FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"SUBSTANTIALLY PURE ZILEUTON AND PROCESS FOR PREPARING THEREOF"
We, CADILA HEALTHCARE LIMITED, of Zydus Tower, Satellite Cross Road, Ahmedabad -380 015, Gujarat, India.
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The invention relates to pure Zileuton. The invention provides a purification process for preparing highly pure Zileuton, Provided also herein are solid state forms of Zileuton. BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
The compounds N-[l-(benzo[b]thien-2-yl)alkyl]-N-hydroxyurea (I) are useful for the treatment

of leukotriene mediated afflictionsin man and animals. Particularly the drug Zileuton (I), which is commercially used in the treatment of Jeukotriene-mediated diseases such as asthma, psoriasis and ulcerative colitis with the name Zyflo®.
Patent US 4,873,259 A discloses the preparation of Zileuton which comprises the reduction of the double bond of an oxime having formula (A)

in the presence of a borane-pyridine complex, and the subsequent reaction of the product of formula (B) thus obtained

with trimethylsilylisocyanate (TMSNCO), or sodium or potassium cyanate in acid solution, or phosgene and ammonia. This process has several drawbacks. In particular borane is a toxic reagent and pyridine is a carcinogenic compound which limits the safety of the process. Stewart and Brooks (A. O, Stewart and D. W. Brooks, J, Org. Chem. 1992, 57, 5020-5023) disclose an alternative process for the preparation of Zileuton comprising the reaction of an alcohol having formula (C)

with 'N,O-bis(phenoxycarbonyl)-hydroxylamine in the presence of diisopropytezodicarboxylate (DIAD) and PPh3 (Mitsunobu reaction), to obtain N,0-bis(phenoxycarbonyl)-N-(l-benzo[b]thien-2-yl-ethyI)-hydroxylamine, and the subsequent aminolysis. This process has several drawbacks from both safety and industrial application points of view, which limit its industrial application. Mitsunobu reaction brings to the formation of difficult to be eliminated by-products requiring, as a consequence, a cumbersome purification of the product by chromatography. Moreover, N,0-bis(phenoxycarbonyl)hydroxylamine is prepared using dichloroformate which is suspected to be mutagenic.
US 5,292,900 A discloses an improved process for the preparation of Zileuton involving the reaction of l-(Benzo[b]thienyl)-l-chIoroethane (D)

with an O-protected hydroxylamine derivative such as O(tetrahydropyran-2-yl)-hydroxyl amine (E).

US 5,420,300 A discloses another process for the preparation of Zileuton which comprises the reaction of a compound of formula (C),

as defined above, with hydrobromic acid to obtain the corresponding halogenated compound 2-(bromoethyl)benzo[b]thiophene. Reacting this compound with O-benzyl-hydroxylamine, N-(benzyloxy)-N-(l-(benzo[b]thien-2-yl)ethyI)-urea is then obtained. This compound is further reacted with trimethylsilylisocyanate, and catalytic hydrogenation of the reaction product so obtained affords zileuton. This process has some drawbacks which limit its industrial application; in particular, the halogenation reaction is scarcely selective and with a poor yield, approximately of about 11%, with a really negative impact on the process costs. Patent US 6,080,874 A discloses a process for the preparation of zileuton in a single step, comprising reacting a compound of formula (C), as defined above, with hydroxyurea in presence of Bronsted acids like sulphuric acid, trifluoroacetic acid, toulenesulphonic acid and hydrochloric acid.
At any rate this process also has some drawbacks since hydroxyurea is carcinogenic and in order to obtain a purer final product many hard-working purifications are necessary to get rid of impurities formed which results in low yields, thus limiting the safety and the industrial application of the process on industrial scale.
Thus the prior art methods discussed above suffer from the following disadvantages: i) use of hazardous and/or expensive chemicals such as pyridine borane complex and diethyazodicarboxylate;
ii) involves multistep synthesis making the process time consuming and laborious; iii) formation of undesired by-products due to side reactions; iv) cumbersome purification process for the removal of impurities.
Thus, there exists a need for the development of an economical process for the preparation of Zileuton that is easy to operate on industrial scale to obtain pure zileuton.
There is therefore the need of a new alternative process for the preparation of zileuton which makes use of easily available, non carcinogenic reagents or reagents suspected to be mutagenic or toxic, and which does not require hard-working purifications to obtain the final product.

The present invention has also found that there remains a need for purification process for obtaining highly pure Zileuton having all impurities less than 0.1% as per the ICH limit for the product. SUMMARY OF THE INVENTION
The invention relates to purification process for obtaining substantially pure Zilueton which avoids number of purification unlike the prior art processes.
The present inventors have surprisingly and unexpectedly found that by single purification step Zileuton can be isolated in a substantially pure solid state form. In another embodiment, the present invention provides substantially pure Zileuton having a total purity of at least about 98%. Preferably, the total purity is at least about 99%, most preferably at least about 99.9%.
The present invention provides the solid state form of substantially pure Zileuton. The present invention provides Zileuton having particle size distribution (PSD) with D(90) in the range that passes in the requirement of surface area of 0.9 to 3.1 (as per USP). In another aspect, the solid state form of substantially pure Zileuton exists in an amorphous form or a crystalline form. In yet another aspect, the solid state form of Zileuton exists in an anhydrous and/or solvent-free form or as a hydrate and/or a solvate form. BRIEF DESCRIPTION OF THE DRAWINGS
FIG.l is a characteristic powder X-ray diffraction (XRD) pattern of substantially pure Zilueton. FIG. 2 is a characteristic differential scanning calorimetry (DSC) thermogram of substantially pure Zilueton.
FIG. 3 is a characteristic infra red (IR) spectrum of substantially pure Zilueton. DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides substantially pure Zileuton, as well as processes for preparing thereof. As used herein, "substantially pure Zileuton" refers to Zileuton containing less than about 0.1% of the total impurities of Zilueton. It refers to the solid state form of Zileuton having a purity of greater than about 99 wt%, specifically greater than about 99.5 wt%, more specifically greater than about 99.8 wt%, and still more specifically greater than about 99.9 wt%. The purity is preferably measured by High Performance Liquid Chromatography (HPLC). For example, the purity of solid state form of Zileuton obtained by the purification process disclosed herein can be about 99% to about 99.95%, or about 99.5% to about 99.99%, as measured by HPLC.
The Zileuton prepared as per the processes cited in the art results with purity of Zileuton at about 70% to 80% and rest of the 20% to 30% is the impurities being intact with the product.

The Zileuton prepared as per the prior art process results in mainly three impurities in the API which are designated as impurity-A, impurity-A' and impurity-B in the present invention. lmpurity-A is 5-Substituted benzothiophene derivative as shown below:



rmpurity-A' is 6-Substituted benzothiophene derivative as shown below:
The genesis for the formation of both the impurities i.e. impurity-A and impurity-A' is the acidic condition during the condensation of l-(Benzo[b]thiophen-2-yl)ethanol with Hydroxy urea.
Impurity-B is Dibenzo[b]thiophene-2-ylmethanone as shown below:

The genesis of impurity-B is during the preparation of Key Starting Material (KSM) i.e. 2-Acetylbenzo[b]-thiophene. So impurity-B is KSM related impurity and being referred as system suitability impurity (as per USP).
The inventors of the present invention has found a majestic purification method by which the intact 20% to 30% of the impurities (mainly impurity-A and impurity-A') are get removed from the product. The purity of the Zileuton obtained after the purification of present invention

is about 99.9% pure and having all impurities less than 0.1% or more preferably less than
0.05%.
Impurity-B being the KSM related impurity is controlled at KSM level only but if any
amount of impurity-B is left at KSM and the further process is carried with that particular
content of Impurity-B for the preparation of Zileuton. In that particular, case the purification of
present invention provides Zileuton substantially free of impurity-B i.e. impurity-B is in not
detected amount in Zileuton API.
Zileuton prepared as per the purification process of the present invention results with
impurity-A, impurity-A', impurity-B and all other unknown impurities less than 0.1% or more
preferably less than 0.05%.
The present invention provides Zileuton substantially free of impurity-A, impurity-A',
impurity-B and all other unknown impurities.
Zileuton obtained after the purification of present invention is about 99.9% pure and having all
impurities less than 0.1 % or more preferably less than 0.05%.
Zilueton may be prepared as per the process disclosed in patent US 4,873,259 A for the reference.
The processes cited in the art involves 3 to 4 purifications of Zileuton to obtain the Zileuton of desired ICH quality with purity above 99.9% and all impurities less than 0.1% or more preferably less than 0.05%.
The present invention provides a single step purification process of Zileuton. This process comprises crystallizing Zileuton from a solvent selected from the group consisting of: C3-6 ketone or a mixture thereof with water, N-methylpyrrolidone, C3-6 amides, halo-substituted C6-12 aromatic hydrocarbons propylene glycol, dimethyl sulfoxide, dimethyl carbonate, C1-4 alkyl alcohols, a mixture of a C)_g alkyl alcohol and water, acetonitrile or a mixture thereof with water, C2-6 alkyl acetates or their mixture with water, cellosolve, dimethyl carbonate, polyethylene glycol methyl ether and C2-8 ethers.
The crystallization is preferably performed by dissolving Zileuton in the above solvent, preferably by heating the reaction mixture to allow complete dissolution, followed by cooling of the obtained solution, whereby Zileuton crystallizes. Preferred C3-6 ketones are acetone, methyl ethyl ketone (MEK) and methyl iso-butyl ketone (MIBK). Preferred C3-6 amides are dimethylacetamide and dimethylformamide. Preferred halo-substituted C6-12 aromatic hydrocarbons are chlorobenzene and dichlorobenzene. Preferred C1-4 alkyl alcohols are methanol, ethanol, n-propanpl, isopropanol, n-butanol, isobutanol and 2-butanol. Preferred C2-6 alkyl acetates are ethyl acetate, isobutyl acetate and n-butyl acetate. Preferred C2-8 ethers are dibutyl ether and polyethylene glycol (PGME). Most preferably, the solvent is a mixture of

isopropanol and n-butyl acetate. When a mixture is used (such as isopropanol: n-butyl acetate), the ratio between the solvents is between about 1:1 to about 1:5 by volume. The ratio of isopropanol to n-butyl acetate is preferably about 0.5:5.5 by volume. Following crystallization, the obtained product is preferably recovered by filtering, washing of the obtained crystals, and drying, preferably overnight under reduced pressure.
Zileuton obtained by the above process preferably contains each impurity in an amount of less than about 0.1%. The above crystallization process may be repeated in order to further purify the obtained Zileuton, so that the level of total impurity may be reduced to less than about 0.05%.
The total purity of the Zileuton obtained by the above processes is of at least about 98%, more preferably, at least about 99% and most preferably at least about 99.9%.
The present invention provides a process for the purification of Zileuton comprising crystallizing Zileuton by combining a solution of Zileuton in a first solvent system. Preferably, the solution is obtained by dissolving Zileuton in n-butyl acetate and isopropanol, preferably at a reflux temperature preferably to a temperature of about 50°C to about 55°C. The obtained solution is then cooled, preferably to a temperature of about 35°C to about 45°C, most preferably to a temperature of about 30°C to about 35°C. The obtained mixture is then preferably maintained for at least about 3 hours or till crystallization occurs, most preferably about 2 hours. The obtained product is preferably recovered by filtering.
Zileuton obtained by the above process preferably contains all impurities in an amount of less than about 0.1%. The above crystallization process may be repeated in order to further purify the obtained Zileuton, so that the level of total impurity may be reduced to less than about 0.05%.
The total purity of the Zileuton obtained by the above processes is of at least about 98%, more preferably, at least about 99% and most preferably at least about 99.9%.
The present invention further provides a process for the purification of Zilueton comprising providing a Zileuton solution containing more than about 20-30% of total impurities; preferably at a reflux temperature preferably to a temperature of about 50°C to about 55°C. The obtained solution is then cooled, preferably to a temperature of about 35°C to about 45°C, most preferably to a temperature of about 30°C to about 35°C. The obtained mixture is then preferably maintained for at least about 3 hours or till crystallization occurs, most preferably about 2 hours. The obtained product is preferably recovered by filtering.
Zileuton obtained by the above process is having purity at least about 98%, more preferably, at least about 99% and most preferably at least about 99.9% with all impurities in

particular impurity-A, impurity-A' and impurity-B in an amount of less than about 0.1% or more preferably to less than about 0.05%.
The total purity of the Zileuton obtained by the above processes is of at least about 98%, more preferably, at least about 99% and most preferably at least about 99.9%.
According to another aspect, the solid state form of substantially pure Zileuton is characterized by at least one, or more, of the following properties: i) a powder X-ray diffraction pattern substantially in accordance with F1G.1.; ii) a powder X-ray diffraction pattern having peaks at about 4.7, 9.5, 15.3, 15.7, 21.9, 22.7, 26.0 and 26.3 ± 0.2 degrees 2-theta substantially as depicted in FIG.l;
iii) a powder X-ray diffraction pattern having additional peaks at about 14.3, 14.8, 17.2,19.3, 19.8, 20.5, 21.1, 23.6, 24.1, 24.5, 27.8, 28.9. 29.5, 30.0 and 31.3 ± 0.2 degrees 2- theta substantially as depicted in FIG. 1;
iv) a DSC thermogram having an endotherm peak at about 163°C substantially as depicted in FIG. 2
v) an IR spectrum substantially in accordance with FIG. 3; and
vi) an IR spectrum having absorption bands at about 3462,3319, 3269, 3178, 2989, 2935, 2877, 2358, 2339, 2260, 1938, 1899, 1789, 1654, 1571, 1467, 1450, 1367, 1321, 1300, 1249, 1192, 1153, 1109, 1026, 1012, 950, 927, 866, 827, 773, 742, 729, 705, 677, 655, 617, 578, 530,497 480 and 422 • 2 cm"'.
The solid state form of substantially pure Zileuton is anhydrous in nature having water content less than about 0.5%.
The solid state form of substantially pure Zileuton is stable, consistently reproducible, and is particularly suitable for bulk preparation and handling.
The solid state form of substantially pure Zileuton has good flow properties and is stable at room temperature, enhanced temperature, at relative high humidities, and in aqueous media.
According to another aspect, Zileuton prepared as per the purification process of the present invention results with particle size distribution specifically D{90) in the range that provides the required surface area of Zileuton in the range of 0.9 to 3.1 (as per USP).
The present invention provides the solid state form of Zileuton having particle size distribution (PSD) specifically D(90) in the range 300 to 350 microns. The achieved PSD of D(90) provides the required surface area of Zileuton in the range of 0.9 to 3.1 (as per USP).
The PSD of D(90) in the range 300 to 350 microns may be achieved by the known techniques in the art such as milling, grinding, seiving etc.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the

specification. The invention is further defined by reference to the following examples describing
in detail the purification of Zileuton. It will be apparent to those skilled in the art that many
modifications, both to materials and methods, may be practiced without departing from the
scope of the invention.
EXAMPLES:
Example-1: Purification of Zileuton
Zileuton Technical (1.0 Kg) having purity 70% to 80% (reference example as per the process cited in patent US 4,873,259 A) were added to a four-neck two litre round bottom flask followed by addition of n-Butyl acetate (4.0 L) and isopropyl alcohol (0.50 L) at 25°C to 35°C. The reaction mass was stirred and heated at 50°C to 55°C for 1 hour at 50°C to 55°C. The reaction mass was cooled to 30°C to 35°C and maintained for 2 hours at 30°C to 35°C. The product was filtered and washed with n-butyl acetate (1.5 L). The wet cake was dried at 25°C to 35°C for 12 hours to afford solid substantially pure anhydrous Zileuton (Purity by HPLC : 99.95%).

We claim:
1. A process for preparing substantially pure Zileuton of formula (I) free from impurities having surface area 0.9 to 3.1

comprising the steps of:
i) obtaining a solution of Zileuton in an organic solvent; ii) beating the solution; iii) cooling the solution; iv) isolating substantially pure Zileuton of formula (I).
2. The process as claimed in claim 1 (i) wherein the solvent is selected from C3.6 ketones, C3.6 amides, halo-substituted C6-12aromatic hydrocarbons, Chalkyl alcohols, C2-6alkyl acetates, C2-8 ethers, polyethylene glycol (PEG) and mixture thereof, preferably mixture of isopropanol and n-butyl acetate.
3. The process as claimed in claim 2 wherein the mixture of isopropanol: n-butyl acetate used is between about 1:1 to about 1:5 by volume, preferably about 0.5:5.5 by volume.
4. The process as claimed in claim l(ii) wherein the heating of the solution is performed at 50°C to 55°C.
5. The process as claimed in claim l(iii) wherein the cooling of the solution is performed at 30°C to 35°C.
6. The process as claimed in claim 1 (iv) wherein isolation of the product is performed by filtering, washing, drying, preferably drying overnight under reduced pressure.
7. Substantially pure Zileuton of formula (I) obtained by the process as claimed in claim 1 is having purity of about 99.9% with all impurities in particular impurity-A, impurity-A' and impurity-B in an amount of less than about 0.1%.
8. Substantially pure Zileuton of formula (I) obtained by the process as claimed in claim 1 is having purity of about 99,9% with all impurities in particular impurity-A, impurity-A' and impurity-B in an amount of less than about 0.05%.

9. Substantially pure Zileuton of formula (I) is characterized by at least one, or more, of the
following properties:
i) a powder X-ray diffraction pattern substantially in accordance with FIG. 1.;
ii) a powder X-ray diffraction pattern having peaks at about 4.7, 9.5, 15.3, 15.7, 21.9, 22.7, 26.0
and 26.3 ± 0.2 degrees 2-theta substantially as depicted in FIG. 1 ;
iii) a powder X-ray diffraction pattern having additional peaks at about 14.3, 14.8, 17.2,19.3,
19.8, 20.5, 21.1, 23.6, 24.1, 24.5, 27.8, 28.9. 29.5, 30.0 and 31.3 ± 0.2 degrees 2- theta
substantially as depicted in FIG. 1;
iv) a DSC thermogram having an endotherm peak at about 163°C substantially as depicted in
FIG. 2
v) an IR spectrum substantially in accordance with FIG. 3; and
vi) an IR spectrum having absorption bands at about 3462,3319, 3269, 3178, 2989, 2935, 2877,
2358, 2339, 2260, 1938, 1899, 1789, 1654, 1571, 1467, 1450, 1367, 1321, 1300, 1249, 1192,
1153, 1109, 1026, 1012, 950, 927, 866, 827, 773, 742, 729, 705, 677, 655, 617, 578, 530,497
480 and 422 ±2 cm"1.
vii) water content less than about 0.5%.
10. A process for preparing substantially pure Zileuton of formula (I) substantially as
hereinbefore described and with references to foregoing examples is in accordance with
accompanying text and examples.