DE102004003925A1 - Continuous flow column reactor for laboratory use has multiple, agitated compartments and can handle solids or gas dispersions - Google Patents

Abstract

A continuous flow, column reactor for laboratory use has multiple, vertically stacked, compartments (7) each agitated (9) via a common axial stirrer shaft (10), and can handle solids or gas dispersions.

Description

Field of use:

The The invention relates to a device according to the preamble of claim 1

State of the art:

continuous Chemical reactors are traditionally used in production plants the large chemical or petrochemical industry. In contrast, chemical Synthesis in the pharmaceutical and fine chemical industry almost exclusively in the Batch process (ie in discontinuously operated stirred tanks) carried out. Corresponding also come in the research and development laboratories of the same preferably glass flask used. Batch processes basically have the Disadvantage that in the transfer from laboratory to production scale only a lengthy scale-up (Scale Up) must, there the ones obtained in small reaction vessels Results can not easily be scaled up (worse mixing and heat transfer in big Boilers leads to worse product quality or security risks). Some reactions can be applied to this Do not even bring the way to production.

In Pharmaceutical research consists of finding one new drug candidates are often in urgent need of larger (kilogram) amounts, to z. B. to carry out clinical tests. These can only after developing a suitable process or through protracted Repetition of small approaches to be provided.

Here Continuous operation can be of great benefit as they are on the one hand without further processing and using the Laboratory equipment allows the generation of variable (small) quantities.

To the For others, scale-up is essential compared to batch processes less problematic, because in continuous systems none at all (Parallelization of the systems = "numbering up") or just a very moderate scale magnification (or a combination of both) must be made to the Increase output.

First For about 10 years, as part of the establishment of the research areas "process intensification" and "Miniaturization of reaction apparatuses (microreaction technology) "continuous reactors for the laboratory scale commercial made available.

Disadvantages of the state of the technique:

The novel laboratory-scale continuous reactors are based on static mixers which at one stage have a microstructuring and are generally combined in a modular manner with a tempered capillary serving as a residence time segment to form a microreaction system. An example is in EP 1 123 734 described. Due to the low flow rates, laminar flow conditions prevail in the pipe. This is caused by the parabolic flow profile a residence time broadening in the pipe, which can have a negative effect on the conversion or selective of a reaction, since the volume elements dwell in the reactor for different lengths of time. For a narrow residence time distribution, a very small tube diameter is required, which has a very large tube length for a given reaction volume and is accompanied by a high pressure loss.

One far greater disadvantage However, the limited use of such reactors, d. H. she are practically exclusive to homogeneous reactions in liquid Phase limited. Since after leaving the mixer no mixing in the residence time tube takes place, this arrangement is z. B. unsuitable for two-phase liquid Systems (it comes to the separation of the phases). Also can out for the same reason no heterogeneous mixtures such as suspensions or gas / liquid phases be processed. The introduction or the formation of gas in a tubular reactor would the liquid drive out and thus shorten the residence time drastically. There is also especially when using microstructured reactors a high Risk of blocking the channels, if during the reaction solids precipitate.

Furthermore become tube reactors (eg "FlexReactor", BHRSolutions, patents pending), which are partly or completely static Filled mixing elements are. Due to the size fit these but not in conventional fume hoods and also the required minimum throughput is well above the for the Laboratory scale usual quantities out. With regard to heterogeneous reaction mixtures z. T. the same restrictions as for the microreactors.

On the other hand, stirred tank cascades have long been commercially available for use in miniplant or pilot plants. However, these consist mostly only of three stages, which has a very wide residence time distribution result. In addition, due to the relatively large volume, they have a throughput in excess of the quantities available or needed in the laboratory. The individual stirred tanks of such cascades are in the Height offset arranged side by side, which has a relatively large space requirement. Furthermore, they work according to the overflow principle, which can lead to thermal or cold bridges during the transfer to the next boiler.

A vertical cascade bubble column reactor is in US 3,853,986 described. Due to the lack of moving mixing elements, however, this is dependent on the introduction of gases and thus not suitable for pure liquid / liquid contacts.

Objects of the invention:

By The underlying invention seeks to be continuous carry out chemical syntheses on a small scale, considerably be extended. It should also reactions in heterogeneous systems (liquid / liquid, gaseous / liquid and solid liquid) allows become. It should comply with well-defined reaction conditions become, whereby the selectivity and yield maximized. The reactors are already being tested on a laboratory scale Synthesis and process development can be used and can be achieved by parallelization or moderate scale up even the larger throughputs of be adapted to continuously operated pilot plants.

Solution of the task:

These The object is achieved by a device having the features of the claim 1 solved.

Advantages of the invention:

Of the contains described reactor efficient moving mixing elements and thus ensures the implementation of Reactions in heterogeneous phases.

By The special construction will be the advantages of a flow tube (size Heat exchange surface, close Residence time distribution) with those of a continuously operated stirred tank (intensive mixing, universally applicable) combined. By the small diameter of the reaction column is one compared to usual continuous stirred kettles very big relationship from surface (Wall) given to volume, resulting in a correspondingly effective heat exchange allows. In conjunction with the precooling The reactants are therefore also strongly exothermic reactions below Avoid local warming (Hot spots) feasible. The small volume requires in combination with a suitable stirrer very fast and efficient mixing of the reactants, thereby local concentration differences are avoided. Through both Effects are ensured very homogeneous reaction conditions, what in many reactions to improve the selectivity and yield to lead can.

A Cascade of infinitely many ideal continuous stirred tanks corresponds to the residence time distribution of an ideal flow tube (Plug flow, no backmixing). The residence time distribution of a real flow tube at low flow rates (laminar Flow, parabolic flow profile) Already with a relatively small number of stirred kettles be achieved. The present invention enables the realization of a huge Number of stages by the series connection of several Column reactors. So z. B. by linking of 5 columns each with 10 reaction chambers a cascade of 50 stirred tanks can be realized. The residence time distribution of such an arrangement corresponds to a capillary of a few millimeters in diameter. This will be The invention also meets chemical reactions in which a preferably uniform reaction time for everyone Volume elements relevant to quality is.

Finally, the described contains Reactor type in proportion to the possible Throughput only a very small stationary volume, which is a security aspect when using highly reactive or toxic chemicals represents. Here is also to mention that the reactor, in contrast to conventional stirred tanks a practically closed System, whereby after completion of the filling process in the continuous Operation on a protective atmosphere can be waived.

Description of exemplary embodiments:

The column reactor consists of a double-walled tube ( 1 . 1 ), wherein in the inner tube, the chemical reaction takes place and between the two tubes, the heat transfer medium ( 2 ) flows to the reaction temperature. Around the outer tube is a thermal insulation ( 3 ). Alternatively, a single-walled design is conceivable, wherein the tube is placed in a tempered and outwardly insulated holder. The frame can be provided with 1-10 holes, are introduced into the individual columns. The temperature control can be effected by an in the holding block circulating heat transfer medium or, if only to be heated, by an electric heating. The maximum temperature range is -80 to 250 ° C, the low temperatures preferably being realized with ethanol as medium and the high temperatures with special synthetic heat carriers (eg silicone oils).

The lower part of the inner tube consists of a pre-tempering zone ( 4 ), in which the reactants by spirals ( 5 ), z. Stainless steel or PTFE, on the way to the entrances to the Reacti onszone be brought to the set reaction temperature.

The lower floor ( 6 ) has 2-4 inputs through which 2-4 reactants can be pumped into the column.

In the middle part follow several (about 5-15) consecutive reaction chambers ( 7 ) through intermediate floors ( 8th ) are separated from each other. Each chamber constitutes a continuous stirred tank. Backflow down is prevented by upward flow. Each chamber contains a mechanical stirrer ( 9 ) of a common continuous wave ( 10 ) is driven. The stirrer shaft rotates in encapsulated bearings ( 11 ), which are embedded in the intermediate plates. Furthermore, each chamber contains one or more holes ( 12 ) in the upper restriction plate through which the liquid or gas can flow to the next chamber. It is conceivable to vary the size of the openings, z. B. by means of a kind of needle valves ( 12a . 3 ), which have a common connection ( 12b ). This allows the flow rate in the following chamber can be adjusted.

Alternatively, the flow into the upper chamber may also be through a gap ( 12c ) between stirrer shaft and intermediate plate.

Furthermore, the liquid can also be applied via lines (outside the reaction space) ( 12d ) enter the overlying chamber.

The reaction mixture occurs at the top plate of the uppermost chamber ( 13 ) and can from here via a three-way valve ( 14 ) are either taken directly or passed into the bottom chamber of the following column reactor. For this purpose, the wiring is carried out within the temperature range in order to avoid heating or cooling before entering the next reactor.

Optionally, a reflux condenser may be located above the uppermost chamber to condense vaporized solvent during operation. Preferably, however, the reactions should be carried out below the boiling temperatures of the solvents used. The upper end of each column reactor is an electrically driven motor ( 15 ), which drives the stirrer shaft. The connection to the stirrer shaft can be made via a mechanical or a magnetic coupling.

Each column reactor can be mounted on the top cover plate with a standpipe ( 16 ) are provided for the discharge of unabsorbed gases in gas / liquid reactions. Furthermore, there may also be attached an overflow valve as a safety device to prevent a sudden pressure build-up.

to Purification of the reactor should either be disassembled or the stirrer shaft should together with the intermediate floors be removable.

in the first case would be to provide a segmental structure of the inner tube of pipe sections, which are provided with internal thread and over shelves with external thread can be screwed together.

One another structure sees a slightly conical, tapering down Pipe before, in which the stirrer shaft together with shelves (provided with different diameters) is inserted and can be pulled upwards if necessary. The sealing of the Chambers against each other takes place between the pipe wall and the with a sealing ring provided intermediate floors by pressing pressure from above.

• 1. Im stationären Zustand können bei einer einstufigen Reaktion nach jeder Säule Proben entnommen werden, die Aufschluß über die erforderliche Gesamtverweilzeit bzw. benötigten Reaktoreinheiten (Verweilzeitverteilung) geben
• 2. In der zweiten Säule kann ein dritter Reaktand (zweistufige Reaktionen), in der dritten Säule ein vierter Reaktionspartner usw. zu der Mischung dosiert werden, so dass mehrstufige Reaktionen ermöglicht werden. Hierbei ist es sinnvoll, wenn die einzelnen Reaktionsstufen unabhängig voneinander temperiert werden können.
• 3. Nach jeder Säule kann ein Reaktand nachdosiert werden, wenn es aus Gründen der Prozessführurug sinnvoll ist. Gleiches gilt für z. B. das Einleiten von Gasen.

The modular design of 1-10 columns allows flexible use, eg. B .:

• 1. In the steady state samples can be taken in a one-step reaction after each column, giving information about the required total residence time or required reactor units (residence time)
• 2. In the second column, a third reactant (two-stage reactions), in the third column a fourth reactant, etc., can be added to the mixture to allow multi-stage reactions. It is useful if the individual reaction stages can be tempered independently.
• 3. After each column, a reactant can be topped up if it makes sense for reasons of litigation. The same applies to z. B. the introduction of gases.

Material:

The parts of the reactor that are affected by chemicals are made of materials with high chemical resistance. Of metallic materials, stainless steel, Hastelloy or titanium are preferred. In addition, the production of a reactor made of glass or plastic, preferably PTFE, PFA or PEEK is conceivable. Furthermore, a combination of several materials, for. B. Teflon-coated steel used. PTFE and Kalrez ^{TM are} suitable as sealant material.

peripherals:

The column reactor forms in conjunction with Peripherals an integrated reaction system. This consists of at least 2 pumps for the first column reactor, eg. As piston pumps or gear pumps, which allow an exact dosage of the reactants. For operation as a multi-stage system, an additional pump must be provided for each additional feedstock fed.

In the lines of the supplied Starting materials or in the reaction space itself can Pressure sensors are located, with a pressure cutoff on the pumps acts as a safety device can be coupled. Farther can Temperature sensors both in the reaction chamber itself and in the heat transfer circuit are located.

In addition, you can in the supply lines of the reactants Flowmeter for continuous flow monitoring or in combination with control valves for regulating the flows.

In the lines of the inputs and outputs of the reactor There are multi-way valves, the z. B. the switching of reactant on solvent u. u. or the transfer to the next reactor column or allow for sampling. These valves can be actuated both mechanically and electromagnetically.

In The lines at the reactor outlet can be Durchfußmesszellen with suitable in-line analysis (eg IR-, Raman, UV spectroscopy are coupled)

Control:

The Reaction system can either manually via the temperature setting on Thermostats and entering the flow rates at the pumps or over one suitable combination of hardware and Software controlled. This should be in addition to the setting of Flow rates, temperatures and maximum allowable pressure visualization and recording all Enable measured data. Furthermore should in the case of the use of electromagnetic valves These are operated by software can.

Claims (45)

Device for carrying out continuous chemical syntheses from the laboratory to the pilot scale, characterized in that reaction chambers arranged vertically one above the other ( 7 . 1 ) form a bottom-flow column reactor, each chamber being a continuously operated stirred tank. Apparatus according to claim 1, characterized in that the individual reaction chambers laterally from the wall of the reaction tube ( 1 ) and up and down of closing ( 6 . 13 ) or intermediate floors ( 8th ) Device according to claim 2, characterized in that the inner tube ( 1 ) has an inner diameter of 10-250 mm Device according to claim 2, characterized in that the height of the chamber ( 7 ) is 0.5 to 3 times the inner tube diameter Apparatus according to claim 1, characterized in that up to 25 chambers are arranged vertically above one another ( 2 ) Device according to claims 3, 4 and 5, characterized in that that the gross volume of a column reactor dependent on from the pipe diameter, the chamber height and number is about 10 ml to 100 1 (laboratory to pilot scale) Device according to claim 2, characterized in that the tube ( 1 ) is made of stainless steel Device according to claim 2, characterized in that the tube ( 1 ) is made of Hastelloy Device according to claim 2, characterized in that the tube ( 1 ) is made of titanium Device according to claim 2, characterized in that the tube ( 1 ) is made of glass Device according to claim 1, characterized in that the tube ( 1 ) is made of PTFE Device according to claim 1, characterized in that the tube ( 1 ) is made of PEEK Device according to claim 1, characterized in that the tube ( 1 ) is made of a suitable metal with PTFE coating Apparatus according to claim 2, characterized in that the lower bottom of the lowest chamber ( 6 ) Has 2-4 inputs for reactants Device according to claim 2, characterized in that the upper floor of the uppermost chamber ( 13 ) has an exit for the reaction mixture, which is provided with a three-way valve ( 14 ), whereby between product removal and forwarding to the next column reactor vice can be switched. Apparatus according to claim 2, characterized in that on the uppermost bottom of a riser ( 16 ) is attached as pressure equalization Device according to claim 2, characterized in that that a safety valve is mounted on the top floor Apparatus according to claim 1, characterized in that the chamber contents by a mechanical stirrer ( 9 . 10 ) is mixed Apparatus according to claim 18, characterized in that the stirring blades ( 9 ) of a common wave ( 10 ) are driven Apparatus according to claim 19, characterized in that the shaft in encapsulated bearings ( 11 ), which are recessed in false floors. Apparatus according to claim 1 and 2, characterized in that the forwarding of the reaction mixture in the overlying chamber by introduced in the upper plate openings ( 12 ) takes place Apparatus according to claim 21, characterized in that the cross section of the bores ( 12 ) varies ( 12a , b, 3 ) Apparatus according to claim 1 and 2, characterized in that the forwarding of the reaction mixture in the overlying chamber by column ( 12c ) takes place between stirrer shaft and intermediate plate Apparatus according to claim 1 and 2, characterized in that the forwarding of the reaction mixture in the overlying chamber by a running outside of the inner tube capillary takes place ( 12d ) Device according to claim 2, characterized in that inner tube ( 1 ) is divided into individual segments and is screwed together with the shelves as connecting parts Device according to claim 2, characterized in that the inner tube ( 1 ) is made of continuous Device according to claim 26, characterized in that that the inner tube tapers down and the intermediate floors a diameter adapted to the pipe diameter and with gaskets are provided so that the shaft reversible together with the stirring blades and shelves and self-sealing can be pressed into the pipe Apparatus according to claim 1 and 2, characterized in that the inner tube is surrounded by an outer tube, so that through the forming gap, a heat transfer medium ( 2 ) can be passed to the temperature of the inner tube Device according to claims 1 and 2, characterized in that that the reaction tube is electrically heated Device according to claims 1 and 2, characterized in that that can put up to 10 tubes in a holder, the a fluidic connection of the individual reactors with each other allowed. Device according to claim 30, characterized in that that the holder by a heat transfer medium is tempered Device according to claim 30, characterized in that that the holder is electrically heated Apparatus according to claim 1, characterized in that the lowermost part of the tube as Vorstemperierzone ( 4 ) is carried out in which the reactants before entering the reactor by capillaries ( 5 ) are pumped, which are located in the temperature control and thereby brought to reaction temperature Device according to claim 1, characterized in that that for each entering a column reactor Reactants a pump is fluidly connected to the inputs Device according to claim 1, characterized in that that every column reactor Has sensors and actuators Device according to claim 35, characterized in that that the column reactors Temperature and pressure sensors in the supply lines of temperature control medium or reactants Device according to claim 35, characterized in that that in the pillar interior Temperature and pressure sensors are available Device according to claim 35, characterized in that that the pressure sensors are linked to a pressure shut-off, which acts on the pumps Device according to claim 35, characterized in that that in front of the entrances for the reactants mechanical three-way valves are located Device according to claim 35, characterized in that that in front of the entrances for the reactants electromagnetic three-way valves are located Device according to claim 35, characterized in that that is in the supply lines for the reactants flow sensors are located Device according to claim 35, characterized in that that is in the supply lines for the reactants flow regulator are located Device according to claim 1, characterized in that that the column reactor via a controller (Hardware and software), which makes the following entries possible: - Temperature specification and regulation - Specification the flow rates - Display and storage of the measured data for Temperature and pressure as well as the entered parameters Device according to claim 43, characterized in that that the controller has additional functions - Input the permissible maximum pressure - Control the electromagnetic valves - Display and regulation of flow rates Device according to claim 1, characterized in that that at the outlet of the reactor, a suitable in-line analysis (z. B. UV, IR or Raman spectroscopy) is coupled.