Process for the preparation of a piperazine derivative

1. A process for preparing (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine dihydrochloride, which comprises:

(1) debenzylating (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)piperazine by chemical reduction with a hydride, a combination of metals or a metal compound with an organic acid or an inorganic acid to produce (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)piperazine;

(2) reacting (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)piperazine with (2S)-4-(2-chloroethyl)-2-(methoxymethyl)morpholine or a salt thereof in the presence of a base to produce (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine; and

(3) converting the (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[2-[(2 S)-2-(methoxymethyl)morpholino]ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine to its hydrochloride salt.

2. The process of claim 1 , wherein the salt of (2S)-4-(2-chloroethyl)-2-(methoxymethyl)morpholine is an organic acid salt, an inorganic acid salt, an amino acid salt, an alkali metal salt, an alkaline earth metal salt or an ammonium salt.

3. The process of claim 1 , wherein the base of step (2) is an alkali metal carbonate, an alkali metal bicarbonate, a tri(lower)alkylamine, pyridine, an N-(lower)-alkylmorpholine, a N,N-di(lower)alkylethylamine or a N,N-di(lower)alkylbenzylamine.

4. A process for preparing (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine dihydrochloride, which comprises:

(1) debenzylating (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)piperazine by reduction in the presence of a palladium catalyst and a formate salt to produce (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)piperazine;

(2) reacting (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)piperazine with (2S)-4-(2-chloroethyl)-2-(methoxymethyl)morpholine or a salt thereof in the presence of a N,N-di(lower)alkylethylamine base to produce (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine; and

(3) converting the (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine to its hydrochloride salt.

5. The process of claim 4 , wherein the temperature of the debenzylation reaction ranges from 40 to 600° C.

6. The process of claim 4 , wherein the temperature of the reaction of step (2) ranges from 40 to 60° C.

7. The process of claim 6 , wherein the reaction with base occurs in a solvent selected from the group consisting of water, an alcohol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide or pyridine.

8. The process of claim 5 , wherein the reduction reaction occurs in a solvent selected from the group consisting of water, an alcohol, tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene chloride, chloroform, N,N-dimethylformamide or N,N-dimethylacetamide.

9. The process of claim 1 , wherein the temperature of the debenzylation reaction ranges from 40 to 60° C.

10. The process of claim 9 , wherein the reduction reaction occurs in a solvent selected from the group consisting of water, an alcohol, tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene chloride, chloroform, N,N-dimethylformamide or N,N-dimethylacetamide.

11. The process of claim 1 , wherein the temperature of the reaction of step (2) ranges from 40 to 60° C.

12. The process of claim 11 , wherein the reaction with base occurs in a solvent selected from the group consisting of water, an alcohol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide or pyridine.