Replacement of the quinoline system in 2-phenyl-4-quinolinecarboxamide NK-3 receptor antagonists

Article abstract of DOI:10.1016/S0014-827X(99)00043-9

Results from a medicinal chemistry approach aimed at replacing the quinoline ring system in the potent and selective human neurokinin-3 (hNK-3) receptor antagonists 1-4 of general formula I are discussed. The data give further insight upon the potential NK-3 pharmacophore. In particular, it is highlighted that both the benzene-condensed ring and the quinoline nitrogen are crucial determinants for optimal binding affinity to the hNK-3 receptor. Some novel compounds maintained part of the binding affinity to the receptor (5, 6, 10 and 13) and compound 5, featuring the naphthalene ring system, appears to be suitable for further modifications: it offers the option to introduce electron-withdrawing groups at position 2 and 4, conferring on the ring an overall electron-deficiency similar to that of the quinoline.

Full text of DOI:10.1016/S0014-827X(99)00043-9

www.elsevier.nl/locate/farmac
Il Farmaco 54 (1999) 364–374
Replacement of the quinoline system in
2-phenyl-4-quinolinecarboxamide NK-3 receptor antagonists
G.A.M. Giardina a,*, M. Artico a, S. Cavagnera a, A. Cerri a, E. Consolandi a,
S. Gagliardi a, D. Graziani a, M. Grugni a, D.W.P. Hay b, M.A. Luttmann b,
R. Mena a, L.F. Raveglia a, R. Rigolio a, H.M. Sarau b, D.B. Schmidt b,
G. Zanoni a,1, C. Farina a
a Department of Medicinal Chemistry, SmithKline Beecham S.p.A., Via Zambeletti, 20021-Baranzate, Milan, Italy
b Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road,
King of Prussia, PA 19406-0939, USA
Received 2 September 1998; accepted 20 March 1999
Abstract
Results from a medicinal chemistry approach aimed at replacing the quinoline ring system in the potent and selective human
neurokinin-3 (hNK-3) receptor antagonists 1–4 of general formula I are discussed. The data give further insight upon the
potential NK-3 pharmacophore. In particular, it is highlighted that both the benzene-condensed ring and the quinoline nitrogen
are crucial determinants for optimal binding affinity to the hNK-3 receptor. Some novel compounds maintained part of the
binding affinity to the receptor (5, 6, 10 and 13) and compound 5, featuring the naphthalene ring system, appears to be suitable
for further modifications; it offers the option to introduce electron-withdrawing groups at position 2 and 4, conferring on the ring
an overall electron-deficiency similar to that of the quinoline. © 1999 Elsevier Science S.A. All rights reserved.
Keywords: Tachykinins; Neurokinin B; Neurokinin-3 receptor antagonists; 2-Phenyl-4-quinolinecarboxamides
NKA for NK-2 and NKB for NK-3 receptors [2]. The
initial focus of the research in this area was mainly on
NK-1 and NK-2 receptors for which potent and selec-
tive non-peptide antagonists have been available since
1991 [3,4]. Only recently, potent and selective ‘peptoid’
and non-peptide NK-3 receptor antagonists from di-
verse chemical classes [5–11] appeared in the literature
and provided improved reagents to assist in the clarifi-
cation of the physiological and pathophysiological role
of NK-3 receptors and the potential therapeutic utility
of selective NK-3 receptor antagonists [12,13]. Our
group recently described 2-phenyl-4-quinolinecarbox-
amides 1–4 of general formula I in Table 1 as potent
and selective hNK-3 receptor antagonists [10] and out-
lined the medicinal chemistry strategy employed to
generate the prototype leads from modifications of
potent NK-1 receptor antagonists [10,11].
1. Introduction
At least three distinct seven transmembrane G
protein-coupled receptors, named neurokinin-1 (NK-1),
neurokinin-2 (NK-2) and neurokinin-3 (NK-3), mediate
the pharmacological actions of tachykinins [1]. These
small neuropeptides share the common carboxy-termi-
nal sequence (Phe–X–Gly–Leu–Met–NH2) and are
present in the CNS and peripheral nervous system; in
the latter, a prominent source of the tachykinins are
sensory nerves. The main mammalian tachykinins are
substance P (SP), neurokinin A (NKA) and neurokinin
B (NKB) and, although they interact with all three
neurokinin receptors, SP is more selective for NK-1,
* Corresponding author. Tel.: +39-02-38062265; fax: +39-02-
38062606.
E-mail address: giuseppe giardina@sbphrd.com (G.A.M. Giar-
–
One of the strategies utilized in the lead optimization
process was the replacement of the quinoline system in
compounds 1–4 by other aromatic (hetero)cycles com-
dina)
1 Present address: Organic Chemistry Department, University of
Pavia, Viale Taramelli 10, 27100 Pavia, Italy.
0014-827X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(99)00043-9

G.A.M. Giardina et al. / Il Farmaco 54 (1999) 364–374
365
2. Chemistry
prising one or two fused rings, resulting in compounds
5–17 (Tables 1 and 2). The present paper describes
chemical syntheses and structure–activity relationships
(SARs) of compounds 5–17, utilizing the radioligand
binding affinity to the hNK-3 receptors stably ex-
pressed in CHO cell lines, as an index of biological
activity (displacement of [125I]–MePhe7–NKB binding).
Synthetic procedures for compounds 1–8 in Table 1
have already been reported [11]. Compound 9 was
prepared according to Scheme 1. Commercially avail-
able N-phenacylpyridinium bromide (18) and 3-benzoyl
acrylic acid (19) were refluxed in a 10:1 mixture of
acetic acid and acetic anhydride in the presence of a
large excess of AcONH4, as described by Blumbergs et
al. [14], to produce 2,6-diphenylpyridine-4-carboxylic
acid (20) which was coupled with 1-phenylpropylamine
in the presence of dicyclohexylcarbodiimide (DCC) and
1-hydroxybenzotriazole (HOBT) to yield the desired
secondary amide 9.
Table 1
Chemical structures and radioligand binding affinities to the human
neurokinin-3 receptor expressed in CHO cells (hNK-3-CHO) of com-
pounds 1–14 of general formula I a,b
Compound 10 was prepared as shown in Scheme 2.
Thus, Guareschi condensation of nitroacetamidine (21)
[15,16] with ethyl 2,4-dioxo-4-phenylbutanoate (22) in
refluxing EtOH resulted in high yields of ethyl 2-amino-
3-nitro-6-phenylpyridine-4-carboxylate (23), which was
transformed into the diamine 24 by catalytic hydro-
genation of the nitro function.
The six-membered fused pyrazine ring was incorpo-
rated by condensation of 24 with a masked dialdehyde,
the 2,3-dihydroxy-1,4-dioxane, producing ethyl 6-
phenylpyrido[2,3-b]pyrazine-8-carboxylate (25) [17].
Subsequent hydrolysis of the ester function under basic
conditions and coupling reaction with (S)-(−)-1-
phenylpropylamine afforded the desired secondary
amide 10.
Compounds 11 and 12 were prepared as shown in
Scheme 3. The five-membered fused imidazole ring was
incorporated by refluxing 24 (Scheme 2) in triethyl-
orthoformate [15,18]. Acidic hydrolysis of the ester 27
produced
5-phenyl-3H-imidazo[4,5-b]pyridine-7-car-
boxylic acid, which was transformed into the final
amide 11 under the usual condensation conditions.
a Inhibition of [125I]MePhe7–NKB binding in hNK-3-CHO cell
membranes [24,25].
b Average of three to eight independent determinations (n=3–8),
unless otherwise indicated in parentheses.
Scheme 1. (a) AcOH/Ac2O, (10:1), AcONH4, 100°C, 5 h; (b) DCC,
HOBT, (9)-Ph(Et)CHNH2, THF/MeCN (1:1), r.t., 20 h.

366
G.A.M. Giardina et al. / Il Farmaco 54 (1999) 364–374
Table 2
Chemical structures and radioligand binding affinities to the human neurokinin-3 receptor expressed in CHO cells (hNK-3-CHO) of compounds
15–17 of general formula II
hNK-3-CHO binding a
Compd.
X
Y
R
*
Formula
24H20N2O3
C25H24N2O
C24H22N2O
Ki9SEM (nM) b
15
16
17
H
H
Ph
Ph
CH2Ph
H
COOMe
Et
Et
(R,S)
(R,S)
(R,S)
C
\10000 (1)
3079955
\10000 (1)
a Inhibition of [125I]MePhe7–NKB binding in hNK-3-CHO cell membranes [24,25].
b Average of three to eight independent determinations (n=3–8), unless otherwise indicated in parentheses.
Finally, regioselective methylation [19] of 11 with MeI
and NaH in DMF afforded the 3-Me analogue 12.
Compound 13 was prepared according to the syn-
thetic procedure described in Scheme 4. The a,b-unsat-
urated ester 30 was obtained through the condensation
of acetophenone 28 with glyoxylic acid, esterification
and subsequent dehydration by p-toluenesulfonic acid
in toluene at reflux. Reaction of compound 30 with
cyclohexanone and AcONH4 in refluxing toluene af-
forded the 5,6,7,8-tetrahydroquinoline (31) which, after
basic hydrolysis, was condensed with (S)-(−)-1-
phenylpropylamine to give compound 13.
ing free acid. In the final coupling reaction, N-(3-
dimethylaminopropyl) - N% - ethylcarbodiimide hydro-
chloride (WSC) was used as the condensing agent to
produce compound 16.
1-Phenylindole (39) was prepared in quantitative
yield by a modified Ullmann reaction, featuring the
Cu2Br2-promoted indole N-arylation in N-methyl-
pyrrolidone (NMP) and PhI at 170°C, as described in
Scheme 8 [22]. Analogously to Scheme 7, the introduc-
tion of the 3-carboxylic function was achieved by the
use of triphosgene. A standard coupling reaction pro-
duced compound 17.
Condensation of ethyl benzoylpiruvate and 4-
aminouracil (33) in refluxing acetic acid afforded ethyl
2,4-dioxo-7-phenyl-1,2,3,4-tetrahydropyrido[2,3-d]pyri-
midine-5-carboxylate (34) as shown in Scheme 5. Basic
hydrolysis and coupling with (R,S)-1-phenylpropyl-
amine provided compound 14.
Chemical structures and binding affinities of the in-
dole derivatives 15–17 of general formula II are re-
ported in Table 2.
The 2-phenylindole derivative 15 was obtained in low
yield by stirring 2-phenylindole (35) with trichloro-
methyl chloroformate in toluene in the presence of a
stoichiometric amount of pyridine [20]; the non-isolated
acyl chloride intermediate was then treated with a
DMF solution of methyl phenylglycinate and Et3N, as
shown in Scheme 6.
A slightly modified procedure (Scheme 7), entailing
the use of triphosgene [bis(trichloromethyl)carbonate]
in a mixture of pyridine and CH2Cl2 as the solvent, was
employed in the case of 2-benzylindole (36), in turn
prepared by following the procedure of Burger and
Bringhen [21]. The carboxylic acid derivative 37 was
isolated in 48% yield by stirring the acyl chloride inter-
mediate with 5% NaHCO3 and Et2O overnight and
then transforming the sodium salt into the correspond-
3. Pharmacology
Cloning and expression of the hNK-3 receptor in
CHO stable cell line were performed as described by
Buell et al. [23] and recently modified by Sarau and
co-workers [24]. Receptor binding assay was performed
with crude membranes. For NK-3 receptor competition
binding studies,
[
125I]–[MePhe7]–NKB binding to
hNK-3-CHO membranes was performed using the pro-
cedure of Sadowski and co-workers [25]. Concentra-
tion–response curves for compounds 1–17 were run
using duplicate samples; among them, compounds
which gave an IC50 binding affinity lower than 1000 nM
in the first experiment were run in three to eight inde-
pendent experiments (n=3–8). Specific binding was
determined by subtracting total binding from non-spe-
cific binding, which was assessed as the binding in the
presence of 0.5 mM cold [MePhe7]–NKB. Percent inhi-
bition of specific binding was determined for each
concentration of the compounds and the IC50, defined
as the concentration required to inhibit 50% of the
specific binding, obtained from concentration–response

G.A.M. Giardina et al. / Il Farmaco 54 (1999) 364–374
367
lective hNK-3 receptor antagonists [10], we decided to
explore in more detail the bicyclic quinoline scaffold as
part of an expanded chemical program for lead opti-
mization. The aromatic nuclei that were investigated
first were those having a (6,6) membered ring system
featuring the benzene condensed ring (in Table 1, A=
benzene, compounds 5–7). The naphthalene derivative
5 and the quinazoline 6 showed a 28–40-fold lower
affinity for hNK-3 receptors compared to the quinoline
corresponding compound, whereas the isoquinoline 7
was far less potent (\320-fold lower affinity). Thus,
the presence of the quinoline nitrogen appears to be
necessary for high hNK-3 binding affinity, whereas the
extra nitrogen in position 3 of the aromatic system is
clearly detrimental; this latter effect might be due to a
negative interaction with the receptor or to the stabi-
lization of an unfavored conformation of the 4-carbox-
amide side chain.
Then, we investigated the role of the condensed
benzene ring (A) by three major approaches: elimina-
tion of this moiety, which gave rise to unsubstituted
pyridines (e.g. 8); benzene-substitution, which produced
the phenyl-substituted pyridine 9, and replacement of
the condensed benzene by various (heteroaromatic)-
cycles (compounds 10–14). The substantial decrease in
hNK-3 binding affinity observed with the pyridines 8
and 9 might indicate that a ring fused to the pyridine
nucleus is crucial for affinity. Since incorporation of
either electron-deficient (i.e. pyrazine) or electron-rich
(i.e. imidazole) rings resulted in the poorly active com-
pounds 10–12, it is possible that the presence of the
basic aromatic nitrogen(s) is responsible for the marked
decrease observed in hNK-3 binding affinity. The im-
portance of the aromatic character of ring A was
assessed through the synthesis of the tetrahydro deriva-
tive 13, which showed an 80-fold reduced binding
affinity. Also, other polar heterocyclic rings, such as the
2,4-dioxo-1,2,3,4-tetrahydropyrimidine, are not toler-
ated (see compound 14).
Scheme 2. (a) 95% EtOH, reflux, 20 h; (b) H2, 10% Pd/C, 95%
EtOH/THF, (1:1), 22 h; (c) 2,3-dihydroxy-1,4-dioxane, 95% EtOH, 30
h; (d) KOH, EtOH/H2O (1:1), reflux, 3 h; then 1 N HCl; (e) DCC,
HOBT, (S)-(−)-Ph(Et)CHNH2, THF/MeCN (1:1), r.t., 15 h.
curves. Values reported in Tables 1 and 2 are the
apparent inhibition constant (Ki), which was calculated
from the IC50 as described by Cheng and Prusoff [26].
4. Results and discussion
Following the discovery of compounds 1–4 possess-
ing the 2-phenylquinoline backbone as potent and se-
Another approach investigated was the replacement
of the (6,6) by a (6,5) aromatic system, and the indole
ring was chosen as the most suitable substitute for the
quinoline (compounds 15–17, Table 2). However, ei-
ther the most immediate modification 15 or the intro-
duction of a methylene spacer between the indole and
the 2-phenyl ring 16, or the 1-phenyl substitution 17
(both maintaining the same number of atoms between
the phenyl substituent and the amidic carbonyl as in the
quinoline) failed to produce compounds with main-
tained hNK-3 binding affinity. The low affinity of all
the indole derivatives in Table 2 might be due either to:
(i) the presence of the five-membered ring that alters the
relative geometry of the 2-phenyl substituent in respect
to the 4-carboxamide side chain and/or (ii) the absence
of a basic nitrogen that was demonstrated to be of
particular importance in the (6,6) series.
Scheme 3. (a) HC(OEt)3, reflux, 24 h; (b) 6 N HCl, reflux, 5 h; (c)
DCC, HOBT, Et3N, (S)-(−)-Ph(Et)CHNH2, THF/MeCN (1:1), r.t.,
9 h; (d) MeI, 60% NaH, DMF, 2 h.

368
G.A.M. Giardina et al. / Il Farmaco 54 (1999) 364–374
Scheme 4. (a) Glyoxylic acid, NaOH, MeOH/H2O (1:1), r.t., 24 h; (b) 1. NaHCO3, MeI, DMF, 18 h; 2. PTSA, PhMe, reflux, 1 h; (c)
cyclohexanone, AcONH4, PhMe, reflux, 4 h; (d) NaOH, 95% EtOH, overnight; (e) DCC, HOBT, (S)-(−)-Ph(Et)CHNH2, THF/MeCN (1:1), r.t.,
16 h.
5. Conclusions
recorded in Nujol mull on sodium chloride disks or
in KBr with a Perkin–Elmer 1420 spectrophotometer;
mass spectra were obtained on a Finnegan MAT
TSQ-700 spectrometer. Optical rotations were deter-
mined in MeOH solution at the indicated concentra-
tion with a Perkin–Elmer 341 polarimeter at the
sodium D-line. Silica gel used for flash column chro-
matography was Kiesegel 60 (230–400 mesh) (E.
Merck AG, Darmstadt, Germany). Evaporations were
performed at reduced pressure, and all oily products
were dried at 0.1 mbar for 16 h. Combustion elemen-
tal analyses were performed at Redox snc, Milan,
Italy. Analyses indicated by the symbols of the ele-
ments were within 90.4% of theoretical values. Syn-
theses of compounds 1–8 are reported elsewhere [11].
Methyl 3-benzoylacrylate (30) was prepared following
the same procedure described by Bennet and Mason
[27] for methyl 3-pivaloylacrylate. Ethyl benzoylpyru-
vate (22) was prepared according to Batt and
Houghton [28].
In conclusion, these data indicate that the quinoline
ring, far from being a mere scaffold for spacing and
correctly orienting the 2-phenyl and the 4-carboxam-
ido substituents, is an essential moiety for optimal
binding affinity to the hNK-3 receptor. In fact, al-
though some novel compounds maintained part of
the binding affinity to the hNK-3 receptor (5, 6, 10
and 13), none of the 13 aromatic nuclei exploited
resulted in similar potency to that of the quinoline
corresponding compounds. However, the naphthalene
ring system (compound 5) appears to be the most
promising and workable framework; it offers the op-
tion for further substitution at the carbons in position
2
and 4, particularly with electron-withdrawing
groups able to mimic the electron-deficiency of the
quinoline ring. In addition, investigation of the opti-
mal substitution pattern of the benzene-condensed
ring (A) offers room for further improvement in
hNK-3 binding affinity.
Taken collectively, these and previously published
data [13] further refine an hypothesis of the NK-3
pharmacophore, helpful in the design of novel potent
compounds from diverse chemical classes.
6. Experimental
6.1. Chemistry
Melting points were determined with a Bu¨chi 530
hot stage apparatus and are uncorrected. Proton
NMR spectra were recorded on a Bruker ARX 300
spectrometer at 303 K unless otherwise indicated.
Chemical shifts were recorded in parts per million (l
units) downfield from tetramethylsilane (TMS); NMR
spectral data are reported as a list. IR spectra were
Scheme 5. (a) AcOH reflux, 20 h; (b) 1. KOH, 95% EtOH, 3 h; 2.
(9)-Ph(Et)CHNH2, Et3N, HBTU, CH2Cl2/CH3CN (1:1), 4 h.

G.A.M. Giardina et al. / Il Farmaco 54 (1999) 364–374
369
Scheme 6. (a) 1. ClCOOCCl3, pyridine, PhMe, r.t., 4 h; 2. (R,S)-
methyl phenyl glycinate, Et3N, DMF, 0°C to r.t., overnight.
6.1.1. 2,6-Diphenylpyridine-4-carboxylic acid (20)
A stirred mixture of N-phenacylpyridinum bromide
(18, 6 g, 20.0 mmol), benzoylacrylic acid (19, 11.1 g,
20.0 mmol), AcOH (40 ml), Ac2O (4 ml), and NH4OAc
(24.0 g, 310 mmol) was refluxed for 5 h. The hot
mixture was then diluted with water (150 ml), allowed
to cool, and filtered. The solid was washed with water
and dissolved in a warm aqueous solution of K2CO3
(200 ml, 0.14 M). The brown solution was extracted
with CH2Cl2 (3×20 ml) and Et2O (2×50 ml) and then
acidified with 37% HCl to pH 2 and filtered. The solid
product was washed with water and evaporated to
dryness to obtain the crude acid 20, which was crystal-
lized from EtOH (2.9 g, 50%), m.p. 279–281°C. IR
(KBr): 3448, 3280–2690, 2658, 2598, 2534, 1700, 1564
Scheme 8. (a) PhI, Cu2Br2, Na2CO3, NMP, 170°C, 6 h; (b) triphos-
gene, pyridine, DCM, 2 h, then MeOH, r.t., 2 h; (c) 1. 40% KOH,
MeOH, 100°C, 0.5 h, 2. WSC, HOBT, (9)-Ph(Et)CHNH2, THF/
CH3CN (1:1), r.t., overnight.
(eluting with EtOAc/n-hexane, 15:85) to give the title
compound 23 (1.9 g, 66%). IR (KBr): 3461, 3308, 1729,
1615, 1562, 1453, 1373, 1351, 1252, 1211, 1033, 840,
1
773, 703 cm−1; H NMR (DMSO-d6): l 8.19–8.11 (m,
2H), 8.01 (s br, 2H), 7.59–7.49 (m, 3H), 7.41 (s, 1H),
4.35 (q, J=6.8 Hz, 2H), 1.31 (t, J=6.8 Hz, 3H);
EI-MS (source 180°C, 70 eV, 200 mA): m/z 287 (M+),
140, 104, 65.
1
cm−1; H NMR (DMSO-d6): l 13.80 (s br, 1H), 8.27
(m, 4H), 8.24 (m, 2H), 7.60–7.48 (m, 6H).
6.1.3. Ethyl 2,3-diamino-6-phenyl-4-
6.1.2. Ethyl 2-amino-3-nitro-6-phenyl-4-
pyridincarboxylate (24)
pyridincarboxylate (23)
The nitropyridine 23 (2.9 g, 10 mmol) was dissolved
in a mixture of 95% EtOH (100 ml) and THF (100 ml)
and hydrogenated with 10% Pd/C (210 mg) at 60 psi for
22 h at room temperature (r.t.). The solution was
filtered through a Celite pad, and the solid was washed
with additional THF. The filtrate was concentrated to
provide the diaminopyridine 24 (2.5 g, quantitative),
which was used without any further purification. IR
(KBr): 3402, 1640, 1620, 1610, 1430, 1213, 775, 698
To a solution of nitroacetamidine [15,16] (21, 1.24 g,
12 mmol) in 95% EtOH (50 ml), ethyl benzoylpyruvate
[28] (22, 2.23 g, 10 mmol) was added; the mixture was
refluxed for 20 h and then evaporated to dryness. The
residue was purified by flash column chromatography
cm−1 1H NMR (DMSO-d6): l 7.85 (d, J=6.7 Hz,
;
2H), 7.38 (s, 1H), 7.37 (dd, J=6.7, 6.7 Hz, 2H), 7.24
(dd, J=6.7, 6.7 Hz, 1H), 6.55 (s br, 2H), 6.10 (s br,
2H), 4.30 (q, J=6.8 Hz, 2H), 1.31 (t, J=6.8 Hz, 3H);
EI-MS (source 180°C, 70 eV, 200 mA): m/z 257 (M+),
183, 155, 140.
6.1.4. Ethyl 6-phenylpyrido[2,3-b]pyrazine-8-
carboxylate (25)
To a solution of diaminopyridine 24 (2.22 g, 8.6
mmol) in 95% EtOH (90 ml), 2,3-dihydroxy-1,4-diox-
ane (1.0 g, 8.3 mmol) was added and the mixture was
stirred for 36 h at r.t. The suspension thus obtained was
filtered and the solid was crystallized from EtOAc/
n-hexane to give the pyrazine derivative as a light green
Scheme 7. (a) Triphosgene, pyridine, CH2Cl2, 3 h; then 5% NaHCO3,
Et2O, overnight; (b) WSC, HOBT, (9)-Ph(Et)CHNH2, THF/
CH3CN (1:1), r.t., overnight.

370
G.A.M. Giardina et al. / Il Farmaco 54 (1999) 364–374
1
powder (0.94 g, 40%), m.p. 171–172°C. IR (KBr): 2990,
1582, 1536, 1460, 1294, 1030, 766, 692 cm−1; H NMR
1
1728, 1604, 1374, 1246 cm−1; H NMR (DMSO-d6): l
(DMSO-d6): l 9.15 (d, J=8.2 Hz, 1H), 8.28 (s, 2H),
8.26 (d, J=6.6 Hz, 4H), 7.60–7.49 (m, 6H), 7.44 (d,
J=7.4 Hz, 2H), 7.36 (dd, J=7.4, 7.4 Hz, 2H), 7.25
(dd, J=7.4, 7.4 Hz, 1H), 5.20 (dt, J=8.2, 8.2 Hz, 1H),
1.91 (dq, J=8.2, 7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H);
ESI POS-MS (solvent MeOH, spray 4.5 kV, skimmer
60 eV, capillary 220°C): m/z 393 (MH+), 415 (MNa+);
Anal. (C27H24N2O): C, H, N.
9.20 (d, J=2.5 Hz, 1H), 9.07 (d, J=2.5 Hz, 1H), 8.69
(s, 1H), 8.39 (m, 2H), 7.60 (m, 3H), 4.49 (q, J=6.8 Hz,
2H), 1.40 (t, J=6.8 Hz, 3H); EI-MS (source 180°C, 70
eV, 200 mA): m/z 279 (M+), 207.
6.1.5. 6-Phenylpyrido[2,3-b]pyrazine-8-carboxylic acid
(26)
The pyrazine ester 25 was suspended in water (10 ml)
and 85% KOH (0.3 g, 4.55 mmol) was added. The
mixture was heated at 80°C for 2 h, the basic solution
was then acidified with 1 N HCl (7 ml) and the solid
thus obtained was filtered, dried and utilized without
any further purification (1.12 g, 97%). IR (KBr): 3824–
3452, 1730, 1608, 1551, 1473, 1389, 1328, 1204, 1048,
6.1.9. (S)-N-(h-Ethylbenzyl)-6-phenylpyrido[2,3-b]-
pyrazine-8-carboxamide (10)
Eluent CH2Cl2/EtOAc (98:2); 94% yield; light brown
needles, m.p. 126–127°C from i-Pr2O/i-PrOH. [a]2D0=
−7 (c=0.53, MeOH). IR (KBr): 3060, 2930, 1666,
1598, 1542, 1486, 1456, 1376, 1184, 784, 696 cm−1; H
1
1
875, 760, 630 cm−1; H NMR (DMSO-d6): l 14.10 (s
NMR (DMSO-d6): l 9.81 (d, J=8.5 Hz, 1H), 9.24 (d,
J=2.2 Hz, 1H), 9.12 (d, J=2.2 Hz, 1H), 8.66 (s, 1H),
8.36 (m, 2H), 7.65–7.56 (m, 3H), 7.48 (d, J=7.8 Hz,
2H), 7.37 (dd, J=7.8, 7.8 Hz, 2H), 7.26 (dd, J=7.8,
7.8 Hz, 1H), 5.10 (dd, J=8.2, 7.3 Hz, 1H), 1.88 (dq,
J=7.3, 7.3 Hz, 2H), 0.99 (t, 7.3 Hz, 3H); EI-MS
(source 180°C, 70 eV, 200 mA): m/z 368 (M+), 339,
234, 206, 179, 152, 134, 103; Anal. (C23H20N4O): C, H,
N.
br, 1H), 9.21 (d, J=2.5 Hz, 1H), 9.08 (d, J=2.5 Hz,
1H), 8.66 (s, 1H), 8.42–8.36 (m, 2H), 7.65–7.58 (m,
3H).
6.1.6. Ethyl 5-phenyl-3H-imidazo[4,5-b]pyridine-7-
carboxylate (27)
A mixture of crude diamine 24 (2.57 g, 10 mmol) and
triethylorthoformate (100 ml) was heated under reflux
for 18 h and then evaporated to dryness. The residue
was purified by flash column chromatography (eluting
with a gradient mixture of CH2Cl2/i-PrOH) to give the
imidazole derivative 27 (0.94 g, 66%). IR (KBr): 3336,
3084, 2984, 1730, 1695, 1636, 1584, 1480, 1465, 1372,
6.1.10. (S)-N-(h-Ethylbenzyl)-2-phenyl-3H-imidazo-
[4,5-b]pyridine-4-carboxamide (11)
The corresponding acid was easily obtained in quan-
titative yield by acidic hydrolysis (6 N HCl, reflux, 5 h)
of the ester 27; eluent PhMe/EtOAc (85:15); 50% yield,
light brown powder, m.p. 166–168°C from PhMe/
n-hexane. [a]2D0= +3.8 (c=0.56, MeOH). IR (KBr):
3298, 2967, 2812, 1670, 1558, 1476, 1381, 1279, 929,
1
1177, 1128, 930, 755 cm−1; H NMR (DMSO-d6): l
12.89 (s br, 1H), 8.61 (s, 1H), 8.19 (s, 1H), 8.15 (d,
J=7.2 Hz, 2H), 7.53 (dd, J=7.2, 7.2 Hz, 2H), 7.45
(dd, J=7.2, 7.2 Hz, 1H), 4.51 (q, J=7.2 Hz, 2H), 1.42
(t, J=7.2 Hz, 3H); EI-MS (source 180°C, 70 eV, 200
mA): m/z 267 (M+), 195, 166, 140.
1
755, 700 cm−1; H NMR (DMSO-d6, 353 K): l 13.3 (s
br, 1H), 9.65 (s br, 1H), 8.60 (s br, 1H), 8.25 (s, 1H),
8.11 (d, J=7.7 Hz, 2H), 7.52 (dd, J=7.7, 7.7 Hz, 2H),
7.45 (d, J=7.7 Hz, 2H), 7.43 (dd, J=7.7, 7.7 Hz, 1H),
7.37 (dd, J=7.7, 7.7 Hz, 2H), 7.26 (dd, J=7.7, 7.7 Hz,
1H), 5.12 (dt, J=8.2, 7.7 Hz, 1H), 1.98 (dq, J=7.7, 7.7
Hz, 2H), 0.99 (t, J=7.7 Hz, 3H); EI-MS (source
180°C, 70 eV, 200 mA): m/z 356 (M+), 327, 222, 194,
140, 134; Anal. (C22H20N4O): C, H, N.
6.1.7. General procedure for the synthesis of amides
(9–11)
To a solution of the corresponding carboxylic acid in
THF/MeCN (1:1, 10 ml/mmol of substrate) DCC (1.5
eq), Et3N (2 eq) and HOBT (1.5 eq) were added. After
1 h at r.t., 1-phenylpropylamine (2 eq) was added and
the reaction mixture stirred overnight. The residue was
evaporated to dryness, dissolved in EtOAc (15 ml/
mmol), washed with 10% HCl, brine, dried over anhy-
drous Na2SO4 and finally evaporated to dryness. The
light brown oil thus obtained was purified by flash
column chromatography. Elution solvents, yields, crys-
tallization solvents and physico–chemical data for com-
pounds 9–11 are reported below.
6.1.11. (S)-N-(h-Ethylbenzyl)-3-methyl-5-
phenylimidazo[4,5-b]pyridine-7-carboxamide (12)
To a DMF solution (3 ml) of compound 11 (215 mg,
0.6 mmol), 60% NaH (27 mg, 0.67 mmol) was added.
The homogeneous solution was stirred at r.t. under
nitrogen for 2 h; MeI (0.06 ml, 0.96 mmol) was then
added and the solution was stirred for additional 2 h.
Solid NH4Cl (1 g) was added and the solvent evapo-
rated to dryness. The residue was taken-up in EtOAc
and the suspension filtered; the light brown oil obtained
after solvent evaporation was crystallized from i-Pr2O
to give the methyl derivative 12 (0.18 g, 78%), m.p.
6.1.8. N-(h-Ethylbenzyl)-2,6-diphenylpyridine-4-
carboxamide (9)
Eluent EtOAc/n-hexane (10:90); 20% yield; white
powder, m.p. 217–218°C. IR (KBr): 3450, 3290, 1634,

G.A.M. Giardina et al. / Il Farmaco 54 (1999) 364–374
371
162–163°C. [a]2D0= +1.1 (c=0.51, MeOH). IR (KBr):
mmol) was added and the mixture was stirred at r.t.
until complete dissolution of the reagents occurred. The
solution was cooled to 0°C and DCC (0.64 g, 3.1
mmol) dissolved in CH2Cl2 (4 ml) was added. The
mixture was stirred at r.t. for 15 min, then left
overnight. Water (0.5 ml) was added under stirring and
after 15 min the suspension was filtered off. The solu-
tion was evaporated to dryness. The residue was dis-
solved in EtOAc and washed with 5% NaOH and brine.
The organic phase was dried over Na2SO4, filtered, and
evaporated to dryness. Crystallization of the crude
product from a mixture of i-Pr2O/Me2CO (1:1) yielded
13 as white crystals (0.4 g, 35%), m.p. 147–148°C.
[a]2D0= −6.8 (c=0.56, MeOH). IR (KBr): 3311, 1032,
3304, 1666, 1586, 1504, 1426, 1358, 1260, 756, 644
cm−1 1H NMR (DMSO-d6): l 9.85 (d, J=9.0 Hz,
;
1H), 8.75 (s, 1H), 8.25 (s, 1H), 8.16 (d, J=7.8 Hz, 2H),
7.54 (dd, J=7.8, 7.8 Hz, 2H), 7.47 (dd, J=7.8, 7.8 Hz,
1H), 7.42 (d, J=7.3 Hz, 2H), 7.37 (dd, J=7.3, 7.3 Hz,
2H), 7.27 (dd, J=7.3, 7.3 Hz, 1H), 5.12 (dt, J=9.0, 7.3
Hz, 1H), 3.98 (s, 3H), 1.94 (dq, J=7.3, 7.3 Hz, 2H),
0.95 (t, J=7.3 Hz, 3H) [18]; ESI POS-MS (solvent
MeOH, spray 4.5 kV, skimmer 60 eV, capillary 220°C):
m/z 371 (MH+), 393 (MNa+); ESI DAU+371 (colli-
sion gas: Argon): m/z 254, 226, 208; Anal.
(C23H22N4O): C, H, N.
1
2935, 1638, 1590, 1528 cm−1; H NMR (DMSO-d6): l
6.1.12. 4-Methoxycarbonyl-2-phenyl-5,6,7,8-
tetrahydroquinoline (31)
8.89 (d, J=8.4 Hz, 1H), 8.04 (d, J=6.5 Hz, 2H), 7.55
(s, 1H), 7.51–7.32 (m, 7H), 7.25 (m, 1H), 4.92 (dt,
J=8.4, 8.4 Hz, 1H), 2.92 (t, J=6.3 Hz, 2H), 2.70 (t,
J=6.3 Hz, 2H), 1.89–1.69 (m, 6H), 0.92 (t, J=7.2 Hz,
3H); ESI POS-MS (solvent MeOH, spray 4.5 kV, skim-
mer 60 eV, capillary 220°C): m/z 371 (MH+); ESI
DAU+371 (collision gas: argon): m/z 371, 253, 208,
180; Anal. (C25H26N2O): C, H, N.
In a round bottomed flask provided with a Dean
Stark apparatus, cyclohexanone (10 ml, 96.5 mmol),
methyl 3-benzoylacrylate [27] (30, 1.9 g, 10 mmol),
AcONH4 (3.85 g, 50 mmol) were refluxed in toluene (50
ml) for 4 h, azeotroping water. After evaporation of the
solvent, the residue was dissolved in Et2O and washed
with water; the organic phase was dried over Na2SO4
and evaporated to dryness. The crude product was
purified by flash column chromatography (eluting with
Et2O/n-hexane, 2:8) yielding 31 as a dark oil which
solidified on standing (0.6 g, 22%). IR (KBr): 2938,
2862, 1732, 1589, 1551 cm−1; 1H NMR (CDCl3): l 8.00
(d, J=6.7 Hz, 2H), 7.89 (s, 1H), 7.50–7.34 (m, 3H),
3.92 (s, 3H), 3.05 (dd, J=6.3, 6.3 Hz, 4H), 2.00–1.80
(m, 4H).
6.1.15. Ethyl 2,4-dihydroxy-7-phenylpyrido[2,3-d]-
pyrimidine-5-carboxylate (34)
A stirred mixture of ethyl benzoylpyruvate (22, 1.1 g,
5 mmol), 4-amino-2,6-dihydroxypyrimidine (33, 0.63 g,
5 mmol) and glacial AcOH (15 ml) was heated at 90°C
for 20 h. The mixture was then evaporated to dryness
and the residue triturated with Et2O yielding 34 as a
white powder (1.1 g, 70%), m.p.\275°C. IR (KBr):
1
3168, 3052, 1728, 1674, 1578 cm−1; H NMR (DMSO-
6.1.13. 4-Carboxy-2-phenyl-5,6,7,8-tetrahydroquinoline
(32)
d6): l 11.83 (s br, 1H), 11.50 (s br, 1H), 8.20 (m, 2H),
7.85 (s, 1H), 7.55 (m, 3H), 4.38 (q, J=7.2 Hz, 2H),
1.31 (t, J=7.2 Hz, 3H); ESI POS-MS (solvent MeOH,
spray 4.5 kV, skimmer 60 eV, capillary 220°C): m/z 312
(MH+), 334 (MNa+); ESI DAU+312 (collision gas:
argon): m/z 311, 266, 248, 197, 168.
To a solution of 31 (2.5 g, 9.4 mmol) in 95% EtOH
(100 ml), 80% pellets KOH (2.5 g, 35.6 mmol) was
added and the solution was stirred for one night at r.t.
The solvent was evaporated, the residue was dissolved
in water and washed with Et2O. The aqueous phase was
acidified with 5 N HCl and extracted with CH2Cl2; the
organic phase was dried over Na2SO4 and evaporated
to dryness. Treatment of the crude product with Et2O
afforded 32 as a slightly pink powder (1.8 g, 75%), m.p.
182–186°C. IR (KBr): 3421, 2937, 1712, 1588, 1551
6.1.16. (R,S)-N-(h-Ethylbenzyl)-2,4-dihydroxy-7-
phenylpyrido[2,3-d]pyrimidine-5-carboxamide (14)
To a solution of compound 34 (7.0 g, 22.5 mmol) in
95% EtOH (70 ml), 80% pellets KOH (1.0 g, 17.8
mmol) was added and the mixture was stirred at r.t.
until complete dissolution of the reagents occurred. The
solvent was evaporated, then the residue dissolved in
water and the solution extracted twice with Et2O. The
aqueous phase was acidified to pH 4 with 6 N HCl and
the precipitate was filtered, washed with water and
dried, yielding a white powder (6.1 g, 95%). The crude
carboxylic acid (2.85 g, 10 mmol) and Et3N (2.8 ml, 20
mmol) were dissolved in a mixture of MeCN/CH2Cl2
(1:1) (200 ml). HBTU (4.55 g, 12 mmol) and (R,S)-1-
phenylpropylamine (1.35 g, 10 mmol) were added and
the mixture was stirred at r.t. for 6 h. The solvent was
1
cm−1; H NMR (DMSO-d6): l 13.50 (s br, 1H), 8.05
(d, J=7.2 Hz, 2H), 7.91 (s, 1H), 7.52–7.39 (m, 3H),
2.96 (dd, J=6.3, 6.3 Hz, 4H), 1.90–1.74 (m, 4H); ESI
NEG-MS (solvent MeOH, spray 4.5 kV, skimmer −60
eV, capillary 220°C): m/z 252 (M−H)−; 505 (2M−
H)−; (CID Offset=32 eV): m/z 252, 208.
6.1.14. (S)-N-(h-Ethylbenzyl)-2-phenyl-5,6,7,8-
tetrahydroquinoline-4-carboxamide (13)
To a solution of 32 (0.9 g, 3.1 mmol) in THF/MeCN
(1:1, 10 ml), (S)-1-phenylpropylamine (0.84 g, 6.2

372
G.A.M. Giardina et al. / Il Farmaco 54 (1999) 364–374
evaporated and the residue dissolved in EtOAc. The
organic phase was washed with water, 5% NaHCO3,
brine, dried over Na2SO4 and evaporated to dryness.
The residue was purified by flash column chromatogra-
phy (eluting with EtOAc) and crystallized from i-PrOH
yielding 14 as a white powder (0.7 g, 17%), m.p.
301–302°C. IR (KBr): 3344, 3184, 3060, 1724, 1656,
(CDCl3): l 8.20 (d, J=8.5 Hz, 1H), 8.08 (s br, 1H),
7.40–7.12 (m, 8H), 4.61 (s, 2H); EI-MS (source 180°C,
70 eV, 200 mA): m/z 251 (M+), 233, 204, 102.
6.1.19. (R,S)-N-(h-Ethylbenzyl)-2-benzyl-3-
indolecarboxamide (16)
To a solution of 37 (0.42 g, 1.67 mmol) in THF/
MeCN (1:1, 10 ml), WSC (N-(3-dimethylaminopropyl)-
N%-ethylcarbodiimide) (0.32 g, 1.67 mmol) and HOBT
(1-hydroxybenzotriazole) (0.23 g, 1.67 mmol) were
added. After 1 h at r.t., (R,S)-1-phenylpropylamine
(0.23 g, 1.67 mmol) was added and the reaction mixture
was stirred overnight. The residue was evaporated to
dryness, dissolved in EtOAc (15 ml), washed with 10%
HCl (10 ml), saturated solution of K2CO3 (10 ml), brine
(10 ml), dried over Na2SO4 and evaporated to dryness.
Treatment with n-hexane and filtration afforded 16
(0.41 g, 1.11 mmol, 67%) as white powder; m.p. 105–
1
1570, 1532 cm−1; H NMR (DMSO-d6): l 11.30 (s br,
2H), 8.41 (d br, J=8.0 Hz, 1H), 8.12 (m, 2H), 7.53 (m,
3H), 7.46 (s, 1H), 7.41 (d, J=7.1 Hz, 2H), 7.34 (dd,
J=7.1, 7.1 Hz, 2H), 7.23 (dd, J=7.1, 7.1 Hz, 1H),
5.00 (dt, J=8.0, 8.0 Hz, 1H), 1.98–1.74 (m, 2H), 0.92
(t, J=7.1 Hz, 3H); ESI POS-MS (solvent MeOH,
spray 4.5 kV, skimmer −60 eV, capillary 220°C): m/z
401 (MH+), 423 (MNa+), 439 (MK+); Anal.
(C23H20N4O3): C, H, N.
6.1.17. (R,S)-N-[h-(Methoxycarbonyl)benzyl]-2-
phenylindole-3-carboxamide (15)
107°C. IR (Nujol): 3400, 1640 cm−1 1H NMR
;
To a solution of 2-phenylindole (35, 1.0 g, 5.1 mmol)
in toluene (20 ml) under nitrogen atmosphere, pyridine
(0.42 ml, 5.2 mmol) and trichloromethyl chloroformate
(0.5 ml, 4.1 mmol) were added. The reaction mixture
was stirred at r.t. for 4 h, then was cooled at 0°C and
(R,S)-methyl 2-phenylglycinate (1.6 g, 9.9 mmol), dis-
solved in DMF (40 ml) and TEA (1.4 ml, 10.2 mmol),
was added dropwise. After stirring at r.t. overnight, the
mixture was evaporated to dryness, dissolved in
CH2Cl2, washed with 1 N HCl, 5% NaHCO3 and brine,
dried over Na2SO4 and evaporated again. The residue
was purified by flash column chromatography (two
columns were necessary, in the first column the eluent
was Et2O/n-hexane/28% NH4OH, 75:25:0.25; in the
second EtOAc/n-hexane/28% NH4OH, 50:50:0.5) to
yield 15 (0.27 g, 14%) as a white solid. IR (KBr):
3460–3120, 3060, 3030, 2920, 1750, 1630, 1580, 1550,
(CDCl3): l 8.01 (s br, 1H), 7.74 (d, J=7.7, 1H),
7.40–7.15 (m, 13H), 6.24 (d br, J=7.0 Hz, 1H), 5.19
(dt, J=7.0, 7.0 Hz, 1H), 4.54 (s, 2H), 2.05–1.90 (m,
2H), 0.99 (t, J=7.9 Hz, 3H); EI-MS (source 180°C, 70
eV, 200 mA): m/z 368 (M+), 249, 234, 204; Anal.
(C25H24N2O): C, H, N.
6.1.20. N-Phenylindole (39)
To a solution of indole (5 g, 42.68 mmol) in NMP
(N-methylpyrrolidone) (88 ml), Cu2Br2 (13 g, 45.35
mmol), Na2CO3 (4.8 g, 45.35 mmol) and iodobenzene
(16 ml, 144.04 mmol) were added and the mixture was
heated at 170°C for 6 h. After cooling to r.t., 5% HCl
(40 ml) and EtOAc (40 ml) were added, and the mixture
was filtered on a Celite pad. The filtrate was separated
and the organic layer was washed with brine (40 ml),
dried over Na2SO4 and evaporated to dryness. The
crude product was purified by flash column chromatog-
raphy, eluting with EtOAc/n-hexane 9:1 to yield 8.2 g
(45.35 mmol, quantitative) of compound 39. IR (neat):
1
1500 cm−1; H NMR (CDCl3): l 8.38 (s br, 1H), 8.23
(m, 1H), 7.66 (m, 2H), 7.50 (m, 3H), 7.42–7.19 (m,
8H), 6.50 (d br, J=7.4 Hz, 1H), 5.77 (d, J=7.4 Hz,
1H), 3.70 (s, 3H); EI-MS (source 180°C, 70 eV, 200
mA): m/z 384 (M+), 325, 220; Anal. (C24H20N2O3): C,
H, N.
1
3056, 1600 cm−1; H NMR (CDCl3): l 7.71 (m, 2H),
7.59 (d, J=7.8 Hz, 1H), 7.40–7.32 (m, 3H), 7.29–7.17
(m, 3H), 7.11 (dd, J=7.8, 7.8 Hz, 1H), 6.70 (d, J=3.1
Hz, 1H); EI-MS (source 180°C, 70 eV, 200 mA): m/z
193 (M+).
6.1.18. 2-Benzyl-3-indolecarboxylic acid (37)
To an ice-cooled solution of 2-benzylindole [21] (36,
1.46 g, 7.04 mmol) in CH2Cl2 (10 ml) under nitrogen
atmosphere, pyridine (0.57 ml, 7.04 mmol) and triphos-
gene (bis(trichloromethyl)carbonate, 2.09 g, 7.04 mmol)
were added. The reaction mixture was allowed to reach
r.t. and stirred overnight. The residue was treated with
5% NaHCO3 (10 ml), Et2O (20 ml) and stirred at r.t.
for 30 min. The organic layer was separated, washed
with 10% HCl (10 ml), brine (10 ml), dried over
Na2SO4 and evaporated to dryness, affording 37 (1.68
g, 6.68 mmol, 95%) as a white powder; m.p. 198–200°C
6.1.21. Methyl N-phenyl-3-indolecarboxylate (40)
To an ice-cooled solution of 39 (1 g, 5.17 mmol) in
CH2Cl2 (10 ml) under nitrogen atmosphere, pyridine
(0.42 ml) and triphosgene (1.53 g, 5.15 mmol) were
added. The reaction mixture was allowed to reach r.t.
and MeOH (20 ml) was added. After stirring for 2 h,
the solvent was evaporated and CH2Cl2 (20 ml) was
added. After washing with 5% NaHCO3 (10 ml) and
brine (10 ml), the mixture was dried over Na2SO4 and
evaporated to dryness, affording 40 (0.74 g, 2.9 mmol,
57%). IR (neat): 3056, 1700, 1600 cm−1; EI-MS (source
;
(dec.). IR (Nujol): 3398, 1600 cm−1 1H NMR

G.A.M. Giardina et al. / Il Farmaco 54 (1999) 364–374
373
180°C, 70 eV, 200 mA): m/z 251 (M+), 220, 193.
165.
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Emonds-Alt, P. Soubrie´, G. Le Fur, Functional characterization
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Meecham, G.S. Ratcliffe, N. Suman-Chauhan, G.N. Woodruff,
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[10] G.A.M. Giardina, H.M. Sarau, C. Farina, A.D. Medhurst, M.
Grugni, J.J. Foley, L.F. Raveglia, D.B. Schmidt, R. Rigolio, M.
Vassallo, V. Vecchietti, D.W.P. Hay, 2-Phenyl-4-quinolinecar-
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[11] G.A.M Giardina, H.M. Sarau, C. Farina, A.D. Medhurst, M.
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V. Vecchietti, D.W.P. Hay, Discovery of a novel class of selec-
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[12] M.C. Pritchard, P. Boden, Tachykinin NK3 receptor: biology
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Drugs Fut. 20 (1995) 1163–1173.
6.1.22. (R,S)-N-(h-Ethylbenzyl)-1-phenyl-3-
indolecarboxamide (17)
A solution of 40 (0.223 g, 0.927 mmol) in MeOH (5
ml) and 40% aqueous KOH (5 ml) was refluxed for 0.5
h, evaporated to dryness, diluted with water (3 ml) and
adjusted to pH 2 with 20% HCl. The precipitate was
filtered and dried under vacuum at 40°C for 3 h,
affording N-phenyl-3-indolecarboxylic acid (0.210 g,
0.885 mmol), which was dissolved in THF/MeCN (1:1,
10 ml) and treated with WSC (N-(3-dimethy-
laminopropyl)-N%-ethylcarbodiimide) (0.170 g, 0.885
mmol) and HOBT (1-hydroxybenzotriazole) (0.12 g,
0.885 mmol). After 1 h at r.t., (R,S)-1-phenylpropy-
lamine (0.12 g, 0.885 mmol) was added and the reaction
mixture was stirred overnight. The residue was evapo-
rated to dryness, dissolved in EtOAc (15 ml), washed
with 10% HCl (10 ml), saturated solution of K2CO3 (10
ml), brine (10 ml), dried over Na2SO4 and evaporated.
Treatment with n-hexane and filtration afforded 17 (0.22
g, 0.62 mmol, 70%) as a light brown powder; m.p.
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[15] D.G. Batt, G.C. Houghton, Polyfunctional pyridines from ni-
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Chem. 32 (1995) 963–969.
173–175°C. IR (Nujol): 3350, 1620, 1600 cm−1 1H
;
NMR (CDCl3): l 8.06–8.00 (m, 1H), 7.86 (s, 1H),
7.57–7.23 (m, 13H), 6.21 (d br, J=7.7 Hz, 1H), 5.21 (dt,
J=7.7, 7.7 Hz, 1H), 2.11–1.91 (m, 2H), 1.01 (t, J=7.2
Hz, 3H); EI-MS (source 180°C, 70 eV, 200 mA): m/z 354
(M+), 325, 236, 220; Anal. (C24H22N2O): C, H, N.
[16] CAUTION: great attention must be paid in each step of the
described preparation of methazonic acid (Ref. [15]), an explo-
sive intermediate in the synthesis of nitroacetamidine 21; in
particular, crude methazonic acid should be maintained in ethe-
real solution after careful in vacuo concentration to a reduced
volume, rigorously performed at a temperature below 20°C.
Acknowledgements
The authors wish to thank Professor L. Merlini for
helpful discussions.
[17] M.C. Venuti, 2,3-Dihydroxy-1,4-dioxane:
a stable synthetic
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