FIELD OF THE INVENITON
The present invention relates an improved process for the preparation of Diazoxide (I). It further relates to a novel process for the purification of Diazoxide or its salts to provide Diazoxide (I) with purity greater than 99.0 %. It further relates to the process for purification of Diazoxide (I) intermediates of formula (V), (III) and (II).
BACKGROUND OF THE INVENTION
Diazoxide (I) is a nondiuretic benzothiadiazide derivative used for the management of symptomatic hypoglycemia caused by certain cancers or other conditions. It is chemically known as chloro-3-methyl-2H-l,2,4-benzothiadiazine 1,1-dioxide and has the structural formula (I). It is marked under the trade names PROGLYCEM® and HYPERSTAT®.
The synthesis of Diazoxide (I) was reported in few patents, the contents of which are hereby incorporated as reference in their entirety.
US 2,986,573 patent describes the synthesis of Diazoxide (I) by reducing 5-chloro-2-nitrobenzenesulfonamide (III) in presence of Iron to form 5-chloro-2-amino benzenesulfonamide (II) and then cyclizing to give Diazoxide (I). It does not disclose the isolation and purification of intermediate or the final compound Diazoxide.
US 3,345,365 patent describes the process for the preparation of Diazoxide (I) by reacting 2-amino-benzenesulfonamide with acetic anhydride and treating with glacial acetic acid and chlorine gas to produce 2-acetamido-5-chloro-acetyl-benzenesulfonamide, which on cyclization at high temperature produces Diazoxide (I). The disadvantage of this process is the use of chlorine gas which is harmful for health and easily pollutes the environment, hence unfavourable for industrial production. Further, cyclization without solvent at high temperatures ranging from 110-225 °C, which leads to more amount of impurities and is not applicable in large scale. Also, the process does not disclose the purity of intermediate or the final compound.

Hence, the inventors hereby provide a modified process for the preparation of Diazoxide (I), using moderate reaction conditions which are feasible at industrial scale. Further, the invention provides isolation and purification of intermediates with more than 95% purity and final compound Diazoxide(I) with more than 99.0% purity.
OBJECTIVE OF THE INEVNTION
The main objective of the present invention is to provide an improved process for the preparation of Diazoxide (I).
Another objective of the present invention is to provide a suitable method for the purification of Diazoxide (I) and its intermediates with more than 95% purity.
In another objective, the present invention is to provide a suitable method for the purification of intermediate benzyl(5-chloro-2-nitrophenyl) sulfane (V), 5-chloro-2-nitrbenzenesulfonamide (III) and 2-amino-5-chlorobenzene sulfonamide (II) with more than 95% purity and limiting the dimer impurity to less than 5.0%>.
Yet, another objective of the invention is to provide pure Diazoxide(I) with more than 99.0%) purity by HPLC (High-performance liquid chromatography).
SUMMARY OF THE INVENTION
Accordingly, one aspect of the present invention is to provide an improved process for the preparation of Diazoxide (I) comprising:
a) reacting 2,4-dichloronitrobenzene (VI) with thiourea and benzyl chloride to form benzyl(5-chloro-2-nitrophenyl) sulfane (V) in presence of a suitable base;
b) converting benzyl(5-chloro-2-nitrophenyl)sulfane (V) to 5-chloro-2-nitrobenzene-1-sulfonyl chloride (IV) in presence of suitable acid;
c) aminating 5-chloro-2-nitrobenzene-l-sulfonyl chloride (IV) to obtain 5-chloro-2-nitrobenzene-l-sulfonamide (III) using a suitable aminating agent;

d) reducing 5-chloro-2-nitrobenzene-l-sulfonamide (III) to 2-amino-5-chlorobenzene sulfonamide (II) using a suitable reducing agent; and
e) cyclizing 2-amino-5-chlorobenzene sulfonamide (II) to Diazoxide (I).
In another aspect, the present invention is to provide a suitable method for the purification of intermediate benzyl(5-chloro-2-nitrophenyl)sulfane (V), 5-chloro-2-nitrbenzenesulfonamide (III) and 2-amino-5-chlorobenzene sulfonamide (II) with more than 95% purity and limiting the dimer impurity to less than 5.0%., which subsequently converting into Diazoxide(l).
In another aspect, the present invention provides a process for the purification of Diazoxide (I) comprising:
i. providing a solution of Diazoxide (I) in a protic solvent or mixtures
thereof; ii. heating the reaction mass;
iii. cooling the reaction mixture to a suitable temperature; and iv. isolating pure Diazoxide (I).
Yet, another aspect of the invention is to provide pure Diazoxide (I) with more than 99.0%) purity by HPLC (High-performance liquid chromatography).
BRIEF DESCRIPTION OF DRAWINGS
Figure 1: illustrates X-Ray powder diffraction (XPRD) pattern of Diazoxide (I).
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, in one embodiment, the present invention provides an improved process for preparing Diazoxide (I), comprising:
a) reacting 2,4-dichloronitrobenzene (VI) with thiourea and benzyl chloride to form benzyl(5-chloro-2-nitrophenyl) sulfane (V) in presence of a suitable base;
b) converting benzyl(5-chloro-2-nitrophenyl) sulfane (V) to 5-chloro-2-nitrobenzene-1-sulfonyl chloride (IV) in presence of suitable acid;

c) animating 5-chloro-2-nitrobenzene-l-sulfonyl chloride (IV) to obtain 5-chloro-2-nitrobenzene-l-sulfonamide (III) using a suitable animating agent;
d) reducing 5-chloro-2-nitrobenzene-1 -sulfonamide (III) to 2-amino-5-chlorobenzene sulfonamide (II) using a suitable reducing agent; and
e) cyclizing 2-amino-5-chlorobenzene sulfonamide (II) to Diazoxide (I).
The above scheme outlines the steps involved in the synthesis of substantially pure Diazoxide (I).
In some embodiment, step a) involves reaction of 2,4-dichloronitrobenzene (VI) with thiourea and benzyl chloride to form Benzyl (5-chloro-2-nitrophenyl)sulfane (V) in presence of a base. The said reaction may be carried out at 50-100° C, preferably at 65-70° C. The obtained product was purified from a suitable solvent or mixtures thereof.
Step b) proceeds with the conversion of benzyl (5-chloro-2-nitrophenyl)sulfane (V) to 5-chloro-2-nitrobenzene-l-sulfonyl chloride (IV) by reacting with 1,3-dichloro-5,5-dimethylhydantoin in the presence of suitable acid. Prior art methods use chlorine and aqueous ammonia for this reaction, which is toxic and not suitable for commercial scale preparation. In the present invention l,3-dichloro-5,5-dimethylhydantoin is used as a chlorinating agent, which is cheaper and easy to handle at industrial levels.

Step c) involves amination of 5-chloro-2-nitrobenzene-l-sulfonyl chloride (IV) using suitable aminating agent, preferably ammonium hydroxide in presence of suitable solvent to produce 5-chloro-2-nitrobenzene-l-sulfonamide (III). Intermediate (III) may be purified using suitable solvents or mixtures thereof to yield intermediate (III) with purity more than 95% purity. Prior art methods do not disclose the purity of the intermediates obtained. The pure intermediate (III), was further used to synthesize Diazoxide (I), which reduced the impurity formation and hence enhanced the purity of the final compound.
Step d) involves reduction of 5-chloro-2-nitrobenzene-l-sulfonamide (III) to 2-amino-5-chlorobenzene sulfonamide (II) using suitable reducing agent in presence of suitable acid. The suitable reducing agents may be selected from a group comprising of iron, sodium hydride, lithium hydride, calcium hydride, lithium aluminum hydride, potassium hydride, barium hydride. 2-amino-5-chlorobenzene sulfonamide (II) so formed was purified by using suitable solvent.
Purification of intermediates (V), (III) and (II) may be carried out using very simple technique involving:
a) providing a solution of suitable intermediate in a suitable solvent or mixtures of solvent;
b) adding a suitable decolorizing agent;
c) filtering and removing the excess solvent;
d) adding a suitable solvent;
e) heating the reaction mass;
f) cooling the reaction mass; and
g) isolating the required intermediate.
Purification of intermediates (V), (III) and (II) was not reported in prior art methods, further use of pure intermediates subsequently enhances the purity of the final compound. Hence, this forms another embodiment of the present invention.

The intermediates (V), (III) and (II) may be added to a suitable solvent or mixtures of solvent and a decolorizing agent, preferably Norit activated carbon may be added at 25-30° C and filtered. The solvent may be removed by distillation and another suitable solvent or mixture of solvents may be added. The reaction mass may be heated to 50-100° C, preferably 60-90° C, more preferably to 60-65° C. The reaction mass may then be cooled to 0-30° C, preferably 25-30° C. The solid formed may be isolated to yield the required pure intermediate.
The suitable solvents used for the purification of intermediates, may be selected from a group comprising of protic or aprotic solvent. Protic solvents may be selected from a group comprising of methanol, ethanol, isopropyl alcohol (IP A), n-propanol, n-butanol, water or the like, preferably water, methanol, isopropyl alcohol or mixtures thereof. The aprotic solvents may be selected from a group comprising of acetone, acetonitrile, nitromethane, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, butyl acetate, cyclohexane, toluene, tetrahydrofuran or mixtures thereof. Preferably, water, methanol, isopropyl alcohol (IPA), dichloromethane, ethyl acetate, cyclohexane or mixtures thereof were used in the present invention.
Step e) involves cyclization of 2-amino-5-chlorobenzene sulfonamide (II) to obtain Diazoxide (I). 2-amino-5-chlorobenzene sulfonamide (II) may be reacted with a suitable reagent, preferably triethyl orthoacetate in presence of suitable base to yield Diazoxide (I).
The suitable base used in the present invention may be selected from a group comprising of inorganic and organic bases. The inorganic base may be selected from the group comprising of sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, ammonium hydroxide, or the like. Suitable organic base used in the present invention may be selected from the group comprising of triethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, or the like.

Preferably, ammonium hydroxide, sodium hydroxide and sodium carbonate were used in the present invention.
The suitable acid used in the present invention may be selected from a group comprising of may be selected from a group comprising of hydrochloric acid, hydrobromic acid, sulphuric acid, formic acid and acetic acid. Preferably, sulphuric acid and hydrochloric acid were used in the present invention.
The suitable aprotic solvents used in the present invention may be selected from a group comprising of acetone, acetonitrile, nitromethane, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, butyl acetate cyclohexane, toluene, tetrahydrofuran or the like. The suitable protic solvents used may be selected from a group comprising of methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, water or the like, preferably water, methanol, isopropyl alcohol, ethyl acetate, dichloromethane, acetonitrile, cyclohexane were used in the present invention.
In another embodiment, the present invention provides a process for the preparation of 2,4-dichloronitrobenzene (VI) by reacting m-dichlorobenzene (VII) with mixed acid and neutralized with a suitable base preferably sodium bicarbonate. The organic layer was separated and 2,4-dichloronitrobenzene was isolated.
In another embodiment, the present invention provides a process for the preparation of 2,4-dichloronitrobenzene (VI) by reacting m-dichlorobenzene at 40° C in a water bath and adding 99.0 g of mixed acid (49.0 g of 99% nitric acid, 50.5 g of 98% sulfuric acid). The hot water formed was removed and cold water added to maintain the temperature at 45 to 50° C. The organic phase was separated and washed with 5% sodium bicarbonate solution and heated to 60-70° C and cooled to 25-30° C to yield 2,4-dichloronitrobenzene (VI).

In another embodiment, the present invention further provides a process for the purification of Diazoxide (I) comprising:
i. providing a solution of Diazoxide (I) in a protic solvent or mixtures
thereof; ii. heating the reaction mass;
iii. cooling the reaction mixture to a suitable temperature; and iv. isolating pure Diazoxide (I).
Diazoxide (I) crude was dissolved in a suitable protic solvent or mixture of protic solvents. Purification may be carried out at the temperature of 60-80° C, more preferably 60-70° C. The reaction mixture may be cooled to 0-30° C, preferably to 10-30° C and more preferably 25-30° C.
As used herein the term "highly pure" refers to the compound with purity greater than 99.0% by HPLC, preferably greater than 99.5% by HPLC.
The suitable solvents used for the purification may be selected from a group comprising of protic or aprotic solvent. Protic solvents may be selected from a group comprising of methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol, water or the like, preferably water, methanol, isopropyl alcohol or mixtures thereof. The aprotic solvents may be selected from a group comprising of acetone, acetonitrile, nitromethane, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, butyl acetate cyclohexane, toluene, tetrahydrofuran or mixtures thereof. Preferably, methanol was used in the present invention.
In some embodiment, Diazoxide (I) obtained after purification is having heavy metals below 10 ppm. Particle size of Diazoxide (1) is controlled less than 200 um
In some embodiment Diazoxide (I) obtained after purification is having impurity A less than 0.15% and impurity B less than 0.15% (w/w).

EXAMPLES
EXAMPLE 1: Preparation of Benzyl(5-chloro-2-nitrophenyI) sulfane (V)
100 g of 2,4-dichloronitrobenzene (VI) dissolved in 500 mL of methanol was added to a reaction mixture containing 65 g of benzyl chloride, 40 g of thiourea dissolved in 500 mL of methanol. To this ammonium hydroxide was added and the reaction mixture was heated to 65-70 °C. To the resulting solution, 138g of sodium carbonate

was added at 65-70 °C and reaction mass was cooled to 25-30 °C, filtered and washed with methanol to yield Benzyl(5-chloro-2-nitrophenyl) sulfane (V). Yield: 50%; Purity: 84%
EXAMPLE 2: Purification of Benzyl (5-chloro-2-nitrophenyl) sulfane (V)
The obtained solid in example-1 was dissolved in 700ml of dichloromethane, treated with 3g of Norit activated charcoal and filtered through Hyflo. The filtrate was distilled off under vacuum at below 50 °C. To this, 50 mL of ethyl acetate and 450 mL of methanol were added and heated to 65-70 °C. The reaction mixture was cooled to 25-30 °C. The solid formed was filtered, washed with 50 mL of methanol and dried under vacuum to yield pure Benzyl(5-chloro-2-nitrophenyl)sulfane (V). Yield: 45%; Purity: 95.6%.
EXAMPLE 3: Preparation of 5-chloro-2-nitrobenzene-l-sulfonyl chloride (IV)
100 g of Benzyl(5-chloro-2-nitrophenyl)sulfane (V) was dissolved in 700 ml of acetonitrile at 25-30° C and cooled to 0-5° C. To the reaction mass 300 ml of 2N hydrochloric acid and 212 g of l,3-dichloro-5,5-dimethylhydantoin were added and stirred at 0-5° C to yield 5-chloro-2-nitrobenzene-l-sulfonyl chloride (IV). The obtained intermediate was directly used in the next step without isolation.
EXAMPLE 4: Preparation of 5-chloro-2-nitrobenzene Sulfonamide (III).
5-chloro-2-nitrobenzene-l-sulfonyl chloride (IV) obtained in example 3 was added to a mixture of 500 mL of water and 1000 mL of dichloromethane at 25-30° C. The organic layer was separated, and 700 mL of ammonium hydroxide was added at 0-5° C. On completion of reaction, the solvent was distilled of and the concentrate was cooled to 25-30° C and filtered.
EXAMPLE 5: Purification of 5-chloro-2-nitrobenzene Sulfonamide (III).
The solid obtained in example-4 was dissolved in 200mL of cyclohexane at 25-30° C, filtered and dried. The solid was then added to 300 mL of methanol and heated to 60-65° C. Further 700 mL of water was added to the reaction mass, cooled to 25-30° C, filtered under vacuum, washed with water and dried under vacuum to yield pure 5-chloro-2-nitrobenzene Sulfonamide (III). Yield: 85%; Purity: 99.5%

Example 6: Preparation of 2-amino-5-chlorobenzene sulfonamide (II)
100 g of 5-chloro-2-nitrobenzene-l-sulfonamide (III) was added to a mixture of 1.33 g of sulfuric acid in 500 mL of ethyl acetate and then 150 g of Iron powder and stirred at 25-30° C. 100 g of 5-chloro-2-nitrobenzene-l-sulfonamide (III) was added to the reaction mass and heated to 70-75° C. 100 mL of water was added and filtered the reaction mass. The filtrate was distilled off under vacuum and the crude was dissolved in 200 mL of isopropyl alcohol and 800 mL of water at 25-30° C. The reaction mixture was heated to 80-85° C for 1 hr and cooled to 25-30° C. The solid formed was filtered under vacuum and washed with 100 mL of water. The obtained solid was dried under vacuum for below 55° C to yield 2-amino-5-chlorobenzene sulfonamide (II). Yield: 92%; Purity: 99.5%
Example 7: Preparation of Diazoxide (I)
100 g of 2-amino-5-chlorobenzene sulphonamide (II) was added to 250 mL of triethyl orthoacetate at 25-30° C. The reaction mixture was heated to 90-95° C for 4-5hrs and then cooled to 25-30° C. The obtained solid was filtered, washed with methanol and dried. The solid was then added to 500 mL of water and 400 mL of aqueous sodium hydroxide solution. The reaction mass was filtered through 0.2-micron filter. 500 mL of ethyl acetate was added to the filtrate and stirred at 25-30 ° C. Aqueous layer was separated and cooled to 10-15° C. 500 mL of hydrochloric acid was then added and maintained the reaction mass at 10-15° C. The solid precipitated was filtered and washed with 500 mL of water and dried to yield Diazoxide (I). Example 8: Purification of Diazoxide (I)
Diazoxide (I) was dissolved in 800 mL of methanol and reaction mixture was heated to 65-70° C. The reaction mixture was stirred for 1-2 hrs and cooled to 25-30° C The precipitated solid was filtered and dried under vacuum at 50-55° C to yield pure Diazoxide (I). Yield: 72%; Purity: 99.98%

We Claim:
1. A process for the preparation of Diazoxide (I)
m
comprising:
a) reacting 2,4-dichloronitrobenzene (VI)
(VI)
with thiourea and benzyl chloride to form benzyl(5-chloro-2-nitrophenyl)sulfane (V)
(V)
in presence of a suitable base; b) converting benzyl (5-chloro-2-nitrophenyl)sulfane (V) to 5-chloro-2-nitrobenzene-1-sulfonyl chloride (IV) in the presence of suitable acid;
c) aminating 5-chloro-2-nitrobenzene-1 -sulfonyl chloride (IV) to obtain 5-chloro-2-nitrobenzene-l-sulfonamide (III), using suitable aminating agent;

d) reducing 5-chloro-2-nitrobenzene-l-sulfonamide (III) to 2-amino-5-chlorobenzene sulfonamide (II)
using suitable reducing agent; and e) cyclizing 2-amino-5-chlorobenzene sulfonamide (II) with a suitable reagent, in presence of suitable base and purifying to form Diazoxide
(I)-
2. The process as claimed, in claim 1, wherein the suitable base used in the
present invention is selected from a group comprising of sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, ammonium hydroxide, triethyl amine, diethyl amine, morpholine, N-methyl morpholine, pyridine .
3. The process as claimed, in claim 1, wherein the suitable acid used in the present invention may be selected from a group comprising of hydrochloric acid (HC1), hydrobromic acid, trifluoroacetic acid (TFA), nitric acid, sulphuric acid, boric acid, periodic acid, phosphoric acid, p-toluene sulfonic acid, methane sulfonic acid, formic acid and acetic acid.
4. The process as claimed, in step b) of claim 1, wherein the suitable aminating agent is ammonium hydroxide.
5. The process as claimed, in step e) of claim 1, wherein the suitable reagent used is triethyl orthoacetate.

6. The process as claimed, in claim 1, wherein the suitable solvents used is selected from a group comprising of acetone, acetonitrile, nitromethane, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, butyl acetate cyclohexane, toluene, tetrahydrofuran, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, water or mixture thereof, preferably water, methanol, isopropyl alcohol, ethyl acetate, dichloromethane, acetonitrile, cyclohexane or mixtures thereof.
7. A process for the purification of Diazoxide (I) comprising:
i. providing a solution of Diazoxide (I) in a protic solvent or mixtures
thereof; ii. heating the reaction mass;
hi. cooling the reaction mixture to a suitable temperature; and iv. isolating pure Diazoxide (I) with purity more than 99.0%.
8. The process as claimed, in claim 7, wherein the suitable solvents used for
the purification, is selected from a group comprising of methanol, ethanol,
isopropyl alcohol (IPA), n-propanol, n-butanol, water ,acetone, acetonitrile,
1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-
dimethylformamide, methyl tertiary butyl ether, hexane, butyl acetate
cyclohexane, toluene, tetrahydrofuran or mixtures thereof.
9. A process for the purification of the intermediates (V), (III) and (II), with
more than 95.0% purity, comprising of:
a) providing a solution of suitable intermediate in a suitable solvent or mixtures of solvent;
b) adding a suitable decolorizing agent;
c) filtering and removing the excess solvent;
d) adding a suitable solvent;
e) heating the reaction mass;
f) cooling the reaction mass; and
g) isolating the required intermediate.

10. The process as claimed, in claim 9, wherein the suitable solvents used for the purification, is selected from a group comprising of methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol, water ,acetone, acetonitrile, nitromethane, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, butyl acetate cyclohexane, toluene, tetrahydrofuran or mixtures thereof.