Title of Invention	NOVEL FUNCTIONALISED POLYETHYLENE GLYCOL-GRAFTED POLYMER AND ITS PROCESS THEREOF
Abstract	The invention relates to novel functionalized polyethylene glycol grafted polymer bound compound of formula (3) as backbone precursor for obtaining pharmaceutical products and its process for preparation from polystyrene-divinylbenzene polymer and invention also relates to the report and preparation of N-aryl ,N-arakyl aziridine resin of formula (1) and PEG - grafted polymer resin of formula (2).

Full Text

Field of the invention The present invention relates to novel functionalized polyethylene glycol-grafted polymer bound compound of general formula (3) which is useful in the preparation of library of combinatorial compounds, further used for obtaining pharmaceutical drugs and its intermediates. The invention also relates to the report of polymer bound aziridine compound of general formula (1) and polyethylene glycol grafted polymer resin of general formula (2) as novel intermediates and a process to obtain functionalized polyethylene glycol grafted polymer bound compound from these intermediates. Background and Prior Art Solid-phase organic synthesis and combinatorial chemistry are widely used in pharmaceutical development research for preparation of libraries of potential drug substances for evaluation. Combinatorial chemistry is a collective term comprising of several recent breakthroughs in the manner of synthesizing organic molecules. In contrast to the classical approach to organic synthesis, wherein one compound at a time is obtained, combinatorial chemistry can be described as the preparation, usually on a solid support, of a group of related molecules, called libraries. In other words, combinatorial chemistry allows large numbers of molecules to be prepared and tested rapidly for biological activity and the technique is, therefore, referred to as "high-throughput screening" technology. Solid-phase organic reactions used in synthesis have been exhaustively compiled and reviewed from the point of view of an organic chemist [ref. 1-3]. For a selection of more descriptive reviews, see [4-9]. The techniques and the principles of combinatorial chemistry have been elaborated by Ferret [5]. Included in this selection are the special issues of Chemical Reviews, entirely devoted to combinatorial chemistry and describing the use of combinatorial techniques to the synthesis of nucleic acids, peptides and peptoids, benzodiazepine, heterocyclic and carbohydrates. In addition to the convenient combinatorial synthesis of selected libraries of compounds, solid phase organic synthesis offers several advantages over the classical organic synthesis. Firstly, the compounds are built on the polymer bead and hence side reactions are minimized. These reactions are generally safer and cleaner than the usual solution phase chemistry. Excess reagents may be used to drive the reactions to completion. The excess reagents and solvents are simply removed by filtration and then the desired compound is released from the resin beads. The compound thus obtained is generally homogenous, obviating the need for extensive purification protocols. In a more recent development, the resins carrying specific functionalities {the so-called scavenger resins) are also used to remove undesired byproducts as well inhibitors of reactions or one of the components in a reversible reaction (to drive the reaction in one direction). The best known example of phenomenal success of the solid phase organic synthesis is in the area of peptide synthesis (initiated by Merrifield) and later nucleic acid assembly which allowed automation. The products for solid-phase organic synthesis are characterized by three main parameters. The most important is probably the backbone, which is generally based on cross-linked polystyrene-divinylbenzene (PS-DVB), first developed by Merrifield for solid-phase peptide synthesis. These resins are still very popular and are widely available and inexpensive. These are characterized by the degree of cross-linkage (generally 1-2%), which imparts a balance between rigidity and swelling properties, the porosity (brought about by use of a photogenic agent during polymerization) and the mesh size (generally 50-100, 70-90, 100-200 and 200-400), which is determined either by sieve analysis or air-floatation technique. Extensive researches on the linker chemistry have led to the introduction innumerable variety of anchoring groups with varying degrees of stability and application not only in solid-phase peptide synthesis and gene-assembly but also in solid-phase organic synthesis in general. The starting materials for multi-step synthesis are linked to the polymer backbone through these linker groups and after the synthesis, the final product is cleaved food the resin using a suitable reagent, which may be a strong or a weak acid or base, hydrazine, catalyst, light, etc., depending on the nature of the linker and the bond between the product molecule and the linker. As can be expected, a larger number of linkers based on carbon, silicon, oxygen, sulphur, nitrogen and phosphorus have already been developed and extensively used. About 25% or all organic chemistry papers in recent years are based on solid-phase organic synthesis and their proportion is growing, thus increasing the demand for these materials from both research laboratories and pharmaceutical and biotechnological industry. Some of the more popular resins in use for solid-phase organic synthesis, peptide synthesis and combinatorial chemistry are given below. More comprehensive lists are given in reviews like that by Guile et al. [10]. The earliest resin to be introduced is the Merrifield resin, which is a polystyrene resin cross-linked with 1-2% divinylbenzene and which is chloromethylated using chloromethyl methyl ether and stannic chloride. The Merrifield resin can be condensed with potassium phthalimide to yield phtalimido polystyrene, which on hydrzinolysis yields aminomethyl polystyrene. Chloromethyl and aminomethyl polystyrenes being the starting points for several other flinctionalised polymers, and chloromethyl methyl ether being carcinogenic, several methods are in development for alternative routes for their preparation. One such has been developed by Merrifield himself and involves direct amidoalkylation of cross-linked polystyrene using hydroxymethylphtalimide and trifluoromethyl sulphonic acid, followed by hydrazinolysis. Another recent development in obtaining more uniform Merrifield resin is to copolynerise styrene with divinylbenzene and chloromethylstyrene. The chemistry of the functional groups on the resin can be tailored to modulate the acid-sensitivity as well as acid-sensitivity of the bond between the resin and the molecule attached to it through the linker. Thus, the Merrifield resin is condensed with hydroxylmethylphenol to yield hydroxymethyl phenyloxymethyl polystyrene, other wise called Wang resin where the linkage is acid sensitive. On the other hand hydoxymethyl phenylacetamido linkage (called the PAM resin) is highly stable to acids. A linker that is extremely sensitive to acids and permit building molecules using acid-sensitive groups like proline and cysteine are the 2-chlorotrityl resin. Further modulation of the stability and sensitivity is achieved by introducing methyl, methoxy or nitro groups on the phenyl rings of the trite linker. Other popular resins link the Rink and Sidebar resins permit synthesis of amides. Swelling of the resin is another important property that determines the reactivity of the functional groups on the resin in a given solvent. Swelling renders the reactive groups more accessible to the reagents. Most of the PS-DVB resins swell appreciably in medium polar non-aqueous solvents like toluene, dichloromethane. tetrahydrofuran, dioxan and dimethylformamide and the resins collapse in hydroxylic solvents such alcohols and water. The solid-phase reactions therefore are generally conducted in the non-hydroxylic medium polar solvents. Recently, attempts are being made to graft hydrophilic moieties such as polyethylene glycol (PEG) to the PS-DVB resins to obtain what are called PEG resins or entangle resins that contain amphiphilic spacers or tentacles [11]. Hydrocarbon (methylene) spacers are also sometimes used with advantage to bring down steric hindrance due to the large polymeric backbone close to the reactive groups and to increase the stability of the linker groups. Novelty The present invention provides a novel functionalized PEG-grafted polymer bound compound derived from a PEG-grafted polymer resin obtained from N-aryl or N-aralkyl polymer aziridine resin. The present approach to achieve the desired objective and also advantages derived by the present invention has not been reported in the prior art. In addition, the present invention circumvents the use of hazardous ethylene oxide and controls the chain length in the process of preparation of PEG-grafted polymer resin to achieve desired swelling properties, thereby obviating the limitations associated with its preparation in the prior art process. Objects of the Invention Main object of the invention is to provide a ftmctionalized polyethylene glycol grafted polymer bound compound of formula (3). An object of the invention is to provide a process for the preparation of compound of formula (3). Another object of the invention is to provide a novel polymer bound aziridine resin of formula (1) as one of the intermediate. Yet another object of the invention is to provide a novel polyethylene glycol grafted polymer resin of formula (2) as another intermediate. Still another object of the invention is to use compounds of general formula (3) to obtain library of dominated compounds. Still yet another object of the invention is to use library of combinatorial compounds as backbone precursor for obtaining pharmaceutical products and its intermediates. Summary of the invention The present invention relates to polyethylene glycol grafted polymer bound compound of formula (3) and its process for preparation by contacting amino or aminoalkyl polystyrene divinylbenzene resin with dihaloethane in an organic solvent at a temperature ranging between ambient and 65°C to obtain polymer bound aziridine resin of formula (1), which is subsequently contacted with polyethylene glycol aminoalky ether to obtain polyethylene grafted polymer resin of formula (2) and finally acylating using an appropriate linker acid in the presence of a mixture of condensing and etherifying agent to yield the required functionalized polyethylene grafted polymer bound compound. The invention also relates to the report of polymer bound aziridine resin of formula (1) and polyethylene grafted polymer resin of formula (2) as novel intermediates. Brief description of Table Table-1: Swelling properties of resin of prior art and present invention. Detailed description of the invention The present invention relates to a novel PEG-grafted polymer boimd product and a convenient route to the preparation of polymer boimd N-aryl and N-aralkyl aziridines and their conversion to polyethylene glycol-grafted polymer product, which have the desired properties required for use in solid-phase organic synthesis and combinatorial chemistry. The PEG-grafted polystyrene resins, with the desirable swelling properties are generally obtained by anionic polymerization of ethylene oxide on Merrifield resin. The major problems in the process are the use of gaseous and poisonous ethylene oxide and the production of undefined chain-length of the PEG chain, which can cause changes in the functional properties of the resin. In order to overcome these drawbacks, we have developed a novel approach which does not require the use of ethylene oxide and which also allows complete control of the length and loading of the PEG chain. The novelty of the present invention also resides in the fact that, we used a new polymer-bound azirdine resin, which reacts with appropriate PEG-alcohol or its derivative to yield the desired PEG-grafted polymer resin. Both the nitrogen loading of the aziridine relative to the polymer backbone and the length of the PEG chain can be controlled to achieve the desired swelling properties of the PEG- grafted polymer resin used subsequently for obtaining PEG-grafted polymer bound product, and used in solid-phase organic synthesis and combinatorial chemistry for the generation of library of combinatorial compounds. Swelling properties have been often the criteria for monitoring the progress of the reaction. The polymer-bound N-aryl (1, m = 0) or N-aralkyl (1, m = 1 to 5) aziridine required for the purpose was conveniently prepared by a novel route (Scheme 1), which consisted of treating amino or aminoalkyi polymer resins respectively with ethylene dibromide in presence of an organic base to trap the hydrogen bromide formed. The aziridine resin so obtained was treated with a polyethylene glycol monoalkyl ether of desired length or molecular weight (for example, the commercially available polyethylene glycol monomethyl ether of molecular weight 350, 550, 750, 2000 daltons, etc.) in the presence of an acid catalyst to yield PEG-grafted polymer resin of the general formula (2) in Scheme-2. Another major advantage of this approach is that the product of general formula (2) still has a reactive amino group, which can be functionalised with different groups required in combinatorial chemistry to yield functionalized PEG-grafted polymer bound compound of general formula (3) in Scheme-2. Representative linker acid used are 4-hydroxymethylphenoxyacetyl, Rink (or Knorr), Sieber, Bayer (4'-carbonyl-2chlorotrityl), Fmoc-3-amino-3-(2-nitrophenyl) propanamide(ANP); Backbone amide linker (BAL): Phenoxypentanoic acid amide linker(PAL); Phenylacetamidomethyl(PAM); Hydroxymethylbenzoic acid (HMBA); 4-(4-Hydroxymethyl-3-methoxyphenoxy)butyric acid (HMPB); 5-(4-Hydroxyraethylphenoxy)pentanoic acid(HMPPA); Super Acid Sensitive Resin (SASRIN) linkers. The functionalized PEG grafted polymer bound compound of general formula (3) having desired chemical and physical properties required in solid-phase organic synthesis for the preparation of library of combinatorial compounds, which is the backbone material for the preparation of potential pharmaceutical products for therapeutic evaluation. The schematic representation of the process is depicted herein below in Schemes 1 and 2:- An embodiment of the invention provides a process for the preparation of compound of formula (3), the said process comprising steps of: a) swelling amino or amino alkyl polymer resin in an organic solvent, b) stirring the swelled resin of step (a) with dihaloethane in presence of a suitable organic base at a temperature ranging between ambient to 65°C for 12 to 48 h. c) filtering resin from the reaction mixture of step (b), washing the filtered resin successively with organic solvents, d) drying the washed resin of step (c) to obtain compound of formula (1) e) swelling the compound of step (d) in an organic solvent, f) treating the swelled resin of step (e) with polyethylene glycol monomethylether of molecular weight ranging between 350 to 2000 in presence of an acid, g) maintaining temperature of the mixture of step (f) between ambient to 110°C for a time period ranging between 24 - 96 h to complete the reaction, h) treating the reaction mixture of step (g) with an organic base, filtering and washing the resin, drying as mentioned above in steps ( c )and (d) to obtain compound of formula (2), i) preparing vacillation mixture in an organic solvent by contacting required linker acid with a mixture of dicyclohexyldicarbodiimide-esterifying agent at an ambient temperature for 1 to 4 h and filtering to obtain a clear filtrate, j) contacting further the clear filtrate of step (i) with compound of formula (2), k) stirring the mixture of step G) ^t a temperature ranging between ambient to 65°C for a period of 16h - 20 h, 1) filtering the resin of step (k) after completion of reaction, washing the filtered resin, drying as mentioned above in steps (c) and (d), and m) obtaining functionalized polyethyleneglycol grafted polymer bound product of formula(3). Another embodiment of the invention provides a process for the preparation of N-aryl or N-aralkyl azirdine resin of formula (1) using a solvent selected from the group consisting of dioxan, dichloromethane, ethylenedichloride, tetrahydrofiiran, dimethylformamide, dimethyl-acetamide and mixtures thereof, preferably dichloromethane. Yet another embodiment of the invention provides a process of wherein amino and aminoaikyl polymer resin used is selected from the group consisting of aminopolystyrene-co-divinylbenzene resin, aminoniethylpolystyrene-co- divinylbenzene resin & aminoalkylpolystyrene-co-divinylbenzene resin for obtaining compound of formula (1). Still another embodiment of the process provides the use of dihaloethane selected from the group consisting of dichloroethane and dibromoethane preferably diboro-methane for obtaining compound of formula (1). Still yet another embodiment of the process provides uses tertiary organic base selected from the group consisting of triethylamine, pyridine and diisopro-pylethylamine, preferably triethylamine for obtaining compound of formula (1). An embodiment of the invention uses organic solvent selected from the group consisting of dioxan, methanol, dichloromethane, diethylether and hexane for washing compound of formula (1). Another embodiment of the invention uses organic solvent used in selected from a group consisting of dioxan, dichloro-methane, ethylenedichloride, tetrahydrofliran, dimethylformamide, dimethylace-tamide and mixtures thereof, preferably for swelling the compound of formula (1). Yet another embodiment of the invention uses process polyethylene glycol alkyl ether used is selected from a group consisting of PEG (mol.wt. up to 2000), PEG-monomethyl ether (mol. up to 2000) & PEG-monobutyl ether (mol.wt. ca.200) preferably PEG-monomethyl ether (mol.wt. up to 2000) for obtaining compound of formula (2), Still another embodiment of the invention uses an acid in selected from the group consisting of sulphuric acid, p-toluene sulphonic acid, perchloric acid and etrafluoroboric acid preferably perchloric acid for obtaining compound of formula (2). Still yet another embodiment of the invention uses organic base selected from a group consisting of triethylamine, pyridine and diisopropylethylamine for work up to obtain compound of formula (2). An embodiment of the invention uses organic solvent selected from the group consisting of dichloromethane, ethylenedichloride, tetrahydrofuran, dimethylformamide, dioxan, dimethylacetamide and mixtures thereof, preferably dixoan for acylation of compound of formula (2) Another embodiment of the invention uses acylation mixture selected from the group consisting of dicyclohexyl carbodiimedie (DCC) - hydroxybenzotriazole, DCC-p-Nitrophenol, DCC-Pentafluorophenol, DCC-trichlorophenol, 2-[7-Aza-lH-Benzotriazole-l-yl]-l, 1,3,3- tetramethyl uranium hexa fluoro phosphate], 2-[lH-Benzotriazole-1-yl] 1,1,3,3 tetramethyl uranium hexa fluoro phosphate] and 2-[lH-Benzotriazole-1-yl] 1,1, 3,3-tetramethylurobnium tetrafluoroborate, preferaby(DCC) -hydroxybenzotriazole for obtaining compound of formula (3). Still another embodiment of the invention uses linker selected from a group consisting of 4-hydroxymethylphenylacetic acid (HMPA or Wang linker), Fmoc-Rink-acetic acid (Rink Amide linker or Fmoc-Rink linker), 4'-carboxytrityl hanker, 4'-carboxy-2-chlorotrityl liner (Bayer linker) & Saber linker (3-carboxymethyloxyxanthone), preferably 4-hydroxymethylphenylacetic acid (HMPA or Wang linker) or Fmoc-Rink-acetic acid for obtaining compound of formula (3) Further embodiment of the invention uses compound of formula (1) as a backbone for the preparation of pharmaceutical products and its intermediates. The following examples should not be construed to limit the scope of the invention and provided for the purpose of illustration only. Examples: Example 1 Preparation of N-Araikyl aziridine resin (formula 1, R= 1) .\minomethyl polystyrene resins are obtained by the procedure as described in the literature [12]. The resins had the following properties: 1% cross-linked with divinylbenzene; 100-200 mesh; 1.2 mmol and 2.8 mmol N/g (It may have a N loading of 1 to 3 mmol/g). The polystyrene-divinylbenzene resin (100 g) with an amino equivalents lo me nitrogen content of ethylene dibromide and 2.2 to 2.5 equiv. of triethylamine. The reaction temperature is maintained between ambient to 65 degrees C to ensure completion of the reaction. The resin is filtered off from the solvents and the triethylamine hydrobromide and washed successively with dioxan, methanol, dichloromethane, methanol, diethyl ether and hexane and dried in a vacuum desiccators over potassium hydroxide to yield 100 g of compound of general formula (1). Example-2 Preparation of N-aryl aziridine resin (formula 1, R= 0) Amino polystyrene divinylbenzene resin is used as starting material in place of aminomethyl polystyrene divinylbenzene and followed the procedure of Example!. The other variations involved are use of ethylenedichloride and pyridine as an organic base to obtain compound of general formula (1). Example-3 Preparation of PEG-grated polymer resin (formula 2) The polymer bound aziridine compound (100 g) of example 1 is swelled in dioxan (1.2 L) and treated with 2.0 to 5.0 equiv. of polyethylene glycol monomethyl ether (MW: 350, 550, 750 or 2000) and 1.0 molar equiv. of perchloric acid. The mixture is stirred overnight and the reaction temperature is maintained between ambient to 110 degrees C to ensure completion of the reaction. The reaction mixture is then treated with 2.5 to 6.0 equiv. of triethylamine prior to filtration and washing of the resins as described in example 1 to obtain compounds general formula (2). Example 4 Preparation of PEG-grafted polymer resin (formula 2) The polymer bound aziridine compound of Example 2 is swelled in dichloromethane and followed the procedure adopted in Example3 to obtain compounds of general (formula 2) Example 5 Preparation of functionalized PEG-grafted polymer bound compound (formula 3) Acylating mixture is first prepared by treating 2.0 equiv. linker acid 4-hydroxymethylphenoxyacetic acid in dichloromethane to ensure solubility of the reactants (1.2 L) with 2.0 equiv. of l-hydroxybenzotriazole and 2.0 equiv. of dicyclohexylcarbodiimide for 2 h and filtering the dicyclohexylurea formed. To this filtrate is added PEG-grafted polymer resin of general formula (2) obtained in Examples 3 or 4 and the reaction mixture is stirred overnight. The reaction temperature is maintained between ambient to 65 degrees C to ensure completion of the reaction. The resin is then filtered off and washed successively with dichloromethane, dioxan, methanol, ether and hexane and dried in a vacuum oven over potassium hydroxide. The product functionalized PEG-grafted polymer product of general formula (3) obtained is characterized by its Infrared spectra, elemental analysis, microscopic examination and swelling characteristics in different solvents. Example 6 Preparation of functionalized PEG-grafted polymer bound compound (formula 3) Acylating mixture is first prepared by treating 2.0 equiv. linker acid 4-hydroxymethylphenoxyacetic acid in tetrahydrofiiran to ensure solubility of the reactants (1.2 L) with 2.0 equiv. of l-hydroxybenzotriazole and 2.0 equiv. of dicyclohexylcarbodiimide for 2 h and filtering the dicyclohexylurea formed. To this filtrate is added PEG-grafted polymer resin of general formula (2) obtained in Examples 3 or 4 and the reaction mixture is stirred overnight. The reaction temperature is maintained between ambient to 65 degrees C to ensure completion of the reaction. The resin is then filtered off and washed successively with dichloromethane, dioxan, methanol, ether and hexane and dried in a vacuum oven over potassium hydroxide. The product functionalized PEG-grafted polymer product of general formula (3) obtained is characterized by its Infrared spectra, elemental analysis, microscopic examination and swelling characteristics in different solvents. Example 7 Preparation of functionalized PEG-grafted polymer bound compound (formula 3) Acylating mixture is first prepared by treating 2.0 equiv. linker acid Fmoc-Rink-acetic acid in tetrahydrofiiran to ensure solubility of the reactants (1.2 L) with 2.0 equiv. of l-hydroxybenzotriazole and 2.0 equiv. of dicyclohexylcarbodiimide for 2 h and filtering the dicyclohexylurea formed. To this filtrate is added PEG-grafted polymer resin of general formula (2) obtained in Examples 3 or 4 and the reaction mixture is stirred overnight. The reaction temperature is maintained between ambient to 65 degrees C to ensure completion of the reaction. The resin is then filtered off and washed successively with dichloromethane, dioxan, methanol, ether and hexane and dried in a vacuum oven over potassium hydroxide. The product functionalized PEG-grafted polymer product of general formula (3) obtained is characterized by its Infrared spectra, elemental analysis, microscopic examination and swelling characteristics in different solvents. Example 8 Preparation of functionalized PEG-grafted polymer bound compound (formula 3) Acylating mixture is prepared using the linker acid Fmoc-Rink-acetic acid in dioxan and DCC-p-Nitrophenol combination. Procedure of Examples is followed to obtain compound of general formula (3) Swelling properties Swelling properties of Bharavi PEG-AM resin (formula 2) and Bharavi PEG-RK (Rink-Knorr, formula 3) and their comparison with two popular commercial resins Tentagel OH and Tentagel NH2 (made by anionic polymerization using ethylene oxide) are given below. For comparison, corresponding swelling characteristics of PS-DVB resin (which swells significantly in DCM, THF and DMF and not at all in methanol and water) are also given. 1. p. H. H. Hermkens, et al., Tetrahedron, 1996, 52, 4527-4554. 2. P. H. H. Hermkens, et al., Tetrahedron, 1997, 53, 5643-5678. 3. P. H. H. Hermkens, et al.. Tetrahedron, 1998, 54, 15385-15443. 4. J. S. Fruchtel & G. Jung, Angew. Chem., 1996, 35, 17-42. 5. N. K. Terrett, et al. Tetrahedron, 1995, 57, 8135-8173. 6. L. A. Thompson & J. A. Ellman, Chem. Rev., 1996, 96, 555-600. 7. S. E. Osborne & A. D. Ellington, Chem. Rev. 1997, 97, 349-370. 8. K. S. Lam et al., Chem. Rev., 1997, 97, 411-448. 9. A. Nefzi et al., Chem. Rev., 1997, 97, 449-472. 10. F. Guillier, et al. Linkers and Cleavage Strategies in Solid-Phase Organic Synthesis and Combinatorial Chemistry, Chem. Revs. 2000, J00, 2091-2157) 11. M. Groti, et al., Physical Properties of Poly(ethyleneglycol) (PEG)-Based resins for Combinatorial Solid-Phase Organic Chemistry, J. Combinatorial Chem., 2000, 2, 108-119. 12. A. R. Mitchell, et al., J. Org. Chem., 1978, 30, 2845 1 / We claim 1. A functionalized polyethylene glycol-grafted-polymer bound compound of formula (3 ) useful as a backbone precursor for the preparation of potential pharmaceutical 2. A process for the preparation of functionalized polyethylene glycol-grafted- polymer bound compound as claimed in claim 1, said process comprising steps of: a) swelling an amino or amino alkyl polymer resin in an organic solvent; b) stirring the swelled resin of step (a) with dihaloethane in presence of a suitable organic base at a temperature ranging between ambient to 65°C for l2 to 48h; ,4,5... ambient to dS^C for a period of 16 - 20 hours; k) filtering the resultant product of step (j)> washing and drying as mentioned above in steps (c) and (d), respectively and obtaining functionalized polyethyleneglycol grafted polymer bound product of formula (3). 3. The process as claimed in claim 2, wherein the organic solvent used in step (a) and step (i) is selected from the group consisting of dioxan, dichloromethane, ethylenedichloride, tetrahydrofuran, dimethylformamide, dimethylacetamide and/or mixtures thereof 4. The process as claimed in claim 3, wherein the preferred organic solvent used in step (a) is dichloromethane. 5. The process as claimed in claim 3, wherein the preferred organic solvent used in step (i) is dioxan. 6. The process as claimed in claim 2, wherein amino and aminoalkyi polymer resin used in step (a) is selected from the group consisting of aminopolystyrene-co-divinylbenzene resin, aminomethylpolystyrene-co-divinylbenzene resin and aminoalkylpolystyrene-co-divinylbenzene resin. 7. The process as claimed in claim 2 wherein in step (b) the dihaloethane used is selected from the group consisting of dichloroethane and dibromoethane. 8. The process as claimed in claim 7, wherein dihaloethane used is preferably dibromoethane. 9. The process as claimed in claim 2, wherein the organic base used in step (b) is selected from the group consisting of triethylamine, pyridine and diisopropylethylamine. 10. The process as claimed in claim 9, wherein the organic base used is preferably triethylamine. 11. The process as claimed in claim 2, wherein the organic solvents used in step (c) are dioxan, methanol, dichloromethane, diethylether and hexane. 12. The process as claimed in claim 2, wherein the organic solvent used in step (e) is selected from the group consisting of dioxan, dichloromethane, ethylenedichloride, tetrahydrofuran, dimethylformamide, dimethylacetamide and/or mixtures thereof. 13. The process as claimed in claim 12, wherein the preferred organic solvent is dioxan. 14. The process as claimed in claim 2, wherein in step(f), the polyethylene glycol alkyl ether used is selected from the group consisting of PEG (mol.wt. up to 2000), PEG-monomethyl ether (mol.wt. up to 2000) and PEG-monobutyl ether (mol.wt. ca.200). 15. The process as claimed in claim 14, wherein the preferred polyethylene glycol alkyl ether is PEG-monomethyl ether (mol.wt. up to 2000), 16. The process as claimed in claim 2, wherein the acid used in step (f) is selected from a group consisting of sulphuric acid, p-toluene sulphonic acid, perchloric acid and tetrafluoroboric acid. 17. The process as claimed in claim 16, wherein the preferable acid used is perchloric acid. 18. The process as claimed in claim 2, wherein the organic base used in step (h) is selected from a group consisting of triethylamine, pyridine and diisopropylethylamine. 19. The process as claimed in claim 18, wherein the preferred organic base is triethylamine. 20. The process as claimed in claim 2, wherein the DCC-esterifying agent used in step (i) is selected from the group consisting of dicyclohexylcarbodiimide (DCC)-hydroxybenzotriazole, DCC-p-Nitrophenol, DCC-Pentafluorophenol, DCC-trichlorophenol, 2-[7-Aza-]H-Benzotriazole-l-yl]-l,l,3,3-tetramethyl uranium hexafluorophosphate], 2-[lH-Benzotriazole-l-yl] 1,1,3,3-tetramethyl uranium hexafluorophosphate] and 2-[lH-Benzotriazole-l-yl] 1,1, 3,3-tetramethylurobnium tetrafluoroborate. 21. The process as claimed in claim 20 wherein the preferred DCC-esterifying agent used is (DCC)-hydroxybenzotriazole. 22. The process as claimed in claim 2, wherein the linker acid used in step(i) is selected from a group consisting of 4-hydroxymethylphenylacetic acid (HMPA or Wang linker), Fmoc-Rink-acetic acid (Rink Amide linker or Fmoc-Rink linker), 4'-carboxytrityl linker, 4'-carboxy-2-chlorotrityl liner (Bayer linker) and Siber linker (3-carboxymethyloxyxanthone). 23. The process as claimed in claim 22, wherein the linker acid used is preferably 4-hydroxymethylphenylacetic acid (HMPA or Wang linker) or Fmoc-Rink-acetic acid. 24. An intermediate compound of formula (1)

Documents:

0692-che-2003 abstract-duplicate.pdf

0692-che-2003 abstract.pdf

0692-che-2003 claims-duplicate.pdf

0692-che-2003 claims.pdf

0692-che-2003 correspondence-others.pdf

0692-che-2003 correspondence-po.pdf

0692-che-2003 description (complete)-duplicate.pdf

0692-che-2003 description (complete).pdf

0692-che-2003 description (provisional).pdf

0692-che-2003 form-1.pdf

0692-che-2003 form-18.pdf

0692-che-2003 form-26.pdf

0692-che-2003 form-3.pdf

0692-che-2003 form-5.pdf