This application claims priority to the Indian patent application number 466/CHE/2011 filed on Feb 18, 2011 , the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to the process of preparation of Naftopidil, which is an antihypertensive agent.

BACKGROUND OF THE INVENTION

Naftopidil, chemically known as l-[4-(2-Methoxyphenyl) piperazin-l-yl]-3-(l-naphthyloxy) propan-2-ol, is antihypertensive drug which acts as a selective al-adrenergic receptor antagonist or alpha blocker. Naftopidil is approved in Japan and is sold under the brand name Flivas.

The structure of Naftopidil is as follows.

Naftopidil is first disclosed in a Belgium patent application Number BE 825755. The US patent US 3997666A discloses the process for the preparation of Naftopidil fi-om 2,3-epoxy-l-(l-naphthyloxy)-propane by reacting with l-(2-methoxy-phenyl)-piperazine,

under neat conditions at a temperature of 120 °C. The product was recrystallized from Isopropyl alcohol and the product was obtained as heavy crystals with a yield of 79.0%.

The Chinese publication CN 101747293 discloses an alternative route for the synthesis of Naftopidil from 1- (2- methoxyphenyl) 4- (epoxy ethyl methyl) piperazine and a - naphthol. The reaction involves dissolving the inorganic base, such as sodium carbonate, in organic solvents and heating the reaction mixture.

The Chinese publication CN 1473820 discloses a process to obtain Naftopidil. The process involves heating of 3- (1-naphthoxy) 1, 2-expoxy propane and l-(2-methoxy benzyl)piperazine in solvents like ethanol, n-butanol and heating the reaction mixture to the solvent boiling point under reflux condition.

Though there exists processes to prepare Naftopidil, still there is a need to develop a process, which is commercially feasible and would result pure Naftopidil free from all the related impurities.

OBJECT AND SUMMARY OF THE INVENTION

The main object of the present invention is to provide a process to prepare Naftopidil with improved yield and quality.

Another object of the present invention is to provide, a process for the preparation of Naftopidil comprising, reacting 2, 3-epoxy-l-(l-naphthyloxy)-propane and l-(2-methoxy-phenyl)-piperazine or its acid addition salt in biphasic medium.

Yet another object of the present invention is to provide a process for the purification of Naftopidil.
Yet another object of the present invention is to prepare Naftopidil which is fi-ee from 2-naphthyl impurity as well as other impurities.

Yet another object of the present invention is to provide, a process for the preparation of 2, 3-epoxy-l-(l-naphthyloxy)-propane.

One aspect of the present invention provides process for the preparation of Naftopidil, comprising reacting 2,3-epoxy-l-(l-naphthyloxy)-propane and l-(2-methoxy-phenyl)-piperazine or its acid addition acid salt in biphasic medium.

Another aspect of the present invention provides, purification of Naftopidil comprising the steps of:

(a) dissolving Naftopidil in ester solvent;

(b) cooling the reaction mass; and

(c) isolating pure Naftopidil.

Another aspect of the present invention provides, purification of Naftopidil comprising the steps of:

(a) dissolving Naftopidil in polar protic solvent;

(b) cooling the reaction mass; and

(c) isolating pure Naftopidil.

Another aspect of the present invention provides process for the preparation of 2, 3-epoxy-l-(l-naphthyloxy)-propane comprising reacting 1-Naphthol with

I
epichlorohydrin in presence of base wherein the improvement comprises isolation of 2, 3-epoxy-l-(l-naphthyloxy)-propane by distillation under reduced pressure.

Drawings:

Fig 1 : represents the XRD spectrum of Crystalline Naftopidil.

DETAILED DESCRIPTION OF THE INVENTION

Present invention relates to process for the preparation of Naftopidil with improved yield and quality by the reaction of 2,3-epoxy-l-(l-naphthyloxy)-propane and l-(2-methoxy-phenyl)-piperazine or its acid addition salt in biphasic medium. The invention fiirther provides a purification process of Naftopidil to obtain pure crystalline Naftopidil free from all the relevant impurities, such as the 2-naphthyl impurity. The present invention also provides a process for the preparation of 2, 3-epoxy-l-(l-naphthyloxy)-propane by reacting 1-Naphthol with epichlorohydrin in presence of base and isolating 2, 3-epoxy-l-(l-naphthyloxy)-propane by distillation under reduced pressure.

Accordingly present invention provides process for the preparation of Naftopidil, by reacting 2,3-epoxy-l-(l-naphthyloxy)-propane and l-(2-methoxy-phenyl)-piperazine or its acid addition salt in biphasic medium as depicted in Scheme-I

SCHEME-I

According to one embodiment of the present invention, 2,3-epoxy-l-(l-naphthyloxy)-propane is reacted with l-(2-methoxy-phenyl)-piperazine or its acid addition salt. Acid addition salt is selected from Hydrochloride, Hydrobromide, sulphate; preferably Hydrochloride. The reaction is carried out at a temperature ranging from 25°-120°C, preferably in the range of 40°-90° C, more preferably in the range of 70°-75°C.

According to another embodiment of the present invention, 2,3-epoxy-l-(l-naphthyloxy)-propane is reacted with l-(2-methoxy-phenyl)-piperazine or its acid addition salt in biphasic medium. The biphasic system is water and water immiscible solvent. Water immiscible solvent is selected from ester solvents such as Methyl acetate, ethylacetate, isopropyl acetate, preferably ethylacetate; halogenated solvents such as chloroform, dichloromethane, 1,2-dichlorethane, preferably dichloromethane; hydrocarbons such as toluene, benzene, cyclohexane preferably toluene. The reaction is carried out optionally in presence of phase transfer catalysts. The preferred phase transfer catalysts include, but not limited to, benzyltrimethylammonium chloride, hexadecyltributylphosphonium bromide, tetra-n-butylammonium bromide, 18-crown ether.

According to another embodiment of the present invention, Naftopidil is isolated after the completion of reaction, by separating the organic layer from the biphasic reaction medium followed by conventional isolation techniques such as cooling the organic layer and filtering the obtained product.

Another aspect of the present invention provides, purification of Naftopidil comprising the steps of:

(a) dissolving Naftopidil in ester solvent;

(b) cooling the reaction mass; and

(c) isolating pure Naftopidil.

According to one embodiment of the present invention Naftopidil is purified by dissolving in ester solvent selected from Methyl acetate, Ethylacetate, and Isopropyl acetate preferably Ethyl acetate. The reaction mixture is maintained at a temperature of 30° - 80°C, preferably in the range of 70°C - 75°C. The reaction mass is cooled to a temperature of 10° C to 30° C, preferably in the range of 10° to 15° C. The obtained solid is filtered to isolate pure Naftopidil.

Another aspect of the present invention provides, purification of Naftopidil comprising the steps of:

(a) dissolving Naftopidil in polar protic solvent;

(b) cooling the reaction mass; and

(c) isolating pure Naftopidil.

According to one embodiment of the present invention Naftopidil is purified by dissolving in polar protic solvent selected from Methanol, Ethanol, Butanol, Propanol, Acetic acid; preferably Methanol. The reaction mixture is maintained at a temperature of 30° - 80°C, preferably in the range of 60°C - 65°C. The reaction mass is cooled to a temperature of 10° C to 30° C, preferably in the range of 10° to 15° C. The obtained solid is filtered to isolate pure Naftopidil.

Another aspect of the present invention provides process for the preparation of 2, 3-epoxy-l-(l-naphthyloxy)-propane by reacting 1-Naphthol with epichlorohydrin in

presence of base wherein the improvement involves isolation of 2, 3-epoxy-l-(l-naphthyloxy)-propane by distillation under a reduced pressure of 25 mmHg to 10 mmHg.

In one embodiment of the present invention, 2, 3-epoxy-l-(l-naphthyloxy)-propane is prepared by reacting 1-Naphthol with epichlorohydrin in presence of organic base. The organic base is selected from Triethyamine, Diisopropylamine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide; preferably Triethylamine. 2, 3-epoxy-l-(l-naphthyloxy)-propane is isolated in pure form by vacuum distillation at a temperature ranging from 100°-300'^ C, preferably in the range of 200°-250° C.

Instrumentation

Powder X-ray Diffraction rPXRD)

The said crystal of the present invention is characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 0/0 configuration and X'Celeraior detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 20 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

Examples:

The following examples should be cited merely to illustrate embodiments and are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention.

Examples:

Preparation of Naftopidil

(a) Preparation of 2,3-epoxy-l-(l-naplithyloxy)-propane

In a one lit. Round bottom flask Epichlorohydrin (321.0 gms) and Triethylamine (Igms) were added at 25-30° followed by 1-Naphthol (lOOgms). Maintained the reaction mass at temperature of 70-75°C for 6-8 hrs. After completion of the reaction, excess epichlorohydrin was distilled under vacuum. To the reaction mass sodium hydroxide solution (40 gms, sodium hydroxide dissolved in 200 ml DM water) was added and maintained the reaction mass at 20°-25°C for 2-4 hours . To this toluene (300 ml) was added and separated the organic layer. The aqueous layer was extracted with toluene. Toluene was completely distilled to get residue (-130-140 g). Finally the product distilled out under reduced pressure at 220-240°C. (120-125g) having purity 98.5%.

(b) Preparation of l-(2-methoxyphenyl)-4-[3-(naphtha-lyloxy)-2-hydroxypropyl]-

piperazine: (Naftopidil)

In a round bottom flask DM water (150 ml) and l-(2-Methoxy-phenyl)-piperazine hydrochloride (lOOgms) were added at 20-30 °C. To this Sodium hydroxide solution (18.4gms in 50ml DM water) and 2,3-epoxy-l-(l-naphthyloxy)-propane (96.3gms), ethyl acetate were added. The reaction mass was maintained at 70-75 °C temperature for 6-8hrs. After completion of the reaction, the organic layer was separated, cooled to 10-15°C. Filtered the solid and washed with Ethyl acetate. The wet material obtained was added to Ethyl acetate (500 ml), heated to 70-75°C temperature and maintained for 30 minutes. Reaction mass was cooled to 25-30 °C and obtained solid was filtered. To wet material methanol (500 ml) was added and heated to 60-65°C temperature for 30 minutes. Reaction mass was cooled to 25-30°C and obtained solid was filtered. The wet material was dried under vacuum to get title compound (125-135 gms, 79%, purity 99.99%).

We claim:

1. A process for the preparation of Naftopidil comprising, reacting 2,3-epoxy-l-(l-naphthyIoxy)-propane and l-(2-methoxy-phenyl)-piperazine or its acid addition salt in a mixture of water and water immiscible solvent, wherein water immiscible solvent is ester solvent.

2. The process according to claim 1, wherein ester solvent is selected from Methyl acetate, Ethylacetate, and Isopropyl acetate.

3. A process for purification of Naftopidil comprising the steps of,

(a) dissolving Naftopidil in ester solvent;

(b) cooling the reaction mass; and

(c) isolating pure Naftopidil.

4. The process according to claim 3, wherein ester solvent is selected from Methyl acetate, Ethylacetate, and Isopropyl acetate.

5. A process for purification of Naftopidil comprising the steps of,

(a) dissolving Naftopidil in polar protic solvent;

(b) cooling the reaction mass; and

(c) isolating pure Naftopidil.

6. The process according to claim 5, wherein polar protic solvent is selected from
Methanol, Ethanol, Butanol and Propanol.

7. A process for the preparation of 2, 3-epoxy-1 -(1 -naphthyloxy)-propane comprising, reacting 1-Naphthol with epichlorohydrin in presence of base wherein the improvement comprises isolation of 2,3-epoxy-l-(l-naphthyloxy)-propane by distillation under reduced pressure.

8. The process according to claim 7, wherein 2, 3-epoxy-l-(l-naphthyloxy)-propane is isolated by distillation under reduced pressure of 25 mmHg to 10 mmHg.

9. The process according to claim 7, wherein distillation is carried out at a temperature of 200°-250°C.