Field of the invention:

The present invention relates to an improved process for preparing Quetiapine fumarate of formula (I).

Background of the invention:

The chemical name of Quetiapine is 2-[2-(4-Dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]ethanol and formula is C21H25N3O2S and molecular weight is 383.51. The drug is used in its fumarate salt. The current pharmaceutical product containing this drug is being sold by Astrazeneca using the tradename Seroquel and Seroquel XR, in the form of oral tablets.

Quetiapine is used as Antipsychotic. It is antipsychotic, psycholeptics and antidepressant class drug. It is dopamine antagonist and 5HT antagonist. 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 4,879,288 describes a process for the preparation of Quetiapine fumarate which is shown in the scheme-I.

Scheme-I

The process involves reacting dibenzo[b,f][1,4]thiazepine-11(10-H)-one (II) with phosphorous oxychloride in the presence of N,N-dimethylaniline to give imino chloride (III); which is further reacted with 1-(2-hydroxyethoxy)ethylpiperazine (IV) in xylene to give Quetiapine (V). Quetiapine is purified by flash chromatography and then converted into its fumarate salt by reacting it with fumaric acid in ethanol to give Quetaipine fumarate (I). The yield and purity obtained by this process is low. Further, this process requires chromatographic purification of Quetiapine before converting it to its fumarate salt. No purification process of Quetiapine fumarate is disclosed in this patent to enhance the purity of Quetiapine fumarate.

It is therefore, a need to develop an easy to operate, industrially feasible process which also provides good yield and high purity of Quetiapine fumarate. The present invention addresses these needs.

Present inventors have directed their research work towards developing a process for the preparation of Quetiapine fumarate which provides good yield and purity. The present inventors observed that using sulfolane as solvent in condensation step of imino chloride (III) with 1-(2-hydroxyethoxy)ethylpiperazine (IV) instead of xylene increases yield and purity of quetiapine and which need not require to purify Quetiapine by chromatography before converting it to its fumarate salt.

Summary of the invention:
Accordingly, it is an object of the present invention to provide a process for the preparation of Quetiapine fumarate.

Another object of the present invention is to provide a process which gives Quetiapine fumarate with high purity.

Another object of the present invention is to provide a process for the preparation of Quetiapine fumarate which is operationally simple and cost effective.

Accordingly, present invention provides a process for preparation of Quetiapine fumarate (I)

comprising a step of reacting 11-chlorodibenzo [b,f][1,4]thiazepine (III)

with 1-(2-hydroxyethoxy)ethylpiperazine dihydrochloride (IV)

in the presence of a base and sulfolane to give Quetiapine (V);

Accordingly, present invention provides a process for preparation of Quetiapine fumarate (I)

comprising steps of:
(i) dibenzo[b,f][1,4]thiazepine-11(10-H)-one (II)

with phosphorous oxychloride in the presence of N,N-dimethylaniline in toluene to give 11-chlorodibenzo [b,f][1,4]thiazepine (III);

(ii) reacting 11-chlorodibenzo [b,f][1,4]thiazepine (III) with 1-(2-hydroxyethoxy)ethylpiperazine dihydrochloride (IV)

in the presence of a base and sulfolane to give Quetiapine (V);

(iii) converting Quetiapine (V) to Quetiapine fumarate (I) by reacting it with fumaric acid in methanol.

The present invention provides a process for purification of Quetiapine fumarate (I) comprising steps of
(a) heating impure Quetiapine fumarate (I) with methanol
(b) adding water dropwise till clear solution obtained
(c) cooling the reaction mixture to obtain pure Quetiapine fumarate (I).

Detailed description of the invention:

The present invention provides an improved process for preparation of Quetiapine fumarate (I)

comprising steps of:
(i) dibenzo[b,f][1,4]thiazepine-11(10-H)-one (II)

with phosphorous oxychloride in the presence of N,N-dimethylaniline in toluene to give 11-chlorodibenzo [b,f][1,4]thiazepine (III);

(ii) reacting 11-chlorodibenzo [b,f][1,4]thiazepine (III) with 1-(2-hydroxyethoxy)ethylpiperazine dihydrochloride (IV)

in the presence of a base and sulfolane to give Quetiapine (V);

(iii) converting Quetiapine (V) to Quetiapine fumarate (I) by reacting it with fumaric acid in methanol.

The synthetic reaction scheme of the present invention is shown in the scheme-II.

Scheme-II

In the process of present invention, dibenzo[b,f][1,4]thiazepine-11(10-H)-one (II) is heated with Phosphorous oxychloride in the presence of N,N-Dimethyl aniline in toluene at about 110°C to about 115°C for 5 to 6 hours. After completion of reaction, organic layer is washed with water. The solvent from organic layer is distilled out under reduced pressure at about 45°C to about 50°C to give 11-chlorodibenzo [b,f][1,4]thiazepine (III) which is used as such for next step. 11-chlorodibenzo [b,f][1,4]thiazepine (III) is heated with 1-(2-hydroxyethoxy)ethylpiperazine dihydrochloride (IV) in the presence of base in sulfolane at about 95°C to about 100°C for about 4 hours. Other solvent in combination with sulfolane can also be used. For example a combination of toluene and sulfolane is used as solvent in this reaction step. The base used is selected from potassium carbonate, sodium carbonate, lithium carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, potassium tert-butoxide, 1,8-diazobicyclo[5,4,0]undecene, N-benzyltrimethylammonium hydroxide, triethyl amine, tributyl amine, N,N-diisopropyl ethylamine, N,N-dimethylaniline, N,N-diethylaniline, pyridine, picolines, N,N-dimethylaminopyridine, N-methylmorpholine and the like or mixtures thereof. An aqueous solution of the base can also be used. After completion of the reaction, the reaction mixture is quenched with water. The reaction mixture is extracted with ethyl acetate. The organic layer is separated and evaporated to dryness to give Quetiapine (V) as viscous oil. A pre-heated solution at about 70°C to about 75°C of fumaric acid in methanol is added to a solution of Quetiapine (V) in methanol at about 70°C to about 75°C and further heated for 30min at the same temperature. The reaction mixture is cooled to about 5°C to about 15°C. The separated solid is filtered, washed with chilled methanol and suck dried. The wet cake is used for purification.

The present invention provides a process for purification of Quetiapine fumarate (I) comprising steps of
(a) heating impure Quetiapine fumarate (I) with methanol
(b) adding water dropwise till clear solution obtained
(c) cooling the reaction mixture to obtain pure Quetiapine fumarate (I).

“Impure Quetiapine fumarate” means Quetiapine fumarate having HPLC purity less than 99.8%.

In the purification of Quetiapine fumarate, methanol is added to the wet cake of impure Quetiapine fumarate obtained in above process and heated at about 65°C to about 70°C. D. M. Water is added drop wise at the same temperature till clear solution is obtained. The reaction mixture is stirred for 30 min at the same temperature and then cooled to about 5°C to about 15 °C. The separated solid is filtered, washed with chilled methanol and suck dried. The solid is dried under vacuum at about 55°C to about 60°C to give pure Quetiapine fumarate (I)

The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.

Example-1
Preparation of 11-chlorodibenzo [b,f][1,4]thiazepine (III)
dibenzo[b,f][1,4]thiazepine-11(10-H)-one (II) (100 g) was heated with phosphorous oxychloride (67.46 g) in the presence of N,N-Dimethyl aniline (106.63 g) in toluene (500 ml) at 110°C to 115°C for 5 to 6 hours. After completion of the reaction, organic layer was washed twice with water (2x 200 ml). The solvent from organic layer was distilled out under reduced pressure at 45°C to 50°C to give residue 11-chlorodibenzo [b,f][1,4]thiazepine (III) which was used as such for next step.

Example-2
Preparation of Quetiapine Base (V)
Residue 11-chlorodibenzo [b,f][1,4]thiazepine (III) obtained from Example-1 was heated with 1-(2-hydroxyethoxy)ethylpiperazine dihydrochloride (IV) (119.65 g) in the presence of potassium carbonate (213.12 g) in sulfolane (400 ml) at 95°C to 100°C for about 4 hours. After completion of reaction, the reaction mixture was quenched with D. M. Water (1000 ml). The reaction mixture is extracted with ethyl acetate (2x300 ml). Organic layer is separated evaporated to dryness under vacuum to give Quetiapine (V) as viscous oil which was used as such for the next step.

Example-3
Preparation of Quetiapine Fumarate (I)
A pre-heated solution at 70°C to 75°C of Fumaric acid (26.55 g) in methanol (300 ml) was added to the solution of Quetiapine [obtained in Example-2] in methanol(300 ml) at 70°C to 75°C. The reaction mixture was stirred for 30 min at 70°C to 75°C. The reaction mixture was cooled to 15°C. The separated solid was filtered, washed with chilled methanol (100 ml) and suck dried. The wet cake of Quetiapine fumarate was used as such for the next step.

Example-4
Purification of Quetiapine Fumarate (I)
Quetiapine fumarate wet cake obtained from Example-4 was heated in methanol (1200 ml) at 65°C to 70°C. D. M. Water (approximately 50 ml) was added drop wise at the same temperature till clear solution was obtained. The reaction mixture was stirred for 30 min at 65-70°C. The reaction mixture was cooled to 15°C. The separated solid was filtered, washed with chilled methanol (100 ml) and dried under vacuum at 55°C to 60°C to give pure Quetiapine fumarate (122.0 g)
Overall yield: 55.56%
Purity (by HPLC): 99.84%