FORM II
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION (See section 10 and rule 13)
1. TITLE OF THE INVENTION
NOVEL PROCESS FOR THE PURIFICATION OF TETRAZOLYLBENZOPYRANONES
2. APPLICANT(S)
(a) NAME : CADILA PHARMACEUTICALS LIMITED
(b) NATIONALITY: An INDIAN Company
(c) ADDRESS : "Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat, Ahmedabad
-382210, Gujarat, India
3. PREAMBLE TO THE DESCRITION
COMPLETE SPECIFICATION
The following specification particularly describes the invention and the manner in which it is to be performed
4. DESCRIPTION
(Description starts from next page)

FIELD OF THE INVENTION
The present invention relates to a novel process for the purification of tetrazolylbenzopyranones.
BACKGROUND OF THE INVENTION
Pranlukast, chemically known as 4-oxo-8-[4-(4'-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)- 4H-1-benzopyran is depicted by Formula-1:

Pranlukast is developed as an anti-asthma drug having a strong antagonist activity to leukotriene C4 (LTC4), leukotriene D4 (LTD.,) and leukotriene E4 (LTE4) receptor and have been used as a therapeutic agent for asthma and allergic rhinitis.
Pranlukast and its hydrates are marketted as capsules named Onon® (112.5 mg, Dong-A pharmaceutical).
EP 0173516 discloses a class of substituted benzbpyran compounds having activity as leukotriene antagonists and 5-a-reductase inhibitors and useful in the treatment of diseases caused or exacerbated by leukotrienes or 5-a-reductase activity.
The processes for the preparation bf pranlukast are disclosed in EP 0173516, US 05587483, US 05596103, US 05616721, US 04780469 and US 05446058.
The prior art processes provide pranlukast having total impurities between 0.5% to 0.2%. In addition, commercially available pranlukast has off white color with pale yellow tinge.
However, it is desirable to produce pranlukast with total impurities < 0.2%, preferably <0.1%.
Further, it is desirable to produce pranlukast devoid of the pale yellow tinge.
The present invention provides a process for the preparation of pranlukast having total impurities < 0.2%, preferably < 0.1% arid without pale yellow tinge.

OBJECT OF THE INVENTION
The object of the present invention is to provide a process for the purification of pranlukast.
Another object of the present invention is to provide a process to obtain pranlukast with total impurities < 0.2%, preferably < 0.1%.
Yet another object of the present invention is to provide a process for the preparation of pranlukast without pale yellow tinch.
DESCRIPTION OF THE DRAWINGS
Figure 1: HPLC Purity of the Pranlukast prepared by the present invention
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention is depicted in following scheme:

M = Metal
In accordance with the above scheme, process for the preparation of pranlukast with total
impurities < 0.2%, preferably < 0.1% and without pale yellow tinge comprises:
A. Reacting crude pranlukast with alkali metal hydroxide/alkoxide in organic solvent;
B. Optionally treating the solution with charcoal;
C. Separating the alkali metal salt of pranlukast;
D. Dissolving the pranlukast alkali metal salt in water miscible polar aprotic solvent and
crystallizing with water;

E. Optionally adding filter aid to the reaction mass, stirring and filtering the solid;
F. Dissolving the solid into alcoholic solvent and filtering;
G. Isolating the crystalline pranlukast from the solution by adjusting the pH.
The phrase "Crude pranlukast" as used herein means that pranlukast contains total impurities less than 2%, preferably less than 1% and more preferably less than 0.5%.
According to the present invention, crude pranlukast was reacted at 25-30°C with alkali metal hydroxide/alkoxide in organic solvent to obtain alkali metal salt of pranlukast. On completion of the reaction, charcoal was added and the reaction mass was filtered followed by washed with organic solvent to obtain residue of alkali metal salt of pranlukast. The residue was dissolved at 60-65°C in water miscible polar aprotic solvent, water was added and stirred at the same temperature. The reaction mass Was cooled at 0-5°C, hyflo was added to the reaction mass and stirred. The reaction mass was filtered and washed with water to obtain solid residue. Organic solvent was added to the solid residue, stirred and filtered. The filtrate was washed with organic solvent, adjusted the pH between 2 to 4 using hydrochloric acid. The reaction mass was filtered, washed and dried at 50-60°C to obtain pranlukast with total impurities < 0.2%, preferably < 0.1% and without pale yellow tinge.
The crude pranlukast may be prepared by known prior art methods such as by coupling of 4-(4-phenyl-butoxy) benzoyl chloride and 8-amino-4-oxo-2-(tetrazol-5-yl)-4H-1-benzopyran in dichloromethane in presence of triethylamine.
The alkali metal hydroxide/alkoxide is selected from sadium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium methoxide and like. The preferable alkali metal hydroxide/alkoxide is sodium hydroxide or sodium methoxide, more preferable is sodium methoxide.
The organic solvent is selected from C1 to C3 alcohol such as methanol, ethanol, isopropyl alcohol and like. The preferable organic solvent is methanol. Optionally, the water miscible polar aprotic solvent is also used.
The water miscible polar aprotic solvent is selected from N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methyl pyrrolidone, tetramethyl urea, 1,3-dimethyl ethylene urea,1,3-dimethyl propylene urea, sulfolane and like. The preferable water miscible polar aprotic solvent is N,N-dimethyl formamide.
The product obtained from the above process has HPLC purity > 99.9% and the total impurity is < 0.1% w/w.
HPLC method for estimation of chemical purity:
Column: Vydac (4.6X100mm), 3 μm
Mobile phase: (A) (KH2P04 (0.01 M, pH-4.0), (B) Acetonitrile

Gradient: From 1 to 5 min (A) 85% and (B) 15%; from 5 to 40 min (B) increases upto 70%; from 40 to 50 min (B) constant 70%; from 50 to 55 min (B) increases at 15%; from 55 to 65 min (A) 85% and (B) 15%. Detection: 259 nm Flow: 1.0 mL/min. Detectiori limit: 0.004%
ADVANTAGES OF THE PRESENT INVENTION
1. The present invention provides cost effective and industrially scalable process for the purification of pranlukast.
2. The present invention provides pranlukast with total impurities < 0.2%, preferably < 0.1%.
3. The present invention provides pranlukast without pale yellow tinge.
The present invention is further explained by the following non-limiting examples:
Example 1: Purification of Pranlukast
Crude pranlukast (65 gm) was stirred at 25-30°C with methanolic solution of sodium hydroxide (5.91gm/1200ml methanol) to obtain an alkali metal salt of pranlukast. Charcoal (13 gm) was added and stirred at room temperature. The reaction mass was filtered through hyflo to obtain residue. The residue was dissolved in 300 ml DMF and 600 ml water was added drop wise at 60-65°C. The solution was slowly cooled to 0-5°C and stirred. Celite (65 gm) was added and the reaction mixture was stirred further. The reaction mixture was filtered and washed with water. The solid was dissolved in 1100 ml methanol and stirred. The readtion mass was filtered and washed with hot methanol. The filtrate was acidified using dilute HCI solution, maintained the pH upto 3 and stirred at room temperature. The resultingsolid was filtered, washed with methanol:water and dried in a vacuum oven at 50-55°C to obtain pranlukast. [Yield = 52 gm, HPLC purity = 99.97%]
Example 2: Purification of pranlukast
Crude Pranlukast (13 gm) was stirred with solution of sodium hydroxide and DMF (1.2 gm / 39 ml water + 39 ml DMF) at 60-65°C. Water (39 ml) was added and cooled the reaction mass at 0-5°C and stirre'd for 1 hr. Celite (13 gm) was added and reaction mixture was stirred further. The reaction mixture was filtered and washed with water. The solid was dissolved in 260 ml methanol and stirred. The reaction mass was filtered and washed with hot methanol. The filtrate was treated with charcoal and stirred at 35-40°C, filtered through

hyflo and washed with methanol. The filtrate was acidified using dilute HCI solution, maintained the pH upto 3 and stirred at room temperature. The resulting solid was filtered, washed with methanoi:water and dried in a vacuum oven at 50-55°C. [Yield = 9.5 gm, HPLC purity = 99.92%]

We claim:
1. A novel process for the preparation of pranlukast with total impurities < 0.2%, preferably
< 0.1% and without pale yellow tinge comprises:
A. Reacting crude pranlukast with alkali metal hydroxide/a I koxide in organic solvent;
B. Optionally treating the solution with charcoal;
C. Separating the alkali metal salt of pranlukast;
D. Dissolving the pranlukast alkali metal salt in water miscible polar aprotic solvent and
crystallizing with water;
E. Optionally adding filter aid to the reaction mass, stirring and filtering the solid;
F. Dissolving the solid into alcoholic solvent and filtering;
G. Isolating the crystalline pranlukast from the solution by adjusting the pH.
2. The process as claimed in claim 1, wherein the alkali metal hydroxide / alkoxide is selected from sadium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium methoxide and like.
3. The process as claimed in claim 2, wherein the preferable alkali metal hydroxide /alkoxide is sodium hydroxide or sodium methoxide, more preferable is sodium methoxide.
4. The process as claimed in claim 1, wherein the organic solvent is selected from C1 to C3 a)cohol such as methanol, ethanol, isopropyl alcohol and like.
5. The process as claimed in claim 4, wherein the preferable organic solvent is methanol.
6. The process as claimed in claim 1, wherein the water miscible polar aprotic solvent is selected from N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methyl pyrrolidone, tetramethyl urea, 1,3-dimethyl ethylene urea,1,3-dimethyl propylene urea, sulfolane and like
7. The claim as claimed in claim 6, wherein the preferable water miscible polar aprotic solvent is N,N-dimethyl formamide.
8. The process as claimed in claim 1, wherein the pH value is adjusted during step - G between 2 to 4, preferably between 3 to 3.5.
9. Pranlukast of HPLC purity a 99.9% and total impurities < 0.1%.