Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Ion-exchange polymer or process of preparing
Reexamination Certificate
1999-10-27
2002-08-20
Lipman, Bernard (Department: 1713)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Ion-exchange polymer or process of preparing
C525S332200, C525S350000, C525S377000, C525S379000, C525S382000
Reexamination Certificate
active
06437012
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the use of low-swelling, highly crosslinked, macroporous styrene polymers as scavengers for removing unreacted compounds and side products from a reaction medium. The styrene polymers of this invention can be functionalized with one or more groups which are designed to be reactive with functional groups contained on the compounds to be removed form the reaction mixture. Typically, such functional groups include isocyanate groups, thiol groups, aldehyde groups, amino groups, and hydrazine groups. The styrene polymers of this invention can be used in purification schemes involving the high throughput parallel synthesis of combinatorial chemical libraries of potential lead drug compounds.
Parallel synthesis, as referred to herein, describes a technology for high throughput organic synthesis characterized by the preparation of a large number of compounds simultaneously and discretely (in parallel). Parallel synthesis generally involves the use of a large number of reaction vessels, such as an array of multi-well plates, which may contain different combinations of a number of reactants of interest. The reactions are allowed to proceed simultaneously and in parallel in each vessel to produce a diverse collection or library of product molecules. The individual compounds in the library can be screened against a suitable target to determine the probability of biological activity. Automation of synthesis and screening procedures is desired to provide high throughput operation using mechanical devices, such as laboratory robots. In this way, many thousands of compounds can be prepared and screened in a relatively short time.
One of the bottlenecks in automated processes such as these is product purification. Ideally, these reactions proceed to completion, and only a single reaction product will be generated in each reaction vessel. However, in many instances the reaction medium may contain unreacted reactants and/or reaction by-products as impurities after a reaction has occurred. These substances represent impurities which must be efficiently removed from the reaction mixture as part of the purification procedure to obtain the desired product. Traditionally, the purification can be accomplished by chromatographic separation, using plain silica or reverse phase silica, such as C
18
modified silica, as a stationary phase. The traditional chromatographic separation is both time and labor intensive, and cannot be run in parallel for a relatively large number of compounds.
Two purification strategies have generally been adapted for high throughput parallel synthesis: a solid phase synthesis; and a solid reagent assisted solution phase synthesis, including the use of soluble polymer reagents that can be precipitated out of the reaction mixture by solvent switching.
In solid phase synthesis, a reactant is first linked with a cleavable linkage to a solid support. The subsequent reaction of the support-anchored reactant with another reactant in solution produces an expected chemical identity anchored to the support. A selective cleavage releases the expected compound from the solid support with relatively high purity. Unreacted reactants and by-products are easily removed from products anchored to the support by washing or filtering the support after the reaction. However, the majority of the well-documented organic reactions is performed in solution phase, and many of these reactions cannot be carried out using a solid phase synthesis without substantial changes to the reaction procedure, if at all. Other drawbacks of solid phase synthesis include the required tolerance of the linker towards the reaction mixture, the required tolerance of the linker against premature cleavage, unnecessary by-products generated from the cleavage reaction, and the presence of trace of the linker in the final product.
The other approach, solid-reagent assisted solution phase synthesis, involves the use of solid-phase reagents, either participating in the synthesis reactions, or removing excess reactants and by-products from the reaction mixture. In the former case, the solid-support reagents, often termed “solid reagents”, are a part of the organic synthesis reaction, and this approach differs from solid phase synthesis by forming and removing by-products in solid form, leaving desired compounds in the solution. In the latter case, the solid-supported reagents, often termed “scavengers”, are not part of the synthesis reactions, and are applied to selectively remove excess reactants and/or by-products in the reaction mixture by ion-pairing or covalent bonding these impurities, leaving the desired compounds in the solution.
The concept and practice of “scavenging”, referring to the selective removal of organic compounds from solution by binding them onto a solid surface, is known in the art. As an example, U.S. Pat. No. 3,576,870 describes the purification of N, N-dimethylacetamide by removing excess acetic anhydride with a basic ion exchange resin. It is also known in the art that organic compounds can be selectively scavenged by covalently bonding them onto a solid surface. Examples of such types of “scavenging” 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. Another example, published in
J. Am. Chem. Soc.,
97, page 4407 (1975), shows the use of an amine bound to a lightly cross-linked polystyrene gel for removing organic anhydrides from an organic solution. While the application of “scavengers” in organic parallel synthesis reactions is relatively new, there have been many recent publications directed to this emerging technology. U.S. Pat. No. 5,767,238 describes the general application of functionalized solid particles for removing impurities in a so-called “inverse solid-phase synthesis” process by either ionic or covalent binding. Scavenger-assisted combinatorial libraries are described in the following European patent publications: EP 816309, for preparing ureas or thioureas; EP 818431, for scavenging secondary amines; EP 825164, for scavenging amides, carbamates and sulfonamides. The scavengers used include amines, isocyantes, and acid chloride functionalities bound to certain polymers and inorganic substrates.
Many functionalized polymer-based particles have been used as scavenger materials, and some commonly used scavengers, based on lightly cross-linked (1% or 2%) polystyrene/divinylbenzene particles, are commercially available from several sources (e.g. Novabiochem, Laufelfingen, Switzerland). However, most of the polymer-based scavengers in the prior art are based on lightly cross-linked (1% or 2%) polystyrene/divinylbenzene, particularly for covalent-bonding scavengers. These materials have some distinct disadvantages. First, these materials can be used only with solvents that produce significant amounts of swelling, such as THF and methylene chloride, which allow accessibility of the functional sites to reactants in solution. Many common solvents, such as methanol and acetonitrile, may result in poor scavenging performance of the materials due to insufficient swelling. Second, using those compatible solvents, the materials may swell greatly, e.g. up to 5-10 fold of the original volume of the dry polymers. The high degree of swelling limits the amount of scavengers which can be put in a small vessel, such as 96 well microtiters which are commonly used in high throughput parallel synthesis reactions. Due to the large volume of absorbed solvent, the amount of solvent required for rinsing the particles must be high, raising concerns over volume constraints of collectors and processing equipment. The swelling also makes the materials unsuitable for being pre-packed in certain desired formats, such as columns, membranes or cartridges.
Although highly cross-linked porous polymer materials have long been used for ion-exchange, catalysis and organic absorption, the application of these materials in organic sy
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