Title of Invention	PROCESS FOR THE SYNTHESIS OF 4-(3-METHANESULFONYLPHENYL)-1-PROPYL-PIPERIDINE
Abstract	The present invention is directed to processes for the preparation of 4-(3-methanesulfonyl-phenyl)-1-N-propylpiperidine (I) or a pharmaceutically acceptable salt thereof, which comprises: oxidizing a sulfide of the formula (II): with a catalytic oxidizing agent and an oxidant; to give a compound of the formula (III): followed by catalytic reduction of the compound of the formula (III).

Full Text

TITLE OF THE INVENTION PROCESS FOR THE SYNTHESIS OF 4-(3-METHANESULFONYLPHENYL)-l-N-PROPYL- PIPERIDINE BACKGROUND OF THE INVENTION 4-(3-MethanesulfonylphenyI)-l-n-propylpiperidiae is useful as a modulator of dopamine neurotransmission and has therapeutic application for example in the treatment of Alzheimer's disease, Parkinson's disease and schizophrenia. Synthetic methods to prepare 4-(3-methanesulfonyiphenyI)-l-n-propylpiperidine have been described in PCT Patent Publication WO 01/46145. In accordance with the present invention, processes are provided for for the preparation of 4-(3-methanesTilfonylphenyl)-l-n-propylpiperidine, and pharmaceutically acceptable salts thereof. The subject process provide 4-(3-methanesulfonylphenyl)-l -N-propylpiperidine in high yield and purity while minimizing the number of synthetic steps. SUMMARY OF THE INVENTION The present invention is directed to processes for the preparation of 4-(3-methane-sulfoHylphenyl)-l-n-propylpiperidine of the formula I: (Figure Removed) and pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to procesess for the preparation of 4-(3-methanesulfonyl-phenyl)-l-n-propylpiperidine which is useful as a pharmaceutical agent. An embodiment of the present invention is directed to a process for the preparation of 4-(3-methanesulfonylphenyl)-l-n-propylpiperidine of the formula I: (Figure Removed) or a pharmaceutically acceptable salt thereof, which comprises: oxidizing a sulfide of the formula II: (Figure Removed) with a catalytic oxidizing agent and an oxidant; to give a compound of the formula III: (Figure Removed) followed by catalytic reduction of the compound of the fonnula III; to give the compound of the formula (I): (Figure Removed) or a pharmaceutically acceptable salt thereof. A further embodiment of the present invention is directed to a process for the preparation of 4-(3-methanesulfonylphenyl)-l-n-propylpiperidineof the formula (I): (Figure Removed) or a pharmaceutically' acceptable salt thereof, which further comprises: dehydrating an alcohol of the formula la: (Figure Removed) with a strong acid; to give a sulfide of the formula II: (Figure Removed) oxidising the sulfide of the formula n with e catalytic oxidizing agent and an oxidant; to give a compound of the formula III: (Figure Removed) followed by catalytic reduction of the compound of the formula III; to give the compound of the formula (I): (Figure Removed) or a pharmaceutically acceptable salt thereof. In an embodiment of the present invention the strong acid is a strong inorganic acid or a strong organic acid. In an embodiment of the present invention the strong acid is selected from sulfuric acid, hydrochloric acid, hydrofluoric acid, nitric acid and trifluoroacetic acid. Optionally, the dehydration of the alcohol of the formula la with a strong acid is conducted in a solvent. In an embodiment of the present invention the solvent is selected from toluene, xylene, hexao.es and water. In an embodiment of the present invention the catalytic oxidizing agent is a tungsten, ruthenium, molybdenum, osmium or chromium oxidizing agent. In an embodiment of the present invention the catalytic oxidizing agent is a tungsten oxidizing agent. In an aspect of this embodiment, the tungsten oxidizing agent is sodium tungstate. In an embodiment of the present invention the oxidant is a peroxide. In an aspect of this embodiment, the peroxide is sodium peroxide, hydrogen peroxide, sodium hypochlorite, sodium bromate, sodium periodate, peroxyacetic acid or peroxybenzoic acid. In a further aspect of this embodiment, the peroxide is sodium peroxide. Within this embodiment, the peroxide is an aqueous solution of sodium peroxide. In an embodiment of the present invention the step of oxidizing the sulfide of the formula II is conducted at less than 3 pH. Within this embodiment, the step of oxidizing the sulfide of the formula II is conducted at less than 2 pH. Further within this embodiment, the step of oxidizing the sulfide of the formula n is conducted at less than 1 pH. In an embodiment of the present invention the step of oxidizing the sulfide of the formula n is conducted conducted at a temperature greater than 30°C (inclusive). Within this embodiment, the step of oxidizing the sulfide of the formula II is conducted at a temperature greater than 40°C (inclusive). Further within this embodiment, the step of oxidizing the sulfide of the formula n is conducted at a temperature between 40°C and 60 °C (inclusive). Further within this embodiment, the step of oxidizing the sulfide of the formula n is conducted at a temperature between 50°C and 55°C (inclusive). Preferred solvents for conducting the step of oxidizing the sulfide of the formula n comprise an aqueous solution with an organic solvent which is selected from toluene, tetrahydrofuran (THF), diethyl ether, diglyme and methyl t-butyl ether. The most preferred organic solvent is toluene. In an embodiment of the present invention the step of catalytic reduction of the compound of the formula III comprises catalytic hydrogenation. Within this embodiment, the step of catalytic reduction of the compound of the formula III comprises catalytic hydrogenation with a palladium catalyst, a platinum catalyst or a ruthenium catalyst. Within this embodiment, the step of catalytic reduction of the compound of the formula III comprises catalytic hydrogenation with a palladium catalyst. Within this embodiment, the step of catalytic reduction of the compound of the formula III comprises catalytic hydrogenation with a palladium on carbon catalyst. Further within this embodiment, the step of catalytic reduction of the compound of the formula in comprises catalytic hydrogenation with a 10% palladium on carbon catalyst or a 5% palladium on carbon catalyst. In an alternate embodiment of the present invention the step of catalytic reduction of the compound of the formula III comprises catalytic transfer hydrogenation. Within this embodiment, the step of catalytic reduction of the compound of the formula III comprises catalytic transfer hydrogenation with a rhodium catalyst or a ruthenium catalyst and a hydrogen transfer source. Within this embodiment, the rhodium catalyst may be selected from bis((pentamethylcyclopentadienyl)rhodium. chloride) and bis((cyclopentadienyl)rhodium chloride), optionally in the presence of alternate ligands. Within this embodiment, the ruthenium catalyst may be selected from bis((4-isopropyl-toluenyl)rarnenium. chloride) and bis((cyclopenta-dienyl)ruthenium chloride), optionally in the presence of alternate ligauds. Within this embodiment, the hydrogen transfer source may be an acid or an alchol, such as formic acid, methanol, ethanol, isopropanol, isobutanol or n-butanol. In this embodiment, a base is optionally present with the hydrogen transfer source. The base may be an inorganic base such as a base selected from potassium or sodium hydroxide, potassium or sodium carbonate, potassium or sodium bicarbonate potassium or sodium alkoxides, and the like. The alkoxides can be derived from lower (C1-C5) or higher (>C6) primary, secondary or tertiary alcohols. Solvents for conducting the step of catalytic reduction of the compound of the formula III include an aqueous solution with an alcohol, such as an alcohol selected from methanol, ethanol, isopropanoi, isobutanol or n-butanol. Within this embodiment, the alcoho] may be methanol. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzole, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, muck, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are benzenesulfonic, citric, hydrobromic, hydrochloric, maleic, fumaric, succinic and tartaric acids. It will be understood that, as used herein, references to the compounds of the present invention are meant to also include the phannaceutically acceptable salts. The starting materials arid reagents for the subject processes are either commercially available or are known in the literature or may be prepared following literature methods described for analogous compounds. The skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures include crystallization, distillation, normal phase or reverse phase chromatography. The following Examples are provided by way of illustration only, and in no way are meant to limit the scope of the invention. EXAMPLE 1 (Figure Removed) To a -45 °C solution of 3-Br-thioanisole in THF was added Hex-Li over 1 h with the reaction temperature maintained EXAMPLE 2 (Figure Removed) The alcohol was slurried ha toluene and sulfuric acid was added. The reaction was heated at reflux for 1-2 h with azeotropic removal of water. Upon completion, the reaction was cooled to 70 °C and water was added. The reaction was cooled to RT and the phases are separated. To the aqueous phase was added toluene (6 L/kg) and 5N NaOH (2 eq., -1.6 L/kg, pH>9) while maintaining temperature EXAMPLES (Figure Removed) To a solution of sulfide-alkene in aqueous H2SO4 was added Na2WO4 x 2H2O. H202 (30%) was added over 0.5 to 1 h while maintaining temperature below 55 °C. The resulting mixture was aged at 50-55 °C until the sulfoxide intermediate was O.5 A% (1 -2 h). The resulting mixture was cooled to 10 °C and toluene (5 L/kg) followed by 5N NaOH was added while maintaining the internal temperature internal temperature at 50-55 °C. To the resulting solution was added more heptane (3ml/g) at 50-55 °C over 1h. The resulting slurry was cooled to 23 °C over 0.5 to In, aged 0.5 h and filtered at it The filter-cake was washed with 1:3 toluene/heptane (4 mL/g, 12 L) and then dried at 50 °C under vacuum with an N2 purge. Typical yield was 75-80 %, with >99 wt.% and 99 A% purity. To the combined aqueous layers (aq layer after 5N NaOH, after IN NaOH wash, after 20% brine wash) at 23 °C was added solid Na3S03 until peroxide test was negative by Quantofix test strips. An exotherm of ~3 °C occurs. EXAMPLE 4 (Figure Removed) To a slurry of sulfone-alkene in PA was added HCO2H (5 eq.). To the resulting solution was added a suspension of 10% Pd/C in -water (5 ml/g). The suspension was aged at RT for 16 to 24 h until sulfone-alkene was While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, reaction conditions other than the particular conditions as set forth herein above may be applicable as a consequence of variations in the reagents or methodology to prepare the compounds from the processes of the invention indicated above. Likewise, the specific reactivity of starting materials may vary according to and depending upon the particular substituents present or the conditions of manufacture, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It was intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable. WHAT IS CLAIMED IS: 1. A process for preparing a compound of the formula 1: (Figure Removed) or a pharmaceutically acceptable salt thereof, which comprises: oxidizing a sulfide of the formula II: (Figure Removed) with a catalytic oxidizing agent and an oxidant; to give a compound of the formula III: (Figure Removed) followed by catalytic reduction of the compound of the formula III; to give the compound of the formula I: (Figure Removed) or a pharmaceutically acceptable salt tereof. 2. The process of Claim 1 which further comprises: dehydrating an alcohol of the formula la: (Figure Removed) with a strong acid; to give the sulfide of the formula II. 3. The process of Claim 2 wherein the strong acid is selected from sulfuric acid, hydrochloric acid, hydrofluoric acid, nitric acid and trifluoroacetic acid. 4. The process of Claim 3 wherein the dehydration of the alcohol of the formula la with a strong acid is conducted in solvent selected from toluene, xylene, hexanes and water. 5. The process of Claim 1 wherein the catalytic oxidizing agent is a tungsten oxidizing agent. 6. The process of Claim 5 wherein the tungsten oxidizing agent is sodium tungstate. 7. The process of Claim 1 wherein the oxidant is a peroxide. 8. The process of Claim 7 wherein the peroxide is sodium peroxide. 9. The process of Claim 1 wherein the step of oxidizing the sulfide of the formula n is conducted at less than 2 pH. 10. The process of Claim 1 wherein the step of oxidizing the sulfide of the formula II is conducted at a temperature between 40°C and 60°C. 11. The process of Claim 1 wherein the catalytic reduction of the compound of the formula III comprises catalytic hydrogenation with a palladium catalyst, a platinum catalyst or a ruthenium catalyst. 12. The process of Claim 11 wherein the catalytic reduction of the compound of the formula III comprises catalytic hydrogenation with a palladium catalyst. 13. The process of Claim 12 wherein the catalytic reduction of the compound of the formula in comprises catalytic hydrogenation with a palladium on carbon catalyst. 14. The process of Claim 13 wherein the catalytic reduction of the compound of the formula III comprises catalytic hydrogenation with a 10% palladium on carbon catalyst. 15. The process of Claim 14 wherein the step of catalytic reduction of the compound of the formula III is conducted in an aqueous solution with an alcohol.

Documents:

3481-delnp-2007-abstract.pdf

3481-DELNP-2007-Assignment-(09-02-2009).pdf

3481-delnp-2007-Assignment-(31-07-2013).pdf

3481-delnp-2007-Claims-(02-05-2013).pdf

3481-delnp-2007-claims.pdf

3481-delnp-2007-Correspondance Others-(02-05-2013).pdf

3481-delnp-2007-Correspondence Others-(01-02-2013).pdf

3481-delnp-2007-Correspondence Others-(09-09-2008).pdf

3481-delnp-2007-Correspondence Others-(31-07-2013).pdf

3481-delnp-2007-Correspondence-Others-(05-11-2012).pdf

3481-DELNP-2007-Correspondence-Others-(09-02-2009).pdf

3481-delnp-2007-correspondence-others.pdf

3481-delnp-2007-Description (Complete)-(02-05-2013).pdf

3481-delnp-2007-description (complete).pdf

3481-delnp-2007-Form-1-(31-07-2013).pdf

3481-delnp-2007-form-1.pdf

3481-delnp-2007-Form-18-(09-09-2008).pdf

3481-delnp-2007-Form-2-(02-05-2013).pdf

3481-delnp-2007-Form-2-(31-07-2013).pdf

3481-delnp-2007-form-2.pdf

3481-delnp-2007-Form-3-(01-02-2013).pdf

3481-delnp-2007-Form-3-(02-05-2013).pdf

3481-delnp-2007-form-3.pdf

3481-delnp-2007-form-5.pdf

3481-delnp-2007-form-6-(09-02-2009).pdf

3481-DELNP-2007-GPA-(09-02-2009).pdf

3481-delnp-2007-GPA-(31-07-2013).pdf

3481-delnp-2007-pct-304.pdf

3481-delnp-2007-pct-306.pdf

3481-delnp-2007-pct-409.pdf

3481-delnp-2007-Petition-137-(02-05-2013).pdf