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1. WO2015171003 - PROCESS FOR OBTAINING OPTICALLY ACTIVE PIRLINDOLE ENANTIOMERS AND SALTS THEREOF

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[ EN ]

CLAIMS

1. Process for obtaining optically active pirlindole enantiomers, in the form of a free base or in the form of a pharmaceutically acceptable salt characterized by carrying out a resolution by crystallization with optically active acids of (rac) -pirlindole in the free base form.

2. Process according to claim 1, characterized in that the optically active pirlindole enantiomers are enantiomerically pure (S) -pirlindole or (R) -pirlindole .

3. Process according to any of claims 1 and 2 characterized by comprising the following steps:

i) Dissolving (rac) -pirlindole hydrochloride in an aqueous solvent, followed by a subsequent extraction with a chlorinated solvent and complete removal of the solvent to obtain (rac) -pirlindole in the free base form;

ii) Dissolving the (rac) -pirlindole obtained in step i) in an organic solvent, followed by adding an optically active acid for resolution;

iii) Stirring for 15 min to 2 h the suspension formed in ii) while diastereomeric salt precipitation occurs;

iv) Filtering the obtained diastereomeric salt and purifying it by suspension in an organic solvent to obtain (S)-pirlindole or (R)- pirlindole enantiomer in the form of a pharmaceutically acceptable salt formed with the optically active acid; and optionally,

v) Obtaining enantiomerically pure (S) -pirlindole and/or (R)- pirlindole as a free base by dissolution of the product obtained in step iv) in an aqueous solvent, subsequent extraction with chlorinated solvent and complete removal of the solvent; and, optionally,

vi) Obtaining S) -pirlindole or (R)- pirlindole in the form of pharmaceutically acceptable acid addition salts by salification of the enantiomerically pure (S) -pirlindole and/or (R)- pirlindole in the form of a free base obtained in step v) with a pharmaceutically acceptable acid to form a pharmaceutically acceptable acid addition salt of S) -pirlindole or (R)- pirlindole enantiomer.

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4. Process according to any of claims 1 to 3 wherein the optically active acid used in step ii) is selected from the group consisting of: (R) -mandelic acid, (R) - (+) - -methoxy-a-trifluorophenylacetic acid, (1R, 3S) -(+) -camphoric acid,D (+)-malic acid, (S) -mandelic acid, (S) - (-) -a-methoxy-a-trifluorophenylacetic acid, (IS, 3R) -(+) -camphoric acid or L (-)-malic acid.

5. Process according to any of claims 1 to 4 wherein the organic solvent used in steps ii) and iv) is selected from the group consisting of: methanol, ethanol, propanol, 1-butanol, 2-butanol, tert-butyl alcohol, 2-butanone, acetone, ethyl methyl ketone, methyl isobutyl ketone, dimethylsulfoxide, 1,2-dichloroethane, diethyl ether, dimethyl ether, dimethylformamide, methyl tert-butyl ether, 2-propanol, pyridine, toluene, xylene or mixtures thereof in any proportion.

6. Process according to any one of the preceding claims characterized in that the compound obtained is enantiomerically pure (S) -pirlindole as (R) -mandelate salt.

7. Process according to any one of claims 1 to 5 characterized in that the compound obtained is enantiomerically pure (R)-pirlindole as (S) -mandelate salt.

8. Process according to any one of claims 1 to 5characterized in that the compound obtained is enantiomerically pure (S)-pirlindole hydrobromide salt.

9. Process according to any one of claims 1 to 5characterized in that the compound obtained is enantiomerically pure (R)-pirlindole hydrobromide salt.

10. Process according to any one of claims 1 to 5 characterized in that the compound obtained is enantiomerically pure (S)-pirlindole citrate salt.

11. Process according to any one of claims 1 to 5 characterized in that the compound obtained is enantiomerically pure (R)-pirlindole citrate salt.

12. Process according to any one of claims 1 to 5 characterized in that the compound obtained is enantiomerically pure (S)-pirlindole mesylate salt.

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13. Process according to any one of claims 1 to 5 characterized in that the compound obtained is enantiomerically pure (R)-pirlindole mesylate salt.

14. Process according to any one of claims 1 to 5 characterized in that the compound obtained is enantiomerically pure (R)-pirlindole R) -(+) -α-metoxi- -trifluorophenylacetate salt.

15. Process according to any one of claims 1 to 5 characterized in that the compound obtained is enantiomerically pure (S)-pirlindole R) -(+) -α-metoxi-a-trifluorophenylacetate salt.

16. Process according to any of claims 1 to 5 characterized in that the compound obtained is enantiomerically pure (R) -pirlindole in the free base form.

17. Process according to any of claims 1 to 5 characterized in that the compound obtained is enantiomerically pure (S)-pirlindole in the free base form.

Lisbon, May 8, 2014.

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