Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-04-06
2001-06-19
Riley, Jezia (Department: 1656)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S022100, C536S023100, C536S024300, C536S025330
Reexamination Certificate
active
06248877
ABSTRACT:
BACKGROUND OF THE INVENTION
The synthesis and screening of small molecule combinatorial libraries has become an important new technology for drug discovery. (For reviews see: (a) Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gordon, E. M.
J. Med. Chem.
1994, 37, 1233. (b) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A.
J. Med. Chem.
1994, 37, 1385. (c) Moos, W. H.; Green, G. D.; Pavia, M. R. Recent Advances in Generation of Molecular Diversity. in
Annual Reports in Medicinal Chemistry;
Bristol, J. A., Ed.; Academic Press, Inc.; San Diego, Calif., 1993; Vol. 28, pp. 315-324. (d) Ecker, D. J.; Crooke, S. T.
Biotechnology
1995, 13, 351. (e) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele J. Tetrahedron 1995, 51, 8135. (f) Thompson, L. A.; Ellman, J. A.
Chem. Rev.
1996, 96, 555. (g) Herkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron, 1996, 52, 4527. (h) Fruchtel, J. S.; Jung, G.
Angew. Chem. Int. Ed. Engl.
1996, 35, 17.) A convenient format for the generation of these libraries is synthesis of organic compounds on a solid phase. Solid phase synthesis is especially useful for reactions where excess reagents can be used to drive the reactions to completion. The excess reagents and soluble byproducts can be easily removed. (See, for example: (a) Kurth, M. J.; Randall, L. A. A.; Chen, C.; Melander, C.; Miller, R. B.
J. Org. Chem.
1994, 59, 5862. (b) Hiroshige, M.; Hauske, J. R.; Zhou, P. J.
Am. Chem. Soc.
1995, 117, 11590. (c) Wipf, P.; Cunningham, A.
Tetrahedron Lett.
1995, 36, 7819. (d) Goff, D. A.; Zuckermann, R. N.
J. Org. Chem.
1995, 60, 5744. (e) Plunkett, M. J.; Ellman, J. A.
J. Org. Chem.
1995, 60, 6006. (f) Kick, E. K.; Ellman, J. A.
J. Med. Chem.
1995, 38, 1427. (g) Forman, F. W.; Sucholeiki, I.
J. Org. Chem.
1995, 60, 523. a) Holmes, C. P.; Jones, D. G.
J. Org. Chem.
1995, 60, 2318. (i) Holmes, C. P.; Chinn, J. P.; Look, G. C.; Gordon, E. M.; Gallop, M. A.
J. Org. Chem.
1995, 60, 7328.) Another important feature of solid phase synthesis is allowing “split and combine” methodology to be employed for library construction. Thus, generating diverse combinatorial libraries requires the development of solid phase syntheses of biologically active molecules on solid support, and the exploration of such synthetic methodologies for preparation of libraries.
Often compounds isolated from natural products have biological activity. For example, derivatives prepared from natural products, nucleic acids, peptides, proteins, and mimics thereof have remarkable biological activities. (See: Boyd, G. V. In
Comprehensive Heterocyclic Chemistry,
Vol. 6; Part 4B, Katritzky, A. R.; Rees, C. W., Eds.; Pergammon: Oxford, 1984; p178.)
Preparation of high molecular weight organic compounds, such as, for example, oligonucleotides, can be synthetically challenging. Often multiple synthetic steps are required to prepare the desired compounds. As a consequence of multistep syntheses, reaction conditions utilized to form oligonucleotides can facilitate degradation of the remaining molecular functionality. Additionally, synthetic manipulation of an oligonucleotide can cause the oligonucleotide to fragment into shorter lower molecular weight portions, thereby reducing the yield of the desired compound.
SUMMARY OF THE INVENTION
The present invention is directed to methods for preparing organic compounds, such as oligonucleotides, via solid phase synthesis.
In one aspect, the invention provides methods, e.g., automated methods, for preparing organic compounds. The methods include combining a substrate having a reactive nucleophilic group and a nucleophilic group protected by a removable protecting group, with a phosphitylating agent, thereby forming an in situ phosphitylated substrate. The in situ phosphitylated substrate is combined with a functionalized support, such that an in situ phosphitylated substrate is bound to the support, thereby forming a support bound phosphitylated substrate.
The method can further include treating the support bound phosphitylated substrate to selectively remove the protecting group from the protected nucleophilic group, thereby forming a support bound phosphitylated substrate bearing a reactive nucleophilic group. Thereafter, the support bound phosphitylated substrate bearing a reactive nucleophilic group can be combined with an in situ formed phosphitylated substrate, such that a support bound phosphitylated substrate bearing a reactive nucleophilic group is formed.
The support bound phosphitylated substrate can be treated to selectively remove the protecting group from the protected nucleophilic group, thereby forming a support bound phosphitylated substrate bearing a reactive nucleophilic group. The aforementioned steps can be repeated until a product formed of a plurality of substrates is obtained. The methods further provide that the product can be cleaved from the support and that optionally, the final deprotection step can be omitted.
In another aspect, the invention provides methods, e.g., automated, for preparing organic compounds, such as oligonucleotides. The methods include treating a support with a phosphitylating agent, thereby forming an a catena phosphitylated support and treating the a catena phosphitylated support with a substrate having a reactive nucleophilic group and a nucleophilic group protected by a removable protecting group, thereby forming a support bound phosphitylated substrate bearing a protecting group. The methods of the invention can further include removal of the protecting group from the support bound phosphitylated substrate, thereby forming a support bound phosphitylated substrate bearing a reactive nucleophilic group.
A substrate having a reactive nucleophilic group and a nucleophilic group protected by a removable protecting group can be combined with a phosphitylating agent, thereby forming an in situ phosphitylated substrate The in situ phosphitylated substrate can then be combined with the phosphitylated substrate bearing a hydroxyl functionality, thereby forming a support bound phosphitylated substrate bearing a protecting group. The protecting group can be removed from the support bound phosphitylated substrate, thereby forming a support bound phosphitylated substrate bearing a reactive nucleophilic group.
Alternatively, the methods of the invention include treating the support bound phosphitylated substrate bearing a reactive nucleophilic group with a phosphitylating agent, thereby forming a phosphitylated support bound substrate. The phosphitylated support bound substrate is then treated with a substrate having a reactive nucleophilic group and a nucleophilic group protected by a removable protecting group, thereby forming a support bound phosphitylated substrate bearing a protecting group. The protecting group is then removed from the support bound phosphitylated substrate, thereby forming a support bound phosphitylated substrate bearing a reactive nucleophilic group.
Optionally, the aforementioned steps can be repeated until a product formed of a plurality of substrates is obtained. The methods of the invention further provide that the product can be cleaved from the support and that optionally, the final step deprotection step can be omitted.
Optionally, the methods of the invention can include more than one substrate having a reactive nucleophilic group and a nucleophilic group protected by a removable protecting group or that more than one substrate can be included which is have a plurality of reactive nucleophilic groups and a plurality of nucleophilic groups protected by removable protecting groups. Moreover, the methods of the invention can include the step of capping failure substrates by reacting a capping agent with reactive nucleophilic groups of failure substrates.
The methods of the invention include the phosphitylating agent having the formula:
wherein one of Z
1
, Z
2
and Z
3
is displaced by said reactive nucleophilic group of the substrate. One example of a phosphitylating agent is where Z
1
is chlorine,
Bonner Alex G.
Udell Lawrence S.
Biolink Partners
DeConti, Jr. Giulio A.
Lahive & Cockfield LLP
Riley Jezia
Triano, III Nicholas P.
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