FORM2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
"PROCESS FOR THE PREPARATION OF BENZIMIDAZOLE DERIVATIVE AS ANTHELMINTIC AGENTS"
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.

PROCESS FOR THE PREPARATION OF BENZIMIDAZOLE DERIVATIVE AS ANTHELMINTIC AGENTS
FIELD OF INVENTION
Present invention relates to a process for the preparation of anthelmintic agents such as benzimidazole derivative compound of structural formula I as shown below.

BACKGROUND OF THE INVENTION
Benzimidazole derivative compound of structural formula I, chemically known as 5-chloro-6-(2,3-dichlorophenoxy)-2-(methylthio)-lH-benzimidazole having anthelmintic activity, developed as an oral route drug and displays high efficacy against both immature and adult liver flukes. 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 gastro¬intestinal tract caused by members of the family Trichostrongyiidae, 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, 5-chloro-6-(2,3-dichlorophenoxy)-2-(methylthio)-1 H-benzimidazole 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.
US 4,197,307 disclosed the process for the preparation of benzimidazole derivative compound of structural formula I as shown in below scheme I.


Scheme I
Chinese patent document 101555231 describes a process for the preparation of benzimidazofe derivative compound of structural formula I as shown below scheme II.

Scheme II
However, the aforementioned prior art processes are not suitable for commercial scale, are high
in costs, operational difficulties, are not environment friendly for the preparation of
benzimidazole derivative compound of structural formula I.
Accordingly there is need in the art to develop an alternate process for the preparation of
benzimidazole derivative compound of structural formula I, which overcomes the prior art
problems.

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
In one aspect, present invention provide a process for the preparation of 5-chloro-6-(2,3-dichlorophenoxy)-2-(methylthio)-lH-benzimidazole compound of structural formula I comprising:

a) reacting compound of structural formula VI with compound of structural formula V in presence of organic solvent and base to obtain compound of structural formula IV,

b) reducing compound of structural formula IV in presence of reducing agent to obtain compound of structural formula III,

c) reacting compound of structural formula III with carbon disulfide to obtain compound of structural formula II,


d) methylating compound of structural formula II using methylating agent to obtain compound of structural formula I,

In second aspect invention provides a process for the purification of 5-chloro-6-(2,3-dichlorophenoxy)-2-(methylthio)-lH-benzimidazole compound of structural formula I comprising, treating solution of compound of structural formula I prepared in mixture of alcohol and aromatic solvent with charcoal at temperature within the range of 70°C to 80°C.
BRIEF DESCRIPTION OF THE DRAWINGS
For 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 figure and in which:
Figure 1 depicts IR of 5-chloro-6-(2,3-dichlorophenoxy)-2-(methylthio)-lH-benzimidazole
Figure 2 depicts HPLC Chromatogram of purified 5-chloro-6-(2,3-dichIorophenoxy)-2-(methylthio)-1 H-benzimidazole
DETAILED 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 first aspect of the present invention relates to a process for the preparation of anthelmintic agents such as benzimidazole derivative, more specifically present invention relates to a process of preparation of 5-chloro-6-(2,3-dichlorophenoxy)-2-(methylthio)-lH-benzimidazole. According to first aspect, invention provides a process for the preparation of 5-chIoro-6-(2,3-dichlorophenoxy)-2-(methylthio)-lH-benzimidazole compound of structural formula I. comprising:

a) reacting compound of structural formula VI with compound of structural formula V in presence of organic solvent and base to obtain compound of structural formula IV,

b) reducing compound of structural formula IV in presence of reducing agent to obtain compound of structural formula III,


c) reacting compound of structural formula III with carbon disulfide to obtain compound of structural formula II,

d) methylating compound of structural formula II using methylating agent to obtain compound of structural formula I,

In one embodiment of the invention, the reaction step a) comprising reaction of compound of structural formula VI and compound of structural formula V for obtaining compound of formula IV as shown in step a) involves coupling and hydrolysis and is carried out in-situ in an organic solvent in presence of base. The coupling reaction is carried out first by maintaining the temperature within the range of 80°C to 100°C, more preferably 88°C to 92°C for 7 to 13 hours. Hydrolysis is carried out at temperature around 45°C to 55°C.
The examples of an organic solvent include but not limited to N,N-dimethyl formamide, dimethyl sulphoxide, dimethyl acetamide, acetonitrile, sulfolane, nitromethane, straight chain alcohol, branched chain alcohol and any combination thereof. More than one solvent can be used at once or in sequentially manner.
The examples of base include but not limited to potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, magnesium hydroxide, sodium amide, sodium hydride, sodium ethanolate and any suitable combination thereof.

In another embodiment of invention, the reduction of compound of structural formula IV in step b) is carried out using one or more reducing agents like Raney cobalt, hydrazine hydrate in suitable solvents like straight chain alcohols, branched chain alcohols, aromatic hydrocarbons or any combination thereof. Reduction is carried out within the temperature range of 45°C to 80°C. The solvent system is not restricted to single solvent. More than one solvent is also suitable for this step. The non limiting examples of suitable solvent for this step are methanol, ethanol, n-. propanol, isopropanol, butanol, isobutanol, pentanol, toluene etc. In addition, base like sodium hydroxide can also be added for reduction.
In yet another embodiment, product obtained in step b) i.e. compound of structural formula III, is reacted with carbon disulfide in presence of strong base to get cyclized product of structural formula II. During this reaction step, the reaction mass is heated at around 55°C to 65°C. Heating can be maintained for 8 to 12 hours. Alternatively, in another embodiment, product obtained in step b) i.e. compound of structural formula III, is reacted with carbon disulfide in presence of strong base and phase transfer catalyst to get cyclized product of structural formula II. The reaction mass is heated at 60°C for 3 to 6 hours. The example of phase transfer catalyst may include but not limited to cetrimide.
Acetic acid can be added to reaction mixture to control the reactivity of carbon disulfide and precipitation of cyclized product of structural formula II.
The examples of strong base include but not limited to potassium hydroxide, calcium hydroxide, sodium hydroxide etc. and one or more from straight or branched chain alcohols are suitable solvents for this step. The non limiting examples of such solvents include methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, pentanol or any mixture thereof. In another embodiment, the methylation of compound of structural formula II is carried out in step d) by using a suitable methylating agent selected from methyl halide, dimethyl sulfate and dimethyl carbonate in presence of suitable solvent. Suitable solvents may be one or more from straight or branched chain alcohols. The non limiting examples of such solvents include methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, pentanol or any mixture thereof. The methanesulfonate salt obtained is then treated with base to obtain compound of structural formula I.
According to another aspect of invention a process for the purification of 5-chloro-6-(2,3-dichlorophenoxy)-2-(methylthio)-lH-benzimidazole compound of structural formula I

comprises, treating solution of compound of structural formula I prepared in mixture of alcohol and aromatic solvent with charcoal at temperature within the range of 70°C to 80°C. This treatment is given for about 30 minutes to 3 hours, more preferably 1 hour. The solvent system is not restricted to single solvent from each class. More than one solvent from any of the class or from both classes is also suitable for this purification. Alcohols preferably include but not limited to straight and branched chain alcohols. The non limiting examples of alcohols include methanol, ethanol, n-propanol, iso-propanol, butanol, isobutanol or pentanol etc. The non limiting examples of suitable solvent include but not limited to aromatic hydrocarbons. The non limiting examples of aromatic hydrocarbons are benzene, toluene, xylene etc.
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:
EXAMPLE 1: Preparation of 5-chloro-6-(2,3-dichlorophenoxy)-2-(methyIthio)-lH-benzimidazole
(a) Preparation of 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (compound of formula IV)
To the solution of 2,3-dichlorophenol (0.0061 mmoles) in N,N,-dimethyl formamide (1.52 liters) was added potassium carbonate (0.0066 mmoles) at 25°C to 30°C and N-(4,5-dichloro-2-nitrophenyl)acetamide (0.0061 mmoles). Then heated to maintain temperature about 88°C to 92°C under vacuum for 8 to 12 hours cooled the reaction mixture up to 25°C to 30°C. Methanol (1.28 liters), solution of sodium hydroxide flakes (0.15 kg in water 0.15 liter) slowly added to the reaction mass below 35°C and heated to 48°C to 52°C. Water (3.64 liters) was added and stirred for 1hour at 25°C to 30°C. Filtered and wash with water till neutral pH. Yield: 95%

(b) Preparation of 4-chJoro-5-(2,3-dichlorophenoxy)benzene-l,2-diamine using Raney
cobalt (compound of formula III)
Raney cobalt (46gm) (23gm on dry basis) (containing 40% cobalt and 60% aluminum is commercially available) charged in reactor containing reaction mixture of 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (0.0029 mmoles), toluene (3.00 liters), methanol (30ml), sodium hydroxide (0.001 lmmoles). Reactor flushed with nitrogen and purged hydrogen with pressure of 3kg. Then the reaction mixture was heated slowly to 60°C to 65°C and maintained for 4 to 6 hours. Cooled to 25°C to 35 °C, washed and filtered. Yield: 98.2%
(c) Preparation of 4-chloro-5-(2,3-dichlorophenoxy)benzene-l,2-diamine using
hydrazine hydrate (compound of formula III)
In reactor containing 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroani)ine (0.0029 mmoles) obtained in example (a) was added toluene (3.0 liters), alumina (0.02 kg), ferric chloride (0.02 kg), activated charcoal (0.04 kg) and methanol (0.60 liters) reaction mixture was heated up to 50°C to 55°C then slowly added Hydrazine hydrate (0.6 kg) over a period of 2 to 3 hours and reaction mass heated at temperature range of 70°C to 75°C. After confirmation of TLC was added water (3.0 liters) and heated up to 80°C reaction mass filtered over hyflow washed with toluene. Then the filtrate heated at about 75°C to 80°C settled for 30 minutes and layers were separated out, organic layer washed with water and organic layer distilled out under vacuum below 70°C.
(d) Preparation of 6-chloro-5-(2,3-dichIorophenoxy)-1H-benzimidazoIe-2-thioI using
phase transfer catalyst (compound of formula II)
Above toluene layer containing 4-chloro-5-(2,3-dichlorophenoxy)benzene-l,2-diamine was charged with methanol (0.101 litre), cetrimide (0.000071 mmoles) and cooled to 15°C to 20°C. 48% sodium hydroxide (0.007 mmoles) and carbon disulfide (0.0037 mmoles) were added slowly. Stirred at 15°C to 20°C for 1 hour, reaction mixture was refluxed for 3 to 6 hours maintaining temperature at 60°C. Then pH of reaction mass was adjusted to 4 to 4.5 with acetic acid while maintaining temperature below 35°C. Then heated to 70°C to 75°C, cooled, filter and washed with water.

Yield: 95%
(e) Preparation of 6-chloro-5-(2,3-dichlorophenoxy)-lH-benzimidazole-2-thiol without
phase transfer catalyst (compound of formula II)
Toluene layer from, the example b) was distilled out. Then charged methanol (1.5 liter) cooled to 20°C to 25°C, slowly added 48% sodium hydroxide (0.0067 mmoles), carbon disulfide (0.0037 mmoles), after completion of addition stirred for 30 minutes maintaining temperature at 20°C to 25°C, then reaction mixture was refluxed for 8 to 12 hours maintaining temperature at 60°C. Then pH of reaction mass was adjusted to 4 to 4.5 with acetic acid while maintaining temperature below 35°C. Then heated to 70°C to 75°C, cooled, filter and washed with water. Yield: 94.6%
(f) Preparation of 5-chloro-6-(2,3-dichlorophenoxy)-2-(methylthio)-lH-benzo[d]
imidazole (compound of formula I)
6-chloro-5-(2,3-dichlorophenoxy)-lH-benzimidazole-2-thiol (0.0028 mmoles) was added to methanol (3.0 liters) at 25°C to 30°C, stirred for 15 minutes, dimethyl sulfate (0.0034mmoles) was added slowly and the reaction mass was heated at 60°C to 65°C maintaining for 1 to 2 hours. Then added charcoal (0.03 kg), heated the reaction mass at 60°C to 65°C, for 1 hour. Filtered and washed with methanol (0.1 liter), then distilled out methanol under vacuum below 50°C, cooled to 0°C to5 °C, maintained for 1 hour. Wet solid charged in water, pH adjusted at 8 to 8.5 with ammonium solution, heated to 30°C to 35°C and maintained for 3 to 4 hours. Product was filtered and washed with water till neutral pH, then dried at 70°C to 75°C. Yield: 98.1%
Melting point: 164°C to 168°C. Purity: 97%
EXAMPLE 2: Purification of 5-chloro-6-(2,3-dichlorophenoxy)-2-(methylthio)-1H-benzimidazole (compound of formula I)

The crude product obtained in above example (f) was added in toluene (3 liters) and methanol (3
liters), reaction mass heated to about 70°C to 75°C to get clear solution. Then charged charcoal
(0.05 kg) by maintaining temperature at 70°C to 75°C for 1 hour and then washed with toluene.
Methanol distilled out from filtrate, cooled to room temperature and further chilled to 5°C to
10°C, filtered and washed with chilled toluene (0.2 liter). Pure product was separated by
filtration and dried.
Yield: 96.4%
Melting Point: 174°C to 178°C
Purity: 99.51% (By HPLC)
IR as depicted in Figure 1.
HPLC Chromatogram: As depicted in figure 2.

WE CLAIM,
1. A process for the preparation of 5-chloro-6-(2,3-dichlorophenoxy)-2-(methylthio)-lH-benzimidazole compound of structural formula I comprising:

Formula I a) reacting compound of structural formula VI with compound of structural formula V in presence of organic solvent and base to obtain compound of structural formula IV,

b) reducing compound of structural formula IV in presence of reducing agent to obtain compound of structural formula III,

c) reacting compound of structural formula III with carbon disulfide to obtain compound of structural formula II,

d) methylating compound of structural formula II using methylating agent to obtain compound of structural formula I,

The process of claims 1, wherein organic solvent in step a) is one or more selected from N,N-dimethyl formamide, dimethyl sulphoxide, dimethyl acetamide, acetonitrile,. sulfolane, nitromethane, straight chain alcohol, branched chain alcohol.
3. The process of claims 1, wherein base in step a) is one or more selected form potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, magnesium hydroxide, sodium amide, sodium hydride or sodium ethanolate.
4. The process of claim 1, wherein reducing agents use in step b) is Raney cobalt.
5. The process of claim 1, wherein reducing agents use in step b) is hydrazine hydrate.
6. The process of claim 1, wherein step c) further comprises use of phase transfer catalyst.
7. The process of claim 6, wherein phase transfer catalyst use in step c) is cetrimide.
8. The process of claims 1, wherein methylating agent in step d) is selected from methyl halide, dimethyl sulfate and dimethyl carbonate.
9. The process of claims 8, wherein methylating agent in step d) is dimethyl sulfate in which the compound of structural formula I is obtained by adjusting the pH of reaction mass at 8 to 8.5.
10. A process for the purification of 5-chloro-6-(2,3-dichlorophenoxy)-2-(methylthio)-1H-benzimidazole compound of structural formula I comprising, treating solution of compound of structural formula I prepared in mixture of alcohol and aromatic solvent with charcoal at temperature within the range of 70°C to 80°C,
11. A process of claim 10, wherein alcoholic solvent is selected from one or more from straight and branched chain alcohols.

12. A process of claim 10, wherein alcoholic solvent is selected from one or more from methanol, ethanol, n-propanol and iso-propanol, butanol, isobutanol or pentanol; and aromatic solvent is selected from one or more from benzene, toluene or xylene.
13. A process of claim 10, wherein solution of compound of structural formula I prepared in mixture of methanol and toluene is treated with charcoal at temperature within the range of 70°C to 80°C.