FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION (See section 10 and rule 13)
1. TITLE OF THE INVENTION
One pot process for the preparation of 4-propylthio-1,2-phenylenediamine, an intermediate in the preparation of albendazole
2. APPLICANT(S)
(a) NAME : CADILA PHARMACEUTICALS LIMITED
(b) NATIONALITY: An INDIAN Company
(c) ADDRESS : "Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat,
Ahmedabad - 382210, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
COMPLETE SPECIFICATION
The following specification particularly describes the invention and the manner in which it is to be performed
4. DESCRIPTION
(Description starts from next page)

FIELD OF THE INVENTION:
The present invention relates to a one pot process for the preparation of 4-propylthio-1,2-phenylenediamine (formula I) from 4-thiocyanato-2-nitroaniline (formula II), an intermediate in the preparation of albendazole.
BACKGROUND OF THE INVENTION:
4-propylthio-o-phenylenediamine [also known as 4-(propylthio-1, 2-Benzenediamine] of formula I is a key intermediate for the preparation of albendazole.

U.S. Patent no. 4152522 describes the preparation of 4-propylthio-o-phenylenediamine from 4-thiocyanato-2-nitroaniline in two steps. 4-propylthio-2-nitroaniline is prepared using n-propyl bromide, phase transfer catalyst and an aqueous solution of sodium cyanide which is further converted to 4-propylthio-o-phenylenediamine using sodium sulfide nonahydrate as a reducing agent. Process involves multiple steps and tedious workup procedure. Additionally, sodium cyanide is a poisonous chemical and use on large scale is unsuitable.
Chinese Patent no. 101270091 describes the preparation of 2-nitro-4-propylthioaniline from 2-nitro-4-thiocyanatoaniline using 1-bromopropane and hydroxide base.
Chinese publication, Chinese Chemical Letters (2004), 15(4), 394-396 uses RU3(CO)12/PEDPA complex as catalyst in the CO for selective reduction of 4-propylthio-2-nitroaniline. Use of Ru3(CO)12/PEDPA complex and carbon monoxide under pressure

which restricts its industrial application.
Chinese publication, Jingxi Huagong (2003), 20(7), 437-439 describes the synthesis of 4-propylthio-o-phenylenediamine by CO selective reduction of 4-propylthio-2-nitroaniline using Ru3(CO)9(TPP)3 [TPP: triphenylphosphine] catalyst. Use of Ru3(CO)9(TPP)3 [TPP: triphenylphosphine] and carbon monoxide under pressure restricts its commercial exploitation.
Hungarian Patent no. 52755 describes the preparation of the diamines (I) (R = alkyl, haloalkyl, phenyl, benzyl, alkenyl; R1 = NH2; X = S, SO) and their salts by reducing the nitroanilines (II) (R1 = NO2) with NH2NH2 using metal catalysts.

There is a need to provide industrially viable process for the preparation of 4-propylthio-1,2-phenylenediamine which reduces number of steps and reaction time. The same is used as an intermediate for the preparation of albendazole.
OBJECT OF THE INVENTION:
The object of the present invention is to provide a one pot process for the preparation of 4-propylthio-1,2-phenylenediamine from 4-thiocyanato-2-nitroaniline, an intermediate in the preparation of albendazole.
Another object of the present invention is to provide a process wherein a single reagent is used to carry out more than one chemical transformation thereby reducing number of reagents.
SUMMARY OF THE INVENTION:
The present invention provides a one pot process for the preparation of 4-propylthio-o-phenylenediamine of formula I by reacting 4-thiocyanato-2-nitroaniline of formula II with

propyl halide using alkali metal sulfide in organic solvent to obtain 4-propylthio-2-nitroaniline of formula III and reducing it using alkali metal sulfide in presence of alkali metal hydroxide to obtain 4-propylthio-o-phenylenediamine of formula I and further converting it to albendazole using prior art methods.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a one pot process for the preparation of 4-propylthio-o-phenylenediamine (formula I) from 4-thiocyanato-2-nitroaniline (formula II) comprising the steps of:
(a) reacting 4-thiocyanato-2-nitroaniline of formula III

with propyl halide using alkali metal sulfide in organic solvent to obtain 4-propylthio-2-nitroaniline of formula III;

(b) reducing 4-propylthio-2-nitroaniline of formula IIIH using alkali metal sulfide in presence of alkali metal hydroxide to obtain 4-propylthio-o-phenylenediamine of formula I; and

(c) converting 4-propylthio-o-phenylenediamine of formula I to albendazole using prior art methods.

Propyl halide is selected from the group of propyl chloride, propyl bromide or propyl iodide; preferably propyl bromide.
Organic solvent is selected from the group of C1-C6 alcohol such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol, pentanol, iso-pentanol, hexano! or mixtures thereof; preferably methanol or ethanol.
Alkali metal sulfide is selected from the group comprising of potassium sulfide or sodium sulfide; preferably sodium sulfide.
Alkali metal hydroxide is selected from the group of sodium hydroxide, potassium hydroxide, lithium hydroxide or cesium hydroxide; preferably sodium hydroxide.
The reaction is carried out at room temperature to reflux temperature.
4-propylthio-o-phenylenediamine (formula I) is further used as an intermediate for the preparation of albendazole using prior art methods.
The present invention provides "a one pot" commercially scalable process wherein alkali metal sulfide is used to convert Ar-SCN group of 4-thiocyanato-2-nitroaniline (formula II) to corresponding Ar-SNa which is further alkylated by alkyl halide to obtain Ar-SAlkyl group of 4-propylthio-2-nitroaniline (formula III) which is reduced by the same alkali metal sulfide to 4-propylthio-o-phenylenediamine (formula I). This invention reduces number of steps, reaction time and provides an easy workup procedure without the use of toxic reagents.

The invention is further illustrated by the following non-limiting examples:
Example-1: Preparation of 4-propylthio-o-phenyIenediamine:
4-thiocyanato-2-nitroaniline (50.0 gm) and ethanol (400 ml) were stirred at room temperature till clear solution was obtained. The solution was cooled to 15-20° C. n-Propyl bromide (31.54 gm) was added at 15-20°C. Sodium sulphide nonahydrate (61.9 gm), ethanol (50 ml) and water (10 ml) were charged and stirred for 15 minutes. The reaction mass was stirred for about 60 minutes at room temperature, reaction was monitored by TLC for the absence of 4-thiocyanato-2-nitroaniline. The reaction mass was cooled to 15-20°C. Sodium sulfide nonahydrate (100.0 gm), sodium hydroxide (46.15 gm) and ethanol (50 ml) were added at 15-20°C. The reaction mass was heated to reflux temperature. The reaction mass was stirred for 2-3 hrs at 75-80°C till TLC complies. Ethanol was distilled off under vacuum at 40-45°C and 4-propylthio-o-phenylenediamine was extracted with ethyl acetate. The ethyl acetate layer was collected and washed with water (2 x 200 ml). The Ethyl acetate layer was dried over anhydrous sodium sulphate and ethyl acetate was distilled off to provide 4-propylthio-o-phenylenediamine as an oily mass. Wt of Oil = 43.0 gm (Yield = 92.16 %), GC Purity = 85.8 %
Example-2: Preparation of 4-propylthio-o-phenylenediamine:
4-thiocyanato-2-nitroaniline (225.0 gm) and methanol (1250 ml) were charged in flask and the reaction mass was stirred at room temperature till clear solution obtained. The solution was cooled to 15-20°C and n-Propyl bromide (141.9 gm) was added at 15-20°C. Sodium sulphide nonahydrate (278.3 gm), methanol (150 ml) and water (50 ml) were charged and the reaction mass was stirred for 15 minutes. The reaction mass was stirred for 60 minutes at room temperature, reaction was monitored by TLC (Checked the absence of 4-thiocyanato-2-nitroaniline). The reaction mass was cooled to 15-20°C and sodium sulfide nonahydrate (450.0 gm), sodium hydroxide (200.0 gm) and methanol (100 ml) were added at 15-20°C. The reaction mass was heated at reflux

temperature for about 2-3 hrs till TLC complies (absence of intermediate formed). The methanol was distilled off under vacuum at 40-45°C and 4-propylthio-o-phenylenediamine was extracted with ethyl acetate. The ethyl acetate layer was collected and washed with water (2 x 200 ml), dried over anhydrous sodium sulphate and ethyl acetate was distilled off under vacuum to give 4-propylthio-o-phenylenediamine as an oily mass (GC Purity = 85.0 %) which was further purified by acid-base treatment to get pure 4-propylthio-o-phenylenediamine [GC Purity = 95.0 %].

We claim:
1. A process for the preparation of 4-propylthio-o-phenylenediamine (formula I) comprising the steps of:
(a) reactinq 4-thiocyanato-2-nitroaniline of formula II

with propyl halide using alkali metal "sulfide in organic solvent to obtain 4-propylthio-2-nitroaniline of formula III;

(b) reducing 4-propylthio-2-nitroaniline of formula III using alkali metal sulfide in presence of alkali metal hydroxide to obtain 4-propylthio-o-phenylenediamine of formula I; and

2. The process as claimed in claim 1, wherein propyl halide is selected from propyl chloride, propyl bromide or propyl iodide.
3. The process as claimed in claim 2, wherein propyl halide is propyl bromide.
4. The process as claimed in claim 1, wherein the alkali metal sulfide is potassium sulfide or sodium sulfide.
5. The process as claimed in claim 4, wherein the alkali metal sulfide is sodium sulfide.

6. The process as claimed in claim 1, wherein the solvent is selected from the group of C1-C6 alcohol such methanol, ethanol, iso-propanol, n-butanol, iso-butanol, pentanol, iso-pentanol, hexanol or mixtures thereof.
7. The process as claimed in claim 6, wherein the organic solvent is methanol or ethanol.
8. The process as claimed in claim 1, wherein the alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide or cesium hydroxide.
9. The process as claimed in claim 8, wherein the alkali metal hydroxide is sodium hydroxide.
10. The process as claimed in claim 1, where the reaction is carried out at room
temperature to reflux temperature.