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
1999-02-23
2001-10-23
Lipman, Bernard (Department: 1713)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Mixing of two or more solid polymers; mixing of solid...
C525S328900, C525S328500, C525S333500, C525S343000, C525S374000
Reexamination Certificate
active
06306977
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method of preparation of novel solid phase reagents useful as solid phase supports for small molecule synthesis, especially synthesis of heterocycles, and as supported nucleophiles to aid purification of solution phase reactions.
BACKGROUND OF THE INVENTION
The advent of combinatorial chemistry has sparked renewed interest in the use of functionalized polymers in the synthesis of small, organic molecules (for recent reviews, see Blackburn et al. “Functionalized Resins and Linkers for Solid-Phase Synthesis of Small Molecules”,
Drugs of the Future
1997, 22(9), 1007-1025; and Shuttleworth et al., “Functionalized Polymers: Recent Developments and New Applications in Synthetic Organic Chemistry”,
Synthesis
1997, 1217-1239). Inexpensive, readily prepared functionalized resins suitable for organic synthesis applications are increasingly needed.
Some thiol-functionalized polystyrene resins are known in the art. Literature methods for preparing thiomethyl-functionalized polystyrene resins involve multiple steps and give resins with low active SH titers unless significant care is taken to remove oxygen from all solvents and equipment (see J. Cerny and Wichterle,
J. Polymer Sci.
1958, 30, 501, J. M. J. Frechet et al.,
Polymer
1979, 20, 675, and S. Kobayashi et al.,
Tetrahedron Lett.
1996, 37, 2809). Commercially available thiol-functionalized resins are expensive, have low loading and generally need pretreatment before use to remove a thiol protecting group.
Thiol-functionalized resins have found use as a solid phase support for the synthesis of substituted heterocycles (see Gayo and Suto,
Tetrahedron Lett.
1997, 38, 211-214) and as supported nucleophiles to aid the purification of solution phase reactions involving excess electrophiles (Hodges, 2nd
Winter Conference on Medicinal and Bioorganic Chemistry,
Steamboat Springs, Colo., Jan. 26-31, 1997).
SUMMARY OF THE INVENTION
This invention pertains to a polymer comprising mercaptoalkylamide-functionalized styrene units of Formula I
wherein
m is an integer from 1 to 3;
R is H or C
1
-C
3
alkyl; and
Q is a bond, —CH
2
—, —CH
2
CH
2
—, —CH
2
CH
2
CH
2
— or
Said polymer is optionally grafted onto other polymers, such as polyethylene and polypropylene.
This invention also relates to beads of aforesaid polymer comprising mercaptoalkylamide-functionalized styrene units of Formula I.
Another aspect of this invention pertains to a process for preparing aforesaid polymer comprising mercaptoalkylamide-functionalized styrene units of Formula I, the process comprising the sequential steps of:
(a) contacting a polymer comprising aminoalkyl-functionalized styrene units of Formula II
with a solvent to swell said polymer; and
(b) reacting said polymer with a thiolactone of Formula III
at temperature of 0 to 120° C.;
wherein m, R, and Q are as previously described.
Another aspect of this invention pertains to a method of using aforesaid polymer comprising mercaptoalkylamide-functionalized styrene units of Formula I as a support for solid phase synthesis of small molecules and as a supported nucleophile to aid solution phase synthesis.
DETAILS OF THE INVENTION
Mercaptoalkylamide-functionalized polystyrene resins with high active SH titers and a simple, single-step method to prepare these resins have now been discovered. The resins are useful as solid phase supports for small molecule synthesis, especially synthesis of heterocycles, and as supported nucleophiles to aid purification of solution phase reactions.
Resin is defined variously in the polymer arts (see M. S. M. Alger,
Polymer Science Dictionary,
Elsevier, N.Y., 1989, p. 415). In this disclosure, resin is synonymous with polymer. Styrene polymer, polymer comprising styrene units, polystyrene, polystyrene resin and styrene polymer resin are all synonymous. Functionalized styrene polymer, polymer comprising functionalized styrene units, functionalized polystyrene, functionalized polystyrene resin and functionalized styrene polymer resin are synonymous and refer to a composition of matter comprising polymer chains formed from units corresponding to a functionalized styrene monomer and optionally also other units corresponding to other monomers such as unfunctionalized styrene. As functionalized polystyrene is often made from unfunctionalized polystyrene and in the functionalization process not every unit is functionalized, functionalized polystyrene typically will comprise unfunctionalized as well as functionalized units. Functionalized polystyrene made from a mixture of functionalized and unfunctionalized styrene monomers will also comprise both functionalized and unfunctionalized units (for a description of copolymerization of chloromethylstyrene with a variety of other monomers, see J.-P. Montheard, M. Chatzopolous and M. Camps, “Functional Polymers via Free-Radical Polymerization of Chloromethylstyrene”, in
Desk Reference of Functional Polymers, Syntheses and Applications,
R. Arshady, Ed., American Chemical Society, Washington, D.C. 1996, Chapter 1.1). In a mercaptoalkylamide-functionalized polystyrene of this invention, the unit corresponding to the functionalized styrene monomer is of Formula I as defined in the Summary of the Invention.
Preferred for reason of ease of synthesis or cost is a polymer comprising mercaptoalkylamide-functionalized styrene units of Formula I wherein m is 1. More preferred for reason of ease of synthesis or cost is said polymer wherein Q is —CH
2
— or —CH(NHC(═O)CH
3
)—. —CH(NHC(═O)CH
3
)— means
More preferred for reason of ease of synthesis or cost is said polymer wherein R is H. Most preferred for reason of highest titer of thiol per weight of polymer is said polymer wherein Q is —CH
2
—.
The polymer chains in a mercaptoalkylamide-functionalized polystyrene of this invention preferably also comprise about 0.5 to about 20% by weight units corresponding to the divinylbenzene monomer to provide cross-linking so as to improve the physical strength and resistance to solvents of the derived resin. About 0.8 to 8% by weight divinylbenzene units is preferred. Most preferred is about 1 to 2% by weight divinylbenzene units, which provides resins with very good physical properties. The polystyrene chains optionally also comprise units derived from vinylethylbenzene and other substituted vinyl benzenes (as described for ion exchange resins by F. W. Billmeyer, Jr.,
Textbook of Polymer Science,
Second Edition, Wiley-Interscience, New York, 1971, p. 407). Furthermore the polystyrene chains are optionally grafted onto other carbonaceous polymeric backbones such as polyethylene, polypropylene or fluoropolymers, as is well known in the art.
For reason of cost and obtaining greatest titer per weight of polymer, a preferred mercaptoalkylamide-functionalized polystyrene resin of the invention is not grafted onto other carbonaceous polymeric backbones, but simply comprises polystyrene chains cross-linked with units derived from divinylbenzene as described and wherein at least 1%, preferably at least 10%, of the styrene units are of Formula I and the remainder of the styrene units are unfunctionalized. Said preferred resin is referred to as consisting essentially of a polystyrene backbone.
A mercaptoalkylamide-functionalized styrene polymer of the invention is usually prepared and used in the form of small microporous or macroporous beads, having average particle diameters typically ranging from about 50 to about 500 &mgr;m, although larger or smaller sizes are possible. Functionalized styrene polymers serving as precursors are commercially available in the form of such beads, conveniently prepared by suspension polymerization (see E. C. Blossey and W. T. Ford, “Polymeric Reagents” in
Comprehensive Polymer Chemistry,
Vol. 6, G. Allen et al. Ed., Pergamon Press, New York, 1989, pp. 81-114, F. W. Billmeyer, Jr.,
Textbook of Polymer Science,
Second Edition, Wiley-Interscience, New York, 1971, pp. 358-359, 407).
The mercaptoalkylamide-functionalized polystyrene resins of the invention comprise uni
E. I. Du Pont de Nemours and Company
Lipman Bernard
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