, it may be cast as a dense, non-supported membrane in the different configurations described above. The non-supported membranes may have thicknesses varying from 5 to 5000 pm. Alternatively, the material may be cast as an asymmetric membrane of a dense 5.0 Sum or less layer on a porous support according to known processes for making asymmetric membranes. Such casting technology is well documented within the state of the art.

Cellulosicsand polysaccharide derivatives for chromatographyhave demonstrated selectivity for many enantiomeric compounds. Some of the compounds which may be separated are cited in the aforementioned references.

To demonstrate the principle of the invention d,l-stilbene oxide is used as a model compound. In one experiment it is placed on one side of a permeation (dialysis) cell composed of a 19.5 cm membrane area separating two 45 ml compartments. The material of which the cell is constructed is polytetrafluoroethylene (Teflon) and both sides are stirred with Teflon-coated magnetic stirrers. The inventive process should not, however, be limited to stilbene oxide as exemplified by the flat sheet analysis configuration. Other configurations, e.g., hollow fiber, spiral wound and tubular, are also possible.

The inventive process can be used to separate/enrich enantiomers from racemic mixtures as they are obtained in a vast numer of chemical syntheses. Examples of such racemic mixtures may be products for technical applications, agrochemicals or pharmaceuticals.

The following examples are presented to illustrate the inventive process. Parts and percentages are by weight unless otherwise indicated. The temperatures are given in degrees centigrade.

Example 1 A multi-pore polyvinylidene fluoride micro-filter membrane with an average pore size of 0.45 P is coated by dipping into a 10% tribenzoyl cellulose solution in methylene chloride for 5 minutes. The coated membrane is then drained in air and dried in a vacuum oven at room temperature for 24 hours.

The thus obtained membrane is then placed in a dialysis cell comprising 2 19.5 cm of membrane area which is separating two 45 ml compartments. The dialysis cell is constructed of peiytetrafluoroethylene (Teflon); both compartments contain stirring devices in order'to operate teflon-coated magnetic stirrers.

Trans-stilbene oxide racemate dissolved in a solvent mixture of n-hexane and isopropyl alcohol (98:2 v/v) is placed at different concentrations in one compartment. Samples of 200 1 are taken periodically on the down-stream side of the membrane. They are injected into a HPLC apparatus to measure the relative concentrations of the d- vs. l-enantiomer.

The HPLC apparatus consists of a Chrom-A-Scope detector (Barspec Ltd.) coupled to an Olivetti computer. A Diacel column (00) 250x4.6 nm) is used; the eluent is a solvent mixture of n-hexane and isopropyl alcohol (9:1 v/v). The flow rate is measured as weight/minute. The wavelength is 230 nm.

(a) The two compartments of the dialysis cell are charged with the n-hexane-isopropyl alcohol solvent mixture; in both compartments this solvent mixture is stirred with magnetic stirrers. To the upstream compartment (feed) 2000 ppm racemic trans-stilbene oxide is added, after 75 minutes the concentration of the d- and l-enantiomer is measured: downstream compartment (permeate): 68,4 pg of l-enantiomer and 50,4 pg of d-enantiomer per 45 ml of solution, respectively, (37 % more 1- than d-enantiomer); (for definition of % see Table 1); after 120 minutes a ratio of 102.6 Fg of l-enantibmer vs.

67.9 Mg of d-enantiomer is found (51 % more 1- than d-enantiomer).

(b) If in the downstream compartment the solvent-mixture charged with the enantiomers (enriched with the l-enantiomer) as indicated in (a) is replaced by a fresh solvent mixture (as in (a), above) and the enantiomer separation is carried out for another 150 minutes, the ratio is 68.4 Zg of l-enantiomer vs.

53.6 ,ug of d-enantiomer in 45 ml of solution, respectively (28 % more 1- than d-enantiomer).

The process of replacing the permeate with a fresh solvent (solvent mixture) is a repeatable cycle giving approximately the same relative enrichment (separation) performance per cycle.

(c) The enantiomer enrichment process is carried out as in (a), 5000 ppm of racemic trans-stilbene oxide are used, however.

The enantiomer ratio in the permeate compartment after 180 minutes is 140.4 yg of l-enantiomer vs.

110.7 ug of d-enantiomer per 45 mol of solution, respectively (27 % more 1- than d-enantiomer).

In a second cycle, after replacing the permeate by a fresh solvent mixture, the following ratio of enantiomers is found after 150 minutes: 124.6 Zg of l-enantiomer vs.

98.1 Sug of d-enantiomer per 45 ml of solution, respectively (27 % more 1- than d-enantiomer).

(d) The enantiomer enrichment process is carried out as in (c), 10.000 ppm of racemic trans-stilbene oxide are used, however. A similar enrich ment of the l-enantiomer in the permeate is found.

Example 2 Example (la) is repeated in a dialysis cell containing a membrane with a cellulose tri-(p-chlorophenyl)-carbamate coating. The coating is effected with a methylene chloride solution of the carbamate. The enantiomer enrichment in the permeate compartment after 60 minutes is 368.8 Mg of l-enantiomer vs.

299.2 pg of d-enantiomer, per 45 ml of solution, respectively (23 % more 1- than d-enantiomer).

In a second dialysis experiment under same conditions and with the same racemic trans-stilbene oxide (2000 ppm) an enantiomer enrichment in the permeate compartment after 40 minutes is observed as 166.5 pg of l-enantiomer vs.

136.8 jig of d-enantiomer, per 45 ml of solution, respectively (22 % more 1- than d-enantiomer).

Example 3 Example (la) is repeated in a dialysis cell containing a membrane with a cellulose tri-(p-chlorophenyl)-carbamate coating. The coating is effected with a solution of the carbamate in tetrahydrofuran.

The enantiomer enrichment in the permeate compartment after 40 minutes is 909 jig of l-enantiomer vs.

770 yg of d-enantiomer, per 45 mol of solution, respectively (18 % more 1- than d-enantiomer).

Example 4 A multi-pore polyvinylidene fluoride micro-filter membrane with an average pore size of 0.45 F is coated by immersion for 2 hours in a 10 % cellulose tri-(p-chlorophenyl)-carbamate solution in methylene chloride. The thus coated membrane is removed from the immersion bath, air dried for 30 minutes and kept in a vacuum desiccator for 12 hours.

The membrane is then placed in a dialysis cell according to Example 1, whose upstream (feed) and downstream (permeate) compartment are charged with 45 ml of a solvent mixture of n-hexane/isopropyl aclohol (98:2,v/v).

2000 ppm of trans-stilbene oxide are added to the feed compartment.

After one minute an enrichment of 30% of the l-enantiomer vs. the d-enantiomer in the downstream compartment is reached; after 30 minutes the enrichment is 35%.

After removal of the enriched permeate from the downs tram compartment and its recharging with fresh solvent (n-hexame/isopropyl alcohol) the enrichment (resolution of the racemate) is continued. Relative enrichmentsas in the first stage are obtained.

The process can be continued in this manner until the feed solution is depleted of (one of) the enantiomers.

If the above membrane is prepared from a 10 % cellulose tri-(p-chlorophenyl)-carbamate solution in methylene chloride/phenol (8:l,v/v), instead of methylene chloride only, an enrichment of the l-enantiomer vs. the d-enantiomer of 57 % after 2 minutes is reached.

Example 5 The process of Example 1 is repeated by using a membrane coated with cellulose tri-(phenyl)-carbamate from an 8 % polymer solution in methylene chloride/phenol (8:1, v/v).

This membrane shows a 90 % enrichment of the l-enantiomer vs. the d-enantiomer in the downstream compartment after 90 minutes. As indicated in Example 4, the process can be continued by removing the enriched permeate and recharging the downstream compartment with fresh solvent (n-hexane/isopropyl alcohol 98:2, v/v).

Example 6 The membrane used in Example 5 is placed in a pressure cell (reverse osmosis apparatus) and operated at 40 bar with a feed of 2000 ppm racemic trans-stilbene oxide in n-hexane/isopropyl alcohol (98:2, v/v) at room temperature for 30 minutes. The permeate which is continuously removed from the downstream side of the membrane is enriched with 35 % of l-enantiomer over d-enantiomer.

Example 7 This example demonstrates the adsorption/desorption mode of enantiomer enrichment by membranes.

2 ml of racemic trans-stilbene oxide in n-hexane/isopropyl alcohol (98:2, v/v)arepassed over 0.2 g of a dense membrane prepared from tribenzoyl cellulose (TBC) and cellulose tri-(p-chlorophenyl)-carbamate (CTPC) (cf. Examples 1 and 2).

Different concentrations of the racemate in the feed solution are used.

After 4 hours, the feed solution is removed and a solvent mixture of n-hexane and isopropyl alcohol (80r20, v/v) is used to remove the enantiomer from the membrane by desorption.

The quantity and ratio of d,l-enantiomers and the quantity of enantiomer per 1 g of polymer membrane are determined.

Details and results are given in the following Table 1.

Enrichments above 50 % can be reached with the membranes coated with cellulose tri-(p-chlorophenyl)-carbamate. These membranes are used in the form of flat sheets; experiments with membranes of different configurations (tubular, hollow fiber or spiral wound membranes) give similar results.

Table 1

Polymer feed Enantiomer conc. Enrichment 1) of (menbrane)conc. Enrichment 1) of conc. in membrane (ppm) micrograms/gramd-enantiomer membrane (%) 1 d TBC 2000 5268 4698 12.1 TBC 5000 11620 9850 17.9 TBC 10000 20874 18106 15.3 CTPC 2000 2055 1257 63.4 CTPC 5000 5000 2360 111.8 CTPC 10000 11533 7197 60.2 Concentration of l-enantiomer in the membrane - concentration of d-enantiomer in the membrane 1% = x 100 concentration of d-enantiomer in the membrane The %-enrichment is derived from the enrichment factor (R.f.), where R.f. = conc. of l-enantiomer conc. of d-enantiomer and %-enrichment is (R.f.-l) x 100.

Example 8 According to the mode of Example 7 a membrane is used prepared by coating a microporous polyvinylidene fluoride membrane with an average pore size of 1.0 zm with a 15 % cellulose tri-(benzyl)-carbamate solution in methylene chloride.

The racemate solution of trans-stilbene oxide in n-hexane/isopropyl alcohol (98:2, v/v) is passed through the pores of the membranes at a pressure of 1 bar. After 4 hours, the feed solution is removed and a solvent mixture of n-hexane and isopropyl alcohol (80:20, v/v) is used to remove the enantiomer from the membrane by desorption. Enrichments above 50% are reached.

Example 9 The process of Example 1 is repeated by using a membrane coated with cellulose tri-(phenyl)-carbamate from an 8 % polymer solution in methylene chloride/phenol (8:1, v/v).

Instead of the trans-stilbene oxide racemate there is used a racemate of compounds of the formula

dissolved in n-hexane/isopropyl alcohol (98:2, v/v).

This membrane shows a 20 % enrichment of the l-enantiomer over the d-enantionmer in the downstream compartment after 90 minutes. As indicated in Example 4, the process can be continued by removing the enriched permeate and recharging the downstream compartment with fresh solvent (n-hexane/isopropyl alcohol, 98:2, v/v).

Claims

1. A continuous membrane adsorption or permeation process for enriching enantiomers from a racemate which comprises passing a feed solution containing the racemate in contact with at least one side of a membrane of essentially chiral polymers, maintaining the feed solution in contact with a dense membrane for sufficient time to effect selective permeation of a quantity of the feed solution through the membrane, optionally to a sweep solution which is simul taneously passed in contact with the other side of the membrane, or to have selective adsorption of a quantity of the feed solution onto the surface of the dense membrane or within the pores of a porous membrane through which the feed solution passes, effecting removal of the permeate or of~the-sweep solution containing the permeated portion of the feed solution from the contact with the membrane or desorption of the adsorbed portion of the feed solution from the membrane, the permeated or adsorbed portion of the feed solution being enriched in at least one enantiomer, and optionally recovering the enriched enantiomer.

2. A process according to claim 1, which comprises passing, optionally by recycling, a feed solution containing the racemate in contact with one side of a dense membrane of essentially chiral polymers, simultaneously passing a sweep solution in contact with the other side of the membrane, maintaining, optionally by recycling, the feed and the sweep solution in contact with the membrane for sufficient time to effect selective permeation of a quantity of the feed solution through the membrane to the sweep solution, removing the sweep solution which is enriched in at least one enantiomer, and optionally recovering the enriched enantiomer therefrom.

3. A process according to claim 2, wherein the selective permeation through the membrane is effected by the choice of solvents and by selective interactions between the chirality centers of the polymer membrane and an enantiomer, and by the differences in chemical concentrations between feed and sweep solution, by a transmembrane pressure difference or by a combination of both.

4. A process according to claim 3, wherein the selective permeation through the membrane is effected by a dialysis (diffusion) transport process.

5. A process according to claim 2, wherein the sweep solution which is enriched in at least one enantiomer is continuously or periodically removed from the contact with the membrane and replaced by a fresh one.

6. A process according to claim 5, wherein the periodical removal of the enriched sweep solution and its replacement by a fresh one is governed by the rate of enrichment which decreases as the sweep solution (permeate) increases in concentration.

7. A process according to claim 5, wherein the removed sweep solution is reused as feed solution in at least one further membrane permeation process to further enrich the enantiomer.

8. A process according to claim 7, wherein the removed sweep solution is concentrated by suitable means before it is fed to the further membrane permeation process.

9. A process according to claim 8, wherein the removed sweep solution is processed to separate the enriched enantiomer.

10. A process according to claim 1, which comprises - passing a feed solution containing the racemate in contact with at least one side of a membrane of essentially chiral polymers, - maintaining, optionally by recycling, the feed solution in contact with the dense membrane for sufficient time to effect selective adsorption of a quantity of the feed solution on the surface of the dense membrane or within the pores of a porous membrane through which the solution passes, - effecting desorption of the absorbed portion of the feed solution from the membrane by a solvent capable to remove, optionally by recycling, the adsorbed portion of the feed solution, which portion being enriched in at least one enantiomer, and - optionally recovering the enriched enantiomer therefrom.

11. A process according to claim 10, wherein the selective adsorption on the membrane is effected by the choice of solvent which allows for selective interactions between chirality centers of the polymer membrane and an enantiomer.

12. A process according to claim 10, wherein the feed is passed in contact with both sides of the membrane.

13. A process according to claim 10, wherein the feed solution is passed in contact with one side of a porous membrane and circulates through the pores having a diameter of 0.01 to 10 urn under a pressure of 1 to 50 bars.

14. A process according to claim 10, wherein the desorption of the adsorbed portion of the feed solution,being enriched in at least one enantiomer,is effected by a solvent capable to remove the adsorbed enantiomer, preferably the solvent used in the feed solution.

15. A process according to claim 14, wherein the desorbing solution is circulated over one or both sides of the membranes.

16. A process according to claim 14, wherein the desorbing solution is circulated through the porous membrane.

17. A process according to claim 1, where the feed solution is passed through a dense membrane by a pressure driven reverse osmosis process.

18. A process according to claim 17, wherein the pressure is in the range of from 5 to 300 bars.

19. A process according to claim 17, wherein the dense membrane is a composite membrane.

20. A process according to claim 19, wherein the composite membrane is composed of a dense membrane having a thickness of 0.01 to 20 fm and a microporous support having a thickness of 10 to 5000 Xum.

21. A process according to any one of claims 1 to 20, wherein the enantiomer enrichment is carried out at temperatures in the range of from -200C to +800C, preferably from +150C to +30do.

22. A process according to any one of claims 1 to 21, wherein the membranes are of chiral polysaccharides, which are optionally chemically modified, or of chiral methacrylic and acrylic homo- or copolymers, optically active polymers based on vinyl carbazole or m-tolyvinyl sulfones, helical polyisocyanides, helical polychlorals, polyamides, polyacids or polydienes.

23. A process according to claim 22, wherein the chiral polysaccharides are acyl or carbamoyl substituted celluloses.

24. Use of the process according to any one of claims 1 to 23 for the separation/enrichment of active enantiomers from racemic mixtures of chemical compounds useful as technical application products, pharmaceuticals or agrochemicals.