Novel dihydropyrazine analogues as NPY antagonists

Article abstract of DOI:10.1016/S0960-894X(01)00765-X

The dihydropyridine 1 is currently one of the lead compounds in the neuropeptide-Y₁ (NPY-Y₁) receptor antagonist program. Compound 1 is a selective, high affinity ligand at the NPY-Y₁ receptors (IC₅₀=4.2 nM) in SK-N-MC cells. To further expand the SAR study surrounding this dihydropyridine core structure we succeeded in synthesizing an analogous series of dihydropyrazine derivatives 2. This structural modification yielded compounds substantially different from the parent molecules in terms of molecular polarization and electron distribution while the overall molecular structure was generally preserved. This altered property should therefore provide us with additional SAR information on the optimal binding requirement with NPY receptors.

Full text of DOI:10.1016/S0960-894X(01)00765-X

Bioorganic & Medicinal Chemistry Letters 12 (2002) 337–340
Novel Dihydropyrazine Analogues as NPY Antagonists
Sing-Yuen Sit,a,* Yazhong Huang,a Ildiko Antal-Zimanyi,b Sally Wardb and
Graham S. Poindextera
aDepartment of Neuroscience/Genitourinary Drug Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute,
5 Research Parkway, Wallingford, CT 06492-7660, USA
bNeuroscience/Genitourinary Drug Discovery Biology, Bristol-Myers Squibb Pharmaceutical Research Institute,
5 Research Parkway, Wallingford, CT 06492-7660, USA
Received 13 September 2001; accepted 5 November 2001
Abstract—The dihydropyridine 1 is currently one of the lead compounds in the neuropeptide-Y1 (NPY-Y1) receptor antagonist
program. Compound 1 is a selective, high affinity ligand at the NPY-Y1 receptors (IC50=4.2 nM) in SK-N-MC cells. To further
expand the SARstudy surrounding this dihydropyridine core structure we succeeded in synthesizing an analogous series of dihy-
dropyrazine derivatives 2. This structural modification yielded compounds substantially different from the parent molecules in
terms of molecular polarization and electron distribution while the overall molecular structure was generally preserved. This altered
property should therefore provide us with additional SARinformation on the optimal binding requirement with NPY receptors.
# 2002 Elsevier Science Ltd. All rights reserved.
One of the fastest growing public health concerns in
most western societies is the increasing number of over-
weight citizens.1 The cause of obesity is largely believed
to be multifactorial. This metabolic disorder is in part
behavioral, environmental, and has also a significant
genetic linkage. While the etiology of obesity is still
unknown its progression is closely associated with the
unbalance between food intake and net energy expendi-
ture.1 Neuropeptide Y (NPY), a 36 amino acid peptide
that is widely distributed in the central and peripheral
nervous systems, is implicated in a variety of biological
functions including feeding behaviors.
While many 1,4-dihydropyrazine-3,5-dicarboxyl esters
are known in the literature, there is only a handful of
published articles on using dihydropyrazines as a sur-
rogate of dihydropyridine in the study of biologically
active compounds.5,6 In the present study, the core
DHP structure of the lead series (1) was replaced with a
1,4-dihydro-4-phenyl-2,6-dimethyl-3,5-pyrazine (DHPZ)
ring. The desired 2,6-dimethyl substituted pyrazine is
unknown. The procedure of Chorvat and Rorig for the
2,6-unsubstitued pyrazine was attempted with suitable
modifications to accommodate the two methyl groups,
however the result was unacceptable.6 To overcome this
obstacle, a modified synthetic approach which ultilized
2-diazo acetoacetate as the alkylating agent was investi-
gated,7 and was found to be very practical for the
preparation of this class of novel 2,6-disubstituted dihydro-
pyrazine system. The key reaction (Scheme 1) is a rhodium
catalyzed N-alkylation of a nitro aniline derivative with
diazo acetoacetate. In this method, the aniline group of
3-nitroaniline (3a), and 4-fluoro-3-nitroaniline (3b) were
smoothly alkylated by the diazo compound in the presence
of catalytic amount (0.2–0.4 mol%) of rhodium acetate
dimer to give the bis-alkylated anilines (4a and 4b). It is
interesting to point out that the X-ray crystallographic
structure of 4a adopts a classical propeller shape in which
two of the three propeller blades are formed by the rigid
enol H-bonded six-membered acetoacetate rings.8
Antagonists of NPY receptors (and its subtypes) have
long been a pharmaceutical targets aimed as a potential
treatment of obesity.2a,2b Our continuing research in this
area has resulted in several novel series of potent NPY
antagonists, especially antagonists at the Y1 receptor
subtype which included the dihydropyridine (DHP)
derivative 1.3 In an effort to further identify the
key structural elements and to define the pharma-
cological prerequisite of potent and selective NPY
inhibitors, an analogous series of dihydropyrazine
compounds was prepared and screened for their Y1
receptor activity in human neuroblastoma (SK-N-MC)
cells (Fig. 1).4
This bis-alkylated aniline was then cyclized with
ammonium acetate in warm tert-butanol. Isopropanol
*Corresponding author. Tel.: +1-203-677-6678; fax: +1-203-677-
5775/7702; e-mail: sits@bms.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00765-X

338
S.-Y. Sit et al. / Bioorg. Med. Chem. Lett. 12 (2002) 337–340
Figure 1.
Scheme 1.
was found to be undesirable for such transformation
due to the facile ester exchange of the methyl group to
isopropyl group thus complicating the final purification
step. However tert-butanol solvent neatly circumvented
this side reaction. The nitro group in 5a was reduced by
iron powder in the presence of acid and the aniline 6a
was converted into the thioisocyanate using thiocar-
bonyl diimidazole in DMF, the desired product was
isolated by crystallization. Conversion of 7a to the final
cyanoguanidine targets (2a and 2b) was accomplished by
a two step procedure of Tilley and Ramuz.9 The amines
used in the second step were chosen to give products that
are analogous to the products previously prepared in the
dihydropyridine series. Likewise the urea and thiourea
Table 1. NPY Binding affinities of dihydropyrazine derivatives (2a–2g)
Compd
Z
Y
RY
(nM)a
Y1 (nM)a
5.4
<1.0
1
2a
2b
2c
2d
2e
2f
N–CN
N–CN
S
S
S
O
O
CH
CH
CH
CH
N
Ph
tert-Bu
tert-Bu
3-MeOPh
cyclo-Hex
3-MeOPh
cyclo-Hex
268
231
>1000
945
>1000
554
434
b
12.8
132
4.2
CH
N
2g
176
a125I-PYY binding in SK-N-MC cell membranes (IC50).
bThe corresponding dihydropyridine analogue is unavailable for comparison.

S.-Y. Sit et al. / Bioorg. Med. Chem. Lett. 12 (2002) 337–340
339
analogues were prepared from the corresponding isocy-
anate and thioisocyanate precursors. The preparation of
some of these compounds were described elsewhere.3,10
benzene (10 mL) dropwise over a period of 2 h. The resulting
mixture was refluxed until all the diazoacetate was consumed.
After cooling to room temperature, the volatiles were removed
in vacuo and the residue was filtered over silica gel, eluted with
20% v/v ethyl acetate in hexanes. The crude material obtained
from the filtration was subjected to further crystallization to
give 4a as orange crystals (0.95 mmol, 26.3%): mp 146–147 ꢀC;
1H NMR(CDCl 3) d 12.76 (s, 1H), 12.73 (s, 1H), 7.56 (dd, 1H,
J=8.2, 2.0 Hz), 7.41 (t, 1H, J=2.2 Hz), 7.31 (t, 1H, J=8.2
Hz), 6.92 (dd, 1H, J=8.2, 2.4 Hz), 3.74 (s, 6H), and 1.84 (s,
6H); 13C NMR(CDCl 3) d 177.1, 172.4, 149.9, 130.2, 120.0,
113.3, 108.3, 52.0, and 19.6. Anal. calcd for C16H18N2O8: C,
52.46; H, 4.95; N, 7.65. Found: C, 52.31; H, 4.95; N, 7.65.
Likewise 4b was prepared from 4-fluoro-3-nitroaniline (ref 3
or commercially available now) as orange crystals (yield not
determined): mp 161–163 ꢀC; 1H NMR(CDCl 3) d 12.73 (s,
2H), 7.19 (dd, 1H, J=5.9, 3.2 Hz), 7.10 (t, 1H, J=9.5 Hz),
6.86 (dt, 1H, Jd=9.2 Hz, Jt=3.6 Hz), 3.75 (s, 6H), and 1.87 (s,
6H); 13C NMR(CDCl 3) d 177.1, 172.3, 150.0, 146.6, 145.6,
120.0 (d, JF=7.1 Hz), 119.3 (d, JF=22.2 Hz), 109.7, 107.1,
52.0, and 19.6. Anal. calcd for C16H17FN2O8: C, 50.00; H,
4.46; N, 7.29. Found: C, 50.21; H, 4.56; N, 7.28.
At first, it was thought that replacing the DHP ring with
a DHPZ would allow us to explore the SARsurround-
ing the DHP ring system. Such modification could also
render the molecule more resistent toward oxidative
metabolism to give the biologically inactive pyridine
derivative. All the targets in this series were screened in
the standard 125I-PYY binding in intact human neuro-
blastoma (SK-N-MC)4 cells and the results are shown in
Table 1. For the purposes of comparison, the corre-
sponding dihydropyridine (DHP) analogues are also
shown on the right hand panel. As it can be seen from
the table, dihydropyridine parent compounds show
consistently higher binding affinities in the identical
assay. Our results echoed that of Chorvat and Rorig in
which DHPZ analogues of nifedipine-like compounds
failed to show calcium antagonism and vasodilation
activity.6 The failure is believed to be attributed to the
near sp2 nitrogen at the 4-position of DHPZ in which
the 4-phenyl appendage projects into a space less
directly above the DHPZ core. Equally important is the
fact that the dihedral angles of the 4-phenyl ring with
respect to either DHP or DHPZ are substantially dif-
ferent. This result strongly suggests that the drug–
receptor interaction is mainly dictated by the simulta-
neous recognition of the 4-aryl ring fragment and the
DHP moiety. Unfortunately DHPZ is too con-
formationally restricted to be efficiently recognized for
high affinity binding.
5a and 5b: 4a (3.1 mmol) was refluxed with ammonium acetate
(290 mg) in tert-butanol (30 mL) and the reaction was com-
pleted in less than 0.5 h. After chromatography (silica gel,
40% v/v ethyl acetate in hexanes), 750 mg product was iso-
lated as orange foam (69%); 1H NMR(CDCl 3) d 7.66 (dd,
1H, J=8.2, 1.4 Hz), 7.47 (t, 1H, J=2.3 Hz), 7.26 (t, 1H,
J=8.2 Hz), 6.95 (dd, 1H, J=8.2, 2.5 Hz), 6.21 (s, 1H), 3.78 (s,
6H), and 2.45 (s, 6H); 13C NMR(CDCl 3) d 165.6, 151.5,
149.5, 148.9, 129.3, 119.1, 114.6, 108.6, 108.1, 52.0, and 18.1.
ꢁ
Anal. calcd for C16H17N3O6 0.25H2O: C, 54.62; H, 5.01; N,
11.94. Found: C, 54.83; H, 5.22; N, 11.39. Likewise 5b was
prepared from 4b, and the material was isolated as an orange
foam (50%); 1H NMR (CDCl3) d 7.19 (dd, 1H, J=5.9, 3.2 Hz),
7.10 (t, 1H, J=9.5 Hz), 6.86 (dt, 1H, Jd=9.2 Hz, Jt=3.6 Hz),
3.75 (s, 6H), and 1.87 (s, 6H); 13C NMR (CDCl3) d 165.5, 151.2,
149.7, 148.0, 147.1, 120.0 (d, JF=7.1 Hz), 118.2 (d, JF=22.2 Hz),
Acknowledgements
109.9,
108.7,
ꢁ
52.0,
and
18.1.
Anal.
calcd
for
X-ray analysis, microanalyses, IRspectra, and mass
spectra were kindly provided by the Bristol-Myers
Squibb Department of Analytical Research and
Development.
C16H16FN3O6 0.35EtOAcꢁ 0.67H2O: C, 51.20; H, 4.97; N, 10.29.
Found: C, 51.19; H, 4.69; N, 10.29.
6a: 5a (219 mg, 0.63 mmol) was dissolved in 30 mL methanol
containing 3 mL of water in a flask equipped with a mechan-
ical stirrer. Iron powder (300 mg) was added, followed by one
drop of 37% hydrochloric acid. The whole mixture was
refluxed gently with mechanical stirring for 3.5 h. Usual
extractive work up furnished 5a as yellow solid (176 mg, 88%):
mp 212–213 ꢀC; H NMR(CDCl ) d 6.91 (t, 1H, J=8.0 Hz),
6.20 (dd, 1H, J=7.8, 2.0 Hz), 6.11 (dd, 1H, J=8.2, 2.3 Hz), 6.00
(t, 1H, J=2.2 Hz), 5.93 (s, 1H), 3.77 (s, 6H), and 2.38 (s, 6H); 13
References and Notes
1. N. Eng. J. Med. 1998, 338, 1156 (discussion 1158).
2. (a) Zimanyi, I. A.; Poindexter, G. S. Drug Dev. Res. 2000,
51, 94. (b) Gehlert, D. R. Neuropeptides 1999, 33, 329.
3. Poindexter, G. S.; Swann, R. T.; Bruce, M. A.; Morton,
M. A.; Huang, Y.; Sit, S.-Y.; Breitenbucher, J. G. PCT Int.
Appl. WO 9854136 A1 19981203, 1998; Chem. Abstr. 1998,
130, 24976.
1
3
C
NMR(CDCl 3) d 166.8, 152.0, 148.5, 146.9, 129.6, 109.5, 107.8,
104.2, 100.3, 51.8, and 17.9. Anal. calcd for C16H19N3O4: C,
60.56; H, 6.04; N, 13.24. Found: C, 60.05; H, 6.14; N, 12.66.
4. Kodukula, K.; Arcuri, M.; Cutrone, J. Q.; Hugill, R. M.;
Lowe, S. E.; Pirnik, D. M.; Shu, Y. J. Antibiot. 1995, 48, 1055.
5. Wehinger, E.; Kazda, S. Ger. Offen. DE 3400765 A1
19850718, 1985. Chem Abstr. 1985, 104, 5894.
6. Chorvat, R. J.; Rorig, K. J. J. Org. Chem. 1988, 53, 5779.
7. Lee, J. C.; Yuk, J. Y. Synth. Commun. 1995, 25, 1511.
8. X-ray structure by Dr. Qi Gao, PhD Analytical Research
and Development.
9. Tilley, J. W.; Ramuz, H.; Hefti, F.; Gerold, M. J. Med.
Chem. 1980, 23, 1438.
10. Experimental details: 4a and 4b: A mixture of 3-nitroani-
line (3.6 mmol), rhodium acetate dimer (0.0086 mmol) and 10
mL of dry benzene was warmed to reflux. To this was added a
solution of methyl a-acetyl-a-diazoacetate7 (13.0 mmol) in
7a: 6a (3.8 mmol) in 16 mL of DMF was slowly added into
a DMF solution (20 mL) of 1,10-thiocarbonyldiimidazole
(5.2 mmol) and the reaction went to completion in 0.5 h.
After DMF was removed in vacuo, the residue was purified
by chromatography on silica gel eluted with 50% v/v ethyl
acetate in hexanes to give a yellow powder (1.19 g, 87%);
1H NMR(CDCl 3) d 7.09 (t, 1H, J=8.1 Hz), 6.73 (dd, 1H,
J=7.8, 1.9 Hz), 6.59 (dd, 1H, J=8.3, 2.4 Hz), 6.47 (t, 1H,
J=2.1 Hz), 6.06 (s, 1H), 3.79 (s, 6H), and 2.43 (s, 6H); 13C
NMR(CDCl 3) d 166.0, 151.7, 149.1, 131.3, 129.6, 117.7,
112.6, 110.3, 108.9, 52.0, and 18.1. Anal. calcd for
C17H17N3O4Sꢁ 0.2H2O: C, 56.25; H, 4.83; N, 11.58. Found: C,
56.28; H, 4.96; N, 11.11.

340
S.-Y. Sit et al. / Bioorg. Med. Chem. Lett. 12 (2002) 337–340
2a: 7a (144 mg, 0.40 mmol) was added into sodium cyanamide (28
mg, 0.44 mmol) in 3 mL of EtOH and the mixture was stirred for
20 min. EtOH was then removed in vacuo and the resultant foam-
like material was mixed 4-phenyl-piperidine-1-propan-amine3
(105 mg, 0.48 mmol) in 5 mL of THF. The mixture was cooled
down to 0ꢀC and HgCl2 (109 mg) was added. The reaction was
completed in 15 min. After filtration and extraction, the organic
layer was concentrated and purified by chromatography (silica
(s, 6H), 2.25–2.50 (m, 3H), 2.03 (m, 2H), 1.60–1.85 (m, 4H),
1.40–1.60 (m, 2H); 13C NMR(CDCl ) d 166.0, 159.6, 152.5,
149.2, 147.7, 130.2, 129.5, 119.5, 115.8, 113.1, 112.2, 111.1,
3
109.7, 108.8, 63.6, 55.2, 54.2, 51.8, 42.5, 32.8, 25.4, and 18.0.
ꢁ
Anal. calcd for C32H41N5O5S 0.64CH2Cl2 1.31H2O: C, 57.17;
H, 6.60; N, 10.21. Found: C, 57.07; H, 6.19; N, 10.22.
2e: 7a (500 mg, 1.4 mmol) was refluxed with 4-cyclohexyl-1-
piperazine-1-propanamine3 (345 mg, 1.5 mmol) in 8 mL of
benzene for 2 h. Chromatographic purification (silica gel,
100% CH2Cl2 first, followed by 10% v/v MeOH in CH2Cl2) of
gel, eluted with 10% v/v MeOH in CH2Cl2), 6a was isolated as
1
a yellow foam (175 mg, 75%); H NMR(CDCl ) d 7.05–7.35
3
(m, 6H), 6.75 (br, 1H), 6.65 (d, 1H, J=7.5 Hz), 6.58 (d, 1H,
J=8.3 Hz), 6.53 (br, 1H), 5.98 (br, 1H), 3.72 (s, 6H), 3.38 (m,
2H), 2.97 (m, 2H), 2.30–2.55 (m, 3H), 2.39 (s, 6H), 2.03 (m,
2H), 1.65–1.80 (m, 4H), 1.40–1.60 (m, 2H); 13C NMR(CDCl 3)
d 166.2, 152.6, 149.4, 129.9, 128.5, 126.9, 126.3, 118.3, 116.3,
112.5, 110.4, 108.7, 54.1, 51.8, 42.4, 41.0, 32.7, 29.8, 25.6, and
the residue after concentration in vacuo gave 2e as a yellow
1
foam (752 mg, 92%); H NMR(CDCl ) d 7.63 (br, 1H), 7.11
3
(t, 1H, J=8.0 Hz), 6.85 (br, 1H), 6.72 (br, 1H), 6.60 (d, 1H,
J=8.2 Hz), 6.56 (dd, 1H, J=8.3, 2.2 Hz), 6.45 (br, 1H), 3.75
(s, 6H), 3.65 (m, 2H), 2.40 (s, 6H), 2.31 (t, 2H, J=6.6 Hz),
2.20–2.60 (m, 8H), 2.16 (m, 1H), 1.50–1.95 (m, 7H), 1.00–1.30
(m, 5H); 13C NMR(CDCl 3) d 165.9, 152.5, 149.2, 130.1,
112.0, 108.8, 63.6, 53.2, 51.9, 48.7, 29.0, 26.2, 25.8, 25.3, and
18.0. Anal. calcd for C30H44N6O4S 0.58H2O: C, 60.54; H,
7.65; N, 14.12. Found: C, 60.53; H, 7.64; N, 13.57.
ꢁ
ꢁ
17.9. Anal. calcd for C32H39N7O4 0.7CH2Cl2 0.24H2O: C,
60.48; H, 6.34; N, 15.10. Found: C, 60.59; H, 6.71; N, 14.45.
2b: Likewise 2b was prepared from 6a (116 mg, 0.32 mmol)
and 4-tert-butyl-piperidine-1-propanamine3 (77 mg, 0.39
mmol). The desired product was isolated as a yellow foam-like
1
material (130 mg, 72%); H NMR(CDCl ) d 7.41 (br, 1H),
2f: 6a (150 mg, 0.47 mmol) was slowly added into a mixture of
1,10-carbonyldiimidazole (117 mg, 0.72 mmol) and triethyl-
amine (145 mg, 1.44 mmol) in 5 mL of DMF and the reaction
mixture was stirred for 60 min. 4-(3-Methoxyphenyl)-piper-
idine-1-propanamine3 (176 mg, 0.69 mmol) was added into the
reaction mixture, and the reaction was stirred at room tem-
perature for 30 min. DMF was removed in vacuo and the
residue was purified by chromatography (silica gel, 10% v/v
MeOH in CH2Cl2 first, followed by 2 M ammonia in MeOH)
to give 2f as an orange foam (200 mg, 72%); 1H NMR
(CDCl3) d 7.55 (br, 1H), 7.35 (br, 1H), 7.20 (t, 1H, J=7.6 Hz),
6.92 (t, 1H, J=8.1 Hz), 6.60–6.80 (m, 4H), 6.54 (d, 1H, J=7.6
Hz), 6.32 (dd, 1H, J=8.2, 2.0 Hz), 5.99 (br, 1H), 3.77 (s, 3H),
3.71 (s, 6H), 3.16 (m, 2H), 3.03 (m, 2H), 2.46 (m, 3H), 2.29 (s,
6H), 1.95–2.20 (m, 2H), 1.60–1.90 (m, 6H); 13C NMR(CDCl 3)
d 166.6, 159.7, 156.8, 151.9, 149.7, 147.4, 139.4, 129.5, 129.2,
119.3, 112.9, 111.4, 108.9, 108.5, 106.1, 56.0, 55.2, 54.1, 51.7,
42.2, 38.6, 32.8, 26.8, and 17.6. Anal. calcd for
3
7.10 (t, 1H, J=8.0 Hz), 6.60 (d, 2H, J=7.6 Hz), 6.54 (br, 1H),
5.70 (br, 1H), 3.76 (s, 6H), 3.31 (m, 2H), 3.06 (m, 2H), 2.51 (m,
2H), 2.42 (m, 6H), 2.07 (m, 2H), 1.79 (m, 2H), 1.62 (m, 2H),
1.15–1.40 (m, 2H), 1.00 (m, 1H), and 0.80 (s, 6H); 13C NMR
(CDCl3) d 166.3, 149.8, 129.9, 118.1, 116.4, 110.5, 108.5, 54.2,
51.9, 45.9, 40.1, 32.1, 27.3, 25.6, and 17.8. Anal. calcd for
ꢁ
ꢁ
C30H43N7O4 0.4CH2Cl2 0.4H2O: C, 60.16; H, 7.41; N, 16.16.
Found: C, 60.36; H, 7.54; N, 16.19.
2c: 7a (25 mg, 0.069 mmol) was refluxed with 4-tert-butyl-
piperidine-1-propanamine3 (16 mg, 0.081 mmol) in 2 mL of
benzene for 30 min. Chromatographic purification (silica gel,
eluted with 10% v/v MeOH in CH2Cl2) of the resultant residue
after concentration in vacuo gave 2c as a yellow powder
1
(64%); H NMR(CDCl ) d 8.20 (br, 1H), 7.98 (br, 1H), 7.05
3
(t, 1H, J=8.1 Hz), 6.79 (br, 1H), 6.66 (d, 1H, J=8.0 Hz),
6.50–6.60 (m, 2H), 3.70 (s, 6H), 3.55 (m, 2H), 3.28 (m, 2H),
2.72 (m, 2H), 2.30–2.55 (m, 2H), 2.37 (s, 6H), 1.86 (m, 2H),
1.50–1.80 (m, 2H), 0.95–1.25 (m, 1H), and 0.79 (s, 6H); 13C
NMR(CDCl 3) d 180.9, 166.3, 152.8, 150.1, 129.9, 116.3,
112.7, 109.9, 108.5, 53.9, 51.8, 44.9, 42.1, 32.1, 29.8, 27.2, 24.7,
24.5, and 17.8. MS matched for C29H43N5O4S.
ꢁ
ꢁ
C32H41N5O6 0.27CH2Cl2 0.51H2O: C, 62.13; H, 6.88; N,
11.23. Found: C, 62.04; H, 7.06; N, 11.08.
2g: Likewise 2g was prepared from 6a (150 mg, 0.47 mmol)
and 4-cyclohexyl-1-piperazine-1-propanamine3 (160 mg, 0.70
mmol). The desired product was isolated as an orange
foam (210 mg, 78%); 1H NMR(CDCl 3) d 7.20 (br, 1H),
7.00 (t, 1H, J=8.0 Hz), 6.87 (br, 1H), 6.68 (d, 1H,
J=7.7 Hz), 6.59 (m, 1H), 6.39 (dd, 1H, J=8.1, 2.3 Hz),
3.75 (s, 6H), 3.19 (m, 2H), 2.36 (s, 6H), 2.29–2.70 (m,
10H), 2.21 (m, 1H), 1.50–1.95 (m, 7H), 0.95–1.30 (m,
5H); 13C NMR(CDCl 3) d 159.2, 108.8, 63.5, 56.4, 53.6,
49.0, 39.8, 29.0, 26.7, 26.3, 25.9, and 17.8. Anal. calcd
2d: 7a (500 mg, 1.4 mmol) was refluxed with 4-(3-methoxy-
phenyl)-piperidine-1-propanamine3 (380 mg, 1.5 mmol) in 8
mL of benzene for 2 h. Chromatographic purification (silica
gel, 100% CH2Cl2 first, followed by 10% v/v MeOH in
CH2Cl2) of the residue after concentration in vacuo gave 2d as
1
a yellow foam (807 mg, 95%); H NMR(CDCl ) d 7.61 (br,
3
1H), 7.20 (t, 1H, J=7.9 Hz), 7.12 (t, 1H, J=8.1 Hz), 6.88 (br,
1H), 6.60 (m, 3H), 6.57 (dd, 1H, J=8.3, 2.1 Hz), 6.47 (br, 1H),
3.78 (s, 3H), 3.73 (s, 6H), 3.60–3.80 (m, 2H), 2.94 (m, 2H), 2.37
ꢁ
for C30H44N6O5 0.02CH2Cl2 0.73H2O: C, 61.79; H, 7.86;
N, 14.40. Found: C, 61.57; H, 8.39; N, 14.73.