Practical synthesis of an orally active CCR5 antagonist, 7-{4-[2-(Butoxy)-ethoxy]phenyl}-N-(4-{[methyl(tetrahydro-2H-pyran-4-yl)amino] methyl}phenyl)-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide

Article abstract of DOI:10.1021/op0497916

A practical method of synthesizing 7-{4-[2-(butoxy)ethoxy]-phenyl}-N-(4- {[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}-phenyl)-1-propyl-2, 3-dihydro-1H-1-benzazepine-4-carboxamide (8), an orally active CCR5 antagonist, has been developed. Methyl 7-bromo-1-propyl-2,3-dihydro-1H-1-benzazepine-4- caboxylate (14a) was synthesized in good yield by the esterification of 4-[(4-bromo-2-formylphenyl)(propyl)amino]butanoic acid (13) followed by an intramolecular Claisen type reaction with 28% sodium methoxide in dimethyl carbonate as a solvent in one pot. The Suzuki-Miyaura reaction of 14a and 1-bromo-4-(2-butoxyethoxy)benzene (10) followed by hydrolysis and amidation gave 8. A new inexpensive method without chromatographic purification was established.

Full text of DOI:10.1021/op0497916

Organic Process Research & Development 2005, 9, 168−173
Practical Synthesis of an Orally Active CCR5 Antagonist, 7-{4-[2-(Butoxy)-
ethoxy]phenyl}-N-(4-{[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-
1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide
Tomomi Ikemoto, Tatsuya Ito,* Atsuko Nishiguchi, Syotaro Miura, and Kiminori Tomimatsu
Chemical DeVelopment Laboratories, Takeda Pharmaceutical Company Limited, 2-17-85 Jusohonmachi,
Yodogawa-ku, Osaka 532-8686, Japan
Scheme 1. Previous synthesis of 8
Abstract:
A practical method of synthesizing 7-{4-[2-(butoxy)ethoxy]-
phenyl}-N-(4-{[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}-
phenyl)-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxam-
ide (8), an orally active CCR5 antagonist, has been developed.
Methyl 7-bromo-1-propyl-2,3-dihydro-1H-1-benzazepine-4-
caboxylate (14a) was synthesized in good yield by the esterifi-
cation of 4-[(4-bromo-2-formylphenyl)(propyl)amino]butanoic
acid (13) followed by an intramolecular Claisen type reaction
with 28% sodium methoxide in dimethyl carbonate as a solvent
in one pot. The Suzuki-Miyaura reaction of 14a and 1-bromo-
4-(2-butoxyethoxy)benzene (10) followed by hydrolysis and
amidation gave 8. A new inexpensive method without chro-
matographic purification was established.
Introduction
In recent years, CC chemokine receptor 5 (CCR5) has
been shown to act as a coreceptor for the entry of macro-
phage-tropic human immunodeficiency virus type 1 (HIV-
1) into the host cell.1 CCR5 antagonists as inhibitors of
HIV-1 entry, having a novel mechanism, differ from well-
known agents for chemotherapy, for example, HIV-1 reverse
transcriptase and protease inhibitors, and have potential in
the treatment of HIV-1. Shiraishi et al. reported a small
molecule, the nonpeptide CCR5 antagonist TAK-779,2 as an
anti-HIV-1 agent for injection. Subsequently, 2,3-dihydro-
1H-1-benzazepine derivatives showed markedly strong activ-
ity as orally active CCR5 antagonists.3 In particular, 7-{4-
[2-(butoxy)ethoxy]phenyl}-N-(4-{[methyl(tetrahydro-2H-
pyran-4-yl)amino]methyl}phenyl)-1-propyl-2,3-dihydro-1H-
1-benzazepine-4-carboxamide (8) was found to be especially
effective.3b Hence, an efficient preparation of 8 on a large
scale was required to support a toxicological evaluation. The
previous synthetic route is shown in Scheme 1.3b However,
* To
whom
correspondence
should
be
addressed.
E-mail:
Ito_Tatsuya@takeda.co.jp. Telephone: +81(6)63006561. Fax: +81(6)63006251.
(1) (a) Deng, H.; Liu, R.; Ellmeier, W.; Choe, S.; Unutmaz, D.; Burkhart, M.;
DiMarzio, P.; Marmon, S.; Sutton, R. E.; Hill, C. M.; Davis, C. B.; Peiper
S. C.; Schall, T. J.; Littman, D. R.; Landau, N. R. Nature (London) 1996,
381, 661. (b) Alkhatib, G.; Combadiere, C.; Broder, C. C.; Feng, Y.;
Kennedy, P. E.; Murphy, P. M.; Berger, E. A. Science 1996, 272, 1955.
(2) (a) Baba, M.; Nishimura, O.; Kanzaki, N.; Okamoto, M.; Sawada, H.; Iizawa,
Y.; Shiraishi, M.; Aramaki, Y.; Okonogi, K.; Ogawa, Y.; Meguro, K.; Fujino,
M. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 5698. (b) Shiraishi, M.; Aramaki,
Y.; Seto, M.; Imoto, H.; Nishikawa, Y.; Kanzaki, N.; Okamoto, M.; Sawada,
H.; Nishimura, O.; Baba, M.; Fujino, M. J. Med. Chem. 2000, 43, 2049.
(3) (a) Aramaki, Y.; Seto, M.; Okawa, T.; Oda, T.; Kanzaki, N.; Shiraishi, M.
Chem. Pharm. Bull. 2004, 52, 254. (b) Seto, M.; Aramaki, Y.; Okawa, T.;
Miyamoto, N.; Aikawa, K.; Kanzaki, N.; Niwa, S.; Iizawa, Y.; Baba, M,
Shiraishi, M. Chem. Pharm. Bull. 2004, 52, 577.
this procedure had several limitations for large-scale produc-
tion, for example, the utilization of expensive materials, the
requirement of multiple steps, repeated tedious chromato-
graphic purification, lower yield, and the use of a large
amount of heavy metal (palladium) in the Suzuki-Miyaura
reaction. To advance the practical preparation, we tried to
develop an alternative method of producing 8 using inex-
pensive materials. Here, we report a new way to prepare 8
168
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Vol. 9, No. 2, 2005 / Organic Process Research & Development
10.1021/op0497916 CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/03/2005

Scheme 2. Efficient synthesis of 12
Table 1. Preparation of 12 by a reductive alkylation of 11a
ratio by
H2
propion-
isolated
yield of
12 (%)
GC (%)
pressure aldehyde Pd-C/11
entry
(MPa)
(equiv)
(wt %)
12
11
1
2
3
4
5
4
4
4
2
2
2
25
25
25
10
5
92.9 NDb
94.6 0.9
93.9 NDb
93.8 0.2
65.8 7.1
94
90
90
90
c
0.5
0.5
0.5
0.5
Scheme 3. New synthesis of 12
a The mixture of 11 (1.0 equiv), propionaldehyde, 20% Pd-C (wet), and
Na2SO4 (1.6 equiv) in AcOEt was stirred for 4 h at 105 °C. b ND ) not detected.
c 12 was not isolated.
of pyrrolidone (11) by 1-halogenopropane5 or 1-propanol in
the presence of additives,6 amidation of γ-butyrolactone by
1-aminopropane,7 the reduction of N-propylsuccinimide,8 and
Rh-catalyzed carbonylation of cyclopropylamine.9 We chose
the alkylation of 11 with 1-bromopropane in the presence
of KOH and a phase transfer catalyst (PTC) in toluene
(Method A)10 because this method did not require special
equipment and expensive reagents. The alkylation under
anhydrous conditions (using the KOH pellet) gave 12 in 72%
yield in a small-scale reaction. However, the reaction
conditions were not suitable for large-scale production, since
a resulting hard solid mass clogged a valve at the bottom of
the vessel. Hence, alkylation under aqueous conditions (using
50% aqueous KOH) was examined and afforded 12 in 66%
yield without a hard solid mass in a small-scale operation.
However, alkylation under the same conditions on a large
scale decreased the yield of 12 (44%). It was presumed that
hydrolysis of 12 and losses in the aqueous layer caused the
decrease in yield. Therefore, an alternative method, the
reductive alkylation of 11 and propionaldehyde by 20%
Pd-C and hydrogen in the presence of Na2SO4 in AcOEt,11
was examined (Method B, Table 1). The reaction under
0.5-4 MPa of hydrogen pressure smoothly proceeded to give
12 in high yield (entry 1-4). However, the reaction in the
presence of 20% Pd-C (5 wt %) was not complete (entry
5). As a result, the reductive alkylation was carried out
smoothly in the presence of 20% Pd-C (10 wt %) under a
lower hydrogen pressure (0.5 MPa) with high conversion
(entry 4). A simple workup (filtration of Pd-C and Na2-
SO4, concentration, and distillation under reduced pressure)
gave 12 in 90% yield (purity 97.9%).
Scheme 4. Improved synthesis of 10
in short steps that is amenable to scale-up without chro-
matographic purification, as outlined in Schemes 2-4.
Practical Synthesis of 14a. Next, we studied the synthesis
of 14a (Scheme 3). Hydrolysis of 12 with 4 N NaOH gave
4-(propylamino)butanoic acid in high conversion (80-90%,
determined by 1H NMR). After neutralization of the reaction
mixture with concentrated HCl, sodium carbonate and
5-bromo-2-fluorobenzaldehyde (3) in DMSO were added and
Results and Discussion
Efficient Synthesis of 1-Propylpyrrolidin-2-one (12).
We had already reported an efficient method of synthesizing
2,3-dihydrobenzazepine derivatives via an intramolecular
Claisen type reaction of 4-[(2-formylaryl)alkylamino]bu-
tanoic acid, which was prepared from o-halogenobenzalde-
hyde and 4-(alkylamino)butanoic acid starting with 1-alkyl-
pyrrolidin-2-one, using dialkyl carbonate as a solvent.4
According to the reported method, we first studied the
synthesis of 12 (Scheme 2). Many procedures for the
synthesis of 12 have been reported, for example, alkylation
(5) Stamatiou, G.; Kolocouris, A.; Kolocouris, N.; Fytas, G.; Foscolos, G. B.;
Neyts, J.; De Clercq, E. Bioorg. Med. Chem. Lett. 2001, 11, 2137.
(6) Enomoto, S.; Takahashi, Y. JP 51016657; Chem. Abstr. 1976, 85, 123752.
(7) Hatada, K.; Ono, Y. Bull. Chem. Soc. Jpn. 1997, 50, 2517.
(8) Olsen, R. J. US 4814464; Chem. Abstr. 1989, 111, 173978.
(9) Iqbal, A. F. M. Tetrahedron Lett. 1971, 37, 3381.
(10) Tahara, T.; Hayano, K.; Murakami, K.; Fukuda, T.; Setoguchi, M.; Ikeda,
K.; Marubayashi, N. Chem. Pharm. Bull. 1990, 38, 1609.
(11) Fache, F.; Jacquot, L.; Lemaire, M. Tetrahedron Lett. 1994, 35, 3313.
(4) Ikemoto, T.; Ito, T.; Nishiguchi, A.; Miura, S.; Tomimatsu, K. Tetrahedron
Lett. 2004, 45, 9335.
Vol. 9, No. 2, 2005 / Organic Process Research & Development
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169

Table 2. Preparation of 13
lization from MeOH afforded high quality 14a (purity 99.8%)
in 60% yield (from 3).
entry
base
solvent
method a
yield (%)
Practical Synthesis of 8. Our attention was focused on
developing a facile process for the synthesis of biaryl
compounds. We tried using the Suzuki-Miyaura reaction
in one pot12 with 14a and 10, instead of 7. In the previous
method,3b the arylbromide derivative 10 was prepared from
9 and an expensive material, 2-chloroethyl n-butyl ether. It
was therefore considered that an alternative method of
preparing 10 was required without the need for expensive
materials (Scheme 4). Hence, we chose 2-phenoxyethanol
(16) as a starting material. Bromination of 16 with bromine
in the presence of sodium acetate in a mixture of AcOH and
water gave 17 quantitatively. Compound 17 was crystallized
by addition of water to the reaction mixture and refined by
filtration (yield 91%, purity 99.4%). Alkylation of 17 with
1-bromobutane using 50% aqueous NaOH as a base in the
presence of PTC13 proceeded quantitatively to give 10 in
98% yield (purity 99.9%) after distillation under reduced
pressure.
Next, the Suzuki-Miyaura reaction in one-pot using 14a
and 10 was examined. The treatment of 10 was carried out
with magnesium in THF under refluxing conditions and
followed by the addition of trimethylborate at -10 °C. The
whole mixture was reacted with 14a, base, water, and Pd
catalyst under refluxing conditions to give 15a in high
conversion (Table 3). To decrease the amount of palladium
catalyst, this reaction was examined in the presence of several
bases and catalysts. The coupling reactions using K2CO3 as
a base in the presence of palladium catalyst (1 mol %)
proceeded slowly and required 5.5-8.5 h to complete (entry
1-3). The utilization of K3PO4 as a base accelerated the
reactions (entry 4-8) and reduced the amount of palladium
catalyst. In particular, the combination of Pd(OAc)2, PPh3,
and K3PO4 diminished the amount of palladium catalyst (0.05
mol %, entry 8) and provided 15a in 91% yield (purity
99.5%, residual palladium 0.3 ppm). A Suzuki-Miyaura
1
2
3
4
Na2CO3
Na2CO3
Na2CO3
Na2HPO4
37% aq DMSO
50% aq DMSO
37% aq DMSO
37% aq DMSO
A
A
B
A
88b
80b
86c
86c
a (A) After 12 was hydrolyzed and neutralized, base, 3, and DMSO were
added. The whole mixture was refluxed. (B) After 12 was hydrolyzed and
neutralized, base and DMSO were added. A solution of 3 in DMSO was added
dropwise under refluxing conditions, and the whole mixture was refluxed.
b Isolated yield. c Determined by HPLC.
the whole mixture was refluxed to afford 13 smoothly in a
one-pot small-scale reaction (Table 2, entry 1). However,
this reaction was not suitable for large-scale production, since
the viscous reaction mixture swelled 2- or 3-fold due to the
resulting carbon dioxide. Though the utilization of 50%
aqueous DMSO as a solvent produced a fluid suspension of
the reaction mixture and improved the stirring, this condition
decreased the yield of 13 slightly (entry 2). The reaction with
Na2HPO4 as a base generated no carbon dioxide and gave
13 in high yield (entry 4). However, in this case, the
separation of the organic layer and the aqueous layer in the
workup was impossible due to a large amount of precipitate.
As a result, slow addition of a solution of 3 in DMSO in the
reaction mixture under refluxing conditions caused the slow
evolution of carbon dioxide and improved the stirring
solution to provide 13 in 86% yield in one pot (entry 3).
Crude 13 (a pale yellow oil), which was obtained by
extraction with aqueous Na2CO3 followed by neutralization,
extraction with a mixture of AcOEt and THF, and concentra-
tion, was used directly in further reactions without purifica-
tion.
The esterification of crude 13 with MeI in the presence
of K2CO3 in DMF followed by an intramolecular Claisen
type reaction triggered by the addition of dimethyl carbonate
and 28% sodium methoxide in one pot gave 14a very
smoothly without a byproduct. After the workup, crystal-
Table 3. Preparation of 15a
ratio by HPLC
entry
R
catalyst
base
time (h)
15
18
14
yieldb(%)
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Me
H
Pd(OAc)2 (1 mol %), PPh3 (4 mol %)
PdCl2(PPh3)2 (1 mol %)
K2CO3
K2CO3
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
8.5
7
5.5
1
2
4
3
5
4
78.8
80.7
85.8
86.2
86.2
49.4
88.4
88.1
64.1
0.9
2.5
0.9
0.7
1.0
0.6
0.2
1.7
16.2
NDc
0.3
1.1
1.0
0.1
38.6
1.0
1.0
2.7
81
84
89
91
92
d
93
91
73
PdCl2(PPh3)2 (1 mol %), PPh3 (2 mol %)
PdCl2(PPh3)2 (1 mol %), PPh3 (2 mol %)
PdCl2(PPh3)2 (0.1 mol %), PPh3 (0.2 mol %)
PdCl2(PPh3)2 (0.05 mol %), PPh3 (0.1 mol %)
Pd(OAc)2 (0.1 mol %), PPh3 (0.4 mol %)
Pd(OAc)2 (0.05 mol %), PPh3 (0.2 mol %)
Pd(OAc)2 (1 mol %), PPh3 (4 mol %)
a Under an argon atmosphere, the treatment of 10 (2.0 equiv) was carried out with magnesium in THF under refluxing conditions followed by addition of trimethylborate
at -10 °C. To the whole mixture was added catalyst, base in water, and 14, and the resulting mixture was refluxed. b Isolated yield. c ND ) not detected. d 15 was not
isolated.
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reaction using acid 14b (R ) H), which was prepared by
hydrolysis of 14a, increased the formation of the impurity
18b and decreased the yield of desired 15b (entry 9).
Therefore, ester 14a was suitable as the substance for this
reaction.
Hydrolysis of 15a was carried out with 2 N NaOH in a
mixture of MeOH and THF to give 15b in 95% yield (purity
99.8%). The treatment of 15b with thionyl chloride in the
presence of a catalytic amount of DMF in THF followed by
a reaction with 4-[N-methyl-N-(tetrahydropyran-4-yl)ami-
nomethyl]aniline dihydrochloride (6)14 gave the desired 8
quantitatively. Crude 8 was crystallized by addition of
aqueous NaOH and MeOH to the reaction mixture and
refined by filtration without chromatographic purification
(yield 92%). Subsequently, recrystallization of crude 8 from
aqueous acetone afforded high-quality 8 in 90% yield (purity
99.3%) on a large scale.
In conclusion, we have been able to achieve the practical
synthesis of 8 in short steps for large-scale production
without chromatographic purification. 2,3-Dihydrobenza-
zepine derivative 14a was synthesized by a convenient
intramolecular Claisen type reaction of 13, which was
prepared from 3 and 12. The Suzuki-Miyaura reaction in
one pot using 14a and 10 was smoothly carried out with the
palladium catalyst (0.05 mol %) to give 15a in excellent
yield. The main route of this new method consisted of six
steps, as compared with eight steps in the previous method.3b
combined and concentrated under reduced pressure. The
concentrate was distilled under reduced pressure, and the
fraction boiling at 63-66 °C/6 mmHg was collected to give
12 (53.8 g, yield 90%) as a colorless oil. 1H NMR (CDCl3,
δ, 300 MHz) 0.90 (3H, t, J ) 7.4 Hz), 1.48-1.61 (2H, m),
1.96-2.07 (2H, m), 2.39 (2H, t, J ) 7.9 Hz), 3.24 (2H, t, J
) 7.5 Hz), 3.38 (2H, t, J ) 7.0 Hz) [lit.15 (δ) 0.96 (3H),
1.13-1.69 (2H), 1.85-2.42 (4H), 3.20 (2H), 3.34 (2H)]. IR
(neat, cm-1) 1673, 1465, 1427. EIMS: m/z 127 (M+). HRMS
(EI): m/z 127 (M+) C7H13NO calcd 127.0997, found
127.0990.
2-(4-Bromophenoxy)ethanol (17). To a solution of
2-phenoxyethanol (16) (440 g, 3.19 mol) and AcONa (340
g, 4.14 mol) in a mixture of AcOH and water (7/3, 880 mL)
was added dropwise a solution of bromine (515 g, 3.22 mol)
in a mixture of AcOH and water (7/3, 1760 mL) at 15-20
°C, and the whole mixture was stirred for 0.5 h at 10-20
°C. A 10% aqueous Na2SO3 solution (6 mL) and water (6.6
L) were added, and the resulting mixture was stirred for 2
h. The resulting crystals were collected by filtration, washed
with water (3 L), and dried under reduced pressure to give
17 (631 g, yield 91%) as a white crystalline powder. Mp
54-55 °C. Anal. Calcd for C8H9O2Br: C, 44.27; H, 4.18;
1
Br, 36.81. Found: C, 44.21; H, 4.32; Br, 36.84. H NMR
(CDCl3, δ, 300 MHz) 2.13 (1H, s), 3.95-3.98 (2H, m),
4.03-4.06 (2H, m), 6.77-6.82 (2H, m), 7.35-7.40 (2H, m).
IR (KBr, cm-1) 3350, 1486, 1241.
1-Bromo-4-(2-butoxyethoxy)benzene (10). To a solution
of 17 (603 g, 2.78 mol), 1-bromobutane (761 g, 5.56 mol),
and nBu4NHSO4 (47.2 g, 0.14 mol) in DMSO (3.02 L) was
added dropwise a 50% aqueous NaOH solution (1111 g, 13.9
mol) at 25-50 °C, and the whole mixture was stirred for
1.5 h at 35-40 °C. Water (6.03 L) was added, and the
mixture was extracted with a mixture of toluene (4.5 L) and
THF (1.26 L). The organic layer was washed succesively
with water (6.03 L), a 20% aqueous NaCl solution (3.02 L),
and water (6.03 L) and concentrated under reduced pressure.
The residue was distilled under reduced pressure, and the
fraction boiling at 125-130 °C/2 mmHg was collected to
give 10 (740.6 g, yield 98%) as a colorless oil. Anal. Calcd
for C12H17O2Br: C, 52.76; H, 6.27; Br, 29.25. Found: C,
Experimental Section
Melting points were recorded on a Bu¨chi B-540 mi-
cromelting apparatus and were uncorrected. IR spectra were
1
recorded on a Horiba FT-210 spectrophotometer. H NMR
spectra were recorded on a Bruker DPX-300 spectrometer
using tetramethylsilane as an internal standard. HPLC was
performed on a YMC-Pack ODS-A302 column (4.6 × 150
mm2) with 0.05 M KH2PO4 aqueous solution-MeCN (3:7)
at 25 °C. Detection was effected with a Shimadzu SPD-10A
spectrophotometric detector at 254 nm. Gas chromatography
was carried out using a Shimadzu GC-14A gas chromato-
graph equipped with an FID detector and Gaskuropack 54
column (1 m × 3 mm) (injector temperature 240 °C, helium
flow rate 50 mL/min, oven temperature 230 °C). The
microanalyses and mass spectral analyses were carried out
by Takeda Analytical Research Laboratories, Ltd.
1-Propylpyrrolidin-2-one (12). 2-Pyrrolidone (11) (40
g, 470 mmol), propionaldehyde (54.6 g, 940 mmol) and
AcOEt (470 mL) were added to a 1-L autoclave. Sodium
sulfate (106 g, 748 mmol) and 20% Pd-C (4.0 g, containing
50% H2O, N. E. Chemcat corporation) were added, and the
whole mixture was stirred at 105 °C for 4 h under 0.5 MPa
of hydrogen pressure. After the mixture was cooled to 20-
30 °C, Pd-C and sodium sulfate were filtered off and
washed with AcOEt (120 mL). The filtrate and washing were
1
52.85; H, 6.27; Br, 29.29. H NMR (CDCl3, δ, 300 MHz)
0.92 (3H, t, J ) 7.4 Hz), 1.30-1.45 (2H, m), 1.52-1.67
(2H, m), 3.52 (2H, t, J ) 6.6 Hz), 3.76 (2H, t, J ) 5.0 Hz),
4.07 (2H, t, J ) 5.0 Hz), 6.80 (2H, d, J ) 9.0 Hz), 7.35
(2H, d, J ) 9.0 Hz) [lit.3b (CDCl3, δ, 200 MHz) 0.92 (3H,
t, J ) 7.4 Hz), 1.27-1.65 (4H, m), 3.53 (2H, t, J ) 6.6 Hz),
3.74-3.79 (2H, m), 4.05-4.11 (2H, m), 6.81 (2H, d, J )
9.0 Hz), 7.36 (2H, d, J ) 9.0 Hz)]. IR (neat, cm-1) 2958,
2871, 1488.
4-[(4-Bromo-2-formylphenyl)(propyl)amino]butanoic
Acid (13). A solution of 12 (500 g, 3.93 mol) in 4 N NaOH
(1.97 L, 7.86 mol) was refluxed for 8 h. After the solution
was cooled to 40 °C, concentrated HCl (655 mL, 7.86 mol)
was added. After addition of DMSO (5 L) and Na2CO3 (834
g, 7.86 mol) to the resulting mixture at 20-30 °C, a solution
of 3 (399 g, 1.97 mol) in DMSO (1 L) was added dropwise
(12) Ikemoto, T.; Ito, T.; Nishiguci, A.; Tomimatsu, K. Tetrahedron 2004, 60,
10851.
(13) Freedman, H. H.; Dubois, R. A. Tetrahedron Lett. 1975, 38, 3251.
(14) Hashimoto, H.; Ikemoto, T.; Itoh, T.; Maruyama, H.; Hanaoka, T.;
Wakimasu, M.; Mitsudera, H.; Tomimatsu, K. Org. Process Res. DeV. 2002,
6, 70.
(15) Kaneniwa, N.; Ikekawa, A. Chem. Pharm. Bull. 1974, 22, 2990.
Vol. 9, No. 2, 2005 / Organic Process Research & Development
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171

to the whole mixture for 1 h under refluxing conditions. The
mixture was refluxed for 4 h. After it was cooled to 30 °C,
the mixture was treated with 4 N HCl (4.6 L) until the pH
was adjusted to 3.4 and extracted with a mixture of AcOEt
and THF (4/1, 3 L × 2). The organic layers were combined
and washed with a 20% aqueous NaCl solution (3 L). The
organic layer was extracted with a 10% aqueous Na2CO3
solution (9 L × 2), and the aqueous layers were combined
and washed with AcOEt (1 L). The aqueous layer was treated
with 6 N HCl (2 L) until the pH was adjusted to 3.3 and
extracted with a mixture of AcOEt and THF (4/1, 2 L × 2).
The organic layers were combined and washed successively
with a 20% aqueous NaCl solution (1 L × 2) and water (1
L) and concentrated under reduced pressure to give crude
13 (613 g) as a brown oil, which was used directly in further
reactions without purification. An analytically pure sample
of 13 was obtained by chromatography on silica gel as a
yellow oil. 1H NMR (CDCl3, δ, 300 MHz) 0.83 (3H, t, J )
7.4 Hz), 1.47-1.54 (2H, m), 1.81-1.88 (2H, m), 2.34 (2H,
t, J ) 7.2 Hz), 3.06-3.11 (2H, m), 3.18-3.22 (2H, m), 7.07
(1H, d, J ) 8.7 Hz), 7.57 (1H, dd, J ) 2.5, 8.7 Hz), 7.90
(1H, d, J ) 2.5 Hz), 10.22 (1H, s). IR (neat, cm-1) 2962,
1708, 1683. FABMS: m/z 328 (MH+), 350 (MNa+). HRMS
(FAB): m/z 350 (MNa+) C14H18NO3BrNa calcd 350.0368,
found 350.0332.
trimethylborate (7.69 g, 74.02 mmol) in THF (28 mL) was
added dropwise and the resulting mixture was stirred for 0.5
h at the same temperature. After the mixture was warmed
to 20 °C, Pd(OAc)2 (4.2 mg, 0.0185 mol) and PPh3 (19.4
mg, 0.074 mmol) were added and the whole mixture was
stirred for 0.5 h at the same temperature. Next, 14a (12.0 g,
37.0 mmol) and a solution of K3PO4 (41.24 g, 194 mmol)
in water (64 mL) were added, and the mixture was refluxed
for 5 h. After it was cooled to 20 °C, 3 N HCl (150 mL)
was added and the mixture was separated. The aqueous layer
was extracted with toluene (136 mL). The organic layers
were combined and washed successively with water (120
mL), 2 N NaOH (120 mL × 2), and water (120 mL × 2).
Activated charcoal (1.2 g) and tri-n-butylphosphine16 (1.2
mL) were added to the organic layer, and the mixture was
stirred for 0.5 h. The charcoal was filtered off and washed
with toluene (60 mL). The filtrate and washing were
combined and concentrated under reduced pressure. The
residue was dissolved in i-Pr2O (40 mL) under refluxing
conditions. After it was cooled to 0 °C, the mixture was
stirred for 2 h at the same temperature. The resulting crystals
were collected by filtration, washed with cold i-Pr2O (32
mL), and dried under reduced pressure to give 15a (14.7 g,
yield 91%) as a yellow crystalline powder. Mp 81-82 °C.
Anal. Calcd for C27H35NO4: C, 74.11; H, 8.06; N, 3.20.
1
Found: C, 73.99; H, 7.86; N, 3.11. H NMR (CDCl3, δ,
Methyl 7-Bromo-1-propyl-2,3-dihydro-1H-1-benza-
zepine-4-carboxylate (14a). To a solution of crude 13 and
K2CO3 (300 g, 2.17 mol) in DMF (1.6 L) was added
dropwise a solution of MeI (336 g, 2.36 mol) in DMF (300
mL) at 25-40 °C, and the mixture was stirred for 1 h at the
same temperature. After addition of dimethyl carbonate (3.9
L) to the mixture, 28% NaOMe in MeOH (912 g, 4.73 mol)
was added and the whole mixture was stirred for 0.5 h at 50
°C. After the mixture was cooled to 5 °C, 2 N HCl (2 L)
was added, and the whole mixture was concentrated and
extracted with toluene (2 L × 2). The organic layers were
combined and washed successively with 1 N NaOH (0.5 L
× 3), a 20% aqueous NaCl solution (1 L × 3), and water (1
L) and concentrated under reduced pressure. The residue was
dissolved in MeOH (1.5 L) at 40 °C. After it was cooled to
0 °C, the mixture was stirred for 2 h at the same temperature.
The resulting crystals were collected by filtration, washed
with cold MeOH (300 mL), and dried under reduced pressure
to give 14a (379 g, yield 60% from 3) as a yellow crystalline
powder. Mp 51-52 °C. Anal. Calcd for C15H18NO2Br: C,
55.57; H, 5.60; N, 4.32; Br, 24.65. Found: C, 55.69; H, 5.71;
N, 4.37; Br, 24.74. 1H NMR (CDCl3, δ, 300 MHz) 0.94 (3H,
t, J ) 7.4 Hz), 1.65-1.72 (2H, m), 2.78-2.81 (2H, m),
3.19-3.25 (4H, m), 3.79 (3H, s), 6.67 (1H, d, J ) 8.9 Hz),
7.22 (1H, dd, J ) 2.4, 8.9 Hz), 7.41 (1H, d, J ) 2.4 Hz),
7.56 (1H, s). IR (KBr, cm-1) 1700, 1496, 1251.
300 MHz) 0.90-0.97 (6H, m), 1.35-1.43 (2H, m), 1.57-
1.63 (2H, m), 1.69-1.76 (2H, m), 2.81 (2H, t, J ) 4.5 Hz),
3.26-3.33 (4H, m), 3.54 (2H, t, J ) 6.7 Hz), 3.57-3.80
(2H, m), 3.78 (3H, s), 4.14 (2H, t, J ) 4.7 Hz), 6.86 (1H, d,
J ) 8.7 Hz), 6.97 (2H, d, J ) 6.7 Hz), 7.39 (1H, dd, J )
2.2, 8.7 Hz), 7.45 (2H, d, J ) 6.7 Hz), 7.50 (1H, d, J ) 2.2
Hz), 7.79 (1H, s). IR (KBr, cm-1) 1706, 1504, 1241.
7-[4-(2-Butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-
1H-1-benzazepine-4-carboxylic acid (15b). To a solution
of 15a (720 g, 1.65 mol) in a mixture of THF (2.88 L) and
MeOH (7.2 L) was added 2N NaOH (1.65 L, 3.29 mol) and
the mixture was refluxed for 3 h. After the mixture was
cooled to 20 °C, activated charcoal (72 g) and tri-n-
butylphosphine16 (72 mL) were added and the mixture was
stirred for 0.5 h. The charcoal was filtered off and washed
with a mixture of MeOH, THF, and water (20/8/5, 1.26 L).
The filtrate and washing were combined. To the whole
mixture was added dropwise 1.5 N HCl (2.3 L, 3.45 mol) at
20-30 °C, and the resulting mixture was stirred for 1 h at
0-5 °C. The resulting crystals were collected by filtration,
washed with a mixture of MeOH and water (1/1, 3 L) and
dried under reduced pressure to give 15b (670 g, yield 96%)
as a yellow crystalline powder. Mp 148-149 °C. Anal. Calcd
for C26H33NO4: C, 73.73; H, 7.85; N, 3.31. Found: C, 73.72;
1
H, 7.71; N, 3.23. H NMR (CDCl3, δ, 300 MHz) 0.90-
1.00 (6H, m), 1.36-1.43 (2H, m), 1.56-1.64 (2H, m), 1.70-
1.78 (2H, m), 2.83 (2H, t, J ) 4.4 Hz), 3.28-3.34 (4H, m),
3.55 (2H, t, J ) 4.9 Hz), 3.82 (2H, t, J ) 4.7 Hz), 4.15 (2H,
t, J ) 5.2 Hz), 6.87 (1H, d, J ) 8.7 Hz), 6.99 (2H, d, J )
6.7 Hz), 7.42 (1H, dd, J ) 2.2, 8.7 Hz), 7.47 (2H, d, J )
Methyl 7-[4-(2-Butoxyethoxy)phenyl]-1-propyl-2,3-di-
hydro-1H-1-benzazepine-4-carboxylate (15a). Under an
argon atmosphere, to a suspension of magnesium (1.85 g,
76.1 mmol) in THF (80 mL) was added dropwise a solution
of 10 (20.22 g, 74.02 mmol) in THF (28 mL) under refluxing
conditions, and the whole mixture was refluxed for 1.5 h.
After the mixture was cooled to -10 °C, a solution of
(16) Larsen, R. D.; King, A. O.; Chen, C. Y.; Corley, E. G.; Foster, B. S.; Roberts,
F. E.; Yang, C.; Lieberman, D. R.; Reamer, R. A.; Tschaen, D. M.;
Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1994, 59, 6391.
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6.7 Hz), 7.52 (1H, d, J ) 2.2 Hz), 7.88 (1H, s). IR (KBr,
cm-1) 1664, 1504, 1249.
whole mixture was stirred for 3 h. The resulting crystals were
collected by filtration, washed with a mixture of acetone and
water (1/1, 1.5 L), and dried under reduced pressure to give
8 (139 g, yield 92%) as a yellow crystalline powder. Mp
123-125 °C (lit.3b mp 118-121 °C). Anal. Calcd for
C39H51N3O4: C, 74.85; H, 8.21; N, 6.71. Found: C, 74.81;
H, 8.30; N, 6.66. 1H NMR (CDCl3, δ, 300 MHz) 0.93 (3H,
t, J ) 7.3 Hz), 0.99 (3H, t, J ) 7.5 Hz), 1.31-1.45 (2H, m),
1.564-1.82 (8H, m), 2.20 (3H, s), 2.55-2.70 (1H, m), 2.80-
2.93 (2H, m), 3.23-3.40 (6H, m), 3.50-3.60 (4H, m), 3.80
(2H, t, J ) 4.7 Hz), 3.98-4.07 (2H, m), 4.14 (2H, t, J )
4.7 Hz), 6.88 (1H, d, J ) 8.7 Hz), 6.99 (2H, d, J ) 8.8 Hz),
7.28 (2H, d, J ) 8.4 Hz), 7.35-7.41 (2H, m), 7.42-7.50
(3H, m), 7.54 (2H, d, J ) 8.4 Hz), 7.63 (1H, s). IR (Nujol,
cm-1) 2954, 2923, 1639, 1517.
7-{4-[2-(Butoxy)ethoxy]phenyl}-N-(4-{[methyl(tetrahy-
dro-2H-pyran-4-yl)amino]methyl}phenyl)-1-propyl-2,3-
dihydro-1H-1-benzazepine-4-carboxamide (8). To a so-
lution of 15b (150 g, 345 mmol) and DMF (1.9 mL, 25
mmol) in THF (650 mL) was added dropwise thionyl
chloride (63.2 g, 531 mmol) at 0-5 °C, and the mixture
was stirred for 1 h at 20-30 °C. The resulting mixture was
added dropwise to a mixture of 4-[N-methyl-N-(tetrahydro-
pyran-4-yl)aminomethyl]aniline dihydrochloride (6) (125 g,
425 mmol) and triethylamine (346 mL, 2.48 mol) in THF
(750 mL) at 25-50 °C, and the whole mixture was stirred
for 1.5 h at 45-55 °C. To the mixture was added dropwise
0.65 N NaOH (2.18 L) and MeOH (750 mL) at the same
temperature. After it had cooled to 20 °C, the mixture was
stirred for 16 h. The resulting crystals were collected by
filtration, washed with a mixture of MeOH and water (1/1,
1.5 L), and dried under reduced pressure to give crude 8
(209 g, yield 94%) as a yellow crystalline powder.
Acknowledgment
We thank Dr. Taiichi Okada and Mr. Kokichi Yoshida
for discussions. We also thank Mr. Shunsuke Shima and Mr.
Tadashi Urai for their technical assistance.
Crude 8 (150 g) was dissolved in a mixture of purified
water (340 mL) and acetone (1.91 L) at 60 °C, and the
mixture was filtered through filter paper. After the filtrate
had cooled to 30 °C, water (375 mL) was added and the
Received for review November 19, 2004.
OP0497916
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