FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 2-[2-(4-dibenzo [b,f] [l,4]thiazepin-ll-yl-l-piperazinyl)ethoxy]-ethanol (referred to as the compound-I) and salts thereof. The compound-I is generically known as quetiapine. Particularly, the present invention provides an improved process for the preparation of quetiapine fumarate (referred to as the compound-II).
BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.

Quetiapine base Quetiapine fumarate
Quetiapine (compound-I), a dopamine antagonist and 5HT antagonist; belongs to antipsychotic, psycholeptics and antidepressant class of drug. The drug is marketed as fumarate salt (compound-II) by Astra Zeneca under the tradename SEROQUEL and SEROQUEL XR, in the form of oral tablets. It is used in the treatment of schizophrenia, bipolar diseases and psychosis. It is also used in the treatment of anxiety and depression.

US patent No. 4,879,288 (the US'288 Patent) describes a process for the synthesis of quetiapine which comprises reaction of dibenzo[b,f][l,4]thiazepin-ll(10H)-one (III) with phosphorous oxychloride (POCI3) and N-N-dimethylaniline to form an iminochloride namely 11-chlorodibenzo[b,fJ[l,4]thiazepine (IV). The US'288 patent further describes condensation of the isolated iminochloride with l-(2-hydroxyethoxy) ethyl piperazine (V) to afford the quetiapine base (compound-I) as viscous oily crude material. The overall reaction time to obtain the compound-I was 30 hours and the yield of the said compound was about 77%. The process described in this patent involved purification of the said product using flash chromatography. In the said process, in the chlorination step phosphorous oxychloride was used quantitatively around 15 equivalents. Also, the said process used the reactant l-(2-hydroxyethoxy) ethyl piperazine (V) in 2 molar equivalents with respect to the iminochloride compound i.e. 11-chlorodibenzo[b,f][l,4]thiazepine (IV).
US patent No. 7,687,622 B2 describes a process for the synthesis of quetiapine which comprises the condensation of 11-chlorodibenzo[b,fJ [l,4]-thiazepine (IV) with l-(2-hydroxyethoxy) ethylpiperazine (V) by using a base, and phase transfer catalyst or a halide that is either an alkali metal halide or a silylhalide.
Published PCT application WO 2006/027789 describes a process for the synthesis of quetiapine which comprises the condensation of iminochloro compound i.e. 11-chlorodibenzo [b,f] [1,4]-thiazepine(IV) with l-(2-hydroxyethoxy)ethylpiperazine (V) in a solvent mixture of toluene and N-methyl pyrrolidone, wherein the latter solvent is used as a co-solvent, using sodium carbonate as base. In this process, the reactant l-(2-hydroxyethoxy) ethylpiperazine (V) was used in excess of more than 2 equivalents. Furthermore, this process is associated with a drawback in that the recovery and reuse of the solvent is difficult because of the presence of co-solvent.
Published PCT application WO2006/117700 describes a process for the synthesis of quetiapine which comprises the reaction of dibenzo[b,f][l,4]thiazepin-11(10H)-one (III) with phosphorous oxychloride in the presence of triethylamine (TEA) in xylene at reflux conditions. After the completion of the reaction and usual work-up, the organic layer was taken forward for the condensation with l-(2-hydroxyethoxy)ethylpiperazine (V). However, the process was carried at

high reaction temperature of about 141°C. Further, the reactant, l-(2-hydroxyethoxy) ethylpiperazine (V) was used in an excess amount of around 2 equivalents.
Published PCT application WO 2007/020011 describes a process for the synthesis of quetiapine which comprises the chlorination of dibenzo [b,f][l,4]thiazepin-ll(10H)-one (III) using phosphorous oxychloride in the presence of N,N-dimethyl aniline as base in toluene under reflux conditions to give the iminochloride compound (IV). The organic layer after usual workup was directly taken further for condensation with l-(2-hydroxyethoxy) ethylpiperazine (V) which is used in an amount of around 2 equivalents with respect to the iminochloride compound (IV).
Published PCT application WO 2010/029458 describes a process for the synthesis of quetiapine which comprises the chlorination of dibenzo [b,f][l,4]thiazepin-ll(10H)-one (III) using phosphorous oxychloride in the presence of N,N-dimethyl aniline as base in toluene to obtain iminochloro compound (IV) as viscous oil. The said product was further reacted with l-(2-hydroxyethoxy) ethylpiperazine (V) dihydrochloride in the presence of potassium carbonate as base and sulfolane as the solvent at 95-100°C for 4 hours to obtain the product quetiapine base as viscous oil.
Published US patent application 2006/0063927 describes a process for the synthesis of quetiapine which comprises the chlorination of dibenzo [b,f][l,4]thiazepin-ll(10H)-one (III) using oxalyl chloride with the reaction set-up consists of a Dean-Stark apparatus. The obtained iminochloro compound was further reacted with l-(2-hydroxyethoxy) ethylpiperazine (V) in toluene as the solvent and optionally along with water, in the presence of potassium carbonate or triethylamine as the base.
Published PCT application WO 2010/070510 describes a process for the synthesis of quetiapine which comprises the condensation of 11-chlorodibenzo [b,fj [l,4]-thiazepine (IV)with l-(2-hydroxyethoxy) ethylpiperazine (V) in a solvent system comprising of a mixture of toluene and water at reflux conditions. The reactant, l-(2-hydroxyethoxy) ethylpiperazine (V) was used in an excess amount of around 2 equivalents with respect to the compound IV.
It is evident from the above discussion of the processes for the synthesis of quetiapine described in afore cited patent documents that the reported processes primarily require longer reaction time

and use of reactants in excess amount. Further, the prior art processes involve additional purification methods such as column chromatography or treatment with solvent. Also, these processes involve use of additional reagents such as phase transfer catalysts, use of organic bases in the chlorination step, use of co-solvent or mixture of solvent system which includes bi-phasic solvent system; which in turn leads to tedious workup procedures and render the process costlier. In view of these drawbacks, there is a need to develop a simple, commercially advantageous and an industrially viable process for the preparation of quetiapine and/or its salt such as quetiapine fumarate with improved yield and purity in shorter duration of time.
Inventors of the present invention have developed an improved process that addresses the problems associated with the processes reported in the prior art. The process of the present invention does not involve use of any additional costly reagents. Moreover, the process does not require additional purification steps and critical workup procedure such as column chromatography. Accordingly, the present invention provides a process for the preparation of quetiapine or its salt, which is cost effective, environmentally friendly and commercially scalable for large scale operations.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to an improved process for the preparation of quetiapine and/or pharmaceutically acceptable salts thereof, comprising the steps of;
(a) reacting dibenzo [b,fj[l,4]thiazapine-l l(10-H)-one (III) with a chlorination reagent to obtain iminochloride compound (IV),
(b) reacting the iminochloride compound (IV) with l-(2-hydroxyethoxy) ethylpiperazine (V) in the presence of an organic base selected from 2, 4, 6-trimethylpyridine(Collidine), triazabicyclodecene (TBD), Tetramethylguanidine (TMG) or l,4-diazabicyclo[2.2.2]octane (DABCO) to obtain quetiapine; and
(c) optionally, converting the product, quetiapine to its pharmaceutically acceptable salt.
In another aspect, the present invention relates to an improved process for the preparation of
quetiapine and/or salts thereof, comprising the steps of;
(a) reacting dibenzo [b,f][l,4]thiazapine-ll(10-H)-one (III) with about 2 mole equivalents of

phosphorus oxychloride to obtain iminochloride compound (IV),
(b) reacting the iminochloride compound (IV) with stoichiometric amount of l-(2-
hydroxyethoxy) ethylpiperazine (V) in the presence of 2, 4, 6-trimethylpyridine (Collidine) to
obtain quetiapine.
(c) optionally, converting the product, quetiapine to its fumarate salt.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to an improved process for the preparation of quetiapine (I) represented by the following formula (I); and/or pharmaceutically acceptable salts thereof;

-OH
N-

i
Quetiapine base said process comprising the steps of; (a) reacting dibenzo [b,fj[l,4]thiazapine-l l(10-H)-one (compound III);

with a chlorination reagent to obtain iminochloride compound (IV) namely 11-chlorodibenzo[b,f][l,4]thiazepine;

IV
(b) reacting the iminochloride compound (IV) with l-(2-hydroxyethoxy) ethylpiperazine (V)

in the presence of an organic base selected from 2, 4, 6-trimethylpyridine (collidine), triazabicyclodecene (TBD), Tetramethylguanidine (TMG) or l,4-diazabicyclo[2.2.2]octane (DABCO) to obtain quetiapine; and
(c) optionally, converting the product, quetiapine to its pharmaceutically acceptable salt.
In an embodiment, the chlorination reagent used in the process step (a) is selected form thionyl chloride, phosphorous pentachloride, phosphorous oxychloride (POCI3) or oxalyl chloride.
In an embodiment, the solvent used in step (a) of the process is selected from an alcohol such as ethyl alcohol, n-propyl alcohol, isopropyl alcohol, isobutyl alcohol and methanol; an ether such as ethyl ether, propylether; other hydrocarbons solvents such as toluene, benzene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isobutyl ketone, acetonitrile, dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide and dimethylacetamide.
In an embodiment, the solvent used in step (a) of the process is toluene.
In an embodiment, the organic base used in the process step (b) is selected from 2, 4, 6 -trimethylpyridine (Collidine), triazabicyclodecene (TBD), Tetramethylguanidine (TMG) and l,4-diazabicyclo[2.2.2]octane (DABCO).
In an embodiment, the organic base used in the process step (b) is 2, 4, 6-trimethylpyridine

(Collidine).
In an embodiment, the intermediate iminochloride compound (IV) formed in the step-(a) of the above process is carried forward for further chemical transformation in organic layer without isolation.
In an embodiment, the product obtained in the step-(b) of the process is isolated as quetiapine free base (I).
In an embodiment, product of the step-(b) of the process is in-situ converted to its pharmaceutically acceptable salt such as fumarate salt and is isolated as quetiapine fumarate (II).
In a specific embodiment, a process for the preparation of quetiapine (compound I) comprises the steps of,
(1) dissolving the compound III in a solvent,
(2) adding a chlorination reagent to the reaction mixture of step (1);
(3) stirring the reaction mixture of the above step (2) at reflux temperature;
(4) quenching the reaction mixture of step (3) by the addition of aqueous base solution at room temperature;
(5) separating the organic layer as formed in step (4);
(6) adding the compound-V and an organic base to the organic layer of step (5);
(7) stirring the reaction mixture of step (6) at reflux temperature;
(8) cooling the reaction mixture of step (7) to a lower temperature of about 5 °C;
(9) acidifying the reaction mixture of step (8) using aqueous acid solution;
(10) separating the aqueous layer of step (9) and treating with a basic solution;

(11)

extracting the aqueous mixture of step (10) using an organic solvent; and

(12) isolating the quetiapine (compound I) or optionally, in-situ converting it to Quetiapine fumarate (compound II) and isolating the said compound II.
The process of the present invention as per a specific embodiment is illustrated in the following Scheme-I,
The solvent used in the step-(l) of the above process is selected from, an alcohol such as ethyl alcohol, n-propyl alcohol, isopropyl alcohol, isobutyl alcohol and methanol; an ether such as ethyl ether, propylether; other hydrocarbons solvents such as toluene, benzene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, methylisobutyl ketone, acetonitrile, dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide and dimethylacetamide.
In an embodiment, the solvent used in step (1) of the process is toluene.
The chlorination reagent used in the step-(2) of the above process is selected from thionyl chloride, phosphorous pentachloride, phosphorous oxychloride or oxalyl chloride.

In anembodiment, the chlorination agent used in step (2) of the process is phosphorous oxychloride.
In an embodiment, in the process of the present invention, the chlorination agent is used in an amount ranging from 1 to 2 mole equivalents with reference to the compound III.
In an embodiment, in the process of the present invention, the chlorination agent is used in 2 mole equivalents with reference to the compound III.
The base used in the step-(4) of the above process is an inorganic base selected from sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide (NaOH) or potassium hydroxide.
In anembodiment, the aqueous base solution used in step (4) of the process is 10% NaOH solution.
The term 'room temperature' referred to in the step (4) of the above process can range from 20°C to 30°C.
In an embodiment, the compound-V used in step (6) of the process is used in an amount of about 1 mole equivalents with reference to the compound IV.
The organic base used in the step-(6) of the above process is selected from 2, 4, 6-trimethylpyridine (Collidine), triazabicyclodecene (TBD), Tetramethylguanidine (TMG) and l,4-diazabicyclo[2.2.2]octane (DABCO).
In an embodiment, the organic base used in the process step (6) is 2, 4, 6-trimethyl pyridine (Collidine).
The term 'lower temperature of about 5 °C referred to in the step (8) of the above process can range from 0°C to 10 °C.
The acid used in the step-(9) of the above process is selected from hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid.
In an embodiment, the acid used in the process step (9) is hydrochloric acid, preferably 3N HC1 solution.

The base used in the step-(lO) of the above process is an inorganic base selected from sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
In an embodiment, the aqueous base solution used in step (10) of the process is sodium carbonate
solution.
The term 'isolating the quetiapine' referred to in the step (12) corresponds to the process of
evaporation of solvent, washing and drying.
The compound III used in the process of the present invention can be prepared by any method reported in the prior art; for instance, the said compound III can be prepared by the process described in US Patent No. 4,879,288 (the US'288 Patent). The process for the preparation of compound-Ill as described in the US'288 patent comprises cyclization of a compound selected from (2-isocyanatophenyl)(phenyl)sulfane, alkyl 2-((2-aminophenyl)thio)benzoate or alkyl (2-(phenylthio)phenyl)carbamate under acidic conditions.
The process of the present invention as illustrated in the above Scheme-I comprises reaction of the compound III with 2 mole equivalents of phosphorous oxychloride in toluene under reflux condition for 4-5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with 10% sodium hydroxide solution. To the separated organic layer, was added about 1 mole equivalent of l-(2-hydroxyethoxy) ethylpiperazine (V) and about 1 mole equivalent of an organic base selected for 2, 4, 6-trimethylpyridine (Collidine), triazabicyclodecene (TBD), Tetramethylguanidine (TMG) and l,4-diazabicyclo[2.2.2]octane (DABCO). The reaction mixture was refluxed for 10-18 hours. After completion of the reaction, the mixture was cooled to lower temperature of about 5 °C and extracted with aqueous acid solution, preferably 3N HC1. Combined aqueous layer was treated with fresh toluene along with sodium carbonate solution. The separated organic layer was evaporated to provide quetiapine base (compound I) in 82% yield with respect to the compound III and having purity of 99.35% (HPLC).

In an embodiment, the product obtained by the process of the present invention is isolated as quetiapine free base (I).
In an embodiment, the isolated product of the present invention namely quetiapine free base (I) is further converted to its pharmaceutically acceptable salt.
In an embodiment, the isolated product of the present invention namely quetiapine free base (I) is further converted to quetiapine fumarate (II).
In an embodiment, the product obtained by the process of the present invention is in-situ converted and isolated as Quetiapine fumarate (II).
It is evident from the processes reported in the prior art that the overall reaction time period required ranged from 30-33 hours, whereas the process of the present invention required a shorter time duration of about 8-18 hours. This amounts to a significant advantage over the processes reported in the prior art.
It is also evident from the processes reported in the prior art that the amount of phosphorous oxychloride used in the chlorination step was about 15 equivalents with respect to the compound III, whereas the process of the present invention required use of phosphorous oxychloride in about 2 mole equivalents only.
It is further evident from the processes reported in the prior art that the amount of l-(2-hydroxyethoxy) ethylpiperazine (compound V) was used in 2 mole equivalents with respect to compound-IV, whereas process of the present invention involved the use of compound IV in about 1 mole equivalent of compound-V.
Advantageously, the above identified elements of the process of the instant invention effectively contribute to the reduction of overall cost of the process.
In an embodiment, the use of organic base such as 2, 4, 6-trimethylpyridine (Collidine), provided an excellent conversion of the compound IV to quetiapine(I) with overall yield of 82-85 % as against yield of 75-77 % reported in the prior art.
In an embodiment, the organic base used in the reaction such as 2, 4, 6-trimethylpyridine

(Collidine), triazabicyclodecene (TBD), Tetramethylguanidine (TMG) and 1,4-diazabicyclo[2.2.2]octane (DABCO) can be recovered and reused in the process.
The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example-1: Preparation of Quetiapine base (I)
A round bottom flask was charged with lOOg of dibenzo[b,f][l,4]thiazepine-ll (10H)- one (III) (0.44 moles) along with 500 mL toluene. To the stirring mixture, was added 134.9 g of POCI3 (0.88 moles) and heated to reflux for 4-5 hours. After completion of the reaction, the mixture was cooled to room temperature and quenched by 10% NaOH solution. The organic layer was separated and dried over sodium sulfate. To this toluene layer, was added 82.6g of l-(2-hydroxyethoxy) ethylpiperazine (V) (0.47 moles) and 47.8g of 2, 4, 6-trimethylpyridine (collidine) (0.4 moles).The reaction mixture was heated to reflux for 10 to 18 hours. After completion of the reaction, the mixture was cooled to 0-5 °C and extracted with 2x 290.5 mL 3N HO. The combined aqueous layer was treated with aqueous sodium carbonate solution and extracted with toluene. The organic layer was separated and treated with charcoal 5.0 g. the Toluene was distilled out under vacuum to afford quetiapine base (I).
Yield: 138.3g (82%, based on dibenzo [b, f] [1, 4] thiazepine-11 (lO-H)-one) Purity by HPLC: 99.35%
Example-2: Preparation of Quetiapine Fumarate salt (II)
A round bottom flask (RBF) was charged with 96.6gm of ll-[4-[2-(2-Hydroxyethoxy)ethyl]-l-

piperaziny]dibenzo[b,f][l,4]thiazepine (Quetiapine base I) in 137 mL of acetone. Another round bottom flask was charged with 14.2 g of Fumaric acid, (0.054 moles) in 43 mL of water and heated to 55- 60°C. The quetiapine free base solution of the first RBF was slowly added to the acid solution of the second RBF and stirred for 2 hours. The mixture was cooled slowly to 0- 5°C and the precipitated product was filtered, washed with acetone and dried under vacuum at 60 -65°C to obtain 96 g quetiapine Fumarate (II) of purity 99.94% (HPLC) and 86% of yield.
We claim:
1. A process for the preparation of quetiapine (the compound I) and/or its pharmaceutically acceptable salt, of the following formula

I
comprising the steps of;
(a) reacting the compound III represented by the following formula;
with a chlorination reagent to obtain the compound (IV) of the following formula;

(b) reacting the compound (IV) with the compound (V) of the following formula;
in the presence of an organic base.
2. The process as claimed in claim 1, wherein said chlorination reagent is selected from thionyl chloride, phosphorous pentachloride, phosphorous oxychloride or oxalyl chloride.
3. The process as claimed in claim 1, wherein said chlorination reagent is used in an amount ranging from about 1 to 2 mole equivalents with reference to the compound III.
4. The process as claimed in claim 1, wherein the compound-V used as about 1 mole equivalents with reference to the compound IV.
5. The process as claimed in claim 1, wherein said organic base is selected from 2, 4, 6-trimethylpyridine (Collidine), triazabicyclodecene (TBD), Tetramethylguanidine (TMG) and l,4-diazabicyclo[2.2.2]octane(DABCO).
6. The process as claimed in claim 1, wherein the product quetiapine free base obtained with purity >99%.
7. The process as claimed in claim 1, wherein the pharmaceutically acceptable salt is quetiapine fumarate.
8. The process as claimed in claim 1, wherein the product further converted to quetiapine fumarate.
9. A process for the preparation of quetiapine (the compound I) and/or its pharmaceutically acceptable salt, of the following formula

comprising the steps of;
(a) reacting the compound III represented by the following formula;
with about 2 mole equivalents of phosphorous oxychloride to obtain the compound (IV) of the following formula;

IV
(b) reacting the compound (IV) with about 1 mole equivalents of compound (V) of the following formula;

H
in the presence of 2,4, 6-trimethylpyridine (Collidine).