Title of Invention	INDUSTRIAL PREPARATION OF 11-[4-{2-(2-HYDROXYETHOXY) ETHYL}-1-PIPERAZINYL] DIBENZO [B,F]-[1,4] THIAZEPINE
Abstract	Disclosed herein is an industrial preparation of Quetiapine by the reaction of 11-piperazinyldibenzo[b,f][1,4]-thiazepine or its salt with 2-(2-chloroethoxy) ethanol in presence of an organic base under neat condition to form 11-[4-{2-(2-hydroxyethoxy)ethyl}-1-piperzinyl] dibenzo [b,f][1,4]-thiazepine. The quetiapine free base obtained is further converted to its hemi-fumarate salt.

Full Text

FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule l3) 1. TITLE OF THE INVENTION: "Industrial preparation of 11-[4-{2-(2-hydroxyethoxy) ethyl}-l-piperazinyl] dibenzo [b,f]-[l, 4]thiazepine" 2. APPLICANT(S): (a) NAME: IPCA LABORATORIES LIMITED (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West), Mumbai-400 067, Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION: The following specification describes the nature of this invention and the manner in which it is to be performed: Related Application: This application is related to our main application no 655/MUMNP/2007 filed on 3rd May 2007, which claims priority of our earlier PCT application no. PCT/IN2005/000028, filed on January 24, 2005 and published as WO2006/077602. Field of invention: This invention relates to improvement in process for preparation of 11-[4-{2-(2-hydroxy-ethoxy) ethyl}-1-piperazinyl] dibenzo [b,f]-[l, 4]thiazepine of Formula I, as claimed in our main application. More particularly, the invention relates to an improved commercial process for preparation of a known pharmaceutical agent Quetiapine, useful in curing schizophrenia. Background of the invention: 11-[4-{2-(2-hydroxyethoxy) ethyl}-1-piperazinyl] dibenzo [b,f]-[l, 4]thiazepine of the Formula I known under the international non-proprietary name quetiapine has anti-dopaminergic and/or serotonin receptor antagonist activity, and is used in the clinical practice as an anti-psychotic or neuroleptic agent especially in the treatment of Schizophrenia. Quetiapine and its process for preparation was first disclosed in the patent specification EP0240228 and various other processes for the preparation were disclosed in EP0282236, WOO 155125, WO9906381, WO 2004076431. ^?^M- U^SAJ Formula II Formula II Formula I In the '228 patent, quetiapine was prepared by condensing a compound of Formula II (11- Piperazinyldibenzo [b,f][l,4]-thiazepine) with 2-(2-chloroethoxy)ethanol of Formula III in polar organic solvents or aprotic organic solvents, e.g., N.N-dimethylformamide, N- methylpyrrolidone. Polar solvents exemplified were methanol, ethanol, isopropanol or hexanol or their isomers. Compound of Formula II may be employed in the reaction as its free base or its acid addition salt. An inorganic base like sodium carbonate or potassium carbonate was used in the reaction. The reaction was optionally carried out in the presence of promoter/catalyst such as sodium iodide also. The reaction times were reported to be 24 hours or more, but in practice even after 35 hours about 7 to 8 % of starting 11-piperazinyldibenzo[b,f][l,4]-thiazepine has been found to be remained unreacted in the reaction. The reaction does not go up to completion, even if excess 2-(2-chloroethoxy)-ethanol is used. This incomplete reaction necessitates further purification, incurring heavy losses of product and the purification is difficult due to similar properties of product and starting material 11-piperazinyldibenzo[b,f][l,4]-thiazepine. A modification of '228 patent was reported in WO2004076431 which deals with an attempt to reduce the reaction time and in this improved process the 11-piperazinyldibenzo[b,f][l,4]-thiazepine dihydrochloride was reacted with 2-(2-chloroethoxy)ethanol in an organic solvent in presence of a base and a phase transfer catalyst in order to complete reaction in a lesser time. According to '431 patent process, after 4 hours of reaction unreacted 11-piperazinyldibenzo[b,f)[l,4]-thiazepine was found to be about 9.7% ( see example 10). As per the details, the reaction completes only in 17 hours and the product obtained in the reaction mass is only 95.5% and unreacted starting material was 1.1% to 0.26%. '431 patent also teaches the use of optional alkali metal halide as a promoter. '431 patent highlights the use of phase transfer catalyst (improved subject matter) for the completion of reaction and the yields reported are still on a lower side ranging from about 60 to 73% ( see examples) Our earlier application no PCT/IN2005/000028 having a priority of January 24, 2005, published as WO2006/077602 and has been filed as National phase application no 665/MUMNP/2007 on May, 3, 2007, addresses the above problems of the prior art and provided a solution, according to which Quetiapine is obtained in high yield and purity in shorter reaction period when an aqueous medium is used during reaction of 11-piperazinyldibenzo[b,f][l,4]-thiazepine and 2-(2-chloroethoxy)-ethanol . However, it was desired to develop a process which can be more operators friendly. In our earlier patent application, the compound of Formula II was reacted with 2-(2-chloroethoxy) ethanol in presence of an organic or inorganic base in aqueous condition to form 11-[4-{2-(2-hydroxyethoxy) ethyl}-1-piperazinyl] dibenzo [b,f]-[l, 4]thiazepine. The reaction was achieved within 4 to 9 hours; and the use of phase transfer catalyst (PTC) in addition to basic substance further reduces the reaction period to 3 - 6 hours. It was observed that, except for the reduction of reaction time by 1 to 2 hours, no other significant advantages were achieved in terms of purity or yield of the product, i.e., the 1 l-[4-2-{2-(2-hydroxyethoxy)ethyl}-l-piperazinyl]dibenzo[b,f]-[l,4]thiazepine, when a PTC was used. But, only the use of aqueous reaction medium improved the yield and purity to a great extent. Hence, there is a need for improvement in the process of making Quetiapine and its pharmaceutical acceptable salts wherein a complete reaction is achieved in much shorter time resulting in high yield and purity, which is provided in the present invention. Objective of the present invention: It is an objective of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art or to provide a useful alternative. It is an objective of the present invention, in its preferred form, to provide an industrial process for ll-[4-{2-(2-hydroxyethoxy) ethyl}-1-piperazinyl] dibenzo [b,f]-[l, 4]thiazepine and its pharmaceutically acceptable salts wherein the complete reaction of ll-piperazinyldibenzo[b,f][l,4]-thiazepine and 2-(2-chloroethoxy)ethanol is achieved in much shorter time leading to a product of higher quality in higher yield. Summary of the invention: Accordingly, in the present invention, the compound of Formula II is reacted with 2-(2-chloroethoxy) ethanol in the absence of solvent (herein also defined as neat condition) to form ll-[4-{2-(2-hydroxyethoxy) ethyl}-1-piperazinyl] dibenzo [b,f]-[l, 4]thiazepine in good yield & purity. The reaction is carried out in presence of a base, preferably selected from an organic base. Optionally, additional catalysts such as metal iodide or phase-transfer catalyst may be used in the reaction to improve the reaction time. In a preferred aspect of the present invention, the compound of Formula II and 2-(2-chloroethoxy) ethanol is reacted in presence an organic base, and an alkali metal iodide in the absence of any solvent (i.e. neat condition) at a temperature of about 80 to 100°C for a period of about 3 to 5 hours during which the reaction is complete to the extent of 99.9% or more. In yet another aspect, the present invention provides quetiapine hemi-fumarate (hereinafter also referred as quetiapine fumarate) made by the process of the present invention. Detailed description of the invention: This invention provides an improved industrial synthesis of Quetiapine and its hemi-fumarate salt by the reaction of an intermediate compound of Formula II with 2-(2-chloroethoxy)ethanol in shorter duration of time with minimal impurity (less than 0.1%) generation and almost complete transformation of compound of 11-piperazinyldibenzo[b,f][l,4]-thiazepine. The quetiapine free base obtained by the process of the present invention is further converted to its hemi-fumarate salt. Another important feature of the present invention is much faster rate of reaction which allows high conversion in shorter duration with minimal impurity. The reaction is found to be reproducible on large scale. The compound of Formula II (ll-piperazinyldibenzo[b,fJ[l,4]-thiazepine) can be used either as free base or its hydrochloride salt in the reaction. When an acid salt of compound of Formula II like hydrochloride salt is used in the reaction, an excess amount of base is used which is required to neutralize the hydrochloride salt to liberate free base during the reaction. In a preferred embodiment, the reaction of compound of Formula II with 2-(2-chloroethoxy)ethanol is completed in much shorter time when the reaction is performed in the absence of a solvent and in the presence of an organic base. In a preferred process, an alkali metal iodide or a phase-transfer catalyst or their combinations are used in the reaction as a promoter. This neat reaction of compound of Formula II with 2-(2-chloroethoxy)ethanol in the presence of an organic base is carried out by mixing and heating the components at about 80 to 100 °C for a period of 3 to 5 hours during which 5 starting compound of Formula II is almost absent (less than 0.05 % by HPLC analysis) in the reaction. The organic base used in the reaction is selected from trialkyl amines such as triethyl amine, trimethyl amine, diisopropyl amine etc., or dialkyl anilines such as dimethyl aniline or dimethylaminopyridine or -methyl morpholine or the like. The organic base used is preferably in molar amounts of about 1 to 3 moles relative to the starting compound of Formula II. The 2-(2-chloroethoxy)ethanol is preferably used in a molar amount ranging from about 1 to 1.5 molar equivalents relative to compound of Formula II. For reasons of economy of the process higher moles of reagent, 2-(2-chloroethoxy)ethanol, are not used. In a preferred embodiment of the reaction, an alkali metal iodide such as sodium iodide or potassium iodide is used as a promoting agent along with mixture of compound of Formula II, 2-(2-chloroethoxy)ethanol and base. The quetiapine free base formed in the reaction is isolated as an oily mass by the steps of extracting the product using an organic solvent selected from hydrocarbon solvents like toluene, xylene, heptane or chlorinated hydrocarbon solvent such as methylene chloride, and removing the organic solvent by distillation, preferably under reduced pressure. The isolated crude quetiapine free base is further converted directly to the hemi-fumarate salt without subjecting to additional purification by suspending the oily mass in ethanol and combining it with fumaric acid in 0.55 to 1.0 molar equivalents relative to free base. The ethanol solution is cooled to precipitate the quetiapine hemi-fumarate in an yield of about 75 to 80%. The purity of quetiapine hemifumarate so obtained is at least 99.5%. The improved process of the present invention results in higher yield, purity in much lesser reaction time, that can lead to an efficient and commercially acceptable synthetic process for the preparation of quetiapine hemi-fumarate. 6 The starting material ll-piperazinyldibenzo[b,fJ[l,4]-thiazepine (II) was prepared according to the process disclosed in US3539573 . The following example is provided to further illustrate the process of the present invention. Example: In a reaction vessel, a mixture of ll-piperazinyldibenzo[b,f][l,4]-thiazepine ( 10 Kg), 2-(2-chloroethoxy)ethanol (6.3 kg), 5.4 kg triethyl amine and 0.2 kg sodium iodide was heated under mixing to about 85°C. The reaction mixture was maintained at about 80° to 85 °C for about 3 hours. Starting ll-piperazinyldibenzo[b,fj[l,4]-thiazepine was about 0.1% by HPLC. Maintained for another 2 hours till ll-piperazinyldibenzo[b,f][l,4]-thiazepine was about less than 0.05 % by HPLC analysis. The reaction mass was cooled to about 30 °C and added 40 litres of water and aqueous layer extracted with methylene chloride. The organic layer was washed with water and concentrated under reduced pressure. The oily residue was so obtained was suspended in 100 litres of ethanol (commercial) and 3.3 kg fumaric acid was added. The mixture was stirred for about 6 hours and cooled to about 15 °C. The precipitated quetiapine hemi-fumarate salt was filtered and dried to give 12.0 Kg (yield 80 % & purity 99.8 % by HPLC analysis). It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. 7 We claim, 1. A process for preparation of quetiapine of Formula I or its pharmaceutically acceptable salt, Formula I wherein the improvement comprises; a) heating a mixture containing the compound of Formula II; Formula I! the compound of Formula III /-. O /C1 OH Formula III in the absence of a solvent; and b) isolating the quetiapine or its pharmaceutically acceptable salt from said mixture. The process as claimed in claim 1, wherein the step (a) further comprises presence of a base. The process as claimed in claim 1, wherein the base is selected from the group consisting of trialkyl amines, dialkyl anilines, and dialkyl amino pyridines. 8 The process as claimed in claim 1, wherein the step a) is performed in the presence of an alkali metal iodide. The process as claimed in 3, wherein the alkali metal iodide is sodium iodide or potassium iodide. The process as claimed in claim 1 or 2, wherein the process step (a) is in presence of a phase-transfer catalyst. The process as claimed in claim 1, wherein the reaction temperature of step a) is about 80 to 100°C. The process as claimed in claim 1, wherein step b) is accomplished by extraction using an organic solvent. The process as claimed in claim 8, wherein the organic solvent is selected from hydrocarbon solvents or chlorinated hydrocarbon solvents. The process as claimed in claim 9, wherein the organic solvent is toluene or methylenedichloride. The process as claimed in claim 1, further comprising the step of converting the quetiapine to quetiapine hemi-fumarate. Quetapine or quetapine hemi-fumarate prepared substantially according to the process of claims 1 to 9. An Industrial process for preparation of Quetapine or quetapine hemi-fumarate as substantially exemplified with reference to the foregoing example 1. 9 ABSTRACT Disclosed herein is an industrial preparation of Quetiapine by the reaction of 11-piperazinyldibenzo[b,fJ[l,4]-thiazepine or its salt with 2-(2-chloroethoxy)ethanol in presence of an organic base under neat condition to form ll-[4-{2-(2-hydroxyethoxy) ethyl}-1-piperazinyl] dibenzo [b,fj-[l, 4]thiazepine. The quetiapine free base obtained is further converted to its hemi-fumarate salt. 10

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