DESC:RELATED PATENT APPLICATION(S)

This application claims the priority to and benefit of Indian Patent Application No. 201741023547 filed on July 04, 2017; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Chlorthalidone and its intermediates thereof.

BACKGROUND OF THE INVENTION

Chlorthalidone is chemically known as a racemic mixture of 2-chloro-5-(1-hydroxy-3-oxo-1-isoindolinyl) benzene sulfonamide and is represented by the Formula I as mentioned below:

Chlorthalidone is a diuretic used in the treatment of hypertension and was first marketed in USA under the name of Hygroton by Sanofi. The product was first disclosed in the US Patent No. 3055904. The commercially efficient process for the preparation of Chlorthalidone was disclosed in the US Patent No. 4331600, as shown in Scheme I.

The publication Indian Journal of Chemistry 1988, Vol-27B, page 1045 by R.K Bansal, Girijesh Kumar, SK Jain and BK Puri, discloses the reaction of o-aroylbenzoic acid with hydroxylamine hydrochloride in the presence of sodium acetate in ethanol for 2 hours.

The major drawback of the process reported in the prior art is that the 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one (an intermediate to Chlorthalidone) obtained from the reaction mass has high impurities. Isolation of the pure product of 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one is cumbersome which leads to poor yield.

Therefore, there is a need for an improved process for the preparation of Chlorthalidone that is commercially efficient than the prior art processes.

SUMMARY OF THE INVENTION

The primary objective of the invention is to provide a process for the preparation of Chlorthalidone involving the steps of:
(i) reacting 2-(4’-chlorobenzoyl)benzoic acid of Formula-VI as mentioned below,

with hydroxylamine or its salts thereof in the presence of N,N-diisopropylethylamine and suitable solvent to obtain 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one of Formula-V as mentioned below,

(ii) treating 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one of Formula-V with zinc in the presence of acetic acid and suitable solvent to obtain 3-(4-chlorophenyl)-2,3-dihydro-1H-isoindol-1-one of Formula-IV as mentioned below,

(iii) treating 3-(4-chlorophenyl)-2,3-dihydro-1H-isoindol-1-one of Formula-IV with chlorosulfonic acid in presence of suitable solvent to obtain 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzene sulfonyl chloride of Formula-III as mentioned below,

(iv) treating 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzene sulfonyl chloride of Formula-III with ammonia in presence of suitable solvent to obtain 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzenesulfonamide of Formula-II as mentioned below,

(v) treating the 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzenesulfonamide of Formula-II with hydrogen peroxide in presence of a base to obtain Chlorthalidone of Formula-I.

Another aspect of the invention is to provide a process for the preparation of 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one of Formula-V as mentioned below,

involving the step of reacting 2-(4’-chlorobenzoyl)benzoic acid of Formula-VI as mentioned below,

with hydroxylamine or its salts thereof in the presence of N,N-diisopropylethylamine and suitable solvent.

Yet another aspect of the invention is to provide a process for the preparation of 3-(4-chlorophenyl)-2,3-dihydro-1H-isoindol-1-one of Formula-IV as mentioned below,

involving the step of treating 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one of Formula-V as mentioned below,

with zinc in the presence of ammonium chloride and suitable solvent.

In some embodiment, the compound of Formula-V is obtained from the compound of Formula-VI in presence of suitable polar solvent selected from the group comprising ethers such as tetrahydrofuran; esters such as ethyl acetate; ketones such as acetone; amides such as dimethylformamide; acetonitrile; dimethyl sulfoxide; alcohols such as ethanol, methanol, propanol, isopropanol, n-butanol; water or mixture thereof.

In some embodiment, the compound of Formula-IV is obtained from the compound of Formula-V in presence of suitable polar solvent selected from the group comprising ethers such as tetrahydrofuran; esters such as ethyl acetate; ketones such as acetone; amides such as dimethylformamide; acetonitrile; dimethylsulfoxide; alcohols such as ethanol, methanol, propanol, isopropanol, n-butanol; water or mixture thereof.

In some other embodiment, the compound of Formula-III is obtained from the compound of Formula-IV in presence of suitable solvent selected from the group comprising ketones such as acetone; chlorinated solvents such as dichloromethane and dichloroethane; acetonitrile; alcohols such as ethanol, methanol, propanol, isopropanol, n-butanol; or mixture thereof.

In some embodiment, the compound of Formula-II is obtained from the compound of Formula-III in presence of suitable solvent selected from the group comprising water miscible polar solvents such as dimethyl formamide, tetrahydrofuran, acetone, dioxane or the like; water or mixture thereof.

In some other embodiment, the compound of Formula-I is obtained from the compound of Formula-II in presence of suitable base selected from the group comprising of suitable alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or the like; or carbonates such as sodium carbonate, potassium carbonate or the like.

In some embodiment, the Chlorthalidone (Formula-I) obtained is further purified by recrystallization from mixture of isopropyl alcohol and water.

DETAILED DESCRIPTION OF THE INVENTION

The inventors of the present invention surprisingly found an improved process for the preparation of Chlorthalidone.

One aspect of the invention is to provide a process for the preparation of Chlorthalidone involving the steps of:
(i) reacting 2-(4’-chlorobenzoyl)benzoic acid of Formula-VI as mentioned below,

with hydroxylamine or its salts thereof in the presence of N,N-diisopropylethylamine and suitable solvent to obtain 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one of Formula-V as mentioned below,

(ii) treating 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one of Formula-V with zinc in the presence of acetic acid and suitable solvent to obtain 3-(4-chlorophenyl)-2,3-dihydro-1H-isoindol-1-one of Formula-IV as mentioned below,

(iii) treating 3-(4-chlorophenyl)-2,3-dihydro-1H-isoindol-1-one of Formula-IV with chlorosulfonic acid in presence of suitable solvent to obtain 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzene sulfonyl chloride of Formula-III as mentioned below,

(iv) treating 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzene sulfonyl chloride of Formula-III with ammonia in presence of suitable solvent to obtain 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzenesulfonamide of Formula-II as mentioned below,

(v) treating the 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzenesulfonamide of Formula-II with hydrogen peroxide in presence of a base to obtain Chlorthalidone of Formula-I.

Surprisingly, the inventors of the present application observed that the preparation of 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one of Formula-V as mentioned in step (i) by reacting 2-(4’-chlorobenzoyl)benzoic acid of Formula-VI with hydroxylamine or its salts thereof in the presence of N,N-diisopropylethylamine gave more yield in comparison to the yields obtained when the reaction was performed with bases such as pyridine, barium carbonate and sodium acetate.

The step (i) of the invented process, wherein the compound of Formula-V is obtained from the compound of Formula-VI, may be carried out in presence of suitable polar solvent selected from the group comprising ethers such as tetrahydrofuran; esters such as ethyl acetate; ketones such as acetone; amides such as dimethylformamide; acetonitrile; dimethyl sulfoxide; alcohols such as ethanol, methanol, propanol, isopropanol, n-butanol; water or mixture thereof.

The step (ii) of the invented process, wherein the compound of Formula-IV is obtained from the compound of Formula-V, may be carried out in presence of suitable polar solvent selected from the group comprising ethers such as tetrahydrofuran; esters such as ethyl acetate; ketones such as acetone; amides such as dimethylformamide; acetonitrile; dimethyl sulfoxide; alcohols such as ethanol, methanol, propanol, isopropanol, n-butanol; water or mixture thereof.

The step (iii) of the invented process, wherein the compound of Formula-III is obtained from the compound of Formula-IV, may be carried out in presence of suitable solvent selected from the group comprising ketones such as acetone; chlorinated solvents such as dichloromethane and dichloroethane; acetonitrile; alcohols such as ethanol, methanol, propanol, isopropanol, n-butanol or mixture thereof.

The step (iv) of the invented process, wherein the compound of Formula-II is obtained from the compound of Formula-III, may be carried out in presence of suitable solvent selected from the group comprising water miscible polar solvents such as dimethyl formamide, tetrahydrofuran, acetone, dioxane or the like; water or mixture thereof.

The treatment of 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzenesulfonamide of Formula-II with hydrogen peroxide in presence of a base to obtain Chlorthalidone of Formula-I in step (v) may be carried out in presence of suitable solvent selected from the group comprising of water miscible polar solvents such as dimethyl formamide, tetrahydrofuran, acetone, dioxane or the like; water or mixture thereof.

In some embodiment, base for the step (v), wherein the compound of Formula-I is obtained from the compound of Formula-II, may be selected from suitable alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or the like; or carbonates such as sodium carbonate, potassium carbonate or the like.

The oxygenatated products obtained in step (v) may be recovered from the aqueous reaction mixture using suitable techniques such as extraction or precipitation.

Second aspect of the invention is to provide a process for the preparation of 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one of Formula-V as mentioned below,

involving the step of reacting 2-(4’-chlorobenzoyl)benzoic acid of Formula-VI as mentioned below,

with hydroxylamine or its salts thereof in the presence of N,N-diisopropylethylamine and suitable solvent.

In some embodiment, the compound of Formula-V is obtained from the compound of Formula-VI in presence of suitable polar solvent selected from the group comprising ethers such as tetrahydrofuran; esters such as ethyl acetate; ketones such as acetone; amides such as dimethylformamide; acetonitrile; dimethylsulfoxide; alcohols such as ethanol, methanol, propanol, isopropanol, n-butanol; water or mixture thereof.

In some embodiment of the invention, there is provided a process for the preparation of Chlorthalidone which involves the step of reacting 2-(4’-chlorobenzoyl)benzoic acid of Formula-VI with hydroxylamine or its salts thereof in the presence of N,N-diisopropylethylamine to obtain 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one of Formula-V.

Third aspect of the invention is to provide a process for the preparation of 3-(4-chlorophenyl)-2,3-dihydro-1H-isoindol-1-one of Formula-IV as mentioned below,

involving the step of treating 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one of Formula-V as mentioned below,

with zinc in the presence of ammonium chloride and suitable solvent.

The inventors of the present invention found that the use of ammonium chloride instead of acetic acid for the preparation of 3-(4-chlorophenyl)-2,3-dihydro-1H-isoindol-1-one of Formula-IV by treatment of 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one of Formula-V with zinc was the simple and efficient in commercial scale.

In some embodiment of the invention, there is provided a process for the preparation of Chlorthalidone which involves the step of treating 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one of Formula-V with zinc in presence of ammonium chloride to obtain 3-(4-chlorophenyl)-2,3-dihydro-1H-isoindol-1-one of Formula-IV.
In some embodiment, the compound of Formula-IV is obtained from the compound of Formula-V in presence of suitable polar solvent selected from the group comprising ethers such as tetrahydrofuran; esters such as ethyl acetate; ketones such as acetone; amides such as dimethylformamide; acetonitrile; dimethyl sulfoxide; alcohols such as ethanol, methanol, propanol, isopropanol, n-butanol; water or mixture thereof.

In some embodiment, the Chlorthalidone (Formula-I) obtained is further purified by recrystallization from mixture of isopropyl alcohol and water.

The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.

EXAMPLES

Example-1: Preparation of 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one (Formula-V):

A mixture of 2-(4’-chlorobenzoyl)benzoic acid (500 g), hydroxylamine hydrochloride (266.6 g), N,N-diisopropyl ethylamine (371.9 g) and isopropyl alcohol (3000 ml) was stirred at 30°C. The reaction mixture was heated for 82.5°C and maintained at the same temperature. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 27°C. Water (3000 ml) was slowly added to the reaction mass at 27°C and stirred for about 2 hours at the same temperature. The resultant solid was filtered, washed with water (1000 ml) and dried to obtain the titled product. Yield: 470 g.

Example-2: Preparation of 3-(4’-chlorophenyl)-2,3-dihydro-1H-isoindol-1-one (Formula-IV):

To a mixture of ammonium chloride solution (Prepared by dissolving 170.2 g ammonium chloride in 820 ml water); tetrahydrofuran (4100 ml); and 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one (obtained from example-1, 410 g), zinc powder (312.1 g) was added portion-wise slowly at 50°C. The reaction mixture was heated to 62.5°C and maintained at 62.5°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 52.5°C and filtered at 50°C. Water (9840 ml) was slowly added to the resultant filtrate at a temperature of 40°C and cooled to 25°C. The cooled contents were stirred for 2 hours at 25°C. The resultant solid was filtered, washed with aqueous hydrochloric acid (3280 ml water mixed with 820 ml concentrated hydrochloric acid), washed with water (820 ml) and dried to obtain the titled product. Yield: 328 g.

Example-2a: Preparation of 3-(4’-chlorophenyl)-2,3-dihydro-1H-isoindol-1-one (Formula-IV):
To a mixture of acetic acid (4100 ml), 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one (obtained from example-1, 410 g) and water (410 ml), zinc powder (312.1 g) was added portion-wise slowly at 50°C. The reaction mixture was heated to 62.5°C and maintained at 62.5°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was filtered at 60°C and washed with acetic acid (820 ml) at the same temperature. The filtrate was cooled to 30°C. Water (7380 ml) was slowly added to the resultant filtrate at a temperature of 35°C and cooled to 25°C. The cooled contents were stirred for 2 hours at 25°C. The resultant solid was filtered, washed with water (1230 ml) and dried to obtain the titled product. Yield: 360 g.

Example-3: Preparation of 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzene sulfonamide (Formula-II):

Step (a): Preparation of 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzene sulfonyl chloride (Formula-III): The compound 3-(4’-chlorophenyl)-2,3-dihydro-1H-isoindol-1-one (obtained from example-2, 50 g) was slowly added to chlorosulfonic acid (250 g) at 30°C. The reaction mixture was heated to 78°C and maintained at the same temperature. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 25°C. The cooled reaction mass was added to cooled water (1000 ml) at 5°C and stirred for 2 hours at 12°C. The resultant solid was filtered, washed with water (300 ml) and dried to obtain the compound of Formula-III.

Step (b): Preparation of 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzene sulfonamide (Formula-II): The product obtained in step (a) 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzene sulfonyl chloride was added to acetone (250 ml) and cooled to 12.5°C. Ammonia (100 ml) was slowly added to the reaction mixture at 12.5°C and maintained the same temperature. The progress of the reaction was monitored by HPLC. After completion of the reaction, water (250 ml) was added into the reaction mass followed by a slow addition of concentrated hydrochloric acid (75 ml). The contents were then stirred for 2 hours at 12.5°C and the resultant solid was filtered, washed with water (250 ml) and dried to obtain the compound of Formula-II. Yield: 42.5 g.

Example-4: Preparation of Chlorthalidone (Formula-I):

To a cooled mixture of 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzenesulfonamide (obtained in example-3, 225 g), sodium hydroxide (69.71 g), water (2250 ml), and hydrogen peroxide (158 g) was slowly added at 27.5°C and maintained at the same temperature. The progress of the reaction was monitored by HPLC. After completion of the reaction, the pH of the reaction mass was adjusted to 3-5 with concentrated hydrochloric acid and stirred for 2 hours at 27.5°C. The resultant solid was filtered, washed with water (1125 ml) and dried to obtain Chlorthalidone. Yield: 198 g.

Example-5: Purification of Chlorthalidone (Formula-I):

A mixture of Chlorthalidone (150 g), isopropyl alcohol (1500 ml) and water (450 ml) was heated to 75°C and then cooled to 55°C. Activated charcoal (15 g) was added to the cooled contents at 55°C and stirred for 1 hour at the same temperature. The contents were filtered through micron filter at 50°C. The filtrate was heated at 75°Cand then cooled to 12.5°C. Then the contents were stirred for 2 hours and 30 minutes at 12.5°C and the resultant solid was filtered, washed with isopropyl alcohol (150 ml) and dried to obtain the purified Chlorthalidone. Yield: 106 g.
,CLAIMS:

1. A process for the preparation of Chlorthalidone of Formula-I comprising the steps of:

(i) reacting 2-(4’-chlorobenzoyl)benzoic acid of Formula-VI

with hydroxylamine or its salts thereof in the presence of N,N-diisopropylethylamine and suitable solvent to obtain 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one of Formula-V;

(ii) treating 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one of Formula-V with zinc in the presence of acetic acid and suitable solvent to obtain 3-(4-chlorophenyl)-2,3-dihydro-1H-isoindol-1-one of Formula-IV;

(iii) treating 3-(4-chlorophenyl)-2,3-dihydro-1H-isoindol-1-one of Formula-IV with chlorosulfonic acid in presence of suitable solvent to obtain 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzene sulfonyl chloride of Formula-III;

(iv) treating 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzene sulfonyl chloride of Formula-III with ammonia in presence of suitable solvent to obtain 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzenesulfonamide of Formula-II; and

(v) treating the 2-chloro-5-(2,3-dihydro-3-oxo-1H-isoindol-1-yl)-benzenesulfonamide of Formula-II with hydrogen peroxide in presence of a base to obtain Chlorthalidone of Formula-I.

2. A process for the preparation of 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one of Formula-V

said process comprising the step of reacting 2-(4’-chlorobenzoyl)benzoic acid of Formula-VI

with hydroxylamine or its salts thereof in the presence of N,N-diisopropylethylamine and suitable solvent.

3. A process for the preparation of 3-(4-chlorophenyl)-2,3-dihydro-1H-isoindol-1-one of Formula-IV

said process comprising the step of treating 4-(4’-chlorophenyl)-1H-2,3-benzoxazin-1-one of Formula-V

with zinc in the presence of ammonium chloride and suitable solvent.

4. The process as claimed in the step (i) of claim 1 or claim 2, wherein the suitable solvent is a polar solvent selected from the group comprising ethers such as tetrahydrofuran; esters such as ethyl acetate; ketones such as acetone; amides such as dimethylformamide; acetonitrile; dimethylsulfoxide; alcohols such as ethanol, methanol, propanol, isopropanol, n-butanol; water or mixture thereof.

5. The process as a claimed in the step (ii) of claim 1 or claim 3, wherein the suitable solvent is a polar solvent selected from the group comprising ethers such as tetrahydrofuran; esters such as ethyl acetate; ketones such as acetone; amides such as dimethylformamide; acetonitrile; dimethylsulfoxide; alcohols such as ethanol, methanol, propanol, isopropanol, n-butanol; water or mixture thereof.

6. The process as claimed in step (iii) of claim 1, wherein the suitable solvent is selected from the group comprising ketones such as acetone; chlorinated solvents such as dichloromethane and dichloroethane; acetonitrile; alcohols such as ethanol, methanol, propanol, isopropanol, n-butanol; or mixture thereof.

7. The process as claimed in the step (iv) of claim 1, wherein the suitable solvent is selected from the group comprising water miscible polar solvents such as dimethyl formamide, tetrahydrofuran, acetone, dioxane or the like; water or mixture thereof.

8. The process as claimed in the step (v) of claim 1, wherein the said base is selected from the group comprising of suitable alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or the like; or carbonates such as sodium carbonate, potassium carbonate or the like.

9. The process as claimed in claim 1, wherein the Chlorthalidone obtained is further purified by recrystallization from mixture of isopropyl alcohol and water.