Process for production of piperidine derivatives

1. 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 sybstituents;

said process comprising:

providing a regioisomer of the following formula:

wherein

Z is

m is an integer from 1 to 6;

Q is O;

Y is selected from the group consisting of O, S, and NR 5 ;

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 , and R 9 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.

2. A process according to claim 1 , wherein said providing the regioisomer comprises:

acylating 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, alkylbalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions

with a compound 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

under conditions effective to produce the regioisomer.

3. A process according to claim 2 further comprising:

reacting an α,α-diunsubstituted-metbylbenzene derivative having the formula:

with a methylating agent under conditions effective to produce the α-α-disubstituted-methylbenzene derivative.

4. A process according to claim 3 , wherein Z has the formula:

and further comprising

reacting an α,α-diunsubstituted benzylic acid derivative having the formula:

with an aminoalkyl derivative having the formula:

H 2 N—(CR 6 R 7 ) m -Q-H

under conditions effective to produce the α,α-diunsubstituted-methylbenzene derivative.

5. A process according to claim 2 , wherein Z has the formula:

and further comprising:

reacting an α,α-disubstituted benzylic acid derivative having the formula:

with an aminoalkyl derivative having the formula:

H 2 N—(CR 6 R 7 ) m -Q-H

under conditions effective to produce the α,α-disubstituted-methylbenzene derivative.

6. A process according to claim 1 , 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.

7. A process according to claim 6 , further comprising:

reacting a 4-(α,α-diunsubstituted)-toluic acid derivative having the formula:

with a methylating agent under conditions effective to produce the 4-(α,α-disubstituted)-toluic acid derivative.

8. A process according to claim 7 , wherein Z has the formula:

and further comprising:

reacting a 4-(α-carboxy-α,α-diunsubstituted)-toluic acid derivative having the formula:

with an aminoalkyl derivative having the formula:

H 2 N—(CR 6 R 7 ) m -Q-H

under conditions effective to produce the 4-(α,α-diunsubstituted)-toluic acid derivative.

9. A process according to claim 6 , wherein Z has the formula:

and further comprising:

reacting a 4-(α-carboxy-α,α-disubstituted)-toluic acid derivative having the formula:

with an aminoalkyl derivative having the formula:

H 2 N—(CR 6 R 7 ) m -Q-H

under conditions effective to produce the 4-(α,α-disubstituted)-toluic acid derivative.

10. A process according to claim 1 , 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.

11. A process according to claim 10 , wherein said providing the α,α-diunsubstituted regioisomer precursor comprises:

acylating an α,α-diunsubstituted-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

with a compound 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

under conditions effective to produce the α,α-diunsubstituted regioisomer precursor.

12. A process according to claim 10 , wherein said providing the α,α-diunsubstituted regioisomer precursor comprises:

reacting a 4-(α,α-diunsubstituted)-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 α,α-diunsubstituted regioisomer precursor.

13. A process according to claim 1 , further comprising:

reducing the piperidine derivative compound under conditions effective to form a hydroxylated piperidine derivative compound of the formula:

14. A process according to claim 1 , wherein m is an integer from 2 to 4.

15. 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 S;

Y is selected from the group consisting of O, S, and NR 5 ;

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 , and R 9 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.

16. A process according to claim 15 , wherein said providing the regioisomer comprises:

acylating an α,α-disubstituted-methylbenzene derivative having the formula:

wherein

X 1 is a halogen, trialkyl or triatyl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions

with a compound 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

under conditions effective to produce the regioisomer.

17. A process according to claim 16 further comprising:

reacting an α,α-diunsubstituted-methylbenzene derivative having the formula:

with a methylating agent under conditions effective to produce the α-α-disubstituted-methylbenzene derivative.

18. A process according to claim 17 , wherein Z has the formula:

and further comprising

reacting an α,α-diunsubstituted benzylic acid derivative having the formula:

with an aminoalkyl derivative having the formula:

H 2 N—(CR 6 R 7 ) m -Q-H

under conditions effective to produce the α,α-diunsubstituted-metbylbenzene derivative.

19. A process according to claim 16 , wherein Z has the formula:

and further comprising:

reacting an α,α-disubstituted benzylic acid derivative having the formula:

with an aminoalkyl derivative having the formula:

 H 2 N—(CR 6 R 7 ) m -Q-H

under conditions effective to produce the α,α-disubstituted-methylbenzene derivative.

20. A process according to claim 15 , 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.

21. A process according to claim 20 , further comprising:

reacting a 4-(α,α-diunsubstituted)-toluic acid derivative having the formula:

with a methylating agent under conditions effective to produce the 4-(α,α-disubstituted)-toluic acid derivative.

22. A process according to claim 21 , wherein Z has the formula:

and further comprising:

reacting a 4-(α-carboxy-α,α-diunsubstituted)-toluic acid derivative having the formula:

with an aminoalkyl derivative having the formula:

H 2 N—(CR 6 R 7 ) m -Q-H

under conditions effective to produce the 4-(α,α-diunsubstituted)-toluic acid derivative.

23. A process according to claim 20 , wherein Z has the formula:

and further comprising:

reacting a 4-(α-carboxy-α,α-disubstituted)-toluic acid derivative having the formula:

with an aminoalkyl derivative having the formula:

H 2 N—(CR 6 R 7 ) m -Q-H

under conditions effective to produce the 4-(α,α-disubstituted)-toluic acid derivative.

24. A process according to claim 15 , 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.

25. A process according to claim 24 , wherein said providing the α,α-diunsubstituted regioisomer precursor comprises:

acylating an α,α-diunsubstituted-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

with a compound 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

under conditions effective to produce the α,α-diunsubstituted regioisomer precursor.

26. A process according to claim 24 , wherein said providing the α,α-diunsubstituted regioisomer precursor comprises:

reacting a 4-(α,α-diunsubstituted)-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 α,α-diunsubstituted regioisomer precursor.

27. A process according to claim 15 , further comprising:

reducing the piperidine derivative compound under conditions effective to form a hydroxylated piperidine derivative compound of the formula:

28. A process according to claim 15 , wherein m is an integer from 2 to 4.

29. 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 ;

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 , and R 9 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.

30. A process according to claim 29 , wherein said providing the regioisomer comprises:

acylating 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

with a compound 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

under conditions effective to produce the regioisomer.

31. A process according to claim 30 further comprising:

reacting an α,α-diunsubstituted-methylbenzene derivative having the formula:

with a methylating agent under conditions effective to produce the α-α-disubstituted-methylbenzene derivative.

32. A process according to claim 31 , wherein Z has the formula:

and further comprising

reacting an α,α-diunsubstituted benzylic acid derivative having the formula:

with an aminoalkyl derivative having the formula:

H 2 N—(CR 6 R 7 ) m -Q-H

under conditions effective to produce the α,α-diunsubstituted-methylbenzene derivative.

33. A process according to claim 30 , wherein Z has the formula:

and further comprising:

reacting an α,α-disubstituted benzylic acid derivative having the formula:

with an aminoalkyl derivative having the formula:

 H 2 N—(CR 6 R 7 ) m -Q-H

under conditions effective to produce the α,α-disubstituted-methylbenzene derivative.

34. A process according to claim 29 , 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.

35. A process according to claim 34 , further comprising:

reacting a 4-(α,α-diunsubstituted)-toluic acid derivative having the formula:

with a methylating agent under conditions effective to produce the 4-(α,α-disubstituted)-toluic acid derivative.

36. A process according to claim 35 , wherein Z has the formula:

and further comprising:

reacting a 4-(α-carboxy-α,α-diunsubstituted)-toluic acid derivative having the formula:

with an aminoalkyl derivative having the formula:

H 2 N—(CR 6 R 7 ) m -Q-H

under conditions effective to produce the 4-(α,α-diunsubstituted)-toluic acid derivative.

37. A process according to claim 34 , wherein Z has the formula:

and further comprising:

reacting a 4-(α-carboxy-α,α-disubstitiuted)-toluic acid derivative having the formula:

with an aminoalkyl derivative having the formula:

H 2 N—(CR 6 R 7 ) m -Q-H

under conditions effective to produce the 4-(α,α-disubstituted)-toluic acid derivative.

38. A process according to claim 29 , 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.

39. A process according to claim 38 , wherein said providing the α,α-diunsubstituted regioisomer precursor comprises:

acylating an α,α-diunsubstituted-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

with a compound 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

under conditions effective to produce the α,α-diunsubstituted regioisomer precursor.

40. A process according to claim 38 , wherein said providing the α,α-diunsubstituted regioisomer precursor comprises:

reacting a 4-(α,α-diunsubstituted)-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 α,α-diunsubstituted regioisomer precursor.

41. A process according to claim 29 , further comprising:

reducing the piperidine derivative compound under conditions effective to form a hydroxylated piperidine derivative compound of the formula:

42. A process according to claim 29 , wherein m is an integer from 2 to 4.

43. A process according to claim 29 , wherein R 5 is hydrogen.

44. A process according to claim 29 , wherein R 5 is a branched or unbranched C1-C7 alkyl group.

45. A process according to claim 29 , wherein R 5 is an aryl or heteroaryl group.