March 2001
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1
1503 cmϪ1. H-NMR (CDCl3) d: 1.81—1.91 (1H, m), 2.09—2.16 (1H, m),
2.53—2.61 (1H, m), 2.76—3.02 (4H, m) 3.77 (3H, s), 5.63 (1H, br s), 5.85
(1H, br s), 6.63 (1H, d, Jϭ2.4 Hz), 6.70 (1H, dd, Jϭ2.4, 8.3 Hz), 6.99 (1H, d,
Jϭ8.3 Hz). 13C-NMR (CDCl3) d: 27.25, 28.13, 32.93, 41.67, 55.66, 112.76,
114.04, 128.15, 130.12, 136.34, 158.10, 178.29. [a]2D5 Ϫ60.8° (cϭ1.0,
MeOH). HR-MS (FAB) m/z: Calcd for C12H15NO2 Mϩ: 205.1103. Found:
205.1059. Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C,
69.88; H, 7.41; N, 6.83.
lized from AcOEt–hexane to give (R)-1 (7.96 g, 95%) as a white solid. The
ee of (R)-1 was determined to be 99.0% ee using the dimethyl ester derived
with TMS–CHN2 (10% solution in hexane) in CH2Cl2–MeOH by HPLC
(mobile phase, hexane–iso-PrOH, 4 : 1). mp 89—89.5 °C. IR (KBr): 3023,
2964, 1710, 1700, 1610, 1586, 1435 cmϪ1. [a]2D7 Ϫ13.0° (cϭ1.0, MeOH).
HR-MS (FAB) m/z: Calcd for C12H14O5 Mϩ: 238.0841. Found: 238.0832.
Anal. Calcd for C12H14O5: C, 60.50; H, 5.92. Found: C, 60.48; H, 5.97.
Recovery of the Chiral Amine 7 The separated toluene solution in the
synthesis of the acid (R)-1 was concentrated under reduced pressure, and the
residue was crystallized from EtOH–water to give 7 (6.78 g, 88%) as a white
solid. [a]2D6 ϩ25.0° (cϭ1.0, MeOH). [Commercially available 7: [a]2D6
ϩ25.0° (cϭ1.0, MeOH)]
Racemization of Recovered (S)-1 The (S)-1 (16.13 g, 60.2% ee) recov-
ered from the mother liquor of the optical resolution was stirred for 3 h at
180 °C. 2 M NaOH (50 ml) was added to the oil and stirred for 1 h at 80 °C.
The solution was acidified with conc. HCl (7.0 ml) and extracted with
AcOEt (50 ml and 30 ml). The combined AcOEt layer was washed with
brine (10 ml), dried over MgSO4, and concentrated under reduced pressure.
The resulting residue was suspended in hot AcOEt–hexane. After cooling,
the solid was collected by filtration to give 1 (9.27 g, 58%, 1.0% ee) as a
white solid. [a]2D6 ϩ0.4° (cϭ1.0, MeOH).
Crystal Structure of (1R,2S)-2-Amino-1-phenylpropan-1-ol (2R)-2-(3-
Methoxybenzyl)succinate (1R,2S)-2-Amino-1-phenylpropan-1-ol [(1R,2S)-
norephedrine] (76 mg, 0.50 mmol) and (R)-1 (120 mg, 0.50 mmol) were dis-
solved in EtOH (1.0 ml) at 50 °C, then cooled to room temperature. The pre-
cipitate was collected by filtration to give the title compound as a white solid
(76 mg, 39%). A colorless crystal was obtained by recrystallization from
EtOH. Crystal data: Monoclinic, P21 (No.4), Zϭ4; aϭ5.514 bϭ33.161 cϭ
11.267 Å; aϭgϭ90.0, bϭ100.459 °. Intensity data were collected under the
cryo stream at 213 K with graphite monochromated Mo–Ka radiation
(lϭ0.71069 Å) on a Rigaku RASA-7R diffarctometer, 2q(max)ϭ55.0°. The
decay of the crystal was monitored by three standard reflections, but no
decay was observed. Of 2713 measured reflections, 1883 had IϾ3s, and
2354 were unique and were used for the structure analysis. The structure
was solved by a direct method (SIR-92) and refined through a full-matrix
least squares method to Rϭ0.051 and Rwϭ0.054 using the TEXSAN-
TEXRAY Structure Analysis Package (Ver. 1.9), Molecular Structure Cor-
poration. Hydrogen atoms were incorporated at fixed positions with C–Hϭ
0.95 Å. mp 139 °C. IR (KBr): 3088, 1586, 1258 cmϪ1. 1H-NMR (DMSO-d6)
d: 0.91 (3H, d, Jϭ6.6 Hz), 2.10—2.21 (2H, m), 2.52—2.60 (1H, m), 2.99
(2H, dd, Jϭ4.7, 13.5 Hz), 3.30—3.40 (1H, m), 3.72 (3H, s), 4.78 (1H, d, Jϭ
3.0 Hz), 6.72—6.75 (3H, m), 7.15—7.18 (1H, m), 7.27—7.40 (5H, m). 13C-
NMR (DMSO-d6) d: 12.54, 37.50, 37.81, 44.52, 51.97, 55.19, 72.29,
111.71, 114.99, 121.63, 126.38, 127.66, 128.49, 129.48, 141.72, 142.19,
159.49, 174.77, 177.25. [a]2D6 Ϫ8.4° (cϭ1.0, MeOH). Anal. Calcd for
C21H27NO6: C, 64.77; H, 6.99; N, 3.60. Found: C, 64.75; H, 7.12; N, 3.76.
(2R)-7-Methoxy-4-oxo-1,2,3,4-tetrahydro-2-naphthoic Acid [(R)-6]
The cyclization of (R)-1 (2.85 g, 12.0 mmol) was carried out as described for
the synthesis of 6 to give (R)-6 (2.23 g, 84%) as a white solid. The ee of (R)-
6 was determined to be 98.5% ee by HPLC (mobile phase, hexane–EtOH–
TFA, 960 : 40 : 1). An analytical sample was prepared by recrystallization
from EtOH to give a white solid. mp 189—189.5 °C. IR (KBr): 3019, 1722,
1644, 1596 cmϪ1. [a]2D7 Ϫ14.6° (cϭ1.0, MeOH). HR-MS (FAB) m/z: Calcd
for C12H13O4 (MϩH)ϩ: 221.0814. Found: 221.0820. Anal. Calcd for
C12H12O4: C, 65.45; H, 5.49. Found: C, 64.95; H, 5.56.
(2S)-2-tert-Butoxycabonylamino-7-methoxy-1,2,3,4-tetrahydronaph-
thalene (11) tert-BuOH (6 ml) was added to a solution of tert-BuONa
(1.27 g, 13.2 mmol) in THF (8 ml) at room temperature and then the white
solid was immediately precipitated. Compound 10 (0.821 g, 4.0 mmol) was
added to the mixture cooled in an ice-bath and, after 10 min, Br2 (0.24 ml,
4.5 mmol) was added. The mixture was warmed in a water-bath (55 °C) for
20 min and concentrated under reduced pressure. Water (10 ml) was added to
the resulting residue and extracted with AcOEt (3ϫ20 ml). The combined
organic layer was washed with Na2SO3 solution (5 ml) and brine (5 ml),
dried over MgSO4, and concentrated under reduced pressure to give 11
(0.961 g, 87%) as a solid. The ee of 11 was determined to be 98.0% ee by
HPLC (mobile phase, hexane–iso-PrOH, 99 : 1). An analytical sample was
prepared by purification using silica gel chromatography (Fuji Silysia Co.,
Ltd.; BW-350; eluent, AcOEt–hexane, 1 : 5) to give a white solid. mp 102—
104 °C. IR (KBr): 3364, 2984, 2927, 1686, 1526 cmϪ1. 1H-NMR (CDCl3) d:
1.45 (9H, s), 1.68—1.77 (1H, m), 2.00—2.07 (1H, m), 2.60 (1H, dd, Jϭ8.1,
16.3 Hz), 2.80 (2H, t, Jϭ6.1 Hz), 3.08 (1H, dd, Jϭ4.8, 16.3 Hz), 3.76 (3H,
s), 3.90—4.02 (1H, br), 4.52—4.64 (1H, br), 6.59 (1H, d, Jϭ2.7 Hz), 6.70
(1H, dd, Jϭ2.7, 8.4 Hz), 6.99 (1H, d, Jϭ8.4 Hz). 13C-NMR (CDCl3) d:
26.67, 28.83, 29.60, 36.74, 46.57, 55.64, 79.62, 112.91, 114.32, 128.02,
130.06, 135.79, 155.74, 158.12. [a]2D7 Ϫ65.0° (cϭ1.0, MeOH). HR-MS
(FAB) m/z: Calcd for C16H23NO3 Mϩ: 277.1678. Found: 277.1675. Anal.
Calcd for C16H23NO3·0.3H2O: C, 67.96; H, 8.41; N, 4.95. Found: C, 68.02;
H, 8.36; N, 5.08.
(2S)-7-Methoxy-1,2,3,4-tetrahydro-2-naphthylamine Hydrochloride
(12)
A mixture of 11 (0.856 g, 3.1 mmol) and conc. HCl (0.8 ml,
9.6 mmol) in EtOH (5 ml) was stirred for 1 h at 60 °C. The mixture was con-
centrated under reduced pressure and the resulting residue was suspended in
EtOH–hexane. The solid was collected by filtration to give 12 (0.631 g,
96%). The ee of 12 was determined to be 98.1% ee using the acetamido de-
rived with Ac2O in ether–1 M NaOH by HPLC (mobile phase, hexane–iso-
PrOH, 9 : 1). An analytical sample was prepared by recrystallization from
iso-PrOH to give a white solid. mp 207—209 °C (lit.3) 203—205 °C). IR
(KBr): 2850, 2008, 1611, 1503 cmϪ1 1H-NMR (DMSO-d6) d: 1.70—1.79
.
(1H, m), 2.09—2.16 (1H, m), 2.72—2.85 (3H, m), 3.06 (1H, dd, Jϭ4.8,
16.2 Hz), 3.35—3.43 (1H, m), 3.71 (3H, s), 6.68 (1H, d, Jϭ2.5 Hz), 6.72
(1H, dd, Jϭ2.5, 8.3 Hz), 7.01 (1H, d, Jϭ8.3 Hz), 8.37 (3H, s). 13C-NMR
(DMSO-d6) d: 26.39, 27.36, 33.55, 46.98, 55.39, 113.13, 113.74, 127.10,
129.85, 134.29, 157.81. [a]2D6 Ϫ67.6° (cϭ1.0, MeOH) [lit.3) [a]2D0 Ϫ66.1°
(cϭ0.5, MeOH)]. Anal. Calcd for C11H16NOCl·0.2H2O: C, 60.80; H, 7.61;
N, 6.45. Found: C, 60.75; H, 7.50; N, 6.45.
Acknowledgment We thank Mr. E. Tsuji, Kissei Pharmaceutical Co.,
Ltd., for the X-ray crystallographic analysis.
References and Notes
1) Kobayashi M., Kojima M., Akahane M., Kawarabayashi T., Int. J. Gy-
necol. Obstet., Suppl., 70, 159 (2000).
(2S)-7-Methoxy-1,2,3,4-tetrahydro-2-naphthoic Acid [(R)-2] The re-
ductive deoxygenation of (R)-6 (2.64 g, 12.0 mmol) was carried out as de-
scribed in the synthesis of 2 to give (R)-2 (2.13 g, 86%) as a white solid. The
ee of (R)-2 was determined to be 97.8% ee using the methyl ester derived
with TMS–CHN2 (10% solution in hexane) in CH2Cl2–MeOH by HPLC
(mobile phase, hexane–iso-PrOH, 99 : 1). An analytical sample was prepared
by recrystallization from EtOH to give a white solid. mp 135—137 °C. IR
(KBr): 3191, 1730, 1610, 1506 cmϪ1. [a]2D7 Ϫ44.6° (cϭ1.0, MeOH). HR-
MS (FAB) m/z: Calcd for C12H15O3 (MϩH)ϩ: 207.1021. Found: 207.1042.
Anal. Calcd for C12H14O3: C, 69.89; H, 6.84. Found: C, 69.94; H, 6.89.
(2S)-7-Methoxy-1,2,3,4-tetrahydro-2-naphthoamide (10) A mixture
of (R)-2 (1.031 g, 5.0 mmol) and SOCl2 (1.45 ml, 20.0 mmol) in toluene
(5 ml) was stirred for 2 h at 80 °C. The solution was concentrated, then the
solution of the resulting residue in toluene (2 ml) was added to 28% ammo-
nium solution (5 ml) cooled in an ice-bath. The precipitate was collected by
filtration to give 10 (0.984 g, 96%) as a white solid. The ee of 10 was deter-
mined to be 98.6% ee by HPLC (mobile phase, hexane–iso-PrOH, 4 : 1). An
analytical sample was prepared by recrystallization from EtOH to give a
white solid. mp 159—160 °C. IR (KBr): 3355, 3190, 1660, 1624,
2) Tomiyama Y., Hayakawa K., Murakami M., Akahane M., Ajisawa Y.,
Park Y.C., Kurita T., J. Urol., 161, 83 (1999).
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(1992).
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(1971); b) Urban R. S., Beavers E. M., J. Am. Chem. Soc., 76, 3042—
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Chem., 24, 149—153 (1981).
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1737—1739 (1982); b) Plattner J. J., Marcotte P. A., Kleinert H. D.,
Stein H. H., Greer J., Bolis G., Fung A. K. L., Bopp B. A., Luly J. R.,
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I., Perum T. J., J. Med. Chem., 31, 2277—2288 (1988).
7) a) Kawano H., Ishii Y., Ikariya T., Saburi M., Yoshikawa S., Uchida Y.,
Kumobayashi H., Tetrahedron Lett., 28, 1905—1908 (1987); b) Mori-