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

The present invention relates to an improved process for the preparation of dibenzothiazepinone compounds of formula I, a key intermediate for the synthesis of Quetiapine.

Formula-I

BACKGROUND OF THE INVENTION
Quetiapine is a tetracyclic antipsychotics compound with a chemical name of 2-(2-(4-dibenzo[b,f][1,4]thiazepine-11-yl-1-piperazinyl)ethoxy)ethanol. The molecular structure of Quetiapine is represented as follows

Dibenzo[b,f][l,4]thiazepine-11-(10H)-one of formula (I) is the key intermediate in the synthesis of antipsychotic agent Quetiapine and pharmaceutically active salts thereof. The process for the preparation of dibenzo[b,f][l,4]thiazepine-11-(10H)-oneis well disclosed in prior art.
The process of dibenzo[b,f][l,4]thiazepine-11-(10H)-one or its analogues are well disclosed in prior art. Some of the reported literature are Helv. Chim. Acta 42,1265,1959, Helv. Chim. Acta 48, 336, 1965, J. Med. Chem. 44, 372, 2001, Chinese Journal of New Drugs 2007,16, 867-868, EP0240228, EP 0282236, EP0536400, EP0583317, WO199219607, WO2001004106, WO2004047722, WO2007102352, WO2011121602, CN103772319, CN103788014, CN104447615, CN104177311, CN104016945, CN105859653, IN2007CH00365,IN2008CHE1370, IN2008DN07167, IN2008MU00821, IN2009CHE3075, IN2010CHE859, IN2010KN03559, IN2011CH03376, IN201941003930 and IN201943054236.

All the process described in above publications are suffering from one or more disadvantages such as use of hazardous and expensive raw material, generation of lot of acidic waste, poor yields, commercially nor viable etc., Thus, there is a need to develop an alternative and improved process for the preparation of derivatives is highly desired.

The present invention is to provide a simple, economical and commercially feasible process for the synthesis of dibenzo[b,f][l,4]thiazepine-11-(10H)-one or its salts with a commercially acceptable yield and high purity.

OBJECT OF THE INVENTION:
The main objective of the present invention is to provide a process for preparation of Quetiapine intermediates.

Another objective of the present invention is to provide an improved and eco-friendly process for the preparation of dibenzo[b,f][l,4]thiazepine-11-(10H)-one, compound of formula-I.
In an another objective of the present invention is to provide an improved process for the preparation of dibenzo[b,f][l,4]thiazepine-11-(10H)-one by limiting the use of various solvents.

Further objective of the present invention is to provide an improved process for the preparation of dibenzo[b,f][l,4]thiazepine-11-(10H)-one in good yield and purity.

SUMMARY OF THE INVENTION
The present invention is to provide a process for preparation of dibenzo[b,f][l,4]thiazepine-11-(10H)-one a compound of formula I, or pharmaceutically acceptable salts thereof, which comprises steps of

Formula-I

a) treating the benzothiazole with base and acid to form 2-aminobenzenethiol
b) condensation of 2-aminobenzenethiol with 2-chloro benzonitrile, in absence of solvent and phase transfer catalyst to give 2-(2-aminopenylthio)benzo nitrile.
(or)
condensation of 2-aminobenzenethiol with 2-chloro benzonitrile, in presence of solvent, base and optionally in presence of phase transfer catalyst to give 2-(2-aminopenylthio)benzo nitrile.
c) hydrolysis of optionally isolating the step-(b) in presence of base and acid to form 2-(2-amino phenyl thio) benzoic acid hydrochloride.
d) cyclization of 2-(2-amino phenyl thio) benzoic acid hydrochloride in presence of acid and suitable solvents to form dibenzo[b,f] [1,4] thiazepin-11(10H)-one.
DETAILED DESCRIPTION OF THE INVENTION
The first aspect of the present invention provides an improved process for the preparation of dibenzo[b,f] [1,4] thiazepin-11(10H)-one of compound of formula-1.

Formula-I
a) treating the benzothiazole with base and acid to form 2-aminobenzenethiol
b) condensation of 2-aminobenzenethiol with 2-chloro benzonitrile, optionally in presence of solvent and base (or) phase transfer catalyst to give 2-(2-aminopenylthio)benzo nitrile.
c) hydrolysis of optionally isolating the step-(b) in presence of base and acid to form 2-(2-amino phenyl thio) benzoic acid hydrochloride.
d) cyclization of 2-(2-Amino phenyl thio) benzoic acid hydrochloride in presence of acid and suitable solvents to form dibenzo[b,f] [1,4] thiazepin-11(10H)-one.

The process of the present invention can be represented schematically as follows

Scheme-1

The ‘‘base’’ used in the present invention can be selected from but not limited to "inorganic bases" selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; ammonia; organic bases’’ like "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; dimethylamine, diethylamine, diisopropyl mine, diisopropylethylamine (DIPEA), diisobutylamine, trimethylamine, triethylamine, triisopropylamine, tributylamine, tert.butyl amine, pyridine, piperidine, 4-dimethylamino pyridine (DMAP), quinoline, imidazole, N-methylimidazole, l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), dimethylaniline, N-methylmorpholine (NMM), l,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine and the like; more preferably inorganic base.

The “acid” used in the present invention can be selected from but not limited to inorganic acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid and the like; organic acid such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, trifluoromethane sulfonic acid, p-toluenesulfonic acid, tartaric acid, mandelic acid, malic acid, oxalic acid, formic acid, ascorbic acid, phosphorous acid, maleic acid, succinic acid, malonic acid, oxalic acid, dibenzoyl tartaric acid, lactic acid, cinnamic acid and the like

The solvent is selected from water, hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid and the like or mixture of any of the afore mentioned solvents.

The phase transfer catalyst used in present invention is selected from TBAB, TBAI, Tetrabutyl ammonium sulfate, TBAC, Tetra phenylphosphoniumbromide.,

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

Example: 1
Step-(a) Preparation of 2-aminobenzenethiol (Formula-a)
Benzo[d]thiazole (100.0 gm) was added to mixture of sodium hydroxide (70.0 gm) in water (170 mL) at 25 0C. The reaction mixture was heated to 1000C and maintained for 12 to 16 h. After completion of reaction (by TLC), reaction mixture was diluted with water and pH adjusted to 6 to 6.5 with acetic acid to get the crude title compound (92.0 gm). This crude compound used for next reaction directly.

Step-b; 2-((2-aminophenyl)thio)benzonitrile (Formula-b)
2-aminobenzenethiol from the example-1 (a) (90.0 g) was slowly added to a mixture of dimethylformamide (160 mL) and potassium carbonate (87.0 gm) at 30 oC. Reaction mixture was heated to 80 oC and maintained for 15 minutes. 2-chlorobenzonitrile (86.0 gm) was added to reaction mixture at 80oC and maintained for 4 h. After completion of the reaction (by TLC), reaction mixture was diluted with water and extracted with ethyl acetate and concentrated. This crude compound was co-distilled with methanol to give 150.0 gm of 2-((2-aminophenyl)thio)benzonitrile.
DSC: 91.8 oC

Example-2: 2-((2-aminophenyl)thio)benzonitrile (Formula-b)
2-aminobenzenethiol (90.0 g) was slowly added to a mixture of dimethylformamide (160 mL) and K2CO3 (87.0 gm) at 30 0C. Reaction mixture was heated to 80 0C and maintained for 15 minutes. 2-chlorobenzonitrile (86.0 gm) and Tetrabutyl ammonium bromide (cat) was added to reaction mixture at 80 0C and maintained for 4 h. After completion of the reaction (by TLC), reaction mixture was diluted with water and extracted with ethylacetate and concentrated. This crude compound was co-distilled with methanol to give 170.0 gm of 2-((2-aminophenyl)thio)benzonitrile

Example-3: 2-((2-aminophenyl)thio)benzonitrile (Formula-b)
2-aminobenzenethiol (90.0 g) was slowly added to a mixture of dimethylformamide (160 mL) and Na2CO3 (87.0 gm) at 30 0C. Reaction mixture was heated to 80 0C and maintained for 15 minutes. 2-chlorobenzonitrile (86.0 gm) and Tetrabutyl ammonium bromide (cat) was added to reaction mixture at 80 0C and maintained for 4 h. After completion of the reaction (by TLC), reaction mixture was diluted with water and extracted with ethylacetate and concentrated. This crude compound was co-distilled with methanol to give 120.0 gm of 2-((2-aminophenyl)thio)benzonitrile.

Example-4: 2-((2-aminophenyl)thio)benzonitrile (Formula-b)
2-aminobenzenethiol (90.0 g) was slowly added to a mixture of dimethylformamide (160 mL) and NaHCO3 (87.0 gm) at 30 0C. Reaction mixture was heated to 80 0C and maintained for 15 minutes. 2-chlorobenzonitrile (86.0 gm) and Tetrabutyl ammonium bromide (cat) was added to reaction mixture at 80 0C and maintained for 4 h. After completion of the reaction (by TLC), reaction mixture was diluted with water and extracted with ethylacetate and concentrated. This crude compound was co-distilled with methanol to give 50.0 gm of 2-((2-aminophenyl)thio)benzonitrile.

Example-5: 2-((2-aminophenyl)thio)benzoic acid (Formula-c)
To a stirred solution of 2-((2-aminophenyl)thio)benzonitrile (100.0 gm) in water (300 mL) was added sodium hydroxide (40.0 gm) at 25 0C. Reaction mixture was heated to 100 0C and maintained for 12 hr. After completion of reaction mass (by TLC), acidified with HCl at 5 0C and filtered to obtained 95.0 gm of 2-((2-aminophenyl)thio)benzoic acid hydrochloride.

Example-6: Dibenzo[b,f][1,4]thiazepin-11(10H)-one (Formula-I)
To a stirred solution of 2-((2-aminophenyl)thio)benzoic acid hydrochloride. (100.0 gm) in monochlorobenzene (300 mL) was added PTSA (2.0 gm) at room temperature. Reaction mass was heated to 130 oC and maintained for 12 h. After completion of the reaction (by TLC), reaction mass cooled to room temperature and maintained for 3 h and solid was filtered. This solid was stirred with water and filtered and washed with methanol to obtained Dibenzo[b,f][1,4]thiazepin-11(10H)-one( 88.0 gm). , Claims:We claim:
1. A process for the preparation of dibenzo[b,f] [1,4] thiazepin-11(10H)-one of compound of formula-1, or pharmaceutically acceptable salts thereof, which comprises steps of

Formula-I
a) treating the benzothiazole with base and acid to form 2-aminobenzenethiol
b)condensation of 2-aminobenzenethiol with 2-chloro benzonitrile, in presence of phase transfer catalyst and in absence of solvent, base to give 2-(2-aminopenylthio)benzonitrile.
(or)
condensation of 2-aminobenzenethiol with 2-chloro benzonitrile, in presence of solvent, base and optionally in presence of phase transfer catalyst to give 2-(2-aminopenylthio)benzonitrile.
c) hydrolysis of optionally isolated step-(b) in presence of base and acid to form 2-(2-amino phenyl thio) benzoic acid hydrochloride.
d) cyclization of 2-(2-amino phenyl thio) benzoic acid hydrochloride in presence of acid and suitable solvents to form dibenzo[b,f] [1,4] thiazepin-11(10H)-one.

2. The process according to claim-1, wherein base in step-a, b & c is selected from inorganic base and acid in step-a & d is selected from organic acid.

3. The process according to claim-1, wherein suitable solvent in step-b is selected from polar-aprotic solvents.

4. The process according to claim-1, wherein acid in step-c is selected from inorganic acid.

5. The process for preparation of dibenzo[b,f] [1,4] thiazepin-11(10H)-one of compound of formula-1, comprises steps of

Formula-I
a) treating the benzothiazole with inorganic base and organic acid to form 2-aminobenzenethiol
b) condensation of 2-aminobenzenethiol with 2-chloro benzonitrile, in presence of phase transfer catalyst and in absence of solvent, base followed by isolation with suitable ester solvent
(or)
condensation of 2-aminobenzenethiol with 2-chloro benzonitrile, in presence of polar aprotic solvent, inorganic base and optionally in presence of phase transfer catalyst and followed by isolation with suitable ester solvent give 2-(2-aminopenylthio)benzo nitrile.

6. The process according to claim-5, wherein dibenzo[b,f] [1,4] thiazepin-11(10H)-one of compound of formula-1, comprises steps of
a) treating the benzothiazole with sodium hydroxide and acetic acid to form 2-aminobenzenethiol
b) condensation of 2-aminobenzenethiol with 2-chloro benzonitrile, in presence of phase transfer catalyst and followed by isolation with suitable ester solvent to give 2-(2-aminopenylthio)benzo nitrile.

7. The process according to claim-5,wherein dibenzo[b,f] [1,4] thiazepin-11(10H)-one of compound of formula-1, comprises steps of
a) treating the benzothiazole with sodium hydroxide and acetic acid to form 2-aminobenzenethiol
b) condensation of 2-aminobenzenethiol with 2-chloro benzonitrile, in presence of polar aprotic solvent, inorganic base and optionally in presence phase transfer catalyst followed by isolation with suitable ester solvent to give 2-(2-aminopenylthio)benzo nitrile.

8. The process according to claim-5, polar aprotic solvent selected from dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) more preferably dimethyl formamide and ester solvent selected from methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate; more preferably ethyl acetate.

9. The process of dibenzo[b,f] [1,4] thiazepin-11(10H)-one of compound of formula-1, according to claim-1, comprises steps of
c) hydrolysis of isolated stage-b, in presence of inorganic base and inorganic acid to form 2-(2-amino phenyl thio) benzoic acid hydrochloride.
d) cyclization of 2-(2-Amino phenyl thio) benzoic acid hydrochloride in presence of organic acid and suitable aromatic chlorinated solvent to give dibenzo[b,f] [1,4] thiazepin-11(10H)-one.

10. The process for the preparation of dibenzo[b,f] [1,4] thiazepin-11(10H)-one of compound of formula-1, according to claim-1, is used to prepare Quetiapine and its salts thereof.