WO2002046774A1

WO2002046774A1 - Chemical reactor with tempering means

Info

Publication number: WO2002046774A1
Application number: PCT/GB2001/005423
Authority: WO
Inventors: Stephen Martyn Dawson; Stephen Nicholas Heaton; Keith Hunt
Original assignee: A H Marks & Company Limited
Priority date: 2000-12-08
Filing date: 2001-12-07
Publication date: 2002-06-13
Also published as: AU2002222140A1

Abstract

A fluid phase chemical reactor comprising a circular or polygonalarray of reactor vessels, a fluid dispenser moveable in relation to the array so that a metered quantity of one or more fluids maybe disposed into each vessel; and heating or cooling means adapted to control the temperature or reagents in said vessels.

Description

CHEMICAL REACTOR WITH TEMPERING MEANS

This invention relates to a chemical reactor wherein a multiplicity of reactions can be carried out by metered addition of liquid or gaseous reagents to a multiplicity of vessels, optionally followed by analysis of the products, the reaction medium or the head space above the reaction medium.

Various configurations of reactors are known, for example rectilinear arrays of tubular cells, for sequential biochemical reactions. However, these reactors have complex and expensive constructions and are not suited for many applications.

According to the present invention, a chemical reactor comprises a circular or polygonal array of reaction vessels, a dispensing and analysis head unit moveable in relation to the array so that a metered quantity of one or more liquids or gases may be dispensed into each vessel and heating or cooling means adapted to control the temperature of reagents in said vessels.

The reactor may further comprise detector means adapted to measure a property of an analyte or analytes in the reaction medium or the head space above the reaction medium in a said vessel and adapted to generate a signal in response thereto, and comparator means adapted to compare said signal with a reference value.

The reactor may also include the mixing means to mix the contents of each tube by means of, for example, but not limited to magnetically coupled stirrer bars, the provision to wash the tip of the dispensing devices, provision to transfer samples of reaction mixture into standard vials, provision of waste or drain(s) to allow surplus material to be discarded, analytical probes or sensor systems, and the provision of an injection port to allow a portion of an analyte from the reaction medium or the head space above the reaction medium to be transferred into, for example, but not limited to a chromatography system.

The reactor may include a circular array of upwardly opening reactor tubes or otherwise shaped vessels. Alternatively a triangular, square or other polygonal array may be employed.

In a first embodiment, the reaction vessel array is disposed in a fixed location about an axis, the dispensing and analysis head unit being located coaxially and including a motor adapted to permit rotation of the dispensing and analysis head unit into alignment with each reaction vessels in the array and ancillary waste, rinsing and sampling stations. Use of a circular array of reactors is preferred.

The liquid dispensing and analysis head may be capable of accommodating a combination of modules including, but not limited to: a fixed height single channel dispensing module; a fixed height multiple channel dispensing module; a Z axis module which is capable of raising and lowering: an analytical probe connected to an analytical instrument. a sensor or multi sensor array providing a signal or signals indicative of a property or properties of an analyte or analytes, in the reaction medium or the head space above the reaction medium. a single channel dispensing or aspirating device which is optionally capable of penetrating a septum seal which closes each of the reaction vessels within the array. a multi channel dispensing or aspirating device which is optionally capable of penetrating a septum seal which closes each of the reaction vessels within the array. a sampling tube capable of extracting a portion of the reaction medium or the head space above the reaction medium for transfer of that sample into another piece of equipment or into a sampling station.

Heating means may comprise a metal heating or cooling block provided with cavities dimensioned to receive the vessels of the array. Alternatively, a liquid medium bath, dimensioned to receive the array of vessels, may be provided with heating or cooling means. As further alternatives, infrared heating or Peltier heating and / or cooling may be employed.

A condensing mechanism may be provided at an upper portion of each vessel. A cooling block or jacket may be located around the neck or upper portion of each vessel. Alternatively or in addition, a liquid coolant condenser may close the mouth of each vessel. A series of successive condensers may be employed.

The dispensing system may incorporate a sampling device adapted to remove an analyte or a portion of the reaction mixture from any selected vessel for analysis. Alternatively or in addition, the dispensing and analysis head unit may accommodate a combination of Z axis modules incorporating sensors, sensor arrays, or probes attached to analytical instruments, capable of being raised and lowered into the head space of each reaction vessel or into the reaction mixture within each reaction vessel, adapted to provide a signal indicative of a property or properties of an analyte or analytes.

A wash station may optionally be attached in place of one of the tubes within the reaction vessel array to provide the facility to wash the tip of any device which is mounted on a Z axis module.

A waste or drain station may optionally be attached between any two adjacent tubes within the reaction vessel array. This provides the facility to dispose of surplus material into a waste container. Multiple waste or drain stations may be accommodated between tubes in the reaction vessel array in order to maintain segregation of reagents, if required.

An injection port may optionally be attached between any two adjacent tubes within the reaction vessel array to provide the facility to transfer a portion of reaction medium or the head space above the reaction medium, in conjunction with a Z axis module, to an analytical instrument, for example, but not limited to, a liquid chromatograph.

The invention is further described by means of example but not in any limitative sense with reference to the accompanying drawings of which:

Figure 1 illustrates a reactor in accordance with this invention fitted with a dispensing and analysis head unit, a fixed dispensing module and a Z axis analytical probe module.

Figure 2 illustrates a dispensing and analysis head unit in accordance with this invention in both plan and elevation views.

Figure 3 illustrates the alignment of the dispensing and analysis head unit in plan view with the reaction vessel array.

Figure 4 illustrates a fixed height dispensing module which can be attached to the dispensing and' analysis head unit either alone or in combination with one or more Z axis modules and other fixed dispensing heads in accordance with this invention.

Figure 5 illustrates how several fixed height dispensing modules can be attached to the dispensing and analysis head unit.

Figure 6 illustrates a Z axis septum piercing dispensing / aspirating module which can be attached to the dispensing and analysis head unit in accordance with this invention. Figure 7 illustrates a Z axis analytical probe module which can be attached to the dispensing and analysis head unit in accordance with this invention.

Figure 8 illustrates how the dispensing and analysis head unit can be used to accommodate a combination of different modules.

Figure 9 illustrates a heated liquid bath arrangement in both elevation and plan views.

Figure 10 illustrates a condenser in elevation and plan view.

Figure 11 illustrates an alternative condenser.

Figure 12 illustrates a waste station which can be affixed between adjacent tubes in the reaction vessel array.

Figure 13 illustrates a sample vial station which can be affixed between adjacent tubes in the reaction vessel array.

Figure 14 illustrates an injection valve arrangement which can be affixed between adjacent tubes in the reaction vessel array to permit samples from any of the tubes in the array to be injected into a chromatograph.

Figure 15 illustrates a rinsing station which can be used to replace one of the tubes in the reaction vessel array.

Figure 1 is a diagrammatic illustration of a reactor in accordance with this invention. A carousel (1) carries a circular array of reaction tubes (2) mounted on a heating block (3) on a magnetic stirrer hotplate (4) which may optionally be fitted with a suitable control interface to permit microprocessor control of temperature and / or stirring speed, temperature feedback being optionally provided by a suitable temperature sensor (5) mounted in the heating block (3). A condenser block (6), in this example fed by liquid coolant (7) supports, by means of pillars (8), the dispensing and analysis head unit (9) (shown in more detail in Figure 2) which, in this illustration, is fitted with a fixed height single channel dispensing module (10) and a Z axis analytical probe module (11).

The motor housing (12) allows the dispensing and analysis head unit (9) to be rotated in order to position any of the attached modules (in this example 10 or 11) directly above any of the tubes in the reaction tube array (2) or any of the optional stations that may be fitted.

The Z axis analytical probe module (11) is capable of raising or lowering an analytical probe (13), which is connected to an analytical instrument (14), into the reaction medium or the head space above the reaction medium in each of the tubes in the reaction vessel array for measurement purposes.

Stirring is provided by magnetic followers placed in the bottom of each tube in conjunction with the magnetic stirrer hotplate (4).

Multiple peristaltic pumps (15), syringe drivers (16), infusion systems (not shown), or any combination of these, connected to dispensing lines (17) permit metered amounts of liquid or gaseous reagents from stock bottles (18) to be dispensed through a multitude of possible combinations of fixed single or multi channel dispensing modules or Z axis dispensing / aspirating modules (not shown in this illustration - shown in detail in Figure 5) into any selected tube in the reaction vessel array.

Figure 2 is an illustration of the dispensing and analysis head unit in more detail. No modules are shown attached to the main rotor for clarity.

The dispensing and analysis head unit is mounted on top of the condenser block by means of pillars (8). The fixed stator (19) is fitted with a bearing and drive shaft (not shown) which extends inside the motor housing (12). A motor fixed inside the motor housing (12) is connected to the drive shaft via a gearing mechanism. The main rotor plate (20) is fixed to the motor housing (12) in such a way that operation of the motor results in the rotation of the motor housing (12) and the main rotor plate (20) about the fixed stator (19). This permits any of the modules attached to the main rotor plate to be brought into alignment with the tubes in the array (see Figure 3) and the ancillary stations mounted between adjacent tubes (if fitted).

Figure 3 illustrates how the dispensing and analysis head unit (9) is coaxially aligned above the reaction vessel array (2). The shape of the main rotor plate permits removal of the tubes from the carousel without having to remove the sampling and analysis head unit.

Figure 4 illustrates the dispensing and analysis head unit (9) fitted with a fixed single or dual channel dispensing probe (10). Several fixed dispensing probes can be used simultaneously as illustrated in Figure 5. Figure 6 illustrates a Z axis module (11) fitted with a septum piercing needle (21) mounted on to the dispensing and analysis head unit. The needle is attached to the Z axis module by means of a clamp (22). A motor and gearbox combination within the Z axis module (11) is used to raise and lower the clamp (22).

The Z axis module (11) when fitted with a dispensing needle (21) can be used to dispense liquids or gases through an open topped or septum sealed tube. A longitudinal groove on the body of the needle (21) permits pressure equalisation within a septum sealed tube. The Z axis module (11) and needle (21) can also be employed to remove material from the reaction medium or head space above the reaction medium in any tube in the array and dispense this material, in whole or in part, into any other tube or tubes in the reaction vessel array or into a sample vial mounted in a sample vial station (see Figure 13) or into an injection port mounted between tubes in the array (see Figure 14).

Figure 7 illustrates a Z axis module (11) fitted with an analytical probe (13) mounted onto the dispensing and analysis head unit.

The analytical probe (13) is attached to the Z axis module by means of a clamp (22). A motor and gearbox combination within the Z axis module (11) is used to raise and lower the clamp (22).

The analytical probe illustrated could be any detector of a suitable size appropriate for the reaction vessel array used. The detector can be used to measure a property of an analyte or analytes, the reaction medium or the head space above the reaction medium and adapted to generate a signal in response thereto.

The analytical probe may also be any sensor system or combination of sensor systems as described above.

Figure 8 illustrates how multiple combinations of fixed dispensing modules (10) and Z-axis modules (11) can be accommodated by the dispensing and analysis head unit. This illustration shows 3 Z axis modules (11), 2 fitted with analytical probes (13) and one fitted with a septum piercing needle (21), together with 3 fixed head dispensing modules (10). Figure 9 illustrates a reactor incorporating a bath (23) for heating oil or coolant. The tubular vessels (24) are disposed in a circular array around a turret (25), the reaction vessel tubes being fastened to the turret by means of clamps (26). A magnetic stirrer bar (27) located in an oil circulation cavity

(28) serves to ensure circulation of oil heated by the magnetic stirrer hotplate (4). The analysis and dispensing head unit (9) is attached to the top of the turret (25) by means of suitable pillars (8). The array of reaction vessel tubes attached to central turret (25) allows the support, tubes and the dispensing and analysis head unit (9) to be removable. The bath can be preheated prior to addition of the reaction vessel array, supporting turret and the dispensing and analysis head unit in order to achieve rapid heating or to allow removal from the heating medium at a particular time.

Alternatively, the magnetic stirrer hotplate can be fitted with an interface in order to allow microprocessor control which would facilitate the use of controlled temperature ramps and optional control of stirring speed.

Figure 10 illustrates a condenser for insertion into the mouth of a tubular reaction vessel. Socket

(29) is adapted to engage a conventional ground glass socket in the tubular reaction vessel (not shown). A water jacket (30), having an inlet (31) and an outlet (32) serves to cool vapour within the condenser tube (33). A further socket (34) may be coupled to an inert gas supply or another condenser. The condenser tube (33) extends axially of the cooling jacket (30) providing a baffle to ensure that there is turbulent flow between the inlet (31) and the outlet (32). In a preferred embodiment, the inlet (31) and outlet (32) are perpendicular to reduce laminar flow through the condenser chamber.

Figure 11 illustrates an alternative embodiment wherein a gas inlet (35) and outlet (36) can be used to provide an inert atmosphere for the reactor tubes.

Figure 12 illustrates a waste station. This station can be fitted between a pair of adjacent tubes in the reaction vessel array and provides the means to dispose of excess sample or rinse the inside of a needle. The housing (37) is a push fit between adjacent tubes and aligns the waste well (38) centrally with the position of any of the dispensing modules fitted to the dispensing and analysis head (9). The waste well (38) is connected to a waste tube (39) which allows waste liquor to be gravity fed to an appropriate waste container. Similar housings can be used to provide access to a sample container (see Figure 13) or an injection port (e.g. for a Rheodyne valve - see Figure 14).

Figure 13 illustrates the use of a housing (40) which can hold a vial (41). Several such housings can be accommodated between adjacent tubes providing the facility to aspirate a sample from any of the tubes in the reaction vessel array (e.g. by means of a Z axis module fitted with a dispensing or aspirating needle capable of septum piercing) and transfer the sample into a vial which is either open topped or sealed by means of a septum. The sample tube(s) can then be manually removed from the housing(s) and transferred to an appropriate analytical instrument for subsequent analysis.

Figure 14 illustrates the use of a housing (42) to provide the facility of an injection port (43) connected to a Rheodyne valve (44) in order to permit samples to be aspirated from any of the tubes in the reaction vessel array and transferred, via the injection port, to an analytical instrument e.g an HPLC or ion chromatograph.

In this illustration, the Rheodyne valve is shown in the 'load sample' position where sample transferred into the injection port is used to fill a calibrated sample loop (48), any excess being transferred to waste via a sample drain tube (45). In this position, eluent from the analytical instrument pump (46) is fed directly onto an analytical column (47) within the analytical instrument.

Figure 15 illustrates how one of the tubes in the reaction vessel array can be replaced by a rinsing station (49) to facilitate wasliing of the inside and outside of a dispensing needle or the outside of an analytical probe or sensor system.

Rinse liquid can be dispensed to the rinsing station using either a fixed head or Z axis dispensing module. Liquid can be removed from the rinsing station by means of a Z axis dispensing module and transferred to a waste station such as that illustrated in Figure 12.

The use of several fixed dispensing or Z axis dispensing modules permits needles and dispensing streams to be largely dedicated to single reagents. Thus, the necessity to rinse a dispensing needle after each addition can be minimised. Because of the relatively large volumes accommodated by the tubes in the reaction vessel array, rinsing of needles after aspiration, or analytical probes after readings have been taken, may not always be necessary unless potential carry over between tubes needs to be minimised.

Any convenient number of reactors may be employed, for example up to 36 arranged preferably in a circular array.

The apparatus in accordance with this invention provides an economical and robust method of carrying out a multiplicity of reactions, for example for physical, chemical or biological transformations and measurements. Reagents such as new catalysts may be screened. Alternatively, processes may be optimised by adjustment of the amounts of reagents employed.

Apparatus in accordance with this invention may incorporate a microprocessor adapted to control the dispensing, reaction, heating and analysis functions. The quantities of liquid can be calibrated to allow control of the weight of reagents added. The mode of addition of reagents may be either sequential or interleaved in order to reduce the risk of localised overheating. The maximum quantity added to each tube and the time between each addition may be controlled and the thermodynamic properties regulated to ensure that the reaction remains within safe limits.

Associated analytical equipment for use with apparatus in accordance with this invention requires no special modification. Microprocessor controlled apparatus will incorporate a multiplicity of electrical inputs and outputs in order to facilitate the set up of a simple handshaking protocol with an analytical instrument, indicating when an analytical probe has been correctly placed ready for a reading to be taken and detecting a signal from the analytical instrument confirming that an analytical measurement has been taken in order that the dispensing and analysis head can continue with a pre-programmed sequence.

The combined synthesis and analysis functions provided by apparatus in accordance with this invention permits chemical or biological reactions to be conducted and monitored in an unattended manner. The availability of analytical data during synthesis should provide a rapid and valuable insight as to the mechanism of the reaction and can be used to detect the end of a reaction stage which can then be used to initiate a further stage of dispensing and analysis.

Claims

1. A fluid phase chemical reactor comprising a circular or polygonal array of reactor vessels; a fluid dispenser moveable in relation to the array so that a metered quantity of one or more fluids may be dispensed into each vessel; and heating or cooling means adapted to control the temperature or reagents in said vessels.

2. A reactor as claimed in claim 1 , further comprising a detector adapted to measure a property of an analyte in said vessel and adapted to generate a signal in response thereto; and comparator means adapted to compare said signal with a reference value.

3. A reactor as claimed in any preceding claim, wherein the reagents are liquids.

4. A reactor as claimed in any preceding claim, including a circular array of upwardly opening reactor tubes.

5. A reactor as claimed in any of claims 1 to 3, including a circular array of downwardly opening reactor tubes.

6. A reactor as claimed in any preceding claim, wherein the array is rotatable about an axis to permit each vessel to be aligned with the liquid dispenser.

7. A reactor as claimed in any of claims 1 to 5, wherein the array is disposed in a fixed location about an axis, the liquid dispenser being located coaxially and including a motor adapted to permit rotation of the dispenser into alignment with each vessel of the array.

8. A reactor as claimed in any preceding claim, including heating means.

9. A reactor as claimed in any preceding claim, including a condenser located at an upper portion of each vessel.

10. A reactor as claimed in claim 9, wherein the condenser comprises a cooling block or jacket located around the neck or upper portion of the vessel.

11. A reactor as claimed in any preceding claim, wherein a cooling or heating block is located around a lower portion of the vessel.

12. A reactor as claimed in any preceding claim, wherein the dispenser incorporates a sampler adapted to remove a portion of an analyte from a selected vessel for analysis.

13. A reactor as claimed in any preceding claim, wherein the dispenser incorporates a sensor adapted to provide a signal indicative of a property of the analyte.

14. A reactor substantially as hereinbefore described with reference to the accompanying drawings.