Asymmetric synthesis of N-3 substituted phenoxypropyl piperidine benzimidazol-2-one derivatives, potent and selective NOP agonists

Article abstract of DOI:10.1016/j.tet.2008.01.125

The asymmetric synthesis of the potent selective NOP agonist 2-(3-{1-[3-(5-methoxy-2-methyl-phenoxy)-4-methyl-pentyl]-piperidin-4-yl} -2-oxo-2,3-dihydro-benzimidazol-1-yl)-N-methyl-acetamide and analogues was developed. The key step, chiral reduction of methyl isobutyryl acetate, was achieved using a mild Noyori-type asymmetric hydrogenation.

Full text of DOI:10.1016/j.tet.2008.01.125

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3119e3126
www.elsevier.com/locate/tet
Asymmetric synthesis of N-3 substituted phenoxypropyl piperidine
benzimidazol-2-one derivatives, potent and selective NOP agonists
b
a
John K. Clark a, Philip S. Jones a, Ronald Palin a, , Georgina Rosair , Mark Weston
*
a Department of Chemistry, Organon Laboratories Ltd, Newhouse, Lanarkshire ML1 5SH, UK
b William Perkin Building, School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, UK
Received 11 September 2007; received in revised form 16 January 2008; accepted 31 January 2008
Available online 3 February 2008
Abstract
The asymmetric synthesis of the potent selective NOP agonist 2-(3-{1-[3-(5-methoxy-2-methyl-phenoxy)-4-methyl-pentyl]-piperidin-4-yl}-
2-oxo-2,3-dihydro-benzimidazol-1-yl)-N-methyl-acetamide and analogues was developed. The key step, chiral reduction of methyl isobutyryl
acetate, was achieved using a mild Noyori-type asymmetric hydrogenation.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: NOP/ORL1 agonist; Chiral reduction; Asymmetric hydrogenation; Noyori catalyst
1. Introduction
Postoperative pain is currently served with opiate based
products such as morphine. Morphine, an MOP agonist, is still
regarded as the ‘gold standard’ treatment for moderate to se-
vere pain,4 however, some patients either do not achieve ade-
quate analgesia or suffer opioid related side effects such as
respiratory depression,5 constipation, nausea and vomiting,
thus leading to non-patient compliance.6 Our primary interest
has been to develop small molecules with high selectivity and
potency for NOP that would be useful for the management of
pain without the detrimental side effects observed with MOP
agonists.
Many small-molecule NOP ligands have now been reported
in the literature.7 Several of these ligands have high selectivity
and potency for the NOP receptor versus the other opioid
receptors. The NOP antagonist, J-113397 (Fig. 1), has been
well described and pharmacologically characterised.8 Roche9
(e.g., Ro 64-6198) and Novo Nordisk10 (NNC 63-0532) have
also described NOP agonists, with Ro 64-6198 showing
>100-fold selectivity for the NOP receptor and displaying
anxiolytic-like activity without causing tolerance in vivo.11
Although this compound may mediate its effects through the
NOP receptor, it shows moderate affinity towards MOP and
KOP receptors as well as other receptor sites.
In 1994, the fourth member of the opioid receptor family,
opioid receptor-like receptor (NOP, ORL1), was identified1
and has led to extensive research into its physiological role.
This G-protein coupled receptor mediates the inhibition of
adenylate cyclase and shares a high degree of sequence homo-
logy with other opioid receptors. The 17 amino acid peptide
nociceptin is an endogenous ligand for the NOP receptor1
and the receptor is localised in various regions of the central
nervous system, which are associated with nociception. Noci-
ceptin binds to the receptor with very high affinity although
activation of NOP receptors is functionally complex.2 For
example, depending on its site of activation in the pain path-
way, NOP can have opposing actions; it appears to have potent
anti-analgesic actions supraspinally1 and analgesic actions spi-
nally.3 The use of this peptide has plagued the interpretation of
these complex results because of the intrinsic limitations with
regard to metabolic stability. However, it is clear that this new
member of the opioid receptor family plays an important role
in pathways of pain, anxiety, learning and memory.2
We have recently published our efforts towards developing
potent and selective NOP agonists based on the benzimidazol-
* Corresponding author. Tel.: þ44 1698 736128; fax: þ44 1698 736187.
E-mail address: r.palin@organon.co.uk (R. Palin).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.125

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J.K. Clark et al. / Tetrahedron 64 (2008) 3119e3126
H
N
O
O
O
HO
H
OMe
O
NH
O
N
N
O
N
N
N
N
O
N
N
N
N
O
N
J-113397
Ro 64-6198
NNC 63-0532
1a
Figure 1. A selection of NOP receptor ligands.
2-one heterocycle.12 Compound 1a was identified with an
NOP Ki of 0.5 nM, and excellent selectivity over other opioid
receptors (NOP/MOP¼108, NOP/DOP¼6822, NOP/KOP¼
1068). Furthermore, 1a was shown to be selective over a fur-
ther 55 unrelated molecular targets at 10ꢀ7 M. In a functional
cAMP assay 1a behaved as a full agonist with excellent po-
tency and good efficacy with respect to the nociceptin response
(IC50¼4 nM, 120% nociceptin response). Given intravenously,
1a produced antinociceptive effects comparable to morphine
in the formalin paw test (FPT).12b
optical resolution using chiral column Chiralpak AD (iso-
hexane/isopropanol/diisopropylethylamine 80/20/0.1) to give
the enantiomers.12b This allowed X-ray crystallography of the
HCl salt (Fig. 2) to determine the absolute configuration of
the active enantiomer 1c as (S). However, given the limitations
of scale with chiral HPLC it was important to develop a facile
asymmetric route that was generally applicable and suitable for
production of multigram quantities. Herein, we report a general
route to 1aec that should be applicable to generate further deri-
vatives, utilising the Noyori type asymmetric hydrogenation.
The data suggest that 1a needed to be profiled further in
order to determine the potential for development as an anal-
gesic. It was clearly seen that the (þ)-enantiomer in this series
was the eutomer in all compounds investigated.12b We had
previously prepared 1aec in a racemic fashion and performed
2. Results and discussion
Retrosynthetic analysis (Scheme 1) indicated that the key
chiral building block towards 1a would be the chiral alcohol
(a)
(b)
Figure 2. ORTEP drawing of (a) (S)-1a and (b) (S)-1c as hydrochloride salts.

J.K. Clark et al. / Tetrahedron 64 (2008) 3119e3126
3121
H
N
H
N
OMe
O
OMe
O
O
N
OMe
O
N
HO
OMs
N
+
+
N
O
OMs
O
N
HN
OH
1a
2
3
4
5
Scheme 1.
5. This would allow Mitsunobu coupling13 involving inversion
of the stereocentre to give the desired (S) stereochemistry
found in 1a. The route to the key chiral intermediate 2 was
carried out as shown in Scheme 2. Genet and co-workers14
have shown that reduction of methyl isobutyryl acetate 6 can
be effected under atmospheric pressure at 60 ꢁC for 18 h to
obtain 7 in excess of 97% ee in quantitative yield, compared
to the extended reaction time utilised by Kitamura and
co-workers15 of 86 atms for 51 h. Following the literature pro-
tocol, the Noyori catalyst16 with the desired absolute configu-
ration was prepared in situ in acetone from (S)-BINAP and
bis-(2-methylallyl)cycloocta-1,5-diene ruthenium,17 followed
by addition of HBr in methanol. Acetone was removed and
replaced with methanol and the hydrogenation of methyl iso-
butyryl acetate 6 was carried out by following the literature
protocol.14 The enantiomeric ratio for 718 was >98:2 as
judged by chiral GC. Standard lithium aluminium hydride
reduction to 819 was followed by mono-mesylation of the
primary alcohol to give 5 in good yield. Mitsunobu coupling13
involving SN2 inversion of the stereocentre of the alcohol 5
with 5-methoxy-2-methylphenol20 4 gave only 40% of the de-
sired phenyl ether 2 together with the isopropenyl by-product
9. The low yield for this step is probably due to the formation
of the volatile 4-methyl-1,3-pentadiene that can be formed
from elimination of the mesylate before nucleophilic substitu-
tion can occur. Limited attempts to optimise this step failed to
substantially increase the yield or reduce the proportion of
isopropenyl impurity.21 At this stage, the first purification
step was required with partial removal of 9 by silica gel chro-
matography. Furthermore, since all of 9 could not be removed
the enantiomeric excess could not be determined.
Piperidinyl-benzimidazolones 12a,b were prepared as previ-
ously published12b by Boc protection of the commercially avail-
able 1-(4-piperidinyl)-1,3-dihydro-2H-benzimadazol-2-one to
give 10. N-Alkylation with the appropriate reagent and then
deprotection of the Boc group with TFA were achieved to
give the desired amine for coupling (Scheme 3). The unsubsti-
tuted triazole derivative 12b was constructed according to the
methods of Ladduwahetty and co-workers22 by preparation of
the alkylating reagent from chloroacetonitrile and formylhydr-
azide to give N-formyl-2-chloroacetamidrazone. After alkyl-
ation, heating to 140 ꢁC effected cyclisation to the desired
triazole 11b, which was de-protected as previously described
to afford 12b.
The final coupling of the chiral intermediate 2 with the
piperidinyl-benzimidazolones 12a,b was carried out in aceto-
nitrile/diisopropylethylamine at 80 ꢁC. Compound 1c was
prepared by direct alkylation of racemic 1d (1d, R¼H) with
OH
MsCl, DIPEA,
DCM
OH
[(S)-BINAP]RuBr2,
H2, MeOH, 60 °C
OH
O
O
O
LiAlH4, THF
87%
OH
OMs
OMe
R
OMe
84%
99%
6
7
8
5
4
DIAD, PPh3,
Toluene
H
N
OMe
O
N
OMe
a R =
b R =
N
O
12a-b, DIPEA,
CH3CN, 80 °C
OMs
O
OMs
+
N
N
N
66%
O
N
H
2
9
40%
1
O
c R =
Scheme 2.
O
O
O
R
R
HN
Boc
N
TFA, DCM
N
N
N
NH
Boc
N
NaH, DMF
R-X
N
N
10
11a-b
12a-b
Scheme 3.

3122
J.K. Clark et al. / Tetrahedron 64 (2008) 3119e3126
2-bromoethyl methyl ether rather than going via 12c. The sin-
gle enantiomer was then isolated by chiral HPLC. The product
1a (13.0 g of a viscous gum) was obtained in 65% yield after
purification on silica gel, with an enantiomeric purity of 100%
as judged by chiral HPLC, confirming complete inversion dur-
ing the Mitsunobu coupling. For 1a, the material was identical
to that initially obtained by preparative chiral HPLC. The
overall yield was 19% for the five steps compared to 5.6%
for the racemate described previously.12b The water soluble
methanesulfonate salt of 1a was prepared and crystallised
from acetone to give 12.8 g of white solid. A sample of the
more crystalline hydrochloride salt of 1a was prepared and
crystallised from isopropanol as fine needles. Subsequent re-
crystallisation from isopropanol resulted in rosettes from a
relatively concentrated solution, while slow crystallisation
from more dilute solutions gave small prisms suitable for
X-ray crystallography as a hydrate of the hydrochloride salt.
The hydrochloride salt of 1c crystallised as the ether solvate.
There are two crystallographically independent molecules
in the crystal structures of both 1a and 1c but only one of
each is shown for clarity (Fig. 2). The two independent mole-
cules have very different conformations in both structures.
They differ significantly in the relative orientations of the
phenoxypropyl groups at C23 with respect to N-methyl acet-
amidide (1a) and ethylmethoxy (1c) substituents on N1. Re-
finement of both (R) and (S) forms was carried out and the
absolute structural parameter, R-factor and standard uncer-
tainties on the bond lengths were best for the (S) form. There-
fore, the stereochemistry was determined to be (S) at C28 and
C280 for 1a and 1c (Fig. 2).
were recorded on an Optical Activity AA-1000 polarimeter.
High resolution mass spectra (HRMS) were recorded on an
Applied Biosystems Inc Mariner (TOF) instrument, error limit
<5 ppm. HPLC analyses were recorded on a Perkin Elmer
Integral 4000 Quaternary HPLC system with UV detection
or a Perkin Elmer Series 200 HPLC system with 200 Diode
Array detectors. Chiralpak AD or Chiracel OD (Daical) columns
(250ꢂ4.6 mm) were used for enantiomeric ratio determinations
and Max RP C12 (Phenomenex) columns (150ꢂ4.6 mm, 4 mm)
or Xterra RP C18 (Waters) columns (100ꢂ4.6 mm, 5 mm) for
purity determinations. The (S) enantiomers were eluted first on
the Chiralpak AD column (isohexane/isopropanol/diisopropyl-
ethyalamine 80/20/0.1), but the order of elution was reversed
on the Chiracel OD columns. Gas chromatographic (GC) anal-
ysis was carried out using a b-cyclodextrin dimethyl column
(30ꢂ0.32 mm, oven temperature 75 ꢁC) on a Agilent GC
6890 instrument with FID detector and ChemStation software.
Thin layer chromatography (TLC) was carried out using
Kieselgel 60 F254 aluminium backed plates (Merck). Matrix
silica gel, particle size 0.040e0.063 mm, was used for column
chromatography. Solvents used were of commercial grades
from either Aldrich or BDH and used without further purifica-
tion. Petrol refers to petroleum ether 40e60 ꢁC fraction.
4.2. (R)-3-Hydroxy-4-methyl-methylpentanoate (7)18
(S)-BINAP (2.5 g, 4.02 mmol) and bis-(2-methylallyl)cy-
cloocta-1,5-diene ruthenium (1.25 g, 3.91 mmol) were sus-
pended in de-gassed acetone (1 L). After stirring for 5 min,
0.29 M HBr in methanol (34.4 mL, 8.44 mmol) was added
and the mixture stirred at room temperature for 1 h to give a
dark brown solution. Acetone was removed under reduced pres-
sure and a de-gassed solution of methyl isobutyrylacetate 6
(60.0 g, 0.42 mol) in methanol (800 mL) was added. This
mixture was heated at 60 ꢁC under hydrogen (1 atm) for 18 h.
Methanol was removed under reduced pressure and the residue
digested with a mixture of petrol/ethyl acetate (200 mL, 1/1).
After filtering off the catalyst residue, the filtrate was concen-
trated and then filtered through silica gel (1 kg), eluting with
petrol/ethyl acetate (1/1) to give (R)-3-hydroxy-4-methyl-
methylpentanoate 7, as an orange liquid, (65.1 g, 99%). Enan-
tiomeric ratio by chiral GC >98:2. Lit.18 [a]D ꢀ43.9 (c 1.00,
CHCl3) for other enantiomer; [a]D þ37.1 (CHCl3). IR (thin
film) 3472, 2961, 1736, 1439, 1369, 1279, 1171, 1055, 996,
The benzimidazolone group is approximately perpendicular
to the mean plane of the piperidine ring and both substituents
on the piperidine ring are in equatorial positions.
3. Conclusion
We have developed an asymmetric synthetic route towards
a potential development candidate acting at the NOP receptor.
The route utilises a Noyori asymmetric reduction to chiral
alcohol 5 followed by inversion of the stereocentre by means
of Mitsunobu coupling to give excellent enantiomeric purity.
The methodology was applied to a series of piperidinyl-benz-
imidazolones suitable for medium scale production to support
early development studies. The desired (S) configuration was
confirmed by X-ray crystallography.
1
880, 847 cmꢀ1. H NMR (CDCl3): d 0.93 (3H, d, J¼6.5 Hz),
0.96 (3H, d, J¼6.5 Hz), 1.71 (1H, m), 2.41 (2H, dd, J¼9.5
and 16.5 Hz), 2.51 (2H, dd, J¼4.0 and 16.5 Hz), 2.80 (1H, d,
J¼4.0 Hz), 3.72 (3H, s), 3.78 (1H, m). 13C NMR (CDCl3):
d 17.7, 18.4, 33.2, 38.3, 51.8, 72.7, 173.9. HRMS (TOF)
(MþH)þ calculated for C7H15O3: 147.1016, found: 147.1013.
4. Experimental section
4.1. Materials and methods
NMR spectra were recorded using a Bruker DPX 400 or
DRX 400 instrument with tetramethylsilane as an internal
standard. The chemical shifts are reported in d values (parts
4.3. (R)-4-Methylpentan-1,3-diol (8)19
1
per million). The following notations are used for H NMR
A 1 M solution of lithium aluminium hydride in THF
(445 mL, 0.45 mol) was added over 40 min to a solution of
(R)-3-hydroxy-4-methyl-methylpentanoate 7 (65.0 g, 0.44 mol)
in THF (600 mL) cooled with an ice/methanol bath. The
signal patterns: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad. IR spectra were recorded on a Perkin
Elmer Spectrum 1000 FT-IR spectrometer. Optical rotations

J.K. Clark et al. / Tetrahedron 64 (2008) 3119e3126
3123
mixture was stirred at room temperature for 30 min and then
for 20 min at 40 ꢁC. Cautious addition of water (17 mL) to
the cooled reaction mixture was followed by the addition of
4 N NaOH (17 mL) and then further by water (51 mL). The
inorganic precipitate was filtered off through Celite and further
extracted with warm ethyl acetate/dichloromethane mixture
(600 mL, 2/1). Solvents were removed from the combined ex-
tracts and the residue dissolved in dichloromethane and dried
over sodium sulfate. Removal of solvents at reduced pressure
gave (R)-4-methylpentan-1,3-diol 8 as a clear liquid (46.0 g,
87%). [a]D þ13.5 (CHCl3). IR (thin film) 3306, 2959, 1469,
ether/heptane to precipitate further triphenylphosphine oxide
on cooling. The crude residue from the filtrate was then chro-
matographed on silica gel (720 g), eluting with a gradient of
petrol/ethyl acetate 6/1 to 3/1. (S)-Methanesulfonic acid
3-(5-methoxy-2-methyl-phenoxy)-4-methyl-pentyl ester 2 was
obtained as a yellow liquid (23.3 g, 40%). (It was found to
contain 15% 4-methyl-pent-3-en-1-ol 1-methanesulfonate 9.)
[a]D ꢀ24.6 (CHCl3, impure). IR (thin film) 2965, 2838,
1698, 1613, 1589, 1506, 1468, 1421, 1355, 1284, 1260,
1197, 1176, 1129, 1112, 1041, 973, 817 cmꢀ1 1H NMR
.
(CDCl3): d 0.95 (3H, d, J¼7.0 Hz), 0.97 (3H, d, J¼7.0 Hz),
2.03e2.11 (3H, m), 2.14 (3H, s), 2.86, (3H, s), 3.77 (3H, s),
4.22e4.33 (2H, m), 4.36e4.42 (1H, m), 6.38 (1H, dd, J¼2.5
and 8.0 Hz), 6.44 (1H, d, J¼2.5 Hz), 7.02 (1H, d, J¼
2.5 Hz). 13C NMR (CDCl3): d 15.7, 17.3, 18.0, 30.1, 30.6,
37.0, 55.4, 67.3, 80.4, 100.1, 103.9, 119.5, 131.0, 157.0,
158.4. HRMS (TOF) (MþH)þ calculated for C15H25O5S:
317.1417, found: 317.1411.
1
1386, 1368, 1139, 1053, 973, 958, 891, 843 cmꢀ1. H NMR
(CDCl3): d 0.92 (3H, d, J¼7.0 Hz), 0.94 (3H, d, J¼7.0 Hz),
1.65e1.71 (3H, br m), 2.42 (1H, br s), 2.57 (1H, br s), 3.61
(1H, br s), 3.80e3.92 (2H, br m). 13C NMR (CDCl3): d
17.6, 18.4, 34.0, 35.0, 62.3. HRMS (TOF) (MþH)þ calculated
for C6H15O2: 119.1067, found: 119.1073 (error 5.5 ppm, due
to poor ionisation).
4.4. (R)-Methanesulfonic acid 3-hydroxy-4-methyl-pentyl
ester (5)12c
4.6. 2-(3-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-
pentyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-benzimidazol-
1-yl)-N-methyl-acetamide methanesulfonate (1a)
(R)-4-Methylpentan-1,3-diol 8 (46.0 g, 0.39 mol) was dis-
solved in dichloromethane (400 mL), cooled with an ice/
methanol bath and diisopropylethylamine (68.0 mL, 0.39 mol)
added. A solution of methanesulfonyl chloride (30.0 mL,
0.39 mol) in dichloromethane (200 mL) was added over 1 h.
The reaction mixture was then poured into ice cold water
(300 mL), the layers separated and the organic layer washed
with chilled water and then with brine. Removal of solvent
after drying with sodium sulfate gave the crude product, which
was filtered through a silica gel column (450 g), eluting with
petrol/ethyl acetate 3/2. (R)-Methanesulfonic acid 3-hy-
droxy-4-methyl-pentyl ester 5 was obtained as a pale yellow
oil (64.4 g, 84%). [a]D þ41.4 (CHCl3). IR (thin film) 3544,
3025, 2964, 2877, 1470, 1351, 1174, 1144, 1094, 1057, 953,
A mixture of (S)-methanesulfonic acid 3-(5-methoxy-2-
methyl-phenoxy)-4-methyl-pentyl ester 2 (17.2 g, 54.4 mmol,
purity w85%), N-methyl-2-(2-oxo-3-piperidin-4-yl-2,3-dihy-
dro-benzimidazol-1-yl)-acetamide 12a12b (16.5 g, 57.2 mmol),
diisopropylethylamine (12.5 mL, 71.7 mmol) and sodium io-
dide (0.5 g, 3.33 mmol) was heated at reflux in acetonitrile
(350 mL) for 10 h. After filtering off a small quantity of
insoluble material, acetonitrile was removed under reduced
pressure and the residue partitioned between water and di-
chloromethane. The organic layer was washed with water
and then with brine and dried over sodium sulfate. The crude
product (32.0 g) was chromatographed on silica gel (1.0 kg),
eluting with dichloromethane and then a gradient of 2%
ethanol increasing to 5%. 2-(3-{1-[3-(5-Methoxy-2-methyl-
phenoxy)-4-methyl-pentyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-
benzimidazol-1-yl)-N-methyl-acetamide 1a was obtained as
viscous gum (13.0 g, 66 %). Purity 97.7% by HPLC (Pheno-
menex RP18 column, 15 cmꢂ0.46 cm, 5 mm, 230 nm, flow
1 mL/min, 30 ꢁC; mobile phase: A¼waterþ0.1% formic
acid, B¼acetonitrileþ0.1% formic acid; gradient of A/B 95/
5 for 5 min then increased to 10/90 over 8 min followed by
5 min at 10/90); enantiomeric ratio 100:0 by chiral HPLC
(Chiralpak AD column, 25 cmꢂ0.46 cm, flow 1 mL/min,
30 ꢁC; mobile phase: isohexane/isopropanol/diethylamine 80/
20/0.1). [a]D ꢀ6.3 (methanol), [a]D ꢀ41.3 (CHCl3). IR
(CH2Cl2) 3684, 3601, 3445, 3356, 2962, 2812, 1698, 1613,
1588, 1536, 1504, 1492, 1468, 1340, 1318, 1196, 1163,
914, 850, 813 cmꢀ1 1H NMR (CDCl3): d 0.94 (6H, d,
.
J¼7.0 Hz), 1.62e1.78 (3H, m), 1.91e2.0 (1H, m), 3.02 (3H,
s), 3.52e3.59 (1H, m), 4.35e4.40 (1H, s), 4.43e4.49 (1H,
m). 13C NMR (CDCl3): d 17.3, 18.5, 33.3, 33.9, 37.2, 68.0,
72.3. HRMS (TOF) (MþH)þ calculated for C7H17O4S:
197.0842, found: 197.0842.
4.5. (S)-Methanesulfonic acid 3-(5-methoxy-2-methyl-
phenoxy)-4-methyl-pentyl ester (2)
Triphenylphosphine (39.3 g, 0.15 mol), 5-methoxy-2-methyl-
phenol20 4 (20.7 g, 0.15 mol) and (R)-1-methanesulfonyl-
oxy-4-methyl-pentan-3-ol 5 (29.4 g, 0.15 mol) were added to
dry toluene (250 mL) and the solution cooled to 5 ꢁC. A
solution of diisopropyl azodicarboxylate (DIAD) (30.3 g,
0.15 mol) in toluene was added over 90 min, maintaining the
temperature below 10 ꢁC. The solution was then left at room
temperature overnight. The precipitated triphenylphosphine
oxide was filtered off and the filtrate washed with water, dilute
sodium hydroxide solution, water and finally brine. Toluene
was removed under reduced pressure and replaced with diethyl
1
1228, 1112, 1016, 997, 837 cmꢀ1. H NMR (CDCl3): d 0.97
(3H, d, J¼7.0 Hz), 1.00 (3H, d, J¼7.0 Hz), 1.75e1.87 (4H,
m), 1.96e2.05 (1H, m), 2.05e2.17 (2H, m), 2.16 (3H, s),
2.38e2.54 (4H, m), 2.79 (3H, d, J¼5.0 Hz), 2.98 (1H, br d,
J¼12.0 Hz), 3.10 (1H, br d, J¼12.0 Hz), 3.76 (3H, s), 4.25
(1H, dd, J¼5.0 and 11.5 Hz), 4.33e4.42 (1H, m), 4.50 (2H,
s), 6.13 (1H, br s), 6.36 (1H, dd, J¼2.5 and 8.0 Hz), 6.63

3124
J.K. Clark et al. / Tetrahedron 64 (2008) 3119e3126
(1H, d, J¼2.5 Hz), 7.02 (1H, d, J¼8.0 Hz), 7.04e7.14 (3H,
m), 7.35 (1H, m). 13C NMR (CDCl3): d 15.8, 17.9, 18.0,
26.3, 28.0, 29.2, 29.4, 31.2, 45.3, 51.6, 52.8, 53.7, 54.8,
55.3, 80.3, 100.8, 102.9, 108.3, 110.3, 119.7, 121.5, 122.0,
128.3, 129.0, 130.6, 153.9, 157.9, 158.8, 167.9. HRMS
(TOF) (MþH)þ calculated for C29H41N4O4: 509.3122, found:
509.3107.
J¼12.5 and 4.2 Hz), 2.84 (2H, t, J¼12.2 Hz), 4.29 (2H, m),
4.47 (1H, tt, J¼4.1 and 12.3 Hz), 5.21 (2H, s), 7.05e7.14
(3H, m), 7.19e7.24 (1H, m), 8.06 (1H, br s), 12.5 (1H, br s).
13C NMR (CD3OD): d 28.7 (3C), 30.1 (2C), 38.7, 43.8e45.3
(br, 2C), 52.9, 81.3, 109.7, 110.1, 122.5, 122.8, 129.7, 130.3,
146.0e147.5 (br, 2C), 155.1, 156.4. (Note: in this CD3OD
spectrum, the triazole carbons are weak and broad, while in
a CDCl3 spectrum they are not detected. In both solvents,
the 13C peaks for the carbons ortho to the piperidine nitrogen
are broad due to restricted rotation of the carbamate group.)
HRMS (TOF) (MþH)þ calculated for C20H27N6O3:
399.21236, found: 399.21391.
The above Boc protected product (11b) was deprotected
with TFA treatment and evaporated to dryness to give 12b.
This crude bis-TFA salt was reacted directly with the mesylate
5. Attempted isolation of the free base resulted in negligible
recovery due to high water solubility.
The above free base 1a (13.0 g, 25.5 mmol) was converted
to the methanesulfonate salt by treatment with methane-
sulfonic acid (2.45 g, 25.5 mmol) in dichloromethane. The
solvent was removed under reduced pressure, replaced with
acetone, taken to low volume and a small volume of diethyl
ether added to give a crystalline solid. A second crystallisation
from acetone gave 2-(3-{1-[3-(5-methoxy-2-methyl-phenoxy)-
4-methyl-pentyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-benzimid-
azol-1-yl)-N-methyl-acetamide methanesulfonate as a white
solid (12.8 g, 83%). Purity by HPLC 99.5%, enantiomeric ra-
tio by chiral HPLC 100:0. [a]D þ27.8 (methanol), [a]D þ7.0
(CHCl3). IR (KBr) 3286, 2964, 2687, 1704, 1613, 1588, 1496,
1467, 1412, 1284, 1260, 1196, 1162, 1128, 1040, 999, 956,
4.8. 1-{1-[(S)-3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-
pentyl]-piperidin-4-yl}-3-(4H-1,2,4-triazol-3-ylmethyl)-
1,3-dihydro-benzimidazol-2-one methanesulfonate (1b)
1
926, 835, 772, 751, 737, 700, 656, 613, 553, 526 cmꢀ1. H
NMR (CD3OD): d 1.01 (3H, d, J¼6.5 Hz), 1.05 (3H, d, J¼
6.5 Hz), 2.02e2.19 (6H, m), 2.16 (3H, s), 2.70 (3H, s), 2.76
(3H, s), 2.73e2.84 (2H, m), 3.18e3.32 (4H, m), 3.69e3.78
(2H, m), 3.76 (3H, s), 4.26 (1H, dd, J¼6.0 and 11.0 Hz),
4.54 (2H, s), 4.53e4.61 (1H, m), 6.43 (1H, dd, J¼2.5 and
8.0 Hz), 6.52 (1H, d, J¼2.5 Hz), 7.04 (2H, m), 7.09 (2H,
m), 7.32 (1H, d, J¼8.0 Hz), 12.5 (1H, br s). 13C NMR
(CDCl3): d 15.4, 17.3, 17.5, 24.7, 25.4, 25.8, 30.0, 39.8,
43.0, 47.2, 51.3, 53.1, 55.0, 78.4, 100.1, 104.3, 108.4, 108.5,
118.3, 120.8, 120.8, 127.6, 129.6, 130.7, 152.8, 156.4,
158.6, 166.9.
Prepared in a similar manner to 1a using 12b in place of
12a, but using 3 equiv of diisopropylamine: purity by HPLC
98.68%, enantiomeric ratio 100:0. [a]D þ26.7 (methanol).
IR (KBr) 3407, 2962, 2644, 1694, 1612, 1589, 1506, 1493,
1409, 1320, 1283, 1259, 1196, 1162, 1128, 1111, 1040,
1000, 978, 955, 834, 795, 752, 700, 635, 600 cmꢀ1 1H
.
NMR (CD3OD): d 1.02 (3H, d, J¼6.5 Hz), 1.05 (3H, d, J¼
6.5 Hz), 2.02e2.24 (5H, m), 2.16 (3H, s), 2.89 (2H, dq,
J¼3.5 and 13.0 Hz), 3.25 (2H, br t, J¼13.0 Hz), 3.26e3.34
(2H, m), 3.72e3.81 (2H, m), 3.76 (3H, s), 4.37 (1H, q,
J¼5.5 Hz), 4.64 (1H, tt, J¼4.0 and 12.5 Hz), 5.32 (2H, s),
6.42 (1H, dd, J¼2.5 and 8.0 Hz), 6.53 (1H, d, J¼2.0 Hz),
7.02 (1H, d, J¼9.0 Hz), 7.08e7.13 (2H, m), 7.13e7.18 (1H,
m), 7.44 (1H, d, J¼7.5 Hz), 8.92 (1H, s). 13C NMR (D2O):
d 14.7, 16.5, 17.2, 24.9, 26.1 (2C), 30.3, 37.5, 48.4, 52.1,
52.3, 54.2, 55.5 (2C), 80.3, 101.0, 105.6, 108.8, 109.3,
120.3, 122.11, 122.2, 127.6, 128.5, 131.4, 145.4, 154.1,
156.4, 156.9, 158.1. HRMS (TOF) (MþH)þ calculated for
C29H39N6O3: 519.3078, found: 519.3061.
4.7. 4-[2-Oxo-3-(4H-[1,2,4]triazol-3-ylmethyl)-2,3-dihydro-
benzimidazol-1-yl]-piperidine-1-carboxylic acid tert-butyl
ester (11b)
A magnetically stirred solution of 10 (4.99 g, 15.7 mmol) in
anhydrous N,N-dimethylformamide (50 mL) was treated with
sodium hydride (60% dispersion in mineral oil, 0.63 g,
15.7 mmol) added portion-wise under a nitrogen atmosphere.
The reaction mixture was stirred for 1 h to give a colourless solu-
tion. N-Formyl-2-chloroacetamidrazone22 (1.78 g, 15.7 mmol)
in anhydrous N,N-dimethylformamide (5.0 mL) was added
dropwise with cooling to maintain ambient temperature and
the resultant mixture stirred overnight. The intermediate
product was not isolated, but ring closure was effected by
heating the reaction mixture in N,N-dimethylformamide at
140 ꢁC for 1 h. The resulting mixture was chromatographed
on silica gel with a gradient elution with dichloromethane/
ethanol 98/2 to 94/6 to give the title compound as a yellow
gum in 27% yield. ESI m/z¼399.3 [MþH]þ. IR (KBr) 3366,
3070, 2978, 2934, 2852, 1689, 1618, 1606, 1493, 1438,
1414, 1367, 1345,1315, 1274, 1240, 1192, 1160, 1137,
1076, 1064, 1048, 1018, 998, 985, 944, 870, 858, 830, 808,
4.9. 1-(2-Methoxy-ethyl)-3-{1-[(S)-3-(5-methoxy-2-methyl-
phenoxy)-4-methyl-pentyl]-piperidin-4-yl}-1,3-dihydro-
benzimidazol-2-one methanesulfonate (1c)
The N-methoxyethyl derivative 1c was prepared prior to the
development of the described chiral synthetic route and the
racemate obtained by direct alkylation of the coupled benz-
imidazole (1d) with 2-bromoethyl methyl ether as the final
step.12b Separation of enantiomers was achieved by chiral
HPLC. Thus 6.5 g of racemic material was separated over sev-
eral runs on a Chiralpak AD (250ꢂ20 mm) column, eluting
with isohexane/isopropanol 9/1, 2.63 g, 5.31 mmol of the first
eluting (S)-enantiomer was obtained and converted to the
methanesulfonate salt by treatment with methanesulfonic
acid (510 mg, 5.31 mmol). Crystallisation from acetone/ether
754, 736, 687, 661, 641, 604 cmꢀ1
.
1H NMR (CDCl3):
d 1.50 (9H, s), 1.78 (2H, d, J¼12.5 Hz), 2.31 (2H, dq,

J.K. Clark et al. / Tetrahedron 64 (2008) 3119e3126
3125
gave 1-(2-methoxy-ethyl)-3-{1-[(S)-3-(5-methoxy-2-methyl-
phenoxy)-4-methyl-pentyl]-piperidin-4-yl}-1,3-dihydro-benz-
imidazol-2-one methanesulfonate 1c as a white solid (2.51 g,
4.24 mmol) in 79.8% yield. Purity by HPLC 99.03%, enantio-
meric ratio by chiral HPLC 100:0. [a]D þ6.4 (CHCl3). IR
(KBr) 3449, 2964, 2938, 2900, 2835, 2677, 2582, 1692,
1614, 1589, 1505, 1496, 1428, 1405, 1368, 1327, 1280,
1257, 1234, 1197, 1130, 1073, 1059, 1032, 993, 976, 960,
930, 896, 844, 804, 768, 743, 700, 645, 591,572, 553, 535,
positions and refined using a riding model with riding isotropic
displacement parameters. Aqua hydrogen atoms for 1a were
found in the difference Fourier map and during refinement,
˚
the OeH distance was restrained to 0.9(5) A. Crystallographic
data for 1a and 1c have been deposited with the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 IEZ, UK as CCDC reference numbers 658438 and
658439, respectively.
523, 507 cmꢀ1
.
1H NMR (CD3OD): d 1.02 (3H, d, J¼
Acknowledgements
7.0 Hz), 1.06 (3H, d, J¼7.0 Hz), 2.05e2.20 (5H, m), 2.16
(3H, s), 2.71 (3H, s), 2.74e2.89 (2H, dq, J¼2.5 and
13.0 Hz), 3.23 (2H, t, J¼17.8 Hz), 3.30 (3H, s), 3.30e3.32
(3H, m), 3.67 (2H, t, J¼5.2 Hz), 3.76 (3H, s), 4.06 (2H, t,
J¼5.2 Hz), 4.35 (1H, q, J¼5.5 Hz), 4.58 (1H, tt, J¼4.2 and
12.0 Hz), 6.42 (1H, dd, J¼2.3 and 8.0 Hz), 6.52 (1H, br s),
7.04 (1H, d, J¼8.0 Hz), 7.10e7.15 (2H, m), 7.20e7.24 (1H,
m), 7.31 (1H, br s). 13C NMR (CDCl3): d 15.8, 17.1, 18.3,
24.9, 26.0, 26.1, 30.5, 39.4, 41.4, 47.4, 52.2, 53.6, 55.2,
55.4, 59.0, 70.4, 79.1, 100.0, 104.3, 108.6, 110.4, 119.2,
121.6, 122.0, 126.9, 129.7, 131.2, 153.6, 156.3, 158.9. HRMS
(TOF) (MþH)þ calculated for C29H41N3O4: 496.3151, found:
496.3169.
The authors thank Robert Roy, Christelle Lamazzi, Patrick
Carlier, Christine Flouzat and Rob ter Halle for the helpful
discussions during development of this synthetic route.
References and notes
1. (a) Reinscheid, R. K.; Nothacker, H. P.; Bourson, A.; Ardati, A.;
Henningsen, R. A.; Bunzow, J. R.; Grandy, D. K.;Langen, H.; Monsma, F. J.;
Civelli, O., Jr. Science 1995, 270, 792; (b) Meunier, J.-C.; Mollereau, C.;
Toll, L.; Suaudeau, C.; Moisand, C.; Alvinerie, P.; Butour, J. L.;
Guillemot, J. C.; Fexrara, P.; Monsarrat, B.; Mazarguil, H.; Vussart, G.;
Parmentier, M.; Costentin, J. Nature 1995, 377, 532; (c) Grisel, J. E.;
Mogil, J. S. Peptides 2000, 21, 1037.
2. (a) Meunier, J.-C. Exp. Opin. Ther. Patents 2000, 10, 371 and references
therein; (b) Calo, G.; Guerrini, R.; Rizzi, A.; Salvadori, S.; Regoli, D.
Br. J. Pharmacol. 2000, 129, 1261 and references therein; (c) Allen,
C. N.; Jiang, Z.-G.; Teshima, K.; Darland, T.; Ikeda, M.; Nelson, C. S.;
Quigley, D. I.; Yoshioka, T.; Allen, R. G.; Rea, M. A.; Grandy, D. K.
J. Neurosci. 1999, 19, 2152.
3. Mogil, J. S.; Pasternak, G. W. Pharmacol. Rev. 2001, 53, 381.
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1999, 17, 164; (b) Jelinek, G. A. BMJ 2000, 321, 1236.
4.10. X-ray structural determination of 1a and 1c
Compound 1a was dissolved in methanol and 1 M HCl in
diethyl ether added to cause precipitation of a white solid.
The solid was filtered and washed with diethyl ether. The solid
was then dissolved in hot isopropanol and left to stand to give
fine colourless needles. A colourless crystal of 1aCl$2(H2O),
˚
˚
space group P21, a¼9.608(2) A, b¼30.059(5) A, c¼
5. Lotsch, J.; Dudziak, R.; Freynhagen, R.; Marschner, J.; Geisslinger, G.
¨
Clin. Pharmacokinet. 2006, 45, 1051.
3
ꢁ
˚
˚
10.868(2) A, b¼100.970(10) , V¼3081.4(10) A , was coated
in Nujol and vacuum grease and then mounted on glass fibres.
Final R indices [I>2s(I), 4920 data] R1¼0.0473, wR2¼
0.1191; R indices (all data, 5760) R1¼0.0621, wR2¼0.1319;
absolute structural parameter ꢀ0.03(9); largest diff. peak and
6. Waller, S. L.; Bailey, M. Lancet 1987, 2, 801.
7. (a) Ronzoni, S.; Peretto, I.; Giardina, G. A. M. Exp. Opin. Ther. Patents
2001, 11, 525; (b) Bignan, G. C.; Connolly, P. J.; Middleton, S. A. Exp.
Opin. Ther. Patents 2005, 15, 357; (c) Zaveri, N. Life Sci. 2003, 73,
663; (d) Barlocco, D.; Toma, L.; Cignarella, G. Mini-Rev. Med. Chem.
2001, 1, 363.
8. (a) 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; (b) Ozaki, S.; Kawamoto, H.; Itoh, Y.; Miyaji, M.; Iwasawa, Y.;
Ohta, H. Eur. J. Pharmacol. 2000, 387, R17; (c) Kawamoto, H.; Ozaki, S.;
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Giardina, G. A. M. Bioorg. Med. Chem. 2001, 9, 1871.
ꢀ3
˚
hole 0.272 and ꢀ0.348 e A
.
Compound 1c was dissolved in methanol and 1 M HCl in
diethyl ether added to cause precipitation of a white solid.
The solid was filtered and washed with diethyl ether. The solid
was then dissolved in acetone and diethyl ether added giving
fine colourless needles on standing. A colourless crystal of
˚
1cCl$0.5(C4H10O), space group P21, a¼8.401(5) A, b¼
3
ꢁ
˚
˚
˚
31.656(5) A, c¼11.955(5) A, b¼98.756(5) , V¼3142(2) A ,
was coated in Nujol and vacuum grease and then mounted
on glass fibres. Final R indices [I>2s(I), 4530 data] R1¼
0.0539, wR2¼0.1368; R indices (all data, 5854) R1¼0.0762,
wR2¼0.1547; absolute structural parameter ꢀ0.10(9); largest
9. (a) Wichmann, J.; Adam, G.; Rover, S.; Hennig, M.; Scalone, M.; Cesura,
A. M.; Dautzenburg, F. M.; Jenck, F. Eur. J. Med. Chem. 2000, 35, 839;
(b) Jenck, F.; Wichmann, J.; Dautzenburg, F. M.; Moreau, J.-L.; Ouagaz-
zal, A. M.; Martin, J. R.; Lundstrom, K.; Cesura, A. M.; Poli, S. M.;
Rover, S.; Kolczewski, S.; Adam, G.; Kilpatrick, G. J. Proc. Natl. Acad.
Sci. U.S.A. 2000, 97, 4938.
10. Thomsen, C.; Hohlweg, R. Br. J. Pharmacol. 2000, 131, 903.
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C.; Malherbe, P.; Kilpatrick, G. J.; Jenck, F. J. Pharmacol. Exp. Ther.
2001, 298, 812.
ꢀ3
˚
diff. peak and hole 0.381 and ꢀ0.302 e A
.
Diffraction data were measured at 160(2) K on a Bruker
AXS P4 four-circle diffractometer23 fitted with graphite-
˚
monochromated Mo Ka radiation, 0.71073 A. Semiempirical
absorption corrections by f-scans were applied. Structural so-
lution and refinements (full-matrix least-squares on F2) were
performed using the SHELXTL 5.1 suite of programs.24 All
hydrogen atoms except aqua were constrained to idealised
12. (a) Palin, R.; Barn, D. R.; Clark, J. K.; Cottney, J. E.; Cowley, P. M.;
Crockatt, M.; Evans, L.; Feilden, H.; Goodwin, R. R.; Griekspoor, F.;
Grove, S. J. A.; Houghton, A. K.; Jones, P. S.; Morphy, R. J.; Smith,
A. R. C.; Sundaram, H.; Vrolijk, D.; Weston, M. A.; Wishart, G.; Wren,

3126
J.K. Clark et al. / Tetrahedron 64 (2008) 3119e3126
P. Bioorg. Med. Chem. Lett. 2005, 15, 589; (b) Palin, R.; Bom, A.; Clark,
J. K.; Evans, L.; Feilden, H.; Houghton, A. K.; Jones, P. S.; Montgomery,
18. Albert, A.; Seebach, D.; Duchardt, E.; Schwalbe, H. Helv. Chim. Acta
2002, 85, 633.
B.; Weston, M. A.; Wishart, G. Bioorg. Med. Chem. 2007, 15, 1828; (c)
Cowley, P. M.; Cottney, J.; Barn, D. R.; Morphy, J. R.; Palin, R.; Grove,
S. J. A. PCT Int. Application, WO 2002100861, 2002.
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Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856.
20. 2-Methyl-5-methoxy phenol was prepared according to Ram, S.; Spicer,
L. D. Tetrahedron Lett. 1988, 29, 3741.
13. (a) Mitsunobu, O. Synthesis 1981, 1; (b) Hughes, D. L. Org. React. 1992,
42, 335; (c) Hughes, D. L. Org. Prep. 1996, 28, 127.
21. The yield can be increased to 44% with only 4% of the isoprenyl
by-product when ADDP is used in place of DIAD and added over 2 h.
See: (a) Lipshutz, B. H.; Chung, D. W.; Rich, B.; Corral, R. Org.
Lett. 2006, 8, 5069; (b) Lepore, S. D.; He, Y. J. Org. Chem. 2003, 68,
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14. Genet, J. P.; Ratovelomanana-Vidal, V.; Cano de Andrade, M. C.; Pfister,
X.; Guerreiro, P.; Lenoir, J. Y. Tetrahedron Lett. 1995, 36, 4801.
15. (a) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Org. Synth.
1993, 71, 1; (b) Kitamura, M.; Hsiao, Y.; Ohta, M.; Tsukamoto, M.;
Ohta, T.; Takaya, H.; Noyori, R. J. Org. Chem. 1994, 59, 297; (c) Kita-
mura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.; Akutagawa,
S.; Ohta, T.; Takaya, H.; Noyori, R. J. Am. Chem. Soc. 1988, 110, 629.
16. Noyori, R.; Ohta, M.; Hsiao, Y.; Kitamura, M.; Ohta, T.; Takaya, H. J. Am.
Chem. Soc. 1986, 108, 7117.
22. Ladduwahetty, T.; Baker, R.; Cascieri, M. A.; Chambers, M. S.;
Haworth, K.; Keown, L. E.; MacIntyre, J. M.; Owen, S.; Rycroft, W.;
Sadowski, S.; Seward, E. M.; Shepheard, S. L.; Swain, C. J.; Tattersall,
F. D.; Watt, A. P.; Williamson, D. W.; Hargreaves, R. J. J. Med. Chem.
1996, 39, 2907.
17. The chloride analogue of the catalyst, [(S)-BINAP]RuCl2, is now commer-
cially available from Strem Chemicals Inc., 7 Mulliken Way, Newbury-
port, MA 01950e4098; www.strem.com.
23. XSCANS Version 2.2; Bruker AXS: Madison, WI, 1996.
24. Sheldrick, G. M. SHELXTL 5.1. Version 5.1; Bruker AXS: Madison,
Wisconsin, USA, 1999.