Claims:We Claim:
1. A telescopic process for the preparation of compound of Formula (V)

Formula (V)
or its salts, wherein the process comprising the steps of :

a) condensing the compound of Formula II,

Formula (II)
with compound of Formula (III)

Formula (III)
using a base in an aprotic solvent to obtain compound of Formula (IV)

Formula (IV)

b) optionally dilution with water and a non-polar solvent, and

c) hydrolyzing the compound of Formula (IV) using alkali hydroxide without isolating to obtain an intermediate compound of Formula (V)

Formula (V)
or its salts.

2. A telescopic process for the preparation of compound of Formula (V)

Formula (V)
or its salts, wherein the process comprising the steps of :

a) condensing the compound of Formula II,

Formula (II)
with compound of Formula (III)

Formula (III)
in presence of a base, in an aprotic solvent to obtain compound of Formula (IV), and

Formula (IV)

b) hydrolyzing the compound of Formula (IV) without isolating using a alkali hydroxide in water followed by acid treatment to adjust the pH between 1.0 to 7.0 to obtain compound of Formula (V)

Formula (V)
or its salts.
3. A telescopic process for the preparation of compound of Formula (V), wherein the compound of Formula (V) after hydrolysis using alkali hydroxide is isolated by extraction with an organic solvent after pH adjustment to 6-7.

4. The process as claimed in claim 3, wherein the organic solvent is selected from ethyl acetate, halogenated solvents such as dichloromethane.

5. The process as claimed in claims 1 to 2 wherein the base is selected from potassium carbonate, sodium carbonate, cesium carbonate.

6. The process as claimed in claims 1 to 3 wherein in the alkali hydroxide is selected from potassium hydroxide and sodium hydroxide.

7. The process as claimed in claims 1 to 2 wherein the aprotic solvents is selected from N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethyl sulfoxide, N-methyl pyrrolidine, xylene, monochlorobenzene, dichlorobenzne; ether solvents like di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol, dimethoxyethane and the like or the mixture thereof.

8. The process as claimed in claim 7, wherein the aprotic solvent is specifically selected from N,N-dimethyl formamide, dimethyl sulfoxide and tetrahydrofuran.

9. The process as claimed in claim 1, wherein the non-polar solvent is selected from benzene, toluene, xylene, hexane, and cyclohexane.

10. The process as claimed in claims 1 to 2, wherein the condensation of compound of Formula II and compound of Formula III is carried out at 75-150 oC.

11. The process as claimed in claims 1 to 3, wherein the hydrolyzation of compound of Formula (IV) is carried out in presence of alkali hydroxide at 100 oC for 4-24 hrs followed by addition of HCl to adjust the pH between 1.0 to 7.0.

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

Dated this Twenty Seventh (27th) day of December, 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)

A TELESCOPIC PROCESS FOR PREPARATION OF 2-(2-AMINOPHENYLTHIO)BENZOIC ACID OR ITS SALTS 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:

This application is a Patent of Addition to the Indian Patent Application No. 201941003930 filed on January 31, 2019 which is incorporated for reference.

FIELD OF THE INVENTION
The present invention relates to a telescopic process for the preparation of 2-(2-aminophenylthio) benzoic acid or its salts.

The present invention more particularly relates to a telescopic process for the preparation of 2-(2-aminophenylthio) benzoic acid of Formula (V)

Formula V
or its salts.

The present invention also relates to the use of 2-(2-aminophenylthio) benzoic acid or its salts in the preparation of dibenzothiazepine of Formula (I) and Quetiapine of Formula (Ia)

Formula (I) Formula (Ia)
or its salts.

BACKGROUND OF THE INVENTION
Quetiapine is a dibenzothiazepine 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 (t-BuOK or t-BuONa) 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 2-(2-aminophenylthio) benzoic acid or its salts with a commercially acceptable yield and high purity.
Conventionally, a telescopic process is a sequential one-pot synthesis with reagents added to a reactor one at a time and without work-up. In chemistry, one-pot synthesis is a strategy to improve the efficiency of a chemical reaction whereby a reactant is subjected to successive chemical reactions in just one reactor. This is much desired by chemists because avoiding a lengthy separation process and purification of the intermediate chemical compounds can save time and resources while increasing chemical yield.

None of the above prior art discloses a telescopic process for the preparation of 2-(2-aminophenylthio) benzoic acid of Formula (V)

Formula V
or its salts.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a telescopic process for preparation of 2-(2-aminophenylthio) benzoic acid or its salts.

In another objective of the present invention is to provide a telescopic process for the preparation of 2-(2-aminophenylthio) benzoic acid, which is commercially feasible / industrially scalable.

In another objective of the present invention is to provide a simple, economical and commercially feasible process for the synthesis of 2-(2-aminophenylthio) benzoic acid or its salts with a high yield and high purity.

In another objective of the present invention is to provide a telescopic process for preparation intermediate compounds that are useful in the preparation of dibenzothiazepine or 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 dibenzothiazepine of Formula (I) or Quetiapine of Formula (Ia) or its salts.

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

Formula (V)
or its salts, wherein the process comprising the steps of :

a) condensing the compound of Formula II,

Formula (II)
with compound of Formula (III)

Formula (III)
using a base in an aprotic solvent to obtain compound of Formula (IV)

Formula (IV)

b) optionally dilution with water and a non-polar solvent, and

c) hydrolyzing the compound of Formula (IV) without isolating to obtain an intermediate compound of Formula (V)

Formula (V)
or its salts.

In yet another aspect, the present invention provides a telescopic 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) without isolating compound of Formula (IV).

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

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a telescopic 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 a telescopic process for the preparation of intermediate compounds of Formula (V) without isolating the compound of Formula (IV).

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

The intermediate compound of Formula (V) is further converted to dibenzothiazepine or Quetiapine or its pharmaceutically acceptable salts in a number of steps by the methods known in the literature.

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

In an embodiment of the present invention, 2-aminobenzene thiol is reacted with 2-chlorobenzonitrile in presence of base in an aprotic solvent at 75-150oC to obtain 2-(2-aminophenylthio) benzoic acid compound of Formula (V) or its salts without isolating 2-(2-aminophenylthio) benzonitrile compound of Formula (IV) hydrolyzed in presence of alkali hydroxide at 100 oC for 4-24 hrs followed by addition of HCl to adjust the pH between 1.0 to 7.0.

The base used in the present invention is selected from potassium carbonate, sodium carbonate, cesium carbonate.

The alkali hydroxide used in the present invention is selected from potassium hydroxide and sodium hydroxide.

The reaction of compound of Formula II and compound of Formula III can be carried out an aprotic solvent solvents like N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethyl sulfoxide, N-methyl pyrrolidine, xylene, chlorobenzene, dichlorobenzene; ether solvents like di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol, dimethoxyethane and the like or the mixture thereof. An aprotic solvent used in the present invention is specifically selected from N,N-dimethyl formamide, dimethyl sulfoxide and tetrahydrofuran.

The non-polar solvent used in the present invention is selected from benzene, toluene, xylene, hexane, and cyclohexane.

In another proffered embodiment of the present invention, a telescopic process for the preparation of compound of Formula (V)

Formula (V)
or its salts, wherein the process comprising the steps of :

a) condensing the compound of Formula II,

Formula (II)
with compound of Formula (III)

Formula (III)
in presence of a base, in an aprotic solvent to obtain compound of Formula (IV),

Formula (IV)

b) optionally dilution with water and a non-polar solvent, and
c) hydrolyzing the compound of Formula (IV) without isolating using a base in water followed by acid treatment to adjust the pH between 1.0 to 7.0 to obtain compound of Formula (V)

Formula (V)
or its salts.

In another embodiment the compound of Formula (V) after hydrolysis is isolated by extraction with an organic solvent after pH adjustment to 6-7.

The organic solvent as used herein in selected from ethyl acetate, halogenated solvents such as dichloromethane

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

The process of the present invention is advantageous over the closest prior-art by way of high yielding, easy scale up in industrial scale, non-hazardous and environment friendly.

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.

EXAMPLES
Example 1: 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 and cooled to room temperature followed by dilution with 500 mL of water and 300 mL of toluene. Aqueous sodium hydroxide (prepared by dissolving 162.5 grams of sodium hydroxide in 575 mL of water) was added to the reaction mixture 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%)

Example 2: Synthesis of 2-(2-aminophenylthio) benzoic acid 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 and cooled to room temperature followed by dilution with 500 mL of water and 300 mL of toluene. Aqueous sodium hydroxide (prepared by dissolving 162.5 grams of sodium hydroxide in 575 mL of water) was added to the reaction mixture 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%)
Example 3: Synthesis of 2-(2-aminophenylthio) benzoic acid 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 grams of 2-chlorobenzonitrile and 108 grams potassium carbonate in 200 mL of DMSO. The reaction mixture was heated at about 85°C. Slowly add 100 grams 2-amniobenzenethiol to the above reaction mixture at about 85°C over the period of 1 hour. The reaction mixture was stirred for 4 hours and cooled to room temperature. Aqueous sodium hydroxide (prepared by dissolving 162.5 grams of sodium hydroxide in 575 mL of water) was added to the above reaction mixture at room temperature. The reaction mixture was heated to 100°C and stirred for about 12 hours. After completion of the reaction, cooled the reaction mixture to about 30°C, the pH of the aqueous layer adjusted to 6.0 to 7.0 with HCl, extracted the aqueous layer with 2 volumes of ethyl acetate thrice. Washed the organic layer with water; the resulting organic layer was concentrated to get residue. Aq.HCl was added to the residue to isolate solid. The solid thus obtained was filtered, and washed with water followed by dried to give the title compound (Yield: 168.4 gm, 75%).

Example 4: Synthesis of 2-(2-aminophenylthio) benzoic acid 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 grams of 2-chlorobenzonitrile and 108 grams potassium carbonate in 200 mL of DMSO. The reaction mixture was heated at about 85°C. Slowly add 100 grams 2-amniobenzenethiol to the above reaction mixture at about 85°C, over the period of 1 hour. The reaction mixture was stirred for 4 hours and cooled to room temperature. Aqueous sodium hydroxide (prepared by dissolving 162.5 grams of sodium hydroxide in 575 mL of water) was added to the above reaction mixture at room temperature. The reaction mixture was heated to 100°C and stirred for about 12 hours. After completion of reaction, the reaction mixture was cooled to about 30°C. Washed the reaction mixture with 1 volume of toluene twice and separated the organic layer. The pH of the aqueous layer adjusted to 1.0 to 2.0 with HCl. The reaction mixture was stirred for about 30 minutes. The solid thus obtained was filtered and washed with water followed by dried to give the title compound (Yield: 157.2 gm, 70%).

Example 5: Synthesis of 2-(2-aminophenylthio) benzoic acid 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 grams of 2-chlorobenzonitrile and 108 grams potassium carbonate in 200 mL of DMSO. The reaction mixture was heated at about 85°C. Slowly add 100 grams 2-amniobenzenethiol to the above reaction mixture at about 85°C, over the period of 1 hour. The reaction mixture was stirred for 4 hours and cooled to room temperature. Aqueous sodium hydroxide (prepared by dissolving 143.4 grams of sodium hydroxide in 575 mL of water) was added to the above reaction mixture at room temperature. The reaction mixture was heated to 100°C and stirred for about 12 hours. After completion 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 HCl. The reaction mixture was stirred for about 30 minutes. The solid thus obtained was filtered and washed with water followed by dried to give the title compound (Yield: 150 gm, 68.8%).

Example 6: Synthesis of 2-(2-aminophenylthio) benzoicacid Hydrochloride:

Experimental procedure with THF solvent:
In to 1000 mL round bottom flask equipped with mechanical stirrer and reflux condenser was charged with 106.5 grams of 2-chlorobenzonitrile and 108 grams potassium carbonate in 500 mL of THF. The reaction mixture was heated to reflux temperature (75°C). Slowly added 100 grams 2-amniobenzenethiol to the above reaction mixture at about 75°C over the period of 1 hour. The reaction mixture was stirred for 8 hours and cooled to room temperature. Aqueous sodium hydroxide (prepared by dissolving 162.5 grams of sodium hydroxide in 575 mL of water) was added to the above reaction mixture at room temperature. The reaction mixture was heated to 100°C and stirred for about 12 hours. After completion of reaction, the reaction mixture was cooled to about 30°C. Washed the reaction mixture with 1 volume of toluene twice and separated the organic layer. The pH of the aqueous layer was adjusted to 1.0 to 2.0 with HCl. The reaction mixture was stirred for about 30 minutes. The solid thus obtained was filtered and washed with water followed by dried to give the title compound (Yield: 128 gm, 57%).

Example 7: Synthesis of 2-(2-aminophenylthio) benzoicacid Hydrochloride:

Experimental procedure with THF solvent:
In to 1000 mL round bottom flask equipped with mechanical stirrer and reflux condenser was charged with 106.5 grams of 2-chlorobenzonitrile and 108 grams potassium carbonate in 500 mL of THF. The reaction mixture was heated to reflux temperature (75°C). Slowly added 100 grams 2-amniobenzenethiol to the above reaction mixture at about 75°C over the period of 1 hour. The reaction mixture was stirred for 8 hours and cooled to room temperature. Aqueous sodium hydroxide (prepared by dissolving 175.24 grams of sodium hydroxide in 575 mL of water) was added to the above reaction mixture at room temperature. The reaction mixture was heated to 100°C and stirred for about 12 hours. After completion 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 HCl. The reaction mixture was stirred for about 30 minutes. The solid thus obtained was filtered and washed with water followed by dried to give the title compound (Yield: 125 gm, 55.6%).