Process for the separation of enantiomers of piperazine derivatives

1. A process for the separation of the enantiomers of a compound of formula I

wherein

X denotes O or CH 2 ,

Y is NH or N-PG,

PG denotes a protective group selected from a carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ) group, tert-butyloxycarbonyl (BOC) group, 9-fluorenylmethyloxycarbonyl (FMOC) group, alkanoyl group, such as the acetyl (Ac) group, benzoyl (Bz) group, benzyl (Bn) group, carbamate group, p-methoxybenzyl (PMB), 4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP) group, or arylsulfonyl group,

and

n denotes 0 or 1,

comprising the steps of:

a) contacting the respective racemate or other enantiomeric mixture of the respective compound of formula I with a chiral, non-racemic acid in a suitable solvent, wherein the chiral, non-racemic acid is selected from (1R or 1S)-10-camphorsulfonic acid, (1R or 1S)-3-bromocamphor-10-sulfonic acid, (D or L)-tartaric acid and substituted analogues such as (D or L)-diacetyltartaric acid, (D or L)-dibenzoyl tartaric acid, (D or L)-di-O,O′-p-toluoyl-tartaric acid, (D or L)-di-O,O′-o-toluoyl-tartaric acid, (R or S)-1,1″-binaphthyl-2,2″-diyl-hydrogenphosphate, (D or L)-N-acetyl-phenylalanine, (D or L)-acetylmandelic acid, (R or S)-cyclohexylphenylglycolic acid, (S)-camphanic acid, (R or S)-2-pyrrolidone-5-carboxylic acid, naproxen, ibuprofen; (D or L)-malic acid, L-lactic acid, (R or S)-3-hydroxybutyric acid, hyodeoxycholic acid, (R or S)-mandelic acid, (R or S)-Me-mandelic acid, (R or S)-4-bromo-mandelic acid, (R or S)-4-chloro-mandelic acid or (R or S)-phenylsuccinic acid, or suitable N-protected amino acids, or substituted (D or L)-tartaric acids;

b) optionally heating the mixture obtained under step a) and allowing the mixture to cool to room temperature;

c) separating the formed crystals from the solution;

d) optionally liberating the free base of the respective enantiomer of formula I from the formed crystals obtained under c) by treatment with a base.

2. The process according to claim 1 , wherein the compound of formula I is the racemate or other enantiomeric mixture of compound (I′) or the racemate or other enantiomeric mixture of compound (I″):

3. The process according to claim 1 , wherein the chiral acid is selected from (S)-Me-mandelic acid, (S)-4-bromo-mandelic acid, (S)-4-chloro-mandelic acid (S)-phenyl succinic acid, dibenzoyl-D-tartaric acid, D-(+)-di-toluoyltartaric acid, D-tartaric acid and di-p-anisoyl-(D)-tartaric acid.

4. The process according to claim 2 , wherein the chiral acid is selected from (S)-Me-mandelic acid, (S)-4-bromo-mandelic acid, (S)-4-chloro-mandelic acid (S)-phenyl succinic acid, dibenzoyl-D-tartaric acid, D-(+)-di-toluoyltartaric acid, D-tartaric acid and di-p-anisoyl-(D)-tartaric acid.

5. The process according to claim 3 , wherein the chiral acid is employed in a molar ratio to the compounds of formula I of between about 1 to 2 (i.e. about 0.5 equivalents based on the compounds of formula I) and about 3 to 1 (i.e. about 3 equivalents).

6. The process according to claim 4 , wherein the chiral acid is employed in a molar ratio to the compounds of formula I of between about 1 to 2 (i.e. about 0.5 equivalents based on the compounds of formula I) and about 3 to 1 (i.e. about 3 equivalents).

7. The process according to claim 5 , wherein the solvent is selected from H 2 O, MeCN, about 2 to about 50% H 2 O in EtOH, EtOH, 2 to 50% H 2 O in MeOH, MeOH, 2 to 50% H 2 O in IPA, IPA, 2 to 50% MeOH in MEK, MEK, 2 to 50% MeOH in iPrOAc, iPrOAc and dioxane.

8. The process according to claim 6 , wherein the solvent is selected from H 2 O, MeCN, about 2 to about 50% H 2 O in EtOH, EtOH, 2 to 50% H 2 O in MeOH, MeOH, 2 to 50% H 2 O in IPA, IPA, 2 to 50% MeOH in MEK, MEK, 2 to 50% MeOH in iPrOAc, iPrOAc and dioxane.

9. A free base of a compound of formula II

wherein

X denotes O or CH 2 ,

Y is NH or N-PG,

PG denotes a protective group selected from a carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ) group, tert-butyloxycarbonyl (BOC) group, 9-fluorenylmethyloxycarbonyl (FMOC) group, alkanoyl group, such as the acetyl (Ac) group, benzoyl (Bz) group, benzyl (Bn) group, carbamate group, p-methoxybenzyl (PMB), 4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP) group, or benzylsulfonyl group, and

n denotes 0.

10. The free base of a compound of formula II of claim 9 , wherein the compound is (S)-1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazine.

11. The free base of a compound of formula II of claim 9 , wherein the compound is (S)-1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine.

12. The free base of a compound of formula II of claim 9 , wherein the compound is racemic 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine.

13. A salt of a compound of formula II

wherein

X denotes O or CH 2 ,

Y is NH or N-PG,

PG denotes a protective group

and

n denotes 0 or 1, with an acid selected from (S)-Me-mandelic acid, (S)-4-bromo-mandelic acid, (S)-4-chloro-mandelic acid, (S)-phenylsuccinic acid, dibenzoyl-D-tartaric acid, D-(+)-di-toluoyltartaric acid, D-tartaric acid and di-p-anisoyl-(D)-tartaric acid.

14. The salt of a compound of formula II of claim 13 , wherein the compound is (S)-1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazine and the acid is selected from (S)-Me-mandelic acid, (S)-4-bromo-mandelic acid, (S)-4-chloro-mandelic acid, (S)-phenylsuccinic acid, dibenzoyl-D-tartaric acid, D-(+)-di-toluoyltartaric acid, D-tartaric acid and di-p-anisoyl-(D)-tartaric acid.

15. The salt of a compound of formula II of claim 13 , wherein the compound is (S)-1-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazine and the acid is selected from (S)-Me-mandelic acid, (S)-4-bromo-mandelic acid, (S)-4-chloro-mandelic acid, (S)-phenylsuccinic acid, dibenzoyl-D-tartaric acid, D-(+)-di-toluoyltartaric acid, D-tartaric acid and di-p-anisoyl-(D)-tartaric acid.

16. The salt of a compound of formula II of claim 13 , wherein the compound is (S)-1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine and the acid is selected from (S)-Me-mandelic acid, (S)-4-bromo-mandelic acid, (S)-4-chloro-mandelic acid, (S)-phenyl succinic acid, dibenzoyl-D-tartaric acid, D-(+)-di-toluoyltartaric acid, D-tartaric acid and di-p-anisoyl-(D)-tartaric acid.

17. The salt according to claim 13 , wherein the molar ratio between the piperazine derivative and the acid is 1 to 1.

18. The salt according to claim 14 , wherein the molar ratio between the piperazine derivative and the acid is 1 to 1.

19. The salt according to claim 15 , wherein the molar ratio between the piperazine derivative and the acid is 1 to 1.

20. The salt according to claim 16 , wherein the molar ratio between the piperazine derivative and the acid is 1 to 1.