4-Acetylamino-3-(imidazol-1-yl)-benzoic acids as novel inhibitors of influenza sialidase

Article abstract of DOI:10.1016/S0223-5234(99)80055-5

Two methods for the synthesis of 4-acetylamino benzoic acids substituted at the 3-position with imidazoles are described. Many of the compounds are inhibitors of influenza virus sialidases with levels of activity similar to the recently described 4-acetylamino-3-guanidino-benzoic acid (BANA 113).

Full text of DOI:10.1016/S0223-5234(99)80055-5

Eur. J. Med. Chem. 34 (1999) 225−234
© Elsevier, Paris
225
Original article
4-Acetylamino-3-(imidazol-1-yl)-benzoic acids as novel inhibitors
of influenza sialidase
Peter D. Howesa*, Anne Cleasbyb, Derek N. Evansa, Helen Feildena,
Paul W. Smitha, Steven L. Sollisa, Neil Taylorb, Alan J. Wonacottb
aDepartment of Enzyme Medicinal Chemistry II, Glaxo Wellcome Medicines Research Centre,
Gunnels Wood Road, Stevenage, SG1 2NY Herts, UK
bBiomolecular Structure, Glaxo Wellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY Herts, UK
(Received 16 February 1998; revised 22 September 1998; accepted 8 October 1998)
Abstract – Two methods for the synthesis of 4-acetylamino benzoic acids substituted at the 3-position with imidazoles are described. Many
of the compounds are inhibitors of influenza virus sialidases with levels of activity similar to the recently described 4-acetylamino-3-
guanidino-benzoic acid (BANA 113). © Elsevier, Paris
influenza virus sialidase / zanamivir / BANA-113 / benzoic acids / 2-amino-imidazole
1. Introduction
zanamivir in which the glycerol sidechain has been
replaced with a lipophilic carboxamide group [5]. Many
of these compounds retained potent activity, especially
against influenza A sialidase. Our observations with the
carboxamides suggested to us the possibility of modulat-
ing the biological activity in compounds related to 2 by
replacing the guanidine with alternative basic groups with
appended lipophilic substituents. We now report some of
our investigations in this area in which replacement of the
guanidine function in 2 with variously substituted imida-
zoles, in particular 2-amino-imidazoles 3, has been stud-
ied, allowing us to seek novel interactions between the
enzyme and substituents attached to the imidazole ring
(figure 1).
Influenza virus sialidase facilitates the release of newly
formed virions from the surface of infected cells. Zan-
amivir (GG167 1) is a potent inhibitor of this enzyme that
is currently being evaluated in phase III clinical trials for
the treatment of influenza [1]. Previous publications from
our group and others have described the syntheses of
analogues of zanamivir in which each of the substituents
around the dihydropyran ring has been either modified or
removed [2]. These studies have shown that all four
dihydropyran substituents are required for good binding
to the sialidase enzyme. Two groups [3, 4] have described
an alternative strategy of modification of zanamivir in
which the dihydropyran ring has been replaced by an
achiral benzene ring and have demonstrated moderate
levels of sialidase inhibition with derivatives such as the
guanidine 2 (BANA 113) [3]. X-ray analysis of the
complex between 2 and influenza sialidase showed,
unexpectedly, that the guanidine group did not bind into
the same region of the active site as does the guanidine in
zanamivir, but instead is bound into the pocket occupied
by the glycerol sidechain in zanamivir [3]. Recently we
have also described a series of dihydropyrans related to
2. Chemistry
The two methods utilised for the preparation of aryl
imidazoles are outlined in figures 2 and 4.
2.1. Amino-imidazoles from substituted anilines:
synthesis of 3a–h
Commercially available 4-acetylamino-3-nitro-benzoic
*Correspondence and reprints
acid was esterified with DMF-di-t-butyl acetal [6] and the

226
ethyl ketones 5a–j isolated by flash chromatography or
by fractional crystallisation in moderate to good yield
(32–95%) (table I). The best yields were obtained when
sodium hydrogen carbonate was used as base. Cyclisation
of 5 was effected with a large excess of cyanamide [7],
either in ethanol at reflux or in molten cyanamide at ca.
60–70 °C affording the 2-amino-imidazoles 6a–h
(table I).Treatment of 6a–h with trifluoroacetic acid in
dichloromethane removed the t-butyl ester groups afford-
ing the target acids 3a–h in high yield (figure 2).
The cyclisation of aminomethyl ketones 5a–j with
cyanamide is often accompanied by one or more of the
by-products (4, 7 and 8) which arise by N-dealkylation of
5 and/or alternative cyclisation to benzimidazole (fig-
ure 3). Indeed, some aminomethyl ketones (5i,j, table I)
failed to give any amino-imidazole under the conditions
examined, and the products (4, 7 and 8) were the only
materials identified from the reaction mixtures. The
compounds 5 which seemed most susceptible to dealky-
lation included those where R was an electron-rich
aromatic or heteroaromatic ring, for example the
N-methylpyrrole 5i and the 2-methoxybenzene 5j. We
postulate that in these cases the electron-rich nature of
these rings renders the neighbouring ketone relatively
unreactive towards nucleophilic attack, which in turn
allows alternative reaction pathways to predominate. In
Figure 1.
nitro group reduced to amine by catalytic transfer hydro-
genation with ammonium formate in the presence of 10%
palladium on carbon, affording 4-acetylamino-3-amino-
benzoic acid t-butyl ester 4 in 65% overall yield. Amine
4 was then alkylated with a range of halomethyl ketones
in DMF in the presence of either potassium carbonate or
sodium hydrogen carbonate and the resulting aminom-
Table I. Amino-imidazoles from substituted anilines.
R
Yield (%)
5
R
Yield (%)
5
6
3
6
3
a
54
80
53
70
f
51
70
71
64
b
36
76
g
34
64
86
c
69
91
24
54
70
75
h
i
Et
95
39
17
–
d
e
69
10
66
j
32
–

227
Figure 2.
particular SN2 displacement of the aniline 4 from 5 by
cyanamide, leading to 8, is likely to be favoured by the
electron withdrawing properties of the ring contained
within the leaving group. The benzimidazoles 7 and 8
arise from 5 and 4 respectively by intramolecular nucleo-
philic attack of the sidechain amino group on the carbo-
nyl group of the neighbouring acetamide. Figure 3
illustrates the competing reaction pathways leading to the
formation of products 6–8.
Figure 3.
toluene followed by esterification with t-butyl
alcohol/DCC/DMAP [9] in 50% overall yield. Treatment
of 2-nitro-imidazole with sodium hydride in DMSO
followed by addition of 9 gave the expected product 10a
in 70% yield. Reduction of 10a with hydrogen in the
presence of 10% palladium on carbon in acetic acid gave
a high yield of the 2-amino-imidazole derivative 11b.
Diamine 11b was selectively acetylated on the less basic
anilino nitrogen by treatment with acetic anhydride/acetic
acid affording amide 12b. Removal of t-butyl ester by
treatment with trifluoroacetic acid as above afforded the
2.2. Nucleophilic substitution of aryl fluoride:
synthesis of 13a–f and 14
The complications described above with our first route
to amino-imidazoles prompted development of an alter-
native synthetic approach. Our second route to aryl
imidazoles involved the nucleophilic displacement of
fluoride from the activated aryl fluoride 9 (figure 4).
Fluoride 9 was prepared by sodium dichromate oxida-
tion [8] of commercially available 3-fluoro-4-nitro-
a
Table II. Inhibitory activity of amino-imidazoles vs. sialidases from influenza viruses A/Aichi and B Victoria.
IC50 (Flu A) µMol
IC50 (Flu B) µMol
IC50 (Flu A) µMol
IC50 (Flu B) µMol
3a
3b
3c
3d
3e
3f
12
43
84
43
26
56
11
3h
13b
13c
13d
9.4
7
> 510
> 560
> 450
27
6.6
3.5
> 510
> 560
> 450
2.6
4.7
150
5.3
210
98
14
130
51
2 (BANA 113)
1 (zanamivir)
3g
0.0019
0.019
a Sialidase assay: the IC50 values are calculated from the percent inhibition of enzyme activity in the presence of inhibitor relative to a positive
(no inhibitor) control. All reactions were carried out in triplicate, and the mean value of these replicates used in the analysis of data.

228
placement of the guanidine function in 2 with a range of
2-amino-imidazoles. The absence of any significant im-
provement in activity as substituents are added to the
imidazole (compare 3a–h with 13b) suggests that none of
the additional substituents introduced at the 4-position of
the imidazole ring achieve additional favourable new
binding interactions with the enzyme. We have previ-
ously reported a similar observation in a series of
carboxamides bearing variously substituted phenyl
rings [12]. These observations are consistent with the
X-ray data shown below. The importance of the acety-
lamino group on the aryl ring is clearly seen when the
activity of 13b is compared with that of 14. Similarly the
amino group attached to the 2-position of the imidazole
ring is essential for good activity, demonstrated by the
lack of any measurable activity in compounds 13c,d.
4. X-ray crystallographic data
The crystal structure has been determined for com-
pound 3a bound to the active site of influenza B sialidase.
Preparation of the crystalline complex, data collection,
structure solution and refinement were carried out as
described previously [12]. The data were 99.9% complete
to 2.0 Å resolution and the R-factor of the final structure
was 20.3% for all data between 8.0 and 2.0 Å. The
difference electron density was well defined and unam-
biguously interpretable. Compound 3a binds to the active
site of influenza B sialidase in a similar fashion to BANA
113 2 [3]. Figure 5 illustrates the active site of the
complex [12]. The three nitrogen atoms of the amino-
imidazole moiety of 3a occupy very similar positions to
the corresponding nitrogen atoms in the guanidino group
of BANA 113, with a salt-bridging interaction to Glu 274
being formed (hydrogen bond distances: Glu 274
Oe1–NH2 = 2.8 Å and Glu 274 Oe2–NH = 2.9 Å). A
favourable electrostatic interaction between Glu 275 and
the amino moiety is also formed (Glu 275 Oe2–NH2 =
2.8 Å) as well as an interaction with a buried water
molecule (Wat O–NH2 = 2.8 Å). The C5 phenyl fragment
occupies a hydrophobic cleft; the sidechains of Ile 220
and Ala 244 define the walls of the cleft with sidechain of
residue Arg 222 forming the base. This mode of binding
for the phenyl moiety in the active site has been observed
previously in a carboxamide series of inhibitors. The
carboxylic acid and acetamide groups in 3a occupy
similar positions to the corresponding groups in BANA
113 except that to relieve a close contact with the
imidazole ring the carbonyl of the acetamide group is
rotated away with a torsion angle change of almost 30°.
This does not affect hydrogen bonding to Arg149 from
the carbonyl group but leads to a modification in the
Figure 4. (i) Appropriate imidazole, 100 °C (+ NaH/DMSO
for 10a), 39–82%; (ii) H2, 10%Pd-C, AcOH, 1 atm., 97%; (iii)
Ac2O, AcOH (58–84%) (12b–d); (iv) TFA, CH2Cl2 (41–92%).
target amide 13b. Similarly the imidazoles 13c,d, which
lack the 2-amino function, were obtained from 9. It is
noteworthy that 2-amino-imidazole reacted with 9 exclu-
sively via the more nucleophilic ring nitrogen, to give
10b, consistent with previous observations [10]. Diamine
14 was obtained by treatment of 11b with trifluoroacetic
acid in dichloromethane.
3. Enzyme inhibition
Inhibition of influenza sialidase was determined in a
fluorimetric assay by measuring the ability of compounds
to inhibit the hydrolysis of 2-(4-methylumbelliferyl)-N-
acetyl-α-D-neuraminic acid (MUN) by whole virus
(A/Aichi N2 or B Victoria) grown in hen eggs [11]. The
IC50 value quoted is the concentration of inhibitor re-
quired to reduce the enzymatic activity in this preparation
by 50%. The results are summarised in table II and
compared with BANA-113 2 and also with zanamivir 1.
The enzyme inhibitory data clearly demonstrate that
activity against influenza sialidase is retained upon re-

229
Figure 5.
hydrogen bond network from the NH of the acetamide to
water molecules at the base of the active site pocket.
acid/acetonitrile at a flow rate of 1 mL per min. Melting
points were not recorded for solid products.
6.1. Method A
5. Conclusions
6.1.1. 4-Acetylamino-3-(2’-oxo-2’-phenyl-ethyl)-amino
benzoic acid t-butyl ester 5a
The synthesis of a series of 4-acetylamino-3-(imidazol-
1-yl)-benzoic acids which have a moderate level of
activity against influenza A and B sialidases clearly
demonstrates that the guanidine function in BANA 113
can be replaced by 2-amino-imidazole without loss in
binding. The importance of some of the functionality
commonly found in sialidase inhibitors has been demon-
strated in this series of compounds. We have also shown
that the level of activity seen is largely independent of the
substituent at the 4-position of the imidazole ring.
4-Acetylamino-3-amino-benzoic acid t-butyl ester 4
(0.125 g, 0.5 mmol) was dissolved in DMF (5 mL) and
stirred for 48 h at room temperature with bromoacetophe-
none (0.20 g, 1 mmol) and potassium carbonate (0.07 g,
0.5 mmol). The resultant mixture was partitioned be-
tween water and ethyl acetate, and the organic extract was
dried, evaporated and purified by flash column chroma-
tography (eluant: ethyl acetate/petroleum ether 1:1). The
title compound was isolated as a pale yellow solid
(0.10 g, 57%). 1H-NMR (DMSO) δ: 9.53 (1H, br s), 8.12
(2H, d, J = 7.5 Hz), 7.71 (1H, t, J = 7.5 Hz), 7.60 (2H, t,
J = 7.5 Hz), 7.35 (1H, d, J = 7.5 Hz), 7.17 (1H, dd, J =
7.5 Hz, 1.5 Hz), 7.07 (1H, d, J = 1.5 Hz), 5.68 (1H, br t,
J = 5 Hz), 4.8 (2H, d, J = 5 Hz), 2.13 (3H, s), 1.49 (9H,
s).
6. Experimental protocols
1H-NMR spectra were recorded either at 250 MHz
using a Bruker AC or AM 250 or at 400 MHz with a
Varian VXR 400. Mass spectra were measured on a HP
Engine (Thermospray positive) or VG Autospec Q
(LSIMS). Routine microanalyses were performed on a
Leco CHNS-932 or Carlo-Erba instrument. Flash chro-
matography was performed with Merck Kieselgel 9385.
Analytical HPLC was performed using a Rainin C18 8
µM column, eluting with 0.1% aqueous trifluoroacetic
6.1.2. 4-Acetylamino-3-(2’-oxo-2’-[3’’-benzofuryl]-
ethyl)-amino benzoic acid t-butyl ester 5g
4-Acetylamino-3-amino-benzoic acid t-butyl ester
(0.50 g, 2 mmol) was dissolved in DMF (10 mL) and
stirred for 24 h at room temperature with bromoacetoben-

230
zofuran (0.50 g, 2.1 mmol) and sodium bicarbonate
(0.17 g, 2 mmol). The resultant mixture was partitioned
between water and ethyl acetate, and the organic extract
was dried and evaporated. Trituration from ether afforded
the title compound as a pale yellow solid (0.57 g, 70%).
1H-NMR (DMSO) δ: 9.49 (1H, br s), 8.20 (1H, s), 7.89
(1H, d, J = 7.5 Hz) 7.78 (1H, d, J = 7.5 Hz), 7.60–7.15
(4H, m), 7.02 (1H, s), 5.84 (1H, br t, J = 5 Hz), 4.70 (2H,
d, J = 5 Hz), 2.11 (3H, s), 1.41 (9H, s). m/z: 409 (M +
H+), 391, 251, 134. Anal. Found C 67.22; H 6.04; N 6.94.
C23H24N2O5 requires C 67.63; H 5.92; N 6.86.
6.1.7. 4-Acetylamino-3-(2’-oxo-2’-[4-methoxycarbo-
nyl-2’’-furyl]-ethyl)-amino benzoic acid t-butyl ester 5f
1
51% yield. H-NMR (250 MHz, DMSO-d6) δ: 9.42
(1H, br s); 8.76 (1H, s); 8.10 (1H, s); 7.40 (1H, d, J = 9
Hz); 7.18 (1H, dd, J = 9 Hz, 2 Hz); 7.02 (1H, d, J = 2 Hz);
5.77 (1H, br t, J = 5 Hz); 4.61 (2H, d, J = 5 Hz); 3.84 (3H,
s); 2.10 (3H, s); 1.46 (9H, s). m/z (M + H+) 417.
6.1.8. 4-Acetylamino 3-(2’-oxobutyl)-amino benzoic
acid t-butyl ester 5h
1
95% yield. H-NMR (250 MHz, DMSO-d6) δ: 9.51
(1H, s); 7.40 (1H, d, J = 7 Hz); 7.21 (1H, d, J = 7 Hz);
6.98 (1H, s); 5.60 (1H, br); 4.15 (2H, br); 2.14 (3H, s);
1.58 (9H, s); 1.05 (3H, t, J = 7 Hz). m/z (M + H+) 321.
Similarly prepared were:
6.1.3. 4-Acetylamino-3-(2’-oxo-2’-[4-chlorophenyl]-
ethyl)-amino benzoic acid t-butyl ester 5b
6.1.9. 4-Acetylamino-3-(2’-oxo-2’-[2’’-N-methylpyrryl]-
1
ethyl)-amino benzoic acid t-butyl ester 5i
80% yield. H-NMR (250 MHz, CDCl3) δ: 7.95 (2H,
1
39% yield. H-NMR (250 MHz, DMSO-d6) δ: 9.47
d, J = 7.5 Hz); 7.6–7.35 (6H, m); 4.80 (1H, br t, J = 5 Hz);
4.62 (2H, d, J = 5 Hz); 2.3 (3H, s); 1.55 (9H, s). m/z (M
+ H+), 403. Anal. Found C 61.20; H 5.90; N 6.85.
C21H23ClN2O4•0.5H2O requires C 61.24; H, 5.87; N,
6.80.
(1H, s); 7.84 (1H, br s); 7.38 (1H, d, J = 9 Hz); 7.17 (1H,
dd, J = 9 Hz, 2 Hz); 7.05 (1H, 2, J = 2 Hz); 6.88 (1H, m);
6.58 (1H, m); 5.67 (1H, t, J = 5 Hz); 4.39 (2H, d, J = 5
Hz); 3.71 (3H, s); 2.12 (3H, s); 1.49 (9H, s).
6.1.10. 4-Acetylamino-3-(2’-oxo-2’-[2-methoxyphenyl]-
6.1.4. 4-Acetylamino-3-(2’-oxo-2’-[4-methylphenyl]-
ethyl)-amino benzoic acid t-butyl ester 5j
ethyl)-amino benzoic acid t-butyl ester 5c
1
32% yield. H-NMR (250 MHz, DMSO-d6) δ: 9.50
1
69% yield. H-NMR (250 MHz, CDCl3) δ: 7.91 (2H,
(1H, br s); 7.73 (1H, dd, J = 7.5 Hz, 1.5 Hz); 7.62 (1H,
td, J = 7.5 Hz, 1.5 Hz); 7.38 (1H, d, J = 8 Hz); 7.26 (1H,
d, J = 8 Hz); 7.18 (1H, dd, J = 7.5 Hz, 1.5 Hz); 7.10 (1H,
t, J = 7.5 Hz); 7.01 (1H, br s); 5.75 (1H, br t, J = 5 Hz);
4.57 (2H, d, J = 5 Hz); 3.98 (3H, s); 2.11 (3H, s); 1.49
(9H, s). m/z (M + H+) 399. Anal. Found: C 65.28; H 6.34;
N 6.91. C22H26N2O5•0.33H2O requires C 65.34; H 6.64;
N 6.93.
d, J = 7.5 Hz); 7.60–7.30 (6H, m); 4.80 (1H, brt, J = 5
Hz); 4.61 (2H, d, J = 5 Hz); 2.42 (3H, s); 2.3 (3H, s); 1.58
(9H, s). m/z (M + H+), 383. Anal. Found C 67.57; H 6.96;
N 7.26. C22H26N2O4•0.5H2O requires C 67.50; H 6.95; N
7.16.
6.1.5.
4-Acetylamino-3-(2’-oxo-2’-[3-nitrophenyl]-
ethyl)-amino benzoic acid t-butyl ester 5d
6.1.11. 4-Acetylamino-3-(2’-amino-4’-phenyl-imidazol-
1’-yl)-benzoic acid t-butyl ester 6a
91% yield.1H-NMR (250 MHz, DMSO-d6) δ: 9.59
(1H br s); 8.80 (1H, s); 8.5–8.6 (2H, m); 7.90 (1H, t, J =
8 Hz); 7.39 (1H, d, J = 8 Hz); 7.18 (1H, br d, J = 8 Hz);
7.10 (1H, br s); 5.80 (1H, br t, J = 5 Hz); 4.92 (2H, d, J
= 5 Hz); 2.13 (3H, s); 1.48 (9H, s). m/z (M + H+) 414.
The amino ketone 5a (0.12 g, 0.32 mmol) was dis-
solved in ethanol (4 mL) and refluxed with cyanamide
(0.13 g, 3.2 mmol). After 24 h a further portion of cyana-
mide (0.13 g) was added and reflux continued for a
further 24 h until all the starting material had been
consumed. The pale brown solution was evaporated, and
the residue partitioned between ethyl acetate and water.
The organic extracts were dried, evaporated and purified
by flash chromatography (eluant: ethyl acetate/dichloro-
methane 3:1) to afford the title compound as an off-white
solid (0.07 g, 53%). 1H-NMR (250 MHz, CDCl3) δ: 8.50
(1H, s), 8.10 (1H, dd, J = 7.5 Hz, J = 1.5 Hz), 7.93 (1H,
d, J = 1.5 Hz), 7.72 (2H, d, J = 7.5 Hz), 7.56 (1H, br s),
7.40 (2H, t, J = 7.5 Hz), 7.27 (1H, t, J = 7.5 Hz), 6.98
(1H, s), 4.25 (2H, br s), 2.16 (3H, s), 1.60 (9H, s). m/z:
393 (M + H+).
Anal. Found
C
59.45;
H
5.68;
N
9.82.
C21H23N3O6•0.67H2O requires C 59.28; H 5.77; N 9.88.
6.1.6. 4-Acetylamino-3-(2’-oxo-2’-[2’’-furyl]-ethyl)-
amino benzoic acid t-butyl ester 5e
1
69% yield. H-NMR (250 MHz, DMSO-d6) δ: 9.45
(1H, br s); 8.08 (1H, br s); 7.75 (1H, d, J = 4 Hz); 7.42
(1H, d, J = 8 Hz); 7.17 (1H, br d, J = 8 Hz); 7.00 (1H, br
s); 6.80 (1H, m); 5.77 (1H, br t, J = 5 Hz); 4.55 (2H, d,
J = 5 Hz); 2.11 (3H, s); 1.46 (9H, s). m/z (M + H+) 359.
Anal. Found C 63.47; H 6.20; N 7.92. C19H22N2O5
requires C 63.68; N 6.19; N 7.82.

231
Similarly prepared were:
(1H, m), 7.3 (2H, m), 7.18 (1H, s), 6.85 (1H, s), 5.61 (2H,
br s), 2.03 (3H, s), 1.53 (9H, s). m/z: (M + H+) 433.
6.1.12. 4-Acetylamino-3-(2’-amino-4’-[4-chlorophenyl]-
imidazol-1’-yl)-benzoic acid t-butyl ester 6b
6.1.18. 4-Acetylamino-3-(2’-amino-4’-ethyl-imidazol-
1
36% yield. H-NMR (250 MHz, DMSO-d6) δ: 9.5
1’-yl)-benzoic acid t-butyl ester 6h
1
(1H, s); 8.18 (1H, d); 7.92 (1H, dd); 7.7 (1H, d); 7.68 (2H,
d); 7.3 (2H, d); 7.25 (1H s); 5.5 (2H, s); 2.05 (3H, s); 1.5
(9H, s). m/z (M + H+) 427, 429. Anal. Found C 61.58; H
5.53; N 13.15. C22H23ClN4O3 requires C 61.90; H 5.43;
N 13.12.
17% yield. H-NMR (250 MHz, DMSO-d6) δ: 9.40
(1H, br s); 8.12 (1H, d, J = 9 Hz); 7.94 (1H, dd, J = 9 Hz,
2 Hz); 7.75 (1H, d, J = 2 Hz); 6.44 (1H, s); 5.38 (2H, br
s); 2.44 (2H, q, J = 7.5 Hz); 2.09 (3H, s); 1.54 (9H, s);
1.14 (3H, t, J = 7.5 Hz). m/z (M + H+) 345.
6.1.13. 4-Acetylamino-3-(2’-amino-4’-[4-methylphenyl]-
6.1.19. Reaction between 5i and cyanamide
imidazol-1’-yl)-benzoic acid t-butyl ester 6c
A solution of 5i (0.37 g, 1 mmol) and cyanamide
(0.85 g, 20.2 mmol) in ethanol (10 mL) was heated under
reflux for 24 h. The mixture was concentrated to ca. 2 mL
and heating was continued for a further 6 h. The crude
mixture was examined by LC/MS which revealed 4
components with molecular ions 372 (unreacted 5i); 354
((7) R = 3-(N-methylpyrryl)); 233 (8); 251 (4).
1
24% yield. H-NMR (250 MHz, DMSO-d6) δ: 9.45
(1H, s); 8.12 (1H, d); 7.9 (1H, dd); 7.72 (1H, d); 7.6 (2H,
d); 7.19 (1H, s); 7.1 (2H, d); 5.42 (2H, s); 2.25 (3H, s);
2.05 (3H, s); 1.5 (9H, s). m/z (M + H+) 407. Anal. Found
C 67.17; H 6.68; N 13.48. C23H26N4O3•0.25H2O requires
C 67.22; H 6.50; N 13.63.
6.1.14. 4-Acetylamino-3-(2’-amino-4’-[3-nitrophenyl]-
6.1.20. 4-Acetylamino-3-(2’-amino-4’-phenyl-imidazol-
1’-yl)-benzoic acid trifluoroacetate 3a
imidazol-1’-yl)-benzoic acid t-butyl ester 6d
1
54% yield. H-NMR (250 MHz, DMSO-d6) δ: 9.54
The t-butyl ester 6a prepared above (0.05 g,
0.13 mmol) was dissolved in 50% trifluoroacetic acid in
dichloromethane (2 mL) and stored at room temperature
for 1 h. The solvent was evaporated and the product
precipitated by trituration from ether, affording the title
compound as a white solid (0.04 g, 70%). 1H-NMR
(DMSO) δ: 13.2 (1H, br s), 9.85 (1H, br s), 8.3 (1H, d),
8.1 (1H, dd), 8.05 (1H, d), 7.85 (2H, br s), 7.7 (2H, d),
7.65 (1H, s), 7.5 (2H, t), 7.4 (1H, t), 2.05 (3H, s). m/z: 337
(M + H+). Anal. Found C 51.0; H 3.7; N 11.96.
C18H16N4O3•CF3CO2H•H2O requires C 51.29; H 4.09; N
11.96.
(1H, br s); 8.54 (1H, br s); 8.14 (2H, m); 7.96 (2H, m);
7.76 (1H, br s); 7.61 (1H, t, J = 8 Hz); 7.55 (1H, s); 5.63
(2H, s); 2.04 (3H, s); 1.55 (9H, s). m/z (M + H+) 438.
Anal. Found C 59.20; H 5.33; N 16.90. C22H23N5O5
requires C 60.40; H 5.30; N 16.01.
6.1.15. 4-Acetylamino-3-(2-amino-4-[2-furyl]-imidazol-
1-yl)-benzoic acid t-butyl ester 6e
1
10% yield. H-NMR (250 MHz, DMSO-d6) δ: 9.48
(1H, br s); 8.11 (1H, d, J = 9 Hz); 7.92 (1H, dd, J = 9 Hz,
2 Hz); 7.72 (1H, d, J = 2 Hz); 7.56 (1H, br s); 6.92 (1H,
s); 6.49 (1H, m); 6.42 (1H, d, J = 3 Hz); 5.51 (2H, br s);
2.03 (3H, s); 1.54 (9H, s).m/z (M + H+) 383. Anal. Found
C 61.64; H 6.01; N 13.98. C20H22N4O4•0.5H2O requires
C 61.37; H 5.92; N 14.31.
Similarly prepared were:
6.1.21. 4-Acetylamino-3-(2’-amino-4-[4-chlorophenyl]-
imidazol-1’-yl)-benzoic acid trifluoroacetate 3b
1
76% yield. H-NMR (250 MHz, DMSO-d6) δ: 13.2
6.1.16.
4-Acetylamino-3-(2-amino-4’-[4-methoxy-
(1H, br s); 9.85 (1H, s); 8.29 (1H, d); 8.1 (1H, dd); 8.02
(1H, d); 7.92 (2H, br s); 7.71 (2H, d); 7.7 (1H, s); 7.55
(2H, d); 2.1 (3H, s). m/z (M + H+) 371, 373. Anal. Found
C 49.05; H 3.37; N 11.34. C18H15ClN4O3•CF3CO2H
requires C 49.55; H 3.33; N 11.56.
carbonyl-2’’-furyl]-imidazol-1’-yl)-benzoic acid t-butyl
ester 6f
1
71% yield. H-NMR (250 MHz, DMSO-d6) δ: 9.51
(1H, br s); 8.30 (1H, s); 8.14 (1H, d, J = 9 Hz); 7.93 (1H,
dd, J = 9 Hz, 2 Hz); 7.71 (1H, d, J = 2 Hz); 7.06 (1H, s);
6.62 (1H, s); 5.58 (2H, s); 3.78 (3H, s); 2.04 (3H, s); 1.54
(9H, s). m/z (M + H+) 441. Anal. Found C 58.60; H 5.40;
N 12.85. C22H24N4O6•0.5H2O requires C 58.79; H 5.61;
N 12.47.
6.1.22. 4-Acetylamino-3-(2’-amino-4’-[4-methylphenyl]-
imidazol-1’-yl)-benzoic acid trifluoroacetate 3c
1
76% yield. H-NMR (250 MHz, DMSO-d6) δ: 13.3
(1H, br s); 9.85 (1H, s); 8.30 (1H, d); 8.09 (1H, dd); 8.02
(1H, d); 7.81 (2H br s); 7.60 (2H, d); 7.55 (1H, s); 7.26
(2H, d); 2.3 (3H, s); 2.0 (3H, s). m/z (M + H+) 351. Anal.
Found C 54.16; H 4.35; N 12.15. C19H18N4O3•CF3CO2H
requires C 54.31; H 4.12; N 12.06.
6.1.17.
4-Acetylamino-3-(2’-amino-4’-[benzofuran-
3’’-yl]-imidazol-1’-yl)-benzoic acid t-butyl ester 6g
1
34% yield. H-NMR (DMSO) δ: 9.57 (1H, br s), 8.12
(1H, d), 7.92 (1H, dd), 7.75 (1H, d), 7.58 (1H, m), 7.50

232
6.1.23. 4-Acetylamino-3-(2’-amino-4’-[3-nitrophenyl]-
the mixture allowed to warm to room temperature and
then heated at ca. 90 °C for 1 h. The mixture was cooled
to room temperature, diluted with water (500 mL) and
extracted with ethyl acetate (4 × 500 mL). The extracts
were concentrated to ca. 500 mL, and extracted with 2 M
sodium hydroxide solution (3 × 250 mL). The aqueous
extracts were acidified with concentrated hydrochloric
acid and extracted with ethyl acetate (4 × 250 mL). The
extracts were washed with brine and dried (MgSO4) and
evaporated to give the product as a yellow crystalline
imidazol-1’-yl)-benzoic acid trifluoroacetate 3d
1
75% yield. H-NMR (250 MHz, MeOD) δ: 8.57 (1H,
br s); 8.26 (1H, d, J = 8 Hz); 8.18 (1H, d, J = 8 Hz); 8.05
(3H, m); 7.74 (1H, t, J = 8 Hz); 7.57 (1H, s); 2.10 (3H, s).
m/z (M + H+) 382.
6.1.24.
4-Acetylamino-3-(2’-amino-4’-[2’’-furyl]-
imidazol-1’-yl)-benzoic acid trifluoroacetate 3e
66% yield. 1H-NMR (250 MHz, D2O) δ: 8.04 (2H, m);
7.55 (1H, d, J = 8 Hz); 7.44 (1H, br s); 6.94 (1H, s); 6.57
(1H, d, J = 3 Hz); 6.44 (1H, m); 1.93 (3H, s). m/z (M +
H+) 327. Anal. Found C 45.72; H 3.51; N 13.93.
C16H14N4O4•CF3CO2H requires C 49.10; H 3.43; N
12.72.
1
solid (17.2 g, 59%). H-NMR (250 MHz, DMSO-d6) δ:
8.27 (1H, t, J = 8 Hz); 7.97 (1H, dd, J = 12 Hz, 2 Hz);
7.95 (1H, dd, J = 8 Hz, 2 Hz). Anal. Found C 45.36; H
2.01; N 7.74. C7H4FNO4 requires C 45.42; H 2.18; N
7.57.
6.1.25.
4-Acetylamino-3-(2’-amino-4’-[4-methoxy-
6.2.2. 3-Fluoro-4-nitrobenzoic acid-t-butyl ester 9
A solution of 3-fluoro-4-nitrobenzoic acid (15.0 g,
0.08 mol) in dichloromethane (160 mL) was stirred and
cooled at ca. 0 °C. DMAP (1.5 g) and t-butyl alcohol
(30.6 mL, 0.325 mol) were added followed by dicyclo-
hexylcarbodiimide (18.4 g, 0.09 mol). The cooling bath
was removed and the mixture was stirred for 24 h. After
basification with 2 M sodium hydroxide solution the
organic phase was collected, washed with water, brine
and dried (MgSO4). Removal of solvent gave the crude
product as a brown solid (32.0 g). This was purified by
passage of a solution through a pad of silica gel, eluting
with 6:1 cyclohexane:ethyl acetate to give the product as
carbonyl-2’’-furyl]-imidazol-1’-yl)-benzoicacidtrifluoro-
acetate 3f
1
64% yield. H-NMR (250 MHz, D2O) δ: 7.96–8.08
(3H, m); 7.52 (1H, d, J = 9 Hz); 7.06 (1H, s); 6.84 (1H,
s); 3.82 (3H, s); 1.92 (3H, s). m/z (M + H+) 385. Anal.
Found:
C
46.27;
H
3.61;
N
10.92.
C18H16N4O6•CF3CO2H•H2O requires C 46.52; 3.71; N
10.85.
6.1.26.
4-Acetylamino-3-(2’-amino-4’-[benzofuran-
3’’-yl]-imidazol-1’-yl)-benzoic acid trifluoroacetate 3g
1
64% yield. H-NMR (DMSO) δ: 9.85 (1H, br s), 8.28
(1H, d), 8.09 (1H, dd), 8.05 (1H, d), 7.9 (2H, br s), 7.7
(1H, d), 7.65 (1H, s), 7.58 (1H, d), 7.4–7.25 (2H, m), 7.25
(1H, s), 2.08 (3H, s). m/z: 377 (M + H+). Anal. Found C
50.98; H 3.52; N 10.61. C20H16N4O4•CF3CO2H•1.5H2O
requires C 51.07; H 3.90; N 10.83.
1
a yellow crystalline solid (15.5 g, 79%). H-NMR (250
MHz, DMSO-d6) δ: 8.28 (1H, t, J = 8 Hz); 7.96 (1H, dd,
J = 12 Hz, 2 Hz); 7.90 (1H, dd, J = 8 Hz, 2 Hz); 1.57 (9H,
+
s). m/z (M + NH4 ) 259. Anal. Found: C 55.36; H 5.06;
N 5.69. C11H12FNO4 requires C 54.77; H 5.01; N 5.81.
6.1.27. 4-Acetylamino-3-(2’-amino-4’-ethyl-imidazol-
1’-yl)-benzoic acid trifluoroacetate 3h
6.2.3. 4-Nitro-3-(2’-nitro-imidazol-1’-yl)-benzoic acid
t-butyl ester 10a
Sodium hydride (60% dispersion, 0.12 g, 3 mmol) was
added to a solution of 2-nitro-imidazole (0.34 g, 3 mmol)
in DMSO (5 mL) and the resulting mixture was stirred
86% yield. 1H-NMR (250 MHz, D2O) δ 8.02 (1H, dd,
J = 8 Hz, 2 Hz); 7.95 (1H, d, J = 2 Hz); 7.51 (1H, d, J =
8 Hz); 6.40 (1H, s); 2.40 (2H, q, J = 7.5 Hz); 1.94 (3H,
s); 1.04 (3H, t, J = 7.5 Hz). m/z (M + H+) 289. Anal.
until
a clear solution was obtained. 3-Fluoro-4-
Found:
C
45.68;
H
4.35;
N
12.87.
nitrobenzoic acid-t-butyl ester 9 (0.48 g, 2 mmol) in
DMSO (5 mL) was added and the resulting solution was
heated at ca. 100 °C for 18 h. The mixture was cooled to
room temperature and partitioned between 50 mL por-
tions of 1:1 ether:ethyl acetate and water. The aqueous
layer was discarded and the organic layer was dried
(MgSO4) and concentrated to a yellow oil. Trituration
with ether afforded the product as a pale yellow solid
C14H16N4O3•CF3CO2H•1.2H2O requires C 45.33; H
4.61; N 13.22.
6.2. Method B
6.2.1. 3-Fluoro-4-nitrobenzoic acid
A mixture of 3-fluoro-4-nitrotoluene (24.4 g, 0.16 mol)
and sodium dichromate dihydrate (65.0 g, 0.22 mol) in
water (190 mL) was stirred and cooled in an ice-water
bath. Concentrated sulfuric acid (147 mL) was added
dropwise over 1.75 h. The cooling bath was removed and
1
(0.38 g, 57%) H-NMR (250 MHz, DMSO-d6) δ: 8.45
(1H, d, J = 9 Hz); 8.35 (1H, d, J = 2 Hz); 8.31 (1H, dd,
J = 9 Hz, 2 Hz); 7.89 (1H, d, J = 1 Hz); 7.45 (1H, d,

233
J = 1 Hz); 1.57 (9H, s). m/z (M + H+) 335. Anal. Found C
50.43; H 4.26; N 16.55. C14H14N4O6 requires C 50.30; H
4.44; N 16.76.
palladium on carbon (0.20 g). The catalyst was removed
by filtration through Celite. The filtrate was evaporated to
dryness to give the product as a brown oil. This was
partitioned between ethyl acetate and saturated sodium
bicarbonate solution. The organic layer was collected,
dried (MgSO4) and evaporated to give the product as a
pale brown solid (0.20 g). A further quantity (0.21 g) of
slightly less pure material was obtained by evaporation of
6.2.4.
4-Nitro-3-(2’-amino-imidazol-1’-yl)-benzoic
acid t-butyl ester 10b
A mixture containing 3-fluoro-4-nitrobenzoic acid-t-
butyl ester 9 (0.48 g, 2 mmol), 2-amino-imidazole sulfate
(1.06 g, 4 mmol) and triethylamine (1.15 mL, 8.2 mmol)
in DMSO (5 mL) was stirred at 100 °C for 3 h. The
mixture was cooled, diluted with 1:1 ethyl acetate/ether
(300 mL) and washed with sodium bicarbonate (4 times)
then brine and dried over magnesium sulfate. Solvent was
removed affording the crude product as a red oil which
was purified by flash chromatography (eluant: ethyl
acetate/methanol 30:1 to 20:1) to give the title product as
1
the mother liquors. Overall yield = 97%. H-NMR (250
MHz, DMSO-d6) δ: 7.65 (1H, dd, J = 8 Hz, 1.5 Hz); 7.48
(1H, d, J = 2 Hz); 6.86 (1H, d, J = 8 Hz); 6.62 (1H, s);
6.60 (1H, s); 5.69 (2H, br s); 5.38 (2H, br s); 1.50 (9H, s).
m/z (M + H+) 275.
Identical material was obtained by hydrogenation of
10b in the presence of 10% palladium on carbon.
Similarly prepared were:
1
an orange coloured foam (0.37 g, 61%). H-NMR (250
MHz, DMSO-d6) δ: 8.24 (1H, d, J = 9 Hz); 8.13 (1H, dd,
J = 9 Hz, 2 Hz); 8.03 (1H, d, J = 2 Hz); 6.79 (1H, d, J =
2 Hz); 6.57 (1H, d, J = 2 Hz); 5.43 (2H, s); 1.58 (9H, s).
m/z (M + H+) 305.
6.2.8. 4-Amino-3-(imidazol-1’-yl)-benzoic acid t-butyl
ester 11c
1
77% yield. H-NMR (250 MHz, DMSO-d6) δ: 7.82
(1H, s); 7.7 (1H, dd, J = 9 Hz, 2 Hz); 7.51 (1H, d, J = 2
Hz); 7.35 (1H, s); 7.16 (1H, s); 6.89 (1H, d, J = 8 Hz);
5.82 (2H, s); 1.53 (9H, s). m/z (M + H+) 260. Anal. Found
C 65.03; H 7.32; N 15.23. C14H17N3O2 requires C 64.85;
H 6.61; N 16.20.
6.2.5. 4-Nitro-3-(imidazol-1’-yl)-benzoic acid t-butyl
ester 10c
A mixture containing 3-fluoro-4-nitrobenzoic acid-t-
butyl ester 9 (1.00 g, 4.1 mmol) and imidazole (1.30 g,
18 mmol) in DMSO was heated at 100 °C for 1 h. After
being cooled to room temperature the mixture was
partitioned between 1:1 ether/ethyl acetate and water. The
organic layer was collected, washed with water and brine
and dried over magnesium sulfate. Solvent was removed
to give the title product as an orange coloured solid
6.2.9. 4-Amino-3-(2’-ethylimidazol-1’-yl)-benzoic acid
t-butyl ester 11d
1
24% yield. H-NMR (250 MHz, DMSO-d6) δ: 7.50
(1H, dd, J = 8 Hz, 2 Hz); 7.23 (1H, 2, J = 2 Hz); 6.89 (1H,
s); 6.79 (1H, s); 6.64 (1H, d, J = 9 Hz); 5.53 (2H, s);
2.26–2.13 (2H, m); 1.30 (9H, s); 0.51 (3H, t, J = 7 Hz).
m/z (M + H+) 288.
1
(0.98 g, 82%). H-NMR (250 MHz, DMSO-d6) δ: 8.29
(1H, d, J = 8 Hz); 8.18 (1H, dd, J = 8 Hz, 2 Hz); 8.04 (1H,
d, J = 2 Hz); 7.99 (1H, s); 7.49 (1H, s); 7.12 (1H, s); 1.57
(9H, s). m/z (M + H+) 290. Anal. Found C 58.62; H 5.32;
N 14.27. C14H15N3O4 requires C 58.13; H 5.23; N 14.53.
Similarly prepared were:
6.2.10.
4-Acetylamino-3-(2’-amino-imidazol-1’-yl)-
benzoic acid t-butyl ester 12b
A solution of the diamine 11b (1.17 g, 4.27 mmol) in
acetic acid (20 mL) was treated with acetic anhydride
(0.40 mL, 1 equivalent) and stirred at room temperature
for 96 h. The mixture was partitioned between sodium
bicarbonate solution and ethyl acetate. The organic layer
was collected and dried over magnesium sulfate. The
crude product was partially purified by flash chromatog-
raphy using 5:1 v:v chloroform/methanol as eluant af-
fording the product as a grey solid (0 51 g), which was
used without further purification (see below).
6.2.6. 4-Nitro-3-(2’-ethylimidazol-1’-yl)-benzoic acid
t-butyl ester 10d
Crude product purified by flash chromatography using
1:1 v/v ethyl acetate/cyclohexane as eluant. 75% yield.
1H-NMR (250 MHz, DMSO-d6) δ: 8.32 (1H, d, J = 8
Hz); 8.23 (1H, dd, J = 8 Hz, 2 Hz); 8.04 (1H, d, J = 2 Hz);
7.27 (1H, d, J = 2 Hz); 6.96 (1H, d, J = 2 Hz); 1.58 (9H,
s).
Similarly prepared were:
6.2.7. 4-Amino-3-(2’-amino-imidazol-1’-yl)-benzoic
acid t-butyl ester 11b
A solution of the dinitro compound 10a (0.51 g,
1.5 mmol) in acetic acid (15 mL) was hydrogenated for
24 h. at 1 atmosphere pressure in the presence of 10%
6.2.11. 4-Acetylamino-3-(imidazol-1’-yl)-benzoic acid
t-butyl ester 12c
1
58% yield. H-NMR (250 MHz, DMSO-d6) δ: 9.60
(1H, s); 7.97–7.87 (3H, m); 7.77 (1H, d, J = 2 Hz); 7.41
(1H, s); 7.12 (1H, s); 1.98 (3H, s); 1.55 (9H, s). m/z (M

234
+ H+) 302. Anal. Found C 62.63; H 6.52; N 13.75.
C16H19N3O3•3.3H2O requires C 62.54; H 6.45; N 13.67.
47.75; H 4.32; N 10.20. C14H15N3O3•CF3CO2H•H2O
requires C 47.41; H 4.48; N 10.37.
6.2.12.
4-Acetylamino-3-(2’-ethylimidazol-1’-yl)-
6.2.16. 4-Amino-3-(2’-aminoimidazol-1’-yl)-benzoic
acid trifluoroacetate 14
benzoic acid t-butyl ester 12d
1
84% yield. H-NMR (250 MHz, DMSO-d6) δ: 9.66
A solution of the t-butyl ester 11b (0.050 g,
0.18 mmol) in dichloromethane (1 mL) and trifluoroace-
tic acid (1 mL) was stirred at room temperature for 2 h.
The mixture was evaporated to dryness and the residue
triturated with ether to give the product as a pale brown
solid (0.055 g, 91% yield). 1H-NMR (250 MHz, DMSO-
d6) δ 7.76 (1H, dd, J = 8 Hz, 1 Hz); 7.76 (1H, d, J = 1
Hz); 7.52 (2H, br s); 7.08 (1H, d, J = 2 Hz); 6.99 (1H, d,
J = 2 Hz); 6.81 (1H, d, J = 8 Hz); 6.25 (2H, br s). m/z (M
+ H+) 219. No satisfactory analysis was obtained for this
compound.
(1H, s); 8.24–8.16 (2H, m); 7.88 (1H, d, J = 2 Hz); 7.36
(1H, s); 7.21 (1H, s); 2.59 (2H, q, J = 8 Hz); 2.21 (3H, s);
1.87 (9H, s); 1.35 (3H, t, J = 8 Hz). m/z (M + H+) 330.
6.2.13.
4-Acetylamino-3-(2’-amino-imidazol-1’-yl)-
benzoic acid trifluoroacetate 13b
A solution of the crude t-butyl ester 12b (0.51 g,
1.6 mmol) in 4:1 trifluoroacetic acid/dichloromethane
(8 mL) was stored at room temperature for 2 h. Solvent
was removed by evaporation and the residue triturated
with ether to give the product as a pale pink solid (0.55g,
92%. 1H-NMR (250 MHz, DMSO-d6) δ 12.3 (1H, br s);
9.85 (1H, br s); 8.15 (1H, d, J = 9 Hz); 8.08 (1H, dd, J =
9 Hz, 1.5 Hz); 7.90 (1H, d, J = 5 Hz); 7.70 (2H, br s); 7.10
(1H, d, J = 2 Hz); 7.00 (1H, d, J = 2 Hz); 2.05 (3H, s). m/z
(M + H+) 261. Anal. Found C 43.64; H 3.18; N 14.48.
C12H12N4O3•CF3CO2H•0.5H2O requires C 43.87; H
3.68; N 14.62.
References
[1] Vonitzstein M., Wu W.Y., Kok G.B. et al., Nature 20 (1994)
418–423.
[2] Smith P.W., Cherry P.C., Howes P.D., Sollis S.L., Taylor N.R., In:
Bentley P.H., O’Hanlon P.J. (Eds.), Anti-Infectives: Recent Advances in
Chemistry and Structure–Activity Relationships, Royal Society of Chem-
istry, Cambridge, 1997, pp. 269–287.
Similarly prepared were:
[3] Singh S., Jedrzejas M.J., Air G.M., Luo M., Laver G.W., Brouil-
lette W.J., J. Med. Chem. 38 (1995) 3217.
6.2.14. 4-Acetylamino-3-(imidazol-1’-yl)-benzoic acid
trifluoroacetate 13c
[4] Williams M., Bischofberger N., Swaminathan S., Kim C.U.,
Bioorg. Med. Chem. Lett. 5 (1995) 2251–2254.
1
80% yield. H-NMR (250 MHz, DMSO-d6) δ: 9.93
[5] Sollis S.L., Smith P.W., Howes P.D., Cherry P.C., Bethell R.C.,
Bioorg. Med. Chem. Lett. 6 (1996) 1805–1808.
(1H, s); 9.42 (1H, s); 8.11 (2H, d, J = 8 Hz); 7.96 (2H, 2,
J = 8 Hz); 7.82 (1H, s); 1.99 (3H, s). m/z (M + H+) 246.
[6] Lancini G.C., Lazzari E., Sartori G., J. Antibiot. 21 (1968)
387–392.
Anal. Found
C
46.81;
H
3.37;
N
11.70.
C12H11N3O3•CF3CO2H•0.33H2O requires C 46.04; H
3.49; N 11.51
[7] Widmer U., Synthesis (1983) 135–136.
[8] This oxidation could also be performed using potassium perman-
ganate, but resulted in lower and less reproducible yields.
6.2.15.
4-Acetylamino-3-(2’-ethylimidazol-1’-yl)-
[9] Superior to the use of isobutene/sulfuric acid.
benzoic acid trifluoroacetate 13d
[10] Janssens F., Torremans J., Janssen M., Stokbroekx R.A., Luyckz
M., Janssen P.A.J., J. Med. Chem. 28 (1985) 1925.
1
41% yield. H-NMR (250 MHz, DMSO-d6) δ: 10.04
[11] Woods J.M., Bethell R.C., Coate J.A. et al., Antimicrob. Agents
Chemother. 37 (1993) 1473–1479.
(1H, s); 8.31 (1H, dd, J = 8 Hz, J = 2 Hz); 8.28 (1H, d,
J = 2 Hz); 8.15 (1H, d, J = 8 Hz); 7.96 (1H, d, J = 1 Hz);
7.81 (1H, d, J = 1 Hz); 3.98–2.81 (2H, m); 2.15 (3H, s);
1.48–1.39 (3H, m). m/z (M + H+) 274. Anal. Found C
[12] Smith P.W., Sollis S.L., Howes P.D., Cherry P.C., Cobley K.N.,
Taylor H., Whittington A.R., Scicinski J., Bethell R.C. et al., Bioorg. Med.
Chem. Lett. 6 (1996) 2931–2936.