Chemical apparatus and process disinfecting – deodorizing – preser – Chemical reactor – Organic polymerization
Reexamination Certificate
1998-11-20
2001-05-01
Tran, Hien (Department: 1764)
Chemical apparatus and process disinfecting, deodorizing, preser
Chemical reactor
Organic polymerization
C422S116000, C422S131000, C435S287100
Reexamination Certificate
active
06224832
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to chemical synthesis, and more particularly to an improved apparatus and method for carrying out combinatorial synthesis. The invention has particular utility in drug discovery and in other applications where it is necessary to generate large numbers of related compounds.
BACKGROUND OF THE INVENTION
Combinatorial synthesis is a process for producing large numbers of compounds which can be screened for possible physiological or chemical activity. Typically, it is carried out in a series of successive stages, in each of which an existing molecule is modified chemically.
Various techniques have been devised for combinatorial synthesis.
One such technique is the so-called “split synthesis” method, in which polystyrene beads are provided as solid substrates on which the reactions take place. In the split synthesis method, the beads are divided into a number of groups of equal size. A different monomer is coupled to the beads in each group. The beads are then washed, recombined, thoroughly mixed, and again divided into a number of groups of equal size. Monomers, which may be the same as or different from the original monomers, are coupled to the beads of the new groups. By repeating the process, it is possible to produce large numbers of different compounds. The collection of compounds produced by this method is referred to as a “library.”
At each stage of the synthesis, identifier molecules can be attached to the beads. The identifier molecules or “tags” attached to a particular bead uniquely represent the reaction history of the bead, and enable the compound of interest on the bead to be reproduced in quantity after it is determined, by screening for activity, to warrant further investigation.
Another technique for distinguishing compounds is “array synthesis,” in which the various compounds are formed at defined locations on a surface. From a knowledge of the reagents added at each location, and the sequence in which they are added, it is possible to determine the reaction history of any compound on the surface.
Robotic systems have been devised to assist in carrying out combinatorial synthesis. For example, robots have been used to automate the synthesis of equimolar peptide mixtures by split synthesis.
On a larger scale, robotic systems have been devised for the automated production of related compounds. These systems typically utilize test tube arrays, or special multi-celled reaction blocks, and include heating or cooling devices to control the temperatures of the tubes or reaction cells, devices for moving the tubes, specialized agitation devices, devices for transferring liquids to and from the tubes or reaction cells, and provisions for maintaining an inert atmosphere.
Peptide synthesis has also been carried out by a continuous flow, solid-phase synthesis method utilizing columns packed with polystyrene-based resin. The flow columns are connected in parallel to provide multiple flow paths, or are connected in series to provide a single flow path. In both cases, complex valving is required to control the flow of various reagents and solvents through the resin-packed columns.
One of the disadvantages of the split synthesis method is that it is carried out on a microscopic scale and requires specialized and expensive techniques to read the molecular tags. The split synthesis method is advantageous in that it is capable of synthesizing very large numbers of compounds. However it is also subject to statistics, in that the splitting and combination of the beads are random, and consequently there is always a statistical probability that not all of the desired variants are present in the library.
Array synthesis is also difficult to carry out in that it requires automated apparatus or masking on a microscopic scale.
The robotic apparatus used for larger scale synthesis is mechanically complex and expensive. The continuous flow, solid-phase synthesis method, used for peptide synthesis, is not well suited for the synthesis of large numbers of related compounds, and requires complex valving to control the flow of the various reagents and other fluids. Both the robotic systems and the continuous flow synthesizers are prone to failure.
Combinatorial synthesis is described in International Patent Application WO 94/08051, published Apr. 14, 1994; and Lowe, Gordon, “
Combinatorial Chemistry
,” Chem. Soc. Rev., 1995, pp. 309-317.
Apparatus and methods for automated synthesis are described in International Patent Application WO 91/17823, published Nov. 28, 1991; Krchnak, Viktor et al., “
Multiple Continuous
-
flow Solid
-
Phase Peptide Synthesis
,” Int. J. Peptide Protein Res. 33, 1989, pp. 209-213; Zuckermann, Ronald N. et al., “
Control of the Zymate Robot with an External Computer, Construction of a Multiple Peptide Synthesizer
,” J. Amer. Chem. Soc., 115, 1993, pp. 2529-2531; and Zuckermann, Ronald N. et al., “
Automated Tools for the Production of Non
-
Natural Molecular Diversity
,” Innovation and Perspectives in Solid Phase Synthesis, Collected Papers, 3rd International Symposium, Roger Epton, Editor, Mayflower Worldwide Ltd., Birmingham, JK. 1994, pp. 397-402.
SUMMARY OF THE INVENTION
An important object of this invention is to provide an apparatus and method that are capable of carrying out combinatorial synthesis of relatively large numbers of compounds on a macroscopic scale, but which avoid the complexities and high cost associated with conventional robotic synthesizers utilizing test tubes or the like as reactors.
Another object of the invention is to provide a method of synthesis that is analogous to the split synthesis method, but which can be carried out on a macroscopic scale.
Another object of the invention is to provide a simple multi-reactor synthesizer which can be easily maintained and operated in an inert atmosphere.
Still another object of the invention is to provide an apparatus and method for synthesis of relatively large numbers of compounds which are inexpensive, but in which the reaction history of each compound produced can be easily determined with certainty.
A preferred multi-reactor synthesizer in accordance with the invention comprises a set of reactor cells, each reactor cell having an inlet and an outlet, pumping means, preferably a multi-channel pump, for producing separate flow of plural reagents, and means for interconnecting the reactor cells with one another and with the pumping means to establish plural reagent flow paths, with a different reagent in each flow path and with a subset of the reactor cells connected in series in each flow path. The reactor cells are connectible to, and disconnectible from, one another so that reagent flow paths can be established through different subsets of reactor cells connected in series.
To effect continuous flow of reagent, the synthesizer may include means for returning each reagent from the subset of reactor cells through which it flows to the pumping means. If the reagents are continuously recirculated through the reactors, the reactors do not need to be agitated. This simplifies the apparatus, and makes it less likely that the supporting medium in the reactors will be broken up.
In a preferred version of the multi-reactor synthesizer, the reactor cells are held in fixed positions during each reaction step, but each reactor cell is movable from any one fixed position to any other one of the fixed positions so that the reactors can be rearranged to provide different subsets of series-connected reactors.
In a particularly simple synthesizer array in accordance with the invention, the inlet of each reactor cell is directly connectible to the outlet of every other reactor cell. This makes it possible to assemble subsets of reactor cells without interconnecting the cells through separate conduits. Preferably the inlet of each reactor cell is at one end of the cell and its outlet is at its opposite end.
The invention also resides in a novel method of synthesis comprising the steps of: interconnecting reactor cells in a first group of subsets, each subset consisting of
Moore Michael Lee
Yamashita Dennis Shinji
Dinner Dara L.
Lentz Edward T.
SmithKline Beecham Corporation
Tran Hien
Venetianer Stephen
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