Liquid purification or separation – Processes – Ion exchange or selective sorption
Reexamination Certificate
2000-02-18
2004-06-15
Baker, Maurie Garcia (Department: 1639)
Liquid purification or separation
Processes
Ion exchange or selective sorption
C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S007100, C435S007200, C436S501000, C436S518000, C530S333000, C530S334000, C530S344000, C530S345000, C210S656000, C210S658000, C210S739000, C210S749000, C210S763000, C570S123000, C570S124000
Reexamination Certificate
active
06749756
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods of carrying out reactions and separations, and, especially, to reactions and separations involving tagging.
BACKGROUND OF THE INVENTION
Interest in expediting the synthesis of organic compounds for use as potential drugs, agricultural agents, catalysts, ligands and other uses has led to the development of a number of methods for synthesis that use “mixtures” of organic compounds rather than pure organic compounds. Simple mathematics demonstrates the potential power of mixture synthesis. For example, to execute a parallel (or sequential) n-step synthesis starting from m different starting materials requires n·m individual reactions with all the attendant equipment (for example, reaction vessels) and manipulations (transfers, workups, chromatography, etc). However, if the m compounds are mixed at the beginning, and then carried through the n-step synthesis and separated, only n separate steps are required.
The value of mixture synthesis has recently been demonstrated in the area of solid phase synthesis with techniques of split synthesis. For example, by using “one bead/one compound” techniques, large libraries of compounds can be made in relatively few steps. See, for example, Lam, K. S., et al., “The ‘One-Bead-One-Compound’ Combinatorial Library Method,”
Chem. Rev.,
96, 411-488 (1996); Thompson, L. A. and Ellman, J. A., “Synthesis and Applications of Small Molecule Libraries,”
Chem. Rev.,
96, 555-600 (1996). Each bead is effectively a kind of reaction vessel that permanently holds its “contents” (substrates and their products) by chemical bonds. The beads are mixed, not the compounds. Likewise, methods such as using “tea bags”, “microkans”, and other physical equipment have been introduced to facilitate mixture synthesis. However, in all those solid phase synthesis techniques it is the container of the supported substrates that is mixed. The substrates themselves are polymer-bound and are not mixed. Such solid phase synthesis techniques are typically limited by difficulty in developing suitable reaction conditions for generally biphasic reactions.
Organized mixtures of organic molecules (libraries) have also been generated by using solution phase chemistry. See, for example, Houghten, R. A., “Mixture-Based Synthetic Combinatorial Libraries,”
J. Med. Chem.,
42, 3743-3778 (1999). Although such libraries can be made in different ways, a common thread in that approach is that no effort is made to separate the mixture into individual pure components. Instead, libraries and sub-libraries are constructed and assays are conducted such that an active component (or components) can be identified by a process of deconvolution. Deconvolution processes are generally methods which attempt to identify the most active members of a library of compounds without isolating the individual components of the library. In general, mixtures of compounds are tested to measure an average activity of the mixture. Mixtures can be separated by HPLC fractionation or other standard techniques for separation of organic molecules, but the separation typically does not provide pure components since mixture components overlap. See, for example, Griffey, H. Y., “Rapid Deconvolution of Combinatorial Libraries Using HPLC Fractionation,”
Tetrahedron,
54, 4067-4076 (1998). Further, the outcome of the separation (that is, which fractions are pure and which are mixtures, as well as which fraction contains which compound(s)) is not generally known in advance.
It is very desirable to develop improved reaction and separation systems to, for example, enhance the utility of mixture synthesis.
SUMMARY OF THE INVENTION
In general, the present invention provides a method of separating compounds that includes the steps of: tagging a first organic compound with a first tagging moiety to result in a first tagged compound; tagging at least a second organic compound with a second tagging moiety different from the first tagging moiety to result in a second tagged compound; and separating the first tagged compound from a mixture including the second tagged compound using a separation technique based upon differences between the first tagging moiety and the second tagging moiety. Preferably, the separation technique is based upon difference in the fluorous nature of the first tagged compound and the second tagged compound, differences in total charge between the first tagged compound and the second tagged compound, differences in size between the first tagged compound and the second tagged compound, and/or differences in polarity between the first tagged compound and the second tagged compound.
As used herein, the term “tagging” refers generally to attaching a moiety or group (referred to as a “tagging moiety” or “tagging group”) to a compound to create a “tagged compound”. Preferably, the tagging moiety is attached via covalent bond. However, other strong attachments such as ionic bonding or chelation can also be used. In the present invention, different tagging moieties are preferably used on different compounds to facilitate separation of such tagged compounds.
For example, the tagging moieties can be fluorous moieties that differ in fluorine nature (for example, fluorine content and/or structure). As used herein, the term “fluorous”, when used in connection with an organic (carbon-containing) molecule, moiety or group, refers generally to an organic molecule, moiety or group having a domain or a portion thereof rich in carbon-fluorine bonds (for example, fluorocarbons, fluorohydrocarbons, fluorinated ethers and fluorinated amines). The term “fluorous substrate,” thus refers generally to a substrate comprising a portion rich in carbon-fluorine bonds. As used herein, the term “perfluorocarbons” refers generally to organic compounds in which all hydrogen atoms bonded to carbon atoms have been replaced by fluorine atoms. The terms “fluorohydrocarbons” and “hydrofluorocarbons” include organic compounds in which at least one hydrogen atom bonded to a carbon atom has been replaced by a fluorine atom. The attachment of fluorous moieties to organic compounds is discussed in U.S. Pat. Nos. 5,859,247 and 5,777,121, the disclosures of which are incorporated herein by reference.
Separation of the tagged compounds of the present invention is achieved by using separation techniques that are complementary to (based upon differences between) the tagging moieties. For example, in the case that compounds are tagged with fluorous moieties that differ in fluorine content, the tagged compounds may be separated using a fluorous separation technique (for example, fluorous reverse phase chromatography).
As used herein, the term “fluorous separation technique” refers generally to a method that is used to separate mixtures containing fluorous molecules or organic molecules bearing fluorous domains or tags from each other based predominantly on the fluorous nature of molecules (for example, size and/or structure of the fluorous molecule or domain). Fluorous separation techniques include but are not limited chromatography over solid fluorous phases such as fluorocarbon bonded phases or fluorinated polymers. See, for example, Danielson, N. D. et al., “Fluoropolymers and Fluorocarbon Bonded Phases as Column Packings for Liquid Chromatography,”
J. Chromat.,
544, 187-199 (1991). Examples of suitable fluorocarbon bonded phases include commercial Fluofix® and Fluophase™ columns available from Keystone Scientific, Inc. (Bellefonte, Pa.), and FluoroSep™-RP-Octyl from ES Industries (Berlin, N.J.). Other fluorous separation techniques include liquid-liquid based separation methods such as countercurrent distribution with a fluorous solvent and an organic solvent.
As indicated above, a number of tagging strategies other than fluorous tagging are suitable for use in the present invention. In general, any tagging strategy that facilitates separation of the tagged compounds based on differences in the tag is suitable. If compounds that are tagged are to undergo one or more reactions to produce tagged
Curran Dennis P.
de Frutos Garcia Oscar
Oderaotoshi Yoji
Baker Maurie Garcia
Bartony & Hare, LLP
University of Pittsburgh
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