US6180718B1
Expired / Lapsed
US
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Process for preparation of aromatic and heteroaromatic molecules
Assignee: Warner Lambert Co LLC
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Filing: 1997-02-18
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Granted: 2001-01-30
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Expires: 2017-02-18
Abstract
Abstract A process for the attachment of aromatic or heteroaromatic rings to a polymeric support via a silyl ether linkage is described. Such process involves the synthesis of a chlorodialkyl aryl or heteroarylsilane which is then coupled to a polymeric support via a hydroxyl functionality to form a polymer-bound silyl ether. Further modification provides a polymer-bound small organic molecule that is cleaved from the polymeric support under mild conditions to give an aryl or heteroaryl silanol or a compound in which the aryl or heteroaryl carbon-silicon bond is replaced with a carbon-hydrogen, carbon-halogen, carbon-hydroxyl, carbon-sulfur, or carbon-carbon bond. Such methods are useful for the preparation of a library of diverse aromatic and heteroaromatic compounds by both manual and automated synthesis.
Inventors
- 👤 Terri L. Boehm
- 👤 John C. Hodges
- 👤 Howard D. H. Showalter
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-09 22:02
CPC Classifications
C; C40; C40B; C40B50/00; C40B50/14; C07; C07B; C07B61/00; C07C; C07C45/00; C07C45/61; C07C45/67; C07C45/673; C07D; C07D307/00; C07D307/77; C07D307/78; C07D307/79; C07D307/80; C08; C08F; C08F8/00; C08F8/42; C40B40/00; C40B40/04; C40B50/18; C07B2200/00; C07B2200/11
Claims Analysis
Total Claims: 28
Claim 1
Independent Claim
93 words
A process for preparing pharmaceuticals or agrochemicals comprising: a) An aryllithium or heteroaryllithium reagent is first reacted with a substituted or unsubstituted 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 reacted, in one or more synthetic steps, to form a solid-supported molecules which, when detached from the support, afford pharmaceuticals or agrochemicals.
Claim 2
Dependent Claim
93 words
A process for preparing pharmaceuticals or agrochemicals comprising: a) An aryllithium or heteroaryllithium reagent is first reacted with a substituted or unsubstituted 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 reacted, in one or more synthetic steps, to form a solid-supported molecules which, when detached from the support, afford pharmaceuticals or agrochemicals.
Claim 3
Dependent Claim
29 words
A process according to claim 1 wherein the dichlorosilane is symmetrically substituted by two identical lower alkyl groups of 1-6 carbon atoms which are straight chain, branched or cyclic.
Claim 4
Dependent Claim
40 words
A process according to claim 1 wherein the dichlorosilane is unsymmetrically substituted by a phenyl ring and an alkyl group or by two different lower alkyl groups of 1 to 6 carbon atoms which are straight chain, branched or cyclic.
Claim 5
Dependent Claim
143 words
A process according to claim 1 wherein the aryllithium is 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, 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 or a suitably protected version thereof, wherein R is 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, CO 2 CH 3 , CONH 2 , and CN and may contain one or two carbon—carbon double bonds.
Claim 6
Dependent Claim
159 words
A process according to claim 1 wherein the heteroaryllithium is 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, 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 or a suitably protected version thereof, wherein R is 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, CO 2 CH 3 , CONH 2 , and CN and may contain one or two carbon—carbon double bonds.
Claim 7
Dependent Claim
29 words
A process according to claim 1 wherein the aryl-chlorosilane is reacted in one step by treatment with a base and a solid-supported hydroxyl group to generate a silyl-ether linkage.
Claim 8
Dependent Claim
36 words
A process according to claim 1 wherein the aryl-chlorosilane is first converted to an aryl-hydroxysilane and then activated by treatment with diethylazodicarboxylate and triphenylphosphine before reacting with a solid-supported hydroxyl group to generate a silyl-ether linkage.
Claim 9
Dependent Claim
31 words
A process according to claim 1 wherein the aryl-chlorosilane is first converted to an aryl-triflate and then reacted with a base and a solid-supported hydroxyl group to generate a silyl-ether linkage.
Claim 10
Dependent Claim
36 words
A process according to claim 1 wherein the solid-supported hydroxyl group is a hydroxyl group of hydroxymethyl polystyrene, p-benzyloxybenzyl alcohol resin, ethyleneglycol 2-chlorotrityl resin, 4-hydroxymethylbenzoic acid BHA resin, 4-hydroxymethylbenzoic acid MBHA resin or polyethyleneglycol-polystyrene composite polymer.
Claim 11
Dependent Claim
49 words
A process according to claim 1 wherein the solid-supported hydroxylgroup is a hydroxyl group of HO(CH 2 ) n X(CH 2 ) m -polystyrene wherein: X is O, S, C(═O)NH, NHC(═)O, N(Me)C(═O), C(═O)O, or OC(═O); n is an integer from 1 to 6 and m is zero or one.
Claim 12
Dependent Claim
42 words
A process according to claim 1 wherein the solid-supported hydroxylgroup is a hydroxyl group of HO(CH 2 ) n X-polyethyleneglycol-polystyrene composite polymer wherein: X is O, S, C(═O)NH, NHC(═)O, N(Me)C(═O), C(═O)O, or OC(═O) and n is an integer from 1 to 6.
Claim 13
Dependent Claim
37 words
A process according to claim 1 wherein the solid-supported hydroxylgroup is a hydroxyl group of HO(CH 2 ) n C(═O)—MBHA resin or HO(CH 2 ) n C(═O)—BHA resin and n is an integer from 1 to 6.
Claim 14
Dependent Claim
49 words
A process according to claim 1 wherein the solid-supported hydroxylgroup is a hydroxyl group of (4-hydroxyphenyl)—(CH 2 ) p X(CH 2 ) m -polystyrene wherein: X is O, S, C(═O)NH, NHC(═)O, N(Me)C(═O), C(═O)O, or OC(═O); p is an integer from 0 to 6 and m is zero or one.
Claim 15
Dependent Claim
43 words
A process according to claim 1 wherein the solid-supported hydroxylgroup is a hydroxyl group of (4-hydroxyphenyl)—(CH 2 ) p X-polyethyleneglycol-polys tyrene composite polymer wherein: X is O, S, C(═O)NH, NHC(═)O, N(Me)C(═O), C(═O)O, or OC(═O) and p is an integer from 0 to 6.
Claim 16
Dependent Claim
47 words
A process according to claim 1 wherein the carbon-silicon bond attaching the pharmaceutical or agrochemical to the solid support is cleaved by treatment with tetrabutylammonium fluoride or tris (dimethylamino) sulfonium difluorotrimethylsilicate in a polar-aprotic solvent or a mixture of polar-aprotic solvents at a temperature above 45° C.
Claim 17
Dependent Claim
42 words
A process according to claim 1 wherein the silicon-oxygen bond attaching the pharmaceutical or agrochemical to the solid support is cleaved by treatment with tetrabutylammonium fluoride in tetrahydrofuran, cesium fluoride in N,N-dimethylformamide, or trifluoroacetic acid in dichloromethane at less than 45° C.
Claim 18
Dependent Claim
60 words
A process according to claim 1 wherein the silicon-oxygen bond attaching the pharmaceutical or agrochemical to the solid-support is first cleaved according to claim 16 and then the silicon-carbon bond of the resulting silanol is cleaved by treatment with tetrabutylammonium fluoride or tris(dimethylamino)sulfonium difluorotrimethylsilicate in a polar-aprotic solvent or a mixture of polar-aprotic solvents at a temperature above 45° C.
Claim 19
Dependent Claim
39 words
A process according to claim 1 wherein the silicon-carbon bond attaching the pharmaceutical or agrochemical to the solid support is converted to an oxygen-carbon bond in one or more steps by treatment with tetrabutylammonium fluoride and an oxidizing agent.
Claim 20
Dependent Claim
35 words
A process according to claim 1 wherein the silicon-carbon bond attaching the pharmaceutical or agrochemical to the solid support is converted to an carbon—carbon bond by treatment with tris(dimethylamino)sulfonium (trimethylsilyl)difluoride and an electrophilic carbon source.
Claim 21
Dependent Claim
35 words
A process according to claim 1 wherein the silicon-carbon bond attaching the pharmaceutical or agrochemical to the solid support is converted to an sulfur-carbon bond by treatment with tris(dimethylamino)sulfonium (trimethylsilyl)difluoride and an electrophilic sulfur source.
Claim 22
Dependent Claim
35 words
A process according to claim 1 wherein the silicon-carbon bond attaching the pharmaceutical or agrochemical to the solid support is converted to an halogen-carbon bond by treatment with tris(dimethylamino)sulfonium (trimethylsilyl)difluoride and an electrophilic halogen source.
Claim 23
Dependent Claim
26 words
A process according to claim 1 wherein a library of greater than twenty pharmaceuticals or agrochemicals bearing aromatic or heteroaromatic moieties are prepared via automated synthesis.
Claim 24
Dependent Claim
26 words
A process according to claim 1 wherein a library of greater than twenty pharmaceuticals or agrochemicals bearing aromatic or heteroaromatic moieties are prepared via manual synthesis.
Claim 25
Dependent Claim
16 words
A process according to claim 18 wherein the oxidizing agent is hydrogen peroxide, or peracetic acid.
Claim 26
Dependent Claim
24 words
A process according to claim 19 wherein the electrophilic carbon source is an aldehyde, an acid chloride, an alkyl halide, or an alkyl sulfonate.
Claim 27
Dependent Claim
23 words
A process according to claim 20 wherein the electrophilic sulfur source is a disulfide, a sulfinyl halide, a sulfonyl chloride, or an thiosulfonate.
Claim 28
Dependent Claim
33 words
A process according to claim 21 wherein the electrophilic halogen source is I 2 , Br 2 , Cl 2 , Icl, or tris(dimethylamino)sulfonium difluorotrimethylsilicate and N-halosuccinimides in DMF or another polar-aprotic solvent.
References Cited (Backward Citations)
WO1995016712A1
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 2004-01-30 | 2004-07-31 | 2005-01-30 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2008-01-30 | 2008-07-31 | 2009-01-30 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2012-01-30 | 2012-07-31 | 2013-01-30 | $7700.00 | Window Closed / Lapsed |