Salicylanilides as inhibitors of the protein tyrosine kinase epidermal growth factor receptor

Article abstract of DOI:10.1016/j.ejmech.2003.09.010

A pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase and a putative binding mode of 4-anilinoquinazoline suggest that a salicylic acid function could serve as the pharmacophore replacement of a pyrimidine ring. Superpositions by CAMM of salicylanilides with the potent EGFR tyrosine kinase inhibitor 4-[(3′-chlorophenyl)amino]-6,7-dimethoxyquinazoline showed that salicylanilides should act as tyrosine kinase inhibitors. A series of salicylanilides was synthesized and their inhibitory activity against tyrosine kinases determined. Some of them indeed proved to be potent and selective EGFR tyrosine kinase inhibitors. The most potent ones being 28, 16, 20, 6, and 15, with IC₅₀ in the 23-71 nM range.

Full text of DOI:10.1016/j.ejmech.2003.09.010

European Journal of Medicinal Chemistry 39 (2004) 11–26
www.elsevier.com/locate/ejmech
Original article
Salicylanilides as inhibitors of the protein tyrosine kinase epidermal
growth factor receptor
Christoph Liechti a, Urs Séquin a,*, Guido Bold b, Pascal Furet b,
Thomas Meyer b, Peter Traxler b
a Department of Chemistry, University of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
b Oncology Research Novartis Pharma AG, CH-4002 Basel, Switzerland
Received 10 June 2003; accepted 9 September 2003
Abstract
A pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase and a putative
binding mode of 4-anilinoquinazoline suggest that a salicylic acid function could serve as the pharmacophore replacement of a pyrimidine
ring. Superpositions by CAMM of salicylanilides with the potent EGFR tyrosine kinase inhibitor 4-[(3′-chlorophenyl)amino]-6,7-
dimethoxyquinazoline showed that salicylanilides should act as tyrosine kinase inhibitors.A series of salicylanilides was synthesized and their
inhibitory activity against tyrosine kinases determined. Some of them indeed proved to be potent and selective EGFR tyrosine kinase
inhibitors. The most potent ones being 28, 16, 20, 6, and 15, with IC50 in the 23–71 nM range.
© 2003 Elsevier SAS. All rights reserved.
Keywords: Salicylanilides; Protein tyrosine kinase inhibitors; EGFR PTK
1. Introduction
Out of the numerous inhibitors of EGFR PTK reported in
the last few years, compounds competing with ATP for bind-
ing at the catalytic domain are of special interest. Because of
the lack of crystal structure data of the kinase, Furet et al. [5]
and Palmer et al. [6] postulated hypothetical models of the
ATP-binding site of the enzyme based on molecular model-
ing. These models were successfully used for the develop-
ment of someATP competitive inhibitors of EGFR PTK such
as the 4-(phenylamino)pyrrolo[2,3-d]pyrimidines 1 [7], the
4-(phenylamino)pyrazolo[3,4-d]pyrimidines 2 [8], and the
4-(phenylamino)quinazolines 3 [9] (see Fig. 1).
From structure activity relationship (SAR) studies, Palmer
et al. [6] postulated a binding mode for 4-anilinoquinazolines
(3) to the EGFR PTK. In this model, the inhibitor binds to the
enzyme via a pyrimidine nitrogen atom through a hydrogen
bond to the backbone NH of amino acid Met769 of EGFR
PTK. According to this model the aniline substituent is occu-
pying a hydrophobic region located at the bottom of the ATP
binding pocket of EGFR PTK (hydrophobic region I in
Fig. 5). Substituents in positions 6 and 7 of the quinazoline
are directed to another hydrophobic region of the enzyme
open to the solvent (hydrophobic region II in Fig. 5).
Quinazolines such as 4 with electron-donating groups in
these positions (Fig. 2) are highly potent EGFR PTK inhibi-
The actions of protein tyrosine kinases (PTK) are funda-
mental to signal transduction pathways. In many prolifera-
tive diseases (e.g. cancer, psoriasis, restenosis, etc.), deregu-
lated PTK activity has been observed [1]. A number of tumor
types have dysfunctional growth factor receptor PTKs,
which result in inappropriate mitogenic signaling. Thus, ty-
rosine kinases are attractive targets for the design of new
therapeutic agents against cancer [2,3]. The inhibition of
these enzymes might stop the growth of the tumor and can,
therefore, be of great therapeutical value.
The family of epidermal growth factor receptor (EGFR)
PTKs belongs to the large class of the trans-membrane
growth factor receptor PTKs and contains four members:
EGFR kinase, p185erbB2, and the gene products of c-erbB3
and c-erbB4. The EGFR and its ligands (EGF, TGF-a) have
been implicated in many different tumors of epithelial origin
(e.g. squamous cell carcinoma; breast, ovarian, and NSC
lung cancer) [1,4].
* Corresponding author.
E-mail address: urs.sequin@unibas.ch (U. Séquin).
© 2003 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2003.09.010

12
C. Liechti et al. / European Journal of Medicinal Chemistry 39 (2004) 11–26
Fig. 1. Structures of 4-(phenylamino)pyrrolo[2,3-d]pyrimidines 1, 4-(phenylamino)pyrazolo[3,4-d]pyrimidines 2, and 4-(phenylamino)quinazolines 3.
Fig. 2. Structures of quinazoline 4, genistein (5), and salicylamide 6.
Fig. 3. Superimpositions. Left: quinazoline 4 (brown) and genistein (5) (green); right: quinazoline 4 (brown) and salicylanilide 6 (green). The crucial structural
motives, the pseudo six-membered rings formed by the intramolecular hydrogen bonds in the isoflavone 5 and the salicylanilide 6, as well as the pyrimidine ring
of the quinazoline 4, are drawn in black.
tors. It was also shown by SAR studies that selectivity for the
EGFR PTK can be achieved with a halogen substituent in the
3-position of the anilino moiety of the inhibitor [10].
A natural yet unselective inhibitor of EGFR PTK is the
isoflavone genistein (5) [11]. A superposition by CAMM of
the structures of 5 and the quinazoline 4 of AstraZeneca
shows a very good spatial match (Fig. 3). Hodge and Pierce
[12] have shown that a pseudo six-membered ring such as the
one in salicylanilides formed by an intramolecular hydrogen
bond may function as a mimic of the pyrimidine ring of the
quinazolines. This led to the hypothesis, that salicylanilides
may adopt the same binding mode to EGFR PTK as the
isoflavonesandthequinazolines. Superpositionofthesalicyl-
amide 6 and the quinazoline 4 indeed shows an excellent
match. These superpositions take into account that salicyl-
anilides exist predominantly in the form with the hydrogen
bridge between OH and the carbonyl oxygen (see formula 7,
Fig. 4) [13]; the other possible conformation (formula 8) with
Fig. 4. Two possible intramolecular hydrogen bond arrangements in salicyl-
amides.
a hydrogen bond between the amide NH and the OH be-
comes relevant when there are substituents in positions
3
and/or 2′/6′. The finding that N-(3-chlorophenyl)
salicylamide (9) without any substituents in the salicylic acid
moiety already proved to be a moderate inhibitor of the
EGFR PTK (57% inhibition at 10 µM; see Table 1), encour-

C. Liechti et al. / European Journal of Medicinal Chemistry 39 (2004) 11–26
13
Table 1
Inhibitory activities of salicylanilides towards EGFR ICD, VEGFR-2 PTK, and c-Abl PTK. Enzyme tests were performed as previously described [14] using
poly(E4Y) (2 µg ml–1) and [33P]ATP (0.4 µM) as substrates. For determination of the VEGFR-2 PTK inhibition see [15,16]
R2
R3
R4
R5
R6
R2′
R3′
EGFR ICD,
IC50 (µM)
VEGFR-2, IC50
(µM)
c-Abl, IC50
(µM)
9
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
57% a
2% a
8.20
0.22
0.24
1.2
5% a
20% a
>10
>1
–
10
11
12
13
14
15
16
17
18
19
20
6
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
Me
Bn
H
H
OMe
H
–
Br
H
–
OH
OMe
Me
H
>10
>10
–
H
H
>1
H
H
>1
H
OH
OH
0.071
0.032
0.82
>10
>1
>10
>10
0.85
–
H
H
>1
H
OH OH
OSO2CF3
H
>1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
>10
>1
H
OMe
H
0.36
0.057
0.064
0.12
>10
>10
>10
>10
>10
–
H
OMe
OH
OMe
H
>1
H
OMe
>1
H
NH2
>1
H
NEt2
H
36% a
>10
>10
>1
H
NH–COMe
Br
H
1.70
2.80
>10
–
H
H
–
H
Me
H
–
H
Annealed phenyl
1-Piperidyl
Ph-p-NH2
H
Ring
H
>10
>1
>10
–
H
37% a
0.023
1.5
25% a
26% a
>1
H
H
–
H
H
>10
–
H
H
Me
H
16% a
15% a
34% a
5% a
19% a
23% a
>10
4.1
H
NH2
OH 54% a
OH 10% a
OBn 0% a
OBn 2% a
–
Me
H
H
H
–
NH–COMe
OH
H
–
H
H
–
Me
H
Ph-p-NO2
Ph-p-NO2
Ph-p-NH2
H
OH
OH 5.1
OH
–
–
H
–
H
H
1
1.0
1.1
a Percent inhibition at 10 µM.
–, not determined.
aged us to investigate a series of salicylanilides with various
substitution patterns.
Based on analogy to the SAR of the 4-(phenylamino)-
pyrrolo[2,3-d]pyrimidines [7], the 4-(phenylamino)pyra-
zolo[3,4-d]pyrimidines [8], and the 4-(phenylamino)quina-
zolines [9], the hypothesis was established that for potent
inhibition of the EGFR PTK by salicylanilides the following
requirements should be fulfilled (Fig. 5): salicylic acid moi-
ety: (i) a pseudo six-membered ring formed through intramo-
lecular hydrogen bonding of the hydroxy group to the carbo-
nyl group, (ii) no substituent in position 3, and (iii)
substitution in positions 4 and 5 with electron-donating
groups; anilino moiety: (i) small, lipophilic and electron-
withdrawing group in position 3′ (e.g. 3′-chloro) and (ii) no
substituents in the positions 2′, 4′, 5′ and 6′. The salicylanil-
ides described here should prove this hypothesis right.
Fig. 5. Schematic representation of the ATP binding site of EGFR PTK and
a salicylanilide as potential inhibitor.

14
C. Liechti et al. / European Journal of Medicinal Chemistry 39 (2004) 11–26
Fig. 6. Synthesis of 4-(4-aminophenyl)-N-(3-hydroxyphenyl)salicylamide (37); (a) (4-nitrophenyl)trimethylstannane, Pd(PPh3)4, 1,3-dioxolane,Ar, 24 h, 49%;
(b) KOH, methanol, reflux, 90 min, 99%; (c) SOCl2, reflux, 70 min, 99%; then 3-aminophenol, pyridine, Ar, 135 °C, 3 h, 61%; (d) BBr3, dichloromethane, Ar,
room temperature, 21 h, 82%; (e) H2, PtO2, ethanol, 12 h, room temperature, 97%.
2. Chemistry
anilide 24 or its acetate 41; as a further alternative the triflate
18 was used. Suzuki coupling with the (aminophenyl)
boronate 42 and [1,1′-bis(diphenylphosphino)ferrocene]-
dichloropalladium(II) (PdCl2(dppf)) as catalyst gave the tar-
get compound 28 in moderate yields only.
The piperidyl substituted salicylanilide 27 (Fig. 8) was
obtained from the reaction of 3-(1-piperidyl)phenol [21] with
3-chlorophenyl isocyanate in low yields; the main product
was the corresponding carbamate.
Most of the salicylanilides listed in Table 1 were synthe-
sized through reaction of the corresponding salicylic acids
with the intermediate formed from 3-chloroaniline with
phosphorus trichloride in boiling dibutyl ether [17]. Direct
acylation of the substituted aniline with either a salicyloyl
chloride or a phenyl salicylate was also used. Compounds 9
[18] and 30 [19,20] were prepared according to the literature.
Salicylanilides 35, 36, and 37 were obtained from methyl
4-bromo-2-methoxybenzoate (38) (Fig. 6). The Pd-catalyzed
coupling of this ester with trimethyl(4-nitrophenyl)stannane
to form the biphenyl moiety could only be achieved in a
moderate yield. The ester 39 thus obtained was hydrolyzed to
the acid 40, which was transformed into the corresponding
acid chloride and then reacted with 3-aminophenol to give
the anilide 35. Ether cleavage with BBr3 gave 36, and reduc-
tion of the nitro group finally yielded 37.
3. Biological results and discussion
The compounds synthesized were tested for their inhibi-
tory potency towards the tyrosine kinases EGFR ICD (the
intracellular domain of EGFR) and VEGFR-2 [22], and in
some cases c-Abl to estimate their selectivity. The results are
presented in Table 1. Inhibitory activities are given as IC50
values; for less active compounds percentage inhibition at a
concentration of 10 µM is shown. It is noteworthy that most
A different approach was used for the biphenylic anilide
28 (Fig. 7). Here the starting material was the bromosalicyl-
Fig. 7. Synthesis of 4-(4-aminophenyl)-N-(3-chlorophenyl)salicylamide (28). (a) Compound 42, PdCl2(dppf), 2 M Na2CO3, DMF, 75 °C, Ar, 37 h, 25%; (b) 42,
PdCl2(dppf), 2 M Na2CO3, DMF, 75 °C, Ar, 38 h, 44%; (c) 42, PdCl2(dppf), K3PO4, DMF, 80 °C, 23 h, 52%.

C. Liechti et al. / European Journal of Medicinal Chemistry 39 (2004) 11–26
15
Fig. 8. Structures of compounds 43, 28, 27 and 26.
compounds with high activities towards EGFR (IC50 < 1 µM)
proved to be rather selective inhibitors with respect to
VEGFR-2 or c-Abl.
dine motif is implicitly necessary. The hypothesis that this
pyrimidine ring can be replaced by the pseudo six-membered
ring formed by the strong intramolecular hydrogen bond in
salicylanilides could be verified. The appropriately substi-
tuted salicylanilides 28, 16, 20, 6, and 15 inhibit the EGFR
PTK with IC50 values in the 23–71 nM range. Salicylanilides
with alkylated phenolic OH groups (10, 11, 32), where this
intramolecular hydrogen bond is not possible, consequently
do not inhibit any of the herein measured kinases EGFR,
VEGFR, or c-Abl. None of the herein described salicylanil-
ides potently inhibits the VEGFR PTK or c-Abl. This dem-
onstrates that 28, 16, 20, 6 or 15 block the EGFR PTK with
good selectivity.
The data presented in Table 1 clearly show that salicyla-
nilides can be potent inhibitors of the EGFR PTK, the best
five compounds (28, 16, 20, 6 and 15) have IC50 values in the
range of 23–71 nM. The structural postulates for potential
salicylanilide inhibitors derived from the quinazolines (e.g.
4) also proved to be correct: the pseudo six-membered ring
formed through the intramolecular hydrogen bond in the
salicylic acid part is important for activity. When this is
broken through methylation or benzylation of the phenolic
OH group, activity is lost (compounds 10, 11, 32 and 35).
Electron-donating groups in positions 4 and 5 of the sali-
cylic acid moiety lead to good inhibitors as demonstrated by
compounds 6, 12, 13, 15, 17, 19, 20, 21, and even 28. When
the electron-donating character of the group in 4-position is
destroyed by acylation, activity goes down (compare 16 with
18, and 21 with 23). Replacing the p-aminophenyl group
(compound 37) by p-nitrophenyl (compound 36) has a simi-
lar effect.A methyl or bromine in 4-position also leads to loss
of activity (24 and 25). With compounds having a 4-hydroxy
group, introduction of a second OH-substituent in the sali-
cylic acid moiety changes the inhibitory activity. An addi-
tional 3-OH (17 vs. 15) reduces it by a factor of 10, whereas
an additional 6-OH (16 vs. 15) is tolerated. Limited varia-
tions of the substitution pattern in the anilino moiety revealed
the 3′-chloro group clearly to be the best. Replacing it with
OH led to loss of activity (31 vs. 21), as did omitting it
completely (30 vs. 14).
The biphenylic compounds 28, 35, 36, 37, and the pip-
eridyl phenyl derivative 27 as well as the naphthalenic com-
pound 26 were prepared with the pyrrolopyrimidine 43 in
mind (see Fig. 8), which had been shown to be a very potent
EGFR inhibitor with an IC50 value of 3 nM [23]. Compound
28 was indeed highly active (IC50 = 23 nM). Here again,
replacement of the 3′ chlorine substituent by OH (compound
37) decreased the activity by a factor of 40. The correspond-
ing nitro compound 36 was even less active. The naphthalinic
compound 26 (see Fig. 8) did not inhibit any of the investi-
gated kinases.
5. Experimental protocols
5.1. General remarks
All reactions with air- or moisture-sensitive reactants and
solvents were carried out under argon atmosphere. Unless
otherwise indicated, materials obtained from commercial
suppliers were used without further purification.
IR spectra were determined with a Perkin Elmer 1600 in-
1
frared spectrometer. H NMR spectra were recorded on a
Varian Gemini 300 or on a Bruker DRX500. The chemical
shifts are reported in parts per million (ppm) downfield from
internal tetramethylsilane (TMS). Splitting patterns are des-
ignated as follows: s, singlet; d, doublet; t, triplet; q, quartet.
13C NMR spectra were recorded on a Varian Gemini 300 and
a Bruker DRX500; for some of the compounds the assign-
ments were corroborated by HETCOR experiments; assign-
ments with asterisks may be interchanged. Chemical shifts
are reported in ppm downfield from TMS. Mass spectra (MS)
were recorded on a VG 70-250 or a Finnigan MAT 312 mass
spectrometer. Analyses indicated by the symbols of the ele-
ments were within 0.4% of the theoretical values and were
performed on Leco CHN-900 and Leco RO-478. Flash chro-
matography was carried out with Merck silica gel 60 (40–
63 µm) and Machery Nagel silica gel (40–63 µm). Medium
pressure liquid chromatography (MPLC) was performed on a
Büchi B680 using LiChroprep (Si60 or RP18 (reverse
phase)) of E. MERCK, Darmstadt. Melting points (m.p.)
were measured on a Kofler–Block and are not corrected.
4. Conclusion
It is well accepted, that for potent binding of
4-(phenylamino)quinazolines to the EGFR PTK, the pyrimi-

16
C. Liechti et al. / European Journal of Medicinal Chemistry 39 (2004) 11–26
5.2. Syntheses
1H NMR (300 MHz, D6-DMSO): 10.30 (s, 1H, HN–CO);
7.96 (s, 1H, H–C(2′)); 7.64 (d, J = 8.0, 1H, H–C(6′)); 7.37
(pseudo-t, J = 8.1, 1H, H–C(5′)); 7.22 (d, J = 2.7, 1H,
H–C(6)); 7.17–7.14 (m, 1H, H–C(4′)); 7.15–7.09 (m, 2H,
H–C(3, 4)); 3.86 (s, 3H, H3CO–C(5)); 3.76 (s, 3H, H3CO–
C(2)). 13C NMR (75 MHz, D6-DMSO): 164.4 (HN–CO);
153.0, 150.6 (C(2), C(5)); 140.4 (C(1′)); 133.0 (C(3′)); 130.4
(C(5′)); 125.0 (C(1)); 123.2 (C(4′)); 119.1 (C(2′)); 118.1
(C(6′)); 117.5 (C(3))*; 114.5 (C(6)); 113.5 (C(4))*; 56.4
(H3CO–C(5)), 55.6 (H3CO–C(2)). EI-MS (70 eV): 294 (1);
293.0 (5); 292 (2, [M + H]+); 291 (13, [M]+); 166 (12); 165
(100); 150 (4); 128 (3); 122 (6); 107 (6); 77 (5). Anal. Found:
C15H14ClNO3 (C, H, N, O).
5.2.1. General procedure for salicylamide preparation
To a solution of 3-chloroaniline (5.71 mmol) in dibutyl
ether was added dropwise at room temperature phosphorous
trichloride (1.14 mmol). The suspension was heated at
140 °C for 2 h and the substituted salicylic acid (2.29 mmol)
was added in small portions. The reaction mixture was stirred
for additional 4 h at 140 °C. After cooling to room tempera-
ture the suspension was added to a saturated solution of
potassium bicarbonate. The dibutyl ether and excess
3-chloroaniline were removed by steam distillation. The re-
sidual hot solution was filtered, cooled to room temperature
and acidified with 2 M hydrochloric acid. The product pre-
cipitated and was collected by filtration.
5.2.4. Synthesis of 2-benzyloxy-4-bromo-N-(3-chlorophenyl)
benzamide (11
)
5.2.2. N-(3-Chlorophenyl)-4,5-dimethoxysalicylamide (6)
Prepared as described in the general procedure from
3-chloroaniline (5.80 ml, 7.04 g, 55.2 mmol), phosphorous
trichloride (1.00 ml, 1.52 g, 11.1 mmol), and 4,5-
dimethoxysalicylic acid [24] (4.38 g, 22.1 mmol) in dibutyl
ether. The compound was purified by recrystallization from
ethanol/water.Yield: 98%, beige solid, m.p.: 177–178 °C. IR
(KBr): 3331m, 3055w, 2936w, 2828w, 1646s, 1590s, 1543s,
1512s, 1501s, 1486s, 1463m, 1446m, 1436m, 1406m,
1371m, 1332s, 1301m, 1286s, 1257s, 1222m, 1204s, 1175m,
1161s, 1103m, 1083w, 1018m, 985m, 900w, 888m, 833m,
807m, 787m, 687m, 557m. 1H NMR (300 MHz, D6-DMSO):
11.97 (s, 1H, HO–C(2)); 10.31 (s, 1H, HN–CO); 7.87 (s, 1H,
H–C(2′)); 7.60 (d, J = 8.0, 1H, H–C(6′)); 7.52 (s, 1H,
H–C(6)); 7.41 (pseudo-t, J = 8.2, 1H, H–C(5′)); 7.20 (d,
J = 7.4, 1H, H–C(4′)); 6.60 (s, 1H, H–C(3)); 3.81 (H3C–O);
3.78 (H3C–O). 13C NMR (75 MHz, D6-DMSO): 170.3 (HN–
CO); 158.9 (C(4)); 157.4 (C(2)); 144.9 (C(5)); 142.8 (C(1′));
136.1 (C(3′)); 133.5 (C(5′)); 126.9 (C(4′)); 123.9 (C(2′));
122.8 (C(6′)); 114.2 (C(6)); 109.6 (C(1)); 104.0 (C(3)); 59.6
(H3C–O); 58.9 (H3C–O). EI-MS (70 eV): 310 (3); 309 (16);
308 (8, [M + H]+); 307 (47, [M]+); 182 (10); 181 (100); 180
(100); 165 (10); 153 (2); 152 (3); 138 (5), 137 (8); 136 (5);
129 (3); 127 (6); 125 (7); 124 (2); 110 (4); 109 (3); 95 (6); 69
(3); 53 (5). Anal. Found: C15H14ClNO4 (C, H, N, O).
5.2.4.1. Benzyl 2-benzyloxy-4-bromobenzoate. To 4-bromo-
salicylic acid (8.00 g, 110 mmol) dissolved in acetone
(375 ml) was added potassium carbonate (18.2 g, 110 mmol)
and then benzyl bromide (20.8 ml, 29.9 g, 176 mmol). The
mixture was heated to boiling for 20 h and then allowed to
cool to room temperature. The solvent was removed and the
residue dissolved in water (1 l) and extracted with tert-butyl
methyl ether (2 × 750 ml). The organic phases were dried
over sodium sulfate and the solvent evaporated. The crude
product was purified by MPLC (SiO2, gradient hexane to
hexane/ethyl acetate).Yield: 12.3 g (80%), colorless needles,
m.p.: 71–74 °C. IR (KBr): 3110w, 3060w, 3034w, 2936w,
2880w, 1698s, 1586s, 1483m, 1458m, 1411m, 1387m,
1294s, 1235s, 1136m, 1108m, 986m, 895m. 1H NMR
(300 MHz, CDCl3): 7.72 (d, J = 8.3, 1H, H–C(6)); 7.42 (m,
2H, H5C6–H2C–O); 7.34 (m, 8H, H5C6–H2C–O); 7.17 (d,
J = 1.6, 1H, H–C(3)); 7.12 (dd, J = 8.3, 1.8, 1H, H–C(5));
5.31 (s, 2H, H5C6–H2C–O); 5.11 (s, 2H, H5C6–H2C–O). 13
C
NMR (75 MHz, D6-DMSO): 165.4 (C=O); 158.7 (C(2));
135.80 (H5C6–H2C–O); 133.1 (C(6)); 128.55, 128.48,
128.19, 128.10, 127.98 (H5C6–H2C–O); 127.6 (C(4));
127.10 (H5C6–H2C–O); 123.7 (C(5)); 119.5 (C(1)); 117.1
(C(3)); 70.9 (H5C6–H2C–O); 66.8 (H5C6–H2C–O). FAB-MS
(NBA): 399 (2); 397 (2, [M + H]+); 201 (1); 199 (1); 181 (4);
124 (8); 91 (100). Anal. Found: C21H17BrO3 (C, H, O).
5.2.3. N-(3-Chlorophenyl)-2,5-dimethoxybenzamide (10)
N
-(3-Chlorophenyl)-5-methoxysalicylamide (13) (355 mg,
5.2.4.2. 2-Benzyloxy-4-bromobenzoic acid. Benzyl 2-benzyl-
oxy4-bromobenzoate (1.05 g, 2.66 mmol) was boiled in a
mixture of KOH solution (6%, 25 ml) and methanol (25 ml)
for 3.5 h. The mixture was allowed to reach room tempera-
ture and acidified with HCl solution (6%) to pH 1. The
precipitate formed was collected by suction filtration, dried
in vacuo and recrystallized from ethanol/water. Yield:
0.775 g (95%), colorless needles, m.p.: 112–116 °C. IR
(KBr): 3100–2500m, 1690s, 1589s, 1489w, 1443m, 1416m,
1385m, 1298s, 1240s, 1145w, 1105w, 1020w, 911w, 890m,
830w, 772m, 740m, 696w. 1H NMR (300 MHz, D6-DMSO):
12.85 (s, 1H, COOH); 7.61 (d, J = 8.2, 1H, H–C(6)); 7.51–
7.32 (m, 6H, H5C6–H2C–O, C(3)); 7.22 (dd, J = 8.2, 1.7, 1H,
1.27 mmol) was dissolved in ethanol (4 ml). To this yellow
solution was added an aqueous solution of sodium hydroxide
(0.330 ml water, 136 mg sodium hydroxide) and dimethyl
sulfate (0.300 ml, 397 mg, 3.15 mmol). The solution was
heated to 85 °C for 3 h when a colorless precipitate was
formed. After cooling to room temperature 2 ml of water
were added. The precipitated product was filtered off,
washed with water and purified by recrystallization from
ethanol/water. Yield: 265 mg (71%) as colorless needles,
m.p.: 94–95 °C. IR (KBr): 3382m, 3329m, 3230m, 1639s,
1610s, 1546s, 1514m, 1492m, 1467m, 1452m, 1377m,
1324w, 1266s, 1179m, 1161m, 972w, 844m, 763m, 685m.

C. Liechti et al. / European Journal of Medicinal Chemistry 39 (2004) 11–26
17
H–C(5)); 5.24 (s, 2H, H5C6–H2C–O). 13C NMR (75 MHz,
D6-DMSO): 166.6 (COOH); 157.7 (C(2)); 136.6 (H5C6–
H2C–O); 132.3 (C(6)); 128.4, 127.7, 127.1 (H5C6–H2C–O);
125.9 (C(4)); 123.3 (C(5)); 121.0 (C(1)); 117.0 (C(3)); 69.9
(H5C6–H2C–O). EI-MS (70 eV): 309 (1); 308 (1, [M + H]+);
307 (1, [M]+); 306 (1); 262 (1); 200 (2); 198 (2); 172 (2); 154
(2); 92 (11); 91 (100); 90 (2); 89 (3); 65 (14); 63 (6); 39 (5).
Anal. Found: C14H11BrO3 (C, H, O).
(C(2′)); 118.9 (C(6′)); 118.1 (C(1)); 117.8 (C(3)); 114.6
(C(6)). EI-MS (70 eV): 266 (2); 265 (15); 264 (7, [M + H]+);
263 (47, [M]+); 138 (8); 137 (100); 136 (91); 135 (4); 130 (3);
129 (29); 128 (11); 127 (92); 109 (25); 108 (22); 99 (13); 81
(53); 80 (18); 69 (21); 63 (28); 53 (69); 52 (45); 51 (25); 39
(25). Anal. Found: C13H10ClNO3 (C, H, N, O).
5.2.6. N-(3-Chlorophenyl)-5-methoxysalicylamide (13)
Prepared according to the general procedure from
3-chloroaniline (600 µl, 728 mg, 5.71 mmol), phosphorous
trichloride (100 µl, 152 mg, 1.14 mmol), and
5-methoxysalicylic acid (385 mg, 2.29 mmol) in dibutyl
ether. The compound was purified by recrystallization from
ethanol/water. Yield: 397 mg (77%), brown powder, m.p.:
163–164 °C. IR (KBr): 3088m, 3006m, 2935m, 2832w,
1639s, 1590s, 1554s, 1506m, 1478m, 1445m, 1433s, 1379m,
1288m, 1278m, 1206s, 1142m, 1049m, 875w, 808m, 768m,
755m, 675m. 1H NMR (300 MHz, D6-DMSO): 11.16 (s, 1H,
HO–C(2)); 10.51 (s, 1H, HN–CO); 7.94 (pseudo-t, J = 2.0,
1H, H–C(2′)); 7.62 (dd, J = 8.2, 1.1, 1H, H–C(6′)); 7.47 (d,
J = 3.2, 1H, H–C(6)); 7.40 (pseudo-t, J = 8.1, 1H, H–C(5′));
7.20 (ddd, J = 8.0, 2.1, 0.9, 1H, H–C(4′)); 7.08 (dd, J = 8.9,
3.1, 1H, H–C(4)); 6.95 (d, J = 9.0, 1H, H–C(3)); 3.77 (s, 3H,
H3C–O). 13C NMR (75 MHz, D6-DMSO): 166.0 (HN–CO);
151.9, 151.8 (C(2, 5)); 139.7 (C(1′)); 133.0 (C(3′)); 130.3
(C(5′)); 123.7 (C(4′)); 120.6 (C(2′)); 120.2 (C(6′)); 119.1
(C(4)); 118.1 (C(3)); 117.7 (C(1)); 112.8 (C(6)); 55.6 (H3C–
O). EI-MS (70 eV): 280 (2); 279 (14); 278 (7, [M + H]+); 277
(43, [M]+); 153 (2), 152 (5), 151 (48); 150 (100), 135 (4); 129
(4), 127 (13), 123 (7); 122 (7); 108 (6); 107 (7); 95 (5); 79 (5);
52 (5). Anal. Found: C14H12ClNO3 (C, H, N).
5.2.4.3. 2-Benzyloxy-4-bromo-N-(3-chlorophenyl)benzamide
(11). Prepared as described in the general procedure from
3-chloroaniline (1.00 ml, 1.21 g, 1.14 mmol), phosphorous
trichloride (0.100 ml, 0.157 g, 1.14 mmol), and 2-benzyloxy-
4-bromobenzoic acid (350 mg, 1.14 mmol). The product was
purified by recrystallization from ethanol/water. Yield:
330 mg (69%), fine, colorless needles, m.p.: 174–176 °C. IR
(KBr): 3338m, 1669s, 1588s, 1544s, 1480m, 1426m, 1408w,
1379w, 1279m, 1225m, 1131w, 995m, 914w, 890w, 757m,
696m, 663w. 1H NMR (500 MHz, D6-DMSO): 10.32 (s, 1H,
HN–CO); 7.72 (pseudo-t, J = 2.0, 1H, H–C(2′)); 7.60 (d,
J = 8.2, 1H, H–C(6)); 7.54 (d, J = 1.7, 1H, H–C(3)); 7.54–
7.52 (m, 2H, H5C6–H2C–O); 7.48–7.46 (m, 1H, H–C(6′)),
7.39–7.34 (m, 3H, H5C6–H2C–O); 7.33 (pseudo-t, J = 8.2,
H–C(5′)); 7.32 (dd, J = 8.2, 1.7, 1H, H–C(5)); 7.13 (ddd,
J = 8.0, 2.1, 0.9, 1H, H–C(4′)); 5.27 (s, 2H, H5C6–H2C–O).
13C NMR (125 MHz, D6-DMSO): 163.9 (HN–CO); 156.3
(C(2)); 140.2 (C(1′)); 136.1 (H5C6–H2C–O); 133.1 (C(3′));
131.4 (C(6)); 130.5 (C(5′)); 128.5 (H5C6–H2C–O); 128.2
(H5C6–H2C–O); 127.9 (H5C6–H2C–O); 125.0 (C(4)); 124.2
(C(1)); 123.8 (C(5)); 123.3 (C(4′)); 118.7 (C(2′)); 117.7
(C(6′)); 116.5 (C(3)); 70.6 (H5C6–H2C–O). EI-MS (70 eV):
419 (1); 418 (1); 417 (2); 416 (1); 415 (2, [M]+); 399 (3); 397
(2), 291 (8); 289 (8); 245 (5); 219 (5); 218 (3); 217 (17); 216
(4); 201 (5); 199 (4); 129 (4); 127 (13); 92 (9); 91 (100); 65
5.2.7. N-(3-Chlorophenyl)-5-methylsalicylamide (14)
Prepared according to the general procedure from
3-chloroaniline (5.20 ml, 6.31 g, 49.5 mmol), phosphorous
trichloride (0.900 ml, 1.37 g, 9.96 mmol), and
5-methylsalicylic acid (3.00 g, 19.7 mmol) in dibutyl ether.
The compound was purified by column chromatography us-
ing pentane/tert-butyl methyl ether (1:1) and recrystalliza-
tion from ethanol/water. Yield: 4.38 g (85%) as beige plate-
lets, m.p.: 175–177 °C. IR (KBr): 3196m, 2923w, 2859w,
1646s, 1612s, 1561s, 1508s, 1482s, 1420m, 1355m, 1329s,
1293m, 1246m, 1224s, 1198m, 1141m, 1099m, 1074w,
995w, 883m, 851m, 813s, 774m, 701m, 675m, 649m, 582w,
535m. 1H NMR (500 MHz, D6-DMSO): 11.38 (s, 1H,
HO–C(2)); 10.46 (s, 1H, HN–CO); 7.93 (pseudo-t, J = 2.0,
1H, H–C(2′)): 7.73 (d, J = 1.7, 1H, H–C(6)); 7.62 (ddd,
J = 8.2, 1.9, 0.8, 1H, H–C(6′)); 7.38 (pseudo-t, J = 8.1, 1H,
H–C(5′)); 7.24 (dd, J = 8.3, 1.8, 1H, H–C(4)); 7.18 (ddd,
J = 8.0, 2.0, 0.8, 1H, H–C(4′)); 6.89 (d, J = 8.3, 1H, H–C(3));
2.27 (s, 3H, H3C–C(5)). 13C NMR (125 MHz, D6-DMSO):
166.6 (HN–CO); 156.0 (C(2)); 139.8 (C(1′)); 134.4 (C(4));
133.0 (C(3′)); 130.4 (C(5′)); 129.0 (C(6)); 127.7 (C(5));
123.7 (C(4′)); 120.1 (C(2′)); 119.1 (C(6′)); 117.2 (C(1));
117.1 (C(3)); 20.0 (H3C–C(5)). EI-MS (70 eV): 264 (6); 263
(26); 262 (15, [M + H]+); 261 (54, [M]+); 136 (19); 135
(5); 63 (4). HR-EI-MS: 414.9982 ([M]+, C20H15BrClNO2 ;
+
Calc. 414.9975).Anal. Found: C20H15BrClNO2 (C, H, N, O).
5.2.5. N-(3-Chlorophenyl)-5-hydroxysalicylamide (12)
Prepared as described in the general procedure from
3-chloroaniline (6.75 ml, 8.19 g, 64.2 mmol), phosphorous
trichloride (1.20 ml, 1.82 g, 13.7 mmol), and
5-hydroxysalicylic acid (3.97 g, 25.8 mmol) in dibutyl ether.
The compound was purified by column chromatography us-
ing pentane/tert-butyl methyl ether (1:1). Yield: 4.30 g
(63%), white powder, m.p.: 193.5–195.5 °C. IR (KBr):
3246s, 1640s, 1618s, 1597s, 1566m, 1518w, 1484m, 1452s,
1360m, 1331w, 1226w, 1194m, 1138w, 819w, 776w, 709w,
676w. 1H NMR (300 MHz, D6-DMSO): 10.86 (s, 1H,
HO–C(2)); 10.49 (s, 1H, HN–CO); 9.12 (s, 1H, HO–C(5));
7.94 (pseudo-t, J = 1.9, 1H, H–C(2′)); 7.58 (ddd, J = 8.2, 2.0,
0.9, 1H, H–C(6′)); 7.38 (pseudo-t, J = 8.1, 1H, H–C(5′));
7.32 (d, J = 2.8, H–C(6)); 7.17 (ddd, J = 8.0, 2.0, 1.0, 1H,
H–C(4′)); 6.87 (dd, J = 8.7, 2.8, 1H, H–C(4)); 6.83 (d,
J = 8.7, 1H, H–C(3)). 13C NMR (75 MHz, D6-DMSO): 165.9
(HN–CO); 150.2, 149.7 (HO–C(2, 5)); 139.9 (C(1′)); 133.0
(C(3′)); 130.4 (C(5′)); 123.5 (C(4′)); 121.2 (C(4)); 119.9

18
C. Liechti et al. / European Journal of Medicinal Chemistry 39 (2004) 11–26
(100); 134 (36); 129 (29); 128 (10); 127 (63); 107 (20); 78
(13); 77 (28); 53 (14); 51 (11). Anal. Found: C14H12ClNO2
(C, H, N, O).
5.2.10. N-(3-Chlorophenyl)-3,4-dihydroxysalicylamide (17)
Prepared as described in the general procedure from
3-chloroaniline (2.20 ml, 2.67 g, 20.9 mmol), phosphorous
trichloride (1.50 ml, 2.28 g, 16.6 mmol), and 2,3,4-
trihydroxybenzoic acid (1.43 g, 8.40 mmol) in dibutyl ether.
The compound was purified by reverse phase MPLC using
water/methanol (gradient towards decreasing polarity).
Yield: 877 mg (37%), beige needles, m.p.: 180.5–182.5 °C.
IR (KBr): 3510m, 3427m, 1654s, 1593s, 1545s, 1509m,
1457m, 1431m, 1376m, 1312s, 1258m, 1221m, 1036m,
775m, 676w. 1H NMR (300 MHz, D6-DMSO): 12.00 (s, 1H,
HO–C(2)); 10.3 (s, 1H, HN–CO); 9.75 (s, 1H, HO–C(4));
8.59 (s, 1H, HO–C(3)); 7.88 (pseudo-t, J = 1.9, 1H, H–C(2′));
7.61 (d, J = 8.6, 1H, H–C(6′)); 7.43 (d, J = 8.8, 1H, H–C(6));
7.38 (d, J = 8.0, 1H, H–C(5′)); 7.19 (d, J = 7.9, 1H, H–C(4′));
6.42 (d, J = 8.8, 1H, H–C(5)). 13C NMR (75 MHz, D6-
DMSO): 168.5 (HN–CO); 150.5, 150.4 (C(2, 4)); 139.7
(C(1′)); 132.9, 132.8 (C(3, 3′)); 130.3 (C(5′)); 123.6 (C(4′));
120.6 (C(2′)); 119.5, 119.0 (C(6, 6′)); 107.6 (C(1)); 107.1
(C(5)). EI-MS (70 eV): 282 (2); 281 (13); 280 (6, [M + H]+);
279 (38, [M]+); 154 (6); 153 (69); 152 (100); 151 (3); 130 (5);
129 (16); 128 (11); 127 (49); 124 (5); 107 (5); 79 (8); 51 (9).
Anal. Found: C13H10ClNO4 (C, H, N, O).
5.2.8. N-(3-Chlorophenyl)-4-hydroxysalicylamide (15)
Prepared as described in the general procedure from
3-chloroaniline (3.60 ml, 4.37 g, 34.3 mmol), phosphorous
trichloride (0.600 ml, 0.912 g, 6.86 mmol), and
4-hydroxysalicylic acid (2.11 g, 13.7 mmol) in dibutyl ether.
The compound was purified by recrystallization from
ethanol/water.Yield: 2.77 g (77%), beige powder, m.p.: 150–
152 °C. IR (KBr): 3314w, 3051–2581m, 1618s, 1591s,
1555m, 1518s, 1482m, 1435m, 1321m, 1290m, 1256m,
1
1206m, 776m, 682m. H NMR (300 MHz, D6-DMSO):
12.02 (s, 1H, HO–C(2)); 10.24 (s, 2H, HO–C(4), HN–CO);
7.89 (pseudo-t, J = 2.0, 1H, H–C(2′)); 7.86 (d, J = 8.8, 1H,
H–C(6)); 7.59 (dd, J = 8.2, 1.1, 1H, H–C(6′)); 7.38 (pseudo-t,
J = 8.1, 1H, H–C(5′)); 7.18 (dd, J = 8.0, 0.9, 1H, H–C(4′));
6.39 (dd, J = 8.8, 2.4, 1H, H–C(3)); 6.34 (d, J = 2.3, 1H,
H–C(5)). 13C NMR (75 MHz, D6-DMSO): 167.2 (HN–CO);
162.7, 161.3 (HO–C(2, 4)); 139.8 (C(1′)); 133.0 (C(3′));
130.5 (C(6)); 130.3 (C(5′)); 123.5 (C(4′)); 120.3 (C(2′));
119.2 (C(6′)); 107.8 (C(1)); 107.6 (C(5)); 102.8 (C(3)).
EI-MS (70 eV): 266 (1); 265 (8); 264 (4, [M + H]+); 263 (24,
[M]+); 138 (8); 137 (100); 130 (2); 129 (19); 128 (4); 127
(59); 81 (13); 69 (8); 53 (9). Anal. Found: C13H10ClNO3 (C,
H, N, O).
5.2.11. N-(3-Chlorophenyl)-4-(trifluoromethanesulfonyloxy)
salicylamide (18)
The amide 22 (500 mg, 2.06 mmol) in abs. acetonitrile
(30 ml) was cooled to –17 °C. Boron trifluoride etherate
(387 µl, 437 mg, 3.08 mmol) and then over a time of 20 min
tert-butyl nitrite (293 µl, 2.47 mmol) in abs. acetonitrile
(2.5 ml) were added. The mixture was stirred at –10 °C for
10 min, when a yellow product precipitated. The suspension
was diluted with diethyl ether (5 ml) and the 4-[(3-
chloroanilino)carbonyl]benzenediazonium tetrafluoroborate
collected by filtration and once washed with diethyl ether by
decantation. An additional crop of product could be obtained
by concentrating the mother liquor and precipitation with
chloroform. Total yield: 385 mg (56%), pink crystals, de-
composition at 250 °C. To this product (277 mg,
0.766 mmol), which was used without further purification,
trifluoromethanesulfonic acid (3.85 ml, 6.62 g, 44.0 mmol)
was added in small portions. The suspension was then heated
to 80 °C for 1 h; a clear brown solution had formed. After
pouring cold water (12 ml) into the solution, the raw product
precipitated. It was filtered off and washed with cold water.
Yield: 230 mg (76%), light brown solid, m.p.: 130–131 °C.
IR (KBr): 3319w, 3145m, 1636s, 1609s, 1561w, 1500w,
1483w, 1424s, 1361w, 1245s, 1228s, 1141s, 1131s, 1102w,
969s, 840m, 622m, 501m. 1H NMR (300 MHz, D6-DMSO):
11.85 (s, 1H, HO–C(2)); 10.49 (s, 1H, HN–CO)); 7.94 (d,
J = 10.9, 1H, H–C(6)); 7.93 (s, 1H, H–C(2′)); 7.62 (ddd,
J = 8.2, 2.0, 0.9, 1H, H–C(6′)); 7.40 (pseudo-t, J = 8.1, 1H,
H–C(5′)); 7.20 (ddd, J = 8.0, 2.0, 1.0, 1H, H–C(4′)); 7.09 (dd,
J = 10.5, 2.5, 1H, H–C(5)); 7.08 (s, 1H, H–C(3)). 13C NMR:
(75 MHz, D6-DMSO): 164.7 (HN–CO); 158.2 (C(2)); 151.1
(C(4)); 139.8 (C(1′)); 133.0 (C(3′)); 131.6, 130.4 (C(6),
5.2.9. N-(3-Chlorophenyl)-4,6-dihydroxysalicylamide (16)
Prepared as described in the general procedure from
3-chloroaniline (2.20 ml, 2.67 g, 20.9 mmol), phosphorous
trichloride (1.50 ml, 2.28 g, 16.6 mmol), and 2,4,6-
trihydroxybenzoic acid (0.800 g, 4.00 mmol) in dibutyl ether.
The compound was purified by reverse phase MPLC using
water/methanol (gradient towards decreasing polarity) and
recrystallization from ethanol/water. Yield: 419 mg (18%),
colorless powder, m.p.: 209–212 °C. IR (KBr): 3463m,
3387m, 3306s, 1654s, 1611s, 1554s, 1476m, 1433w, 1391m,
1296s, 1253s, 1182m, 1060m, 861w, 829w, 796m, 770m,
1
702w, 683w, 648w, 549w, 530w. H NMR (300 MHz, D6-
DMSO): 12.49 (s, 2H, HO–C(2))*; 10.66 (s, 1H, HO–
C(6))*; 10.16 (s, 1H, HN–CO)*; 7.86 (pseudo-t, J = 2.0, 1H,
H–C(2′)); 7.48 (ddd, J = 8.2, 1.9, 1.0, 1H, H–C(6′)); 7.39
(pseudo-t, J = 8.0, 1H, H–C(5′)); 7.21 (dd, J = 2.1, 1.0, 1H,
H–C(4′)); 7.18 (dd, J = 2.1, 1.0, 1H, H–C(2′)); 5.91 (s, 2H,
H–C(3, 5)). 13C NMR (75 MHz, D6-DMSO): 168.8 (HN–
CO); 162.7 (C(4)); 161.7 (C(2, 6)); 139.0 (C(1′)); 133.2
(C(3′)); 130.5 (C(5′)); 123.8 (C(4′)); 120.4 (C(2′)); 119.4
(C(6′)); 95.1 (C(3, 5)). EI-MS (70 eV): 282 (2, [M(37Cl) +
H]+); 281 (14, [M(37Cl)]+); 280 (6, [M(35Cl) + H]+); 279 (44,
[M(35Cl)]+); 154 (5); 153 (59); 152 (8); 130 (3); 129 (33);
128 (10); 127 (100); 111 (13); 95 (5); 69 (13); 65 (5); 44 (8);
+
43 (8). HR-EI-MS: 279.0298 ([M]+, C13H10ClNO4 ; Calc.
279.0298).

C. Liechti et al. / European Journal of Medicinal Chemistry 39 (2004) 11–26
19
C(5′)); 123.8 (C(4′)); 121.0 (C(1)); 119.8 (C(2′)); 118.8
5.2.14. 4-Amino-N-(3-chlorophenyl)salicylamide (21)
(C(6′)); 118.2 (q, J = 321, F3C–S); 111.9 (C(5)); 109.6
(C(3)). EI-MS: (70 eV): 398 (2); 397 (7); 396 (4, [M + H]+);
395 (18, [M]+); 270 (4); 269 (37); 205 (7); 137 (4); 136 (10);
129 (36); 128 (9); 127 (100); 108 (12); 69 (10). HR-EI-MS:
394.9845 ([M]+, C14H9ClF3NO5S+; Calc. 394.9842). Anal.
Found: C14H9ClF3NO5S (C, H, N, O).
Prepared as described in the general procedure from
3-chloroaniline (26.2 ml, 31.8 g, 250 mmol), phosphorous
trichloride (1.09 ml, 1.71 g, 12.5 mmol), and
4-aminosalicylic acid (3.83 g, 25.0 mmol) in dibutyl ether.
The compound was purified by column chromatography us-
ing hexane/tert-butyl methyl ether (3:1 to increasing polar-
ity). Yield: 2.71 g (41%), beige needles, m.p.: 183–185 °C.
IR (KBr): 3474m, 3403w, 3374s, 1631s, 1585s, 1510s,
1444w, 1426m, 1387s, 1328m, 1288s, 1251s, 1239s, 1197w,
1163m, 852w, 839w, 779m. 1H NMR (300 MHz, D6-
DMSO): 12.13 (s, 1H, HO–(C(2)); 10.30 (s, 1H, HN–CO);
7.87 (pseudo-t, J = 2.0, 1H, H–C(2′)); 7.71 (d, J = 8.8, 1H,
H–C(6)); 7.57 (ddd, J = 8.3, 2.0, 0.9, 1H, H–C(6′)); 7.33
(pseudo-t, J = 8.1, 1H, H–C(5′)); 7.13 (ddd, J = 8.0, 2.0, 0.9,
1H, H–C(4′)); 6.14 (dd, J = 8.7, 2.1, 1H, H–C(5)); 6.03 (d,
J = 2.1, 1H, H–C(3)); 5.94 (s, 2H, H2N–C(4)). 13C NMR
(75 MHz, D6-DMSO): 168.1 (HN–CO); 162.2 (C(2)); 154.7
(C(4)); 140.1 (C(1′)); 132.9 (C (3′)), 130.2 (C(5′)); 129.8
(C(6)); 123.1 (C(4′)); 120.2 (C(2′)); 119.1 (C(6′)); 106.0
(C(5)); 103.2 (C(1)); 99.4 (C(3)). EI-MS (70 eV): 265 (1);
264 (8); 263 (3, [M + H]+); 262 (23, [M]+); 137 (13); 136
(100); 135 (5); 127 (8); 114 (5); 80 (13); 79 (4); 53 (5). Anal.
Found: C13H11ClN2O2 (C, H, N, O).
5.2.12. N-(3-Chlorophenyl)-4-methoxysalicylamide (19)
Prepared as described in the general procedure from
3-chloroaniline (600 µl, 728 mg, 5.71 mmol), phosphorous
trichloride (100 µl, 152 mg, 1.14 mmol), and
4-methoxysalicylic acid (386 mg, 2.29 mmol) in dibutyl
ether. The compound was purified by recrystallization from
ethanol/water. Yield: 273 mg (43%), colorless needles, m.p.:
168.5–169.5 °C. IR (KBr): 3325m, 1592s, 1542s, 1516s,
1479m, 1426m, 1381m, 1282s, 1252s, 1105w, 981w, 773m,
697w, 678w. 1H NMR (300 MHz, D6-DMSO): 12.17 (s, 1H,
HO–C(2)); 10.32 (s, 1H, HN–CO); 7.98 (d, J = 9.0, 1H,
H–C(6)); 7.89 (pseudo-t, J = 1.9, 1H, H–C(2′)); 7.62 (d,
J = 8.3, 1H, H–C(6′)); 7.39 (pseudo-t, J = 8.1, 1H, H–C(5′));
7.19 (dd, J = 8.0, 1.2, 1H, H–C(4′)); 6.58 (dd, J = 8.8, 2,5, 1H,
H–C(5)); 6.51 (d, J = 2.5, 1H, H–C(3)); 3.81 (s, 3H, H3C–O).
13C NMR (75 MHz, D6-DMSO): 167.2 (HN–CO); 163.9,
161.4 (HO–C(2), CH3O–C(4)); 139.7 (C(1′)); 132.9 (C(3′));
130.33, 130.29 (C(5′), C(6)); 123.7 (C(4′)); 120.4 (C(2′);
119.3 (C(6′)); 109.0 (C(1)); 106.4 (C(5)); 101.3 (C(3)); 55.4
(H3C–O). EI-MS (70 eV): 280 (1); 279 (7); 278 (4, [M +
H]+); 277 (22, [M]+); 152 (11); 151 (100); 129 (6); 127 (18);
108 (7); 95 (6); 52 (4).Anal. Found: C14H12ClNO3 (C, H, N).
5.2.15. N-(3-Chlorophenyl)-4-(diethylamino)salicylanilide
(22)
Prepared similar to the general procedure from
3-chloroaniline (1.22 g, 9.60 mmol), phosphorous trichloride
(0.220 g, 1.60 mmol), and 4-(diethylamino)salicylic acid
[26] (1.00 g, 4.78 mmol) in p-xylene. The product was
purified by recrystallization from ethanol/water.Yield: 360 g
(12%), colorless needles, m.p.: 165–166 °C.
5.2.13. N-(3-Chlorophenyl)-5-hydroxy-4-methoxysalicyl-
amide (20)
Prepared as described in the general procedure from
3-chloroaniline (0.80 ml, 0.97 g, 7.6 mmol), phosphorous
trichloride (0.15 ml, 0.23 g, 1.7 mmol), and 5-hydroxy-4-
methoxysalicylic acid [25] (0.55 g, 3.0 mmol) in dibutyl
ether. The product was purified by recrystallization from
ethanol/water. Yield: 500 mg (57%), beige solid, 180 °C
(decomposition). IR (KBr): 3322m, 3221m, 1624s, 1588s,
1560s, 1521s, 1483m, 1446m, 1426m, 1387w, 1322m,
1274s, 1238m, 1189s, 1164m, 1101w, 1079m, 1014w, 900w,
885w, 849w, 836w, 778m, 680w, 658w. 1H NMR (300 MHz,
CD3OD): 7.78 (pseudo-t, J = 1.9, 1H, H–C(2′)); 7.44 (d,
J = 7.4, 1H, H–C(6′)); 7.33 (s, 1H, H–C(6)); 7.28 (pseudo-t,
J = 8.0, 1H, H–C(5′)); 7.06 (dd, J = 7.9, 1.5, 1H, H–C(4′));
6.46 (s, 1H, H–C(3)); 3.84 (s, 3H, H3C–O). 13C NMR
(75 MHz, CD3OD): 169.0 (HN–CO); 155.8 (HO–C(2))*;
154.5 (HO–C(4))*; 141.0 (C(5)); 140.5 (C(1′)); 135.3
(C(3′)); 131.0 (C(5′)); 125.1 (C(4′)); 122.0 (C(2′)); 120.3
(C(6′)); 114.7 (C(6)); 108.9 (C(1)); 101.1 (C(3)); 56.4 (H3C–
O). EI-MS (70 eV): 296 (3); 295 (22); 294 (12, [M + H]+);
293 (52, [M]+); 275 (3); 168 (17); 167 (100); 166 (90), 138
(7); 129 (12); 127 (30); 124 (8); 123 (18); 111 (12); 96 (13);
95 (10); 79 (7); 78 (6); 69 (15); 53 (14); 39 (10). HR-EI-MS:
5.2.15.1. Alternate method.To3-(diethylamino)phenol (1.00 g,
6.05 mmol) in 1,2-dichlorobenzene (23 ml) was added
3-chlorophenyl isocyanate (0.730 ml, 0.926 g, 6.05 mmol).
The reaction mixture was heated to 150 °C for 5 h and after
cooling to room temperature the solvent was distilled off.
The residue was suspended in a mixture of n-hexane (50 ml)
and benzene (10 ml), heated to reflux for 5 min and collected
by filtration; this was repeated two times to give 22, which
finally was purified by recrystallization from ethanol/
water. Yield: 950 mg (49%), colorless needles, m.p.:
165–166 °C.
Data of 22: IR (KBr): 3312m, 2979w, 2932w, 2892w,
1639s, 1585s, 1517s, 1427m, 1408s, 1360s, 1333s, 1274s,
1256s, 1200m, 1150m, 1078m, 829m, 773s, 692m, 679m. 1H
NMR (300 MHz, D6-DMSO): 10.08 (s, 1H, HN–CO); 7.89
(pseudo-t, J = 2,1, 1H, H–C(2′)); 7.83 (d, J = 9.1, H–C(6));
7.61 (d, J = 8.2, 1H, H–C(6′)); 7.37 (pseudo-t, J = 8.0,
H–C(5′)); 7.15 (d, J = 9.2, H–C(4′)); 6.30 (dd, J = 9.3, 2.6,
1H, H–C(5)); 6.08 (d, J = 2.5, H–C(3)); 3.38 (q, J = 7.1, 4H,
H3CH2C–N); 1.12 (t, J = 6.9, 6H, H3CH2C–N). 13C NMR
(75 MHz, D6-DMSO): 168.0 (HN–CO); 162.2 (C(2)); 152.0
(C(4)); 140.1 (C(1′)); 132.9 (C(3′)); 130.2 (C(5′)); 129.8
+
279.0410 ([M]+, C14H12ClNO4 ; Calc. 293.0455).

20
C. Liechti et al. / European Journal of Medicinal Chemistry 39 (2004) 11–26
(C(6)); 123.1 (C(4′)); 120.2 (C(2′)); 119.1 (C(6′)); 103.3
(C(5)); 102.5 (C(1)); 97.2 (C(3)); 43.8 (H3CH2C–N); 12.5
(H3CH2C–N). EI-MS (70 eV): 321 (1); 320 (7); 319 (4, [M +
H]+); 318 (21, [M]+); 193 (19); 192 (100); 191 (7); 176 (15);
162 (5); 149 (5); 148 (10); 127 (5). HR-EI-MS: 279.0298
1H NMR (300 MHz, D6-DMSO): 11.84 (s, 1H, HO–C(2));
10.45 (s, 1H, HN–CO); 7.93 (pseudo-t, J = 2.1, 1H,
H–C(2′)); 7.81 (d, J = 8.4, 1H, H–C(6)); 7.61 (d, J = 7.8, 1H,
H–C(6′)); 7.40 (pseudo-t, J = 8.1, 1H, H–C(5′)); 7.21 (d,
J = 1.7, 1H, H–C(3)); 7.17 (dd, J = 8.3, 1.9, 2H, H–C(4′, 5)).
13C NMR (75 MHz, D6-DMSO): 165.4 (HN–CO); 158.3
(C(2)); 139.6 (C(1′)); 133.0 (C(3′)); 131.1 (C(6)); 130.4
(C(5′)); 126.1 (C(4)); 123.8 (C(5)); 122.1 (C(4′)); 120.0
(C(3)); 119.6 (C(2′)); 119.0 (C(6′)); 118.0 (C(1)). EI-MS
(70 eV): 330 (1); 329 (5); 328 (3); 327 (19); 326 (3, [M]+);
325 (15); 202 (3); 201 (38); 200 (4); 199 (38); 145 (6); 143
(6); 129 (36); 128 (9); 127 (100); 63 (10). Anal. Found:
C13H9BrClNO2 (C, H, N, O).
+
([M]+, C17H19ClN2O2 ; Calc. 318.115). Anal. Found:
C17H19ClN2O2 (C, H, N, O).
5.2.16. 4-Acetamido-N-(3-chlorophenyl)salicylamide (23)
To 4-acetamidosalicyloyl chloride prepared from
4-acetamidosalicylic acid [27] (7.62 g, 39.0 mmol) and thio-
nyl chloride (15.0 ml, 24.5 g, 77.1 mmol) at 0 °C as described
for 33, toluene (40 ml) and 3-chloroaniline (4.10 ml, 4.98 g,
39.0 mmol) were added and the reaction mixture was stirred
for 1 h at room temperature. After the addition of pyridine
(13 ml) and toluene (20 ml) and additional stirring for 3.5 h,
hydrochloric acid (7.5%, 200 ml) and then tert-butyl methyl
ether (200 ml) were added, whereupon a violet solid precipi-
tated. The crude product (1.47 g, 77%) was filtered off and a
sample of it purified by column chromatography using tert-
butyl methyl ether and recrystallization from DMF/water.
Beige needles, m.p.: 257–261 °C. IR (KBr): 3421w, 3312m,
3112m, 2926w, 1648s, 1591s, 1545s, 1483s, 1458w, 1426s,
1373m, 1317m, 1292m, 1251s, 876w, 776m, 681m. 1H NMR
(500 MHz, D6-DMSO): 11.85 (s, 1H, HO–C(2)); 10.34 (s,
1H, HN–CO); 10.16 (s, 1H, HNCO); 7.90 (pseudo-t, J = 2.0,
1H, H–C(2′)); 7.87 (d, J = 8.7, 1H, H–C(6)); 7.58 (ddd,
J = 8.2, 2.0, 0.9, 1H, H–C(6′)); 7.44 (d, J = 2.0, 1H, H–C(3));
7.37 (pseudo-t, J = 8.1, 1H, H–C(5′)); 7.16 (ddd, J = 8.0, 2.1,
0.9, 1H, H–C(4′)); 7.05 (dd, J = 8.7, 2.0, 1H, H–C(5)); 2.06
(s, 3H, H3C–C). 13C NMR (125 MHz, D6-DMSO): 169.0
(HN–CO); 166.3 (HN–CO); 159.3 (C(2)); 144.2 (C(4));
139.8 (C(1′)); 133.0 (C(3′)); 130.4 (C(5′)); 129.9 (C(6));
123.6 (C(4′)); 120.2 (C(2′)); 119.1 (C(6′)); 111.7 (C(1));
109.9 (C(5)); 106.2 (C(3)); 24.2 (H3C–C). EI-MS (70 eV):
307 (1); 306 (5); 305 (3, [M + H]+); 304 (13, M]+); 179 (11);
178 (100); 153 (4); 137 (8); 136 (63); 129 (8); 127 (26); 109
(4); 80 (6); 43 (10). Anal. Calc. for C15H13ClN2O3 (304.73):
C, 59.12; H, 4.30; N, 9.19; O, 15.75. Found: C, 59.17; H,
4.23; N, 9.62; O, 15.78.
5.2.18. N-(3-Chlorophenyl)-4-methylsalicylamide (25)
Prepared as described in the general procedure from
3-chloroaniline (5.20 ml, 6.31 g, 49.5 mmol), phosphorous
trichloride (0.900 ml, 1.37 g, 9.96 mmol), and
4-methylsalicylic acid (3.00 g, 19.7 mmol) in dibutyl ether.
The compound was purified by recrystallization from
ethanol/water. Yield: 3.57 g (69%), colorless platelets, m.p.:
207.2–207.5 °C. IR (KBr): 3420w, 3310w, 3044m, 2923m,
2867m, 1622s, 1590s, 1558s, 1482s, 1426s, 1384m, 1325m,
1247s, 1206w, 1174m, 1103w, 1075w, 878w, 855m, 824w,
774m, 707m, 686m. 1H NMR (500 MHz, D6-DMSO): 11.73
(s, 1H, HO–C(2)); 10.41 (s, 1H, HN–CO); 7.92 (pseudo-t,
J = 1.9, 1H, H–C(2′)); 7.86 (d, J = 8.0, 1H, H–C(6)); 7.62
(ddd, J = 8.2, 1.9, 0.7, 1H, H–C(6′)); 7.38 (pseudo-t, J = 8.1,
1H, H–C(5′)); 7.19 (ddd, J = 7.9, 2.0, 0.8, 1H, H–C(4′)); 6.80
(s, 1H, H–C(3)); 6.79 (d, J = 8.5, 1H, H–C(5)); 2.31 (s, 3H,
H3C–C(4)). 13C NMR (125 MHz, D6-DMSO): 166.9 (HN–
CO); 158.7 (C(2)); 144.5 (C(4)); 139.7 (C(1′)); 133.0 (C(3′));
130.3 (C(5′)); 129.0 (C(6)); 123.7 (C(4′)); 120.3 (C(2′));
120.1 (C(5)); 119.2 (C(6′)); 117.5 (C(3)); 114.3 (C(1)); 21.1
(H3C–C(4)). EI-MS (70 eV): 264 (5); 263 (20); 262 (12, [M
+ H]+); 261 (43, [M]+); 136 (18); 135 (100); 134 (13); 129
(22); 128 (8); 127 (50); 107 (13); 77 (22); 53 (10). Anal.
Found: C14H12ClNO2 (C, H, N, O).
5.2.19. N-(3-Chlorophenyl)-3-hydroxynaphthalene-2-car-
boxamide (26)
5.2.17. 4-Bromo-N-(3-chlorophenyl)salicylamide (24)
Prepared as described in the general procedure from
3-chloroaniline (10.0 ml, 12.1 g, 95.1 mmol), phosphorous
trichloride (1.66 ml, 2.52 g, 19.0 mmol), and
4-bromosalicylic acid [28] (2.11 g, 13.7 mmol) in dibutyl
ether. After the steam distillation a remaining orange precipi-
tate was collected by filtration of the hot suspension. After
acidification of the filtrate with 6 M hydrochloric acid to pH
3, a brown precipitate was formed which was isolated by
filtration. The two solids were combined and purified by
column chromatography using hexane/ethyl acetate (10:1 to
increasing polarity). Yield: 4.82 g (62%), colorless needles,
m.p.: 222–223 °C. IR (KBr): 3321w, 3019w, 2925w, 2851w,
2666w, 2568w, 1616s, 1561s, 1508w, 1483s, 1424s, 1388m,
1324w, 1270w, 1236m, 1223s, 1205m, 849m, 778m, 677m.
3-Hydroxynaphthalene-2-carboxylic acid (1.00 g,
5.31 mmol) and sodium carbonate (1.68 g, 15.9 mmol) were
suspended in dichloromethyl methyl ether (6.00 ml, 7.77 g,
67.6 mmol). The suspension was stirred at room temperature
for 21 h. After evaporating the dichloromethyl methyl ether,
dichloromethane (20 ml) and 3-chloroaniline (0.619 ml,
0.753 g, 5.90 mmol) were added. The reaction mixture was
stirred at room temperature for 90 min. The suspension was
filtered and the remaining solid was washed with dichlo-
romethane. The solid was taken up in saturated sodium car-
bonate solution and then washed with tert-butyl methyl ether.
The aqueous phase was adjusted to pH 5 with 2 M hydrochlo-
ric acid and was left at room temperature overnight. The
precipitated 26 was filtered off and purified by recrystalliza-
tion from ethanol/water. Yield: 411 mg (26%), brownish

C. Liechti et al. / European Journal of Medicinal Chemistry 39 (2004) 11–26
21
solid, m.p.: 258–261 °C. IR (KBr): 3301w, 3057m, 1626s,
1548m, 1478w, 1451w, 1426m, 1403m, 1365m, 1248m,
1214m, 1175w, 1065w, 867w, 776w, 745m, 707w. 1H NMR
(300 MHz, D6-DMSO): 11.18 (s, 1H, HO–C(3)); 10.70 (s,
1H, HN–CO); 8.46 (s, 1H, H–C(1)); 8.00 (d, J = 1.8, 1H,
H–C(2′)); 7.94 (d, J = 8.0, 1H, H–C(8)); 7.77 (d, J = 8.3, 1H,
H–C(5)); 7.68 (d, J = 8.0, 1H, H–C(6′)); 7.52 (pseudo-t,
J = 7.0, 1H, H–C(7)); 7.49–7.36 (m, 2H, H–C(5′)), H–C(6));
5.2.21. 4-(4-Aminophenyl)-N-(3-chlorophenyl)salicylamide
(28)
5.2.21.1. Method 1 (from 24). A mixture of DMF (6.00 ml),
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (42,
268 mg, 1.22 mmol), 4-bromo-N-(3-chlorophenyl)salicyl-
amide (24, 400 mg, 1.22 mmol), PdCl2(dppf) (27 mg,
0.037 mmol), and 2 M sodium carbonate solution (646 mg,
6.09 mmol, in 3.00 ml water) was heated to 75 °C for 7 h.
After cooling to room temperature and the addition of water
(25 ml), the red mixture was extracted with ethyl acetate
(75 ml). The organic phase was dried over sodium sulfate and
the solvent evaporated. The crude product was purified by
flash chromatography on silica gel using hexane/ethyl ac-
etate (1:1) as the eluent. Yield: 104 mg (25%), dark yellow
solid, m.p.: 202–205 °C.
7.35 (s, 1H, H–C(4)); 7.20 (ddd, J = 8.0, 1H, H–C(4′)). 13
C
NMR (75 MHz, D6-DMSO): 165.8 (HN–CO); 153.4 (C(3));
140.0 (C(1′)); 135.7 (C(4a)); 133.1 (C(3′)); 130.5 (C(1));
130.4 (C(5′)); 128.6 (C(8)); 128.1 (C(5)); 126.8 (C(8a));
125.8 (C(6)); 123.7 (C(7)); 123.6 (C(4′)); 122.1 (C(2)); 119.8
(C(2′)); 118.7 (C(6′)); 110.5 (C(4)). EI-MS (70 eV): 300 (2);
299 (11); 298 (6, [M + H]+); 297 (34, [M]+); 172 (8); 171
(73); 170 (100); 143 (6); 142 (27); 131 (8); 127 (5); 116 (6);
115 (53); 114 (15); 113 (5); 89 (7), 65 (5). Anal. Found:
C14H12ClNO2 (C, H, N).
5.2.21.2. Method 2 (from 41). To 2-acetoxy-4-bromo-N-(3-
chlorophenyl)benzamide (41, 400 mg, 1.08 mmol) abs. DMF
(5.0 ml), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)aniline (42, 238 mg, 1.08 mmol), PdCl2(dppf) (23 mg,
0.031 mmol), and a solution of sodium carbonate (575 mg,
5.42 mmol, in 2.7 ml water) were added. The red solution
was heated to 75 °C for 38 h with stirring and then cooled
down to room temperature. Water (40 ml) was added and
stirring continued for 10 h. The grey suspension that had
formed was filtered and the residue washed once with aque-
ous DMF (5 ml). The filtrate was diluted with water (10 ml)
and the brown precipitate that formed collected by filtration
and washed with a small amount of water. Then the crude
product was suspended in a mixture of DMF (0.5 ml) and
water (5 ml), heated briefly to 100 °C filtered hot, washed
with water, and dried in vacuo. Yield: 160 mg (44%), brown
solid.
5.2.20. N-(3-Chlorophenyl)-4-(1-piperidyl)salicylamide
(27)
To 3-(1-piperidyl)phenol (0.309 g, 1.74 mmol [21]) dis-
solved in 1,2-dichlorobenzene (5 ml), 3-chlorophenyl isocy-
anate (0.210 ml, 0.267 g, 1.74 mmol) was added in drops.
The mixture was heated to 150 °C and stirred for 5 h. After
removal of the solvent under reduced pressure, the residue
was dried in vacuo and then triturated for 1 h with a boiling
mixture of benzene and hexane (25 ml each). After cooling,
the residue was collected by filtration and dried in vacuo.
This crude product (555 mg) was adsorbed at silica gel (5 g)
and put on top of a silica gel column (75 g); elution was
carried out with hexane/tert-butyl methyl ether (3:1) to
give N-(3-chlorophenyl)-4-(1-piperidyl)salicylamide (27,
0.113 g, 0.341 mmol, 20%) and N-(3-chlorophenyl)-[3-(1-
piperidyl)phenyl] carbamate (0.383 g, 1.16 mmol, 67%, light
brown powder, m.p.: 123 °C).
5.2.21.3. Method 3 (from 18). A mixture of 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (42, 81 mg,
0.36 mmol), potassium phosphate (0.12 g, 0.49 mmol), abs.
DMF (2.2 ml), N-(3-chlorophenyl)-4-(trifluoromethane-
sulfonyloxy)salicylamide (18, 0.15 g, 0.37 mmol), and
PdCl2(dppf) (9 mg, 0.01 mmol) was heated underAr to 80 °C
for 23 h, whereupon it changed its color from orange to deep
brown.After cooling to room temperature and the addition of
water (50 ml), the mixture was extracted with ethyl acetate
(300 ml). The organic extract was dried over sodium sulfate
and the solvent distilled off. The brown oil was adsorbed on
silica gel (2.5 g) and put on top of a flash column. Elution was
carried out with hexane/ethyl acetate (3:1). Yield: 76 mg
(52%), light brown solid.
Data of 27: light brown powder, m.p.: 166–169 °C. IR
(KBr): 3322w, 3077w, 2935m, 2852w, 1641s, 1587s, 1516s,
1481w, 1425m, 1401m, 1332m, 1310m, 1268m, 1244s,
1
1179w, 1126m, 824w, 772m, 679w. H NMR (300 MHz,
D6-DMSO): 12.15 (s, 1H, HO–C(2)); 10.15 (s, 1H,
HN–CO); 7.88 (dd, J = 2.0, 2.0, 1H, H–C(2′)); 7.84 (d,
J = 9.2, 1H, H–C(6)); 7.61 (m, 1H, H–C(4′)); 7.37 (pseudo-t,
J = 8.1, 1H, H–C(5′)); 7.15 (m, 1H, H–C( 6′)); 6.55 (dd,
J = 9.2, 2.4, 1H, H–C(5)); 6.31 (d, J = 2.4, 1H, H–C(3)); 3.32
(s, 4H, H2C–H2C–H2C–N); 1.58 (m, 6H, H2C–H2C–H2C–
N)). 13C NMR (75 MHz, D6-DMSO): 167.8 (HN–CO);
161.9 (C(2)); 155.0 (C(4)); 140.0 (C(1′)); 133.0 (C(3′));
130.2 (C(6)); 129.5 (C(5′)); 123.3 (C(4′)); 120.3 (C(2′));
119.2 (C(6′)); 105.8 (C(5)); 104.3 (C(1)); 100.2 (C(3)); 47.7
(H2C–H2C–H2C–N); 24.8 (H2C–H2C–H2C–N); 24.0 (H2C–
H2C–H2C–N). EI-MS (70 eV): 333 (1); 332 (6); 331 (3, [M +
H+]); 330 (17, [M]+); 206 (2); 205 (17); 204 (100); 203 (8);
202 (5); 177 (3); 176 (4); 153 (3); 148 (5); 127 (3); 73 (5); 41
(6). Anal. Found: C12H19ClN2O2 (C, H, N, O).
Data of 28: IR (KBr): 3379m, 3333m, 3190w, 1634s,
1595s, 1532s, 1493s, 1412m, 1356w, 1320m, 1265m,
1
1188m, 1100w, 820w, 778m, 682w. H NMR (500 MHz,
CDCl3): 11.9 (s, 1H, HO–C(2)); 7.89 (s, 1H, HN–CO); 7.74
(pseudo-t, J = 1.9, 1H, H–C(2′)); 7.50 (d, J = 8.4, 1H,
H–C(6)); 7.47 (d, J = 8.7, 2H, H–C(2″, 6″); 7.45 (ddd, J = 8.2,
1.9, 0.8, 1H, H–C(6′)); 7.33 (pseudo-t, J = 8.1, 1H, H–C(5′));

22
C. Liechti et al. / European Journal of Medicinal Chemistry 39 (2004) 11–26
7.22 (d, J = 1.7, 1H, H–C(3)); 7.18 (ddd, J = 8.0, 1.9, 0.9, 1H,
H–C(4′)); 7.12 (dd, J = 8.4, 1.9, 1H, H–C(5)); 6.76 (d,
J = 8.6, 2H, H–C(3″, 5″)); 3.84 (s, 2H, H2N–C(4″)). 13C
NMR (125 MHz, CDCl3): 168.3 (HN–CO); 162.3 (C(2));
147.8 (C(4)); 147.1 (C(4″)); 138.0 (C(1′)); 134.9 (C(3′));
130.1 (C(5′)); 129.2 (C(1″)); 128.2 (C(2″, 6″)); 125.6 (C(6));
125.2 (C(4′)); 121.0 (C(2′)); 118.8 (C(6′)); 117.1 (C(5));
115.8 (C(3)); 115.3 (C(3″, 5″)); 111.9 (C(1)). EI-MS
(70 eV): 341 (3); 340 (14); 339 (9, [M + H]+); 338 (39, [M]+);
262 (5); 213 (17); 212 (100); 211 (47); 210 (3); 184 (5); 183
(8); 182 (3); 156 (8); 155 (4); 154 (8); 130 (4); 128 (4); 127
methanol/water. Yield: 69 mg (16%), brown powder, m.p.:
202 °C (decomposition). IR (KBr): 3382m, 3329m, 3230–
2598w, 1639s, 1622s, 1610s, 1546s, 1514s, 1492m, 1467m,
1452m, 1377m, 1324w, 1266s, 1179m, 1161m, 972w, 844w,
763m, 685w. 1H NMR (500 MHz, D6-DMSO): 12.35 (s, 1H,
HO–C(2)); 9.78 (s, 1H, HN–CO)*; 9.38 (s, 1H, HO–
(C(3′))*; 7.72 (d, J = 8.8, 1H, H–C(6)); 7.22 (pseudo-t,
J = 2.2, 1H, H–C(2′)); 7.09 (pseudo-t, J = 8.0, 1H, H–C(5′));
7.02 (dd, J = 8.1, 0.8, 1H, H–C(6′)); 6.49 (ddd, J = 8.0, 2.3,
0.9, 1H, H–C(4′)); 6.12 (dd, J = 8.7, 2.2, 1H, H–C(5)); 6.01
(d, J = 2.1, 1H, H–C(3)); 5.88 (s, 2H, H2N–C(4)). 13C NMR
(125 MHz, D6-DMSO): 168.0 (C(2)); 162.2 (HN–CO);
157.5 (C(3′)); 154.4 (C(4)); 139.5 (C(1′)); 129.6 (C(6));
129.2 (C(5′)); 111.6 (C(6′)); 110.7 (C(4′)); 108.0 (C(2′));
105.7 (C(5)); 103.4 (C(1)); 99.4 (C(3)). EI-MS (70 eV): 245
(3, [M + 1]+); 244 (21, [M]+); 199 (3); 137 (9); 136 (100);
109 (18); 80 (10); 68 (3); 53 (4). HR-EI-MS: 244.0853
+
(6); 92 (4). HR-EI-MS: 338.0822 ([M]+, C19H15ClN2O2 ;
Calc. 338.0822). Anal. Calc. for C19H15ClN2O2 (338.79): C,
67.36; H, 4.46; N, 8.27; O, 9.45. Found: C, 67.14; H, 4.75; N,
7.78; O, 9.94.
5.2.22. N-(3-Chloro-2-methylphenyl)salicylamide (29)
A solution of phenyl salicylate (2.14 g, 10.0 mmol), 1,2,4-
trichlorobenzene (2.0 ml) and 3-chloro-2-methylaniline
(1.50 ml, 1.78 g, 12.6 mmol) was heated to 200 °C for 5 h.
The solution, which had turned black, was cooled to room
temperature, and activated charcoal (0.15 g) and 1,2,4-
trichlorobenzene (0.5 ml) were added. The mixture was
heated to 180 °C for 10 min. The mixture was filtered hot
(Celite) and allowed to stand at 4 °C for 72 h, after which a
brown solid had precipitated. The crude 29 was filtered off
and purified by column chromatography using pentane/
dichloromethane (1:1) followed by recrystallization from
ethanol. Yield: 2.02 g (77%), beige powder, m.p.: 195–
196 °C. IR (KBr): 3316w, 3076m, 2863w, 1633s, 1614s,
1575s, 1551m, 1508w, 1456m, 1437m, 1382m, 1322m,
1230s, 1204w, 1157w, 1125w, 773m, 743m, 706w, 644w. 1H
NMR (300 MHz, D6-DMSO): 12.00 (s, 1H, HO–C(2));
10.44 (s, 1H, HN–CO); 8.01 (dd, J = 7.8, 1.6, 1H, H–C(6));
7.72 (d, J = 7.8, 1H, H–C(6′)); 7.48–7.42 (m, 1H, H–C(5));
7.34 (dd, J = 8.0, 1.4, 1H, H–C(3)); 7.27 (pseudo-t, J = 8.0,
1H, H–C(5′)); 7.01 (d, J = 8.3, 1H, H–C(4′)); 7.01–6.95 (m,
1H, H–(C(4)); 2.31 (s, 3H, H3C–C(2′)). 13C NMR (75 MHz,
D6-DMSO): 166.0 (HN–CO); 158.2 (C(2)); 137.7 (C(1′));
133.8 (C(5))*; 133.7 (C(3′))*; 129.6 (C(2′)); 129.5 (C(6));
127.1 (C(5′)); 126.0 (C(3)); 123.7 (C(6′); 119.3 (C(4)); 117.2
(C(4′)); 117.0 (C(1)); 14.9 (H3C–C(2′)). EI-MS (70 eV): 264
(1); 263 (8); 262 (4, [M + H]+); 261 (25, [M]+); 144 (3); 143
(31); 142 (9); 141 (100); 140 (4); 122 (6); 121 (78); 106 (12);
93 (17); 77 (7); 65 (23); 39 (13). Anal. Found: C14H12ClNO2
(C, H, N).
+
([M]+, C13H12N2O3 ; Calc. 244.0848).
5.2.24. N-(3-Hydroxyphenyl)-2-methoxybenzamide (32)
2-Methoxybenzoic acid (3.07 g, 20.2 mmol) was dis-
solved in thionyl chloride (10.0 ml, 137 mmol). DMF (three
drops) was added and the solution heated to boiling for 1 h.
After removal of the excess thionyl chloride, 2-methoxy-
benzoyl chloride (3.33 g, 19.5 mmol) was obtained. To a
solution of this acid chloride (1.30 g, 7.62 mmol) in pyridine
(1 ml) 3-hydroxyaniline (0.832 g, 7.62 mmol) in pyridine
(10 ml) was added. The solution was heated to 130 °C for 4 h.
After removal of the solvent the crude product was purified
by column chromatography using pentane/ethyl acetate (1:1)
followed by crystallization from ethanol/water. Yield: 1.57 g
(31%), colorless solid, m.p.: 159–161 °C. IR (KBr): 3300m,
3108m, 2874w, 2839w, 1610s, 1560s, 1488m, 1446s,
1389m, 1306m, 1275m, 1240s, 1182w, 1159w, 1020w,
878w, 778w, 752m, 691w. 1H NMR (300 MHz, D6-DMSO):
9.99 (s, 1H, HN–CO); 9.39 (s, 1H, HO–C(3′)); 7.62 (dd,
J = 7.6, 1.7, 1H, H–C(6)); 7.49 (pseudo-t, J = 8.0, H–C(5));
7.36 (s, 1H, H–C(2′)); 7.16 (d, J = 8.3, 1H, H–C(3)); 7.13–
7.03 (m, 3H, H–(C(4, 5′, 6′)); 6.49 (dd, J = 9.0, 2.3, 1H,
H–C(4′)); 3.89 (s, 3H, H3C–O). 13C NMR (75 MHz, D6-
DMSO): 164.4 (HN–CO); 157.6, 156.4 (C(2), C(3′)); 140.1
(C(1′)); 131.9 (C(4)); 129.6 (C(6)); 129.3 (C(5)); 125.1
(C(1)); 120.5 (C(3)); 112.0 (C(6′)); 110.6 (C(4′)); 106.8
(C(2′)); 55.9 (H3C–O). EI-MS (70 eV): 244 (4, [M + 1]+);
243 (27, [M]+); 136 (9); 135 (100); 92 (8); 77 (15); 64 (2).
+
HR-EI-MS: 243.0891 ([M]+, C14H13NO3 ; Calc. 243.0895).
5.2.23. 4-Amino-N-(3-hydroxyphenyl)salicylamide (31)
Compound 33 (0.67 g, 1.8 mmol), conc. hydrochloric acid
(5.0 ml), and conc. acetic acid (5.0 ml) were heated to reflux
for 16 h to completely cleave the acetamide and benzyl ether
groups. The now turbid solution was filtered and the mother
liquor adjusted to pH 8 with 6 M sodium hydroxide solution
and extracted with ethyl acetate. The organic phase was dried
over sodium sulfate and the solvent was distilled off to give
31, which was purified by recrystallization from
5.2.25. 4-Acetamido-N-[(3-benzyloxy)phenyl]salicylamide
(33)
To 4-acetamidosalicylic acid [27] (5.37 g, 27.5 mmol)
thionyl chloride (10.0 ml, 16.3 g, 138 mmol) was added at
0 °C. After a slow warm up to room temperature and 2 h of
stirring an additional amount of thionyl chloride (10 ml,
16.3 g, 138 mmol) was added and the reaction mixture was
heated to 50 °C for 3.5 h. After removal of the excess thionyl
chloride, 4-acetamidosalicyloyl chloride was obtained as a

C. Liechti et al. / European Journal of Medicinal Chemistry 39 (2004) 11–26
23
yellow solid. To the latter toluene (30 ml) and a suspension of
3-(benzyloxy)aniline (5.48 g, 27.5 mmol) in toluene were
added and the reaction mixture was stirred for 30 min at room
temperature. Pyridine (4.40 ml) was added to the suspension,
which resulted in an orange solution. After acidification
with 7.5% hydrochloric acid, a brown solid was formed
which was collected by filtration and purified by MPLC
using hexane/ethyl acetate (gradient towards increasing
polarity). Yield: 5.88 g (57%), colorless platelets, m.p.:
226–227 °C.
reflux for 3 h. The excess thionyl chloride was removed
under vacuum. Then benzene (3.2 ml) and a solution of
3-benzyloxyaniline (1.28 g, 6.42 mmol) in benzene (3.2 ml)
were added and the reaction mixture was refluxed for 8 h.
The solvent was evaporated and 2 M hydrochloric acid was
added whereupon a beige precipitate formed, which was
collected by filtration, washed with 2 M hydrochloric acid
and dried under high vacuum to give 2,4-diacetoxy-N-[3-
(benzyloxy)phenyl]benzamide. To this 10% sodium hydrox-
ide (8.0 ml) was added, and the reaction mixture was heated
to 60 °C for 1 h, cooled down to 0 °C and poured onto
ice-cold 2 M hydrochloric acid. The precipitated bright
brown 34 was filtered off, washed with water and purified by
recrystallization from ethanol/water. Yield: 0.945 g (50%),
bright brown powder, m.p.: 147–150 °C. IR (KBr): 3347m,
3065w, 3033w, 1646s, 1598s, 1544s, 1515s, 1491s, 1444s,
1380m, 1255s, 1183s, 1162s, 1028w, 979w, 846w, 773m,
738m, 687m. 1H NMR (300 MHz, D6-DMSO): 12.18 (s, 1H,
HN–CO); 10.11 (s, 1H, HO–C(2)); 7.87 (d, J = 8.6, 1H,
H–C(6)); 7.50–7.35 (m, 6H, O–CH2–C6H5, H–C(2′)); 7.33–
7.24 (m, 2H, H–C(6′), H–C(5′)); 6.78 (m, 1H, H–C(4′)); 6.38
(dd, J = 8.6, 2.3, 1H, H–C(5)); 6.33 (d, J = 2.3, 1H, H–C(3));
5.10 (s, 2H, O–CH2–C6H5). 13C NMR (75 MHz, D6-
DMSO): 167.2, 162.6, 161.4, 158.5 (HN–CO, C(2), C(4),
C(3′)); 139.5 (C(1′)); 137.0 (H5C6–H2C–O); 130.4, 129.4
(C(6′), C(6)); 128.4 (H5C6–H2C–O); 127.8 (H5C6–H2C–O);
127.6 (H5C6–H2C–O); 113.5 (C(5′)); 110.2 (C(4′)); 107.9,
107.7, 107.5 (C(2′), C(5)); 102.8 (C(3)); 69.2 (H5C6–H2C–
O). FAB-MS (NBA): 338 (1, [M + 2H]+); 337 (16, [M + H]+);
336 (70, [M]+); 335 (28); 242 (4); 200 (14); 199 (31); 130 (5);
125 (8); 92 (6); 91 (100); 69 (12); 55 (8). FAB-MS (NBA +
KCl): 376 (1, [M + K + H]+); 375 (2, [M + K]+); 374 (11);
338 (1, [M + 2H]+); 337 (10, [M + H]+); 336 (47, [M]+); 335
(19); 200 (12); 199 (25); 92 (8); 91 (100); 55 (11). Anal.
Found: C20H17NO4 (C, H, N, O).
5.2.25.1. Alternate method. 4-Acetamido-2-acetoxybenzoic
acid [27] (2.08 g, 8.77 mmol) and thionyl chloride (2.00 ml,
3.27 g, 27.5 mmol) were stirred at room temperature for 5 h.
The excess thionyl chloride was removed under vacuum and
pyridine (5 ml) and a solution of 3-(benzyloxy)aniline
(1.75 g, 8.77 mmol) in pyridine (5 ml) were added. The
reaction mixture was stirred at room temperature for 62 h.
Hydrochloric acid (2 M, 60 ml) was added in portions to
bring the pH to 1. The red solid that precipitated was col-
lected by filtration, washed with tert-butyl methyl ether and
purified by column chromatography using hexane/tert-butyl
methyl ether (1:3, gradient towards increasing polarity). An
additional crop of product was obtained from the work-up of
the mother liquor by extraction with cold 2 M sodium hy-
droxide (100 ml), adjusting to pH 8 with 2 M hydrochloric
acid and saturated sodium bicarbonate, extraction with tert-
butyl methyl ether, drying of the organic phase over sodium
sulfate and evaporation of the solvent. Total yield: 1.77 g
(54%).
Data of 33: IR (KBr): 3304w, 3117w, 3051w, 2872w,
2769w, 2706w, 2613w, 1642s, 1610s, 1542s, 1478w, 1448s,
1414s, 1370m, 1293s, 1264s, 1245s, 1190m, 1163m, 1047w,
1028w, 882w, 831w, 757m, 732w, 687w. 1H NMR
(500 MHz, D6-DMSO): 12.00 (s, 1H, HO–C(2)); 10.21 (s,
1H, HN–CO); 10.16 (s, 1H, HN–CO); 7.89 (d, J = 8.7, 1H,
H–C(6)); 7.46–7.44 (m, 3H, H–C(2′), H5C6–H2C–O); 7.42
(d, J = 2.0, 1H, H–C(3)); 7.40–7.37 (m, 2H, H5C6–H2C–O);
7.34–7.31 (m, 1H, H5C6–H2C–O); 7.25 (pseudo-t, J = 8.0,
1H, H–C(5′)); 7.23–7.21 (m, 1H, H–C(6′)); 7.05 (dd, J = 8.8,
2.0, 1H, H–C(5)); 6.78 (ddd, J = 7.6, 2.5, 1.5, 1H, H–C(4′));
5.09 (s, 2H, H5C6–H2C–O); 2.06 (s, 3H, H3C–C). 13C NMR
(125 MHz, D6-DMSO): 169.4 (HN–CO); 166.6 (HN–CO);
159.9 (C(2))*; 159.0 (C(3′))*; 144.5 (C(4)); 139.8 (C(1′));
137.5 (H5C6–H2C–O); 130.2 (C(6)); 130.0 (C(6′)); 128.9
(H5C6–H2C–O); 128.3 (O–CH2–C6H6); 128.1 (O–CH2–
C6H6); 113.8 (C(5′)); 112.1 (C(1)); 110.7 (C(4′)); 110.2
(C(5)); 108.0 (C(2′)); 106.7 (C(3)); 69.6 (H5C6–H2C–O);
24.6 (H3C–C). EI-MS (70 eV): 377 (5, [M + H]+); 376 (19,
[M]+); 268 (4); 200 (11); 199 (66); 178 (25); 136 (18); 109
(5); 92 (10); 91 (100); 80 (5); 65 (7); 43 (5). Anal. Found:
C22H20N2O4 (C, H, N, O).
5.2.27. N-(3-Hydroxyphenyl)-2-methoxy-4-(4-nitrophenyl)-
benzamide (35)
A solution of the acid 40 (76 mg, 0.28 mmol) in thionyl
chloride (1.0 ml, 1.6 g, 14 mmol) and one drop of DMF was
heated to reflux for 70 min. After cooling to room tempera-
ture, the excess thionyl chloride was removed under vacuum
to give 81 mg of the corresponding acid chloride as a yellow
solid, m.p.: 225–238 °C, which was used without further
purification. To this acid chloride (0.20 g, 0.68 mmol)
3-aminophenol (0.074 g, 0.68 mmol) and pyridine (12 ml)
were added. The mixture was heated to boiling for 3.5 h, then
cooled to 0 °C and acidified with hydrochloric acid (2 N,
30 ml). The precipitate obtained was filtered off, dried in
vacuo and purified by suspending it twice in chloroform
(5 ml) followed by decantation.Yield: 160 mg (60%), yellow
powder, m.p.: 304.0–307.5 °C. IR (KBr): 3323m, 1649s,
1606s, 1567s, 1515s, 1478m, 1452s, 1399m, 1343s, 1306m,
1282s, 1217s, 1182m, 1160m, 1017w, 849m, 770w, 750w,
685m. 1H NMR (300 MHz, D6-DMSO): 10.06 (s, 1H,
HN–CO); 9.40 (s, 1H, HO–C(3′)); 8.34 (d, J = 8.8, 2H,
5.2.26. N-[3-(Benzyloxy)phenyl]-4-hydroxysalicylamide
(34)
2,4-Diacetoxybenzoic acid [29] (0.776 g, 3.26 mmol) and
thionyl chloride (1.16 ml, 1.90 g, 16.0 mmol) were heated to

24
C. Liechti et al. / European Journal of Medicinal Chemistry 39 (2004) 11–26
H–C(3″, 5″)); 8.07 (d, J = 8.6, 2H, H–C(2″, 6″)); 7.75 (d,
J = 7.7, 1H, H–C(6)); 7.52 (s, 1H, H–C(3)); 7.47 (d, J = 8.0,
1H, H–C(5)); 7.36 (s, 1H, H–C(2′)); 7.11–7.07 (m, 2H,
H–C(5′), H–C(6′)); 6.50 (m, 1H, H–C(4′)); 4.02 (s, 3H,
H3C–O). 13C NMR (75 MHz, D6-DMSO): 163.9 (HN–CO);
157.6 (C(2)); 156.9 (C(3′)); 147.1 (C(1″)); 145.8 (C(4″));
141.3 (C(4)); 140.0 (C(1′)); 130.4 (C(5′)); 129.3 (C(6));
128.3 (C(2″, 6″)); 125.5 (C(1)); 124.0 (C(3″, 5″)); 119.4
(C(5)); 110.9 (C(6′)); 110.5 (C(4′)); 106.8 (C(2′))*; 106.7
(C(3))*; 56.2 (H3C–O). EI-MS (70 eV): 365 (9, [M + H]+);
364 (32, [M]+); 257 (26); 256 (100); 242 (3); 241 (3); 226 (4);
211 (5); 210 (30); 153 (2); 152 (9); 151 (4); 140 (3); 139 (14);
109 (7). Anal. Found: C20H16N2O5 (C, H, N, O).
13C NMR (125 MHz, D6-DMSO): 165.8 (HN–CO); 158.7,
157.6 (C(3′, 2)); 147.1 (C(4″)); 145.3 (C(1″)); 142.5 (C(4));
139.1 (C(1′)); 130.1 (C(5′)); 129.4 (C(6)); 128.1 (C(2″, 6″));
124.1 (C(3″, 5″)); 118.0 (C(1)); 117.9 (C(5)); 115.6 (C(3));
111.5 (C(6′)); 111.4 (C(4′)); 108.0 (C(2′)). EI-MS (70 eV):
352 (1, [M + 2H]+); 351 (4, [M + H]+); 350 (17, [M]+); 349
(2); 348 (4); 320 (3); 243 (6); 242 (38); 215 (4); 212 (8); 197
(4); 196 (23); 140 (4); 139 (14); 110 (8); 109 (100). HR-EI-
+
MS: 350.0918 ([M]+, C19H14N2O5 ; Calc. 350.0903).
5.2.29. 4-(4-Aminophenyl)-N-(3-hydroxyphenyl)salicylamide
(37)
Amide 36 (35 mg, 0.10 mmol) was suspended in ethanol
(10 ml) and platinum dioxide (aq., 10 mg) was added. After
shaking overnight under hydrogen, the dark yellow suspen-
sion was concentrated to half its volume. tert-Butyl methyl
ether and 1 N sodium hydroxide solution were added, and the
mixture was filtered through Celite. The aqueous phase of the
filtrate was acidified with conc. HCl to pH 6 and left over-
night at 4 °C. Extraction with tert-butyl methyl ether gave
after evaporation a brown solid which was purified by heat-
ing it in a mixture of water (5 ml) and DMSO (1 ml) to
100 °C. After filtration of the hot turbid solution, 37 precipi-
tated upon cooling and was collected by filtration. Yield:
31 mg (97% containing a slight impurity), yellow solid, m.p.:
236–239 °C. IR (KBr): 3373m, 3326m, 3036w, 1605s,
1546s, 1494s, 1449m, 1406m, 1347m, 1314m, 1265m,
1192m, 1159w, 856w, 818w, 770w, 687w. 1H NMR
(500 MHz, D6-DMSO): 12.05 (s, 1H, HO–C(2)); 10.23 (s,
1H, HN–CO); 9.46 (s, 1H, HO–C(3′)); 7.99 (d, J = 8.3, 1H,
H–C(6)); 7.43 (d, J = 8.6, 2H, H–C(2″, 6″)); 7.28 (pseudo-t,
J = 2.1, 1H, H–C(2′)); 7.17 (dd, J = 8.4, 1.8, 1H, H–C(5));
7.14 (pseudo-t, J = 8.0, 1H, H–C(5′)); 7.10 (d, J = 1.8, 1H,
H–C(3)); 7.08 (ddd, J = 8.1, 1.8, 1.0, 1H, H–C(6′)); 6.64 (d,
J = 8.6, 2H, H–C(3″, 5″)); 6.54 (ddd, J = 8.0, 2.3, 1.0, 1H,
H–C(4′)); 5.41 (s, 2H, H2N–C(4″)). 13C NMR (125 MHz,
D6-DMSO): 166.7 (HN–CO); 159.5 (C(2)); 157.6 (C(3′));
149.4 (C(4″)); 146.0 (C(4)); 139.2 (C(1′)); 129.4 (C(5′))*;
129.3 (C(6))*; 127.5 (C(2″, 6″)); 125.4 (C(1″)); 116.0 (C(1));
114.0 (C(5)); 113.9 (C(3″, 5″)); 112.9 (C(3)); 111.6 (C(6′));
111.2 (C(4′)); 108.0 (C(2′)). EI-MS (70 eV): 321 (11, [M +
1]+); 320 (44, [M]+); 292 (9); 290 (10); 213 (19); 212 (100);
211 (21); 183 (8); 156 (9); 154 (10); 109 (45); 80 (12).
5.2.28. N-(3-Hydroxyphenyl)-4-(4-nitrophenyl)salicylamide
(36)
5.2.28.1. Method 1: with boron tribromide-dimethyl sulfide
complex. To 1,2-dichloroethane (10 ml) were added boron
tribromide-dimethyl sulfide complex (0.66 g, 2.1 mmol) and
amide 35 (90 mg, 0.25 mmol). After heating the light brown
suspension to boiling for 24 h, the suspension, which had
turned dark brown, was cooled to room temperature, and
water (10 ml) was added. The mixture was stirred for 3 d at
room temperature and then partitioned between tert-butyl
methyl ether (120 ml) and sodium hydroxide (2 N, 120 ml).
The aqueous phase was washed with tert-butyl methyl ether
(50 ml), acidified with conc. hydrochloric acid to pH 1, and
re-extracted with tert-butyl methyl ether (150 ml). The or-
ganic extract was dried over sodium sulfate and the solvent
distilled off. Yield: 64 mg (74%), beige solid, m.p.: 277–
282 °C.
5.2.28.2. Method 2: with boron tribromide. To a suspen-
sion of amide 35 (193 mg, 0.530 mmol) in abs. dichlo-
romethane (5 ml) was added a 1 M solution of boron tribro-
mide in dichloromethane (5.00 ml, 12.4 g, 4.77 mmol). The
suspension was stirred for 24 h at room temperature. Water
(5 ml) was added and the stirring continued for another
15 min. Dichloromethane (50 ml) was added and the mixture
was extracted with 1 N sodium hydroxide solution (100 ml).
The aqueous phase was acidified with conc. hydrochloric
acid to pH 1 and, after standing overnight at 4 °C, the bright
brown raw product had precipitated and was collected by
filtration and dried in vacuo. Yield: 140 mg (76%), beige
amorphous solid.
+
HR-EI-MS: 320.1159 ([M]+, C19H16N2O3 ; Calc.
320.1161).
Data of 36: IR (KBr): 3455–2500w, 1604s, 1562m, 1512s,
1492m, 1433m, 1397m, 1343s, 1272m, 1202m, 1160m,
1109w, 955w, 916w, 853m, 774w, 750m, 685w. H NMR
(500 MHz, D6-DMSO): 12.15 (s, 1H, HO–C(2)); 10.39 (s,
1H, HN–CO); 9.50 (s, 1H, HO–C(3′)); 8.33 (d, J = 8.9, 2H,
H–C(3″, 5″)); 8.13 (d, J = 8.2, 1H, H–C(6)); 7.99 (d, J = 9.0,
2H, H–C(2″, 6″)); 7.41 (d, J = 1.7, 1H, H–C(3)); 7.37 (dd,
J = 8.2, 1.8, 1H, H–C(5)); 7.31 (pseudo-t, J = 2.1, 1H,
H–C(2′)); 7.16 (pseudo-t, J = 7.9, 1H, H–C(5′)); 7.13–7.10
(m, 1H, H–C(6′)); 6.57 (ddd, J = 7.8, 2.3, 1.2, 1H, H–C(4′)).
5.2.30. Methyl 2-methoxy-4-(4-nitrophenyl)benzoate (39)
To methyl 4-bromo-2-methoxybenzoate (38) [28]
(720 mg, 3.10 mmol), 1,3-dioxolane (1.0 ml), and a catalyti-
cal amount of tetrakis-(triphenylphosphine)palladium(0)
was added a solution of trimethyl(4-nitrophenyl)stannane
[30] (999 mg, 3.50 mmol) in 1,3-dioxolane (1.5 ml). The
yellow solution was heated to reflux for 24 h whereupon the
color of the solution changed to dark brown. After the addi-
tion of water (2.5 ml) the solution was extracted with tert-
butyl methyl ether. The organic phase was washed with
1

C. Liechti et al. / European Journal of Medicinal Chemistry 39 (2004) 11–26
25
water, dried over sodium sulfate and evaporated to a solid,
which was purified by column chromatography using
pentane/tert-butyl methyl ether (4:1). Yield: 438 mg (49%),
yellow powder, m.p.: 150–152 °C. IR (KBr): 3103w, 2954w,
2922w, 2851w, 1712s, 1596s, 1564m, 1513s, 1480m, 1431s,
1394m, 1348s, 1297s, 1258s, 1226s, 1188m, 1142m, 1103m,
IR (KBr): 3340m, 3079w, 3033w, 2935w, 1770s, 1659s,
1592s, 1521s, 1480s, 1403m, 1373m, 1307m, 1231m, 1190s,
1094m, 933m, 885w, 856w, 780m, 678m. 1H NMR
(300 MHz, D6-DMSO): 10.57 (s, 1H, HN–CO); 7.86
(pseudo-t, J = 1.9, 1H, H–C(2′)); 7.65–7.61 (m, 3H, H–(C(6),
H–C(5), H–C(3)); 7.57 (d, J = 8.2, 1H, H–C(6′)); 7.38
(pseudo-t, J = 8.1, 1H, H–C(5′)); 7.17 (ddd, J = 8.0, 2.1, 1.0,
1H, H–C(4′)); 2.21 (s, 3H, H3C–C). 13C NMR (75 MHz,
CDCl3): 168.6 (HN–CO); 162.8 (H3C–CO); 148.1 (C(2));
138.6 (C(1′)); 134.9 (C(3′)); 131.0 (C(5)), 130.2 (C(5′));
129.9 (C(6)); 127.2 (C(4)); 126.7 (C(3)); 125.8 (C(1)); 124.9
(C(4′)); 120.0 (C(2′)); 117.8 (C(6′)); 21.0 (H3C–CO).
FAB-MS (NBA): 372 (15); 371 (14); 370 (58); 369 (25); 368
(44); 367 (14, [M]+); 330 (24); 329 (22); 328 (100); 327 (43);
326 (79); 325 (24); 243 (15); 241 (14); 201 (46); 199 (48);
127 (30); 77 (13); 43 (54). Anal. Found: C15H11BrClNO3 (C,
H, N, O).
1
1025m, 848m, 778w, 752m, 696w. H NMR (300 MHz,
CDCl3): 8.32 (dd, J = 2.0, 6.0, 2H, H–C(3′, 5′)); 7.92 (d,
J = 8.0, 2H, H–C(6)); 7.75 (dd, J = 2.0, 6.8, 1H, H–C(2′, 6′));
7.22 (dd, J = 1.6, 8.0, 1H, H–C(5)); 7.17 (d, J = 1.6, 1H,
H–C(3)); 4.00 (s, 3H, H3C–O); 3.93 (s, 3H, H3C–O). 13C
NMR (75 MHz, CDCl3): 166.1 (C=O); 159.6 (C(2)); 147.6
(C(1′)); 144.0 (C(4′)); 132.5 (C(4)); 128.1 (C(6)); 124.1
(C(2′, 6′)); 120.3 (C(3′, 5′)); 119.2 (C(5)); 111.0 (C(3)); 56.2
(H3C–O); 52.2 (H3C–O). EI-MS (70 eV): 290 (1); 289 (2);
288 (15, [M + H]+); 287 (68, [M]+); 271 (2); 270 (7); 259 (2);
258 (15); 257 (24); 256 (100); 255 (18); 254 (66); 228 (4);
227 (7); 226 (21); 211 (9); 210 (45); 153 (7); 152 (23); 151
(12); 140 (7); 139 (33); 63 (7). Anal. Found: C15H13NO5 (C,
H, N, O).
5.3. Kinase assays
Purification of protein kinases and in vitro enzyme tests
were performed as previously described [14–16] using
poly(E4Y) (2 µg ml–1) and [33P]ATP (0.4 µM) as substrates.
All compounds were dissolved in DMSO and diluted in
buffer giving a final DMSO concentration of 1% in the assay.
IC50 values represent averages of at least three determina-
tions. Genistein (IC50 = 1 µM) and the dianilinophthalimide
CGP52411 (IC50 = 1 µM) served as an internal standard
inhibitor in all EGFR kinase assays [31,32].
5.2.31. 2-Methoxy-4-(4-nitrophenyl)benzoic acid (40)
Benzoate 39 (515 mg, 1.79 mmol), methanol (120 ml),
and 6% potassium hydroxide solution (120 ml) were heated
to reflux for 3 h. The greenish solution was cooled to room
temperature and a precipitate formed. The mixture was acidi-
fied with 6 M hydrochloric acid to pH 1 and the solid
collected by filtration and dried in vacuo. Yield: 485 mg
(99%), yellow solid, m.p.: 235–238 °C. IR (KBr): 3446m,
3080w, 2925m, 2856w, 1691s, 1597m, 1562m, 1514s,
1461w, 1422w, 1394m, 1344s, 1313m, 1260s, 1225m,
1
1099m, 1018m, 851w. H NMR (300 MHz, D6-DMSO):
Acknowledgements
12.71 (s, 1H, COOH); 8.33 (d, J = 8.8, 2H, H–C(3′, 5′)); 8.06
(d, J = 8.8, 2H, H–C(2′, 6′)); 7.77 (d, J = 8.0, 1H, H–C(6));
7.46 (s, 1H, H–C(3)); 7.40 (dd, J = 1.5, 1H, H–C(5)); 3.95 (s,
3H, H3C–O). 13C NMR (75 MHz, D6-DMSO): 166.9
(COOH); 158.5 (C(2)); 147.1 (C(1′))*; 145.6 (C(4′))*; 142.3
(C(4))*; 131.4 (C(6)); 128.3 (C(2′, 6′)); 124.0 (C(3′, 5′));
121.5 (C(1)); 119.0 (C(5)); 111.4 (C(3)); 56.0 (H3C–O).
EI-MS (70 eV): 275 (2); 274 (18); 273 (100, [M]+); 257 (9);
256 (20); 255 (6); 254 (9); 245 (6); 244 (38); 243 (7); 227
(12); 226 (32); 210 (11); 182 (7); 168 (11); 154 (18); 153
(13); 152 (22); 151 (14); 140 (9); 139 (34); 63 (7). Anal.
Found: C14H11NO5 (C, H, N, O).
This work was supported by the Swiss National Science
Foundation (Grant No. 2000-063344).
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