Method of preparing 4-r-substituted 4-demethoxydaunorubicin

Abstract

A method of synthesizing 4-R-substituted anthracyclines and their corresponding salts from 4-demethyldaunorubicin includes the steps of treating 4-demethyldaunorubicin with a sulfonylating agent to form 4-demethyl-4-sulfonyl-R 3 -daunorubicin. 4-Demethyl-4-R 3 -sulfonyl-daunorubicin is then subject to a reducing agent in the presence of a transition metal catalyst in a temperature range of about 30° C. to about 100° C. in a polar aprotic solvent in an inert atmosphere. Protected 4-demethoxy-4-R-daunomycin then undergoes hydrolysis in a basic solution to form the 4-R-substituted anthracyclines. The novel method lacks the step of forming a stereospecific glycoside bond between aglycone and aminoglycoside. The method also increases the yield of the final product up to 30 to 40%.

1 . A process for preparing 4-R-substituted anthracyclines of formula (I)  
     
       
         
         
             
             
         
       
     
     wherein R is defined as hydrogen, a linear or branched oxy[alkyl, alkenyl or alkynyl] group comprised of one to sixteen carbon atoms, or a complex ester group COOR 1 ′, wherein R 1 ′ is a linear or branched alkyl, alkenyl or alkyne group of up to ten carbon atoms, comprising the steps of: 
 (1) providing 4-demethyldaunorubicin or a derivative of 4-demethyldaunorubicin of formula (II)  
                     
  wherein R 1  comprises H, acyl or acyl halide and R 2  comprises H, acyl or acyl halide, carbonate, or Schiff's base;  
 (2) treating the 4-demethyldaunorubicin or the derivative of 4-demethyldaunorubicin of formula (II) with a sulfonylating agent having a chemical formula R 3 —SO 2 —X, wherein R 3  comprises an acyl group, acyl halide group or aryl group, X comprises a halide or —O—SO 2 —R 3  to form 4-demethyl-4-sulfonyl-daunorubicin having formula (III)  
                     
  wherein R 3  comprises an alkyl group, alkyl halide group or an aryl group, R 1  comprises hydrogen, acyl, or acyl halide, and R 2  comprises hydrogen, acyl, acyl halide, carbonate, or Schiff's base;  
 (3) reacting the 4-demethyl-4-sulfonyl-daunorubicin of formula (III) with a reducing agent in the presence of catalytic quantities of a compound having formula (IV)  
   ML p L′ q   (IV)  
  wherein M represent a transition metal atom; L and L′, wherein L and L′ represent the same or different anions or a neutral molecule, and p and q may vary from zero to four, to produce protected 4-demethoxydaunomycin having a formula (V),  
                     
 (4) hydrolyzing the protected 4-demethoxydaunomycin in a basic solution to produce 4-R-substituted anthracyclines of formula (I).  
 
   
   
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