WO1999041216A1

WO1999041216A1 - Supports for solid state chemical reactions and method of use thereof

Info

Publication number: WO1999041216A1
Application number: PCT/US1999/002452
Authority: WO
Inventors: Thomas R. Webb
Original assignee: Chembridge Corporation
Priority date: 1998-02-17
Filing date: 1999-02-05
Publication date: 1999-08-19
Also published as: AU2495499A

Abstract

Supports for solid state chemistry are disclosed, each of which includes a substrate, a linker and one or more reactive centers, which permit a variety of advantageous chemical reactions, each of which provides unique results not heretofore possible. These include conducting solid state reactions which produce traceless products or products which cannot be made readily in solution. Some of the supports are regenerable and recyclable, so that they may be reused in an ongoing series of reactions and product production. Various supports also can be used in novel separation columns to capture and recover individual compounds in high purity from solutions of large numbers of compounds. Supports of the present invention can also avoid prior art problems of support instability in the presence of various liquid organic solvents and especially in the presence of water. Some of the supports can also be advantageously used in separation columns to effect separation and purification of individual compounds from a liquid body containing a plurality of different compounds.

Description

- 1 -

SUPPORTS FOR SOLID STATE CHEMICAL REACTIONS AND METHOD OF USE THEREOF

BACKGROUND OF THE INVENTION Field of the Invention:

The invention herein relates to the field of solid phase chemistry. More particularly it relates to supports which find use in processes for solid phase and combinatorial synthesis of organic compounds. Description of the Prior Art: Combinatorial chemistry is a relatively new field which involves the formation of libraries of chemical compounds of known structure. By use of these libraries, researchers can rapidly screen numerous compounds for interaction with reactive centers, enzymes, etc. and thereby develop a better understanding of various significant factors in molecular recognition, which in turn provides guidance in the development of new therapeutic agents. An overview of the general field of combinatorial chemistry is presented in Wilson et al. (eds.), COMBINATORIAL CHEMISTRY: SYNTHESIS AND APPLICATION (John Wiley & Sons, Inc.,: 1 997).

Solid phase synthesis in which reactions occur on the surface of solid substrates is an important tool in combinatorial chemistry. Some reactions can be conducted on solid surfaces which are difficult or impossible to conduct in solution. Consequently, significant time and effort have been devoted by researchers to studying solid phase synthesis.

The present invention is focused on solid phase synthesis methods which involve the use of supports comprising substrates to which a linker is covalently bound, with one or more reactive centers in turn covalently bound to the linker. Various species responsive to those reactive centers are then sequentially reacted, starting from each reactive center, to create compounds of interest, which are separated by cleavage from the support for recovery, further reaction, etc. (The term "support" will be used herein to refer to the combination of substrate, linker and reactive centers,)

This procedure, while widely used, has several shortcomings. First, cleavage may leave a residue "trace" attached to the product, in that the cleaved compound contains a terminal moiety which is a function of the reaction. While some "traceless" cleavages are known, the present common supports do not yield traceless cleavages on a consistent basis.

Further, supports are not presently recyclable. Since production of libraries requires that many reactions be performed, the volume of support materials needed represents a significant cost to researchers. An additional major advantage of recyclable resins is that significant operator time is saved, since significantly fewer manual interventions are required using resins of the present invention of this type.

The desirability of regeneration of a functionality on solid supports has previously been recognized. For instance, Dinh et al, Tetrahedron Letters, 37:8, 1 1 61 -1 1 64 (1 996) speculate that the chemistry they discuss "potentially regenerates" the polymer-bound methoxyamine. However, the article does not disclose how such regeneration would actually be obtained, nor are the reactions and materials they disclose capable of regeneration, since the linker they use is reactive towards LiAIH₄ or Grignard reagents. As reflected in the Dinh et al. article, until the present invention, regeneration or recycleability of synthetic solid supports has only been desired, not achieved.

Also, the substrates of many supports are susceptible to dimensional changes in the presence of various organic solvents or water. Since the dimensional changes for a particular support will usually vary from solvent to solvent, the effectiveness of a particular support for a range of reactions in which the various moieties are deposited from solvents is dependent upon the particular solvents involved. It would be valuable to have a traceless and/or recycleable support which also maintains dimensional integrity over a range of different solvents, particularly including water.

Finally, most supports for library creation cannot be used for other purposes. It would be valuable to have a support which could be used not only to form compounds but also to purify compounds from a mixture.

SUMMARY OF THE INVENTION

The present invention is of novel supports each comprising a substrate, a linker and one or more reactive centers, which permit a variety of advantageous chemical reactions, each of which provides unique results not heretofore possible. These include conducting solid state reactions which produce traceless products or products which cannot be made readily in solution. Some of the supports are regenerable and recyclable, so that they may be reused in an ongoing series of reactions and product synthesis. Various supports also can be used in novel separation columns to capture and recover individual compounds in high purity from solutions of large numbers of compounds. Supports of the present invention can also avoid prior art problems of support instability in the presence of various liquid organic solvents and especially in the presence of water.

Therefore, in a broad embodiment the invention is of a support for conducting solid phase synthesis of chemical compounds which comprises a polymeric substrate having dimensional stability in the present of a solvent; a linker covalently bound to the substrate; and at least one reactive center covalently bound to the linker, the reactive center being specific for bonding to a reagent and which retains the modified reagent during subsequent reactions in which a desired compound is synthesized by seriatim addition of chemical moieties beginning with a moiety attached to the reagent; the reactive center and linker comprising chemical structures such that a compound synthesized thereon can be cleaved from the support leaving the linker and reactive center in their original chemical form; whereby the support may be recycled for repeated use in the synthesis of additional compounds.

In another broad embodiment the invention is of a support for conducting solid phase synthesis of chemical compounds which comprises a polymeric substrate having dimensional stability in the present of a solvent; a linker covalently bound to the substrate; and at least one reactive center covalently bound to the linker, the reactive center being specific for bonding to a reagent and which retains the reagent during subsequent reactions in which a desired compound is synthesized by seriatim addition of chemical moieties beginning with a moiety attached to the reagent; the reactive center comprising covalently bound to the linker through an oxygen atom and having a terminal substituted phenyl group.

Among the useful substrates for such supports are highly cross-linked polystyrene macroporous materials as well as a group of crosslinked copolymers of macroreticular structure formed by copolymerization of a monovinyl carbocyclic compound with a polyvinyl carbocyclic aromatic - 4 -

compound. Other useful substrates, such as kieselguhr and macroporous glass, will be evident from the discussions below.

In yet another broad embodiment the invention is of a support for conducting solid phase separation of chemical compounds from mixtures of chemical compounds which comprises a polymeric substrate having dimensional stability in the present of a solvent; a linker covalently bound to the substrate; and at least one reactive center covalently bound to the linker, the reactive center being specific for bonding to a reagent, extracting the reagent from a first solution containing a plurality of compounds including the reagent when the solution is in contact with the reactive center, and retaining the covalently bound reagent following removal of contact of the solution with the reactive center; the reactive center further capable of having the compound cleaved therefrom by subsequent contact of a second solution comprising a cleaving agent; whereby the compound is purified by separation from the first solution by the reactive center and subsequent cleavage from the reactive center by the cleaving agent while isolated from the first solution. Such supports may be disposed in a flow path for a liquid stream having dispersed therein a plurality of compounds, the reactive center being specific for bonding to molecules of one compound of the plurality of compounds, such that upon flow of the liquid stream through the flow path in contact with the support the reactive center bonds with the molecules of the one compound to the exclusion of molecules of other compounds in the plurality of compounds and removes the molecules of the one compound from the liquid stream. In yet a further broad embodiment the invention is of a purification column comprising a fluid flow conduit for flow therethrough of a fluid stream having dispersed therein a plurality of compounds, the conduit having disposed therein a support comprising a reactive center specific for bonding to molecules of one compound of the plurality of compounds, such that upon flow of the liquid stream through the conduit in contact with the support the reactive center bonds with the molecules of the one compound to the exclusion of other compounds in the plurality of compounds and removes the molecules of the one compound from the liquid stream. There may be a plurality of such purification columns, with each comprising a - 5 -

conduit for flow therethrough of a fluid stream having dispersed therein a plurality of compound, each conduit having disposed therein a support comprising a reactive center specific for bonding to molecules of one compound of the plurality of compounds, such that upon flow of the liquid stream through the conduit in contact with the support the reactive center bonds with the molecules of the one compound to the exclusion of other compounds in the plurality of compounds and removes the molecules of the one compound from the liquid stream, each purification column of the plurality having therein a support different from supports in each other column in the plurality, such that the reactive center on a support in a column is specific for molecules of a different one compound in the plurality of compounds from all other support reactive centers in other columns of the plurality of columns.

Other embodiments and features of the various aspects of this invention will be readily apparent from the detailed descriptions and Figures herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The various Figures 1 -1 6 schematically illustrate various reactions and supports of this invention. Each will be described below in detail in connection with the description of the aspect of the invention to which it pertains.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS The present invention involves unique supports having three principal components: a resin substrate, a linker covalently bound to the substrate, and one or more reactive centers covalently bound to the linker. For the purposes of this invention, the substrate may be considered to be an insoluble or partially insoluble material to which compounds (linkers) may be covalently attached. Substrates are generally inorganic macroporous materials or organic or inorganic polymeric or oligomeric compounds with various degrees of crosslinking. Materials which are generally suitable for substrates include highly crosslinked polystyrenes or polyethylene glycols, controlled pore glasses, kieselguhr (diatomaceous earth), grafted resins or - 6 -

resins of the type described by Rapp, "Macro Beads as Microreactors: New Solid-Phase Synthesis Methodology", ch. 4 in Wilson et al., supra. As will be discussed below, not all of the members of all of these classes will be suitable for every aspect of the present invention. It will be evident from the description where specific properties are required which will determine those materials which are best suited as substrates for the particular purpose.

Substrates useful in the present invention are those which are highly porous but which exhibit good dimensional stability in the present of organic solvents and of water. Many resin substrates shrink or swell extensively in the presence of water and solvents. This causes significant and detrimental closure of the internal pores (channels) preventing access of the reactants to the reactive centers which are disposed within the resin pores. In the past it has been considered that this is an unavoidable aspect of combinatorial chemistry, and the resulting low product yields have been accepted as the nature of the process.

By use as substrates in this invention those materials which form stable macroporous matrices supports are obtained which resist the swelling influences of water and organic solvents and yet provide ample attachment sites for the linker molecules and pore sizes commensurate with the sizes of reactive centers, reactant and product molecules. A number of such materials are known and described in the literature. As noted above, aside from the macroporous glasses, they are generally copolymers which during their formation crosslink extensively, usually in generally rectangular matrices. The substrates must be unreactive during use. One class of copolymers which has been found to be particularly useful consists of copolymers formed by the solution polymerization of a polyvinylidene monomer and a monovinyl aromatic hydrocarbon monomer. The product copolymers are highly stable and do not swell appreciably in either water or solvents. Such resins are described in U.S. Patents Nos. 4,224,41 5; 4,297,220 and 4,382, 1 24. Commercial resin products which are believed to be formed from among the copolymers described in these patents are available from Argonaut Technologies of San Carlos, California, under the trade name "Argo-Pore." These commercial materials are described as - 7 -

crosslinked copolymers of polystyrene and divinylbenzene, functionalized with a chloromethyl functionality.

Other environmental reaction conditions under which the resin substrates must be stable include the conditions of normal chemical "work up" of samples, in this case to extract the formed products from within the macroporous structure of the resin, followed by an aqueous wash of the substrate matrix. In particular the substrate must not be adversely affected by contact with organometalic materials, such as metal alkyls or Grignard reagents. The resins must be stable to these materials since Grignard reagents, for instance, may be used in the reactions related to the present invention to cleave reaction products from supports where they were formed and aqueous solutions may be used to purge the pores following reaction and cleavage of the products.

Linkers are those molecules with at least two reactive sites which permit its covalent bonding to the substrate at one site and to other molecules (e.g., reactive centers) at the other site(s). For the purposes of this invention, linker moieties will be useful as long as they are such that cleavage will normally occur at the bond between the linker and reactive center or between the reactive center and other molecule(s) attached to it rather than at the bond between the linker and the substrate. Typical linkers that may be applied are low carbon number polyalkyl chain moieties.

Cleavage generally will occur through a reaction with a specific reagent or mixture of reagents, e.g., through exposure to an acid or alkaline medium.

Reactive centers are those compounds or moieties which have an affinity for a specific reagent or class of reagents. In the present invention, one or more reactive centers are covalently bound to the linker. Illustrative examples of reactive centers useful in the present invention will be presented below and in the Figures.

The invention is best understood by reference to its three major aspects. The references below to "Wang-like" and "Merrifield-like" functionalities are to structures in the support which are analogous to those described in Wang, J.Am. Chem.Soc , 95, 1 328 (1 973) and in Merrifield, J.Am. Chem.Soc , 85, 21 49 ( 1 963), respectively. - 8 -

The first aspect focuses on those supports which produce traceless products and which are recyclable. "Traceless" supports are those which cleave from the reaction product leaving a C-C or C-H terminal group on the product, rather than leaving a terminal group containing a heteroatom (e.g., N, O or S) . In the preparation methods to be described below, a preferred substrate is an Argo-Pore resin of the type described above; alternatively similar resin supports can be made according to the reactions described in Fehrentz et al., Tetrahedron Letters, 36:43, 7871 -7874 (1 995) . Three examples of supports are shown in Figures 1 , 2 and 3, in which R is a lower alkyl group and the linker L is an alkylene group (specifically methylene in Figure 1 ); the system is acid-stable and organometallic reagent-stable. (Throughout the Figures, the substrate is illustrated graphically as a sphere or circle, or labeled "polymer.") Three representative methods of making this class of supports are described in the following examples.

Synthesis of N-methoxy-N-benzylamine linked traceless recyclable support

Example 1 :

As shown in Figure 4, an Argo-Pore or equivalent resin substrate (0.5 millimoles; with a Merrifield-like functionality) with desirable swelling properties and a synthetically useful loading of chlorobenzyl functionality (0.1 -1 .2 millimoles/gram) is suspended in a shaker flask. Dry dimethyl- formamide (DMF, 1 0 mL/g of resin) is added and the resin is agitated, washed and filtered two more times with additional dry DMF (1 0 mL/g of resin). The resin is resuspended in dry DMF (4 mL/g of resin), following which a mixture of NaH and t-butoxycarbonyl-N-methoxyamine (4 mmole of each, pre-suspended in 2 ml of dry DMF) is added, with agitation, under an atmosphere of dry nitrogen gas. Agitation with heating to 60°C is continued for 48 hours. The resin is then filtered, DMF (1 0 mL/g of resin) is added and the resin is agitated and filtered. The resin is washed and filtered two more times with additional dry DMF (10 mL/g of resin). This gives Product (I).

The t-butoxycarbonyl group is then removed from Product (I) as follows. The material is washed (then filtered) three times with dichloro- methane (DCM, 10 mL/g of resin for each wash) . A mixture of 50% trifluoroacetic acid (TFA) in DCM (5 mL/g of resin) is added and the mixture agitated for 20 minutes. The material is then washed (then filtered) three times with dichloromethane (DCM, 1 0 mL/g of resin for each wash) . This gives the support of Figure 1 , in which L is a methylene group.

Example 2:

As shown in Figure 5, an Argo-Pore or equivalent resin substrate (0.5 millimoles; with a Wang-like functionality, but without a 4-alkoxy group attached to the phenyl ring of the linker) with desirable swelling properties and a synthetically useful loading of benzyl alcohol functionality (0.1 -1 .2 millimoles/gram) is suspended in a shaker flask. Dry THF (1 0 mL/g of resin) is added and the resin is agitated, washed and filtered two more times with additional dry THF (1 0 mL/g of resin). The resin is resuspended in dry THF (4 mL/g of resin), following which t-butoxycarbonyl-N-methoxyamine and diethylazodicarboxylate (4 mmole of each, pre-suspended in 2 ml of dry THF) are added, with agitation, after which solid triphenylphosphine (4 mmole) is added, all under an atmosphere of dry nitrogen gas with good mixing at ^"22°C. Agitation with heating to 60°C is continued for 48 hours. The resin is then filtered , THF (10 mL/g of resin) is added and the resin is agitated and filtered. The resin is washed and filtered two more times with additional dry THF (1 0 mL/g of resin). This gives the Product (I) .

The t-butoxycarbonyl group is removed from this product resin as follows. The product is washed (then filtered) three times with DCM ( 1 0 mL/g of resin for each wash). A mixture of 50% TFA in DCM (5 mL/g of product) is added and the mixture agitated for 20 minutes. The product is washed (then filtered) three times with DCM (1 0 mL/g of product for each wash). This gives the support of Figure 1 .

Example 3: As shown in Figure 6, an Argo-Pore or equivalent resin substrate (0.5 millimoles; with a Merrifield-like functionality) with desirable swelling properties and a synthetically useful loading of chlorobenzyl functionality (0.1 -1 .2 millimoles/gram) is suspended in a shaker flask. Dry DMF (1 0 mL/g of resin) is added and the resin is agitated, washed and filtered two more - 1 0 -

times with additional dry DMF (10 mL/g of resin). The resin is resuspended in dry DMF (4 mL/g of resin) then a mixture of Nal and N-methoxyamine (4 mmole of each, pre-suspended in 2 ml of DMF) is added, with agitation, under an atmosphere of dry nitrogen gas; this is shaken for 2 hours. Agitation with heating to 60°C is continued for 48 hours. The resin is then filtered, DMF ( 1 0 mL/g of resin) is added and the resin is agitated and filtered. The resin is washed and filtered two more times with additional dry THF (1 0 mL/g of resin). This gives the support of Figure 1 .

The support of Figure 2 can be made by analogous methods, in which the methyl group is replaced by a different lower alkyl (R) group. Analogous methods will also produce the support of Figure 3. In such case the N- methoxyamine compound would be replaced by an N-alkoxyamine such as N-propyloxyamine or the like.

An example of the recycleability of the supports of Figures 1 , 2 and 3 is illustrated in Figure 7. In the example, a support as in Figure 1 is reacted to form Product (II). Various additional addition and replacement reactions can continue, as exemplified by production of Product (III), which is the precursor to the traceless ketone Product (IV), which is cleaved from the support by reaction with an organometalic reagent followed by mild hydrolysis with aqueous acid. This regenerates the support of Figure 1 , which can be recycled for repeated reactions.

Synthesis of 4-iodobenzoyl-N-methoxy-N-benzylamine linked loaded traceless recyclable support

Example 4:

As shown in Figure 8, an Argo-Pore or equivalent resin substrate (0.5 millimoles; with a Merrifield-like functionality) with desirable swelling properties and a synthetically useful loading of chlorobenzyl functionality (0.1 -1 .2 millimoles/gram) is suspended in a shaker flask. Dry DMF ( 1 0 mL/g of resin) is added and the resin is agitated, washed and filtered two more times with additional dry DMF ( 10 mL/g of resin) . The resin is resuspended in dry DMF (4 mL/g of resin), following which a mixture of NaH and 4-iodobenzoyl-N-methoxy-amine (4 mmole of each, pre-suspended in 2 ml of - 1 1 -

dry DMF) is added, with agitation, under an atmosphere of dry nitrogen gas. Agitation with heating to 60°C is continued for 48 hours. The resin is then filtered and DMF (1 0 mL/g of resin) is added and the resin is agitated and filtered. The resin is washed and filtered two more times with additional dry DMF (10 mL/g of resin). This gives the support of Figure 9, in which R is I.

Example 5:

As shown in Figure 10, an Argo-Pore or equivalent resin support (0.5 millimoles, with a Wang-like functionality, and with desirable swelling properties and a synthetically useful loading of benzyl alcohol functionality (0.1 -1 .2 millimoles/gram) is suspended in a shaker flask. Dry THF (10 mL/g of resin) is added and the resin is agitated, washed and filtered two more times with additional dry THF ( 1 0 mL/g of resin) . The resin is resuspended in dry THF (4 mL/g of resin), following which 4-iodobenzoyl-N-methoxyamine and diethylazodicarboxylate (DEAD) (4 mmole of each, pre-suspended in 2 ml of dry THF) are added, with agitation. Finally solid triphenylphosphine (4 mmole) is added, all under an atmosphere of dry nitrogen gas with good mixing at 22°C. Agitation with heating to 60°C is continued for 48 hours. The resin is then filtered , THF (10 mL/g of resin) is added and the resin is agitated and filtered. The resin is washed and filtered two more times with additional dry THF (10 mL/g of resin). This gives the support of Figure 9, in which R is H.

The second aspect of the invention involves the production of the unique supports of Figure 1 1 , which produce traceless products but which are not recyclable. In the supports of Figure 1 1 , Y may be Cl, Br, I, CN, OH, RCO, RCOO, C(O)RCN, C(O)RC(O)OR', NHNH₂, CH₂X or NH₂ moieties and Z, if present, may be Y, X, R or R', where R and R' are alkyl, aryl or heteroaryl groups.

As with the previous aspect, there are alternative methods to produce the supports of Figure 1 1 , as indicated by the following examples.

Synthesis of bromobenzyl ether linked traceless support - 1 2 -

Example 6:

As shown in Figure 1 2, an Argo-Pore or equivalent resin supports (0.5 millimoles; with a Merrifield-like functionality) with desirable swelling properties and a synthetically useful loading of chlorobenzyl functionality (0.1 -1 .2 millimoles/gram) is suspended in a shaker flask. Dry DMF (1 0 mL/g of resin) is added and the resin is agitated, washed and filtered two more times with additional dry DMF (1 0 mL/g of resin). The resin is resuspended in dry DMF (4 mL/g of resin) then a mixture of NaH and 2-, 3- or 4-bromobenzyl alcohol (4 mmole of each, pre-suspended in 2 ml of dry DMF) is added, with agitation, under an atmosphere of dry nitrogen gas. Agitation with heating to 40°C is continued for 48 hours. The resin is then filtered, DMF (1 0 mL/g of resin) is added and the resin is agitated and filtered. The resin is washed and filtered two more times with additional dry DMF ( 1 0 mL/g of resin). This gives the support of Figure 1 1 . Compounds formed on the support of Figure 1 1 by addition to the reactive center can be cleaved with TFA or in a hydrogen atmosphere and a palladium metal catalyst or a palladium tetra(triphenyl)phosphine catalyst.

Example 7: As shown in Figure 1 3, an Argo-Pore or equivalent resin substrate (0.5 millimoles, with a Wang-like functionality) with desirable swelling properties and a synthetically useful loading of benzyl alcohol functionality (0.1 -1 .2 millimoles/gram) is suspended in a shaker flask. Dry THF ( 1 0 mL/g of resin) is added and the resin is agitated, washed and filtered two more times with additional dry THF (1 0 mL/g of resin). The resin is resuspended in dry THF (4 mL/g of resin), then 2-, 3- or 4-bromobenzyl chloride and NaH (4 mmole of each, pre-suspended in 2 ml of dry THF) are added, with agitation under an atmosphere of dry nitrogen gas with good mixing at 22°C. Agitation with heating to 40°C is continued for 48 hours. The resin is then filtered, THF ( 1 0 mL/g of resin) is added and the resin is agitated and filtered. The resin is washed and filtered two more times with additional dry THF (1 0 mL/g of resin) . This gives the support of Figure 1 1 .

The third aspect of the invention is the production and use of capture supports. Because of the ability of some supports of this invention to isolate - 1 3 -

and purify specific reaction products from mixed solutions, it is feasible to use such supports in unique separation columns. For instance, it is known to make ketones by conversion of secondary alcohols or acid chlorides in solution. Where there is a mixture of alcohols or acid chlorides as reactants, however, the solution after reaction contains a number of different ketone (and perhaps other) reaction products, only one of which may be a desired ketone. Separation using conventional prior art techniques is usually difficult, time consuming and incomplete. However, by using the supports of this aspect of the present invention, with a reactive center chosen for specificity in binding with the desired ketone, one can construct a column packed with the support. The reaction solution is then run through the packed column, with the desired ketone being selectively adsorbed and retained by the support. The effluent solution is drained from the column and collected or discarded, as desired. The column is then flushed with water to cleave the ketone from the linker and allow collection of the specific desired ketone, purified by complete separation from the mixed solution.

This technique can advantageously also be used to separate a plurality of compounds in purified form from a mixed solution, simply by having the same plurality of columns in series, each packed with a regenerable support specific for the compound of interest. For instance, the effluent solution from the single column discussed immediately above could be directed to a second column packed with a support specific for a second ketone in the reaction mixture, where a similar separation would take place. The effluent of the second column could then be directed to a third column packed with a support specific for a third ketone, and so forth.

By using supports of the formulas of Figures 14 and 1 5, one can capture and separate ketones and aldehydes, which are released from the individual separation columns by flushing of the columns with aqueous acid. Similarly, by use of the supports of Figure 1 6, where X is F or alkoxy, one can capture and separate alcohols and amines. Alcohols can be released from the column by use of an alkaline solution and the amines can be released by use of an aqueous acid solution. The resin my be regenerated by carbonyl diimidazole. - 1 4 -

One may also convert some extracted products (e.g., ketones) into different product (e.g., different ketones) by reaction with an organometalic compound, where the organic moiety of the organometalic compound replaces an organic moiety of the extracted compound.

It will be recognized that there are numerous additional embodiments of this invention which, while not expressly described above, are clearly within the scope and spirit of the invention. The above description will therefore be understood to be exemplary only, and the actual scope of the invention is to be determined solely from the appended claims.

WHAT IS CLAIMED IS:

Claims

- 1 5 -CLAIMS

1 . A support for conducting solid phase synthesis of chemical compounds which comprises: a polymeric substrate having dimensional stability in the present of a solvent; a linker covalently bound to said substrate; and at least one reactive center covalently bound to said linker, said reactive center being specific for bonding to a reagent and which retains said reagent during subsequent reactions in which a desired compound is synthesized by seriatim addition of chemical moieties beginning with a moiety attached to said reagent; said reactive center and linker comprising chemical structures such that a compound synthesized thereon can be cleaved from said support leaving said linker and reactive center in their original chemical structures; whereby said support may be recycled for repeated use in the synthesis of additional compounds.

2. A support as in Claim 1 wherein said substrate comprises a solid polymeric matrix having disposed therethrough a plurality of channels, said linker and reactive center being disposed in at least one of said plurality of channels.

3. A support as in Claim 2 wherein said support is selected from the group consisting of the species of Figure 1 , 2, 3 or 9.

4. A support as in Claim 2 wherein said substrate comprises a macroporous glass or a highly crosslinked organic polymer or oligopolymer.

5. A support as in Claim 4 wherein said substrate comprises a highly crosslinked polystyrene. - 1 6 -

6. A support as in Claim 4 wherein said substrate comprises a highly crosslinked copolymer of macroreticular structure formed by copolymer- ization of a monovinyl carbocyclic compound with a polyvinyl carbocyclic aromatic compound.

7. A support as in Claim 1 comprising a plurality of reactive centers, each specific for bonding with a different reagent.

8. A support as in Claim 1 wherein cleavage of said compound from said support produces a terminal C-C or C-H group on said compound, such that said compound does not retain identification of the support on which it was formed.

9. A support as in Claim 1 wherein cleaving of said compound occurs by chemical reaction of the bond to be cleaved with a cleaving reagent.

1 0. A support as in Claim 9 wherein said cleaving reagent comprises an aqueous acid or alkaline compound.

1 1 . A support as in Claim 1 wherein said solvent comprises an organic solvent, water or mixtures thereof.

1 2. A support for conducting solid phase synthesis of chemical compounds which comprises: a polymeric substrate having dimensional stability in the present of a solvent; a linker covalently bound to said substrate; and at least one reactive center covalently bound to said linker, said reactive center being specific for bonding to a reagent and which retains said reagent during subsequent reactions in which a desired compound is synthesized by seriatim addition of chemical moieties beginning with a moiety attached to said reagent; said reactive center comprising covalently bound to said linker through an oxygen atom and having a terminal substituted phenyl group. - 1 7 -

1 3. A support as in Claim 1 3 wherein said phenyl group is substituted with a first substituent comprising Cl, Br, I, CN, OH, RCO, RCOO, C(O)RCN, C(O)RC(O)OR', NHNH₂, CH₂X or NH₂ moieties.

1 4. A support as in Claim 1 3 wherein said phenyl group is further substituted with a second substituent comprising Y, X, R or R', where R and R' are alkyl, aryl or heteroaryl groups.

1 5. A support as in Claim 1 2 wherein said substrate comprises a macroporous glass or a highly crosslinked organic polymer or oligopolymer.

1 6. A support as in Claim 1 5 wherein said substrate comprises a highly crosslinked polystyrene.

1 7. A support as in Claim 1 5 wherein said substrate comprises a highly crosslinked copolymer of macroreticular structure formed by copolymer- ization of a monovinyl carbocyclic compound with a polyvinyl carbocyclic aromatic compound.

1 8. A support as in Claim 1 2 comprising a compound as in Figure 1 1 .

1 9. A support as in Claim 1 2 wherein said solvent comprises an organic solvent, water or mixtures thereof.

20. A support for conducting solid phase separation of chemical compounds from mixtures of chemical compounds which comprises: a polymeric substrate having dimensional stability in the present of a solvent; a linker covalently bound to said substrate; and at least one reactive center covalently bound to said linker, said reactive center being specific for bonding to a reagent, extracting said reagent from a first solution containing a plurality of compounds including said reagent when said solution is in contact with said reactive center, and - 1 8 -

retaining said covalently bound reagent following removal of contact of said solution with said reactive center; said reactive center further capable of having said compound cleaved therefrom by subsequent contact of a second solution comprising a cleaving agent; whereby said compound is purified by separation from said first solution by said reactive center and subsequent cleavage from said reactive center by said cleaving agent while isolated from said first solution.

21 . A support as in Claim 20 comprising a compound as in one of Figures 14-1 6 inclusive.

22. A support as in Claim 21 comprising a compound as in one of Figures 1 4-1 5 and being specific for bonding with an aldehyde or ketone reagent.

23. A support as in Claim 21 comprising a compound as in Figure 1 6 being specific for bonding with an alcohol or amine reagent.

24. A support as in Claim 20 wherein said substrate comprises a macroporous glass or a highly crosslinked organic polymer or oligopolymer.

25. A support as in Claim 24 wherein said substrate comprises a highly crosslinked polystyrene.

26. A support as in Claim 24 wherein said substrate comprises a highly crosslinked copolymer of macroreticular structure formed by copolymer- ization of a monovinyl carbocyclic compound with a polyvinyl carbocyclic aromatic compound.

27. A support as in Claim 20 disposed in a flow path for a liquid stream having dispersed therein a plurality of compounds, said reactive center being specific for bonding to molecules of one compound of said plurality of compounds, such that upon flow of said liquid stream through said flow path in contact with said support said reactive center bonds with said molecules - 1 9 -

of said one compound to the exclusion of molecules of other compounds in said plurality of compounds and removes said molecules of said one compound from said liquid stream.

28. A purification column comprising a fluid flow conduit for flow therethrough of a fluid stream having dispersed therein a plurality of compound, said conduit having disposed therein a support comprising a reactive center specific for bonding to molecules of one compound of said plurality of compounds, such that upon flow of said liquid stream through said conduit in contact with said support said reactive center bonds with said molecules of said one compound to the exclusion of other compounds in said plurality of compounds and removes said molecules of said one compound from said liquid stream.

29. A plurality of purification columns as in Claim 28, each comprising a conduit for flow therethrough of a fluid stream having dispersed therein a plurality of compound, each said conduit having disposed therein a support comprising a reactive center specific for bonding to molecules of one compound of said plurality of compounds, such that upon flow of said liquid stream through said conduit in contact with said support said reactive center bonds with said molecules of said one compound to the exclusion of other compounds in said plurality of compounds and removes said molecules of said one compound from said liquid stream, each purification column of said plurality having therein a support different from supports in each other column in said plurality, such that the reactive center on a support in a column is specific for molecules of a different one compound in said plurality of compounds from all other support reactive centers in other columns of said plurality of columns.

30. A plurality of purification columns as in Claim 28 wherein said flow stream passed through all of said column seriatim, whereby a different said one compound is removed from said flow stream in each of said columns. - 20 -

31 . A purification column as in Claim 28 where said support is regenerable through cleavage of said one compound from said support by a cleaving agent.

32. A plurality of purification columns as in Claim 29 where each said support in each said column is regenerable through cleavage of said one compound from said support by a cleaving agent.