WO2006027789A1

WO2006027789A1 - PROCESS FOR PRODUCING 11-[4-[2-(2-HYDROXYETHOXY)ETHYL]-1-PIPERAZINYL]DIBENZO[b,f][1,4]THIAZEPINE AND A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

Info

Publication number: WO2006027789A1
Application number: PCT/IN2004/000281
Authority: WO
Inventors: Shailendra Pathak; Jitendra Sharma; Geetesh Kaushik; Rajesh Kumar Thaper; Sushil Kumar Dubey
Original assignee: Jubilant Organosys Limited
Priority date: 2004-09-08
Filing date: 2004-09-08
Publication date: 2006-03-16

Abstract

A process for producing 11-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo [b,f][1,4]thiazepine [I] and a pharmaceutically suitable acid addition salt is disclosed. Accordingly, thiosalicylic acid [XVI] is reacted with o-halonitrobenzene [XVII] using a phase transfer catalyst to obtain 2-nitro-2'-carboxydiphenylsulphide [XI]. It is hydrogenated in the presence of a noble metal catalyst to obtain 2-amino-2' carboxydiphenyl sulphide [X]. The 2-amino-2'-carboxydiphenylsulphide [X] is reacted with halide or oxyhalide of the phosphorous to obtain in situ iminohalide [VI], which further reacts as such with 1-hydroxyethoxyethylpiperazine or condenses with piperazine to obtain 11-piperazinyldi.benzo[b,f][1,4]thiazepine [XIX] which further reacts with 2- chloroethoxyethanol or reacts with 1-(2-hydroxyethyl)piperazine to give 11-[4-(2-hydroxyethyl)piperazine-1-yl]dibenzo[b,f][ 1,4]thiazepine [XXXI] which further converts to an intermediate 11-[4-(2-substitutedethyl)piperazin-1- yl)dibenzo[b,f][1,4]thiazepine wherein the substituent at the 2-position is selected from mesyloxy or tosyloxy or halo group [XXXII] followed by reaction with ethylene glycol to give quetiapine [1].

Description

PROCESS FOR PRODUCING 11-[4-[2-(2-HYDROXYETHOXY)ETHYL]-I-

PIPERAZINYL]DIBENZO[b,fl[l,4]THIAZEPINE AND A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

Field of the Invention

This invention in general relates to a process for producing an atypical neuroleptic or anti-psychotic and its pharmaceutically acceptable salt. More particularly, this invention provides an improved, concise and industrially favorable process for producing 1 l-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,f][l,4]thiazepine (Quetiapine) and its fumarate salt.

Background of the Invention

l l-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,fJ[l,4]thiazepine [I] and its fumarate salt is used in treating symptoms associated with psychiatric disorders and other psychoses such as delusions, hallucinations, disorganized thinking and speech and bizarre behavior.

[I] There are several methods known in the prior art for producing quetiapine and the use thereof for the treatment of symptoms associated with psychiatric disorders.

According to United States Patent No. 4,879,288 to Warawa et al, (Scheme 1), the compound of Formula [I] and its pharmaceutically acceptable salts are prepared from dibenzo[b,fJ[l,4]thiazepine-l l-(10H)one [II] which is prepared by a variety of methods; for example as described in the literature e.g. J. Scmutz et al. HeIv. Chim. Acta, 48: 336 (1965), by cyclizing a compound selected from compounds of the Formula [III], [IV] and [V] in acidic conditions preferably in the presence of concentrated sulfuric acid or polyphosphoric acid at high temperature.

The compound iminohalide [VI] is prepared from lactam [II] using a dehydrating agent e.g. phosphorous pentahalide or oxyhalide in the presence of N,N-dimethylaniline at reflux temperature. The iminohalide [VI] thus prepared reacts with 1- hydroxyethoxyethylpiperazine to give the title compound [I].

Another preferred method to prepare the title compound [I] is by reacting compound [Vπ] with 2-substituted ethoxyethanol whereby the substituting group Z is an atom or a group removable as anion e.g. mesyloxy, tosyloxy or halogen in polar organic solvent or aprotic solvent e.g. n-propanol, N-methyl pyrrolidone in the presence of alkali metal halide e.g. NaI and alkali metal carbonate e.g. Na₂CO₃.

The compound [VII] is prepared by reacting iminohalide [VI] with piperazine in an inert organic solvent e.g. toluene or xylene under reflux for 5 hours.

Alternatively, the lactam [II] may convert into a thiolactam of Formula [VIII] by reacting with a polysulfur compound e.g. P₂S₅, which on alkylation gives thioether of the Formula [IX] wherein R₃ is chosen such that S-R₃ is a leaving group. The thioether on reaction with 1-hydroxyethoxyethylpiperazine gives title compound [I].

The said patent discloses preparing quetiapine from iminohalide [VI] via dibenzothiazepine [H]. Iminohalide [VI] disclosed in the above patent is an unstable intermediate and hydrolyzes during work up by addition of water and part of it is converted back into_* dibenzothiazepine [H]. When handling larger quantities, this side- reaction reduces the yield and the product of the hydrolysis contaminates the end product. This affects the overall yield and cost in the quetiapine preparation and thus is disadvantageous on a commercial manufacturing scale. Scheme 1

[I]

Z, OR,,and OR₂= atom or group removable as an anion SR₃= leaving group

According to European Patent EP0282236 to Barker, et al, (Scheme 2), the piperazine derivative [VII] reacts with 2-haloethoxyethanol e.g. 2-chloroethoxyethanol to give compound of the Formula [I]. The compound of formula [VII] is obtained from iminohalide [VI] by reaction with piperazine in the presence of an inert organic solvent e.g. xylene or toluene. The compound of formula [VII] is obtained from dibenzothiazepine [II] in the presence of dehydrating agent e.g. phosphorous oxychloride. Scheme 2

According to the method reported in European patent application EP 1201663 to Harada, et al, (Scheme 3), lactam [II] a key intermediate for quetiapine is prepared from 2-amino-2'-carboxydiphenylsulphide [X] under reflux temperature optionally in the presence of an organic solvent e.g. toluene or xylene in 20 hours. The 2-amino-2'- carboxydiphenylsulphide [X] is prepared by the reduction of the 2-nitro-2'- carboxydiphenylsulphide [XI]. The 2-nitro-2'-carboxydiphenylsulphide [XI] is prepared from thiosalicylic acid [XVI] and o-halonitrobenzene [XVII] with a suitable base e.g. potassium carbonate or sodium carbonate or sodium hydroxide in the presence of solvents like water or amides or alcohol at O⁰C to 15O⁰C within 20 hours. Scheme 3

X= halog

According to another method disclosed in the European Patent EP 1252151 to Bozsing, et al, (Scheme 4), compound of the Formula [I] is prepared by reacting haloethylpiperazinylthiazepine derivative [XV] with sodium and ethylene glycol following Williamson's synthesis. The haloethylpiperazinylthiazepine derivative [XV] is prepared by the cyclization of haloethylpiperazine derivative [XIV] using a dehydrating agent e.g. phosphorous pentaoxide or phosphorous oxychloride, which itself is prepared from halogenation of hydroxyethylpiperazine derivative [XIII]. The hydroxyethylpiperazine derivative [XIII], a novel piperazine derivative is prepared by reaction of l-(2-hydroxyethyl) piperazine with urethane derivative [XII] in the presence of solvent e.g. toluene under reflux. The urethane derivative [XII] can be prepared by a method known in the prior art by reacting 2-aminodiphenylsulfide with phenyl chloroformate.

In the European Patent EP1252151 quetiapine is prepared in multiple steps, which increases the manufacturing time thus reduces the overall yield of the final product and thus not industrially feasible. Scheme 4

The main intermediate for the preparation of quetiapine is dibenzothiazepine [II], which was first described in the United Kingdom Patent GB802901, assigned to CIBA Ltd. The process for preparation of dibenzothiazepine [II] is described in many patents such as EP1201663, US 5,607,929, EP419861, US 4,728,735 and US 3,367,930.

The synthetic processes reported in prior art for the preparation of quetiapine have disadvantages at the commercial scale. The known processes include multiple steps, increased cycle time and isolation of unstable intermediate like iminohalide. Thus the processes recited in the known art involve long manufacturing time, result in low yield, thereby increasing the production cost. Therefore, there is a need to provide an industrially feasible process for synthesizing quetiapine and its salt, which involves minimum steps, is cost effective and convenient to operate on an industrial scale.

Summary of the Invention

According to the principal aspect of the present invention, there is provided a process for preparing 1 l-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,fJ[l,4] thiazepine [I] and a pharmaceutically acceptable acid addition salt thereof, wherein the process is performed in a manner to avoid multi-steps, longer reaction period and provide an industrially feasible and economical viable process.

According to another aspect of the present invention, there is provided an improved and industrially feasible process for producing l l-[4-[2-(2-hydroxyethoxy)ethyl]-l- piperazinyl]dibenzo[b,fj[l,4]thiazepine [I] and a pharmaceutically acceptable acid addition salt which comprises reacting thiosalicylic acid with o-halonitrobenzene using phase transfer catalyst to obtain 2-nitro-2'-carboxydiphenylsulphide, reducing 2-nitro- 2'-carboxydiphenylsulphide in the presence of a noble metal catalyst to obtain 2- amino-2'-carboxydiphenyl sulphide, reacting 2-amino-2'-carboxydiphenylsulphide with a halide or an oxyhalide of phosphorous to obtain in situ iminohalide [VI], reacting said iminohalide with 1-hydroxyethoxyethylpiperazine to produce l l-[4-[2-(2- hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,fj[l,4]thiazepine [I] and a pharmaceutically acceptable acid addition salt thereof.

According to one other aspect of the present invention, there is provided an improved and industrially feasible process for producing ll-[4-[2-(2-hydroxyethoxy)ethyl]-l- piperazinyl]dibenzo[b,fj[l,4]thiazepine [I] and a pharmaceutically acceptable acid addition salt, wherein the process comprises further reacting said iminohalide [VI] which is obtained in situ by the process mentioned above, with piperazine to obtain 11- piperazinyldibenzo[b,f][l,4]thiazepine, followed by reacting with 2- chloroethoxyethanol to produce l l-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl] dibenzo[b,fj[l,4]thiazepine [I] and a pharmaceutically acceptable acid addition salt thereof. According to another aspect of the present invention, there is provided an improved and industrially feasible process for producing ll-[4-[2-(2-hydroxyethoxy)ethyl]-l- piperazinyl]dibenzo[b,f][l,4]thiazepine [I] and a pharmaceutically acceptable acid addition salt, wherein the process comprises further reacting said iminohalide [VI] which is obtained in situ by the process mentioned above, with l-(2-hydroxyethyl) piperazine to obtain ll-[4-(2-hydroxyethyl)piperazine-l-yl]dibenzo[b,fJ[l,4]thiazepine [XXXI], converting said ll-[4-(2-hydroxyethyl)piperazine-l-yl]dibenzo[b,f][l,4] thiazepine [XXXI] to an intermediate l l-[4-(2-substitutedethyl)piperazin-l-yl)dibenzo [b,f][l,4]thiazepine [XXXII] wherein the substituent at the 2-position is selected from mesyloxy or tosyloxy or halo group followed by reaction with ethylene glycol to produce 1 l-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,f][l,4]thiazepine [I] and a pharmaceutically acceptable acid addition salt thereof.

According to yet another aspect of the present invention, a catalytic amount of phase transfer catalyst is added while condensing thiosalicyclic acid with o-halonitrobenzene to obtain 2-nitro-2'-carboxydiphenylsulphide, which increases the rate of reaction and reduces the reaction time cycle.

According to still another aspect of the present invention, in situ formation of iminohalide [VI] by reacting 2-amino-2'-carboxydiphenylsulphide [X] with a halide or an oxyhalide of phosphorous is provided, wherein the isolation or purification step of intermediate (lactam) [II] is avoided, which reduces the number of operations involved in quetiapine preparation and thereby increasing the operational efficiency and convenience on large-scale manufacturing.

Detailed Description of the Invention

The present invention provides an improved and industrially feasible process for producing 11 -[4-[2-(2-hydroxyethoxy)ethyl] - 1 -piperazinyl]dibenzo[b,f] [ 1 ,4]thiazepine [I] and a pharmaceutically acceptable acid addition salt thereof. Synthetic Scheme

R is good leaving group nal is halo atom quetiapine hemifumarate

The process involves reacting thiosalicylic acid with o-halonitrobenzene using phase transfer catalyst to obtain 2-nitro-2'-carboxydiphenylsulphide, reducing 2-nitro-2'- carboxydiphenylsulphide in the presence of a noble metal catalyst to obtain 2-amino- 2'-carboxydiphenylsulphide, reacting 2-amino-2'-carboxydiphenylsulphide with a halide or an oxyhalide of phosphorous to obtain in situ iminohalide [VFj and reacting iminohalide with 1-hydroxyethoxyethylpiperazine to produce ll-[4-[2-(2- hydroxyethoxy)ethyl]-l-piperazinyl] dibenzo[b,f][l,4]thiazepme [I]. The invention also discloses the process where iminohalide [VI] is obtained in situ and reacts with piperazine to obtain ll-piperazinyldibenzo[b,f][l,4]thiazepine followed by reaction with 2-chloroethoxyethanol to produce ll-[4-[2-(2-hydroxyethoxy)ethyl]-l- piperazinyl]dibenzo [b,fj[l,4]thiazepine [I].

The process also involves reaction of iminohalide [VI] which is obtained in situ with 1- (2-hydroxyethyl)piperazine to obtain l l-[4-(2-hydroxyethyl)piperazine-l-yl]dibenzo [b,f][l,4]thiazepine [XXXI], which' converts to an intermediate l l-[4-(2- substitutedethyl)piperazm-l-yl)dibenzo[b,f][l,4]thiazepine [XXXII] wherein the substituent at the 2-position is selected from mesyloxy or tosyloxy or halo group followed by reaction with ethylene glycol to produce l l-[4-[2-(2-hydroxyethoxy) ethyl] - 1 -piper azinyl] dibenzo [b , f] [ 1 ,4] thiazepine [I] .

According to the one aspect of the present invention thiosalicylic acid [XVI] condenses with o-halonitrobenzene [XVII] using phase transfer catalyst to obtain 2-nitro-2'- carboxydiphenylsulphide [XI].

It is surprisingly found that when a catalytic amount of phase transfer catalyst is added to the reaction mixture, the rate of the reaction increases tremendously and the reaction completes within 3-4 hours.

As used herein, the phase transfer catalyst acts as a shuttling agent between the anion and the organic substrate, and thereby increases the rate of the reaction and reduces the reaction cycle time.

As described, any phase transfer catalyst can be used and is not limited to the examples incorporated herein. The phase transfer catalyst used in the process herein can be from a group comprising ammonium based phase transfer catalyst, phosphonium based phase transfer catalyst, PEG based phase transfer catalyst, crown ethers etc. Few examples of such phase transfer catalyst are tetrabutylammonium bromide, tetrabutyl ammonium iodide, tetrabutylammonium hydrogen sulfate, benzyl tributylamrhonium chloride, benzyl triethylammonium chloride, tetramethylammonium chloride, tetrabutylphosphonium chloride, Polyethylene glycol 200, Polyethylene glycol 400, Polyethylene glycol 600, dibenzo- 18-crown-6 and the like. Condensation of thiosalicylic acid [XVI] with b-halonitrobenzene [XVII], wherein halogen atom is selected from fluorine, chlorine, bromine or iodine takes place in the presence of a solvent selected from alcohol, ester, ketone, amides or mixture thereof. Preferably the solvent is selected from a group comprising methanol, ethanol, n- propanol, isopropanol, n-butanol, ethyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethyl formamide, N,N-dimethylacetamide, N- methylpyrrolidone or mixture thereof.

Reaction of thiosalicylic acid [XVI] with o-halonitrobenzene [XVII] optionally takes place in the presence of a base selected from carbonates, bicarbonates, hydroxides, alkoxides or hydrides of alkali metal or alkaline earth metal in an amount corresponding to 0.5-3 moles and most preferably 0.7-2.0 moles. The reaction is performed at a temperature of 50 to 100⁰C and most preferably at 60 to 7O⁰C under inert atmosphere.

Reduction of 2-nitro-2'-carboxydiphenylsulphide [XI] to 2-amino-2'-carboxydiphenyl sulphide [X] is carried out in the presence of a noble metal catalyst. The noble metal catalyst is selected from a group comprising palladium, platinum or its compounds, Raney-nickel, ferrous sulfate heptahydrate in aqueous ammonia and the like. The reaction is preferably carried out in the presence of an alcoholic solvent e.g. methanol or ethanol. The reaction is conveniently performed at a temperature of 25-4O⁰C using hydrogen gas.

The iminohalide [VI] disclosed in the present invention is formed in situ and is taken as such without any isolation or purification, for further reaction, thus avoiding its decomposition. This reduces the number of operations involved in quetiapine preparation and thereby increases the operational efficiency and convenience on large- scale manufacturing.

Reaction of 2-amino-2'-carboxydiphenylsulphide [X] with a halide or an oxyhalide of phosphorous, wherein the halide or the oxyhalide of phosphorous is selected from a group comprising phosphorous pentahalide (PXs), phosphorous trihalide (PX₃), phosphorous oxyhalide (POX₃) wherein X can be chlorine, bromine or iodine preferably chlorine or bromine optionally takes place in the presence of a non-polar solvent such as toluene or xylene or a mixture thereof. The reaction is carried out optionally in the presence of an organic or an inorganic base. The base used in the reaction is selected from triethylamine, N,N-dimethylaniline or heterocyclic amines such as pyridine, N-methyl morpholine, dimethyl amino pyridine more preferably triethylamine. The reaction is carried out at the reflux temperature of the reaction mixture for a period of preferably 5-8 hours and most preferably 5-6 hours.

It is postulated that the reaction of 2-amino-2'-carboxydiphenylsulphide [X] with a halide or an oxyhalide of phosphorous proceeds via intermediate [XXX], which leads to reduction in the reaction time to 5-6 hours from 20 hours, as reported in the prior art. The reduction in the reaction time reduces the formation of impurities.

The resulting iminohalide [VI], which is formed in situ, condenses with 1- hydroxyethoxyethylpiperazine, without the isolation of lactam [II], in the presence of a solvent, preferably non-polar solvents such as toluene or xylene and optionally in the presence of a co-solvent selected from the group comprising dimethylsulphoxide, N₅N- dimethylformamide, N,N-dimetylacetamide, N-methylpyrrolidone, dimethylimidazolidone or a mixture thereof.

According to another aspect of the present invention, the resulting iminohalide [VI] which is formed in situ without the isolation of lactam [II], condenses with piperazine to obtain ll-piperazinyldibenzo[b,f][l,4]thiazepine [XI] which reacts with 2- haloethoxyethanol to give quetiapine [I].

The resulting iminohalide [VI] which is formed in situ condenses with piperazine in the presence of a solvent preferably non polar solvent such as toluene, xylene, anisole or its mixture thereof to obtain l l-piperazinyldibenzo[b,f][l,4]thiazepine [XIX]. Reaction of ll-piperazinyldibenzo[b,fj[l,4]thiazepine [XIX] with 2-haloethoxyethanol where halogen is most preferably a chlorine atom takes place in the presence of polar or non polar solvents such as n-butanol or toluene. The reaction takes place optionally in the presence of a base selected from alkali metal or alkaline earth metal carbonates or bicarbonates wherein the alkali metal and alkaline earth metal is selected from lithium, sodium, potassium, calcium or magnesium etc, in an amount corresponding to 1 to 5 moles, preferably 2-4 moles.

According to yet another aspect of the present invention, the resulting iminohalide [VI] which is formed in situ without the isolation of lactam [II], reacts with l-(2- hydroxyethyl) piperazine in the presence of a non-polar solvent such as toluene or xylene to obtain ll-[4-(2-hydroxyethyl)piperazin-lyl]dibenzo[b,f][l₃4]thiazepine

[XXXI], which converts to an intermediate ll-[4-(2-substitutedethyl)piperazin-l- yl)dibenzo[b,fj[l,4]thiazepine [XXXII] followed by reaction with ethylene glycol to obtain quetiapine [I].

ll-[4-(2-hydroxyethyl)piperazin-l-yl)dibenzo[b,fj[l,4]thiazepine [XXXI] converts to an intermediate 1 l-[4-(2-substitutedethyl)piperazin-l-yl)dibenzo[b,f][l,4]thiazepine [XXXII] wherein the substituent at the 2-position is selected from mesyloxy or tosyloxy or halo group. This intermediate ll-[4-(2-substitutedethyl)piperazin-l- yl)dibenzo[b,fj[l,4]thiazepine [XXXII] further reacts with ethylene glycol in the presence of a non polar solvent such as toluene or xylene and a base to obtain quetiapine [I]. The base is selected from alkali metal hydrides or alkoxide and the like. The base used in the reaction is selected from sodium hydride, potassium hydride and potassium tertiary butoxide etc, more preferably sodium hydride. The reaction is carried out at an elevated temperature preferably at the reflux temperature of the reaction mixture.

The salts of the compound of the Formula [I] are also prepared in the present invention, preferably the pharmaceutically acceptable salts. These may be obtained by reacting the quetiapine [I] in the presence of a suitable solvent e.g. acetone, ethyl acetate, isopropyl alcohol, methanol etc with a suitable acid such as hydrochloric acid, maleic acid, fumaric acid, citric acid, phosphoric acid, methane sulphonic acid or sulphuric acid most preferred salt is the hemifumarate. The examples mentioned below explain all the aspects of the present invention. The examples are given to illustrate the details of the invention and should not be construed to limit the scope of the present invention.

Example 1

Preparation of 2-nitro-2^r-carboxydiphenylsulphide [XI]

Potassium carbonate (134 g) was taken in methanol (600 ml). To the resulting mixture thiosalicylic acid (100 g), o-chloronitrobenzene (123 g) and catalytic amount of terra butyl ammonium iodide was added. The reaction mixture was heated to 65-7O⁰C for 4-6 hours. Methanol was distilled off under vacuum, water (600 ml) and dichloromethane (200 ml) was added to the reaction mixture. The organic layer was separated off and the aqueous layer was acidified with concentrated hydrochloric acid. The precipitated product was collected by filtration, washed with water and dried to give the title compound as a yellow powder.

Example 2 Preparation of 2-amino-2^r-carboxydiphenylsulphide [X]

In a 2 liter capacity autoclave, 2-nitro-2'-carboxydiphenylsulphide (100 g) and methanol (1000 ml) were taken and 5%Pd/C (10 g) was added. The reaction mixture was then hydrogenated for 10-15 hours at a pressure of 100 psi at 30-35⁰C. The resulting mixture was filtered and the filtrate was concentrated under vacuum at 45- 5O⁰C to obtain the title compound.

Example 3

Preparation of ll-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,f] [1,4] thiazepine [I]

2-Amino-2'-carboxydiphenylsulphide (100 g) was taken in phosphorus oxychloride (500 ml). The reaction mixture was heated to reflux at 105-110⁰C for 5-6 hours. The reaction mixture was subjected to vacuum distillation to remove unreacted phosphorous oxychloride. The resulting mass was taken in toluene (800 ml) and 1- hydroxyethoxyethylpiperazine (213 g) and N-methyl pyrrolidone (100 ml) was added. To the above reaction mixture, sodium carbonate (260 g) was added. The reaction mixture was heated to reflux for 6-8 hours. After completion of reaction, toluene was distilled off under vacuum and a mixture of ethyl acetate and water was added. After separation, the ethyl acetate layer was extracted with dilute hydrochloric acid and the solution was made alkaline by the addition of aqueous ammonia solution, extracted with ethyl acetate (800 ml) and organic layer was distilled off under vacuum to yield the title compound.

Example 4

Preparation of 11 - [4- [2-(2-hydroxy ethoxy)ethy 1] -1 -piperazinyl] dibenzo [b,fj [1 ,4] thiazepine [I] 2-Amino-2'-carboxydiphenylsulphide (100 g) was taken in toluene (2000 ml) and phosphorus oxychloride (500 ml) was added. The reaction mixture was heated to reflux at 105-110⁰C for 5-6 hours. The reaction mixture was subjected to vacuum distillation to remove unreacted phosphorous oxychloride along with toluene: The resulting mass was taken in toluene (800 ml) and 1-hydroxyethoxyethylpiperazine (213 g) and N- methyl pyrrolidone (100 ml) was added. To the above reaction mixture, sodium carbonate (260 g) was added. The reaction mixture was heated to reflux for 6-8 hours. After completion of reaction, toluene was distilled off under vacuum and a mixture of ethyl acetate and water was added. After separation, the ethyl acetate layer was extracted with dilute hydrochloric acid and the solution was made alkaline with aqueous ammonia solution, extracted with ethyl acetate (800 ml) and organic layer was distilled off under vacuum to yield the title compound.

Example 5

Preparation of 1 l-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,fj [1,4] thiazepine [I]

2-Amino-2'~carboxydiphenylsulphide (100 g) was taken in toluene (500 ml) and phosphorus oxychloride (500 ml) and triethylamine (57 ml) was added. The reaction mixture was heated to reflux at 105-110⁰C for 5-6 hours. The reaction mixture was subjected to vacuum distillation to remove unreacted phosphorous oxychloride along with toluene. The resulting mass was taken in toluene (800 ml) and 1- hydroxyethoxyethylpiperazine (213 g) and N-methyl pyrrolidone (100 ml) was added. To the above reaction mixture, sodium carbonate (260 g) was added. The reaction mixture was heated to reflux for 6-8 hours. After completion of reaction, toluene was distilled off under vacuum and a mixture of ethyl acetate and water was added. After separation, the ethyl acetate layer was extracted with dilute hydrochloric acid and the solution was made alkaline with aqueous ammonia solution, extracted with ethyl acetate (800 ml) and organic layer was combined and distilled off under vacuum to yield the title compound.

Example 6

Preparation of ll-piperazinyldibenzo[b,f][l,4] thiazepine [XIX] 2-Amino-2'-carboxydiphenylsulphide (100 g) was taken in phosphorus oxychloride (500 ml). The reaction mixture was heated to reflux at 105-110⁰C for 5-6 hours. The reaction mixture was subjected to vacuum distillation to remove unreacted phosphorous oxychloride. The resulting mass was taken in toluene (800 ml) and piperazine (21Og) was added. The reaction mixture was heated to reflux at 110-120⁰C for 6-8 hours. The reaction mixture was cooled, filter and the organic phase was washed with water, dried and solvent was distilled off under vacuum to obtain the title compound.

Example 7

Preparation of ll-piperazinyldibenzo[b,f][l,4]thiazepine [XIX] 2-Amino-2'-carboxydiphenylsulphide (100 g) was taken in toluene (250 ml). To this mixture phosphorus oxychloride (500 ml) was added. The resulting mixture was heated to reflux at 105-110⁰C for 5-6 hours. The reaction mixture was subjected to vacuum distillation to remove unreacted phosphorous oxychloride along with toluene. The resulting mass was taken in toluene (800 ml) and piperazine (210 g) was added. The reaction mixture was heated to reflux at 110-120⁰C for 6-8 hours. The reaction mixture was cooled, filtered and the organic phase was washed with water, dried and solvent was distilled off under vacuum to yield the title compound.

Example 8

Preparation of ll-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,f][l,4] thiazepine [I] ll-piperazinyldibenzo[b,fj[l,4]thiazepine (100 g) was taken in n-butanol (600 ml). Sodium carbonate (53 g) and 2-chloroethoxyethanol (46 g) was added. The reaction mixture was heated to reflux at 110-120⁰C for 10-12 hours. The reaction mixture was cooled and n-butanol was distilled off under vacuum. Ethyl acetate (600 ml) and water (500 ml) was added. The organic layer was separated off and the aqueous layer was first extracted with dilute hydrochloric acid and then basified with aqueous ammonia solution and extracted with ethyl acetate (800 ml). The organic layer was distilled off under vacuum to yield the title compound.

Example 9

Preparation of ll-[4-(2-hydroxyethyl)-l-piperazinyI]dibenzo[b,fJ [l,4]thiazepine [XXXI]

2-Amino-2'-carboxydiphenylsulphide (100 g) was taken in toluene (2000 ml). To this mixture phosphorus oxychloride (500 ml) was added. The reaction mixture was heated to reflux at 105-110⁰C for 5-6 hours. The reaction mixture was subjected to vacuum distillation to remove unreacted phosphorous oxychloride. The resulting mass was taken in toluene (800 ml), l-(2-hydroxyethyl) piperazine (80 g) and N-methyl pyrrolidone (100 ml) was added. The reaction mixture was heated to reflux at 110- 120⁰C for 6-8 hours. The reaction mixture was cooled, filtered and the organic phase was washed with water, dried and solvent was distilled off under vacuum to obtain the title compound.

Example 10

Preparation of H-[4-(2-methanesulphonylethyl)-l-piperazinyI]dibenzo[b,fJ [1,4] thiazepine [XXXII] l l-[4-(2-hydroxyethyl)piperazin-l-yl)dibenzo[b,fj[l,4]thiazepine (100 gm) was taken in dichloromethane (500 ml), triethylemine (60, g) was added at 0-5°C. Methane sulphonyl chloride (50 g) was added drop wise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was treated with water followed by treatment with bicarbonate solution. The organic layer was separated off and distilled under vacuum to obtain the title compound.

Example 11

Preparation of ll-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,f][l,4] thiazepine [I]

7 gm of sodium hydride was dissolved in ethylene glycol (500 ml) and to the mixture obtained, a solution of l l-[4-(2-methanesulphonylethyl)piperazin-l-yl]dibenzo[b,fj [1,4] thiazepine (100 g) taken in toluene (500 ml) was added. The reaction mixture was heated to reflux at 110-120⁰C for 10-12 hours. The reaction mixture was cooled and water was added. After separation, the toluene phase was extracted with dilute hydrochloric acid, the solution was made alkaline by the addition of aqueous ammonia solution, extracted with ethyl acetate (800 ml). The organic layer was distilled off under vacuum to yield the title compound.

Example 12

Preparation of ll-[4-[2-(2-hydroxyethoxy)ethyI]-l-piperazinyl]dibenzo[b,f] [1,4] thiazepine hemifumerate l l-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,fj[l,4]thiazeρine (100 g) was dissolved in acetone (1000 ml) and treated with fumaric acid (15 g). The mixture was stirred at room temperature and the resulting solid was filtered off, which was washed with acetone and dried under vacuum to get the product as hemifumarate.

Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.

Claims

We Claim:

1. A process for producing l l-[4-[2-(2-hydroxyethoxy)ethyl]-l- piperazinyl] dibenzo[b,fj[l,4]thiazepine [I] comprising reacting 2-amino-2'- carboxydiphenylsulphide [X] with a halide or an oxyhalide of phosphorous to obtain in situ iminohalide [VI] and without isolating lactam, reacting said iminohalide with 1- hydroxyethoxyethylpiperazine to produce l l-[4-[2-(2-hydroxyethoxy)ethyl]-l- piperazinyl]dibenzo[b,fj[l,4]thiazepine [I].

2. The process according to claim 1, wherein said halide or oxyhalide of phosphorous is selected from the group comprising oxyhalide, pentahalide or trihalide.

3. The process according to claim 1, wherein 2-amino-2'-carboxydiphenyl sulphide [X] is reacted with halide: or oxyhalide of phosphorous optionally in the presence of a base.

4. The process according to claim 3, wherein the base is an organic or an inorganic base.

5. The process according to claim 1, wherein the resulting iminohalide [VI] formed in situ reacts with 1-hydroxyethoxyethylpiperazine optionally in the presence of a co-solvent.

6. The process according to claim 5, wherein the co-solvent is selected from dimethylsulphoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidone, dimethylimidazolidone.

7. A process according to claim 1, further comprising condensing said iminohalide, without isolating lactam, with piperazine to obtain 11- piperazinyldibenzo[b,f][l,4]thiazepine [XIX] and reacting l l-piperazinyldibenzo[b,fj [l,4]thiazepine [XIX] with 2-haloethoxyethanol optionally in the presence of a base to produce l l-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,fj[l,4]thiazepine

[I]-

8. The process according to claim 7, wherein the base is selected from alkali or alkaline earth metal carbonates or bicarbonates.

9. The process according to claim 8, wherein the alkali metal or alkaline earth metal is selected from lithium, sodium, potassium, calcium or magnesium.

10. A process according to claim 1, further comprising reacting said iminohalide, without isolating lactam, with l-(2-hydroxyethyl)piperazine to give 11 -[4- (2-hydroxyethyl)piperazine-l-yl]dibenzo[b,f][l,4]thiazepine [XXXI], converting said l l-[4-(2-hydroxyethyl)pipefazine-l-yl]dibenzo[b,f][l,4]thiazepme [XXXI] to an intermediate 11 -[4-(2-substitutedethyl)piperazin-l -yl)dibenzo[b,f] [ 1 ,4]thiazepine, followed by reaction with ethylene glycol optionally in the presence of a base to produce 11 -[4-[2-(2-hydroxyethoxy)ethyi]- 1 -piperazinyl]dibenzo[b,f] [ 1 ,4]thiazepine [I].

11. The process according to claim 10, wherein the substituent at the 2- position of l l-[4-(2-substitutedethyl)piperazin-l-yl)dibenzo[b,f][l,4]thiazepine is selected from mesyloxy or tosyloxy or halo group.

12. The process according to claim 10, wherein the base is selected from alkali metal hydrides or alkoxides.

13. A process for producing hemifumarate salt of ll-[4-[2-(2- hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,f][l,4]thiazepme [I], as claimed in any of claims 1, 7 or 10 comprising reacting l l-[4-[2-(2-hydroxyethoxy)ethyl]-l- piperazinyl]dibenzo[b,f][l,4] thiazepine [I] with fumaric acid in the presence of a solvent.

14. The process according to claim 13, wherein the solvent is selected from a group comprising acetone, ethyl acetate, methanol, isopropyl alcohol or a mixture thereof.

15. A process for producing l l-[4-[2-(2-hydroxyethoxy)ethyl]-l- piperazinyl]dibenzo[b,f][l,4]thiazepine [I], the process comprising reacting thiosalicylic acid [XVI] with o-halonitrobenzene [XVII] using a phase transfer catalyst to obtain 2-nitro-2'-carboxydiphenylsulphide [XI], reducing 2-nitro-2'- carboxydiphenylsulphide to form 2-amino-2'-carboxydiphenylsulphide [X] and further producing l l-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,f][l,4]thiazepine [I] as recited in claim 1, 7 or 10.

16. The process according to claim 15, wherein said o-halonitrbenzene is selected from the group comprising o-fluoronitrobenzene, o-chloronitrobenzene, o- bromonitrobenzene or o-iodonitrobenzene.

17. The process according to claim 15, wherein the phase transfer catalyst is selected from the group comprising ammonium based phase transfer catalyst, phosphonium based phase transfer catalyst, PEG based phase transfer catalyst and crown ethers.

18. The process according to claim 15, wherein thiosalicylic acid [XVI] is reacted with o-halonitrobenzene [XVII] optionally in the presence of a base.

19. The process according to claim 18, wherein the base is selected from the group comprising carbonates, bicarbonates, hydroxides, alkoxides, hydrides of the alkali metal or alkaline earth metal.

20. The process according to claim 19, wherein the alkali metal or alkaline earth metal is selected from lithium, sodium, potassium, calcium or magnesium.