MXPA99007287A - Annular chromatograph - Google Patents

Abstract

The invention relates to an annular chromatograph with a particle bed in its annular gap. Said chromatograph is characterised in that at least one reaction zone for conducting the chemical reactions and at least one associated separation zone for the chromatographic separation are provided.

Description

ANNULAR CHROMATROGRAPH DESCRIPTION OF THE INVENTION The present invention relates to an annular crook with a particle bed in its annular groove. Annular chromatography represents a variety that has been recognized for some years and practiced in an ever growing area of preparative chromatographic separation. Annular chromatography is preferably used when large amounts of mixtures of substances have been separated, since this type of chromatography can be carried out continuously, and is a relatively high degree of separation or dissolution.

A typical P-CAC apparatus ("P-CAC" preparative continuous annul chromatography) consists of a circular ring-shaped particle bed. This is "annular" that in the intermediate space (notch the ring) is packed between two concentric cylinders. Under rotation of the particle bed around its axis, continuous feed solutions as well as one or more eluents are produced at the upper end. Such process forms are known in accordance with the state of the art and widely used, for example P-A 371 64 In preparative chemistry, especially in the field of biochemistry and medicinal chemistry, the degree of purity of the products of chemical reactions has a decisive significance, since complex processes of pr-e purification, elaboration REF .: 31053 final purification, to lower the inevitable impurity content to the lowest possible values, in the case ide below the detectable limit. Said purification methods are carried out mostly in separate apparatuses and in a p-lot operation, that is the purification of the starting products and the final product is carried out for example chromatographically in columns or in separate columns which prevents a continuous operation, since the separating agent after separation of the mixtures of substance has to be re-rinsed, regenerate or equilibrate. In the best of cases, an intermittent feed stream is possible in the performance of a semi-continuous process. But with this it limits the passage of such facilities, the expenditure on appliances, time and finances is high for such procedures as a result of the price for the products so manufactured. Another problem that the technician must confront in the chromatographic separations is the compromise between the space of time necessary for the separation, that is, the time the substances remain in the columns and the dissolution reached of the mixtures of substances. Usually the residence time is reduced - however (in most cases also the dissolution - with an increasing current velocity of the eluent and vice versa, where in order to achieve a separation efficiency in general, relatively low current velocity is preferred.

In contrast to the above, it is normally desired for the chemical reactions in the step reactors to increase step quantities and also high current speeds which is additionally against the operation of the reaction and the separation. The purpose of the invention is the preparation of annular chromatographic installation for the continuous realization of chemical reactions and steps of pre-purification or post-purification in a continuous process and with economic form. Another objective is the optimization of the permanence times of the substances in the individual sections of the installation. This object is achieved according to the invention by an annular chromatograph with a particle bed in an annular notch, which is characterized in that it at least provides a reaction zone for carrying out the chemical reactions with at least one coordinated separation zone for the reaction. chromatographically separated. Such arrangement of reaction zone and separation in a single chromatographic column (in any succession) allows successive reactions and separation (s) or purification (s) reaction (s) in a perfectly continuous operation, that is, not only the feed stream is intermittently fed, but in the annular chromathography the desired product or products have desired local positions along the periphery of the columns from the column or in the column. present case from the corresponding zone and in the following areas. Another advantage of this system is that, in such a reaction chromatograph, the products formed in the reaction zones are continuously withdrawn from the reaction zones, which shifts the reaction equilibrium towards the product side, thereby resulting in rapid transformations. and in what is quantitatively important. For the separation of the mixtures contained in such "fixed-bed reactors" and separation and / or purification, the reaction products formed in the reaction zone have, according to the invention, a reaction zone up to at least one zone of reaction. separation. Alternatively, in addition to this, for the pre-purification of at least one starting product available for the chemical reactions that develop in at least one reaction zone also according to the invention, preferably a separation zone above at least one reaction zone. Also combinations of reaction zones and separation to almost any number and sequence are possible according to the invention. Thus, for example, after a separation zone for pre-purification, one or several reaction zones can be followed one behind the other or one below the other where one or more separation areas of the product are connected again. reaction and byproducts. In this way, reactions of multiple steps can be carried out as well as of the specific and selective type and separations of a single reactor / chromatograph. The material for the separation zones may consist of ion exchange resins, cation exchange resin, justification gels, gel permeation gels, affinity gels, hydrophobic chromatography gels (HIC), displacement resins, reverse phase gels , and electrophoresis gels any other separation means usually applicable in chromatographic separation procedures. Here, depending on the separation problem, it is possible to apply desirable combinations of gels and separating resins. In the use of electrophoresis gels, electrodes for tension are placed on the upper and lower edge of electrophoretic separating layer. electrical connection is made for example by means of a collector ring contact on the axis of rotation of the column Details for this are found in the dependent Austrian patent application filed on December 1, 1997 by the present applicant under number A 2030/97 . The material for the reaction zone or zones can in general be selected from the same materials as the separation zones as well as from materials inert to the reactions that they develop, depending on the type of reaction, for example, glass perl, activated carbon, ( given the modified case), polymer aluminum oxide, silica gel. According to the invention, it prefers glass beads as well as activated carbon. The material for the reaction zones can however be impregnated coated in the preferred embodiments of the invention with one or more reaction catalysts, such as metals, metal complexes, or enzymes, for example Pd / C, Pt / C, etc. . These measures allow for example common feeding of multiple reaction components in a single feed stream, where only a real reaction is reached upon contact with an immobilized catalyst in the reaction zone. Alternatively to that, the material for at least one reaction zone according to the invention can also be coated with at least one reactant, that is, one or more reactants can together with catalyst (and be conducted in a feed stream)., but the reaction again presents only up to the reaction zone in chromatograph; according to the invention, however, all the reactants can also be immobilized in the particle material of the reaction zone and only the catalyst, the catalysts necessary to be fed with the feed stream, in the event that one or more components of feed current move when less one reactant the solid phase, to put this or the remaining reactants in contact. The particle bed in the annular chromatograph of the invention may consist of a single material or of different materials for the reaction and separation zone, where material of the reaction zone may be impregnated or coated and the two particle matter given the case pass one inside the other continuous way. In a preferred embodiment, however, all the zones contained in the chromatograph separate from one another by separating layers, so as to avoid mixing both the particle materials and the individual materials between the respective zones. Such separation layers may be selected from membranes, inert non-porous particle material and especially in the application electrophoresis of non-electrically conductive material. they also prefer glass beads, which also p a large part of the reactions considered are both inert and non-electrically conductive. In another preferred embodiment, the particle bed is covered with a cover layer and / or with a base layer or below, wherein the cover or base consists preferably of the same material as the separating layer (s), especially glass beads. If, for example, the upper or lower zone determines the electrophoretic separation, it is advisable in each case to provide a covered or base layer, to keep the electric cam as constant as possible. In the annular chromatograph, a bed is common in the cylinder liner of a single thickness, which has the consequence that the current velocity of the liquid in the essential is kept constant or the density of the bed packet is determined. of particle. According to the invention it is proposed that the annular notch in the chromatogram be formed on their height are areas of different thickness, where intermediate equalization zones exist, which cause a variation of current as far as possible without steps, and which rule general will be curved or conical. In preferred embodiments it is or is at least a part of the height of the lec of particles of the inner cylinder and / or of the outer cylinder of the reactor, conical or preferably, where the others are commonly constructed, which increases the flow velocity. in the bed of particles and by the shortening of the distance d of the dissolved materials and corresponding shrinkage of the diffusion and migration thereof in the particle bed, as a consequence a decrease in the width of the band and with this a concentration effect. Alternatively or in addition to this, it is possible in other embodiments of the internal cylinder and / or the outer cylinder of the reactor to make at least a part of the height of the bed of particles, preferably conical, each constructed away from the others. In this way the flow velocity in the particle bed is decreased, which, for example, results in an increase in the dissolution of the separation zones. Correspondingly they find the narrowing that is positions with approaching column walls, according to the invention preferably at the end of the reactor zones with subsequent separation zone, to give power at the beginning of the separation zone the concentrated m possible as long as possible. that the enlargements will preferably be made in the region of the separation zones where, as mentioned, the separation performance of the column is improved. The conformation of the narrowing or widening in cone shape guarantees the uniformity of the current in the regions, with which also in those places it will be able to produce a zone of accumulation, secondary currents or return mixture. In preferred embodiments in the chromatograph of the invention in the region of at least one zone in the inner and / or outer cylinder a temperature jacket is provided for heating or cooling the solutions transported in the column. This may have significance especially in the reaction zone, where a certain reaction temperature must be maintained, but the chromatographic separation in the zones of separation by the temperature may also be included, which also a quenching jacket in both the reaction zones as in those of separation is within the claim of the invention. In another embodiment in the region, at least one region in the internal and / or external cylinder, or radiation source as a heat source and / or as a catalyst is provided for the reaction or initiator. This means, for example, only for heating a particular region of the chromatograph by means of infrared or microwave radiation, but also for the initiation of photochemical reactions (by means of eg visible light or invisible UV) within the column. DESCRIPTION OF THE DRAWINGS A detailed description of the invention follows and reference to the attached drawings where it shows: Figure la) and Ib) schematic views of embodiments d of the annular chromatograph of the invention; Figures 2a and 2b) schematic views of other embodiments of the annular chromatograph of the invention: Figure 3 a schematic sectional view of an embodiment of an annular chromatograph according to the invention with radiation sources and tempering jacket Figure 4 is a schematic sectional view of an annular chromatograph according to the invention with modifications of the cross section of the stream; Figures 5a-5f diagrams of possible embodiments of the annular chromatograph according to the invention c narrowing and widening of the fluid stream. L. Figure i schematically shows two embodiments of the present invention, properly an annular chromatograph with a reaction zone and one or two separation zones 2, 3 in an annular column made of an inert material with respect to the components of the solutions of reaction and preferably glass separation, consisting of an internal cylinder 8 and external cylinder 9 (where in Figure 1 only s represents the cylinder 9). The column mounted rotatably about axis 12 (by means of a motor not shown) and fed continuously by means of connecting conduits 13 with the supply and solvent means, by a distribution head 14 as well as driving channels 15 The channels 15 can have the usual shaping forms, ie single, multiple or slit nozzles or the like, however, for the invention, curved slot nozzles adjusted to the periphery of the column of different widths are preferred in order to determine what is required. more exactly possible between the feeding currents and the eluent. At the lower end of the columns, channels or exit tubes 16 have been provided for eluyent accumulation These outlets 16 can be joined with the columns (this rotates with them around the axis 12) but also be fixed on the shaft 12 and for example by means of a sliding ring being in contact with the rotating column with respect thereto, where it prefers the latter. embodiment. The material of the supreme zone 1 or 2 is each time covered with a covered layer 6, in which the feed channel 15 preferentially drains, in order to guarantee a uniform supply. In FIG. 1), a base layer 7 is additionally shown, which in addition to a porous floor plate, does not represent, for example, glass mass, membrane disc, etc. ) serves to prevent an exit of particle material in the column floor. The individual reaction and separation zones are usually separated by separation layers 5, to prevent or mix the materials of the particles in the two zones. The material for the separation layers, base cover 5, 8, 9 is selected from membranes thus inert particle material with respect to the set of components of the respective reaction and separation solutions and can for the three layers be equal or different, where however, special for electrophoretic separations must be non-conductive. According to the invention, glass beads are preferred, since they are practically for all applications inert and easily applicable.

In FIG. 1) a reaction zone 1 is provided with a separation zone 2. The material for the reaction zone can be made of inert particle materials with respect to the reactions to be developed, such as, for example, glass beads, preferably those with a diameter approximately 150-240 microns, as well as material c separate effect, such as for example ions exchange resins, exclusion resins, etc. where the material itself can take part in the reactions (for example H-ion exchanger, catalysis or others) or not take part The reaction zone material 1 can also be coated with a number of reactants and / or catalysts (e.g. metallic complexes, enzymes, pH modifiers, etc.), so that reaction develops in the solid phase.Theoretically also all the reactants can be immobilized in the carrier in case at least one component driven together with the current power supply (for example the same solvent) when at least one component of the reaction displaces it from the bond in the solid phase, that is, it starts from it, during the operation of that annular chromatograph it encourages a feeding solution that contains one of the reactants, via the conduit channel 15 to the column, arrives there from the reaction zone 1, where the desired chemical reaction of the the reaction partners. This is separated at the lower end of zone 1 in the separating cap 5 and then in the separating zone 2, where it performs the separation and purification of the substance mixture.

The components thus separated, product, catalyzed starting products and possible secondary products) salts d system at the lower end of the column by the tubes outlet 16 at defined positions 9 that is, at a defined angular position) along the periphery of the annular chromatop, and are captured there and if necessary led to tanqu or processing devices (to condense them, precipitate them etc.

The height and diameter of the individual zones influenced by the reaction and separation class, the desired residence time of the substances in the column, the particle material class, the packing density of the corresponding zones, the desired solution of separation and other factors, known to technicians. The efficient technician is in a position to give the corresponding dimensions when raising the specific problem, for example empirically or by previous testing. In Figure Ib, three zones 1, 2 are provided, separated from each other by separating layers 5. From zones 2 and 3 they conceive as separating zones and the intermediate zone as a reaction zone. With this, a plurality of components of the feed solution supplied by the supply tubes can be pre-purified in the separation zone 2, before the desired reaction is developed in zone l. Then follow in a similar manner as described in reference to Fig. 1) a separation of the reaction products in the separation zone 3. Other embodiments of the invention are shown in Figures 2a and 2b. In Figure 2a) are represented each two zones of separation and reaction 2, 3 or 1, 4. In the annular chromatograph can be carried out a synthesis multiple steps continuously, where in the connection in the first reaction step in the area of reaction i can perform an intermediate purification in the separation zone then a second reaction step in the reaction zone 4 finally the final purification in the separation zone 3. Figure 2b) shows an embodiment with a zo reaction and two separation zones 1 or 2, 3 in which a mixture exiting the reaction zone 1 can be purified in two stages, which allows very pure products in the outlet of column 16. In FIG. 3 a schematic representation is shown for a particularly preferred embodiment of the invention. Here, two separation zones and two reaction zones have been provided, in each case a zone 2 for pre-purification similarly to Figure Ib), two reaction zones 1, successive for the realization of a two-stage synthesis as well as again a separation zone 3 for a final purification step. The first reaction zone 1 is provided with a radiation source 11, which is disposed along the internal periphery of the internal cylinder * and the outer periphery of the outer cylinder 9, so that a full volume of the zone can be applied uniform radiation. As radiation, any type of electromagnetic radiation, for example, visible light and UV light, such as catalysts, radiation and microwaves as UV sources, and UV radiation and UV radiation are preferred. In connection with the above there follows another reaction zone 4 for the second reaction stage, which is provided with a quenching jacket, for heating or cooling, which serves either to bring the reaction mixture to the required reaction temperature, or also (as in this case) for after the effect of the radiation in zone 1 to cool before final separation. Such tempering jackets may also apply, as is understandable, to separation zones, to directly temper the mixture, in most cases to cool it. The supply of energy to the radiation source and the quenching jacket can be done on the inside through shaft 12, or on the outside. Although in FIGS. 1-3 each time a maximum of two reaction zones and two separation zones has been presented, it can be any desired number and zone succession as claimed in the present invention. To regulate the current velocity of the mobile phase in the individual zones, arrangements can be made for modifying the current cross section. narrowing of the same causes for example a fast current m in that section and with that - as already described - a concentration effect, while a widening of the cross section of the current results in a slow effect in the current and in that way better exchanger effect with the stationary phase. In a reacted zone such widening produces a complete reaction, in a separation zone an improvement of the separation efficiency, this and dissolution. Figure 4 shows a possible modification in the passage from a reaction zone 1 to a separation zone 2. At the lower end of zone 1 the transverse section of the column is narrowed, in the Figure at 1/4 of the value original, which leads to an increase in the speed of the current (here for example to 16 times) and with that to a concentration of the mixture leaving the reaction zone, which then travels through a layer d separation 5, for example made of glass beads, which include inter alia a region with a narrow cross section but parallel cylindrical walls, which can be indicated as a concentration zone 17. Finally, the mixture penetrates the separation zone 2. In the passage of the separation layer 5 in the separation zone 2, the cross section (and low current speed) is widened again to the starting value; the exchange effects with the solid phase become stronger and the dissolution of the mixture in its components is improved. widening of the cross section to higher values than in zone 1 would bring more improvement in separation performance. The conformation of the cone-shaped widening gaps guarantees the uniformity of the current in those regions, so that there will be no accumulation, secondary currents or mixtures backwards, since the turbulence has thus been reduced a minimum. But in general it is necessary a compromise between the time of permanence of the mixture in the column, that is, the column travel on the one hand and the reaction or dissolution on the other hand, to bring the annular chromatography to an optimum state in accordance with the invention for a given system d reaction / separation, this is the cross section of the current can not be made large or small at will. The ratio between the maximum and minimum annular notch widths is preferably between 10: 1 and 1.5: 1 especially between 5: 1 and 1.5: 1. The height of the concentration zones 17 or the areas with improved dissolution can preferably be extended over a corresponding minimum width of the annular notch to 2/3 of the bed height, where a value corresponding to the maximum width of the annular notch is preferred. . Figure 5 shows schematically different embodiment of the cross section of the column, where Figure 5a) and 5e) represent a narrowing and widening, which are formed by a tilt d only a cylinder stop (to select the internal cylinder) or external) towards another or on the contrary a distance. Figures 5b) and 5f) analogously show a narrowing of a widening by a two-sided inclination of the cylinder walls, and in Figures 5c) and 5d) a narrowing of one side or both is shown with an area of previous concentration 17. In this way, as already shown in Figure 4, it can be recognized that many widening and narrowing can also occur, in order to regulate the flow of the fluid in stages, making it faster or slower, in case this is necessary for l of the annular chromatograph of the present invention. The number of possibilities of application of annular chromatograph according to the invention is unlimited, for which we will only refer and in general to various homogeneous heterogeneous catalytic processes, different hydrogenations, dehydrogenations Redox reactions, hydrolysis or Sol ol reactions. Reactions of enzymes. A specific example is the hydrolysis and subsequent separation of oligomeric carbohydrates, for example by acid catális H-Raffinose < -? D-fructose + D-glucose + D-galactose or by enzymatic dissociation: or -galactosidase Raffinose «-» D-fructose + D-Glucose + D-galactose It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Having described the invention as above, the content of the following is claimed as property.

Claims (16)

1. CLAIMS 1. - Annular chromatograph with a bed of particles its annular notch, characterized because, at least, it provides a reaction zone to carry out chemical reactions with at least one coordinated separation zone, for the chromatographic separation.
2. 2. -Cromatograph according to claim characterized in that at least one reaction zone is arranged above at least one separation zone for the separation and / or purification of the products formed in at least one reaction zone.
3. 3. Annular chromatograph according to claim 1 to 3, characterized in that, for the pre-purification of at least one practicing product for the reaction of chemical reactions that take place in at least one reaction zone, a separation zone is arranged above. d at least the only reaction zone.
4. 4. An annular chromatograph according to one of claims 1 to 3, characterized in that the material for the separation zone is selected from ion exchange resins, cation exchange resins, justification gels, gel permeation gels, gels. of affinity gels (HiC) of hydrophobic chromatography, d-displacement resins, reverse phase gels and electrofsrosis gels.
5. 5. - Annular chromatograph according to one of the preceding claims, characterized in that the material for the reaction zone (s) is selected from the same material as for the separation zone (s) as well as inert material with respect to the reactions developed, for example glass beads or activated carbon.
6. 6. An annular chromatograph according to one of the preceding claims, characterized in that the material for the at least one reaction zone is impregnated or coated with a reaction catalyst, such as, for example, metals, metal complexes or enzymes.
7. 7. - Annular chromatograph according to one of the preceding claims, characterized in that the material for the at least one reaction zone is coated with at least one of the reactants.
8. 8. - Annular chromatograph according to one of the preceding claims, characterized in that all the reaction zones are separated from one another, especially by separation layers.
9. 9. - Annular chromatograph according to one of the preceding claims, characterized in that the at least one separating layer is made of non-porous membrane, selected from inert particle material, and electrically conductive material, preferably glass bead.
10. 10. - Chromatograph according to one of the preceding claims, characterized in that the particle bed is covered with a cover layer and / or has a base layer below, where the layer and the base preferably are made of a material such as the separating layers.
11. 11. - Chromatograph according to one of the preceding claims, characterized in that, when part of the height of the particle bed of the inner cylinder and / or the outer cylinder of the reactor, in order to increase the speed of flow in the bed of particles, is preferably conical or curved, approaching a corresponding ot. .
12. 12. - Annular chromatograph according to one of the preceding claims, characterized in that, when on a part of the height of the particle bed of the internal cylinder and / or of the external cylinder of the reactor, in order to decrease the flow velocity in the particle bed, makes conical or curved, moving away from another corresponding one.
13. 13. - Chromatograph according to claim 12, characterized in that the internal cylinder and / or the outer cylinder of the reactor in the lower end region are formed with a reaction zone, preferably conical, that approaches one or more others.
14. 14. - Annular chromatograph according to one of claims 11 to 13, characterized in that the internal cylinder and / or the external cylinder of the reactor have a region at least one separation zone, preferably conical q moves away from another or others.
15. 15. - Annular chromatograph according to one of the preceding claims, characterized in that a jacket for tempering the temperature is provided in the region of at least one zone in the internal and / or external cylinder.
16. 16. - Annular chromatograph according to one of the preceding claims, characterized in that, in the region of at least one area in the internal and / or external cylinder, a radiation source is provided as a heat source and / or as a reaction catalyst or reaction initiator.