FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
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 INVENTION:
The present invention relates to a process for the preparation of pranlukast substantially free of brominated impurities.
BACKGROUND OF 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 an anti-asthma drug having a strong antagonist activity to leukotriene C4 {LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4) receptor.
The processes for preparing pranlukast are disclosed in EP 0173516, US 05587483, US 05596103, US 05616721, US 04780469 and US 05446058.
US 05587483 disclosed the process for the preparation of pranlukast from 4-phenylbutyl bromide and is described by the following process:

(Formula - 5) In US 05587483, 4-phenyl butyl bromide (1) is treated with methyl 4-hydroxybenzoate (2) in the presence of base to obtain methyl 4-(4-phenylbutoxy) benzoate

(3). The methyl 4-(4-phenylbutoxy) benzoate (3) is reacted with aqueous NaOH followed by acidification to obtain 4-(4-phenylbutoxy) benzoic acid (4).
4-phenylbutyl bromide is generally contaminated with brominated impurities such as compound of formula 2(a) and compound of formula 2(b). These impurities are carried forward in the reaction sequence and are converted to corresponding analogue of formula 5(a) and formula 5(b). These are resulting undesirable impurities in the compound of formula 5.
There is no teaching in the prior art about how to remove these impurities to obtain pranlukast substantially free of these impurities.

Thus, there is a need to provide a process for the preparation of pranlukast substantially free of brominated impurities.

OBJECT OF THE INVENTION:
An object of the invention is to provide a process for the preparation of pranlukast free of brominated impurities.
Another object of the invention is to remove the brominated impurities at an intermediate stage during the process for the preparation of pranlukast.
Yet another object of the present invention is to remove the brominated impurities during the purification process of pranlukast.
DESCRIPTION OF THE DRAWINGS:
Figure 1: HPLC of Pranlukast free of undesirable brominated impurities
THE DETAILED DESCRIPTION:
We have surprisingly found that these impurities can be removed either at intermediate stage of the reaction sequence or from the pranlukast by catalytic hydrodebromination.
The hydrodebromination is carried out using hydrogen and metal catalyst in organic solvent to remove the said impurities.
The process of the present invention is depicted in following scheme:


In accordance with the scheme 1, pranlukast is prepared by the process comprising steps:
A. Reacting the mixture of 4-(4-phenylbutoxy) benzoic acid (Formula 5) and
formula (5a) or (5b) with hydrogen and metal catalyst in organic solvent;
B. Washing the reaction mixture of step - A with organic solvent followed by
filtration and drying to yield 4-(4-phenylbutoxy) benzoic acid free of
brominated impurities (formula 6);
C. Reacting compound of formula 6 obtained in step - B with carboxyl group
activating agent using organic solvent to obtain carboxyl activated 4-(4-
phenylbutoxy) benzoic acid derivatives (formula 7);
D. Reacting compound of formula 7 obtained in step - C with 8-amino-4-oxo-2-
(tetrazol-5-yl)-4H-1-benzopyran (formula 8) in organic solvent to obtain 4-oxo-
8-[4-(4'-phenylbutoxy) benzoyiamino] -2- (tetrazol-5-yl) - 4H-1-benzopyran
(formula 1).
Scheme 2:
In another embodiment of the invention, pranlukast is prepared as per scheme 2:


Iri accordance with the scheme 2, pranlukast is prepared by the process comprising steps:
A. Reacting the mixture of 4-(4-phenyl-butoxy) benzoic acid (Formula 5) and formula (5a) or (5b) with carboxyl group activating agent using organic solvent to obtain mixture of carboxyl activated 4-(4-phenylbutoxy) benzoic acid derivatives (formula 9) and formula (9a) or (9b);

B. Reacting the mixture of 4-(4-phenylbutoxy) benzoic acid derivatives (formula
9) and formula (9a) or (9b) obtained in step - C with 8-amino-4-oxo-2-
99.95% and free from brominated impurities is prepared by
process as claimed in the preceding claims.
9. The process for the preparation of pranlukast free of brominated impurities involves
catalytic hydrodebromination for the removal of brominated impurities at any stage of the
process.