FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
"METHOD FOR THE SIMPLIFIED PRODUCTION OF FASCIOLICIDE AND DERIVATIVE THEREOF"
2. APPLICANT
NAME : LASA LABORATORY PVT. LTD
NATIONALITY: INDIAN
ADDRESS : PLOT NO. C-105, MAHAD M.I.D.C,
INOL AREA, MAHAD, DIST- RAIGAD, PIN-402309, MAHARASHTRA, INDIA.
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION
Present invention is related to method for the simplified production of fasciolicide and derivative thereof. According to present invention, the derivative of fasciolicide is produced by nitration and iodination of base compound in controlled manner.
BACKGROUND OF INVENTION
Helminth infestations are conditions of major importance causing serious health problems,, including mortality in domestic animals such as cattle, sheep, pigs, goats, dogs and poultry. Helminth infestations of particular importance in domestic animals are those of the gastrointestinal tract caused by members of the family Trichostrongylidae, for example members of the genus Haemonchus and those caused by members of the genus Fasciola, otherwise known as liver flukes.
Fascioliasis widely distributed around the world, for many countries, causing serious economic losses. In India due to this disease each year there is huge economic losses of several hundred million livestock. 4-hydroxy-3-iodo-5- nitrobenzonitrile is effective to control cattle, goat liver Fasciola infection. There is a need of synthesis technology innovation for this drug, not only to create good economic and social benefits but also to fill the gaps in production technology.
Considering the worldwide spread pollution resulted mainly due to the use and production of hazardous chemicals in industry, many countries are encouraging industries to follow green chemistry.
The synthesis method known in art are high in costs, operational difficulties, serious environmental pollution, hydrogen peroxide decomposition, dangerous, total yield is low.

The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.
SUMMARY OF THE INVENTION
Present invention provides a process for the preparation of 4-Hydroxy-3-iodo-5-
nitrobenzonitrile comprising reacting 4-hydroxybenzonitrile with nitrating agent to obtain 4-
hydroxy-3-nitrobenzonitrile and iodinating4-hydroxy-3-nitrobenzonitrile with iodine source
in presence of alcoholic solvent and oxidizing agent. Varity of nitrating agents are suitable
for this reaction like dinitrogen pentoxide, nitric acid, liquid nitrogen dioxide with gaseous
oxygen and any combination thereof. Further, an organic acid may be used in this reaction.
Iodination is accomplished by using one or more iodine source preferably selected from
potassium iodide, sodium iodide and solid iodine.
Obtained 4-Hydroxy-3-iodo-5-nitrobenzonitrile is purified preferably using alcoholic solvents.
BRIEF DESCRIPTION OF THE DRAWINGS:
For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention along with the accompanying figures and in which:
Figure 1 depicts IR spectra of 4-hydroxy-3-nitrobenzonitrile
Figure 2 depicts GC Chromatogram of 4-hydroxy-3-nitrobenzonitrile
Figure 3 depicts IR of 4-Hydroxy-3-iodo-5-nitrobenzonitrile

Figure 4 depicts HPLC Chromatogram of 4-Hydroxy-3-iodo-5-nitrobenzonitrile
DESCRIPTION OF INVENTION
While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not delimit the scope of the invention.
To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as "a", "an" and "the" are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.
The present invention relates to simplified production of fasciolicide and its derivatives.
In first aspect, present invention provides a method for production of 4-hydroxy-3-nitrobenzonitrile and its derivatives by carrying out controlled nitration by operating reactor at optimized parameters which will provide selective nitration of base compound resulting in lower operating cost of reactor and higher selective yield.
In second aspect, derivative of fasciolicide is produced by iodinating the 4-hydroxy-3-nitrobenzonitrile.


The invention is described as shown in below scheme!:
According to first aspect of the invention, production of 4-hydroxy-3-nitrobenzonitrile is carried out by reacting 4-hydroxybenzonitrile with nitrating agent. Various nitrating agents may be used for this reaction. Some of the non-limiting examples of such nitrating agents include dinitrogen pentoxide. nitric acid, liquid nitrogen dioxide with gaseous oxygen and any combination thereof. Nitration of 4-hydroxybenzonitrile is preferably carried out in presence of organic acid and more preferably in presence of aliphatic carboxylic acids at controlled temperature. Preferably nitrating agent includes nitric acid and organic acid include acetic acid. Alternatively nitration reactions can be readily carried out by placing the nitrating agents, 4-hydroxybenzonitrile and the solvent in a reaction vessel and efficiently stirring the resultant heterogeneous mixture at room temperature. The resulting nitrobenzonitriles can be obtained by simple techniques like filtration, evaporation of the solvent etc.

in second aspect of the invention, production of derivative of fasciolicide is carried out by jodinating the 4-hydroxy-3-nitrobenzonitrile. The iodination is carried out with iodine source in presence of alcoholic solvent and oxidizing agent. Any suitable iodine source may be selected from but not limited to the group consisting of potassium iodide, sodium iodide, solid iodine or any mixture thereof. The suitable alcoholic solvents include Ci to Cio straight and branched chain alcohols. Non limiting examples of such solvents include methanol, ethanol, propanol. butanol and mixture(s) thereof. Suitable oxidation agent include but not limited to oxygen, nitrous oxide, silver oxide, hydrogen peroxide and any mixture thereof. More preferably the iodination is carried out in step wise manner by controlling temperature and is carried out in presence of solid iodine, methanol and oxidation agent.
As per first embodiment of present invention, 4-hydroxybenzonitrile is reacted with nitric acid in presence of acetic acid by maintaining temperature within the range of 10°C to 25°C, more preferably in the range of 15°C to 20°C for 2 to 3 hours. After raising the temperature to up to 25°C to 30°C for 30 minutes to 1 hour, the reaction mixture is added with water under stirring and the product is isolated by simple filtration which is further dried to get solid product.
As per another embodiment of present invention, firstly methanol is diluted with water in reactor and solid iodine is added and stirred for 30 minutes at ambient temperature. Temperature is raised and maintained within the temperature range of 30°C to 40°C, more preferably at 35°C over a period of 30 minutes. 4-hydroxy-3-nitrobenzonitrile is added to reaction mass while maintaining the temperature within the range of 30°C to 35°C and the resulting reaction mixture is heated up to 60°C. Maintaining the reaction mixture temperature within the range of 50°C to 65°C and more preferably within the range of 55°C to 60°C, oxidation agent is added. More preferably, hydrogen peroxide is added as oxidation agent over a period of 2 to 3 hours and thereafter temperature is maintained for 1 hour. Heating is

applied to achieve the reflux temperature preferably within the range of 70°C to 85°C and more preferably within the range of 75°C to 79°C for 1 to 4 hours.
The present invention is further described with the help of the following examples, which are given by way of illustration all the parts, percent's and ratios are by weight unless otherwise indicated and therefore should not be construed to limit the scope of the invention in any manner.
EXAMPLES:
Ingredients of composition in weight percentage range or in other unit in following conditions:
1. Nitration of 4-hydroxybenzonitrile to obtain 4-hydroxy-3-nitrobenzonitrile:
To the solution of 4-hydroxybenzonitrile (0.0010 mmoles) in acetic acid (520 ml), was added
nitric acid solution (0.0021 mmoles) at 15°C to 20°C. The reaction mixture was stirred and
temperature was maintained at 10°C to 20°C for 2 to 3 hours. Temperature was raised slowly
up to 30°C and maintained for 60 minutes. DM water (400 ml) was added and stirred for 2
hours. Product was obtained by filtering the solid and drying at 65°C to 70°C.
Yield: 98.71%
Melting point: !44.5°Cto I45.9°C
Purity: 99.73% (By GC)
IR: As depicted in Figure I
GC Chromatogram: As depicted in Figure 2
2. Preparation of 4-Hydroxy-3-iodo-5-nitrobenzonitrile:
The mixture of water (164.5 ml) and methanol (373 ml) was taken and added solid iodine (0.00078 mmoles) and stirred for 30 minutes at ambient temperature. Then heated to 35°C and added 4-hydroxy-3-nitrobenzonitrile (0.00095 mmoles) while maintaining the

temperature within the range of 30°C to 35°C. The reaction mixture was further heated up to 50°C to 55°C. Started addition of Hydrogen peroxide at controlled rate over period of 2 to 3 hours by maintaining the temperature within the range of 55°C to 60°C. This temperature was maintained for further 1 hour. Reaction mixture was heated within the temperature range of 75°C to 79°C for 2 hours. Then it was cooled to ambient temperature and added with DM water (1050 ml). Mixture was stirred for 2 hours, filtered, washed with water. Obtained crude was taken in water and given solid sodium thiosulphate (0.00001 mmoles) wash for 30 minutes with stirring and product i.e. 4-Hydroxy-3-iodo-5-nitrobenzonitrile was collected by filtration.
3. Purification of 4-Hydroxy-3-iodo-5-nitrobenzonitrile:
Charged methanol (445 ml) and added crude 4-Hydroxy-3-iodo-5-nitrobenzonitrile (0.00090
mmoles) from example 2. Heated the reaction mixture up to 60°C to 65°C for 2 hours. Then
cooled to 25°C to 20°C, filtered and washed with methanol. The product was dried at 55°C
to 60°C.
Yield: 71.81%
Melting point: 136°Cto 139°C.
Purity: 99.49% (By HPLC)
IR: As depicted in Figure 3
HPLC Chromatogram: As depicted in Figure 4
All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to

be within the spirit, scope and concept of the invention as defined by the appended claims.

WE CLAIM:
1. A process for the preparation of 4-Hydroxy-3-iodo-5-nitrobenzonitrile comprising
the steps of:
a) reacting 4-hydroxybenzonitrile with nitrating agent to obtain 4-hydroxy-3-nitrobenzonitrile
b) iodinating 4-hydroxy-3-nitrobenzonitrile with iodine source in presence of alcoholic solvent and oxidizing agent.

2. The process of claims 1, wherein the nitrating agent in step a) is selected from dinitrogen pentoxide. nitric acid, liquid nitrogen dioxide with gaseous oxygen and any combination thereof.
3. The process of claims 2, wherein reaction step a) is carried out in presence of an organic acid.
4. The process of claim 1 and 3, wherein reaction step a) is carried out by reacting 4-hydroxybenzonitrile with nitric acid in presence of acetic acid.
5. The process of claims 1, wherein the iodine source in step b) is selected from potassium iodide, sodium iodide, solid iodine and any mixture thereof.
6. The process of claim 1. wherein the alcoholic solvent in step b) is selected from methanol, ethanol, propanol, butanol and mixture(s) thereof.
7. The process of claim 1, wherein the oxidizing agent in step b) is selected from oxygen, nitrous oxide, silver oxide, hydrogen peroxide and any mixture thereof.

8. The process of claim 1, wherein the reaction step a) is carried out by maintaining temperature within the range of 10°C to 25°C for 2 to 3 hours followed by raising temperature to up to 25°C to 30°C for 30 minutes to 1 hour.
9. The process of claim 1, wherein the reaction step b) is carried out within the temperature range of about 25°C to about 85°C.

10. The process of claim 1, further comprising purifying obtained 4-Hydroxy-3-iodo-5-nitrobenzonitrile with alcohol.
11. The process of claim 1. wherein alcohol is methanol.