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.

What is claimed:  
     
         1 . A process of preparing a piperidine derivative compound of the formula:  
       
         
           
           
               
               
           
         
         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 rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, or other substituents  
 said process comprising:  
 
         providing a substantially pure regioisomer of the following formula:  
         
           
             
             
                 
                 
             
           
         
         and  
         converting the substantially pure regioisomer to the piperidine derivative compound with a piperidine compound of the formula:  
         
           
             
             
                 
                 
             
           
         
       
     
     
         2 . A process according to  claim 1 , wherein said providing comprises: 
 acylating a starting compound of the formula:                          wherein 
 R 5  is —OR 6 , —N(R 6 ) 2 , and —SR 6 , and  
 R 6  is an alkyl with 1 to 6 carbons,  
 with a compound of the formula:  
                     
   wherein 
 X is a halogen,  
 under conditions effective to produce a first mixture of regioisomers of the formula:  
                     
   hydrolyzing the first mixture of regioisomers under conditions effective to form a second mixture of a regioisomers of the formula:                          recovering from the second mixture of regioisomers the substantially pure regioisomer of the formula:                          
     
     
         3 . A process according to  claim 2 , wherein said recovering comprises: 
 crystallizing from the second mixture of regioisomers a substantially pure regioisomer salt of the formula:                          wherein X +  is a Lewis Acid;    isolating the substantially pure regioisomer salt; and    converting the substantially pure regioisomer salt to the substantially pure regioisomer of the formula:                          
     
     
         4 . A process according to  claim 3 , 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  are individually 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.  
     
     
         5 . A process according to  claim 4 , wherein X +  is cinchonidine and A is hydrogen.  
     
     
         6 . A process according to  claim 2 , wherein said acylating is carried out by a Friedel-Crafts reaction using AlCl 3  catalyst.  
     
     
         7 . A process according to  claim 1 , wherein said providing comprises: 
 acylating a starting compound of the formula:                          with a compound of the formula                          wherein 
 X 1  is a halogen, trialkyl tin triflate, or substituents useful in a organometalic coupling reactions  
 under conditions effective to produce the substantially pure regioisomer of the formula:  
                     
   
     
     
         8 . A process according to  claim 1 , wherein said providing comprises: 
 acylating a starting compound of the formula:                          wherein 
 R 5  is —OR 6 , —N(R 6 ) 2 , and —SR 6  and  
 R 6  is an alkyl with 1 to 6 carbon atoms  
 with a compound of the formula:  
                     
 under conditions effective to produce a first mixture of regioisomers of the formula:  
                     
   hydrolyzing the first mixture of regioisomers under conditions effective to form a second mixture of regioisomers of the formula:                          and    recovering from the second mixture of regioisomers the substantially pure regioisomer of the following formula:                          
     
     
         9 . A process according to  claim 8 , wherein said recovering comprises: 
 crystallizing a substantially pure regioisomer salt of the formula:                          wherein X +  is a Lewis Acid    from the second mixture of regioisomers;    isolating the substantially pure regioisomer salt; and    converting the substantially pure regioisomer salt to the substantially pure regioisomer of the formula:                          
     
     
         10 . A process according to  claim 9 , 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.  
     
     
         11 . A process according to  claim 10  wherein X +  is cinchonidine and A is hydrogen.  
     
     
         12 . A process according to  claim 8 , wherein said acylating is carried out with a catalyst containing palladium, nickel, or mixtures thereof.  
     
     
         13 . A process according to  claim 1  further comprising: 
 reducing the piperidine derivative under conditions effective to form a hydroxylated piperidine derivative of the formula:  
                     
 
     
     
         14 . A process according to  claim 13 , wherein the hydroxylated piperidine derivative has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         15 . A process according to  claim 13 , wherein the hydroxylated piperidine derivative has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         16 . A process according to  claim 1 , wherein said converting comprises: 
 halogenating the substantially pure regioisomer of the following formula:                          under conditions effective to form a first intermediate compound of the formula:                          wherein 
 X is a halogen and  
 reacting the first intermediate compound with a piperidine compound of the formula:  
                     
 under conditions effective to form the piperidine derivative of the following formula:  
                     
   
     
     
         17 . A process according to  claim 1 , wherein said converting comprises: 
 reacting the substantially pure regioisomer of the following formula:                          with a piperidine compound of the formula:                          under conditions effective to form the piperidine derivative of the formula:                          
     
     
         18 . A process according to  claim 1 , wherein the piperidine derivative has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         19 . A process according to  claim 1 , wherein the piperidine derivative has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         20 . A substantially pure piperidine derivative compound 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  is an alkyl with 1 to 6 carbon atoms;  
 A, B, and D can be one or more different substituents of their rings and are individually hydrogen, halogens, alkyl, hydroxy, alkoxy, or other substituents.  
 or a salt thereof.  
 
 
     
     
         21 . A substantially pure piperidine derivative compound according to  claim 20 , wherein the compound has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         22 . A substantially pure piperidine derivative compound according to  claim 20 , wherein the compound has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         23 . A substantially pure piperidine derivative compound according to  claim 20 , wherein the compound has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         24 . A substantially pure piperidine derivative compound according to  claim 23 , wherein the compound has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         25 . A substantially pure piperidine derivative compound according to  claim 20 , wherein the compound has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         26 . A substantially pure piperidine derivative compound according to  claim 25 , wherein the compound has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         27 . A pharmaceutical composition comprising: 
 a pharmaceutical carrier and    the substantially pure piperidine derivative compound according to  claim 20 .    
     
     
         28 . A pharmaceutical composition according to  claim 27 , wherein said substantially pure piperidine derivative compound is present in an effective antiallergic amount.  
     
     
         29 . A pharmaceutical composition according to  claim 27 , wherein said composition consists essentially of said substantially pure piperidine derivative compound.  
     
     
         30 . A method of treating allergic reactions in a patient comprising: 
 administering to the patient said pharmaceutical composition according to  claim 27  in an effective amount.    
     
     
         31 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 3  is —COOH or —COOR 4 ;  
 R 4  is an alkyl with 1 to 6 carbon atoms;  
 A is the substituents of its ring, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, or other substituents.