Chemical apparatus and process disinfecting – deodorizing – preser – Chemical reactor – Organic polymerization
Reexamination Certificate
1998-06-10
2001-02-20
Beck, Shrive (Department: 1764)
Chemical apparatus and process disinfecting, deodorizing, preser
Chemical reactor
Organic polymerization
C422S105000, C422S105000, C422S916000, C422S938000, C422S937000
Reexamination Certificate
active
06190619
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention generally relates to methods and apparatus for the parallel synthesis of large numbers of molecularly diverse compounds. The present invention is particularly useful in generating combinatorial libraries of chemical compounds by simultaneously employing solid phase synthesis in a plurality of reaction vessels.
A standard method for searching for new chemical compounds employs the screening of pre-existing compounds in assays which have been designated to test particular properties of the compound being screened. Similarly, in designing compounds having desired physiochemical properties for general chemical applications, numerous compounds must be individually prepared and tested.
To reduce the time and expense involved in preparing and screening a large number of compounds for biological activity or for desirable physiochemical properties, technology has been developed for providing libraries of compounds for the discovery of lead compounds. Current methods for generating large numbers of molecularly diverse compounds focus on the use of solid phase synthesis. The generation of combinatorial libraries of chemical compounds by employing solid phase synthesis is well known in the art. For example, Geysen, et al. (
Proc. Natl. Acad. Sci. USA,
3998 (1984) describe the construction of multi-amino acid peptide libraries; Houghton, et al. (
Nature
, 354, 84 (1991) and PCT Patent Pub. No. WO 92/09300) describe the generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery; Lam, et al. (
Nature
,354, 82 (1991) and PCT Patent Pub. No. WO 92/00091) describe a method of synthesis of linear peptides on a solid support such as polystyrene or polyacrylamide resin.
The growing importance of combinatorial chemistry as an integral component of the drug discovery process has spurred extensive technological and synthetic advances in the field (Thompson, L. A.; Ellman, J. A. (1996)
Chem. Rev
. 96, 555-600). Founded in peptide synthesis devised by Merrifield, solid phase chemistry has emerged as the prominent method for construction of small molecule combinatorial libraries (see e.g. Merrifield, R. B. (1963)
J. AM. Chem. Soc
. 85, 2149-2154; (a) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. (1995) Tetrahedron 51(30), 8135-8173. (b) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. (1994)
J. Med. Chem
. 37, 1385-1401.).
To aid in the generation of chemical compounds, such as present combinatorial chemical libraries, scientific instruments should be developed which automatically perform many or all of the steps required to generate such compounds. In the past, multiple solid phase reactions have been conducted by heating a substrate attached to resin beads with appropriate reagents and solvents in a test tube immersed in a hot oil bath with rotating magnetic stir bar. Draining was accomplished by pouring the contents of the test tube through a filter. Back and forth operation between reacting and draining operation was very tedious and potentially exposed the reaction mixture to air.
Certain chemical processes require that the chemical reagents be kept under an inert or anhydrous atmosphere to prevent reactive groups from reacting with molecular oxygen, water vapor, or other agents commonly found in air. Working with repeated solvent and reagent washes in a number of reaction vessels was time consuming and possibly compromised the inert atmosphere in the reaction vessels. Conventional septum type devices may loose seal integrity after repeated penetrations by needles during such synthesis. Accordingly, there is a need for systems and methods for rapid synthesis of chemical compounds.
SUMMARY OF THE INVENTION
The present invention is directed to systems and methods for synthesizing chemical compounds. In particular, the present invention provides a synthesis apparatus for use with a plurality of reaction vessels for parallel synthesis of multiple discrete compounds or for combinatorial libraries of compounds.
In one aspect of the present invention, the synthesis apparatus of the present invention includes a frame having a plurality of reaction vessel-holding openings and a plurality of valves, where the reaction vessel-holding openings and the valves are aligned with one another. Each valve is movable between an open position and a closed position. In the open position, fluid can be delivered through the valve, and in the closed position, fluid is prevented from passing through the valve. In a preferred embodiment, the valve includes a first valve portion having a first sealing surface and a second valve portion having a second sealing surface. The sealing surfaces are slidably movable relative to one another. Preferably, the second valve portion comprises separate cap vents movable between first and second positions corresponding to the open and closed positions of said valve. The first valve portion may define a first manifold passage and a second manifold passage. Each cap vent preferably has a bypass path that connects the first manifold passage to the second manifold passage when the cap vent is in the second position. Advantageously, the bypass path allows for flushing of the first and second manifold passages to remove any contaminants or reagents left from previous fluid washes. The reduces the likelihood of accidentally introducing residual reagents into the environment of the reaction vessel. The first valve portion is also preferably adapted to be slidably connectable with a fluid conduit. The first manifold passage, second manifold passages, and the bypass path typically define a U-shaped passage when the valve is in the second position.
Additionally, the present invention typically includes an actuator for simultaneously actuating a plurality of valves. The simultaneously opening and closing of the valves for several reaction vessels allows for the parallel distribution of fluids to the reaction vessels, which increases the speed of the entire procedure. Furthermore, the first valve portion preferably comprises of elastomeric material capable of maintaining a seal between the first and second sealing surfaces over a temperature range of about −400 to 150° C. Use of such elastomeric materials increases the temperature range over which the present invention can operate. The first valve portion may be a fluid manifold made from an elastomeric material and an inert material. The elastomeric material may be directly integrated with the fluid manifold or be a separate layer attached to the manifold. In one embodiment, the separate layer of elastomeric material may be covered with a layer of friction-resistant material to improve durability while retaining the compliant nature of the elastomeric material. Preferably, the valve is compressed between the lid and the reaction vessel when the apparatus is in operation. The apparatus may include a bias element to maintain a seal between the valve and the fluid manifold during apparatus operation. The seal typically isolates the reaction vessel interior from molecular oxygen, water vapor or other agents in the external, ambient atmosphere.
In another aspect of the invention, the reaction vessels each have a cap vent mountable to an open top of the reaction vessel. The cap vent preferably comprises an outer sealing surface and an inner surface facing the interior, where the cap vent defines first and second fluid passages extending between the outer and inner surfaces. In one embodiment, the cap vent defines a bypass path opening onto the outer surface at spaced-apart positions on the outer surface. The spaced-apart positions are separated by a bypass distance. The first and second fluid passageways may open on to the outer surface at first and second positions. The first and second positions are separated by a distance equal to the bypass distance. Typically, the bypass path comprises a groove on the outer surface of the cap vent. The cap vent is rotatable relative to a sealing surface of said syn
Kilcoin Christopher
Long Terry
Miller Steve
Argonaut Technologies, Inc.
Beck Shrive
Ohorodnik Susan
Townsend and Townsend / and Crew LLP
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