JP2003514876A - New functionalized polymer reagent - Google Patents

Abstract

  (57) [Summary] The present invention relates to functionalized polymer reagents useful for liquid and solid phase synthesis. More specifically, it relates to functionalized polymeric reagents that include an acid labile isonitrile moiety. In a further aspect, the present invention also relates to the use of such functionalized polymer reagents in liquid and solid phase synthesis, a process for the preparation of organic compounds by liquid and solid phase synthesis using such functionalized reagents, The present invention relates to a method for producing a polymer reagent and a kit containing the functionalized polymer reagent of the present invention. The invention also relates to the use of the novel intermediate in the preparation of a novel functionalized polymer reagent. In one embodiment, the invention provides functionalized polymer reagents for use in liquid and solid phase synthesis, eg, multi-component reactions. The functionalized polymer reagent includes a linker, which includes an acid labile isonitrile moiety. The linker is covalently attached to the polymer support.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to polymeric supports useful for liquid phase and solid phase synthesis. More specifically, it relates to functionalized polymeric reagents that include acid labile isonitrile moieties. In a further aspect, the invention also relates to the use of such functionalized polymeric reagents in liquid phase and solid phase synthesis, a process for the preparation of organic compounds by liquid phase or solid phase synthesis using such functionalized reagents, such as And a kit containing the functionalized polymeric reagent of the present invention. The invention also relates to the use of the novel intermediates in the production of novel functionalized polymeric reagents.

BACKGROUND OF THE INVENTION Much attention has been directed in recent years to the use of solid phase synthesis for the synthesis of organic compounds. The reason for this is that solid phase synthesis has several advantages over traditional solution phase synthesis. Examples of such advantages include the ease with which the product can be separated and purified from excess reagents by simple washing steps and the rapid isolation of the product when cleaved and washed from the polymeric support.

Concomitant development of combinatorial chemistry and improved automated synthesis have spurred functionalized polymeric reagents. Combinatorial chemistry in combination with high-throughput screening is fundamentally changing the rate at which the pharmaceutical industry can manufacture and screen compounds.

A prerequisite for solid phase synthesis is a functionalized and stable polymer support. Many commercially available polymer supports have been developed for solid phase peptide synthesis and are therefore necessarily not suitable for solid phase synthesis of compounds of non-peptide structure.

There are several drawbacks due to the nature of heterogeneous reaction conditions, one being non-linear kinetic behavior. Replacing insoluble polymers such as cross-linked polystyrene with soluble polymers such as PEG restores the general reaction conditions of traditional organic chemistry, and further, product formation is still facilitated through the application of polymeric properties. To be done. This method
While preserving its positive aspects, the difficulties of solid phase synthesis are essentially avoided.

A key step in the synthesis of libraries of non-peptide structures, or other physiologically active compounds in general, is the optimization of chemistry and the discovery of shortest synthetic routes to accelerate production steps. One alternative is the use of multi-component reactions involving at least three reactants, which feed the product directly in a very efficient process. Several multicomponent reactions (MCR) have been described in the literature, one of the most widely used is the Ugi MCR. The multi-component reaction can be carried out either in liquid phase or solid phase. Liquid phase separation methods have proven effective in the synthesis of many biological compounds, the main drawback of which is the need for a production step to remove excess starting material.
This slows down the overall manufacturing process and / or limits its suitability for automated or semi-automated synthesis.

One commercially available functionalized polymeric reagent containing an isonitrile moiety is
It is shown in FIG. 1 below. The isonitrile moiety cannot be cleaved from the polymer support by acid treatment.

[Chemical 5]

This drawback is solved by the present invention, thereby incorporating a novel use of functionalized polymeric reagents containing isonitrile moieties. Isonitrile is always a source of poor diversity in combinatorial chemistry. This is because of the low number of commercially available isonitriles and the costs associated with the time consuming labor of custom production of large quantities of diverse nitriles. The present invention solves these problems through the use of a resin immobilization strategy in which the reactive isonitrile moiety is attached to the polymer support such that it is acid cleavable. The compounds synthesized by this resin immobilization strategy and liberated by acid cleavage are pure and require no further purification steps.

SUMMARY OF THE INVENTION The present invention provides functionalized polymeric reagents containing linker moieties for use in solution phase and solid phase synthesis. The linker is compatible with many reagents and reaction conditions used in the synthesis of organic compounds. Functionalized polymeric reagents are also useful in combinatorial chemistry.

Accordingly, one aspect of the present invention is a functionalized polymeric reagent for use in solution and solid phase synthesis. The functionalized polymeric reagent comprises a linker, which comprises an acid labile isonitrile moiety. The linker is covalently attached to the polymer support.

In another aspect, the invention provides a method of making an organic compound by liquid or solid phase synthesis. The method comprises immobilizing a substrate compound on the polymer support via the isonitrile moiety. The substrate compound thus bound is then subjected to at least one further organic reaction step to produce the desired compound, which is then dissociated from the polymer support and isolated. In a preferred embodiment, the method is performed with a diverse population of substrates and / or many organic reactions to provide a library of organic compounds.

In another aspect, the invention provides a method of making an organic compound by liquid or solid phase synthesis. The method involves the step of a multi-component reaction performed on the acid labile nitrile portion of the functionalized polymeric reagent. In a preferred embodiment, the multi-component reaction is a Ugi or Ugi type reaction.

In another aspect, the invention provides a method of making a functionalized polymeric reagent. The method involves reacting a suitable polymeric support containing amino groups with a "formylation" reagent. The formamide group so produced is then converted to the isonitrile moiety. In a preferred embodiment, the amino group is treated with 2,4,5-trichlorophenyl formate in DMA and the resulting formamide group is treated with triphenylphosphine / carbon tetrachloride and triethylamine in dichloromethane.

In another aspect, the invention provides novel intermediates for use in making novel functionalized polymeric reagents.

Accordingly, it is an object of the present invention to provide functionalized polymeric reagents for use in liquid or solid phase synthesis. It is another object of the present invention to provide a method for producing an organic compound by liquid phase or solid phase synthesis. It is another object of the present invention to provide a method for producing a library of organic compounds. It is another object of the present invention to provide a method of making a functionalized polymeric reagent. It is another object of the present invention to provide new intermediates for use in the production of functionalized polymeric reagents.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a functionalized polymeric reagent suitable for liquid phase and solid phase synthesis, the preparation of the functionalized polymeric reagent, and liquid phase and solid phase synthesis of organic compounds, including libraries. It relates to the use of functionalized polymeric reagents.

In another aspect, the invention provides functionalized polymeric reagents for use in solution and solid phase synthesis. The functionalized polymeric reagent comprises a polymeric support and an acid labile isonitrile moiety, where the polymeric support comprises a polymer and a linker. The linker is covalently attached to the polymer and the isonitrile moiety is covalently attached to the linker.

[0018]   The preferred functionalized polymeric reagents of the present invention are of Formula I

[Chemical 6] [In the formula, X is oxygen, a PEG chain or a-(CH ₂ ) _n- CONH- group, R ¹ is carbon, hydrogen, phenyl, or a substituted phenyl group, R ² is hydrogen, phenyl, or a substituted phenyl group, R ³ Is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or phenoxy,
R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or phenoxy,
And n is an integer of 1 to 4].

[0019]   More preferred functionalized polymeric reagents of the present invention are

[Chemical 7] [Wherein, R is directly or PEG- chain or - (CH ₂₎ via the _n -CONH- group is a polymer attached to the linker] it is.

The following definitions should apply throughout the specification and claims: The term “functionalized polymeric reagent” is covalently attached to a linker moiety, which linker is covalently attached to the polymer. Means a reagent bound to. The term "polymer support" means a polymer that is covalently attached to a linker moiety that can optionally be attached to a substrate compound. The term "linker" means a reactive functional group that can be used to link a molecule onto a polymeric support. The term "acid-labile isonitrile" means an isonitrile moiety that is cleaved from a linker with a half-life of 30 minutes or less when treated with aqueous trifluoroacetic acid (95%) at room temperature. The term "substrate compound" means a compound that is modified in subsequent reaction steps.

The term “immobilization” refers to the action of linking, for example, a substrate compound, to a polymeric support by means of chemical or biological processes. The term "multi-component reaction" refers to a one-pot reaction that forms products from at least three different starting materials and incorporates substantial amounts of these reagents into the product. This involves reactions involving at least three different functional groups, some of which may be part of the same reagent molecule. The term “diversified population” means, for example, a population that comprises at least two different chemical entities of different chemical structures. For example, a "diversified population" of nucleophiles contains at least two different nucleophiles. "Substituted phenyl" The term at least one of the following _ones: C 1 -C _{6 alkyl,} C 1 -C ₆ alkoxy, means a phenyl group substituted by halogen or phenoxy group. The term "formylating reagent" means a reagent capable of converting an amino group to a formamide group.

Polymer Support The choice of soluble or insoluble polymer for the polymer support is not critical. Suitable soluble and insoluble polymers therefore include those known to those skilled in the art of solution or solid phase synthesis. Examples of suitable insoluble polymers include inorganic substrates such as kies
Elguhr, silica gel and controlled pore glass and polymeric organic substrates, such as polystyrene, polypropylene, polyethylene glycol, and hybrid inorganic / polymeric substrates such as polyacrylamide supported within a matrix of kieselguhr particles. , But not limited to these. Preferred insoluble polymers are 1% DVB polystyrene and polystyrene-PEG.

Examples of suitable soluble polymers are polystyrene (uncrosslinked, polyvinyl alcohol, polyethyleneimine, polyacrylic acid, polymethylene oxide, PEG, polypropylene oxide, cellulose, polyacrylamide, 3,5-PEG and 3,5- Diisocyanate benzyl chloride, PEG and 3-nitro-3-azapentane 1,5-diisocyanate, polyvinyl alcohol-poly (1-vinyl-
2-pyrrolidinone, polystyrene-poly (vinyl-substituted monosaccharide), poly (
N-isopolyacrylamide) -poly (acrylic acid derivatives), but is not limited thereto.

By replacing the insoluble polymer with a soluble polymer, the general reaction conditions of traditional organic chemistry are restored and, furthermore, product formation is still facilitated through the application of polymeric properties. This method essentially avoids the difficulties of solid phase synthesis while preserving its positive aspects.

Linker The choice of linker is not limited to MAMP resin (amino- (4-methoxyphenyl) methylpolystyrene) (A), and thus also the Rink amide (B) shown in FIG. 2 below.
, Wang amino (C), Sasrin amino (D), Sieber amide (E) and 2-chlorotrityl linker (F).

[Chemical 8]

In FIG. 2, R is direct or PEG-chain or-(CH ₂ ) _n- CONH-
A polymer linked to a linker via a group.

Preparation of Functionalized Polymeric Reagents A simple synthesis of functionalized polymeric reagents is shown schematically in FIG. 3 and detailed in Example 1.

[Chemical 9]

In this example, the functionalized resin in a polar solvent (eg, DMF) was applied to a polymer support (eg, amino MAMP linker 100-200 mesh or 200-4).
00 mesh, commercially available from Novabiochem), suitable "formylated"
It is prepared by mixing reagents, such as 2,4,5-trichlorophenyl formate, as shown in FIG. The reaction can be carried out at room temperature or, in some embodiments, at elevated temperature to ensure completion of the reaction and / or to shorten reaction time. The time required for the reaction is about 3 hours to 24 hours or longer; a typical reaction time is 12 hours, room temperature.

The formamide intermediate formed is then treated with carbon tetrachloride (CCl ₄ ) / triphenylphosphine (PPh ₃ ) and a non-polar solvent such as dichloromethane (DCM) at room temperature for about 3 hours in a base such as triethylamine. Reacting in the presence of (Et ₃ N),
The corresponding isonitrile is obtained. This method has the advantages of requiring only a minimal number of synthetic steps, using readily available reagents, and providing functionalized polymeric reagents in good yield with simple purification steps. .

Completion of the reaction with the functionalized polymeric reagent or polymeric support is assessed by standard methods such as microanalysis, spectral analysis or colorimetric tests. For example, the formation of the isonitrile moiety may be performed by Fourier transform infrared spectroscopy (FT-IR), for example, 21
This can be followed by monitoring the isonitrile extension at 38 cm- ¹ . When the reaction reaches a preselected end point, the resin is purified, preferably by washing. In order to ensure removal of excess reagents, preferably several cycles of washing with solvents of different polarities can be carried out.

Once the functionalized polymeric reagent or polymeric support has been prepared and washed, it is stable at room temperature for extended periods of time. The functionalized polymeric reagent can be stored for long periods of time without loss of activity.

Cleavage of Compounds from Polymer Supports From the foregoing, it will be appreciated that the present invention provides functionalized polymeric reagents containing acid labile isonitrile moieties for use in solution and solid phase synthesis. Compounds were removed from the polymer support by various acids including but not limited to: TFA in DCM (20%), 4M HCl in dioxane, acetic acid in DCM (80%). Can be cleaved. One of ordinary skill in the art can easily optimize the conditions that give the best possible result in the cleavage step. Generally, the resin-bound compound is
Pre-swell in M for 10 min, filter the resin, DCM: TFA: water (80:18
: 2) or a solution of 4M HCl in dioxane is added and the reaction mixture is allowed to reach 1
Stir for hours. The solution is filtered and the crude final compound is evaporated.

Synthesis of Organic Compounds on Polymer Supports The present invention provides methods for synthesizing organic compounds by liquid or solid phase synthesis. In one embodiment, the method comprises the steps of immobilizing a substrate compound on a polymeric support and, at a later stage, acid cleaving the product from the polymeric support. As detailed below, in certain embodiments, the substrate compounds are provided as a diverse population of substrate compounds so that a library of organic compounds can be produced.

Those skilled in the art will recognize that the immobilized support can be chemically compatible with the polymer support attached. Thus, in certain embodiments, methods of synthesizing organic compounds by liquid or solid phase synthesis may include a number of additional reaction steps after the immobilization step but prior to the cleavage step. Such synthetic procedures include standard reactions in liquid and solid phase synthesis. The reaction conditions for such manipulations are generally chosen to avoid cleavage of the substrate compound from the support, except where such simultaneous cleavage is desired.

Combinatorial Chemistry on Polymer Supports The functionalized polymeric reagents of the present invention are suitable for use in combinatorial chemistry. Thus, in another aspect, the invention provides methods for liquid-phase or solid-phase supported chemical synthesis of libraries. In one embodiment, the method comprises the step of reacting a support compound immobilized on a polymeric support of the present invention with a reagent molecule under conditions which produce a library of compounds. In this embodiment, at least one substrate compound or reagent molecule is provided in its diverse population. It will be appreciated that the method involves the step of cleaving the library of compounds from the polymer support. Such cleavage steps may be accompanied by reaction steps or, in some embodiments, may be separate cleavage steps.

Combinatorial libraries can be screened to determine if any member of the library has the desired activity and, if so, to identify active compounds. Screening the soluble compound library by affinity chromatography at the appropriate receptor for the isolated ligand for the receptor, followed by identification of the isolated ligand by conventional methods (eg, mass spectroscopy, NMR, etc.) You can Immobilized compounds can be screened by contacting the compound with a soluble receptor; preferably, the soluble receptor is a detectable label to indicate ligand binding (eg, fluorophore, calorimetric enzyme, radioisotope, luminescent compound, etc.). ) Combined with Alternatively, the immobilized compound is selectively released and allowed to diffuse through the membrane to interact with the receptor.

Combinatorial libraries of compounds can also be synthesized with "tags" to encode the identity of each member of the library. In general, the method features the use of an inert but readily detectable tag attached to a solid support or compound. When detecting an active compound (eg, by one of the methods described above), compound identity is determined by the identification of a unique associated tag. This tagging method allows the synthesis of large libraries of compounds that can be identified at very low levels.

A diverse population of substrate compounds can provide diversity in combinatorial synthesis. Several methodologies have been developed to perform combinatorial chemistry. Examples of such methodologies are mix and split technology.
ogy) and IRORI MiniKans.

Multicomponent Reactions on Polymer Supports The polymer supports of the present invention are suitable for use in, but not limited to, multicomponent reactions. Multicomponent reactions are generally increasing and are widely reviewed, for example Lutz Weber, Synlett 1999, no 3, 366-374; Kevin Short, Tetrahedron vol.
53, no 19, 6653-6679, 1997; Sang Kim, Tetrahedron Letters, 39 (1998) 69
93-6996; Blacburn. Tetrahedron Letters (1998) 39, 5469-5472, Bienayme, A
ngew. Chem. Int. Ed. (1998) 37, no. 16; Blackburn 39, (1998) 3635-3638 T
See etrahedron Letters.

In a multi-component reaction, three or more component molecules can react with each other at the same time or at about the same time to provide a molecule containing a substantial amount of these reagent molecules without isolation of intermediates. This involves reactions involving at least three different functional groups, some of which may be part of the same reagent molecule. In general, a multicomponent reaction is a series of biomolecular reaction steps that proceed according to the zipper principle, that is, each reaction step is essential for the next step. Examples of multi-component reactions are α-aminoalkylation (Mannich), Passe
Including but not limited to riini, Ugi and Ugi types. Ugi and Ugi type reactions are preferred multi-component reactions for use with the polymeric supports of the present invention.
Ugi and Ugi-type reactions provide access to compounds and functionalities that are of great interest to pharmaceutical scientists, eg, heterocyclic compounds.

Accordingly, in another aspect, the invention provides a method for multi-component synthesis of organic compounds. In one embodiment, the method comprises reacting an isonitrile moiety under conditions such that a multi-component reaction is achieved simultaneously with at least two reagent moieties.

[0042]   A preferred embodiment of the present invention is schematically shown in FIG. 4 below.

[Chemical 10]

The preferred embodiment shown in FIG. 4 is advantageous because it allows multi-component reactions to be carried out directly on the acid labile isonitrile moiety of the functionalized polymeric reagent.

The example outlined above consists of a multi-component Ugi-type condensation in which the isonitrile portion of the functionalized polymeric reagent reacts with two different sources of diversity, aldehydes and heteroaromatic amidines. This Ugi-type reaction leads to 3-aminoimidazole efficiently and in a one-step process using a resin immobilization strategy. The final compound is of high purity after acid cleavage.

3-Aminoimidazole can be synthesized according to the present invention. A wide range of aldehydes and heteroaromatic amidines were used to test the functionalized polymeric reagents, demonstrating the efficiency of resin capture by obtaining high yields and excellent purity of the final product. A Ugi-type reaction of condensed 3-aminoimidazole and a synthetic method by a resin supplementing strategy are shown in Example 3 below.

The fused 3-aminoimidazole contains a nitrogen atom that participates in an amine bond with the polymer support, which is further capable of reacting with a variety of electrophiles, such as acyl halides, alkyl halides, or sulfonyl halides, , Can be cleaved from the polymer support. This competitive reaction step (MCR + acylation / alkylation) increases the versatility that can be introduced onto the 3-fused aminoimidazole core. The additional versatility so introduced is that the access to these compounds by traditional liquid phases without polymer support is either due to the corresponding isonitrile being commercially available or time-consuming to synthesize. It is a further advantage of the present invention as it is cumbersome. Due to the small number of commercially available isonitriles (<20) available for combinatorial chemistry, and due to the cost and time consumption of custom production, isonitrile is always
It is the poorest source of diversity involved in the Ugi reaction.

One of the advantages of the present invention is the solution of this type of problem. The amino functionality of aminoimidazole can be used for further reactions such as acylation or alkylation reactions. For example, acyl chlorides, sulfonyl chlorides or alkyl halides can be used as a source of diversity, promoting the diversity of aminoimidazoles.
The competitive reaction concept by combining multi-component reactions with additional alkylation or acylation steps makes the whole process very efficient with respect to the final diversity of the aminoimidazole synthesized. The present invention also has a positive impact on the size and speed with which libraries can be produced. The tethered 3CC + 1 strategy promotes the diversity of fused 3-aminoimidazoles through the use of three imperfect sources of diversity: acyl chlorides, alkyl halides and sulfonyl chlorides. A typical method for the synthesis of these compounds is described in Example 3 below.

The polymeric supports of the present invention can also be used as dehydrating agents or scavengers in general organic chemistry operations such as cycloaddition reactions to remove, for example, alkyl halides, phosphines, acid chlorides, aldehydes and ketones.

Kits The present invention also provides kits for use in solution and solid phase synthesis. The kit comprises functionalized polymeric reagents of the invention, ie for use in liquid phase and solid phase chemistry, preferably in a container or package.

Intermediates It is an object of the present invention to provide new intermediates for use in the preparation of novel functionalized polymeric reagents.

[0051]   Useful intermediates of the present invention have the formula II

[Chemical 11] Wherein, X is carbon, oxygen, PEG-chain or - (CH _{2) n} -CONH- group, ^{R 1} is hydrogen, phenyl or substituted phenyl group,, ^{R 2} is hydrogen, phenyl or substituted phenyl group,, R ³ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or phenoxy,
R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or phenoxy,
And n is an integer of 1 to 4].

[0052]   Preferred intermediates of the present invention are the following compounds;

[Chemical 12] [Wherein, R is directly or PEG- chain or - a polymer attached to the linker via a (CH _{2) n} -CONH- group].

Examples Example 1 Preparation of functionalized polymeric reagent The starting MAMP amino resin (1 gr; 1.64 mmol / g) was pre-swelled in DMF for 10 minutes. 2,4,5-trichlorophenyl formate (560 mg
2.46 mmol, 1.5 eq) in 10 mL of DMF solution was added. The reaction mixture was stirred at room temperature for 12 hours. The resin was filtered, DMF (2 x 10 mL), DCM (2 x 10 mL)
, MeOH (2 x 10 mL) and finally dried under vacuum for 1 h. The resin tested negative for chloranil, indicating the completion of the reaction. The resin (1.64 mmol) was then washed with dry dichloromethane (2 x 10 mL), pre-swelled with dry dichloromethane for 10 minutes and filtered. Triphenylphosphine (2.16 g, 8.2 mmol,
5 eq), carbon tetrachloride (1.27 g, 8.2 mmol, 5 eq) and triethylamine (
A solution of 830 mg, 8.2 mmol, 5 eq) in 10 mL of a dry dichlororomethane solution was added, followed by a little activated molecular sieves (4 Å). The reaction mixture was shaken at room temperature for 3 hours. The resin was filtered, dichloromethane (2 x 10 mL), methanol (2 x 1 mL).
(0 mL), and dichloromethane was added to separate the floating resin from the molecular sieve. Resin 10 mL dichloromethane and diethyl ether (2 x 10 mL)
Washed with and dried under vacuum for 12 hours. The resin was kept under nitrogen at room temperature in the dark for 6 months without changing its effect.

Example 2. Resin Immobilization Strategy for Synthesis of Fused 3-Aminoimidazole Heterocyclic Aromatic Amidine (323 μmol, 200 mol%), Aldehyde (323 μm
ol, 200 mol%) and DC of catalyst Sc (OTf) ₃ (16.2 μmol, 10 mol%)
1 mL of M: MeOH (3: 1) solution was incubated for 30 minutes. Resin isonitrile linker (100 mg, 163 μmol, 100 mol%) was pre-swelled in DCM for 20 minutes and the resin filtered. The solution of aldehyde, heteroaromatic amidine and catalyst was then added to the resin and the solution was shaken for 2 days at room temperature. Filter the resin, D
Washed with CM (2 x 3 mL), MeOH (2 x 3 mL), 20% DIPEA in DCM (3 mL) and DCM (2 x 3 mL). A sample of resin (3-5 mg) from the resin, DCM:
Cleavage with 4M HCl in dioxane (1: 1) for 1 hour at room temperature. The resin was dried under vacuum and analyzed by LC-MS to give the expected product in high purity (75-99%).

[Chemical 13]

Example 3. Synthesis of Amido-Substituted Condensed 3-Aminoimidazole Resin compound D (60 mg, 74 μmol, 100 mol%) was pre-swelled in DCM for 20 minutes and the resin was filtered. 1 mL of a solution of acyl chloride (370 μmol, 500 mol%) and DIPEA (600 μmol, 800 mol%) in DCM was added to resin bound compound D and the reaction mixture was stirred for 20 hours at room temperature. The resin was filtered and washed with DCM (2x
3 mL), washed with MeOH (2 x 3 mL) and DCM (2 x 3 mL). A sample of resin (3-5 mg) was cleaved from the resin with DCM: TFA: water (80: 18: 2) for 1 hour at room temperature. The resin was dried under vacuum and analyzed by LC-MS to give the expected product in high purity (75-99%).

Example 4. Synthesis of alkylated 3-aminoimidazole Resin compound D (60 mg, 74 μmol, 100 mol%) was pre-swelled in DCM for 20 minutes and the resin was filtered. 1.2 mL of a solution of alkyl halide (370 μmol, 500 mol%) and DIPEA (740 μmol, 1000 mol%) in DCM was added to resin bound compound D and the reaction mixture was stirred for 20 h at 80 ° C. Filter the resin, DM
F (2 x 3 mL), DCM (2 x 3 mL), MeOH (2 x 3 mL) and DCM (2 x 3 mL)
Washed with. A sample of resin (3-5 mg) was taken from the resin from DCM: TFA: water (80
: 18: 2) for 1 hour at room temperature. The resin is dried under vacuum and LC-M
Analysis by S gave the expected product in high purity (75-99%).

Example 5. Synthesis of Sulfonamide-Substituted 3-Aminoimidazole Resin Compound D (60 mg, 74 μmol, 100 mol%) was preswelled in DCM for 20 minutes and the resin filtered. Sulfonyl chloride (370 μmol, 500 mol%) and DIPEA (740 μmol, 1000 mol%) in 1.2 mL of DCM: dioxane (1: 1) was added to resin bound compound D and the reaction mixture was stirred for 20 h at 60 ° C. The resin was filtered, DCM (2 x 3 mL), dioxane (2 x 3 mL), MeOH (2
X 3 mL) and DCM (2 x 3 mL). A sample of resin (3-5 mg) was cleaved from the resin with DCM: TFA: water (80: 18: 2) for 1 hour at room temperature. The resin was dried under vacuum and analyzed by LC-MS to give the expected product in high purity.

[Procedure for Amendment] Submission for translation of Article 34 Amendment of Patent Cooperation Treaty

[Submission date] January 23, 2002 (2002.23)

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Contents of correction]

[Claims]

[Chemical 1] Wherein, X is carbon, oxygen, PEG chain or - (CH _{2) n} -CONH- group, ^{R 1} is hydrogen, phenyl or substituted phenyl group,, ^{R 2} is hydrogen, phenyl or substituted phenyl group,, ^{R 3} Is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or phenoxy,
R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or phenoxy,
And n is an integer from 1 to 4], a functionalized polymer reagent for liquid phase and solid phase synthesis.

[Chemical 2] [Wherein, R is directly or - (CH _{2) n} -CONH- through a group or PEG- chain is a polymer attached to the linker] is functionalized polymeric reagent of claim 1 or 2 .

[Chemical 3] Wherein, X is carbon, oxygen, PEG-chain or - (CH _{2) n} -CONH- group, ^{R 1} is hydrogen, phenyl or substituted phenyl group,, ^{R 2} is hydrogen, phenyl or substituted phenyl group,, R ³ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or phenoxy,
R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or phenoxy,
And n is an integer of 1 to 4].

[Chemical 4] [Wherein, R is directly or PEG- chain or - (CH ₂₎ via the _n -CONH- group is a polymer attached to a linker] A compound according to claim 13.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE, TR), OA (BF , BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, G M, KE, LS, MW, MZ, SD, SL, SZ, TZ , UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, B Z, CA, CH, CN, CR, CU, CZ, DE, DK , DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, J P, KE, KG, KP, KR, KZ, LC, LK, LR , LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, R O, RU, SD, SE, SG, SI, SK, SL, TJ , TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW

Claims (15)

[Claims] 1. A functionalized polymeric reagent for liquid phase and solid phase synthesis comprising a polymer and a linker moiety, the linker comprising an acid labile isonitrile moiety. 2. Formula I Wherein, X is carbon, oxygen, PEG chain or - (CH _{2) n} -CONH- group, ^{R 1} is hydrogen, phenyl or substituted phenyl group,, ^{R 2} is hydrogen, phenyl or substituted phenyl group,, ^{R 3} Is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or phenoxy,
R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or phenoxy,
And n is an integer from 1 to 4], a functionalized polymer reagent for liquid phase and solid phase synthesis. 3. A chemical formula: [Wherein, R is directly or - (CH _{2) n} -CONH- through a group or PEG- chain is a polymer attached to the linker] is functionalized polymeric reagent of claim 1 or 2 . 4. The functionalized polymeric reagent according to any of claims 1 to 3, characterized in that the polymer is a soluble polymer. 5. The functionalized polymeric reagent according to any of claims 1 to 3, characterized in that the polymer is an insoluble polymer. 6. A) reacting a polymeric support with a formylation reagent; b) The formamide group so formed is then converted to the isonitrile moiety. A method of making a functionalized polymeric reagent according to any one of claims 1 to 5, comprising a step. 7. Process according to claim 6, characterized in that the formylation reagent used in step a) is 2,4,5-trichlorophenyl formate. 8. A process according to claim 6 or 7, characterized in that the reagent used in step b) is carbon tetrachloride / triphenylphosphine in the presence of triethylamine. 9. A) immobilizing a substrate compound on the isonitrile part of the functionalized polymeric support according to any of claims 1 to 4, b) carrying out at least one further reaction step, and c) an acid. A method for producing an organic compound by liquid phase or solid phase synthesis, comprising the step of dissociating the compound from a polymer support by treatment. 10. An additional reaction step after cleavage from the polymer support,
The method according to claim 9. 11. The method according to claim 9, characterized in that the method is carried out with a number of substrate compounds and / or a number of further reaction steps to provide a library of organic compounds. 12. Process according to claim 9, characterized in that at least one of the reaction steps is a multi-component reaction. 13. A kit comprising a container of functionalized polymeric reagent according to any of claims 1 to 4. 14. Formula II: Wherein, X is carbon, oxygen, PEG-chain or - (CH _{2) n} -CONH- group, ^{R 1} is hydrogen, phenyl or substituted phenyl group,, ^{R 2} is hydrogen, phenyl or substituted phenyl group,, R ³ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or phenoxy,
R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or phenoxy,
And n is an integer of 1 to 4]. 15. embedded image [Wherein, R is directly or PEG- chain or - (CH ₂₎ via the _n -CONH- group is a polymer attached to a linker] A compound according to claim 13.