A scalable process for the synthesis of 2-methyl-1,4,5,6- tetrahydroimidazo[4,5-d][1]benzazepine monohydrate and 4-[(biphenyl-2- ylcarbonyl)amino]benzoic acid: Two new key intermediates for the synthesis of the AVP antagonist conivaptan hydrochloride

Article abstract of DOI:10.1021/op050061n

A process for the multikilogram synthesis of the dual vasopressin-receptor antagonist, conivaptan hydrochloride, has been developed. This method relies on the introduction of operationally simple chemistry during the final stages of the process when two k

Full text of DOI:10.1021/op050061n

Organic Process Research & Development 2005, 9, 593−598
A Scalable Process for the Synthesis of
2-Methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine Monohydrate and
4-[(Biphenyl-2-ylcarbonyl)amino]benzoic Acid: Two New Key Intermediates for
the Synthesis of the AVP Antagonist Conivaptan Hydrochloride
Takashi Tsunoda,* Atsuki Yamazaki, Toshiyasu Mase, and Shuichi Sakamoto
Process Chemistry Labs., Astellas Pharma Inc., 160-2, Akahama, Takahagi-shi, Ibaraki 318-0001, Japan
Abstract:
A process for the multikilogram synthesis of the dual vaso-
pressin-receptor antagonist, conivaptan hydrochloride, has been
developed. This method relies on the introduction of operation-
ally simple chemistry during the final stages of the process when
two key intermediates, isolated by crystallization, are reacted
to assemble the final molecule. A three-stage sequence has been
developed for the synthesis of the first key amine hydrate
intermediate, and modifications of the original process are
described here. Major strategic improvements have been made
in defining the final route to the “side chain” precursor
molecule, which is the second key intermediate. These advances
revolve around the acylation of an unprotected amino benzoic
acid and subsequent high-yield telescoped processes for the
synthesis of 4-[(biphenyl-2-ylcarbonyl)amino]benzoic acid. This
novel method leads to a 4-fold increase in the overall yield of
the target materials, circumvents the restricted synthetic
intermediates, and constitutes a safe, reliable, adaptable,
environmentally friendly, and cost-effective approach with
improved manipulability.
Figure 1. Chemical structure of 1.
Scheme 1. Published route for 1a
Introduction
Arginine vasopressin (AVP) is a neurohypophysial hor-
mone that has been shown to play important physiological
roles in vasoconstriction and antidiuresis. It exerts its effects
through binding to specific receptors that are coupled to
distinct second messengers. Thus, small-molecule inhibitors
of AVP are promising agents for the treatment of cardio-
vascular pathologies, such as congestive heart failure and
renal disease.1 Conivaptan hydrochloride (1; Figure 1) is a
newly synthesized potent nonpeptide antagonist of the AVP
V1A and V2 receptors.2 We reported previously our first-
a Reagents and conditions: (a) acetic acid, hydrochloric acid, 43%; (b) i.
4-nitrobenzoyl chloride, triethylamine, dichloromethane; ii. crystallization:
chloroform, methanol, 75%; (c) bromine, chloroform, 88%; (d) i. ethanimidamide
monohydrochloride, potassium carbonate, chloroform, 67%; (e) H2, Raney nickel,
methanol, DMF, 94%; (f) i. biphenyl-2-carboxylic acid, oxalyl chloride, DMF,
dichloromethane; ii. acetonitrile, 7, pyridine; iii. hydrogen chloride in ethyl
acetate, 74%.
generation route for 1, which involved the elimination of
chromatographic purification and crystallizations from highly
inflammable solvents.3 However, both the overall yield and
the problems associated with this route made it unsuitable
for use as a cost-effective method of synthesis to develop a
competitive drug candidate (Scheme 1). This approach used
chlorinated solvents at several stages and included a catalytic-
reduction technique that required specialized facilities.
Furthermore, some of the intermediates might infringe upon
existing patents. Consequently, we sought to establish a more
suitable synthetic strategy for 1 by manufacturing this
compound via a novel route.
* Corresponding author: E-mail: takashi.tsunoda@jp.astellas.com Tele-
phone: +81 293 23 4485. Fax: +81 293 24 2708.
(1) Naitoh, M.; Suzuki, H.; Murakami, M.; Matsumoto, A.; Arakawa, K.;
Ichihara, A.; Nakamoto, H.; Oka, K.; Yamamura, Y.; Saruta, T. Am. J.
Physiol. 1994, 267, H2245. Okada, H.; Suzuki, H.; Kanno, Y.; Yamamura,
Y.; Saruta, T. Clin. Sci. 1994, 86, 399.
(2) 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.
(3) Tsunoda, T.; Yamazaki, A.; Iwamoto, H.; Sakamoto, S. Org. Process Res.
DeV. 2003, 7, 883.
10.1021/op050061n CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/23/2005
Vol. 9, No. 5, 2005 / Organic Process Research & Development
•
593

Scheme 2. New synthesis route for 1
Table 1. Imidazole-ring formation of 12 in chloroforma
H2Ob in
K2CO3
H2Oc
charged
reactiond
(13:16:12)
reaction time
(h)
yield
(%)
0
5
10
15
0
0
0
-
-
-
-
5
10
15
49:35:6
84:11:0
89:5:0
88:7:1
83:10:1
91:3:0
85:5:1
190
60
50
60
70
24
24
20
74
78
76
73
79
75
a Ethanimidamide monohydrochloride and K2CO3 at 5 and 6 mol per mol of
12, respectively. b Amount of water absorbed in K2CO3 (w/w %).7 c Amount
of liquid water charged in the reaction system (w/w % based on the weight of
K2CO3). d Monitored by HPLC.
Scheme 3. Target and byproduct of imidazole-ring
formation from 12
Results and Discussion
optimization to obtain a routine production method due to
the low manipulability of the process.
As target material, 1 has a unique imidazobenzazepine
structure; our strategy was to introduce an imidazole synthon
into a readily available benzazepine compound and eliminate
the catalytic reduction step, thus reducing the costs of the
process. Moreover, the two key intermediates, 4-[(biphenyl-
2-ylcarbonyl)amino]benzoic acid (10, YM-175043) and
2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine
monohydrate (14, YM-53132 monohydrate), in the proposed
convergent synthesis can be produced separately in different
reactors, thus providing a more competitive system for large-
scale production by reducing the manufacturing period
(Scheme 2). This approach enhanced the overall yield of 1
to 56% from 13%, that in the original synthesis, after the
completion of the process development described below.
Imidazole-Ring-Formation Stage. The known com-
pound 1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-
1-benzazepin-5-one (11) was selected as the source of the
benzazepine skeleton for the alternative route, as it can be
produced using the method reported by Proctor and col-
leagues, and McCall and co-workers.4 High-quality 4-bromo-
1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benz-
azepin-5-one (12) was produced by the bromination of 11
with pyridinium hydrobromide perbromide5 in chloroform,
following recrystallization from ethanol.
Table 1 summarizes the findings of our investigation into
the imidazole-ring formation by the reaction of 12 with
ethanimidamide (15). The reactions with moist potassium
carbonate produced similar results to those observed in our
previous research, although the reactants were different.3
Considerable side-reaction formation of the oxazole byprod-
uct (16) (Scheme 3) was seen in the reaction with fresh
potassium carbonate; this side reaction decreased when
5-15% moist potassium carbonate7 was employed. This
confirmed that our theory was sufficiently robust to be
applied to the reaction of various R-bromoketones. By
contrast, the reaction of 12 with fresh potassium carbonate
in the presence of liquid water produced imidazole 13 in
good yield and also shortened the reaction time when 10 or
15% liquid water was employed. This approach allowed us
to manufacture the novel imidazobenzazepine, 13, with a
consistently good yield, through to kilogram-scale production
whilst eliminating the awkward moisture-absorption process.
The fact that 12 is a mutagen,8 together with increased
environmental concerns, led us to consider a modified
method; imidazole-ring formation in non-chlorinated solvents
and omission of the crystallization of 12 were both inves-
tigated.
Previously, we reported a novel imidazole-ring-formation
approach.3,6 Although this method might be applicable to
the reaction of 12 to give 13 (Scheme 3), it required further
In the first study, the reaction of 12 in toluene produced
the largest quantity of 13, although none of the reactions in
non-chlorinated solvents produced results superior to those
obtained in chloroform (Table 2). In the second study,
(4) Proctor, G. R.; Thomson, R. H. J. Chem. Soc. 1957, 2312. McCall, I.;
Proctor, G. R.; Purdie, L. J. Chem. Soc. C 1970, 1126.
(5) Djerassi, C.; Scholz, C. R. J. Am. Chem. Soc. 1948, 70, 417.
(6) Although the importance of the small amount of water in the reaction was
not discussed, a report of the reaction between R-bromopropiophenone and
benzamidine has been reported, see: Krieg, B.; Brandt, L.; Carl, B.;
Manecke, G. Chem. Ber. 1967, 100, 4042.
(7) Moist potassium carbonate, containing 5-15% of water, was prepared by
the exposure of anhydrous potassium carbonate to the ambient humidity in
the air. Up to 16% water was observed, which is the level reported for the
1.5 hydrate of this material.
(8) The result for the Ames test for 12 was positive.
594
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Vol. 9, No. 5, 2005 / Organic Process Research & Development

Table 2. Imidazole formation in non-chlorinated solvents
Table 4. Detosylation of 13
compared to that in chloroforma,b
form
of 13
conditions
reagents, temperature
reaction timea
(h)
reactionc
(13:16:12)
reaction time
(h)
run
solvents
1
2
3
4
5
free
free
free
free
c.H2SO4/AcOH,b 70 °C
NaOH aquous, 90 °C
c.HCl, 70 °C
50
(NR)
(NR)
1
toluene
2-butanone
MeCN
acetone
DMF
EtOH
MeOH
CHCl3
77:7:0
68:16:1
66:11:0
56:20:2
53:1:0
24:0:0
10:0:1
91:3:0
2
25
25
26
20
23
23
24
c.H2SO4,c 60 °C
HCl salt
c.H2SO4,c 60 °C
1
a The time at which the residual starting material could no longer be detected
by HPLC (for 13a; not more than 4%). NR ) no reaction. b Concentrated sulfuric
acid and glacial acetic acid at 2 and 3 volumes per weight of 13a, respectively.
c Concentrated sulfuric acid at 6 volumes per weight of 13a or 13b.
a Ethanimidamide monohydrochloride and K2CO3 at 5 and 6 mol per mol of
12, respectively. b In the presence of 10 w/w% liquid water (based on the weight
of K2CO3) at reflux (for toluene; at 100 °C). c Monitored by HPLC.
Table 5. Efficacy of various solvents in the extraction of 14
from a basic solution
solventsa
14b (%)
Table 3. Sequential reaction of 11 to 13a,b
productd
yielde
(%)
toluene
dichloromethane
chloroform
ethyl acetate
2-butanone
76
29
19
12
2
solventsc
(13:16:12)
toluene
CHCl3
99:0:0
99:0:0
69
77
a The ratio of the volume of the solvent to the original basic solution was
0.5:1.0. b The amount of 14 remaining in the aqueous solution as a percentage
of the initial volume detected by HPLC.
a Ethanimidamide monohydrochloride and K2CO3 at 5 and 6 mol per mol of
12, respectively. b In the presence of 10 w/w% liquid water (based on the weight
of K2CO3) at reflux (for toluene; at 100 °C). c Reaction solvent for imidazole-
ring formation. d Monitored by HPLC. e Total yield of two steps (bromination
and imidazole-ring formation). 2-Propanol and ethanol were used as salt-
formation solvents in the studies with toluene and chloroform, respectively.
Scheme 4. Target and byproduct of the detosylation of 13
successive reactions consisting of bromination and imidazole-
ring formation in both chloroform and toluene were inves-
tigated. As expected, the reaction in chloroform produced a
greater yield and a better quality of 13 than that in toluene
during the first run. However, modifications of the post-
treatment process in the experiments with toluene, which
involved using a back-extraction with an aqueous acid
solution and replacing ethanol with 2-propanol in the salt-
formation process, improved the yield of 13 and provided
material of comparable quality to that obtained by reaction
in chloroform (Table 3).
Although the sequential reaction in chloroform remained
superior to that in toluene in terms of yield, environmental
concerns compelled us to choose the latter approach.
Consequently, we produced a safer, more environmentally
favorable, and highly reproducible technique for the manu-
facture of 13.
Hydrolysis Stage. Several previous studies have inves-
tigated the cleavage of aryl sulfonamides.9,10 Initially, the
detosylation of novel compound 13 (Scheme 4) was carried
out using the method described for benzazepinone (11),
which was reported to be generally applicable to aryl
sulfonamides (Table 4, run 1).10 However, the reaction of
13a was incomplete, and more than 3% of the starting
material persisted for 50 h after the reaction was initiated.
Consequently, we sought an alternative method for the
detosylation of 13. Using concentrated sulfuric acid as the
reagent, the reaction proceeded remarkably rapidly, despite
the lower temperature.11 This method was applicable to both
forms of 13 (free base (13a) and hydrochloride salt (13b))
obtained during the development of the preceding imidazole-
ring-formation stage.
As 14 is highly water soluble, it was difficult to isolate it
from the aqueous solution obtained after the reaction; thus,
the efficiency of the extraction of 14 was investigated after
the neutralization of the reaction mixture. As shown in Table
5, 2-butanone had the greatest effect on the extraction of 14
and minimized expansion of the batch scale.
In these experiments, the use of 2-butanone for the
extraction afforded sufficient amounts of the crystalline
product 14, which was subsequently recrystallized from ethyl
acetate. Although optimizing the solvent for the extraction
minimized the batch volume, the reaction in concentrated
sulfuric acid required a huge amount of water to dissolve
the sodium sulfate that was produced during the post-
treatment processes. This led us to investigate the use of
dilute sulfuric acid for detosylation of 13b, which now
represented the chosen form of the product of the imidazole-
ring-formation stage.
(9) Proctor, G. R. J. Chem. Soc. 1961, 3989.
(10) Lennon, M.; McLean, A.; McWatt, I.; Proctor, G. R. J. Chem. Soc., Perkin
Trans. 1 1974, 1828. Carpenter, P. D.; Lennon, M. J. Chem. Soc., Chem.
Commun. 1973, 664.
(11) Wiese, M.; Schmalz, D.; Seydel, J. K. Arch. Pharm. (Weinheim, Ger.) 1996,
329, 161.
Vol. 9, No. 5, 2005 / Organic Process Research & Development
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595

Table 6. Detosylation of 13b in sulfuric acid
Scheme 6. Applied process for 10a
temperature
timeb
(h)
batch-scalec
(mL/g)
reagentsa
(C°)
c.H2SO4
80% H2SO4
60
80
1
1
210
130
a c.H2SO4: concentrated sulfuric acid. 80% H2SO4: v/v%. b The time point
at which the residual starting material could no longer be detected by HPLC.
c The maximum volume in a batch per volume of product 14.
Table 7. Crystallization solvents for 14
a Reagents and conditions: i. thionyl chloride, DMF, toluene; ii. 9c, N,N-
dimethylaniline, acetone, water; iii. DMF, water, 95%.
yield
(%)
productb
(14:17)
solventsa
Table 8. Comparison of recrystallization solvents for 10
EtOH-H2O(3:5)
2-butanone
AcOEt
63
70
77
90
99.7:0.1
99.1:0.5
99.0:0.5
99.9:0.0
recovery
(%)
purityb
(%)
batch-scalec
(mL/g)
solventsa
2-PrOH
MeCN
MeCN-H2O(1:1)
MeOH
MeCN-H2O(3:10)
88
-
-
59
a Crystallization solvents expressed in volumes. b Monitored by HPLC.
-
-
50<
40<
40
40
10
-
75
78
95
-
91d f 99
83e f 99
As shown in Table 6, the detosylation of 13b in 80%
sulfuric acid was accomplished within 1 h and reduced the
batch scale by almost half; the reaction would fail if the
sulfuric acid content of the solution was less than 80%, due
to the low solubility of 13b. Finally, to optimize both the
quality and yield of 14, a suitable crystallization solvent was
required. 14 could be crystallized from an aqueous ethanol
solution, 2-butanone, or ethyl acetate; however, aqueous
acetonitrile solution produced higher quality 14, in excellent
yield, thus optimizing the detosylation stage (Table 7).
Production of a Synthon of 10. Initially, we chose not
to explore this pathway, because the existing methods for
the preparation of 10 did not appear attractive for the
manufacturing process. For example, using ethyl12 and
methyl13 benzoates as intermediates produced 10 in 7 and
48% yields, respectively (Scheme 5). However, the reaction
EtOH
DMF-H2O(1:1)
a Crystallization solvents expressed in volumes. b The purity (crude f
purified) of 10 before and after recrystallization as detected by HPLC. c The
maximum volume in a batch per amount of crude 10. d Samples of 10 mol % of
8 and 9c were spiked. e Samples of 20 mol % of 8 and 9c were spiked.
of biphenyl-2-carboxylic acid (8) with unprotected 4-amino
benzoic acid (9c) produced 10 in a sufficiently high yield
using N,N-dimethylaniline as a base (Scheme 6).14,15 Al-
though the fluidity of the resultant suspension reduced the
efficiency of agitation, it was suitable for use in the synthesis
of 10 for the production of conivaptan hydrochloride. The
low fluidity of the reaction mixture may result, on production
scale, in large quantities of the starting materials 8 and 9c
remaining at the end of the reaction; therefore, a suitable
purification method for the reliable generation of high-quality
10 was sought. As shown in Table 8, recrystallization of 10
in the 1:1 mixture of N,N-dimethylformamide and water
removed any unreacted 8 and 9c, even in cases beyond the
expectation in extremely high yield with the smallest batch
scale. Using this simple method (Scheme 6), high-quality
10 was generated in high yield during kilogram-scale
production.
Scheme 5. Published routes to 10a
Final Reaction Stage. The synthetic strategy described
in our previous paper was applied to the regioselective
acylation of 14 with 10.3,16 Sufficiently high-quality 1 has
been manufactured in a kilogram-scale process in high yield,
using these two key intermediates produced in pilot plants
(Scheme 7).
(12) Matsuhisa, A.; Koshio, H.; Sakamoto, K.; Taniguchi, N.; Yatsu, T.; Tanaka,
A. Chem. Pharm. Bull. 1998, 46, 1566.
(13) Albright, J. D.; Venkatesan, A. M.; Delos Santos, E. G.; U.S. Patent
5,849,735, 1998.
(14) Bredereck, H.; Von Shuh, H. Chem. Ber. 1948, 81, 215.
(15) Thionyl chloride replaced oxalyl chloride which was used as a reagent for
acyl halide formation in ref 3 due to the unit price.
a Reagents and conditions: (a-1) i. 9a, WSC, HOBT, tetrahydrofuran; ii. ethyl
acetate; iii. Silica gel chromatography: chloroform/methanol; iv. crystalliza-
tion: ethanol, 8%; (a-2) i. sodium hydroxide, ethanol; ii. water, diethyl ether,
hydrochloric acid, 86%; (b-1) i. oxalyl chloride, dichloromethane; ii. 9b, N,N-
diisopropylethylamine; iii. n-hexane, 50%; (b-2) i. ethanol, sodium hydroxide,
water, 96%.
(16) Tsunoda, T.; Koshio, H.; Taniguchi, N.; Asakura, T. Jpn. Kokai Tokkyo
Koho JP 200287962, 2002.
596
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Vol. 9, No. 5, 2005 / Organic Process Research & Development

Scheme 7. Final reaction step for 1a
1
(area). H NMR (400 MHz, CDCl3): δ 2.16 (m, 1H), 2.42
(s, 3H), 2.66 (m, 1H), 3.70 (m, 1H), 4.36 (m, 1H), 4.58 (q,
1H), 7.25-7.59 (m, 8H). MS m/z: 394 (M+ + 1).
2-Methyl-6-[(4-methylphenyl)sulfonyl]-1,4,5,6-tetrahy-
droimidazo[4,5-d][1]benzazepine Monohydrochloride (13b).
Bromine (13.7 g, 85.6 mmol) was added to a mixture of 114
(27.0 g, 85.6 mmol) and 48% hydrobromic acid (1.5 g, 8.9
mmol) in acetic acid (260 g) at an internal temperature of
25-35 °C over 1 h, and the mixture was stirred for 1 h at
the same temperature. Water (880 mL) and toluene (880 mL)
were added, and the mixture was stirred. The organic and
aqueous layers were separated, and the former was washed
with 5% aqueous sodium carbonate solution (880 mL) and
water (880 mL), and then toluene (340 mL) was added.
Ethanimidamide monohydrochloride (36.5 g, 386 mmol),
water (7.5 g, 417 mmol), and potassium carbonate (67.1 g,
485 mmol) were added to the toluene solution, and the
mixture was heated at 95-110 °C for 3 h before cooling to
35-45 °C. Methanol (310 mL), water (430 mL), and
concentrated hydrochloric acid (67.6 g) were added, and the
mixture was stirred before the organic and aqueous layers
were separated. The aqueous layer was basified with sodium
carbonate (20.4 g) and extracted with ethyl acetate (two
extractions of 800 mL). The organic layer was washed with
water (two washes of 410 mL) and then concentrated to
dryness at 40 °C. The resultant residue was dissolved in
2-propanol (210 mL), concentrated hydrochloric acid (7.0
g) was added at 20-30 °C, and the mixture was cooled to
0-5 °C. The resultant crystals were filtered and dried at 60
°C to give 13b as grayish-white crystals (22.9 g, 69%).
a Reagents and conditions: i. thionyl chloride, acetonitrile, then toluene; ii.
14, acetonitrile; iii. ethanol, 90%.
Conclusion
A process for the multikilogram production of 1 has been
developed based on a convergent synthesis involving the key
intermediates 14 and 10, and has been implemented at a pilot
plant. This method leads to a 4-fold increase in the overall
yield of 1, circumvents the restricted synthetic intermediates,
and provides a safe, reliable, flexible, environmentally
friendly, and cost-effective approach with improved ma-
nipulability.
Experimental Section
All reagents and solvents were used as received from
commercial suppliers, unless otherwise stated. All equipment
was inspected visually for cleanliness and integrity before
use.
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 elution with 0.2 M ammonium chloride aqueous
solution-acetonitrile (2:1) to (2:3) or 0.05 M Na2HPO4
1
Mp > 250 °C. HPLC assay: 99.5% (area). H NMR (500
MHz, DMSO-d6): δ 2.34 (s, 3H), 2.57 (s, 3H), 3.14 (br s,
2H), 3.44 (br s, 2H), 7.22-7.95 (m, 8H), 14.7 (br s, 2H).
Anal. Calcd for C19H19N3O2S‚HCl: C, 58.53; H, 5.17; N,
10.78; S, 8.22; Cl, 9.09. Found: C, 58.19; H, 5.14; N, 10.59;
S, 8.17; Cl, 9.43. MS m/z: 354 (M+ + 1).
1
aqueous solution adjusted to pH 5.7-acetonitrile (2:3). H
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 LX-2000, JMS-DX300, or 700T
spectrometer. Melting points were determined using a
Yanagimoto micro-melting-point apparatus and are uncor-
rected. All of the potassium carbonate used in this research
was in powder form with a particle size of less than 105 µm
and was purchased from commercial suppliers. The water
content of the potassium carbonate was determined using
the loss-on-ignition test described in Japan Industrial Stan-
dard (JIS) K 0067.
4-Bromo-1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahy-
dro-5H-1-benzazepin-5-one (12). Pyridinium hydrobromide
perbromide (25.7 g, 80.3 mmol) was added to a solution of
1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benz-
azepin-5-one 114 (25.3 g, 80.2 mmol) in chloroform (230
mL), and the mixture was stirred at an internal temperature
of 15-30 °C for 1 h, washed with water (180 mL, then 110
mL), 5% aqueous sodium bicarbonate solution (110 mL),
and water (110 mL), successively, and then concentrated to
dryness at 40 °C. The resultant residue was dissolved in
ethanol (300 mL) at reflux, cooled to 0 °C, and stirred for
16 h. The resultant crystals were isolated by filtration and
dried at 25-40 °C to give 12 (28.1 g, 89%) as a yellowish-
white powder. Mp: 128-130 °C.9 HPLC assay: 96.0%
Chloroform Method. Bromine (1.21 g, 7.55 mmol) was
added to a mixture of 114 (2.38 g, 7.55 mmol) and 48%
hydrobromic acid (0.13 g, 0.75 mmol) in chloroform (21
mL) below -15 °C, and the mixture was stirred for 24 h at
15 °C. Water (11 mL) was added, and the mixture was
stirred. The organic and aqueous layers were separated, and
the former was washed with 5% aqueous sodium bicarbonate
solution (11 mL) and water (11 mL), and then chloroform
(100 mL) was added. Ethanimidamide monohydrochloride
(3.57 g, 37.7 mmol), water (0.73 g, 40.6 mmol), and
potassium carbonate (6.57 g, 47.5 mmol) were added to the
chloroform solution, and the mixture was heated at reflux
for 25 h before cooling to 25 °C. Water (60 mL) was added,
and the mixture was stirred before the organic and aqueous
layers were separated. The organic layer was washed with
water (60 mL) and then concentrated to dryness at 40 °C.
The resultant residue was dissolved in ethanol (11 mL),
concentrated hydrochloric acid (0.76 g) was added at 20-
30 °C, and the mixture was cooled to 0-5 °C. The resultant
crystals were filtered and dried at 45 °C to give 13b as
grayish-white crystals (2.28 g, 77%). Mp > 250 °C. HPLC
assay: 98.7% (area).
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597

2-Methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzaze-
pine Monohydrate (14, YM-53132 Monohydrate). N-
Substituted imidazobenzazepine 13b (22.4 g, 57.5 mmol) was
heated in 80 v/v% sulfuric acid (227 g) at an internal
temperature of 80 °C for 1 h. The mixture was cooled, poured
into water (270 mL) below 30 °C, and basified with 20%
aqueous sodium hydroxide solution (860 g) before 2-bu-
tanone (200 mL) was added. The organic and aqueous layers
were separated, and the organic layer was concentrated to
dryness at 40 °C. Acetonitrile (58 mL) and water (58 mL)
were added to the resultant residue, which was then
concentrated to dryness at 60 °C; then acetonitrile (34 mL)
and water (115 mL) were added to the resultant residue and
heated at reflux. The resultant solution was cooled to 0-5
°C. The resultant crystals were filtered and dried at 60 °C
to give 14 as brownish-yellow crystals (11.2 g, 90%). Mp:
60 °C, and the process was repeated again to give biphenyl-
2-carbonyl chloride as an oil. Acetone (100 mL) was added
to the oil, and 4-amino benzoic acid (9c; 10.4 g, 75.8 mmol)
and N,N-dimethylaniline (10.1 g, 83.3 mmol) were added to
the resultant solution at 25 °C. The mixture was stirred at
this temperature for more than 2 h. Water (100 mL) was
then poured into the mixture, and it was stirred at 25 °C for
more than 1 h. The resultant crystals were filtered and
dissolved in N,N-dimethylformamide (100 mL) at 25 °C. The
solution was then filtered to remove insoluble materials,
water (100 mL) was poured into the filtrate, and it was stirred
at 25 °C for more than 2 h. The resultant crystals were
filtered and dried at 40 °C to give 10 as white crystals (22.7
g, 95%). Mp: 246-248 °C. HPLC assay: 98.7% (area). 1H
NMR (500 MHz, DMSO-d6): δ 7.28-7.87 (m, 13H), 10.55
(s, 1H), 12.71 (br s, 1H). Anal. Calcd for C20H15NO3‚
0.1H2O: C, 75.27; H, 4.80; N, 4.39. Found: C, 75.30; H,
4.77; N, 4.56. MS m/z: 318 (M+ + 1).
1
189-191 °C. HPLC assay: 99.9% (area). H NMR (500
MHz, DMSO-d6): δ 2.26 (s, 3H), 2.82 (t, 2H), 3.17 (q, 2H),
3.40 (br s, 2H), 5.84 (br s, 1H), 6.69-6.88 (m, 3H), 7.94
(br s, 1H), 11.6 (br s, 1H). Anal. Calcd for C12H13N3‚H2O:
C, 66.34; H, 6.96; N, 19.34. Found: C, 66.39; H, 6.92; N,
19.33. MS m/z: 200 (M+ + 1).
4-[(Biphenyl-2-ylcarbonyl)amino]benzoic Acid (10, YM-
175043). Thionyl chloride (10.4 g, 87.4 mmol) was added
to a mixture of biphenyl-2-carboxylic acid 8 (15.0 g, 75.7
mmol) and N,N-dimethylformamide (0.28 g, 3.83 mmol) in
toluene (72 mL) at an internal temperature of 40 °C. The
mixture was stirred at this temperature for more than 2 h.
After completion of the reaction, the mixture was concen-
trated to dryness at 60 °C. The resultant residue was then
diluted with toluene (36 mL) and concentrated to dryness at
Acknowledgment
We are grateful to Mr. Hidenori Iwamoto (Goei Shoji Co.
Ltd., Tokyo, Japan) and Dr. Akihiro Tanaka (Astellas Pharma
Inc., Tokyo, Japan) for their helpful advice. We also thank
the staff of the Process Chemistry Laboratories (Astellas
Pharma Inc., Takahagi, Japan) for technical assistance, and
the staff of the Analysis and Pharmacokinetics Research
Laboratories (Astellas Pharma Inc., Tsukuba, Japan) for
elemental analysis and spectral measurements.
Received for review April 20, 2005.
OP050061N
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