The practical synthesis of a uterine relaxant, Bis( 2-{[(2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl) -phenyl]ethyl}amino) -1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-dimethylacetamide) sulfate (KUR-1246)

Article abstract of DOI:10.1248/cpb.49.1018

The synthetic route for a uterine relaxant, bis(2-{[ (2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3- (2-hydroxyethyl)-phenyl]ethyl}amino) -1,2,3,4-tetrahydronaphthalen-7-y1]oxy}-N,N-dimethylacetamide) sulfate (KUR-1246), was established by the coupling of optically active components, the bromohydrin 14 and the amine 24. We now describe the practical synthesis of these two optically active components. Bromohydrin 14 was obtained by the asymmetric borane reduction of the prochiral phenacyl bromide 13 using a catalyst prepared from aluminum triethoxide and a chiral amino alcohol. The other optically active component 24 was prepared from (S)-AMT.

Full text of DOI:10.1248/cpb.49.1018

1018
Chem. Pharm. Bull. 49(8) 1018—1023 (2001)
Vol. 49, No. 8
The Practical Synthesis of a Uterine Relaxant,
Bis(2-{[(2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)-
phenyl]ethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-
N,N-dimethylacetamide) Sulfate (KUR-1246)
Takashi YANAGI, ,a Ken KIKUCHI,a Hideki TAKEUCHI,a Takehiro ISHIKAWA,a Toshihiro NISHIMURA,a and
*
b
Iwao YAMAMOTO
Central Research Laboratories, Kissei Pharmaceutical Co., Ltd.,a Hotaka, Minamiazumi, Nagano 399–8304, Japan and
Faculty of Textile Science and Technology, Shinshu University,b Ueda, Nagano 386–8567, Japan.
Received April 9, 2001; accepted May 30, 2001
The synthetic route for a uterine relaxant, bis(2-{[(2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)-
phenyl]ethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-dimethylacetamide) sulfate (KUR-1246), was
established by the coupling of optically active components, the bromohydrin 14 and the amine 24. We now de-
scribe the practical synthesis of these two optically active components. Bromohydrin 14 was obtained by the
asymmetric borane reduction of the prochiral phenacyl bromide 13 using a catalyst prepared from aluminum
triethoxide and a chiral amino alcohol. The other optically active component 24 was prepared from (S)-AMT.
Key words KUR-1246; b2-adrenoceptor agonist; uterine relaxant; asymmetric borane reduction
Preterm labor is the leading cause of neonatal morbidity rane reduction of the phenacyl halide 13 that would be de-
and mortality in clinical practice. b-Adrenoceptor (AR) ago- rived from 4Ј-hydroxyacetophenone (7). The amine 24 was
nists such as ritodrine and terbutaline are the drugs of first prepared from (S)-2-amino-7-methoxytetraline [(S)-AMT].
choice for preventing this preterm labor. However, the useful-
The Synthesis of the Optically Pure (R)-Bromohydrin
ness of these drugs is limited by the occurrence of side ef- 14 The phenacyl bromide 13 was synthesized from the ke-
fects such as maternal tachycardia and metabolic systems. To tone 7 that was inexpensive and easily available in large
resolve this problem, we have developed a new selective b2- quantity, as shown in Chart 3. The methyl ester 11 was ob-
AR agonist, bis(2-{[(2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy- tained from 7 through chloromethylation,3) cyanation with
3-(2-hydroxyethyl)phenyl]ethyl}amino)-1,2,3,4-tetrahydro- NaCN, hydrolysis with aqueous NaOH, and esterification
naphthalen-7-yl]oxy}-N,N-dimethylacetamide) sulfate (KUR- with MeOH in the presence of H2SO4. The methyl ester 11
1246), as shown in Fig. 1. KUR-1246 at doses of 0.13 mg/ was reacted with benzyl chloride in the presence of KI and
kg/min intravenously suppressed 30% of the uterine contrac- K2CO3 to give the ketone 12 in 78% yield. The bromination
tions in late pregnant rats. The inhibitory potency with which of 12 with Br2 gave 13 in 72% yield.
KUR-1246 produced this effect was about 6 times that of
Recently, we reported the efficient catalysts prepared from
terbutaline, and 400 times that of ritodrine. Moreover, it has aluminum triethoxide [Al(OEt)3] and chiral amino alcohols
been reported that KUR-1246 has an excellent selectivity for for asymmetric borane reduction.4) We investigated our
the myometrial b2-AR.1) We now require a large amount of asymmetric reduction methodology to obtain this optically
optically pure KUR-1246 for further evaluation of this com- active bromohydrin 14 from 13 (Chart 4). These results are
pound as a uterine relaxant. In this paper, we describe the summarized in Table 1. The reaction of 13 with the borane
convenient and practical method for the synthesis of KUR- dimethyl sulfide complex (BH3·Me2S) (120 mol%), Al(OEt)3
1246.
(12 mol%) and (R)-a,a-diphenyl-2-pyrrolidinemethanol (15)
Our group reported the synthesis of KUR-1246, as shown (10 mol%) reduced both the ketone and the ester groups to
in Chart 1.2) The racemic mandelic acid derivative 2 was syn- give the crude 14 with 98.0% ee. After the recrystallization
thesized from the O-protected hydroxyethylphenol 1 through of the crude product, 14 was obtained in the good yield of
bromination, lithiation and reaction with diethyl oxalate 86% with the excellent optical purity of 99.9% ee (entry 1).
under Ϫ95 °C, and hydrolysis with aqueous NaOH. The con- The absolute configuration of the bromohydrin 14 was deter-
densation of the acid 2 and (S)-2-amino-7-hydroxytetraline mined to be the R-configuration by X-ray crystallographic
hydrobromide [(S)-AHT·HBr, 3] gave a mixture of diastere- analysis using the anomalous dispersion effect of the
omer, which was separated by column chromatography on bromine atoms, as shown in Fig. 2. Furthermore, we exam-
silica gel to obtain the single isomer 4. This synthetic method ined the possibility of decreasing the quantity of 15. Using
was unsuitable for large-scale synthesis, because of the inef- 5 mol% of 15 and 6 mol% of Al(OEt)3 under these conditions
fective diastereomer separation, the use of column chro-
matography, and the low reaction temperature.
We developed a synthetic strategy for KUR-1246, as
shown in Chart 2, should be the condensation of the optically
active halide 14 and the optically active amine 24 in order to
avoid the above-mentioned difficulties. Furthermore, we
planned the synthesis of the halide 14 by the asymmetric bo-
Fig. 1
To whom correspondence should be addressed. e-mail: takashi_yanagi@pharm.kissei.co.jp
© 2001 Pharmaceutical Society of Japan

August 2001
1019
Chart 1
Chart 2
Chart 3
Chart 4
Fig. 2. ORTEP of 14
that the reduction of 13 using of (Ϫ)-18 prepared from inex-
pensive (ϩ)-camphor produced 14. (ϩ)-Camphor was easily
led to a good result (90% yield, 99.5% ee, entry 2). However, converted to (Ϫ)-18, which included ca. 11% of the endo
the further reduction in the amount of 15 to 2 mol% gave 14 form, and the intricate purification via the cyclic carbamate
with the unsatisfactory optical purity of 95.4% ee in spite of was reported.7) We found that (Ϫ)-18 was readily purified by
recrystallization (entry 3). And furthermore, 15 had to be recrystallization of its methanesulfonic acid salt (Chart 5).
prepared from expensive D-proline.5)
We then examined this asymmetric reduction using (Ϫ)-18.
The asymmetric borane reduction of acetophenone using The optical purity of the crude product was 94.6% ee, and 14
the amino alcohol (ϩ)-18 prepared from (Ϫ)-camphor gave was obtained in 85% yield with 98.3% ee after recrystalliza-
(R)-1-phenylethanol with 88% ee.6) The result was suggested tion (entry 4).

1020
Vol. 49, No. 8
The Synthesis of the Optically Pure (S)-Amine 24 prepared by the asymmetric borane reduction of the phenacyl
Some synthetic methods of the optically pure (S)-AMT have bromide 13 using Al(OEt)3 and the chiral amino alcohol 15
been reported8) and we also published that (S)-AMT·HCl (20) or (Ϫ)-18.
was prepared from (R)-2-(3-methoxybenzyl)succinic acid.9)
The amine 20 was demethylated in 48% hydrobromic acid
under reflux to (S)-AHT·HBr (3) in 99% yield. The reaction
of 3 with di-tert-butyl dicarbonate (Boc2O) followed O-alky-
lation with 2-chloro-N,N-dimethylacetamide (22) gave the
amide 23 in 76% yield. Compound 23 was treated with con-
centrated hydrochloric acid (conc. HCl) in iso-PrOH, and
then the precipitate from the reaction solution was collected
by filtration to give the amine 24 in 79% (Chart 6).
The Synthesis of KUR-1246 by Coupling of 14 and 24
These two optically active components, the bromohydrin 14
and the amine 24, were coupled to produce KUR-1246, as
shown in Chart 7. The bromide 25, obtained from 14 with
protection of the two hydroxyl groups using tert-butylchloro-
dimethylsilane (TBS-Cl), was reacted with 24 to give com-
pound 26. The TBS ethers of the crude 26 were cleaved by p-
toluenesulfonic acid (TosOH) in aqueous tetrahydrofuran
(THF), followed by crystallization with oxalic acid to pro-
Chart 5
duce the oxalate 27 in 69% yield from 14. The benzyl group
of the free amine of 27 underwent catalytic hydrogenolysis to
give compound 28 in 89% yield. Finally, 0.5 M H2SO4
Table 1. Asymmetric Borane Reduction of 13
(50 mol%) was added to a solution of 28 in MeOH, and then
the precipitate was collected by filtration to give KUR-1246
in 87% yield.
Catalyst
14
Entry
Amino alcohol mol%
Yield (%) ee (%)a) (Crude)
In conclusion, we established an efficient and practical
route for the synthesis of the optically active uterine relaxant
KUR-1246 by the coupling of the optically active bromohy-
drin 14 and the optically active amine 24 prepared from 4Ј-
hydroxyacetophenone (7) and (S)-AMT·HCl (20), respec-
1
2
3
4
15
15
15
10
5
2
86
90
89
85
99.9 (98.0)
99.5 (94.5)
95.4 (92.9)
98.3 (94.6)
(Ϫ)-18
10
a) The optical purity was measured by HPLC analysis using a chiral column (Chiral-
tively. Furthermore, the optically active bromohydrin 14 was pak AD).
Chart 6
Chart 7

August 2001
1021
13 (29.9 g, 72%) as a white solid. mp 95 °C. IR (KBr): 1731, 1689 cmϪ1. 1H-
NMR (CDCl3) d: 3.64 (3H, s), 3.71 (2H, s), 4.39 (2H, s), 5.17 (2H, s), 6.98
(1H, d, Jϭ8.6 Hz), 7.30—7.42 (5H, m), 7.88 (1H, d, Jϭ2.3 Hz), 7.92 (1H,
dd, Jϭ2.3, 8.6 Hz). 13C-NMR (CDCl3) d: 31.14, 36.42, 52.37, 70.77,
111.76, 124.55, 127.29, 127.51, 128.62, 129.07, 131.18, 132.65, 136.31,
161.60, 171.88, 190.22. HR-MS (FAB) m/z: Calcd for C18H18BrO4 (MϩH)ϩ:
377.0388. Found: 377.0391. Anal. Calcd for C18H17BrO4: C, 57.31; H, 4.54.
Found: C, 57.22; H, 4.52.
Experimental
All melting points were determined on a Yanagimoto melting point appa-
ratus and are uncorrected. IR spectra were recorded on a Nicolet 510 FT-IR
1
spectrometer. H- and 13C-NMR spectra were recorded on a Bruker DRX-
500 using tetramethylsilane or sodium 3-(trimethylsilyl)propionate-2,2,3,3-
d4 as the internal standard. Mass spectra were measured using a JEOL JMS-
SX102A mass spectrometer. Optical rotations were measured with a JASCO
DIP-370 polarimeter.
1-(3-Chloromethyl-4-hydroxyphenyl)ethanone (8) Formaldehyde (37%
solution, 340 ml, 4.6 mol) was added to a suspension of 1-(4-hydroxy-
phenyl)ethanone (7) (136.0 g, 1.00 mol) in conc.HCl (1000 ml, 12.2 mol),
and then the mixture was stirred for 4 h at 50 °C. The resulting red precipi-
tate was collected by filtration and washed with water to give 8 (203.2 g,
wet, 110%) as a red solid. The solid was used for the next reaction without
further purification. An analytical sample was prepared by recrystallization
from THF as a white solid. mp 172—175 °C. IR (KBr): 3154, 1656, 1586,
(1R,2S,3R,4S)-3-Amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol
Methansulfonate (19)
A solution of (1R,4S)-3-hydroxyimino-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-one (17)6) (8.52 g, 47 mmol) in ether
(120 ml) was added dropwise to a suspension of LiAlH4 (5.32 g, 140 mmol)
in ether (140 ml) over 45 min at room temperature, and then stirred
overnight. 2 M NaOH (25 ml) was carefully added to the mixture and the
mixture was dried over MgSO4. The solid was removed by filtration, and the
filtrate was concentrated under reduced pressure. A solution of methanesul-
fonic acid (4.50 g, 47 mmol) in ether (20 ml) was added to the solution of the
obtained residue in ether (120 ml). The precipitate was collected by filtration
to give the crude methansulfonic acid salt (10.4 g, 84%, (Ϫ)-18: endo-
18ϭ88.9 : 11.1). The crude salt (8.00 g) was recrystallized twice from
EtOH–hexane to give the pure salt 19 (3.25 g, 41%, (Ϫ)-18: endo-
18ϭ99.6 : 0.4). mp 193—195 °C. IR (KBr): 3329, 2948, 1195, 1163,
1
1289 cmϪ1. H-NMR (DMSO-d6) d: 2.50 (3H, s), 4.75 (2H, s), 6.97 (1H, d,
Jϭ8.4 Hz), 7.84 (1H, d, Jϭ8.4 Hz), 7.99 (1H, s), 10.89 (1H, s). 13C-NMR
(DMSO-d6) d: 26.60, 41.93, 115.64, 124.22, 128.94, 131.31, 132.07,
160.54, 196.23. HR-MS (FAB) m/z: Calcd for C9H10O2Cl (MϩH)ϩ:
185.0370. Found: 185.0380. Anal. Calcd for C9H9O2Cl: C, 58.55; H, 4.91.
Found: C, 58.54; H, 5.00.
1
1043 cmϪ1. H-NMR (DMSO-d6) d: 0.77 (3H, s), 0.85 (3H, s), 0.99—1.08
(5-Acetyl-2-hydroxyphenyl)acetic Acid (10) A suspension of NaCN
(98.0 g, 2.00 mol) in dimethylsulfoxide (0.5 l) was stirred for 30 min at
60 °C. Compound 8 (203.2 g, wet) in limited amounts was added to the mix-
ture over 1 h and stirred for 1 h at the same temperature. A solution of NaOH
(140.0 g, 3.50 mol) in water (0.5 l) was then added to the mixture and re-
fluxed for 2 h. After cooling to room temperature, the mixture was diluted
with water (2.5 l), washed with toluene (0.5 l), acidified with conc.HCl
(0.4 l), and extracted with AcOEt (3ϫ1 l). The organic layers were com-
bined, washed with water (1.0 l), dried over MgSO4, and concentrated under
reduced pressure. Toluene (300 ml) was added dropwise to the suspension of
the residue in AcOEt (100 ml) at 50 °C, and then cooled. The precipitate was
collected by filtration to give 10 (97.6 g, 50% from 7). An analytical sample
was prepared by recrystallization from MeOH as a white solid. mp 204—
(5H, m), 1.38—1.43 (1H, m), 1.63—1.70 (1H, m), 1.82 (1H, d, Jϭ4.6 Hz),
2.29 (3H, s), 3.09—3.14 (1H, m), 3.64 (1H, dd, Jϭ5.7, 7.5 Hz), 6.04 (1H, d,
Jϭ5.9 Hz), 7.57 (3H, br s). 13C-NMR (D2O) d: 10.70, 20.46, 20.92, 26.09,
32.37, 38.79, 46.74, 48.94, 49.25, 57.02, 77.69. [a]D25 ϩ1.4° (cϭ1.85,
MeOH). Anal. Calcd for C11H23NO4S: C, 49.79; H, 8.74; N, 5.28. Found: C,
49.57; H, 8.96; N, 5.62. The ratio of (Ϫ)-18 to endo-18 was measured by
GC [column, CAM, 30 mϫ0.25 mm i.d.ϫ0.25 mm, J&W Scientific; mobile
phase, He 1.0 ml/min; sprit, 50/1; detection, FDI; column temperature,
160 °C; injection temperature, 220 °C; detection temperature, 230 °C].
(1R,2S,3R,4S)-3-Amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol [(؊)-
18] 5 M NaOH (5 ml) was added to a solution of the pure salt 19 (3.24 g,
12 mmol) in water (5 ml), and extracted with ether (3ϫ10 ml). The organic
layers were combined, washed with brine (5 ml), dried over MgSO4, and
concentrated under reduced pressure to give (Ϫ)-18 (1.90, 92%) as a white
solid. An analytical sample was prepared by sublimation at 100 °C/
206 °C. IR (KBr): 3345, 1712, 1645 cmϪ1 1H-NMR (DMSO-d6) d: 2.47
.
(3H, s), 3.55 (2H, s), 6.89 (1H, d, Jϭ8.4 Hz), 7.75 (1H, dd, Jϭ2.0, 8.4 Hz),
7.78 (1H, d, Jϭ2.0 Hz), 10.18—10.75 (1H, br), 11.81—12.49 (1H, br). 13C-
NMR (DMSO-d6) d: 26.57, 35.64, 114.80, 122.53, 128.73, 129.67, 132.29,
160.56, 172.78, 196.43. HR-MS (FAB) m/z: Calcd for C10H11O4 (MϩH)ϩ:
195.0657. Found: 195.0661. Anal. Calcd for C10H10O4: C, 61.85; H, 5.19.
Found: C, 61.72; H, 5.30.
1
0.5 mmHg. mp 200—202 °C. IR (KBr): 2952, 1095, 1061 cmϪ1. H-NMR
(CDCl3) d: 0.79 (3H, s), 0.95 (3H, s), 0.98—1.07 (5H, m), 1.40—1.45 (1H,
m), 1.56 (1H, d, Jϭ4.5 Hz), 1.67—1.74 (1H, m), 3.06 (1H, d, Jϭ7.1 Hz),
2.10—1.80 (3H, br), 3.38 (1H, d, Jϭ7.1 Hz). 13C-NMR (CDCl3) d: 11.80,
21.62, 22.35, 27.29, 33.54, 47.01, 49.11, 53.83, 57.76, 79.43. [a]D25 Ϫ6.2°
(cϭ1.0, MeOH). HR-MS (FAB) m/z: Calcd for C10H20NO (MϩH)ϩ:
170.1545. Found: 170.1542. Anal. Calcd for C10H19NO: C, 70.96; H, 11.31;
N, 8.28. Found: C, 70.51; H, 11.14; N, 8.16.
Methyl (5-Acetyl-2-hydroxyphenyl)acetate (11)
A mixture of 10
(97.6 g, 500 mmol) and H2SO4 (4.9 g, 48 mmol) in MeOH (200 ml) was re-
fluxed for 1 h. A solution of K2CO3 (8.1 g, 96 mmol) in water (200 ml) was
added to the mixture and cooled to room temperature. The precipitate was
collected by filtration to give 11 (90.9 g, 87%). An analytical sample was
prepared by recrystallization from MeOH as a white solid. mp 167—168 °C.
(1R)-1-[4-Benzyloxy-3-(2-hydroxyethyl)phenyl]-2-bromoethan-1-ol
(14) Al(OEt)3 (59 mg, 0.36 mmol) was added to a solution of (R)-a,a-
diphenyl-2-pyrolidinylmethanol (15) (76 mg, 0.30 mmol) in THF (3 ml), and
the mixture was stirred at room temperature for 1 h under a N2 atmosphere.
After BH3·Me2S (10 M, 0.6 ml, 6 mmol) was added, a solution of 13
(1.132 g, 3 mmol) in THF (6 ml) was added dropwise via a syringe pump
over 1 h at 25 °C. After 10 min, the mixture was stirred for 2 h at 50 °C,
quenched with MeOH (1 ml), and concentrated under reduced pressure.
AcOEt (10 ml) and 1 M HCl (3 ml) were added to the resulting residue, and
then the separated aqueous layer was extracted with AcOEt (10 ml). The or-
ganic layers were combined, washed with water (5 ml) and brine (5 ml),
dried over MgSO4, and concentrated under reduced pressure. The resulting
residue was recrystallized from AcOEt–hexane to give 14 (0.910 g, 86%) as
a white solid. The ee of 14 was determined to be 99.9% by HPLC using a
chiral column [column, Chiralpak AD 4.6 mm i.d.ϫ250 mm, Daicel Chemi-
cal Industries Co., Ltd.; mobile phase, hexane–iso-PrOH, 9 : 1; flow rate,
1.0 ml/min; detection, UV at 230 nm]. mp 86—87 °C. IR (KBr): 3249, 1568,
IR (KBr): 3238, 1728, 1655 cmϪ1 1H-NMR (DMSO-d6) d: 2.47 (3H, s),
.
3.60 (3H, s), 3.64 (2H, s), 6.90 (1H, d, Jϭ8.4 Hz), 7.77 (1H, dd, Jϭ2.2,
8.4 Hz), 7.80 (1H, d, Jϭ2.2 Hz), 10.52 (1H, s). 13C-NMR (DMSO-d6) d:
26.57, 35.33, 51.90, 114.86, 121.90, 128.80, 129.91, 132.29, 160.52, 171.75,
196.38. HR-MS (FAB) m/z: Calcd for C11H13O4 (MϩH)ϩ: 209.0814. Found:
209.0815. Anal. Calcd for C11H12O4: C, 63.45; H, 5.81. Found: C, 63.22; H,
5.83.
Methyl (5-Acetyl-2-benzyloxyphenyl)acetate (12) A mixture of 11
(90.9 g, 440 mmol), benzylchloride (58.0 g, 460 mmol), KI (7.3 g, 44 mmol),
and K2CO3 (63.4 g, 460 mmol) in N,N-dimethylformamide (DMF) (150 ml)
was stirred for 1.5 h at 50 °C. Water (600 ml) was then added to the mixture
and the precipitate was collected by filtration. The crude product was recrys-
tallized from AcOEt–hexane to give 12 (101.4 g, 78%). mp 90 °C. IR (KBr):
1743, 1664 cmϪ1. 1H-NMR (CDCl3) d: 2.53 (3H, s), 3.63 (3H, s), 3.70 (2H,
s), 5.14 (2H, s), 6.95 (1H, d, Jϭ8.6 Hz), 7.30—7.40 (5H, m), 7.84 (1H, d,
Jϭ2.2 Hz), 7.88 (1H, dd, Jϭ2.2, 8.6 Hz,). 13C-NMR (CDCl3) d: 26.72,
36.50, 52.31, 70.64, 111.49, 124.04, 127.48, 128.51, 129.02, 130.39, 130.67,
132.01, 136.54, 160.93, 172.07, 197.07. HR-MS (FAB) m/z: Calcd for
C18H19O4 (MϩH)ϩ: 299.1283. Found: 299.1293. Anal. Calcd for C18H18O4:
C, 72.47; H, 6.08. Found: C, 72.65; H, 6.13.
Methyl (2-Benzyloxy-5-bromoacetylphenyl)acetate (13) A solution of
Br2 (6.2 ml, 120 mmol) in hexane (15 ml) was added dropwise to a solution
of 12 (32.8 g, 110 mmol) in AcOEt (160 ml) over 20 min. After 30 min,
water was added to the mixture and the separated organic layer was washed
with brine (50 ml), dried over MgSO4, and concentrated under reduced pres-
sure. The resulting residue was recrystallized from AcOEt–hexane to give
1
1448, 1253 cmϪ1. H-NMR (CDCl3) d: 1.85 (1H, s), 2.89—2.95 (3H, m),
3.51 (1H, dd, Jϭ8.9, 10.4 Hz), 3.57 (1H, dd, Jϭ3.6, 10.4 Hz), 3.80—3.87
(2H, m), 4.79—4.84 (1H, m), 5.07 (2H, s), 6.90 (1H, d, Jϭ8.1 Hz), 7.15—
7.20 (2H, m), 7.29—7.42 (5H, m). 13C-NMR (CDCl3) d: 34.55, 40.53,
62.94, 70.55, 73.83, 112.19, 125.91, 127.65, 128.19, 128.44, 129.07, 129.16,
133.11, 137.22, 157.21. [a]D29 Ϫ17.6° (cϭ1.0, MeOH). HR-MS (FAB) m/z:
Calcd for C17H19BrO3 Mϩ: 350.0518. Found: 350.0509. Anal. Calcd for
C17H19BrO3: C, 58.13; H, 5.45. Found: C, 57.97; H, 5.52.
Determination of the Absolute Configuration of 14 The absolute con-
figuration of 14 was determined by a single crystal X-ray diffraction analy-
sis. The recrystallization of 14 from AcOEt gave a colorless prism. Crystal

1022
Vol. 49, No. 8
tate was collected by filtration to give 24 (7.94 g, 79%) as a white solid. The
ee of 24 was determined to be Ͼ99.9% by HPLC using a chiral column [col-
umn, SUMICHIRAL CBH 4.0 mm i.d.ϫ100 mm, Sumika Chemical Analy-
sis Service, Ltd.; mobile phase, 1% CH3CN in 20 mM potassium phosphate
buffer pH 6.5 ϩ50 mM disodium ethylenediaminetetraacetate; flow rate,
1.0 ml/min; detection, UV at 230 nm]. mp 122—124 °C. IR (KBr): 3451,
data were: C17H19BrO3, monoclinic, P21 (No. 4), Zϭ2; aϭ4.985, bϭ11.139,
cϭ14.445 Å; aϭgϭ90.000, bϭ94.586°; Vϭ799.55 Å3; Dcϭ1.38 g·cmϪ3
;
mϭ17.98 cmϪ1. Intensity data were collected at room temperature using
graphite monochromated Mo-Ka radiation (lϭ0.71069 Å) on a Rigaku
RASA-7R diffractometer, 2q(max)ϭ55.0°. Of 4225 measured reflections,
2184 had IϾ3s, and 1893, including Bijvoet pairs, were unique and used
for the structure analysis. The structure was solved by the direct method
(SIR-92) and refined through full-matrix least square method to Rϭ0.042
and Rwϭ0.045 using the TEXSAN-TEXRAY Structure Analysis Package
(Ver 1.9), Molecular Structure Corporation. Hydrogen atoms were incorpo-
rated at fixed position as with C–Hϭ0.95 Å. The absolute configuration was
confirmed by refining the inverted configuration which converged to a higher
residual of R/(Rw)ϭ0.0716/(0.0778) (heavy atoms only). The absolute con-
figuration of 14 was confirmed to be R as shown in Fig. 2.
1
1641 cmϪ1. H-NMR (DMSO-d6) d: 1.70—1.81 (1H, m), 2.10—2.18 (1H,
m), 2.68—2.87 (6H, m), 2.99 (3H, s), 3.06 (1H, dd, Jϭ4.7, 16.1 Hz), 3.37—
3.50 (5H, m), 4.74 (2H, s), 6.68 (1H, s), 6.71 (1H, d, Jϭ8.4 Hz), 6.99 (1H, d,
Jϭ8.4 Hz), 8.47 (3H, br). 13C-NMR (DMSO-d6) d: 26.45, 27.31, 33.51,
35.30, 35.99, 47.02, 66.15, 113.64, 114.52, 127.45, 129.73, 134.20, 156.59,
167.61. [a]D29 Ϫ45.4° (cϭ1.0, MeOH). Anal. Calcd for C14H21ClN2O2·
2H2O: C, 52.41; H, 7.85; N, 8.73. Found: C, 52.44; H, 8.02; N, 8.75.
(1R)-1-[4-Benzyloxy-3-(2-tert-butyldimethylsilyloxyethyl)phenyl]-2-
bromo-1-tert-butyldimethylsilyloxyethane (25) A solution of TBS-Cl
(32.18 g, 214 mmol) in toluene (32 ml) was added to a solution of 14
(30.00 g, 85 mmol) and imidazole (29.07 g, 427 mmol) in DMF (100 ml)
cooled in an ice bath, and then the mixture was stirred at room temperature
for 6 h. A solution of TBS-Cl (2.57 g, 17 mmol) in toluene (2.5 ml) was
added to the reaction mixture. After 2 h, water (100 ml) was added to the
mixture and extracted with AcOEt (2ϫ100 ml). The organic layers were
combined, washed with water (2ϫ100 ml) and brine (50 ml), dried over
MgSO4, and concentrated under reduced pressure to give 25 (52.2 g, 118%)
as a colorless oil. The oil was used for the next step without purification. An
analytical sample was prepared by purification using silica gel column chro-
matography (eluent; hexane) that produced a colorless oil. IR (neat): 2955,
2929, 1501, 1251 cmϪ1. 1H-NMR (CDCl3) d: Ϫ0.09 (3H, s), Ϫ0.04 (6H, s),
0.10 (3H, s), 0.85 (9H, s), 0.89 (9H, s), 2.90 (2H, t, Jϭ7.3 Hz), 3.35—3.46
(2H, m), 3.80 (2H, t, Jϭ7.3 Hz), 4.78 (1H, dd, Jϭ4.4, 7.9 Hz), 5.05 (2H, s),
6.86 (1H, d, Jϭ8.3 Hz), 7.12—7.15 (2H, m), 7.32—7.44 (5H, m). 13C-NMR
(CDCl3) d: Ϫ4.95, Ϫ4.47, Ϫ4.24, 18.69, 18.75, 26.20, 26.37, 34.83, 40.34,
63.38, 70.38, 75.38, 111.53, 125.58, 127.72, 127.95, 128.25, 128.94, 129.33,
134.67, 137.58, 156.96. [a]D31 Ϫ33.0° (cϭ1.0, MeOH). HR-MS (FAB) m/z:
Calcd for C29H46BrO3Si2 (MϪH)ϩ: 577.2169. Found: 577.2155. Anal. Calcd
for C29H47BrO3Si2: C, 60.08; H, 8.17. Found: C, 59.97; H, 8.28.
(7S)-7-Amino-5,6,7,8-tetrahydro-2-naphtol Hydrobromide (3)
A
mixture of 20 (10.0 g, 48 mmol) and NaOH (2.3 g, 58 mmol) in water
(40 ml) was extracted with toluene (2ϫ20 ml). The organic layers were com-
bined, washed with water (10 ml), and concentrated under reduced pressure
to give an oil. A mixture of the oil in 48% hydrobromic acid (27 ml) was re-
fluxed for 4 h in a 140 °C oil bath. After concentration under reduced pres-
sure, the resulting residue was recrystallized from iso-PrOH to give 3
(11.3 g, 99%) as a white solid. mp 154—156 °C. IR (KBr): 3372, 3027,
1
1504, 1267 cmϪ1. H-NMR (DMSO-d6) d: 1.65—1.75 (1H, m), 2.04—2.11
(1H, m), 2.67—2.78 (3H, m), 2.97 (1H, dd, Jϭ4.7, 16.4 Hz), 3.38—3.45
(1H, m), 6.50 (1H, d, Jϭ2.6 Hz), 6.57 (1H, dd, Jϭ2.6, 8.4 Hz), 6.89 (1H, d,
Jϭ8.4 Hz), 8.01 (3H, br s), 9.13 (1H, s). 13C-NMR (DMSO-d6) d: 26.30,
27.43, 33.43, 47.14, 114.25, 115.29, 125.22, 129.79, 133.87, 155.72. [a]D28
Ϫ61.4° (cϭ1.0, MeOH). Anal. Calcd for C10H14BrNO: C, 49.20; H, 5.78; N,
5.74. Found: C, 49.16; H, 6.17; N, 5.78.
(7S)-7-tert-Butoxycabonylamino-5,6,7,8-tetrahydro-2-naphthol (21)
A solution of Boc2O (11.1 g, 51 mmol) in DMF (30 ml) was added dropwise
to a mixture of 3 (11.3 g, 46 mmol) and triethylamine (32 ml, 230 mmol) in
DMF (70 ml) cooled in an ice bath over 10 min, and then the mixture was
stirred overnight at room temperature. Water (200 ml) was added to the mix-
ture and extracted with AcOEt (2ϫ100 ml). The organic layers were com-
bined, washed with water (100 ml), 4% citric acid (100 ml), water (100 ml),
and brine (100 ml), dried over MgSO4, and concentrated under reduced pres-
sure to give 21 (12.4 g, 102%) as a viscous oil. The oil was used for the next
step without purification. An analytical sample was prepared by purification
using silica gel chromatography (eluent; AcOEt : hexaneϭ1 : 2) that pro-
2-{[(2S)-2-({(2R)-2-[4-Benzyloxy-3-(2-tert-butyldimethylsilyloxyethyl)-
phenyl]-2-tert-butyldimethylsilyloxyethyl}amino)-1,2,3,4-tetrahydron-
aphthalen-7-yl]oxy}-N,N-dimethylacetamide (26)
A mixture of 25
(58.2 g, 85 mmol), 24 (30.2 g, 94 mmol), and K2CO3 (18.9 g, 137 mmol) in
N,N-dimethylacetamide (85 ml) was stirred for 6 h under an argon atmos-
phere in a 120 °C oil bath. After cooling to room temperature, water
(200 ml) was added to the mixture and extracted with AcOEt (2ϫ200 ml).
The organic layers were combined, washed with water (2ϫ100 ml) and brine
(100 ml), dried over MgSO4, and concentrated under reduced pressure to
give 26 (68.6 g, 108% from 14) as a brown oil. The oil was used for the next
step without purification. An analytical sample was prepared by purification
using silica gel column chromatography (eluent; CH2Cl2 : MeOHϭ30 : 1)
duced a colorless oil. IR (neat): 3336, 1681, 1504, 1166 cmϪ1 1H-NMR
.
(CDCl3) d: 1.46 (9H, s), 1.66—1.75 (1H, m), 1.98—2.06 (1H, m), 2.55 (1H,
dd, Jϭ8.2, 16.3 Hz), 2.77 (2H, t, Jϭ6.5 Hz), 3.03 (1H, dd, Jϭ3.8, 16.3 Hz),
3.86—4.00 (1H, br), 4.52—4.68 (1H, br), 5.13—5.28 (1H, br), 6.53 (1H, d,
Jϭ2.6 Hz), 6.62 (1H, dd, Jϭ2.6, 8.4 Hz), 6.93 (1H, d, Jϭ8.4 Hz). 13C-NMR
(CDCl3) d: 26.84, 28.87, 29.69, 36.67, 46.77, 80.20, 114.22, 116.00, 127.28,
130.12, 135.69, 154.64, 156.13. [a]D26 Ϫ67.8° (cϭ1.0, MeOH). HR-MS
(FAB) m/z: Calcd for C15H22NO3 (MϩH)ϩ: 264.1599. Found: 264.1643.
Anal. Calcd for C15H21NO3: C, 68.42; H, 8.04;N, 5.32. Found: C, 68.19; H,
8.05; N, 5.15.
2-{[(2S)-2-tert-Butyloxycabonylamino-1,2,3,4-tetrahydronaphthalen-
7-yl]oxy}-N,N-dimethylacetamide (23) A solution of 2-chloro-N,N-di-
methylacetamide (22) (6.2 g, 51 mmol) in THF (10 ml) was added dropwise
to a mixture of 21 (12.4 g, 46 mmol), KI (8.5 g, 51 mmol), NaOH (3.9 g,
98 mmol), water (20 ml), and THF (50 ml) at room temperature. After stir-
ring for 0.5 h, 22 (1.7 g, 14 mmol) was added dropwise to the mixture. After
stirring for 1 h, AcOEt (200 ml) was added and the organic solution was
washed with water (100 ml) and brine (50 ml), dried over MgSO4, and con-
centrated under reduced pressure. The resulting residue was recrystallized
from AcOEt–hexane to give 23 (12.3 g, 76%) as a white solid. mp 88—
89 °C. IR (KBr): 3330, 1704, 1655 cmϪ1. 1H-NMR (CDCl3) d: 1.45 (9H, s),
1.68—1.75 (1H, m), 2.00—2.07 (1H, m), 2.59 (1H, dd, Jϭ8.2, 16.3 Hz),
2.80 (2H, t, Jϭ6.4 Hz), 2.97 (3H, s), 3.05—3.11 (4H, m), 3.89—4.01 (1H,
br), 4.51—4.62 (1H, br), 4.64 (2H, s), 6.64 (1H, d, Jϭ2.6 Hz), 6.75 (1H, dd,
Jϭ2.6, 8.3 Hz), 7.00 (1H, d, Jϭ8.3 Hz). 13C-NMR (CDCl3) d: 26.75, 28.83,
29.52, 36.10, 36.68, 36.99, 46.53, 60.77, 67.99, 113.41, 115.26, 129.01,
130.18, 136.01, 155.72, 156.50, 168.36. [a]D27 Ϫ60.8° (cϭ1.0, MeOH). HR-
MS (FAB) m/z: Calcd for C19H29N2O4 (MϩH)ϩ: 349.2127 Found: 349.2140.
Anal. Calcd for C19H28N2O4·0.4AcOEt: C, 64.49; H, 8.20; N, 7.30. Found:
C, 64.50; H, 8.39; N, 7.39.
that produced a colorless oil. IR (neat): 2953, 2928, 1657, 1502, 1250 cmϪ1
.
1H-NMR (CDCl3) d: Ϫ0.16 (3H, s), Ϫ0.04 (6H, s), 0.03 (3H, s), 0.85 (9H,
s), 0.88 (9H, s), 1.49—1.59 (1H, m), 1,63—1.75 (2H, m), 1.99—2.02 (1H,
s), 2.52—2.96 (9H, m), 2.97 (3H, s), 3.08 (3H, s), 3.81 (2H, t, Jϭ7.4 Hz),
4.64 (2H, s), 4.75 (1H, dd, Jϭ4.2, 8.2 Hz), 5.05 (2H, s), 6.66 (1H, d,
Jϭ2.6 Hz), 6.73 (1H, dd, Jϭ2.6, 8.4 Hz), 6.85 (1H, d, Jϭ8.3 Hz), 6.98 (1H,
d, Jϭ8.4 Hz), 7.12 (1H, dd, Jϭ2.1, 8.3 Hz), 7.15 (1H, d, Jϭ2.1 Hz), 7.32—
7.44 (5H, m). 13C-NMR (CDCl3) d: Ϫ4.92, Ϫ4.53, Ϫ3.94, 18.57, 18.76,
26.27, 26.39, 27.71, 30.43, 34.90, 36.12, 37.06, 37.22, 53.53, 56.67, 63.48,
68.15, 70.37, 74.46, 111.46, 113.14, 115.15, 125.49, 127.66, 127.71, 128.19,
128.90, 129.32, 129.85, 130.04, 136.00, 137.01, 137.71, 156.39, 156.56,
168.50. [a]D31 Ϫ56.9° (cϭ0.7, MeOH). HR-MS (FAB) m/z: Calcd for
C43H67N2O5Si2 (MϩH)ϩ: 747.4588. Found: 747.4569. Anal. Calcd for
C43H66N2O5Si2·0.5H2O: C, 68.30; H, 8.93; N, 3.70. Found: C, 68.17; H,
9.10; N, 3.84.
2-{[(2S)-2-({(2R)-2-[4-Benzyloxy-3-(2-hydroxyethyl)phenyl]-2-hydrox-
yethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-dimethylac-
etamide Oxalate Hydrate (27) A mixture of 26 (68.6 g, 85 mmol) and
TosOH·H2O (48.7 g, 256 mmol) in THF (480 ml) and water (24 ml) was
stirred at room temperature overnight. After the addition of a solution of
K2CO3 (39 g, 281 mmol) in water (300 ml), the mixture was extracted with
AcOEt (300 ml) and 10% EtOH–AcOEt (300 ml). The organic layers were
combined, washed with aqueous 0.4 M K2CO3 solution (200 ml) and brine
(200 ml), then concentrated under reduced pressure. A solution of oxalic
acid dihydrate (10.7 g, 85 mmol) in EtOH (80 ml) was added to the solution
of the resulting residue in EtOH (120 ml) at 50 °C, and then toluene (430 ml)
was added to the mixture and cooled to room temperature. The precipitate
2-{[(2S)-2-Amino-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-di-
methylacetamide Hydrochloride Dihydrate (24) conc. HCl (17.5 ml)
was added to a solution of 23 (12.29 g, 35 mmol) in iso-PrOH (50 ml) at
room temperature, and then the mixture was stirred overnight. The precipi-

August 2001
1023
1
white solid. mp 211—215 °C (dec.). IR (KBr): 3418, 1636 cmϪ1. H-NMR
(DMSO-d6) d: 1.57—1.68 (1H, m), 2.03—2.11 (1H, m), 2.60—3.22 (16H,
m), 3.57 (2H, t, Jϭ7.4 Hz), 4.66 (1H, dd, Jϭ2.8, 9.4 Hz), 4.71 (2H, s), 6.63
(1H, d, Jϭ2.6 Hz), 6.67 (1H, dd, Jϭ2.6, 8.4 Hz), 6.74 (1H, d, Jϭ8.2 Hz),
6.96 (1H, d, Jϭ8.4 Hz), 7.03 (1H, dd, Jϭ1.9, 8.2 Hz), 7.08 (1H, d,
Jϭ1.9 Hz), 9.24 (1H, br s). 13C-NMR (DMSO-d6) d: 26.89, 27.00, 32.89,
34.37, 35.28, 35.96, 52.80, 53.70, 61.32, 66.15, 69.39, 113.29, 114.67,
115.01, 125.07, 125.37, 127.94, 128.64, 129.55, 133.29, 135.05, 155.05,
156.50, 167.58. [a]D25 Ϫ70.8° (cϭ1.0, H2O). Anal. Calcd for C48H66N4O14S:
C, 60.36; H, 6.96; N, 5.87. Found: C, 60.18; H, 7.09; N, 5.82.
was collected by filtration to give 27 (36.7 g, 69% from 14) as a white solid.
mp 169—173 °C. IR (KBr): 1635, 1506 cmϪ1 1H-NMR (DMSO-d6) d:
.
1.71—1.87 (1H, m), 2.21—2.31 (1H, m), 2.61—3.25 (14H, m), 3.39—3.50
(1H, m), 3.61 (2H, t, Jϭ7.3 Hz), 4.73 (2H, s), 4.92 (1H, d, Jϭ9.1 Hz), 5.13
(2H, s), 6.66 (1H, s), 6.70 (1H, d, Jϭ8.4 Hz), 6.99 (1H, d, Jϭ8.5 Hz), 7.03
(1H, d, Jϭ8.4 Hz), 7.22 (1H, d, Jϭ8.5 Hz), 7.25 (1H, s), 7.34 (1H, t,
Jϭ7.2 Hz), 7.38—7.45 (4H, m). 13C-NMR (DMSO-d6) d: 26.09, 26.93,
31.61, 34.32, 35.29, 35.94, 51.58, 54.02, 61.14, 66.11, 68.52, 69.57, 112.20,
113.57, 114.65, 125.24, 127.59, 127.69, 128.06, 128.66, 128.77, 128.82,
129.62, 134.17, 134.33, 137.75, 156.14, 156.62, 165.29, 167.55. [a]D29
Ϫ67.8° (cϭ1.0, MeOH). Anal. Calcd for C33H40N2O9·H2O: C, 63.25; H,
6.75; N, 4.47. Found: C, 63.07; H, 6.54; N, 4.43.
Acknowledgment We thank Mr. E. Tsuji, Kissei Pharmaceutical Co.,
2-{[(2S)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)phenyl]-
ethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-dimethylac-
etamide (28) A mixture of 37 (36.7 g, 59 mmol) and K2CO3 (24.3 g,
176 mmol) in water (200 ml) and 10% EtOH–AcOEt (200 ml) was stirred for
1 h at 40 °C. The separated aqueous layer was extracted with 10%
EtOH–AcOEt (2ϫ100 ml), and then the organic layers were combined,
washed with brine (50 ml), and concentrated under reduced pressure to give
an oil. The solution of the oil in EtOH (150 ml) was hydrogenated over 10%
Pd-C (50% wet, 3.7 g) for 8 h at 40 °C under atmospheric pressure. The
Pd–C was filtered off, the filtrate was concentrated under reduced pressure,
and the resulting residue was recrystallized from EtOH–hexane to give 28
(22.3 g, 89%) as a white solid. mp 136—137 °C. IR (KBr): 3310,
Ltd., for the X-ray crystallographic analysis.
References and Notes
1) Kobayashi M., Takeda K., Murata S., Kojima M., Akahane M., Inoue
Y., Kitamura K., Kawarabayashi T., J. Pharmacol. Exp. Ther., 297,
666—671 (2001).
2) Kitazawa M., Okazaki K., Tamai T., Saito M., Tanaka N., Kobayashi
H., Kikuchi K., PCT, WO97/30023 (1997).
3) Sohda S., Fujimoto M., Tamegai T., Hirose N., J. Med. Chem., 22,
279—286 (1979).
4) Yanagi T., Kikuchi K., Takeuchi H., Ishikawa T., Nishimura T., Kamijo
T., Chem. Lett., 1999, 1203—1204.
1
1654 cmϪ1. H-NMR (DMSO-d6) d: 1.39—1.49 (1H, m), 1.52—1.75 (1H,
5) Mathre D. J., Jones T. K., Xavier L. C., Blacklock T. J., Reamer R. A.,
Mohan J. J., Jones E. T. T., Hoogsteen K., Baum M. W., Grabowski E.
J. J., J. Org. Chem., 56, 751—762 (1991).
br), 1.85—1.95 (1H, m), 2.43 (1H, dd, Jϭ8.3, 16.0 Hz), 2.55—2.87 (10H,
m), 2.90 (1H, dd, Jϭ4.8, 16.0 Hz), 2.98 (3H, s), 3.55 (2H, t, Jϭ7.4 Hz), 4.47
(1H, dd, Jϭ3.9, 8.3 Hz), 4.69 (2H, s), 5.03 (1H, br s), 6.61 (1H, d,
Jϭ2.4 Hz), 6.64 (1H, dd, Jϭ2.4, 8.1 Hz), 6.70 (1H, d, Jϭ8.2 Hz), 6.93 (1H,
d, Jϭ8.1 Hz), 6.97 (1H, dd, Jϭ2.0, 8.2 Hz), 7.03 (1H, d, Jϭ2.0 Hz), 8.80—
9.04 (1H, br). 13C-NMR (DMSO-d6) d: 26.76, 29.68, 34.41, 35.28, 36.01,
36.83, 52.88, 55.38, 61.39, 66.23, 71.91, 112.69, 114.81, 114.87, 124.97,
125.11, 128.68, 128.79, 129.44, 135.12, 136.76, 154.57, 156.32, 167.67.
[a]D25 Ϫ59.6° (cϭ1.1, MeOH). HR-MS (FAB) m/z: Calcd for C24H33N2O5
(MϩH)ϩ: 429.2389. Found: 429.2369. Anal. Calcd for C24H32N2O5: C,
66.27; H, 7.53; N, 6.54. Found: C, 66.92; H, 7.69; N, 6.52.
Bis(2-{[(2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)-
phenyl]ethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-di-
methylacetamide) Sulfate (KUR-1246) 2 M H2SO4 (26.0 ml, 26.0 mmol)
was added to a solution of 28 (22.3 g, 52.0 mmol) in MeOH (130 ml) at
50 °C, and then the mixture was stirred overnight at room temperature. The
precipitate was collected by filtration to give KUR-1246 (21.47 g, 87%) as a
6) George J., PCT, WO94/26751 (1994).
7) a) Tanaka K., Ushio H., Kawabata Y., Suzuki H., J. Chem. Soc. Perkin
Trans. 1, 1991, 1445—1452; b) Beckett A. H., Lan N. T., McDonough
G. R., Tetrahedron, 25, 5689—5692 (1969); c) Gawley R. E., Zhang
P., J. Org. Chem., 61, 8103—8112 (1996).
8) a) Cecchi R., Croci T., Boigegrain R., Boveri S., Baroni M., Boccardi
G., Guimbard J. P., Guzzi U., Eur. J. Med. Chem., 29, 259—267
(1994); b) Stirling D. I., Matcham G. W., Zeitlin A. L., U.S. Patent
5300437 (1992); c) Devocelle M., Mortreux A., Agbossou F., Dormoy
J. R., Tetrahedron Lett., 40, 4551—4554 (1999); d) Buisson D., Cec-
chi R., Laffitte J. A., Guzzi U., Azerad R., ibid., 35, 3091—3094
(1994).
9) Yanagi T., Kikuchi K., Takeuchi H., Ishikawa T., Nishimura T., Kamijo
T., Yamamoto I., Chem. Pharm. Bull., 49, 340—344 (2001).