New Process For The Preparation Of Oxabispidines

Abstract

There is provided a process for the preparation of a compound of formula (I): which process comprises reaction of a compound of formula (TI): with either a compound of formula (ITT): or acrylamide, followed, in the latter case, by reaction of the resulting intermediate of formula (IV): with an alcohol of formula R 2 ═OH and an agent that promotes, or agents that in combination promote, rearrangement and oxidation of the compound of formula IV to an intermediate isocyanate, which may then react with the alcohol of formula R 2 ═OH, and wherein R 1 , R 2 and R 16 have meanings given in the description.

1 . A process for the preparation of a compound of formula I,  
     
       
         
         
             
             
         
       
     
     wherein R 1  represents H, an amino protective group or a structural fragment of formula la,  
     
       
         
         
             
             
         
       
     
     in which 
 R 3  represents H, halo, C 1-6  alkyl, —OR 6 , -E-N(R 7 )R 8  or, together with R 4 , represents ═O;  
 R 4  represents H, C 1-6  alkyl or, together with R 3 represents ═O;  
 R 6  represents H, C 1-6  alkyl, -E-aryl, -E-Het 1 , —C(O)R 9a , —C(O)OR 9b  or —C(O)N(R 10a )R 10b ;  
 R 7  represents H, C 1-6  alkyl, -E-aryl, -E-Het 1 , —C(O)R 9a , —C(O)OR 9b , —S(O) 2 R 9c , —[C(O)] p N(R 10a )R 10b  or —C(NH)NH 2 ;  
 R 8  represents H, C 1-6  alkyl, -E-aryl or —C(O)R 9d ;  
 R 9a  to R 9d  independently represent, at each occurrence, C 1-6  alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het 2 ), aryl, Het 3 , or R 9a  and R 9d  independently represent H;  
 R 10a  and R 10b  independently represent, at each occurrence, H or C 1-6  alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het 4 ), aryl, Het 5 , or together represent C 3-6  alkylene, optionally interrupted by an O atom;  
 E represents, at each occurrence, a direct bond or C 1-4  alkylene;  
 p represents 1 or 2;  
 A represents -G-, -J-N(R 11 )— or -J-O— (in which latter two groups, N(R 11 )— or O— is attached to the carbon atom bearing R 3  and R 4 );  
 B represents -Z-, -Z-N(R 12 )—, —N(R 12 )-Z-, -Z-S(O) n — or -Z-O— (in which latter two groups, Z is attached to the carbon atom bearing R 3  and R 4 ;  
 G represents a direct bond or C 1-6  alkylene;  
 J represents C 2-6  alkylene;  
 Z represents a direct bond or C 1-4  alkylene;  
 R 11  and R 12  independently represent H or C 1-6  alkyl;  
 n represents 0, 1 or 2;  
 R 5  represents phenyl or pyridyl, both of which groups are optionally substituted by one or more substituents selected from —OH, cyano, halo, nitro, C 1-6  alkyl (optionally terminated by —N(H)C(O)OR 13a ), C 1-6  alkoxy, —N(R 14a )R 14b , —C(O)R 14c , —C(O)OR 14d , —C(O)N(R 14e )R 14f , —N(R 14g )C(O)R 14h , —N(R 14i )C(O)N(R 14j )R 14k , —N(R 14m )S(O) 2 R 13b , —S(O) 2 R 13c  and/or —OS(P) 2 R 13d ;  
 R 13a  to R 13d  independently represent C 1-6  alkyl;  
 R 14a  and R 14b  independently represent H, C 1-6  alkyl or together represent C 3-6  alkylene, resulting in a four- to seven-membered nitrogen-containing ring;  
 R 14c  to R 14m  independently represent H or C 1-6  alkyl; and  
 Het 1  to Het 5  independently represent, at each occurrence, five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which heterocyclic groups are optionally substituted by one or more substituents selected from ═O, —OH, cyano, halo, nitro, C 1-6  alkyl, C 1-6  alkoxy, aryl, aryloxy, —N(R 15a )R 15b , —C(O)R 15c , —C(O)R 15d , —C(O)N(R 15e )R 15f , —N(R 15g )C(O)R 15h  and —N(R 15i )S(O) 2 R 15j ;  
 R 15a  to R 15i  independently represent C 1-6  alkyl, aryl or R 15a  to R 15i  independently represent H;  
 provided that:  
 (a) when R 4  represents H or C 1-4  alkyl; and 
 A represents -J-N(R 11 )— or -J-O—;  
 then B does not represent —N(R 12 )—, —S(O) n —, —O— or —N(R 12 )-Z- (in which latter group —N(R 12 ) is attached to the carbon atom bearing R 3  and R 4 );  
 
 (b) when R 3  represent OR 6  or -E-N(R 7 )R 8  in which E represents a direct bond, then: 
 (i) A does not represent a direct bond, -J-N(R 11 )— or J-O—; and  
 (ii) B does not represent —N(R 12 )—, —S(O) n —, —O— or —N(R 12 )-Z- (in which latter group —N(R 12 ) is attached to the carbon atom bearing R 3  and R 4 ); and  
 
 R 2  represents C 1-6  alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl) or aryl,  
 wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted by one or more of —OH, cyano, halo, nitro, C 1-6  alkyl, C 1-6  alkoxy, —N(R 14a )R 14b , —C(O)R 14c , —C(O)OR 14d , —C(O)N(R 14c )R 14f , —N(R 14g )C(O)R 14h , —N(R 14m )S(O)R 2 R 13b , —S(O) 2 R 13c  and/or —OS(O) 2 R 13d ;  
 which process comprises reaction of a compound of formula II,  
                     
 wherein as defined above, with either:  
 (i) a compound of formula ITT,  
                     
 wherein R 16  represents unsubstituted C 1-4  alkyl, C 1-4  perfluoroalkyl or phenyl, which latter group is optionally substituted by one or more substituents selected from C 1-6  alkyl, halo, nitro and C 1-6  alkoxy, and R 2  is as defined above; or  
 (ii) acrylamide, followed by reaction of the resulting intermediate of formula IV,  
                     
 wherein R 1  as defined above, with an alcohol of formula R 2 —OH and an agent that promotes, or agents that in combination promote, rearrangement and oxidation of the compound of formula IV to an intermediate isocyanate, which may then react with the alcohol of formula R 2 —OH, wherein R 2  is as defined above.  
 
   
   
       2 - 34 . (canceled)  
   
   
       35 . A process for the preparation of a compound of formula I, as defined in  claim 1 , in which R 1  represents H, which process comprises removal of the amino protective group from a corresponding compound of formula I in which R 1  represents an amino protective group.  
   
   
       36 - 77 . (canceled)