DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of Indian provisional patent application No. 201741007242 filed on March 01, 2017.
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of chlorthalidone.
BACKGROUND OF THE INVENTION
The chemical name of chlorthalidone is 3-hydroxy-3-(3'-sulfamyI-4'-chlorophenyl)phthalimidine and is represented by the structural formula 1 shown below.

Formula 1
Chlorthalidone is used to treat high blood pressure and fluid retention caused by various conditions, including heart disease. Chlorthalidone also may be used to treat patients with diabetes insipidus and certain electrolyte disturbances and to prevent kidney stones in patients with high levels of calcium in their blood. Chlorthalidone is a valuable pharmaceutical and has been recently prescribed for use in combination with other anti-hypertensive agents.
Chlorthalidone, its related compounds and their methods of preparation were first disclosed in Helv. Chim. Acta 42, 1085, (1959) and also in United States Patent No. 3,055,904.
United States Patent No. 4,331,600 and International Patent Application Publication No. WO2005065046 also disclose a process for the preparation of chlorthalidone.
The present disclosure provides an improved process of making chlorthalidone that is both feasible on a large scale and industrial level and results in a product with high purity.
SUMMARY THE INVENTION
In one aspect, the present invention provides a process for the preparation of compound of formula 10.

In another aspect, formula 10 may be prepared by a process that includes the step of treating a compound of formula 9 with a chlorinating agent in the presence of chlorosulphonic acid.

In yet another aspect, the chlorinating agent is phosphorus oxychloride.
In yet another aspect, the present invention provides a process of converting the compound of Formula 10 to chlorthalidone comprising the steps of following steps:
a. reacting the compound of formula 10 with ammonia to obtain a compound of formula 11
; and
b. reacting the compound of formula 11 sequentially with a peroxide and then with a base to obtain crude chlorthalidone
.
In yet another aspect, the ammonia may be gaseous or aqueous ammonia and this reaction is carried out in a solvent. Examples of suitable solvents include, but are not limited to, water, methanol, acetone, dimethyl formamide, dimethylacetamide, and mixtures thereof.
In yet another aspect, the step of converting the compound of formula 11 to crude chlorthalidone is carried out in presence of a base particularly sodium hydroxide and a peroxide selected from sodium peroxide, barium peroxide, or hydrogen peroxide.
In yet another aspect, the present invention provides a method of purifying crude chlorthalidone using a solvent selected from the group consisting of water, water-miscible polar solvents, and mixtures thereof. Particularly useful solvents include, but are not limited to, dimethylformamide, tetrahydrofuran, acetone, dioxane, isopropyl alcohol, methanol, and mixtures thereof.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process that is industrially viable for the preparation of chlorthalidone, as summarized in scheme 1 below.

Scheme 1
Chlorthalidone may be synthesized by first converting a compound of formula 2, which is commercially available, into a compound of formula 8. This may be carried out by reacting a compound of formula 2 with hydroxylamine hydrochloride in the presence of a suitable base and a solvent. Examples of suitable bases include, but are not limited to, potassium hydroxide, sodium hydroxide, and mixtures thereof. In particularly useful embodiments, the base is sodium hydroxide. Within the context of this embodiment, the solvent is an alcohol. In particularly useful embodiments, methanol is used as the solvent.
Next, a compound of formula 8 may be treated with an acid in the presence of zinc dust to obtain compound of formula 9. Examples of suitable acids include, but are not limited to, formic acid, propionic acid, acetic acid, and mixtures thereof. In particularly useful embodiments, the acid is acetic acid.
Next, the compound of formula 9 may be treated with a chlorosulphonic acid in the presence of a chlorinating agent to obtain compound of formula 10. In particularly useful embodiments, the chlorinating agent is phosphorus oxychloride, as shown below:

While not wishing to be bound by theory, it is believed that the use of phosphorus oxychloride reduces the amount of chlorosulphonic acid required and helps in reaction completion.
Next, the compound of Formula 10 may be treated with ammonia in a suitable solvent to obtain compound of Formula 11. Within the context of the present invention, the ammonia may be in gaseous form or may be aqueous ammonia. Examples of suitable solvents include acetone, water, methanol, dimethyl formamide, dimethylacetamide, and mixtures thereof.
The compound of formula 11 may then be treated sequentially with a peroxide followed by a base to obtain a crude chlorthalidone. Examples of suitable peroxides include, but are not limited to, hydrogen peroxide, barium peroxide, sodium peroxide, and mixtures thereof. Examples of suitable bases include sodium hydroxide, potassium hydroxide and potassium carbonate.
While not wishing to be bound by theory, adding the peroxide before the base in the conversion of formula 11 to chlorthalidone minimizes the formation of process impurities and aids in providing substantially pure chlorthalidone. This is in contrast to prior art processes such as those disclosed in PCT Int. Pat. App. Pub. No. WO2005065046, wherein this step is carried out by first adding sodium hydroxide followed by a peroxide.
Substantially pure chlorthalidone may then be obtained by treating crude chlorthalidone with a solvent. Examples of suitable solvents include water or water in a mixture with a water-miscible polar solvent. Examples of suitable water-miscible polar solvents include but are not limited to, dimethylformamide, tetrahydrofuran, acetone, dioxane, isopropyl alcohol, methanol, and mixtures thereof.
Substantially pure chlorthalidone may then be isolated by removing the solvent. This may be carried out by methods well known in the art, for example, by filtering the chlorthalidone/solvent mixture.
Optionally, the collected solid may be further refined, for example, by drying, to result in substantially pure chlorthalidone. One of skill in the art would readily recognize a variety of useful methods that may be undertaken to isolate the final product.
Within the context of the present disclosure, substantially pure means a purity of 99.9% or more when measured by HPLC. By using the methods disclosed herein, this high purity is routinely achievable when chlorthalidone is synthesized in batches suitable for industrial manufacturing.
Substantially pure chlorthalidone, as prepared by the processes described herein, may be formulated into a pharmaceutical dosage form, for example, one for oral administration such as tablets or capsules. Such tablets or capsules may include other pharmaceutically acceptable excipients such as colloidal silicon dioxide, microcrystalline cellulose, starch, sodium starch glycolate, stearic acid, ammonium chloride, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, sodium lauryl sulfate, polyethylene glycol, povidone, hydroxypropyl methyl cellulose, mannitol, fumaric acid, sodium hydroxide, crospovidone, talc, and artificial colorings and flavorings. Some tablets or capsules may contain other active pharmaceutical ingredients such as atenolol, azilsartan, betaxolol, clonidine, losartan, and pharmaceutically acceptable salts thereof.
Oral dosage forms containing the substantially pure chlorthalidone as prepared by methods disclosed herein may be particularly useful in the treatment or management of hypertension.
In some embodiments, tablets containing the substantially pure chlorthalidone as prepared by methods disclosed herein may be co-administered with other antihypertensive agents such as such as atenolol, azilsartan, betaxolol, chlonidine, and pharmaceutically acceptable salts thereof.
In particularly useful embodiments, tablets containing chlorthalidone contain 20 mg or 50 mg of chlorthalidone.
The following non-limiting specific examples presented to illustrate the best mode of carrying out the process of the present invention. The examples are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious set forth in the description.
Examples
Example-1: Preparation of (4-(4’-chlorophenyl)-5,6-benz-2,3-oxazin-1-one (Formula 8)
Sodium hydroxide (34.55 g, 0.8653 moles, 1.5 eq.) was added to a stirred solution of 2-(4-chlorobenzoyl) benzoic acid (150.0 g, 0.5769 moles, 1 eq.) and hydroxylamine hydrochloride (140.0 g, 2.019 moles, 3.5 eq.) in methanol (900 ml, 6.0 V) at 25 – 30 °C. The reaction mass was heated to 60 – 65 °C and maintained for 6 – 8 hours, resulting in a precipitate. The mixture was cooled to 25 – 30 °C and stirred for 1 – 2 hours. The mixture was filtered and the collected solid product was washed with water (900 ml, 6.0V) and dried under vacuum at 60 °C for 6 – 8 hours to give (4-(4’-chlorophenyl)-5,6-benz-2,3-oxazin-1-one (Formula 8). Yield = 142 g (95%); HPLC purity – 99.78%.
Example-2: Preparation of 3-(4’-chlorophenyl) phthalimidine (Formula 9)
Zinc dust (66.15 g ,2.0 eq.) was added portion-wise to a stirred solution of 4-(4’-chlorophenyl)-5,6-benz-2,3-oxazin-1-one (130.0 g, 0.5045 moles, 1 eq.) and acetic acid (1300 ml, 10.0 V) at 70 – 75 °C over a 10 – 15 minute interval. The suspension was stirred for 30 – 40 minutes. An additional portion of zinc dust (33.0 g, 1.0 eq.) was added and stirred for 60 – 70 minutes. The hot solution was filtered through Celite and washed with acetic acid (260 ml, 2.0 V). Water (780 ml, 6.0 V) was added to the filtrate at 60 – 70 °C and subsequently heated to 85 – 95 °C to get a clear solution. The solution was gradually cooled to room temperature and then further cooled to 5 – 10 °C and stirred for 1 – 2 hours to form a precipitate. The mixture containing the precipitate was filtered and the collected solid was washed with water (780 ml, 6.0 V) and dried under vacuum at 60 °C for 6 – 8 hours to give 3-(4’-chlorophenyl) phthalimidine (Formula 9). Yield = 112.0 g (91%); HPLC Purity – 99.88%
Example-3: Preparation of 3-(3’-sulfamyl-4’-chlorophenyl) phthalimidine (Formula 11)
3-(4’-chlorophenyl) phthalimidine (100.0 g, 1 eq.) was added portion-wise to a stirred solution of chlorosulphonic acid (328 m1, 12 eq.) at 0 – 5 °C. The reaction mass was heated to 75 – 80 °C for 3 – 4 hours then cooled to room temperature. Phosphorus oxychloride (76.0 ml, 2.0 eq.) was added into the reaction mass and then heated to 75 – 80 °C for 2 hours. The reaction mass was then cooled to room temperature and quenched into ice cold water (3000.0 ml, 30.0 V) and stirred for 1 hour at 0 – 5 °C to result in a precipitate. The mixture containing the precipitate was filtered and washed with water (1000 ml, 10.0 V) to give 3-(3’-chlorosulphonyl-4’-chlorophenyl) phthalimidine (Formula 10, 500 g, wet cake). Acetone (1500 ml, 15.0 V) was added to the wet cake at 0 – 5 °C and 20 – 25% aqueous ammonia solution (300 ml, 3.0 V) was added slowly. The reaction mixture was stirred for 1 – 2 hours. After completion of the reaction, the pH of the reaction mixture was adjusted to 5 – 7 using concentrated hydrochloric acid (100.0 ml). The reaction mixture was stirred for 2 hours to result in a precipitate. The reaction mixture was then filtered and the collected solid was washed with water (1000 ml). The wet cake was charged into methanol (1200 ml, 12.0V) and the reaction mixture was heated to 60 – 65 °C followed by cooling to 20 – 25 °C for 1 hour. The reaction mixture was filtered and the collected solid product was washed with methanol (200 ml, 2.0 V) and dried under vacuum at 60 – 65 °C for 6 – 8 hours to give 3-(3’-sulfamyl-4’-chlorophenyl) phthalimidine (Formula 11). Yield = 101.0 g (77%); HPLC purity – 99.67%
Example-4: Preparation of 2-chloro -5-[(1RS)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] benzene sulfonamide (crude chlorthalidone, Formula 1)
Sodium hydroxide solution (prepared by dissolving 44.6 g NaOH in 270 ml water) was added to a stirred solution of 3-(3’-sulfamyl-4’-chlorophenyl) phthalimidine (90.0 g, 1.0 eq.) and 50% hydrogen peroxide (62.49 ml, 3.5 eq.) in water (630 ml, 7.0 V) at 0 – 5 °C and stirred for 30 minutes. The reaction mass was further stirred at 15 – 20 °C for 30 – 40 minutes then gradually warmed to 23 – 26 °C and stirred for an additional 3 – 4 hours. Charcoal was added to the reaction mixture after which it was filtered through Celite. The pH of the filtrate was adjusted to 4.5 – 5.5 using concentrated hydrochloric acid (90.0 ml) and stirred for 1 hour to result in formation of a precipitate. The reaction mixture was filtered and the collected solid was dried for 6 – 8 hours at 60 °C. The dried product was dissolved in methanol (850 ml, 9.5 V) at 60 – 65 °C and slowly added into water (850 ml, 9.5V) at 45 – 50 °C. The reaction mass was cooled to room temperature and then further cooled to 5-10 °C and stirred for 1 hour. The reaction mixture was filtered and the collected solid was washed with water (900 ml, 10.0 V) then dried under vacuum at 60 °C for 6 – 8 hours to give 2-chloro-5-[(1RS)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] benzenesulfonamide (Crude chlorthalidone). Yield = 72 g (76%); HPLC purity – 99.50%.
Example-5: Purification of 2-chloro -5-[(1RS)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] benzenesulfonamide (crude chlorthalidone)
2-chloro-5-[(1RS)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] benzenesulfonamide (crude chlorthalidone, 65.0 g,1 eq.) was added portion-wise to a stirred solution of sodium hydroxide (11.51 g, 1.5 eq.) and water (975 ml, 15.0 V) in isopropanol (130 ml, 2.0 V) at 20-25 °C. A clear solution was formed which was then filtered through 0.45 micron filter. The pH of the filtrate was adjusted to 4.5 – 5.5 using concentrated hydrochloric acid (30 ml) and stirred for 1 hour to result in a precipitate. The reaction mixture was filtered and the collected solid was washed with water (1300 ml, 20.0V) and dried under vacuum at 75 – 80 °C for 8 – 10 hours to give substantially pure 2-chloro-5-[(1RS)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] benzene sulfonamide. Yield = 60 g (92%); HPLC Purity – 99.90%.
Example-6: Purification of 2-chloro-5-[(1RS)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] benzenesulfonamide (crude chlorthalidone)
2-chloro-5-[(1RS)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] benzenesulfonamide (crude chlorthalidone) was added to a stirred mixture of acetone (225 ml, 5.0 V) and water (90 ml, 2.0V) at 25 – 30 °C. The reaction mixture was heated to 45 – 55 °C and stirred for 10 – 15 minutes to get a clear solution. The solution was then cooled to 30 – 35 °C, filtered through 0.45 micron paper and washed with an acetone (8 ml):water (4 ml) mixture. The filtrate was added slowly into water (675 ml, 15.0V) at 56 – 64 °C, maintaining temperature. The reaction mixture was stirred for 30 – 40 minutes then gradually cooled to 40 – 50 °C and stirred for an additional 10 – 15 minutes. The reaction mixture was then further cooled to 25 – 30 °C, stirred for 25 – 30 minutes, cooled to 0 – 6 °C, and stirred for 120 – 150 minutes to form a slurry. The slurry was filtered and the collected solid was washed with water (450 ml, 10.0 V) and dried at 70 – 80 °C under vacuum for 6 – 8 hours to give substantially pure 2-chloro -5-[(1RS)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] benzenesulfonamide (chlorthalidone). Yield = 90.0 g (90%), appearance is white crystalline solid; HPLC Purity – 99.90%

,CLAIMS:We claim

1. A process for the preparation of compound of formula 10 comprising the step of treating the compound of formula 9 with a chlorinating agent in the presence of chlorosulphonic acid.

2. The process as claimed in claim 1, wherein the chlorinating agent is phosphorus oxychloride.
3. The process as claimed in claim 1, further comprising converting formula 10 to chlorthalidone by a process comprising the following steps:
a) reacting the compound of formula 10 with ammonia to obtain a compound of formula 11; and
;
b) reacting the compound of formula 11 sequentially with a peroxide and then with a base to obtain crude chlorthalidone

c) optionally purifying the crude chlorthalidone
4. The process as claimed in claim 3, wherein the ammonia may be gaseous or aqueous ammonia.
5. The process as claimed in claim 3, wherein reacting of compound 10 with ammonia is carried out in a solvent selected from the group consisting of water, methanol, acetone, dimethyl formamide, dimethylacetamide, and mixtures thereof.
6. The process as claimed in claim 3, wherein the base is sodium hydroxide.
7. The process as claimed in claim 3, wherein the peroxide is selected from the group consisting of sodium peroxide, barium peroxide, and hydrogen peroxide.
8. The process as claimed in claim 3, wherein the purification of chlorthalidone is carried using a solvent selected from the group consisting of water, water-miscible polar solvents, and mixtures thereof.
9. The method as claimed in claim 8, wherein the water-miscible solvent is selected from the group consisting of dimethylformamide, tetrahydrofuran, acetone, dioxane, isopropyl alcohol, methanol, and mixtures thereof.
10. Pharmaceutical composition comprising chlorthalidone prepared according to claim 3 for the treatment of hypertension.