Methods for preparing 2-alkynyladenosine derivatives

Abstract

Disclosed are methods for preparing 2-alkynyladenosine derivatives of formula A: or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate or isomorphic crystalline form thereof, the method comprising the step of: contacting 2-iodoadenosine-5′-N-ethyluronamide with a compound of formula B: wherein Z is —C(═O)OR or —CH 2 OC(═O)R, where R is a C 1 to C 5 alkyl, preferably methyl. The methods are useful for preparing 2-alkynyladenosine derivatives that are, in certain embodiments, adenosine receptor agonists.

1 . A method for preparing a compound of formula A:  
       
         
           
           
               
               
           
         
         or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate or isomorphic crystalline form thereof, the method comprising the step of:  
         contacting 2-iodoadenosine-5′-N-ethyluronamide with a compound of formula B:  
         
           
             
             
                 
                 
             
           
         
         wherein Z is —C(═O)OR or —CH 2 OC(═O)R, where R is a C 1  to C 5  alkyl.  
       
     
     
         2 . A method according to  claim 1 , wherein Z is —C(═O)OCH 3  or —CH 2 OC(═O)CH 3 .  
     
     
         3 . A method according to  claim 1 , wherein said 2-iodoadenosine-5′-N-ethyluronamide is prepared from 2-iodoadenosine.  
     
     
         4 . A method according to  claim 3 , further comprising the step of converting said 2-iodoadenosine to the acetonide-protected form of said 2-iodoadenosine of the formula:  
       
         
           
           
               
               
           
         
       
     
     
         5 . A method according to  claim 4 , further comprising the step of oxidizing said acetonide-protected form of said 2-iodoadenosine to a compound of the formula:  
       
         
           
           
               
               
           
         
       
     
     
         6 . A method according to  claim 5 , wherein said oxidizing step is a radical oxidation.  
     
     
         7 . A method according to  claim 5 , wherein said oxidizing step comprises the use of a mixture comprising bis-acetoxyiodobenzene and 2,2,6,6-tetramethyl piperidinyloxy free radical (TEMPO).  
     
     
         8 . A method according to  claim 5 , further comprising the step of converting said compound of the formula:  
       
         
           
           
               
               
           
         
       
       to a compound of the formula:  
       
         
           
           
               
               
           
         
       
     
     
         9 . A method according to  claim 8 , wherein said converting step proceeds as a one pot reaction.  
     
     
         10 . A method according to  claim 8 , wherein said converting step comprises the use of a succinimide derivative and an excess of ethylamine.  
     
     
         11 . A method according to  claim 8 , wherein said converting step comprises the use of a composition comprising 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, ethanol and ethylamine.  
     
     
         12 . A method according to  claim 8 , further comprising the step of deprotecting said compound of the formula:  
       
         
           
           
               
               
           
         
       
       to form said 2-iodoadenosine-5′-N-ethyluronamide.  
     
     
         13 . A method according to  claim 1 , wherein said compound of formula B is prepared from 1,4-methanol cyclohexane.  
     
     
         14 . A method according to  claim 13 , wherein said 1,4-methanol cyclohexane is prepared from a reaction mixture comprising trans-1,4-dimethyl-cyclohexanedicarboxylate.  
     
     
         15 . A method according to  claim 14 , wherein said reaction mixture comprises less than about 0.2% by weight, based on the total weight of the 1,4-dimethyl-cyclohexanedicarboxylate, of cis-1,4-dimethyl-cyclohexanedicarboxylate.  
     
     
         16 . A method according to  claim 13 , wherein said 1,4-methanol cyclohexane is prepared by a process comprising the step of reducing 1,4-dimethyl-cyclohexanedicarboxylate.  
     
     
         17 . A method according to  claim 13 , further comprising the step of preparing the mono-tosyl derivative of said 1,4-methanol cyclohexane.  
     
     
         18 . A method according to  claim 17 , further comprising the step of acetylide substitution of said tosyl derivative of the formula:  
       
         
           
           
               
               
           
         
       
       to form an acetylide-substituted compound of the formula:  
       
         
           
           
               
               
           
         
       
     
     
         19 . A method according to  claim 18 , further comprising the step of converting said acetylide-substituted compound to a compound of formula B, where Z is —CH 2 OC(═O)R.  
     
     
         20 . A method according to  claim 18 , further comprising the steps of oxidizing said acetylide-substituted compound and esterifying said product of said oxidation to a compound of formula B, where Z is —C(═O)OR.  
     
     
         21 . A method for preparing 2-iodoadenosine-5′-N-ethyluronamide, comprising the steps of: 
 providing 2-iodoadenosine;    protecting the hydroxyl groups of said 2-iodoadenosine with an acetonide group;    oxidizing the primary alcohol of said acetonide-protected 2-iodoadenosine to an acid derivative of said acetonide-protected 2-iodoadenosine;    converting said acid derivative to an N-ethylamide derivative of said acetonide-protected 2-iodoadenosine; and    deprotecting said N-ethylamide of said acetonide-protected 2-iodoadenosine to form said 2-iodoadenosine-5′-N-ethyluronamide.    
     
     
         22 . A method for preparing a compound of formula B:  
       
         
           
           
               
               
           
         
         wherein Z is —CH 2 OC(═O)R, where R is a C 1  to C 5  alkyl, comprising the steps of.  
         providing 1,4-methanol cyclohexane; and  
         preparing a mono-tosyl derivative of said 1,4-methanol cyclohexane;  
         preparing an acetylide-substituted compound of the formula:  
         
           
             
             
                 
                 
             
           
         
         from said mono-tosyl derivative of said 1,4-methanol cyclohexane; and  
         converting said acetylide-substituted compound to a compound of formula B:  
         
           
             
             
                 
                 
             
           
         
       
     
     
         23 . A method for preparing a compound of formula B:  
       
         
           
           
               
               
           
         
         wherein Z is —C(═O)OR, where R is a C 1  to C 5  alkyl, comprising the steps of.  
         providing 1,4-methanol cyclohexane;  
         preparing a mono-tosyl derivative of said 1,4-methanol cyclohexane;  
         preparing an acetylide-substituted compound of the formula:  
         
           
             
             
                 
                 
             
           
         
         from said mono-tosyl derivative of said 1,4-methanol cyclohexane;  
         oxidizing said acetylide-substituted compound using radical oxidation; and  
         esterifying said product of said oxidation to a compound of formula B:  
         
           
             
             
                 
                 
             
           
         
       
     
     
         24 . A method according to  claim 23 , wherein said oxidizing step comprises the use of a mixture comprising bis-acetoxyiodobenzene and 2,2,6,6-tetramethyl piperidinyloxy free radical (TEMPO).  
     
     
         25 . A method according to  claim 22  or  claim 23 , wherein said 1,4-methanol cyclohexane is prepared from a reaction mixture comprising trans-1,4-dimethyl-cyclohexanedicarboxylate.  
     
     
         26 . A method according to  claim 25 , wherein said reaction mixture comprises less than about 0.2% by weight, based on the total weight of the 1,4-dimethyl-cyclohexanedicarboxylate, of cis-1,4-dimethyl-cyclohexanedicarboxylate.  
     
     
         27 . A method according to  claim 22  or  claim 23 , wherein said 1,4-methanol cyclohexane is prepared by a process comprising the step of reducing 1,4-dimethyl-cyclohexanedicarboxylate.