Stock material or miscellaneous articles – Coated or structually defined flake – particle – cell – strand,... – Rod – strand – filament or fiber
Reexamination Certificate
2000-02-15
2002-07-09
Moore, Margaret G. (Department: 1712)
Stock material or miscellaneous articles
Coated or structually defined flake, particle, cell, strand,...
Rod, strand, filament or fiber
C428S405000
Reexamination Certificate
active
06416861
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides organosilicon compounds containing an aromatic moiety group and methods for using the same for the solid-phase synthesis of libraries of compounds.
BACKGROUND OF THE INVENTION
Combinatorial chemistry, combined with recent advances in robotic screening which enable the testing of a large number of compounds in a short period of time, is becoming an important tool in accelerating drug discovery. This technique generally involves the preparation of a large number of structurally related compounds either as mixtures in the same reaction vessel or individually by parallel synthesis. In this manner large pools of similar compounds can be synthesized rather quickly. Combinatorial libraries have been prepared using both solution chemistry and by solid phase synthesis. Solid phase synthesis allows the use of excess reagents to drive the reaction to near completion, and easy removal of the reagents and side-products by simple washing with solvent. Therefore, solid phase synthesis generally offers a more attractive approach to the generation of combinatorial libraries.
One of the key elements in solid phase chemistry is the polymeric resin. Many of the resins which are currently employed were originally developed for the synthesis of peptides. Polar functionality such as carboxylic acids and amides were released upon cleavage of products from the resins. Recent advances in linker technology allowed other polar functional groups such as an alcohol and a thiol to be attached to the polymer support. However, most of the linkers available for solid support synthesis to date require polar functional groups for binding and release the same polar groups after cleavage. For the generation of libraries of biological activity, such polar functionalities may possess unfavorable pharmacological properties. In many cases, attempts have been made to render the lead compounds found in vitro less polar to increase the pharmacological properties such as high cellular uptake and hydrophobic membrane transport. Therefore, the focus in this field has been on designing new solid support linkers for non-polar or aromatic compounds which are commonly found in pharmaceutical agents.
To address this concern, several novel strategies utilizing resin. bound arylsilane as a “traceless linker” have been developed for solid phase synthesis of aromatics or heteroaromatic compounds. This method allows the attachment of substrates to the support at an inert site within the molecule. Upon cleavage from the resin by desilylation (with TFA, HF, or TBAF), no trace or “memory” of attachment to the polymer support is left. Also, silicone-directed ipso-substitution of arylsilanes is frequently used for regiospecific introduction of electrophilic functional groups such as bromine and iodine to the aromatic ring. (see for example, Chan et al., “Electrophilic substitution of organosilicon compounds. Applications to organic synthesis,”
Synthesis
1979, 761-786; Han et al., “Silicon directed ipso-substitution of polymer bound arylsilanes: Preparation of biaryls via the Suzuki cross reaction,”
Tet. Lett
. 1996, 37, 2703-2706) Therefore, silicon-based linkers have been proved to be useful tools for the traceless synthesis of aromatics or halide substituted aromatics.
To date, several different arylsilane linkers have been devised and employed for the solid-phase synthesis of diverse aromatic systems. (see for example, Plunkett et al., “Germanium and silicon linking strategies for traceless solid-phase synthesis,”
J. Org. Chem
. 1997, 62, 1885-2893; Chenera et al., “Protodetachable arylsilane polymer linkages for use in solid phase organic synthesis,”
J. Am. Chem. Soc
. 1995, 117, 11999-12000; Boehm et al., “Development of a novel silyl ether linker for solid-phase organic synthesis,”
J. Org. Chem
. 1996, 61, 6498-6499; Woolard et al., “A silicon linker for direct loading of aromatic compounds to supports. Traceless synthesis of pyridine-based tricyclics,”
J. Org. Chem
. 1997, 62, 6102-6103, Hu et al., “Novel polymer-supported trialkylsilanes and their use in solid-phase organic synthesis,”
J. Org. Chem
. 1998, 63, 4518-4521; and PCT Publication Nos. WO 98/05671 and WO 98/17695) Most of the known silicone linkers are generally designed to facilitate the solid-phase synthesis of focused libraries of aromatics, such as 1,4-benzodiazephines, biaryls, benzofurans, and tricyclics. Some of the silicone based linkers, [for example, (4-bromophenyl)diisopropylsilyloxymethyl polystyrene, (4-formylphenyl)diisopropylsilyloxymethyl polystyrene, and (4-trityloxyphenyl)diisopropylsilyloxymethyl polystyrene] from commercial sources are designed for the solid phase organic synthesis of substituted benzenes.
One of the limitations associated with the linkers described above is that linker itself has to be attached to the polymer by reaction of the polar group (alcohol, or carboxylic acid). Polar groups on the aromatic ring which would be utilized for attachment to the polymer requires protection/deprotection steps during the construction of other desired functional group on the aromatic. This protection/deprotection step requirement slows the construction of silyl linker. In addition, in some cases many functional groups can not be introduced due to compatibility problems. The other limitation of these linkers is that the appropriately functionalized aryl group must be first attached to the silicon linker, prior to attaching it to the solid support. Therefore, a separate linker must be prepared for each aryl group. To overcome this limitation, (4-methoxyphenyl)dimethylsilylpropyl polystyrene has been developed. Although this linker can be used to attach various aryllithiums or Grignard reagents to form the appropriate arylsilyl linkage, the application is still limited because other essential functional groups on the aryl ring must be able to tolerate strong basic conditions and/or must be protected.
Completely different class of linkers for traceless synthesis of arenes is triazine-based resins. Reaction of diazonium compound to the N-benzylaminomethyl polystyrene (or piperazinomethyl polystyrene) leads to formation of a polymer bound triazine. This functionality is stable under a wide range of reaction conditions (e.g., n-BuLi and DIBAL) but is readily cleaved by treatment with HCl in THF to liberate the aromatic moieties containing hydrogen at the original point of attachment. Although this approach is generally applicable to a wide range of simple anilines, other functional groups (which would be used for diversification) attached to the aniline are limited to ones which can tolerate acidic conditions employed for diazotization.
Despite these advances in a solid-support chemistry, there is a need for compounds which are useful in the solid-phase synthesis of aromatic containing molecules.
SUMMARY OF THE INVENTION
One embodiment of the present invention provides a compound of the formula:
wherein
each of R
1
and R
2
is independently aryl, C
1
-C
6
alkyl, or C
3
-C
20
cycloalkyl;
R
3
is a bond or C
1
-C
10
alkylene;
R
4
is C
1
-C
10
alkylene;
each of R
5
, R
6
and R
7
is independently H or C
1
-C
6
alkyl;
Ar
1
is aryl or heteroaryl; and
X is a functional group.
Another embodiment of the present invention provides a resin-bound compound of the formula:
where Ar
1
, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, and X are those described above, L
1
is a bond or a link and P is a solid-support.
Another embodiment of the present invention provides a method for preparing a resin-bound compound comprising coupling a silane compound, preferably of formula I described above, to a polymeric resin using a transition metal, preferably palladium, mediated coupling reaction. Preferably, the silane compound comprises an alkenyl moiety, which allows a formation of silylalkylborane compound when the alkenyl moiety is contacted with a hydroborating agent. The silylalkylborane compound can be coupled to a polymeric resin which has an aryl halide moiety. In this manner, the coupling react
Lee Young-hee
Silverman Richard B.
Marshall Gerstein & Borun.
Moore Margaret G.
Northwestern University
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