Field of Invention
The present invention relates to a novel, cost-effective process for the preparation of an anti-parasitic drug, which is commonly known as febantel.
Background of the Invention
Febantel is an anti-parasitic drug marketed under the trade names "Drontal Plus" and "Rintal" manufactured by Bayer AG. It was first developed in the laboratories for parasitological research of Bayer AG in Germany in the late 1970s. It is used for the treatment and control of gastro-intestinal roundworms, lung worms and tapeworms etc.
Febantel is a veterinary anthelmintic drug belonging to the chemical class of the benzimidazoles, i.e. Febantel is a prodrug metabolised in vivo into fenbendazole in the stomach and the intestine of the host, shortly after ingestion. Once it gets metabolised, its behaviour is comparable to that of fenbendazole. Since febantel itself has no anthelmintic properties, its efficacy depends on its successful transformation to fenbendazole and to oxfendazole. The chemical name of febantel is [[2-[(Methoxyacetyl)amino]-4-(phenylthio)phenyl]-arbonimidoyl]biscarbamicaciddimethylester which is represented by formula I,
Bayer AG, a German pharmaceutical company is first one to report febantel in the US patent 3993682A, which describes a process for the preparation of febantel in which 2'-Amino-2-methoxy-5'-(phenylthio)acetanilide in methanol is heated with O-methyl isothiourea diamino methyl carbamate and p-toluenesulphonic acid to obtain febantel as shown in below reaction scheme-1.

EP195971 patent describes a process for preparing febantel which comprises reacting o-Methyl isourea methyl carbamate with methyl chloroformate to obtain o-Methyl isourea diamino methyl carbamate, which on further condensation with 2'-Amino-2-methoxy-5'-(phenylthio)acetanilide gives febantel of formula I.
Chinese patent 101412689 describes a process for the preparation of febantel which comprises the following steps: reacting a solution of o-methylisourea methylcarbamate in toluene with dimethyl carbonate to obtain o-methyl isoureadiamino methyl carbamate. On the other hand involves the reaction of 2-nitro-5-thiophenyl-(2-methoxy) acetanilide with hydrazine hydrate to obtain 2-amino-5-thiophenyl-(2-methoxy) acetanilide and finally " treating the o-methyl isoureadiamino methyl carbamate with the 2-amino-5-thiophenyl-(2-methoxy) acetanilide to obtain febantel of formula I.
The major drawbacks of prior art process is the formation of hazardous by-products i.e. methyl mercaptan which is highly poisonous, hence it is very difficult to handle in the commercial batches. Moreover, it requires a special scrubbing system during manufacturing of febantel to prevent the escape of methyl mercaptan gas.
Thus it is highly desirable to develop a process which overcomes the drawbacks of the prior art. The present inventors have developed a very cost effective process for the preparation of febantel of formula I, which gives better purity, better yield and avoids the formation of unwanted by-products.
Summary of the invention
According to the principal aspect, the present invention provides a novel process for the preparation of febantel of formula I which comprises:
a) reacting 1-decyl bromide of formula V with thiourea in a solvent to obtain S-decyl pseudothiourea hydrobromide of formula IV;

b) reacting S-decyl pseudothiourea hydrobromide of formula IV with methyl chloroformate in presence of base and solvent to obtain 1,3 -Bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of formula III; and
c) condensing l,3-Bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of formula III with 2-methoxy-N-[2-amino-5-(phenylsulfanyl) phenyl] acetamide of formula II in presence of an acid and solvent to give febantel of formula I.
The present invention can be illustrated by the below reaction scheme 2:

DETAIL DESCRIPTION OF THE INVENTION
Accordingly in an embodiment of the invention, 1-decyl bromide of formula V in step (a) is reacted slowly with hot solution of thiourea in presence of a solvent selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol and the mixture thereof, most preferably in methanol. The reaction is carried out at reflux temperature for 8 to 12 hours preferably for about 10 hours, to form S-decyl pseudothiourea hydrobromide of formula IV.
In another embodiment of the invention, S-decyl pseudothiourea hydrobromide of formula IV obtained in step (a) is reacted with methylchloroformate in presence of a base selected from a group comprising sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, preferably potassium carbonate more preferably anhydrous potassium carbonate and in presence of a solvent selected from the group comprising of methylene dichloride, chlorobenzene, carbon tetrachloride, ethylene dichloride, N,N-dimethyl formamide, Tetrahydrofuron and the like, preferably methylene dichloride. The reaction is carried out at a temperature in the range of about 10 to 40°C, preferably at 25 to 30°C to give l,3-Bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of formula III.
In yet another embodiment of the invention, l,3-Bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of formula III obtained in step (b) is condensed with 2-methoxy-iV-[2-amino-5-(phenylsulfanyl) phenyl] acetamide of formula II in presence of an acid selected from a group comprising hydrochloric acid, sulphuric acid, oxalic acid, acetic acid and the mixture thereof, preferably acetic acid, and presence of an alcoholic solvent selected from the group comprising methanol, ethanol, propanol, isopropanol, butanol and the mixture thereof, preferably in methanol, at the temperature in the range of 20 to 50°C, preferably 35 to 40°C. The reaction is carried out for 14 to 18 hours, most preferably for about 16 hours, to form Febantel of formula I.
In still further embodiment, the process of present invention has following advantages:
1. The process of the present invention avoids the formation of hazardous by-product methyl mercaptan, which is very difficult to handle in the commercial batches.

2. In the process of the present invention 1-Decane thiol is formed as a bi-product, which can be easily separated by filtration as it goes along with mother liquor during filtration.
3. The process of the present invention improves the yield and purity of febantel by more than 50% as compared to the process in the prior arts.
4. The process of the present invention is very user friendly avoids the lengthy workup and in turn minimises the generation of hazardous effluent.
The present invention is illustrated by the following examples, which are not to limit the scope of the invention.
Example:
a) Preparation of S-Decyl pseudothiourea hydrobromide:
1-Decyl bromide (145g) was charged slowly to a hot solution of thiourea (50g) in methanol under stirring. The content of the flask was refluxed for 10 hours under stirring. After the completion of the reaction, methanol was distilled out under reduced pressure to get white solid. The material was isolated by filtration or directly taken for next reaction.
Yield: 190 g
Melting point: 96-98°C
b) Preparation of l,3-Bis(methoxycarbonyI)-2-decyl-2-thiopseudourea:
Anhydrous potassium carbonate (69.6g) was charged to a solution of S-decyl pseudothiourea hydrobromide (50g) in methylene dichloride at 25-30°C under stirring. Methyl chloroformate (31.6g) was added slowly to the reaction mass at a temperature 25-30°C. The entire reaction mass was stirred at 25-30°C for 8 hours. After the completion of the reaction, it was charged with 200ml DM water. The layers were separated, organic layer was washed with 50 ml DM water and methylene dichloride was distilled out to get thick syrupy mass. Methanol (100ml) was added to the reaction mass and heated to 50°C to get clear solution. The white crystals obtained after cooling the reaction mass were collected by filtration. The material was dried below 40°C under reduced pressure.
Yield: 52g
Melting point: 48-50°C

c) Preparation of Febantel
l,3-Bis(methoxycarbonyl)-2-decyl-2-thiopseudourea (28.8g) was charged to a solution of 7V-[2-amino-5-(phenylsulfanyl)phenyl]-2-methoxyacetamide (25g) in methanol at 25-30°C under stirring. Acetic acid (12.5g) was charged to the reaction mass under stirring at 25-30°C. The reaction mass was heated to 35-40°C and stirred for 16 hours. After completion of the reaction, it is cooled to 0-5°C. The solids were separated by filtration. White crystalline material obtained was dried at 50-55°C under vacuum.
Yield: 35.0g

We claim:
1. A process for the preparation of febantel of formula I, which comprises:
a) reacting 1-decyl bromide of formula V with thiourea in a solvent to obtain S-decyl pseudothiourea hydrobromide of formula IV;
b) reacting S-decyl pseudothiourea hydrobromide of formula IV with methyl chloroformate in presence of base and solvent to obtain 1,3-Bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of formula III; and

c) condensing l,3-Bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of formula III with 2-methoxy-N-[2-amino-5-(phenylsulfanyl) phenyl] acetamide of formula II in presence of an acid and solvent to give febantel of formula I.
2. A process according to claim 1, wherein solvent in step (a) is selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol and the mixture thereof, preferably methanol.
3. A process according to claim 1, wherein the base in step (b) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, sodium bicarbonate and mixture thereof, preferably potassium carbonate.

4. A process according to claim 1, wherein solvent in step (b) is selected from methylene dichloride, carbon tetrachloride, ethylene dichloride, N,N-dimethyl formamide, tetrahydrofuran and the like, preferably methylene dichloride.
5. A process according to claim 1, wherein the reaction in step (b) is carried out at temperature 10 to 40°C, preferably at 25 to 30°C.
6. A process according to claim 1, wherein acid in step (c) is selected from a group comprising hydrochloric acid, sulphuric acid, oxalic acid, acetic acid and the mixture thereof, preferably acetic acid.
7. A process according to claim 1, wherein alcoholic solvent in step (c) is selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol and the mixture thereof, preferably methanol.
8. A process according to claim 1, wherein the reaction in step (c) is carried out at temperature 20 to 50°C, preferably 35 to 40°C.
9. A compound l,3-Bis(methoxycarbonyl)-2-decyl-2-thiopseudourea of formula III.
10. A process for the preparation of febantel which comprises the use of compound III as claimed in claim 9.