Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Mixing of two or more solid polymers; mixing of solid...
Reexamination Certificate
1998-08-13
2001-01-30
Celsa, Bennett (Department: 1627)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Mixing of two or more solid polymers; mixing of solid...
C525S105000, C525S106000, C436S518000, C548S110000, C548S118000
Reexamination Certificate
active
06180718
ABSTRACT:
TECHNICAL FIELD
This invention pertains to processes in solid-supported organic synthesis which have utility in the construction of libraries of molecules bearing aromatic or heteroaromatic functionality that are to be screened for biological activities which would render them useful as pharmaceuticals or agrochemicals. More specifically, it pertains to the use of aryl- and heteroaryl-silyl ethers in linking synthetic intermediates to a solid-support during an organic synthesis, methods for attaching starting materials and methods for cleaving final products.
BACKGROUND OF THE INVENTION
Combinatorial chemistry and automated organic synthesis have proven to be highly effective means for the generation of multiplicities of novel molecules known as libraries. As the size of such a library grows, so does the likelihood that it will contain individual molecules with useful biological activities which may be employed in the treatment of human, animal, and plant diseases.
One strategy for increasing the speed at which novel libraries can be generated is to attach a synthetic starting material, also known as a synthon, to a solid-support. Subsequent synthetic transformations are carried out on the solid-supported synthon to elaborate it into the molecules of interest which are either tested for biological activity while still attached to the support or cleaved from the support prior to biological evaluation. Efficiency is introduced into the syntheses relative to traditional solution methods because tedious and time consuming purifications at each intermediate synthetic step are reduced to a simple filtration and rinsing of the polymer supported intermediate. Solid-supported methodologies, combined with automation can dramatically increase the rate at which a library of synthetic molecules may be prepared. While the disciplines of solid-supported peptide and nucleic acid chemistry are well known and have been widely practiced, the solid-supported synthesis of small organic molecules with pharmaceutical and agrochemical utility is a burgeoning science.
Since an overwhelming majority of pharmaceutical and agrochemical agents bear at least one aromatic or heteroaromatic ring, flexible processes for attachment of aromatic and heteroaromatic synthons to solid supports have tremendous value to those interested in generating libraries of molecules with pertinent biological activities. Cleavage of carbon-silicon bonds by ipso-desilylation is a strategy by which an aromatic or heteroaromatic ring may be cleaved from a silicon ether linkage to a polymeric support. A major advantage of this method is that it is possible to have no trace of the linker remain in the target molecule, unlike the amide and ester linkages commonly used in solid-supported peptide chemistry, which leave a portion of the linker functionality, typically acid, ester, amide, amine or phenol behind. Proto-ipsodesilylations will provide pharmaceuticals and agrochemicals in which the carbon-silicon bond is replaced with a carbon-hydrogen bond. By using other ipso-desilylation reactions, it is also possible to incorporate desirable functionality which is unrelated to the linker by replacing the carbon-silicon bond with carbon-oxygen, carbon-sulfur, carbon—carbon or carbon-halogen bonds in the course of cleavage from the solid-support.
WO 95/16712 describes silicon-based polymer resins and silane linkers, methods for their preparation and their use in the synthesis of libraries of aromatic carbocycles to be screened as pharmaceutical agents. Plunkett and Ellman describe “A Silicon-Based Linker for Traceless Solid-Phase Synthesis in
The Journal of organic Chemistry,
1995, 60, 6006-6007. Both of these disclosures pertain to the use of silane linkers in solid-supported organic synthesis which involve chemically distinct processes for attachment and cleavage of molecules to and from solid-supports from the instant invention which involves silyl ether linkers. Randolph, McClure and Danishefsky describe “Major simplifications in Oligosaccharide syntheses arising from a Solid-Phase Based Method: An Application to the Synthesis of Lewis b Antigen” in
The Journal of the American Chemical Society,
1995, 117, 5712-5719. This disclosure involves the use of silicon bearing polymers to which sugar molecules are attached and cleaved via silicon-oxygen forming and breaking reactions which is also chemically distinct from the instant invention wherein molecules are attached to a solid support by silicon-oxygen bond formation and cleaved by silicon-carbon bond breaking. The methods above do not disclose the utility of aryl- and heteroaryl-silyl ethers in solid-supported organic synthesis nor do they teach a skilled practitioner of this art how to use said silyl ethers effectively therein.
SUMMARY OF INVENTION
Accordingly, the present invention is a process for preparing pharmaceuticals or agrochemicals comprising:
a) An aryllithium or heteroaryllithium reagent is first reacted with a dichlorosilane forming a silicon-carbon bond;
b) The resulting aryl-chlorosilane is reacted in one or more synthetic steps with a solid-supported hydroxyl group to form a silicon-oxygen bond (silyl ether) which thereby links the aromatic or heteroaromatic synthon to the solid support;
c) The solid-supported aromatic or heteroaromatic synthon is elaborated, in one or more synthetic steps, into solid-supported molecules which, when detached from the support, afford pharmaceuticals or agrochemicals.
DETAILED DESCRIPTION OF THE INVENTION
Specifically, the instant invention pertains to the use of silyl ethers in the attachment of molecules bearing aromatic and heteroaromatic rings to solid-supports for the purpose of engaging in solid-supported organic synthesis of libraries of small organic molecules. The use of silyl ethers in this fashion requires methods for forming silicon-carbon bonds between the aromatic or heteroaromatic ring and a dichlorosilane, methods for formation of a silicon-oxygen bond between the resulting aryl-chlorosilane and a solid-supported hydroxyl group, knowledge of the range of compatible solid-supports to which this hydroxyl group is attached, and methods for selective cleavage of a silicon-carbon bond that will liberate the desired product from the solid-support.
Throughout the detailed description and claims the following definitions will apply unless otherwise specified:
General Terms
1. Alkyl
A straight or branched
chain of eight or fewer
carbon atoms that is
unsubstituted or
substituted by one or two
functional groups selected
from the group consisting
of: OH, NH
2
, OCH
3
, CO
2
H,
2. Lower Alkyl
A subset of alkyl which
includes straight chain,
branched or cyclic groups
of 1-6 carbon atoms which
lacks substitution by
heteroatoms.
3. Alkenyl
An alkyl group defined as
above with one or two
carbon double bonds.
4. Aryl
A phenyl, a 1-naphthyl or a
2-naphthyl ring which is
unsubstituted or
substituted by 2-5 groups
selected from the group
consisting of: HO, H
2
N,
SH, F, Br, Cl, I, CH
3
, CHO,
CH
2
OH, CO
2
H, CN, CF
3
, CCl
3
,
NO
2
, phenyl, OR, NHR, NR
2
,
SR, C(═O)NHR, C(═O)OR,
C(═O)R, SO
2
NHR and SO
2
R and
suitably protected versions
thereof wherein R is an
alkyl or alkenyl group as
described above.
5. Heteroaryl
A 5- or 6-membered aromatic
ring or a benzo-fused 5-or
6-membered aromatic ring
system containing at least
one N, O, or S atom which
is unsubstituted or
substituted by 2-5 groups
selected from the group
consisting of: HO, H
2
N,
SH, F, Br, Cl, I, CH
3
, CHO,
CH
2
OH, CO
2
H, CN, CF
3
, CCl
3
,
NO
2
, phenyl, OR, NHR, NR
2
,
SR, C(═O)NHR, C(═O)OR,
C(═O)R, SO
2
NHR and SO
2
R and
suitably protected versions
thereof wherein R is an
alkyl or alkenyl group as
described above.
6. Protecting Group
A chemical functionality
that is temporarily
installed to avoid an
unwanted side reaction.
Protection and deprotection
strategies are well known
to those skilled in the art
of organic synthesis and
are described in detail by
Theodora W. Greene in
Protective Groups in
Organic Synthesis John
Wiley and Sons
Boehm Terri L.
Hodges John C.
Showalter Howard D. H.
Celsa Bennett
Merchant & Gould P.C.
Warner-Lambert & Company
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