Claims:1. An improved process for the preparation of 2-chloro-5-(1-hydroxy-3-oxoisoindolin-1-yl)
benzene sulfonamide the compound of formula-1;
comprising of :
5 a). i) Reacting compound of formula-2,
Formula-2
with chlorobenzene in presence of aluminium chloride at 55-65°C,
10 ii) treating the reaction mixture with dichloro methane, hydrochloric acid and sodium
hydroxide solutions simultaneously,
iii) reacting the above aqueous solution with hydroxylamine sulfate at 50-110°C,
iv) optionally purifying the reaction mixture to obtain the compound of formula-3.
15 Formula-3
b) reacting the compound obtained in step-a) with zinc and acetic acid at 90-100°C to provide
the compound of formula-4,
Formula-4
20
c) refluxing the compound obtained in step-b) in chlorosulphonic acid followed by treatment
with ammonia gas to provide the compound of formula-5,
15
Formula-5
d) optionally purifying the compound obtain in step-c) in methanol,
e) reacting the compound obtained in step-d) with hydrogen peroxide and sodium hydroxide
5 solution at 30-40°C to provide the compound of formula-1,
f) purifying the obtained compound in acetone, water mixture.
2. One pot synthesis for the preparation of 4-(4-chlorophenyl)1Hbenzo[d][1,2]oxazin-1-one the
compound of formula-3
10
Formula-3
comprising of:
a) Reacting the compound of formula-2,
15 Formula-2
with chlorbenzene in presence of aluminium chloride at suitable temperature 20-110°C,
b) further treating with dichloromethane, acid and base solutions simultaneously,
c) treating the above aqueous solution with hydroxylamine sulfate at 45-100°C,
d) optionally purifying the reaction mixture to obtain the compound of formula-3.
20 Wherein the acid is selected from organic acid, inorganic acid; suitable acid is hydrochloric acid.
Base is selected from organic base, inorganic base; suitable base is sodium hydroxide.
3.One pot synthesis for the preparation of 4-(4-chloro phenyl) 1Hbenzo[d][1,2]oxazin-1-one the
compound of formula-3 comprising of:
16
a) Reacting the compound of formula-2, chlorobenzene in presence of aluminium chloride at 55-
65°C,
b) further treating the reaction mixture with dichloromethane, hydrochloric acid and sodium
hydroxide solution simultaneously,
5 c) treating the above aqueous solution with hydroxylamine sulfate at 90-100°C,
d) purifying the reaction mixture to obtained the compound of formula-3.
4. An improved process for the preparation of 2-chloro-5-(1-hydroxy-3-oxoisoindolin-1-yl)
benzenesulfonamide the compound of formula-1.
10
Formula-1
comprising of:
a) Reacting the compound of formula-3
15 Formula-3
with zinc and acetic acid at 90-100°C to provide the compound of formula-4,
Formula-4
20 b) refluxing the compound obtained in step-a) in chlorosulphonic acid followed by treatment
with ammonia gas to provide the compound of formula-5,
17
Formula-5
c) optionally purifying the compound of formula-5 in a suitable solvent,
d) reacting the compound obtained in step-c) in hydrogen peroxide and sodium hydroxide
5 solution to provide the compound of formula-1,
e) purifying the obtained compound in a suitable solvent.
Wherein step-c, e ) the suitable solvent is selected from alcoholic solvents such as methanol,
ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol; ketone solvents are selected
from acetone, methyl ethyl ketone, methyl isobutyl ketone; polar solvents, water and mixture
10 thereof.
5. A process for the preparation of crystalline form-1 of compound of formula-1
comprising of :
a) Dissolving the compound of formula-1 in a suitable solvent and water,
b) stirring the reaction mixture at a suitable temperature,
15 c) distilling the reaction mixture at a suitable temperature,
d) cooling the reaction mixture to provide the compound of formula-1.
Wherein suitable solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol,
isobutanol, t-butanol; ketone solvents are selected from acetone, methyl ethyl ketone, methyl
isobutyl ketone; polar solvents, water and mixture thereof; suitable temperature : 25-110°C,
20 preferably: 40-100°C.
6. A process for the preparation of crystalline form-1 of compound of formula-1
comprising of :
a) Dissolving the compound of formula-1 in a acetone and water,
b) stirring the reaction mixture at 50- 65°C,
25 c) distilling the reaction mixture at 60-100°C,
d) cooling the reaction mixture to provide the compound of formula-1.
18
7. Use of the 2-chloro-5-(1-hydroxy-3-oxoisoindolin-1-yl) benzenesulfonamide compound of formula-1 obtained according to any of preceding claims in the preparation of pharmaceutical composition. 8. The compound of formula-l obtained according to any of the preceding claims having
HPLC purity more than 99% ; 5
9. The compound of formula-1 obtained according to any of the proceeding claims having particle size of D(90) < 25 microns , D(90) < 100 microns.
10. The compound of formula-1 obtained according to any of the proceeding claims having particle size of 100 microns > D(90) < 200 microns ; preferably D(90) < 155 microns. , Description:Field of the Invention:
The present invention relates to an improved process for the preparation of 2-chloro-5-(1-
hydroxy-3-oxoisoindolin-1-yl)benzenesulfonamide compound of formula-1, which is
represented by the following structural formula:
5
Formula-1
Background of the Invention:
2-chloro-5-(1-hydroxy-3-oxoisoindolin-1-yl)benzenesulfonamide compound of formula-
10 1 is known as chlorthalidone. It is a diuretic medication used to treat hypertension (high blood
pressure), originally marketed as HYGROTON® in the USA.
The US3055904 (herein after referred as US’904) patent first discloses the process for
chlorthalidone and its intermediates, Isoindoline derivatives preparation thereof. US4188330
(herein after referred as US’330) patent discloses the process for the preparation of
15 chlorthalidone derivatives using with novel intermediates and processes thereof. US4331600
(herein after referred as US’600) patent discloses the processes for the preparation chlorthalidone
and its derivative using novel intermediates and their processes.
However, there is a need for an alternative preparative routes which for example, use
reagents that are less expensive and easier to handle, consume smaller amount of reagents,
20 provide a high yield of product, involve fewer steps, have smaller and / or more eco-friendly
waste products, to provide a product of higher purity and quantity.
The present invention describes an improved process for the preparation of compound of
formula-1 over the existing processes. The invention also provides one pot synthesis for the
preparation of compound of formula-3, which is a key intermediate compound for the
25 preparation of chlorthalidone compound of formula-1. It gives good yields with less impurities in
fewer steps.
3
Brief Description:
The first aspect of the present invention is to provide an improved process for the preparation of 2-chloro-5-(1-hydroxy-3-oxoisoindolin-1-yl)benzenesulfonamide compound of formula-1.
The second aspect of the present invention is to provide one pot synthesis of 4-(4-chloro 5 phenyl)-1H-benzo[d][1,2]oxazin-1-one compound of formula-3.
The third aspect of the present invention is to provide an improved process for the preparation of the compound of formula-1.
The fourth aspect of the present invention is to provide a process for the preparation of crystalline form-I of the compound of formula-1. 10
Brief description of the drawings:
Figure-1. Illustrates the PXRD histogram of crystalline Form-I of 2-chloro-5-(1-hydroxy-3-oxoiso indolin-1-yl)benzenesulfonamide compound of formula-1 obtained from example-5.
Figure-2. Illustrates the IR absorption spectrum of crystalline Form-I of 2-chloro-5-(1-hydroxy-15 3-oxoiso indolin-1-yl)benzenesulfonamide compound of formula-1 obtained from example-5.
Figure-3. Illustrates the DSC thermogram of crystalline Form-I of 2-chloro-5-(1-hydroxy-3-oxoiso indolin-1-yl)benzenesulfonamide compound of formula-1 obtained from example-5.
Figure-4. Illustrates the PXRD histogram of crystalline Form-I of 2-chloro-5-(1-hydroxy-3-oxoiso indolin-1-yl)benzenesulfonamide compound of formula-1 obtained from example-6. 20
Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene 25 glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the 30 like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra
4
chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl
ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the
like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol,
isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-
5 methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, tpentyl
alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or
glycerol and the like; “polar solvents” such as water or mixtures thereof.
The term “acid” used in the present invention refers to inorganic acids selected from
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc; organic acids
10 such as acetic acid, maleic acid, malic acid, tartaric acid, oxalic acid, trifluoroacetic acid,
methane sulfonic acid, p-toluene sulfonic acid etc;
As used herein the present invention the term “suitable base” refers to inorganic or
organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate,
potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium
15 bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium
hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as
sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium
tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides
such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides
20 such as sodium amide, potassium amide, lithium amide and the like; and organic bases like
dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine,
triethylamine, pyridine, 4-dimethylamino pyridine (DMAP), N-methyl morpholine (NMM), 2,6-
lutidine, lithium diisopropylamide; DBU.
The first aspect of the present invention is to provide an improved process for the
25 preparation of 2-chloro-5-(1-hydroxy-3-oxoisoindolin-1-yl)benzenesulfonamide the compound
of formula-1.
Formula-1
5
comprising of :
1) a) Reacting the compound of formula-2,
Formula-2
with chlorobenzene 5 in presence of aluminium chloride at 55-65°C,
b) further treating the reaction mixture with dichloromethane, hydrochloric acid and sodium
hydroxide solutions simultaneously,
c) treating the above aqueous solution with hydroxyl amine sulfate at 90-100°C,
d) optionally purifying the reaction mixture to obtain the compound of formula-3.
10
Formula-3
2) reacting the compound obtained in step-1) using zinc and acetic acid at 90-100°C to provide
the compound of formula-4,
15 Formula-4
3) refluxing the compound obtained in step-2) in chlorosulphonic acid followed by treatment
with ammonia gas to provide the compound of formula-5,
Formula-5
20 4) optionally purifying the compound obtained in step-3) in methanol,
5) reacting the compound obtained in step-4) with hydrogen peroxide and sodium hydroxide
solution at 30-40°C to provide the compound of formula-1.
6
6) purifying the compound obtained in step-5) in mixture of acetone, water to provide the
compound of formula-1.
The second aspect of the present invention is to provide one pot synthesis of 4-(4-chloro
phenyl) 1Hbenzo[d][1,2]oxazin-1-one the compound of formula-3,
5
Formula-3
comprising of:
a) Reacting the compound of formula-1,
10 Formula-2
with chlorbenzene in presence of aluminium chloride at suitable temperature 20-110°C,
b) further treating with dichloromethane, acid and base solutions simultaneously,
c) treating the above aqueous solution with hydroxylamine sulfate at 45-100°C,
d) purifying the reaction mixture to obtain the compound of formula-3.
15 Wherein the acid is selected from organic acid, inorganic acid; suitable acid is hydrochloric
acid. Base is selected from organic base, inorganic base; suitable base is sodium hydroxide.
Preferred embodiment of the present invention is to provide an improved process for the
preparation of 4-(4-chloro phenyl) 1Hbenzo[d][1,2]oxazin-1-one compound of formula-3,
comprising of :
20 a) Reacting the compound of formula-2, chlorobenzene in presence of aluminium chloride at
55-65°C,
b) further treating the reaction mixture with dichloromethane, hydrochloric acid and sodium
hydroxide solution simultaneously,
c) treating the above aqueous solution with hydroxylamine sulfate at 90-100°C,
25 d) purifying the reaction mixture to obtained the compound of formula-3.
7
The third aspect of the present invention is to provide an improved process for the
preparation of 2-chloro-5-(1-hydroxy-3-oxoisoindolin-1-yl)benzenesulfonamide the compound
of formula-1.
5
Formula-1
comprising of:
a) Treating the compound of formula-3,
10 Formula-3
using zinc and acetic acid to provide the compound of formula-4,
Formula-4
15 b) refluxing the compound obtained in step-a) in chlorosulphonic acid followed by treatment
with ammonia gas to provide the compound of formula-5,
Formula-5
c) optionally purifying the compound obtained in step-b) in a suitable solvent,
20 d) reacting the compound obtained in step-c) using hydrogen peroxide and sodium hydroxide to
provide the compound of formula-1.
8
e) optionally purifying the compound of formula-1 in a suitable solvent at suitable temperature
to obtain the pure compound of formula-1.
Wherein step-c, e ) the suitable solvent is selected from alcoholic solvents such as methanol,
ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol; ketone solvents are selected
5 from acetone, methyl ethyl ketone, methyl isobutyl ketone; polar solvents, water and mixture
thereof.
Preferred embodiment of the present invention is to provide an improved process for the
preparation of 2-chloro-5-(1-hydroxy-3-oxoisoindolin-1-yl)benzenesulfonamide the compound
of formula-1.
10
Formula-1
Comprising:
15 a) Reacting the compound of formula-3
Formula-3
using zinc and acetic acid at 90-100°C, to provide the compound of formula-4,
20 Formula-4
b) refluxing the compound obtained in step-a) in chlorosulphonic acid followed by treatment
with ammonia gas to provide the compound of formula-5,
9
Formula-5
c) optionally purifying the compound obtained in step-b) in methanol
d) reacting the compound obtained in step-c) using hydrogen peroxide and sodium hydroxide at
5 30-40°C to provide the compound of formula-1.
e) purifying the compound obtained in step-d) in acetone, water mixture.
The fourth aspect of the present invention is to provide a process for the preparation of
crystalline form-1 of compound of formula-1
comprising of :
10 a) dissolving the compound of formula-1 in a suitable solvent and water,
b) stirring the reaction mixture at a suitable temperature,
c) distilling the reaction mixture at a suitable temperature,
d) cooling the solution to provide the compound of formula-1.
Wherein the suitable solvent is selected from methanol, ethanol, n-propanol, isopropanol, n15
butanol, isobutanol, t-butanol; ketone solvents are selected from acetone, methyl ethyl ketone,
methyl isobutyl ketone; polar solvents, water and mixture thereof; suitable temperature : 50-
110°C, preferably: 60-100°C.
Preferred embodiment of present invention is to provide a process for the preparation of
crystalline form-1 of compound of formula-1
20 comprising of :
a) dissolving the compound of formula-1 in a acetone and water,
e) stirring the reaction mixture at 60- 75°C,
c) distilling the reaction mixture at 60-100°C,
d) cooling the solution to provide the compound of formula-1.
25 The compound of the formula-1 or its pharmaceutically acceptable salts produced by the
present invention can be further micronized or milled using conventional techniques to get the
desired particle size to achieve desired solubility profile based on different forms of
pharmaceutical composition requirements. Techniques that may be used for particle size
10
reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or
micronization may be performed before drying, or after the completion of drying of the product.
The process of the present invention can be represented schematically as follows:
5
The process described in the present invention was demonstrated in examples illustrated
below. These examples are provided as illustration only and therefore should not be construed as
limitation of the scope of the invention.
10
Examples:
Example-1: Preparation of 4-(4-chlorophenyl)-1H-benzo[d][1,2]oxazin-1-one(Formula-3).
A round bottom flask charged with chlorobenzene (304 gm), aluminium chloride (270.4 gm) and
stirred for 15 mints at 25-35°C. The compound of formula-2 (100 gm) was lot wise added to this
15 reaction mixture and heated to 55-65°C and stirring continued for 6 hours. The reaction mixture
was cooled to 15-25°C and diluted with dichloromethane (800 ml). The obtained solution was
11
slowly added to a solution of diluted. hydrochloric acid (300 ml) and stirred at 25-35°C for 1 hour, separated both the organic and aqueous layers. The aqueous layer was extracted with dichloromethane (200 ml), the combined organic layers were washed with water (100 ml). The obtained organic layer was added slowly to a solution of sodium hydroxide (47 gr in 700 ml water) at 20-30°C and stirred for 20 mints and both the layers were separated. Hydroxylamine 5 sulphate (250 gm) was added to the above aqueous layer, was heated to 90-100°C and stirring continued for 6 hours. The reaction mixture was cooled to 50°C, filter the obtained solid washed with water (200 ml) and dried to get the title compound.
Yield: 148 gm.
Example-2: Preparation of 3-(4-chlorophenyl)isoindolin-1-one (Formula-4). 10
A round bottom flask charged with the compound of formula-3 (100 gm) and acetic acid (800 ml) the obtained heterogeneous mixture was stirred for 30 mints. Zinc dust (114 gm) was added to the above reaction mixtureat 20-30°C, heated to 90-100°C and stirred for 4 hours. The reaction mixture was cooled to 70-80°C, filtered the unwanted material and washed with acetic acid (100 ml). The filtrate was evaporated, the obtained solid was diluted with water (400 ml) 15 and stirred for 45 mints. Filter the precipitated solid, washed with water (100 ml) and dried to get the title compound.
Yield: 90 gm.
Example-3: Preparation of 2-chloro-5-(3-oxoisoindolin-1-yl)benzenesulfonamide.
(Formula-5). 20
A round bottom flask was charged with chlorosulfonic acid (480 gm), compound of formula-4 (100 gm) at 10-25°C, heated to 75-85°C and stirred for 5 hours. The reaction mixture was slowly added in to a precooled water (1000 ml) at 15-25°C and further stirred for 45 mints. The obtained solid was filtered under nitrogen atmosphere, washed with water (200 ml). The wet compound was charged into a mixture of acetone (500 ml) and water (200 ml), ammonia gas 25 was purged upto pH 9.5-10.5 at below 20°C. The reaction mixture was diluted with water (500 ml), the PH was adjusted to 6.5 -7.5 and stirred for 1 hour. The obtained material was further purified in methanol to get the title compound.
Yield: 94 gm.
30
12
Example-4: Preparation of 2-chloro-5-(1-hydroxy-3-oxoisoindolin-1-yl)benzenesulfonamide (Formula-1)
A round bottom flask was charged with the compound of formula-4 (100 gm) and sodium hydroxide solution ( 62 gm in 1000 ml of water) and stirred for 15 mints. Hydrogen peroxide (50 % aqueous solution, 95 gm) was added slowly at 5-15°C to the above solution and stirred 4 5 hours at 30-40°C. The reaction mixture was cooled to 20°C, adjusted the pH to 3 - 4 using Conc. hydrochloric acid (150 ml) stirred for 45 mints. The obtained solid was filtered and diluted with water (200 ml) adjusted the pH to 12-13 using sodium hydroxide solution (50 gr) stirred for 30 mints. Toluene (200 ml) was added to the above solution stirred for 15 mints, separated both the layers. The aqueous layer was charged with activated carbon stirred for 15 mints, filtered through 10 high flow bed and washed with water. The obtained aqueous layer was acidified the pH to 4-5 with Conc. hydrochloric acid (50 ml) and stirred for 45 mints. Filtered the obtain solid and washed with water. The obtained material was purified in water to get the title compound.
HPLC purity: > 99 %
Yield: 81 gm. 15
Example-5: preparation of crystalline form-1 of 2-chloro-5-(1-hydroxy-3-oxoisoindolin-1-yl) benzenesulfonamide (Formula-1).
In a round bottom flask charged a compound of formula-1(100 gm), methanol (1000 ml) the heterogeneous mixture was heated to 55-65°C and stirred for 30 mints. The reaction mixture was added slowly to water (1000 ml) at 40-45°C and stirring was continued for 45 mints. The 20 reaction mixture was cooled to 25-35°C stirred for 45 mints. Filtered the obtain solid, washed with water to get the title compound.
HPLC purity : >99 %
Yield: 85.0 gm.
Example-6: Preparation of crystalline form-1 of 2-chloro-5-(1-hydroxy-3-oxoisoindolin-1-25 yl) benzenesulfonamide (Formula-1)
A round bottom flask was charged with a mixture of acetone, water (5:2, 80 ml), the compound of formula-1 (10 gm), heated to 60-65°C and stirred for 30 mints. The obtained solution was slowly added to water at below 100°C, with a simultaneous distillation of acetone. After completion of addition the solution stirred for 30 mints at same temperature. Cool the reaction 30
13
mixture to 25-30°C stirred for 30 mints. Filter the obtained solid, washed with water (10 ml) and dried to get the title compound. PXRD attached in the figure-4.
HPLC purity: >99 %
Yield: 8.5 gm.
Example-7: Preparation of crystalline form-1 of 2-chloro-5-(1-hydroxy-3-oxoisoindolin-1-5 yl)benzenesulfonamide (Formula-1)
A round bottom flask was charged with a mixture of acetone, water ( 5:2, 80 ml ), the compound of formula-1 (10 gm), heated to 60-65°C and stirred for 30 mints. The acetone was evaporated from the reaction mixture and stirred at 25-30°C for 30 mints. Filter the obtained solid and washed with water (25 ml) dried to get the title compound. 10
HPLC purity: >99 %
Yield: 8.5 gm.
Example-8: Preparation of 2-chloro-5-(1-hydroxy-3-oxoisoindolin-1-yl)benzenesulfonamide (Formula-1)
A round bottom flask was charged with the compound of formula-4 (50 gm) and aqueous sodium 15 hydroxide solution ( 31 gm in 500 ml) and stirred for 15 mints. Hydrogen peroxide (50 % aqueous solution, 48 gm) was added slowly to the above solution at 5-15°C and stirred for 4 hours at 30-40°C. The reaction mixture was cooled to 20°C, adjusted the pH to 3 - 4 using Conc.hydrochloric acid (80 ml) and stirred for 45 mints. The obtained solid was filtered, diluted with water (100 ml) adjusted the pH to 12-13 using aqueous sodium hydroxide solution (25 gr) 20 stirred for 30 mints. Toluene (100 ml) was added to the above reaction mixture and stirred for 15 mints. separated both the layers. The aqueous layer was charged with activated carbon and stirred for 15 mints, The solution was filtered through high flow bed and washed with water. The obtained aqueous layer was acidified the pH to 4-5 with diluted hydrochloric acid (25 ml) and stirred for 45 mints. Filtered the obtain solid and washed with water. The obtained crude material 25 was further purified in a mixture of water, acetone. The wet compound was dried to get the the title compound .
HPLC purity: > 99 %
Yield: 38.5 gm.