Field of the Invention
The present invention relates to a novel process for the preparation N-[l-(benzo[b]thien-
2-yl)alkyl]-N-hydroxyurea (I).
Background of the Invention
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 (la), which is chemically known as N-[l-(benzo[b]thien-2-yl)ethyl]-N-
hydroxyurea is commercially used in the treatment of leukotriene-mediated diseases such
as asthma, psoriasis and ulcerative colitis. Zileuton is represented by the formula (la) as
given below.

Zileuton (la) and its derivatives with pharmaceutically acceptable cations were first
disclosed by Abbott laboratories in US Pat No. 4,873,259. Since the discovery of
zileuton, a number of hydroxamic acid derivatives have been synthesized and tested for
similar type of biological activity.
Several synthetic routes are documented in the patent as well as in academic literature for
the preparation of zileuton.
US Pat No. 4,873,259 discloses a process for the preparation of zileuton (la) that involves
the treatment of hydroxylamines (4) with an isocyante or potassium cyanate wherein the
hydroxylamines can be obtained from acid catalyzed reduction of the corresponding
oxime (3) using borane pyridine complex.
2


The pyridine borane complex is expensive and hazardous in nature, which leads to
handling and storage problems.
US Pat No. 4,873,259 further discloses an alternative process for the preparation of
zileuton (la) involving the steps of reacting l-(benzo[b]thien-2-yl)-l-chloroethane (5)
with a O-benzyl-hydroxylamine and then converting the resulting product (6) to
corresponding hydroxyl urea (la) by treatment with TMSCNO [Trimethylsilyl isocynate],
followed by catalytic hydrogenation.

This process has a drawback that it involves the protection and deprotection steps, which
make the process lengthy.
US Pat No. 5,292,900 discloses an improved process for the preparation of zileuton (la)
involving the reaction of l-(benzo[b]thienyl)-l-chloroethane (5) with an O-protected
hydroxylamine derivative such as 0-(tetrahydropyran-2-yl)-hydroxylamine (8).
3


The protection and deprotection of N-hydroxyurea increases the number of steps, thus
making the process inefficient on large scale.
The publication A O Stewart et al in J. Org. Chem., 57(18), 5020 (1992) describes the
reaction of l-(benzo[b]thien-2-yl)-l-hydroxyethane (10a) with N,0-bis(phenoxy
carbonyl)-hydroxylamine (11) resulting in N-hydroxyphenylurethane (12) using
Mitsunobu coupling and then obtaining zileuton (la) by aminolysis of N-
hydroxyphenylurethane.

US Pat. No. 6,080,874 discloses a process for the preparation of zileuton (la) involving
the displacement of the hydroxy group of l-(benzo[b]thien-2-yl)-l-hydroxyethane (10a)
with N-hydroxyurea (13) in the presence of bronsted acids like sulphuric acid,
trifluoroacetic acid, toluenesulphonic acid and hydrochloric acid.

The impurities formed in this reaction require multiple steps of purification, thereby
making the process cumbersome. This multistep purification procedure is further
4

complicated by poor separation of layers during work-up, which result in very low yield,
the fact noticed by us while repeating this process. The formation of impurities in the
bronsted acid catalyzed reaction is also suggested by the publication Alvarez F et al,
Pharmaceutical Research 1992, 9, Page 1465 which mentions the decomposition of
zileuton in acidic medium.
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 exist 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.
Summary of the Invention
The present invention relates to a novel process for the preparation N-[l-(benzo[b]thien-
2-yl)alkyl]-N-hydroxyurea (I) by reacting l-(benzo[b]thien-2-yl)-alkan-l-ol (10) withN-
hydroxyurea (13) in the presence of lewis acid.
5
The term alkyl herein refers to a straight or branched chain saturated hydrocarbon,
preferably methyl, ethyl, n- and iso-propyl.


Detailed Description of the Invention
The present invention provides a novel process for the preparation of N-[l-
(benzo[b]thien-2-yl)alkyl]-N-hydroxyurea (I) in purity greater than 99.5% by HPLC
method. The process of the present invention comprises the step of reacting 1-
(benzo[b]thien-2-yl)-alkan-l-ol (10) with N-hydroxyurea (13) in the presence of lewis
acid to give crude N-[l-(benzo[b]thien-2-yl)alkyl]-N-hydroxyurea (I), which can be
purified by acid-base treatment.
The term alkyl herein refers to a straight or branched chain saturated hydrocarbon,
preferably methyl, ethyl, n- and iso-propyl.

The use of Lewis acid in the aforementioned reaction has the following surprising effects:
i) it enhances the reaction rate;
ii) it increases the selectivity of the reaction;
iii) it decreases the formation of by-products and;
iv) the purity of the product (I) is higher than 99.5%.
The term "Lewis acid " refers to the type of chemical moieties described in Olah,
"Friedel-Crafts and Related Reactions," Interscience Publishing Co., New York, 1963
and includes aluminum bromide, aluminum chloride, boron trifluoride, boron trichloride,
borontrifluoride-diethyetherate, boron tribromide, titanium tetrachloride, titanium
tetrabromide, stannic chloride, stannic bromide, bismuth trichloride, ferric chloride but
not limited. As known in the state of art lewis acid encompasses chemical moieties that
accepts a pair of electron particularly the chemical moieties with no transferable protons.
6

The reaction is preferably carried out by employing borontrifluoride-diethyetherate as
lewis acid.
The process of the present invention can be carried out in an aprotic-polar or aprotic-non-
polar organic solvent. The typical solvents for the reaction, which can be used singly or
in combination, include aromatic hydrocarbons like benzene, toluene, xylene, esters like
ethyl acetate and isopropyl acetate, ethers such as ethyl ether, methyl t-butyl ether and
tetrahydrofuran, amides such as formamide, dimethylforamide and N-methyl-
pyrrolidone, nitriles such as acetonitrile and propionitrile, ketones such as acetone and
ethylmethyl ketone and the likes, most preferred solvent is ethylacetate.
The temperature of the reaction is selected from 0°C to 100°C, preferably 0°C to 40°C
and most preferably 10°C - 20°C.
Molar ratio of the l-(benzo[b]thien-2-yl)-alkan-l-ol (10) to that of lewis acid is in the
range of 1:0.1 to 1:10, preferably 1:1 to 1:5 and most preferably 1:2 to 1:3..
In a typical example, to the mixture of l-(benzo[b]thien-2-yl)ethanol (10a) and N-
hydroxy urea (13) in ethylacetate, borontrifluoride-diethyletherate was slowly added at a
temperature of 10°C - 20°C. The reaction mixture was stirred, usually the reaction
completes within 1 to 2 hours and then worked up to give crude N-[l-(benzo[b]thien-2-
yl)ethyl]-N-hydroxyurea, i.e., zileuton, which is subjected for purification.
The purification process involves suspending the crude zileuton in water and
dichloromethane, biphasic mixture and adjusting the pH of the aqueous phase to 12-13
with 10% sodium hydroxide. The aqueous phase is separated and pH is adjusted to 2.5-
2.7 with aqueous HC1. The solid was filtered, refluxed in toluene and then cooled to
ambient temperature. The solid was filtered and dried.
The following examples illustrate the specific aspects of the present invention. These
examples should not be construed to limit the scope of the invention in any respect.
7

Experimental
Preparation of crude N-[(benzo[b]thien-2-yl)ethyl]-N-hydroxyurea
l-(Benzo[b]thien-2-yl)ethanol (10 g, 0.056 moles) and N-hydroxy urea (7.68 g, 0.101
moles) were suspended in 100 ml ethylacetate. To this reaction mixture borontrifluoride-
diethyletherate (40 ml, 0.168 moles) was slowly added at 10°C - 20°C. Reaction mixture
was stirred for 1 hour at 10°C - 20°C and monitored by HPLC. On completion of the
reaction, the pH was adjusted to 5 - 6 with 25% sodium hydroxide solution and stirred
for 30 minutes. The resulting solid was filtered and dried to give crude zileuton having a
purity of 96-98%.
Purification of crude N-[(benzo[b]thien-2-yI)ethyI]-N-hydroxyurea
The crude zileuton (10 gm) was suspended in biphasic mixture of water (50 ml) and
dichloromethane (80 ml). After adjusting the pH of the aqueous phase in the biphasic
mixture to 12-13 with 10% sodium hydroxide, the biphasic mixture was stirred for 30
minutes. The aqueous layer was then separated and washed with dichloromethane (50
ml). The pH of the resulting aqueous phase was adjusted to pH 2.5-2.7 using aqueous
HC1 and stirred for 30 minutes. The solid separated was filtered and washed with water
(50 ml). The wet solid was suspended in toluene (80 ml) and refluxed. The refluxed
suspension was then cooled to ambient temperature. The resulting solid mass was
filtered, washed with toluene (20 ml) and dried under vacuum at 40-45°C. The HPLC
purity was 99.75%.
Mass spectra: 237 (m+1), 254(m+18); 'H NMR (200 MHz) (DMSO, S): 9.26 (s, 1H),
7.89-7.74 (m, 2H), 7.36-7.25 (m, 3H), 6.45 (s, 2H), 5.61-5.51 (q, 1H), 1.52-1.49 (d, 3H).
Dated this 23rd day of November 2007
8

The present invention relates to novel processes for the preparation of zileuton (I). The present invention further relates to novel anhydrous crystalline form of zileuton and process for its preparation.