FIELD OF THE INVENTION
The present invention also relates to an improved purification process of Naftopidil (I).
Formula I
BACKGROUND OF THE INVENTION
Naftopidil is chemically known as (±)-l-[4-(2-methoxyphenyl)piperazinyl]-3-(l-napthyloxy)propan-2-ol. Naftopidil is a selective oti-adrenergic receptor antagonist or alpha blocker. Naftopidil is approved for the treatment of Benign Prostate Hypertrophy and is being marketed under the brand name Flivas®.
Naftopidil and its pharmacologically compatible salts are disclosed in US 3,997,666.
US '666 also discloses a process for the preparation of Naftopidil by condensing (2,3-epoxy)propoxy-l-naphthol (II) with l-(2-methoxyphenyl)piperazine (III) without using a solvent, under heating to 120°C to produce Naftopidil (I), which is crystallized from isopropanol.
The process is as shown in Scheme-I below:


Scheme I
The major disadvantage with the above process is that the formation of unwanted impurities selected from Diol (IV), Dimer impurity (V) and Desmethyl Naftopidil (VI). It was observed that these impurities are not eliminated by purification using isopropanol crystallization and requires additional purification step. This results in the poor yield and quality of Naftopidil.

Hence, there is a need to have improved purification process for the preparation of Naftopidil (I) with high chemical purity and high yields.
The present invention is specifically directed towards an improved purification process for the preparation of Naftopidil (I), which is substantially free from their diol (IV), dimer (V) and desmethyl Naftopidil (VI) impurities.

OBJECTIVE OF INVENTION
The main objective of present invention is to provide an improved purification process of Naftopidil (I).
SUMMARY OF THE INVENTION
Accordingly, the present invention relates to Naftopidil comprising reduced content (less than 0.05%) of impurities of formulae IV, V and VI, which are shown below:

In another embodiment, the present invention relates to a purification process of Naftopidil (I), with reduced content of impurities of formulae IV, V and VI,
Formula I
which comprises:
(i) suspending Naftopidil in methanol,
(ii) optionally, heating to provide a clear solution,
(iii) optionally, cooling the solution of step (ii),

(iv) optionally, treating the solution of step(ii) or step (iii) with carbon, (v) optionally, heating to reflux temperature (vi) optionally, concentrating the filtrate partially, (vii) optionally, cooling the solution, and (viii) isolating pure Naftopidil.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved purification process of Naftopidil (I), with reduced content of impurities of formulae IV, V and VI.
The process comprises, suspending Naftopidil in methanol at 25-30°C and optionally heating to reflux temperature to provide a clear solution. The resulting solution is optionally treated with carbon under hot condition and cooled the filtrate and partially concentrated to get slurry containing Naftopidil. Further, the resulting slurry is cooled and the solid is filtered and dried under vacuum to produce pure Naftopidil (I).
It has been observed that impurities of formulae IV, V and VI are reduced to less than 0.05% by purification from methanol.
Naftopidil (I) used in the present invention is prepared by reacting l-(2-methoxyphenyl)piperazine hydrochloride (II) with (2,3-epoxy)propoxy-l-naphthol (III) in an alcoholic solvent comprises methanol, ethanol, propanol, n-butanol, isopropyl alcohol, more preferably methanol.
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES
1. 4-(2-Methoxyphenyl)-a-[(l-naphthalenyloxy)-methyl]-l-piperazine ethanol
(Naftopidil):
l-(2-Methoxyphenyl)piperazine hydrochloride (II) (4.664 Kg) was suspended in methanol (12 Lt) at 25-30°C. The suspension was cooled to 0-5°C. Sodium hydroxide granules (0.83 Kg) were added at 0-5°C. The contents were stirred at 5-15°C for 15 min. The inorganic salts were filtered through hyflo and the residue was washed with methanol (6 Lt). This filtrate was added to (2,3-epoxy)propoxy-1-naphthol (III) (4.10 Kg) at 25-30°C. The contents were heated to reflux at 60-65°C. The stirring was continued at reflux (60-65°C) till (2,3-epoxy)propoxy-1-naphthol left unreacted is < 0.5% by qualitative HPLC analysis. Thereafter, the resulting slurry was cooled to 0-5°C. The slurry was stirred at 0-5°C for 1 hour. Filtered the product (Naftopidil-crude) and washed with precooled methanol (6 Lt, 0-5°C).
2. Purification of 4-(2-Methoxyphenyl)-a-[(l-naphthalenyloxy)-methyl]-l-
piperazine ethanol (Naftopidil)
Naftopidil (-7.60 Kg, Naftopidil crude, wet) was suspended in methanol (150 Lt) at 25-30°C. Carbon (0.60 Kg) was added at 25-30°C and the contents were heated to reflux at 60-65°C and stirring was continued at this temperature for 60 min. The contents are cooled to 55-60°C. Filter the carbon at 55-60°C through hyflo and wash the residue with preheated methanol (6 Lt, 55-60°C). The filtrate was concentrated at 60-65 °C at atmospheric pressure to collect 114 Lt of the distillate. The solution was cooled to 55-45°C and stir for 30 min at 45-55°C. Further, the suspension was cooled to 0-5°C and stirring was continued at this temperature for 30 min. The product was filtered and washed with pre-cooled methanol (6 Lt, 0-5°C). The product was dried at 60-65°C under reduced pressure to obtain Naftopidil. Yield: 5.85 Kg (73.09%).

WE CLAIM:
1. Pure Naftopidil comprising reduced content (less than 0.05%) of impurities of
formulae IV, V and VI, which are shown below:

2. A process for the purification of Naftopidil (I),
Formula I
which comprises:
(i) suspending Naftopidil in methanol,
(ii) optionally, heating to provide a clear solution,
(iii) optionally, cooling the solution of step (ii),
(iv) optionally, treating the solution of step (ii) or step (iii) with carbon,
(v) optionally, heating to reflux temperature
(vi) optionally, partially concentrating the filtrate,
(vii) optionally, cooling the solution, and
(viii) isolating pure Naftopidil.

3. The process according to claim 1, wherein Naftopidil is suspending in methanol at a temperature range of 25-30°C.
4. The process according to claim 1, wherein step (v) is carried out at a temperature range of 60-65°C.
5. The process according to claim 1, wherein, cooling the solution in the step-(vii) to about 0-5°C.
6. A process for the purification of Naftopidil (I),
Formula I
which comprises:
(i) dissolving Naftopidil in methanol
(ii) optionally, cooling the solution of step (i),
(iii) treating the solution of step (i) or step (ii) with carbon,
(iv) heating to reflux temperature
(v) partially concentrating the filtrate,
(vi) cooling the solution, and
(vii) isolating pure Naftopidil.
7. The process according to claim 6, wherein treating the solution of step (i) or step (ii) with carbon at a temperature range of 25-30°C.
8. The process according to claim 6, wherein step (iv) is carried out at a temperature range of 60-65°C

9. The process according to claim 6, wherein, cooling the solution in the step-(vi) to about 0-5°C.