Development of a new synthetic route of a non-peptide CCR5 antagonist, TAK-779, for large-scale preparation

Article abstract of DOI:10.1021/op000074v

A new large-scalable preparation of TAK-779 (1), a non-peptide CCR5 antagonist, has been developed. The route selection was focused on in the process research. The selective reduction of commercially available benzonitrile derivative (4) as the starting material with sodium bis(2-methoxyethoxy)aluminum hydride followed by the Wittig reaction, hydrogenation, and intramolecular acylation gave benzocycloheptanone (7) in good yield. The conversion of α,α-unsaturated carboxylic acid (8) led from 7 to benzyl alcohol (9) and shortened the number of steps using non-protected 4-aminobenzyl alcohol. The reductive alkylation of Me₂NH and tetrahydro-4H-pyran-4-one (12) smoothly gave a tertiary amine (3). The coupling of 2 chlorinated 9, and 3 successfully led to an ammonium chloride (1). A new inexpensive preparation which did not require a chromatographic method was achieved.

Full text of DOI:10.1021/op000074v

Organic Process Research & Development 2000, 4, 520−525
Development of a New Synthetic Route of a Non-Peptide CCR5 Antagonist,
TAK-779, for Large-Scale Preparation
Tomomi Ikemoto,* Tatsuya Ito, Hideo Hashimoto, Tadao Kawarasaki, Atsuko Nishiguchi, Hiroyuki Mitsudera,
Mitsuhiro Wakimasu, and Kiminori Tomimatsu
Chemical DeVelopment Laboratories, Takeda Chemical Industries, Ltd., 2-17-85 Jusohonmachi,
Yodogawa-ku, Osaka 532-8686, Japan
Abstract:
especially effective.4 Hence, an efficient preparation of 1 on
large scale was required to support toxicological evaluation.
Two independent preparations of 1 comprising the am-
monium chloride moiety have been reported.4b,c One method
uses methylation of a tertiary amine followed by anion
exchange, and the other uses the reaction of benzyl chloride
(2) and tertiary amine (3) as shown in Scheme 1. The latter
synthesis produced a high-quality product, since this treat-
ment afforded only ammonium chloride without contamina-
tion by other counterions. However, the original synthesis
involved several limitations from the standpoint of large-
scale preparation, for example, utilization of expensive
reagents, requirement of a protective process, and repeated
tedious chromatographic methods, and lower yield. To
advance the practical preparation, we tried to develop an
alternative synthesis of 1 using inexpensive reagents. Here,
we report a new preparation of TAK-779 (1) that was
amenable to scale-up, and in which protective processes and
repeated chromatographic methods were not required, as
outlined in Scheme 2.
A new large-scalable preparation of TAK-779 (1), a non-peptide
CCR5 antagonist, has been developed. The route selection was
focused on in the process research. The selective reduction of
commercially available benzonitrile derivative (4) as the starting
material with sodium bis(2-methoxyethoxy)aluminum hydride
followed by the Wittig reaction, hydrogenation, and intramo-
lecular acylation gave benzocycloheptanone (7) in good yield.
The conversion of r,â-unsaturated carboxylic acid (8) led from
7 to benzyl alcohol (9) and shortened the number of steps using
non-protected 4-aminobenzyl alcohol. The reductive alkylation
of Me2NH and tetrahydro-4H-pyran-4-one (12) smoothly gave
a tertiary amine (3). The coupling of 2 chlorinated 9, and 3
successfully led to an ammonium chloride (1). A new inexpen-
sive preparation which did not require a chromatographic
method was achieved.
Introduction
In recent years, the â-chemokine receptor CCR5 has been
shown to act as a major coreceptor for fusion and entry of
macrophage-tropic HIV-1 into the host cell.1 This new
generation, having a novel mechanism, differs from well-
known chemotherapy, for example, HIV-1 reverse tran-
scriptase2 and protease inhibitors,3 and has been attractive
as a strong candidate for the therapy of HIV-1. In the search
of derivatives of many types, small-molecule non-peptide
compounds synthesized by Takeda chemists, anilido deriva-
tives, showed highly potent activities. In particular, N,N-
dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-ben-
zocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-
pyran-4-aminium chloride (TAK-779, 1) was found to be
Results and Discussion
Alternative Synthesis of 7-Tolylbenzocycloheptanone
(7). In an early report,4b,c 3-(4-methylphenyl)-6,7,8,9-tet-
rahydro-5H-benzocyclohepten-5-one (7) was synthesized by
cyclization of 5-(4-bromophenyl)pentanoic acid prepared
from bromobenzene as the starting material, followed by the
aryl-aryl cross-coupling using arylboronic acid. However,
intramolecular acylation of 5-(4-bromophenyl)pentanoic acid
using PPA produced 3-bromo-6,7,8,9-tetrahydro-5H-benzo-
cyclohepten-5-one in 67% yield accompanied with a tar
product, thus requiring chromatographic purification. To
resolve the hazardous problem described above, we attempted
to change the electron donor group from bromide as the
substituted group, that is, the cyclization of 5-(4-methylphen-
yl)pentanoic acid (6), since it was known that the substituted
groups in aromatic compounds affected the yields of the
intramolecular acylation. First, 4-(4-methylphenyl)benzal-
dehyde (5) as an intermediate of 6 was prepared in about
50% yield from the treatment of 4-methylphenylbenzene with
* Correspondence address: Tomomi Ikemoto, Chemical Development Labo-
ratories, Takeda Chemical Industries, Ltd., 2-17-85 Jusohonmachi, Yodogawa-
ku, Osaka 532-8686, Japan. E-mail: Ikemoto_Tomomi@takeda.co.jp.
(1) (a) Feng, Y.; Broder, C. C.; Kennedy, P. E.; Berger, E.A. Science 1996,
272, 872. (b) Alkhatib, G.; Combadiere, C.; Broder, C. C.; Feng, Y.;
Kennedy, P. E.; Murphy, P. M.; Berger, E.A. Science 1996, 272, 1955. (c)
Deng, H.; Liu, R.; Ellmeier, W.; Choe, S.; Unutmaz, D.; Burkhart, M.;
Marzio, P. D.; Marmon, S.; Shutton, R. E.; Hill, C. M.; Davis, C. B.; Peiper,
S. C.; Schall, T. J.; Littman, D. R.; Landau, N. R. Nature 1996, 381, 661.
(d) Dragic, T.; Litwin, V.; Allaway, G. P.; Martin, S. R.; Huang, Y.;
Nagashima, K. A.; Cayanan, C.; Maddon, P. J.; Koup, R. A.; Moore, J. P.;
Paxton, W. A. Nature 1996, 381, 667.
(2) Carpenter, C. C. J.; Fischl, M. A.; Hammer, S. M.; Hirsch, M. S.; Jacobsen,
D. M.; Katzenstein, D. A.; Montaner, J. S. G.; Richman, D. D.; Saag, M.
S.; Schooley, R. T.; Thompson, M. A.; Vella, S.; Yeni, P. G.; Volberding,
P. A. JAMA, J. Am. Med. Assoc. 1998, 280, 78.
(3) Deeks, S. G.; Smith, M.; Holodniy, M.; Kahn, J. O. JAMA, J. Am. Med.
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(4) (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) Kanzaki, N.; Shiraishi,
M.; Iizawa, Y.; Baba, M.; Nishimura, O.; Fujino, M. Drugs Future 2000,
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Y.; Kanzaki, N.; Okamoto, M.; Sawada, H.; Nishimura. O.; Baba, M.;
Fujino, M. J. Med. Chem. 2000, 43, 2049.
520
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10.1021/op000074v CCC: $19.00 © 2000 American Chemical Society and The Royal Society of Chemistry
Published on Web 10/12/2000

Scheme 1. Retrosynthesis of TAK-779 (1)
Table 1. Reduction of 4 with SBMEAa
entry
solvent
conditions
yield (%)
1
2
3
4
5
THF
-20 °C, 3 h
-20 °C, 3 h
-10 °C, 3 h
-10 °C, 3 h
0 °C, 3 h
98
91
87
96
89
toluene
DME
THF
THF
a SBMEA (1.0 equiv) was used.
Scheme 3. Original synthesis to benzylalcohol (9)4b,c
Scheme 2. New preparation for TAK-779 (1)
Short-Step Synthesis of Benzyl Alchohol (9). The
original synthetic approach to cinnamic acid derivative (8)
involved reduction with NaBH4 of the â-ketoester prepared
by the treatment of 7 and dimethyl carbonate in the presence
of NaOMe, followed by dehydration with MsCl/Et3N/DBU
and hydrolysis. However, the reduction of the â-ketoester
was performed in the hazardous dichloromethane solution
using the tedious, portionwise additions of NaBH4 and gave
the desired hydroxyester with a hydroxy-hydroxymethyl
derivative, which was an excess reductant. In view of these
results, chromatographic purification was required. To solve
this problem for large-scale preparation, optimization of the
reduction was examined. As a result, the reaction of the
â-ketoester with NaBH4 at -10 °C in THF/water (10/1)
afforded the target with a hydroxy-hydroxymethyl derivative.
Subsequently, the dehydration of the resulting mixture,
followed by the hydrolysis by NaOH solution, led to the
crude 8. The purification of 8 was performed by extraction
with NaOH solution and crystallization from acetone to get
the high-quality 8 in 54% isolated yield from 7 without a
chromatographic method.
In the original procedure, benzyl alchohol derivative (9)
was obtained by the amidation of 8 and expensive O-
TBDMS-protected 4-aminobenzyl alcohol (11), followed by
the deprotection with HCl (Scheme 3). The chemoselective
coupling of 8 and the commercially available 4-aminobenzyl
alcohol was carried out. The treatment of carboxylic acid
(8) and a DMF catalytic oxalyl chloride (2.0 equiv) in THF
followed by concentration and the reaction with 4-aminoben-
zyl alcohol (1.1 equiv) smoothly proceeded to give directly
the desired 9 in 95% yield. However, this procedure showed
inconstant yields, in pilot scale. It was thought that the
remaining oxalyl chloride reacted with 4-aminobenzyl al-
cohol to give undesired effects, because the ester of 8
remained in about 50% yield when the reaction mixture using
acid-chloride prepared from 2.0 equiv of oxalyl chloride
hexamethylenetetramine in TFA,5a not prepared by the
Vielsmier reagent.5b When the selective reduction of com-
mercially available 4-(4-methylphenyl)benzonitrile (4) was
also carried out, the reaction using sodium bis(2-methoxy-
ethoxy)aluminum hydride (SBMEA)6 in THF at -20 °C gave
benzaldehyde (5) in 98% yield (89% yield in pilot-scale
preparation) as shown in Table 1, although the yield of 5 by
DIBAL7 in toluene solution was lower. The Wittig reaction
of 5 followed by hydrogenation led to 6 in 80% yield. The
acylation of 6 using PPA smoothly gave cycloheptanone (7)
in 79% isolated yield without the byproduct. Friedel-Crafts
acylation of acid-chloride of 6 with AlCl3 led to contamina-
tion by inorganic products to inhibit the crystallization of 7.
Moreover, our approach did not require the tedious aryl-
aryl cross-coupling conditions.
(5) (a) Smith, E. S. J. Org. Chem. 1972, 37, 3972. (b) Barnett, G. H.; Anderson,
H. J.; Loader, C. E. Can. J. Chem. 1980, 58, 409.
(6) (a) Bo¨hme, B.; Sutoya, P. N. Ann. 1982, 1643. (b) Kato, K.; Takita, T.;
Umezawa, H. Tetrahedron Lett. 1980, 21, 4925. (c) Schlosser, M.; Brich,
Z. HelV. Chim. Acta 1978, 61, 1903.
(7) (a) Winterfeldt, E. Synthesis 1975, 617. (b) Yoon, N. M.; Gyoung, Y. S. J.
Org. Chem. 1985, 50, 2443.
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521

Table 2. Reaction of 8 with 4-aminobenzyl alcohola
Table 3. Condensation of 2 and 3a
ratio of productsb
entry
conditions
yield(%) of 1
purity(%) of 1
entry
(COCl)2 (equiv)
8
9
ester of 8
1
2
3
4
5
25 °C, 3 h
40-45 °C, 2 h
50-55 °C, 2 h
55-60 °C, 2 h
65-70 °C, 2 h
92
91
89
89
87
97.6
97.2
99.8
99.8
99.5
1
2
3
4
5
1.00
1.04
1.10
1.14
2.00
4.6
5.5
0.1
0.1
0.2
90.4
88.4
95.3
93.8
31.7
NDc
ND
0.2
ND
48.0
a 3 (1.5 equiv) was used.
a 4-Aminobenzyl alcohol (1 equiv) was used, and the reaction mixture was
quenched by MeOH. b Analyzed by HPLC at 254 nm. c ND ) not detected.
°C smoothly gave the desired 1 in 89% yield (99.8% purity),
although the reaction at room temperature gave a small
residual quantity of 2 as shown in Table 3. Subsequently,
recrystallization from 15% aqueous EtOH successfully
prepared the high-quality 1 in 81% yield.
Scheme 4. Improved synthesis of tertiary amine (3)a
In conclusion, we have been able to achieve practical
preparation of 1 for large scale using commercially available
reagents. The process development focused on a search for
a suitable route selection of 1. This alternative synthesis has
been used to prepare multikilogram quantities of the bulk
substance for toxicological trials.
a Reagents and conditions. a:4b,c HCO2H, DMF, water, 100 °C, 6 h, 29%. b:
5% Pd-C, Me2NH in THF, 2 kgf/cm2 H2, rt, 4 h, 75%.
was quenched by MeOH. The amidation was, therefore,
optimized without concentration of the acid-chloride solution,
as shown in Table 2. As a result, the amidation using acid-
chloride prepared from 1.1 equiv of oxalyl chloride gave 9
in 89% yield in multikilogram preparation. Separately, we
sought an alternative preparation of benzyl chloride derivative
(2). The acid-chloride of 8 reacted with aniline to give
N-phenyl-2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclo-
hepten-8-carboxamide quantitatively. However, the chlo-
romethylation of the resulting anilide was not entirely
successful with the reagents, for example, HCl/HCHO and
chloromethyl methyl ether/Lewis acids.8
Convenient Synthesis of Tertiary Amine (3). In previ-
ous synthesis, the result of the treatment of tetrahydro-4H-
pyran-4-one (12) with formic acid and DMF was unsatis-
factory, giving 4-dimethylaminotetrahydro-2H-pyran-4-one
(3) in 29% yield. This outcome was thought to result from
the difficult extraction due to the high solubility of tertiary
amine (3) in water. It was therefore considered that an
alternative preparation of 3 was required without the extrac-
tion. The reductive alkylation9 of 12 and Me2NH in THF
under conditions of 2 kgf/cm2 hydrogen atmosphere, fol-
lowed by only distillation produced 3 in 75% isolated yield
(the yield of 3 was almost quantitative by GC). The decreased
yield in distillation was caused by the lower boiling point
(bp29 75-82 °C1c) and large amounts of forerun as the water
azeotrope (Scheme 4).
Experimental Section
Melting points were recorded on a Bu¨chi B-540 micro
melting apparatus and were uncorrected. IR spectra were
1
recorded on a Horiba FT-210 spectrophotometer. H NMR
spectra was recorded on a Bruker DPX-300 spectrometer
using tetramethylsilane as an internal standard. HPLC was
performed on a YMC-Pack ODS-A302 column (6 i.d. × 150
mm) with 0.05 M KH2PO4 aqueous solution-MeCN (2:8,
3:7, 4:6, and 7:3) at 25 °C. Detection was effected with a
Shimadzu SPD-10A spectrophotometric detector at 254 nm.
Elemental analysis was carried out by Takeda Analytical
Research Laboratories, Ltd.
4-(4-Methylphenyl)benzaldehyde (5). A solution of 70%
sodium bis(2-methoxyethoxy)aluminum hydride in toluene
(16.5 kg) was added dropwise over 1 h to a solution of 4-(4-
methylphenyl)benzonitrile (4, 11.0 kg) in THF (110 L)
keeping the temperature at -15 to -5 °C under nitrogen
atmosphere, and the resulting mixture was stirred for 2 h
under the same conditions. After the reaction was completed,
the whole was added to a solution of concentrated H2SO4
(36 kg) in water (88 L) at -5-5 °C, and then water (110 L)
and AcOEt (110 L) were added to the mixture. The mixture
was stirred at 40-50 °C and allowed to stand. After the
layers were separated, the aqueous layer was extracted with
a mixture of THF (11 L) and AcOEt (33 L). The organic
layers were combined, washed successively with 5% NaCl
solution (55 L) and 7% NaHCO3 solution (55 L), concen-
trated, and diluted with 2-propanol (39 L). The mixture was
stirred under refluxing condition for 1 h and then at -5-5
°C for 4 h. The resulting crystals were collected by filtration,
washed with cold 2-propanol (5 L), and dried under reduced
pressure at 40-60 °C to give 5 (10.0 kg, yield 89%) as a
white crystalline powder: mp 111-112 °C. Anal for
C14H12O. Calcd: C, 85.68; H, 6.16. Found: C, 85.61; H,
6.01. 1H NMR (CDCl3, δ, 300 MHz) 2.41 (3H, s), 7.29 (2H,
d, J ) 8.1 Hz), 7.54 (2H, d, J ) 8.1 Hz), 7.74 (2H, d, J )
Synthesis of TAK-779 (1). The chlorination of 9 with
thionyl chloride in THF instead of the previously reported
solvent CHCl3 at room temperature for 2 h gave benzyl
chloride (2) in 87% yield. In the final stage, the coupling of
benzyl chloride (2) and a tertiary amine (3) in DMF at 50
(8) (a) McCarthy, J.R.; Huffman, J. C. J. Org. Chem. 1984, 49, 4995. (b)
Tashiro, M.; Yamamoto, T.; Kobayashi, K. ibid 1984, 49, 4724. (c)
McKillop, A.; Madjdabadi, F. A.; Long, D. A. Tetrahedron Lett. 1983, 24,
1933.
(9) (a) Heinzelman, R. V.; Aspergren, B. D. J. Am. Chem. Soc. 1953, 75, 3409.
(b) Frahm, A. W.; Knupp, G. Tetrahedron Lett. 1981, 22, 2633. (c) Glaser,
R.; Gabbay, E. J. J. Org. Chem. 1970, 35, 2907. (d) Bringmann, G.; Kunkel,
G.; Geuder, T. Synlett 1990, 5, 253.
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8.4 Hz), 7.93 (2H, d, J ) 8.4 Hz), 10.04 (1H, s). IR (KBr,
cm-1) 1700, 1602, 1209, 1186, 1166, 809.
was extracted with toluene (18 L), the organic layers were
combined, washed successively with water (55 L × 2), 25%
ammonia solution (145 L), and water (73 L), concentrated
under reduced pressure, and dissolved in acetone (8 L). The
seed crystals (5 g) were added to the solution at 0-10 °C,
and then the mixture was diluted with MeOH (8 L) and water
(16 L) and stirred at 0-10 °C for 40 min. The resulting
crystals were collected by filtration, washed with a mixture
of acetone (6 L), MeOH (6 L) and water (12 L), and dried
under reduced pressure at 30-40 °C to give 7 (8.0 kg, yield
79%) as a white crystalline powder: mp 61-64 °C. Anal
for C18H18O. Calcd: C, 86.36; H, 7.25. Found: C, 86.54;
5-[4-(4-Methylphenyl)phenyl]-4-pentenoic acid. A solu-
tion of 28% NaOMe in MeOH (29.5 kg) and a solution of
5 (10.0 kg) in THF (100 L) were successsively added to a
suspension of (3-carboxypropyl)triphenylphosphonium bro-
mide (32.7 kg) and THF (330 L) at about 60 °C, and the
resulting mixture was stirred at 55-60 °C for 1 h. After the
reaction was completed, a solution of KOH (8.6kg) and water
(300 L) and diisopropyl ether (130 L) were successively
added to the reaction mixture at 20-40 °C, and the resulting
mixture was allowed to stand. The layers were separated,
and the organic layer was extracted twice with a solution of
KOH (9.3 kg) and water (200 L). After the aqueous solution
was combined, THF (200 L) and AcOEt (200 L) were added
to the mixture, and then the resulting mixture was acidified
(pH ) 1.5) with 6 N HCl. After the mixture was allowed to
stand, the organic layer was separated, washed with 10%
NaCl solution( 300 L), and concentrated under reduced
pressure. The concentrate was diluted with EtOH (94 L) and
water (40 L), and stirred at 5-30 °C for 1 h and then at
0-5 °C for 1 h. The resulting crystals were collected by
filtration, washed with a mixture of EtOH (35 L) and water
(15 L), and dried under reduced pressure at 40-60 °C to
give 5-[4-(4-methylphenyl)phenyl]-4-pentenoic acid (11.5 kg,
yield 85%) as a white crystalline powder: mp 198-199 °C.
Anal for C18H18O2. Calcd: C, 81.17; H, 6.81. Found: C,
81.20; H, 6.68. 1H NMR (DMSO-d6, δ, 300 MHz) 2.34 (3H,
s), 2.39-2.41 (4H, m), 6.27-6.39 (1H, m), 6.46 (1H, d, J
) 15.6 Hz), 7.26 (2H, d, J ) 8.1 Hz), 7.44 (2H, d, J ) 8.1
Hz), 7.54-7.60 (4H, m), 12.13 (1H, brs). IR (KBr, cm-1)
2730, 2653, 2578, 1691, 1496, 1255, 790.
1
H, 7.25. H NMR (CDCl3, δ, 300 MHz) 1.83-1.92 (4H,
m), 2.38 (3H, s), 2.76 (2H, m), 2.96 (2H, m), 7.22-7.26
(3H, m), 7.50 (2H, d, J ) 8.0 Hz), 7.62-7.64 (1H, m), 7.95
(1H, d, J ) 2.0 Hz). IR (KBr, cm-1) 1660, 1486, 819.
2-(4-Methylphenyl)-6,7-dihydro-5H-benzocyclohepten-
8-carboxylic acid (8). To a solution of 7 (8.0 kg) in dimethyl
carbonate (40 L) was added NaOMe (8.6 kg), and the whole
was refluxed for 2 h. After the reaction was completed, the
reaction mixture was cooled to 0-10 °C and acidified (pH
) 1) with 6 N HCl. After diisopropyl ether (31 L) and water
(15 L) were added to the mixture, the resulting mixture was
allowed to stand. The organic layer was separated, washed
with water (15 L), and concentrated under reduced pressure.
To a solution of the residue in a mixture of THF (44 L)
and water (4 L) was added NaBH4 (1.86 kg) at -15 to -5
°C under nitrogen atmosphere, the whole was stirred for 2.5
h under the same conditions. After the reaction was
completed, water (44 L) and diisopropyl ether (44 L) were
added to the reaction mixture under the same conditions,
and the resulting mixture was allowed to stand. After the
layers were separated, the aqueous layer was extracted with
diisopropyl ether (44 L). The organic layers were combined,
washed successively with 1 N HCl (46 L × 2) and water
(46 L), concentrated under reduced pressure, and dissolved
in THF (46 L).
To the resulting solution was added NEt3 (10.0 kg), and
the whole was cooled to 0-10 °C. MsCl (5.7 kg) was added
dropwise to the mixture at the same temperature, and the
whole was stirred for 2 h at 20-30 °C. DBU (10.0 kg) was
added to the mixture at 20-30 °C, and the resulting mixture
was stirred for 3 h at the same temperature. After the reaction
was completed, water (46 L) and diisopropyl ether (46 L)
were added to the reaction mixture, and the resulting mixture
was allowed to stand. After the layers were separated, the
aqueous layer was extracted with diisopropyl ether (46 L).
The organic layers were combined, washed successively with
1 N HCl (46 L), 1 N NaOH (46 L), and water (46 L × 2),
concentrated under reduced pressure, and dissolved in THF
(49 L).
5-[4-(4-Methylphenyl)phenyl]-4-pentanoic Acid (6). To
a solution of 5-[4-(4-methylphenyl)phenyl]-4-pentenoic acid
(11.5 kg) in THF (231 L) was added 5% Pd-C (wet, 0.6 kg)
at 35-40 °C under nitrogen atmosphere. The whole was
stirred for 1.5 h at 35-40 °C under the condition of 1.5 kgf/
cm2 hydrogen pressure. After the reaction was completed,
Pd-C was filtered off and washed with THF (23 L). The
filtrate and washings were combined and concentrated under
reduced pressure. The concentrate was diluted with diiso-
propyl ether (46 L) and stirred at 0-5 °C for 1.5 h. The
resulting crystals were collected by filtration, washed with
diisopropyl ether (23 L), and dried under reduced pressure
at 50-60 °C to give 6( 10.9 kg, yield 94%) as a white
crystalline powder: mp 175-176 °C. Anal for C18H20O2.
1
Calcd: C, 80.56; H, 7.51. Found: C, 80.67; H, 7.41. H
NMR (CDCl3, δ, 300 MHz) 1.69-1.73 (4H, m), 2.38-2.40
(5H, m), 2.64-2.68 (2H, m), 7.21-7.24 (4H, m), 7.43-
7.48 (4H, m). IR (KBr, cm-1) 1700, 1500, 810.
3-(4-Methylphenyl)-6,7,8,9-tetrahydro-5H-benzocyclo-
hepten-5-one (7). To polyphosphoric acid (221kg) was added
6 (10.9kg) at 70-90 °C, and the whole was stirred for 12 h
at 95-105 °C. After the reaction was completed, ice (145
kg) was added to the reaction mixture keeping the temper-
ature at 40-85 °C, and toluene (73 L) was added to the
mixture at 30-50 °C. The resulting mixture was allowed to
stand, and the layers were separated. After the aqueous layer
To the resulting solution were added MeOH (49 L) and
1 N NaOH (49 L), and the whole was stirred for 2 h at 55-
60 °C. After the reaction was completed, toluene (31 L) was
added to the reaction mixture at 50-60 °C, and the resulting
mixture was allowed to stand at the same temperature. The
aqueous layer was separated, washed with toluene (31 L ×
2) at the same temperature, cooled to 0-20 °C, and acidified
Vol. 4, No. 6, 2000 / Organic Process Research & Development
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523

(pH ) about 1.5) with concentrated HCl. The resulting
crystals were collected by filtration and washed with water
(80 L).
were combined, washed successively with 7% NaHCO3
solution (22 L) and 10% NaCl solution(17 L), and 30% NaCl
solution (24 L × 2). To the resulting organic layer was added
MgSO4 (7.0 kg), and the resulting suspension was stirred
for about 10 min. The magnesium sulfate was filtered off
and washed with a mixture of THF (4.5 L) and AcOEt(4.5
L). The filtrate and washings were combined and concen-
trated under reduced pressure, and AcOEt (64 L) was added
intermittently without interruption of the concentration. After
the resulting mixture was stirred for about 2 h at 0-10 °C,
the resulting crystals were collected by filtration and washed
with a mixture of AcOEt (3 L) and diisopropyl ether (6 L),
and dried under reduced pressure at about 40 °C to give 2
(3.2 kg, yield 87%) as a white crystalline powder: mp 173-
175 °C. Anal for C26H24NOCl. Calcd: C, 77.70; H, 6.02;
N, 3.48; Cl, 8.82. Found: C, 77.69; H, 6.13; N, 3.43; Cl,
The resulting wet crystals were dissolved in acetone (123
L) at 50-60 °C, and then activated charcoal was added to
the solution. After the mixture was stirred for 45 min at the
same temperature, the charcoal was filtered off at the same
temperature and washed with warm acetone (15 L, about 50
°C). The filtrate and washings were combined and concen-
trated under reduced pressure to 45 L, and the resulting
concentrate was gradually cooled to -5-0 °C for 1.5 h. The
resulting crystals were collected by filtration and washed with
cold acetone (8 L, about -10 °C), and dried at about 35-
45 °C to give 8 (4.8 kg, yield 54%) as a white crystalline
powder: mp 186-188 °C. Anal for C19H18O2. Calcd: C,
81.99; H, 6.52. Found: C, 81.91; H, 6.52. 1H NMR (CDCl3,
δ, 300 MHz) 2.07-2.13 (2H, m), 2.39 (3H, s), 2.67-2.71
(2H, m), 2.86-2.89 (2H, m), 7.20-7.26 (4H, m), 7.43-
7.55 (3H, m), 7.91 (1H, s). IR (KBr, cm-1) 2923, 1671.
N-(4-Hydroxymethylphenyl)-2-(4-methylphenyl)-6,7-
dihydro-5H-benzocyclohepten-8-carboxamide (9). Oxalyl
chloride (1.5kg) was added dropwise to a solution of 8 (3.0
kg) and DMF (30 mL) in THF (24 L) at 0-10 °C, and the
whole was stirred for 1 h at 20-30 °C. After the reaction
was completed, the reaction mixture was added dropwise to
a solution of 4-aminobenzyl alcohol (1.6 kg) and NEt3 (4.5
L) in THF (30 L) at 0-10 °C. The whole was stirred for 1.5
h at the same temperature. After the reaction was completed,
water (12 L) was added dropwise to the reaction mixture at
the same temperature, and the resulting mixture was allowed
to stand. The layers were separated, and the aqueous layer
was extracted with AcOEt (60 L). The organic layers were
combined, washed successively with 7% NaHCO3 solution
(12 L) and 30% NaCl solution (18 L), 1 N HCl (18 L × 3),
and 15% NaCl solution (18 L × 4). The resulting organic
layer was concentrated under reduced pressure, and AcOEt
(24 L) was added to the concentrate, and then the mixture
was concentrated again under reduced pressure. After AcOEt
(48 L) was added intermittently without interruption of the
concentration, the resulting concentrate was stirred for about
1 h at 10-30 °C. The resulting crystals were collected by
filtration and washed with AcOEt (9 L), and dried under
reduced pressure at about 40 °C to give 9 (3.7 kg, yield 89%)
as a white crystalline powder: mp 184-185 °C. Anal. for
C26H25NO2. Calcd: C, 81.43; H, 6.57; N, 3.65. Found: C,
1
8.69. H NMR (CDCl3, δ, 300 MHz) 2.13-2.19 (2H,m),
2.39 (3H, s), 2.68-2.72 (2H, m), 2.85-2.89 (2H, m), 4.58
(2H, s), 7.20-7.69 (12H, m). IR(KBr, cm-1) 3336, 1644,
1517.
N,N-Dimethyl-N-tetrahydro-2H-pyran-4-ylamine(3).
Dimethylamine(4.3kg) was dissolved in THF (15.1kg) at
0-10 °C. To the resulting solution were added tetrahydro-
4H-pyran-4-one (12, 3.0 kg) and 5% Pd-C (wet, 0.3 kg)
under nitrogen atmosphere, and the whole was stirred for 4
h under the conditions of 2 kgf/cm2 hydrogen. After the
reaction was completed, Pd-C was filtered off and washed
with THF (5 L). The filtrate and washings were combined
and concentrated at 15-45 °C under reduced pressure (50-
100 mmHg). The concentrate was distilled under reduced
pressure, the fraction boiling at 60-80 °C/30-40 mmHg
was collected to give 3 (2.9 kg, yield 75%) as a colorless
oil. Anal for C7H15NO‚H2O. Calcd: C, 64.16; H, 11.70; N,
10.70. Found: C, 64.02; H, 11.44; N,11.03. 1H NMR
(CDCl3, δ, 300 MHz) 1.5-1.6 (2H, m), 1.7-1.8 (2H, m),
2.1-2.4 (7H, m), 3.3-3.5 (2H, m), 3.9-4.1 (2H, m). IR
(neat, cm-1) 2952, 2836, 2771, 1213, 1135.
N,N-Dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-
5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahy-
dro-2H-pyran-4-aminium chloride (TAK-779, 1). A so-
lution of 2 (3.1 kg) in DMF (16 L) was added dropwise to
a solution of 3 (1.5 kg) in DMF (16 L) at 50-60 °C, and
the resulting mixture was stirred for 2 h at the same
temperature. After the reaction was completed, acetone (31
L) was added to the reaction mixture at the same temperature.
The resulting mixture was stirred for about 30 min at the
same temperature, cooled to 20-30 °C, and stirred for about
1 h at the same temperature. The resulting crystals were
collected by filtration and washed with acetone (13 L), and
dried under reduced pressure at about 40 °C to give crude 1
(3.8 kg, yield 91%) as a white crystalline powder.
1
81.19; H, 6.40; N, 3.63. H NMR (CDCl3, δ, 300 MHz);
2.16 (2H, tt, J ) 6.8, 5.8 Hz), 2.39 (3H, s), 2.72 (2H, t, J )
6.8 Hz), 2.88 (2H, t, J ) 5.8 Hz), 4.67 (2H, s), 7.21-7.63
(12H, m). IR (KBr, cm-1)1649, 1519.
N-(4-Chloromethylphenyl)-2-(4-methylphenyl)-6,7-di-
hydro-5H-benzocyclohepten-8-carboxamide(2). To a sus-
pension of 9 (3.6 kg) in THF (36 L) was added dropwise
SOCl2 (1.7 kg) at 0-10 °C, and the whole was stirred for 2
h at 20-30 °C. After the reaction was completed, AcOEt
(36 L) and 10% NaCl solution (15 L) were added to the
reaction mixture at 0-10 °C, and the resulting mixture was
allowed to stand. The layers were separated, and the aqueous
layer was extracted with AcOEt (22 L). The organic layers
To a solution of crude 1 (2.9 kg) and purified water (4.5
L) in EtOH (25.5 L) was added activated charcoal (87 g) at
60-80 °C, and the resulting suspension was stirred for about
15 min at the same temperature. The charcoal was filtered
off and washed with a mixture of EtOH (0.7 L) and purified
water (0.1 L). The filtrate and washings were combined and
filtered through N66POSIDYNE to remove pyrogens, and
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then the N66POSIDYNE was washed with a mixture of EtOH
(0.7 L) and purified water (0.1 L). The filtrate and washings
were combined and gradually cooled to 0-10 °C. The
resulting crystals were collected by filtration, washed with
ethanol (5 L), and dried under reduced pressure at about 40
°C to give 1 (2.3 kg, yield 81%) as a white crystalline
powder: mp 222-223 °C (dec). Anal for C33H39N2O2Cl.
Calcd: C, 74.62; H, 7.40; N, 5.27; Cl, 6.67. Found: C, 74.37;
H, 7.32; N, 5.23; Cl, 6.53. 1H NMR (DMSO-d6, δ, 300 MHz)
1.85-2.18 (6H, m), 2.34 (3H, s), 2.64 (2H, m), 2.78 (8H,
m), 3.35 (2H, m), 3.50-3.75 (1H, m), 4.04-4.07 (2H, m),
4.46 (2H, s), 7.26-7.88 (12H, m), 10.22 (1H, s). IR (KBr,
cm-1) 1652, 1521.
Acknowledgment
We thank Drs. Taiichi Okada, Mitsuru Shiraishi, Mrs.
Yoshio Aramaki, and Masaki Seto for helpful discussions.
Received for review July 5, 2000.
OP000074V
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