Claims:
We claim:
1. An improved process for the preparation of compound of Formula (V)

Formula (V)
or its salts
wherein the process comprises the steps of
a) condensing the compound of Formula II,

Formula (II)
with compound of Formula (III), and

Formula (III)
b) to obtain directly an intermediate compound of Formula (V)

Formula (V)
or its salts
without isolating the compound of Formula (IV) formed as intermediate.

Formula (IV)

2. The process of claim 1,wherein the condensation of compound of Formula II and compound of Formula III is carried out in high boiling solvent like dimethyl formamide, dimethyl sulfoxide, N,N-Dimethyl acetamide, N-methyl pyrrolidine more preferably dimethyl formamide.

3. The process as claimed in claim 1, wherein the reaction is carried out in single pot.

4. The process of claim 2, wherein the reaction is carried out at 65-100 oC for about 1-2 hrs.

5. The process of claim 2, wherein the solvent used for isolation is toluene.

6. The process of claim 1, wherein the compound of Formula (V) is further converted to Quetiapine or its pharmaceutically acceptable salts.

Dated this Thirty First (31st) day of January, 2019

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883
, Description:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

PROCESS FOR PREPARATION OF QUETIAPINE INTERMEDIATES AND USE THEREOF

We, SREENI LABS PRIVATE LIMITED.,
a company incorporated under the companies act, 1956 having address at
Sy.No.124/P, Plot No.24, 25, 26, IDA- Industrial Development Area, Nacharam, Secunderabad, 500076, Telangana, INDIA.

The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of antipsychotic agent intermediates.

The present invention particularly relates to a process for the preparation of Quetiapine intermediates.

The present invention relates to a process for the preparation of Quetiapine intermediates compound of Formula (V)

Formula V
or its salts.

The present invention relates to the use of Quetiapine intermediate compounds in the preparation of Quetiapine Formula I or

Formula I
or its salts.

BACKGROUND OF THE INVENTION
Quetiapine is a dibenzodiazepine derivative indicated for the treatment of schizophrenia, psychiatric conditions such as hallucinations, delusions, hostility and other bipolar disorder. It is chemically described as 2-[2-(4-dibenzo[b,f]1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]ethanol fumarate (2:1) and its molecular formula is C42H50N6O4S2.C4H4O4 having the structure or formula (Ia)

Formula Ia

Quetiapine hemifumarate was first described, for example, in patent publication US 4,879,288 which discloses a process for the preparation of Quetiapine and the synthesis of quetiapine hemifumarate as follows:

US 5,399,703 discloses the process for the preparation of 2-(2-aminophenylthio) benzonitrile compound as shown below :

In this patent 2-aminobenzenethiol in DMF was treated with chlorobenzonitrile in presence of K2CO3 followed by extraction with ethyl acetate. The residue was crystallised from n-hexane-isopropyl ether.

US 5,589,474 discloses a process for the preparation of 2-(2-aminophenylthio) benzoic acid as follows:

US 7,214,793 B2 issued to SK Corp, claims a process for the preparation of Quetiapine intermediate as shown in the scheme given below:

CN 103304515 A assigned to Univ East China, claims a process for the preparation of Quetiapine intermediate as shown in the scheme below

IN 3075/CHE/2009 A assigned to Dr. Reddy’s Laboratories limited shows the preparation of Quetiapine which is depicted below:

US 8,420,807 B2 discloses a method for preparation of dibenzo[b,f][1,4] thiazepin-11-ylamine include the use of K2CO3 in the first step and potassium or sodium tert-butoxide (tBuOK or tBuONa) in the second step to avoid the use of sodium hydride all together. Also other halogenobenzonitriles like 2-chloro-, 2-bromo- or 2-iodobenzonitrile can be used as starting materials. In addition to the first two steps and further the formation of the acid addition salt can be perfomed in a one-pot fashion using dimethylformamide, tetrahydrofuran, toluene or a mixture thereof as a solvent.

The present invention is to provide a simple, economical and commercially feasible process for the synthesis of Quetiapine intermediates with a commercially acceptable yield and high purity.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a process for preparation of Quetiapine intermediates.

In another objective of the present invention is to provide a process for the preparation of Quetiapine intermediates, which is commercially feasible / industrially scalable.

It is therefore an object of the present invention to provide a simple, economical and commercially feasible process for the synthesis of Quetiapine intermediates with a high yield and high purity.

In another objective of the present invention is to provide a process for preparation intermediate compound that are useful in the preparation of Quetiapine that gives high yield and high purity.

In another preferred objective of the present invention is to provide the use of intermediate compounds in the preparation of Quetiapine of Formula (I) or its salts.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of compound of Formula (V)

Formula (V)
or its salts

wherein the process comprises the steps of
a) condensing the compound of Formula II,

Formula (II)
with compound of Formula (III),

Formula (III)
b) to obtain directly an intermediate compound of Formula (V)

Formula (V)
or its salts, and
without isolating the compound of Formula (IV) formed as intermediate.

Formula (IV)

In yet another aspect, the present invention provides an improved process for the preparation of compound of Formula (V) which comprises condensation of the compound of Formula II and compound of Formula (III) to give compound of Formula (V).

In yet another aspect, the present invention provides the use of compound of Formula V in the preparation of Quetiapine or its pharmaceutically acceptable salts

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of intermediate compound of Formula (V) by condensation of compounds of Formula (II) and Formula (III).

The present invention also provides an improved process for the preparation of intermediate compounds of Formula (V) without isolating the compound of Formula (IV)

The present invention also provides process for the preparation of intermediate compound of Formula (IV) and compound of formula (V). The intermediate compounds of Formula (IV) is not isolated.

The above compound of Formula (V) may be isolated as salts or free bases.

The intermediate compound of Formula (V) is further converted to Quetiapine or its pharmaceutically acceptable salts in a number of steps.

The preparation of intermediate compound of Formula (V) is shown in the given scheme below:

In an embodiment of the present invention, the 2-aminobenzene thiol is reacted with 2-chlorobenzonitrile in presence of bases such as potassium carbonate, sodium carbonate in an aprotic solvent like dimethyl formamide at 80-85oC to obtain 2-(2-aminophenylthio) benzonitrile which is not isolated. The formed 2-(2-aminophenylthio) benzonitrile was hydrolyzed in-situ in presence of aq. NaOH at 100 oC for 10-12 hrs followed by addition of HCl (pH 2) to obtain 2-(2-aminophenylthio) benzoic acid The compound of Formula V is extracted in toluene.

The 2-chlorobenzonitrile and potassium carbonate in N,N-dimethylformamide is heated to about 85 oC followed by slow addition of 2-aminobenzenthiol to the above reaction mixture over a period of 1 hr. The reaction mixture is stirred for 4 hrs. After completion of reaction, the reaction mixture is cooled to room temperature and diluted with water and toluene. The organic layer was separated and aqueous layer was extracted with toluene. The combined organic layer is separated and aqueous layer is extracted with toluene to obtain crude 2-(2-anibophenylthio) benzonitrile. Aqueous sodium hydroxide is added to crude 2-(2-anibophenylthio) benzonitrile at room temperature. The reaction mixture is heated to 100 oC and stirred for 12 hrs. After completion of the reaction mixture, the reaction mixture is cooled at room temperature and pH of the reaction mixture is adjusted to 1.0 to 2.0 with hydrochloric acid. The solid obtained is filtered.

The reaction of compound of Formula II and compound of Formula III can be carried out in other high boiling solvents like N,N-Dimethyl acetamide, Dimethyl sulfoxide, N-methyl pyrrolidine and the like or the mixture thereof. The preferred solvent is N,N-Dimethyl formamide

The obtained compound of Formula (V) is converted to Quetiapine or its pharmaceutically acceptable salts by known methods.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. 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.

Example 1:
2-(2-aminophenylthio) benzoic acid Hydrochloride RoS

Synthesis of 2-(2-aminophenylthio) benzoic acid Hydrochloride: Experimental procedure with DMF solvent
In to 1000 mL round bottom flask equipped with mechanical stirrer and reflux condenser was charged with 106.5 gms of 2-chlorobenzonitrile and 108 gms potassium carbonate in 200 mL of N, N-dimethylformamide. The reaction mixture was heated at about 85°C. Slowly 100 grams 2-amniobenzenethiol was added to the above reaction mixture at about 85°C over the period of 1 hour. The reaction mixture was stirred for 4 hours. After completion of reaction, the reaction mixture was cooled to room temperature and diluted with 500 mL of water and 300 mL of toluene. The organic layer was separated and aqueous layer was extracted with toluene. The combined organic layer was washed with water and organic layer was concentrated at a temperature about 65°C under reduced pressure to obtain crude compound of 2-(2-aminophenylthio) benzonitrile. Aqueous sodium hydroxide (prepared by dissolving 162.5 grams of sodium hydroxide in 575 mL of water) was added to a crude compound of 2-(2-aminophenylthio)benzonitrile at room temperature. The reaction mixture was heated to 100°C and stirred for about 12 hours. After completion of reaction of reaction, the reaction mixture was cooled to about 30°C. The pH of the reaction mixture adjusted to 1.0 to 2.0 with 6N HCl. The reaction mixture was stirred for about 30 minutes. The solid thus obtained was filtered, washed with water and dried to give the title compound (Yield: 160 gm, 71%)

Synthesis of 2-(2-aminophenylthio) benzoicacid Hydrochloride: Experimental procedure with DMSO solvent:
In to 1000 mL round bottom flask equipped with mechanical stirrer and reflux condenser was charged with 106.5 gms of 2-chlorobenzonitrile and 108 gms potassium carbonate in 200 mL of DMSO. The reaction mixture was heated at about 85°C. Slowly 100 grams of 2-amniobenzenethiol was added to the above reaction mixture at about 85°C over the period of 1 hour. The reaction mixture was stirred for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with 500 mL of water and 300 mL of toluene. The organic layer was separated and aqueous layer was extracted with toluene. The combined organic layer were washed with water and organic layer was concentrated at a temperature about 65°C under reduced pressure to obtain crude compound of 2-(2-aminophenylthio) benzonitrile. Aqueous sodium hydroxide (prepared by dissolving 162.5 grams of sodium hydroxide in 575 mL of water) was added to a crude compound of 2-(2-aminophenylthio)benzonitrile at room temperature. The reaction mixture was heated to 100°C and stirred for about 12 hours. After completion of reaction of reaction, the reaction mixture was cooled to about 30 °C. The pH of the reaction mixture was adjusted to 1.0 to 2.0 with 6N HCl. The reaction mixture was stirred for about 30 minutes. The solid thus obtained was filtered, washed with water and dried to give the title compound (Yield: 146 gm, 65%).