Piperidine derivatives and process for their production

Abstract

The present invention relates to substantially pure piperidine derivative compounds of the formulae: wherein R 1 is hydrogen or hydroxy; R 2 is hydrogen; or R 1 and R 2 taken together form a second bond between the carbon atoms bearing R 1 and R 2 ; R 3 is —COOH or —COOR 4 ; R 4 has 1 to 6 carbon atoms; A, B, and D are the substituents of their respective rings, each of which may be different or the same and are hydrogen, halogens, alkyl, hydroxy, alkoxy, or other substituents. A process of preparing such piperidine derivative compounds in substantially pure form is also disclosed.

1 - 31 . (canceled) 
     
     
         32 . A process of preparing a compound of formula I: 
       
         
           
           
               
               
           
         
         R 1  is hydrogen or hydroxy; 
         R 2  is hydrogen; 
         or R 1  and R 2  taken together form a second bond between the carbon atoms bearing R 1  and R 2 ; 
         R 3  is —COOH or —COOR 4 ; 
         R 4  is an alkyl of 1 to 6 carbon atoms; 
       
       said process comprising:
 acylating a starting compound of formula II: 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 5  is —SR 6  and 
 R 6  is an alkyl of 1 to 6 carbon atoms 
 
       with a compound of formula III: 
       
         
           
           
               
               
           
         
       
       under conditions effective to produce a first mixture of regioisomers of formula IV: 
       
         
           
           
               
               
           
         
         hydrolyzing the first mixture of regioisomers of formula IV under conditions effective to form a second mixture of regioisomers of formula V: 
       
       
         
           
           
               
               
           
         
         recovering from the second mixture of regioisomers of formula V the regioisomer of formula VI: 
       
       
         
           
           
               
               
           
         
         converting the regioisomer of formula VI to the compound of formula I with a piperidine compound of formula VII: 
       
       
         
           
           
               
               
           
         
       
     
     
         33 . A process according to  claim 32 , wherein said recovering comprises:
 crystallizing a regioisomer salt of formula VIII:   
       
         
           
           
               
               
           
         
         wherein X +  is a Lewis Acid 
       
       from the second mixture of regioisomers of formula V;
 isolating the regioisomer salt of formula VIII; and 
 converting the regioisomer salt of formula VIII to a regioisomer of formula VI: 
 
       
         
           
           
               
               
           
         
       
     
     
         34 . A process according to  claim 33 , wherein X +  is an alkali metal salt or an ammonium salt of the form NR 7 R 8 R 9  wherein R 7 , R 8 , and R 9  is hydrogen or a straight or branched alkyl of 1 to 6 carbon atoms, or an alkyl substituted at any position with a phenyl ring or a substituted phenyl ring. 
     
     
         35 . A process according to  claim 34 , wherein X +  is cinchonidine. 
     
     
         36 . A process according to  claim 32 , wherein said acylating is carried out by a Friedel-Crafts reaction using AlCl 3 . 
     
     
         37 . A process according to  claim 32 , further comprising:
 reducing the compound of formula I under conditions effective to form a compound of formula IX:   
       
         
           
           
               
               
           
         
       
     
     
         38 . A process according to  claim 37 , wherein the compound of formula IX is: 
       
         
           
           
               
               
           
         
       
     
     
         39 . A process according to  claim 32 , wherein said converting comprises:
 hydrohalogenating a regioisomer of formula X:   
       
         
           
           
               
               
           
         
       
       under conditions effective to form a first intermediate compound of formula XI: 
       
         
           
           
               
               
           
         
       
       wherein
 X is a halogen and 
 reacting the first intermediate compound of formula XI with the piperidine compound of formula VII: 
 
       
         
           
           
               
               
           
         
       
       under conditions effective to form the compound of formula I: 
       
         
           
           
               
               
           
         
       
     
     
         40 . A process according to  claim 32 , wherein said converting comprises:
 reacting a regioisomer of formula X:   
       
         
           
           
               
               
           
         
       
       with the piperidine compound of formula VII: 
       
         
           
           
               
               
           
         
       
       under conditions effective to form the compound of formula I: 
       
         
           
           
               
               
           
         
       
     
     
         41 . A process according to  claim 32 , wherein the compound of formula I is: