Classifications

• • C—CHEMISTRY; METALLURGY
  • C40—COMBINATORIAL TECHNOLOGY
  • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
  • C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
  • C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00279—Features relating to reactor vessels
  • B01J2219/00281—Individual reactor vessels
  • B01J2219/00283—Reactor vessels with top opening
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00279—Features relating to reactor vessels
  • B01J2219/00306—Reactor vessels in a multiple arrangement
  • B01J2219/00324—Reactor vessels in a multiple arrangement the reactor vessels or wells being arranged in plates moving in parallel to each other
  • B01J2219/00326—Movement by rotation
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00351—Means for dispensing and evacuation of reagents
  • B01J2219/0036—Nozzles
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00351—Means for dispensing and evacuation of reagents
  • B01J2219/00423—Means for dispensing and evacuation of reagents using filtration, e.g. through porous frits
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/0054—Means for coding or tagging the apparatus or the reagents
  • B01J2219/00545—Colours
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/0054—Means for coding or tagging the apparatus or the reagents
  • B01J2219/00547—Bar codes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00583—Features relative to the processes being carried out
  • B01J2219/00585—Parallel processes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00583—Features relative to the processes being carried out
  • B01J2219/0059—Sequential processes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00583—Features relative to the processes being carried out
  • B01J2219/00596—Solid-phase processes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00583—Features relative to the processes being carried out
  • B01J2219/00599—Solution-phase processes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/0068—Means for controlling the apparatus of the process
  • B01J2219/00686—Automatic
  • B01J2219/00689—Automatic using computers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/0068—Means for controlling the apparatus of the process
  • B01J2219/00702—Processes involving means for analysing and characterising the products
  • B01J2219/00704—Processes involving means for analysing and characterising the products integrated with the reactor apparatus
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00718—Type of compounds synthesised
  • B01J2219/0072—Organic compounds
  • B01J2219/00725—Peptides

Definitions

• This invention relates to automated chemical synthesizers and more particularly to improved automated rotary chemical synthesizer.
• Another feature of the synthesizer allows one to input to the control system of the synthesizer a sequence of reagents for the synthesis of one or more compounds and the process steps for synthesis of the compounds can be automatically generated as well as the calculated reagent volume.
• the synthesizer may input an amino acid sequence and have the synthesizer through pre-programmed protocols automatically generate all required process steps, including calculated dispense volumes
• the control system of the synthesizer provides the ability to log all communication and status messages to a file that can be stored in a database maintained in the control system. Process reports can then be generated from the status messages stored in the database.
• Yet another feature of the present invention is the ability to manually define steps for each process and to create reusable subroutines (a sequence of commands that are used frequently) to expedite manual creation of a process.
• the control system provides the ability to copy and paste entire programs or groups of commands from one location to another, and from one protocol to another
• an improved automated synthesizer in which the reaction wells are moved into alignment with reactant and wash solution dispensing stations.
• the reactant and wash solution dispensing stations comprise stationary nozzles that are in communication with the source of reactants and/or wash solutions.
• reaction wells are purged by the introduction of an inert gas into well.
• the purging stations may be combined with the washing stations or may comprise separate stations dedicated to purging the wells.
• the automated synthesizer comprises a rotatable carousel having at least one reaction well disposed at the periphery of the rotatable carousel.
• a reaction well includes a reaction chamber and an injection port.
• a reaction well includes an access port for an inert gas and a drain port for emptying the well.
• Rotation of the carousel brings at least one of the reaction wells into alignment with a dispensing nozzle of a stationary delivery system for delivery of reagent or a wash solution into the reaction chamber of the reaction well.
• the reaction wells may be integrally formed in the carousel or may be removably carried by the carousel.
• a reversible stepper motor powers the rotatable carousel for rotation in either direction.
• the stationary delivery system comprises at least one reagent station comprising a container for reactants and a dispensing nozzle that is in fluid communication with the reactant in the container.
• a syringe is activated to draw reagent from the container and to dispense a controlled amount of reagent through the dispensing nozzle into the reaction chamber.
• a stationary wash station and purge system includes a plurality of wash injectors that are in fluid communication with one or more wash fluids. As with the reagent delivery system a syringe is activated to draw a wash fluid from the container and to dispense a controlled amount of reagent through the dispensing nozzle into the reaction chamber.
• One or more linear actuators are provided to lower the wash nozzles into the injection ports of the reaction wells for an essentially pressure tight seal and to raise the nozzle for clearance during rotation of the carousel. A pressure tight seal is required for purging the reaction well by inert gas pressure.
• a frame member in the housing supports the reactant containers and wash fluid containers.
• the purge function can be combined with the wash fluid delivery stations. However, the purge function can be advantageously separated from the wash fluid delivery function and be provided by one or more dedicated purge stations. In this embodiment the reagent stations and wash station are configured and function in the same way. The need for linear actuators for the wash fluid containers is eliminated and the design of the purge station is simplified as there is no necessity for a fluid container.
• a control system including a CPU, keyboard and monitor are provided for programming and, controlling the sequence of reactions and washing steps carried out by the automated synthesizer. Pulses of nitrogen gas are introduced into the reaction chamber to purge the liquid portion out of the reaction chamber through the drain port for disposal or for collection.
• the drain port includes a suitable retainer such as a filter element to maintain solids such as solid support resins in the reaction chamber while permitting liquids to escape and a device to prevent backflow of liquid or gas into the reaction chamber.
• a device may include a conventional mechanical valve, for example a check valve or a duckbill or pinch valve with a set cracking pressure, an electronically controlled solenoid valve, or a vertical trap.
• the stationary delivery system includes one or more removable cartridges that contain reactant and other liquids required for the reaction.
• a dispensing nozzle is also associated with the cartridge so that each cartridge of the delivery system is self-contained.
• a suitable sensor is provided to indicate the level of reactant in the cartridge.
• reaction wells are carried by a conveyor belt for movement in a linear manner rather than rotatably.
• reaction wells are carried by a motor driven endless conveyor belt for alignment with reactant and wash solution delivery stations disposed on a platform along one or both sides of the conveyor belt.
• the path of the conveyor may comprise a conventional circular or curvilinear loop or may take different configuration such as, for example, a rectangular or triangular path
• the driving motor is preferably bi-directional so that the reaction wells can be moved in either direction.
• reaction wells are carried by a linear conveyor for bi-directional linear movement under the reactant and wash solution delivery stations.
• the reaction wells are stationary and the delivery stations are moved to the reaction wells, the same configurations for the reaction wells, the reagent stations and the wash stations are used.
• the platform carrying the delivery stations is movable to bring the dispensing nozzles of the delivery stations into alignment with corresponding reaction wells to dispense reagent or wash fluid in accordance with the protocols being carried out.
• the delivery stations may be carried by an annular platform for rotary movement or on a rectangular platform for bidirectional linear movement.
• the delivery stations may also be carried by a motor driven conveyor system.
• the embodiments of the invention described herein have utility for peptide synthesis. Other solid phase and liquid phase chemical reactions can also be carried out both manually as well as by automated protocols using the synthesizer of the present invention.
• FIG. 1 is a schematic diagram of an automated synthesizer designed in accordance with the present invention
• FIG. 2 is a perspective view of one embodiment of the invention.
• FIG 3 illustrates portion of the carousel platform carrying the reaction wells
• FIG. 4 illustrates the carousel platform support and drive system
• FIG. 5 is an exploded view of a segment of the carousel showing reaction cavities and reaction wells;
• FIG. 6 is a side sectional view of a reaction well
• FIG. 7 is a perspective view of the reagent delivery and wash stations of the synthesizer of the invention.
• FIG. 8 is a top plan view of an embodiment of the invention showing six reagent or wash fluid delivery stations;
• FIG. 9 is a side sectional view of a station for delivery of reagent or wash fluid to a reaction well
• FIG. 10 illustrates the front elevation of a cartridge adapted for use at a wash
• FIG. 11 is a side elevation of the cartridge of FIG. 10;
• FIG. 12 is a side sectional view of another embodiment of a reaction well
• FIG. 13 A is a top plan view of the carousel showing reaction wells oriented with their long dimensions normal to the carousel axis of rotation;
• FIG. 13B is a top plan view of the carousel showing reaction wells oriented with their long dimensions disposed at an angle to the carousel axis of rotation;
• FIG. 14 is a sectional view, partially broken away for compactness of illustration, showing a collection vessel and its attachment to a carousel;
• FIG. 15 is a top plan view of an embodiment of the invention in which the reaction well are carried by an endless conveyer belt;
• FIG. 16 is a side elevation of the embodiment of FIG. 15;
• FIG. 17 is a top plan view of the invention in which the reaction wells are carried by a rectangular conveyer;
• FIG. 18 is a top plan view of an embodiment of the invention in which the reaction wells are carried by a linear conveyance
• FIG. 19 is a top plan view of an embodiment of the invention in which the reactant and wash solution systems are movable and the reaction wells are stationary; and
• FIG. 20 is a flow chart illustrating a method for synthesizing a compound.
• FIG. 1 there is illustrated in schematic form an automated chemical synthesizer in accordance with the present invention.
• Reaction wells 12 are carried by a rotatable carousel 10 that is drivingly engaged to a drive motor 14 for moving at least one of the reaction wells into alignment with a stationary reagent delivery station, shown generally as 20.
• the reagent delivery station includes a fluid pump 22 that is in fluid communication with a reservoir 24 and a dispensing nozzle 26. Valves 28 are provided to insure one-way flow from the reservoir 24 through the pump 22 to the nozzle 26 and from the reaction wells 12 to a collection drain 40 for collecting spent reagent.
• a source 29 of inert gas communicates with the nozzle for providing an inert atmosphere in the reaction well 12 and for aid in emptying the reaction well.
• a fluid collection system 30 receives fluid from the reaction well 12 during purging as well as the reaction products and cleavage fluids from solid state reactions.
• a control system includes a drive motor controller 32 for control of the drive motor 14 and a pump controller 34 for activation of the fluid pump 22. Both of the controllers, 32 and 34, are in communication with a central processing unit (CPU) 36 for receiving protocol commands.
• CPU central processing unit
• a user interface 38 is provided for input of commands to the CPU 36.
• a housing 8 is provided having a top wall 16, a base mounting plate 58 (FIG. 4) and front, rear and side walls 18 which cooperate to define an interior in which the drive motor 14, the drive motor controller 32 and the pump controller 34 are disposed.
• the CPU 36 can also be located in the housing 8 or alternatively the CPU can be located on the exterior of the housing for communication with the controllers 32 and 34 by cable or wireless communication.
• the rotatable carousel 10 comprises an annulus 42 (FIG. 3) having a downwardly extending ring 44 about its inner circumference.
• the annulus 42 is provided with a plurality of openings 46 for communication between a reaction well 12 and the collection drain 40.
• four arcuate segments 48 are removably secured on the annulus 42 by clamping brackets 50.
• FIG. 1 As most clearly shown by FIG.
• a series of reaction well cavities 52 are formed in the segment 48 for receiving corresponding reaction wells 12 and the cavities are provided with corresponding openings 54 which are aligned with the openings 46 in the annulus 42.
• a collection drain 40 and ancillary lines 41 are supported on the base mounting plate 58 for receiving fluid from the reaction wells 12..
• the carousel may comprise a solid circular plate and that the reaction wells 12 may be permanently formed about the plate or may be removably carried on the plate as described above. In this embodiment the openings 46 are provided for purging the reaction wells 12.
• a carousel mount shown generally as 46 consists of a fixed cylindrical outer sleeve 56, carried on the base mounting plate 58. Concentrically disposed in the outer sleeve 56 is a rotatable inner sleeve 59 having an open end that extends above the outer sleeve. The ring 44 of the annulus 42 is fit within the mouth of the inner sleeve for attachment of the annulus to the inner sleeve for rotation therewith.
• Bearing assemblies (not shown) are provided within the outer sleeve 56 for essentially friction free rotation of the inner sleeve 59 and to absorb forces imposed on the inner sleeve as the carousel 10 is being driven.
• a stepper motor 60 is mounted on the mounting plate 58.
• a pulley 62 driven by the stepper motor
• the stepper motor 60 is drivingly connected to the inner sleeve 58 by a belt 64.
• the stepper motor 60 is capable of driving the carousel 10 in either direction.
• the drive motor controller 32 is electronically connected to the stepper motor 60 for controlling the rotation of the carousel 10 through the stepper motor. It will be understood that other systems for driving the carousel, can be employed equally as well, for example, by connecting the carousel 10 directly to the motor 60 so long as the driving system is capable of driving the carousel in either direction.
• the reaction wells 12 are removable from the reaction well cavities 52 and can be disposable.
• the preferred reaction well 12 comprises end walls 66, sidewalls 68, a bottom wall 70 and a closure 72 that cooperate to form a reaction chamber 74.
• the closure 72 is provided with an inlet port 76 that is surrounded by an upstanding collar 78 for receiving the discharge end of the dispensing nozzle 26 during delivery of reactants to the reaction chamber 74.
• the bottom wall 70 has a drain opening 80 that communicates with a collection drain 40 for removal of reactant.
• Valve 86 Surrounding the outlet of the drain opening 80 is a housing 82 in which is located a filter element 84 and a valve 86 to prevent the back flow of purged reactant back into the reaction chamber 74. Valve 86 also is designed to open when pressure in the reaction well 12 reaches a pre-selected level during purging of the reaction chamber under pressurized inert gas.
• the bottom wall 70 of the reaction well 12 slopes downwardly toward the drain opening 80.
• the angle of slope may range from between about 1° to about 45°, preferably between about 5° and about 30° from the horizontal. This allows fluids to collect at the drain opening 80 which facilitates their removal from the reaction well.
• the longitudinal dimension of the reaction well 12 is greater than its transverse dimension. Mixing and agitation of reagents in the reaction well 12 without the necessity of a separate agitator is achieved by the orientation of the wells on the carousel 10. As shown in FIG. 13A the reaction wells 12 are oriented with their longitudinal dimensions normal to the axis of rotation of the carousel 10. Even more agitation is achieved by another embodiment, illustrated in FIG.
• reaction wells 12 are positioned so that the longitudinal dimension is oriented at an angle to the axis of rotation of the carousel 10.
• the reaction well 12 may be oriented on the carousel 10 so that the longitudinal dimension ranges between 0° to about 90° to the axis of rotation of the carousel.
• the reaction wells 12 are oriented with their longitudinal dimension is between about 30° and about 70°.
• the housing 82 in which the filter 84 and valve 86 are disposed is formed as part of the reaction well 12.
• the housing 82 may be removably attached to the reaction well or attached to the annulus 42 at each of the openings 46 in the event the reaction wells are to be disposable.
• FIG. 12 Another embodiment of the reaction well 12 is shown in FIG. 12 where like reference numbers denote like parts and functions.
• An inverted U-shaped tube 92 communicates between the reaction chamber 74 and the drain opening 80.
• the inverted U-shaped tube 92 forms a trap to prevent back flow of ed reactant into the reaction chamber 74.
• the final step necessary to recover the end product is the step of cleaving the product from the solid phase. This is similar to a washing step except that the liquid from the reaction well 12 must be recovered rather than sent to waste.
• a recovery vessel 94 can be aligned with the drain opening 80 from a reaction well 12 to recover the product along with the cleavage fluid.
• carousel 10 can be adapted for conveniently capturing cleavage fluid and the final product by attachment of a recovery container to the annulus 42.
• an opposed pair of L-shaped brackets 47 are disposed on the undersurface of the annulus 42 on opposite sides an opening 46 with their horizontal arms facing one another.
• the recovery container 94 is provided with a flange 96 formed about its mouth.
• the recovery container 94 is supported by the flange 96 and the brackets 47 with the container mouth aligned with a corresponding opening 46.
• a stop (not shown) may be disposed on the annulus 42 to limit the insertion of the flange 96 of the recovery container 94 to insure its mouth is correctly aligned with the corresponding opening 46.
• the recovery container 94 may be attached to the housing 82 of the reaction well 12 of the type shown in FIG. 6 by bayonet lug attachment points (not shown) on the housing and the inner surface of the recovery container adjacent its mouth.
• Reagents are controllably dispensed to the reaction chamber 74 at a delivery station 20.
• the reaction chamber 74 is washed with a suitable washing fluid at a wash station similar to the delivery station 20 .
• the number and arrangement of the delivery and wash stations varies depending on the complexity and the number of steps in the reaction protocol being carried out.
• FIG. 7 and FIG. 8 there are illustrated six stations of which four are delivery stations 20 and two are wash stations 88.
• the stations 20 and 88 are mounted on a fixed platform 90 above the carousel 10.
• the fixed platform 90 is carried by supports 91 in the housing 8 in which the components of the synthesizer are contained.
• rotation of the carousel moves the inlet port 76 of a reaction well 12 into alignment with the nozzle 26 of a desired station containing the particular reagent called for at that step of the protocol.
• the protocol calls for a washing step the carousel is rotated to bring the inlet port 76 of the reaction well 12 into alignment with the nozzle 26 of the wash fluid station.
• Positioning of the carousel at the proper angular position is directed by the drive motor controller 32 that receives commands from the CPU 36 (FIG. 1).
• the reagent delivery station 20 and wash station 88 comprise cartridges 100, having a front wall 101, side walls 104, a rear wall 106 a bottom wall 108 and a top wall 110, the inner surfaces of which cooperate to define a reservoir 112.
• the top wall 110 is open at the mouth of the reservoir 112 and a closure 114 normally seals the reservoir mouth.
• a check valve 116 is disposed in an opening 118 in the closure 114 prevent vapors from leaving the reservoir 112 and to allow air into the reservoir 112 to displace the withdrawn fluid volume.
• the reservoir 112 may be in fluid communication with a source of reagent or wash fluid to replenish the reservoir from time to time or continuously as reagent or wash fluid is withdrawn fro the reservoir.
• the bottom wall 108 is extended past the front wall 102 and an upwardly extending member 124 having a through running bore 125 receives a syringe 126 and a syringe plunger 128.
• the syringe 126 and plunger 128 are disposable.
• a fluid port 118 in the bottom wall 108 communicates between the reservoir 112 and a fluid supply line 120 that opens to the rear wall and extends through the bottom wall to a fluid dispensing line 130 that communicates between the syringe 126 and the dispensing nozzle 26.
• a check valve 122 is disposed in the fluid supply line 122 and a plug 123 normally seals the opening of the fluid supply line at the rear wall 106 of the cartridge 100.
• the top wall 110 extends beyond the front wall and a linear motor 132 is mounted thereon.
• a lead screw 134 operated by the linear motor for bi-directional vertical movement extends through the top wall.
• the extending end of the lead screw 134 carries a plunger block that, responsive to the vertical movement of the lead screw, slides vertically along the outer surface of the front wall 102.
• a spaced apart upper and lower pair of fingers 138 extend from the face of the plunger block 136 and the flange of the syringe plunger 128 is received the upper and lower pair for the vertical movement of the plunger responsive to the vertical movement of the plunger block.
• the linear motor is in electrical communication with the pump controller 34 for control of the vertical movement of the plunger block and resultant operation of the syringe 126 through control of the linear motor.
• An inert gas supply line 140 extends through the bottom wall 108 for communication between a source of inert gas (not shown) and the fluid dispensing line 130 for introduction of an inert gas into a reaction well 12.
• An electronically controlled valve (not shown) is provided in the line 130 to remotely open and close the valve for opening and closing communication between a reaction well 12 and a source of inert gas.
• a check valve 142 in the inert gas supply line 140 prevents a back flow from the dispensing line 130 to the source of inert gas.
• a micro-fluidic pump In lieu of the syringe 126, syringe housing 124 and motor driven lead screw 134, a micro-fluidic pump, a rotary pump, a piston pump, a solenoid pump, a confluent pump, a diaphragm pump or a peristaltic can be used.
• a confluent pump and valve module distributed by Sapphire Engineering, Pocasset MA can be used with equal results .
• a self contained unit comprising a reservoir and fluid dispensing jets of the type found in ink jet printers can be used to dispense controlled amounts of fluid into the reaction wells 12.
• the cartridge 100 operates in the same fashion as a washing station 88 with the following differences. For washing it is necessary to insure that the wash solution is removed from the reaction well 12. Pressurized inert gas is introduced though the dispensing nozzle 26 to flush the reaction chamber 74. To accomplish flushing the dispensing nozzle 144 is longer than for nozzle 26 of the regent delivery stations in order for it to extend into the inlet port 76 of the reaction well 12 during a flushing step to form a pressure tight seal.
• the extended dispensing nozzle 26 will normally interfere with the rotation of the carousel 10 and accordingly a suitable linear actuator for lifting the cartridge 100 is provided to move the extended dispensing nozzle out of interference to permit rotation of the carousel 10 and to lower the cartridge for a pressure tight seal between the extended dispensing nozzle 26 and the inlet port 76 of the reaction well 12.
• the Linear Actuator may comprise any apparatus that will lift the and lower the dispensing nozzle including, but not limited to solenoids, linear motors, motors with cam/lifter, motors with lead screw drive and the like.
• FIG. 10 and FIG. 11 where like reference numbers refer to like parts having like functions, a front and a side view of a cartridge 100 adapted for use as a washing station 88 is shown.
• the configuration and operation of the cartridge is as described above in connection with the cartridge of FIG. 8.
• the reservoir 112 is defined by the front wall 102, the rear wall 106 and the bottom wall 108 and is normally sealed by the closure 114.
• the fluid port 118 communicates between the reservoir 112 and the fluid supply line 120.
• the operation of the syringe plunger 128 is responsive to the vertical movement of the plunger block 136 as driven by the lead screw 134 and linear motor 132.
• the flange of the syringe plunger is disposed between the upper pair and the lower pair of fingers 138 for vertical movement with the plunger block 136.
• an extended dispensing nozzle 144 extends below the bottom wall 108 for a sealed fit in the inlet port 76 of the reaction well 12.
• a linear actuator such as solenoids 146 is provided to raise the cartridge 100 so that the extended dispensing nozzle 144 is clear of the reaction well 12.
• the solenoids 146 may be attached to the fixed platform 90 to act against the bottom wall 70 of the cartridge 100 or may be received in sockets 148 formed in the bottom wall. In either case guide pins (not shown) on the fixed platform 90 are received in pin sockets 150 formed in the front wall 101 of the cartridge 100 to provide positioning and to guide vertical motion during the lifting sequence.
• the pump controller 34 is programmed to activate and deactivate the solenoids 146.
• the fixed platform 90 that carries the delivery stations 20 is provided with a linear actuator (not shown) on the base mounting plate 58 for contact with the lower surface of the platform to lower the entire platform for inserting the extended dispensing nozzles 144 of the wash fluid stations and for raising the platform to provide clearance between the extended dispensing nozzles and the reaction wells 12.
• the carousel 10 is adapted to be raised to insert the extended dispensing nozzles 144 into the inlet ports 76 of aligned reaction wells 12 by mounting a linear actuator (not shown) on the base mounting plate 58 at opposite sides of the carousel 10. Ring 44 is extended to permit telescoping movement in the rotatable inner sleeve 59.
• the liner actuators contact the bottom surface of the carousel 10 to raise it for insertion of the extended dispensing nozzles into the inlet ports 76 of aligned reaction wells 12 to form a fluid tight seal.
• a program for each reaction well 12 consisting of a series of sequential steps for synthesizing a compound is input to the CPU 36 from the user interface 38 or is pre-programmed in the CPU data base.
• the protocol will include the reagents required, the order of dispensing the reagents, the dispensing amounts, reaction time, purge instructions and in certain cases, such as solid state reactions, any washing and cleavage instructions.
• the data base will include quantities of liquid to be dispensed to the reaction well covered by the program.
• Instructions from the CPU 36 are sent to the drive motor controller 32 which controls the rotation of the carousel 10. Depending on its program, a reaction well 12 is rotated into alignment with a reagent delivery station 20.
• the pump controller 34 causes the linear motor 132 and plunger block 136 of the cartridge 100 of the reagent delivery station to fully depress and fully retract the syringe plunger 128 which produces a vacuum in the syringe 126 to draw the desired reagent from the reservoir 112 through the fluid port 118 and fluid supply line 120 into the syringe.
• the pump controller 34 reverses the vertical movement of the plunger block 136 and syringe plunger 128 to dispense the reagent through the dispensing nozzle 26 into the reaction chamber 74 of the reaction well 12.
• the sequence of rotation and dispensing steps are repeated until all of the reagents have been dispensed into the reaction chamber 74 of the reaction well 12.
• the need for an agitator to mix the reactants in the reaction well 12 is unnecessary.
• the carousel can be programmed to use the drive motor 14 to agitate the reaction wells 12 with small cyclic motion at a user defined amplitude, duration and frequency.
• the pump controller 34 deactivates the solenoids 146 for lowering the cartridge 100 which is guided by the guide pins in the pin sockets to bring the extended dispensing nozzle 144 into a tight fit in the inlet port 76 of the reaction well 12.
• high-pressure nitrogen, or suitable inert gas is directed into the extended dispensing nozzle 144 to force the contents of the reaction well through the drain opening 80 for recovery of the contents.
• the pump controller 146 signals the linear motor 132 to cause the syringe plunger 128 to fully depress and retract to create a vacuum to draw wash fluid from the reservoir 112 of the cartridge 100.
• the linear motor 132 is then commanded to depress the syringe plunger 128 to force the wash fluid into the chamber 74 of the reaction well 12. Following this the flow of pressurized inert gas pressurizes the chamber 74 causing the valve 86 to open to flush the wash fluid from the reaction chamber through the drain opening 80 to the collection drain.
• the filter 84 in the filter housing 82 retains the solid phase products in the reaction chamber 74 for subsequent cleavage steps.
• FIG. 20 is a flow diagram illustrating the program steps for a reaction well 12 for the synthesis of a compound.
• the synthesizer is constructed in accordance with the embodiment of the invention utilizing a rotary carousel to move the reaction well into alignment with stationary delivery stations. As illustrated direction of the synthesizer will take the following sequence of commands:
• each reaction well which will be involved in synthesis of a compound will be controlled by its individual program.
• an synthesizer carrying 108 reaction wells and 36 delivery stations a number of reaction wells simultaneously may be receiving reactant or being purged according to the program for each reaction well.
• each reaction well 12 may be synthesizing a different compound or may be in different stages of synthesis.
• the recovery container 94 may be attached to the reaction well 12 as described above.
• a separate vessel may be placed beneath the carousel 10 in alignment with the drain opening 80 of the reaction well 12 undergoing cleavage. Cleavage is carried out in accordance with well-understood procedures and in the same manner as the washing steps except that the cleavage fluid and finished product are recovered for subsequent separation steps.
• the dedicated purge station 158 comprises a body 160 through which a bore 162 extends between an extended nozzle 164 and a section of flexible tubing 166 that communicates with a source of inert gas.
• a collar 168 may be provided on the extended nozzle to aid in forming a pressure tight seal when the nozzle is positioned in the inlet port 76 of a reaction well 12.
• a housing 168 is formed on the front wall of the body 160 in which is disposed a linear actuator such as a solenoid 170.
• a fulcrum 172 is provided adjacent the rear wall of the body 160 about which the body can pivot in response to the extension of the piston of the solenoid 170 to raise the extended nozzle 164 away from the reaction well 12 so that the reaction well can move without interference from the nozzle.
• the reagent delivery stations 20 and the wash stations 88 need not be lifted because there is no need to form a fluid tight seal and thus their nozzles are shorter and do interfere with the movement of the reaction wells 12.
• the removable segments 48 allow for flexibility in the number of reaction wells 12 on the carousel 10. Depending on the diameter of the carousel 10 and the size of the reaction wells 12 there may conveniently be as many as 108 reaction wells and as few as one.
• a scanner may be employed to identify the function, location and contents of each station.
• a scanner may read an identifying bar code, a two dimensional pixel code, a color code and the like.
• Fluid level monitors such as Hall effect sensors, optical sensors or other conventionally available fluid sensors may be employed to determine fluid levels in the cartridge reservoirs 24.
• Means for heating or cooling the contents of the reaction well 12 can be provided, such as, for example, a thermoelectric Peltier effect chiller, a resistive heating element or conductive fluid lines that circulate hot or cold fluid around the reaction wells 12 and the reservoir 112 of the cartridges 100.
• one or more monitoring stations can be carried on the carousel for monitoring temperature, performing spectroscopic analysis of the contents of a reaction well 12, pH, purity of the product and the like.
• reaction wells 12 are carried by an endless conveyor belt 152.
• a drive pulley 154 powered by a bi-directional drive motor 153 and idler pulley 156 are mounted on mounting plate 58 to drive and support the conveyor belt 152 for movement in either direction.
• the reaction wells 12 and their function are as described above. As illustrated there are two reagent delivery stations 20 and two wash stations 85. In addition two stations 158 are dedicated to purging the fluid from a reaction well 12. A recovery container 94 is provided at each purge station 158. The stations 20, 85 and 158 are mounted on the fixed platform 90. The purge stations 158 are provided with the solenoids 146 to lower the purge station in order to form a fluid tight seal between its dispensing tip 144 and the inlet ports 76 of the reaction wells 12. As shown the purge stations 158 are in the lowered position.
• the solenoids 146 are activated by the control system to raise the purge stations 158 to move the dispensing tips 144 upwardly from the reaction wells 12 so as to not interfere with movement of the reaction wells.
• the delivery stations are located along one outer side of the conveyor belt.152, however, it will be understood that the delivery stations can be arranged on both outer sides of the conveyor belt 152.
• the conveyor belt 152 is caused to move in a rectangular path.
• the drive system is similar to that described in connection with FIG. 16.
• the drive pulley and bi-directional motor (not shown) are located at one corner of the rectangle while the idler pulleys (not shown) are positioned at the remaining three corners.
• the function of the conveyor belt 152, the reaction wells 12 and the delivery stations 20 and 85 are as described above in connection with the embodiments described above.
• the reaction wells 12 are disposed on an elongated carrier 180 for bi-directional linear movement.
• the carrier 180 is driven by at least one bi-directional motor (not shown) powered driver 180.
• the driver 180 may comprise a pinion gear that meshes with a rack disposed along an edge of the elongated carrier 180.
• the driver 180 may comprise a bi-directional motor powered wheel having a high friction peripheral edge in engagement with a high friction edge of the carrier 180.
• the machine base 58 is provided with a suitable track in which the carrier 180 moves. The linear travel of the carrier 180 to the right is such that the leftmost reaction well 12 can be aligned with the right most station 158 and to the left so that the right most reaction well can be aligned with the leftmost station 20.
• control system for the embodiments shown in FIGS. 15, 16, 18 and 19 includes the drive motor controller 32 and the pump controller 34 for activation of the fluid pumps at the dispensing stations 20 and 85 that function in the manner described. Both of the controllers, 32 and 34, are in communication with a central processing unit (CPU) 36 for receiving protocol commands.
• CPU central processing unit
• a user interface 38 is provided for input of commands to the CPU 36.
• the delivery stations may be carried by an annular carousel for rotation of the delivery stations into alignment with the stationary reaction wells.
• the drive system includes a bi-directional motor driving the carousel directly or a belt drive as described above in connection with the carousel carrying the reaction wells.
• the delivery stations are carried by a motor conveyor belt that is driven by a bi-directional motor and idler pulley system as described above.
• the delivery stations can be supported on an elongated plate for bi-directional linear motion that is driven by rack and pinion system also as described above.

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• 2006
  • 2006-11-09 JP JP2008540339A patent/JP2009515682A/ja not_active Withdrawn
  • 2006-11-09 WO PCT/US2006/060706 patent/WO2007059403A2/en active Application Filing
  • 2006-11-09 EP EP06839790A patent/EP1951421A2/de not_active Withdrawn

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