Liquid purification or separation – Processes – Chromatography
Reexamination Certificate
2001-12-26
2002-11-19
Fortuna, Ana (Department: 1723)
Liquid purification or separation
Processes
Chromatography
C210S198200, C210S502100, C502S408000
Reexamination Certificate
active
06482324
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to modified porous silica microspheres used to selectively separate unreacted reactants from desired products and undesirable side products in a reaction medium, and to methods for using such microspheres.
The need to improve the efficiency of drug discovery and basic research efforts has led to laster and more convenient methods for synthesizing organic compounds. In the synthesis of organic compounds, reactants are combined under appropriate conditions to produce desired products. These products must then be purified by separation from other undesired products or unreacted reactants. Solid phase synthesis methods facilitate such purifications. In the solid phase synthesis approach, a reactant first is linked, usually covalently, to a solid support. A binding interaction between this support-anchored functional group and a solubilized reactant produces a product that is ionically or covalently linked to the functionalized solid support.
The solid phase synthesis methods have strong advantages over traditional solution synthesis methods. Unreacted reactants or by-products arc easily removed from the products linked to the support by washing or filtering the support after the synthesis reaction. This approach allows a large excess of reactants to be used so that the desired reaction often can be rapidly driven to completion. In addition, the synthesis and separation of desired products from unreacted reagents or reaction by-products can be readily automated for the convenient and rapid synthesis of multiple compounds.
Modern drug discovery techniques are based on the use of combinatorial chemistry to generate large numbers of compounds that are often referred to as libraries. The objective of this approach is to generate lead compounds for pharmaceutical research. Preferred combinatorial chemistry approaches, usually automated, often involve parallel array synthesis where individual reaction products are generated as mixtures. Such library compounds may be contained in the individual wells of 96-well microtiter plates. The use of such standardized plates is advantageous because they can be manipulated automatically by robotic machines.
Combinatorial chemistry often is performed under conditions such that, after the reaction, unwanted unreacted reactants and possible side reaction materials must be removed so that the desired product can be recovered, hopefully in a purified form. For the removal of such materials, solid particles called “scavengers” often are used. These scavenger particles have traditionally consisted of porous polymeric or inorganic supports that have been functionalized with reactive groups that can readily react with the excess reactants or unwanted side products.
These functionalized reactive groups can be ionic in form, such as, for example, a sulfonic acid functional group used to remove excess basic amine reactants. An example of such ionic reactions is found in U.S. Pat. No. 3,576,870, which describes the purification of dimethylacetamide by removing excess acetic anhydride with a basic ion exchange resin containing primary or secondary amino groups.
Alternatively, the scavenger support can contain a reactive group that can covalently react with and remove a reactant, such as, for example, an isocyanate that can react with a primary amine. Other examples of a covalent scavenging reactions are found in U.S. Pat. Nos. 5,087,671 and 5,244,582, which describe the use of various reactive groups immobilized on inorganic substrates to remove carcinogenic nitrosating agents from liquids. The substrates disclosed in these patents include organic polymers and inorganic derivatized glass and silica, and the functional groups include pyrrole groups, indole groups and hydroquinone.
U.S. Pat. No. 5,767,238 describes a method for the inverse solid phase synthesis of a variety of organic compounds in the liquid phase. Unreacted reactants are removed from the reaction mixture and separated from the desired products using a solid phase support matrix which binds covalently or ionically to the reactants. The solid phase support matrix is a macromolecular structure which is insoluble in the reaction medium, and which can be a porous or non-porous structure. Suitable solid phase support structures include anion exchange resins, cation exchange resins and acrylic resins.
Scavenger-assisted combinatorial processes for preparing ureas or thioureas are described in the following European patent publications: EP 816309, which discloses the use of particles functionalized with amines for scavenging ureas, thioureas, and isothiocyanates; EP 818431, which discloses the use of particles functionalized with aldehyde groups for scavenging secondary amines; and EP 825164, which discloses the use of particles functionalized with amines for scavenging amides and carbamates. Suitable substrates disclosed in these patent applications include polystyrene divinylbenzene, cellulose, silica gel, alumina and controlled pore size glass.
Commercial scavenger materials based on polystyrene-divinylbenzene particles are available as scavengers for combinatorial synthesis reactions (e.g., Argonaut Technologies, San Carlos, Calif.). While such polymeric materials can be prepared with a variety of functionalities for scavenging, they have a distinct disadvantage: polymers absorb most organic solvents, causing them to swell significantly. As a result, the use of polystyrene-based polymers in many organic solvents causes polymeric scavengers to increase their volume two-fold or more, making their use quite difficult in certain applications, such as with 96-well plates. Because of the strong swelling propensity, there are restraints on the amount of the polymer that can be used in the wells, limiting the capacity of the scavenging process. Furthermore, to be used properly, polymeric scavengers must be in a swollen state to effectively expose the bound functionality for the desired interactions. To adequately swell polystyrene-divinylbenzene-based scavenger particles, non-polar solvents such as methylene chloride generally must be used. Desirable polar reaction solvents such as methanol and N, N′-dimethylformamide, often needed for sample solubility, generally cannot be used with these polymeric scavengers. The handling properties of polystyrene-divinylbenzene particles is also poor (typically because of problems with static charge), making the loading inconvenient, particularly into small 96-wells plates.
U.S. Pat. No. 5,230,806 describes the use of functionalized polystyrene-divinyl benzene adsorbent resins in solid-phase extraction methods for removing organic solutes from solutions. In particular, the reference describes the use of neutral polystyrene-divinyl benzene resins containing functional hydroxymethyl, acetyl or cyanomethyl groups for removing or scavenging phenols from solutions. The use of neutral polymers is preferred since charged resins can pick up undesirable material present in the solution. The reference further states that silica containing a chemically-bonded organic group is not particularly suited for use in solid phase extractions since they are hydrophobic and do not make good surface contact, and many types of organics are incompletely extracted from aqueous solutions. See, also, Capillary Columns,
J. Am. Chem. Soc
., 97, 15 (1975), which shows the use of an isocyanate bound to a cross-linked polystyrene for removing anhydrides and acids from a solution of pyridine.
U.S. Pat. Nos. 4,874,518, 5,032,266 and 5,108,595, relate to chromatographic materials comprising porous silica microspheres having silanol-enriched surfaces with favorable sorptive properties for separating organic compounds. The silica microspheres are formed by contacting microspheres which have been thermally-dehydroxylated with water in the presence of an activator, such as ammonium hydroxide, to generate a surface concentration of silanol groups. This procedure serves to maintain the activity of the microspheres, while providing the requisite cru
Kirkland Joseph J.
Langlois Timothy J.
Wang Ounjie
Agilent Technologie,s Inc.
Fortuna Ana
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