Regioselective synthesis of rapamycin derivatives

Abstract

This invention provides a regioselective process for preparing a 42-ester or ether of rapamycin, and 31-silyl ether intermediates.

What is claimed is:  
     
         1 . A process for preparing a 42-ester or ether of rapamycin having the structure  
       
         
           
           
               
               
           
         
       
       wherein R is an ester or ether, which comprises: 
 (a) treating rapamycin with a silylating agent to form rapamycin 31,42-bis-silyl ether;  
 (b) selectively hydrolyzing the 42-silyl ether in mild acid to provide rapamycin 31-silyl ether;  
 (c) treating the rapamycin 31-silyl ether with a suitable esterifying or etherifying reagent to form rapamycin 31-silyl ether 42-ester or ether; and  
 (d) selectively hydrolyzing the 31-silyl ether in mild acid to provide the desired rapamycin 42-ester or ether.  
 
     
     
         2 . The process according to    claim 1   , wherein the silylating agent in step (a) is a trialkylsilyl halide.  
     
     
         3 . The process according to    claim 2   , wherein the silylating agent in step (a) is trimethylsilyl chloride.  
     
     
         4 . The process according to    claim 3   , wherein the acid used to perform the hydrolysis in step (b) is dilute sulfuric acid.  
     
     
         5 . A process for preparing rapamycin 31-trimethylsilyl ether, which comprises: 
 (a) treating rapamycin with chlorotrimethylsilane in an inert solvent in the presence of a suitable base to provide rapamycin 31,42-bis-trimethylsilyl ether; and    (b) treating the 31,42-bis-trimethylsilyl ether with dilute acid to provide rapamycin 31-trimethylsilyl ether.    
     
     
         6 . The process according to    claim 5   , wherein the base in step (a) is imidazole, 1-methylimidazole, triethylamine, or N,N-diisopropylethylamine.  
     
     
         7 . The process according to    claim 6   , wherein the acid in step (b) is sulfuric acid.  
     
     
         8 . A process for preparing rapamycin 42-ester with 2,2-bis-(hydroxymethyl)propionic acid, which comprises: 
 (a) treating rapamycin with a silylating agent to form rapamycin 31,42-bis-silyl ether;    (b) selectively hydrolyzing the 42-silyl ether in mild acid to provide rapamycin 31-silyl ether;    (c) acylating the rapamycin 31-silyl ether with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid chloride or the 2,4,6-trichlorobenzoyl mixed anhydride of 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid to give rapamycin-31-O-trimethylsilyl ether, 42-ester with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid;    (d) selectively hydrolyzing the 31-silyl ether in mild dilute acid to provide rapamycin 42-ester with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid; and    (e) treatment of rapamycin 42-ester with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid with mild acid to provide 42-ester with 2,2-bis-(hydroxymethyl)propionic acid.    
     
     
         9 . The process according to    claim 8   , wherein the silylating agent is a trialkylsilyl halide.  
     
     
         10 . The process according to    claim 9   , wherein the silylating agent is chlorotrimethylsilane.  
     
     
         11 . The process according to    claim 10   , wherein the acid used in steps (b) and (d) is sulfuric acid.  
     
     
         12 . The process according to    claim 11   , wherein the acylation in step (c) is carried out at less than 0° C.  
     
     
         13 . A process for preparing 42-O-(2-hydroxy)ethyl-rapamycin which comprises: 
 (a) treating rapamycin with a silylating agent to form rapamycin 31,42-bis-silyl ether;    (b) selectively hydrolyzing the 42-silyl ether in mild acid to provide rapamycin 31-silyl ether;    (c) treating the rapamycin 31-silyl ether with a an ethylene glycol equivalent containing an acid labile hydroxyl protecting group protecting on one terminus of the ethylene glycol equivalent and a leaving group suitable of alkylating a hydrxyl group as the other terminus of the ethylene glycol equivalent.    (d) hydrolying the protecting groups on the 31-postion and on the 42-hydroxyethyl position under mildly acidic conditions.    
     
     
         14 . The process according to    claim 13   , wherein the silylating agent is is a trialkylsilyl halide.  
     
     
         15 . The process according to    claim 14   , wherein the silylating agent is chlorotrimethylsilane.  
     
     
         16 . The process according to    claim 15   , wherein the ethylene glycol equivalent is 2-(t-butyldimethylsilyl)oxyethyl triflate).  
     
     
         17 . The process according to    claim 16   , wherein the acid used in steps (b) and (d) is sulfuric acid.  
     
     
         18 . A compound which is a rapamycin 31-O-silyl ether.  
     
     
         19 . The compound of    claim 18   , in which the 31-O-silyl ether is a trialkylsilyl ether.  
     
     
         20 . The compound of    claim 19   , which is rapamycin 31-O-trimethylsilyl ether.