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WO1996011894A1 - Procede destine a separer des enantiomeres d'un melange racemique - Google Patents

Procede destine a separer des enantiomeres d'un melange racemique Download PDF

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Publication number
WO1996011894A1
WO1996011894A1 PCT/EP1995/004063 EP9504063W WO9611894A1 WO 1996011894 A1 WO1996011894 A1 WO 1996011894A1 EP 9504063 W EP9504063 W EP 9504063W WO 9611894 A1 WO9611894 A1 WO 9611894A1
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WO
WIPO (PCT)
Prior art keywords
process according
gel forming
particles
separated
liquid
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PCT/EP1995/004063
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English (en)
Inventor
Cor Peter Mathilde Gerard A'campo
Maria Sabina Leloux
Original Assignee
Akzo Nobel N.V.
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Filing date
Publication date
Application filed by Akzo Nobel N.V. filed Critical Akzo Nobel N.V.
Priority to AU38427/95A priority Critical patent/AU3842795A/en
Priority to JP8512950A priority patent/JPH10507192A/ja
Priority to EP95936506A priority patent/EP0787116A1/fr
Publication of WO1996011894A1 publication Critical patent/WO1996011894A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/24—Dialysis ; Membrane extraction
    • B01D61/246—Membrane extraction
    • B01D61/2461—Membrane extraction comprising multiple membrane extraction steps
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/007—Separation by stereostructure, steric separation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds

Definitions

  • the invention pertains to a process for separating enantiomers from a racemic mixture by countercurrent extraction using at least two substances, one of them a liquid in which the racemic mixture to be separated is present, the other containing a chiral adjuvant.
  • Such a process has earlier been proposed in WO 94/07814.
  • the process disclosed therein specifies the countercurrent extraction of a racemic mixture using at least two liquids at least one of which is chiral or contains a chiral adjuvant, said liquids being wholly iscible and separated from each other by a phase with which they are immiscible.
  • the separating, immiscible phase can be incorporated into a solid carrier which may be porous or not, preferably in the form of a hollow fibre.
  • racemic mixtures can be separated very effectively by the process disclosed in said document, providing that the racemate is not only readily soluble in the extracting liquids, but also in the phase which separates these liquids and is immiscible therewith.
  • examples of substances which cannot be separated by the known process, or can be separated only with great difficulty are chiral substances which do not have a functional group, such as an amino group, keto group, ester or hydroxyl group, as well as certain aromatics.
  • the invention is characterised in that in the process of the known type mentioned in the opening paragraph the chiral adjuvant is combined with or part of a gel forming substance in the form of discrete particles in a liquid separated from the countercurrently flowing liquid containing the race ate to be separated by a microporous membrane having a pore size such that the pores can no longer be penetrated by the gel forming particles separated on conclusion of the extraction, followed by the setting free therefrom of one of the enantiomers under the influence of a stimulus, after which the particles are re-incorporated into the extracting process if so desired.
  • SMBA simulated moving bed adsorption
  • a major advantage of the now proposed process is that the liquid containing the racemic mixture need no longer be separated from the chiral adjuvant-containing phase by a phase immiscible therewith, enabling a much more rapid exchange than was possible with the known process.
  • a further advantage of the now proposed process is that because the chiral adjuvant is combined with or part of the gel forming substance, its separation, and that of the enantiomer extracted therewith, can be simplified significantly.
  • the chiral adjuvant may be covalently bonded to the gel forming substance in that case.
  • the chiral adjuvant is a gel forming substance in the form of a molecularly imprinted polymer (MIP) prepared against one of the enantiomers to be separated.
  • MIP molecularly imprinted polymer
  • This stimulus may take the form of a change in temperature, in pH, in salt concentration, electric or magnetic field, and/or solvent composition.
  • the enantiomer After having been released from the gel forming particles, the enantiomer is generally extracted and, if so desired, purified further by evaporation of the extracting agent and/or crystallisation.
  • the gel forming substance is present in the form of discrete particles. These particles may be of 50 nm to 300 ⁇ m in size, though particles of a larger size also qualify. When larger particles are employed, preference is given to an embodiment in which the gel forming substance no longer comprises the entire particle but is provided on a carrier and physically, preferably covalently, bonded thereto. In such a process favourable results can be attained both when the gel forming substance is provided in the pores of a carrier and when it is provided on its surface.
  • the carriers can be of either inorganic or organic material. Examples of inorganic carriers are ⁇ - alu ina, y-alumina, carbon, ceramic material, or combinations thereof such as alumina on a porous carbon carrier.
  • porous organic carriers based on organic polymers have been described in detail in US-A-4247 498 and US-A-4519909.
  • the force of gravity can be employed to effect countercurrent flow in relation to the liquid flowing in the opposite direction.
  • the porous membrane to be used in the process according to the invention preferably has the largest possible pores, with the proviso that their maximum size is selected such that the pores are just too small to be penetrated by the swollen particles.
  • the membrane depending on whether the liquid flowing around it has polar or apolar properties, is rendered hydrophilic or hydrophobic by physical modification, for instance by treatment with a surface-active compound.
  • the liquid flowing around the microporous membrane is tailored to the polarity of the membrane by the incorporation of a small amount of a compound compatible with the membrane.
  • a porous membrane based on polypropylene very favourable results are attained by incorporating 0,1 to 5 wt of n-hexane into the alcoholic extracting liquid.
  • non-thermoplastic polymers such as cuprophane, cellulose acetate, cellulose triacetate, cellulose nitrate, polytetrafluorethylene, polyacrylonitrile or (regenerated) cellulose
  • thermoplastic materials such as polyolefins, condensation polymers, oxidation polymers, and mixtures thereof can be employed when making the membranes to be used according to the invention.
  • suitable polymers to make membranes from are low-pressure and high-pressure polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyvinylidene chloride, acrylonitrile-butadiene-styrene-terpoly er, styrene- acrylonitrile-copolymer, styrene-butadiene-copolymer, poly(4-methyl-pentene-l) , polybutene, polyvinyl butyral , chlorinated polyethylene, polyvinyl acetate, polyvinyl alcohol, polymethyl methacrylate, polymethyl acrylate, polyimide, polyvinyl disulphide, polyphenylene oxide, polyethylene terephthalate, polybutylene terephthalate, polyaramid, copolyetheresters based on butylene terephthalate and polyethylene oxide glycol having a molecular weight in the range of 800 to 6000, polyamide 6, polyamide 6,6, polyethylene
  • the hollow fibre membranes are commonly arranged in a hollow fibre module.
  • the gel forming particles will then flow through the hollow fibres as a rule, while the racemic mixture flows around them.
  • generally only one chiral adjuvant is used in the process according to the present invention.
  • it is still possible to make use of a symmetrical system such as described in the aforesaid document, though in that case two gel forming substances which differ only in terms of discrimination by the chiral adjuvant have to be available.
  • a acroporous membrane of minimal thickness commonly in the range of 0,1 ⁇ to 1 mm, with preference being given to a membrane thickness in the range of 1 ⁇ m to 100 ⁇ m.
  • the gel forming substance which is chiral in itself, is covalently bonded to a chiral adjuvant, or is a molecularly imprinted polymer (MIP) prepared against one of the enantiomers to be separated.
  • MIP molecularly imprinted polymer
  • the liquid employed as a solvent for the racemate to be separated is one which is capable of swelling the gel forming substance.
  • the person skilled in the art will know which solvent or combination of solvents to select.
  • the chiral adjuvant is incorporated into or part of the gel forming material.
  • a gel forming material which is chiral in itself may be mentioned cellulose triacetate.
  • Another example is a gel forming polyester into the polymer chain of which, say, a chiral diol or dicarboxylic acid has been incorporated.
  • the gel forming material can be combined with a chiral adjuvant.
  • New synthetic routes to optically active monomers and polymers are disclosed by Kevin D. Belfield et al . in TRIP Vol. 3, No. 6 (June 1995), 180-185. The following compounds, including their salts and derivatives, are eligible for incorporation into the gel forming material as chiral adjuvant:
  • racemates of the most widely varying nature.
  • the racemates may be compounds of the pharmacon group, as well as synthons, aromatics, and flavourings, or pesticides.
  • chiral, gel forming materials are eligible for use in separating an even wider variety of racemic mixtures
  • the use of certain combinations of chiral, gel forming materials and racemic mixtures to be separated is greatly preferred.
  • those chiral polymers which display a strong interaction with the racemic substances to be separated. Such strong interaction may be due to hydrogen bridging or Coulomb and/or Van der Waals forces, but may also be due to, e.g., the fact that one of the enantiomers to be separated is more readily incorporated into a cavity of the chiral, gel forming polymer.
  • MIPs molecularly imprinted polymers
  • MIPs are prepared, according to Nicholls et al., Trends Biochem. Sci . 13 (1995), 47-51, by mixing a monomer or monomer mixture judiciously selected to ensure chemical functionality complementary to that of the imprint species with the imprint molecule in the presence of a suitable cross-linking agent.
  • the complementarily interacting functionalities form predictable solution structures, which, after polymerisation and extraction of the imprint species, always results in longer retention times for the imprinted enantiomer. This effect is reflected by the differing binding affinities of enantiomers at MIP recognition sites.
  • finely parti culate cellulose esters of aromatic or aromatic-aliphatic carboxylic acids in the form of substantially spherical, partially crystalline particles having an average diameter of 1 to 200 ⁇ m and a specific surface area of 10 to 300 m 2 /g are disclosed in US-A-5066793. Specifically mentioned are cellulose tribenzoate, cellulose tri (paramethylbenzoate) , cellulose tri (m-methylbenzoate) , cellulose tricinnamate, o-methylbenzoyl cellulose, p-ethylbenzoyl cellulose, p-chlorobenzoyl cellulose, and m- chlorobenzoyl cellulose.
  • optically active adsorbents are disclosed in US-A-5347042. They are derived from sulphur-containing ami no acids which in combination with specific ester and amide radicals, in particular with sterically bulky and rigid ester or amide radicals, lead to optically active adsorbents.
  • the cross-linked polymers are preferably in the form of small particles. The degree of swelling of the particles can be adjusted by customary methods through the nature and the amount of the cross-linking agents, e.g., 1,6-hexane diol diacrylate and 1,2-ethylene glycol diacrylate.
  • the adsorbents are particularly suitable for the separation of amino acids, hexahydrocarbazole derivatives, such as 3-r-(4-f1uorophenylsulphonamido)-9-
  • microcrystalline cellulose I such as: a) cellulose triacetate for separating a racemic mixture of: /3-butyrolactone, keta in, cyanofenfos, dihydro-3-hydroxy-4,4-dimethyl-2(3H)-furanone, 4-hydroxy-2-cyclo-pentenone, 4-phenyl-l,3-dioxane, ⁇ -fenyl- ⁇ - valerolactone, quinazolinone, l-(9-anthryl)-2,2,2-trifluoroethanol; mandelic amide, praziquantel, trans-2,3-diphenyl oxirane.
  • cellulose trisphenyl carbamate for separating a racemic mixture of: acephate, alboatrin, benzoin, benzoin ethyl ether, benzyl vinyl tolyl sulphoxide, catechim, corylbulbine, corydaline, 2-cyclopenten-l-on-4-acetic ester, 1,3-di(9-anthryl)butanol, 2,2'-dihydroxy-6,6'-dimethyl biphenyl, DIOP, guaifenesine, ⁇ -(l-hydroxyethyl)naphthalene, isofenfos, isoprothiolane sulphoxide, ⁇ -lactam, laudanosine, oxazepam, 2-phenyl cyclohexanone, 2-phenyl propionic acid, phosphinoxide, sulphilimine, sulphoxide, tetrahydrocrysamine, tetra
  • Biopoly ers such as albumin and acid ⁇ -glycoprotein for separating a racemic mixture of:
  • / -.-blocking drugs local anaesthetics such as bupivacaine and prilocaine; benzodiazepines such as oxazepam; disopyramide and tocainide; anti-coagulants such as warfarin; NSAIDs such as ibuprofen, fenoprofen, and naproxen; atropine, clidinium, mepenzolate, oxyphencyclidine; antineoplastic alkylating agents such as cyclophosphamide; verapa il; histamine antagonists such as chlorphenira ine, bromodiphenhydra ine, pro ethazine; mianserin; doxy1amine; cocaine, butorphanol, methadon, propoxyphene, and pentazocine; ephedrine and pseudo-ephedrine; catecholamines such as dobutamine; terbutaline; phenmetrazine.
  • local anaesthetics such as bupi
  • Amylose gels such as amylose carbamate for separating a racemic mixture of: chlorpheniramine, dihydropyridine, dimethothiazine, NSAIDs such as fl urbiprofen, ketoprofen, and i buprofen, methyl succiliens acid, 5-norbornene, p-cyclophane, 2-phenyl butyri c acid, l-phenyl -l ,2-ethane diol , porphyri n, promethazi ne, sul i ndac methyl ester, thiaprofeni c aci d, l, l, l-trichl oro-2-hetanol , 4-acetoxy-2-azetidi ne, afloqual one, 2-chl oro-2-butanone, 2-cyano-4-phenyl butyri c acid, ethiazide, ofl
  • Gels based on polyurethanes modified with tartaric acid, mandelic acid or amino acid derivatives for separating ethanolamines such as 3-sympathicomimetics and ⁇ -sympathicolytics, amino acids, and arylpropionic acids.
  • the process according to the invention may be carried out by means of a single countercurrent extraction, but preferably takes place using a number of extracting units connected in series. Preference will be given to an embodiment utilising hollow fibre membranes whose maximum pore size is a fraction smaller than the smallest diameter of the swollen gel particles. Best results are obtained by convection in macroporous polymer modules operated in the closed shell and closed lumen mode.
  • Fig.l shows the hollow fibre module assembly used in the experiment described in Example II
  • Fig.2 shows the hollow fibre module assembly used in the experiment described in Example V
  • Fig.3 shows the hollow fibre module assembly used in the experiment described in Example VI.
  • the aforementioned hollow fibre module consists of a tubular case 1 connected at both ends via a thread to a socket 7 or an end cap 8.
  • the case 1 is partially filled in longitudinal direction with hollow fibres 4, of which the hollow ends open into the epoxy pottings 5 and 6.
  • the hollow cap 8 above said pottings is provided with connections 9 and 10, through which the suspension is kept in constant movement via pump 23.
  • Cap 8 is further connected, via a tube and pump 12, to vessel 11, which contains a suspension kept in constant motion with magnetic bar 13.
  • the suspension passes from vessel 11 via pump 12, cap 8, fibres 4, socket 7, fibres 4a, cap 8a, and pump 14 into vessel 15.
  • the solvent in vessel 16 passes, via pump 17, to the shell side of fibres 4a, side connection 2a, and pump 18 to the shell side of fibres 4 and pump 19, to end in vessel 20.
  • the solution of the racemic mixture in vessel 22 is fed, via pump 21, to socket 7.
  • Fig. 2 shows a set-up of eight modules.
  • Each module consists of a 254 mm long glass tube with two side connections. The inside diameter of each glass tube is 10 mm, the effective length between the side connections 200 mm.
  • Each module contains 300 hollow fibres of Oxyphan 0x-pp5045/02.01. The inside diameter of each fibre is 280 ⁇ m and the outside diameter 380 ⁇ m. The fibres are bundled in the form of mats.
  • the solvent passed from vessel 1 via pump 5 and the lumen side entrance 10a into module case 9a and left said case via connection 12a.
  • the solvent passed the lumen of the other seven modules in an analogous manner to end up in vessel 2 via pump 6.
  • the suspension in vessel 3 passed, via pump 7 and shell side connection 13h, to the shell side connection of module 9h to leave via the shell side connection llh. Then the suspension passed the shell of the other seven modules in an analogous manner to end in vessel 4 via pump 8.
  • Fig. 3 shows a set-up of eight modules of the same type as those of Fig. 2.
  • the magnetically stirred suspension in vessel 1 is recirculated via pumps 2, 4, 5, and 6 to pass the solvent regeneration modules 9a and 9b, the stripper modules 9c and 9d, the extraction modules 9e and 9f, and the washing modules 9g and 9h, respectively.
  • the cleaned suspension is returned via pump 8 to end in vessel 1.
  • the cleaned solvent leaves cap 19 and flows, via pump 20, to the solvent supply vessel 10.
  • the dissolved racemic mixture in vessel 22 is fed to the system via pump 21.
  • a solution of the less well retained enantiomer is collected in vessel 17, use being made of a difference in flow rate between the metering pumps 16 and 18.
  • a solution of the more strongly retained enantiomer is collected in a similar way in vessel 14, use being made of a difference in flow rate between the metering pumps 13 and 15.
  • Ten suspensions were prepared, each containing about 250 mg of swollen CTA-I particles and about 750 mg of a sodium carbonate neutralised alcoholic solution containing approximately 1 mg of ketamine.HCl/ml (90, 96, and 100% ethanol, and 90, 96, and 100% 2-propanol , respectively) .
  • the suspensions were left to settle.
  • the concentration of ketamine enantiomer was determined on the filtrate using capillary zone electrophoresis.
  • the alcoholic solutions used to prepare the suspensions were taken as external standards to calculate the ketamine enantiomer content in the filtrate.
  • ket.HCl stands for ketamine.HC1
  • ETOH represents ethanol
  • IPA stands for 2-propanol .
  • the standard solutions contain 1,17 g of ket.HCl/ml ETOH and 1,02 g of ket.HCl/ml IPA, respectively.
  • the measured quantities of R- and S- 15 are 1,17 g of ket.HCl/ml ETOH and 1,02 g of ket.HCl/ml IPA, respectively.
  • a racemic mixture of R- and S-ketamine.HCl was separated using two hollow fibre modules 1 and la having an inner diameter of 23 mm and a length of 155 mm, which were connected in series. Each module contained 2100 porous polypropylene fibres of 240 ⁇ m inner diameter.
  • the apparatus Prior to the start of the passage of dispersion, the apparatus was filled with solvent and de-aerated on the shell side by the application of a vacuum.
  • the solvent in question was a mixture composed of 96% of ethanol and 4% of an 0,01 M Na2HP ⁇ 4 solution in water.
  • the dispersion of gel particles was composed of CTA-I particles having the same dimensions as in Example I.
  • the dispersion was subjected to ultrasonic vibration. For the same reason the modules were arranged vertically and the dispersion was passed through the modules from the top downwards. Further, there were two membrane pumps 23 and 24 to ensure that the dispersion was kept in motion over the potting and to create a pulsed flow in the lumen. After 80 minutes the amount of solids was reduced from about 11,1 wt.% to about 8 wt.%. The concentration of the feed in the channel connected to the lumen of the two modules was 1 g/100 ml for the first 30 minutes. After 50 minutes a feed of a different composition was employed, which also contained salt used for neutralising.
  • Example II In a manner analogous to that disclosed in Example I it was determined on a racemic mixture of 4-phenyl-l,3-dioxan at room temperature how much more (-)-configuration than (+)-configuration was incorporated into a suspension of swollen cellulose triacetate (CTA-I) particles.
  • the eluent used was 96% ethanol.
  • the sample of the suspension was composed of 1 g of CTA-I and 7 g of 96% ethanol in which 1,16 mg/ml of ( ⁇ )-4-phenyl-l,3-dioxan had been dissolved. After one hour of shaking at room temperature the suspension was left to settle.
  • Example III The experiment of Example III was repeated, except that this time the gel forming chiral adjuvant used was tribenzoyl cellulose, which was obtained in accordance with the synthesis specifications in K.H. Rimboeck, J. of Chromatography 351 (1986), 346-350, It was found that the affinity of tribenzoyl cellulose was opposite to that of CTA-I, resulting in the concentrations in the liquid and the gel phase being inversely distributed.
  • the sample of the suspension was composed of 1,0 g of tribenzoyl cellulose (CTB) and 7 g of 96% ethanol in which 1,16 mg/ml of ( ⁇ )-4-phenyl-l,3-dioxan had been dissolved. After one hour the upper liquid contained 0,37 mg/ml of (+)-4-phenyl-l,3-dioxan and 0,40 mg/ml of (-)-4-phenyl-l,3-dioxan.
  • CTB tribenzoyl cellulose
  • the example below shows that it is possible to separate a 50/50 mixture of enantiomers of 4-phenyl-l,3-dioxan by subjecting it to countercurrent separation using a set-up of hollow fibre modules such as depicted in Fig. 2.
  • the hollow fibre modules had an inner diameter of 10 mm and an effective length of 200 mm.
  • Each glass module contained 300 porous polypropylene fibres with an inner and an outer diameter of 280 and 380 ⁇ , respectively (Oxyphan ox-pp5045/02.01) in an epoxy potting.
  • the hollow fibres were bundled on a knitting machine at one stitch per centimeter.
  • the fluid streams were pumped from vessel 1 (solvent) and vessel 3 (suspension) through the shell and the lumen in the modules with the aid of four membrane pumps with back pressure valves mounted at the ends of the separating column.
  • the pair of pumps 5 and 6 in the lumen stream was coupled to give a simultaneous membrane stroke in the pumps and create a pulsed flow in the lumen.
  • the pair of pumps 7 and 8 in the shell stream was synchronised in the same way.
  • the displacement of liquid on the lumen side was alternated 20 times per minute with the displacement of suspension on the shell side.
  • the air bubbles were expelled by recirculation of the solvent via a buffer vessel and recirculation of the suspension via a second buffer vessel.
  • the amount of liquid in each of the buffer vessels during the recirculation was kept constant. Where necessary, the difference in delivery capacity of the synchronised pumps was reduced by adjusting the pumps' stroke volume.
  • the liquid used for separating the racemate of ( ⁇ )-4-phenyl-l,3-dioxan was made up of 96% ethanol.
  • the separation was carried out using a suspension of CTA-I of the same proportions as indicated in Example I.
  • the suspension was composed of a mixture of 100 g of CTA-I in 700 g of ethanol-water mixture (96+4).
  • the suspension was subjected to ultrasonic vibration and sieved. For the same reason the modules were arranged vertically and the dispersion was passed through the modules from the top downwards. Settling of the suspension was counteracted by pulsing the movement in the tubes and the modules.
  • Table 4 sample flow through enantiomer after lumen (solvent) concentration excess minutes or mg/ml mg/ml ee + % shell (d ispersion) 4-phenyl- •1,3-dioxan i ⁇ l
  • an enantiomers mixture can be separated into the (+)- and (-)-constituents with a set-up such as depicted schematically in Fig. 3.
  • the suspension of vessel 1 is recirculated, being first passed, via pump 2, through the shell of the two solvent regeneration modules 9a and 9b, where the remainder of one of the enantiomers is removed from the solvent flowing through the lumen.
  • the flow of suspension is passed through the shell of the two extraction modules 9c and 9d, the stripper modules 9e and 9f, and the washing modules 9g and 9h. From there the virtually enantiomer-free suspension is passed to vessel 1.
  • the virtually enantiomer-free solvent is passed from vessel 10, via pump 11, through the lumen of the washing modules 9h and 9g, where the suspension containing one of the enantiomers is washed such that practically all of the enantiomer absorbed by the chiral adjuvant is re-released, before ending up in vessel 14, from where a portion is passed countercurrently through the lumen of the stripper modules 9f and 9e.
  • the racemic mixture of vessel 22 is dosed using pump 21. From 9c the lumen flow is passed, via pump 16, into vessel 17, from where because of a difference in pump discharge between the pumps 16 and 18 a portion of the liquid is passed into the lumen of the solvent regeneration modules 9b and 9a.
  • the mean flow rate of the suspension in the scheme depicted in Fig. 3 is kept constant and equal in each module by an alternating pump action similar to that described in Example V.
  • the solid flow rate can be calculated from the suspension flow rate.
  • the mean flow rate of the liquid is set per module section, and the differences in liquid flow rate between sections are compensated for by the solvent, raffinate, feed, and extract streams. Net liquid flow rates are calculated from the countercurrent suspension flow rate and the liquid flow rate. The net liquid flow rate and the solid flow rate are the parameters used in the aforementioned design procedure.
  • a module section can be used as a washer, stripper, extractor or solvent regenerator by adjusting a flow rate ratio within a specified range.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
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  • Urology & Nephrology (AREA)
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Abstract

On décrit un procédé destiné à séparer des énantiomères d'un mélange racémique, par extraction à contre courant à l'aide d'au moins deux substances, l'une de celles-ci étant un liquide dans lequel le mélange racémique à séparer est présent, l'autre contenant un additif chiral combiné à une substance ou faisant partie d'une substance formant un gel sous la forme de particules distinctes dans un liquide séparé du liquide circulant à contre courant et contenant les racémates à séparer à l'aide d'une membrane microporeuse possédant une dimension des pores telle que ces pores ne laissent pas passer les particules qui forment le gel et qui ont été séparées à la fin du processus d'extraction; cette extraction est suivie par la libération d'un des énantiomères, à partir des particules formant le gel et sous l'influence d'un stimulus, après quoi les particules sont incorporées à nouveau dans le processus d'extraction, si nécessaire. Au cours de ce processus, le matériau formant le gel est, de préférence, dans un état gonflé, prenant la forme de particules distinctes, et il circule à travers une membrane microporeuse réalisée préférablement en polypropylène.
PCT/EP1995/004063 1994-10-17 1995-10-16 Procede destine a separer des enantiomeres d'un melange racemique WO1996011894A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU38427/95A AU3842795A (en) 1994-10-17 1995-10-16 Process for separating enantiomers from a racemic mixture
JP8512950A JPH10507192A (ja) 1994-10-17 1995-10-16 ラセミ混合物から鏡像異性体を分離する方法
EP95936506A EP0787116A1 (fr) 1994-10-17 1995-10-16 Procede destine a separer des enantiomeres d'un melange racemique

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NL9401705 1994-10-17
NL9401705 1994-10-17

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001098265A2 (fr) * 2000-06-19 2001-12-27 Cristália Produtos Químicos E Farmacéuticos Ltda. Procede d'obtention d'enantiomeres de cetamine racemique, procede d'obtention de sels pharmaceutiquement acceptables a partir d'enantiomeres de cetamine racemique et utilisation de sels pharmaceutiquement acceptables obtenus au moyen dudit procede mentionne
WO2015029072A2 (fr) 2013-08-30 2015-03-05 Council Of Scientific And Industrial Research Dédoublement des médicaments racémiques à l'aide d'un sélecteur chiral supporté sur polymère
US10815196B2 (en) 2015-05-13 2020-10-27 Janssen Pharmaceutica Nv (S)-CSA salt of S-ketamine, (R)-CSA salt of S-ketamine and processes for the preparation of S-ketamine

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7049245B2 (ja) 2015-09-16 2022-04-06 アピール テクノロジー，インコーポレイテッド 分子コーティングのための前駆体化合物

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EP0121776A1 (fr) * 1983-03-10 1984-10-17 Daicel Chemical Industries, Ltd. Agent de résolution
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EP0121776A1 (fr) * 1983-03-10 1984-10-17 Daicel Chemical Industries, Ltd. Agent de résolution
GB2233248A (en) * 1989-06-07 1991-01-09 Aligena Ag Enantiomer enrichment by membrane processes
WO1991017816A1 (fr) * 1990-05-23 1991-11-28 Research Corporation Technologies, Inc. Membrane liquide chirale soutenue pour la separation d'enantiomeres
WO1994007814A1 (fr) * 1992-10-07 1994-04-14 Akzo Nobel N.V. Procede de separation d'enantiomeres d'un melange racemique

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001098265A2 (fr) * 2000-06-19 2001-12-27 Cristália Produtos Químicos E Farmacéuticos Ltda. Procede d'obtention d'enantiomeres de cetamine racemique, procede d'obtention de sels pharmaceutiquement acceptables a partir d'enantiomeres de cetamine racemique et utilisation de sels pharmaceutiquement acceptables obtenus au moyen dudit procede mentionne
WO2001098265A3 (fr) * 2000-06-19 2002-08-15 Cristalia Produtos Quimicos E Procede d'obtention d'enantiomeres de cetamine racemique, procede d'obtention de sels pharmaceutiquement acceptables a partir d'enantiomeres de cetamine racemique et utilisation de sels pharmaceutiquement acceptables obtenus au moyen dudit procede mentionne
US6743949B2 (en) 2000-06-19 2004-06-01 Cristália Produtos Químicos e Farmacêuticos Ltda. Process of obtainment of racemic cetamine enantiomers; process of obtainment of pharmaceutically acceptable salts from racemic cetamine enantiomes and use of pharmaceutically acceptable salts obtained by means of said mentioned process
WO2015029072A2 (fr) 2013-08-30 2015-03-05 Council Of Scientific And Industrial Research Dédoublement des médicaments racémiques à l'aide d'un sélecteur chiral supporté sur polymère
WO2015029072A3 (fr) * 2013-08-30 2015-06-04 Council Of Scientific And Industrial Research Dédoublement des médicaments racémiques à l'aide d'un sélecteur chiral supporté sur polymère
US9809706B2 (en) 2013-08-30 2017-11-07 Council Of Scientific & Industrial Research Racemic drug resolution using polymer supported chiral selector
US10815196B2 (en) 2015-05-13 2020-10-27 Janssen Pharmaceutica Nv (S)-CSA salt of S-ketamine, (R)-CSA salt of S-ketamine and processes for the preparation of S-ketamine

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JPH10507192A (ja) 1998-07-14
AU3842795A (en) 1996-05-06
CA2202911A1 (fr) 1996-04-25
EP0787116A1 (fr) 1997-08-06

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