FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
A Process for Preparation of 4-amino-6-(trichloroethenyl)-l,3-benzenedisuIfonamide
SeQuent Scientific Limited
A Company Incorporated Under The Companies Act, 1956
Having Registered Office at 301, 'Dosti Pinnacle', 3rd Floor,
Plot No.E7, Road No.22, Wagle Industrial Area,
Thane (W)-400 604
The following specification particularly describes the invention and the manner in which it is to be performed;

FIELD OF INVENTION
The present invention relates to a novel, cost-effective process for preparation of an anthelmintic drug. Specifically, it relates to a process for the preparation of 4-amino-6-(trichloroemenyl)-l,3-berizenedisulfonamide, commonly known as Chlorsulon.
BACKGROUND OF THE INVENTION Clorsulon is a specific narrow-spectrum veteran flukicide, approved for use in the treatment of immature and adult forms of Fasciola hepatica (Liver fluke) in cattle. It is not effective against immature flukes less than 8 weeks old. It also has activity against Fasciola gigantica. Although not approved, the drug has been used in practice in various other species (e.g., sheep, llamas). It has activity against F. magna in sheep, but is not completely effective in eradicating the organism after a single dose, thereby severely limiting its clinical usefulness against this parasite.
Clorsulon having chemical name 4-amino-6-(trichloroethenyl)-l,3-benzenedisulfonamide is represented by formula I,

The compound 3-(trichloroethenyl)aniline hydrochloride of formula III is a key starting material in the preparation of 4-amino-6-(trichloroethenyl)-l,3-benzenedisulfonamide of formula I.


There are limited literatures available for the process for preparation of clorsulon. British patent 1485897 describes a two-step process for preparation of clorsulon by treating 2-(3-aminophenyl)-l,l,2-trichloro ethylene with chlorosulfonic acid and thionylchloride to form 4-amino-6-(l,2)2-urichloro vinyl)-1,3-benzenedisulfonylchloride. Further reacting the obtained 4-amino-6-(1,2,2-urichlorovinyl)-l,3-benzenedisulfonylchloride in methylene chloride with liquid ammonia gives 4-amino-6-(trichloroethenyl)-l,3-benzenedisulfonamide.
Journal of Medicinal Chemistry, 1977, Volume 20, Issue 9, describes a process for preparing clorsulon by bischlorosulfonylating 3-(trichloroethenyl) aniline followed by reaction with ammonia.
The reported prior art process prepare key starting material 3-(trichloroethenyl)aniline hydrochloride of formula III in four steps which involves four isolation and corresponding workups. This results in lot of effluent generation which is not environment friendly. The cycle time increases significantly and thus reduces the optimum utilisation of plant. The present inventors have developed a very environment friendly in-situ process which avoids four isolations leading to drastic decrease in solvent uses, effluent generation and cycle time. The obtained 3-(trichloroethenyl)aniline hydrochloride of formula III is futher treated to get the final compound 4-amino-6-(trichloroethenyl)-l,3-benzenedisulfonamide of formula I in good yield in comparatively short reaction time.
SUMMARY OF THE INVENTION
The principal aspect of the present invention is to provide a process for the preparation of 3-(trichloroethenyl)aniline hydrochloride of formula III, which comprises:
a) reaction of 3-nitrobenzaldehyde of formula VII with chloroform in presence of a base and solvent to give 2,2,2-trichloro-l-(3-nitrophenyl)ethanoI of formula VI;

b) chlorination of 2,2,2-trichloro-l-(3-nitrophenyl)ethanol of formula VI using a chlorinating agent in presence solvent to give l-nitro-3-(l,2,2,2-tetrachloroethyl)benzene of formula V;
c) dehydrohalogenation of l-nitro-3-(l,2,2,2-tetrachloroethyl)benzene of formula V using a base in presence of a solvent to obtain l-nitro-3-(trichloroethenyl)benzene of formula IV; and
d) reduction of l-nitro-3-(trichloroethenyl)benzene of formula IV using a catalyst and a reagent to give 3-(trichloroethenyl)aniline hydrochloride of formula III.
Another aspect of the invention is to provide a process for the preparation of 4-amino-6-(trichloroethenyl)-1,3-benzenedisulfonamide of formula I, which comprises:
a) chlorosulfonylation of 3-(trichloroethenyl)aniline hydrochloride of formula III using a reagent in presence of a solvent to obtain 4-amino-6-(trichloroethenyl)benzene-l,3-disulfonyl dichloride of formula II; and
b) amination of 4-amino-6-(trichloroethenyl)benzene-l,3-disulfonyl dichloride of formula II using base in presence of a solvent to form 4-amino-6-(trichloroethenyl)-l,3-benzenedisulfonamide of formula I.
The entire process of the present invention may be illustrated by the below scheme:


DETAIL DESCRIPTION OF THE INVENTION
Accordingly in an embodiment of the invention, the reaction of 3-nitrobenzaldehyde of formula VII with chloroform is carried out in presence of a base selected from an alkali metal hydroxide solution preferably alcoholic solution of alkali metal hydroxide more preferably methanolic potassium hydroxide solution and solvent selected from the group consisting of ethyl acetate, toluene, benzene, xylene, DMF, THF and the like, preferably DMF at temperature in the range of -10 to 20°C, preferably at 0-10°C to obtain to give 2,2,2-trichloro-l-(3-nitrophenyl)ethanol of formula VI.
In another embodiment of the invention, chlorination of 2,2,2-trichloro-l-(3-nitrophenyl)ethanol of formula VI is carried out using a chlorinating agent which is a phosphorus halide selected from the group comprising phosphorus trichloride, phosphorus triiodide, phosphorus tribromide, phosphorus pentachloride, phosphorus pentafluoride preferably phosphorus pentachloride and in a solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chloroform etc. preferably chloroform at temperature in the range of -

10 to 20°C, preferably at below 10°C to obtain 1 -nitro-3-(l ,2,2,2-tetrachloroethyI)benzene of formula V .
In another embodiment of the invention, dehydrohalogenation of l-nitro-3-(l,2,2,2-tetrachloroethyl)benzene of formula V is carried out using a base selected from an alkali metal hydroxide solution preferably alcoholic solution of alkali metal hydroxide more preferably methanolic potassium hydroxide solution, and a solvent selected from the group consisting of ethyl acetate, toluene, benzene, xylene, DMF, THF and the like, preferably toluene at a temperature in the range of 70-90 °C, preferably at 70-75°C to obtain l-nitro-3-(trichloroethenyl)benzene of formula IV.
In still another embodiment of the invention, reduction of 1 -nitro-3-(trichloroethenyl)benzene of formula IV is carried out in presence a catalyst selected from the group consisting of ferric chloride, aluminium chloride, and the like, preferably ferric chloride The reagent for the reduction is preferably hydrazine hydrate and reduction is carried out at 60-90°C temperature to obtain 3-(tricnloroethenyl)aniline hydrochloride of formula III.
In still another embodiment of the invention the entire process of preparation of 3-(trichloroethenyl)aniline hydrochloride of formula III from 3-nitrobenzaldehyde of formula VII is carried out preferably in in-situ condition.
In yet another embodiment of the invention, chlorosulfonylation of 3-(trichlorovinyl)aniline hydrochloride of formula III is carried out using a reagent selected from thionyl chloride and a solvent preferably chlorosulphonic acid, at reflux temperature in the temperature range 100-140°C, preferably 115-125°C to obtain 4-amino-6-(trichloroethenyl)benzene-l,3-disulfonyl dichloride of formula II.
In still further embodiment of the invention, the amination of 4-amino-6-(trichloroethenyl)benzene-l,3-disulfonyl dichloride of formula II is carried out using a base preferably ammonia to form 4-amino-6-(trichloroethenyl)-l,3-benzenedisulfonamide of formula I. The amination of 4-amino-6-(trichloroethenyl)benzene-l,3-disulfonyl dichloride of formula II to form 4-amino-6-(trichloroethenyl)-l,3-benzenedisulfonamide of formula I is carried out preferably in in-situ condition.

In still other embodiment of the invention, the crude product obtained is purified using a solvent which is a mixture of alcohols and water selected from the group consisting of methanol, isopropanol, n-propanol and water.
In still another embodiment, the present invention has following advantages over the state of the art:
a) The four steps involved in the preparation of 3-(trichlorovinyl)aniline hydrochloride of formula III is carried out in in-situ condition.
b) The process of the present invention avoids the isolation of three intermediates.
c) The process of the present invention is very user friendly avoids the lengthy workup and in turn minimises the generation of hazardous effluent.
The present invention can be illustrated by the following examples, which are not to limit the scope of invention.
Example 1: Preparation of 4-amino-6-(trichIoroethenyl)-l,3-
benzenedisulfonamide of formula I
(a)Preparation of 3-trichloroethenyl aniline hydrochloride of formula III
Dimethylformamide (300 ml), MNBA (100 g) and Chloroform (200 ml) were taken in a round bottom flask under Nitrogen and was cooled to 0-5°C under stirring. KOH solution was added slowly in 4-6 hours under nitrogen atmosphere and stirred for 3 hours at 0-10°C. After completion of reaction, pH of reaction mass was adjusted to 5-6 by using concentrated hydrochloric acid at 0-10°C. The temperature was allowed to rise to 25-30 °C. The layers were separated, organic layer was washed with water (200 ml). Again the two layers were separated and organic layer was washed with 10% brine solution (200 ml). Two layers were separated, organic layer was distilled at 80 -85°C. The reaction mass was cooled to 30±5°C. Chloroform 400 ml was taken in a RBF and cooled to below 10°C. Phosphorus pentachloride (200 gm) was added into it. To this the above obtained

reaction mass containing 2,2,2-trichloro-l-(3-nitrophe nyl)ethanol was added slowly in 2-4 hours at 0-10°C and stirred till completion of reaction. After completion of reaction, reaction mass was quenched into ice (600 g) under stirring at below 15°C. The layers were separated, the organic layer was washed with 600 ml water and further the organic layer was washed with 10% sodium bicarbonate solution till neutral pH at 25±5°C, stirred for 30 minutes. The layers were separated, organic layer was washed with 200 ml water and chloroform was distilled out completely atmospherically from organic layer at 80±5°C. The reaction mass was cooled to 45±5°C and 70 ml methanol was added to remove chloroform traces. Methanol was charged in the obtained l-nitro-3-(l,2,2,2-tetrachloroethyl)benzene in a flask. KOH solution was added slowly to the above reaction mass at 0-5°C in 1- 3hrs. The reaction mass was allowed to attain at 25-30°C under stirring. Methanol (80-85% ) was distilled out at temperature 70-75°C. The reaction mixture was cooled to 40-50°C and toluene (545ml) and water (330 ml) was added to the above reaction mass and heated to 70-75°C. The bottom aqueous layer was separated and toluene layer was washed with water (330 ml). Activated charcoal (6.6g), anhydrous ferric chloride (3.3g) and methanol (26ml) were charged into the above reaction mass and heated to 50-55°C. Hydrazine hydrate (1 lOg) was added slowly to the above reaction mass for 2 hrs and refluxed under stirring at 60-80°C for 3 hrs. Water (200ml) was added, stirred for 30 min at 70-75°C. The reaction mixture was then passed through the Hyflo supercel, washed with hot toluene (50ml) and hot water (50ml) at 60°C. The layers were separated and organic layer was washed with 200ml water under stirring and stirred for 30 min at 70-75°C. Clear filtrate obtained was heated to 70-75°C, layers were separated and organic layer was cooled to 30±5°C. Concontrated HC1 (85g) was added slowly at 30±5°C for 2 hrs. Reaction mass was filtered, suck dried, washed with 250 ml Acetone and suck dried to obtain 3-trichloroethenyl aniline hydrochloride.
Dry weight: 115±2g.
(b) Preparation of 4-amino-6-(trichloroethenyl)benzene-l,3-
disulfonyl dichloride of formula II

Chlorosulphonic Acid (850g) and 3-(trichloroethenyl)aniline hydrochloride (150kg) were charged into a flask at 30±5°C. The temperature was then raised slowly to 120°C, maintained for 2 hours. After completion of reaction, reaction mass was cooled to 60°C. Thionyl chloride (245g) was added to the above reaction mass over 3-4 hrs. The temperature was raised to 80°C, maintained for 2 hrs and quenched to Quencher containing l000g ice+800ml EDC. The reaction mass was stirred and layers were separated.
(c) Preparation of 4-amino-6-(trichloroethenyl)-l,3-benzene
disulfonamide of formula I
Organic Layer was charged to RBF. Water (600ml) was added, cooled to 15°C. Purging of Ammonia gas below 20°C (qty 75-80g) over 6-8 hrs. Heat to reflux and maintain at reflux for 8 hrs, cooled to 30±5°C and centrifuged. Washed with water till neutral pH and dried at 70°C for 6hrs.
Dry weight: 108g
(d) Purification of 4-amino-6-(trichIoroethenyI)-l,3-benzene
disulfonamide of formula I
Methanol (766ml) and water (300ml) were charged to a cleaned RBF. Clorsulon crude (250g) was charged into the flask under stirring and heated. Charcoal (7g) was added to the flask at 70 - 75°C and refluxed for lhr. Reaction mass was filtered through Hyflo at 70 - 75°C. Filtrate back transferred to RBF. Charcoal (7g) was charged at 70 - 75°C, refluxed for lhr and filtered through Hyflo at 70 - 75°C. Filtrate again transferred to RBF, charcoal (7g) was added at 70 -75°Cand refluxed for lhr. The reaction mass was filtered through Hyflo at 70 -75°C, filtrate was transferred to RBF and cooled to 30°C. Water (200ml) was charged under stirring, cooled to 10°C, filtered and suck dried. The material obtained was unloaded. IPA (400ml) was added to the wet material 261g in a RBF under stirring. Temperature maintained to 80 - 85°Cfor lhr, cooled to 5 - 10°C, filtered and suck dried. The material was dried at 70 - 75°C for 6hrs. n-propanol (350ml) and

water (200ml) was charged into RBF. Clorsulon material (185g) was charged and heated to 65°C under stirring. Charcoal (7g) was charged into the above flask at 65°C, refluxed for 30 minutes at 80°C and filtered through Hyflo at 80 - 82°C. Filtrate was transferred to RBF, solvents were d distilled out solvents applying vacuum at 95 - 96°C up to full dryness. 150 ml water was added at 80°C under stirring, cooled to 30°C filtered, and suck dried. The material was dried at 70 - 75°C for 8hrs.
Dry weight: 132g

We claim:
1. A process for the preparation of 3-(trichloroethenyl)aniline hydrochloride of formula III, which comprises:

a) reaction of 3-nitrobenzaldehyde of formula VII with chloroform in presence of a base and solvent to give 2,2,2-trichIoro-l-(3-nitrophenyl)ethanol of formula VI;

b) chlorination of 2,252-trichloro-l-(3-nitrophenyl)ethanol of formula VI using a chlorinating agent in presence solvent to give l-nitro-3-(l,2,2,2-tetrachloroethyl)benzene of formula V;

c) dehydrohalogenation of l-nitro-3-(l,2,2,2-tetrachloroethyl)benzene of formula V using a base in presence of a solvent to obtain l-nitro-3-(trichloroethenyl)benzene of formula IV; and


d) reduction of l-nitro-3-(trichloroethenyl)benzene of formula IV using a catalyst and a reagent to give 3-(trichloroethenyl)aniline hydrochloride of formula III.
2. A process according to claim 1, wherein the base in step (a) is methanolic potassium hydroxide solution and the solvent is DMF.
3. A process according to claim 1, wherein the solvent in step (b) is selected from the group consisting of dichloromethane, dichloroethane, chloroform, carbon tetrachloride and chloroform.
4. A process according to claim 1, wherein the base for dehydrohalogenation in step (c) is selected from a solution alcoholic solution of alkali metals preferably methanolic potassium hydroxide solution, and a solvent is selected from the group consisting of ethyl acetate, toluene, benzene, xylene, DMF, and THF.
5. A process according to claim 1, wherein the catalyst for reduction in step d) is ferric chloride or aluminium chloride and the reagent for the reduction is hydrazine hydrate.
6. A process according to claim 1, wherein the 3-(trichloroethenyl)aniline hydrochloride of formula III is further converted into 4-amino-6-(trichloroethenyl)-l,3-benzenedisulfonamide of formula I comprising:


a) chlorosulfonylation of 3-(trichloroethenyl)aniline hydrochloride of formula III, using a reagent in presence of a solvent to obtain 4-amino-6-(trichloroethenyl)benzene-l,3-disulfonyl dichloride of formula II; and
b) animation of 4-amino-6-(trichloroethenyl)benzene-l,3-disulfonyl dichloride of formula II using base in presence of a solvent to form 4-amino-6-(trichloroethenyl)-l,3-benzenedisulfonamide of formula I.

7. A process according to claim 6, wherein the reagent and solvent in step a) are thionyl chloride and chlorosulphonic acid respectively.
8. A process according to claim 6, wherein the base in step b) is ammonia.
9. A process according to claim 6, wherein the obtained 4-amino-6-(trichloroethenyl)-l,3-benzenedisulfonamide of formula I is further purified by solvent selected from the group consisting of methanol, isopropanol, n-propanol, water and mixture thereof.