Most effective process for base-free preparation of ketone intermediates usable for manufacture of nebivolol

Abstract

The invention relates to a process for the preparation of a ketone of a general formula 1 with X being Cl or Br, in particular with X being Cl, with Y being F, Cl, Br, I or H, in particular with Y being F, comprising the steps of: activation of a carboxylic acid by using a peptide coupling agent, coupling of the activated carboxylic acid with a malonic acid derivative providing a β-ketoester precursor and converting the β-ketoester precursor to the ketone of the general formula 1.

We claim: 
     
         1 . A process for the preparation of a ketone of a general formula 1 
       
         
           
           
               
               
           
         
         with X being Cl or Br, in particular with X being Cl, 
       
       comprising the steps of:
 a. reacting a carboxylic acid of a general formula 2 
 
       
         
           
           
               
               
           
         
       
       with a peptide coupling agent to yield an activated carboxylic acid,
 b. reacting the activated carboxylic acid with a malonic acid derivative, yielding a β-ketoester precursor, in particular a β-ketoester precursor of the general formula 6a or 6b, 
 
       
         
           
           
               
               
           
         
         c. converting the β-ketoester precursor to the ketone of the general formula 1, 
       
       wherein R 4  and R 6  independently of one another are H or C 1  to C 6  alkyl, R 5  is C 1  to C 6  alkyl, R 7  is C 1  to C 6  alkyl or a substituted or unsubstituted phenyl, in particular R 6  is C 1  to C 3  alkyl and R 7  is C 1  to C 3  alkyl, and Y is F, Cl, Br, I or H, in particular F. 
     
     
         2 . The process according to  claim 1 , wherein the malonic acid derivative is
 a malonic diester of the formula R 4 —O—C(═O)—CH 2 —C(═O)—O—R 5 , or   a malonic acid derivative of a formula 8   
       
         
           
           
               
               
           
         
       
       or
 a malonic half ester of the formula R 4 —O—C(═O)—CH 2 —C(═O)—O—H or its Na- and Mg salts, with R 4  being a C 1  to C 6  alkyl, 
 
       wherein R 4  is a C 1  to C 6  alkyl and R 5  is a C 1  to C 6  alkyl, R 6  is C 1  to C 6  alkyl and R 7  is C 1  to C 6  alkyl or a substituted or unsubstituted phenyl, in particular R 6  and R 7  is C 1  to C 3  alkyl, more particularly R 6  and R 7  are C 1  alkyl. 
     
     
         3 . The process according to  claim 1 , wherein the activated carboxylic acid of step a is coupled with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) providing the meldrumate of a general formula 3 
       
         
           
           
               
               
           
         
       
       as the β-ketoester precursor. 
     
     
         4 . The process according to  claim 1 , wherein the peptide coupling agent is selected from the group of triazoles, carbonylimidazoles or imminoacetates, in particular carbonylimidazoles. 
     
     
         5 . The process according to  claim 4 , wherein the peptide coupling agent is selected from the group of 1-hydroxybenzotriazol (HOBT), 1-hydroxy-7-azabenzotriazol (HOAT), 1,1′-carbonyldiimidazol (CDI), 1,1′-carbonylbis(3-methylimidazoliumtriflate) (CBMIT) or ethylcyan(hydroxyl-imino)acetat (Oximapure). 
     
     
         6 . The process according to  claim 1 , wherein no base additive is present in step b (reacting the activated carboxylic acid). 
     
     
         7 . The process according to  claim 1 , wherein the step a is conducted in a reaction mixture comprising a pH in the range of 8 or less, in particular a pH in the range of 7 or less. 
     
     
         8 . The process according to  claim 1 , wherein a β-ketoester of the general formula 4 
       
         
           
           
               
               
           
         
       
       is an intermediate, in particular provided by alcoholysis of the ft-ketoester precursor of the general formula 6b, in particular by alcoholysis of the meldrumate of the general formula 3, with an alcohol R 3 OH, with R 3  being C 1 -C 6  alkyl. 
     
     
         9 . The process according to  claim 8 , wherein the compound of the general formula 4 is halogenated, optionally hydrolyzed, and decarboxylized, to give the ketone of the general formula 1. 
     
     
         10 . The process according to  claim 1 , wherein
 the β-ketoester precursor of formula 6a, in case the β-ketoester precursor derived from a reaction with a malonic half ester of the formula R 4 —O—C(═O)—CH 2 —C(═O)—O—H or its Na- and Mg salts, is decarboxylized to a β-ketoester of the general formula 4, subsequently halogenated and decarboxylized, to give the ketone of the general formula 1,   
       with R 4  having the same meaning as defined above. 
     
     
         11 . The process according  claim 1 , wherein the chiral ketone of the general formula 1a or 1b 
       
         
           
           
               
               
           
         
       
       is provided by using the correspondent carboxylic acids of the general formula 2a or 2b 
       
         
           
           
               
               
           
         
         with X and Y having the same meaning as defined previously. 
       
     
     
         12 . A preparation of a chiral ketone of the general formula 1a or 1b 
       
         
           
           
               
               
           
         
         with X and Y having the same meaning as defined previously, 
         having a purity of ee>98%, in particular a preparation of a chiral ketone of the general formula 1a or 1b producible by the process according to any one of the  claims 1  to  11 , having a purity of ee>98%. 
       
     
     
         13 . Use of the preparation of a chiral ketone according to  claim 12 , or of the preparation of a chiral ketone of the general formula 1a or 1b produced by the process according to  claim 1 , in the production of chiral alcohols of the general formula 5a to 5d, 
       
         
           
           
               
               
           
         
         wherein X and Y have the same meaning as defined previously. 
       
     
     
         14 . Use of the preparation of a chiral ketone of the general formula 1a or 1b according to  claim 12  or of the preparation of a chiral ketone of the general formula 1a or 1b produced by the process according to  claim 1  in the production of d-nebivolol, l-nebivolol or a mixture of d-nebivolol and l-nebivolol, in particular a racemic mixture of d-nebivolol and l-nebivolol, or the hydrochloride salts thereof. 
     
     
         15 . A preparation of a chiral alcohol of the general formula 5a to 5d 
       
         
           
           
               
               
           
         
         having a diastereochemical purity >98%.