Field of the Invention:

The present invention relates to an improved process for the preparation of o-ethoxybenzamidine Hydrochloride which is. the key starting material in the preparation of various Active Pharmaceutical Ingredients.

Background of the Invention:

Benzamidines are important pharmaceutical Intermediate compounds; these are widely used antibiotics, anti-inflammatories and deworming drugs. Meanwhile, starting from amidine compounds, heterocyclic compounds can be synthesised which have important synthetic value. o-Ethoxybenzamidine is an important intermediate used in the preparation of Vardenafil Hydrochloride.

Vardenafil hydrochloride is useful in the treatment of erectile dysfunction. It is commercially available in the market under the brand name Levitra as capsules containing 2.5, 5, 10 and 20 mg equivalents of Vardenafil hydrochloride for oral administration.

Considering importance of o-Ethoxybenzamidine hydrochloride, several patents and non-patent literature describes the synthesis of the same.

WO 1999/24433 Al, WO 1999/67244 Al, WO 2001/47928 A2, WO 2001/67244 A2, WO 2002/064593 Al, WO 2004/101567 Al, WO 2009/037556 Al, Journal of Labelled Compounds and Radiopharmaceuticals vol. 46; nb. 11;(2003); p. 1019 - 1032, Bioorganic and Medicinal Chemistry Letters; vol. 12; nb. 6; (2002); p. 865 - 868, Tetrahedron letters 1969-1970, 1990 describes a process for the preparation of o-Ethoxybenzamidine hydrochloride which comprises reacting o Ethoxybenzonitrile with ammonium chloride in hexane in a temperature range of from -20°C to room temperature and atmospheric pressure resulting in the formation of o-Ethoxybenzamidine hydrochloride. The reaction is shown in scheme 1 shown below:

US 3,819,631 A and The Journal of Organic Chemistry 33, 1679, 1968, describes a process i.e pinner method wherein a amidine derivative is prepared starting from a nitrile compound, which is treated with hydrochloric acid and absolute ethanol and the obtained intermediate is treated with ammonia to yield an amidine compound. Tetrahedron; vol. 69; nb. 2; (2013); p. 474 - 480 describes a similar process for the preparation of o-Ethoxybenzamidine hydrochloride. The process is represented in the scheme-2 given below:

The Journal of Organic Chemistry 33, 1679, US 4,082,751 A and US 4,031,093 A describes a process for the preparation of o-Ethoxybenzamidine hydrochloride comprising alkylation of amides with ethyl chloroformate, dimethyl sulphate and triethyloxonium fluoroborate to obtain imidate salts which on treatment with ammonia yield amidine compound. The said process is represented in the scheme-3 given below:

US 3,819,631 A, US 4,082,751 A and US 4,031,093 A describes a process for the preparation of o-Ethoxybenzamidine hydrochloride which comprises treating a nitrile compound with hydroxylamine hydrochloride in the presence of base and followed by reducing the obtained oxime under catalytic hydrogenation. The process is shown in the schemc-4 given below:

CN 103086920 A describes a process for the preparation of o-Ethoxybenzamidine hydrochloride comprising reacting o-Ethoxybenzonitrile with hydroxylamine hydrochloride followed by treating the oxime formed with Fe-HCl or Zn-HCl to get amidine compound of formula 1 as represented in the scheme-5 given below:

WG2002/050076 A2, IN 2010CH01365 A describes a process for the preparation of oEthoxybenzamidine hydrochloride comprising reacting o-ethoxybenzonitrile with hydroxylamine hydrochloride followed by hydrogenating the oxime formed with palladium carbon in the presence of acetic acid under hydrogen pressure. The process is represented in Scheme-6 given below:

The above referred references disclose various methods for reduction of oxime ; into amidine using N2/Pd/C5 H2/Raney nickel or Pd/C in acetic acid. However, use of Pd/C alone.requires higher volumes of Pd/C. results in low yield of the product, which in turn increases the cost of production.

Use of Raney nickel may pose a serious risk of fire or explosion as well as the process is always accompanied with the formation of byproducts and is quite uneconomical for manufacturing point of view.

None of the references disclosed the reduction of oEthoxy-N'-hydroxybenzamidine into o-Ethoxybenzamidine using metal catalyst in the presence of Ammonium formate.

Considering the importance of Vardenafil and its Intermediates, there is need for a simple, economical process for the preparation of Vardenafil. With a view to find a simple process the present applicant diligently worked and identified a robust and economical process for the preparation of o-Ethoxybenzamidine hydrochloride.

Objectives of the Invention:

The primary object of the invention is to provide an improved process for the preparation of o-Ethoxybenzamidine hydrochloride.

Another object of the invention is to produce o-Ethoxybenzamidine hydrochloride in a cost effective and industrially feasible manner.

Summary of the Invention:

In an embodiment, the present invention relates to a process for the preparation of o-

Ethoxybenzamidine hydrochloride which comprises reduction of o-Ethoxy-N'-hydroxybenzamidine with a Metal catalyst, Hydrogen donor in the presence of a solvent.

In an embodiment, the present invention relates to a process for the preparation of o-

Ethoxybenzamidine hydrochloride comprising the steps:

a) treating o-Ethoxybenzonitrile with hydroxylamine hydrochloride in the presence of a base to obtain o-Ethoxy-N'-hydroxybenzamidine; and

b) reducing o-Ethoxy-N'-hydroxybenzamidine of step a) with Metal catalyst in the presence of ammonium formate in a solvent.

Detailed Description of the Invention:

The Present invention relates to a process for the preparation of oEthoxybenzamidine hydrochloride which comprises reduction of o-Ethoxy-N'-hydroxybenzamidine with a Metal catalyst, Hydrogen donor in the presence of a solvent.

In another embodiment of the present invention, the metal catalyst used in the present invention is selected from metal platinum, palladium, palladium on carbon (Pd/C), Raney nickel, magnesium tunings, etc.

In still another embodiment of the present invention the hydrogen donor compound used selected from alkali metal and amine esters of.fatty acids such as sodium acetate, ammonium formate, sodium formate and potassium formate preferably ammonium formate.

In another embodiment of the present invention the preferred hydrogenation catalyst/hydrogen donor system is selected from Pd/C & ammonium formate. The use of ammonium formate also has advantages of being readily available, inexpensive, stable and nontoxic compound. Thus the present invention offers a novel reduction method, which is more efficient because it is faster, easier and results in substantially improved yield of the desired product. It is also more convenient for scale up at plant. In addition use of ammonium formate drops the use of higher volume of Pd/C required for reduction which in turn reduces the cost of the production.

In an embodiment, the present invention relates to a process for the preparation of o-Ethoxybenzamidine hydrochloride comprising the steps:

a) treating o-ethoxybenzonitrile with hydroxylamine hydrochloride in the presence of a base to obtain oEthoxy-N'-hydroxybenzamidine; and

b) reducing o-Ethoxy-N'-hydroxybenzamidine of step a) with Metal catalyst in the presence of ammonium formate in a. solvent.

In an embodiment, the present invention relates to a process for the preparation of o-Ethoxybenzamidine hydrochloride comprising the steps:

a) treating o-ethoxybenzonitrile with hydroxylamine hydrochloride in the presence of a base to obtain o-Ethoxy-N'-hydroxybenzamidine; and

b) reducing o-Ethoxy-N'-hydroxybenzamidine of step a) with Palladium/Carbon in the presence of ammonium formate in a solvent.

Yet another embodiment of the present invention the solvent used in the present invention is selected from group comprising alcohols such as methanol, ethanol, isopropyl alcohol and the like.

The staring material o-Ethoxybenzonitrile or o-Ethoxy-N'-hydroxybenzamidine are prepared by utilizing the process disclosed in the prior art.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting; but merely as exemplifications of preferred embodiments.The present invention is . exemplified by the following example, which is provided for illustration only and should not be construed to limit the scope of the invention.

Examples:

Reference Example 1:

Preparation of 0-Ethoxybenzamindine Hydrochloride using Pd/C with Hydrogen Pressure:

Charged o-Ethoxy-N?-hydroxybenzamidine (80 g) into a hydrogenation apparatus containing acetic acid (800 mL) and wet palladium on carbon (80 g). The resulting reaction mixture was maintained at about 4-5 kg/cm hydrogen pressure for about 7-8 hours at 30-60°C until completion of the reaction. To the resulting filtrate, concentrated hydrochloric acid (67 mL) was added, and removed completely by distillation under vacuum below 80°C. The resultant crude was cooled to 20-30°C and 400 mL of toluene was added and stirred for solid separation for about 30-45 minutes.

The separated solid was filtered and washed the solid with toluene (80 mL) and dried under vacuum for about 40-45°C for 2-3 hours to afford 84.2 g of the title compound

Example 1: Preparation of 0-Ethoxy-N-hydroxy benzamidine:

Charged o-Ethoxybenzonitrile (125 g) in to a clean, dry, round-bottom flask containing methanol (750 mL) and stirred for about 10-15 minutes, added triethylamine (175 g), and the resulting mixture stirred for about 10-15 minutes at 25-30°C. To the resulting reaction mixture added hydroxylamine hydrochloride (105 g), heated to about 65-70°C, and stirred for about 10 hours until completion of the reaction. After completion of the reaction, treated with water (5 1) and dichloromethane (625 ml), separated the layers. Dichloromethane layer is distilled and charged Isopropyl ether (375 ml) isolated, washed with Isopropyl ether (125 ml) and dried to afford o-Ethoxy-N-hydroxy benzamidine (110 g).

Example 2: Preparation of 0-Ethoxybenzamidine Hydrochloride using Pd/C with Ammonium formate Charged o-Ethoxy-N-hydroxy benzamidine ( 100 gm, 0.554 mole) and Methanol (1500 ml), 5 % Pd/C (10 gm) and Ammonium formate (70 gm, l.llmoles) at temperature in between 20-30°C. Reaction mass heated to 50-60°C and allowed to stir for 10-12 hrs at same temperature and monitored by TLC (Thin layer Chromatography). Once TLC shows absence of starting material, RM filtered through Hyflo and washed with Methanol (120 ml). Added HC1 to the above filtrate and total Methanol layer distilled below 45-50°C under vacuum and crude product dissolved in Isopropanol (500 ml) and heated to 75 to 80°C for 20-30 mins. Filtered and washed with Isopropanol (50-60 ml). Total Isopropanol layer distilled below 65°C under vacuum. Charged Isopropanol (120 ml) and Isopropyl ether (380 ml) and maintained for 1. hr. Filtered, washed with Isopropanol and Isopropyl ether (48 + 120 ml). Dried at:55-60°C to. afford oEthoxybeiizamindine Hydrochloride (106 gm) (96% Yield) (HPLC purity 99.9).

Example 2: Preparation of o-Ethoxybenzamidine Hydrochloride Charged o-Ethoxy-N-hydroxy benzamidine ( 25 gm, 0.138 mole) and Methanol (375 ml), 5 % Pd/C (2.5 gm) and Ammonium formate (17.5 gm,0.277 moles) at temperature in between 20-30°C. Applied 4-5 kg/cm hydrogen pressure for about 10-13 hours at 30-60°C until completion of the reaction and monitored by TLC (Thin layer Chromatography). Once TLC shows absence of starting material, RM filtered through Hyflo and washed with Methanol (30 ml). Added HC1 to the above filtrate and total Methanol layer distilled below 45-50°C under vacuum and crude product dissolved in Isopropanol (125 ml) and heated to 75 to 80°C for 20-30 mins. Filtered and washed with Isopropanol (12.5-15 ml). Total Isopropanol layer distilled below 65°C under vacuum. Charged Isopropanol (30 ml) and Isopropyl ether (95 ml) and maintained for 1 hr. Filtered, washed with Isopropanol and Isopropyl ether (12 + 30 ml). Dried at 55-60°C to afford of o-Ethoxybenzamidine Hydrochloride (26 gm) (94% Yield) (HPLC purity 99.8)

We Claim:

1. A process for the preparation of o-Ethoxybenzamidine hydrochloride which comprises reduction of o-Ethoxy-N'-hydroxybenzamidine with a Metal catalyst, Hydrogen donor in the presence of a solvent.

2. A process according to claim 1, oEthoxybenzamidine hydrochloride is prepared by a process comprising the steps:

a) treating o-ethoxybenzonitrile with hydroxylamine hydrochloride in the presence of a base to obtain o-Ethoxy-N'-hydroxybenzamidine; and

b) reducing o-Ethoxy-N'-hydroxybenzamidine of step a) with Palladium carbon in the presence of ammonium formate in a solvent.

3. A process according to claim 1 and 2. wherein metal catalyst used is selected from metal platinum, palladium, palladium on carbon (Pd/C), Raney nickel, magnesium tunings.

4. A process according to claim 1 and 2, hydrogen donor compound used selected from alkali metal and amine esters of fatty acids such as sodium acetate, ammonium formate, sodium formate and potassium formate

5. A process according to claim 1 and 2, the solvent used is selected from group comprising methanol, ethanol, isopropyl alcohol and the like.

6. A process according to claim 1 and 2, hydrogenation catalyst/hydrogen donor svstem is selected from Pd/C & ammonium formate

7. A process according to claim 2, the base used in step a) is an organic or inorganic base selected from triethylamine, diisopropylethylamine, sodium carbonate and potassium carbonate and like.

8. A process according to claim 1, o-Ethoxybenzamidine hydrochloride is prepared by treating o-Ethoxy-N'-hydroxybenzamidine with Palladium on carbon, Ammonium formate in Methanol.

9. An improved and industrial viable, economical process for the preparation of o Ethoxybenzamidine hydrochloride such as herein described in accompanying description and examples.