FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
A Process for Preparation of l-(4-Isothiocyanatophenoxy)-4-nitrobenzene
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 l-(4-Isothiocyanatophenoxy)-4-nitrobenzene, commonly known as Nitroscanate.
BACKGROUND OF THE INVENTION
Nitroscanate having chemical name l-(4-Isothiocyanatophenoxy)-4-nitrobenzene represented by formula I, is used in veterinary medicine to treat Toxocara canis, Toxascaris leonina, Ancylostoma caninum, Uncinaria stenocephalia, Taenia, and Dipylidium caninum (roundworms, hookworms and tapeworms).

There are number of literatures available which describe the process for preparation of nitroscanate. US product patent 3697555 describes one step process for preparation of nitroscanate by treating a suspension of 4-nitro-4'-amino-diphenyl ether in water with thiophosgene in ice-water.
CN85104247 patent describes one step process for preparation of nitroscanate by treating 4-nitro-4'-amino-diphenyl ether with carbon disulfide and triethyl amine.
GB2328435 patent describes a process for preparation of nitroscanate by reacting l-chloro-4-Nitrobenzene with 4-Acetamidophenol using dimethylformamide as a solvent to give N-[4-(4-nitrophenoxy)phenyl]acetamide. Treating N-[4-(4-nitrophenoxy)phenyl]acetamide with concentrated hydrochloric

acid in presence of water and IMS to give 4-(4-nitrophenoxy)aniIine and further treating 4-(4-nitrophenoxy)aniline with ammonium thiocyanate gives l-[4-(4-nitrophenoxy)phenyl]thiourea, which on further treating with chlorobenzene gives crude nitroscanate. This process involves crystallisation of N-[4-(4-nitrophenoxy)phenyl]acetamide using IMS.
Most of the reported prior art process for the preparation of nitroscanate involves the reagents such as carbon disulphide and thiophosgene. These reagents are hazardous, teratogenic and mutagenic. Also prior art process is time consuming and requires additional recrystallization in step (a) to obtain pure intermediate compounds. Thus there is a need to develop a process for the preparation of nitroscanate, which avoids the use of hazardous, teratogenic and mutagenic reagents, as well as reduces the reaction time significantly.
The present inventors have developed a cost effective process for the preparation of pure nitroscanate in good yield which avoids the above stated reagents have comparatively short reaction time.
SUMMARY OF THE INVENTION
The principal aspect of the present invention is to provide a process for the preparation of l-(4-Isothiocyanatophenoxy)-4-nitrobenzene of formula I, which comprises:
a) condensation of l-chloro-4-nitrobenzene of formula V with N-(4-hydroxyphenyl)acetamide of formula VI in presence of a base and solvent to give N-[4-(4-nitrophenoxy)phenyl]acetamide of formula IV;
b) hydrolysis of N-[4-(4-nitrophenoxy)phenyl]acetamide of formula IV in presence of an acid in a solvent to give 4-(4-nitrophenoxy)aniline hydrochloride of formula III;

c) reaction of 4-(4-nitrophenoxy)aniline hydrochloride of formula III with ammonium thiocyanate in presence of a solvent to obtain l-[4-(4-nitrophenoxy)phenyl]thiourea of formula II; and
d) deamination of l-[4-(4-nitrophenoxy)phenyl]thiourea of formula II using base in presence of a solvent forms l-(4-Isothiocyanatophenoxy)-4-nitrobenzene of formula I.
The process of the present invention may be illustrated as in the scheme below:


DETAIL DESCRIPTION OF THE INVENTION
Accordingly in an embodiment of the invention, the condensation of 1-chloro-4-nitrobenzene of formula V with N-(4-hydroxyphenyl)acetamide of formula VI is carried out in presence of a base selected from an alkali metal carbonates and bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate etc. preferably potassium carbonate. The solvent for the said condensation selected from the group consisting of ethyl acetate, toluene, benzene, xylene, DMF, THF and the like, preferably DMF and the condensation is carried out at reflux temperature in the range of 120-160° C, preferably at 135-145° C to obtain N-[4-(4-nitrophenoxy)phenyl]acetamide of formula IV.
In another embodiment of the invention, N-[4-(4-nitrophenoxy)phenyI] acetamide of formufa IV in step (b) is hydrofysed by an acid selected from the group comprising hydrochloric acid, sulphuric acid and the like, preferably hydrochloric acid in presence of solvent selected from the group consisting of methanol, ethanol, propanol, butanol, isopropanol, preferably methanol at temperature 60-100°C preferably at 75-85°C to obtain 4-(4-nitrophenoxy)aniline hydrochloride of formula III.
In still another embodiment of the invention, reaction of 4-(4-nitrophenoxy)aniline hydrochloride of formula III with ammonium thiocyanate in step (c) is carried out in a solvent selected from the group consisting of toluene, isopropanol and mixtures thereof, preferably toluene and isopropanol at a temperature in the range of 70-90 °C to form l-[4-(4-nitrophenoxy)phenyl]thiourea of formula II. The obtained compound of formula II is further crystallised in an alcoholic solvent preferably in methanol.
In yet another embodiment of the invention, deamination of l-[4-(4-nitrophenoxy)phenyl]thiourea of formula II is carried out in presence of a base selected from the group consisting of pyridine, methyl amine, triethylamine, imidazole, benzimidazole, histidine, N-methyl morpholine and the like, preferably in presence of pyridine. The solvent for deamination is selected from the group of

inert organic solvents comprising ethyl acetate, toluene, benzene, xylene, DMF, THF and the like. Preferably the solvent is xylene. The deamination is carried out at reflux temperature to form l-(4-Isothiocyanatophenoxy)-4-nitrobenzene of formula I. The use of base as a catalyst reduces the deamination time significantly.
In still further embodiment of the invention, the crude product obtained is purified using a ketonic solvent selected from the group consisting of acetone, methyl ethyl ketone, methyl butyl ketone or its mixture thereof. Preferably it is purified in methyl ethyl ketone at the temperature range 60-100°C preferably at 75-85°C.
The present invention can be illustrated by the following examples, which are not to limit the scope of invention.
Example 1: Preparation of l-(4-Isothiocyanatophenoxy)-4-nitrobenzene of formula I
(a) Preparation of N-[4-(4-nitrophenoxy)phenylacetamide
Dimethyl formamide (810 mL), N-(4-hydroxyphenyl)acetamide (244 g) and p-Chloronitrobenzene (PCNB) (250 g) were charged into a flask at room temp with stirring. Potassium carbonate (124 g) was charged to the above flask at room temperature and heated to 138-140°C (reflux) for 10-18 hrs. After completion of reaction, reaction mass was cooled to room temperature. Water was charged to another flask, above reaction mass was transferred to this flask, yellow solids were observed at room temperature. 25 %NaOH solution (41 g) was slowly added and dark yellow solids were observed. The reaction mass was filtered, washed with hot water then with cold water suck dried and dried at 60~65°C for 6-8 hrs.
(b) Preparation of 4-(4-nitrophenoxy)aniline hydrochloride
Methanol (600 mL), step (a) material was charged into a flask under stirring at room temperature and. heated to 60-65°C. Concentrated hydrochloric acid (465 g) was added slowly added, after complete addition reaction mass was

heated to reflux at 80-82°C for 6-8 hrs. After completion of reaction, reaction mass was cooled to room temperature, water (840±20 mL) was added to the above reaction mass, cooled to 10-15°C and maintain for lhour at 10-15°C. Reaction mass was filtered, suck dried and dried at 60-65°C for 8-10 hrs.
(c) Preparation of l-[4-(4-nitrophenoxy)phenyllthiourea
Toluene (1400 mL), IPA (350 mL) and step (b) material (400 g) was charged into a flask, stirred at 30°C for 30 minutes. Ammonium thiocyanate (390 g) was added to the above reaction mass, temperature was raised to 80°C within I-
2 hours. Sulphuric Acid (16 g) was slowly added to the above reaction mass at
80°C within 2 hrs, refluxed for 6-8 hrs. After completion of reaction, reaction mass
was cooled to room temperature (30°C) and maintained for 1 hour, washed with
50-80 liters of Toluene and with hot water (80-90°C) for 4 to 5 hrs, suck dried for
1 hr. Methanol (800 mL) and wet cake were charged into another flask at 30°C,
reflux for 2 hours and cooled to 30°C. Solids were filtered, washed with methanol
and dried at 60-70°C for 6-8 hrs.
(d) Preparation of l-(4-Isothiocyanatophenoxy)-4-nitrobenzene
Xylene (1000 mL) and step (c) material (100 g) was charged into a flask under stirring, stirred for 15 minutes. Pyridine (2.5 ml) was slowly added to the above reaction mass, heated to reflux temperature [I35-140°C]. After refluxing for
3 hours 2 ml of pyridine was added through dropping funnel. Again after 6 hours
of reflux. 1.5 ml of pyridine was added through dropping funnel. Further after 9
hours of reflux, 1.5 ml of pyridine was added through dropping funnel. After 12
hours of reflux, the reaction mass becomes almost clear solution. TLC was
checked for completion of reaction, if reaction is incomplete, additional 0.5 ml of
Pyridine is charged and reflux continued for next 3 hrs. After completion of
reaction, reaction mass was cooled to 25-30°C. Reaction mass was filtered, filtrate
was collected. Filter bed was washed with xylene (100 mL). Xylene was distilled
under vacuum by maintaining the temperature below 95°C (600 to 650 mm of
Hg).The reaction mass was chilled till temperature reaches 8 - 10 °C, maintained

for 1 hour at 8 - 10 °C. The reaction mass was filtered, wash with xylene and suck dried.
(e) Purification of l-(4-Isothiocyanatophenoxy)-4-nitrobenzene
Methyl ethyl ketone (MEK) (1350-1710 g) and crude step (d) material was charged into the flask under stirring at room temperature, heated to 55-65 °C to get clear solution, if not clear add more MEK with stirring. Activated carbon (4.5 ± 0.45 g) was added to the above reaction mass, stirred for 30 minutes and heated to 75-85°C for 2hours. The reaction mass was filtered through hyflo bed, MEK was distilled out and cooled to room temperature, again cooled to 0-5°C, maintained for 2 hours and filtered. MEK was charged to another flask containing wet cake in the ratio 1:0.8, refluxed for 2hours (75-80°C). The reaction mass cooled to room temperature, further to 0-5°C, maintain for 2 hours and filtered. This step is once again repeated. The wet cake was dried at 50-60°C for 3-4 hours.

We claim;
1. A process for preparation of l-(4-Isothiocyanatophenoxy)-4-nitrobenzene (nitroscanate) of formula I comprising:

a) condensation of l-chIoro-4-nitrobenzene of formula V with N-(4-hydroxyphenyI)acetamide of formula VI in presence of a base and solvent to give N-[4-(4-nitrophenoxy)phenyl]acetamide of formula IV;

b) hydrolysis of N-[4-(4-nitrophenoxy)phenyl]acetamide of formula IV in presence of an acid in a solvent to give 4-(4-nitrophenoxy)aniline hydrochloride of formula III;


c) reaction of 4-(4-nitrophenoxy)aniline hydrochloride of formula III with ammonium thiocyanate in presence of a solvent to obtain l-[4-(4-nitrophenoxy)phenyl]thiourea of formula II; and

deamination of l-[4-(4-nitrophenoxy)phenyl]thiourea of formula II using base in presence of a solvent forms l-(4-Isothiocyanatophenoxy)-4-nitrobenzene of formula I.
2. A process according to claim 1, wherein the base in step (a) is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate etc.
3. A process according to claim 1, wherein the solvent in step (a) is selected from ethyl acetate, toluene, benzene, xylene, DMF, THF and the like.
4. A process according to claim 1, wherein the condensation in step (a) is carried out at 135-145° C.
5. A process according to claim 1, wherein the acid in step (b) is selected from hydrochloric acid, sulphuric acid and the like.
6. A process according to claim 1, wherein the solvent in step (b) is selected from methanol, ethanol, propanol, butanol, isopropanol.
7. A process according to claim 1, wherein the reaction in step (b) is carried out at 75-85°C.

8. A process according to claim 1, wherein solvent in step (c) is selected from toluene, isopropanol and mixtures thereof.
9. A process according to claim 1, wherein base in step (d) is selected from pyridine, methyl amine, triethylamine, imidazole, benzimidazole, histidine, N-methyl morpholine and the like.
10. A process according to claim 1, wherein solvent in step (d) is selected from ethyl acetate, toluene, benzene, xylene, DMF, THF and the like.