A new synthetic route to YM087, an arginine vasopressin antagonist

Article abstract of DOI:10.3987/COM-04-10025

A new synthesis of N-{4-[(2-methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-6(1H)-yl)carbonyl]phenyl} biphenyl-2-carboxamide monohydrochloride (1, YM087) via new imidazobenzazepine intermediates is described. This method remarkably improves the overall yiel

Full text of DOI:10.3987/COM-04-10025

HETEROCYCLES, Vol. 63, No. 5, 2004, pp. 1113 - 1122
Received, 26th January, 2004, Accepted, 23rd March, 2004, Published online, 26th March, 2004
A NEW SYNTHETIC ROUTE TO YM087, AN ARGININE VASOPRESSIN
ANTAGONIST
Takashi Tsunoda,* Akihiro Tanaka, Toshiyasu Mase, and Shuichi Sakamoto
Chemical Technology Labs., Yamanouchi Pharmaceutical Co., Ltd., 160-2,
Akahama, Takahagi-shi, Ibaraki 318-0001, Japan
E-mail: tsunoda.takashi@yamanouchi.co.jp
Abstract – A new synthesis of N-{4-[(2-methyl-4,5-dihydroimidazo[4,5-
d][1]benzazepin-6(1H)-yl)carbonyl]phenyl}biphenyl-2-carboxamide monohydro-
chloride (1, YM087) via new imidazobenzazepine intermediates is described. This
method remarkably improves the overall yield of 1 compared to the original
synthesis providing a more safe, reliable and cost-efficient approach to 1.
INTRODUCTION
Since the late 1970s, the role of arginine vasopressin (AVP) has been extensively investigated. Michel et
al.1 identified two classes of vasopressin receptor, V1A and V2, and proved that the former mediates
phospholipase C activation and causes the effects of AVP on the cardiovascular system; for example, the
vasoconstrictive effect on arterial smooth muscle. Jard2 showed that the latter mediates adenylate cyclase
and plays a major role in the kidney; for example, the antidiuretic response to AVP that promotes water
reabsorption. In 1994, Naitoh et al.3 reported that the combined administration of vasopressin V1A- and
V2-receptor antagonists confers a more beneficial effect than that produced by each antagonist alone in
dogs with congestive heart failure. Okada et al.4 reported that a combination of vasopressin V1A- and
V2-receptor antagonists produces renal protective effects in rats with progressive renal failure. Scientists
have attempted to develop non-peptide dual arginine vasopressin-receptor antagonists that can be used as
a novel treatment for patients with cardiovascular pathology—in particular congestive heart failure and
renal disease. Yatsu et al.5 revealed that N-{4-[(2-methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-6(1H)-
yl)carbonyl]phenyl}biphenyl-2-carboxamide monohydrochloride (1, YM087; Figure 1) is an antagonist

of both receptors. A significant quantity of 1 was required during drug development and clinical trials, so
studies to identify a more reliable and cost-effective synthetic route to 1 were undertaken.
HN
N
HCl
N
O
O
N
H
1
Figure 1
RESULTS AND DISCUSSION
Matsuhisa et al.6 reported the original synthesis of 1. The overall yield of their route is 5% and that
includes several low-yielding steps in the final stages of the synthesis; in particular, the overall yield of
the last two steps is only 38% (Scheme 1), which might jeopardize the quality of the final product and
result in increased production costs.
O
R
N
ii
O
1
O
N
YM087
H
2, R = H
3, R = Br
i
Reagents: i, CuBr2, CHCl3, AcOEt; ii, ethanimidamide monohydrochloride, K2CO3, MeCN, CHCl3, silica gel chromatography:
CHCl3/MeOH, AcOEt, HCl/AcOEt, EtOH, 38% over two steps.
Scheme 1
Since the original synthesis includes a low-yielding imidazole-ring formation, our strategy aimed to
install this structure in the early stages. A retrosynthetic analysis suggested that the N-substituted
imidazobenzazepine (4) might be a key intermediate for our strategy (Scheme 2).
O
HN
N
COOR
NH2
1
N
N
YM087
-Tos
-Tos
p
p
4
5
6
Scheme 2

The precursor of 4, benzazepinone (5), was envisaged to be accessed by a Dieckmann cyclization of the
N-substituted derivative of 6. The new synthetic pathway to prepare YM087 (1) is outlined in Scheme 3.
O
HN
N
R3
COOMe
iii
vi
R2
N
N
N
R1
R1
R1
6a, R1 = H, R2 = H
9, R1 = p-Tos, R3 = CN
5, R1 = p-Tos, R3 = H
10, R1 = p-Tos, R3 = Br
4, R1 = p-Tos
11, R1 = H
i
iv
v
vii
7, R1 = p-Tos, R2 = H
8, R1 = p-Tos, R2 = (CH2)3CN
ii
HN
N
viii
x
1
N
YM087
O
R4
12, R4 = NO2
ix
13, R4 = NH2
Reagents: i, p-TosCl, pyridine; ii, 4-chlorobutanenitrile, K2CO3, KI, 2-butanone; iii, t-BuOK, DMF; iv, AcOH, HCl; v,
pyridinium hydrobromide perbromide, CHCl3; vi, ethanimidamide monohydrochloride, K2CO3, CHCl3; vii, H2SO4, AcOH; viii,
4-nitrobenzoyl chloride, DMF, pyridine monohydrochloride; ix, H2, Raney nickel, MeOH; x, biphenyl-2-carboxylic acid,
oxalyl chloride, DMF, CH2Cl2, MeCN, pyridine, HCl-AcOEt.
Scheme 3
Although methyl 2-aminobenzoate (6a) was tosylated using the method reported by Proctor and
Thomson,7 diluting the reaction mixture with the antisolvent, water, afforded methyl 2-{[(4-methyl-
phenyl)sulfonyl]amino}benzoate (7) in high purity, improving the yield from 91.0% to 99.8%. The
introduction of the 3-methylene unit to the benzazepine structure was performed using the procedure
reported by Hirota et al.8 with the exception that 2-butanone was used in place of acetone, which
remarkably shortened the reaction time from 7 d to 12 h and conferred a slight improvement in the yield
of methyl 2-{(3-cyanopropyl)[(4-methylphenyl)sulfonyl]amino}benzoate (8) from 95% to 98%. Although
Hirota et al.8 had effected a successful Dieckmann cyclization of 8 with sodium hydride, the handling
difficulty for large-scale synthesis led us to investigate a modified method. The use of potassium
t-butoxide instead of sodium hydride in the Dieckmann cyclization circumvented the risk of hydrogen gas
evolution as well as the need for purification to remove the oil used to disperse sodium hydride. This
improved the yield of 1-[(4-methylphenyl)sulfonyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carbo-
nitrile (9) from 88% in the published method8 to 93%. The proton NMR spectrum of 9 in CDCl3 showed
that the hydrogen at the 4-position was in the keto form. However, the NMR spectrum in DMSO-d6 and
the IR spectrum showed the presence of an OH at the 5-position in the enol form, which is consistent with

the information reported by Hirota et al.8 A comparison of the spectra of 9 and 4-bromo-1-[(4-methyl-
phenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one (10) indicated that 9 was stabilized by an
internal hydrogen bond forming a six-membered ring type structure in both the solid state and DMSO-d6
solution (Scheme 4).9, 10
H
N
N
O
O
N
N
-Tos
-Tos
p
p
9 in DMSO-d6 or solid state
9 in CDCl3
H
O
N
O
Br
Br
N
-Tos
p
-Tos
p
10 in CDCl3, DMSO-d6,
or solid state
Scheme 4
9 was converted to 1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one (5) in good
yield. Bromination of 5 with pyridinium hydrobromide perbromide11 instead of bromine improved both
manipulability and the yield of 10 from 85%12 to 89%. The reaction of 10 with ethanimidamide
monohydrochloride in the presence of potassium carbonate afforded 2-methyl-6-[(4-methyl-
phenyl)sulfonyl]-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine (4) accompanied by the oxazole by-
product 2-methyl-6-[(4-methylphenyl)sulfonyl]-5,6-dihydro-4H-[1,3]oxazolo[4,5-d][1]benzazepine, as
expected.13 The NMR spectrum of 4 in DMSO-d6 showed a three-proton singlet at δ 2.20 and a
one-proton singlet that exchanged in deuterium oxide at δ 11.61. These were attributed to a newly
introduced methyl group and the amine of the imidazole ring, respectively. The presence of the proton of
the imidazole amine and mass spectra distinguished 4 from the oxazole byproduct.
The N-tosyl group of 4 was hydrolyzed using a mixture of sulfuric and acetic acid.14 The NMR spectrum
of 2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine (11) showed the N-H proton of the
benzazepine ring at δ 5.84 and the disappearance of the CH3 protons, which were observed at δ 2.30 in
the NMR spectrum of 4. The selective acylation of the benzazepine nitrogen of 11 was accomplished by
reaction with 4-nitrobenzoyl chloride and pyridine monohydrochloride in dimethylformamide.15 The
NMR spectrum of 2-methyl-6-(4-nitrobenzoyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine mono-
hydrochloride (12) showed the aromatic protons of the nitrobenzoyl group to be present between δ 6.95

and 8.15, and the disappearance of the N-H proton of the benzazepine ring, which was previously
observed at δ 5.84 for compound (11). Treatment of 12 with Raney nickel under a hydrogen atmosphere in
methanol afforded {4-[(2-methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-6(1H)-yl)carbonyl]phenyl}-
amine (13) in good yield.16 The NMR spectrum of 13 showed a two-proton singlet that exchanged in
deuterium oxide at δ 5.42 and was therefore attributed to the N-H proton of aniline. The selective
acylation of the aniline nitrogen of 13 was accomplished by reaction with biphenyl-2-carbonyl chloride
and pyridine in acetonitrile to provide 1. The NMR spectrum of 1 proved consistent with that reported by
Matsuhisa et al.6
Herein, we have described a successful new synthetic route to 1 which remarkably improves the overall
yield of 1 to 13% from the 5% in the original route,6 using new imidazobenzazepine derivatives as key
intermediates. This method notably doubles the overall yield of the final two steps in the original route,6
as well as providing a more safe, reliable and cost-efficient approach to 1, which maximizes atom
economy and circumvents jeopardizing the quality of the active pharmaceutical ingredient.
EXPERIMENTAL
Reagents and solvents were used as received from commercial suppliers, unless otherwise stated.
Analytical HPLC was performed on a Hitachi D-2500 system with UV detection at a wavelength of 220
or 240 nm using a YMC-pack ODS-A A-302 150 mm × 4.6 mm column and eluting with 0.2 M aqueous
ammonium chloride solution-acetonitrile (1:1). 1H NMR spectra were recorded on a JEOL JNM-AL400,
AL500 or A500 spectrometer with chemical shifts given in ppm relative to TMS at δ = 0. MS spectra
were determined on a Hitachi M-80, JEOL LX-2000, JMS-DX300 or 700T spectrometer. Mps were
determined using a Yanagimoto micro-melting-point apparatus and are uncorrected. IR spectra were
taken on a Perkin-Elmer 1600 spectrophotometer. Column chromatography was carried out on silica gel
(Wako, Wakogel C-200; particle size 75-150 µm).
Methyl 2-{[(4-methylphenyl)sulfonyl]amino}benzoate (7)
4-Methylbenzenesulfonyl chloride (377 g, 1.98 mol) was added to a solution of methyl 2-aminobenzoate
(6a) (260 g, 1.72 mol) in pyridine (520 g) at an internal temperature of 0-25˚C and the mixture was stirred
at 25˚C for more than 3 h. Water was poured into the mixture at 5-25˚C and the mixture was stirred for 1
h, then cooled to 5-10˚C. The resulting crystals were isolated by filtration and dried to afford 7 (524 g,
100%) as a pale yellow powder. mp: 113˚C.7 HPLC assay: 99.7% (area).
Methyl 2-{(3-cyanopropyl)[(4-methylphenyl)sulfonyl]amino}benzoate (8)

A mixture of N-tosyl benzoate (7) (204 g, 668 mmol), 4-chlorobutanenitrile (81.5 g, 787 mmol),
potassium carbonate (183 g, 1.32 mol) and potassium iodide (32.6 g, 196 mmol) in 2-butanone (306 g)
was stirred at reflux for 12 h. The mixture was then poured into water at 0-5˚C and the mixture stirred for
1 h. The resulting crystals were isolated by filtration and dried to provide 8 (243 g, 98%) as a white
powder. mp: 103-104˚C.8 HPLC assay: 99.4% (area).
1-[(4-Methylphenyl)sulfonyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carbonitrile (9)
Potassium t-butoxide (176 g, 1.57 mol) was added to a solution of 8 (291 g, 781 mmol) in DMF (874 mL)
at an internal temperature of −10-0˚C and the mixture was stirred at 0-5 ˚C for 2 h. Water was poured into
the mixture at 0-5˚C, then 30% hydrochloric acid was added dropwise at 0-20˚C and the mixture was
stirred at 5˚C for 1 h. The resulting crystals were isolated by filtration to give crude 9. A mixture of the
crude 9 in methanol was stirred at reflux for 30 min, then cooled to 5˚C and stirred for 1 h. The resulting
crystals were isolated by filtration and dried to afford 9 (248 g, 93%) as a white powder. mp:
1
153-154˚C.17 HPLC assay: 99.7% (area). H NMR (400 MHz, DMSO-d6): δ 2.09 (2H, m), 2.40 (3H, s),
3.95 (2H, br s), 7.30-7.54 (8H, m), 11.0 (1H, br s). 1H NMR (400 MHz, CDCl3): δ 2.23 (1H, m), 2.46 (3H,
s), 2.77 (1H, m), 3.49 (1H, m), 3.86 (1H, q, J = 4.0 Hz), 4.35 (1H, m), 7.34-7.88 (8H, m). IR (KBr): 3,122,
2,221 cm−1. Anal. Calcd for C18H16N2O3S: C, 63.51; H, 4.74; N, 8.23; S, 9.42. Found: C, 63.30; H, 4.64;
N, 8.15; S, 9.43. MS m/z: 339 (M+ −1).
1-[(4-Methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one (5)
9 (248 g, 729 mmol) was added to a mixture of acetic acid (470 g) and concentrated hydrochloric acid
(576 g), and the mixture stirred at an internal temperature of 80˚C for 11 h. The mixture was cooled, then
water was added dropwise at 0-20 ˚C. The mixture was stirred at 5˚C for 1 h, and the resulting crystals
were isolated by filtration and dried to provide 5. 30% aqueous sodium hydroxide solution and ethyl
acetate were added to the filtrate and the mixture was stirred. The organic and aqueous layers were
separated and the organic layer was washed with water, then concentrated. The resulting residue was
dissolved in pyridine (179 g), 4-methylbenzenesulfonyl chloride (95.2 g, 499 mmol) was added to the
solution at an internal temperature of 10-20˚C and the mixture was stirred for more than 1 h. Water was
added at 10-20 ˚C and the mixture was cooled to 5˚C. The resulting crystals were isolated by filtration
and dried to afford 5. The combined mass of 5 was 224 g (97%). mp: 125-126˚C.7 HPLC assay: 99.1%
(area).
4-Bromo-1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one (10)

Pyridinium hydrobromide perbromide (198 g, 619 mmol) was added to a solution of 5 (195 g, 618 mmol)
in chloroform (1800 mL) and the mixture stirred at an internal temperature of 15-30˚C for 1 h. The
mixture was washed with water and 5% aqueous sodium bicarbonate solution, then concentrated. The
resulting residue was dissolved in ethanol at reflux, then cooled to 0˚C and stirred for 1 h. The resulting
crystals were isolated by filtration and dried to give 10 (216 g, 89%) as a slightly yellowish-white powder.
mp: 128-130˚C.12 HPLC assay: 96.0% (area). 1H NMR (400 MHz, DMSO-d6): δ 2.19 (1H, m), 2.40 (3H,
s), 2.53 (1H, m), 3.74 (1H, m), 4.13 (1H, dt, J = 4.8, 14.4 Hz), 4.93 (1H, dd, J = 4.4, 7.8 Hz), 7.30-7.62
(8H, m). 1H NMR (400 MHz, CDCl3): δ 2.16 (1H, m), 2.42 (3H, s), 2.66 (1H, m), 3.70 (1H, m), 4.36 (1H,
dt, J = 4.4, 14.8 Hz), 4.58 (1H, dd, J = 4.4, 7.6 Hz), 7.25-7.59 (8H, m). IR (KBr): 1697 cm−1. MS m/z:
394 (M+ +1).
2-Methyl-6-[(4-methylphenyl)sulfonyl]-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine (4)
Ethanimidamide monohydrochloride (14.5 g, 153 mmol) and potassium carbonate (21.2 g, 153 mmol)
were added to a solution of 10 (12.1 g, 30.7 mmol) in chloroform (480 mL), and the resulting mixture
stirred at reflux for 4 d, using Dean-Stark apparatus to remove water by azeotropic distillation. The
mixture was washed with water, then concentrated. The resulting residue was purified by column
chromatography on silica gel, eluting with CHCl3/AcOEt (2:1), then recrystallized in ethanol to provide 4
(5.71 g, 53%) as a slightly brownish-white powder and the oxazole, 2-methyl-6-[(4-methylphenyl)-
sulfonyl]-5,6-dihydro-4H-[1,3]oxazolo[4,5-d][1]benzazepine (3.04 g, 28%) as a slightly yellowish-white
1
powder. Imidazole (4): mp: 111-112˚C. HPLC assay: 99.6% (area). H NMR (400 MHz, DMSO-d6): δ
2.20 (3H, s), 2.30 (3H, s), 2.99 (2H, br s), 3.33 (2H, s), 7.12-7.41 (7H, m), 8.00 (1H, br s), 11.61 (1H, br
s). Anal. Calcd for C19H19N3O2S·0.5C2H6O·0.5H2O: C, 62.32; H, 6.01; N, 10.90; S, 8.32. Found: C,
62.32; H, 5.92; N, 10.86; S, 8.39. MS m/z: 354 (M+ +1). Oxazole: mp: 109-110˚C. HPLC assay: 98.2%
1
(area). H NMR (500 MHz, CDCl3): δ 2.29 (3H, s), 2.38 (3H, s), 2.82 (1H, m), 3.20 (2H, m), 4.60 (1H,
m), 7.02 (2H, d, J = 10.0 Hz), 7.27-7.35 (4H, m), 7.64 (2H, m). Anal. Calcd for C19H18N2O3S: C, 64.39;
H, 5.12; N, 7.90; S, 9.05. Found: C, 64.19; H, 5.08; N, 7.81; S, 9.03. MS m/z: 355 (M+ +1).
2-Methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine (11)
Imidazole (4) (3.00 g, 8.49 mmol) was heated in a mixture of acetic acid (9.3 mL) and concentrated
sulfuric acid (6.0 mL) at 70˚C for 51 h. The mixture was cooled, then water was added dropwise at 10-35
˚C. Ethyl acetate was added to the mixture, and the organic and aqueous layers were separated. The
aqueous layer was basified with 25% sodium hydroxide solution, and ethyl acetate was added to the
mixture. The organic layer was separated, then concentrated. The resulting residue was dissolved in ethyl
acetate at reflux, then cooled to 0˚C and stirred for 30 min. The resulting crystals were isolated by

filtration and dried to provide 11 (1.04 g, 61%) as a slightly brownish-white powder. mp: 178-180˚C.
HPLC assay: 99.0% (area). 1H NMR (500 MHz, DMSO-d6): δ 2.25 (3H, s), 2.81 (2H, t, J = 5.0 Hz), 3.16
(2H, q, J = 5.0 Hz), 5.84 (1H, br s), 6.68-6.87 (3H, m), 7.85 (1H, br s) 11.6 (1H, br s). Anal. Calcd for
C12H13N3·0.15H2O: C, 71.37; H, 6.64; N, 20.81. Found: C, 71.64; H, 6.52; N, 20.53. MS m/z: 200 (M+
+1).
2-Methyl-6-(4-nitrobenzoyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine monohydrochloride
(12)
Pyridine monohydrochloride (1.74 g, 15.1 mmol) was added to a solution of 11 (1.00 g, 5.02 mmol) in
DMF (20 mL) at 25˚C. The mixture was cooled, then 4-nitrobenzoyl chloride (1.02 g, 5.50 mmol) was
added at 0˚C. The mixture was warmed to 25˚C and stirred for 3 h. The mixture was cooled to 0˚C and
the resulting crystals were isolated by filtration and dried to afford 12 (1.40 g, 73%) as a slightly
brownish-white powder. mp: >250˚C. 1H NMR (400 MHz, DMSO-d6): δ 2.70 (3H, s), 3.10 (2H, m), 3.31
(1H, m), 3.37 (2H, br s), 4.97 (1H, m), 6.95 (1H, d, J = 7.6 Hz), 7.07 (1H, t, J = 7.6 Hz), 7.11-7.41 (3H,
m), 8.04 (2H, d, J = 8.8 Hz), 8.15 (1H, d, J = 8.0 Hz). Anal. Calcd for C19H16N4O3·HCl: C, 59.30; H,
4.45; N, 14.56; Cl, 9.21. Found: C, 59.04; H, 4.47; N, 14.75; Cl, 9.21. MS m/z: 349 (M+ +1).
{4-[(2-Methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-6(1H)-yl)carbonyl]phenyl}amine (13)
Nitro compound (12) (1.30 g, 3.38 mmol) was hydrogenated by stirring with Raney nickel (0.4 g) at 25˚C
under a hydrogen atmosphere in methanol (26 mL) for 1 h. The catalyst was removed by filtration and the
filtrate was concentrated. Water was added to the resulting residue and the mixture was basified with
saturated sodium bicarbonate solution and stirred at 25˚C for 1 h. The resulting crystals were isolated by
1
filtration and dried to give 13 (1.01 g, 94%) as a grayish-white solid. mp: >250˚C. H NMR (400 MHz,
DMSO-d6)18: δ 2.31 (3H, s), 2.77-3.12 (3H, m), 4.98 (1H, d, J = 12.2 Hz), 5.42 (2H, s), 6.22 (2H, d, J =
8.8 Hz), 6.66 (3H, m), 6.86 (1H, t, J = 7.8 Hz), 7.14 (1H, t, J = 7.8 Hz), 8.10 (1H, d, J = 7.8 Hz), 11.88
(1H, s). Anal. Calcd for C19H18N4O·1.5H2O: C, 66.07; H, 6.13; N, 16.22. Found: C, 65.98; H, 6.08; N,
16.19. MS m/z: 319 (M+ +1).
N-{4-[(2-Methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-6(1H)-yl)carbonyl]phenyl}biphenyl-2-
carboxamide monohydrochloride (1, YM087)
DMF (22 mg, 0.30 mmol) and oxalyl chloride (942 mg, 7.42 mmol) were added to a solution of
biphenyl-2-carboxylic acid (746 mg, 3.76 mmol) in dichloromethane (15 mL) at −15˚C, and the mixture
was warmed slowly to 25˚C and stirred for more than 2 h, then concentrated. The resulting residue was
diluted with dichloromethane and concentrated. This process was repeated three times to give

biphenyl-2-carbonyl chloride as an oily product. Acetonitrile (10 mL) was added to the oil, and the
mixture was poured into a suspension of amine (13) (1.00 g, 3.14 mmol) and pyridine (0.76 mL, 9.44
mmol) in acetonitrile (20 mL) at 0˚C. The mixture was warmed slowly to 25˚C, then heated at reflux for
more than 30 min and cooled. A solution of hydrogen chloride in ethyl acetate was added to the mixture
at an internal temperature of 5-30˚C and the mixture was stirred at 25˚C for 30 min. The resulting crystals
were isolated by filtration and dried to give 1 (1.24 g, 74%) as a slightly grayish-white powder. mp
1
>250˚C. H NMR (500 MHz, DMSO-d6): δ 2.68 (3H, s), 2.99 (1H, t, J = 11.6 Hz), 3.09-3.20 (2H, m),
4.99 (1H, d, J = 11.6 Hz), 6.86 (1H, d, J = 7.3 Hz), 6.93 (2H, d, J = 7.3 Hz), 7.14 (1H, t, J = 7.3 Hz),
7.25-7.58 (12H, m), 8.09 (1H, d, J = 7.3 Hz), 10.31 (1H, s), 14.73 (2H, br s). Anal. Calcd for
C32H26N4O2·HCl·0.5H2O: C, 70.65; H, 5.19; N, 10.30; Cl, 6.52. Found: C, 70.68; H, 5.16; N, 10.33; Cl,
6.41. MS m/z: 499 (M+ +1).
ACKNOWLEDGEMENTS
We are grateful to Hidenori Iwamoto (Goei Shoji Co. Ltd., Tokyo) for helpful advice and to the staff of
the Chemistry laboratory (Yamanouchi Pharmaceutical Co. Ltd., Tsukuba) for technical assistance. We
are also grateful to the Analysis and Metabolism laboratories (Yamanouchi Pharmaceutical Co. Ltd.,
Tsukuba) for elemental analysis and spectral measurements.
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8. T. Hirota, M. Fukumoto, K. Sasaki, T. Namba, and S. Hayakawa, Heterocycles, 1986, 24, 143.
9. Both the NMR and IR spectra of 10 showed the keto form rather than the enol form.
10. J. March, 'Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 3rd ed.' Wiley &
Sons, New York, 1985, pp. 66-68.
11. C. Djerassi and C. R. Scholz, J. Am. Chem. Soc., 1948, 70, 417.
12. G. R. Proctor, J. Chem. Soc., 1961, 3989.

13. M. R. Grimmett, Adv. Heterocycl. Chem., 1970, 12, 103.
14. M. Lennon, A. McLean, I. McWatt, and G. R. Proctor, J. Chem. Soc., Perkin Trans. 1, 1974, 1828.
15. H. Ogawa, H. Yamamoto, K. Kondo, Y. Yamamura, H. Miyamoto, K. Kan, K. Kitano, M. Tanaka,
K. Nakaya, S. Nakamura, T. Mori, M. Tominaga, and Y. Yabuuchi, J. Med. Chem., 1996, 39, 3547.
16. M. J. S. Dewar and F. E. King, J. Chem. Soc., 1945, 114.
17. G. R. Proctor and B. M. L. Smith, J. Chem. Soc., Perkin Trans. 1, 1978, 862.
18. The data indicated that tautomers of compound (13) (-N=C-NH- or –NH-C=N-) existed in a ratio of
3:1 in DMSO-d6.