Process for the manufacturing of betamimetics

Abstract

The present invention relates to a process for preparing betamimetics of formula 1, wherein n denotes 1 or 2; R 1 denotes hydrogen, halogen, C 1-4 -alkyl or O—C 1-4 -alkyl; R 2 denotes hydrogen, halogen, C 1-4 -alkyl or O—C 1-4 -alkyl; R 3 denotes hydrogen, C 1-4 -alkyl, OH, halogen, O—C 1-4 -alkyl, O—C 1-4 -alkylene-COOH, O—C 1-4 -alkylene-COO—C 1-4 -alkyl.

1 . A process for preparing a compound of formula 1,  
     
       
         
         
             
             
         
       
     
     wherein 
 n denotes 1 or 2;  
 R 1  denotes hydrogen, halogen, C 1-4 -alkyl or O—C 1-4 -alkyl;  
 R 2  denotes hydrogen, halogen, C 1-4 -alkyl or O—C 1-4 -alkyl;  
 R 3  denotes hydrogen, C 1-4 -alkyl, OH, halogen, O—C 1-4 -alkyl, O—C 1-4 -alkylene-COOH, O—C 1-4 -alkylene-COO—C 1-4 -alkyl;  
 said process comprising reacting a compound of formula 1a,  
                     
 wherein PG represents a protective group, with a compound of formula 1b,  
                     
 wherein R 1 , R 2 , R 3  and n have the meanings given above, in an organic solvent to obtain a compound of formula 1c,  
                     
 wherein R 1 , R 2 , R 3 , n and PG have the meanings given above, and cleaving the protective group PG to obtain the compound of formula 1.  
 
   
   
       2 . A process for preparing a compound of formula 1 according to  claim 1 , wherein 
 n denotes 1 or 2;    R 1  denotes hydrogen, halogen or C 1-4 -alkyl;    R 2  denotes hydrogen, halogen or C 1-4 -alkyl; and    R 3  denotes hydrogen, C 1-4 -alkyl, OH, halogen, O—C 1-4 -alkyl, O—C 1-4 -alkylene-COOH or O—C 1-4 -alkylene-COO—C 1-4 -alkyl.    
   
   
       3 . A process for preparing a compound of formula 1 according to  claim 1 , wherein 
 n denotes 1 or 2;    R 1  denotes hydrogen, fluorine, chlorine, methyl or ethyl;    R 2  denotes hydrogen, fluorine, chlorine, methyl or ethyl; and    R 3  denotes hydrogen, C 1-4 -alkyl, OH, fluorine, chlorine, bromine, O—C 1-4 -alkyl, O—C 1-4 -alkylene-COOH, O—C 1-4 -alkylene-COO—C 1-4 -alkyl.    
   
   
       4 . A process for preparing a compound of formula 1 according to  claim 1 , wherein 
 n denotes 1 or 2;    R 1  denotes hydrogen, methyl or ethyl;    R 2  denotes hydrogen, methyl or ethyl; and    R 3  denotes hydrogen, methyl, ethyl, OH, methoxy, ethoxy, O—CH 2 —COOH, O—CH 2 —COO-methyl or O—CH 2 —COO-ethyl.    
   
   
       5 . A process for preparing a compound of formula 1 according to  claim 1 , wherein 
 n denotes 1 or 2;    R 1  denotes hydrogen or methyl;    R 2  denotes hydrogen or methyl; and    R 3  denotes hydrogen, methyl, OH, methoxy, O—CH 2 —COOH or O—CH 2 —COO-ethyl.    
   
   
       6 . A process according to  claim 1 , wherein the compound of formula 1a is prepared by reacting a compound of formula 2a,  
     
       
         
         
             
             
         
       
       wherein PG is as defined in  claim 1  and R 4  denotes halogen with DIP chloride in a suitable solvent.  
     
   
   
       7 . A process according to  claim 6  wherein the compound of formula 2a is prepared by reacting a compound of formula 3a,  
     
       
         
         
             
             
         
       
     
     wherein PG has the meaning given in  claim 6 , with a halogenating reagent in a suitable solvent.  
   
   
       8 . A process according to  claim 7  wherein the compound of formula 3a is prepared by hydrogenating a compound of formula 4a in a suitable solvent,  
     
       
         
         
             
             
         
       
     
     wherein PG has the meaning given in  claim 7 .  
   
   
       9 . A process according to  claim 8  wherein the compound of formula 4a is prepared by reacting a compound of formula 5a,  
     
       
         
         
             
             
         
       
     
     wherein PG has the meaning given in  claim 8 , with a nitrogenating reagent in a suitable solvent.  
   
   
       10 . A process according to  claim 9  wherein the compound of formula 5a is prepared by reacting a compound of formula 6a in a suitable solvent with a compound PG-A, wherein PG is a protective group and A is a leaving group,  
     
       
         
         
             
             
         
       
     
   
   
       11 . A process according to  claim 1 , wherein the compound of formula 1b is prepared by reacting a compound of formula 2b with a strong base in a suitable solvent,  
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3  and n have are as defined in  claim 1  and 
 R 5  denotes Me.  
 
   
   
       12 . A process according to  claim 11  wherein the compound of formula 2b is prepared by reacting a compound of formula 3b with acetonitrile in the presence of an acid in a suitable solvent,  
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3  and n are as defined in  claim 11 .  
   
   
       13 . A process according to  claim 12  wherein the compound of formula 3b is prepared by reacting in a suitable solvent a compound of formula 4b with methylmagnesium bromide or methylmagnesium chloride,  
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3  and n are as defined in  claim 12 .  
   
   
       14 . A compound of formula 3a,  
     
       
         
         
             
             
         
       
       wherein PG is as defined in  claim 1 .  
     
   
   
       15 . A compound of formula 4a,  
     
       
         
         
             
             
         
       
     
     wherein PG is as defined in  claim 1 .  
   
   
       16 . A compound of formula 4a # ,  
     
       
         
         
             
             
         
       
     
     wherein PG is as defined in  claim 1 .  
   
   
       17 . A compound of formula 2b,  
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3  and n are as defined in  claim 1 , and 
 R 5  denotes Me.  
 
   
   
       18 . A process for preparing a compound of formula 2a,  
     
       
         
         
             
             
         
       
     
     wherein PG is as defined in  claim 1  and R 4  denotes halogen, said process comprising reacting a compound of formula 3a,  
     
       
         
         
             
             
         
       
     
     wherein PG is as defined in  claim 1 , with a halogenating reagent selected from tetrabutylammonium tribromide, benzyltrimethyl ammonium dichloriodide, N-bromo-succinimide, N-chloro-succinimide, sulphuryl chloride and bromine/dioxane.  
   
   
       19 . A process for preparing a compound of formula 3a,  
     
       
         
         
             
             
         
       
     
     wherein PG is as defined in  claim 1 , said process comprising subjecting a compound of formula 4a to catalytic hydrogenation and then reaction with chloroacetyl chloride,  
     
       
         
         
             
             
         
       
     
     wherein PG is as defined in  claim 1 .  
   
   
       20 . A process according to  claim 19 , wherein a compound of formula 4a # ,  
     
       
         
         
             
             
         
       
     
     wherein PG is as defined in  claim 19 , is formed as an intermediate product of the hydrogenation.  
   
   
       21 . A process for preparing a compound of formula 4a,  
     
       
         
         
             
             
         
       
     
     wherein PG is as defined in  claim 1 , said process comprising reacting a compound of formula 5a,  
     
       
         
         
             
             
         
       
     
     wherein PG is as defined in  claim 1 , with a nitrogenating reagent selected from 65% nitric acid, potassium nitrate/sulphuric acid and nitronium tetrafluoroborate.  
   
   
       22 . A process for preparing a compound of formula 1b,  
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3  and n are as defined in  claim 1 , said process comprising reacting a compound of formula 2b,  
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3  and n are as defined in  claim 1  and 
 R 5  denotes Me,  
 with a base selected from potassium hydroxide, sodium hydroxide, lithium hydroxide and caesium hydroxide.  
 
   
   
       23 . A process for preparing a compound of formula 2b,  
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3  and n are as defined in  claim 1  and 
 R 5  denotes Me,  
 said process comprising reacting a compound of formula 3b,  
                     
 wherein R 1 , R 2 , R 3  and n are as defined in  claim 1 , with a compound of formula  
                     
 wherein R 5  has the meaning given above, in the presence of a hygroscopic reagent selected from sulphuric acid, formic acid, p-toluenesulphonic acid, methanesulphonic acid, perchloric acid and polyphosphoric acid and then with a base selected from aqueous solutions of ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.