Field of Invention

The present invention relates to a novel, cost-effective process for preparing the 1,3-Bis[3-(4,5-dihydro-lH-imidazol-2-yl)phenyl]ureadipropionate, an antiprotozoal agent, having the formula I:

Background of the Invention
Imidocarb is a urea derivative used in veterinary medicine as an antiprotozoal agent for the treatment of infection with Babesia (babesiosis) and other parasites.

Imidocarb dihydrochloride has been disclosed for the first time in US patent 3338917. This patent describes a process for the preparation of Imidocarb dihydrochloride by reacting 3-(2-imidazolin-2-yl)-aniline dihydrochloride with phosgene gas in presence of aqueous sodium acetate, soda lye and concentrated HC1.

Chinese patent 100390150 describes a process for the preparation of Imidocarb dihydrochloride in three steps starting from 3-amino benzonitrile.Treatment of 3-amino benzonitrile with triphosgene yields 1,3-Bis-(3-cyano-phenyl)-urea, which on further treating with Sulphur and ethylene diamine forms l,3-bis[3-(4,5-dihydro-lH-imidazol-2-yl)phenyl]urea i.e., imidocarb. This on further treating with concentrated HC1 forms imidocarb dihydrochloride. This can be illustrated by the below scheme.

The primary drawback of this process is that the use of highly hazardous triphosgene for the preparation of l,3-Bis-(3-cyano-phenyl)-urea from 3-amino benzonitrile. Also, this process utilizes sulphur one and half times of a reactant for preparing imidcarb. The use of sulphur may lead to formation of huge quantity of solid waste.

Thus there is a need to develop a scalable, eco-friendly process for the preparation of imidocarb which gives high yield and better purity, avoids the use of highly hazardous triphosgene and reduces drastically the ratio of sulphur used. The present inventors have developed a novel process for the preparation of Imidocarb, which overcomes most of the above stated drawbacks and yields highly pure product.

Summary of the Invention

The principal aspect of the present invention is to provide a process for the preparation of l,3-Bis[3-(4,5-dihydro-lH-imidazol-2-yl)phenyl]urea dipropionate of formula I, which comprises:

a) reacting 3-amino benzonitrile of formula IV with carbonyl diimidazole in presence of an organic base and solvent to form l,3-Bis-(3-cyano-phenyl)-urea of formula III;

b) cyclizing l,3-Bis-(3-cyano-phenyl)-urea of formula III with Ethylene diamine in presence of catalytic amount of sulphur to obtain 1,3-bis [3-

(4,5-dihydro-lH-imidazol-2-yl)phenyl]urea i.e., imidocarb of formula II; and

c) converting l,3-bis[3-(4,5-dihydro-lH-imidazol-2-yl)phenyl]urea of formula II into its dipropionate salt of formula I using propionic acid in presence of solvent.

The process of the present invention may be illustrated by the below scheme 1:

In another aspect, the present invention provides a simple and cost effective process for the preparation of dipropionate salt of Imidocarb of formula I from Imidocarb of formula II in high purity and good quality.

Detail Description of the Invention

Accordingly in an embodiment of the invention the reaction of 3-amino benzonitrile of formula IV and carbonyl diimidazole is carried out in presence of a ketonic solvent selected from acetone, ethyl isopropyl ketone, methyl isobutyl ketone, butanone and 3-pentanone, preferably acetone and an organic base selected from amines, preferably trialkylamines, more preferably trimethylamine, triethylamine most preferably triethylamine.

In another embodiment of the invention the cyclization of l,3-Bis-(3-cyano-phenyl)-urea of formula III with ethylenediamine is carried out in the absence of solvent and presence of catalytic amount of sulphur. The amount of sulphur used is normally less than 0.1 times of a reactant, preferably less than 0.05 times of a reactant.

In yet another embodiment of the invention, the solvent for the conversion of l,3-bis[3-(4,5-dihydro-lH-imidazol-2-yl)phenyl]urea of formula II into its dipropionate salt of formula I using propionic acid is an alcoholic solvent selected from methanol, ethanol, propanol, etc. preferably methanol. Further the obtained dipropionate salt is crystallised using an organic solvent selected from the group comprising acetone, methyl acetate, ethyl acetate and hexane, preferably acetone.

Example:
(a) Preparation of 1.3-Bis-(3-cvano-phenvl)-urea:
3-amino benzonitrile (100 g) in acetone (500 ml) was treated with carbonyl diimidazole (103 g) and triethylamine (42.8 g) at 50-55°C, stirred for 6-8 hours and distilled. Water (1000 ml) was charged into above reaction mass, distilled to remove traces of acetone, and stirred at 60-65°C for 30-45 minutes. The reaction mass was cooled to 25-35°C and stirred for 1-2 hours. The solid was filtered, washed with water and suck dried.

Yield: 88.92%

(b) Preparation of lt3-bis[3-(4,5-dihvdro-lH-imidazol-2-yl)phenvllurea:
l,3-Bis-(3-cyano-phenyl)-urea(100 g) was reacted with sulphur (4 g) and ethylenediamine (100 ml) at 80-85°C and stirred for 6-8 hrs. After the completion of reaction the reaction mass was cooled to 0-5°C and water (1000 ml) was added into it. The reaction mass was heated to 60-65°C and further stirred at 25-35°C for 1-2 hours. The solid was filtered, washed with water and suck dried. The obtained crude material and methanol (1000 ml) were heated to 60-65°C and stirred for 30-45 minutes. Reaction mass was cooled to 25-35°C and stirred for 1-2 hours. The solid was filtered, washed with methanol and suck dried.

Yield: 86.5%

(c) Preparation of 1,3-bis f3-(4,5-dihvdro-lH-imidazol-2-vl)phenvll urea dipropionate;
l,3-bis[3-(4,5-dihydro-lH-imidazol-2-yl)phenyl]urea (100g) and methanol (400 ml) were stirred at 25-35°C for 5-10 minutes. Propionic acid (42.5g) and activated carbon (20g) were added to the above reaction mass, stirred for 30-45 minutes. Reaction mass was filtered through hyflow bed and washed with methanol (100 ml). Acetone (1500 ml) was charged into the reaction mass, heated to 50-55°C, stirred. The reaction mas was cooled to 25-35°C and stirred for 1-2 hours. The solid was filtered, washed with acetone and suck dried.

Yield: 84.2%

We claim:

1. A process for the preparation of l,3-Bis[3-(4,5-dihydro-lH-imidazol-2-yl)phenyl]ureadipropionateof formula I,
which comprises:

a. reaction of 3-amino benzonitrile of formula IV with carbonyl
diimidazole in presence of an organic base and a ketonic solvent to give
l,3-Bis-(3-cyano-phenyl)-urea of formula III;

b. cyclization ofl,3-Bis-(3-cyano-phenyl)-urea of formula III with
ethylenediamine in presence of catalytic amount of sulphur to form 1,3-
bis[3-(4,5-dihydro-lH-imidazol-2-yl)phenyl]urea of formula II; and

c. conversion of l,3-bis[3-(4,5-dihydro-lH-imidazol-2-yl)phenyl]urea of formula II into its dipropionate salt of formula I using propionic acid in presence of a solvent.

2. A process according to claim 1 wherein, step a) is carried out in presence of organic base selected from amines, preferably trialkylamines, more preferably trimethylamine, triethylamine most preferably triethylamine.

3. A process according to claim 1 wherein, step a) is carried out in presence of a ketonic solvent selected from acetone, ethyl isopropyl ketone, methyl isobutyl ketone, butanone and 3-pentanone, preferably acetone.

4. A process according to claim 1 wherein, the amount of sulphur in step b) is less than 0.1 time of a reactant.

5. A process according to claim 1 wherein, the reaction in step c) is carried out in an alcoholic solvent selected from methanol, ethanol, propanol, and the like, preferably methanol.

6. A process according to claim 1 wherein, the solvent for crystallisation in step c) is selected from the group comprising acetone, methyl acetate, ethyl acetate and hexane, preferably acetone.