Acid-catalyzed addition of N-hydroxyurea to 1-aryl alcohol derivatives: A new synthesis of Zileuton

Article abstract of DOI:10.1081/SCC-100105880

A highly efficient synthesis of Zileuton is described in which the key step involves a site-specific alkylation of hydroxyurea under acid catalysis. Various aryl alcohol electrophiles were tested and the reaction was found to be highly substrate-specific, favoring benzothiophene and benzofuran-based alcohols.

Full text of DOI:10.1081/SCC-100105880

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ACID-CATALYZED ADDITION OF N-HYDROXYUREA TO
1-ARYL ALCOHOL DERIVATIVES: A NEW SYNTHESIS OF
ZILEUTON
Richard R. Copp , Brian T. Fohey & Gregory Lannoye
Version of record first published: 16 Aug 2006.
To cite this article: Richard R. Copp , Brian T. Fohey & Gregory Lannoye (2001): ACID-CATALYZED ADDITION OF N-
HYDROXYUREA TO 1-ARYL ALCOHOL DERIVATIVES: A NEW SYNTHESIS OF ZILEUTON, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:20, 3081-3086
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SYNTHETIC COMMUNICATIONS, 31(20), 3081–3086 (2001)
ACID-CATALYZED ADDITION
OF N-HYDROXYUREA TO 1-ARYL
ALCOHOL DERIVATIVES: A NEW
SYNTHESIS OF ZILEUTON
Richard R. Copp,* Brian T. Fohey,
and Gregory Lannoye
Specialty Products Division, Abbott Laboratories,
1401 Sheridan Rd., North Chicago, IL 60064-4000
ABSTRACT
A highly efficient synthesis of Zileuton is described in which
the key step involves a site-specific alkylation of hydroxyurea
under acid catalysis. Various aryl alcohol electrophiles were
tested and the reaction was found to be highly substrate-
specific, favoringbenzothiophene and benzofuran-based
alcohols.
Key Words: Alkylation; Hydroxamic Acids and Derivatives;
Regioselection
*Correspondingauthor. E-mail: rcopp@tetrionics.com
3081
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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COPP,FOHEY,AND LANNOYE
ABT-077 (1), Zileuton, is a 5-lipoxygenase enzyme inhibitor1 devel-
oped by Abbott for the treatment of leukotriene-mediated diseases such as
asthma,2 psoriasis3 and ulcerative colitis.4 Several syntheses of Zileuton
5,6
have been reported, includingracemic
and chiral7–9 protocols. The first
chemically efficient and scaleable process10 for 1 is outlined in Scheme 1.
Scheme 1. a) H2NOH, HCl; b) BH3-Pyridine, HCl; c) KOCN, HCl.
The two major drawbacks of this process are: 1) The oxime isomer
mixture requires a large excess of pyridine borane for complete reduction.
2) Pyridine borane is comparatively expensive and is a handlingand storage
hazard. Due to cost and safety concerns, we found it necessary to develop a
more economical process usingless hazardous raw materials. Since the dis-
covery of Zileuton, a number of hydroxamic acid derivatives8,11 have been
reported with similar biological activity. Despite the numerous synthetic
approaches available, a search of the literature did not reveal any obvious
alternative methodologies for the preparation of N-alkylated, N-hydroxy-
ureas that would suit our manufacturingcriteria. The common literature
methods for constructing N-1 substituted hydroxyureas 8, involve the
assembly of the urea moiety from N-substituted hydroxylamines or amino-
lysis of carbamate precursors. An appealingstrategy that would provide a
more rapid entry to 1 appeared to be the couplingof N-hydroxyurea 6, with
alcohol 7 (Scheme 2).
Scheme 2.

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ZILEUTON
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Acid catalysis12 proved successful for effectingthe alkylation. The high
regioselectivity and efficiency for reaction at Nꢀ1 of urea 6 prompted us to
study the utility of the reaction with various aryl alcohols (Table 1).
To compare the reactivity of various aryl alcohol substrates, we chose
a standard solvent (THF) and acid (HCl) catalyst. For most of the entries
in Table 1, the reaction was conducted at 50ꢁC for 6 hours. With the excep-
tion of entry 1, yields were not optimized. In general, products were isolated
by coolingthe reaction mixture and collectingthe solid product by filtration.
Some of the isolated yields were low due to high solubility of the product
in the reaction solvent. Prolonged exposure to the acidic medium following
completion of the reaction may also result in product decomposition.13
With entry 5, higher temperature and longer reaction time resulted in a
lower yield.
General Procedure for Hydroxyurea Additions: (Entry 1,Zileuton)
Substrate alcohol (25 mmol) was stirred in THF (15 mL) and water
(5 mL) at room temperature and treated with hydroxyurea (37.5 mmol,
1.5 equiv.), followed by conc. HCl (7.59 g, 75 mmol, 3 equiv.). The reaction
was warmed to 50ꢁC for 4 hours then cooled to room temperature and
partitioned between EtOAc (25 mL) and water (20 mL). The aqueous
layer was extracted with EtOAc (25 mL) and the combined organic layers
washed with water (20 mL) and brine (20 mL). Solvents were removed in
vacuo and the residue was slurried for 10 minutes in a mixture of EtOAc
(10 mL), toluene (20 mL) and water (10 mL). The slurry was filtered and the
solids washed with 10 mL of water and 15 mL of toluene. Drying in vacuo
for 18 hours at 60ꢁC afforded 3.52 g(59.7%) white solid, spectroscopically
identical to authentic material.
Higher yields of ABT-077 were realized when THF co-solvent was
replaced with ethyl acetate. On a multi kilogram scale in the pilot plant,14
isolated yields averaged 80–90%.
All isolated products from Table 1 were fully characterized by spectro-
scopic techniques. Analytical data for new compounds are shown below.
N-(Diphenylmethyl)-N-hydroxyurea (entry 8): Yield: 26%. Mp 156–57;
1H NMR (300 MHz, DMSO-D6/TMS) 6.44 (2H, s), 6.49 (1H, s), 7.22–7.35
(10H, m), 9.24 (1H, s); 13C NMR (75.5 MHz, DMSO-D6/TMS) 63.5, 126.8,
127.9, 128.8, 140.4, 161.7; IR (MIC, cmꢀ1) 1420, 1655, 3260, 3450; MS (CI)
m/z 243 (M þ 1)+; Anal. Calcd. for C14H14N2O2: C, 69.40; H, 5.82; N,
11.56. Found: C, 69.34; H, 5.89; N, 11.53.

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COPP,FOHEY,AND LANNOYE
Table 1. Acid-Catalyzed Reaction of Hydroxyurea with Aryl Alcohols
a Determined by peak area % in HPLC of crude product mixtures.

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N-Hydroxy-N-[1-(2-methoxyphenyl)ethyl]urea (entry 9): Yield: 37.2%.
Mp 144–45; 1H NMR (300 MHz, DMSO-D6/TMS) 1.31 (3H, d), 3.77 (3H, s),
5.54 (1H, q), 6.28 (2H, bs), 6.84–6.94 (2H, m), 7.15–7.23 (1H, m), 7.40–7.45
(1H, dd), 9.14 (1H, s); 13C NMR (75.5 MHz, DMSO-D6/TMS) 17.2, 49.7,
55.4, 110.5, 120.0, 127.1 127.6, 131.6, 156.0, 161.1. MS (CI) m/z 211
(M þ 1)+; Anal. Calcd. for C10H14N2O3: C, 57.13; H, 6.71; N, 13.32.
Found: C, 57.26; H, 6.68; N, 13.20.
N-Hydroxy-N-[1-(4-methoxyphenyl)ethyl]urea (entry 10): Yield:
1
30.0%. Mp 138–139; H NMR (300 MHz, DMSO-D6/TMS) 1.37 (3H, d),
3.72 (3H, s), 5.25 (1H, q), 6.27 (2H, s), 6.85 (2H, d), 7.25 (2H, d), 8.99 (1H,
s); 13C NMR (75.5 MHz, DMSO-D6/TMS) 17.3, 54.4, 55.0, 90.0, 113.2,
128.6, 134.0, 158.1, 161.6; MS (CI) m/z 243 (M þ 1)+; Anal. Calcd. for
C10H14N2O3: C, 57.13; H, 6.71; N, 13.32. Found: C, 57.04; H, 6.75; N, 13.28.
In summary, we have shown that acid-catalyzed addition of hydro-
xyurea to benzo[b]thiophen-2-yl-ethanol provides a simple, safe and highly
efficient route to Zileuton. This alkylation methodology is efficient with only
a small class of electron-rich heteroaromatic substrates and isolated yields
may depend on product solubility and stability in the reaction medium.
ACKNOWLEDGMENT
The authors wish to thank Professor H. Rapoport for helpful
discussions.
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COPP,FOHEY,AND LANNOYE
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Received in the USA December 4, 2000

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