Synthesis of J-113397, the first potent and selective ORL1 antagonist

Article abstract of DOI:10.1016/S0040-4020(00)01064-4

The first potent and selective small molecule ORL1 antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dih ydro-2H-benzimidazol-2-one (J-113397) was synthesized. J-113397 is the only available potent and selective ORL1 antagonist, which is a very useful pharmacological tool for elucidating the physiological roles of the nociceptin-ORL1 system. J-113397 was synthesized from ethyl 4-oxo-3-piperidinecarboxylate and a coupling reaction of 2-fluorobenzene with 4-amino-ethoxycarbonylpiperidine is a key step.

Full text of DOI:10.1016/S0040-4020(00)01064-4

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 981±986
Synthesis of J-113397, the ®rst potent and
selective ORL1 antagonist
p
Hiroshi Kawamoto, Hiroshi Nakashima, Tetsuya Kato, Sachie Arai, Kenji Kamata and
Yoshikazu Iwasawa
Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Banyu Pharmaceutical Co. Ltd, Okubo 3,
Tsukuba, Ibaraki 300-2611, Japan
Received 22 September 2000; accepted 6 November 2000
AbstractÐThe ®rst potent and selective small molecule ORL1 antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-
ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) was synthesized. J-113397 is the only available potent and selective ORL1 antagonist,
which is a very useful pharmacological tool for elucidating the physiological roles of the nociceptin±ORL1 system. J-113397 was synthe-
sized from ethyl 4-oxo-3-piperidinecarboxylate and a coupling reaction of 2-¯uorobenzene with 4-amino-ethoxycarbonylpiperidine is a key
step. q 2001 Elsevier Science Ltd. All rights reserved.
1
. Introduction
for the ORL1 receptor with a selectivity greater than 600-
fold over the opioid m, k, and d receptors (Scheme 1).
J-113397 behaves as an antagonist at the ORL1 receptor
in in vitro functional assays, as well as in in vivo assays.
Since J-113397 is the only available potent and selective
small molecule ORL1 antagonist, which is a useful pharma-
cological tool for elucidating the physiological roles of the
nociceptin±ORL1 receptor system, development of an
ef®cient synthetic method is necessary to supply enough
of the compound. In this paper, we report the details of
the synthesis of J-113397.
In 1994, the ORL1 receptor was identi®ed as the fourth
opioid receptor using a cloning technique. This is a
1
G-protein-coupled receptor having signi®cant sequence
homology with the classical opioid receptors (m, k, d),
however, none of the classical opioid ligands show signi®-
cant af®nity for the ORL1 receptor. Nociceptin, also termed
orphanin FQ (NC/OFQ), is a peptide consisting of 17 amino
acids that was identi®ed as an endogenous ligand for the
2
ORL1 receptor in 1995. Although nociceptin has homology
with the classical opioid peptide dynorphin A, it has no
signi®cant activity at the classical opioid receptors.
Nociceptin and ORL1 receptors are widely distributed in
the central nervous system. Pharmacological studies using
nociceptin and ORL1-de®cient mice have shown that the
NC/OFQ±ORL1 system may have important roles in the
2
. Results and discussion
Retrosynthetic analysis indicated that J-113397 could be
synthesized through a coupling reaction of 2-¯uoronitro-
benzene 2 with 4-amino-3-alchoxycarbonylpiperidine 3 as
a key step. Nothing had been reported about an ef®cient
synthetic method of 4-amino-3-alchoxycarbonylpiperidine
when we started the study. We chose commercially avail-
able ethyl 4-oxo-3-piperidinecarboxylate 4 as the starting
material (Scheme 2).
3
4
regulation of pain response, morphine tolerance, learning
5
6
and memory, food intake, anxiety, the cardiovascular
7
8
9
10
system, locomotor activity, and so on. Unfortunately,
further pharmacological evaluation of the nociceptin±
ORL1 receptor system has been hampered due to the lack
of selective ORL1 antagonists. In order to understand the
physiological roles of the nociceptin±ORL1 receptor
system, development of a potent and selective ORL1
antagonist has been desired. Recently we reported
J-113397 to be the ®rst potent and selective small molecule
1
2
1
1
ORL1 antagonist. J-113397 has trisubstituted piperidine
and benzimidazolidinone structure and shows high af®nity
Keywords: biologically active compounds; coupling reactions; ORL1
receptors.
*
Corresponding author. Tel.: 181-298-77-2000; fax: 181-298-77-2029;
e-mail: kawmtohr@banyu.co.jp
Scheme 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01064-4

9
82
H. Kawamoto et al. / Tetrahedron 57 (2001) 981±986
Scheme 2.
Scheme 3.
Scheme 4.
Cyclooctanecarbaldehyde 7 was prepared from com-
mercially available cyclooctanone according to the known
procedure with small modi®cations as shown in Scheme 3.
reduction conditions (NaBH CN/MeOH, NaBH /EtOH and
3 4
hydrogenolysis). We found that the reduction of the
enamine 10 was achieved with NaBH CN in n-BuOH at
1
3
3
Thus, vilsmeier formylation of cyclooctanone 5 with POCl3
and DMF at room temperature gave b-chloro-a,b-
unsaturated aldehyde 6. Compound 6 was hydrogenated
with Pd±C in MeOH, followed by hydrolysis of the
resultant aldehyde dimethyl acetal with aqueous hydro-
chloric acid in THF after distillation to give the cyclo-
octanecarbaldehyde 7 in 75% yield.
re¯ux temperature for 1 h. By adding ¯uoronitrobenzene
and sodium carbonate to the reaction mixture, the reduction
and coupling were achieved in a one-pot manner. Thus, a
solution of the enamine 10, ¯uoronitrobenzene, the
NaBH CN, and Na CO in n-BuOH was heated at re¯ux
temperature for 3 h, affording compounds 11 and 12 as a
mixture of cis- and trans-isomers. The isomers were easily
separated by silica gel column chromatography by eluting
with 5% AcOEt±hexane to give 11 as a less-polar isomer in
3
2
3
Synthesis of J-113397 is summarized in Scheme 4. Reduc-
tive alkylation reaction of commercially available ethyl
4-oxo-piperidine-3-carboxylate 8 with the cyclooctane-
carbaldehyde 7 in the presence of NaB(OAc) H was
3
achieved at room temperature in THF in 64% yield. The
resultant ketoester 9 was treated with 10-fold excess
ammonium acetate in MeOH at room temperature to give
the corresponding enamine 10. Because the enamine 10 is
very stable, the desired amine was not obtained under usual
Scheme 5.

H. Kawamoto et al. / Tetrahedron 57 (2001) 981±986
983
Figure 1. ORTEP drawing of (1)-1 J-113397 d-tartaric salt.
37% yield and 12 as a polar isomer in 31% yield, respec-
tively. The trans con®guration of compound 11 was deter-
were recorded in ppm (d) and are reported relative to the
solvent peak of TMS. IR spectra were measured on a Horiba
FT-200 spectrometer. High-resolution mass spectra were
recorded on a JEOL JMS-SX102A spectrometer. Column
chromatography separations were carried out using Merck
silica gel 60 (mesh 63±200 nm).
1
mined by H NMR. The coupling constant of the methyne
proton at the 3-position of the piperidine of the less-polar
isomer showed triplet of doublet (J ˆ3.7 Hz and
d
J ˆ9.2 Hz), suggesting that the relationship between
t
protons at the 3- and 4-positions to be di-axial (Scheme 5).
The trans-isomer 11 was hydrogenated in the presence of
4.1.1. Cyclooctanecarbaldehyde (7). Phosphorous oxy-
chloride (115 ml, 1.2 mol) was added dropwise to DMF
(200 ml, 2.6 mol) at 08C, and the mixture was stirred for
0.5 h at the same temperature. Cyclooctanone 5 (100 g,
0.8 mol) in DMF (140 ml) was added dropwise to the
mixture at 08C and stirred for 1 h at room temperature.
The reaction mixture was partitioned between AcOEt and
water. The organic layer was washed with 1M NaOH and
brine, dried over Na SO , ®ltered and concentrated in vacuo
Pd±C in MeOH and CHCl , and the resultant phenylene
3
diamine was cyclized with carbonyldiimidazole (CDI) in
CHCl at room temperature to give benzimidazolidinone
3
1
3 in 84% yield. Treatment of imidazolidinone 13 with
4
1
NaH and ethyliodide in DMF at room temperature gave 14
in 90% yield. Reduction of 14 with LiAlH at 08C afforded 1
4
as a racemate in 89% yield. Optical resolution of the
racemate 1 was achieved by using chiral column CHIRAL-
2
4
w
PAK
give (1)-1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-
AD (hexane/2-propanol/Et NHˆ800/200/1) to
to give a crude 2-chloro-1-cyclooctene-1-carbaldehyde 6.
To a solution of crude 6 in MeOH (1 l) was added 10%
Pd±C (10 g) and pyridine (65 ml). The mixture was stirred
under a hydrogen atmosphere for 20 h. The catalyst was
2
4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one,
J-113397.
®ltered off and washed with MeOH. The eluent was concen-
The absolute con®guration of the active enantiomer
J-113397 was determined to be 3R and 4R by X-ray crystal-
lography of its d-tartaric salt (Fig. 1).
trated in vacuo, and the residue was partitioned between
AcOEt and 1M HCl. The organic layer was concentrated
in vacuo to give a crude aldehyde dimethylacetal. To a
solution of the acetal in THF (1 l) was added 1M HCl
(
50 ml) at room temperature, and the reaction mixture was
3
. Summary
stirred for 3 h and concentrated in vacuo. The residue was
partitioned between AcOEt and 1M NaOH, and the organic
We achieved the synthesis of a potent and selective ORL1
antagonist J-113397 from commercially available cyclo-
octanone and ethyl-4-oxo-piperidine-3-carboxlate.
layer was washed with brine, dried over Na SO , ®ltered and
2 4
concentrated in vacuo. The resulting residue was puri®ed by
distillation (908C, 20 mmHg) to give 84 g (yield: 75%) of 7
as a colorless oil.
2
1 1
4. Experimental section
IR (®lm): 2852, 1726, 1469, 1446 cm . H NMR (CDCl ):
3
d 1.40±1.84 (m, 12H), 1.88±2.05 (m, 2H), 2.33±2.42 (m,
1H), 9.61 (s, 1H).
4.1. Materials and methods
1
H NMR spectra were recorded on a Varian VXR 300 spec-
trometer and JEOL JNM-A500, and the abbreviations for
the signal patterns are as follows: s, singlet; d, doublet; t,
4.1.2. Ethyl 1-cyclooctylmethyl-4-oxo-3-piperidinecar-
boxylate (9). To a solution of ethyl 4-oxo-3-piperidinecar-
boxylate hydrochloride 8 (100 g, 0.48 mol) in THF (1 l) was
added cyclooctanecarbaldehyde (82 g, 0.58 mol) and
1
3
triplet; q, quartet; m, multiplet; br, broad. C NMR spectra
were recorded on a Varian INOVA 600. Chemical shifts
NaB(OAc) H (155 g, 0.72 mol) at 08C. The reaction mixture
3

9
84
H. Kawamoto et al. / Tetrahedron 57 (2001) 981±986
21 1
12: IR (®lm): 2913, 2848, 1730, 1618, 1571, 1511 cm . H
was warmed up to room temperature and stirred for 5.5 h.
The mixture was partitioned between AcOEt and water, and
the organic layer was washed with 1M NaOH and brine,
dried over Na SO , ®ltered and concentrated in vacuo.
The residue was puri®ed by silica gel column chromato-
graphy (hexane/AcOEtˆ50/1) to give 90.8 g (yield: 64%)
of 9 as a colorless oil.
NMR (CDCl ): d 1.21 (t, Jˆ7.5 Hz, 3H), 1.12±1.28 (m,
3
2H), 1.35±1.77 (m, 12H), 1.78±1.92 (m, 2H), 2.03±2.19
(m, 3H), 2.31±2.43 (m, 1H), 2.50±2.66 (m, 2H), 2.90±
3.12 (m, 2H), 3.94±4.07 (m, 1H), 4.08±4.19 (m, 2H),
6.58±6.64 (m, 1H), 6.89 (d, Jˆ8.4 Hz, 1H), 7.36±7.43
2
4
1
3
(m, 1H), 8.16 (br d, Jˆ8.4 Hz, 1H) 8.74 (br, 1H).
C
NMR (CDCl ): d 14.0, 25.4, 25.5, 26.3, 27.1, 27.1, 29.1,
3
2
1
IR (®lm): 2927, 2917, 2910, 1718, 1653 cm . H NMR
1
30.5, 30.6, 34.9, 44.9, 49.4, 51.2, 53.2, 60.7, 65.7, 113.6,
115.0, 127.1, 132.3, 135.9, 144.3, 171.7. HRMS(FAB)
(M1H) calculated for C H N O 418.2706, found
(
2
CDCl ): d 1.29 (t, Jˆ7.5 Hz, 3H), 1.42±1.95 (m, 15H),
3
1
.20 (d, Jˆ7.2 Hz, 2H), 2.38±2.43 (m, 2H), 2.57 (t,
2
3
36
3
4
Jˆ6.0 Hz, 2H), 3.09 (t, Jˆ1.5 Hz, 2H), 4.21 (q, Jˆ7.5 Hz,
418.2722.
1
H), 11.98 (s, 1H). C NMR (CDCl ): d 14.2, 25.4, 25.4,
3
2
2
6
3
6.3, 27.0, 27.1, 29.4, 30.6, 30.6, 34.9, 49.2, 50.3, 60.0,
5.2, 96.9, 170.2, 171.0. HRMS(FAB) (M1H) calculated
4.1.5. 1-[(3R*,4R*)-1-Cyclooctylmethyl-3-ethoxycarbonyl-
4-piperidyl]-1,3-dihydro-2H-benzimidazol-2-one (13). To
a solution of 11 (47.8 g, 0.11 mol) in MeOH (800 ml) and
1
for C H NO 296.2226, found 296.2221.
1
7
30
3
CHCl (100 ml) was added 10% Pd±C (8 g) and 10% HCl±
3
4.1.3. Ethyl 4-amino-1-cyclooctylmethyl-1,2,5,6-tetrahy-
dro-3-pyridinecarboxylate (10). To a solution of 9 (90.8 g,
MeOH (100 ml), and the mixture was stirred under a hydro-
gen atmosphere for 22 h. The catalyst was ®ltered off and
washed with MeOH. The eluent was concentrated in vacuo
and the residue was partitioned between AcOEt and 2M
NaOH. The organic layer was washed with brine, dried
over Na SO , ®ltered and concentrated in vacuo to give a
0
3
.31 mol) in MeOH (900 ml) was added AcONH (237 g,
4
.1 mol) at room temperature, and the reaction mixture
was stirred for 1 h and concentrated in vacuo. The residue
was partitioned between AcOEt and 1M NaOH, and
the organic layer was washed with brine, dried over
Na SO , ®ltered and concentrated to give 91.0 g (yield:
2
4
brown oil. To a solution of the crude brown oil in CHCl3
(500 ml) was added carbonyldiimidazole (CDI) (27.0 g,
0.17 mol) at room temperature, and the mixture was stirred
for 10 h. The mixture was partitioned between AcOEt and
water, and the organic layer was washed with brine, dried
over Na SO , ®ltered and concentrated in vacuo. The residue
2
4
100%) of 10.
IR (®lm): 3442, 3328, 2925, 2910, 1722, 1716, 1672,
2
1 1
1
1
622 cm . H NMR (CDCl ): d 1.27 (t, Jˆ7.5 Hz, 3H),
3
2
4
.38±1.92 (m, 15H), 2.20 (d, Jˆ7.2 Hz, 2H), 2.33 (t,
was puri®ed by silica gel column chromatography (CHCl3/
lMe ses Oo Hi lˆ. 200/1) to give 38.7 g (yield: 84%) of 13 as a color-
Jˆ6.0 Hz, 2H), 2.51 (t, Jˆ6.0 Hz, 2H), 3.11 (s, 2H), 4.14
1
3
(
2
5
q, Jˆ7.5 Hz, 2H), 5.95 (br, 2H). C NMR (CDCl ): d 14.5,
3
5.5, 25.5, 26.4, 27.1, 27.1, 30.4, 30.7, 30.7, 34.8, 49.3,
1.7, 58.8, 65.6, 91.4, 154.7, 168.8. HRMS(FAB)
21 1
IR (®lm): 2913, 2915, 1730, 1701 cm . H NMR (CDCl ):
3
1
(
M1H) calculated for C H N O 295.2386, found
2
d 0.96 (t, Jˆ7.5 Hz, 3H), 1.18±1.30 (m, 2H), 1.44±1.83 (m,
1
7
31
2
295.2383.
14H), 2.14±2.21 (m, 3H), 2.25 (t, Jˆ11.7 Hz, 1H), 2.48±
2
.62 (m, 1H), 2.96±3.08 (m, 1H), 3.16±3.23 (m, 1H), 3.58±
4
.1.4. Ethyl (3R*,4R*)-1-cyclooctylmethyl-4-(2-nitro-
3.70 (m, 1H), 3.90 (q, Jˆ7.5 Hz, 2H), 4.32±4.48 (m, 1H),
1
7.02±7.10 (m, 3H), 7.15±7.20 (m, 1H), 8.40 (br, 1H). C
3
phenylamino)-3-piperidinecarboxylate (11). To a solu-
tion of 10 (91.0 g, 0.31 mol) in n-BuOH (300 ml) was
added 2-¯uoronitrobenzene (87.0 g, 0.62 mol), Na CO3
NMR (CDCl ): d 13.6, 25.5, 25.5, 26.4, 27.1, 27.1, 28.1,
3
30.6, 30.7, 35.0, 44.4, 52.8, 53.0, 55.8, 60.5, 65.2, 108.9,
109.3, 121.0, 121.1, 127.8, 129.5, 154.8, 171.9.
2
(
65.0 g, 0.62 mol) and NaBH CN (39.0 g, 0.62 mol) at
3
1
room temperature, and the reaction mixture was re¯uxed
for 3 h. After cooling, the mixture was partitioned between
AcOEt and water, and the organic layer was washed with
brine, dried over Na SO , ®ltered and concentrated in
HRMS(FAB) (M1H)
414.2757, found 414.2757.
calculated for C H N O
24 36 3 3
4.1.6. 1-[(3R*,4R*)-1-Cyclooctylmethyl-3-ethoxycarbonyl-
4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one
(14). To a solution of 13 (38.7 g, 94 mmol) in DMF
(400 ml) was added 60% NaH (4.5 g, 112 mmol) at 08C.
The reaction temperature was then warmed up to room
temperature, and the solution was stirred for 0.5 h. Ethyl-
iodide (15 ml, 188 mmol) was added to the reaction
mixture, and the mixture was stirred for 1 h at room
temperature. The mixture was partitioned between AcOEt
and water, and the organic layer was washed with brine,
dried over Na SO , ®ltered and concentrated in vacuo.
2
4
vacuo. The residue was puri®ed by silica gel column chro-
matography (hexane/AcOEtˆ50/1) to give 47.8 g (yield:
3
7%) of (3R*,4R*)-isomer 11 as a yellow oil and 40 g
(
yield: 31%) of the (3R*,4S*)-isomer 12 as a yellow oil.
21 1
1: IR (®lm): 2913, 2923, 1731, 1618, 1576, 1510 cm . H
1
NMR (CDCl ): d 1.16 (t, Jˆ7.5 Hz, 3H), 1.17±1.28 (m,
3
2
2
1
1
H), 1.36±1.74 (m, 14H), 2.11 (d, Jˆ6.9 Hz, 2H), 2.15±
.28 (m, 2H), 2.39±2.49 (m, 1H), 2.73 (dt, Jˆ3.7, 9.2 Hz,
H), 2.75±2.82 (m, 1H), 2.88±2.95 (m, 1H), 3.86±3.97 (m,
H), 4.06 (q, Jˆ7.5 Hz, 2H), 6.59±6.65 (m, 1H), 6.93 (d,
2
4
The residue was puri®ed by silica gel column chromato-
graphy (hexane/AcOEtˆ4/1) to give 37.3 g (yield: 90%)
of 14 as a colorless oil.
1
3
Jˆ8.4 Hz, 1H), 7.38±7.43 (m, 1H), 8.12±8.17 (m, 2H).
C
NMR (CDCl ): d 14.0, 25.5, 25.5, 26.3, 27.1, 27.1, 30.5,
3
3
1
0.6, 30.9, 34.9, 48.0, 51.0, 51.8, 54.5, 60.8, 65.4, 114.1,
15.4, 126.9, 132.0, 136.0, 144.4, 172.6. HRMS(FAB)
2
1
IR (®lm): 2913, 1730, 1709, 1495, 1398 cm . H NMR
1
1
(
M1H) calculated for C H N O 418.2706, found
3
(CDCl ): d 0.91 (t, Jˆ7.2 Hz, 3H), 1.91±1.29 (m, 2H),
2
3
36
4
3
418.2715.
1.32 (t, Jˆ7.2 Hz, 3H), 1.42±1.80 (m, 13H), 2.14±2.12

H. Kawamoto et al. / Tetrahedron 57 (2001) 981±986
985
(
(
m, 4H), 2.22±2.30 (m, 1H), 2.50±2.64 (1H, m), 2.94±3.04
m, 1H), 3.13±3.20 (m, 1H), 3.61±3.69 (m, 1H), 3.86 (q,
been deposited at Cambridge Crystallographic Data Centre
(CCDC 151492).
Jˆ7.2 Hz, 2H), 3.91 (q, Jˆ7.2 Hz, 2H), 4.30±4.45 (m, 1H),
1
3
6.96±7.00 (m, 1H), 7.04±7.10 (m, 2H), 7.13 (m, 1H).
NMR (CDCl ): d 13.4, 13.6, 25.5, 25.5, 26.3, 27.1, 27.1,
C
3
Acknowledgements
2
6
1
4
7.9, 30.6, 30.6, 35.0, 35.5, 44.2, 52.9, 53.8, 55.7, 60.3,
4.9, 107.2, 108.5, 120.7, 120.7, 128.8, 129.0, 153.2,
72.1. HRMS(FAB) (M1H) calculated for C H N O
42.3070, found 442.3065.
We thank Dr Susumu Nishimura, Dr Hajime Morishima,
and Dr Shigeru Nakajima for useful suggestions. We
also thank Ms A. Dobbins for critical reading of this
manuscript.
1
2
6
40
3
3
4
4
.1.7. 1-[(3R,4R)-1-Cyclooctylmethyl-3-hydroxymethyl-
-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one
(
(
11). To a solution of 14 (37.3 g, 85 mmol) in THF
750 ml) was added LiAlH (3.9 g, 102 mmol) at 08C. The
References
4
reaction mixture was then warmed up to room temperature
and stirred for 0.5 h. AcOEt was added to the reaction
mixture at 08C, and the mixture was stirred for 5 min. The
reaction mixture was partitioned between AcOEt and 2M
NaOH, and the organic layer was washed with brine, dried
over Na SO , ®ltered and concentrated in vacuo. The resi-
1. (a) Mollereau, C.; Parmentier, M.; Mailleux, P.; Butour, J.;
Moisand, C.; Chalon, P.; Caput, D.; Vassart, G.; Meunier,
J.-C. FEBS Lett. 1994, 341, 33±38. (b) Fukuda, K.; Kato,
S.; Mori, K.; Nishi, M.; Takeshima, H.; Iwabe, N.; Miyata,
T.; Houtani, T.; Sugimoto, T. FEBS Lett. 1994, 343, 42±46.
(c) Chen, Y.; Fan, Y.; Liu, J.; Mestek, A.; Tian, M.; Kozak,
C. A.; Yu, L. FEBS Lett. 1994, 347, 279±283. (d) Pan, Y.-X.;
Cheng, J.; Xu, J.; Rossi, G.; Jacobson, E.; Ryan-Moro, J.;
Brooks, A. I.; Dean, G. E.; Standifer, K. M.; Pasternak,
G. W. Molecular Pharmacology 1995, 47, 1180±1188.
2
4
due was puri®ed by silica gel column chromatography
(
CHCl /MeOHˆ150/1) to give 30.0 g (yield: 89%) of
3
(
1/2)-1 as white solids.
Optical resolution was performed by chromatography using
2. (a) Meunier, J.-C.; Mollereau, C.; Toll, L.; Suaudeau, C.;
Moisand, C.; Alvinerie, P.; Butour, J.-L.; Guillemot, J.-C.;
Ferrara, P.; Monsarrat, B.; Mazargil, H.; Vassart, G.;
Parmentier, M.; Costentin, J. Nature (London) 1995, 377
w
CHIRALPAK AD (hexane/2-propanol/Et NHˆ800/200/
2
1), to give 14.0 g (yield: 93%) of (1)-1 (J-113397) as
white solids.
(
6549), 532±535. (b) Reinscheid, R. K.; Nothacker, H.-P.;
21 1
: IR (KBr): 3446, 2919, 1704 cm . H NMR (CDCl ): d
1
1
1
Bourson, A.; Ardati, A.; Henningsen, R. A.; Bunzow, J. R.;
Grady, D. K.; Langen, H.; Monsma Jr, F. J.; Civelli, O.
Science (Washington, D.C.) 1995, 270 (5237), 792±794.
(c) Okuda-Ashitaka, E.; Tachibana, S.; Houtani, T.; Minami,
T.; Masu, Y.; Nishi, M.; Takeshima, H.; Sugimoto, T.; Ito, S.
Mol. Brain Res. 1996, 43, 96±104.
3
.15±1.30 (m, 2H), 1.34 (t, Jˆ7.2 Hz, 3H), 1.40±1.78 (m,
3H), 1.84±1.91 (m, 1H), 2.04±2.33 (m, 6H), 2.54±2.64
(
m, 1H), 2.96±3.05 (m, 2H), 3.32±3.36 (m, 2H), 3.91±
4
7
2
5
1
.01 (m, 2H), 4.34±4.45 (m, 1H), 7.02±7.13 (m, 3H),
.29±7.35 (m, 1H). C NMR (CDCl ): d 13.6, 25.6, 25.6,
1
3
3
6.5, 27.1, 27.1, 28.7, 30.9, 30.9, 34.8, 36.1, 41.0, 51.7,
3.6, 56.4, 61.9, 66.1, 108.0, 110.2, 121.1, 121.1, 128.0,
29.2, 154.6. HRMS(FAB) (M1H) calculated for
3. Mogil, J. S.; Grisel, J. E.; Reinscheid, R. K.; Civelli, O.;
Belknap, J. K.; Grandy, D. K. Neuroscience (Oxford) 1996,
75, 333±337.
1
C H N O 400.2964, found 400.2979.
2
4. Ueda, H.; Yamaguchi, T.; Tokuyama, S.; Inoue, M.; Nishi,
M.; Takeshima, H. Neuroscience Lett. 1997, 237, 136±138.
5. (a) Manabe, T.; Noda, Y.; Mamiya, T.; Katagiri, H.; Houtani,
T.; Nishi, M.; Noda, T.; Takahashi, T.; Sugimoto, T.;
Nabeshima, T.; Takeshima, H. Nature (London) 1998, 394
2
4
38
3
The free amine was dissolved in 10% HCl±MeOH and
concentrated in vacuo, and the resulting crystalline powder
was washed with Et O to give hydrochloride salt as a white
2
powder. Mp 218±2208C. Anal. (C H ClN O ´0.7H O) C,
2
(6693), 577±581. (b) Sandin, J.; Georgieva, J.; Sch oÈ tt, P. A.;
OÈ gren, S. O.; Terenius, L. Eur. J. Neurosci. 1997, 9, 194±197.
4
38
3
2
2
2
0
H, N. ‰aŠD ˆ 16:4 (cˆ1.0, 0.1N HCl).
.2. X-Ray crystallography
(c) Yu, T.-P.; Fein, J.; Phan, T.; Evans, C. J.; Xie, C.-W.
Hippocampus 1997, 7, 88±94.
4
6
. Pomonis, J. D.; Billington, C. J.; Levine, A. S. NeuroReport
1996, 8, 369±371.
J-113397 (20 mg, 0.05 mmol) and d-tartaric acid (7 mg,
.05 mmol) were dissolved in hot AcOEt (2 ml) and
MeOH (0.1 ml). After being slowly cooled to room
temperature, the mixture was left standing for one day.
The precipitates were recrystallized from AcOEt (1.5 ml)
and MeOH (0.1 ml) to give colorless plate crystals, triclinic
0
7. Jenck, F.; Moreau, J.-L.; Martin, J. R.; Kilpatric, G. J.;
Reinscheid, R. K.; Monsma Jr, F. J.; Nothacker, H.-P.; Civelli,
O. Proc. Natl Acad. Sci. U.S.A. 1997, 94, 14854±14858.
8. (a) Champion, H. C.; Kadowitz, P. J. Life Sciences 1997, 60,
241±245. (b) Gumusel, B.; Hao, Q.; Hyman, A.; Chang, J.-K.;
Kapusta, D. R.; Lippton, H. Life Sciences 1997, 60, 141±
145.
Ê
Ê
space group P1, aˆ9.778(3) A, bˆ14.898(5) A,
Ê
cˆ9.731(3) A, aˆ96.90(3)8, bˆ109.83(2)8, gˆ97.02(3)8,
3
23
Ê
Vˆ1303.6(8) A , Zˆ1, r
ˆ1.21 g cm . The crystallo-
9. Florin, S.; Suaudeau, C.; Meunier, J.-C.; Costentin, J. Eur. J.
Pharmacol. 1996, 317, 9±13.
calcd
graphic data were obtained with a Rigaku AFC-7 four
cycle diffractometer (Cu-Ka radiation) at 296.2 K. The
structure was solved using direct methods and re®ned on
10. Champion, H. C.; Wang, R.; Hellstrom, W. J. G.; Kadowitz,
P. J. Am. J. Physiol. 1997, 273 (Endocrinol. Metab. 36),
E214±E219.
2
15
16
17
F using teXsan, SHELXS-86 and SHELXL-97, where
the ®nal R was 0.051 for 4023 re¯ections. Atomic coordi-
nates, the thermal parameters, bond lengths and angles have
11. (a) Kawamoto, H.; Ozaki, S.; Itoh, Y.; Miyaji, M.; Arai, S.;
Nakashima, H.; Kato, T.; Ohta, H.; Iwasawa, Y. J. Med. Chem.

9
86
H. Kawamoto et al. / Tetrahedron 57 (2001) 981±986
1985, 175±189. (b) Ozaki, S.; Kawamoto, H.; Itoh, Y.; Miyaji,
M.; Iwasawa, Y.; Ohta, H. Eur. J. Pharmacol. 2000, 387,
14. Henning, R.; Lattrell, R.; Gerhards, H. J.; Leven, M. J. Med.
Chem. 1987, 30, 814±819.
R17±R18.
2. Micovic, I. V.; Ivanovic, M. D.; Vuckovic, S.; Jovanovic-
15. Molecular Structure Corporation (1985±1992): teXsan, Single
Crystal Structure Analysis Software Package, Version 1.9.
MSC, 3200 Research Forest Drive, The Woodlands, TX
77381, USA.
1
1
Micic, D.; Beleslin, D.; Dosen-Micovic, Lj.; Kincojevic,
V. D. Heterocycl. Commun. 1998, 4, 171±179. Recently, a
Yugoslavian group reported the synthesis of 4-amino-3-
alchoxycarbonylpiperidine.
16. Sheldrick, G. M. SHELXS86. In Crystallographic Computing
3, Oxford University Press: Oxford, 1985; pp 175±189.
17. Sheldrick, G. M. SHELXL-97: Program for the Re®nement of
Crystal Structuers, University of G oÈ ttingen, Germany, 1997.
3. Traas, P. C.; Takken, H. J.; Boelens, H. Tetrahedron Lett.
1
977, 23, 2027±2030.