F0RM 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
"GREEN PROCESS FOR THE PREPARATION OF METHYL 5-(PHENYL THIO)-lH-BENZO[D]IMIDAZOLE-2-YLCARBAMATE"
2. APPLICANT
a) NAME : LASA LABORATORY PVT. LTD.
b) NATIONALITY: INDIAN
c) ADDRESS : PLOTNO. C-105, MAHAD M.J.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.

GREEN PROCESS FOR THE PREPARATION OF METHYL 5-(PHENYL THI0)-1H-BENZO[D]TMIDAZOLE-2-YLCARBAMATE
FIELD OF THE INVENTION:
Present invention relates to green process for the preparation of benzimidazole derivative methyl 5-(phenyJ thio)-lh-benzo[d]imidazole-2-yIcarbamate compound of structural formula (V) use as an anthelmintic.

BACKGROUND OF INVENTION:
Benzimidazole derivative compound of structural formula (V), chemically designated as methyl 5-(phenyl thio)-lh-benzo[d]imidazole-2-ylcarbamate is known from US patent no. 3,954,791 as a broad spectrum benzimidazole anthelmintic used against gastrointestinal parasites including giardia, roundworms, hookworms, whipworms, the taenia species of tapeworms, pinworms, aelurostrongylus, paragonimiasis, strongyles and strongyloides and can be administered to sheep, cattle, horses, fish, dogs, cats, rabbits and seals. Drug interactions may occur if using bromsalan flukicides such as dibromsalan and tribromsalan. Abortions in cattle and death in sheep have been reported after using these medications together.
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. Methyl 5-(phenyl thio)-lh-benzo[d]imidazole-2-ylcarbamate is effective to control cattle, sheep 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 Patent no. 3,954,791 disclosed process for preparing benzimidazole compound of the formula (V) as shown below in scheme I.

Above process of US'791 disclosed the steps of preparing compound of formula (III) in DMF solvent, its recrystallization in isopropanol and its conversion into formula (IV) by reduction using SnCl2 in acetic acid . The process is tedious and requires extra steps of isolation of intermediates from solvents, adding cost as well as efforts to the process. SnCl2 is highly corrosive, moisture sensitive and causes explosion when contacted with air or oxidizing agent. Further, there are many practical difficulties in use of SnCl2 as it generates strong exotherm. It is categorized as toxic chemical its inhalation, ingestion and skin contact may lead to severe injury or death. Its inhalation produces irritation to gastro-intestinal or respiratory tract, characterized by burning, sneezing and coughing. Skin contact can produce inflammation and blistering. Its contact may cause severe burns to eyes. The consumption of SnCl2 is very high therefore at commercially it is highly expensive. The solvent waste generated in this process containing DMF and acetic acid is hazardous to environment and its disposal is costly.

The Chinese patent no. CN102304090 disclosed process for the preparation of benzimidazole compound of the formula (V) as shown below in scheme II.

Above process of CN'090 disclosed reaction of compound of formula (I) with compound of formula (11) in DMF solvent to get the nitro intermediate compound of formula (III). The product is filtered and dried and then reduced using sodium borohydride in presence of methanol. This process use two different solvents and requires isolation and drying of the obtained intermediates from the solvents at each stage. It adds work up steps, consumes more operational time, efforts and energy as well as special equipments set up also. The reducing agent sodium borohydride used here generates borate salt as a byproduct which affects quality as well as quantity of the desired product and causes problem in isolation of pure product. Due to its pyrophoric nature, there is always fear of ignition when contacted with oxygen. Thus, it is available as dispersion in mineral oil or its 10% aqueous solution stabilized with sodium hydroxide is sold commercially. Its high cost and high consumption put restriction on its commercial scale use. Further, the yield for this reduction step is only 40%. There is further treatment needed while releasing it as waste product. In order to effect decomposition, the solid or aqueous solution is added to enough water to make the borohydride concentration less than 3%, and then excess equivalents of dilute aqueous acetic acid are added drop wise with stirring under nitrogen. Alternatively, the solid or aqueous solution is added to enough water to make the borohydride concentration less than 3%, and then excess equivalents of dilute aqueous acetic acid are added drop wise with stirring under nitrogen. These reasons make sodium borohydride an unpopular choice for use. Still disposal of acetic acid is also problematic and costly, and not ecofriendly.

The Chinese patent no. CN103242237 disclosed process for the preparation of benzimidazole compound of the formula (V) as shown below in scheme III.

Disclosed process of CN'237 also use two different solvents while preparing compound of formula (III) and (IV). Compound of formula (III) is prepared in ethanol whereas compound of formula (IV) in prepared in propanol. Reduction of compound of formula (III) with Palladium on carbon is disclosed in first example. Palladium also has pyrophoric nature particularly when dry and at elevated temperatures. Palladium is prone to ignite on exposure to air, particularly when containing adsorbed hydrogen; readily causes ignition of flammable solvents in the presence of air. In particular, palladium on carbon should always be handled under an inert atmosphere (preferably argon or nitrogen), and reaction vessels should be flushed with inert gas before the catalyst is added. It is never added to an organic solvent in the presence of air which requires extreme care to be followed while handling this reagent. Palladium on carbon recovered from catalytic hydrogenation reactions by filtration requires careful handling because it is usually saturated with hydrogen and will ignite spontaneously on exposure to air. The filter cake is never be allowed to dry, and the moist material should be added to a large quantity of water and disposed with due care. Thus, special equipments for handling as well as for storage are mandatory for palladium. The use of palladium for reduction of compounds containing sulphur is highly poisonous. It is one of the highly expensive reagents. These practical difficulties make palladium a problematic reagent for use, handle and storage.
Alternatively reduction using hydrazine hydrate and ferric chloride is disclosed in second example. However said process has many disadvantages like hydrazine hydrate used with ferric

chloride is highly reactive and may adversely affect the reagents as well as produced diamine compound also. The byproducts generated in the reaction contain the degradation products as well as the metallic impurities, organic impurities and unreacted reducing agent from which the diamine product isolation is difficult and though isolated using costlier advanced techniques, it is highly unstable. If the filtered diamine product is directly carried forward to next step for preparing compound of formula (V) as shown in the patent example, it affect the yield and impurity profile of the final product as well.
Above prior art processes have disadvantages of being tedious, consumes more operational time, efforts and energy as well as special equipments set up and also of using either costly or hazardous chemicals for reduction like stannous chloride with HC1 gas, sodium borohydride and palladium with hydrogen gas purging. Solvent and acid disposal is challenging. It further adds operational cost and the waste generated is not ecofriendly. There is a need to provide a simple, safe, ecofriendly and cost effective process for preparing compound of formula (V) with good quality and quantity.
SUMMARY OF THE INVENTION:
(a) coupling compound of formula (I)
The invention provides a process for preparing benzimidazole derivative compound of formula (V) comprising:



with compound of formula (II)

in presence of an organic solvent, a phase transfer catalyst and an aqueous base to obtain compound of formula (III)

(b) subjecting the organic layer from step (a) contaning compound of formula (III) to reduction using aluminium oxide, EDTA, iron or acid salt of iron and hydrazine hydrate to obtain compound of formula (IV),

(c) adding water and mineral acid to obtained organic layer containing compound of formula (IV) followed by stirring and allowing layer separation to get mineral acid salt of compound of formula (IV) in aqueous layer;
(d) treating mineral acid salt of compound of formula (IV) in aqueous layer with methyl cyano carbamate or its salt in presence of ketone solvent to obtain compound of formula (V).
The process of current invention is simple, safe, ecofriendly and cost effective with good yield and better quality product. The same organic solvent is used for coupling, reduction and salt

formation and is recovered and stored for reuse. The process supports green chemistry approach by using same solvents in process which further recovered and preventing pollution at its source.
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 methyl 5-(phenyl thio)-lh-benzo[d]imidazole-2-ylcarbamate compound of structural formula (V)
Figure 2 depicts HPLC Chromatogram of methyl 5-(phenyl thio)-lh-benzo[d]imidazo]e-2-ylcarbamate compound of structural formula (V)
DETAIL DESCRIPTION OF INVENTION:
(a) coupling compound of formula (I)
Present invention provides a process for preparation of benzimidazole derivative compound of formula (V) which comprises:



with compound of formula (II)

in presence of an organic solvent, a phase transfer catalyst and an aqueous base to obtain compound of formula (III)

(b) subjecting the organic layer from step (a) contaning compound of formula (III) to reduction using aluminium oxide, EDTA, iron or acid salt of iron and hydrazine hydrate to obtain compound of formula (IV),

(c) adding water and mineral acid to obtained organic layer containing compound of formula (IV) followed by stirring and allowing layer separation to get mineral acid salt of compound of formula (IV) in aqueous layer;
(d) treating mineral acid salt of compound of formula (IV) in aqueous layer with methyl cyano carbamate or its salt in presence of ketone solvent to obtain compound of formula (V).
The process of current invention is simple, safe, ecofriendly and cost effective with good yield and better quality product. The same organic solvent is used for coupling, reduction and salt formation and is recovered and stored for reuse. The process supports green chemistry approach by using same solvents in process which further recovered and preventing pollution at its source.

The process avoids the need of special isolation, purification and crystallization of intermediates at each step, thereby reducing operational cost.
According to first aspect, in step (a) the compound of formula (1) is coupled with compound of formula (II) in presence of an organic solvent, a phase transfer catalyst and an aqueous base to obtain compound of formula (III). Preferably this step is carried out in water immiscible aromatic hydrocarbon or water immiscibfe aliphatic hydrocarbon solvent or their mixture, the quaternary ammonium salt phase transfer catalyst (PTC) and aqueous solution of alkali metal hydroxide. Non limiting examples of aromatic and aliphatic water immiscible hydrocarbon solvents include toluene, xylenes, hexanes, heptanes etc. Tetra-n-butylammonium bromide, Tetra-n-butylammonium chloride, Tetra-n-butylammonium iodide, Tetra-n-butylammonium fluoride and cetrimide are some of the suitable quaternary ammonium salt for this coupling reaction. Alkali metal hydroxides include sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide etc. More than one solvent, PTC and base can also be employed in this reaction step.
In second aspect of the invention, the reduction of compound of formula (III) in step (b) using aluminium oxide, EDTA, iron or acid salt of iron and hydrazine hydrate is carried out in same organic solvent at reflux temperature. Preferably, the organic layer obtained in step (a) is carried forward to this reduction step. There is no special need of isolation and purification, crystallization of product obtained in step (a) and a simple water wash to organic layer obtained in step (a) is sufficient to remove the unwanted byproducts generated in step (a). Thus, this layer can be readily utilized for further reduction step. Moreover, alcohols can also be used additionally in this step. The non-limiting examples of alcohol solvents are C1 to C10 straight chain or branch chain alcohols. Methanol is being preferred alcohol. Preferably this reduction step is carried out in presence of activated carbon. The reduction with hydrazine hydrate is catalyzed using heterogeneous catalysts system. The aluminium oxide and iron or acid salt of iron acts as heterogeneous catalysts and catalyze the reaction. EDTA helps in removal of generated metal impurities. After reduction the reaction mass containing compound of formula (IV) can be simply washed with water by which most of the byproducts are removed and the organic layer obtained is then taken forward to prepare mineral acid salt of compound of formula

(IV). The reaction proceed without any hazardous chemical and operable at usual working conditions at plant.
According to third aspect, the obtained organic layer is added with water and mineral acid, stirred well and allowed to settle for layer separation to get mineral acid salt of compound of formula (IV) in aqueous layer. The examples of mineral acid are selected from hydrohalic acids, nitric acid, phosphoric acid, sulphuric acid, boric acid and perchloric acid etc. More preferably hydrochloric acid. The organic layer is collected in another container and the organic solvent is recovered by simple techniques like distillation.
According to fourth aspect, the mineral acid salt of compound of formula (IV) in aqueous layer is treated with methyl cyano carbamate or its salt in presence of ketone solvent to obtain compound of formula (V). This step is preferably carried out at reflux temperature. The exemplary list of ketone solvent suitable for this reaction step contains acetone, methyl isobutyl ketone, methyl ethyl ketone and methyl n-butyl ketone etc. The product is washed with water, methanol and dried. No alkaline or acidic waste is generated in this step and the aqueous effluent of this step has neutral pH.
The product obtained through this process has good yield and superior purity. The process is simple, cost effective and ecofriendly.

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.
EXAMPLES:
Example 1: Preparation of compound of formula (III) i.e. 2-nitro-5-(phenyIthio)aniIine
In clean reactor was charged toluene (365 liters) by vacuum, 5-chloro-2-nitroaniline (0.81 moles), tetra butyl ammonium bromide (0.022 moles) and thiophenol (0.85 moles) then mixture were heated at 50°C to 55°C. Sodium hydroxide solution (1.04 moles) was added and temperature was raised to reflux for 3 hours. Then added (720 liters) toluene and heated up to 90°C for 1 hour. Then allowed the reaction mass to settle down, bottom aqueous layer was separated and organic layer washed till the pH of the aqueous layer was 6.5.
Example 2: Preparation of compound of formula (IV) i.e. 4-(phenylthio)benzene-l,2-diamine
Organic layer obtained from above example 1, was cooled up to 50°C to 55°C. Aluminium oxide (0.0022 moles), EDTA (0.012 moles), activated carbon (0.76 moles), ferric chloride (0.022 motes) and methanol (90 liters) was charged then slowly added hydrazine hydrate (2.53 moles) after complete addition reaction mass were refluxed for 8 hours. Thereafter, reaction mass was filtered, stirred well and allowed to settle, aqueous layer discarded from organic layer and given repeated water wash till neutral pH.
Example 3: Preparation of N-cyanocarbamic acid methyl ester (part B)
In clean reactor water (246 liters) was charged and cooled to below 10°C, cyanamide (2.02 moles) was added followed by adding methyl chloroformate (1.2 moles) and sodium hydroxide solution (143 liter) (2.37 moles) maintaining pH 7.0, temperature below 15°C stirred well.

Example 4: Preparation of compound of formula (V) i.e. methyl 5-(phenylthio)-lH-benzo[d]imidazole-2-ylcarbamate
In clean reactor water (427 liters) and hydrochloric acid (5.26 moles) was added, stirred for 5
minutes then added product obtained in example 2, stirring continued for 15 minutes and
reaction mass allowed to settle down for 30 minutes. Bottom layer containing product was
separated. The upper layer was collected in another container and solvent was recovered through
distillation. Product layer and acetone (140 liters) was charged in reactor and stirred well then
charged N-cyanocarbamic acid methyl ester (prepared in e.g. 3) to reaction mass, heated to
reflux and maintained for 1 hour. Reaction mass was centrifuged, washed with water, then
washed with methanol and dried.
Yield: 85.2%
Purity: 99.75%
IR: As depicted in Figure I.
HPLC Chromatogram: As depicted in Figure II.

WE CLAIM:
1. A process for preparing benzimidazole derivative compound of formula (V) comprising:

(a) coupling compound of formula (I)

with compound of formula (II)

in presence of an organic solvent, a phase transfer catalyst and an aqueous base to obtain compound of formula (III)

(b) subjecting the organic layer from step (a) contaning compound of formula (III) to reduction using aluminium oxide, EDTA, iron or acid salt of iron and hydrazine hydrate to obtain compound of formula (IV);


(c) adding water and mineral acid to the organic layer from step (b) containing compound of formula (IV), followed by stirring and allowing layer separation to get mineral acid salt of compound of formula (IV) in aqueous layer;
(d) treating mineral acid salt of compound of formula (IV) in aqueous layer with methyl cyano carbamate or its salt in presence of ketone solvent to obtain compound of formula (V).

2. The process of claim 1, wherein the organic solvent is one or more selected from water immiscible aromatic hydrocarbon solvent and water immiscible aliphatic hydrocarbon solvent.
3. The process of claim 1, wherein in step (a), the organic solvent is toluene, the phase transfer catalyst is quaternary ammonium salt and the base is alkali metal hydroxide.
4. The process of claim 3, wherein in step (a), the phase transfer catalyst is tetra-n-butylammonium bromide and the base is aqueous sodium hydroxide.
5. The process of claim 1, wherein in the organic layer in step (b) is further added with alcohol solvent.
6. The process of claim 5, wherein the alcohol solvent is one or more selected from Ci to C10 straight chain or branch chain alcohols.
7. The process of claim 1, wherein reduction in step (b) is carried out in presence of activated carbon.
8. The process of claim 1, wherein reduction in step (b) is carried out at reflux temperature.

9. The process of claim 1, wherein in step (d) mineral acid salt of compound of formula (IV) in aqueous layer is treated with methyl cyano carbamate in ketone solvent at reflux temperature.
10. The process of claim 9, wherein in ketone solvent is acetone.