WO2006087556A1

WO2006087556A1 - Method for separation

Info

Publication number: WO2006087556A1
Application number: PCT/GB2006/000547
Authority: WO
Inventors: Andrew Guy Livingston; Andrew Timothy Boam; Nazlee Faisal Ghazali
Original assignee: Membrane Extraction Technology Ltd
Priority date: 2005-02-17
Filing date: 2006-02-16
Publication date: 2006-08-24
Also published as: GB0503244D0; GB2423300A

Abstract

A process for separating enantiomers or isomers present in a liquid phase through formation and then subsequent decomposition of a host-guest complex coupled to membrane nanofiltration, comprising the steps of: (a) providing a first solution comprising at least two enantiomers or isomers A and B of a guest molecule; (b) adding a host molecule to this first solution; (c) forming a host-guest complex, such that the ratio between the enantiomers or isomers A and B in the host-guest complex is enriched in A over B relative to the first solution; (d) substantially separating the host-guest complex from the non-complexed B enantiomer or isomer; (e) decomposing the host-guest complex into the host and guest molecules to form a second solution; (f) providing a selectively permeable membrane having a first surface and a second surface; (g) separating the guest molecule and host molecule by transferring the guest molecule from the first surface to the second surface across the membrane by contacting the second solution with the first surface. In step (g), the pressure at the first surface is greater than the pressure at the second surface, and the membrane is a selectively permeable such that the membrane rejection (Rhost) of the host molecule is greater than the rejection (Rguest) of the guest molecule.

Description

METHOD FOR SEPARATION

TECHNICAL FIELD

The present invention relates to separating enantiomers or isomers. In particular, the process of the present invention relates to separating enantiomers or isomers through a combination of formation and decomposition of molecular complexes with membrane filtration.

BACKGROUND ART

Isomers are molecules with the same molecular formula but different chemical structure. Enantiomers are chiral molecules which have the same molecular formula and chemical structure, but differ only in their spatial orientation. Though they differ only in their orientation, the practical effects of stereoisomerism of enantiomers are often significant and important. For example, the biological and pharmaceutical activities of many compounds are strongly influenced by the spatial configuration involved. For many chiral compounds, the utility of the compound may be improved by enrichment in one or other enantiomer.

The separation of enantiomers presents a difficult problem as their physical properties are identical. A number of techniques for separating enantiomers are known in the art such as diastereomeric resolutions, enzyme catalysed reactions, various chromatographic methods, the application of liquid membranes, molecular recognition techniques, and inclusion complexation techniques.

Diastereomeric resolutions are known in the art and are used when the enantiomers to be separated have acidic or basic functionality. Resolving agents are added that enable molecular complexes to form through proton transfer from acid to amine. This technique is described for example in "CRC Handbook of Optical Resolutions via Diasteromeric Salt Formation" Kozma D., 2002 ISBN: 0849300193. Further enhancements on this technique are described in US 6,465,684 which discusses the use of families of resolving agents. US 4,800,162 and US 5,077,217 utilise multiphasic and extractive enzyme bioreactors for the resolution of racemic mixtures. Molecular recognition, liquid membranes and chromatographic techniques are known in the art and are discussed in "Chiral Separation Techniques — A Practical Approach" Second Edition, Edited by G. Subramanian ISBN 3-527-29875-4. US 6,379,552 describes the application of discriminating liquid phases to separate enantiomers. US 6,485,650 and EP 0 532 664 describe applications of liquid membranes to enantiomer separation. US 6,313,247 discusses the application of membranes in which a chiral selector is incorporated into or made a part of the membrane polymer itself.

Molecular recognition phenomena have been reported in applications to enantiomer separation, for example "Chiral Separation Techniques - A Practical Approach" Second Edition, Edited by G. Subramanian ISBN 3-527-29875-4 and in various reviews in the open literature such as "Enantiomeric Recognition of Amine Compounds by Chiral Macrocyclic Receptors", Zhang XX, Bradshaw JS and Izatt RM Chemical Reviews 97 (2001) pp 3313-3361. Molecular recognition involves a host compound which forms a complex with a guest molecule. When the host and guest molecules are chiral, the host may preferentially bind with one enantiomer over another. In this case, the host is often referred to as a chiral selector. This principle is known in the art and is employed in many chiral stationary phases in chromatographic separations of enantiomers, when the chiral selector is tethered to a support matrix via a linker molecule so that it can interact with enantiomers in solution. Chiral selectors are also well known in prior art for applications in liquid membranes. Chiral selectors have been reported in the patent literature - US 5,254,258, US 5,674,387, US 5,484,530, US 5,387,338, US 5,256,293, US 6,313,247, US 5,422,004, US 5,290,440, US 6,610,671, US 6,686,479, US 6,391,862. Enzymes have been used as chiral selectors for separation of ibuprofen, where the enzyme-ibuprofen complex was separated from the liquid phase using an ultrafiltration membrane ("Membrane Assisted Chiral Resolution of Pharmaceuticals: Ibuprofen Separation By Ultrafiltration Using Bovine Serum Albumin as Chiral Selector" Bowen WR and Nigmatullin RR Separation Science and Technology 37 (14) 3227-3244 (2002)). However, the application of chiral selectors with molecular weights under 10,000 directly to a solution phase has been limited by the lack of means both to separate the chiral selector - guest complex from homogenous solution and to separate the chiral selector from the guest molecule.

Inclusion complexes are formed by the non-covalent insertion of guest molecules into host lattices, where the hosts are crystalline solids. This may occur when the solid host is suspended as a powder in a solution containing the guest molecules, or when both host and guest are dissolved into a solution and then crystallised from that solution through evaporation of solvent or solvent exchange. Several factors, such as topographic complementarity, hydrophobic effects, van der Waals and dispersive forces, as well as much stronger ionic- and hydrogen-bond interactions, play a key role in molecular recognition between two molecules forming an inclusion complex. Chiral host molecules have been employed to separate enantiomers of a guest molecule through inclusion complexation. "Inclusion Complexation as a Tool in Resolution of Racemates and

Separation of Isomers" Lipowska-Urbanczyk Z and Toda F, Chapter 1 in "Separations and

Reactions in Organic Supraniolecular Chemistry" John Wiley and Sons (2004) ISBN-O-

470-085448-0 and "Inclusion complex crystals formed by alcohol host compounds"

Fumio Toda Supramolecular Science 3 (1996) pp 139-148 discuss the classes of chiral host molecules and the separation methods used to separate enantiomers from racemates using inclusion complexation technology. "TADDOLs, Their Derivatives, and TADDOL

Analogues: Versatile Chiral Auxiliaries" Seebach, D, Beck AK, and Heckel A

Angew.Chem.Int.Ed. 40 (2001) pp 92-138 further discuss enantiomer separations that have been carried out using host molecules containing diarylhydroxymethyl groups. Chiral host molecules for inclusion complexation are also described in US 5,334,776 and US

5,395,985.

Inclusion complexation results in a solid phase comprising the crystals of the host compound and guest molecule, usually suspended in a solvent. The enantiomer that has been less preferentially complexed into the host crystals may be removed by distillation, or the crystals may be separated from the solvent by simple solid-liquid filtration, leaving a mother liquor enriched in the non-complexed enantiomer. The crystals may subsequently be heated under vacuum to release the enantiomer which has preferentially adsorbed into the host crystals. The need for a vacuum distillation step to release the adsorbed enantiomer is one of the limitations of this technique.

Membrane processes are well known in the art of separation science, and can be applied to a range of separations of species of varying molecular weights in liquid and gas phases (see for example "Membrane Technology" in Kirk Othmer Encyclopedia of Chemical Technology, 4^th Edition 1993, VoI 16, pages 135-193). Nanofiltration is a membrane process utilising membranes whose pores are in the range 0.5-5 nm, and which have MW cutoffs of 200-1000 Daltons. Nanofiltration has been widely applied to filtration of aqueous fluids, but due to a lack of suitable solvent stable membranes has not been widely applied to separation of solutes in organic solvents.

US 5,205,934 and US 5,265,734 describe processes for producing composite nanofiltration membranes which comprise a layer of silicone immobilised onto a support, preferably a polyacrylonitrile support. These composite membranes are claimed to be solvent stable and are claimed to have utility for separation of high molecular weight solutes, including organometallic catalyst complexes, from organic solvents. The performance of these composite membranes in separating solutes from methanol solutions has been described in the open literature ("Nanofiltration studies of larger organic microsolutes in methanol solutions", Whu J.A., Baltzis B.C., Sirkar K.K. Journal of Membrane Science 170 (2000) pages 159-172), and their performance in permeation of pure solvent phases has also been reported ("Effect of solvent properties on permeate flow through nanofiltration membranes. Part I - investigation of parameters affecting solvent flux" Machado D.R., Hasson D., Semiat R. Journal of Membrane Science 163 (1999) pages 93-102). The application of these membranes to recovering solvents from chromatographic systems is described in US 5,676,832.

US 5,264,166 and US 6,180,008 describe processes for the production of asymmetric polyimide membranes which are claimed to be stable in solvents such as toluene, benzene, xylene, methyl ethyl ketone (MEK) and methyl iso butyl ketone (MIBK). These asymmetric membranes are claimed to have utility for the separation of low molecular weight organic materials with a molecular weight in the range 300-400 Daltons from solvents with molecular weight of around 100 Daltons. The application of these membranes to solvent recovery from lube oil filtrates are described in US Patent Nos 5,360,530; 5,494,566; 5,651,877, and in the open literature in "Solvent recovery from lube oil filtrates with a polyimide membrane" White L.S., Nitsch A.R. Journal of Membrane Science 179 (2000) pages 267-274.

The use of membranes to separate catalysts from organic solvents is known in the art and has been described in the open literature. "Reverse Osmosis in Homogeneous Catalysis" Gosser L.W., Knoth W.H., Parshall G. W. Journal of Molecular Catalysis 2 (1977) pages 253-263 describes experiments using selectively permeable polyimide membranes to separate soluble transition metal catalysts from reaction mixtures by reverse osmosis. "Modeling of nanofiltration - assisted organic synthesis", J.A. Whu, B.C. Baltzis, K.K. Sirkar, Journal of Membrane Science, 163 (1999) 319-331 describes modelling used to investigate the potential application of solvent stable nanofiltration membranes to catalyst separation and recycle.

"Recycling of the homogeneous Co-Jacobsen catalyst through solvent resistant nanofiltration (SRNF)", Aerts S, Weyten H, Buekenhoudt A, Gevers LEM, Vankelecom IFJ, Jacobs PA Chemical Communications (6) 710-711 Mar 21 2004 discusses membranes comprising a separating layer of silicone rubber containing an inorganic filler to reduce swelling supported by a porous polyacrylonitrile membrane for recovering a Co based catalyst.

The patent literature also describes the use of membranes to separate catalysts from organic solvents. US 5,174,899 discloses the separation of organometallic compounds and/or metal carbonyls from their solutions in organic media with the aid of semipermeable membranes made of aromatic polyamides. I W l / UO tWUM / w ^{« »}* ~ -'

US Patent Nos 5,215,667; 5,288,818 5,298,669 and 5,395,979 describe the use of a hydrophobic membrane to separate water-soluble noble metal ionic phosphine ligand complex catalysts from aldehyde containing hydroformylation reaction mediums comprising aqueous solutions, emulsions or suspensions of said catalysts. US 5,681,473 describes the application of solvent-resistant composite membranes to the separation of organic-solubilised rhodium-organophosphite complex catalyst and free organophosphite ligand from a homogeneous non-aqueous hydroformylation reaction mixture.

In the above prior art, nanofiltration separation in organic solvents has not been applied to enantiomer separations.

SUMMARY OF THDB INVENTION

The present invention addresses the problems of the prior art.

hi one aspect the present invention provides a process for separating enantiomers or isomers present in a liquid phase through formation and then subsequent decomposition of a host-guest complex coupled to membrane nanofiltration, comprising the steps of: (a) providing a first solution comprising at least two enantiomers or isomers A and B of a guest molecule; (b) adding a host molecule to this first solution; (c) forming a host-guest complex, such that the ratio between the enantiomers or isomers A and B in the host-guest complex is enriched in A over B relative to the same ratio in the first solution; (d) substantially separating the host-guest complex from the non-complexed B enantiomer or isomer; (e) decomposing the host-guest complex into the host and guest molecules to form a second solution; (f) providing a selectively permeable membrane having a first surface and a second surface; (g) separating the guest molecule and host molecule present in the second solution by transferring the guest molecule from the first surface to the second surface across the membrane by contacting the second solution with the first surface, wherein the pressure at the first surface is greater than the pressure at the second surface, and wherein the membrane is a selectively permeable membrane such that the membrane rejection (R_host) of the host molecule is greater than the rejection (R_gUest) of the guest molecule.

In a preferred embodiment of the present invention, the first solution comprises at least two enantiomers A and B of a guest molecule and a solvent.

In a preferred embodiment of the present invention, the decomposition of the host-guest complex into host and guest molecules in step (e) is effected by the addition of a solvent.

In a further preferred embodiment, the solvent added in step (e) is different in composition from the solvent present in the first solution of step (a).

In yet a further preferred embodiment, the solvent added in step (e) is the same in composition as the solvent present in the first solution of step (a).

In yet a further preferred embodiment the decomposition of the host-guest complex into host and guest molecules in step (e) is effected by altering the temperature of the first solution from an initial temperature at which the host-guest molecule complex exists to a temperature at which it decomposes into host and guest molecules.

In a preferred embodiment a solution enriched in the B enantiomer or isomer from Step (d) is subjected to further separation to separate the guest molecule from the host molecule and host-guest complex present through the steps of: (h) providing a selectively permeable membrane having a first surface and a second surface; (i) separating the guest molecule from both the host molecule and host-guest complex by transferring the guest molecule from the first surface to the second surface across the membrane as in step (g).

In a further preferred embodiment, the separation in step (d) is carried out by membrane filtration. In yet a further preferred embodiment, the separation step (d) is carried out on a homogeneous solution using nanofiltration so that the host molecule and host-guest complex are retained and non-complexed B enantiomer or isomer is passed through the membrane. In yet a further preferred embodiment, solvent is added during filtration in step (d) to increase the extent to which non-complexed B enantiomer or isomer is separated from the host-guest complex enriched in A.

In a further preferred embodiment the solution containing the guest molecule resulting from step (g) is further enriched in enantiomer or isomer A through repeating the process one or more times using the solution resulting from step (g) as the feed solution in step (a).

In a further preferred embodiment the host molecule is not completely soluble in the first solution in step (b), so that it forms a solid phase and the host-guest complex may be separated from the first solution by means including solid-liquid filtration in step (d).

In yet a further preferred embodiment the solution formed when the host molecule is added to the first solution in step (b) may be a homogeneous liquid solution. Step (c) may be carried out by altering the composition of this homogeneous liquid through means such as evaporation or addition of a further solvent to the solution, so that the host-guest complex forms a solid phase.

In a further preferred embodiment, at least one solvent may be added to the at least one guest molecule to comprise the first solution. In yet a further preferred embodiment, the host molecule may be dissolved or suspended in at least one solvent prior to addition to the first solution in step (b).

Preferably, the host molecule remaining at the first surface of the membrane at step (g) is used again in step (b) after drying or transfer into a suitable solvent, thereby reducing the requirement of the process for fresh host molecule.

A selectively permeable membrane will be familiar to one of skill in the art and includes a membrane which will allow the passage of the guest molecule while retarding the passage of both the host molecule and host-guest complex. The selective permeability may be defined in terms of membrane rejection Ri, a common measure known by those skilled in the art and defined as:

where Cp_;i = concentration of species i in the permeate, permeate being the liquid which has passed through the membrane, and Cjy = concentration of species i in the retentate, retentate being the liquid which has not passed through the membrane. It will be appreciated that a membrane is selectively permeable for a species i if Ri>0.

The term "guest" will be familiar to those skilled in the art of separation sciences (see for example "Inclusion Complexation as a Tool in Resolution of Racemates and Separation of Isomers" Lipowska-Urbanczyk Z and Toda F, Chapter 1 in "Separations and Reactions in Organic Supramolecular Chemistry" John Wiley and Sons (2004) ISBN-0-470-085448-0). A "guest" molecule includes an organic molecule which in preferred embodiments may have a molecular weight in the range 50 - 5,000 Daltons, and which exists in at least two enantiomeric forms or in at least two isomeric forms.

The term "host" will be familiar to those skilled in the art of separation sciences (see for example "Inclusion Complexation as a Tool in Resolution of Racemates and Separation of Isomers" Lipowska-Urbanczyk Z and Toda F, Chapter 1 in "Separations and Reactions in Organic Supramolecular Chemistry" John Wiley and Sons (2004) ISBN-0-470-085448-0). A "host" molecule includes an organic molecule which in preferred embodiment may have a molecular weight in the range 200 - 10,000 Daltons, and which is added to the first solution to cause host-guest complexes enriched in A relative to B to form.

The term "host-guest complex" will be well understood by those skilled in the art of separation sciences (see for example "Inclusion Complexation as a Tool in Resolution of Racemates and Separation of Isomers" Lipowska-Urbanczyk Z and Toda F, Chapter 1 in "Separations and Reactions in Organic Supramolecular Chemistry" John Wiley and Sons (2004) ISBN-0-470-085448-0). A "host-guest complex" includes a complex formed by chemical interaction of one or more host molecules with one or more guest molecules. A "solvent" will be familiar to those skilled in the art and may include an organic or aqueous liquid. Preferred solvents have a molecular weight less than 300 Daltons. It is understood that the term solvent also applies to a mixture of solvents. GB 2 373 743 provides further examples of solvents that the skilled reader will be aware of.

In yet a further aspect the process may be carried out continuously so that any of steps (a) to (i) are performed simultaneously.

In yet a further aspect, the process may be carried out discontinuously.

hi yet a further aspect, the membrane fϊltrations of steps (g) and (i) may each comprise two or more sequential membrane filtrations.

In yet a further aspect, more than one selectively permeable membrane may be employed, so that the membranes used in steps (g) and (i), or in sequential filtrations in any one of these steps, may be different. This allows the membrane to be chosen to provide the best combination of solvent flux and solute rejection for a specific composition of the solution to be contacted with the membrane.

In yet further cases there may be more than one guest molecule present in the first solution, and more than one of these guest molecules may be retained at the first surface of the membrane employed.

In yet further cases there may be more than one host molecule added in step (b), and more than one of these host molecules and the host-guest complexes formed may be retained by membrane filtration in steps (g) or (i).

We have found that in some cases during the membrane separation steps (g) or (i) the host molecule or the host guest complex can attach itself loosely to the membrane surface. In these cases it can be readily washed off using fresh solvent. We have also found that in some cases during membrane separation steps (g) or (i) the host molecule or host-guest complex can begin to form crystals or other solids as solvent passes through the membrane and solute concentration in the retained liquid rises. In these cases the solids may be re-dissolved in fresh second solvent or the solids may be kept from reducing the flux of the membrane to an unacceptable level by operating with a high fluid velocity at the liquid-membrane interface, or by addition of sufficient solvent to the system to maintain the components in solution.

In yet a further preferred embodiment, the membrane may be backflushed using either solvent or gas, to remove deposited material and improve flux.

hi some cases it may be necessary to heat or cool the solutions prior to contact with the membrane in steps (g) or (i). For cases in which crystallisation is employed to effect the separation in step (d), it may prove useful to heat the solution prior to step (c), thus increasing host-guest complex solubility, and then to subsequently decrease temperature during step (d) to effect crystallisation.

Preferably the guest molecule will have a molecular weight of above 50 Daltons; yet more preferably above 100 Daltons, and yet more preferably above 200 Daltons.

Guest molecules may be any molecule which exists in enantiomeric or isomeric form, including by way of non-limiting example alcohols, ketones, aldehydes, esters, ethers, amides, amines, nitrosamines, N-heterocycles, nitriles, sulfoxides, sulfides, aromatics, biaryls, phosphrous containing compounds, esters of hydroxy or amino acids, cyanohydrins, alkoxylactones, oximes, oxaziridines.

Preferably the host molecule will have a molecular weight of above 200 Daltons; yet more preferably above 300 Daltons, and yet more preferably above 400 Daltons. The host molecule will form a host-guest complex which is enriched in enantiomer or isomer A relative to enantiomer or isomer B compared to the relative concentrations of A and B in the first solution. Host molecules include by way of non-limiting example chiral selectors reported in the prior art discussed above and compounds which can be used in the inclusion complexation technology of the prior ait. Suitable host molecules include those described in "Chiral Separation Techniques - A Practical Approach" Second Edition, Edited by G. Subramanian ISBN 3-527-29875-4 and in "Enantiomeric Recognition of Amine Compounds by Chiral Macrocyclic Receptors", Zhang XX, Bradshaw JS and Izatt RM Chemical Reviews 97 (2001) pp 3313-3361 and in US 5,254,258, US 5,674,387, US 5,484,530, US 5,387,338, US 5,256,293, US 6,313,247, US 5,422,004, US 5,290,440, US 6,610,671, US 6,686,479, US 6,391,862. Further suitable hosts are described by "Inclusion Complexation as a Tool in Resolution of Racemates and Separation of Isomers" Lipowska-Urbanczyk Z and Toda F, Chapter 1 in "Separations and Reactions in Organic Supramolecular Chemistry" John Wiley and Sons (2004) ISBN-0-470-085448-0, "Inclusion complex crystals formed by alcohol host compounds" Fumio Toda Supramolecular Science 3 (1996) pp 139-148 and "TADDOLs, Their Derivatives, and TADDOL Analogues: Versatile Chiral Auxiliaries" Seebach, D, Beck AK, and Heckel A Angew.Chem.Int.Ed. 40 (2001). US 5,334,776 and US 5,395,985 mention suitable host molecules. Diols, including TADDOLs and their derivatives, BINOLs, acetylene alcohols, cinchonium salts, cyclodextrins and crown ethers may all be employed as host molecules.

The solvents will be chosen with regard to solubility of guest molecules, host molecules, and host-guest complexes, viscosity, and miscibility with other solvents, among other factors such as cost and safety. Suitable inert solvents are numerous and well known to those skilled in the art. By way of non-limiting example, suitable solvents include aromatics, alkanes, ketones, glycols, chlorinated solvents, esters, ethers, amines, nitriles, aldehydes, phenols, amides, carboxylic acids, alcohols and dipolar aprotic solvents, and mixtures thereof.

By way of non-limiting example, specific examples of solvents include toluene, xylene, benzene, styrene, anisole, chlύrobenzene, dichlorobenzene, chloroform, dichloromethane, dichloroethane, methyl acetate, ethyl acetate, butyl acetate, methyl ether ketone (MEK), methyl iso butyl ketone (MEBK), acetone, ethylene glycols, ethanol, methanol, propanol, butanol, hexane, cyclohexane, dimethoxyethane, methyl tert butyl ether (MTBE), diethyl ether, adiponitrile, N₅N dimethylfomamide, dimethyl sulfoxide, dioxane, nitromethane, nitrobenzene, pyridine, carbon disulfide, tetrahydrofuran, N-methyl pyrrolidone, acetonitrile, water, and mixtures thereof.

The membrane of the present invention can be configured in accordance with any of the designs known to those skilled in the art, such as spiral wound, plate and frame, shell and tube, and derivative designs thereof. The membranes may be of cylindrical or planar geometry.

The membrane of the present invention may be a porous or a non-porous membrane. Suitable membranes will have a rejection for both the host molecule and host-guest complex that is greater than the rejection for the guest molecule.

The membrane of the present invention may be formed from any polymeric or ceramic material which provides a separating layer capable of preferentially separating the guest molecule from both the host molecule and host-guest complex in steps (g) or (i). Preferably the membrane is formed from or comprises a material selected from polymeric materials suitable for fabricating microfiltration, ultrafiltration, nanofiltration or reverse osmosis membranes, including polyethylene, polypropylene, polytetrafluoroethylene (PTFE), polyvinylidene difluoride (PVDF), polyethersulfone, polyacrylonitrile, polyamide, polyimide, cellulose acetate, and mixtures thereof. The membranes can be made by any technique known to the art, including sintering, stretching, track etching, template leaching, interfacial polymerisation or phase inversion. Yet more preferably the membrane is prepared from an inorganic material such as by way of non-limiting example silicon carbide, silicon oxide, zirconium oxide, titanium oxide, or zeolites, using any technique known to those skilled in the art such as sintering, leaching or sol-gel processes.

In a preferred aspect the membrane is non-porous and the non-porous, selectively permeable layer thereof is formed from or comprises a material selected from modified polysiloxane based elastomers including polydimethylsiloxane (PDMS) based elastomers, ethylene-propylene diene (EPDM) based elastomers, polynorbornene based elastomers, polyoctenamer based elastomers, polyurethane based elastomers, butadiene and nitrile butadiene rubber based elastomers, natural rubber, butyl rubber based elastomers, polychloroprene (Neoprene) based elastomers, epichlorohydrin elastomers, polyacrylate elastomers, polyethylene, polypropylene, polytetrafluoroethylene (PTFE), polyvinylidene difluoride (PVDF) based elastomers, polyetherblock amides (PEBAX), polyurethane elastomers, crosslmked polyether, and mixtures thereof.

In a preferred aspect the membrane comprises a reinforcing material selected from an external mesh and support. This is particularly advantageous for homogenous tubes or sheets. Such tubes or sheets may be reinforced to increase their burst pressure, for example by overbraiding tubes using fibres of metal or plastic, or by providing a supporting mesh for flat sheets.

When the membrane comprises a non-porous layer and an additional component, the additional component may be a supporting layer. The supporting layer may be a porous support layer. Suitable materials for the open porous support structure are well known to those skilled in the art of membrane processing. Preferably the porous support is formed from or comprises a material selected from polymeric material suitable for fabricating microfiltration, ultrafiltration, nanofiltration or reverse osmosis membranes, including polyethylene, polypropylene, polytetrafluoroethylene (PTFE), polyvinylidene difluoride (PVDF), polyethersulfone, polyacrylonitrile, polyamide, polyimide, and mixtures thereof.

Selectively permeable membranes useful for the present invention are disclosed in US Patent Nos 5,205,934; 5,265,734; 4,985,138; 5,093,002; 5,102,551; 4,748,288; 4,990,275; 4,368,112 and 5,067,970. Preferred membranes are produced by WR Grace & Co and are described in US 5,264,166 and US 6,180,008

The rejection performance of the membrane may be improved by pre-soaking the membrane in one or more of the solvents to be used in the membrane separation. The process may be performed in a continuous, semi-continuous or discontinuous (batch mode) manner.

The process may be performed using dead-end or cross-flow filtration. In cases where dead-end filtration is used the pressure may be supplied through a suitable pump or through a pressurizing gas, or through any other device designed to exert pressure at the first surface of the membrane.

BRIEF DESCRIPTION OF DRAWINGS

The invention will now be described, by way of example only, with reference to the accompanying drawings in which:

Figure 1 shows a schematic of one embodiment of the process. Step 1 - A first solution comprising guest molecule in the form of enantiomer or isomer A and enantiomer or isomer B dissolved in Solvent C (1) is added to a mixing chamber (2) equipped with a nanofϊltration membrane (3). A solution or slurry of crystals of host molecule H dissolved or suspended in Solvent C (4) is added to the mixing chamber and a host-guest complex HA forms between enantiomer or isomer A and host molecule H in the mixing chamber. Step 2 - Pressure is applied to the mixing chamber through an inert gas added to the mixing chamber (5). A portion of the liquid from the mixing chamber passes through the membrane carrying enantiomer or isomer B and exits the chamber (6). Fresh Solvent C is fed to the chamber (7) to carry further enantiomer or isomer B from the system with stream (6). This substantially removes enantiomer or isomer B from the mixing chamber. Step 3 - Solvent D is added (8) to the solution in the mixing chamber while a mixture containing Solvent C and Solvent D passes through the membrane and exits the chamber (9). As further Solvent D is added the host-guest complex HA decomposes into host molecule H and enantiomer or isomer A, and enantiomer or isomer A passes through the membrane with Solvent D and traces of Solvent C and exits the chamber (9). This substantially removes enantiomer or isomer A from the mixing chamber. Step 4 - Fresh Solvent C (10) is added to the mixing chamber while a mixture containing Solvent C and Solvent D passes through the membrane and exits the chamber (11). This alters the composition of the solution in the mixing chamber as Solvent C replaces Solvent D. Step 5 - When the solution in the mixing chamber comprises substantially host molecule H dissolved or suspended in Solvent C, this stream may be recycled (12) back into the first stage and added as stream (4). In some cases host molecule H and the host guest complex HA may be partially insoluble in Solvent C, and soluble in Solvent D, so that there is a slurry present in Steps 1 and 2 which dissolves in Step 3 and re-precipitates in Step 4.

Figure 2 shows another embodiment of the process. Step 1 - A first solution comprising guest molecule in the form of enantiomer or isomer A and enantiomer or isomer B dissolved in Solvent E (13) is added to a mixing vessel (14). A solution of host molecule H dissolved in Solvent E (15) is added to the mixing vessel. Step 2 - Solvent E is then removed via evaporation (16) from the mixing chamber, and a solid host-guest complex HA forms between enantiomer or isomer A and host molecule H in the mixing vessel. Enantiomer or isomer B remains in the mixing vessel as an oily liquid. Step 3 - Solvent F is added (17) to the mixing vessel. The host-guest complex HA remains a solid and is suspended as a slurry in Solvent F. Enantiomer or isomer B dissolves into Solvent F. Step 4 - The slurry in the mixing vessel (14) is transferred to a mixing chamber (2) equipped with a nanofiltration membrane (3). Pressure is applied to the mixing chamber through an inert gas added to the mixing chamber (5). A portion of the liquid from the mixing chamber passes through the membrane carrying enantiomer or isomer B and exits the chamber (18). Fresh Solvent F is fed to the mixing chamber (19) to carry further enantiomer or isomer B from the system with stream (18). This substantially removes enantiomer or isomer B from the mixing chamber. Step 5 - Fresh Solvent E is added (20) to the solution in the mixing chamber while a mixture containing Solvent E and Solvent F passes through the membrane and exits the chamber (21). This alters the composition of the solution in the mixing chamber as Solvent E replaces Solvent F. As further Solvent E is added the host-guest complex HA decomposes and enantiomer or isomer A passes through the membrane with Solvent E and traces of Solvent F and exits the chamber (21). This substantially removes enantiomer or isomer A from the mixing chamber. Step 6 - Fresh Solvent E (22) is added to the mixing chamber while a mixture containing Solvent E and Solvent F passes through the membrane and exits the chamber (23). Step 7 - When the solution in the mixing chamber comprises substantially host molecule H dissolved in Solvent E, this stream may be recycled (23) back into the first stage and added as stream (15).

DETAILED DESCRIPTION QF THE INVENTION

The invention will now be described in further detail in the following non-limiting Examples.

EXAMPLES

Enantiomeric excess is defined for two enantiomers A and B as:

(2)

EXAMPLE 1

In this example the guest molecule is 1-phenylethanol (PE), the host molecule is (4R,5R)- 2,2-Dimethyl-o:, a,a',a -tetraphenyldioxolane-4,5-dimethanol (TADDOL) and

STARMEM™ organic solvent nanofiltration membranes manufactured by W.R,Grace and Co Limited are used. Racemic PE and TADDOL were obtained commercially. STARMEM™122 membranes are integrally skinned asymmetric membranes prepared as generally described in US 5,264,166 and US 6,180,008. The 122 membrane has a nominal molecular weight cutoff of 220 Daltons, obtained by plotting rejection Ri versus molecular weight for a series of n-alkanes dissolved in toluene, and taking the nominal molecular weigh cutoff by interpolation of this curve at a rejection of 90%. These membranes are commercially available from Membrane Extraction Technology (MET) (UK) Limited. Rejections were determined using an Osmonics/Desal (USA) SEPA-ST test cell Membrane discs were cut from A4 sheets in circular discs 49 mm in diameter, giving an active membrane area of 16.9 cm². AU experiments were carried out in a fume cupboard. The cell was pressurised with compressed nitrogen gas at pressures of 5-50 bar. The volume of feed solution was 20 mL and the volume of permeate was measured with a measuring cylinder. Rejections were determined by equation (1) using a solution of 4.35 mM PE in toluene, and a solution of 7.1 mM TADDOL in toluene.

Table 1 - Rejection of PE and TADDOL using STARMEM™122

Vf-feed volume (ml); Vp-volume permeated through membrane (ml), and Vr-retained volume

The results in Table 1 illustrate the combination of PE, TADDOL and STARMEM™122 are suitable for use in the claimed process.

Racemic PE (0.262g) was added to a mixture of TADDOL (1.002g) in 20 ml toluene. After stirring for one hour, the mixture was evaporated to remove the toluene, leaving a damp solid residual. 50 ml hexane was then added to this damp solid residual and the slurry stirred for 24 hours. The solid material was recovered using a vacuum filter with a microfiltration membrane. 0.846g of TADDOL-PE complex was recovered, with an enantiomeric excess of 60% in S-PE.

0.61 Ig of the TADDOL-PE complex was dissolved in 50 ml methanol and transferred to the SEPA-ST cell fitted with a STARMEM™122 membrane. This was subjected to filtration (Filtration 1) and three 40 ml volumes of methanol were subsequently added to the cell (Filtrations 2 and 3) as shown in Table 2 below:

Vf-feed volume (ml); Vp-volume permeated through membrane (ml), and Vr-retained volume; Cf- feed concentration, Cp permeate concentration, Cr - retentate concentration. BD - below detection.

The PE recovered in the methanol permeate had an enantiomeric excess of 60% in S-PE.

EXAMPLE 2

This example illustrates the re-use of the host molecule in sequential resolutions. 0.632g of TADDOL was recovered from the methanol solution remaining as retentate at the end of filtration 3 in Example 1, by drying the TADDOL to drive off the methanol. This TADDOL was dissolved in 20 ml toluene and 0.173 g of racemic PE was added. After stirring for one hour, the mixture was evaporated to remove the toluene, leaving a damp solid residual. 50 ml hexane was then added to this damp solid residual and the slurry stirred for 24 hours. The solid material was recovered using a vacuum filter with a microfiltration membrane. 0.2899g of TADDOL-PE complex was recovered, with an enantiomeric excess of 86% in S-PE.

0.61 Ig of the TADDOL-PE complex was dissolved in 50 ml methanol and transferred to the SEPA-ST cell from Example 1. This was subjected to three filtrations as in Example 1, providing an overall recovery of S-PE of 96% at an enantiomeric excess of 86% in S- PE. This example illustrates that TADDOL may be re-used in multiple resolutions.

EXAMPLE 3

Racemic PE (0.262g) was added to a mixture of TADDOL (1.002g) in 20 ml toluene. After stirring for one hour, the mixture was evaporated to remove the toluene, leaving a damp solid residual. 50 ml hexane was then added to this damp solid residual and the slurry stirred for 24 hours. The solid material was recovered using a vacuum filter with a microfiltration membrane. 0.846g of TADDOL-PE complex was recovered, with an enantiomeric excess of 86% in S-PE.

0.8 g of the TADDOL-PE complex was dissolved in 50 ml toluene and transferred to the SEPA-ST cell fitted with a STARMEM™122 membrane as in Example 1. This was subjected to three filtrations as in Example 1, except that toluene was used in all filtrations in place of methanol. The recovered S-PE had an ee of 86%.

EXAMPLE 4

In a preferred example, racemic PE (0.262g) was added to a slurry of TADDOL (1.002g) suspended in 20 ml hexane in the SEPA-ST cell fitted with a STARMEM™122 membrane as in Example 1. The cell was mixed vigorously with a magnetic stirrer to maintain the solids in suspension. After stirring for ten hours, the slurry was subjected to three filtrations in which 20 ml hexane was added and the suspension filtered to reduce the volume back to the starting volume of approximately 21 ml. The ee of the PE permeating the membrane with the hexane was 83% in R-PE.

Five aliquots of 20 ml each toluene were then added to the cell above the membrane, and each time the mixture was filtered to reduce the volume back to the starting volume of 20 ml. The ee of the PE permeating the membrane with the toluene was 85% in S-PE. At the completion of this step, the cell was depressurized and opened, and a homogeneous liquid presumed to contain primarily TADDOL dissolved in toluene was observed. The cell was then closed and repressurized.

Five aliquots of 20 ml each hexane were then added to the cell above the membrane and each time the mixture was filtered to reduce the volume back to the starting volume of approximately 21 ml. At the completion of this step, the cell was depressurized and opened, and a slurry presumed to be TADDOL solids present in the hexane was observed. The cell was then closed and repressurized.

Racemic PE (0.262g) was added to this slurry of TADDOL in 20 ml hexane. After stirring for ten hours, the slurry was subjected to a three filtrations in which 20 ml hexane was added and the suspension filtered to reduce the volume back to the starting volume of 20 ml. The ee of the PE permeating the membrane with the hexane was 81% in R-PE.

EXAMPLE 5

Racemic PE (0.256g) was added to a slurry of TADDOL (1.042Ig) suspended in 40 ml of a mixture of toluene and hexane (33wt% toluene, 67wt% heptane) in the SEPA-ST cell fitted with a STARMEM™122 membrane as in Example 1. The cell was mixed vigorously with a magnetic stirrer to maintain the solids in suspension and the cell and contents were held at 22⁰C. After stirring for 2 hours, the slurry was subjected to a filtration in which 25 ml of liquid was permeated through the membrane to leave a residual volume of 15 ml. The ee of the PE permeating the membrane with the solvent mixture was 36 % in R-PE.

25 ml of a mixture of toluene and hexane (33wt% toluene, 67wt% heptane) was men added to the cell above the membrane, and after 30 minutes the mixture was filtered to remove 25 ml of liquid through the membrane. The ee of the PE permeating the membrane with the solvent mixture was 28 % in S-PE. This illustrates how continued solvent addition and removal can decompose the host-guest complex when the solvent used in step (a) has the same composition as the solvent used in step (e).

A further 25 ml of a mixture of toluene and hexane (33wt% toluene, 67wt% heptane) was then added to the cell above the membrane, and the contents of the cell (now around 40 ml) were heated to 5O⁰C and stirred for 30 minutes. The mixture was then filtered to remove 17 ml of liquid. The ee of the PE permeating the membrane with the liquid was 85% in S-PE. At the completion of this step, the cell was cooled to ambient, depressurized and opened, and a slurry containing 1.008 g TADDOL and 0.006 g of PE was observed remaining above the membrane. This illustrates how altering the temperature can be used to decompose the host-guest complex.

EXAMPLE 6

Racemic α-methylbenzylamine (αMBA) (0.606g) was added to a slurry of TADDOL (2.33g) suspended in 100 ml octane in the SEPA-ST cell fitted with a STARMEM™122 membrane as in Example 1. The cell was mixed vigorously with a magnetic stirrer to maintain the solids in suspension. After stirring for ten hours, the slurry was subjected to a filtration in which 50 ml liquid was removed by permeation through the membrane. The ee of the αMBA permeating the membrane with the octane was 26 % in R-PE. The cell was then de-pressurized and the solid material found above the membrane was recovered using a vacuum filter with a microfiltration membrane. 0.587g of TADDOL- αMBA complex was recovered, with an enantiomeric excess of 89% in S- αMBA.

0.575g of the TADDOL- αMBA complex was dissolved in 50 ml methanol and transferred to the SEPA-ST cell fitted with a STARMEM™122 membrane. This was subjected to filtration using 2 x 50 ml additions of methanol. The αMBA recovered in the permeate had an enantiomeric excess of 85%.

EXAMPLE 7

Racemic Methyl Phenyl Sulfoxide (MPS) (C₆H₅SOCH₃) (0.875g) was added to a slurry of TADDOL (1.45g) suspended in a mixture of toluene and hexane (50wt% toluene, 50wt% heptane) in a glass reaction tube. The tube was mixed vigorously with a magnetic stirrer to maintain the solids in suspension. The solution initially containing solids, was heated from 3O⁰C to 5O⁰C, at which point the solids became dissolved. After stirring for two hours, the tube was cooled again to 3O⁰C and the solids re-appeared. The solid material was recovered using centrifugation. 0.76g of TADDOL- MPS complex was recovered.

0.72g of the TADDOL- MPS complex was dissolved in 50 ml methanol and transferred to the SEPA-ST cell fitted with a STARMEM™122 membrane. This was subjected to filtration using 2 x 50 ml additions of methanol. The MPS recovered in the permeate had an enantiomeric excess of 22%.

All publications mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described methods and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in chemistry or related fields are intended to be within the scope of the following claims.

Claims

1. A process for separating enantiomers or isomers through formation and then subsequent decomposition of a host-guest complex coupled to membrane nanofiltration, comprising the steps of: (a) providing a first solution comprising at least two enantiomers or isomers A and B of a guest molecule; (b) adding a host molecule to this first solution; (c) forming a host-guest complex, such that the ratio between the enantiomers or isomers A and B in the host-guest complex is enriched in A over B relative to the same ratio in the first solution; (d) substantially separating the host-guest complex from the non-complexed B enantiomer or isomer; (e) decomposing the host-guest complex into the host and guest molecules to form a second solution; (f) providing a selectively permeable membrane having a first surface and a second surface; (g) separating the guest molecule and host molecule by transferring the guest molecule from the first surface to the second surface across the membrane by contacting the second solution with the first surface, wherein the pressure at the first surface is greater than the pressure at the second surface, and wherein the membrane is a selectively permeable membrane such that the membrane rejection (Rho_st) of the host molecule is greater than the rejection (R_gues_t) of the guest molecule.

2. A process according to claim 1 in which the host guest complex is decomposed to host and guest molecules by addition of one or more solvents.

3. A process according to claim 1 in which the host-guest complex is decomposed into host and guest molecules by altering the temperature of the first solution.

4. A process according to claims 1-3 where the solution enriched in the B enantiomer or isomer from Step (d) is subjected to further separation to separate the guest molecule from the host molecule and host-guest complex present through the steps of: (h) providing a selectively permeable membrane having a first surface and a second surface; (i) separating the guest molecule from the host molecule and host-guest complex by transferring the guest molecule from the first surface to the second surface across the membrane as in step (g)-

5. A process according to claims 1-4 in which the solution containing guest molecule resulting from step (g) is further enriched in enantiomer or isomer A through repeating the process one or more times using the solution resulting from step (g) as the first solution in step (a).

6. A process according to any of claims 1 to 5 in which the separation in step (d) is carried out by membrane filtration.

7. A process according to any of claims 2 to 6 in which the one or more solvents are added during filtration in step (d) to increase the extent to which enantiomer or isomer B is separated from the host-guest complex enriched in A.

8. A process according to claims 1 to 7 in which the separation step (d) is carried out on a homogeneous solution using nanofiltration so that the host molecule and host-guest complex are retained and enantiomer or isomer B is passed through the membrane.

9. A process according to any of claims 1 to 8 in which the host molecule is partially insoluble in the first solution in step (c), so that it forms a solid phase and may be separated from the first solution by means including solid-liquid filtration in step (d).

10. A process according to any of claims 1 to 8 in which the solution formed when the host molecule is added to the first solution in step (b) is a homogeneous liquid solution and step (c) is results in a host-guest complex which forms a solid phase.

11. A process according to any of claims 1 to 10 in which at least one host molecule is recovered in the process and re-used in multiple cycles of the process.

12. A process according to any of claims 1 to 11 wherein at least one solvent may be added to the at least one guest molecule to comprise the first solution.

13. A process according to claims 1 to 12 wherein at least one solvent may be added to the at least one host molecule prior to addition to the first solution.

14. A process according to any of claims 1 to 13 wherein more than one species of host molecules is employed in step (b).

15. A process according to any of claims 1 to 14 in which the guest molecule has a molecular weight above 50 Daltons.

16. A process according to any of claims 1 to 15 in which the host molecule has a molecular weight above 200 Daltons.

17. A process according to any of claims 2 to 16 in which the one or more solvents are chosen from aromatics, alkanes, ketones, glycols, chlorinated solvents, esters, ethers, amines, nitriles, aldehydes, phenols, amides, carboxylic acids, alcohols, water and dipolar aprotic solvents, and mixtures thereof.

18. A process according to any of the above claims 1 to 17 in which the selectively permeable membrane has cylindrical or planar geometry and is configured as spiral wound, plate and frame, shell and tube, or derivative designs thereof.

19. A process according to any of claims 1 to 18 where one or more of the membrane separation steps is operated in a dead-end filtration mode.

20. A process according to any of claims 1 to 18 where one or more of the membrane separation steps is operated in a cross-flow filtration mode.

21. A process according to any of claims 1 to 20 in which the selectively permeable membrane is formed from a polymeric or ceramic material.

22. A process according to any of claims 1 to 21 in which the selectively permeable membrane is formed from or comprises a material selected from polymeric material suitable for fabricating microfiltration, ultrafiltration, nanofiltration or reverse osmosis membranes, including polyethylene, polypropylene, polytetrafluoroethylene (PTFE), polyvinylidene difluoride (PVDF), polyethersulfone, polyacrylonitrile, polyamide, polyimide, cellulose acetate, and mixtures thereof.

23. A process according to any of claims 1 to 22 wherein the membrane consists essentially of a polyimide polymer based on any of the following:

(i) a polymer based on 5(6)-amino-l-(4'-aminophenyl)-l,3-trimethylindane and benzophenone tetracarboxylic acid;

(ii) a polymer with 1 (or 3)-(4-aminophenyl)-2,3-dihydro-l,3,3 (or

mden-S-amme and 5,5'-carbonylbis-l,3-isobenzofurandione;

(iii) a copolymer derived from the co-condensation of benzophenone 3,3',4,4'~ tetracarboxylic acid dianhydride and a mixture of di(4-aminophenyl) methane and toluene diamine of the corresponding diisocyanates, 4,4'-methylenebis(phenyl isocyanate) and toluene diisocyanate;

(iv) a copolymer derived from the co-condensation of lH,3H-Benzo[l,2-c:4,5-c'] difuran- 1,3,5,7-tetrone with 5,5'-carbonylbis[l,3-isobenzofurandione], l,3-diisocyanato-2- methylbenzene and 2,4-diisocyanato-l-methylbenzene.

24. A process according to any of claims 1 to 21 in which the selectively permeable membrane is formed from or comprises a material selected from a ceramic material suitable for constructing microporous membranes including silicon carbide, silicon oxide, zirconium oxide, titanium oxide, and zeolites.

25. A process according to any of claims 1 to 24 in which the selectively permeable membrane is a composite membrane.

26. A process according to any of claims 1 to 25 in which the membrane is non-porous and is formed from or comprises a material selected from modified polysiloxane based elastomers including polydimethylsiloxane (PDMS) based elastomers, ethylene-propylene diene (EPDM) based elastomers, polynorbornene based elastomers, polyoctenamer based elastomers, polyurethane based elastomers, butadiene and nitrile butadiene rubber based elastomers, natural rubber, butyl rubber based elastomers, polychloroprene (Neoprene) based elastomers, epichlorohydrin elastomers, polyacrylate elastomers, polyethylene, polypropylene, polytetrafluoroethylene (PTFE), polyvinylidene difluoride (PVDF) based elastomers, and mixtures thereof.

27. A process according to any of claims 1 to 26 wherein the membrane is a composite membrane comprising a porous support and at least one non-porous layer.

28. A process according to any of claims 1 to 27 wherein the process is performed in a continuous manner.

29. A process^' according to any of claims 1 to 28 wherein the process is performed in a discontinuous manner.

30. A process according to claim 1 and substantially as herein described.

31. A process for separating the components of a mixture substantially as described in any of the specific Examples.