A new approach to the synthesis of the nonpeptide NOP receptor antagonist J-113397

Article abstract of DOI:10.1055/s-2007-966037

A new synthesis that eliminates the need for chromatographic separation in order to obtain multigram quantities of J-113397, a competitive antagonist of the N/OFQ-NOP receptor system, is reported. N-Benzyl protected 4-oxopiperidinecarboxylate was used as the starting material to obtain an N-benzyl intermediate that could be resolved at a relatively early stage in the synthesis. The crucial step in the synthesis was reduction of the double bond of the β-enaminoester functionality of 1-benzyl-4-(3-ethyl-2-oxo-2,3- dihydrobenzoimidazol-1-yl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester, since Pd/C reduction gave inseparable mixtures. It could be reduced and epimerized to the desired trans diastereoisomer in a one-pot reaction by treatment with magnesium metal in methanol. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-966037

PAPER
1547
A New Approach to the Synthesis of the Nonpeptide NOP Receptor Antagonist
J-113397
Synthesis of
a
N
O
P
Receptor
A
n
ntagonist ieszka Sulima, John Folk, Arthur E. Jacobson, Kenner C. Rice*
Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, National Institutes of Health,
Department of Health and Human Services, Bethesda, MD 20892-0815, USA
Fax +1(301)020589; E-mail: kr21f@nih.gov
Received 18 January 2007; revised 4 March 2007
Recently, several small-molecule ligands for the NOP re-
Abstract: A new synthesis that eliminates the need for chromato-
ceptor have been reported in the literature.6,7 A highly po-
graphic separation in order to obtain multigram quantities of J-
113397, a competitive antagonist of the N/OFQ-NOP receptor sys-
tem, is reported. N-Benzyl protected 4-oxopiperidinecarboxylate
tent and selective agonist (Ro 64-6198)8 and a few
antagonists (J-113397,9 JTC-80110) were among these.
was used as the starting material to obtain an N-benzyl intermediate These ligands have been instrumental in the pharmacolog-
that could be resolved at a relatively early stage in the synthesis. The
ical evaluation of the N/OFQ-NOP receptor system. The
antagonist J-1133979 [trans-1-(1-cyclooctylmethyl-3-hy-
crucial step in the synthesis was reduction of the double bond of the
b-enaminoester functionality of 1-benzyl-4-(3-ethyl-2-oxo-2,3-di-
droxymethyl-4-piperidyl)-3-ethyl-1,3-dihydro-2H-benz-
hydrobenzoimidazol-1-yl)-1,2,5,6-tetrahydropyridine-3-carboxyl-
ic acid methyl ester, since Pd/C reduction gave inseparable
mixtures. It could be reduced and epimerized to the desired trans
imidazol-2-one, Figure 1], acts as a high affinity, selective
and competitive antagonist of the NOP receptor.11 How-
ever, it also appears to have pharmacological actions that
are independent of the NOP receptor. In particular, J-
113397 has been found to stimulate mesolimbic dopamine
release and to have a rewarding effect in mice by a non-
NOP mechanism.12
diastereoisomer in a one-pot reaction by treatment with magnesium
metal in methanol.
Key words: NOP antagonist, receptor, synthesis, enantiomeric
resolution, b-enaminoester reduction
The fourth opioid receptor, called opioid receptor-like 1
(ORL1), or the NOP receptor, was identified1 in 1994
through cDNA expression cloning techniques. It was
found to be a member of the G-protein coupled receptor
superfamily and shares a high sequence homology with
the well-known m-, k- and d-opioid receptors. However,
none of the classical opioid ligands showed significant af-
finity for the NOP receptor. An endogenous ligand for the
NOP receptor was identified as a 17-amino acid neu-
ropeptide called nociceptin2 or orphanin FQ,3 shortly
thereafter. Despite the similarity of this peptide, now
called the N/OFQ peptide (NOP) receptor,4 with the opio-
id ligand, dynorphin A, nociceptin does not bind to the
classical opioid receptors with high affinity. A number of
studies have indicated that the NOP receptor might be an
important new molecular target for the development of
novel therapeutics for various human disorders.5,6 The
N/OFQ and its receptor have been implicated in several
physiological pathways including morphine tolerance,
neurotransmitter release, inhibition of learning and mem-
ory, modulation of cardiovascular and respiratory func-
tion, food intake, anxiety and locomotion. It has also been
found to play a direct role on pain perception. However,
the precise effect of N/OFQ on nociceptive sensitivity is
still unclear.
N
N
N
O
OH
1
Figure 1 Structure of NOP receptor antagonist J-113397 (1)
Our interest in this opioid field led us to consider further
pharmacological investigation of the N/OFQ-NOP recep-
tor system but, in order to do that, we needed a relatively
large quantity of the unavailable NOP antagonist, J-
113397. Although some total syntheses of J-113397 have
been developed over the past few years,13,14 these methods
have significant drawbacks. A major disadvantage is the
necessity of using chromatographic methods in the purifi-
cation process as well as for the separation of the enan-
tiomers of ( )-1. This is problematic in large-scale
syntheses, and we preferred to develop synthetic proce-
dures that would obviate the necessity for chromatograph-
ic separation. Also, most of the intermediates are oils and
some of these were found to be unstable in our hands.
Thus, it was important to develop an alternative, more
general synthetic procedure. We now wish to report an ef-
ficient and non-chromatographic synthesis of J-113397
using 1-benzyl-4-oxo-3-piperidinecarboxylate (3) as the
starting material. Our synthesis utilizes compound 7 as an
early chiral intermediate (Scheme 1). The enantiomers of
SYNTHESIS 2007, No. 10, pp 1547–1553
x
x.
x
x
.
2
0
0
7
Advanced online publication: 02.05.2007
DOI: 10.1055/s-2007-966037; Art ID: M00407SS
© Georg Thieme Verlag Stuttgart · New York

1548
A. Sulima et al.
PAPER
compound 7 were obtained via optical resolution. The
secondary amine 8 could prove useful as an intermediate
for the future synthesis of new N-substituted analogues of
J-113397. The capability of the new synthetic route to 1
was demonstrated on a multigram scale.
N
N
O
NH
N
N
O
NH
Pd/C
6
O
O
OMe
OMe
The outline of the synthetic pathway to J-113397 is shown
in Scheme 1. In order to access the chiral N-nor
intermediate (e.g., 8) we decided to use N-benzyl protected
4-oxopiperidinecarboxylate 3 as the starting material. Ac-
cordingly, condensation of o-phenylenediamine (2) with 3
in toluene (Method A) under reflux in the presence of a
catalytic amount of AcOH gave the enamine 4. Fewer im-
purities were formed and a better yield was obtained un-
der the same reaction conditions using benzene as a
solvent (Method B). The benzimidazolone core in 5 was
derived by treatment of the enamine 4 with a 2.2-fold ex-
cess of di-tert-butyl dicarbonate (Boc2O) followed by
subsequent hydrolysis of the resulting N-Boc derivative
with TFA. N-Alkylation of intermediate 5 with ethyl io-
dide in the presence of NaH furnished 6 in high yield.
15
16
Scheme 2
Different solvent systems were tried and different
amounts of catalyst, as well as different temperatures,
without success. Apparently, compound 16, with its un-
saturated bond is stable and could not be easily hydroge-
nated under these conditions. It was found, however, that
6 could be reduced and epimerized to the desired trans-
isomer 7 in a one-pot reaction by treatment with magne-
sium metal in methanol under reflux.15 The cis-isomer
was not obtained in pure form. The trans- and cis-isomers
of 7 could be distinguished by NMR spectroscopy. The
cis/trans-isomer mixture had peaks at d = 1.96–1.99 (m),
2.43–2.47 (m), and 7.55 (br s) that were not found in the
spectra of pure trans-7. The intermediate 7 was then
smoothly transformed to 8 by catalytic hydrogenation in
the presence of Pd/C. NMR spectra and TLC indicated
that the crude product 8 was pure enough for the next step
The crucial step of the synthesis was reduction of the dou-
ble bond of the b-enaminoester functionality of 6. In the
first attempt we used catalytic hydrogenation in the pres-
ence of Pd/C, which gave an inseparable mixture of de-
sired 15 and N-deprotected enamine 16 (Scheme 2).
O
O
N
AcOH
+
H2N
HN
N
H2N
NH2
A: PhMe, 63%
B: PhH, 83%
OMe
O
2
3
OMe
4
1. (Boc)2O, CH2Cl2
2. TFA, 91%
NaH, EtI
HN
N
O
N
N
N
O
N
DMF, 95%
O
O
OMe
OMe
6
5
Mg, MeOH, 61%
Pd/C
N
N
NH
N
N
N
MeOH, 100%
O
O
O
O
OMe
OMe
7
8
LiAlH4
CHO
1. ZnCl2, DCE
1
8
+
THF, 66–75%
N
N
N
2. NaB(OAc)3H
81–84%
11
O
O
OMe
14
Scheme 1 Synthesis of J-113397 (1)
Synthesis 2007, No. 10, 1547–1553 © Thieme Stuttgart · New York

PAPER
Synthesis of a NOP Receptor Antagonist
1549
without need for additional purification. It is noteworthy
that the direct conversion of 6 into 8 or into 7 was unsuc-
cessful under Birch reduction with lithium metal in liquid
ammonia16 providing a complex mixture of products.
CHO
Cl
O
POCl3, DMF
CHCl3
Pd/C
MeOH, NaOAc
80% over
2 steps
9
10
We next envisioned optical resolution of intermediates 7
or 8 taking advantage of the amine functionality. Screen-
ing of twenty different acids resulted in a diastereomeric
salt of 7 with (R)-(–)-3-chloromandelic acid. The isolated
free base from the diastereomer showed 94.7% ee. Re-
crystallization from a mixture of ethanol and propan-2-ol
CHO
CH2OH
LAH
THF, 88%
11
12
CH2OTs
TsCl, Et3N
20
(5.6:1) furnished optically pure (–)-7, [a]D –33.1 (c =
CH2Cl2, 85%
1.26, MeOH). The purity of the separated enantiomer was
evaluated by chiral analytical HPLC. The analysis was
performed on a Shimadzu analytical instrument using a
mixture of hexane–propan-2-ol–Et2NH (85:15:0.2) as the
eluent system. The enantiomers of 7 were found to be
>98% ee. A 98:2 enantiomeric mixture was easily esti-
mated by HPLC. Once we had obtained optically pure
amine (–)-7 as the free base, we were able to use (R)-(–)-
mandelic acid to generate the salt [(–)-7·(R)-(–)-mandelic
acid], and it crystallized from propan-2-ol. This approach
allowed us to change the protocol for the optical resolu-
tion of ( )-7 to a more practical procedure utilizing both
enantiomers of mandelic acid itself, since (S)-(+)-3-chlo-
romandelic acid is not commercially available. Thus,
treatment of racemic amine ( )-7 with (S)-(+)-mandelic
acid gave the enantiomeric salt [(+)-7·(S)-(+)-mandelic
acid] that, after reconversion into the base, provided (+)-
7, [a]20D +33.5 (c 0.98, MeOH). All attempts to obtain dia-
stereomeric salts of ( )-8 with various chiral acids failed,
affording mostly viscous oils.
13
Scheme 3
cohol 12 with LiAlH4, which was then converted into 13
in a reaction with p-toluenesulfonyl chloride in the pres-
ence of triethylamine.
The target compound 1 was obtained by reduction of the
ester group of 14 with LiAlH4 described previously.13,14
Using 30% excess LiAlH4 and a low temperature (0 °C)
we were able to obtain the desired product 1 in high yield
(93–96%) on a small scale (up to 1 g). Since the reaction
conditions were not optimized for the multigram scale, the
yield was somewhat lower, in the range of 66–75%. The
NMR spectra of 1 were in good agreement with the pub-
lished 1H and 13C NMR spectra of J-113397.13,14 The ele-
mental analysis of the compound was consistent with the
structure of 1, as was the HRMS spectra. The optical pu-
rity of both enantiomers was evaluated by chiral analytical
HPLC. The specific rotation was comparable to literature
data.14
The last two steps of the synthesis involved reductive
amination of compound 8 and the reduction of the ester
group in 14 to a primary alcohol, as shown in Scheme 1.
For the addition of the cyclooctylmethyl substituent of 14,
different approaches were used, including reductive alky-
lation with aldehyde 11 and N-alkylation with tosyl deriv-
ative 13 (Scheme 3) in the presence of K2CO3 (3 equiv) in
DMF at 80 °C (data not published). The reductive amina-
tion was found to be more efficient and was further ex-
plored. For reductive alkylation different borohydride
reducing agents, as well as different additives such as mo-
lecular sieves or Lewis acids were tried.
TLC analyses were carried out on Analtech silica gel GHLF 0.25
mm plates with UV and I2 detection. Melting points were deter-
mined in open glass capillaries on a Thomas-Hoover melting point
apparatus and are uncorrected. Elemental analyses (C,H,N) were
performed by Atlantic Microlabs, Norcross, GA and were within
0.3% of the theoretical values. H NMR and 13C NMR spectra
1
were recorded on a Varian Gemini spectrometer at 300 MHz and 75
MHz, respectively. For H NMR, 0.1% v/v tetramethylsilane was
1
used as an internal standard. Chemical shifts (d) are given in parts
per million (ppm), coupling constants J values are given in Hertz
(Hz) and are reported to the nearest 0.1 Hz. The accurate mass Elec-
trospray Ionization (ESI) and Atmospheric Pressure Chemical Ion-
ization (APCI) mass spectra were obtained on a Waters LCT
Premier time-of-flight (TOF) mass spectrometer. The chiral HPLC
analysis was performed on a Shimadzu LC-6A analytical instru-
ment equipped with UV detector SPD-6AV using Chiralcel OD col-
umn (manufactured by Daicel), 250 × 4.6 mm. The samples for
HPLC analyses were dissolved in mixture of hexane–propan-2-ol
(6:4). Gradient grade quality solvents for HPLC were employed.
The specific rotation was measured with a PerkinElmer 341 pola-
rimeter.
Compound 14 was obtained under mild conditions, in
good yield by reductive alkylation of 8 with aldehyde 11
and NaBH(OAc)3 in the presence of ZnCl217 and molecu-
lar sieves in 1,2-dichloroethane (DCE). The addition of
ZnCl2 was found to be essential for the formation of 14
(Scheme 1). Intermediate 11 was prepared from commer-
cially available cyclooctanone (9) according to the known
procedure13 with a few modifications as shown in
Scheme 3. Conversion of 9 into b-chloro-a,b-unsaturated
aldehyde 10 proceeded via Vilsmeier formylation with
phosphorus oxychloride and DMF in CHCl3.18 Reductive
dehalogenation of 10 over Pd/C catalyst in MeOH using
NaOAc·3H2O as a hydrogen chloride scavenger afforded
11 in 87% yield over two steps. The tosyl derivative 13
was obtained via reduction of aldehyde 11 to primary al-
4-(2-Aminophenylamino)-1-benzyl-1,2,5,6-tetrahydropyridine-
3-carboxylic Acid Methyl Ester (4)
Method A: A solution of o-phenylenediamine (2; 114 g, 1.05 mol)
and methyl 1-benzyl-4-oxo-3-piperidinecarboxylate (3; 260 g, 1.05
mol) in toluene (1.6 L) was refluxed for 4 h in the presence of AcOH
Synthesis 2007, No. 10, 1547–1553 © Thieme Stuttgart · New York

1550
A. Sulima et al.
PAPER
(14.6 mL, 0.26 mol) with azeotropic removal of H2O. After cooling,
the mixture was quenched with aq sat. NaHCO3 solution to pH 8.5–
9, followed by washing with H2O (400 mL) and brine (300 mL).
The solution was dried and the solvent was evaporated under re-
duced pressure to give a brown oil (342 g). The crude product was
purified by crystallization from a mixture of propan-2-ol and H2O
(6:1, 0.6 L), seeding with crystals from previous experiments to af-
ford 223 g (63%) of white crystals, mp 109–110 °C. An analytical
sample was recrystallized from EtOH; mp 112–112.5 °C.
1H NMR (CDCl3): d = 2.26 (t, J = 5.77 Hz, 2 H), 2.45 (t, J = 5.77
Hz, 2 H), 3.30 (br s, 2 H), 3.62 (s, 2 H), 3.70 (s, 3 H), 3.85 (br s, 2
H), 6.65–6.74 (m, 2 H), 6.96–7.07 (m, 2 H), 7.22–7.36 (m, 5 H),
9.84 (br s, 1 H).
crystallization with oxalic acid (64 g) from acetone (0.6 L) afford-
ing 325.6 g of 6 as a salt; mp 107–108 °C. Cleavage of the oxalic
salt with base gave 267 g (95%) of free base as an oil that could be
crystallized from a mixture of EtOH and propan-2-ol (2:1); mp
116–116.5 °C.
1H NMR (CDCl3): d = 1.35 (t, J = 7.14 Hz, 3 H), 2.68 (br s, 2 H),
2.78 (br s, 2 H), 3.39 (s, 3 H), 3.50 (br s, 2 H), 3.73 (s, 2 H), 3.95 (q,
J = 7.14 Hz, 2 H), 6.87–6.92 (m, 1 H), 6.98–7.12 (m, 3 H), 7.26–
7.42 (m, 5 H).
13C NMR (CDCl3): d = 13.72, 29.83, 36.03, 48.66, 51.91, 52.86,
61.86, 107.82, 108.57, 121.35, 121.63, 127.34, 127.48, 128.55,
129.17, 129.21, 129.43, 137.91, 138.78, 152.30, 164.86.
HRMS (ESI) m/z [M + H]+ calcd for C23H26N3O3: 392.1974; found:
392.1984.
13C NMR (CD3OD): d = 28.17, 50.21, 51.25, 52.61, 63.57, 91.21,
117.16, 118.98, 125.56, 128.69, 129.24, 129.55, 129.99, 130.84,
138.47, 146.12, 158.76, 171.03.
Anal. Calcd for C23H25N3O3: C, 70.57; H, 6.44; N, 10.73. Found: C,
70.74; H, 6.41; N, 10.75.
HRMS (ESI): m/z [M + H]+ calcd for C20H24N3O2: 338.1869; found:
338.1858.
( )-trans-1-Benzyl-4-(3-ethyl-2-oxo-2,3-dihydrobenzoimidazol-
1-yl)piperidine-3-carboxylic Acid Methyl Ester (7)
Anal. Calcd for C20H23N3O2: C, 71.19; H, 6.87; N, 12.45. Found: C,
70.98; H, 6.78; N, 12.31.
Mg turnings (120 g, 4.95 mol) were added portionwise to a solution
of 6 (128 g, 0.33 mol) in MeOH (2 L) at 0–5 °C. When the exother-
mic reaction was completed, the mixture was refluxed under argon
until the epimerization was accomplished (5–6 h). The resulting
suspension was cooled and quenched by careful addition of aq 10%
HCl (ca. 4 L). The mixture was brought to pH 8 by addition of
NH4OH and extracted with CHCl3 (4 × 500 mL). The organic layer
was washed with brine (400 mL), dried, and evaporated in vacuo.
The crude product was purified by crystallization from (i-Pr)2O,
furnishing 79.9 g (61%) of 7 as white crystals; mp 117–118 °C.
1H NMR (CDCl3): d = 1.32 (t, J = 7.14 Hz, 3 H), 1.74–1.84 (m, 1
H), 2.23 (dt, J = 11.95, 2.34 Hz, 1 H), 2.32 (t, J = 11.26 Hz, 1 H),
2.62 (dq, J = 12.64, 3.57 Hz, 1 H), 2.98–3.08 (m, 1 H), 3.17–3.25
(m, 1 H), 3.40 (s, 3 H), 3.61 (s, 2 H), 3.65–3.78 (m, 1 H), 3.92 (q,
J = 7.14 Hz, 2 H), 4.35–4.50 (m, 1 H), 6.95–7.01 (m, 1 H), 7.03–
7.10 (m, 2 H), 7.15–7.21 (m, 1 H), 7.25–7.40 (m, 5 H).
13C NMR (CDCl3): d = 13.72, 28.17, 35.89, 44.46, 51.97, 52.73,
53.08, 55.44, 62.35, 107.69, 108.86, 121.07, 121.07, 127.40,
128.54, 128.54, 128.90, 129.13, 129.13, 129.35, 138.30, 153.56,
172.64.
HRMS (ESI): m/z [M + H]+ calcd for C23H28N3O3: 394.2131; found:
394.2149.
Method B: A solution of o-phenylenediamine (2; 17.9 g, 0.165 mol)
and methyl 1-benzyl-4-oxo-3-piperidinecarboxylate (3; 41 g, 0.165
mol) in benzene (0.4 L) was refluxed for 3 h in the presence of
AcOH (2.85 mL) with azeotropic removal of H2O. The mixture was
worked up according to the procedure described in method A. The
crude solid was purified by crystallization from propan-2-ol afford-
ing 46.4 g (83%) of 4 as white crystals; mp 109.5–110 °C.
1-Benzyl-4-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)-1,2,5,6-tet-
rahydropyridine-3-carboxylic Acid Methyl Ester (5)
To a solution of 4 (269 g, 0.8 mol) in CH2Cl2 (540 mL) was added
di-tert-butyl dicarbonate (Boc2O) (384 g, 1.76 mol) in CH2Cl2 (360
mL) followed by addition of a catalytic amount of DMAP (0.98 g).
The mixture was stirred under argon for 4 h at 0 °C. TFA (250 mL)
was added dropwise and the stirring was continued for 3 h at 0 °C.
The second portion of TFA (300 mL) was added and the mixture
was kept over night at r.t. The next portion of TFA (150 mL) was
added at 0 °C and the mixture was left for 8 h at r.t. The solvent and
excess TFA were distilled off under reduced pressure. The residue
was quenched with aq sat. Na2CO3 solution to pH 8.5–9, and ex-
tracted with CHCl3–MeOH (9:1) (4 × 300 mL). The extracts were
dried and the solvents were removed under reduced pressure to af-
ford a crude solid, that was washed with propan-2-ol (0.4 L), col-
lected, and dried to give 264.9 g (91%) of 5; mp 178.5–179.0 °C.
Anal. Calcd for C23H27N3O3: C, 70.21; H, 6.92; N, 10.68. Found: C,
70.16; H, 6.95; N, 10.73.
1H NMR (CDCl3): d = 2.70 (br s, 2 H), 2.79 (br s, 2 H), 3.43 (s, 3
H), 3.49 (br s, 2 H), 3.75 (s, 2 H), 6.86–6.92 (m, 1 H), 7.00–7.11 (m,
3 H), 7.26–7.42 (m, 5 H), 9.41 (br s, 1 H).
13C NMR (CDCl3): d = 29.92, 48.69, 52.09, 52.89, 61.97, 108.69,
110.09, 121.68, 122.09, 127.54, 127.98, 128.37, 128.61, 129.27,
130.11, 137.91, 138.38, 154.16, 164.94.
Optical Resolution of ( )-7
(R)-(–)-3-Chloromandelic acid (27.5 mg, 0.147 mM) was added to
a solution of amine ( )-7 (58 mg, 0.147 mol) in a mixture of EtOH
and propan-2-ol (5.6:1) (0.5 mL). The mixture was kept at r.t. for
0.5 h, and then in an ice-bath for 10 min. The formed salt (30 mg)
was collected [(–)-7, 95% ee; mp 133.5–134 °C]. Recrystallization
from the same solvent system afforded the pure enantiomer (–)-7;
yield: 15.1 mg (free base); [a]D20 –33.1 (c = 1.26, MeOH). The pu-
rity of the enantiomer was determined by chiral analytical HPLC. A
mixture of hexane–propan-2-ol–Et2NH (85:15:0.2) was used as the
eluent system. The faster (+)-enantiomer eluted at 8.50 min and the
slower (–)-enantiomer at 10.75 min. The free base of (–)-7 (29 mg)
was then crystallized with (R)-(–)-mandelic acid (11.2 mg) from
EtOAc to give 34 mg of seed crystals; mp 132.5–133 °C. Treatment
of a solution of ( )-7 (158 g) in propan-2-ol (450 mL) with (R)-(–)-
mandelic acid (10% excess) with seeds from the previous experi-
ment yielded the diastereomeric salt [(–)-7·(R)-(–)-mandelic acid];
93% ee; mp 130–131 °C. Two recrystallizations from propan-2-ol
followed by conversion of the diastereomeric salt into its free base
with aq sat. solution of NaHCO3 gave pure (–)-7; yield: 73 g (free
HRMS (ESI): m/z [M + H]+ calcd for C21H22N3O3:364.1661; found:
364.1658.
Anal. Calcd for C21H21N3O3: C, 69.40; H, 5.82; N, 11.56. Found: C,
69.20; H, 5.81; N, 11.50.
1-Benzyl-4-(3-ethyl-2-oxo-2,3-dihydrobenzoimidazol-1-yl)-
1,2,5,6-tetrahydropyridine-3-carboxylic Acid Methyl Ester (6)
To a suspension of compound 5 (263 g, 0.72 mol) in DMF (0.6 L)
was added 60% NaH (32 g, 0.79 mol) portionwise at 0 °C. After 40
min, EtI (63 mL, 0.79 mol) was added dropwise. The temperature
was allowed to warm to r.t., and the mixture was allowed to stand
overnight. The mixture was poured onto ice and extracted with
CHCl3 (4 × 300 mL). The organic layer was washed with brine (300
mL), dried and evaporated. The crude oily product was purified by
Synthesis 2007, No. 10, 1547–1553 © Thieme Stuttgart · New York

PAPER
Synthesis of a NOP Receptor Antagonist
1551
base); [a]D20 –33.4 (c = 0.92, MeOH); >98% ee. The pooled mother
liquor was concentrated in vacuo and the residue dissolved in
CHCl3 (300 mL), treated with aq sat. solution of NaHCO3 to pH
8.5–9, and the organic solvent was separated and the solvent re-
moved in vacuo. The liberated free base was then treated with (S)-
(+)-mandelic acid (10% excess) to provide the enriched enantio-
meric salt (+)-7·(S)-(+)-mandelic acid. The pure free base (+)-7
(70.8 g), was obtained after two recrystallizations of the salt from
propan-2-ol; [a]D20 +33.5 (c = 0.975, MeOH); >98% ee.
The product was purified by distillation (ca. 107–110 °C/0.5 Torr)
to give 11 (63.4 g, 87% over two steps).
1H NMR (CDCl3): d = 1.46–1.64 (m, 10 H), 1.64–1.80 (m, 2 H),
1.88–2.05 (m, 2 H), 2.32–2.43 (m, 1 H), 9.61 (s, 1 H).
13C NMR (CDCl3): d = 25.45, 25.76, 26.39, 26.92, 50.95, 205.08.
Cyclooctylmethanol (12)
A solution of freshly distilled 11 (2.3 g, 16.4 mmol) in THF (20 mL)
was added dropwise to a cooled slurry of LiAlH4 (0.68 g) in THF
(10 mL) under argon. After 2 h, the mixture was quenched with
H2O, filtered through a pad of Celite and extracted with Et2O (3 ×
30 mL). The organic layer was washed with brine (60 mL), dried
and evaporated to give 12 (2.25 g) as an oil. The crude product was
distilled in vacuo to give pure 12 (2.04 g, 88%); bp 120–123 °C/
ca. 0.5 Torr (oil bath ca. 170–200 °C).
1H NMR (CDCl3): d = 1.18–1.78 (m, 15 H), 3.40 (d, J = 6.32 Hz, 2
H).
13C NMR (CDCl3): d = 25.78, 25.78, 26.68, 27.13, 27.13, 29.53,
29.53, 40.56, 69.39.
(+)- and (–)-trans-4-(3-Ethyl-2-oxo-2,3-dihydrobenzoimidazol-
1-yl)piperidine-3-carboxylic Acid Methyl Ester [(+)- and (–)-8]
The obtained (+)- or (–)-7 in MeOH (900 mL) was hydrogenated in
a Parr apparatus at 50 psi in the presence of Pd/C (5%, 0.2 equiv)
overnight. The catalyst was filtered off and washed with MeOH (3 ×
100 mL). The solvent was evaporated in vacuo yielding (+)- or (–)-
8 as hygroscopic, colorless oil/foam. The crude product (+)- or (–)-
8 was used in the next step without further purification. A sample
for NMR and mass spectra was prepared by filtration through a
short pad of silica gel.
1H NMR (CDCl3): d = 1.32 (t, J = 7.15 Hz, 3 H), 2.00–2.11 (m, 1
H), 3.03 (dq, J = 12.93, 3.85 Hz, 1 H), 3.20–3.47 (m, 2 H), 3.42 (s,
3 H), 3.70–3.97 (m, 4 H), 4.07 (dt, J = 11.83, 3.85 Hz, 1 H), 4.70–
4.85 (m, 1 H), 6.96–7.28 (m, 3 H), 7.52 (br s, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C9H19O: 143.1436; found:
143.1430.
Anal. Calcd for C9H18O·0.05 H2O: C, 75.52; H, 12.74. Found: C,
75.49; H, 12.65.
13C NMR (CDCl3): d = 13.69, 26.27, 36.04, 42.00, 44.28, 45.85,
50.87, 52.48, 107.89, 109.53, 121.60, 121.74, 128.01, 129.09,
153.46, 170.47.
Toluene-4-sulfonic Acid Cyclooctylmethyl Ester (13)
To a solution of 12 (0.67 g, 4.7 mmol) in CH2Cl2 (5 mL) was added
p-toluenesulfonyl chloride (0.98 g, 5.17 mmol) in CH2Cl2 (7 mL)
followed by addition of Et3N (0.72 mL, 5.17 mmol) at 5–10 °C. The
temperature of the mixture was allowed to reach r.t. overnight. The
mixture was then treated with aq 1 N HCl and the organic layer was
separated, washed with H2O (15 mL) and brine (15 mL). The sol-
vent was evaporated to give crude 13 (1.18 g, 85%) as an oil. The
crude product 13 was pure enough (NMR and TLC) to use in the
next step.
1H NMR (CDCl3): d = 1.16–1.33 (m, 2 H), 1.33–1.77 (m, 12 H),
1.77–1.92 (m, 1 H), 2.45 (s, 3 H), 3.78 (d, J = 6.59 Hz, 2 H), 7.32–
7.40 (m, 2 H), 7.76–7.83 (m, 2 H).
13C NMR (CDCl3): d = 21.85, 25.28, 25.28, 26.44, 26.89, 26.89,
28.95, 28.95, 37.11, 75.96, 128.09, 128.09, 129.99, 129.99, 133.49,
133.49, 144.78.
(+)-trans-8
Yield: 53.8 g (quant); [a]D20 +2.0 (c = 1.15, MeOH).
HRMS-TOF (APCI): m/z [M + H]+ calcd for C16H22N3O3:
304.1661; found: 304.1658.
(–)-trans-8
Yield: 56 g (quant); [a]D20 –2.4 (c = 1, MeOH).
HRMS-TOF (APCI): m/z [M + H]+ calcd for C16H22N3O3:
304.1661; found: 304.1674.
2-Chlorocyclooct-1-enecarbaldehyde (10)18
POCl3 (57.1 mL, 0.62 mol) was dissolved in CHCl3 (75 mL) and the
solution was added dropwise to a mixture of DMF (48.1 mL, 0.62
mol) and CHCl3 (145 mL) at 5–10 °C under argon. After 0.5 h, the
temperature was allowed to reach r.t. and a solution of cyclooc-
tanone (9; 66 g, 0.52 mol) in CHCl3 (75 mL) was added dropwise.
The mixture was reflux for 3 h, cooled to r.t. and quenched with
NaOAc·3H2O (84.5 g in 200 mL H2O). The mixture was stirred for
0.5 h. The layers were separated and the aqueous layer was extract-
ed with CHCl3 (3 × 100 mL). The organic extracts were washed
with brine (200 mL) and the solvent was evaporated in vacuo to give
96 g of crude 10. NMR spectra showed that the crude product 10
was sufficiently pure for the following step.
HRMS-TOF (APCI): m/z [M + H]+ calcd for C16H23O3S: 295.1368;
found: 295.1377.
(+)- and (–)-trans-1-(1-Cyclooctylmethyl-3-methoxycarbonyl-4-
piperidyl)-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one [(+)-
and (–)-14]14
Cyclooctanecarbaldehyde (11; 1.1 equiv) was added under argon to
(+)- or (–)-8 (1 equiv, 1 M solution in dichloroethane containing 4
Å MS) and ZnCl2 (1.5 equiv) at r.t. The mixture was stirred for 0.5
h and then treated portionwise with NaBH(OAc)3 (1.5 equiv). The
stirring was continued for 2 h. The resulting suspension was
quenched with aq sat. NaHCO3 solution to pH 8–8.5, and extracted
with CHCl3 (4 × 200 mL). The organic layer was washed with brine
(300 mL) and evaporated to give (+)- or (–)-14. The crude product
(+)- or (–)-14 was purified by crystallization from 90% aq acetone
to give white crystals.
1H NMR (CDCl3): d = 1.40–1.60 (m, 6 H), 1.76–1.86 (m, 2 H),
2.42–2.50 (m, 2 H), 2.71–2.79 (m, 2 H), 10.17 (s, 1 H).
13C NMR (CDCl3): d = 25.48, 25.93, 26.68, 28.34, 30.17, 37.59,
136.43, 153.83, 191.12.
Cyclooctanecarbaldehyde (11)13
A solution of crude 10 (96 g) in a MeOH–H2O mixture (90:10, 0.5
L) was hydrogenated overnight in a Parr apparatus at 40 psi in the
presence of 5% Pd/C (16 g) and NaOAc·3H2O (283 g, 2 mol). The
catalyst was filtered off and washed with MeOH (3 × 100 mL). The
combined extracts were evaporated in vacuo. The residue was dis-
solved in CHCl3 (300 mL), washed with H2O (100 mL), and brine
(100 mL) and evaporated to give crude 11 (72.6 g) as a colorless oil.
1H NMR (CDCl3): d = 1.14–1.28 (m, 2 H), 1.32 (t, J = 7.29 Hz, 3
H), 1.38–1.81 (m, 14 H), 2.11–2.30 (m, 4 H), 2.57 (dq, J = 12.38,
3.3 Hz, 1 H), 2.95–3.04 (m, 1 H), 3.14–3.23 (m, 1 H), 3.44 (s, 3 H),
3.62–3.76 (m, 1 H), 3.92 (q, J = 7.29 Hz, 2 H), 4.31–4.49 (m, 1 H),
6.95–7.02 (m, 1 H), 7.03–7.11 (m, 2 H), 7.14–7.20 (m, 1 H).
13C NMR (CD3OD): d = 13.95, 26.78, 26.78, 27.68, 28.39, 28.39,
29.07, 32.03, 32.11, 36.34, 36.82, 45.46, 52.41, 54.25, 54.67, 57.11,
Synthesis 2007, No. 10, 1547–1553 © Thieme Stuttgart · New York

1552
A. Sulima et al.
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66.65, 109.28, 109.28, 110.34, 122.63, 122.71, 130.22, 155.14,
173.88.
Acknowledgment
This work was initiated while the authors were members of the
Drug Design and Synthesis Section, Laboratory of Medicinal
Chemistry, National Institute of Diabetes, Digestive and Kidney
Diseases, NIH. The work was supported by the NIH Intramural Re-
search Program of the National Institute on Drug Abuse, and by the
NIH Intramural Research Program of the National Institute of Dia-
betes and Digestive and Kidney Diseases. We also thank Dr. John
Lloyd (NIDDK, NIH) for the mass spectral data.
(+)-trans-14
20
Yield: 63.1 g (84%); mp 117.5–118 °C; [a]D +27.3 (c = 0.765,
MeOH).
HRMS-ESI: m/z [M + H]+ calcd for C25H38N3O3: 428.2913; found:
428.2911.
Anal. Calcd for C25H37N3O3: C, 70.22; H, 8.72; N, 9.83. Found: C,
70.39; H, 8.72; N, 9.80.
References
(–)-trans-14
20
Yield: 61.6 g (81%); mp 118–118.5 °C; [a]D –27.4 (c = 0.87,
MeOH).
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HRMS-ESI: m/z [M + H]+ calcd for C25H38N3O3: 428.2913; found:
428.2927.
Anal. Calcd for C25H37N3O3: C, 70.22; H, 8.72; N, 9.83. Found: C,
70.04; H, 8.67; N, 9.73.
(+)- and (-)-trans-1-(1-Cyclooctylmethyl-3-hydroxymethyl-
4-piperidyl)-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one
[(+)-(3R,4R)- and (–)-(3S,4S)-trans-1]13,14
A 0.7 M solution of (+)- or (–)-14 in a mixture of Et2O–THF (1:1)
was added dropwise to a slurry of LiAlH4 (0.75 equiv) in Et2O at 0–
5 °C. The total concentration of (+)- or (–)-14 in the solution was
0.5 M. The mixture was stirred for 15 min and then decomposed fol-
lowing known procedures.19 The stirring was continued for 20 min.
The resulting precipitate was filtered off and washed with Et2O (3 ×
150 mL). The combined organic washings were evaporated. The
residue was dissolved in CHCl3 (400 mL), washed with brine (150
mL), dried, and the solvent was evaporated. The crude product was
crystallized from EtOAc, affording white crystals.
1H NMR (CDCl3): d = 1.18–1.30 (m, 2 H), 1.34 (t, J = 7.28 Hz, 3
H), 1.40–1.76 (m, 13 H), 1.83–1.91 (m, 1 H), 2.02–2.36 (m, 6 H),
2.60 (dq, J = 12.36, 3.98 Hz, 1 H), 2.98–3.06 (m, 2 H), 3.33 (br s, 2
H), 3.87–4.04 (m, 2 H), 4.38 (dt, J = 11.88, 3.75 Hz, 1 H), 7.03–
7.14 (m, 3 H), 7.31–7.34 (m, 1 H).
13C NMR (CDCl3): d = 13.78, 25.80, 25.83, 26.67, 27.33, 27.36,
28.95, 31.06, 31.11, 35.06, 36.29, 41.22, 51.94, 53.79, 56.67, 62.08,
66.28, 108.14, 110.44, 121.31, 121.34, 128.22, 129.44, 154.79.
The purity of the enantiomers was evaluated by chiral analytical
HPLC. A mixture of hexane–propan-2-ol–Et2NH (95:5:0.2) was
used as the eluent system. The faster (+)-enantiomer eluted at 9.43
min and the slower (–)-enantiomer at 11.24 min. Since each enan-
tiomer only showed a single peak in the HPLC assay, the enan-
tiomers were estimated to be >98% ee.
(6) Zaveri, N. Life Sci. 2003, 73, 663.
(7) (a) Zaveri, N.; Jiang, F.; Olsen, C.; Polgar, W.; Toll, L. AAPS
J. 2005, 7, E345. (b) Goto, Y.; Arai-Otsuki, S.; Tachibana,
Y.; Ichikawa, D.; Ozaki, S.; Takahashi, H.; Iwasawa, Y.;
Okamoto, O.; Okuda, S.; Ohta, H.; Sagara, T. J. Med. Chem.
2006, 49, 847. (c) Trapella, C.; Guerrini, R.; Piccagli, L.;
Calo, G.; Carra, G.; Spagnolo, B.; Rubini, S.; Fanton, G.;
Hebbes, C.; McDonald, J.; Lambert, D. G.; Regoli, D.;
Salvadori, S. Bioorg. Med. Chem. 2006, 14, 692.
(8) Wichmann, J.; Adam, G.; Rover, S.; Hennig, M.; Scalone,
M.; Cesura, A. M.; Dautzenberg, F. M.; Jenck, F. Eur. J.
Med. Chem. 2000, 35, 839.
(+)-(3R,4R)-trans-1
Yield: 42 g (75%); mp 145–145.5 °C; [a]D20 +8.6 (c = 1, propan-2-
ol) {Lit.14 [a]D20 +7.6 (c = 1, propan-2-ol)}.
HRMS-TOF (APCI): m/z [M + H]+ calcd for C24H38N3O2:
400.2964; found: 400.2955.
Anal. Calcd for C24H37N3O2: C, 72.14; H, 9.33; N, 10.52. Found: C,
72.16; H, 9.29; N, 10.41.
(9) Kawamoto, H.; Ozaki, S.; Itoh, Y.; Miyaji, M.; Arai, S.;
Nakashima, H.; Kato, T.; Ohta, H.; Iwasawa, Y. J. Med.
Chem. 1999, 42, 5061.
(–)-(3S,4S)-trans-1
(10) Shinkai, H.; Ito, T.; Iida, T.; Kitao, Y.; Yamada, H.; Uchida,
Yield: 37 g (66%); mp 144–145 °C; [a]D20 –8.5 (c = 1.02, propan-2-
I. J. Med. Chem. 2000, 43, 4667.
ol) {Lit.14 [a]D20 –7.2 (c = 1, propan-2-ol)}.
(11) Ozaki, S.; Kawamoto, H.; Itoh, Y.; Miyaji, M.; Azuma, T.;
Ichikawa, D.; Nambu, H.; Iguchi, T.; Iwasawa, Y.; Ohta, H.
Eur. J. Pharmacol. 2000, 402, 45.
HRMS-TOF (APCI): m/z [M + H]+ calcd for C24H38N3O2:
400.2964; found: 400.2969.
(12) Koizumi, M.; Sakoori, K.; Midorikawa, N.; Murphy, N. P.
Br. J. Pharmacol. 2004, 143, 53.
Anal. Calcd for C24H37N3O2: C, 72.14; H, 9.33; N, 10.52. Found: C,
72.33; H, 9.31; N, 10.44.
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Synthesis of a NOP Receptor Antagonist
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Synthesis 2007, No. 10, 1547–1553 © Thieme Stuttgart · New York