Process and diastereomeric salts useful for the optical resolution of racemic alpha-(4-(1, 1-dimethylethyl) phenyl] -4- (hydroxydiphenylmethyl) -1-piperidinebutanol and derivative compounds

• US 20060014793A1
• Filed: 09/15/2005
• Published: 01/19/2006
• Est. Priority Date: 05/16/1994
• Status: Abandoned Application

• Current Assignee: Merrell Pharmaceuticals Incorporated (Dow, Inc.)
• Original Assignee: Merrell Pharmaceuticals Incorporated (Dow, Inc.)
• Inventors: Nakamura, Mitsuo, Shiga, Masatoshi
• Application Number:
  US11/227,246
• Publication Number:
  US 20060014793A1
• Time in Patent Office: Days
• US Class Current: 514/317
• CPC Class Codes: C07D 211/22 by oxygen atoms
• CPC Class Codes: Y02P 20/582 Recycling of unreacted starting or intermediate materials

Abstract

A process and diastereomeric salts useful for the optical resolution of racemic α-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1 -piperidinebutanol, 4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid and lower alkyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetates. The process comprises placing into solution a chiral resolving agent, either (+)/(−)-di-paratoluoyltartaric acid or (−)/(+)-mandelic acid, in an amount equimolar to a compound corresponding to the desired enantiomer of the above compound, precipitating the resulting diastereomeric salt between the chiral resolving agent and the target enantiomer and separating the enantiomer.

Claims

1. A process for preparing a compound of a formula:

wherein R is —

CH₃, —

COOH or lower alkyl ester;

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

wherein R is defined as above;

with an equimolar amount of an optically active resolving agent, (+)-di-para-toluoyltartaric acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the diastereomeric salt;

d) collecting the diastereomeric salt; and

e) hydrolysing the diastereomeric salt to isolate the compound.

2. A process according to claim 1 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of an optically active resolving agent, (+)-di-para-toluoyltartaric acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the diastereomeric salt;

d) collecting the diastereomeric salt; and

e) hydrolysing the diastereomeric salt to isolate the compound.

3. A process according to claim 1 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of an optically active resolving agent, (+)-di-para-toluoyltartaric acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the diastereomeric salt;

d) collecting the diastereomeric salt; and

e) hydrolysing the diastereomeric salt to isolate the compound.

4. A process according to claim 1 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of an optically active resolving agent, (+)-di-para-toluoyltartaric acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the diastereomeric salt;

d) collecting the diastereomeric salt; and

e) hydrolysing the diastereomeric salt to isolate the compound.

5. A process for preparing a compound of a formula:

wherein R is —

CH₃ or lower alkyl ester;

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

wherein R is defined as above;

with an equimolar amount of an optically active resolving agent, (−

)-mandelic acid, into a suitable organic solvent;

b) heating the solution'"'"'to an elevated temperature suitable for formation of a solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the diastereomeric salt;

d) collecting the diastereomeric salt; and

e) hydrolysing the diastereomeric salt to isolate the compound.

6. A process according to claim 5 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of an optically active resolving agent, (−

)-mandelic acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the diastereomeric salt;

d) collecting the diastereomeric salt; and

e) hydrolysing the diastereomeric salt to isolate the compound.

7. A process according to claim 5 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of an optically active resolving agent, (−

)-mandelic acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the diastereomeric salt;

d) collecting the diastereomeric salt; and

e) hydrolysing the diastereomeric salt to isolate the compound.

8. A process for preparing a compound of a formula:

wherein R is —

CH₃, —

COOH or lower alkyl ester;

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

wherein R is defined as above;

with an equimolar amount of optically active resolving agent, (−

)-di-para-toluoyltartaric acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for the formation of a solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the diastereomeric salt;

d) collecting the diastereomeric salt; and

e) hydrolysing the diastereomeric salt to isolate the compound.

9. A process according to claim 8 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of optically active resolving agent, (−

)-di-para-toluoyltartaric acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for the formation of a solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the diastereomeric salt;

d) collecting the diastereomeric salt; and

e) hydrolysing the diastereomeric salt to isolate the compound.

10. A process according to claim 8 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of optically active resolving agent, (−

)-di-para-toluoyltartaric acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for the formation of a solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the diastereomeric salt;

d) collecting the diastereomeric salt; and

e) hydrolysing the diastereomeric salt to isolate the compound.

11. A process according to claim 8 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of optically active resolving agent, (−

)-di-para-toluoyltartaric acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for the formation of a solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the interactive complex as a diastereomeric salt;

d) collecting the diastereomeric salt; and

e) hydrolysing the diastereomeric salt to isolate the compound.

12. A process for preparing a compound of a formula:

wherein R is —

CH₃ or lower alkyl ester;

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

wherein R is defined as above;

with an equimolar amount of optically active resolving agent, (+)-mandelic acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for the formation of a solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the diastereomeric salt;

d) collecting the diastereomeric salt; and

e) hydrolysing the diastereomeric salt to isolate the compound.

13. A process according to claim 12 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of optically active resolving agent, (+)-mandelic acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for the formation of a solubilized diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the diastereomeric salt;

d) collecting the diastereomeric salt; and

e) hydrolysing the diastereomeric salt to isolate the compound.

14. A process according to claim 12 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

comprising;

_p1 a) dissolving into a solution an amount of a racemic _p1 compound of a formula;

with an equimolar amount of optically active resolving agent, (+)-mandelic acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for the formation of a solubilized diastereomeric salt

between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the interactive complex as a diastereomeric salt;

d) collecting the diastereomeric salt; and

e) hydrolysing the diastereomeric salt to isolate the compound.

15. A process for preparing a compound of a formula:

wherein R is —

CH₃, —

COOH or lower alkyl ester;

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

wherein R is defined as above;

with an equimolar amount of an optically active resolving agent, (−

)-di-para-toluoyltartaric acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized first diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the first diastereomeric salt;

d) removing the first diastereomeric salt and preserving the solution as a filtrate;

e) hydrolysing and separating the compound from the filtrate;

f) dissolving into solution the compound with an optically active resolving agent'"'"', (+)-di-para-toluoyltartaric acid, in an amount equimolar to an amount of the compound in such manner as to form a solubilized second diastereomeric salt between the same;

g) precipitating the second diastereomeric salt;

h) collecting the second diastereomeric salt; and

i) hydrolysing the second diastereomeric salt to isolate the compound.

16. A process according to claim 15 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of an optically active resolving agent, (−

)-di-para-toluoyltartaric acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized first diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the first diastereomeric salt;

d) removing the first diastereomeric salt and preserving the solution as a filtrate;

e) hydrolysing and separating the compound from the filtrate;

f) dissolving into solution the compound with an optically active resolving agent'"'"', (+)-di-para-toluoyltartaric acid, in an amount equimolar to an amount of the compound in such manner as to form a solubilized second diastereomeric salt between the same;

g) precipitating the second diastereomeric salt;

h) collecting the second diastereomeric salt; and

i) hydrolysing the second diastereomeric salt to isolate the compound.

17. A process according to claim 15 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of an optically active resolving agent, (−

)-di-para-toluoyltartaric acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized first diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the first diastereomeric salt;

d) removing the first diastereomeric salt and preserving the solution as a filtrate;

e) hydrolysing and separating the compound from the filtrate;

f) dissolving into solution the compound with an optically active resolving agent'"'"', (+)-di-para-toluoyltartaric acid, in an amount equimolar to an amount of the compound in such manner as to form a solubilized second diastereomeric salt between the same;

g) precipitating the second diastereomeric salt;

h) collecting the second diastereomeric salt; and

i) hydrolysing the second diastereomeric salt to isolate the compound.

18. A process according to claim 15 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of an optically active resolving agent, (−

)-di-para-toluoyltartaric acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized first diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the first diastereomeric salt;

d) removing the first diastereomeric salt and preserving the solution as a filtrate;

e) hydrolysing and separating the compound from the filtrate;

f) dissolving into solution the compound with an optically active resolving agent'"'"', (+)-di-para-toluoyltartaric acid in an amount equimolar to an amount of the compound in such manner as to form a solubilized second diastereomeric salt between the same;

g) precipitating the second diastereomeric salt;

h) collecting the second diastereomeric salt; and

i) hydrolysing the second diastereomeric salt to isolate the compound.

19. A process for preparing a compound of a formula:

wherein R is —

CH₃ or lower alkyl ester;

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

wherein R is defined as above;

with an equimolar amount of an optically active resolving agent, (+)-mandelic acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized first diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the first diastereomeric salt;

d) removing the first diastereomeric salt and preserving the solution as a filtrate;

e) hydrolysing and separating the compound from the filtrate;

f) dissolving into solution the compound with an optically active resolving agent'"'"', (−

)-mandelic acid, in an amount equimolar to an amount of the compound in such manner as to form a solubilized second diastereomeric salt between the same;

g) precipitating the second diastereomeric salt;

h) collecting the second diastereomeric salt; and

i) hydrolysing the second diastereomeric salt to isolate the compound.

20. A process according to claim 19 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of an optically active resolving agent, (+)-mandelic acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized first diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the first diastereomeric salt;

d) removing the first diastereomeric salt and preserving the solution as a filtrate;

e) hydrolysing and separating the compound from the filtrate;

f) dissolving into solution the compound with an optically active resolving agent'"'"', (−

)-mandelic acid, in an amount equimolar to an amount of the compound in such manner as to form a solubilized second diastereomeric salt between the same;

g) precipitating the second diastereomeric salt;

h) collecting the second diastereomeric salt; and

i) hydrolysing the second diastereomeric salt to isolate the compound.

21. A process according to claim 19 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of an optically active resolving agent, (+)-mandelic acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized first diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the first diastereomeric salt;

d) removing the first diastereomeric salt and preserving the solution as a filtrate;

e) hydrolysing and separating the compound from the filtrate;

f) dissolving into solution the compound with an optically active resolving agent'"'"', (−

)-mandelic acid, in an amount equimolar to an amount of the compound in such manner as to form a solubilized second diastereomeric salt between the same;

g) precipitating the second diastereomeric salt;

h) collecting the second diastereomeric salt; and

i) hydrolysing the second diastereomeric salt to isolate the compound.

22. A process for preparing a compound of a formula:

wherein R is —

CH₃, —

COOH or a lower alkyl ester;

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

wherein R is defined as above;

with an equimolar amount of an optically active resolving agent, (+)-di-para-toluoyltartaric acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized first diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the first diastereomeric salt;

d) removing the first diastereomeric salt and preserving the solution as a filtrate;

e) hydrolysing and separating the compound from the filtrate;

f) dissolving into solution the compound with an optically active resolving agent'"'"', (−

)-di-para-toluoyltartaric acid, in an amount equimolar to an amount of the compound in such manner as to form a solubilized second diastereomeric salt between the same;

g) precipitating the second diastereomeric salt;

h) collecting the second diastereomeric salt; and

i) hydrolysing the second diastereomeric salt to isolate the compound.

23. A process according to claim 22 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of an optically active resolving agent, (+)-di-para-toluoyltartaric acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized first diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the first diastereomeric salt;

d) removing the first diastereomeric salt and preserving the solution as a filtrate;

e) hydrolysing and separating the compound from the filtrate;

f) dissolving into solution the compound with an optically active resolving agent'"'"', (−

)-di-para-toluoyltartaric acid, in an amount equimolar to an amount of the compound in such manner as to form a solubilized second diastereomeric salt between the same;

g) precipitating the second diastereomeric salt;

h) collecting the second diastereomeric salt; and

i) hydrolysing the second diastereomeric salt to isolate the compound.

24. A process according to claim 22 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of an optically active resolving agent, (+)-di-para-toluoyltartaric acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized first diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the first diastereomeric salt;

d) removing the first diastereomeric salt and preserving the solution as a filtrate;

e) hydrolysing and separating the compound from the filtrate;

f) dissolving into solution the compound with an optically active resolving agent'"'"', (−

)-di-para-toluoyltartaric acid, in an amount equimolar to an amount of the compound in such manner as to form a solubilized second diastereomeric salt between the same;

g) precipitating the second diastereomeric salt;

h) collecting the second diastereomeric salt; and

i) hydrolysing the second diastereomeric salt to isolate the compound.

25. A process according to claim 22 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of an optically active resolving agent, (+)-di-para-toluoyltartaric acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized first diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the first diastereomeric salt;

d) removing the first diastereomeric salt and preserving the solution as a filtrate;

e) hydrolysing and separating the compound from the filtrate;

f) dissolving into solution the compound with an optically active resolving agent'"'"', (−

)-di-para-toluoyltartaric acid, in an amount equimolar to an amount of the compound in such manner as to form a solubilized second diastereomeric salt between the same;

g) precipitating the second diastereomeric salt;

h) collecting the second diastereomeric salt; and

i) hydrolysing the second diastereomeric salt to isolate the compound.

26. A process for preparing a compound of a formula:

wherein R is —

CH₃ or lower alkyl ester;

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

wherein R is defined as above;

with an equimolar amount of an optically active resolving agent, (−

)-mandelic acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized first diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the first diastereomeric salt;

d) removing the first diastereomeric salt and preserving the solution as a filtrate;

e) hydrolysing and separating the compound from the filtrate;

f) dissolving into solution the compound with an optically active resolving agent'"'"', (+)-mandelic acid, in an amount equimolar to an amount of the compound in such manner as to form a solubilized second diastereomeric salt between the same;

g) precipitating the second diastereomeric salt;

h) collecting the second diastereomeric salt; and

i) hydrolysing the second diastereomeric salt to isolate the compound.

27. A process according to claim 26 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of an optically active resolving agent, (−

)-mandelic acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized first diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the first diastereomeric salt;

d) removing the first diastereomeric salt and preserving the solution as a filtrate;

e) hydrolysing and separating the compound from the filtrate;

f) dissolving into solution the compound with an optically active resolving agent'"'"', (+)-mandelic acid, in an amount equimolar to an amount of the compound in such manner as to form a solubilized second diastereomeric salt between the same;

g) precipitating the second diastereomeric salt;

h) collecting the second diastereomeric salt; and

i) hydrolysing the second diastereomeric salt to isolate the compound.

28. A process according to claim 26 for preparing a compound of a formula:

comprising;

a) dissolving into a solution an amount of a racemic compound of a formula;

with an equimolar amount of an optically active resolving agent, (−

)-mandelic acid, into a suitable organic solvent;

b) heating the solution to an elevated temperature suitable for formation of a solubilized first diastereomeric salt between the optically active resolving agent and the compound;

c) cooling the solution for a period of time sufficient to precipitate the first diastereomeric salt;

d) removing the first diastereomeric salt and preserving the solution as a filtrate;

e) hydrolysing and separating the compound from the filtrate;

f) dissolving into solution the compound with an optically active resolving agent'"'"', (+)-mandelic acid, in an amount equimolar to an amount of the compound in such manner as to form a solubilized second diastereomeric salt between the same;

g) precipitating the second diastereomeric salt;

h) collecting the second diastereomeric salt; and

i) hydrolysing the second diastereomeric salt to isolate the compound.

29. A compound consisting essentially of a diastereomeric salt between (R)-(+)-α

-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1-piperidinebutanol and either (2S,3S)-(+)-di-para-toluoyltartaric acid or (R)-(−

)-mandelic acid.

30. A compound consisting essentially of a diastereomeric salt between (S)-(−

)-α

-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1-piperidinebutanol and either (2R,3R)-(−

)-di-para-toluoyltartaric acid or (S)-(+)-mandelic acid.

31. A compound consisting essentially of a diastereomeric salt between (R)-(+)-4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α

,α

-dimethylbenzeneacetic acid and (2S,3S)-(+)-di-para-toluoyltartaric acid.

32. A compound consisting essentially of a diastereomeric salt between (S)-(−

)-4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α

,α

-dimethylbenzeneacetic acid and (2R,3R)-(−

)-di-para-toluoyltartaric acid.

33. A compound consisting essentially of a diastereomeric salt between a compound of a formula:

wherein R is lower alkyl ester;

and either (2S,3S)-(+)-di-para-toluoyltartaric acid or (R)-(−

)-mandelic acid.

34. A compound according to claim 33 consisting essentially of a diastereomeric salt between (R)-(+)-ethyl

4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α

,α

-dimethylbenzeneacetate and either (2S,3S)-(+)-di-para-toluoyltartaric acid or (R)-(−

)-mandelic acid.

35. A compound consisting essentially of a diastereomeric salt between a compound of a formula:

wherein R is lower alkyl ester;

and either (2R,3R)-(−

)-di-para-toluoyltartaric acid or (S)-(+)-mandelic acid.

36. A compound according to claim 35 consisting essentially of a diastereomeric salt between (S)-(−

)-ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α

,α

-dimethylbenzeneacetate and either (2R,3R)-(−

)-di-para-toluoyltartaric acid or (S)-(+)-mandelic acid.