Improved synthesis of the ORL antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3- ethoxycarbonyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397)

Article abstract of DOI:10.1080/00397910801997579

A practical synthesis of optically pure 1-[(3R,4R)-1-cyclooctylmethyl-3- ethoxycarbonyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) was developed that avoids the use of chiral columns. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910801997579

Synthetic Communications1, 38: 1926–1930, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801997579
Improved Synthesis of the ORL Antagonist
1-[(3R,4R)-1-Cyclooctylmethyl-3-
ethoxycarbonyl-4-piperidinyl]-3-ethyl-1,3-
dihydro-2H-benzimidazol-2-one (J-113397)
F. Ivy Carroll and Lawrence E. Brieaddy
Center for Organic and Medicinal Chemistry, Research Triangle Institute,
Research Triangle Park, North Carolina, USA
Abstract: A practical synthesis of optically pure 1-[(3R,4R)-1-cyclooctylmethyl-
3-ethoxycarbonyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-
113397) was developed that avoids the use of chiral columns.
Keywords: Antagonist; Chiral auxiliary; J-113397; ORL-1; Synthesis
Four subtypes of opioid receptors have been identified based on structur-
al homology. These include the classical mu, delta, and kappa receptors
(MOP, DOP, and KOP, respectively) and the more recently identified
opioid-receptor-like-1 (ORL-1), which has been named NOP.[1–3] The
endogenous ligand for NOP is a heptadecapeptide identified and named
nociceptin by one group[4] and orphanin FQ (N=OFQ) (Figure 1) by
another group.[5] A number of pharmacological studies have shown that
NOP may be involved in pain regulation, drug dependence, anxiety and
stress, depression, feeling, learning and memory, motor activity, epilepsy=
seizures, cardiovascular effects, urinary incontinence, cough and
immunoregulation.[1,6]
A number of ORL-1 receptor agonists and antagonists have been
synthesized and used to characterize the pharmacological effects of the
NOP system.[6,7] The first and most studied small-molecule antagonist
Received in the USA January 10, 2008.
Address correspondence to Dr. F. Ivy Carroll, Research Triangle Institute,
Post Office Box 12194, Research Triangle Park, NC 27709-2194, USA. E-mail:
fic@rti.org
1926

Synthesis of ORL Antagonist J-113397
1927
Figure 1. Structure of N=OFQ and J-113397.
is 1-[(3R,4R)-1-cyclooctylmethyl-3-ethoxycarbonyl-4-piperidinyl]-3-ethyl-
1,3-dihydro-2H-benzimidazol-2-one (1, J-113397) (Figure 1). Kawamoto
et al. reported a seven-step synthesis of (þ)-1 starting from ethyl 4-oxo-3-
pyridinecarboxylate (2) (Scheme 1).[8,9] De Risi et al. reported an alter-
nate method (13 steps) to synthesize (ꢀ)-1.[10] In both syntheses, optical
resolution of racemate 1 was achieved by chromatography using a chiral
column. Recently, Rice and coworkers reported a new synthesis of
(þ)- and (ꢁ)-1.[11] The synthesis starts with methyl N-benzyl-4-oxo-3-
pyridinecarboxylate (3) and proceeds through optical resolution of
intermediate 4, followed by conversion to (þ)- and (ꢁ)-1 (Scheme 1).
To provide an alternate practical synthesis of (þ)-1, which avoids the
expense of a large-scale chiral column, we developed a resolution of
(ꢀ)-1 using a chiral auxiliary (Scheme 1). Coupling of (ꢀ)-1, which could
be prepared using any one of the reported methods,[7,8,11] with N-Boc-
L-alanine using benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium
hexafluorophosphate (BOP reagents) in methylene chloride containing
N,N-diisopropylethylamine provided the diastereomeric esters 5 and 6,
which could be easily separated by normal chromatography on a silica-
gel column. Subjection of 5 to hydrolysis using lithium hydroxide in
aqueous tetrahydrofuran yielded the desired (þ)-1. The melting point
and optical rotation of the hydrochloride salt were essentially identical
to reported values.[8]
In summary, a practical separation of (ꢀ)-J113397 into an individual
(þ)- and (ꢁ)-isomers were developed using a chiral auxiliary.

1928
F. I. Carroll and L. E. Brieaddy
Scheme 1. Reagents: (a) Boc-L-alanine, BOP, EtN(iPr)2, CH2Cl2; (b) silica-gel
chromatography separation; (c) LiOH, THF, H2O.
EXPERIMENTAL
Melting points were determined on a Mel-temp (Laboratory Devices, Inc.)
capillary tube apparatus. NMR spectra were recorded on a Bruker Avance
300 or AMX 500 spectrometer using tetramethylsilane as internal
standard. Optical rotations were measured on an Auto Pol III Polarimeter.
Thin-layer chromatography (TLC) was carried out on Whatman silica-gel
60 plates. Visualization was accomplished under UV or in an iodine
chamber. Microanalysis was carried out by Atlantic Microlab, Inc. Flash
chromatography was carried out using silica gel 60 (230–400 mesh).
Resolution of 1-[(3Rꢂ,4Rꢂ)-1-Cyclooctylmethyl-3-ethoxycarbonyl-4-
piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one [( )-1]
N-(tert-Butoxyl)-L-alanine (0.73 g, 0.0038 mol), N,N-diisopropylethyla-
mine (0.74 g, 0.0057 mol), and (ꢀ)-1 (1.54 g, 0.0038 mol) were mixed in

Synthesis of ORL Antagonist J-113397
1929
CH2Cl2 (20 mL) and stirred at ꢁ20ꢃC. The reaction mixture was stirred
for 15 min, and BOP (1.73 g, 0.0038 mol) was added. The reaction mix-
ture was stirred for an additional 17 h, during which time the bath was
allowed to warm to room temperature. The reaction mixture was diluted
with CH2Cl2 and extracted with brine (2ꢄ), 1.5% HOAc (2ꢄ), 10%
NaHCO3 (2ꢄ), and brine (2ꢄ). The organic layer was separated, dried
(Na2SO4), and concentrated to give 2.2 g of a mixture of 5 and 6 as
an amorphous solid. Separation by silica-gel chromatography, using
hexane=EtOAc (65:35) as the eluent, afforded 0.64 g of 5, 0.64 g of 6,
and 0.18 g of a mixture of products.
Lithium hydroxide (0.094 g, 0.0022 mol) was added to an ice-chilled
solution of compound 5 (0.64 g, 0.0011 mol) in 3:1 THF–H2O (40 mL).
The purplish reaction mixture was stirred at 0 ꢃC for 90 min, then at
room temperature for 2.5 h. The reaction mixture was added to 10%
NaHCO3 (100 mL); the organic layer was separated, dried (Na2SO4),
and concentrated in vacuo to afford 0.42 g of (þ)-1 as a white solid.
The free base was converted to the hydrochloride salt with ethereal
HCl. The resulting solid was recrystallized from CH2Cl2-diethyl ether
to give 0.311 g (63%) of (þ)-1 as a beige solid: mp 218–219 ꢃC; lit.[8]
mp 218–220 ꢃC; [a]D ¼ þ6.25 (c ¼ 0.27, 0.1 M HCl); Lit.[8] [a]20D þ 6.4
(c1.0, 0.1 MHCl)ꢃ (c ¼ 0.41, MeOH); Rf ¼ 0.42 (silica gel, 95:5
CH2Cl2–MeOH). Anal. calcd. for C24H37ClN3O2.H2O: C, 43.49; H,
8.88; N 9.25. Found: C, 63.78; H, 8.70; N, 8.95.
ACKNOWLEDGMENT
This research was supported by the National Institute on Drug Abuse
Project DA-3-7736.
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