FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
A Process for Preparation of Albendazole intermediate
SeQuent Scientific Limited
A Company Incorporated Under The Companies Act, 1956
Having Registered Office at
116 Vardhman Industrial Complex, L.B.S Marg,
Thane (W), Mumbai - 400601, India
The following specification particularly describes the nature of the invention and the manner in which it has to be performed:

FIELD OF INVENTION
The present invention relates to a novel process for the preparation of 4-(propylthio)benzene-l,2-diamine, a key intermediate of an anti-parasite bulk drug albendazole.
BACKGROUND OF THE INVENTION
Albendazole having chemical name methyl-[6-(propylthio)-lH-benzoimidazol-2-yl]carbamate of formula 1, is a member of the benzimidazole compounds used as a drug indicated for the treatment of a variety of worm infestations. Albendazole was first discovered at- the SmithKline Animal Health Laboratories in 1972. It is a broad spectrum anthelmintic, effective against roundworms, tapeworms, and flukes of domestic animals and humans. It is efficient antiparasitic agent that has good result of treatment not only to pinworm, ascarid, hookworm and whipworm in the animal bodies such as pig, ox, sheep, but it is also suitable for the treatment to prop up testis trematode, cestode, Echinococcus hydatid cyst, trichina, cysticercus worm etc.

The compound 4-(propylthio)benzene-l,2-diamine of formula II is a key intermediate in the preparation of albendazole of formula I.


There are number of literatures available which describe the process for preparation of albendazole using 4-(propylthio)benzene-l,2-diamine of formula II. US patent 4152522 describes a process in which 2-nitroaniline is thiocyanated to obtain 2-nitro-4-thiocyanoaniline, then alkylated with n-propyl bromide in presence of n-propanol and methyl tributyl ammonium chloride or tetrabutyl ammonium bromide as the phase-transfer catalyst and an alkali metal cyanide or alkaline metal cyanide to generate 4-propylthio-2-nitroaniline. 4-propylthio-2-nitroaniline is reduced by sodium sulphide monohydrate in presence of water to obtain 4-(propylthio)benzene-l,2-diamine. This diamine is further reacted with sodium salt of methyl-N-cyano carbamate to obtain the albendazole. In this process phase transfer catalyst as well as an alkali metal cyanide or alkaline metal cyanide is used for condensation of 2-nitro-4-thiocyanoaniline with n-propylbromide, which adds to the cost of production, increases the organic material content in effluent and may facilitate the formation of impurity and uses toxic cyanide compound. The reduction of 4-propylthio-2-nitroaniline is done in presence of water as a solvent which makes the reaction sluggish.
CN 10270068 describes a process for the preparation of 2-nitro-4-(propylthio) aniline in which 2-nitro-4-thiocyanatoanaline in C1-4 alkyl alcohol was treated with 20-60 wt.% sodium hydroxide or potassium hydroxide solution at 50-120°C for 6-11 hours, cooled to room temperature. n-Propyl bromide and polyethylene glycol were added to the above reaction mass, refluxed, cooled to room temperature. Two layers were separated, 20-80 wt.% zinc chloride solution was added under stirring, filtered and aqueous methanol solution was added. 20-60 wt. % sodium hydroxide or potassium hydroxide solution was added, stirred, filtered and vacuum dried to obtain the final product.
CN 101270091 describes a process for the preparation of albendazole in which 2-nitro-4-thiocyanatoaniline in CI-4 alkyl alcohol was treated with NaOH or KOH solution and n-propyl bromide and poly(ethylene glycol) were added to the above reaction mass and refluxed. The obtained two layers were separated and treated with 20-80 wt. % zinc chloride in presence of aqueous methanol solution and NaOH or KOH to obtain 2-nitro-4-propylthioaniline. The obtained 2-nitro-4-propylthioaniline

was dissolved in C1-4 alkyl alcohol, treated with activated carbon, FeCl3 and hydrazine hydrate to obtain 4-(propylthio)benzene-l,2-diamine. This is further used to make Albendazole.
The major drawbacks of the prior art process is the use of costly alkyl halide such as n-propyl bromide for the alkylation of 4-(propylthio)benzene-l,2-diamine. It also involves isolation of 4-propylthio-2-nitroaniline, which makes the preparation a two steps process. The prior art process also uses additional alcoholic solvent for the reduction of 4-propylthio-2-nitroaniIine. Further the prior art process generates large quantity of effluents. Theses drawbacks provide a good opportunity to develop a process which will overcome these drawbacks.
The present inventors have developed a very cost effective and environment friendly process, which overcomes most of the above stated drawbacks.
SUMMARY OF THE INVENTION
Accordingly, the main aspect of the invention is to provide a process for the preparation of 4-(propylthio)benzene-l,2-diamine of formula 11, comprising:
a) alkylating 2-nitro-4-thiocyanoaniline of formula IV using n-propanol and a base in absence of a alkyl halide to obtain 4-propylthio-2-nitroaniline of formula III; and
b) reacting, optionally insitu, 4-propylthio-2-nitroanitine prepared in step a) with an aqueous alkali metal sulfide, alkali metal bisulfide or an alkaline metal sulfide to obtain 4-(propylthio)benzene-l,2-diamine of formula II.
The above process may be illustrated by the below reaction scheme:


DETAIL DESCRIPTION OF THE INVENTION
Accordingly in an embodiment of the invention, the base for alkylation of 2-nitro-4-thiocyanoaniline of formula IV is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, sodium bicarbonate and mixture thereof. Potassium carbonate and sodium hydroxide are used as base preferably. The alkylation is carried out at temperature in the range of 85-110°C preferably at 90-100°C.
In another embodiment of the invention, the reduction in step b) is carried out insitu using aqueous alkali metal sulfide, alkali metal bisulfide or an alkaline metal sulfide selected from the group consisting of sodium hydrogen sulfide, sodium disulfide, magnesium sulfide and calcium sulfide, preferably sodium hydrogen sulfide. The reduction may be carried out at a temperature in the range of 30-80°C preferably at 50-60°C for 2 to 7 hours preferably for 3-4 hours. The obtained 4-(propylthio)benzene-l,2-diamine of formula II is distilled at the temperature range 180-230 °C under high vacuum.
Some of the key advantages of the present invention are stated below:
1. The present invention provides an insitu process for the preparation of 4-(propylthio)benzene-l,2-diamine of formula II, whereas in the prior art it is prepared by two steps process.
2. The present invention avoids the use of costly n-propyl bromide for alkylation of 2-nitro-4-thiocyanoaniline, thus making the process of the present invention very cost effective.
3. The reduction in the present invention is carried out insitu which avoids the workup for isolation of 4-propylthio-2-nitroaniline and also avoids the use of additional solvent for the reduction. Thus the generation of effluent is minimized.

The present invention can be illustrated by the following examples, which are not to limit the scope of invention.
Example 1: Preparation of 4-(propylthio)benzene-l,2-diamine of formula II
(a) Preparation of 4-propylthio-2-nitroaniline
2-Nitro-4-thiocyanoaniline (200 g) in 1600 mL of n-propanol was stirred for 10-15 minutes at 25-30 °C and potassium carbonate (144 g) was added to it. The reaction mass was heated to reflux at 90-100 °C and maintained for 3 hours. Sodium hydroxide (50 g) was added, heated to reflux at 90-100°C for 2 hours. After completion of the reaction, the reaction mass was cooled to 25-30°C under stirring and distilled out to remove n-propanol completely at 50-60°C under vacuum to afford the title compound.
(b) Preparation of 4-(propylthio)benzene-l,2-diamine
Sodium hydrogen sulfide (900 mL) was added slowly to the residue obtained from example 1 (a) at 50-60°C and stirred for 3-4 hours at 50-60°C. After completion of the reaction, reaction mass was cooled and two layers were separated. Organic layer containing the product was subjected to a high vacuum distillation to obtain title compound.
Yield: 80%. Purity: 98.99%

We claim:
1. A process for the preparation of 4-(propylthio)benzene-l,2-diamine of formula II, comprising:

a) alkylating 2-nitro-4-thiocyanoaniline of formula IV using n-propanol and a base in absence of a alkyl halide to obtain 4-propylthio-2-nitroaniline of formula III; and

b) reacting, optionally insitu, 4-propylthio-2-nitroaniline prepared in step a) with an aqueous alkali metal sulfide, alkali metal bisulfide or an alkaline metal sulfide to obtain 4-(propylthio)benzene-l,2-diamine of formula II.
2. A process according to claim 1, wherein the step (b) is carried out insitu.
3. A process according to claim 1, wherein the base in step (a) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, sodium bicarbonate and mixture thereof.
4. A process according to claim 1, wherein the base in step (a) is potassium carbonate and sodium hydroxide.
5. A process according to claim 1, wherein the alkylation in step (a) is carried out at temperature in the range of 85-110°C.

6. A process according to claim 1, wherein the alkylation in step (a) is carried out at temperature in the range of 90-100°C.
7. A process according to claim 1, wherein the alkali metal sulphide, alkali metal bisulfide or an alkaline metal sulphide in step (b) is selected from the group consisting of sodium hydrogen sulfide, sodium disulfide, magnesium sulfide and calcium sulfide.
8. A process according to claim 1, wherein the reaction in step (b) is carried out in presence of sodium hydrogen sulfide.