Synthesis of acyclic nucleoside derivatives

Abstract

Methods and novel intermediates for the preparation of acyclic nucleoside derivatives of the formula: where one of R 1 and R 2 is an amino acid acyl group and the other of R 1 and R 2 is a —C(O)C 3 -C 21 saturated or monounsaturated, optionally substituted alkyl and R 3 is OH or H; or a pharmaceutically acceptable salt thereof.

1 . A process for the preparation of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 10  is C 3 -C 21  saturated or monounsaturated, optionally substituted alkyl and R 11  is isopropyl or isobutyl, comprising 
 a) deprotecting the acetal of the compound of the formula:  
                     
 wherein R 6  and R 7  are loweralkyl or benzyl or R 6  and R 7  taken together are —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 — and R 10  is as defined above;  
 b) reducing the aldehyde substituent of the product of step a) to provide the alcohol of the formula:  
                     
 wherein R 10  is as defined above; and  
 c) reacting the product of step b) with P 1 NHCH(R 11 )COOH or an activated derivative thereof or with P 1 NHCH(R 11 )C(O)—O—C(O)CH(R 11 )NHP 1  wherein R 11  is as defined above and P 1  is an N-protecting group.  
 
     
     
         2 . The process of  claim 1  further comprising N-deprotecting the product of step c).  
     
     
         3 . The process of  claim 1  wherein R 6  and R 7  are —CH 3  or —CH 2 CH 3  or R 6  and R 7  taken together are —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —, R 10  is C 9 -C 19  alkyl and P 1  is t-butyloxycarbonyl or benzyloxycarbonyl.  
     
     
         4 . The process of  claim 1  wherein R 6  and R 7  are —CH 2 CH 3 , R 10  is —(CH 2 ) 16 CH 3  and P 1  is t-butyloxycarbonyl or benzyloxycarbonyl.  
     
     
         5 . The process of  claim 1  wherein the acetal is deprotected by reaction with an acid or an acidic resin.  
     
     
         6 . The process of  claim 1  wherein the aldehyde substituent of the product of step a) is reduced with borane t-butyl amine complex.  
     
     
         7 . A process for the preparation of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 6  and R 7  are loweralkyl or benzyl or R 6  and R 7  taken together are —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 — and R 10  is C 3 -C 21  saturated or monounsaturated, optionally substituted alkyl, comprising reacting a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 6  and R 7  are as defined above with R 10 COOH or an activated derivative thereof.  
     
     
         8 . The process of  claim 7  wherein the activated derivative of R 10 COOH is R 10 C(O)OS(O) 2 R 30  wherein R 30  is loweralkyl, phenyl or toluyl or R 10 C(O)OC(O)R 10  or R 10 C(O)OC(O)R 10a  wherein R 10a  is loweralkyl and wherein R 10  is —(CH 2 ) 16 CH 3 .  
     
     
         9 . The process of  claim 7  wherein the activated derivative of R 10 COOH is CH 3 (CH 2 ) 16 C(O)OC(O)C(CH 3 ) 3 .  
     
     
         10 . The process of  claim 7  wherein CH 3 (CH 2 ) 16 C(O)OC(O)C(CH 3 ) 3  is prepared in situ.  
     
     
         11 . A process for preparing a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 10  is C 3 -C 21  saturated or monounsaturated, optionally substituted alkyl comprising: 
 a) reacting a compound of the formula:  
                     
 wherein wherein R 6  and R 7  are loweralkyl or benzyl or R 6  and R 7  taken together are —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 — with R 10 COOH or an activated derivative thereof wherein R 10  is C 3 -C 21  saturated or monounsaturated, optionally substituted alkyl to provide a compound of the formula:  
                     
 wherein R 6 , R 7  and R 10  are defined as above,  
 b) deprotecting the acetal of the product of step a) and  
 c) reducing the aldehyde substituent of the product of step b).  
 
     
     
         12 . The process of  claim 11  wherein the products of steps a) and b) are not isolated.  
     
     
         13 . The process of  claim 11  wherein R 6  and R 7  are —CH 2 CH 3  and R 10  is —(CH 2 ) 16 CH 3 .  
     
     
         14 . The process of  claim 11  wherein the activated derivative of R 10 COOH is CH 3 (CH 2 ) 16 C(O)OC(O)C(CH 3 ) 3 .  
     
     
         15 . The process of  claim 11  wherein the acetal is deprotected with triflic acid and the aldehyde substituent of the product of step b) is reduced with borane t-butyl amine complex.