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
"AN IMPROVED PROCESS FOR THE PREPARATION OF METHYL 5-(PROPYLTHIO)-IH-BENZO [D] IMIDAZOL-2-YLCARBAMATE"
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.

AN IMPROVED PROCESS FOR THE PREPARATION OF METHYL 5-(PROPYLTHIO)-IH-BENZO [D] IMIDAZOL-2-YLCARBAMATE
FIELD OF THE INVENTION:
Present invention relates to an improved process for the preparation of benzimidazole derivative methyl 5-(propylthio)-lh-benzo [d] imidazol-2-ylcarbamate compound of structural formula (V)

BACKGROUND OF INVENTION:
Benzimidazole derivative methyl 5-(propylthio)-lh-benzo [d] imidazol-2-ylcarbamate compound
of structural formula (V) is originally developed as plant fungicides and later as veterinary
anthelminthics. It is marketed as Albenzain United States, a benzimidazole drug used for the
treatment of a variety of parasitic worm infestations. It is marketed by Amedra Pharmaceuticals
in the United State and by GlaxoSmithKline in international markets and was first discovered at
the SmithKline Animal Health Laboratories. It is an orally administered broad-spectrum
anthelmintic, effective against roundworms, tapeworms, and flukes of domestic
animals and humans.
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-(propylthio)-lh-benzo [d] imidazol-2-ylcarbamate 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.
The US patent no. 3,915,986 disclosed process for the preparation of benzimidazole derivative compound of structural formula (V) as shown below in scheme I. The first step of propylation need overnight reflux which results in lengthening the time of overall process as well as necessity of continuous supply of energy to maintain reflux temperature overnight.

The US patent no. 4,152,522 disclosed process for the preparation of benzimidazole derivative compound of structural formula (V) as shown below in scheme II.


The above process of US'522 in propylation step, make use of an alkali metal cyanide or alkaline metal cyanide which are toxic compounds for coupling reaction of 2-nitro-4-thiocyanoaniline with n-propyl bromide which surplus hazardous organic substances in the effluents.
Chinese patent document CN101270068 disclosed the process of propylation in which 2-nitro-4-sulfur cyano aniline is treated with base such as NaOH and KOH at temperature 65°C to 95°C respectively for at least 9 hours. Then cooled and added with propyl bromide and polyethylene glycol and again heated till reflux. Further, the zinc chloride is added under stirring within half hour to get zinc complex and obtained zinc complex is treated with sodium hydroxide for half hour to get 2-nitryI-4-propyIthioaniline.
The aforementioned prior art processes are not suitable for commercial scale due to use of lengthy reaction steps, need of continuous overnight supply of energy and operational difficulties while providing controlled temperature for long hours. Also, use of hazardous chemicals in process and waste products generated through it endangers the working premises as well as the environment. Accordingly there is need in the art to develop an alternate process for the preparation of benzimidazole derivative compound of structural formula (V), 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:
The invention provides a process for preparing benzimidazole derivative compound of formula (V) comprising:

(a) thiocynating compound of formula (I),


(b) converting obtained compound of formula (II) in compound of formula (III) by heating together compound of formula (II), propylating agent, base and phase transfer catalyst in an aqueous alcoholic solvent system,

(c) subjecting obtained compound of formula (III) to reduction to obtain compound of formula (IV),


(d) treating obtained compound of formula (IV) with methyl cyano carbamate or its salt to obtain compound of formula (V)
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-(propylthio)-lh-benzo [d] imidazol-2-y[carbamate compound of formula (V)
Figure 2 depicts HPLC Chromatogram of methyl 5-(propylthio)-lh-benzo [d] imidazol-2-ylcarbamate compound of formula (V)
DETAIL DESCRIPTION OF INVENTION:
(a) thiocynating compound of formula (I),
Present invention provides a process for preparation of benzimidazole derivative compound of formula (V) which comprises:



to obtain compound of formula (II)

(b) converting obtained compound of formula (II) in compound of formula (III) by heating together compound of formula (II), propylating agent, base and phase transfer catalyst in an aqueous alcoholic solvent system,

(c) subjecting obtained compound of formula (III) to reduction to obtain compound of formula (IV),

(d) treating obtained compound of formula (IV) with methyl cyano carbamate or its salt to obtain compound of formula (V).

According to first aspect, the compound of formula (I) is thiocynated by treatment of ammonium or alkali metal thiocyanate and any suitable oxidizing agent and preferably halogens like chlorine and bromine is employed for the reaction. This step is carried out preferably in alcoholic solvents.
In second aspect of the invention, the conversion of compound of formula (II) in compound of formula (III) is achieved by heating together compound of formula (II), propylating agent, base and phase transfer catalyst in aqueous alcoholic solvent system. Heating temperature is preferably with the range of 70°C to 105°C. The aqueous alcoholic solvent system primarily contains at least one alcohol with water.. More preferably solvent system comprises water and n-propanol. The non-limiting examples of propylating agent include n-propyl bromide, n-propyl iodide, n-propyl chloride and n-propanol etc. Preferably, the propylating agent is n-propyl bromide. Alkali metal hydroxides are the suitable bases for this propylation reaction. Preferably sodium hydroxide and potassium hydroxide and more preferably sodium hydroxide is suitably employed for the reaction. The phase transfer catalyst is one or more selected from quaternary ammonium salt, phosphontum salt and cetrimide. Tetrabutyl ammonium chloride and methyl tributyl ammonium chloride are the non-limiting examples of quaternary ammonium salt which can be used as phase transfer catalyst. The mixture of these two can also be used. The catalyst is preferably cetrimide. The reaction time is 4 to 5 hours. Faster reaction rate is achieved for this step without using any hazardous metal cyanide.
In third aspect of the invention the reduction of compound of formula (III) obtained above to get compound of formula (IV) is carried out using one or more selected from alkali metal sulfide, alkali metal hydrosulfide, palladium, stannous chloride and platinum oxide. Preferable the alkali metal hydrosuifides for this step are sodium hydrosulfide or potassium hydrosulfide and alkali metal sulfide are sodium sulfide or sodium disulfide. The mixture of these can also be used for reduction. Various reduction techniques are available in prior art. Preferably the reduction using alkali metal sulfide is achieved by heating compound of formula (III) with alkali metal sulfide.
In fourth aspect of the invention, obtained compound of formula (IV) is treated with methyl cyano carbamate or its salt to obtain compound of formula (V). This conversion reaction proceeds under acidic conditions. Acidic environment for this conversion step may be

maintained using mineral acids or organic acids. Preferably, strong mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, Acetic acid or citric acid etc. can be used for this purpose.
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: Thiocynating compound of formula (I) to get compound of formula (II) i.e. 2-
nitro-4-thiocyanatoaniline
In clean reactor methanol (3 liters) and compound of formula (I) (7.24 moles) was heated to get clear solution. Reaction mass cooled up to 25°C to 35°C and added (15.23 moles) ammonium thiocyanate followed by stirring and cooling up to 10°C. Chlorine gas (11.28 moles) passed slowly in uniform rate and after confirming TLC, the product was added with fresh water and centrifuged. The wet cake of title compound was separated.
Example 2: Conversion of compound of formula (II) in compound of formula (III) i.e. 2-nitro-4-(propylthio) aniline
The reactor was added with compound of formula (II) (5.12 moles), water (1.58 liters) and n-propanol (0.8 liter). After stirring for 15 minutes the reaction mass was added with n-propyl bromide (5.41 moles) and cetrimide (0.015 moles) and cooled. Caustic lye (11.07 moles) slowly added by stirring and maintaining temperature within range of 25°C to 35°C. The temperature was raised up to 75°C to 80°C and maintained for 5 hours, n-propanol distilled out and water (7 liters) was added to reactor. The reaction mass heated up to 95°C to 100°C followed by stirring for 30 minutes. The product was allowed to settle down and the compound of formula (III) was obtained as organic layer.
Example 3: Reduction of compound of formula (III) to obtain compound of formula (IV) i.e. 4-(propylthio) benzene-l,2-diamine

Organic layer containing compound of formula (III) obtained in example 3 was heated up to 60°C to 65°C and then slowly added with sodium hydrosulfide solution 30% (10.7 moles). Reaction mass then heated up to 95°C to 98°C and temperature was maintained for 5 hours. Reaction mass was allowed to settle and organic layer was distilled out to obtain compound of formula (IV).
Example 4: Preparation of methyl cyano carbamate sodium salt
In clean reactor charged water (1.6 liters), cooled to 10°C. Then added cyanamide solution 40% (5.83 moles) followed by slow addition of methyl chloroformate (7.94 moles) and sodium hydroxide solution (18 moles). Maintained pH 7.0 to 7.5 and temperature 10°C to15°C to obtain methyl cyano carbamate sodium salt.
Example 5: Treating compound of formula (IV) with methyl cyano carbamate sodium salt to obtain compound of formula (V)
In clean reactor charged demineralized water (2.35 liters), hydrogen chloride solution 35%
(12.36 moles), compound of formula (IV) (5.48 moles), acetone (1.00 liter) and methyl cyano
carbamate sodium salt prepared in example 4 was added, reaction mass then heated and refluxed
at temperature 65°C to 85°C for 1 hour. Product obtained i.e. compound of formula (V) was
given alcoholic solvent wash and water wash and dried at 80°C to 85°C.
Yield; 87 to 90%
Purity: 99.19%
1R; As depicted in Figure I.
HPLC Chromatogram: As depicted in Figure II.

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

(b) converting obtained compound of formula (II) in compound of formula (III) by heating together compound of formula (II), propylating agent, base and phase transfer catalyst in an aqueous alcoholic solvent system,



(c) subjecting obtained compound of formula (III) to reduction to obtain compound of formula (IV),
(d) treating obtained compound of formula (IV) with methyl cyano carbamate or its salt to obtain compound of formula (V).
2. The process of claim 1, wherein in step (a), the compound of formula (I) is thiocynated by treatment of ammonium or alkali metal thiocyanate.
3. The process of claim 2, wherein in step (a), the compound of formula (I) is thiocynated in presence of oxidizing agent.
4. The process of claim 1, wherein propylating agent in step (b) is selected from n-propyl bromide, n-propyl iodide, n-propyl chloride and n-propanol, preferably n-propyl bromide.
5. The process of claim 1, wherein the base in step (b) is alkali metal hydroxide.
6. The process of claim 1, wherein the phase transfer catalyst in step (b) is one or more selected from quaternary ammonium salt, phosphonium salt and cetrimide.
7. The process of claim 6, wherein the quaternary ammonium salt is selected from tetrabutyl ammonium chloride, methyl tributyl ammonium chloride and combination thereof.
8. The process of claim 1, wherein in step (b) the base is sodium hydroxide and phase transfer catalyst is cetrimide.

9. The process of claim 1, wherein the aqueous alcoholic solvent system in step (b) comprises water and n-propanol.
10. The process of claim 1, wherein reduction in step (c) is carried out using one or more selected from alkali metal hydrosulfide and alkali metal sulfide etc.
11. The process of claim 10, wherein alkali metal hydrosulfide is selected from sodium hydrosulfide, potassium hydrosulfide and mixture thereof.
12. The process of claim 1, wherein in step (d) compound of formula (IV) is treated with methyl cyano carbamate or its salt at acidic conditions.