Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-22
2003-09-02
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S289000, C549S334000, C568S591000, C568S592000, C568S595000
Reexamination Certificate
active
06613918
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the synthesis of cyclic and spiro ortho esters and cyclic and spiro ortho carbonates, and to the synthesis and use of intermediates useful in the synthesis and production of cyclic and spiro ortho esters as well as cyclic and spiro ortho carbonates. The synthesis of anti-first-pass effect compounds containing spiro ortho ester groups is also included in the invention.
2. Discussion of the Background
Compositions exhibiting anti-first-pass effect activity are known to contain spiro ortho ester groups. Specifically, it has recently been shown that the compounds in citrus extracts responsible for the anti-first-pass effect contain spiro ortho esters (see e.g., U.S. Pat. Nos. 6,063,809 and 6,054,477, both incorporated herein by reference). In pharmaceutical applications, polymers synthesized from ortho esters have shown usefulness in drug delivery devices (see e.g. U.S. Pat. No. 4,990,631, incorporated herein by reference).
Molecules containing cyclic and spiro ortho ester and ortho carbonate groups have been shown to exhibit properties and chemical behavior of potential economic value. For example, monomers containing spiro ortho ester and spiro ortho carbonate groups, when incorporated into polymer systems, can reduce or eliminate the shrinkage that is commonly associated with thermosetting or thermoplastic polymerization processes. In fact, polymerization of monomers containing spiro ortho ester and spiro ortho carbonate groups can afford a product whose volume is nearly 10% greater than the volume of the monomer starting material (R. K. Sadhir and R. M. Luck,
Expanding Monomers: Synthesis. Characterization and Applications
, CRC Press, Inc., 1992). Advantages of monomers that expand (or do not shrink) upon polymerization include the ability to effect complete mold filling and mold replication (i.e., to produce precision-cast parts), the production of strain-free parts, and the increase in bonding strength of adhesive glues, coatings, etc.
While molecules and materials containing or synthesized from spiro ortho esters and spiro ortho carbonates have shown significant promise in both the medical and polymer industries, their commercial use remains limited. The lack of availability of sufficient quantities of spiro ortho ester and spiro ortho carbonate materials is one factor inhibiting the economic exploitation and further development of these materials. Although synthetic routes to spiro ortho esters and spiro ortho carbonates are known and have been described in the literature, they have thus far not lent themselves to inexpensive, large-scale production. For example, a reference book on the subject estimates that the high cost of the monomers (approximately $1000 per pound for spiro ortho carbonates) has severely limited the competitiveness of the technology (R. K. Sadhir and R. M. Luck,
Expanding Monomers: Synthesis, Characterization, and Applications
, CRC Press, Inc., 1992, page 385). As a further example, U.S. Pat. No. 4,387,215 addresses the cost and availability issue by suggesting that spiro ortho ester and spiro ortho carbonate monomers can be diluted with cheaper materials that do not expand upon polymerization. A synthetic method operable on a large scale would offer formulators, researchers, and developers greater opportunity to take advantage of the unique physical and chemical properties of spiro ortho esters and spiro ortho carbonates.
The improved syntheses of cyclic ortho esters and cyclic ortho carbonates, as described herein, are useful because these chemicals serve as intermediates for the valuable spiro ortho ester and spiro ortho carbonate materials discussed above. Cyclic ortho esters and cyclic ortho carbonates have direct, additional value, however, because they have proven useful in making drug delivery devices. For example, polymers produced from cyclic ortho esters have demonstrated sustained systemic delivery of proteins and other expensive agents for periods ranging from days to weeks (see, for example, Alza Technologies website, “Alzamer Depot Technology”;
Advances in Polymer Science
, 107, pp. 41-92, (1992)).
DESCRIPTION OF THE RELATED ART
The polymerization of spiro ortho esters in the presence of oxonium ions stabilized with, for example, antimonate salts can yield polymeric materials having low volume shrinkage and special optical properties. The oxonium salt is used to initiate polymerization via ring opening metathesis polymerization (ROMP), see U.S. Pat. No. 4,387,215. Similar salts have been used in the bulk polymerization of spiro ortho esters. The use of either an oxonium or carbonium salt is a common feature in the polymerization or ring opening of cyclic and spiro ortho esters.
The difficulty in purifying and isolating spiro ortho ester monomers led practitioners to initiate and complete polymerization on unpurified spiro ortho ester starting materials (U.S. Pat. No. 4,738,899). Poly ortho esters can be formed in a “one-pot” reaction by heating intermediate ortho esters. Combining a vicinal diol with a compound of formula R′C(OEt)
3
was shown to first form an intermediate cyclic ortho ester. Heating the reaction mixture to 100° C. in a high boiling solvent allowed removal of the EtOH formed as a by-product of the trans orthoesterification reaction which subsequently allowed an increased rate of reaction to be realized (Advances in Polymer Science, 107, pp. 41-92, (1992).
The use of “Meerwein's reagent” to form ortho esters or ortho carbonates is known in the art (see for example,
Tetrahedron
, 53(11), 3863 (1997);
Tetrahedron
, 47(47), 9939 (1991);
Can. J. Chem
., 63, 2485 (1985);
Can. J. Chem
., 57, 1601 (1979);
Can. J. Chem
., 57, 2260 (1979)). Meerwein's reagent is an alkylating agent of formula [R
3
O][X] where the R group can be Me, Et, etc. and the counterion X is usually BF
4
. The reaction conditions call for reacting a stoichiometric or an excess amount of the alkylating agent with a lactone or cyclic carbonate followed by the addition of a large excess of a nucleophile at low temperature. This reaction strategy can give low yields and complicated reaction product mixtures depending on the functionalization of the lactone or the cyclic carbonate.
U.S. Pat. No. 4,990,631 describes a process for preparing cyclic ortho esters from lactones using tetrafluoroborate salts generated from triethyl formate and boron trifluoride. Spiro ortho carbonates containing an ipso carbon sigma bonded to four oxygen atoms have been prepared in the presence of nucleophiles (U.S. Pat. Nos. 4,891,436; 4,870,193 and 4,849,529).
In view of the state of the art, a reliable synthetic method for cyclic and spiro ortho esters and ortho carbonates has so far not been forwarded. What is more, the complex mixture of materials obtained by extracting a citrus product makes it expensive to isolate a pure anti-first-pass effect product of reliable and consistent quality. In this regard a reliable and reproducible synthetic method for constructing spiro and cyclic ortho esters and carbonates will aid in the synthesis of these materials that in turn will allow their commercial exploitation in medical applications, polymer technology, etc.
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Russell M. Luck et al.; “Shrinkage in Conventional Monomer
Liang Jack
Seemayer Robert
Bioavailability Systems, LLC
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Owens Amelia
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