Practical Synthesis of N-{4-[(2-Methyl-4,5-dihydroimidazo[4,5-d][1] benzazepin-6(1H)-yl)carbonyl]phenyl}biphenyl-2-carboxamide Monohydrochloride: An Arginine Vasopressin Antagonist

Article abstract of DOI:10.1021/op034079e

A novel, reliable, and cost-effective synthetic route to N-{4-[(2-methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-6(1H)-yl)carbonyl] -phenyl}biphenyl-2-carboxamide monohydrochloride (1, YM087), a potent Arginine vasopressin antagonist, has been developed. Using moisture-controlled potassium carbonate, imidazole formation from α-bromoketone furnished imidazobenzazepine, avoiding potential oxazole-ring formation. Catalytic reduction of nitro imidazobenzazepine afforded the corresponding amine in high yields. Treatment of the imidazole-containing amine directly, with a carbonyl chloride, afforded the target amide circumventing protection of the imidazole.

Full text of DOI:10.1021/op034079e

Organic Process Research & Development 2003, 7, 883−887
Practical Synthesis of N-{4-[(2-Methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-
6(1H)-yl)carbonyl]phenyl}biphenyl-2-carboxamide Monohydrochloride: an
Arginine Vasopressin Antagonist
Takashi Tsunoda,* Atsuki Yamazaki,† Hidenori Iwamoto,‡ and Shuichi Sakamoto
Chemical Technology Labs, Yamanouchi Pharmaceutical Co., Ltd.,
160-2, Akahama, Takahagi-shi, Ibaraki 318-0001, Japan
Abstract:
A novel, reliable, and cost-effective synthetic route to N-{4-[(2-
methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-6(1H)-yl)carbonyl]-
phenyl}biphenyl-2-carboxamide monohydrochloride (1, YM087),
a potent Arginine vasopressin antagonist, has been developed.
Using moisture-controlled potassium carbonate, imidazole
formation from r-bromoketone furnished imidazobenzazepine,
avoiding potential oxazole-ring formation. Catalytic reduction
of nitro imidazobenzazepine afforded the corresponding amine
in high yields. Treatment of the imidazole-containing amine
Figure 1. YM087 (1).
approximately 70% of 4 is wasted. Our strategy was to
introduce 4 towards the end of the synthesis, as described
in Scheme 2, thus improving the cost efficiency.
directly, with a carbonyl chloride, afforded the target amide
circumventing protection of the imidazole.
To accomplish this, there were three key points to be
addressed. These were the development of robust synthesis
procedures for (1) a novel imidazobenzazepine derivative
10, (2) a novel imidazobenzazepine derivative 9, and (3) a
selective acylation on aniline of 9.
Synthesis of Nitro Compound 2. The primary objective
for the synthesis of YM087 was the introduction of the
benzazepine skeleton. On the basis of information obtained
in the discovery synthesis, benzazepine derivative 123 was
selected as a source of the skeleton. Scheme 3 illustrates
the synthetic route used to prepare nitro compound 2.
Although benzazepinone 13 was an oil and difficult to purify,
crystallization of the nitro compound 2, following acylation
of 13, provided material of sufficient quality for use in the
next step.
Synthesis of a Novel Imidazobenzazepine 10. Develop-
ment of the protocol for imidazole ring formation, which
provides the important basic skeleton, was the most chal-
lenging step of this synthesis. In the discovery synthesis, the
selectivity of the imidazole ring formation was low and
column chromatography on silica afforded 8 and 14, an
awkward byproduct to separate, in 53% and 7% yield,
respectively. (Scheme 4).2
In the new route, R-bromoketone 11 was produced in 88%
yield by bromination of nitro compound 2, with a solution
of bromine in chloroform, followed by crystallization in
ethanol. The following imidazole ring formation was at-
tempted with the optimal conditions identified in the
discovery synthesis studies.2 However, the reaction did not
proceed cleanly, and large quantities of oxazole 15, an
awkward byproduct to separate, was isolated. Purification
Introduction
N-{4-[(2-Methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-
6(1H)-yl)carbonyl]phenyl}biphenyl-2-carboxamide mono-
hydrochloride (1, YM087, Figure 1) represents a new series
of dual vasopressin (AVP) V1A and V2 receptor antagonists.
It is an orally active nonpeptide agent for the potential
treatment of congestive heart failure (CHF), hypertension,
hyponatremia, renal disease, edema, and syndrome of inap-
propriate antidiuretic hormone secretion (SIADH).1 The
discovery synthesis of YM087 is depicted in Scheme 1.2 This
route includes a capricious imidazole ring formation, column
chromatography, and crystallization from highly flammable
solvents. Low cost-performance and operational difficulties
led to the investigation of a new sequence appropriate for
large-scale production.
Results and Discussion
The most costly raw material, carboxylic acid 4 ($1013/
kg), is used in early stages of the discovery synthesis. The
overall yield from 4 to YM087 in this route is 31%; namely
* Author for correspondence. E-mail: tsunoda.takashi@yamanouchi.co.jp.
Telephone: +81 0293 23 4485. Fax: +81 0293 24 2708.
† Current address: Yamanouchi Ireland Co. Ltd., Dublin, Ireland.
‡ Current address: Goei Shoji Co. Ltd., Tokyo, Japan.
(1) Yatsu, T.; Tomura, Y.; Tahara, A.; Wada, K.; Tsukada, J.; Uchida, W.;
Tanaka, A.; Takenaka, T. Eur. J. Pharmacol. 1997, 321, 225. Tahara, A.;
Tomura, Y.; Wada, K.; Kusayama, T.; Tsukada, J.; Takanashi, M.; Yatsu,
T.; Uchida, W.; Tanaka, A. J. Pharmacol. Exp. Ther. 1997, 282, 301. Tahara,
A.; Saito, M.; Sugimoto, T.; Tomura, Y.; Wada, K.; Kusayama, T.; Tsukada,
J.; Ishii, N.; Yatsu, T.; Uchida, W.; Tanaka, A. Naunyn-Shmiedeberg’s Arch.
Pharmacol. 1998, 357, 63. Tahara, A.; Tomura, Y.; Wada, K.; Kusayama,
T.; Tsukada, J.; Ishii, N.; Yatsu, T.; Uchida, W.; Tanaka, A. Peptides 1998,
19, 691.
(2) Matsuhisa, A.; Taniguchi, N.; Koshio, H.; Yatsu, T.; Tanaka, A. Chem.
Pharm. Bull. 2000, 48 (1), 21.
(3) Hirota, T.; Fukumoto, M.; Sasaki, K.; Namba, T.; Hayakawa, S. Heterocycles
1986, 24 (1), 143.
10.1021/op034079e CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/01/2003
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883

Scheme 1. Discovery synthesis route for YM087 (1)a
a (a) (i) H2, palladium/carbon, ethanol; (ii) crystallization: dichloromethane, then n-hexane, 94%; (b) oxalyl chloride (excess), DMF (catalyst), dichloromethane; (c)
(i) 5, triethylamine, dichloromethane; (ii) crystallization: diethyl ether, 82% over 2 steps; (d) CuBr2, chloroform, ethyl acetate; (e) (i) ethanimidamide monohydrochloride,
potassium carbonate, acetonitrile; (ii) chloroform; (iii) silica gel chromatography: chloroform/methanol; (iv) crystallization: ethyl acetate, 53% over 2 steps; (f)
hydrochloride in ethyl acetate, ethanol, 72%.
Scheme 2. New synthesis route for YM087 (1)
Scheme 4. Target and byproduct of imidazole ring
formation from 7 or 11
of the hygroscopic potassium carbonate powder, although
not by stirring speed, particle size of potassium carbonate,4
and batch-to-batch variability of potassium carbonate or
ethanimidamide monohydrochloride.
Table 1 shows the effect of the water content of the
potassium carbonate on the reaction. The yield of byproduct
15 was inversely proportional to the water content and was
controlled below 20% in the reactions with 10 to 15% moist
potassium carbonate.5
Scheme 3. Synthesis route for nitro compound (2)
The possible reaction mechanism in the higher water
content systems is described in Scheme 5. Assuming the
formation of stable internal hydrogen bonds in the enol form
17, in the lower water content systems,6 we can explain the
results shown in Table 1 as follows: (1) In the lower water
by column chromatography on silica afforded target imida-
zole 10 and byproduct 15 in 38% and 21% yield, respec-
tively.
A further series of experiments were performed in order
to suppress the undesired side reaction. It was discovered
that the reaction is seriously affected by the moisture content
(4) The particle size of potassium carbonate examined was less than 105 µm,
and the variation in this range showed no difference in the reaction.
(5) Moist potassium carbonate containing various amounts of water was prepared
by exposing to the humidity in the ambient air. Up to 16%, which is the
same water-content level with 1.5 hydrate, of water absorption to potassium
carbonate, was observed in the experiments.
(6) March, J. AdVanced Organic Chemistry: Reactions, Mechanisms, and
Structure, 3rd ed.; Wiley & Sons: New York, 1985; pp 66-68.
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Table 1. Effect of water content in K2CO3 on imidazole
Table 2. Reduction of nitro compound 10
ring formation
batch scalea
(mL/g)
purity % b
H2O contenta
(w/w %)
reaction
timec (h)
condition
yield %
ratio (10:15)b
SnCl2
Pd-C
Ra-Ni
1600
89
59
25
93
94
99<
99<
99<
0
2.5
5
10
15
38:51
62:27
66:23
71:17
79:8
97
64
63
45
21
a Maximum volume in a batch per amount of product 9. b HPLC assay (area
%) of 9.
Reduction of 10 by SnCl2‚2H2O in ethanol appeared to
reach completion, although amine 9 was isolated in only 25%
yield. It was proposed that this low yield was due to the
capture of 9 in resulting insoluble materials.
a Amount of water in K2CO3.5 b Monitored by HPLC. c The time that residual
starting material was not observed or not more than 1% by HPLC.
Scheme 5. Possible reaction mechanism of 10 and 15 in the
systems with higher water content
Catalytic hydrogenations over palladium/carbon or Raney
nickel in methanol or a mixture of methanol and DMF,
respectively, also proceeded to completion. However, a high
quality novel key intermediate 9 was obtained in good yield
in each case, after the removal of the catalyst followed by
recrystallization in a mixture of methanol and water. There
were no significant operational problems in these catalytic
hydrogenations; hence an efficient, practical large-scale
production method for a novel key intermediate 9 was
identified.
Synthesis of YM087 (1). A selective acylation on the
aniline of 9 was the last key objective in the synthesis of
YM087. There are two potential reaction sites for acylation
of amine 9, namely the nitrogen of imidazole and aniline.
As we had expected, based on the unstable property of acyl
imidazoles,10 the reaction of amine 9 with 5 occurred without
the need to protect the imidazole, and YM087 was obtained
in good yield. This one step acylation is ideal for large-scale
productions, shortening the manufacturing period, reducing
the production cost, and eliminating useless chemical ele-
ments.
Conclusion
We have developed a practical, efficient, comparatively
safe, and inexpensive sequence for large-scale production
of YM087 in a controlled and reproducible manner. This
straightforward process provides a 2-fold increase in the yield
of YM087 over the discovery synthesis with respect to 4,
the most costly raw material. All of the intermediates and
the final target are isolated cleanly in high yield without
chromatographic purification and crystallization from highly
flammable solvents. The key features of this procedure are
(1) a reliable imidazole formation from R-bromoketones by
controlling the amount of water in potassium carbonate, thus
preventing unwanted side reactions; (2) an efficient catalytic
reduction of nitro imidazole compounds avoiding expansion
of batch size; and (3) a selective acylation of amines in the
presence of unprotected imidazoles.
content systems, the equilibrium between the keto and enol
form would lie towards the enol due to stabilization by
internal hydrogen bonds. This might retard the internal
nucleophilic attack on the carbonyl carbon in keto form 16
by the terminal amine, which would result in oxazole 15
being isolated as the major product. (2) In the higher water
content systems, water could reduce the enol 17 concentration
by hydrogen bonding with the R-amine, making this group
less available for internal hydrogen bonding, so imidazole
10 was obtained as a main product.
Reaction with 15% moist potassium carbonate afforded
the target imidazole, following crystallization in ethyl acetate,
in good yield and purity, namely 98% area by HPLC assay,
67% yield. This novel approach for imidazole ring formation
allowed manufacture of the key intermediate 10 on a large
scale, avoiding column chromatography as a result of the
consistent control of the unwanted side reaction.
Experimental Section
Reagents and solvents were used as received from
commercial suppliers, unless otherwise stated. All equipment
Synthesis of a Novel Imidazobenzazepine 9. For the
reduction of imidazobenzazepine 10, reduction by tin chlo-
ride7 and catalytic hydrogenation over palladium/carbon8 and
Raney nickel9 were investigated (Table 2).
(7) Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25 (8), 839.
(8) Bakke, J. M.; Riha, J. J. Heterocycl. Chem. 1999, 36, 1143.
(9) Dewar, M. J. S.; King, F. E. J. Chem. Soc. 1945, 114.
(10) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis,
2nd ed.; Wiley & Sons: New York, 1991; pp 385-397.
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885

were inspected visually for cleanliness and integrity before
use. Chlorinated solvents were used in some experimental
procedures because of the low solubility of the materials.
Analytical HPLC was performed on a Hitachi D-2500
system with UV detection at a wavelength of 240 nm using
a YMC-pack ODS-A A-302 150 mm × 4.6 mm column and
elution with 0.2 M ammonium chloride aqueous solution-
acetonitrile 2:3 to 2:1 or 0.02 M K2HPO4 aqueous solution
adjusted at pH 6.0-acetonitrile 2:3 to 2:1. 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. Mass spectra were determined on a Hitachi
M-80, JEOL JMS-DX300, or 700T spectrometer. Melting
points were determined using a Yanagimoto micromelting
point apparatus and are uncorrected. All the potassium
carbonate used in this article was powder potassium carbon-
ate purchased from commercial suppliers, and its particle
size was less than 105 µm. The particle size was determined
using a Tsutsui-Rikagaku-Kikai M-2 type electromagnetic
vibration sieve. The water content of potassium carbonate
was determined by a test for loss on ignition, described in
JIS (Japan Industrial Standard) K 0067.
1,2,3,4-Tetrahydro-5H-1-benzazepin-5-one (13). 1-[(4-
Methylphenyl)sulfonyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-
benzazepine-4-carbonitrile 123 (180 g, 529 mmol) was heated
in a mixture of acetic acid (830 mL, 14.5 mol) and
concentrated hydrochloric acid (830 mL, 7.97 mol) at reflux
for 10 h. The mixture was cooled, poured into water, and
filtered to remove insoluble materials. To the filtrate, 33%
sodium hydroxide aqueous solution and ethyl acetate were
added. The organic and aqueous layers were separated, and
the organic layer was washed with water then concentrated
to give 13 (36.6 g, 43%) as an oily product.11 HPLC assay:
88.5% (area). 1H NMR (400 MHz, CDCl3): δ 2.18 (m, 2H),
2.84 (t, 2H), 3.26 (t, 2H), 4.62 (br s, 1H), 6.74-6.85 (m,
2H), 7.22-7.28 (m, 1H), 7.73 (d, 1H).
1-(4-Nitrobenzoyl)-1,2,3,4-tetrahydro-5H-1-benzazepin-
5-one (2). Triethylamine (29.4 g, 291 mmol) and 4-nitroben-
zoyl chloride (43.1 g, 232 mmol) were added to a solution
of benzazepinone 13 (31.2 g, 194 mmol) in dichloromethane
(310 mL), and the mixture was stirred at 25 °C for 2 h. The
mixture was washed with saturated sodium bicarbonate
aqueous solution, water, 1 M hydrochloric acid, and brine
then concentrated. The resulting residue was dissolved in
chloroform (90 mL), methanol (620 mL) was added, and
the mixture was stirred at 25 °C for 20 h. The resulting
crystals were filtered off and dried to give 2 as slightly brown
crystals (45.0 g, 75%). HPLC assay: 99.9% (area). 1H NMR
(400 MHz, CDCl3): δ 2.17 (m, 2H), 2.90 (m, 3H), 4.10 (m,
1H), 6.70 (m, 1H), 7.20-7.55 (m, 4H), 7.85 (d, 1H), 8.05
(d, 2H). MS m/z: 311 (M+ + 1).
10% sodium bicarbonate aqueous solution then concentrated.
Ethanol was added to the resulting residue and the mixture
was heated at reflux, then cooled to 15 to 30 °C. The resulting
crystals were filtered off and dried to give 11 (16.9 g, 88%).
Mp: 134.0-137.0 °C. 1H NMR (500 MHz, CDCl3): δ 2.49
(m, 1H), 2.71 (m, 1H), 3.57 (m, 1H), 4.93 (m, 2H), 6.69 (s,
1H), 7.23-7.35 (m, 4H), 7.74 (s, 1H), 8.03 (d, 2H). Anal.
Calcd for C17H13N2O4Br: C, 52.46; H, 3.37; N, 7.20; Br,
20.53. Found: C, 52.14; H, 3.33; N, 7.11; Br, 20.78. MS
m/z: 390 (M+ + 1).
2-Methyl-6-(4-nitrobenzoyl)-1,4,5,6-tetrahydroimidazo-
[4,5-d][1]benzazepine (10). Ethanimidamide monohydro-
chloride (15.2 g, 161 mmol) and potassium carbonate (26.1
g, 161 mmol)12 were added to a solution of R-bromoketone
11 (12.5 g, 32.1 mmol) in chloroform (440 mL), and the
mixture was heated at reflux for 18 h. The mixture was
cooled to 25 °C, washed with water, and then concentrated.
Ethyl acetate was added to the resulting residue, and the
mixture was heated at reflux and then cooled to 0-5 °C.
The resulting crystals were filtered off and dried to give 10
as yellowish brown crystals (7.50 g, 67%). Mp > 250 °C.
1H NMR (500 MHz, CDCl3): δ 2.51 (s, 3H), 2.98 (d, 1H),
3.12 (t, 1H), 3.46 (m, 1H), 5.10 (d, 1H), 6.60 (d, 1H), 6.86
1
(t, 1H), 7.25 (m, 4H), 7.95 (d, 2H), 8.24 (br s, /2H),13 9.10
1
13
(br s, /2H). Anal. Calcd for C19H16N4O3: C, 65.51; H,
4.63; N, 16.08. Found: C, 65.49; H, 4.64; N, 16.03. MS
m/z: 349 (M+ + 1).
{4-[(2-Methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-
6(1H)-yl)carbonyl]phenyl}amine (9). Nitro compound 10
(6 g, 17.2 mmol) was hydrogenated over Raney nickel at 25
°C under hydrogen atmosphere for 1 h in the mixture of
methanol (60 mL) and DMF (20 mL). The catalyst was
removed by filtration and washed with methanol. Water was
poured into the filtrate, and the resulting crystals were filtered
off and dried to give 9. The filtrate was concentrated, and
methanol and water were added to the resulting residue. The
mixture was heated at reflux and then cooled to 25 °C. The
resulting crystals were filtered off and dried to afford 9. The
1
combined mass of 9 was 5.59 g (94%). Mp > 250 °C. H
NMR (400 MHz, DMSO-d6):14 δ 2.31 (s, 3H), 2.77-3.12
(m, 3H), 4.98 (d, 1H), 5.42 (s, 2H), 6.22 (d, 2H), 6.66 (m,
3H), 6.86 (t, 1H), 7.14 (t, 1H), 8.10 (d, 1H), 11.88 (s, 1H).
Anal. Calcd for C19H18N4O‚3/2H2O: 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-carbox-
amide Monohydrochloride (1, YM087). To a solution of
biphenyl-2-carboxylic acid 4 (3.66 g, 18.5 mmol) in dichlo-
romethane (74 mL) DMF (0.11 g, 1.50 mmol) and oxalyl
chloride (4.62 g, 36.4 mmol) were added at -15 °C, and
the mixture was warmed slowly to 25 °C and stirred for over
2 h. After completion of the reaction, the mixture was
4-Bromo-1-(4-nitrobenzoyl)-1,2,3,4-tetrahydro-5H-1-
benzazepin-5-one (11). Bromine (7.88 g, 49.3 mmol) was
added to a solution of nitro compound 2 (15.3 g, 49.3 mmol)
in chloroform (125 mL) at an internal temperature of 5 to
30 °C over 1 h. The mixture was washed with water and
(12) 15% moist potassium carbonate (5.0 mol per mol of R-bromoketone 11)
was used.
(13) The data indicated that tautomers of compound 10 (sNdCsNHs or s
NHsCdNs) existed in the ratio of 1 to 1 in CDCl3.
(14) The data indicated that tautomers of compound 9 (sNdCsNHs or s
NHsCdNs) existed in the ratio of 3 to 1 in DMSO-d6.
(11) The experiments showed no evidence of HCN gas, and this suggested that
the reaction consisted of the hydrolysis and decarboxylation of the nitrile.
For example, see: Coan, S. B.; Becker, E. I. Org. Synth. 1955, 35, 32.
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concentrated. The resulting residue was diluted with dichlo-
romethane and concentrated. This process was repeated 3
times to give biphenyl-2-carbonyl chloride 5 as an oily
product. Acetonitrile (50 mL) was added to 5, and the
mixture was poured into a suspension of amine 9 (5.32 g,
15.4 mmol) and pyridine (3.8 mL, 47.2 mmol) in acetonitrile
(100 mL) at 0 °C. The mixture was warmed slowly to 25
°C, then heated at reflux for over 30 min, and cooled. A
solution of hydrogen chloride in ethyl acetate was added to
the mixture at an internal temperature of 5 to 30 °C, and the
mixture was stirred at 25 °C for 30 min. The resulting crystals
were filtered off and dried to give 1 (6.20 g, 74%). Mp >
Acknowledgment
We are grateful to Drs. Toshiyasu Mase (Yamanouchi
Pharmaceutical Co. Ltd., Takahagi) and Akihiro Tanaka
(Yamanouchi U.K. Ltd., Surrey) for their helpful advice and
to the staff of the Chemistry Laboratory (Yamanouchi
Pharmaceutical Co. Ltd., Tsukuba) for technical assistance.
We also are grateful to the Analysis and Metabolism
Laboratories (Yamanouchi Pharmaceutical Co. Ltd., Tsuku-
ba) for elemental analysis and spectral measurements.
Note Added after ASAP. Errors were introduced in the
data in the last paragraph during processing of galley
corrections, and the tables were numbered out of sequence
in the version published on the Web 11/1/2003. The corrected
version, published 11/6/2003, and the print version are
correct.
1
250 °C. H NMR (500 MHz, DMSO-d6): δ 2.68 (s, 3H),
2.99 (t, 1H, J ) 11.6 Hz), 3.09-3.20 (m, 2H), 4.99 (d, 1H,
J ) 11.6 Hz), 6.86 (d, 1H, J ) 7.3 Hz), 6.93 (d, 2H, J )
7.3 Hz), 7.14 (t, 1H, J ) 7.3 Hz), 7.25-7.58 (m, 12H), 8.09
(d, 1H, J ) 7.3 Hz), 10.31 (s, 1H), 14.73 (br s, 2H). Anal.
Calcd for C32H26N4O2‚HCl‚1/2H2O: C, 70.65; H, 5.19; N,
10.30; Cl, 6.52. Found: C, 70.84; H, 5.10; N, 10.40; Cl,
6.47. MS m/z: 499 (M+ + 1).
Received for review June 19, 2003.
OP034079E
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