F0RM2
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 PREPARATION OF SALICYLANILIDE ANTIPARASITIC DERIVATIVE"
2. APPLICANT
NAME : LASA LABORATORY PVT. LTD.
NATIONALITY; INDIAN
ADDRESS : PLOT NO. C-105, MAHAD M.I.D.C.,
INOLAREA,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 relates to simplified production method of antiparasitics. More preferably the present invention relates to method for preparing derivative of Salicylanilide antiparasitics compound.
BACKGROUND OF INVENTION
Parasites, such as helminths, are found in many animals, particularly grazing animals, and are responsible for significant economic losses throughout the world. Among the helminths most frequently encountered in grazing animals such as cattle, horses, goats and sheep are trematodes, i.e., flukes, for instance, Fasciola hepatica, and nematodes such as Haemonchus contortus. A valuable tool for the treatment of homeothermic animals suffering from such parasites is N-(5-chloro-4-((4-chlorophenyi)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide (U.S. Pat. No. 4,005,218 and Merck Index, 13th Edition)
N-(5-chloro-4-((4-chlorophenyI)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide is a derivative of Salicylanilide antiparasitics compound. It is effective to control cattle, goat liver Fasciola infection. N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide and its sodium salts belongs to Salicylanilide anthelmintic for the treatment and prevention of cattle, sheep and other parasitic infections, through oral or parenteral dosage forms. It has a narrow spectrum of activity against blood sucking parasites like Barber's Pole

Worm and liver fluke. Because of its high level of effectiveness and its sustained activity, it has formed the basis of strategic drenching programs for Barbers Pole Worm caused due to parasites such as Haemonchus contortus.
The method for synthesis of N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-
hydroxy-3,5-diiodo benzamide and its salts disclosed in prior art are complicated and costly
process.
US4005218 patent disclosed iron reduction process using large amount of iron sludge resulting in
generating waste water and pollutants. Also, the products must be purified by recrystallization
which makes overall operations complicated.
CNI02180811 patent document disclosed catalytic hydrogenation method which involves use of expensive metal catalyst. Further the reaction pressure generated in this process mandates the use of higher safety devices.
Current inventions provide a simple, economical, industrially feasible and safe process for preparation of N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide.
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 INVENTION:
Invention provides a novel process for preparation of N-(5-chloro-4-((4-chlorophenyl) (cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide- Further the invention provides the process for preparation of its sodium salt. It also provides novel process for purification of N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide.
Accordingly, in one aspect the invention provides, novel process for preparation of N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide and its suitable salts comprising steps of:
a) reacting 4-chloro-l-methyl-2-nitrobenzene with 2-(4-chlorophenyl)acetonitrile in presence of alcoholic base to obtain nitro intermediate
b) reducing nitro intermediate obtained in step a) to obtain amino intermediate 2-(4-amino-2-chloro-5-methylphenyl)-2-(4-chlorophenyl)acetonitrile
c) reacting amino intermediate obtained in step b) with 2-hydroxy-3,5-diiodobenzoic acid and phosphorous trichloride to obtain N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide
d) optionally converting N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-
hydroxy-3.5-diiodo benzamide into suitable salt.

In second aspect the invention provide novel process for preparation of sodium salt of N-(5-chloro-4-((4-chIoropheny])(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide comprising treating N-(5-chloro-4-((4-chiorophenyl)(cyano)methyl)-2-methy!phenyi)-2-hydroxy-3,5-diiodo benzamide base with sodium base to obtain its sodium salt
In third aspect the invention provide novel process for purification of N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide comprising steps of:
a) refluxing the mixture of N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide and chloroaromatic solvent,
b) cooling the refluxed mixture and isolating pure N-(5-chloro-4-((4-chlorophenyt)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,s5-diiodo benzamide.
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 IRof 2-(4-amino-2-chloro-5-methylphenyl)-2-(4-chlorophenyl) acetonitrile Figure 2 depicts HPLC Chromatogram of 2-(4-amino-2-chloro-5-methylphenyl)-2-(4-chloro phenyl) acetonitrile

Figure 3 depicts IR of N-(5-chloro-4-((4-chloropheny])(cyano)methyl)-2-methyl phenyl) -2-
hydroxy-3,5-diiodo benzamide Base
Figure 4 depicts HPLC Chromatogram of N-(5-chloro-4-((4-chlorophenyl) (cyano) methyl) -2-
methylphenyl)-2-hydroxy-3,5-diiodo benzamide Base
Figure 5 depicts IR of N-(5-chloro-4-((4-chlorophenyl)(cyano) methyl)-2-methyl phenyl)-2-
hydroxy-3,5-diiodo benzamide sodium salt
Figure 6 depicts HPLC Chromatogram of N-(5-chloro-4-((4-chlorophenyl) (cyano) methyl)-2-
Figure 7 depicts HPLC Chromatogram of crude N-(5-chloro-4-((4-chlorophenyl) (cyano)methyl)-2-
methyIphenyi)-2-hydroxy-3,5-diiodo benzamide
Figure 8 depicts HPLC Chromatogram of purified N-(5-chloro-4-((4-chlorophenyl) (cyano)methyl)-
2-rnethylphenyl)-2-hydroxy-3,5-diiodo benzamide.
DESCRIPTION OF INVENTION
While the making and using of various embodiments of the preset 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 processes for production of Salicylanilide fasciolicide compound and its salts. These processes are carried out in controlled and selective manner. The present invention specifically related to production of N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide and its salts. It specifically provides the process for preparation of its sodium salt. The processes disclosed herein are operable at optimized reaction parameters which will result in to lower operating cost of reactor and higher selective yield.
According to first aspect of the invention, the process for preparation of N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide and its suitable salt comprises steps of:
a) reacting 4-chloro-l-methyl-2-nitrobenzene with 2-(4-chlorophenyI)acetonitrile in presence of alcoholic base to obtain nitro intermediate
b) reducing nitro intermediate obtained in step a) with alkali hydrosulfide to obtain amino intermediate 2-(4-amino-2-chloro-5-methyIphenyl)-2-(4-chlorophenyl)acetonitrile

c) reacting amino intermediate obtained in step b) with 2-hydroxy~3,5-diiodobenzoic acid and phosphorous trichloride to obtain N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide
d) optionally converting N-(5-chloro-4-((4-ch]orophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide into suitable salt.
The reaction scheme is represented below as Scheme 1:

Scheme 1
The reaction step a) is the coupling reaction carried out in presence of alcoholic base. Preferably alcohol in alcoholic base is selected from one or more alcohols having general formula R-OH. in which R is selected from C1 to C10 alkyl group and include straight chain alcohols and branched chain alcohols. The base can be one or more from the group having general formula X-OH wherein X is sodium, potassium, lithium or magnesium. Alternatively or additionally other bases can also be

utilized for this reaction which include but not limited to alkali metal amides and hydrides, alkali metal alkoxides and any mixture thereof. The non limiting examples of bases are sodium hydroxide, potassium hydroxide, lithium hydroxide, Magnesium hydroxide, sodium amide, sodium hydride, sodium ethanolate etc. In addition to alcoholic base, other suitable solvents may be used in this reaction which include but not limited to aromatic hydrocarbons such as benzene, toluene, xylene etc. and ethers such as dioxane, tetrahydrofuran, diethylether and the like. Preferably, this reaction is carried out by maintaining temperature in the range of about 40°C to 55°C, more preferably in the range of 45°C to 50°C for 3 to 6 hours and more preferably for 5 hours.
Reduction in step b) is achieved in situ using one or more reducing agents and in the same solvent system. Additionally water can be added to reaction mixture. The non limiting examples of reducing agents include alkali metal sulfides, alkali metal hydrosulfides and any mixture thereof in the presence of alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate etc. These reducing agents can be added in their aqueous solution form.
Additional aromatic hydrocarbon solvents may be added before or after reduction step. When in addition to another solvent water is added at any stage in step a) and b), the reduction product is obtained by discarding aqueous layer and recovering product from organic layer. Various recovery techniques available in the art can be utilized for this purpose. The simplest techniques like chilling and filtration, centrifugation are efficient for recovering product from organic layer. Some non-limiting examples of aromatic hydrocarbons are benzene, toluene, and xylene. Reduction is carried

out at maintaining the temperature ranging from 55°C to 75°C, more preferably at 50°C to 70°C for 1 to 4 hours.
Obtained reduction product in step b) i.e. amino intermediate 2-(4-amino-2-chloro-5-methylphenyl)-2-(4-chlorophenyl)acetonitrile is reacted with 2-hydroxy-3,5-diiodobenzoic acid and phosphorous trichloride in suitable solvent to get N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide. Hydrocarbon solvents are more suitable for this reaction. Such hydrocarbon solvents include but not limited to one or more from aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, halogenated aromatic hydrocarbons for example hexane, cyclohexane, petroleum ether, benzene, toluene, xylene, chloroform, methylene chloride, tetrachloroethane, chlorobenzene. 1,2-dichlorobenzene. 1,2,4-trichlorobenzene etc. More preferably toluene is suitably employed in this reaction. Heating up to reflux temperature may be applied for this reaction for 5 to 12 hours. Preferably reflux temperature is within the range of about 90°C to about 120°C, more preferably about 100°C to about 115°C and most preferably it is about 110°C. Obtained product may be washed with C1 to C10 alcohols.
N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide base is further converted to its desired salt form. Preferably, sodium salt has wide applications in medical preparations.
According to second aspect of the invention, process for preparation of sodium salt of N-(5-chioro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyi)-2-hydroxy-3,5-diiodo benzamide comprises contacting N-(5-chIoro-4-((4-chlorophenyl)(cyano)methyl)-2-methyiphenyl)-2-hydroxy-3,5-diiodo

faenzamide base with sodium containing basic compound. Preferably, such compound is selected from sodium hydroxide, sodium alkoxide, sodium carbonate and any mixture thereof. Suitable solvent for this salt formation is preferably selected from water, organic solvents and their mixtures. Straight and branched chain alcohols having general formula R-OH, in which R is selected from C1 to C10 are amongst the preferable organic solvents for salt formation. Non limiting examples of straight and branched chain alcohols include methanol, ethanol, n-propanol, iso-propanol etc.
According to third aspect of the invention, process for purification of N-(5-chloro-4-((4-
chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide comprises
refluxing the mixture of N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-
hydroxy-3,5-diiodo benzamide and chloroaromatic solvent, and cooling the refluxed mixture and
isolating pure N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-
diiodobenzamide. This purification reduces the individual polar impurities in product below 0.05%
and individual non-polar impurities below 0.10%. Preferable chloroaromatic solvent include
chlorobenzenes, monochlorbenzene, 2-chlorotoluene and mixtures thereof. Reflux temperature and
time may vary according to the solvent. Ideally reflux for 15 to 30 minutes is sufficient. More
preferably reflux for 15 to 20 minutes at 125°C to 133°C using Monochlorbenzene solvent gives
pure N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo
benzamide having individual polar impurities less than 0.05% and individual non-polar impurities less than 0.10% without significant yield loss.

The present invention is further described with the help of the following examples, which are given by way of illustration and should not be construed to limit the scope of the invention in any manner. All the parts, percent's and ratios are by weight unless otherwise indicated.
EXAMPLES:
Ingredients of composition in weight percentage range or in other unit in following conditions:
(a) Preparation of amino intermediate i.e. 2-(4-amino-2-chloro-5-methylphenyI)-2-(4-chlorophenyl) acetonitrile.
Separately added 4-chloro-l-methyl-2-nitrobenzene (0.0003 mmoles) and 2-(4-chlorophenyl) acetonitrile (0.0006 mmoles) in methanol and potassium hydroxide (0.0027 mmoles) at 20°C temperature. Temperature of reaction is raised to 45°C to 50°C and maintained for about 5 hr. To the reaction mass is added 300 ltrs of water followed by adding aqueous solution of sodium bicarbonate (0.0015 mmoles) and sodium sulfide (0.0027 mmoles) in 800 ml water. The reaction is carried out for 1 hr. at 60°C and then added with toluene and water followed by heating for 1 hr. at 70°C to 80°C. The layers are allowed to separate. The organic layer was separated and chilled to obtained product, washed with methanol, and dried at 70°C. Melting point: 152.0 °C to 153.0 °C Purity: 99.62% (By HPLC) IR: As depicted in Figure 1 HPLC Chromatogram: As depicted in Figure 2

(b) Preparation of N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methyIphenyl)-2-
hydroxy-3,5-diiodo benzamide Base
A solution of 2-(4-amino-2-chloro-5-methylphenyl)-2-(4-chloropheny[)acetonitrile (0.0006
mmoles) was dissolved in toluene (1863 kg) and 2-hydroxy-3,5-diiodobenzoic acid (0.0006
mmoles) was added slowly to it at about 60°C. Then added phosphorus trichloride (0.00036
mmoles). The reaction mass was heated to reflux temperature at above 105°C. After completion of
the reaction, the reaction mass was subjected to distillation to recover toluene and to the residue
obtain was added methanol to kill chlorides, if any. Obtained product was further washed with
methanol and dried at 80°C to 95°C.
Melting Point: 220.2°C to 224.9 °C
Purity: 99.18% (By HPLC)
IR: As depicted in Figure 3
HPLC Chromatogram: As depicted in Figure 4
(c) Preparation of N-(5-chloro-4-((4-ch]orophenyl)(cyano)methyl)-2-methyiphenyl)-2-
hydroxy-3,5-diiodo benzamide sodium salt
In methanol (6.96 kg) and 10 N sodium hydroxide solution and N-(5-chloro-4-((4-chlorophenyl) (cyano) methyl)-2-methylphenyl)-2-hydroxy-3, 5-diiodo benzamide base (0.00016 mmoles) was added. To this chilled Water (1100 ltr) was added while maintaining the temperature below 10°C. After addition reaction maintained for 3 hr. at 10 C to obtain the N-(5-chloro-4-((4-chlorophenyl)

(cyano) methyl)-2-methylphenyl)-2-hydroxy-3, 5-diiodo benzamide sodium compound. The
product was separated from reaction mixture and dried at 65°C.
Purity: 99.42% (By HPLC)
IR: As depicted in Figure 5
HPLC Chromatogram: As depicted in Figure 6
(d) Purification of N-(5-chIoro-4-((4-chIorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide
0.00015 mmoles of (98.33% with M.P. 220.2°C to 224.9°C.) crude N-(5-chIoro-4-((4-
chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide having 0.51% and
0.17% % polar impurities and 0.12% and 0.15% non-polar impurities were added to 1 volumes of
monochlorobenzene and 3 volumes of methanol at room temperature and the mixture was heated to
reflux. After 20 minutes reflux, the mixture was cooled to 5°C and filtered to obtain pure N-(5-
chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide.
Melting point: 230°C to 233°C
Purity: 99.64% (By HPLC)
Polar impurities: 0.02% and 0.03%,
Non polar impurities: 0.08% and 0.08%.
HPLC Chromatogram of Crude: As depicted in Figure 7
HPLC Chromatogram of Pure: As depicted in Figure 8
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 preparation of N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide and salt thereof comprising;
a) reacting 4-chloro-l-methyl-2-nitrobenzene with 2-(4-chlorophenyl)acetonitrile in presence of alcoholic base to obtain nitro intermediate
b) reducing nitro intermediate obtained in step a) to obtain amino intermediate 2-(4-amino-2-chloro-5-methylphenyl)-2-(4-chlorophenyl)acetonitrile
c) reacting amino intermediate obtained in step b) with 2-hydroxy-3,5-diiodobenzoic acid and phosphorous trichloride to obtain N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide
d) optionally converting N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide into suitable salt

2. The process of claim 1, wherein the reaction step a) is carried out in presence of alcoholic base.
3. The process of claim 2, wherein the alcohol in alcoholic base is selected from one or more alcohols having general formula R-OH, in which R is selected from C1 to C10 alkyl group and include straight chain alcohols and branched chain alcohols; and the base is selected from one or more from alkali metal amides, alkali metal hydrides, alkali metal alkoxides and the group having general formula X-OH in which X is sodium, potassium, lithium or magnesium.

4. The process of claim 1. wherein the reduction in step b) is carried out using reducing agents selected from group consisting of alkali metal sulfides, alkali metal hydrosulfides and any mixture thereof in the presence of alkali metal carbonates.
5. The process of claim 4, wherein the reduction in step b) is carried out using is sodium sulfide in presence of sodium bicarbonate.
6. The process of claim 1, wherein step a) and step b) are carried out in situ in same solvent system.
7. The process of claim 1, wherein reaction in step c) is carried out in a hydrocarbon solvent selected from group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, halogenated aromatic hydrocarbons and any mixture thereof.
8. The process of claim 7, wherein hydrocarbon solvent is selected from group consisting of hexane, cyclohexane, petroleum ether, benzene, toluene, xylene, chloroform, methylene chloride, tetrachloroethane, chlorobenzene, 1, 2-dichlorobenzene, 1, 2, 4-trichlorobenzene and any mixture thereof.
9. The process of claim 1, wherein the reaction in step c) is carried out within the temperature range of about 90°C to about 120°C.

10. A process for preparation of sodium salt of N-(5-chloro-4-((4-chlorophenyI)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide comprising contacting N-(5-chIoro-4-((4-chlorophenyl)(cyano)methyI)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide base with sodium containing basic compound in a solvent selected from group of water, organic solvent or mixtures thereof.
11. The process of claim 10, wherein sodium containing basic compound is selected from a group consisting of sodium hydroxide, sodium alkoxide, sodium carbonate and any mixtures thereof.
12. The process of claim 10, wherein the organic solvent is alcohol having general formula R-OH, in which R is selected from C1 to C10 and include straight and branched chain alcohols and mixtures thereof.
13. A process for purification of N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide comprising;
a) refluxing the mixture of N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-
hydroxy-3,5-diiodo benzamide and chloroaromatic solvent, and
b) cooling the refluxed mixture and isolating pureN-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-
2-methylphenyl)-2-hydroxy-3,5-diiodo benzamide.
14. The process of claim 13, wherein the chloroaromatic solvent is selected from chlorobenzenes,
monochlorobenzene. 2-chlorotoluene and mixtures thereof.

15. The process of claim 13, wherein the reflux in step a) is carried out for 20 minutes using monochlorobenzene and cooling in step b) is at 5°C.