JP2012521869A - Method for producing enantioselective composite membrane - Google Patents

Abstract

The present invention provides an enantioselective composite membrane useful for separation of optical isomers and a method for producing the same. The invention further provides a membrane for separating enantiomers from their mixtures to obtain optically pure isomers based on a pressure driven separation process. The present invention also provides a membrane-based method for optically resolving racemic mixtures of amino acids to obtain optically pure amino acids.
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Description

The present invention relates to a process for the production of enantioselective composite membranes for the separation of amino acids from their aqueous solutions and for the optical resolution of racemic mixtures. The present invention particularly relates to a method for producing an enantioselective composite nanofiltration membrane useful for separation of optical isomers of amino acids.

  The enantioselective composite membranes of the present invention are useful for the separation of enantiomers from their mixtures to obtain optically pure isomers. The enantioselective composite membranes of the present invention may be useful for the optical resolution of racemic mixtures of amino acids and chiral compounds in pressure-driven membrane processes such as reverse osmosis, nanofiltration, etc. to obtain optically pure enantiomers .

BACKGROUND OF THE INVENTION Stereoisomers are molecules that differ from each other only in the arrangement of their atoms in space. Stereoisomers are broadly classified as diastereomers or enantiomers; the latter include those that are mirror images of one another, the former being those that are not mirror images. Enantiomers (mirror images), also known as optical isomers, have the same physical and chemical properties. Therefore, a mixture of enantiomers is usually used in conventional separation methods such as fractional distillation (boiling point is the same), normal crystallization (due to the same solubility) if the solvent is not optically active, adsorption If the agents are not optically active, they cannot be separated by conventional chromatography (because they are held equally by ordinary adsorbents). The problem of separating enantiomers is exacerbated by the fact that conventional synthetic techniques often produce a mixture of enantiomers. Thus, separation of enantiomeric mixtures is the most challenging problem in analytical chemistry.

  Separation of enantiomers is very important for organic compounds such as amino acids, drugs, pesticides, insecticides and the like. This is because most are optically active and exist as pairs of optical isomers (enantiomers). The enantiomers of many chiral drugs show significant differences in their biological and pharmacological properties. Even if one enantiomer has drug activity, the other may be inactive and even harmful. For example, (S) -verapamil is effective as a calcium channel blocker, but (R) -verapamil causes cardiac side effects; the l-enantiomer of the β-blocker propranolol is more potent than the d form. About 100 times more active; the (R) (+)-enantiomer of thalidomide has a sleep effect, but the (S) (−)-enantiomer has a teratogenic effect, and the difference in the pharmacological action of this thalidomide Has been found to be the cause of a severe malformation of a female newborn taken during pregnancy (“thalidomide tragedy” in the 1960s). Therefore, the “US Food and Drug Administration” recently issued new regulations governing the marketing of chiral drugs. In compliance with this new regulation, the pharmacological properties of each enantiomer of a chiral drug must be tested separately for therapeutic efficacy and safety.

  Various methods are known for separating enantiomers, such as diastereomeric resolution, enzyme catalysis, chromatographic methods, liquid film coating, molecular recognition techniques, and inclusion complexation techniques. Preferential crystallization, diastereomeric resolution, enzyme-catalyzed reactions, etc. involve combining enantiomers with auxiliary chiral reagents to convert them to diastereomers that can be separated by any conventional separation technique. . The diastereomeric resolution can be stated as described in "CRC Handbook of Optical Resolutions via Diasteromeric Salt Formation" Kozma D., 2002 ISBN: 0849300193. The main drawback of diastereomeric resolution is the need for large amounts of optically pure derivatization reagents (chiral reagents or solvents) that can be expensive and often not recoverable.

  Chromatographic techniques (GC, HPLC, CE, etc.) can be described, but these are described in "Chiral Separation Techniques-A Practical Approach" Second Edition, Edited by G. Subramanian ISBN 3-527-29875-4 Here, the chromatographic method requires the incorporation of a suitable chiral selector into the stationary phase (chiral stationary phase) or coating the surface of the column packing (chiral coated stationary phase). Enantioselective chiral columns with a chiral stationary phase are expensive and have a finite usable life. Therefore, the cost of separation is quite high.

  The molecular recognition phenomenon for enantiomer separation can be described as reported in "Chiral Separation Techniques-A Practical Approach" Second Edition, Edited by G. Subramanian ISBN 3-527-29875-4. Various chiral stationary phases, complexes, and the like based on fractional recognition have been developed.

  Reference may be made to US Pat. No. 6,759,488 entitled “Molecularly imprinted polymers grafted on solid supports”, where the separation of enantiomers is based on the phenomenon of molecular recognition. The disadvantage of MIP technology is that only crosslinkable monomers can be used to produce molecularly imprinted membranes.

  Reference is made to US Pat. No. 5,080,795 entitled “Supported chiral liquid membrane for the separation of enantiomers”, where a supported chiral liquid membrane containing a chiral carrier forms a complex with one of two enantiomers. And separate it from the other. The main disadvantages of this membrane are poor stability and a decrease in enantioselectivity over time.

  Reference may be made to US Pat. No. 6,485,650 entitled “Liquid membrane separation of enantiomers”, where the enantiomers in a supported liquid membrane module containing a carrier fluid with a racemic mixture and a phase transfer reagent are described. The separation method describes moving the enantiomer to a liquid membrane, which is then contacted with a sweep fluid. The enantiomer is then recovered from the sweep fluid. The membrane module is configured such that the supply fluid and sweep fluid are in close proximity but in contact with the opposite side of the liquid membrane, and the supply fluid and sweep fluid have substantially continuous interface contacts along the length of the liquid membrane. . The disadvantages of this liquid-liquid extraction technique are the low productivity and the danger of mixing the two solutions at the membrane interface.

  Reference can be made to US Pat. No. 4,277,344 entitled “Interfacially synthesized reverse osmosis membrane”, where the aromatic polyamide membrane has an aromatic polyamide having at least two primary amine groups and at least three acyl halide groups. Interfacial reaction product with halogenated aromatic acyl. According to this patent, a porous polysulfone carrier is coated with m-phenylenediamine dissolved in water. After the excess m-phenylenediamine solution is removed from the coated carrier, the coated carrier is coated with trimesic acid chloride dissolved in “FREON” TF solvent (trichlorotrifluoroethane). The contact time for the interfacial reaction is 10 seconds and the reaction is substantially complete in 1 second. Next, the obtained polysulfone / polyamide composite membrane is air-dried. This membrane claims to show good flux and salt inhibition. However, various types of additives have been incorporated into the solutions used in the interfacial polycondensation reaction to improve membrane performance. The disadvantage of this membrane is that it is not enantioselective.

  Reference can be made to US Pat. No. 5,205,934 entitled “Silicone-derived solvent stable membranes”, where a method for producing a composite nanofiltration membrane comprising a phase of silicone immobilized on a support, preferably a polyacrylonitrile support Is described. These composite membranes are claimed to be solvent stable and claimed to have utility for the separation of high molecular weight solutes such as organometallic catalyst complexes from organic solvents. This membrane does not have enantioselectivity.

  Reference may be made to U.S. Pat.No. 6,743,373 entitled `` Process for the separation of enantiomers and enantiopure reagent '', where a mixture containing enantiomers is based on an enantiomerically pure amino acid in a basic medium. And the resulting mixture of shear stereomers is separated. The disadvantage of this process is that for the separation of enantiomers, the enantiomer must have at least one free organic functional group and the reagent must be at least one amino group of an amino acid with an active group. And forms an active precursor of an isocyanate group, wherein at least one carboxyl group of the amino acid is substituted.

  The enantioselective polymer membranes described in the prior art detailed above are asymmetric and dense membranes made from chiral polymers such as polysaccharides and their derivatives, poly α-amino acids, polyacetylene derivatives and the like. Most of these polymers are crystalline in nature and do not have film-forming ability. Therefore, membranes made from such polymers are brittle and thus difficult to handle. The poor mechanical properties limited their use to dialysis mode separations. In dialysis mode separation, the driving force was only a solute gradient, and therefore these membranes exhibited very low permeation rates. Other types of enantiomeric separation membranes are made from non-chiral polymers with grafted enantiomer recognition molecules, ie amino acids, proteins, oligopeptides and the like. Although these membranes have excellent mechanical properties, during permeation, the recognition sites quickly saturate and become anchored in the polymer matrix, thereby reducing the selectivity of the membrane with time.

  As described in various patents, composite membranes can be prepared by coating a porous carrier membrane with an aqueous solution of a polyfunctional amine and then with a solution of a polyfunctional acyl halide in an organic solvent. It is typically produced by producing a thin film discriminating layer of polyamide by an interfacial polycondensation reaction between a functional amine and a polyfunctional acyl halide.

  The inventive step of the present invention is as follows: i) the recognition layer of the composite membrane was obtained as a result of an interfacial polymerization reaction of chiral amino acids and polyfunctional amines with polyfunctional acyl chlorides, (ii) The production of chiral enantioselective layers by interfacial methods requires very little chiral compound and can produce very large membranes with a homogeneous and chiral environment, (iii) this method is a racemic mixture Minimizing the need for optically pure chiral reagents essential for the separation of, and (iv) this method is an enantioselective thin film supported on an ultrafiltration layer that provides high flux and high selectivity The polymer film in the form of

Objects of the invention The main object of the present invention is to provide a process for the production of self-supporting and permselective membranes for the separation of enantiomers by pressure-driven membrane treatment such as reverse osmosis, nanofiltration and the like.

  Another object of the present invention is to provide a composite membrane based on piperazine and trimesic acid chloride which is non-enantioselective and therefore does not undergo enantiomeric separation.

  Another object of the present invention is to provide high stability and enantioselectivity over time invariance.

  Yet another object of the present invention is to provide a process for producing enantioselective composite nanofiltration membranes for the separation of enantiomers of chiral molecules.

  Yet another object of the present invention is to provide a membrane based method for optical resolution of racemic mixtures into optically pure isomers.

FIG. 1 shows an ATR-FTIR spectrum for the chemical structure of the enantioselective layer of the enantioselective composite membrane.

SUMMARY OF THE INVENTION Accordingly, the present invention provides a process for the production of enantioselective composite membranes useful for separating enantiomers from their mixtures to obtain optically pure isomers comprising:
(A) providing an ultrafiltration (UF) membrane produced by a wet phase inversion process;
(B) Dip coating the ultrafiltration membrane obtained in step (a) with a 1-2% aqueous solution of amino acid or amino acid mixture, polyfunctional amine and acid acceptor over a period of 1 to 5 minutes. And maintaining the pH in the range of 10 to 13;
(C) removing the coated UF membrane from the mixture obtained in step (b) and removing excess solution from the UF membrane over a period of 5 to 30 minutes;
(D) The coated film obtained in step (c) is dipped again in a 0.1-1% hexane solution of triacyl halide over a period of 1 to 5 minutes, and the excess solution is applied for 1 to 5 minutes. And removing;
(E) drying the membrane obtained in step (d) over a period of 1 to 4 hours;
(F) heating the membrane obtained in step (e) at a temperature in the range of 70 ° C. to 100 ° C. for a period of 1 to 15 minutes, then cooling and air drying for 1 to 2 hours;
(G) Soaking the membrane obtained in step (f) in deionized water for up to 24 hours to obtain an enantioselective composite membrane comprising an enantioselective layer in contact with the ultrafiltration membrane, Testing for separation from aqueous solution.

  In one embodiment of the invention, the enantioselective layer of the composite membrane used is enantioselective and has a thickness in the range of 400 to 1600 mm.

  In another embodiment of the invention, the amino acid or mixture of amino acids used is selected from the group consisting of at least two primary amino groups.

  In another embodiment, the enantioselective layer of the composite membrane used consists of a crosslinked polyamide polymer having at least one chiral carbon atom.

  In another embodiment, the multifunctional amine used is selected from metaphenylenediamine, piperidine, and the acid acceptor used is selected from triethylamine or NaOH.

  In yet another embodiment, the multifunctional triacyl halide used is trimesic acid chloride.

  In another embodiment, the ultrafiltration membrane used is selected from polysulfone, polyethersulfone, and polyvinylidene fluoride and has a thickness in the range of 20-60 μm.

  In yet another embodiment, the enantioselective composite membrane separates 50-70% arginine and 80-90% lysine from the aqueous solution.

  In yet another embodiment, a method for enantiomeric separation of a racemic mixture of amino acids using an enantioselective composite membrane, wherein the method is within the range of 345 KPa to 862 KPa in a reverse osmosis membrane test unit. At a transmembrane pressure difference, an aqueous solution of amino acids and / or buffers in the range of 0.1 to 1% is used as a feed at a flow rate in the range of 300 to 800 ml per minute, at 20-30 ° C. Do.

  In yet another embodiment, the concentration of amino acids in the permeate is measured by a UV-visible spectrophotometer, and the ratio of d and l-enantiomer in the permeate is measured on a chiral column in an HPLC equipped with a PDA detector. Was evaluated by using.

DETAILED DESCRIPTION OF THE INVENTION The enantioselective thin film composite membrane of the present invention comprises a basic amino acid (amino acids having two primary amino groups, ie, arginine, lysine, etc.) or a mixture of basic amino acids, multifunctional, on a microporous carrier. A functional amine (eg metaphenylenediamine, piperazine, preferably piperazine) and an acid acceptor (triethylamine, NaOH, preferably NaOH) and then a polyfunctional acyl halide (having one or more reactivity) (preferably trimesin Acid chloride). The coating steps need not be in any particular order, but preferably the amino acid or mixture of amino acids, the polyfunctional amine and the acid acceptor are first coated, followed by the coating of the polyfunctional acyl halide. Do. The amino acid or mixture of amino acids and the polyfunctional amine are coated from an aqueous solution, and the polyfunctional acyl halide is coated from an organic solution.

  First, an ultrafiltration membrane is made by a phase inversion technique from a polymer material such as polysulfone, polyethersulfone, polyvinylidene fluoride, preferably polysulfone. In this technique, a solution of the above-mentioned polymer at a desired concentration of 12 to 18% by weight (more precisely 18% by weight) dissolved in an aprotic solvent such as dimethylformamide, N, N dimethylacetamide or the like is added to a polyester nonwoven fabric. It is applied to the (carrier) with a uniform thickness, and after a specified time of 10 to 40 seconds, the carrier is immersed in a coagulation bath containing a 2% aqueous solution of dimethylformamide. Wash the membrane several times with deionized water.

  The ultrafiltration membrane produced in this way can be obtained by combining an amino acid or a mixture of amino acids (arginine) in 1-2% aqueous solution, a polyfunctional amine, preferably piperazine (ratio of arginine and piperazine is 50-50%) and acid. Enantioselection of the present invention by producing in situ an enantioselective membrane on the enantioselective layer of an ultrafiltration membrane by an interfacial polymerization technique by reacting a receptor, ie triethylamine, NaOH, etc., preferably NaOH. Used for the production of porous composite nanofiltration membranes. The pH of the aqueous solution is maintained at 10-13, preferably 12, using a hexane solution of 0.1-1% trimesic acid chloride.

  In order to produce the enantioselective layer on the enantioselective layer of the ultrafiltration membrane, it can be prepared by combining it with an aqueous amino acid or a mixture of amino acids, a polyfunctional amine, preferably piperazine (the ratio of arginine and piperazine is 50-50). %) And acid acceptors, ie triethylamine and NaOH, first dip coat for 1-5 minutes, exactly 3 minutes. The coated UF membrane is removed from the solution and the excess solution is removed from the UF membrane over about 5-30 minutes, precisely 15 minutes, to maintain the desired amount of monomer.

  The UF membrane is then dip-coated over a period of about 1-5 minutes, exactly 3 minutes, in 0.1-1%, precisely 0.5% trimesic acid chloride in hexane. The coated UF membrane is removed from the trimesic acid chloride solution mixture, and the membrane is drained for 1-5 minutes, more precisely 5 minutes, to remove excess trimesic acid chloride solution. The membrane is then air dried for 1-4 hours, exactly 4 hours, then heated to a temperature of 70-100 ° C., exactly 90 ° C. for 1-15 minutes, exactly 10 minutes. To cure. The resulting membrane is then cooled and air dried for 2 hours and then immersed in water for up to 24 hours to obtain the desired enantioselective composite membrane.

FIG. 1: The enantioselective composite membrane was characterized for the chemical structure of its enantioselective layer by ATR-FTIR spectrophotometer. ATR-FTIR spectra of polysulfone films before and after coating were obtained on a Perkin-Elmer spectrometer (Perkin-Elmer Spectrum GX, ATR-FTIR) using germanium crystals at 100 ° nominal incident angle of 100 °. Recorded at 2 cm ^-1 resolution at scan speed. The ATR-FTIR spectrum of (B) after in situ coating of polysulfone membrane (A) and it with a poly (piperazine coarginine trimesamide) membrane is shown below. The peaks at 1487-90 cm ^-1 and 1584 cm ^-1 are characteristic of polysulfone carriers. The appearance of an absorption band in the region of 1472-1644 cm ⁻¹ can be attributed to C═O and C═N stretching vibrations. The peak at 1667 cm ⁻¹ in the spectrum of the coated film represents the formation of amide. There are characteristic absorptions at 1731 cm ⁻¹ (imide ring C═O), 1369 cm ⁻¹ (C—N—C, imide in plane) and 747 cm ⁻¹ (C—N—C, out-of-plane variable angle).

  These membranes are in the range of 345-862 KPa on a reverse osmosis membrane test unit for separation of amino acids, preferably arginine, lysine, alanine etc. from their aqueous solutions and buffers and enantiomeric separation of racemic mixtures of amino acids. The transmembrane pressure difference in the water, exactly 552 KPa, and the flow rate in the range of 300-800 ml per minute using the amino acid aqueous solution and buffer solution in the range of 0.1-1% as the raw water, precisely Used at 500 ml per minute and tested at a temperature of 25 ° C. The concentration of amino acids in the permeate was measured at 290 nm by a UV-visible spectrophotometer, and the ratio of d and l-enantiomer in the permeate to determine the enantiomeric excess (ee%) was determined by the PDA detector. Was evaluated using a Chiral column Chromapack (+) supplied by Diacel Chemical Industries, USA.

  Enantiomers are chiral molecules that have the same molecular formula and chemical structure, but differ only in their configuration. The difference in configuration has many implications because the biological and pharmacological activities of many chiral compounds are completely different. The use of these compounds in optically pure form is therefore urgent. Separation of enantiomers presents a challenge. Many techniques for the separation of enantiomers based on various techniques are known in the art. All enantiomeric separation techniques are based on a chiral microenvironment in the vicinity of the racemic mixture to identify paired enantiomers.

  The presence of a homochiral environment is essential to distinguish paired enantiomers. The novelty of the membrane of the present invention provides a chiral microenvironment to the polymer membrane in the form of an enantioselective layer film supported on an ultrafiltration membrane, resulting in higher flux and higher selectivity. is there.

  The composite membrane of the present invention has a chiral discriminating layer of an enantioselective layer produced in situ on an ultrafiltration membrane. The enantioselective layer discriminating layer was obtained as a result of the interfacial polymerization reaction of chiral amino acids and polyfunctional amines with polyfunctional acyl chlorides. The production of chiral enantioselective layers by interfacial methods can produce very large membranes with a very small amount of chiral compounds and a homochiral environment. Thus, the need for optically pure chiral reagents essential for the separation of racemic mixtures is minimized.

  The following examples are given by way of illustration and should not be construed to limit the scope of the invention.

Example 1
A polysulfone UF membrane is impregnated with a 1% aqueous solution of arginine and piperazine (50:50) for 3 minutes, the pH of the solution is maintained at 12 by adding 1N NaOH, and excess solution is removed over 15 minutes. The membrane was then immersed in a 0.5% hexane solution of trimesic acid chloride for 2 minutes, excess solution was removed over 2 minutes, and the membrane was then allowed to dry in air for 4 hours. An enantioselective composite membrane was produced. The film was heat cured at 90 ° C. for 5 minutes, cooled to a temperature of 25 ° C., allowed to air dry for 2 hours, and then immersed in deionized water for up to 24 hours. The membranes were tested for separation and enantioselectivity for arginine using, as standard, a 0.1% aqueous solution of racemic arginine as a feed at a flow rate of 500 ml per minute at 552 KPa. The membrane showed a permeation rate of 636 l / m ² / day and 75% arginine inhibition. The enantioselectivity for d-arginine was observed to be 65%.

Example 2
A polysulfone UF membrane is impregnated with a 1% aqueous solution of arginine and piperazine (50:50) for 3 minutes, the pH of the solution is maintained at 12 by adding 1N NaOH, and excess solution is removed over 15 minutes. The membrane was then immersed in a 1% hexane solution of trimesic acid chloride for 2 minutes, excess solution was removed over 5 minutes, and the membrane was then allowed to dry in air for 4 hours before enantiose A selective composite membrane was produced. The film was heat cured at 90 ° C. for 5 minutes, cooled to a temperature of 25 ° C., allowed to air dry for 2 hours, and then immersed in deionized water for up to 24 hours. The membranes were tested for separation and enantioselectivity for arginine using, as standard, a 0.1% aqueous solution of racemic arginine as a feed at a flow rate of 500 ml per minute at 552 KPa. The membrane showed a permeation rate of 734 l / m ² / day and 66% arginine inhibition after 6 hours. The enantioselectivity for d-arginine was 50.

Example 3
A polysulfone UF membrane is impregnated with a 1% aqueous solution of piperazine for 3 minutes, the pH of the solution is maintained at 12 by adding 1N NaOH, excess solution is removed over 15 minutes, and then the membrane is trimesin. Immersion in 0.5% hexane solution of acid chloride for 2 minutes, excess solution is removed over 5 minutes, then the membrane is dried in air for 4 hours to form an enantioselective composite membrane. Manufactured. The film was heat cured at 90 ° C. for 5 minutes, cooled to a temperature of 25 ° C., allowed to air dry for 2 hours, and then immersed in deionized water for up to 24 hours. The membranes were tested for separation and enantioselectivity for arginine using, as standard, a 0.1% aqueous solution of racemic arginine as a feed at a flow rate of 500 ml per minute at 552 KPa. The membrane showed a permeation rate of 1125 l / m ² / day and 60% arginine inhibition. The membrane did not show enantioselectivity for d-arginine.

Example 4
A polysulfone UF membrane is impregnated with a 1% aqueous solution of arginine adjusted to pH 12 by adding 1N NaOH over 3 minutes, the excess solution is removed over 15 minutes, then the membrane is trimesic acid chloride Was immersed in a 0.5% hexane solution for 2 minutes, excess solution was removed over 2 minutes, and the membrane was then dried in air for 4 hours to produce an enantioselective composite membrane. The film was heat cured at 90 ° C. for 5 minutes, cooled to a temperature of 25 ° C., allowed to air dry for 2 hours, and then immersed in deionized water for up to 24 hours. The membranes were tested for separation and enantioselectivity for arginine using, as standard, a 0.1% aqueous solution of racemic arginine as a feed at a flow rate of 500 ml per minute at 552 KPa. The membrane showed a permeation rate of 1125 l / m ² / day and an inhibition of 48% arginine, and the membrane showed 50% enantioselectivity for d-arginine.

Example 5
A polysulfone UF membrane was impregnated with a 1% aqueous solution of 12 pH lysine and piperazine (50:50) for 5 minutes, excess solution was removed over 15 minutes, and then the membrane was treated with 0.5% of trimesic acid chloride. An enantioselective composite membrane was made by immersing in a hexane solution for 5 minutes, removing excess solution over 5 minutes, and then drying the membrane in air for 4 hours. The membrane was heat cured at 90 ° C. over 5 minutes, cooled to a temperature of 25 ° C .; air dried over 2 hours, and then immersed in deionized water for up to 24 hours. The membrane was tested under standard conditions using a 0.1% aqueous solution of racemic lysine as a feed at a flow rate of 500 ml per minute at 552 KPa. The membrane showed a permeation rate of 58.719 l / m ² / day and 83% lysine exclusion. The membrane exhibited 90% enantioselectivity for d-lysine.

Example 6
The enantioselective composite membrane prepared in Example 1 was tested under standard conditions using a 0.1% aqueous solution of racemic lysine as feed at a flow rate of 500 ml per minute at 552 KPa. This membrane showed a permeation rate of 293.54 l / m ² / day, 46% inhibition of lysine, and the enantioselectivity for d-lysine was 60%.

Example 7
The enantioselective composite membrane prepared in Example 1 was tested under standard conditions using a 0.05% aqueous solution of racemic alanine as a feed at a flow rate of 500 ml per minute and 552 KPa. The membrane exhibited a 342.30 l / m ² / day flux and 72% lysine inhibition. The enantioselectivity for d-alanine was 56%.

Main advantages of the present invention 1) The enantioselective polymer membranes described in the prior art are asymmetric and dense membranes, such as chiral polymers such as polysaccharides and their derivatives, poly α-amino acids, polyacetylene derivatives, etc. Manufactured from. Most membranes are brittle and have poor mechanical properties, which makes them difficult to handle, so that their use is limited to dialysis mode separations. In dialysis mode separation, the driving force is the concentration of solute across the membrane, so the membrane exhibits a very low drop rate. Membranes with excellent mechanical properties initially exhibit enantioselectivity, but the selectivity rapidly decreases with time due to the recognition site saturation.
2) The composite membrane of the present invention avoids the above-mentioned drawbacks of membranes described in the prior art.
3) The composite membrane of the present invention can be used to perform enantiomeric separations on a commercial scale.
4) The composite membrane of the present invention exhibits a permeation rate of 6-24 gallons / ft ² / day, depending on the transmembrane pressure difference.
5) The composite membrane of the present invention can be used in a pressure driven separation process at a pressure in the range of 345 to 862 KPa. The higher the transmembrane pressure difference, the higher the flow rate, thereby improving productivity.
6) The composite membrane of the present invention is stable and mechanically superior so that it is processed and converted into a modular form.
7) The enantiomeric separation described in the prior art is often a batch process, and even if it is continuous, it has not been applicable to continuous-scale continuous separation. Enantiomeric separations using the membranes of the present invention are a continuous process and can be adapted to large-scale continuous separations.
8) The enantiomeric separation methods of the present invention exhibit high migration rates and resolutions in a reasonable period that allows separation of large scale amino acids from their aqueous solutions and mixtures.

Claims (10)

A process for making enantioselective composite membranes useful for separating enantiomers from their mixtures to obtain optically pure isomers:
(A) preparing an ultrafiltration (UF) membrane produced by a wet phase inversion method;
(B) Dip coating the ultrafiltration membrane obtained in step (a) with a 1-2% aqueous solution of amino acid or amino acid mixture, polyfunctional amine and acid acceptor over a period of 1 to 5 minutes. And maintaining the pH in the range of 10 to 13;
(C) removing the coated UF membrane from the mixture obtained in step (b) and removing excess solution from the UF membrane over 5 to 30 minutes;
(D) The coated film obtained in step (c) is dipped again in a 0.1-1% hexane solution of triacyl halide over a period of 1 to 5 minutes, and the excess solution is added for 1 to 5 minutes. Removing it over time;
(E) drying the membrane obtained in step (d) over a period of 1 to 4 hours;
(F) heating the membrane obtained in step (e) at a temperature in the range of 70 ° C. to 100 ° C. over a period of 1 to 15 minutes, then cooling and air drying for 1 to 2 hours;
(G) Soaking the membrane obtained in step (f) in deionized water for up to 24 hours to obtain an enantioselective composite membrane comprising an enantioselective layer in contact with the ultrafiltration membrane, Testing for separation from an aqueous solution.   The method of claim 1, wherein the enantioselective layer of the composite membrane has a thickness in the range of 400 to 1600cm.   The process according to claim 1, wherein the amino acid or mixture of amino acids used is selected from the group consisting of at least two primary amino groups.   The method of claim 1, wherein the enantioselective layer of the composite membrane comprises a crosslinked polyamide polymer having at least one chiral carbon atom.   The process according to claim 1 (b), wherein the polyfunctional amine used is selected from metaphenylenediamine and piperidine, and the acid acceptor used is selected from triethylamine or NaOH.   The process according to claim 1 (d), wherein the multifunctional triacyl halide used is trimesic acid chloride.   The method according to claim 1, wherein the ultrafiltration membrane used in the manufacture of the composite membrane is selected from polysulfone, polyethersulfone, and polyvinylidene fluoride having a thickness in the range of 20-60 μm.   The method of claim 1, wherein the enantioselective composite membrane separates 50-70% arginine and 80-90% lysine from an aqueous solution.   A method for enantiomeric separation of a racemic mixture of amino acids using an enantioselective composite membrane obtained by the method of claim 1, wherein the membrane is in the range of 345 KPa to 862 KPa in a reverse osmosis membrane test unit. A method using an aqueous solution of amino acids and / or buffers in the range of 0.1 to 1% with a flow rate in the range of 300 to 800 ml / min as feed.   The concentration of amino acids in the permeate was measured by a UV-visible spectrophotometer and the ratio of d and l-enantiomer in the permeate was evaluated by using a chiral column in an HPLC equipped with a PDA detector Item 10. The method according to Item 9.

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