PROCESS FOR PREPARING QUETIAPINE INTRODUCTION TO THE INVENTION

The present invention relates to an alternate process for the preparation of Quetiapine and its pharmaceutically acceptable salts.

Quetiapine is chemically known as 2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol and can be represented structurally by Formula I.

Quetiapine is used as its fumarate salt for the treatment of schizophrenia and is commercially available in the market under the brand name SEROQUEL as 25, 50, 100, 200, 300, and 400 mg tablets.

Quetiapine was first described in the patent publication U.S. Patent No. 4,879,288. The patent also provides a process for its preparation involving halogenation of dibenzo[b,f][1,4] thiazepin-11-[10H]one with phosphorous oxychloride, then isolated and condensed with 1-(2-hydroxyethoxy) ethyl piperazine to obtain Quetiapine.

Various alternative processes for the preparation of Quetiapine and its
intermediates have also been described in EP282236, WO2006/117700, WO2006/113425, WO2006/094549, US2006/0063927, WO2007/020011,
WO2007/004234, WO2005/014590, WO2005/028457, WO2005/028458, and WO2005/028459 and many others.

The reported schemes involve costly reagents along with highly complex procedures to isolate the intermediates resulting in excessive time cycles to afford the desired product with good quality. Therefore, to overcome these difficulties, the present inventors have developed a new alternate process for the preparation of Quetiapine.

SUMMARY OF THE INVENTION

The present invention relates to an alternate process for the preparation of Quetiapine of Formula I, and pharmaceutically acceptable salts thereof, comprising the steps of:

a) Reaction of 2-mercapto benzoic acid of Formula II with 1-Chloro-2-nitrobenzene
of Formula III to give 2-(2-nitrophenylthio)benzoic acid of Formula IV;

b) conversion of the acid group in 2-(2-nitrophenylthio)benzoic acid of Formula IV to
an amide to give 2-(2-Nitrophenylthio) benzamide of Formula V, which is treated with POCbto yield 2-(2-nitrophenylthio) benzonitrile of Formula VI;

c) reaction of the nitrlle compound of Formula VI with SnCb and HCI to get the three member cyclic dibenzo[b,f][1,4]thiazepin-11-amine of Formula VII;

d) reaction of the amine of Formula VII with N,N-bis(2-chloroethyl)-4-
methylbenzenesulfonamide to provide the tosylpiperazine derivative of 11-(4-
tosylpiperazin-1-yl)dibenzo[b,f] [1,4] thiazepine of Formula VIII;

e) treatment of the tosylpiperazine derivative with hydrobromic acid in the presence
of acetic acid to yield 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine of Formula IX;
and

f) finally reaction of the 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine of Formula IX with 2-chloroethoxy ethanol to yield Quetiapine;

g) optionally conversion of Quetiapine to the pharmaceutically acceptable salts.

DETAILED DESCRIPTION

The present invention relates to an alternate process for the preparation of Quetiapine of Formula I, and pharmaceutically acceptable salts thereof, comprising the steps of:

a) Reaction of 2-mercapto benzoic acid of Formula II with 1-Chloro-2-nitrobenzene of Formula III to give 2-(2-nitrophenylthio)benzoic acid of Formula IV;

b) conversion of the acid group in 2-(2-nitrophenylthio)benzoic acid of Formula IV
to an amide to give 2-(2-Nitrophenylthio) benzamide of Formula V, which is treated with POCI3 to yield 2-(2-nitrophenylthio) benzonitrile of Formula VI;

c) reaction of the nitrile compound of Formula VI with SnCl2 and HCI to get the
three member cyclic dibenzo[b,f][1,4]thiazepin-11-amine of Formula VII;

d) reaction of the amine of Formula VII with N,N-bis(2-chloroethyl)-4-
methylbenzenesulfonamide to provide the tosylpiperazine derivative of 11-(4-
tosylpiperazin-1-yl)dibenzo[b,f] [1,4] thiazepine of Formula VIII;

e) treatment of the tosylpiperazine derivative with hydrobromic acid in the
presence of acetic acid to yield 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine of Formula IX;
finally reaction of the 11-(piperazin-1-yl)clibenzo[b,fI[1,4]thiazepine of Formula IX with 2-chloroethoxy ethanol to yield Quetiapine;

f) optionally conversion of Quetiapine to the pharmaceutically acceptable salts.
Suitable solvents which can be used for conducting the reactions of steps a to f include, but are not limited to aprotic polar solvents such as N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide, acetonitrile and the like; ethers such as tetrahydrofuran, 1,4-dioxane and the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; alcohols such as methanol, ethanol and the like; ketonic solvents such as acetone, methylisobutylketone and the like; hydrocarbons such as toluene and the like; or mixtures thereof or their combination with water in various proportions without limitation.

Suitable temperatures for conducting the reactions range from about 0 to about 100 °C, or from about 10 to about 70 °C.

Suitably, the intermediates at each of the stages are isolated and purified by recrystallization or slurry in a suitable solvent. Also Quetiapine obtained may be suitably recrystallized in a suitable solvent.

Suitable solvents which can be used for recrystallisation or slurry of the compound at each stage and the final compound include, but are not limited to alcoholic solvents such as methanol, ethanol, propanol, isopropyl alcohol, n-butanol and the like; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; halogenated solvents such as dichloromethane, chloroform, ethylene dichloride, carbon tetrachloride and the like; and esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tertiary-butyl acetate and the like or mixtures thereof, or their mixtures with water in various proportions.

For recrystallization, a solution can be prepared at an elevated temperature, if desired, to achieve a desired high solute concentration. The solution may be brought down to lower temperatures, such as in the range of -5 to 30 °C, for further isolation if required or an elevated temperature may be used.

Quetiapine obtained above may be converted to its pharmaceutically acceptable salts by reacting it with the desired acid in the presence of a suitable solvent.

Suitable acids which may be used include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, and the like; and organic acids such as fumaric acid, tartaric acid, succinic acid, acetic acid, citric acid, and the like.

Still another aspect of the present invention provides a pharmaceutical composition comprising Quetiapine or its pharmaceutically acceptable salt, prepared according to the process of the present invention, together with one or more pharmaceutically acceptable excipients.

The pharmaceutical composition comprising Quetiapine or its salts may be further formulated into solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms, such as but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations, such as but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients that find use in the present invention include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

In the compositions of the present invention, Quetiapine is a useful active ingredient in the range of about 1 to about 10 mg, per dosage unit.

Certain aspects and embodiments of the processes described herein are further described in the following examples. These examples are provided solely for the purpose of illustrating certain aspects and embodiments of the invention and therefore should not be construed as limiting the scope of the invention.

EXAMPLE 1

PREPARATION OF 2-(2-NITROPHENYLTHIO) BENZOIC ACID (FORMULA IV):

To a mixture of 2-Mercapto benzoic acid (50 g, 0.325mol), sodium hydroxide (26.1 g, 0.653 mol) and water (170 mL), 1-chloro-2-nitrobenzene (54 g, 0.34 mol) was added and refluxed at 100 -105 °C for 5 hours. The reaction mixture was cooled to room temperature and washed with ethyl acetate (200 mL) to remove the un-reacted 1-chloro-2-nitrobenzene. The aqueous layer was neutralized with an aqueous hydrochloric acid (125 mL) and the product was extracted in to ethyl acetate (400 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give 2-(2-nitrophenylthio) benzoic acid (80.7 g. Yield: 90.7%)
.
EXAMPLE 2

PREPARATION OF 2-(2-NITROPHENYLTHIO) BENZAMIDE (FORMULA V):

To a mixture of 2-(2-Nitrophenylthio) benzoic acid (50 g, 0.182 mol), DMF (2 mL) and chloroform (500 mL), thionyl chloride (26 g, 0.21 mol) was added and refluxed for two hours. The mixture was cooled to 20 °C, poured into a mixture of 25% aqueous ammonia solution (500 mL) and ice (100 g), and then stirred for 2 hours. The separated solid product was filtered, washed with water (100 mL) and dried at 60 °C to afford the title compound 2-(2-nitrophenylthio)benzamide (11) (40 g. Yield: 80%).

EXAMPLE 3

PREPARATION OF 2-(2-NITROPHENYLTHIO) BENZONITRILE (FORMULA VI):

A mixture of 2-(2-Nitrophenylthio)benzamide (30 g, 0.109 mol), phosphorus oxychloride (51.2 mL 0.55 mol) and chloroform (750 mL) were refluxed for two hours. The reaction mixture was cooled to 20 °C, poured into water (100 ml), and then stirred for one hour. The organic layer was separated, dried over sodium sulfate and the solvent was removed under reduced pressure to yield 2-(2-nitrophenylthio) benzonitrile (19 g. Yield: 67.8%).

EXAMPLE 4

PREPARATION OF DIBENZ0[B,F][1,4]THIAZEPIN-11-AMINE (FORMULA VII)

A mixture of 2-(2-Nitrophenylthio) benzonitrile (16 g, 0.063 mol) and ethanol (200 ml) was heated to 50 °C and to this, a solution of anhydrous stannous chloride (39 g, 0.20 mol) in concentrated hydrochloric acid (60 mL) was added and stirred for 1 hour at reflux. The reaction mixture was concentrated under reduced pressure to yield title compound. (12.8 g. Yield: 90.0%)

EXAMPLE 5

PREPARATION OF 11-(4-T0SYLPIPERAZIN-1-YL) DIBENZO[B,F] [1,4]THIAZEPINE (FORMULA VIII):

A mixture containing dibenzo[b,f][1,4]thiazepin-11-amine (12 g, 0.053 mol), methylene chloride (80 mL), N,N-Bis-(2-chloroethyl)-4-methyl benzene sulfonamide (20.3 g, 0.068 mol) and triethyl amine (19 g, 0.19 mol) was stirred at room temperature for 3 hours. The reaction mixture was washed with water, dried over sodium sulfate and the solvent was removed under reduced pressure to afford the title compound. (22 g, Yield 92.8%).

EXAMPLE 6

PREPARATION OF 11-(PIPERAZIN-1-YL)DIBENZ0[B,F][1,4] THIAZEPINE

(FORMULA XI):

A mixture of 11-(4-tosylpiperazin-1-yl)dibenzo[b,f] [1,4]thiazepine (20 g, 0.045 mol) and 30% HBr in acetic acid (80 mL) were heated to 75°C and maintained for 4 hours for reaction completion. The mixture was cooled to room temperature, water (100 mL), toluene was added and layers were separated. The aqueous layer pH was adjusted to 10-11 with 20% aqueous acetic acid solution and the product was extracted in to methylene chloride (100 mL). Organic layer was concentrated under vacuum to yield the 11-(Piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (10.5 g, Yield: 80.0%).

EXAMPLE 7

PREPARATION OF 2-(2-(4-(DIBENZO[B,F][1,4]THIAZEPIN-11-YL)PIPERAZIN-1-YL)ETHOXY)ETHANOL (FORMULA I):

A mixture of 11-(Pipera2in-1-yl)dibenzo[b,f][1,4]thiazepine (6 g, 0.020 mol), toluene (20 mL) and Soda ash (3.3 g) were stirred for 3 hours at 40 °C. To this mixture, N-Methyl pyrrolidine (11 mL), Sodium iodide (0.5 g) and 2 chloroethoxy ethanol (2.7g) were added sequentially, stirred for 15 hours at 110 °C for reaction completion. The reaction mixture was cooled to room temperature, washed with water for three times( 3x40 mL). The organic layer was concentrated under reduced pressure to afford the title compound (6.6 g, Yield: 85.0%)

We Claim:

1. A process for the preparation of Quetiapine and its pharmaceutically acceptable salts thereof, comprising the steps of:

(a) Reaction of 2-mercapto benzoic acid of Formula II with 1-Chloro-2-nitrobenzene of Formula III to give 2-(2-nitrophenylthio)benzoic acid of Formula IV;

(b) conversion of the acid group in 2-(2-nitrophenylthio)benzoic acid of Formula IV to an amide to give 2-(2-Nitrophenylthio) benzamide of Formula V, which is treated with POCIato yield 2-(2-nitrophenylthio) benzonitrile of Formula VI;

(c) reaction of the nitrile compound of Formula VI with SnCb and HCI to get the
three member cyclic dibenzo[b,f][1,4]thiazepin-11-amine of Formula VII;

(d) reaction of the amine of Formula VII with N,N-bis(2-chloroethyl)-4-
methylbenzenesulfonamide to provide the tosylpiperazine derivative of 11-(4-tosylpiperazin-1-yl)dibenzo[b,f] [1,4] thiazepine of Formula VIII;

e) treatment of the tosylpiperazine derivative with hydrobromic acid in the presence of acetic acid to yield 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine of Formula IX;
and

f) finally reaction of the 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine of Formula IX with 2-chloroethoxy ethanol to yield Quetiapine;

g) optionally conversion of Quetiapine to its pharmaceutically acceptable salts.

2. The process of claim 1, wherein step a) is conducted in the presence of a base.

3. The process of claim 1, wherein the solvent used in step a) is water.

4. The process of claim 1, wherein the solvent used in step b) is aprotic polar solvent such as for example N, N-dimethylformamide, dimethylsulfoxide, N, N-dimethylacetamide.

5. The process of claim 1, wherein the solvent used in step b) is
dimethylfomiamide.

6. The process of claim 1, wherein quetiapine obtained in step f) is further
recrystallized in a solvent.