Selective process for producing an anomer of a 1-phosphorylated saccharide derivative and process for producing a nucleoside

Abstract

A desired isomer is selectively prepared by phosphorolyzing and isomerizing an anomer mixture of a 1-phosphorylated saccharide derivative while crystallizing one of the isomers to displace the equilibrium. Furthermore, using the action of a nucleoside phosphorylase, a nucleoside is prepared from the 1-phosphorylated saccharide derivative obtained and a base with improved stereoselectivity and a higher yield. This process is an anomer-selective process for preparing a 1-phosphorylated saccharide derivative and a nucleoside.

1 . A process for selectively preparing either α or β isomer of a 1-phosphorylated saccharide derivative monomer comprising the steps of phosphorolyzing and isomerizing an anomer mixture of a 1-phosphorylated saccharide derivative to give α and β isomers of the 1-phosphorylated saccharide derivative monomer and selectively crystallizing one of these isomers to displace the equilibrium between these anomers.  
   
   
       2 . A process for selectively preparing either α or β isomer of a 1-phosphorylated saccharide derivative monomer comprising the steps of phosphorolyzing and isomerizing an anomer mixture of a 1-phosphorylated saccharide derivative represented by formula (1):  
     
       
         
         
             
             
         
       
       where R 1  and R 2  independently represents hydrogen, methyl, protected hydroxymethyl or protected carboxyl; R 3  represents acyl; R 4  represents a protective group for hydroxy; X represents halogen, alkoxy or alkylthio; W represents oxygen or sulfur; Z represents oxygen, sulfur or optionally substituted carbon; m represents an integer of 1 to 3; n represents 0 or 1; p and q represents an integer of 0 to 4; and r represents 0 or 1; provided that p, q, r and n meet the conditions of p+r≦n+1 and q≦2x(n+1)−2x(p+r) when Z is oxygen or sulfur and of p+r≦n+2 and q≦2x(n+2)−2x(p+r) when Z is carbon, to give α and β isomers of the 1-phosphorylated saccharide derivative monomer and selectively crystallizing one of these isomers to displace the equilibrium between these anomers:  
     
   
   
       3 . A process for preparing a 1-phosphorylated saccharide derivative monomer represented by formula (3):  
     
       
         
         
             
             
         
       
       wherein R 1  and R 2  independently represents hydrogen, methyl, hydroxymethyl or carboxyl; R 3  represents hydrogen or acyl; and X, W, Z, n, p, q and r are as defined above, comprising the steps of phosphorolyzing and isomerizing an anomer mixture of a 1-phosphorylated saccharide derivative represented by formula (1):  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , R 4 , X, W, Z, m, n, p, q and r are as defined in  claim 2 , to give α and β isomers of the 1-phosphorylated saccharide derivative monomer; selectively crystallizing one of these isomers to displace the equilibrium between these anomers; and then removing the protective group represented by R 4 .  
     
   
   
       4 . A trimer, dimer or monomer of a 1-phosphorylated saccharide derivative represented by formula (4):  
     
       
         
         
             
             
         
       
       wherein R 1  and R 2  independently represents hydrogen, methyl, hydroxymethyl protected with substituted benzoyl or protected carboxyl; R 4  represents hydrogen or a protective group for hydroxy; and R 3 , X, W, Z, m, n, p, q and r are as defined in  claim 2 , or salts thereof.  
     
   
   
       5 . A 1-phosphorylated saccharide derivative monomer represented by formula (5):  
     
       
         
         
             
             
         
       
       wherein p and q represents an integer of 0 to 3; r represents 0 or 1; and R 1 , R 2 , R 3 , R 4 , X, W and Z are as defined in  claim 2;  provided that p, q and r meet the conditions of p+q+r≦3 when Z is oxygen or sulfur and of p+q+r≦5 when Z is carbon, or salts thereof.  
     
   
   
       6 . A 1-phosphorylated saccharide derivative monomer represented by formula (6):  
     
       
         
         
             
             
         
       
       wherein R 1  and R 2  independently represents hydrogen, methyl, hydroxymethyl or carboxy; and R 3 , X, W, Z, n, p, q and r are as defined in  claim 2  other than natural products, or salts thereof.  
     
   
   
       7 . The 1-phosphorylated saccharide derivative monomer as claimed in  claim 6  wherein n=1 in formula (6), or its salt.  
   
   
       8 . The 1-phosphorylated saccharide derivative monomer as claimed in  claim 7  wherein R 1  is hydroxymethyl; R 2  is hydrogen; p and r are 0; and X is fluorine, or its salt.  
   
   
       9 . A process for preparing a 1-phosphorylated saccharide represented by formula (20):  
     
       
         
         
             
             
         
       
       wherein R 11  represents protected hydroxymethyl and R 14  represents a protective group for hydroxy, comprising the steps of treating a compound represented by formula (18):  
       
         
           
           
               
               
           
         
       
       wherein R 11  and R 14  are as defined above, with phosphoric acid in the presence of a base to give an anomer mixture of a 1-phosphorylated saccharide derivative represented by formula (19):  
       
         
           
           
               
               
           
         
       
       wherein R 11  and R 14  are as defined above and m is as defined in  claim 2;  phosphorolyzing and isomerizing the mixture; and displacing the equilibrium between the anomer isomers by selectively crystallizing an α-isomer formed.  
     
   
   
       10 . A process for preparing 2-deoxy-α-D-ribose-1-phosphate comprising the steps of treating a compound represented by formula (18):  
     
       
         
         
             
             
         
       
       wherein R 11  represents protected hydroxymethyl and R 14  represents a protective group for hydroxy, with phosphoric acid in the presence of a base to give an anomer mixture of a 1-phosphorylated saccharide derivative represented by formula (19):  
       
         
           
           
               
               
           
         
       
       wherein R 11  and R 14  are as defined above and m is as defined in  claim 2;  phosphorolyzing and isomerizing the mixture; displacing the equilibrium between the anomer isomers by selectively crystallizing an α-isomer formed to give the α-isomer; and then removing the protective group.  
     
   
   
       11 - 20 . (canceled)  
   
   
       21 . A synthetic nucleoside represented by formula (11):  
     
       
         
         
             
             
         
       
       wherein B, R 1 , R 2 , R 3 , R 4 , X, W, Z, n, p, q and r are as defined for formulas (8) in claim  11  or its salt, excluding trifluorothymidine, ribavirin, orotidine, uracil arabinoside, adenine arabinoside, 2-methyl-adenine arabinoside, 2-chloro-hypoxanthine arabinoside, thioguanine arabinoside, 2,6-diaminopurine arabinoside, cytosine arabinoside, guanine arabinoside, thymine arabinoside, enocitabine, gemcitabine, azidothymidine, idoxuridine, dideoxyadenosine, dideoxyinosine, dideoxycytidine, didehydrodeoxythymidine, thiadideoxycytidine, sorivudine, 5-methyluridine, virazole, thioinosine, tegafur, doxifluridine, bredinin, nebularine, allopurinol uracil, 5-fluorouracil, 2′-aminouridine, 2′-aminoadenosine, 2′-aminoguanidine, 2-chloro-2′-aminoinosine, DMDC and FMDC.  
     
   
   
       22 . A synthetic nucleoside represented by formula (12):  
     
       
         
         
             
             
         
       
       wherein B, R 1 , R 2 , R 3 , R 4 , X, W, Z, n, p, q and r are as defined for formulas (8) in claim  11  or its salt, excluding trifluorothymidine, ribavirin, orotidine, uracil arabinoside, adenine arabinoside, 2-methyl-adenine arabinoside, 2-chloro-hypoxanthine arabinoside, thioguanine arabinoside, 2,6-diaminopurine arabinoside, cytosine arabinoside, guanine arabinoside, thymine arabinoside, enocitabine, gemcitabine, azidothymidine, idoxuridine, dideoxyadenosine, dideoxyinosine, dideoxycytidine, didehydrodeoxythymidine, thiadideoxycytidine, sorivudine, 5-methyluridine, virazole, thioinosine, tegafur, doxifluridine, bredinin, nebularine, allopurinol uracil, 5-fluorouracil, 2′-aminouridine, 2′-aminoadenosine, 2′-aminoguanidine, 2-chloro-2′-aminoinosine, DMDC and FMDC.  
     
   
   
       23 . A nucleoside represented by formula (13):  
     
       
         
         
             
             
         
       
       wherein B, R 1 , R 2 , R 3 , R 4 , X, W, Z, n, p, q and r are as defined for formulas (8) in claim  11  or its salt, excluding trifluorothymidine, ribavirin, orotidine, uracil arabinoside, adenine arabinoside, 2-methyl-adenine arabinoside, 2-chloro-hypoxanthine arabinoside, thioguanine arabinoside, 2,6-diaminopurine arabinoside, cytosine arabinoside, guanine arabinoside, thymine arabinoside, enocitabine, gemcitabine, azidothymidine, idoxuridine, dideoxyadenosine, dideoxyinosine, dideoxycytidine, didehydrodeoxythymidine, thiadideoxycytidine, sorivudine, 5-methyluridine, virazole, thioinosine, tegafur, doxifluridine, bredinin, nebularine, allopurinol uracil, 5-fluorouracil, 2′-aminouridine, 2′-aminoadenosine, 2′-aminoguanidine, 2-chloro-2′-aminoinosine, DMDC and FMDC.  
     
   
   
       24 . A 1-phosphorylated saccharide represented by formula (20):  
     
       
         
         
             
             
         
       
       wherein R 11  represents protected hydroxymethyl; and R 14  represents a protective group for hydroxy, or its salt.