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WO1998010857A1 - Moyen d'actionnement s'utilisant dans la synthese chimique en phase solide avec des alignements de recipients de reaction modulaires - Google Patents

Moyen d'actionnement s'utilisant dans la synthese chimique en phase solide avec des alignements de recipients de reaction modulaires Download PDF

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Publication number
WO1998010857A1
WO1998010857A1 PCT/US1997/016343 US9716343W WO9810857A1 WO 1998010857 A1 WO1998010857 A1 WO 1998010857A1 US 9716343 W US9716343 W US 9716343W WO 9810857 A1 WO9810857 A1 WO 9810857A1
Authority
WO
WIPO (PCT)
Prior art keywords
bore
valve body
reaction vessel
reaction
drain
Prior art date
Application number
PCT/US1997/016343
Other languages
English (en)
Other versions
WO1998010857A9 (fr
Inventor
Ronald Zuckermann
Aaron C. Siegmund
Kerry L. Spear
Original Assignee
Chiron Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chiron Corporation filed Critical Chiron Corporation
Priority to JP10513963A priority Critical patent/JP2001500426A/ja
Priority to AU44170/97A priority patent/AU4417097A/en
Priority to EP97942483A priority patent/EP0949964A1/fr
Publication of WO1998010857A1 publication Critical patent/WO1998010857A1/fr
Publication of WO1998010857A9 publication Critical patent/WO1998010857A9/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5025—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures for parallel transport of multiple samples
    • B01L3/50255—Multi-well filtration
    • 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
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K27/00—Construction of housing; Use of materials therefor
    • F16K27/003—Housing formed from a plurality of the same valve elements
    • 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
    • B01J2219/00286—Reactor vessels with top and bottom openings
    • 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
    • B01J2219/00308—Reactor vessels in a multiple arrangement interchangeably mounted in racks or blocks
    • 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
    • B01J2219/00308—Reactor vessels in a multiple arrangement interchangeably mounted in racks or blocks
    • B01J2219/0031—Reactor vessels in a multiple arrangement interchangeably mounted in racks or blocks the racks or blocks being mounted in stacked arrangements
    • 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
    • B01J2219/00331—Details of the reactor vessels
    • B01J2219/00333—Closures attached to the reactor vessels
    • B01J2219/00344—Caps
    • B01J2219/00346—Screw-caps
    • 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
    • B01J2219/00389—Feeding through valves
    • B01J2219/00391—Rotary valves
    • B01J2219/00394—Rotary valves in multiple arrangements
    • 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
    • B01J2219/00414—Means for dispensing and evacuation of reagents using suction
    • B01J2219/00416—Vacuum
    • 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
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/005—Beads
    • 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
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • 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
    • B01J2219/00722—Nucleotides
    • 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
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/06—Libraries containing nucleotides or polynucleotides, or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/10—Libraries containing peptides or polypeptides, or derivatives thereof
    • 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

Definitions

  • the invention relates generally to solid phase chemical synthesis. More particularly, the invention relates to novel reaction vessels and an apparatus containing them in which a new kind of actuation means is incorporated.
  • the invention extends to the synthesis of polypeptides, peptoids, polynucleotides and other syntheses utilizing solid phase organic chemistries.
  • polymers or oligomers of amino acids, nucleotides, or the like can be easily prepared using conventional solid phase synthetic technologies.
  • a defined polynucleotide can be prepared using conventional phosphoramidite or phosphotriester chemistry. Beaucage et al., Tetrahedron Lett. 22:1859-62 (1981); Itakura et al., J. Biol. Chem. 250:4592 (1975).
  • a single defined polypeptide can be synthesized using Merrifield solid phase synthetic schemes. Merrifield, J. Am. Chem. Soc. 85:2149-2154 (1963); Tarn et al., The Peptides, Academic Press (New York), pp. 185-249 ( 1987).
  • 5,240,680 to Zuckermann et al. relates to the synthesis of polypeptides using an apparatus having structure for automated transfer of reaction solutions into and out of a cleavage vessel, peptide solution from the cleavage vessel to the extraction vessel, and transfer of extraction solvent into and out of the extraction vessel.
  • an apparatus for conducting chemical syntheses involving a sequence of reaction steps to be conducted on a solid phase includes a plurality of reaction vessels arranged in a substantially linear array, wherein each vessel contains a substrate bearing a solid phase on which chemical synthesis steps are carried out and a passageway through which the vessels may be drained.
  • Each reaction vessel further includes a valving means associated therewith, wherein the valving means is configured to yield a first position allowing drainage of the container and a second position preventing drainage of the container.
  • the valving means is configured to enable the simultaneous draining of the containers in the array, or simultaneous closing of the containers in the array so as to prevent drainage of the vessels.
  • a modular reaction vessel for use in solid phase synthesis chemistry.
  • the modular reaction vessel is configured to be arranged in a substantially linear array of like vessels to provide a means for conducting parallel reaction steps in solid phase chemical syntheses such as polynucleotide or polypeptide preparation.
  • the reaction vessels feature a valve body containing a drain that is capable of being simultaneously actuated with the drains in the other vessels in the same array.
  • a matrix of reaction vessels is provided.
  • the matrix is formed by a plurality of substantially parallel linear arrays of modular reaction vessels, wherein the vessels in each discrete linear array of vessels in the matrix can be actuated in tandem to the exclusion of vessels in other linear arrays.
  • the present invention thus also provides an efficient method for carrying out the parallel syntheses of a plurality of compounds in a plurality of reaction vessels.
  • Figure 1 is a cross-sectional view of an embodiment of the reaction vessel of the invention having a container disposed within a modular valve body.
  • Figure 2 is a pictorial representation of a linear array of reaction vessels coupled together in the array by an actuation means capable of simultaneously actuating the valves in the entire array of vessels.
  • Figure 3 is a cross-sectional view of another embodiment of the reaction vessel of the invention having optional locking and sealing means which provides a liquid-tight and pressure-tight interface between the container and the modular valve body.
  • Figure 4 is an exploded view of a linear array of reaction vessels and their alignment within an associated rack.
  • Figure 5 is an exploded view of a linear array of reaction vessels and their operative relationship to various associated devices for use in conducting chemical syntheses within the reaction vessels.
  • the term "monomer” as used herein refers to a chemical entity that may be covalently linked to one or more other entities to form an oligomer. Monomers are subunits that include, for example, amino acids, nucleotides, saccharides, alkylators, nucleophiles, and the like.
  • solid phase intends any solid support or substrate on which the reaction steps of chemical syntheses involving a sequence of reaction steps can be carried out. Thus, the term includes particulate substrates such as polystyrene resins which have traditionally been employed in standard Fmoc chemical syntheses.
  • substantially linear refers to an arrangement of such vessels wherein the novel actuation means of the invention can be used to simultaneously actuate the draining of all of the vessels in the array using the methods and devices described herein.
  • pressure-tight when used herein in reference to a particular seal or an interface between two components, refers to the capability of such seal or interface to withstand pressures of at least about 5 psi, more preferably at least about 10 to 15 psi, and most preferably at least about 20 psi, without leaking (e.g., allowing the passage of gases therethrough).
  • an apparatus for conducting chemical syntheses involving reaction steps that are conducted on a solid phase.
  • the apparatus includes a plurality of reaction vessels arranged in a linear array.
  • the reaction vessels are operatively coupled to each other in the linear array by way of a novel valving means which enables a broad range of synthetic manipulations to be carried out in parallel.
  • each of the reaction vessels in the linear array contains a substrate bearing a solid phase on which chemical syntheses involving a sequence of reaction steps can be carried out.
  • the vessels have an upper opening through which chemical reagents can be introduced, and a lower opening through which the vessels can be drained.
  • the architecture of the reaction vessels is particularly well suited for use in the parallel synthesis of polypeptides, peptoids, polynucleotides and other synthetic organic chemistries that are synthesized by solid phase methods in which monomeric units are added step-wise to a growing polymer chain immobilized on a solid support.
  • the substrates disposed within the vessels physically retain the solid support, e.g., discrete particles such as resins or polymer beads, and allow for efficient mixing between reactants contained within the vessels and the supports.
  • the lower "drain" opening allows separation of solid support-bound intermediates from excess reagents, solvents and byproducts.
  • each reaction vessel has a modular valving means associated therewith.
  • the modular valving mean is operatively associated with the lower drain opening in the reaction vessel, allowing the vessel to be sealed, or opened to drain therethrough.
  • the valving means also contains an actuation means which cooperates with a universal mechanism capable of simultaneously actuating all of the valving means in a linear array between their respective sealed and open positions.
  • the vessel includes a container 4 having a top opening 6, and a bottom opening 8 comprised of a protruding elongate conduit 10 with an upstream terminus 12 and a downstream terminus 14.
  • the container 4 has an integral filter substrate 16 disposed within the container and arranged above the upstream terminus 12 of the elongate conduit 10.
  • the filter substrate 16 physically supports a solid phase on which solid phase synthesis chemistry can be carried out.
  • the modular reaction vessel 2 further includes a valve body, generally indicated at 18, having an upper surface 20 and a lower surface 22 with a vertical bore 24 extending therebetween.
  • a horizontal bore 26 is arranged in valve body 18 such that the major axis thereof is substantially normal to the major axis of vertical bore 24, thereby dividing the vertical bore into an upper portion 28 and lower portion 30.
  • Upper surface 20 of the valve body contains a valve seat 32 coaxially aligned with the vertical bore 24 and configured to accept and retain the elongate conduit 10 of the container 4.
  • a barrel drain 34 is disposed within the horizontal bore 26.
  • a drain bore 36 extends through the body 38 of the barrel drain.
  • Actuation means 40 allows the barrel drain to be rotated between a first position wherein the drain bore 36 is coaxially aligned with the vertical bore 24 in the valve body 18 and allows fluid communication between upper portion 28 and lower portion 30 of the vertical bore via drain bore 36.
  • container 4 can be drained to separate solid phase- bound intermediates that are retained in the container by the filter substrate 16, from excess reagents, solvents and byproducts.
  • the reaction container can also be drained to isolate the desired synthesized molecules from the retained solid phase support in a cleavage step.
  • the barrel drain 34 can also be rotated to a second position wherein the outer surface of the body 38 of the barrel drain blocks passage of reagents or products from the container 4 by preventing fluid communication between upper and lower portions 28 and 30 of vertical bore 24.
  • Actuation means 40 is adapted such that the barrel drains in at least two valve bodies can be actuated simultaneously when two or more modular reaction vessels are disposed in a substantially linear array of reaction vessels.
  • the modular reaction vessel 2 is specially adapted for use in solid phase synthesis chemistry reactions in which a sequence of reaction steps arc carried out in parallel using a plurality of reaction vessels.
  • the container 4 can be comprised of any suitable material selected for chemical inertness and physical resiliency.
  • the container can be comprised of Pyrex® or any other suitable borosilicate or other material commonly used in the construction of chemical reaction containers. Borosilicate materials are generally preferred.
  • the container 4 can comprise external threads disposed around the periphery of the top opening 6 to facilitate the liquid- and/or pressure-tight closure of the container using a threaded cap.
  • borosilicate materials in the construction of the container 4 also facilitates formation of the protruding elongate conduit 10 which extends from the bottom of the container, i.e., because borosilicate structures can be formed by glass drawing techniques that are routine in the art. Further, this process readily allows the addition of the integral filter substrate 16 in the container 4 during formation of the reaction container.
  • the filter substrate can be comprised of any material capable of retaining common solid supports on which chemical syntheses .are conducted.
  • the filter substrate material should also be chemically inert with respect to the reagents used in the chemical syntheses conducted in the reaction vessels, durable, reusable and generally nondeformable over multiple uses.
  • the filter generally has a mesh size ranging from about 10 to about 50 ⁇ m, although much larger mesh sizes are equally suitable for use in vessels where "pins” or “crowns” are to be used as the solid support.
  • filter substrate 16 is a glass frit having, for example, a 16 to 40 ⁇ m filter size.
  • valve body 18 can be formed from any suitable chemically inert polymeric material that is also substantially rigid and nonexpanding.
  • the valve body can be formed from a poly(chlorotrifluoroethylene) such as Kel-F® or the like.
  • substantially rigid, nonexpanding materials in the construction of the valve body 18 allows for compression fitting of a compressible barrel drain 34 within the horizontal bore 26 of the valve body. More specifically, the material used in the construction of the barrel drain should have good frictional characteristics relative to the valve body material.
  • a compressible barrel drain for use in a valve body comprised of a substantially rigid material, one is able to achieve a positive pressure- and liquid-tight seal between those components by compression fitting the compressible barrel drain 34 within the horizontal bore 24 of the rigid valve body 18.
  • Selection of a barrel drain material that has good frictional characteristics relative to the valve body material enables rotation of the barrel drain within the valve body without compromising the sealing between those materials.
  • the barrel drain can be comprised of high density polyethylenes which have superior frictional characteristics relative to such valve body materials.
  • the barrel drain 34 can be comprised of a polymeric material that is chemically inert .and structurally sound, yet compressible, such as polytetrafluoroethylene (e.g., Teflon®).
  • the actuation means 40 of the barrel drain 34 is shown as comprising a pair of key bores which extend through the barrel drain and are arranged such that the major axis of the drain bore 36 is substantially normal to the major axes of the key bores.
  • the key bores depicted in Figure 1 are disposed on opposites sides of the drain bore in the barrel drain.
  • the key bores allow actuation of the barrel drain between its first and second positions by a turning key that fits within the bores.
  • Such key bores can be configured in any suitable geometry, such as oval, semi-circular, C-shaped or D-shaped to accommodate complementary-shaped turning keys.
  • the actuation means 40 can comprise a single key bore shaped as described above, or a plurality of bores arranged on one or both sides of the drain bore.
  • a linear array of modular valve bodies is generally indicated at 52.
  • the array comprises a plurality of valve bodies 54 having barrel drains 56 disposed within horizontal bores 58 extending through the valve bodies 54.
  • the barrel drains contain drain bores 60 which allow communication between upper and lower portions of vertical bores 62 which extend through the valve bodies 54.
  • the barrel drains also contain first and second key bores, respectively indicated at 64 and 66, which cooperate with a turning key 68 capable of simultaneously actuating the barrel drains 56 in each of the valve bodies 54 disposed in the linear array 52.
  • the turning key 68 is formed from a suitable material that exhibits little or substantially negligible twist such that the turning key can simultaneously actuate each of the barrel drains 56 to accurately align the drain bores 60 with the upper and lower portions of the vertical bores 62.
  • the turning key 68 can be formed from two tungsten/carbide rods which extend through the key bores 64 and 66. Tungsten/carbide materials are selected herein due to the high modulus of elasticity of such composite materials; however, any other material having a high modulus of elasticity can be substituted therefor in the construction of the turning keys.
  • another component interface in the modular reaction vessel 2 comprises the mating surface between the elongate conduit 10 and the valve seat 32 in the valve body 18.
  • this interface provides a sealing surface that needs to be both liquid- and pressure-tight in order to facilitate use of such reaction vessels in common solid phase synthesis processes.
  • the valve body is comprised of a substantially rigid polymer such as poly(chlorotrifluoroethylene)
  • the container 4 can be formed from a substantially rigid borosilicate and configured such that the external diameter of the elongate conduit 10 and the internal diameter of the valve seat 32 provide for a tight compression-fit between the elongate conduit and the valve body.
  • a biasing means such as a spring clip or other tensioning device, can be used to maintain the conduit firmly in place within the valve seat 32 to provide a liquid-tight and/or pressure-tight seal.
  • the reaction vessel includes a container 104 having a top opening 106 and a bottom opening 108 comprised of a protruding elongate conduit 110 with an upstream terminus 112 and a downstream terminus 114.
  • the modular reaction vessel 102 also includes a valve body, generally indicated at 118, having an upper surface 120 and a lower surface 122 with a vertical bore 124 extending therebetween.
  • a horizontal bore 126 is arranged in the valve body 118 such that the major axis thereof is substantially normal to the major axis of the vertical bore 124, thereby dividing the vertical bore into an upper 128 and lower 130 portion.
  • the upper surface 120 of the valve body contains a valve seat 132 that is coaxially aligned with the vertical bore 124 and configured to accept and retain the elongate conduit 110 of the container 104.
  • annular sealing means 150 is provided which encircles the base of the elongate conduit and engages with a mating notch 152 arranged within the valve seat 132.
  • the annular sealing means thus provides a liquid-tight interface between the conduit and the valve body.
  • the annular sealing means can be formed from any suitable gasket or sealing material.
  • the sealing means is comprised of a compressible polymeric material poly(ethylenetetrafluoroethylene), for example Tefzel®, and is configured as a flangeless ferrule.
  • the valve seat 132 contains optional lock means for detachably coupling the elongate conduit 110 with the valve body 118 to provide a pressure-tight interface therebetween.
  • the valve seat 132 comprises internal threads 154 which engage a threaded coupler 156 which holds the elongate conduit in place relative to the valve body and provides a resilient pressure-tight seal between those two components of the modular reaction vessel 102.
  • the threaded coupler 156 can include optional means for tightening and loosening the hold on the elongate conduit, such as wherein the coupler is an externally-threaded hex nut.
  • a linear ordered array 202 of modular reaction vessels is shown in exploded view to illustrate the various components thereof.
  • a plurality of reaction vessels are provided having a container 204 with a top opening 206, a bottom opening 208 comprised of a protruding elongate conduit 210, and an internally disposed filter substrate 212 arranged above the elongate conduit 210 and capable of retaining a solid phase within the container.
  • Each container 204 is disposed within a modular valve body 214 which contains a vertical bore 216 and a horizontal bore 218 disposed within the valve body as previously described hereinabove.
  • a barrel drain 220 is arranged within each horizontal bore 218.
  • the barrel drain can be switched between a first position in which a drain bore 222 extending through the barrel drain is aligned with the vertical bore 216 extending through the valve body 214 thereby allowing communication of contents from the container 204 through the valve body, and a second position which prevents communication through the valve body as also described hereinabove.
  • the array 202 of modular reaction vessels is maintained in linear spaced apart relation to each other within a rack 224 having a plurality of receptacles 226 configured to retain the array of reaction vessels.
  • An actuation means 228 is provided which enables simultaneous actuation of the barrel drains 220 (e.g., between their respective first and second positions) in each reaction vessel arranged in the linear array 202.
  • a number of like arrays can be retained within the rack 224, wherein the barrel drains in each of the vessels present in discrete linear arrays can be simultaneously actuated by an individual actuation means.
  • a matrix can be formed by a plurality of linear arrays of two or more such modular reaction vessels. Chemical synthesis steps can be conducted in parallel in each discrete linear array.
  • the rack 224 also contains openings 230 which accommodate the insertion of actuation means 228 for each linear array.
  • the openings 230 also allow metallic or semi-metallic actuation means to be readily removed from the arrays, such as where it is desired to insert the rack 224 and reaction vessels into a microwave for a quick temperature adjustment. After heating, the actuation means can be easily reinserted.
  • the present invention thus provides a method for carrying out parallel reaction steps in the solid phase chemical synthesis of a plurality of compounds, said method comprising:
  • each vessel contains a substrate bearing a solid phase on which the reaction steps are carried out and (b) has associated with it a valving means configured to yield a first position allowing drainage of the vessel and a second position preventing drainage of the vessel;
  • linear arrays of reaction vessels can be comprised of any number of individual containers, and matrices formed from such linear arrays can be comprised of any number of discrete linear arrays.
  • the spacing between vessels in each linear array, and between linear arrays of vessels in a matrix can be adjusted to accommodate the use of various liquid handling devices such as multi-channel pipettors, aspirators and the like which can have a wide degree of variation in the spacing of individual liquid channeling means.
  • the vessels can be arranged relative to each other in such a way as to facilitate the placement or removal of screw-cap closures for the containers, where it is convenient to have adequate finger space between vessels in order to manipulate individual caps.
  • the vessel array depicted in Figure 4 is designed for ready use with associated devices, such as vacuum manifolds which facilitate the simultaneous draining of reagents from linear arrays of vessels, collection racks which can be used to retain filtrates from the vessels and temperature control devices which can be used to provide various reaction conditions for chemical syntheses conducted within the reaction vessels.
  • associated devices such as vacuum manifolds which facilitate the simultaneous draining of reagents from linear arrays of vessels, collection racks which can be used to retain filtrates from the vessels and temperature control devices which can be used to provide various reaction conditions for chemical syntheses conducted within the reaction vessels.
  • a rack 252 which contains a plurality of linear arrays of reaction vessels 254, wherein all of the barrel drains in each linear array are individually actuated by an actuation means 256 coupled to that array.
  • the rack 252, containing one or more linear arrays of reaction vessels, can be placed upon an associated vacuum manifold 258, having means 260 for connecting the manifold with a vacuum source.
  • the rack 252 can be placed in vacuum-tight relation with the vacuum manifold 258 which is then evacuated to provide a vacuum under the reaction vessels contained within the rack.
  • the barrel drains in each of the reaction vessels can be opened, thereby allowing communication of excess reagents, solvents, byproducts from the reaction vessels to drain into the vacuum manifold for collection by an associated waste receptacle during washing steps.
  • a gasket 262 such as a closed-cell foam comprised of a polyethylene, can be placed between the rack 252 and the lid 264 of the vacuum manifold 258 to improve the vacuum-tight seal between those components.
  • a collection rack 266, containing a plurality of collection vials that correspond to each reaction vessel 254 included in the rack 252, can be inserted into the vacuum manifold 258 prior to placing the rack 252 into operative position with the vacuum manifold. In this manner, the filtrates from each reaction vessel can be individually collected and retained by the collection vials.
  • a temperature control element 270 configured to fit over the top of each reaction vessel 254 in the rack 252, can be applied to regulate or adjust the temperature in the reaction vials.
  • the temperature control element 270 is comprised of an aluminum block having heating elements attached thereto which can be placed over the reaction vials 254 to incubate the vessels at elevated temperatures.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Engineering & Computer Science (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Mechanical Engineering (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)

Abstract

Cette invention se rapporte à un appareil qui est conçu pour être utilisé dans des procédés de synthèse chimique en phase solide, tels que la synthèse de polypeptides, de peptoïdes, de polynucléotides et d'autres molécules synthétisées par des procédés en phase solide. Cet appareil contient plusieurs récipients de réaction (2, 102, 202, 254) disposés dans un alignement essentiellement régulier (202), ces récipients de réaction (2, 102, 202, 254) comportant des robinets modulaires (18, 52, 118, 214) pouvant être actionnés simultanément pour ouvrir ou fermer chacun des récipients de réaction (2, 102, 202, 254) de l'alignement (202). Cette invention se rapporte en outre à plusieurs alignements réguliers essentiellement parallèles (202) de tels récipients (2, 102, 202, 254), dans lesquels les robinets (18, 52, 118, 214) de chaque récipient (2, 102, 202, 254) dans un seul alignement (202) peuvent être actionnés simultanément.
PCT/US1997/016343 1996-09-12 1997-09-11 Moyen d'actionnement s'utilisant dans la synthese chimique en phase solide avec des alignements de recipients de reaction modulaires WO1998010857A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP10513963A JP2001500426A (ja) 1996-09-12 1997-09-11 モジュラー反応容器の配列を含む固相化学合成における使用のための作動手段
AU44170/97A AU4417097A (en) 1996-09-12 1997-09-11 Actuation means for use in solid phase chemical synthesis involving arrays of modular reaction vessels
EP97942483A EP0949964A1 (fr) 1996-09-12 1997-09-11 Moyen d'actionnement s'utilisant dans la synthese chimique en phase solide avec des alignements de recipients de reaction modulaires

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2600296P 1996-09-12 1996-09-12
US60/026,002 1996-09-12

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WO1998010857A1 true WO1998010857A1 (fr) 1998-03-19
WO1998010857A9 WO1998010857A9 (fr) 1998-07-09

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AU (1) AU4417097A (fr)
WO (1) WO1998010857A1 (fr)

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WO1999065602A3 (fr) * 1998-06-16 2000-06-15 Northwest Engineering Inc Synthetiseur rotatif a puits multiples
DE19917398A1 (de) * 1999-04-16 2000-10-19 Norbert Schwesinger Modulares chemisches Mikrosystem
JP2001129386A (ja) * 1999-08-24 2001-05-15 Tokyo Electron Ltd ガス処理装置およびそれに用いられる集合バルブ
DE20201753U1 (de) 2002-02-05 2002-04-11 Ehrfeld Mikrotechnik GmbH, 55234 Wendelsheim Modulares Mikroreaktorsystem
WO2002099003A3 (fr) * 2001-06-06 2003-10-02 Monsanto Technology Llc Systeme de reacteur parallele et procede correspondant
EP1479434A1 (fr) * 2003-05-17 2004-11-24 Heidolph Instruments GmbH & Co.KG Vanne rotative pour la synthèse à phase solide
DE10345029A1 (de) * 2003-09-25 2005-04-21 Microfluidic Chipshop Gmbh Vorrichtung zum Kontaktieren und Verbinden von mikrofluidischen Systemen mittels Steckern
US6932943B1 (en) 2001-01-26 2005-08-23 Third Wave Technologies Nucleic acid synthesizers
US7422861B2 (en) 2000-12-23 2008-09-09 Novartis Vaccines And Diagnostics, Inc. Oligonucleotide transfection screening method
US7435390B2 (en) 2001-01-26 2008-10-14 Third Wave Technologies, Inc. Nucleic acid synthesizers
US7828016B2 (en) 1999-08-24 2010-11-09 Tokyo Electron Limited Gas processing apparatus, gas processing method and integrated valve unit for gas processing apparatus
EP3817851A4 (fr) * 2018-07-05 2022-06-08 Synthego Corporation Système modulaire automatisé et procédé pour la production de biopolymères
US11439971B2 (en) 2014-09-25 2022-09-13 Synthego Corporation Automated modular system and method for production of biopolymers

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WO1993012427A1 (fr) * 1991-12-19 1993-06-24 Chiron Corporation Appareil automatique de synthese des peptides
US5503805A (en) * 1993-11-02 1996-04-02 Affymax Technologies N.V. Apparatus and method for parallel coupling reactions
WO1997010896A1 (fr) * 1995-09-22 1997-03-27 Berlex Laboratories, Inc. Appareil et procede pour reactions chimiques multiples

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US5053454A (en) * 1989-02-15 1991-10-01 Sri International Multiple polymer synthesizer
DE4008085A1 (de) * 1990-03-14 1991-09-19 Abimed Analysen Technik Gmbh Vorrichtung zum durchfuehren chemischer, biochemischer und biologischer reaktionen in reaktionsgefaessen
WO1993012427A1 (fr) * 1991-12-19 1993-06-24 Chiron Corporation Appareil automatique de synthese des peptides
US5503805A (en) * 1993-11-02 1996-04-02 Affymax Technologies N.V. Apparatus and method for parallel coupling reactions
WO1997010896A1 (fr) * 1995-09-22 1997-03-27 Berlex Laboratories, Inc. Appareil et procede pour reactions chimiques multiples

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7150998B2 (en) 1998-06-16 2006-12-19 Mcluen Design, Inc. Multi-well rotary synthesizer
US7192558B2 (en) 1998-06-16 2007-03-20 Mcluen Design, Inc. Multi-well rotary synthesizer
US6811755B2 (en) 1998-06-16 2004-11-02 Mcluen Design, Inc. Multi-well rotary synthesizer
WO1999065602A3 (fr) * 1998-06-16 2000-06-15 Northwest Engineering Inc Synthetiseur rotatif a puits multiples
US6270730B1 (en) 1998-06-16 2001-08-07 Northwest Engineering Inc. Multi-well rotary synthesizer
AU748030B2 (en) * 1998-06-16 2002-05-30 Mcluen Design, Inc. Multi-well rotary synthesizer
DE19917398A1 (de) * 1999-04-16 2000-10-19 Norbert Schwesinger Modulares chemisches Mikrosystem
DE19917398C2 (de) * 1999-04-16 2002-06-20 Accoris Gmbh Modulares chemisches Mikrosystem
US7828016B2 (en) 1999-08-24 2010-11-09 Tokyo Electron Limited Gas processing apparatus, gas processing method and integrated valve unit for gas processing apparatus
JP2001129386A (ja) * 1999-08-24 2001-05-15 Tokyo Electron Ltd ガス処理装置およびそれに用いられる集合バルブ
US7422861B2 (en) 2000-12-23 2008-09-09 Novartis Vaccines And Diagnostics, Inc. Oligonucleotide transfection screening method
US6932943B1 (en) 2001-01-26 2005-08-23 Third Wave Technologies Nucleic acid synthesizers
US7435390B2 (en) 2001-01-26 2008-10-14 Third Wave Technologies, Inc. Nucleic acid synthesizers
WO2002099003A3 (fr) * 2001-06-06 2003-10-02 Monsanto Technology Llc Systeme de reacteur parallele et procede correspondant
DE20201753U1 (de) 2002-02-05 2002-04-11 Ehrfeld Mikrotechnik GmbH, 55234 Wendelsheim Modulares Mikroreaktorsystem
EP1479434A1 (fr) * 2003-05-17 2004-11-24 Heidolph Instruments GmbH & Co.KG Vanne rotative pour la synthèse à phase solide
DE10345029A1 (de) * 2003-09-25 2005-04-21 Microfluidic Chipshop Gmbh Vorrichtung zum Kontaktieren und Verbinden von mikrofluidischen Systemen mittels Steckern
US11439971B2 (en) 2014-09-25 2022-09-13 Synthego Corporation Automated modular system and method for production of biopolymers
EP3817851A4 (fr) * 2018-07-05 2022-06-08 Synthego Corporation Système modulaire automatisé et procédé pour la production de biopolymères

Also Published As

Publication number Publication date
EP0949964A1 (fr) 1999-10-20
JP2001500426A (ja) 2001-01-16
AU4417097A (en) 1998-04-02

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