Process for production of piperidine derivatives

Abstract

The present invention discloses processes for preparing piperidine derivative compounds of the formulae: wherein n is 0 or 1; R 1 is hydrogen or hydroxy; R 2 is hydrogen; or, when n is 0, R 1 and R 2 taken together form a second bond between the carbon atoms bearing R 1 and R 2 , provided that when n is 1, R 1 and R 2 are each hydrogen; R 3 is —COOH or —COOR 4 ; R 4 is an alkyl or aryl moiety; 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, and other substituents. One process comprises providing a regiosomer of the following formula: wherein Z is —CG 1 G 2 G 3 , m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of O, S, and NR 5 ; G 1 , G 2 , and G 3 are the same or different and are selected from the group consisting of OR 8 , SR 8 , and NR 8 R 9 ; X 3 is halogen, OR 15 , SR 15 , NR 15 R 16 , OSO 2 R 15 , or NHSO 2 R 15 ; R 6 and R 7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR 8 , SR 8 , and NR 8 R 9 ; and R 5 , R 8 , R 9 , R 15 , and R 16 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety and converting the regioisomer to the piperidine derivative compound with a piperidine compound. Another process for producing piperidine derivative compounds comprises providing an α,α-disubstituted-methylbenzene derivative having the formula: wherein X 1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions and converting the α,α-disubstituted-methylbenzene derivative to the piperidine derivative compound with a piperidine compound. In yet another process, a 4-(α,α-disubstituted)-toluic acid derivative having the formula: wherein X 2 is a halogen; an alkali metal oxide; a moiety having the formula —OR 10 ; a moiety having the formula —SR 10 ; or an amine; and R 10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety is provided and converted to the piperidine derivative compound with a piperidine compound.

1 - 71 . (canceled) 
     
     
         72 . A process of preparing a piperidine derivative compound of the formula: 
       
         
           
           
               
               
           
         
         wherein
 n is 0 or 1; 
 R 1  is hydrogen or hydroxy; 
 R 2  is hydrogen; 
 or, when n is 0, R 1  and R 2  taken together form a second bond between the carbon atoms bearing R 1  and R 2 , provided that when n is 1, R 1  and R 2  are each hydrogen; 
 R 3  is —COOH or —COOR 4 ; 
 R 4  is an alkyl or aryl moiety; 
 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, and other substituents, 
 
       
       said process comprising:
 providing a regioisomer of the following formula: 
 
       
         
           
           
               
               
           
         
         wherein
 Z is 
 
       
       
         
           
           
               
               
           
         
         
           m is an integer from 1 to 6; 
           Q is NR 5 ; 
           Y is selected from the group consisting of O, S, and NR 5 ; 
           X 3  is halogen, OR 15 , SR 15 , NR 15 R 16 , OSO 2 R 15 , or NHSO 2 R 15 ; 
           R 6  and R 7  are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR 8 , SR 8 , and NR 8 R 9 ; and 
           R 5 , R 8 , R 9 , R 15 , and R 16  are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety 
         
       
       and
 converting the regioisomer to the piperidine derivative compound with a piperidine compound. 
 
     
     
         73 . A process according to  claim 72 , wherein said providing the regioisomer comprises:
 reacting a 4-(α,α-disubstituted)-toluic acid derivative having the formula:   
       
         
           
           
               
               
           
         
         wherein
 X 2  is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula —OR 10 ; a moiety having the formula —SR 10 ; or an amine; and 
 R 10  is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety 
 
       
       with a compound having the formula: 
       
         
           
           
               
               
           
         
         wherein
 X 1  is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions 
 
       
       under conditions effective to produce the regioisomer. 
     
     
         74 . A process according to  claim 72 , wherein said providing the regioisomer comprises:
 providing an α,α-diunsubstituted regioisomer precursor having the formula:   
       
         
           
           
               
               
           
         
       
       and
 methylating the α,α-diunsubstituted regioisomer precursor under conditions effective to produce the regioisomer. 
 
     
     
         75 . A process according to  claim 72 , further comprising:
 reducing the piperidine derivative compound under conditions effective to form a hydroxylated piperidine derivative compound of the formula:   
       
         
           
           
               
               
           
         
       
     
     
         76 . A process according to  claim 72 , wherein m is an integer from 2 to 4. 
     
     
         77 . A process according to  claim 72 , wherein R 5  is hydrogen. 
     
     
         78 . A process according to  claim 72 , wherein R 5  is a branched or unbranched C1-C7 alkyl group. 
     
     
         79 . A process according to  claim 72 , wherein R 5  is an aryl or heteroaryl group.