Solid phase synthesis supports and methods

Details Solid phase synthesis supports and methods Solid phase synthesis supports and methods

2001-04-05

2004-09-07

Low, Christopher S. F. (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Synthesis of peptides

C522S113000, C522S134000, C524S001000, C524S017000

Reexamination Certificate

active

06787635

ABSTRACT:

BACKGROUND
The recent surge of interest in combinatorial chemistry and automated synthesis has created a renewed interest in polymer-supported reactions. Combinatorial chemistry is a synthetic strategy that leads to large chemical libraries by the systematic and repetitive covalent connection of a set of different “building blocks” of varying structures to each other to yield a large “library” of diverse molecules. It is particularly useful in producing polypeptides or polynucleotides that are currently of interest in the biotechnology area. Polymer-supported reactions or solid phase synthesis is the main methodology used in combinatorial chemistry.
In order to perform combinatorial chemistry in the solid phase, the starting materials are covalently bonded to a polymeric support. Reagents can then be added that react with the starting materials to yield products that are still attached to the support. The main advantage of solid phase synthesis is that the products don't need to be purified. They can be retained on the solid phase while excess reagents and byproducts are washed away. Then, by successive treatment with different reagents, new molecules are built up on the solid phase. By using a variety of starting materials it is possible to simultaneously build up a library of related compounds by using a single reagent or set of reagents. In this way many new products can be produced in a single reaction vessel.
A wide variety of materials have been developed as polymeric supports and are commercially available. Most of these materials are based on lightly crosslinked polystyrene, a relatively hydrophobic polymer. The crosslinker most commonly used has been divinylbenzene. Crosslinking improves the mechanical properties of the resin but prevents swelling of the resin, which is essential for rapid and thorough reactivity within the polymer system. The hydrophobicity of polystyrene limits its usefulness in many solvents and with many reagents. In order to overcome the problems associated with hydrophobicity, a more hydrophilic material, such as polyethylene glycol (PEG) has been coated onto or grafted to the polystyrene to make it more versatile for solid phase synthesis. This is a very expensive process and still does not completely address the problems associated with the hydrophobic polystyrene matrix. Polystyrene resins have also been crosslinked with more hydrophilic crosslinkers such as bifunctional styrene derivatized PEG chains to crosslink polystyrene in order to improve general resin performance. Improved swelling and mechanical properties have been observed with these resins. However, PEG-based crosslinkers cannot be used with strong bases or organometallic reagents; thus, their usefulness is limited. Additionally, many prior art matrices used for solid phase synthesis have generally low crosslink density and are gel-type polymers. This polymer structure, however, can lead to problems related to reagent diffusion during synthesis. Thus, new and improved resins that can be used for solid phase synthesis are needed.
The purpose of combinatorial chemistry is to generate a large library of related compounds in order to test them for a desired property. For instance, in the drug industry, there is an interest in screening a large number of related compounds for biological activity. Usually these compounds are screened after cleavage from the support. Under these circumstances, the synthesis of combinatorial libraries requires immobilization of the first building block to the support via a linker and cleavage of the compound from the linker after the library synthesis is complete.
The linker is a molecule that can be permanently attached to the support via covalent bonds and also has a reactive group capable of binding, for example, the first building block molecule of the intended synthetic library. After the first building block is attached, further groups are systematically added sequentially until a terminal building block is attached. Finally, the desired library molecules are cleaved from the linker and thus the support. Chloromethylated crosslinked polystyrene is conventionally used to immobilize carboxylic acid building blocks via an unsubstituted benzyl ester. However, these unsubstituted benzyl-type linkers require harsh cleavage conditions, usually liquid HF. There is a need for new linker-functionalized supports that are stable to the reaction conditions used to build the library molecules on the support, but are also able to form an easily cleavable bond with the library molecule under mild conditions to release those compounds at the end of the synthesis.
SUMMARY OF THE INVENTION
The present invention provides functionalized supports and methods for use for solid phase synthesis, which are useful in combinatorial chemistry, for example. Functionalized supports described herein can be in the form of a plurality of particles or a membrane, for example. Furthermore, the functionalized support can form a combinatorial library in preferred embodiments.
Generally, preferred functionalized support material (with linker incorporated therein, herein referred to as a “linker-functionalized support”) of the present invention has the formula SS—[NH—(C(R
1
)(R
2
))
p
—C(R
3
)(R
4
)(OR
7
)]
m
wherein SS represents a support material; R
1
, R
2
, R
3
, and R
4
are each independently hydrogen or an organic group (preferably, a (C1-C14)alkyl group, a (C3-C14)cycloalkyl group, or a (C5-C12)aryl group) with the proviso that at least one of R
3
and R
4
is an aromatic group (preferably, a (C5-C12)aryl group); R
7
is hydrogen or an organic group (preferably, including a reactive site, which may optionally be protected by a protecting group); p is at least 1 (preferably, 1 to 20, and more preferably, 1 to 2); and m is 1 to the resin capacity of the support material. Typically and preferably, the NH—(C(R
1
)(R
2
))
p
—C(R
3
)(R
4
)(OR
7
) groups are bound to the support material through a carbonyl group.
Alternatively, preferred functionalized support material (with linker incorporated therein) of the present invention has the formula SS—[C(O)—NH—C(R
5
)(R
6
)—(CH
2
)
n
—C(O)—NH—(C(R
1
)(R
2
))
p
—C(R
3
)(R
4
)(OR
7
)]
m
wherein SS represents a support material; R
1
, R
2
, R
3
, and R
4
are each independently hydrogen or an organic group (preferably, a (C1-C14)alkyl group, a (C3-C14)cycloalkyl group, or a (C5-C12)aryl group) with the proviso that at least one of R
3
and R
4
is an aromatic group (preferably, a (C5-C12)aryl group); R
5
and R
6
are each independently an organic group (preferably, a (C1-C14)alkyl group, a (C3-C14)cycloalkyl group, or a (C5-C12)aryl group); R
7
is hydrogen or an organic group (preferably, including a reactive site, which may optionally be protected by a protecting group); n is 0 to 1; p is at least 1 (preferably, 1 to 20, and more preferably, 1 to 2); and m is 1 to the resin capacity of the support material. This material is a preferred example of an azlactone-functionalized support material having a linker attached thereto, wherein C(O)—NH—C(R
5
)(R
6
)—(CH
2
)
n
—C(O) is derived from an azlactone group.
Yet another preferred functionalized support material (with linker incorporated therein) of the present invention has the formula SS—[C(O)—NH—C(R
5
)(R
6
)—(CH
2
)
n
—C(O)—NH—(R
8
)—NH—C(O)—R
9
]
m
wherein SS represents a support material; R
5
, R
6
, and R
9
are each independently an organic group; R
8
is an organic connecting group; n is 0 to 1; and m is 1 to the resin capacity of the support material. Preferably, R
9
includes a reactive site, which may optionally be protected by a protecting group. Preferably, R
5
and R
6
are independently a (C1-C14)alkyl group, a (C3-C14)cycloalkyl group, or a (C5-C12)aryl group), and R
8
is a (C1-C1000)alkylene group. This material is a preferred example of an amine-modified-azlactone-functionalized support material having a linker attached thereto, wherein NH—(R
8
)—NH is derived from a diamine.
Use of the functionalized support materials in solid phase synt

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