Technical Field of the Invention
The present invention relates to a novel process for the preparation zileuton (1).
Background of the Invention
The compounds N-[l-(benzo[b]thien-2-yl)alkyl]-N-hydroxyurea are useful for the
treatment of leukotriene mediated afflictions in man and animals. Particularly the drug
zileuton (1), 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 and is represented by the formula (1) as given
below.

Zileuton (1) 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 disclosed in the patent as well as in academic literature for
the preparation of zileuton (1). Some of these methods that involve the formation of
hydroxylamine (4) are discussed below:
US Patent No. 4,873,259 and US Patent No. 5,516,909 discloses a process for the
preparation of zileuton (1) that involves acid catalyzed reduction of the oxime (3) by
using borane complex to obtain hydroxylamine (4). The boran complexes used in this
reaction include borane-trimethylamine, borane-tetrahydrofuran and boran-pyridine. The
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borane complexes are highly expensive and hazardous in nature, which causes handling
and storage problems.

The reduction of oxime ethers by using a combination of tributyl tin hydride and
borantrifluoride-dietherate to afford hydroxylamines is known in the publication
Masafumi Ueda et al, Tetrahydron Letters (2002), 43, 4369-4371 as shown below.

US Patent No. 4,873,259 teaches an alternative process for the preparation of zileuton (1)
involving the steps of reacting l-(benzo[b]thien-2-yl)-l-chloroethane (5) with a O-
benzyl-hydroxylamine to obtain a benzyloxyamine intermediate (6), which is converted
into zileuton (1) by treatment with TMSNCO [Trimethylsilyl isocynate], followed by
catalytic hydrogenation. This process has a drawback that it involves the protection and
deprotection steps, which make the process laborious.
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The prior art methods for the preparation of zileuton discussed above suffer from the
disadvantages such as the use of hazardous reagents like borane complexes and involves
the protection and deprotection steps, making the process time consuming and laborious.
The present invention provides a novel process for the preparation of zileuton (1).
Summary of the Invention
The present invention relates to a novel process for the preparation zileuton (1) involving
the steps of:
i) preparation of 2-acetylbenzo[b]thiophene oxime (3) by reacting 2-
acetylbenzo[b]thiophene (2) with hydroxylamine hydrochloride;
ii) reduction of the 2-acetylbenzo[b]thiophene oxime (3) with organotinhydride
in presence of lewis acid to obtain l-benzo[b]thien-2-yl ethyl hydroxylamine
(4); and
iii) conversion of the l-benzo[b]thien-2-yl ethyl hydroxylamine (4) to ziletuon (1)
by the treatment with alkali metal cyanate in presence of hydrochloric acid.
Detailed Description of the Invention
The present invention provides a novel process for the preparation of zileuton (1), which
comprises the following steps:
i) preparation of 2-acetylbenzo[b]thiophene oxime (3) by reacting 2-
acetylbenzo[b]thiophene (2) with hydroxylamine hydrochloride;
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ii) reduction of the 2-acetylbenzo[b]thiophene oxime (3) with organotinhydride
in presence of lewis acid to obtain l-benzo[b]thien-2-yl ethyl hydroxylamine
(4); and
iii) conversion of the l-benzo[b]thien-2-yl ethyl hydroxylamine (4) to ziletuon (1)
by the treatment with alkali metal cyanate in presence of hydrochloric acid.
The process of the present invention is given below:

The preparation of 2-acetylbenzo[b]thiophene oxime (3) in the present invention is
carried out by treating 2-acetylbenzo[b]thiophene (2) with hydroxylamine or
hydroxylamine hydrochloride in a suitable organic solvent and in presence of a base.
The organic solvent for the preparation of 2-acetylbenzo[b]thiophene oxime (3) is
selected from the group including amides such as formamide, dimethylforamide and N-
methyl-pyrrolidone; ethers such as ethyl ether, methyl t-butyl ether and tetrahydrofuran;
nitriles such as acetonitrile and propionitrile; CI - C4 alcohols such as ethanol, methanol,
propanol and isopropanol; and the likes. Preferred solvents are alcohols, most preferably
isopropanol.
The base employed for the preparation of 2-acetylbenzo[b]thiophene oxime (3) is
selected from the group consisting of organic bases such as triethylamine, N-methyl
pyrrolidine and pyridine; and inorganic bases selected from the alkali metal carbonates
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like potassium carbonate, sodium carbonate; alkali metal bicarbonates like potassium
bicarbonate, sodium bicarbonate. Most preferred base is potassium carbonate.
In an preferred embodiment of the present invention, the reduction of the 2-
acetylbenzo[b]thiophene oxime (3) to obtain l-benzo[b]thien-2-yl ethyl hydroxylamine
(4) is carried out in the presence of organotinhydride and lewis acid
The organotin hydrides that can be used in the present invention include tri-n-butyltin
hydride, triphenyltin hydride di-n-butylin hydride and the likes. The most preferred
organotin hydride is tri-n-butyltin hydride.
The lewis acids include 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 are not limited thereto. The reaction is preferably carried out by employing
borontrifluoride-diethyletherate as lewis acid.
The reduction of oxime (3) is carried out in a suitable organic solvent selected from a
group consisting of aromatic hydrocarbons like benzene, toluene, xylene, esters like ethyl
acetate and isopropyl acetate, ethers such as ethyl ether, methyl t-butyl ether and
tetrahydrofuran, nitriles such as acetonitrile and propionitrile, chlorinated solvents such
as chloroform and dichloromethane, sulphoxides such as dimethyl sulfoxides and the
likes. More preferably chlorinated solvent is employed, most preferably dichloromethane.
The reduction step of the present invention is carried out at temperatures ranging from
-15°C to 50°C, more preferably at -5°C to 20°C and most preferably at 0°C to 5°C.
The reduction step is carried out for 1 to 10 hours, preferably 3 to 8 hours, most
preferably 4 to 6 hours.
Molar ratio of the 2-acetylbenzo[b]thiophene oxime (3) to that of organotin hydride is in
the range of 1: 1 to 1:5. Most preferred molar ratio is 1: 2 to 1:3.
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Molar ratio of the organotin hydride to that of lewis acid is in the range of 1: 0.1 to 1:5.
Most preferred molar ratio is 1: 0.35.
The conversion of the l-benzo[b]thien-2-yl ethyl hydroxylamine (4) to zileuton (1) is
carried with alkali metal cyanate in acidic medium at a temperature ranging from 10°C -
25°C . The typical solvents for the conversion, 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, nitriles such as acetonitrile and propionitrile and the likes, the most
preferred solvent is ethylacetate. The preferred alkali metal cyanates include potassium
cyanate, sodium cyanate and the likes.
The conversion of the l-benzo[b]thien-2-yl ethyl hydroxylamine (4) to zileuton (1) may
also be carried out with trimethyl silylisocyanate (TMSNCO) followed by work up with
ammonium chloride.
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.
Example-1
Step-1: Synthesis of l-(l-benzothiophen-2-yl)ethanone oxime:
A mixture of 2-acetyl benzothiophene (10 gm, 0.056 moles), potassium carbonate (15.7
gm, 0.11 moles) and hydroxylamine hydrochloride (5.8 gm, 0.083 moles) in isopropyl
alcohol (100 ml) was refluxed for 4 hours. On completion of the reaction, the reaction
mixture was concentrated under vacuum and water (70 ml) was added to the reaction
mass. Solid thus separated was filtered and dried (8.74 gms).
Mass spectrum: M+1T91.9; 'H NMR spectrum: 5 2.39(s,3H,-CH3), S 3.6 (s,lH), 5 7.25-
7.8(m,5H ,aromatic).
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Example-2
Step-2: Synthesis of l-(l-benzothiophen-2-yl)-N-hydroxyethanamine:
l-(l-Benzothiophen-2-yl)ethanone oxime (5 gm,0.026 moles) was suspended in
dichloromethane (50 ml) and cooled to 5°C. To the cooled reaction mixture, boron
trifluoride etherate(7.3 ml,0.026 moles) was added followed by the addition of tributyltin
hydride( 20 ml,0.074 moles) at 5°C and then stirred for 4 to 6 hrs at ambient temperature.
On completion of the reaction, the reaction mixture was washed with aqueous sodium
bicarbonate solution followed by water and then concentrated under vacuum to obtain 1 -
(l-benzothiophen-2-yl)-N-hydroxyethanamine (2.6 gms).
Mass spectrum: 194.3 (M+l); ]H NMR spectrum: S 1.54-1.29(d,3H,-CH3), § 4.46-4.42
(q,lH), 84.52-4.49(s,2H), 57.36-7.2l(m,Ar), 57.82-7.69(m,2H).
Example-3
Step-3: Synthesis of Zileuton:
Sodium cyanate (0.65 gm, 0.01 moles) in water (4 ml) was added to l-(l-benzothiophen-
2-yl)-N-hydroxyethanamine (2 gm, 0.01 moles) in ethyl acetate (20 ml) and cooled to
10°C. Aqueous hydrochloric acid was added to the reaction mixture till the pH 2 and then
stirred for 30 minutes at ambient temperature. Ethyl acetate layer was separated, washed
with water, dried over anhydrous sodium sulphate and evaporated under vacuum to get
yellow colored solid. The solid was then crystallized from toluene (10 ml) to obtain white
crystalline solid (1.2 gms).
HPLC Purity: 97.46%; 'H NMR spectral data: 51.52-1.49 (d, 3H), 5 5.58-5.51(q, 1H),
56.45(s, 2H), 57.36-7.26(m, 3H), 57.9-7.74(d, 2H), 59.23(s, 1H).
Dated this 24th day of March 2008

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The present invention relates to a novel process for the preparation zileuton (1) involving
the steps of:
i) preparation of 2-acetylbenzo[b]thiophene oxime (3) by reacting 2-
acetylbenzo[b]thiophene (2) with hydroxylamine hydrochloride;
ii) reduction of the 2-acetylbenzo[b]thiophene oxime (3) with organotinhydride
in presence of lewis acid to obtain l-benzo[b]thien-2-yl ethyl hydroxylamine
(4); and
iii) conversion of the l-benzo[b]thien-2-yl ethyl hydroxylamine (4) to ziletuon (1)
by the treatment with alkali metal cyanate in presence of hydrochloric acid.