Process development of 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline dihydrochloride: A key intermediate for TAK-779, a small-molecule nonpeptide CCR5 antagonist

Article abstract of DOI:10.1021/op010052o

A new and efficient synthesis of 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline dihydrochloride, a key intermediate for the CCR5 antagonist TAK-779, is described. Reductive alkylation of methylamine with tetrahydro-4H-pyran-4-one followed by alkylation of N-methyl-N-(tetrahydropyran-4-yl)amine with 4-nitrobenzylbromide and reduction of N-(4-nitrobenzyl)-N-(tetrahydropyran-4-yl)amine results in a 78% isolated yield from the starting materials by a scalable method, using only commercially available reagents.

Full text of DOI:10.1021/op010052o

Organic Process Research & Development 2002, 6, 70−73
Process Development of
4-[N-Methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline Dihydrochloride: A Key
Intermediate for TAK-779, a Small-Molecule Nonpeptide CCR5 Antagonist
Hideo Hashimoto,* Tomomi Ikemoto, Tatsuya Itoh, Hideaki Maruyama, Tadashi Hanaoka, Mitsuhiro Wakimasu,†
Hiroyuki Mitsudera, and Kiminori Tomimatsu
Chemical DeVelopment Laboratories, Takeda Chemical Industries, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku,
Osaka 532-8686, Japan
Scheme 1. Reported synthesis of 6
Abstract:
A new and efficient synthesis of 4-[N-methyl-N-(tetrahydropy-
ran-4-yl)aminomethyl]aniline dihydrochloride, a key intermedi-
ate for the CCR5 antagonist TAK-779, is described. Reductive
alkylation of methylamine with tetrahydro-4H-pyran-4-one
followed by alkylation of N-methyl-N-(tetrahydropyran-4-yl)-
amine with 4-nitrobenzylbromide and reduction of N-(4-
nitrobenzyl)-N-(tetrahydropyran-4-yl)amine results in a 78%
isolated yield from the starting materials by a scalable method,
using only commercially available reagents.
Results and Discussion
Recently, the â-chemokine receptor CCR5 has been
reported to act as a major coreceptor for fusion and entry of
macrophage-tropic HIV-1 into the host cell.1 CCR5 antago-
nists are attractive as candidates for HIV-1 therapy, having
a new mechanism of action in comparison with that of well-
known chemotherapy represented by HIV-1 reverse tran-
scriptase and protease inhibitors.2,3 During our intensive
research of many derivatives, N,N-dimethyl-N-[4-[[[2-(4-
methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbo-
nyl]-amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride
(1, TAK-779) was identified as a small-molecule nonpeptide
CCR5 antagonist.4
mononuclear cells (PBMCs). Synthesis of 1 was accom-
plished by amidation followed by methylation and anion
exchange from two key intermediates, 4-[N-methyl-N-
(tetrahydropyran-4-yl)aminomethyl]aniline (6) and 2-(4-
methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-carbox-
ylic acid.5 In the initial screening stage, key intermediate 6
was synthesized by reductive alkylation of 4-nitrobenzyl-
amine (2) followed by a second reductive alkylation and
reduction (Scheme 1). 6 was prepared in gram quantities via
this Scheme for initial pharmacological screening.6 However,
the reported methods involved the following shortcomings
from the viewpoint of large-scale manufacturability: use in
bulk of starting material 2 with limited availability, separation
of a large amount of solid waste including reducing reagents,
and use of an environmentally unfriendly solvent, 1,2-
dichloroethane. In particular, the difficulty of purchasing the
starting materials was a serious problem in manufacturing 6
This compound inhibits the replication of macrophage (M)-
tropic HIV-1 in both MAGI-CCR5 cells and peripheral blood
* Correspondence address. Hideo Hashimoto. Chemical Development Labo-
ratories, Takeda Chemical Industries, Ltd., 2-17-85, Jusohonmachi, Yodogawa-
ku, Osaka 532-8686, Japan. Telephone: +81-6-6300-6283. Fax: +81-6-6300-
6251. E-mail: hashimoto_hideo@takeda.co.jp.
(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. J. Am. Med. Assoc. 1998, 280, 78.
† Scientific Information Pharmaceutical Business Development.
(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.
(3) Deeks, S. G.; Smith, M.; Holodniy, M.; Kahn, J. O. J. Am. Med. Assoc.
1997, 277, 145.
(4) 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.
(5) Kanzaki, N.; Shiraishi, M.; Iizawa, Y.; Baba, M.; Nishimura, O.; Fujino,
M. Drugs Future 2000, 25, 252.
(6) 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.
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10.1021/op010052o CCC: $22.00 © 2002 American Chemical Society and The Royal Society of Chemistry
Published on Web 11/30/2001

Scheme 2
Table 1. Reductive alkylation of methylamine
hydrochloride with 3a
yield
of 8b
(%)
recovery
yield of
by-productb
(%)
time
(h)
of 3b
entry base equiv
Kb
(%)
1
2
3
4
5
6
7
8
Et3N
Et3N
Et3N
Bu3N
Pr3N
1.00 5.5 × 10-4
0.03 5.5 × 10-4
0.01 5.5 × 10-4
0.03 7.8 × 10-4
0.03 4.5 × 10-4
2
2
3
3
3
3
3
96.1
0
0
0
0.5
0.8
0
0
6.1
0.5
0.4
1.0
1.5
1.4
9.9
7.9
9.0
96.2 (91.6)
96.1 (91.9)
97.0
90.9
89.5
Me3N 0.03 0.6 × 10-4
aniline 0.03 4.2 × 10-10
none
88.1
10 84.8
a The reaction was carried out in methanol at 60 °C under the condition of 5
kgf/cm2 hydrogen atmosphere. [CH3NH2‚HCl]:[3]:[5%Pd/C] ) 1:1:0.002. b Yield
and recovery based on initial quantity of CH3NH2‚HCl charged were determined
by GC analysis. The value in parentheses indicates the isolated yield of 9.
Scheme 3. Hypothetical catalytic cycle for the synthesis of
9
for toxicological studies. Herein, we wish to report new and
efficient methods amenable to a large-scale synthesis of 6.
We focused on a synthetic route using 4-nitrobenzylbro-
mide (10) and tetrahydro-4H-pyran-4-one (3) as a suitable
process for large-scale synthesis (Scheme 2) since both are
commercially available in large quantities. The synthesis of
6 was initiated by reductive alkylation of methylamine with
3, followed by alkylation of N-methyl-N-(tetrahydropyran-
4-yl)amine (8) with 10, and reduction of N-(4-nitrobenzyl)-
N-(tetrahydropyran-4-yl)methylamine (5).
Synthesis of N-Methyl-N-(tetrahydropyran-4-yl)amine
Hydrochloride (9). Synthetic methods avoiding the use of
sodium triacetoxyborohydride were first investigated to avoid
the tedious removal of the catalyst and 1,2-dichloroethane
for environmental considerations.7 Thus, reductive alkylation
of methylamine and 3 in the presence of Pd-C under
hydrogen atmosphere in methanol as solvent proceeded
almost quantitatively to give 8 in 69% isolated yield after
distillation (95% purity).8,9 However, further studies indicated
that the yield is not consistent, presumably due to the low
boiling point of 8 (72 °C/28 mmHg) or to its high solubility
in water. To overcome this problem, crystallization of the
product as its hydrochloride salt was developed.
Although the isolated yield was improved in this way,
we still continued our efforts to improve the process. One
of the most significant issues on scale is the use of
methylamine gas. In our early studies, methylamine gas was
first dissolved in methanol; however, the quantity of meth-
ylamine absorbed was quite inconsistent and difficult to
control. Furthermore, excess methylamine led to a large
amount of by-products, whilst a lack of methylamine resulted
in giving other by-products, including N-methyl-N,N-bis-
(tetrahydropyran-4-yl)amine. We investigated solid methyl-
amine hydrochloride as an alternative agent, expecting to
control the quantity of methylamine more easily. We
envisaged that the reductive alkylation of methylamine with
3 would proceed in the presence of 1 equiv of a strong
enough base to neutralize methylamine hydrochloride. 8 was
prepared in 96.1% yield in the presence of 1 equiv of
triethylamine as expected (Table 1, entry 1). However, a
considerable amount of triethylamine hydrochloride was
involved. Although extraction of the product into an organic
solvent and washing with water is a well-known method to
remove salts, this procedure markedly decreased the yield
due to solubility of 8 that was too high in water. To overcome
this problem, we investigated the new process which does
not require the neutralization procedure, allowing isolation
of 8 as hydrochloride salt.
Reaction in the presence of trimethylamine as base
involved a considerable amount of a by-product due to too
low basicity (Kb ) 0.6 × 10-4, entry 6). Aniline (Kb ) 4.2
× 10-10) also failed to give satisfactory results. The
by-product was assumed to be N-methyl-N,N-bis(tetrahy-
dropyran-4-yl)amine. When weak amines represented by
trimethylamine and aniline were used, methylamine did not
sufficiently generate (Scheme 3). Thus, the catalytic cycle
did not work well, resulting in by-products formed by the
reaction of 8 with 3. The reaction proceeded sluggishly in
the absence of amines, involving a large amount of the by-
product (entry 8). Kb of methylamine is 4.4 × 10-4, and that
of 8 is 9.5 × 10-4. We speculated that 8 could be isolated
as the hydrochloride salt via a hydrochloride salt of a base
for which the Kb is 4.4 × 10-4 to 9.5 × 10-4 (Scheme 3).
Amongst various tertiary amines of suitable basicity, we
(7) Abdel-Magid, A. F.; Garson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah,
R. D. J. Org. Chem. 1996, 61, 3849.
(8) Emerson, W. S. Org. React. 1948, 4, 174.
(9) Hancock, E. M.; Cope, A. C. Organic Syntheses; Wiley & Sons: New
York, 1955; Collect. Vol. III, p 501.
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Table 2. Alkylation of 9 with 10a
Table 3. Reduction of 5
entry
K2CO3 (equiv)
conditions
yield (%) of 5b
entry
reducing agent
yield (%) of 6a
1
2
3
4
2
1.05
1
25 °C, 5 h
25 °C, 5 h
25 °C, 6 h
60 °C, 2 h
82.3
95.4
90.4
97.4
1
2
3
4
5
6
7
8
9
Pd/C, H2
Raney-Ni, H2
Raney-Ni, NH2NH2‚H2O
Pd/C, NH2NH2‚H2O
FeCl3, C, NH2NH2‚H2O
NaSH, H2O
SnCl2, H2O
SnCl2, hydrochloric acid
Sn, hydrochloric acid
trace
trace
81
76
1
94
a The reaction was carried out in N,N-dimethylformamide. [9]:[10] ) 1:1.
b Yield based on initial quantity of 9 charged were determined by HPLC analysis.
92.8 (65.4)
99.6 (56.8)
99.5 (96.0)
98.8 (86.2)
selected triethylamine (Kb ) 5.5 × 10-4), and satisfactory
results were realized (entries 2, 3). Several other tertiary
amines also gave good results (entries 4, 5). On the other
hand, we selected the reaction conditions of entry 2 as the
most suitable for large-scale synthesis after consideration of
the yield and the amount of by-products involved. The
hydrochloride salt of 8 was crystallized and isolated (in
2-propanol as solvent) in high quality (99.0% purity) and
high isolated yield (91.6%).
Synthesis of N-(4-Nitrobenzyl)-N-(tetrahydropyran-4-
yl)methylamine (5). N-(4-Nitrobenzyl)-N-(tetrahydropyran-
4-yl)methylamine (5) was synthesized in 82.3% yield by the
reaction of 10 and the hydrochloride salt of 8 in the presence
of K2CO3 (2 equiv) at room temperature (Table 2, entry 1).
When an optimized amount of K2CO3 was applied, the yield
was improved (entries 2, 3). The reaction temperature also
played an important role to ensure the high yield of 5 (entry
4). We observed that a large excess of K2CO3 led to the
further reaction of 5 with 10, resulting in an inferior yield.
The reaction condition of entry 4 was selected as the most
suitable condition for large-scale synthesis from the view-
point of the yield. 5 was isolated in high quality (99.5%
purity) and in 88.0% isolated yield.
a Yield based on initial quantity of 5 charged were determined by HPLC
analysis. The value in parentheses indicates the isolated yield of 7.
reducing reagent in the presence of metal catalysts gave 6
in good yields (entries 3, 4).13 Further studies indicated that
the product was cleanly prepared in excellent yield in the
presence of FeCl3 and activated charcoal (entry 5). Despite
these results, we continued our efforts, centering on other
reducing agents because of the carcinogenicity of hydrazine.
When NaSH/H2O or SnCl2/H2O were used as reducing
reagents, the reaction proceeded almost quantitatively.
However, the isolated yield of 4-[N-methyl-N-(tetrahydro-
pyran-4-yl)aminomethyl]aniline dihydrochloride (7) was only
about 60% (entries 6, 7). These decreased isolated yields
were caused by difficulties in separating a large amount of
reagents generated during extraction. On the other hand,
SnC12/HCl or Sn/HCl proceeded almost quantitatively to give
7 in excellent isolated yield (entries 8, 9).14 In these cases,
the catalysts were easily removed by extraction. 6 was
isolated as its hydrogen chloride salt by extraction followed
by crystallization in the presence of HCl in excellent quality
(99.6% purity) and in high yield (96.0% isolated yield, entry
8).
Synthesis of 4-[N-Methyl-N-(tetrahydropyran-4-yl)-
aminomethyl]aniline Dihydrochloride (7). 6 was crystal-
lized by completely evaporating the solvent to prevent
decreasing the yield of 6 in the original synthesis because
the solubility of 6 is too high in various solvents. However,
this procedure is not suitable for large-scale synthesis. To
overcome this problem, crystallization of the product as its
hydrochloride salt from a solution was developed.
In conclusion, we demonstrated a new and efficient
synthesis of 7, a key intermediate for the CCR5 antagonist
TAK-779. These methods required only commercially avail-
able reagents and were applied on multikilogram scale to
give 7 in 78% yield suitable for toxicological studies.
Experimental Section
Although the method of crystallization was improved in
this way, we still continued our efforts to improve the
process. The synthesis of 6 was initially conducted by the
reduction of 5 using the methods of the original synthesis.
However, Fe/AcOH as the reducing reagent involved tedious
work-up procedures including removal of the reagent from
the system after the reaction. Thus, we investigated alterna-
tive reducing reagents more suitable for large-scale synthesis.
The hydrogenation of 5 in the presence of metal catalysts
produced 4-aminotoluene and N-methyl-N-(tetrahydropyran-
4-yl)amine instead of 6 (Table 3, entries 1, 2). These by-
products were presumably produced by using hydrogen gas
as the hydrogen source, resulting in the hydrogenolysis of
6.12 On the other hand, the reduction using hydrazine as the
All reagents and solvents were commercially available.
Melting points were determined on a Bu¨chi B-540 micro-
melting apparatus and are uncorrected. IR spectra were
recorded with a Horiba FT-210 spectrophotometer. 1H NMR
spectra were recorded with a Bruker DPX-300 spectrometer
using tetramethylsilane as an internal standard. HPLC
analysis was performed with a Hitachi L-7000, and GC
analysis, with a Shimadzu GC-17A. Elemental analysis was
carried out by Takeda Analytical Research Laboratories, Ltd.
N-Methyl-N-(tetrahydropyran-4-yl)amine Hydrochlo-
ride (9). A mixture of methylamine hydrochloride (540 g,
8.0 mol), tetrahydro-4H-pyran-4-one (3; 800 g, 8.0 mol),
triethylamine (24 g, 240 mmol), 5% palladium on carbon
(13) (a) Furst, A.; Berlo, R. C.; Hooton, S. Chem. ReV. 1965, 65, 51. (b) Bavin,
P. M. G. Organic Syntheses; Wiley & Sons: New York, 1973; Collect.
Vol. V, p 30. (c) Yuste, F.; Saldana, M.; Walls, F. Tetrahedron Lett. 1982,
23, 147.
(10) Morrison, R. T.; Boyd, R. N. Organic Chemistry; Allyn and Bacon, Inc.:
Boston, 1959; pp 520, 521.
(11) Wilson, T. G.; Wheeler, T. S. Organic Syntheses; Wiley & Sons: New
York, 1941; Collect. Vol. I, p 102 .
(12) Hartung, W. H.; Simonoff, R. Org. React. 1953, VII, 263.
(14) (a) Woodward, R. B. Organic Syntheses; Wiley & Sons: New York, 1955;
Collect. Vol. III, p 453. (b) Buck, J. S.; Ide, W. S. Organic Syntheses;
Wiley & Sons: New York, 1945; Collect. Vol. II, p 130.
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(wet type, 40 g, 19 mmol), and methanol (5.6 L) was stirred
at 60 °C for 3 h under a 5 kgf/cm2 hydrogen atmosphere.
The palladium on carbon was filtered off and washed with
methanol (800 mL). The filtrate and washings were combined
and concentrated to about 190 mL at about 40 °C under
reduced pressure. After addition of 2-propanol (5.6 L) to the
residue, the mixture was concentrated to about 1.9 L at about
40 °C under reduced pressure. After addition of isopropyl
ether (1.7 L) to the residue, the mixture was stirred at 0-10
°C for 1 h. The resulting crystals were collected by filtration,
washed with a mixture of 2-propanol (200 mL) and isopropyl
ether (600 mL) and dried at about 40 °C under reduced
pressure to give 1.11 kg (91.6%) of 9 as colorless crystals;
mp 216 °C (dec).
pressure. Ethyl acetate (20 mL) and tetrahydrofuran (10 mL)
were added to the residue, and then the resulting solution
was washed with brine. Concentrated hydrochloric acid (0.81
mL) was added to the organic layer. The resulting crystals
were collected by filtration, washed with 2-propanol, and
dried under reduced pressure to give 0.95 g (81.1%) of 7 as
yellow crystals.
Synthesis of 7 with FeCl3/NH2NH2‚H2O from 5 (Refer to
Table 3). 5 (185.2 g, 740 mmol), iron (III) chloride (1.8 g,
11.1 mmol), activated charcoal (18.5 g), and tetrahydrofuran
(1.8 L) were mixed, and then hydrazine monohydrate (126
mL, 2600 mol) was added dropwise to the mixture to keep
the temperature at 60-65 °C. The mixture was stirred at
the same temperature for 4 h. After cooling, the insoluble
matter was filtered off and washed with tetrahydrofuran (1.8
L). The filtrate and washings were combined and concen-
trated under reduced pressure. After addition of ethyl acetate
(3.6 L) to the residue, the resulting solution was washed twice
with brine (1.8 L portions). The organic layer was concen-
trated under reduced pressure. 2-Propanol (2.7 L) was added
to the residue to make a solution. Concentrated hydrochloric
acid (150 mL) was added dropwise to the solution, and then
the resulting mixture was stirred at 0-5 °C. The resulting
crystals were collected by filtration, washed with 2-propanol
(1.8 L), and dried at about 40 °C under reduced pressure to
give 204 g (94%) of 7 as yellow crystals.
1H NMR (300 MHz, DMSO-d6): δ ) 1.3-1.5 (m, 3H),
1.7-1.9 (m, 2H), 2.42 (s, 3H), 2.5-2.6 (m, 1H), 3.3-3.5
(m, 2H), 3.8-4.0 (m, 2H) ppm.
N-(4-Nitrobenzyl)-N-(tetrahydropyran-4-yl)methyl-
amine (5). 9 (1.15 kg, 7.58 mol), potassium carbonate (1.05
kg, 7.60 mol), 4-nitrobenzylbromide (10; 1.64 kg, 7.6 mol),
and N,N-dimethylformamide (4.5 L) were mixed at 0-10
°C, and the resulting mixture was stirred at room temperature
for 3 h. After addition of ethyl acetate (27 L) to the reaction,
the resulting mixture was washed successively with 5% brine
(9 L) and water (9 L). After addition of 1 N hydrochloric
acid (18 L) to the organic layer, the layers were separated.
The resulting aqueous layer was washed with ethyl acetate
(18 L). After addition of ethyl acetate (18 L) and saturated
aqueous sodium hydrogen carbonate (27 L) to the aqueous
layer, the layers were separated. The resulting organic layer
was washed three times with water (9 L portions) and
concentrated under reduced pressure to give 1.674 kg
(87.8%) of 5 as a yellow oil.
Synthesis of 7 with SnCl2/HCl from 5 (Refer to Table 3).
A solution of tin (II) chloride dihydrate (1.235 kg, 5.47 mol)
in concentrated hydrochloric acid (1.08 L) was added
dropwise to a solution of 5 (425 g, 1.70 mol) in tetrahydro-
furan (500 mL) at 20-40 °C. The resulting mixture was
stirred for 1 h at the same temperature. Tetrahydrofuran (1.5
L) and water (1.2 L) were added to the reaction mixture.
The mixture was made basic with 30% aqueous sodium
hydroxide solution. The layers were separated, and the
resulting aqueous layer was extracted with tetrahydrofuran
(1.5 L). The organic layers were combined and concentrated
to about 900 mL under reduced pressure. After addition of
2-propanol (1.5 L) to the residue, the resulting solution was
concentrated to about 900 mL under reduced pressure. After
addition of 2-propanol (3.9 L), concentrated hydrochloric
acid (350 mL) was added dropwise to the solution at 20-
40 °C. The resulting mixture was stirred for 1 h at 0-10
°C. The crystals were collected by filtration, washed with
2-propanol (1.5 L), and dried at about 40 °C under reduced
pressure to give 478 g (96.0%) of 7 as yellow crystals.
1H NMR (300 MHz, CDCl3): δ ) 1.5-1.9 (m, 4H), 2.45
(s, 3H), 3.22 (t, J ) 11.6 Hz, 2H), 3.3-3.4 (m, 1H), 3.84
(d, J ) 11.6 Hz, 2H), 3.95 (d, J ) 13.0 Hz, 1H), 4.31 (d, J
) 13.0 Hz, 1H), 7.21 (d, J ) 8.4 Hz, 2H), 7.35 (d, J ) 8.4
Hz, 2H) ppm.
1H NMR (300 MHz, CDCl3): δ ) 1.5-1.8 (m, 4H), 2.21
(s, 3H), 2.5-2.7 (m, 1H), 3.38 (dt, J ) 11.5, 2.5 Hz, 2H),
3.68 (s, 2H), 4.0-4.1 (m, 2H), 7.51 (d, J ) 8.8 Hz, 2H),
8.18 (d, J ) 8.8 Hz, 2H) ppm.
IR (neat): ν ) 2928, 2846, 1517, 1446, 1380, 1344, 1141,
856 cm-1.
4-[N-Methyl-N-(tetrahydropyran-4-yl)aminomethyl]-
aniline Dihydrochloride (7). Synthesis of 7 with Pd/C from
5 (Refer to Table 3). A solution of 5 (10 g, 40 mmol) in
tetrahydrofuran (50 mL) was added dropwise to a mixture
of 5% palladium on carbon (wet type, 1 g), hydrazine
monohydrate (9.7 mL, 200 mmol), and methanol (50 mL)
at 0-10 °C under nitrogen. The mixture was stirred for 1 h
at 30 °C. The insoluble matter was filtered off, and then the
filtrate was concentrated under reduced pressure. Tetrahy-
drofuran (50 mL) and concentrated hydrochloric acid (8.1
mL) were added to the residue, and the mixture was stirred
for 1 h at room temperature. The resulting crystals were
collected by filtration, washed with 2-propanol, and dried
under reduced pressure to give 8.9 g (76%) of 7 as yellow
crystals.
IR (KBr): ν ) 2856, 1519, 1463, 1012 cm-1.
Anal. Calcd for C13H22N2OCl2 (293.2): C 53.25, H 7.56,
N 9.53, Cl 24.18; found C 53.21, H 7.54, N 9.53, Cl 24.16.
Synthesis of 7 with Raney-Nickel from 5 (Refer to Table
3). Hydrazine monohydrate (0.97 mL, 20.0 mol) was added
dropwise to a suspension of Raney-nickel (0.2 g) in methanol
(5 mL) at 0-10 °C. A solution of 5 (1.0 g, 4.0 mmol) in
tetrahydrofuran (5 mL) was added dropwise to the suspension
at the same temperature. The resulting mixture was stirred
at 25 °C. After reaction, the insoluble matter was filtered
off and washed with tetrahydrofuran. The filtrate and
washings were combined and concentrated under reduced
Acknowledgment
We thank Drs. Taiichi Okada, Mitsuru Siraishi, Mrs.
Kokichi Yoshida, Yoshio Aramaki, Masaki Seto, and Ms.
Nishiguchi for helpful discussions.
Received for review July 2, 2001.
OP010052O
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