9-hydrazone and 9-azine erythromycin derivatives and a process for making the same

Abstract

Disclosed are 9-hydrazone erythromycin and 9-azine erythromycin derivatives and the processes for making the same. The compounds are useful intermediates for conversion into 6-O-alkyl erythromycin. Also disclosed are the processes for converting the compounds into 6-O-alkyl erythromycin.

1. A compound having the formula: 
                 
 
       wherein R and R 1  are independently a hydrogen or a nitrogen-protecting group;
 R 2  and R 4  are independently a hydrogen or a hydroxy-protecting group;  
 R 3  is a loweralkyl or an aryl group;  
 R 5  is a hydrogen, hydroxy or a protected hydroxy group; and  
 R 6  and R 7  are independently at each occurrence a hydrogen, an alkyl or an aryl group.  
 
     
     
       2. The compound of Formula I according to  claim 1 , wherein R and R 1  are independently a hydrogen and triisopropylsilyl, R 2  and R 4  are each trimethylsilyl, R 3  is methyl and R 5  is hydroxy. 
     
     
       3. The compound of Formula I according to  claim 1 , wherein R and R 1  are independently a hydrogen and N-t-butyldimethylsilyl, R 2  and R 4  are each trimethylsilyl, R 3  is methyl and R 5  is hydroxy. 
     
     
       4. The compound of Formula II according to  claim 1 , wherein R 6  and R 7  are independently a hydrogen and N-isopropylidene, R 2  and R 4  are each trimethylsilyl, R 3  is methyl and R 5  is hydroxy. 
     
     
       5. The compound of Formula II according to  claim 1 , wherein R 6  and R 7  are independently a hydrogen and N-cyclohexylidene, R 2  and R 4  are each trimethylsilyl, R 3  is methyl and R 5  is hydroxy. 
     
     
       6. A process for preparing a compound of the formula: 
                 
 wherein R and R 1  are independently a hydrogen or a nitrogen-protecting group;  
 R 2  and R 4  are independently a hydrogen or a hydroxy-protecting group;  
 R 3  is a loweralkyl or aryl group; and  
 R 5  is a hydrogen, hydroxy or a protected hydroxy group; comprising:  
 a) reacting an erythromycin of the formula: 
                 
 
 
       wherein R 5  is as defined above, with hydrazine to convert the 9-keto into a corresponding 9-hydrazone erythromycin derivative;
 b) protecting the 2′-hydroxy, and optionally the 4″-hydroxy, and the hydrazone nitrogen with hydroxy and nitrogen protecting groups, respectively; and  
 c) selectively alkylating the 6-hydroxy group.  
 
     
     
       7. The process according to  claim 6 , wherein R and R 1  are independently a hydrogen and triisopropylsilyl, R 2  and R 4  are each trimethylsilyl, R 3  is methyl and R 5  is hydroxy. 
     
     
       8. The process according to  claim 6 , wherein R and R 1  are independently a hydrogen and N-t-butyldimethylsilyl, R 2  and R 4  are each trimethylsilyl, R 3  is methyl and R 5  is hydroxy. 
     
     
       9. A process for preparing a compound of the formula: 
                 
 wherein R 2  and R 4  are independently a hydrogen or a hydroxy-protecting group;  
 R 3  is a loweralkyl or aryl group;  
 R 5  is a hydrogen, hydroxy or a protected hydroxy group; and  
 R 6  and R 7  are independently at each occurrence a hydrogen, an alkyl or an aryl group; comprising:  
 a) reacting an erythromycin of the formula: 
                 
 
 
       wherein R 5  is as defined above, with hydrazine to convert the 9-keto into a corresponding 9-hydrazone erythromycin derivative;
 b) reacting the hydrazone from step (a) with a ketone, an aldehyde or an acetal thereof or an orthoformate to produce a corresponding 9-azine erythromycin derivative;  
 c) protecting the 2′- and optionally the 4″-hydroxy and azine nitrogen with hydroxy and nitrogen protecting groups, respectively; and  
 d) selectively alkylating the 6-hydroxy group.  
 
     
     
       10. The process according to  claim 9 , wherein R 6  and R 7  are independently a hydrogen and N-isopropylidene, R 2  and R 4  are each trimethylsilyl, R 3  is methyl and R 5  is hydroxy. 
     
     
       11. The process according to  claim 9 , wherein R 6  and R 7  are independently a hydrogen and N-isopropylidene  N- cyclohexylidene , R 2  and R 4  are each trimethylsilyl, R 3  is methyl and R 5  is hydroxy. 
     
     
       12. The process according to  claim 6 , wherein the protected hydroxyl and nitrogen groups in the product of step (c) are deprotected to yield the corresponding 6-O-loweralkyl or aryl erythromycin A 9-hydrazone. 
     
     
       13. The process according to  claim 9 , further comprising deprotecting the product obtained in step (d) with hydroxylamine to afford the corresponding 6-O-loweralkyl or aryl erythromycin A 9-oxime derivative. 
     
     
       14. The process according to  claim 9 , further comprising:
 (a) reacting the compound obtained in step (d) with hydrazine to afford a corresponding 9-hydrazone; and  
 (b) deprotecting the 9-hydrazone with nitrous acid to afford the corresponding 6-O-loweralkyl or aryl erythromycin A 9-hydrazone.  
 
     
     
       15. A process for preparing  6 - O - alkylerythromycins comprising:      performing the steps of    claim 6   ; then        converting the  9   - N - alkylhydrazone into a  9   - keto; and        deprotecting the  2 ′ - hydroxyl and optionally the  4 ″ - hydroxyl groups.     
     
     
       16. The process of  claim 15 , wherein R and R 1    are independently a hydrogen and triisopropylsilyl, R   2    and R   4    are each trimethylsilyl, R   3    is methyl and R   5    is hydroxy.   
     
     
       17. The process of  claim 15 , wherein R and R 1    are independently a hydrogen and t - butyldimethylsilyl, R   2    and R   4    are each trimethylsilyl, R   3    is methyl and R   5    is hydroxy.   
     
     
       18. A process for preparing  6 - O - alkylerythromycins comprising:      performing the steps of    claim 9   ; then        converting the  9   - N - alkylhydrazine into  9   - keto; and        deprotecting the  2 ′ - hydroxyl and optionally the  4 ″ - hydroxyl groups.     
     
     
       19. The process of  claim 18 , wherein R 6    and R   7    are independently a hydrogen and isopropylidene, R   2    and R   4    are each trimethylsilyl, R   3    is methyl and R   5    is hydroxy.   
     
     
       20. The process of  claim 18 , wherein R 6    and R   7    are independently a hydrogen and cyclohexylidene, R   2    and R   4    are each trimethylsilyl, R   3    is methyl and R   5    is hydroxy.   
     
     
       21. The process according to  claim 14 , further comprising converting the  9 - hydrazone into a  9   - keto to afford a  6   - O - loweralkyl or aryl erythromycin A.   
     
     
       22. A process for preparing  6 - O - alkylerythromycins comprising:      performing the steps of    claim 6   ; then        deprotecting the hydroxy and nitrogen protecting groups.     
     
     
       23. A process for preparing  6 - O - alkylerythromycins comprising:      performing the steps of    claim 9   ; then        reacting with hydroxylamine; and then        deprotecting with sodium hydrogen sulfite.     
     
     
       24. A process for preparing  6 - O - alkylerythromycins comprising:      performing the steps of    claim 9   ; then        reacting with hydrazine; and then      deprotecting with nitrous acid.