Coupling process and intermediates useful for preparing cephalosporins

Abstract

The process of the present invention and the preparation of the compound of the present invention are illustrated in the following reaction schemes. Except where otherwise indicated, in the reaction schemes and discussion that follow, substituents R 1 , R 2 , R 3 , L, A 1 , A 2 and X are as defined above unless otherwise described. This invention relates to a novel process for the preparation of 3 -cyclic-ether-substituted cephalosporins of formula I wherein the group CO 2 R 1 is a carboxylic acid or a carboxylate salt and R 2 has the formula: wherein A 1 is selected from the group consisting of C 6-10 aryl, C 1-10 heteroaryl and C 1-10 heterocyclyl; A 2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 1-6 alkyl(CO)(C 1-6 )alkyl-O—, HO(CO)(C 1-6 )alkyl, mono-(C 6-10 aryl)(C 1-6 alkyl), di-(C 6-10 aryl)(C 1-6 alkyl) and tri-(C 6-10 aryl)(C 1-6 alkyl); from a zwitterionic compound of formula II; or from a compound of formula V: wherein R 2 is as defined above and R 3 is para-nitrobenzyl or allyl. The invention also relates to the preparation of the above compounds of formulae II and V.

1 . A process for preparing a 3-cyclic-ether-substituted cephalosporin of the formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
 wherein  
 the group CO 2 R 1  is a carboxylic acid or a carboxylate salt; and  
 R 2  has the formula:  
                     
 wherein  
 A 1  is selected from the group consisting of C 6-10 aryl, C 1-10 heteroaryl and C 1-10 heterocyclyl;  
 A 2  is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 1-6 alkyl(CO)(C 1-6 )alkyl-O—, HO(CO)(C 1-6 )alkyl, mono-(C 6-10 aryl)(C 1-6 alkyl), di-(C 6-10 aryl)(C 1-6 alkyl), and tri-(C 6-10 aryl)(C 1-6 alkyl);  
 comprising reacting a compound of formula II:  
                     
 with a compound of the formula III: 
 R 2 L  III; 
 wherein  
 R 2  is as defined above; and  
 L is selected from the group consisting of hydroxy, halo, azido, mono(C 1-6 alkyl)carbonate, (C 1-6 alkyl)carboxylate, (C 6-10 aryl)carboxylate, mono-(C 6-10 aryl)(C 1-6 alkyl)carboxylate, di-(C 6-10 aryl)(C 1-6 alkyl)carboxylate, di(C 1-6 alkyl)phosphorothioate, (C 1-6 alkyl)sulfonyl, mono-(C 1-6 alkyl)(C 6-10 aryl)sulfonyl, di-(C 1-6 alkyl)(C 6-10 aryl)sulfonyl, (C 1-6 alkyl)-(CO)—S—, cyano-C 1-6 alkoxy, C 6-10 aryloxy, 3-benzthiazolyloxy, 8-quinolinyloxy and N-oxy-succinimidyl;  
 in the presence of a solvent, a base, an optional coupling agent and an optional catalyst.  
 
     
     
         2 . The process according to  claim 1  further comprising the step of preparing said compound of formula II by reacting a compound of formula IV:  
       
         
           
           
               
               
           
         
       
       wherein R 3  is para-nitrobenzyl or allyl; and X is halo; 
 with a suitable deprotecting agent; in the presence of a solvent.  
 
     
     
         3 . A process for preparing a 3-cyclic-ether-substituted cephalosporin of the formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
 wherein the group CO 2 R 1  is a carboxylic acid or a carboxylate salt; and  
 R 2  has the formula:  
                     
 wherein A 1  is selected from the group consisting of C 6-10 aryl, C 1-10 heteroaryl and C 1-10 heterocyclyl;  
 A 2  is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 1-6 alkyl(CO)(C 1-6 )alkyl-O—, HO(CO)(C 1-6 )alkyl, mono-(C 6-10 aryl)(C 1-6 alkyl), di-(C 6-10 aryl)(C 1-6 alkyl) and tri-(C 6-10 aryl)(C 1-6 alkyl);  
 comprising reacting a compound of formula V:  
                     
 wherein R 2  is as defined above; and R 3  is para-nitrobenzyl or allyl;  
 with a suitable deprotecting agent in the presence of a solvent.  
 
     
     
         4 . The process according to  claim 3  further comprising preparing said compound of formula V by reacting a compound of formula IV:  
       
         
           
           
               
               
           
         
       
       wherein R 3  is para-nitrobenzyl or allyl; and X is halo; 
 with a compound of the formula III: 
 R 2 L  III; 
 wherein R 2  has the formula:  
                     
 wherein A 1  is selected from the group consisting of C 6-10 aryl, C 1-10 heteroaryl and C 1-10 heterocyclyl;  
 A 2  is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 1-6 alkyl(CO)(C 1-6 )alkyl-O—, HO(CO)(C 1-6 )alkyl, mono-(C 6-10 aryl)(C 1-6 alkyl), di-(C 6-10 aryl)(C 1-6 alkyl) and tri-(C 6-10 aryl)(C 1-6 alkyl); and  
 L is selected from the group consisting of hydroxy, halo, azido, mono(C 1-6 alkyl)carbonate, (C 1-6 alkyl)carboxylate, (C 6-10 aryl)carboxylate, mono-(C 6-10 aryl)(C 1-6 alkyl)carboxylate, di-(C 6-10 aryl)(C 1-6 alkyl)carboxylate, di(C 1-6 alkyl)phosphorothioate, (C 1-6 alkyl)sulfonyl, mono-(C 1-6 alkyl)(C 6-10 aryl)sulfonyl, di-(C 1-6 alkyl)(C 6-10 aryl)sulfonyl, (C 1-6 alkyl)-(CO)—S—, cyano-C 1-6 alkoxy, C 6-10 aryloxy, 3-benzthiazolyloxy, 8-quinolinyloxy and N-oxy-succinimidyl;  
 in the presence of a solvent.  
 
     
     
         5 . The process according to  claim 1 , wherein said A 1  moiety of said R 2  is C 1-10 heteroaryl selected from the group consisting of furyl, thienyl, pyridyl, aminothiazolyl and aminothiadiazolyl, wherein said amino moiety of said aminothiazolyl or aminothiadiazolyl is optionally protected.  
     
     
         6 . A process according to  claim 1 , wherein said A 2  moiety of said R 2  is C 1-6 alkyl.  
     
     
         7 . A process according to  claim 1 , wherein L of said compound of the formula III is selected from the group consisting of halo, methanesulfonyl, diethylphosphorothioate and 3-benzthiazolyloxy.  
     
     
         8 . A process according to  claim 1 , wherein said compound of formula III has a formula IIIa:  
       
         
           
           
               
               
           
         
       
       and wherein L is selected from the group consisting of halo, methanesulfonyl, diethylphosphorothioate and 3-benzthiazolyloxy.  
     
     
         9 . A process according to  claim 1 , wherein said solvent is water, acetone, tetrahydrofuran, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile, methylene chloride, 1,2-dichloroethane or mixtures thereof.  
     
     
         10 . A process according to  claim 1 , wherein said solvent is water, acetone, or mixtures thereof.  
     
     
         11 . A process according to  claim 1 , wherein a catalyst is used.  
     
     
         12 . A process according to  claim 11  wherein said catalyst is a Lewis acid catalyst selected from the group consisting of boron trihalide and aluminum halide.  
     
     
         13 . A process according to  claim 1  wherein said base is diisopropylethylamine or sodium hydroxide.  
     
     
         14 . A process according to  claim 1 , wherein said coupling agent is selected from the group consisting of N,N′-diethylcarbodiimide, N,N′-dipropyl carbodiimide, N,N′-diisopropylcarbodiimide, N,N′-dicyclohexylcarbodiimide, N-ethyl-N′-[3-(dimethylamino)propyl]carbodiimide, N,N′-carbonyldiimidazole and N,N′-carbonyldithiazole.  
     
     
         15 . A process according to  claim 1 , wherein said coupling agent is N,N′-dicyclohexylcarbodiimide.  
     
     
         16 . A process according to  claim 1 , wherein said X is chloro.  
     
     
         17 . A process according to  claim 2 , wherein said R 3  is para-nitrobenzyl and said suitable deprotecting agent is sodium dithionite or a catalytic hydrogenating agent.  
     
     
         18 . A process according to  claim 2 , wherein said R 3  is allyl and said suitable deprotecting agent is tetrakis triphenylphosphine palladium (0).  
     
     
         19 . A process according to  claim 17 , wherein said solvent is acetone, water, tetrahydrofuran or mixtures thereof.  
     
     
         20 . A process according to  claim 4 , wherein said solvent is methylene chloride, tetrahydrofuran or mixtures thereof.  
     
     
         21 . A compound of formula II:  
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound according to  claim 21  wherein said compound of the formula II has an enantiomeric or diastereomeric purity of 96% to 100%.  
     
     
         23 . A compound of formula V:  
       
         
           
           
               
               
           
         
       
       wherein R 2  is acyl; and R 3  is para-nitrobenzyl or allyl.  
     
     
         24 . The compound according to  claim 23  wherein said compound of the formula V has an enantiomeric or diastereomeric purity of 96% to 100%.