A new synthetic approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one (J-113397), the first non-peptide ORL-1 receptor antagonist

Article abstract of DOI:10.1016/S0968-0896(01)00085-2

An efficient approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one (J-113397)1, the first non-peptide ORL-1 receptor antagonist described in literature, is outlined. After construction of the piperidine framework through Dieckmann cyclization of the Michael adduct 8 of cyclooctylmethylamine to methyl acrylate, condensation with o-phenylendiamine produced the β-enamino ester 2, which has been conveniently used to construct the benzimidazolone substituent at C-4. Catalytic hydrogenation of intermediate 11 followed by base-promoted cis-trans isomerization of the key compound 12 led to the formation of ester 13, which was converted to the racemic title compound by LiAlH₄ reduction. The pure enantiomers were obtained by chiral preparative HPLC separation using a derivatized celllose-based stationary phase. Copyright

Full text of DOI:10.1016/S0968-0896(01)00085-2

Bioorganic & Medicinal Chemistry 9 (2001) 1871–1877
A New Synthetic Approach to 1-[(3R,4R)-1-Cyclooctylmethyl-3-
hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one
(J-113397), the First Non-peptide ORL-1 Receptor Antagonist
Carmela De Risi,a Gian Piero Pollini,a,* Claudio Trapella,a Ilaria Peretto,b
Silvano Ronzonib and Giuseppe A. M. Giardinab
a
`
Dipartimento di Scienze Farmaceutiche, Universita di Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy
bDepartment of Medicinal Chemistry, SmithKline Beecham SpA, via Zambeletti, 20021 Baranzate di Bollate, Milan, Italy
Received 7 February 2001; accepted 21 March 2001
Abstract—An efficient approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-
2-one (J-113397) 1, the first non-peptide ORL-1 receptor antagonist described in literature, is outlined. After construction of the
piperidine framework through Dieckmann cyclization of the Michael adduct 8 of cyclooctylmethylamine to methyl acrylate, con-
densation with o-phenylendiamine produced the b-enamino ester 2, which has been conveniently used to construct the benzimida-
zolone substituent at C-4. Catalytic hydrogenation of intermediate 11 followed by base-promoted cis–trans isomerization of the key
compound 12 led to the formation of ester 13, which was converted to the racemic title compound by LiAlH4 reduction. The pure
enantiomers were obtained by chiral preparative HPLC separation using a derivatized cellulose-based stationary phase. # 2001
Elsevier Science Ltd. All rights reserved.
Introduction
Ozaki et al. reported in 1998 the discovery of J-113397,
The opioid receptor-like 1 (ORL-1) receptor, discovered
in 1994 through cDNA expression cloning techniques,1
is a member of the G-protein coupled receptor super-
family and shows high sequence homology with the
classical d, m and k opioid receptors. Notwithstanding,
the classical opioid ligands do not bind to this new
receptor with appreciable affinity;1c this finding led to
the search of the endogenous ligand of the ORL-1
receptor, which was identified as a heptadecapeptide
named nociceptin/orphaninFQ.2 Despite the significant
similarity of this peptide with the endogenous k ligand
dynorphinA, nociceptin/orphaninFQ does not bind the
other opioid receptors with high affinity.1,2
namely 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-
4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one
(1), as the first non-peptide ORL-1 receptor antagonist.4
This compound, which features a trans-3,4-disubstituted
piperidine nucleus, showed a very interesting in vivo
and in vitro pharmacological profile, acting as a potent
ORL-1 antagonist with no residual agonist activity and a
high selectivity over classical opioid receptors5 (Fig. 1).
Following our interest in this field, we tried unsuccess-
fully to prepare 1 through the reported route,4 probably
due to the lack of experimental details in the procedures
Several experiments have shown that the ORL-1/noci-
ceptin system is involved in many crucial biological
functions,3 but a definitive understanding of its func-
tions has been hampered by the lack of potent and
selective non-peptide ligands for this receptor.
*Corresponding author. Tel.: +39-532-291286; fax: +39-532-291296;
e-mail: pol@dns.unife.it
Figure 1.
0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00085-2

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C. De Risi et al. / Bioorg. Med. Chem. 9 (2001) 1871–1877
described in the patent, not completely clarified in the
recently published full paper.6 In particular, the intro-
duction of the benzimidazolone moiety seemed to be a
capricious operation. Therefore, we decided to develop
an alternative synthetic approach to 1, which relies on
the use of the b-enaminoester 2 as the key intermediate
for the construction of the benzimidazolone framework
at C-4. Compound 2 would in turn be obtained through
condensation of o-phenylendiamine with b-ketoester 3
(Scheme 1).
tedious but convenient procedure which allowed to
obtain 7 in 63% overall yield. LiAlH4 reduction of 4
yielded the corresponding allylamine, which was pro-
tected as acetamide and subsequently reduced by cata-
lytic hydrogenation to compound 6; the saturated
acetamide 6 was then hydrolyzed in acidic conditions to
give the amine 7. Once 7 was obtained, the preparation
of 3 was easily achieved in a high-yield two-step
sequence involving Michael addition of 7 to methyl
acrylate followed by t-BuOK promoted Dieckmann
cyclization8 of the diester adduct 8 (Scheme 2).
A mixture of b-ketoester 3 and o-phenylenediamine in
benzene was heated at reflux in the presence of a cata-
lytic amount of AcOH and 4 A molecular sieves to give
the stable enamine 2 (Scheme 3).
Results and Discussion
Having established the essential features of the synthetic
approach, the preparation of the starting molecule 3
required a suitable source for cyclooctylmethylamine 7.
The most direct route to this compound appeared to be
the reduction of the easily available 1-nitromethyl-
cyclooctene 4.7 Disappointingly, this reaction proceeded
with considerable decomposition, and the desired com-
pound could be obtained only in very low yield. A dif-
ferent approach was eventually found through a rather
Attempts to reduce the conjugated double bond in 2
either catalytically or with mild reducing agents, for
example, NaBH3CN proved to be unsuccessful, giving
in all cases complex mixtures in which only small traces
of the desired reduction product were present. We deci-
ded to postpone the reductive step after the introduction
Scheme 1.
Scheme 2. (a) i: LiAlH4, EtO, 0ꢀC; ii: Et3N, Ac2O, CH2Cl2, 0ꢀC 78% over two steps. (b) H2, Pd/C 10%, EtOH, 96%. (c) HCl, EtOH/H2O, Á, 84%.
(d) CH2¼CH-CO2OMe, MeOH rt, 72%. (e) t-BuOK, toluene, rt, 78%.

C. De Risi et al. / Bioorg. Med. Chem. 9 (2001) 1871–1877
1873
of the benzimidazolone moiety. This operation pro-
ceeded smoothly at room temperature by treatment of 2
with di-tert-butyldicarbonate (Boc2O) and DMAP
yielding 9 in 89% yield, the N-3 nitrogen atom being
concomitantly protected. After removal of the tert-
butoxycarbonyl protecting group by treatment with
TFA, the intermediate 10 was transformed into the key
compound 11 by treatment with NaH and ethyl bromide.
the side-products, probably arising by palladium-
promoted b-elimination processes.
The required trans- stereochemistry between the sub-
stituents at C-3 and C-4 was quantitatively achieved
under very mild conditions by stirring (ꢁ)-cis-12 with
MeONa in methanol at room temperature, yielding
(ꢁ)-trans-13, which was eventually converted to
racemic 1 through LiAlH4 reduction.
The next synthetical step required the reduction of the
double bond of the b-enaminoester functionality of 11
(Scheme 4).
The separation of the enantiomers of (ꢁ)-1 was
achieved by preparative chiral HPLC, performed on a
cellulose-based chiral column (Chiralcel OD). The elu-
tion was isocratic, employing a mixture of hexane and
2-propanol (100:2). The separation of the two peaks (see
Fig. 2) allowed to obtain both the enantiomers with
enantiomeric excess greater than 99% (other enantiomer
not detectable under the utilized analytical conditions).
While reduction of 11 with hydrides (e.g., NaBH3CN)
was unsuccessful, catalytic hydrogenation in presence of
10% Pd/C allowed us to obtain in moderate yield (50%)
the expected derivative (ꢁ)-cis-12; purification by silica
gel column chromatography was necessary to separate
Scheme 3. (a) o-phenylenediamine, AcOH, molecular sieves, benzene, Á, 83%. (b) (Boc)2O, DMAP, CH2Cl2, 0ꢀC, 89%. (c) TFA, CH2Cl2, rt, 97%.
(d) NaH, EtBr, DMF, rt, 75%.
Scheme 4. (a) H2, Pd/C 10%, MeOH, 50%. (b) MeONa, MeOH, rt, 92%. (c) LiAlH4, Et2O, 0ꢀC, 80%.

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C. De Risi et al. / Bioorg. Med. Chem. 9 (2001) 1871–1877
Figure 2.
NMR and MS data for the enantiomers thus obtained
were consistent with the data reported in literature4 and
with the data measured for the racemate (ꢁ)-1.
Chemical shifts are given in parts per million upfield
from tetramethylsilane as the internal standard.
MALDI-TOFmass spectra were recorded on a Hewlett
Packard G 2025 A LD-TOFsystem. Elemental analyses
were performed by the microanalytical laboratory of
Dipartimento di Chimica, University of Ferrara.
On the basis of literature data and in-house binding
studies in CHO cell membranes stably expressing the
human ORL-1 receptor (displacement of 3[H]-nociceptin),
the faster running (+)-enantiomer was established to be
J-113397.
N-(Cyclooct-1-enylmethyl)-ethanamide (5). A solution of
4 (12 g, 71 mmol) in Et2O (40 mL) was added dropwise
to a cooled (0 ꢀC) slurry of LiAlH4 (8 g, 213 mmol) in
Et2O (160 mL) and the reaction mixture was stirred at
the same temperature for 6 h. Excess hydride was
quenched by careful addition of H2O, then the pre-
cipitated salts were filtered through a Celite pad and
washed with CH2Cl2 (100 mL). The filtrate was evapo-
rated under reduced pressure to give a yellow oil, which
was immediately dissolved in CH2Cl2 (50 mL). The
resulting solution was cooled at 0 ꢀC and treated with
Et3N (10.2 mL, 71 mmol) and acetic anhydride (6.7 mL,
71 mmol). The reaction mixture was kept for 6 h at the
same temperature, then the solvent was evaporated and
the residue purified by flash chromatography (EtOAc/
light petroleum/NH4OH, 1:2:0.1) to afford 5 (10 g,
78%) as a yellowish oil. Anal. calcd for C11H19NO: C,
72.88; H, 10.56; N, 7.73. Found: C, 72.91; H, 10.55; N,
Conclusions
In summary, an alternative approach to 1-[(3R,4R)-1-
cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-
1,3-dihydro-benzimidazol-2-one (J-113397) 1, which
could open the way to the enantioselective synthesis of
the target compound or to structurally modified analo-
gues for pharmacological studies, has been described. A
major advantage of this approach is represented by the
possibility to obtain pure compounds, which may be useful
tools for structure–activity relationship studies, having
both cis- and trans- relationship between the substituents
at C-3 and C-4 carbon atoms of the piperidine framework,
thus avoiding their chromatographic separation.
1
7.71. IR (film): 3288, 3080, 1651, 1557 cmꢂ1. H NMR
(CDCl3): 5.49 (t, 1H, J=8.1 Hz), 5.30 (br s, 1H), 3.78
(d, 2H, J=5.8 Hz), 2.20–2.07 (m, 4H), 1.99 (s, 3H),
1.70–1.40 (m, 8H).
Experimental
All reactions were run under nitrogen or argon atmo-
sphere. Organic solutions were dried over anhydrous
MgSO4 and evaporated with a rotary evaporator. Light
petroleum refers to the fractions boiling in the range 40–
60 ꢀC. Flash chromatography was carried out on silica
gel (Merck, 230–400 mesh). Melting points were deter-
mined on a Buchi–Tottoli apparatus and are uncor-
rected. IR spectra were recorded on a Perkin-Elmer FT-
N-(Cyclooctylmethyl)-ethanamide (6). A solution of 5
(8.4 g, 46.40 mmol) in EtOH (100 mL) was hydro-
genated in a Parr apparatus at 70 psi for 24 h in the
presence of 10% Pd/C (0.5 g). Filtration of the catalyst
through Celite pad and solvent evaporation gave 6 (8.2
g, 96%) as a colorless oil, which could be used in the
next step without further purification. A small aliquot
was purified by flash chromatography (EtOAc/light
petroleum/NH4OH, 1:2:0.1) to give a pure sample of 6.
1
IR Paragon 500 spectrometer. H NMR spectra were
recorded on a Bruker AC spectrometer at 200 MHz.

C. De Risi et al. / Bioorg. Med. Chem. 9 (2001) 1871–1877
1875
Anal. calcd for C11H21NO: C, 72.08; H, 11.55; N, 7.64.
Found: C, 72.04; H, 11.57; N, 7.66. IR (film): 3292,
3087, 1651 cmꢂ1. 1H NMR (CDCl3): 5.60 (br s, 1H), 3.07
(t, 2H, J=6.4 Hz), 1.97 (s, 3H), 1.70–1.20 (m, 15H).
1-(1-Cyclooctylmethyl-3-methoxycarbonyl-1,2,5,6-tetra-
hydro-pyridin-4-yl)-3-tert-butoxycarbonyl-1,3-dihydro-2H-
benzimidazol-2-one (9). A cooled (0 ꢀC) solution of 2
(2 g, 5.39 mmol) in CH2Cl2 (40 mL) was treated with
di-tert-butyldicarbonate (5.88 g, 26.95 mmol) and a
catalytic amount of DMAP. The reaction mixture was
stirred at the same temperature for 3 h, then the solvent
was evaporated in vacuo and the residue purified by
flash chromatography (EtOAc/light petroleum, 1:6),
yielding 9 (2.4 g, 89%) as an orange oil. Anal. calcd for
C28H39N3O5: C, 67.58; H, 7.90; N, 8.44. Found: C,
Methyl 3-[cyclooctylmethyl-(2-methoxycarbonyl-ethyl)-
amino]-propanoate (8). HCl 37% (150 mL) was slowly
added to a solution of 6 (8.3 g, 45.35 mmol) in EtOH/
H2O (1:2, 150 mL) and the reaction mixture was
refluxed overnight. After cooling, most of the solvent
was evaporated in vacuo and the residue brought to pH
12 by careful addition of NaOH 20%. Extraction with
EtOAc (5ꢃ50 mL) followed by evaporation of the dried
organic phases gave 7 (5.4 g, 84%) as a yellowish oil,
which was immediately used for the next reaction. A
solution of 7 (5 g, 35.46 mmol) in MeOH (20 mL) was
added dropwise to a cooled (0 ꢀC) solution of methyl
acrylate (7 mL, 78.01 mmol) in MeOH (50 mL). After
being stirred for 24 h at rt, the solvent was evaporated
and the residue was purified by flash chromatography
(EtOAc/light petroleum 1:6) to give 8 (8 g, 72%) as a
yellow oil. Anal. calcd for C17H31NO4: C, 65.14; H,
9.97; N, 4.47. Found: C, 65.17; H, 9.95; N, 4.46. IR
+
67.61; H, 7.88; N, 8.43. MALDI-TOFMS: [MH] 498.
1
IR (film): 1742, 1724, 1647, 1580, 1500 cmꢂ1. H NMR
(CDCl3): 7.90–7.83 (m, 1H), 7.18–7.08 (m, 2H), 6.90–
6.80 (m, 1H), 3.47 (s, 3H), 3.45 (AB system, 2H, J=15
Hz), 3.00–2.60 (m, 4H), 2.29 (d, 2H, J=7.2 Hz), 1.90–
1.20 (m, 24H).
1-(1-Cyclooctylmethyl-3-methoxycarbonyl-1,2,5,6-tetra-
hydro-pyridin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one
(10). A solution of 9 (2 g, 4.02 mmol) in CH2Cl2 (20
mL) was cooled at 0 ꢀC and TFA (2.17 mL, 28.14
mmol) was added dropwise. The reaction mixture was
kept at rt until completion (8 h), then saturated aq
NaHCO3 (20 mL) was carefully added. The phases were
separated, the aqueous phase was extracted with
CH2Cl2 (3ꢃ20 mL) and the combined organic extracts
were dried. Evaporation of the solvent gave 10 (1.54 g,
97%) as a brownish amorphous solid (mp 28–30 ꢀC).
Anal. calcd for C23H31N3O3: C, 69.49; H, 7.86; N,
1
(film): 1741 cmꢂ1. H NMR (CDCl3): 3.66 (s, 6H), 2.74
(t, 4H, J=7 Hz), 2.42 (t, 4H, J=7 Hz), 2.11 (d, 2H,
J=7 Hz), 1.80–1.10 (m, 15H).
1-Cyclooctylmethyl-3-methoxycarbonyl-piperidin-4-one (3).
t-BuOK (4.3 g, 38.34 mmol) was added in one portion
to a cooled (0 ꢀC) solution of 8 (8 g, 25.56 mmol) in
toluene (80 mL) and, after being stirred at the same
temperature for 30 min, the reaction mixture was kept
at rt overnight. H2O (100 mL) was added, the phases
were separated and the aqueous phase was extracted
with EtOAc (3ꢃ100 mL). The combined organic
extracts were dried and evaporated. Purification of the
residue by flash chromatography (EtOAc/light petro-
leum 1:9) gave 3 (5.6 g, 78%) as an orange oil. Anal.
calcd for C16H27NO3: C, 68.29; H, 9.67; N, 4.98. Found:
10.57. Found: C, 69.51; H, 7.85; N, 10.56. MALDI-
+
TOFMS: [MH]
398. IR (KBr): 3422, 1707, 1487
cmꢂ1. H NMR (CDCl3): 9.64 (s, 1H), 7.20–7.05 (m,
3H), 7.00–6.85 (m, 1H), 3.60–3.30 (m, 2H superimposed
to s, 3H at 3.44), 2.90–2.60 (m, 4H), 2.31 (d, 2H, J=7.1
Hz), 1.90–1.20 (m, 15H).
1
1-(1-Cyclooctylmethyl-3-methoxycarbonyl-1,2,5,6-tetra-
hydro-pyridin-4-yl)-3-ethyl-1,3-dihydro-2H-benzimidazol-
2-one (11). A solution of 10 (1.5 g, 3.78 mmol) in DMF
(10 mL) was added dropwise to a stirred suspension of
75% NaH (0.12 g, 3.78 mmol) in DMF(5 mL) at 0 ꢀC.
The reaction mixture was stirred for 30 min at the same
temperature, then a solution of ethyl bromide (0.31 mL,
4.16 mmol) in DMF(5 mL) was added slowly and stir-
ring was continued at rt overnight. Most of the solvent
was evaporated and the residue was diluted with Et2O
(50 mL). The precipitated salts were filtered through a
Celite pad, the solvent was removed under reduced
pressure and the residue was purified by flash chroma-
tography (EtOAc/light petroleum/NH4OH, 1:4:0.1) to
give 11 (1.2 g, 75%) as a yellow oil. Anal. calcd for
C25H35N3O3: C, 70.56; H, 8.29; N, 9.87. Found: C,
+
C, 68.32; H, 9.65; N, 4.97. MALDI-TOFMS: [MH]
1
282. IR (film): 1747, 1722, 1667, 1625 cmꢂ1. H NMR
(CDCl3): 11.87 (br s, 1H, enol form), 3.73 (s, 3H), 3.07
(AB system, 2H, J=10 Hz), 2.56 (t, 2H, J=7 Hz), 2.37 (t,
2H, J=7 Hz), 2.19 (d, 2H, J=7.3 Hz), 1.85–1.15 (m, 15H).
Methyl 1-cyclooctylmethyl-4-(o-phenylendiamino)-1,2,5,6-
tetrahydro-pyridine-3-carboxylate (2). A solution of 3 (3
g, 10.67 mmol) and o-phenylenediamine (1.77 g, 16.43
mmol) in benzene (50 mL) was refluxed overnight in the
presence of AcOH (0.3 mL) and 4 A powdered mole-
cular sieves (1 g), with azeotropic removal of water.
After being cooled, the reaction mixture was filtered and
the filtrate was evaporated under reduced pressure. The
residue was purified by flash chromatography (EtOAc/
light petroleum/NH4OH, 1:4:0.1) to yield 2 (3.3 g, 83%)
as a white solid (mp 88–90 ꢀC). Anal. calcd for
C22H33N3O2: C, 71.12; H, 8.95; N, 11.31. Found: C,
+
70.58; H, 8.28; N, 9.86. MALDI-TOFMS: [MH] 426.
IR (film): 1714, 1647, 1616, 1493 cmꢂ1 1H NMR
.
(CDCl3): 7.10–6.92 (m, 3H), 6.90–6.80 (m, 1H), 3.88 (q,
2H, J=7.2 Hz), 3.50–3.30 (m, 2H superimposed to s,
3H at 3.34), 2.80–2.50 (m, 4H), 2.22 (d, 2H, J=7.2 Hz),
1.80–1.40 (m, 15H), 1.28 (t, 3H, J=7.2 Hz).
+
71.09; H, 8.96; N, 11.33. MALDI-TOFMS: [MH]
372. IR (KBr): 3459, 3367, 3265, 1647, 1588, 1503 cmꢂ1
.
1H NMR (CDCl3): 9.83 (s, 1H), 7.12–6.95 (m, 2H),
6.80–6.60 (m, 2H), 3.80 (s, 2H), 3.72 (s, 3H), 3.20 (s,
2H), 2.18 (d, 2H, J=7.3 Hz), 2.50–2.20 (m, 4H), 1.90–
1.20 (m, 15H).
(ꢁ)-cis-1-(1-Cyclooctylmethyl-3-methoxycarbonyl-4-pi-
peridyl)-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (12).
A solution of 11 (1 g, 2.35 mmol) in MeOH (200 mL)

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C. De Risi et al. / Bioorg. Med. Chem. 9 (2001) 1871–1877
was hydrogenated in a Parr apparatus at 70 psi for 24 h
in the presence of Pd/C 10% (0.1 g). Filtration of the
catalyst through Celite pad, solvent evaporation and
Column:
Chiralcel OD (manufactured by Daicel),
250ꢃ20 mm, 10 mm;
Eluent:
Elution:
Detection:
hexane/2-propanol (100:2 v/v);
isocratic, 20 mL/min;
UV absorption at 210 nm.
flash
chromatography
(EtOAc/light
petroleum/
NH4OH, 1:4:0.1) of the residue gave 12 (0.5 g, 50%) as
a colourless oil. Anal. calcd for C25H37N3O3: C, 70.23;
H, 8.72; N, 9.83. Found: C, 70.26; H, 8.70; N, 9.81.
MALDI-TOFMS: [MH] +428. IR (film): 1745, 1698,
Typically, 30 mg of racemic sample were dissolved in
100 mL of 2-propanol and injected. The faster enantio-
mer was eluted typically between 20.6 and 26.6 min,
while the slower enantiomer between 26.8 and 34.6 min.
Fractions collected between 26.6 and 26.8 min were
discarded due to the presence of both the enantiomers.
A single purification run typically yielded 13 mg of each
enantiomer with ee>99%.
1616, 1490 cmꢂ1 1H NMR (CDCl3): 7.70–7.50 (m,
.
1H), 7.10–6.95 (m, 3H), 4.39 (dt, 1H, J=13.3, 4 Hz),
3.93 (dq, 2H, J=7, 2.4 Hz), 3.53 (s, 3H), 3.48–3.20 (m,
2H), 3.15–3.00 (m, 1H), 2.37 (dd, 1H, J=11.6, 3 Hz),
2.30–1.90 (m, 5H), 1.80–1.40 (m, 15H), 1.33 (t, 3H, J=7
Hz).
(ꢁ)-trans-1-(1-Cyclooctylmethyl-3-methoxycarbonyl-4-
piperidyl)-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one
(13). A solution of MeONa, freshly prepared dissolving
sodium (0.19 g, 8.26 mmol) in MeOH (5 mL), was
added in one portion to a cooled (0 ꢀC) solution of 12
(0.5 g, 1.17 mmol) in MeOH (5 mL). The reaction mix-
ture was stirred at rt for 60 h, then adsorbed on silica gel
(1 g) and subjected to flash chromatography (EtOAc/
light petroleum/NH4OH, 1:4:0.1) to give 13 (0.46 g,
92%) as a white solid (mp 68–70 ꢀC). Anal. calcd for
C25H37N3O3: C, 70.23; H, 8.72; N, 9.83. Found: C,
The purity of the separated enantiomers was evaluated
by chiral analytical HPLC. The analysis was performed
on a Shimadzu analytical instrument, equipped with
automated injector system and UV diode array detec-
tor. Gradient grade quality solvents for HPLC (Merck)
were employed.
Column:
Chiralcel OD (manufactured by Daicel),
250ꢃ4 mm, 10 mm;
Eluent:
Elution:
Detection:
hexane/2-propanol (100:2 v/v);
isocratic, 0.8 mL/min;
UV absorption at 210 nm.
+
70.19; H, 8.73; N, 9.85. MALDI-TOFMS: [MH] 428.
IR (KBr): 1745, 1698, 1616, 1490 cmꢂ1 1H NMR
.
(CDCl3): 7.20–7.00 (m, 4H), 4.39 (dt, 1H, J=12.2, 5
Hz), 3.91 (q, 2H, J=7 Hz), 3.68 (m, 1H), 3.43 (s, 3H),
3.25–3.10 (m, 1H), 3.08–2.90 (m, 1H), 2.56 (dq, 1H,
J=12.5, 3.9 Hz), 2.30–2.08 (m, 5H), 1.80–1.40 (m,
15H), 1.33 (t, 3H, J=7 Hz).
The optical rotation of both the enantiomers was mea-
sured with a Perkin-Elmer 341 instrument. 2-propanol
Uvasol (Merck) for spectroscopy was employed as solvent.
Faster-running [a]D (20 ꢀC)=+7.6ꢀ (c=1, 2-propanol)
enantiomer
(ꢁ)-1-(1-Cyclooctylmethyl-3-hydroxymethyl-4-piperidyl)-
3-ethyl-1,3-dihydro-2H-benzimidazol-2-one ((ꢁ)ꢂ1). A
solution of 13 (1 g, 2.34 mmol) in Et2O (20 mL) was
added dropwise to a cooled (0 ꢀC) slurry of LiAlH4
(0.19 g, 5.01 mmol) in Et2O (20 mL). After stirring for
30 min at the same temperature, H2O (10 mL) was
slowly added and the precipitated aluminium salts were
filtered through Celite pad. Evaporation of the solvent
and purification of the residue by flash chromatography
(EtOAc/light petroleum/NH4OH, 1:2:0.1) gave racemic
1 (0.74 g, 80%) as a white solid (mp 93–95 ꢀC). Anal.
calcd for C24H37N3O2: C, 72.14; H, 9.33; N, 10.52.
Found: C, 72.18; H, 9.30; N, 10.51. MALDI-TOF MS:
[MH]+ 400. IR (KBr): 3435, 1686, 1491 cmꢂ1. 1H NMR
(CDCl3): 7.40–7.30 (m, 1H), 7.20–7.00 (m, 3H), 4.39 (dt,
1H, J=12.2, 5 Hz), 3.93 (dq, 2H, J=7, 2.2 Hz), 3.34 (br
s, 2H), 3.10–2.91 (m, 2H), 2.61 (dq, 1H, J=12.2, 3.7
Hz), 2.40–2.00 (m, 6H), 2.10–1.40 (m, 16H), 1.34 (t, 3H,
J=7 Hz). The spectral data were consistent with those
reported by H. Kawamoto et al. for racemic 1.4
(J-113397):
Slower-running [a]D (20 ꢀC)=ꢂ7.2ꢀ (c=1, 2-propanol).
enantiomer:
Literature optical rotation data have been obtained for
4
the hydrochloric salts of the two enantiomers:
(J-113397):
Other enantiomer:[a]D (20 ꢀC)=ꢂ6.2ꢀ (c=1, 0.1 N HCl).
[a]D (20 ꢀC)=+6.4ꢀ (c=1, 0.1 N HCl)
Acknowledgements
The authors would like to thank Dr. Alberto Cerri, Dr.
Renzo Mena and Dr. Massimo Sbacchi (SmithKline
Beecham SpA, via Zambeletti, 20021 Baranzate di Bol-
late, Milano, Italy) for performing NMR-MS analyses
and binding assays.
References and Notes
Separation of the enantiomers of (ꢁ)-1-(1-Cyclooctyl-
methyl-3-hydroxymethyl-4-piperidyl)-3-ethyl-1,3-dihydro-
2H-benzimidazol-2-one (1) by preparative chiral HPLC.
The separation was performed on a Shimadzu pre-
parative instrument, equipped with UV detector, auto-
mated injector and automated fraction-collector system.
Gradient grade quality solvents for HPLC (Merck) were
employed.
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