Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-06-10
2001-08-14
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S025310, C536S025330, C536S025340
Reexamination Certificate
active
06274724
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds and polymers based on and formed from imidazoles and methods for preparing same.
BACKGROUND OF THE INVENTION
Heterocyclic compounds are commonly used in industry. Imidazoles are monocyclic heteroatomic ring compounds. Derivatives of imidazoles are used for dewatering of aqueous suspensions of organic and inorganic materials in waste water treatment. They are used for diverse purposes such as agricultural chemicals, insecticides, and catalysts. The Encyclopedia of Polymer Science and Engineering, Vol. 12 (1988) reports that it is very difficult to synthesize imidazole monomers. Imidazole polymers can also be very difficult to synthesize. For this reason, imidazole compounds and polymers are used in limited quantities and are very costly.
Presently, there is a need for new polymers having heterocyclic monomer units which provide properties derived from their relatively low hydrogen content and relatively high nitrogen content. For example, polymers formed from heterocyclic compounds are expected to provide a number of useful characteristics including flame resistance. Other important uses are anticipated if such polymers are able to be synthesized cost-effectively.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a new family of cyclic imidazole ring compounds which are generally based on new 2-vinyl-4,5-dicyanoimidazoles. Another object is to provide polymers and copolymers formed from such compounds. Another object is to provide methods of synthesis which permit production of the new compounds and polymers from relatively inexpensive precursors, and which are suitable for scale-up to commercial processing. Still another object is to provide methods for using the new compounds and polymers of the invention. In particular, another object is to provide a method for using the new polymers in oligonucleotide synthesis.
The invention provides new compounds having a cyclic imidazole ring structure with specialized functional groups carried on the ring. Such groups are included prior to polymerization or after. In one embodiment, a given group is included prior to polymerization, then removed, and replaced by another group after polymerization.
In one embodiment, the cyclic compound of the invention has the formula as per
FIG. 1
, where R1 is characterized by being hydrogen or organic substituent that does not interfere with polymerization, and by being attachable to the cyclic compound by an electrophilic agent. It is preferred that the cyclic compound have the formula as shown in
FIG. 1
, where R1 represents an organic group, or hydrogen, and is preferably an organic group having one or more carbon atoms. Most preferably, R1 is a substituted or unsubstituted alkyl having 1 to 10 carbon atoms. Preferably, R1 is selected from the group consisting of methyl, ethyl, propyl, isobutyl, benzyl, nonyl, and carbamoyl. In a variation on the embodiment shown in
FIG. 1
, the substituent carried at the 1-nitrogen position may be more generally represented as E, which is any substituent, and preferably is attachable to the nitrogen by an electrophilic agent, and is not necessarily hydrogen or organic.
Referring to
FIG. 2
, the cyclic compound has the formula as shown where R1, R2 and R3 are identical or different and are each independently selected from the group consisting of hydrogen and organic substituents having 1 to 10 carbon atoms. It is preferred that at least of R1 and R2 is selected from the class of organic substituents where such substituents do not interfere with polymerization. It is preferred that R1 be any group attachable to the cyclic compound by an electrophilic agent. As in the case earlier described with respect to
FIG. 1
, R1 may be a substituent such as hydrogen or an organic substituent, with R1 being E as per above.
In one preferred embodiment, R1 and R2 are each hydrogen or substituted or unsubstituted alkyls, with R2 having 1 to 4 carbon atoms and R1 having 1 to 10 carbon atoms. It is necessary that the substituent, whether hydrogen, organic (R), or more broadly E, is sterically non-hindering. In the most preferred embodiment, R3 is hydrogen and R2 is selected from the group of methyl, ethyl, propyl and butyl.
Polymers formed by monomeric units of the invention are the polymers exemplified in
FIGS. 3
,
3
A,
4
,
4
A,
9
and
10
. The polymer generally comprises cyclic imidazole units having nitrogen at the 1 and 3 positions; a carbon at each of the 2, 4 and 5 positions; and radical substituents G1 and G2 carried at respective 4 and 5 positions. In one embodiment, G1 and G2 are each independently selected from cyano, substituents derived from cyano, and substituents which replace cyano. Polymers of the invention are formed by at least two of the cyclic imidazole units joined by linkage through any combination of linking carbon six and carbon seven carried on the ring at the 2 position carbon. Such linking carbons 6 and 7 are derived from vinyl carried at said 2 position carbon. In one embodiment the cyclic imidazole units are connected to a main polymer chain through linkage at the 2 position providing a polymer as exemplified in
FIGS. 4
,
4
A, and
10
.
In another embodiment, the polymer units are connected to one another by linkage through both the 1 and 7 positions. This is referred to in the art as “in chain linkage” or “ring in chain polymer”. This is exemplified by
FIGS. 3
,
3
A and
9
.
The polymer of the invention provides surprising flexibility for substituents at the 1-nitrogen and 4,5 positions on the ring. This is exemplified in
FIGS. 3A and 4A
. Referring to
FIGS. 3A and 4A
, G1 and G2 are each independently selected from cyano, derivatives of cyano, and substituents which replace cyano on an imidazole ring. Examples include cyano, carboxy, carbamoyl, amide, amine, carboxylic acid and carboxylic ester. Broadly, E is essentially any substituent, and desirably E is attachable to the nitrogen by an electrophilic agent. Advantageously, E may serve a variety of functional uses such as provide fluorescence in an assay, or facilitate crosslinking. Examples of substituents carried at the E position include hydrogen, organic group, organic group having up to 10 carbon atoms, a catalytic substituent, a fluorescent substituent, a hydrophobic modifier substituent, a hydrophilic modifier substituent, and a crosslinking substituent.
The compounds and polymers of the invention are useful in a variety of applications, including synthesis of oligonucleotides. It is particularly preferred to use a vinylic polymer of the invention as exemplified in
FIGS. 4
,
4
A and
10
for facilitating chemical synthesis of oligonucleotides. For this purpose, it is preferred to use the polymer exemplified in the figures, with R1 being hydrogen, namely, poly[1-(1H-4,5-dicyano-2-imidazoyl)ethylene]. To promote the coupling reaction used in laboratory synthesis of oligomers. In a typical synthesis method which exemplifies utility of the present polymer, deprotected nucleotide reacts with a protected monomer unit in a reaction mixture in the presence of a coupling agent. This forms a product of the reaction which is a 5′-protected oligonucleotide having its length increased by joining the monomer unit to the oligonucleotide. The desired product is separated from other reagents and unreacted substituents.
In accordance with the invention, the coupling agent is the polymer of the invention comprising cyclic imidazole units having nitrogen at the 1 and 3 positions; a carbon at each of the 2, 4 and 5 positions; and substituents G1 and G2 carried at respective 4 and 5 positions, where G1 and G2 are as defined earlier. It is preferred that each of G1 and G2 be an electron-withdrawing group, but need not necessarily be the same electron-withdrawing group. It is preferred that G1 and G2 are each independently selected from a group consisting of cyano, substituents derived from cyano, and substituents which replace cyano. It is most preferred that G1 and G2 each be cyano. As sho
Johnson David M.
Lawton Richard G.
Rasmussen Paul G.
Reybuck Sarah E.
Harness & Dickey & Pierce P.L.C.
Higel Floyd D.
The Regents of the University of Michigan
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