New Method for Preparing Isofagomine and Its Derivatives

Abstract

A method for preparing isofagomine, its derivatives, intermediates and salts thereof using novel processes to make isofagomine from D-(−)-arabinose and L-(−)-xylose.

1 . A method for preparing isofagomine, its derivatives, or acid salts thereof, comprising:
 protecting the anomeric hydroxyl group of D-(−)-arabinose with a protecting group to form a glycoside;   further protecting by converting said protected glycoside to an acetonide using a ketal or ketone;   converting said acetonide to an alkoxide and reacting with an alkylating agent to form an ether;   converting said ether to a diol having two protecting groups;   further protecting said diol using selective etherification to form a triprotected arabinose derivative;   converting said arabinose derivative to a triprotected xylose derivative using an activated system;   converting said xylose derivative to a triprotected nitrile using an activated system;   converting said nitrile using catalytic hydrogenation.   
     
     
         2 - 8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the protecting group is selected from benzyl, methoxybenzyl, chlorobenzyl, diphenylmethyl, methyl, ethyl, isopropyl or cyclohexylmethyl. 
     
     
         10 . The method of  claim 1 , wherein the ketone or ketal is selected from acetone, 2-butanone, benzophenone, cyclohexanone, acetophenone, or their corresponding dialkylketals. 
     
     
         11 . The method of  claim 1 , wherein the activated system is selected from p-toluenesulfonate, methanesulfonate, and trifluoromethanesulfonate 
     
     
         12 . A method for preparing isofagomine, its derivatives, or acid salts thereof, comprising:
 protecting the anomeric hydroxyl group of D-(−)-arabinose with a protecting group to form a glycoside having the structure of compound A:   
       
         
           
           
               
               
           
         
         wherein the protecting group is selected from benzyl, methoxybenzyl, chlorobenzyl, diphenylmethyl, methyl, ethyl, isopropyl or cyclohexylmethyl; 
         further protecting by converting said protected glycoside to an acetonide using a ketal or ketone, wherein the ketone or ketal is selected from acetone, 2-butanone, benzophenone, cyclohexanone, acetophenone, or their corresponding dialkylketals, and wherein the acetonide has the structure of compound L: 
       
       
         
           
           
               
               
           
         
         converting said acetonide to an alkoxide and reacting with an alkylating agent to form an ether, wherein the ether has the structure of compound M: 
       
       
         
           
           
               
               
           
         
         converting said ether to a diol having two protecting groups, wherein the diol has the structure of compound N: 
       
       
         
           
           
               
               
           
         
         further protecting said diol using selective etherification to form a triprotected arabinose derivative, wherein the arabinose derivative has the structure of compound O: 
       
       
         
           
           
               
               
           
         
         converting said arabinose derivative to a triprotected xylose derivative through an intermediate comprising a leaving group selected from p-toluenesulfonate, methanesulfonate, and trifluoromethanesulfonate, and wherein the xylose derivative has the structure of compound Q: 
       
       
         
           
           
               
               
           
         
         converting said xylose derivative to a triprotected nitrile through an intermediate comprising a leaving group selected from p-toluenesulfonate, methanesulfonate, and trifluoromethanesulfonate, and wherein the nitrile has the structure of compound S: 
       
       
         
           
           
               
               
           
         
       
       and
 converting said nitrile using catalytic hydrogenation. 
 
     
     
         13 . The method of  claim 12 , wherein the protecting group is benzyl. 
     
     
         14 . The method of  claim 12 , wherein the ketone or ketal is selected from acetone, 2,2-dimethoxypropane, or combinations thereof. 
     
     
         15 . The method of  claim 12 , wherein the leaving group is trifluoromethanesulfonate.