Field of Invention

The present invention relates to a novel, cost-effective process for the preparation of a diminazene diaceturate. This invention further relates to a process for the preparation of diazoamino benzene compound also called diminazene.

Background of the Invention

Diminazene diaceturate having chemical name 4-[2-(4 carbamimidoylphenyl)iminohydrazinyl]benzenecarboximidamide diaceturate of formula I, which is used in the treatment of trypanosomiasis and babesiosis.

There are number of literatures available which describe the process for preparation of diminazene diaceturate. US patent 2673197 describes a process for the preparation of diminazene by diazotising p-amino benzamidine hydrochloride using sodium nitrite and concentrated hydrochloric acid in presence of water and sodium acetate, followed by coupling of diazonium salt of p-amino benzamidine hydrochloride with p-amino benzamidine hydrochloride. The drawback of this process is long reaction time and low yield.
US2838485 describes a process for the preparation of diminazene diaceturate by reacting diminazene with aceturic acid in presence of methanol.

US3853893 describes a process for the preparation of p-nitro benzamidoxime compounds by treating p-nitro benzonitrile with an acid salt of hydroxylamine in presence of alcohol.

JP 2002114750 describes a process for the preparation of p-amino benzamidine compounds by reducing p-nitro benzamidine with anhydrous SnC^ and concentrated hydrochloric acid in presence of ethanol. The p-nitro benzamidine compounds were prepared by treating p-nitro benzonitrile in methanol with sodium methoxide, acetic acid, ammonium chloride and sodium hydroxide.

Thus it is highly desirable to develop a process whose reaction time is comparatively short and the yield is high. The present inventors have developed a very cost effective and environment friendly process, which provides greater yield and have a short reaction.

Summary of the Invention

The principal aspect of the present invention is to provide a process for the preparation of Diminazene diaceturate comprising:

a) converting p-nitro benzamide of formula VI into p-nitro benzonitrile of formula V in presence of phosphorous oxychloride toluene and DMF;

b) converting optionally insitu, p-nitro benzonitrile of formula V into p-nitro benzamidoxime of formula IV using hydroxyl amine sulphate and sodium hydroxide in methanol;

c) reducing the p-nitro benzamidoxime of formula IV to obtain p-amino benzamidine dihydrochloride of formula III by pressurizing with external hydrogen gas or in absence of any external hydrogen gas and using palladium as catalyst;

d) diazotising p-amino benzamidine dihydrochloride of formula III in presence of sodium nitrite and concentrated hydrochloric acid, followed by coupling of diazonium salt of p-amino benzamidine dihydrochloride with p-amino benzamidine dihydrochloride in presence of catalytic amount of sulphamic acid to obtain diminazene of formula II; and

e) reacting diminazene of formula II obtained in step d) with acetic acid in presence of methanol to form diminazene diaceturate of formula I.

The process of the present invention is illustrated in scheme 1 below:

Detail Description of the Invention

Accordingly in an embodiment of the invention, the conversion of p-nitro benzamide into p-nitro benzonitrile is carried out in presence of a dehydrating agent such as phosphorous oxychloride or phosphorous pentachloride preferably phosphorous oxychloride and mixture of organic solvents selected from toluene and DMF or toluene and THF preferably toluene and DMF.

In another embodiment of the invention, the conversion of p-nitro benzonitrile into p-nitro benzamidoxime is carried out in presence of an acid salt of hydroxyl amine, such as hydrochloride, sulphate or phosphate most preferably sulphate and a base such as potassium hydroxide, sodium hydroxide most preferably sodium hydroxide, in an alcoholic solvent, more preferably selected from methanol, ethanol or propanol, most preferably methanol, preferably in the pH range 6.2, in the temperature range 35-50°C preferably in the temperature range 40-45°C.

In another embodiment of the invention, the reduction in step c) is carried out using a reducing agent selected from Raney nickel, Palladium or Platinum, preferably Palladium, in an alcoholic solvent like methanol, ethanol, propanol, preferably in presence of methanol. The reduction is carried out at 5 kg H2 pressure or without using any external H2 gas and at a temperature about 6O0C to obtain p-amino benzamidine dihydrochloride.

In another embodiment of the invention, the step d) is carried out in presence of an acid, preferably mineral acid, more preferably concentrated hydrochloric acid, and an aqueous sodium nitrite solution. It is further treated with catalytic amount of sulphamic acid and a base, preferably sodium acetate to form diminazine.

In another embodiment of the invention, diminazene of formula II obtained in step d) is reacted with aceturic acid in presence of a base such as potassium hydroxide, sodium hydroxide most preferably sodium hydroxide, and in presence of a solvent preferably aqueous methanol. The reaction is carried out at a temperature preferably at 40°C to obtain Diminazene diaceturate.

The present invention has advantage over prior art because its reaction time is significantly short and yield comparatively high.

The present invention can be illustrated by the following examples, which are not to limit the scope of the invention.

Example-1: Preparation of 4-[2-(4-carbamimidoylphenyl)iminohydrazinyl] benzenecarboximidamide diaceturate I

(a) Preparation of p-nitro benzamidoxime

p-Nitro benzamide (90 g), toluene(54 g) and DMF (54 g) were taken in round bottom flask and heated to 60°C. Phosphorous oxychloride (45.5 g) was added to it and heated to 100°C for two hours. After completion of the reaction, the reaction mass was cooled to 60°C. Methanol (150 g), hydroxyl amine sulphate (68 g in 130mL of water) and 30-33% sodium hydroxide solution were added to the obtained solution, and the pH was adjusted to 6.2 at 40-45°C. The above solution was heated to 60°C for 5 hours and pH was adjusted by caustic solution to 6.2 if needed. After completion of the reaction, methanol was distilled out completely under vacuum and cooled to room temperature, water was added and stirred for half an hour. The solids were filtered, washed with water till pH was neutral and then washed with methanol.

(b) Preparation of p-amino benzamidine dihydrochloride: (Using Hydrogen gas pressure)

p-nitro benzamidoxime (125 g), methanol (1.35 L) were charged into flask. To the above solution palladium on charcoal (2.5 g) and acetic acid (90 g) slurry was added. 4 kg N2 gas in portion and 4 kg H2 gas in portion at 5 kg H2 pressure was flushed to the above solution, heated slowly to 60° C. TLC was checked. Heat the reaction mass to 80°C and maintained for 3 hours. Cooled to room temperature, H2 pressure was released and N2 gas was flushed into. Reaction mass was filtered over hyflo under nitrogen, hyflo bed was washed with methanol. The filtrate was cooled to 20°C and concentrated HC1(243 g) was added drop wise, maintained for 1 hour. The solids were filtered, washed with methanol.

(c) Preparation of p-amino benzamidine dihydrochloride (Transfer hydrogenation)

p-nitro benzamidoxime (125 g), methanol (1.35 L) were charged into flask. To the above solution palladium on charcoal (2.5 g) and Formic acid (90 g) were added. The solution, heated slowly to 60° C. Monitor the reaction by TLC till the reaction mass shows absence of the reactant. Cool the reaction mass & filter over hyflo under nitrogen, hyflo bed was washed with methanol. The filtrate was concentrated & cooled the residue to 20°C and concentrated HC1 (243 g) was added drop wise, maintained for 1 hour. The solids were filtered, washed with methanol.

(d) Preparation of Diminazine

p-amino benzamidine dihydrochloride (100 g), water (320 mL) were charged into four necked round bottom flask, cooled to 10-15°C. Concentrated HC1 (96g) was added drop wise at 10°C for VA hour, cooled to 0-5°C. To the above solution sodium nitrite (16gm sodium nitrite in 50ml water) solution was added drop wise for 1 lA hour, maintained for 0-5°C for 1 hour. Sulphamic acid (1 g) was added, stirred for 10 minutes at 0-5°C. pH was adjusted to 1-2, stirred for 10 minutes. Sodium acetate trihydrate (101.5 g sodium acetate in 100 mL water) solution was added drop wise for 1-2 hours at 0-5°C, maintained the same for 6 hours. Filtered, washed with chilled solution of NH4CI (15 g in 190 mL of water) and with chilled solution of NaCl (15 g in 190 mL of water), yellow solids were observed, suck dried. Yellow solids in water were taken in round bottom flask, cooled to 10-15°C. At 15°C caustic soda solution (28.8 g NaOH flakes in 270ml water) was added drop wise for 1 hour, orange slurry was formed, maintained for 1 hour at 10-15°C. Filtered, washed with a solution of 1.5% of NaOH.

(e) Preparation of Diminazine

Wet Diminazene (149g) obtained in step c) and water (420 mL) were taken in round bottom flask. Aceturic acid (58.8 g) was charged slowly at the room temperature. pH was adjusted to 4.5-4.7, heated to 40-45°C. Activated carbon (1 g) was charged into the flask at 40°C and maintained for half an hour. The reaction mixture was filtered by hyflow, washed with hot water. Filtrate was collected and taken in round bottom flask, cooled to room temperature. Methanol (300 mL) was added slowly to form yellow colour solids, after complete addition reaction mixture was cooled to 0-5 °C for 1 hour. Solids were filtered at 0-5° C under nitrogen.

We claim: 1. A process for the preparation of Diminazene diaceturate of formula I: which comprises:

a) converting p-nitro benzamide of formula VI into p-nitro benzonitrile of formula V;

b) converting optionally insitu, p-nitro benzonitrile of formula V into p-nitro benzamidoxime of formula IV;

c) reducing the p-nitro benzamidoxime of formula IV to obtain p-amino benzamidine dihydrochloride of formula III;

d) diazotising p-amino benzamidine dihydrochloride of formula III, followed by coupling of diazonium salt of p-amino benzamidine dihydrochloride with p-amino benzamidine dihydrochloride in presence of a catalytic amount of sulphamic acid to obtain diminazene of formula II; and

e) reacting diminazene of formula II obtained in step d) with aceturic acid to form diminazene diaceturate of formula I.

2. A process according to claim 1 wherein, the conversion in step a) is carried out in presence of a dehydrating agent and mixture of organic solvents.

3. A process according to claim 1 wherein, the conversion in step a) is carried out in presence of phosphorous oxychloride and a mixture of solvents containing toluene and DMF.

4. A process according to claim 1wherein, the conversion in step b) is carried out in presence of an acid salt of hydroxyl amine and a base in an alcoholic solvent.

5. A process according to claim 1wherein, the conversion in step b) is carried out in presence of a sulphate salt of hydroxyl amine and sodium hydroxide in methanol.

6. A process according to claim 1wherein, the reduction in step c) is carried out in presence of a reducing agent preferably Palladium, in an alcoholic solvent.

7. A process according to claim 1wherein, the reduction in step c) is carried out in presence of Palladium in acetic acid, in the solvent methanol at about 5 kg hydrogen pressure in presence or absence of external hydrogen gas at a temperature about 60°C.
8. A process according to claim 1wherein, the diazotization in step d) is carried out in presence of an acid, an aqueous sodium nitrite solution and in presence of a base.

9. A process according to claim 1wherein, the diazotization in step d) is carried out in presence concentrated hydrochloric acid, an aqueous sodium nitrite solution, sodium acetate and a catalytic amount of sulphamic acid.

10. A process according to claim 1wherein, step e) is carried out in presence of aceturic acid, in presence of a base preferably sodium hydroxide, and in presence of a solvent preferably aqueous methanol.