Erythromycin A derivatives and method for preparing same

Abstract

Erythromycin A derivatives represented by the general formula wherein R 1 is a 2-alkenyl group having 3 to 15 carbon atoms, an arylmethyl group, or an arylmethyl group substituted by 1 to 3 of a halogen atom, an alkoxy group 1 to 4 carbon atoms, a nitro group or an alkoxycarbonyl group having 2 to 6 carbon atoms, R 2 is a substituted silyl group and R 3 is a hydrogen atom or R 2 , are disclosed. These compounds are useful as intermediates of the anti-bacterial agents.

1. A process for preparing a 6-O-methylerythromycin A derivative represented by the formula: 
                 
 
       wherein R 1  is:
 a 2-alkenyl group having 3 to 15 carbon atoms,  
 a benzyl group, or  
 a benzyl group substitued substituted by 1 to 3 of a chlorine atom, an alkoxy group having 1 to 4 carbon atoms, a nitro group or an alkoxycarbonyl group having 2 to 6 carbon atoms, and  
 R 2  and R 3  are trimethylsilyl,  
 which comprises reacting, in any desired sequence, erythromycin A 9-oxime with a compound of formula R 1 —X (wherein R 1  is as defined above, and X is a halogen atom) and with a substituted silylating agent having an R 2  group to give a compound represented by the formula; :
                 
 
 
       (wherein R 1 , R 2  and R 3  are as defined above), and then reacting said compound of formula II with a methylating agent selected from the group consisting of methyl bromide, methyl iodide, dimethyl sulfate, methyl p-toluene sulfonate and methyl methane sulfonate, the amount of said methylating agent being 1-3 molar equivalents of said compound of formula II, said trimethylsilyl group (R 2 ) protecting the 2′ hydroxyl group against methylation and preventing the 3′-dimethylamino group from being quaternized with the methylating agent. 
     
     
       2. A process for preparing  6 - O - methylerythromycin A comprising:      reacting, in any desired sequence, erythromycin A  9   - oxime with a compound of formula R   1   —X  ( wherein R   1    is as defined below, and X is a halogen atom )  and with a substituted silylating agent having an R   2    group to give a compound represented by the formula:                          wherein R   1    is:      a  2   - alkenyl group having  3  to  15  carbon atoms,        a benzyl group, or        a benzyl group substituted by  1  to  3  of a chlorine atom, an alkoxy group having  1  to  4  carbon atoms, a nitro group or an alkoxycarbonyl group having  2  to  6  carbon atoms, and          R   2    and R   3    are trimethylsilyl;        then reacting said compound of formula II with a methylating agent selected from the group consisting of methyl bromide, methyl iodide, dimethyl sulfate, methyl p - toluene sulfonate and methyl methane sulfonate, the amount of said methylating agent being  1 - 3  molar equivalents of said compound of formula II, said trimethylsilyl group  ( R   2 )  protecting the  2 ′ hydroxyl group against methylation and preventing the  3   ′- dimethylamino group from being quaternized with the methylating agent;        then eliminating in any desired sequence the R   1   , R   2   , and R   3    groups, wherein the elimination of R   1    is performed by hydrogenolysis;        and then, deoximating with a deoximating agent.     
     
     
       3. A process for preparing  6 - O - methylerythromycin A comprising:      reacting, in any desired sequence, erythromycin A  9   - oxime with a compound of formula R   1   —X  ( wherein R   1    is as defined below, and X is a halogen atom )  and with a substituted silylating agent having an R   2    group to give a compound represented by the formula:                         wherein R   1    is:      a  2   - alkenyl group having  3  to  15  carbon atoms,        a benzyl group, or        a benzyl group substituted by  1  to  3  of a chlorine atom, an alkoxy group having  1  to  4  carbon atoms, a nitro group or an alkoxycarbonyl group having  2  to  6  carbon atoms, and        R   2    and R   3    are trimethylsilyl;          then reacting said compound of formula II with a methylating agent selected from the group consisting of methyl bromide, methyl iodide, dimethyl sulfate, methyl p - toluene sulfonate and methyl methane sulfonate, the amount of said methylating agent being  1 - 3  molar equivalents of said compound of formula II, said trimethylsilyl group  ( R   2 )  protecting the  2 ′ hydroxyl group against methylation and preventing the  3   ′- dimethylamino group from being quaternized with the methylating agent;        eliminating in any desired sequence the R   1   , R   2   , and R   3    groups, wherein the elimination of R   2    and R   3    is performed by treatment with acid in an alcohol;      
       
         and then, deoximating with a deoximating agent. 
       
     
     
       4. A process for preparing  6 - O - methylerythromycin A comprising:      reacting, in any desired sequence, erythromycin A  9   - oxime with a compound of formula R   1   —X  ( wherein R   1    is as defined below, and X is a halogen atom )  and with a substituted silylating agent having an R   2    group to give a compound represented by the formula:                         wherein R   1    is:      a  2   - alkenyl group having  3  to  15  carbon atoms,        a benzyl group, or        a benzyl group substituted by  1  to  3  of a chlorine atom, an alkoxy group having  1  to  4  carbon atoms, a nitro group or an alkoxycarbonyl group having  2  to  6  carbon atoms, and          R   2    and R   3    are trimethylsilyl;      
         then reacting said compound of formula II with a methylating agent selected from the group consisting of methyl bromide, methyl iodide, dimethyl sulfate, methyl p - toluene sulfonate and methyl methane sulfonate, the amount of said methylating agent being  1 - 3  molar equivalents of said compound of formula II, said trimethylsilyl group  ( R   2 )  protecting the  2 ′ hydroxyl group against methylation and preventing the  3   ′- dimethylamino group from being quaternized with the methylating agent;    
       
         eliminating in any desired sequence the R 
         1 
         , R 
         2 
         , and R 
         3  
         groups, wherein the elimination of R 
         2  
         and R 
         3  
         is performed by treatment with tetrabutyl ammoniumfluoride in tetrahydrofuran;  
       
       
         and then, deoximating with a deoximating agent. 
       
     
     
       5. A process for preparing  6 - O - methylerythromycin A comprising:      performing the steps of    claim 1   ; then      eliminating in any desired sequence the R 1   , R   2   , and R   3    groups;  
   wherein the R   1    group is eliminated by homogeneous or heterogeneous hydrogenolysis;    
   and wherein the R   2    and R   3    groups are eliminated by treatment with an acid in an alcohol or with tetrabutyl ammonium fluoride;    
     and then deoximating with a deoximating agent.     
     
     
       6. The process of  claim 5 , wehrein the elimination of R 1    is performed by homogeneous hydrogenolysis.   
     
     
       7. The process of  claim 5 , wherein the elimination of R 1    is performed by heterogeneous hydrogenolysis.   
     
     
       8. The process of  claim 5 , wherein the elimination of R 2    and R   3    is performed by treatment with acid in an alcohol.   
     
     
       9. The process of  claim 5 , wherein the elimination of R 2    and R   3    is performed by treatment with tetrabutyl ammonium fluoride.   
     
     
       10. A process for preparing  6 - O - methylerythromycin A comprising:      performing the steps of    claim 1   ; then        eliminating in any desired sequence the R   1   , R   2   , and R   3    groups;      wherein the R   1    group is eliminated by homogeneous or heterogeneous hydrogenylysis;        and wherein the R   2    and R   3    groups are eliminated by treatment with an acid in an alcohol or with tetrabutyl ammonium fluoride;          and then        deoximating by using sodium hydrogen sulfite, titanium trichloride - ammonium acetate, sodium nitrate - hydrochloric acid, or sodium hydrosulfite.     
     
     
       11. The process of  claim 10 , wherein the elimination of R 1    is performed by homogeneous hydrogenolysis.   
     
     
       12. The process of  claim 10 , wherein the elmination of R 1    is performed by hetergeneous hydrogenolysis.   
     
     
       13. The process of  claim 10 , wherein the elimination of R 2    and R   3    is performed by treatment with acid in an alcohol.   
     
     
       14. The process of  claim 10 , wherein the elimination of R 2    and R   3    is performed by treatment with tetrabutyl ammonium fluoride.   
     
     
       15. The process of  claim 10 , wherein the deoximation is performed by using sodium hydroen sulfite. 
     
     
       16. The process of  claim 10 , wherein the deoximation is performed by using titanium trichloride- ammonium acetate.   
     
     
       17. The process of  claim 10 , wherein the deoximation is performed by using sodium nitrate- hydrochloric acid.   
     
     
       18. The process of  claim 10 , wherein the deoximation is performed by using sodium hydrosulfite.