Title of Invention	A PROCESS FOR PREPARATION OF RACEMIC OR OPTICALLY ACTIVE 3-[(1,3-BENZODIOXOL-5-YLOXY)METHYL]-4-(4-FLUOROPHENYL)-1-METHYLPIPERIDINE
Abstract	Disclosed herein is a process for the preparation of racemic or optically active compound of 3-[(l,3-benzodioxol-5-yloxy) methyl]-4-(4-fluorophenyl)-l-methylpiperidine by condensing racemic or optically active alkyl sulphonate esters of [4-(4-fluorophenyl)-l-methylpiperidin-3-yl] methanol with alkali metal salt of l,3-benzodioxol-5-ol (Sesamol) in presence of an aprotic solvent.

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FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rulel3) 1. TITLE OF THE INVENTION: "A process for synthesis of (35,4R)-3-[(l,3-benzodioxol-5-yloxy) methyl]-4-(4-fluorophenyl)-l-methylpiperidine, an intermediate for Paroxetine" 2. APPLICANT (S) (a) NAME: WANBURY LIMITED (b) NATIONALITY: Indian Company incorporated under the Indian Companies Act, 1956 (c) ADDRESS: Plot No.28,1st floor, Sector 19C, Kopri Road, Vashi, Navi Mumbai - 400703, Maharashtra, India 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed: Technical field: This invention relates to a simplified process for synthesis of racemic or optically active (35,4R)-3-[(l,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-l-methylpiperidine, an intermediate for paroxetine hydrochloride, with high purity. Background of the invention: Paroxetine is an orally administered psychotropic drug used for the treatment of major depressive, social anxiety, obsessive compulsive, panic, generalized anxiety disorders and posttraumatic stress disorder. It is the hydrochloride salt of a phenyl piperidine compound, identified chemically as (-)-trans-4R-(4'-fluorophenyl)-3S-[(3',4,-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemi hydrate. It has structural formula I. Synthesis of Paroxetine hydrochloride is described in U.S. Patents 3912743, 4007196, 6657062 (and references cited therein.) The process described in the above patents comprises condensation of alkyl or aryl sulphonate esters of 3-hydroxymethyl-l -methyl-4-phenylpiperidine or corresponding halo compounds derived from it (III) with alkali metal salt of Sesamol (IV) to yield an important key intermediate (3S,4R)-3-[(l,3-benzodioxol-5-yloxy)methyl]-4-(4-fiuorophenyl)-l-methylpiperidine (V) also called as N-Methyl Paroxetine which is subsequently converted to Paroxetine (Scheme:-1) Condensation reaction of alkyl or aryl sulphonate esters of Formula III with Sesamol is carried out in a suitable solvents and alkali metal salt is generated in situ by the use of suitable base. 2 US3912743 describes reaction of sodium salt of phenolic compound with alkyl sulphonate ester of 3-hydroxymethyl-l-methyl-4 phenyl piperidine in dry methanol at reflux temperature for 16 hours yield 3-((4-methoxyphenoxy)-methyl)-l-methyl-4-phenylpiperidine (45%). Also disclose another reaction of phenolic compound with 3-hydroxymethyl-l-methyl-4 phenyl piperidine in presence of DCC at 160-180°C 24 hrs. US4007196 describes conversion of alpha-carbinol compound to its chloro compound which is then reacted with sesamol sodium in methanol for 16 hrs giving 25% yield of 4-(4-fluorophenyl)-3-(l,3-benzdioxolyl-(3))-oxymethylpiperidine. Processes described in US6657062 are the reaction of N-benzyl sulphonate esters with sesamol in solvents like toluene, isopropanol, tertiary butanol or mixture of isobutanol and xylene in presence of bases like 50% aqueous sodium hydroxide, potassium tertiary butoxide, anhydrous potassium carbonate etc to prepare N-benzyl paroxetine. The isolated yield of the condensed product (N-benzyl Paroxetine) varies from 64-70 % and reaction times are 12-16 hrs at reflux conditions. Reaction conditions used for condensation in all above processes are drastic and /or lengthy. The reason for moderate yields and low purity obtained is because of longer heating of 3 the reaction mass in highly alkaline conditions. The quantity of Sesamol used in the above reactions is also in excess than the theoretical requirement. The excess use of sesamol leads to the use of excess alkali requirement to convert the sesamol into metal salt as well as for removal of un-reacted sesamol from the reaction mass, creating problems in effluent processing. The prior art leaves ample scope for further investigations to provide racemic or optically active (3S,4R)-3-[(l,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-l-methylpiperidine in high purity with good isolated yields. Therefore, the object of the present invention is aimed to prepare racemic or optically active (35',4i?)-3-[(l,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-l-methylpiperidine in highly pure form with increased yield. The process of the present invention also increases the throughput per reactor volume, substantially. Summary of the invention: The invention discloses a simple process for the synthesis of racemic or the strereo isomers of N-methyl Paroxetine by condensation of racemic or optically pure alkyl sulphonate esters of [4-(4-fluorophenyl)-l-methylpiperidin-3-yl] methanol with sodium sesamol in presence of an aprotic solvent. The sodium salt of sesamol is generated in situ by using alkali metal hydride. The reaction is carried out at low temperature to reduce the associated impurity generation, thereby enhancing the product purity. Detailed description of the invention: In accordance with the present invention, a simple process is provided for the synthesis of racemic or stereoisomers of N-Methyl Paroxetine in which racemic or optically pure alkyl sulphonate esters of [4-(4-fiuorophenyl)-l-methylpiperidin-3-yl] methanol are reacted with sodium salt of sesamol in presence of an aprotic solvent. The sodium salt of sesamol is generated in situ in the reaction by using a metal hydride. 4 The reaction is carried out at a temperature of 0 to 50°C, in an aprotic solvent selected from dimethyl acetamide, dimethyl sulphoxide, dimethyl formamide and the like. The reaction is carried out preferably at 25 to 30°C. Since the reaction is carried out at low temperature, no side products are formed there by enhancing the purity of the product up to 99.5%, which could be directly used for next step without any additional purification. Further, the molar ratio of sesamol: sulphonate ester being ~1, lengthy work-up to remove excess sesamol by alkali washing is avoided, whereby reducing the effluent treatment load. In the process of the present invention, the complete consumption of sulphonate esters is observed within 1.5 to 2 hrs. The highly pure N-methyl Paroxetine obtained by this process is isolated upon addition of water followed by extraction with suitable solvent and subsequent recovery of the solvent. The metal hydride used in the reaction is selected from lithium hydride, potassium hydride and sodium hydride. One preferable metal hydride is sodium hydride. The sulfonate esters used in the present invention are selected from methane sulphonate, benzene sulphonate and 4-methyl benzene sulphonate, preferably p-toluene-sulphonate ester. Best results are achieved using /7-toluene sulphonate ester of [4-(4-fluorophenyl)-l-methylpiperidin-3-yl] methanol. Similarly, optically active N-methyl paroxetine can be prepared by condensing the optical isomer of alkyl sulphonate ester of [4-(4-fluorophenyl)-l-methylpiperidin-3-yl] methanol with sodium salt of sesamol in presence of an aprotic solvent. The optical isomer of alkyl sulphonate ester of [4-(4-fluorophenyl)-l-methylpiperidin-3-yl] methanol can be achieved by using suitable resolving agent. 5 The following non-limiting examples are provided to further illustrate the invention with specific embodiments stipulated in the present invention. Example 1: - 9.44 gm [(3S,4/?)-4-(4-fluorophenyl)-l-methylpiperidin-3-yl] methyl 4-methylbenzenesulfonate (25mmol.) and 3.8 gm sesamol (27.5mmol) were dissolved in 25 ml dimethyl formamide. This solution was chilled to 0-5°C and 1.15 gm sodium hydride (60% suspension in mineral oil =28.75 mmol) was charged to it under nitrogen atmosphere at such a rate that temperature do not rise above 10°C. After the addition of sodium hydride, the temperature was gradually increased and maintained at 20-25°C for 90 minutes. There after 50 ml chilled water was charged and stirred for 15 min. The product was extracted twice with 50 ml toluene and the combined toluene extracts were washed with 50 ml water, dried over anhydrous sodium sulphate. The toluene extract was concentrated and 30 ml of n-hexane was added to precipitate the product. The product thus obtained was filtered and washed with n- Hexane. Yield :7.13 grams (83% of theoretical i.e. 8.5848 gm) Purity by HPLC 99.7% Example 2: - 9.44 gm (±) [4-(4-fluorophenyl)-l-methylpiperidin-3-yl] methyl 4-methylbenzenesulfonate (25mmol.) and 3.8 gm sesamol (27.5mmol) were dissolved in 25 ml dimethyl formamide. This solution was chilled to 0-5°C and 1.15 gm sodium hydride (60% suspension in mineral oil =28.75 mmol) was charged to it under nitrogen atmosphere at such a rate that temperature do not rise above 10°C. After the addition of sodium hydride, the temperature was gradually increased and maintained at 20-25°C for 90 minutes. There after 50 ml chilled water was charged and stirred for 15 min. The product was extracted twice with 50 ml toluene and the combined toluene extracts were washed with 50 ml water, dried over anhydrous sodium sulphate. The solution was concentrated and 30 ml n-hexane was added to precipitate the product. The product thus obtained was filtered and washed with n- Hexane. Yield :7.06 grams (82.2 % of theoretical) Purity by HPLC 99.5% 6 Example 3: - 9.00 gm (+) [4-(4-fluorophenyl)-l-methylpiperidin-3-yl] methyl benzenesulfonate (25mmol.) and 3.8 gm sesamol (27.5mmol) were dissolved in 25 ml dimethyl formamide. This solution was chilled to 0-5°C and 1.15 gm sodium hydride (60% suspension in mineral oil =28.75 mmol) was charged to it under nitrogen atmosphere at such a rate that temperature do not rise above 10°C. After the addition of sodium hydride, the temperature was gradually increased and maintained at 20-25°C for 2 hrs. There after 50 ml chilled water was charged and stirred for 15 min. The product was extracted twice with 50 ml toluene and the combined toluene extracts were washed with 50 ml water, dried over anhydrous sodium sulphate. The solution was concentrated and 30 ml n-hexane was added to precipitate the product. The product thus obtained was filtered and washed with n- Hexane. Yield: 6.39 gm (74.43 %of theoretical) Purity by HPLC 98.6% Example 4: - 9.00 gm [(3S,4i?)-4-(4-fluorophenyl)-l-methylpiperidin-3-yl]methyl benzenesulfonate (25mmol.) and 3.8 gm Sesamol (27.5mmol) were dissolved in 25 ml dimethyl formamide. This solution was chilled to 0-5°C and 1.15 gm sodium hydride (60% suspension in mineral oil =28.75 mmol) was charged to it under nitrogen atmosphere at such a rate that temperature do not rise above 10°C. After the addition of sodium hydride, the temperature was gradually increased and maintained at 20-25°C for 2 hrs. There after 50 ml chilled water was charged and stirred for 15 min. The product was extracted twice with 50 ml toluene, the combined toluene extracts were washed with 50 ml water and dried over anhydrous sodium sulphate. The solution was concentrated and 30 ml n-hexane added to precipitate the product. The product thus precipitated was filtered and washed with n- Hexane. Yield: 6.3 g. (73.38 % of theoretical) Purity by HPLC 98.8 % 7 Example 5: - 7.53 gm [(3S,4i?)-4-(4-fluorophenyl)-l-methylpiperidin-3-yl]methyl methanesulfonate (25mmol.) and 3.8 gm sesamol (27.5mmol) were dissolved in 25 ml dimethyl formamide. This solution was chilled to 0-5°C and 1.15 gm sodium hydride (60% suspension in mineral oil =28.75 mmol) was charged to it under nitrogen atmosphere at such a rate that temperature do not rise above 10°C. After the addition of sodium hydride, the temperature was gradually increased and maintained at 20-25°C for 4 hrs. There after 50 ml chilled water was charged and stirred for 15 min. The product was extracted twice with 50 ml toluene; the combined toluene extracts were washed with 50 ml water and dried over anhydrous sodium sulphate. The solution was concentrated and 30 ml n-hexane added to precipitate the product. The product thus precipitated was filtered and washed with n- Hexane. Yield : 5.9 g. (68.72 % of theoretical) Purity by HPLC 98.2% Example 6: - 7.53 gm (±) [4-(4-fluorophenyl)-l-methylpiperidin-3-yl]methyl methanesulfonate (25mmol.) and 3.8 gm Sesamol (27.5mmol) were dissolved in 25 ml Dimethyl formamide. This solution was chilled to 0-5°C and 1.15 gm sodium hydride (60% suspension in mineral oil =28.75 mmol) was charged to it under nitrogen atmosphere at such a rate that temperature do not rise above 10°C. After the addition of sodium hydride, the temperature was gradually increased and maintained at 20-25°C for 4 hrs. There after 50 ml chilled water was charged and stirred for 15 min. The product was extracted twice with 50 ml toluene; the combined toluene extracts were washed with 50 ml water and dried over anhydrous sodium sulphate. The solution was concentrated and 30 ml n-hexane added to precipitate the product. The product thus obtained was filtered and washed with n- Hexane. Yield: 6.1 g. (71.05 % of theoretical) Purity by HPLC 98.3 % 8 We claim 1) A process for the preparation of racemic or optically active compound of 3-[(l,3-benzodioxol-5-yloxy) methyl]-4-(4-fluorophenyl)-1 -methylpiperidine comprising: condensing racemic or optically active alkyl sulphonate esters of [4-(4-fluorophenyl)-l-methylpiperidin-3-yl] methanol with alkali metal salt of l,3-benzodioxol-5-ol (Sesamol) in presence of an aprotic solvent; and isolating the product from the reaction mass. 2) The process as claimed in claim 1, where in alkali metal salt of sesamol is sodium salt. 3) The process as claimed in claim 1, where in sodium salt of sesamol is generated using Metal hydride. 4) The process as claimed in claim 3, where in said metal hydride is selected from lithium hydride, potassium hydride and sodium hydride. 5) The process as claimed in claims 3 and 4, wherein said metal hydride is sodium hydride. 6) The process as claimed in claim 1, where in alkyl sulphonate esters are selected from methane sulphonate, benzene sulphonate and 4-methyl benzene sulphonate. 7) The process as claimed in claims 1 and 6, wherein said alkyl sulphonate ester is 4-methyl benzene sulphonate. 8) The process as claimed in claim 1, wherein said aprotic solvent is selected from dimethyl formamide, dimethyl acetamide and dimethyl sulphoxide. 9 9) The process as claimed in claims 1 and 8, wherein said aprotic solvent is dimethyl formamide. 10) The process as claimed in any of the preceding claims, wherein said reaction is carried out at 0-50°C. 11) The process as claimed in claims 1 to 10, wherein said reaction is carried out at 25-30°C. 12)A process for the preparation of racemic or optically active compound of 3-[(l,3-benzodioxol-5-yloxy) methyl]-4-(4-fluorophenyl)-l-methylpiperidine substantially as described herein with reference to the foregoing examples 1 to 6. Dated this 20th day of March 2006 Dr. Gopakumar G. Nair Agent for the Applicant 10 ABSTRACT: Disclosed herein is a process for the preparation of racemic or optically active compound of 3-[(l,3-benzodioxol-5-yloxy) methyl]-4-(4-fluorophenyl)-l-methylpiperidine by condensing racemic or optically active alkyl sulphonate esters of [4-(4-fluorophenyl)-l-methylpiperidin-3-yl] methanol with alkali metal salt of l,3-benzodioxol-5-ol (Sesamol) in presence of an aprotic solvent. 11

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