Liquid phase parallel synthesis of chemical libraries

Abstract

This invention features methods of biphasic synthesis for synthesizing combinatorial libraries and combinatorial libraries of chemical compounds utilizing the template, and combinatorial libraries of chemical compounds formed by the methods of this invention.

What is claimed is:  
     
         1 . A method of synthesizing a combinatorial library comprising the following steps: 
 (a) reacting, in solution, a template with polyethylene glycol to form a PEG-template;    (b) dividing said PEG-template into at least two portions;    (c) reacting each said portion of PEG-template with at least one reactant to form a functionalized PEG-template;    (d) precipitating each said portion of functionalized PEG-template;    (e) washing excess reactant from each said portion of functionalized PEG-templates;    (f) dividing each said portion of functionalized PEG-template into at least two portions;    (g) repeating steps (c)-(f) at least once.    
     
     
         2 . A method of synthesizing a combinatorial library comprising the following steps: 
 (a) reacting, in solution, an iminodiacetic acid anhydride template with polyethylene glycol monomethyl ether to form a PEG-monoacid template;    (b) dividing said PEG-monoacid template into at least two portions;    (c) reacting each said portion of PEG-monoacid template with at least one reactant to form a monofunctionalized PEG-template;    (d) precipitating said monofunctionalized PEG-template;    (e) washing excess reactant from each said portion of monofunctionalized PEG-template;    (f) dividing each said portion of monofunctionalized PEG-template into at least 2 portions;    (g) reaction each said portion of monofunctionalized PEG-template with at least one reactant to form a difunctionalized PEG-template;    (h) precipitating said difunctionalized PEG-template;    (i) washing each said portion of difunctionalized PEG-template;    (j) cleaving the polyethylene glycol monomethyl ether from said difunctionalized PEG-template to form a diamide.    
     
     
         3 . The method in  claim 2  wherein the reactant in step (c) is an amine selected from the following group:  
       
         
           
           
               
               
           
         
       
       and wherein Y is selected from the group consisting of alkyl, aryl; heteroaryl; heterocyclic; cycloalkyl, and cycloalkenyl; 
 the protecting group (PG) is selected from the group consisting of benzyloxycarbonyl (CBZ), 2-bromobenzyloxycarbonyl, 2-chlorobenzycarbonyl, 9-toluenesulfonyl, mesitylene-2-sulfonyl, and tert-butyloxcarbonyl, t-butoxycarbonyl (BOC), or 9-fluorenylmethoxycarbonyl (Fmoc);  
 X is selected from the group consisting of COO—PG1, wherein PG1 is selected from the group consisting of benzyl, methyl, 2-adamantyl, cyclohexyl, 9-fluorenylmethyl, tert-butyl, 1-adamantyl, 4-methoxy-2,3,6-trimethyl benzensulfonyl, and 1,2,2,5,7,8-pentamethylchroman-6-sulfonyl.  
 
     
     
         4 . A combinatorial library comprising a collection of compounds having the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  has a formula selected from the following formulas:  
       
         
           
           
               
               
           
         
       
       wherein Y is selected from the group consisting of alkyl, aryl; heteroaryl; heterocyclic; cycloalkyl, and cycloalkenyl; 
 the protecting group (PG) is selected from the group consisting of benzyloxycarbonyl (CBZ), 2-bromobenzyloxycarbonyl, 2-chlorobenzycarbonyl, 9-toluenesulfonyl, mesitylene-2-sulfonyl, and tert-butyloxcarconyl, t-butoxycarbonyl (BOC), or 9-fluorenylmethoxycarbonyl (Fmoc);  
 X is selected from the group consisting of COO—PG 1 , wherein PG 1  is selected from the group consisting of benzyl, methyl, 2-adamantyl, cyclohexyl, 9-fluorenylmethyl, tert-butyl, 1-adamantyl, 4-methoxy-2,3,6-trimethyl benzensulfonyl, and 1,2,2,5,7,8-pentamethylchroman-6 sulfonyl;  
 R 2  is selected from the group consisting of aryl, alkyl, wherein aryl is a mono- or polycyclic aromatic system comprised of 5 or 6 membered rings containing 0, 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted, wherein the substituents may be one or more groups selected from hydroxyl, halogen, cyano, trifluoromethyl, C 1-3 alkoxy, C 1-5 alkylcarbonyloxy, C 1-5 alkoxycarbonyl, C 1-5 alkyl, aminoC 1-5 alkyl, hydroxycarbonylC 0-5 alkyl, or hydroxycarbonylC 1-5 alkoxy;  
 wherein alkyl is C 1-10 alkyl, either unsubstituted or substituted, with one or more groups selected from halogen, hydroxyl, C 1-5 alkycarbonylamino, arylC 1-5- alkylcarbonylamino, aryloxy, C 1-5 alkoxy, C 1-5 alkoxycarbonyl, C 0-5 alkylaminocarbonyl, C 1-5 alkylcarbonyloxy, C 3-8 cycloalkyl, aryl, oxo, amino, C 1-6 alkyl, C 1-3 alkylamino, arylC 0-5 alkylaminocarbonyl, phenylC 1-3 alkylamino, aminocarbonylC 0-4 alkyl, hydroxycarbonyl C 0-5 alkyl, C 1-8 alkylsulfonylamino, arylC 0-10 alkylsulfonylamino, C 1-8 alkylsufonyl, arylC 0-10 alkylsulfonyl, C 1-5 alkyloxycarbonylamino, arylC 1-5- alkyloxycarbonylamino, or arylC 1-5 alkyloxy.  
 
     
     
         5 . A combinatorial library comprising a collection of compounds formed by reactions of a PEG-template, said PEG-template comprising a densely functionalized core having two functionalization sites, wherein PEG is attached at one of said three functionalization sites, and one of said other two functionalization sites are blocked, said functionalization sites comprising: 
 a secondary amine blocked with a protecting group, a carboxylic acid, and a PEG ester; said reactions comprising the following steps:    (a) reacting, in solution, one functionalziation site of said template with at least one reactant to form a monofunctionalized PEG-template;    (b) precipitating said monofunctionalized PEG-template;    (c) washing excess reactant from said monofunctionalized PEG-template;    and    (d) repeating steps (a), (b), and (c) at least once.    
     
     
         6 . A method of forming a multifunctionalized PEG-template utilizing a template having three functionalization sites, wherein one of said functionalization sites are blocked, said functionalization sites comprising: 
 a secondary amine blocked with a protecting group; and    an anhydride, said method comprising the following steps:    (a) reacting, in solution, the anhydride functionalization site with polyethylene glycol monomethyl ether to form a PEG-monoacid.    
     
     
         7 . The method of  claim 3 , wherein the first reactant is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and said second reactant is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         8 . A method of generating a template for combinatorial synthesis comprising the step of treating an iminodiacetic acid having a protected amine group with EDCI in situ to form a protected iminodiacetic acid anhydride.  
     
     
         9 . The method of  claim 7  where the iminodicarboxylic acid further comprises N-BOC-iminodiacetic acid.