Synthesis of the optical isomers of a new anticholinergic drug, penehyclidine hydrochloride (8018)

Article abstract of DOI:10.1016/j.bmcl.2005.02.071

A practical diastereoselective synthetic method for 8018 enantiopure isomers is described. The intramolecular asymmetric epoxidation of mono-sulfonate 4 was applied for the execution of the synthesis of the key chiral building block for the first time. The isomers were obtained with 70-76% yields in 99-100% ee.

Full text of DOI:10.1016/j.bmcl.2005.02.071

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1979–1982
Synthesis of the optical isomers of a new anticholinergic drug,
penehyclidine hydrochloride (8018)
Xiang-Yu Han,* He Liu, Chun-He Liu, Bo Wu, Lan-Fu Chen,
Bo-Hua Zhong and Ke-Liang Liu
No. 7 Department, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China
Received 16 December 2004; revised 21 February 2005; accepted 23 February 2005
Abstract—A practical diastereoselective synthetic method for 8018 enantiopure isomers is described. The intramolecular asymmetric
epoxidation of mono-sulfonate 4 was applied for the execution of the synthesis of the key chiral building block for the first time. The
isomers were obtained with 70–76% yields in 99–100% ee.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Furthermore, many other muscarinic receptor antago-
nists were reported in recent years.5 So there are still
many developing rooms in searching for better chiral
selective muscarinic receptor antagonists with new
molecular structures.
The design, development, and marketing of new chiral
drugs are now a major theme in the drug chirality re-
search and industry.1 The awareness and interest in
the stereochemistry of drug action have increased, and
the worldwide sales of chiral drugs in single-enantiomer
form continued to grow. In January 1996, the FDA an-
nounced it would consider further incentives for devel-
oping single isomer drugs, owing to their better
pharmacokinetics prosperity, safety, and tolerability.2
Over the past century classical anticholinergic drugs
have been widely used for the treatment of certain dis-
eases, such as chronic obstructive pulmonary diseases
(COPD), AlzheimerÕs disease (AD), and urinary inconti-
nence (UI). However, their therapeutic applicability was
limited, due to side effects in both the peripheral and
central nervous system. For example, oxybutynin
(Ditropan),3 a widely prescribed muscarinic receptor
antagonist for the treatment of urinary incontinence, ex-
hibit classical antimuscarine side effects, such as dry
mouth. However, another chiral drug candidate, J-
104129,4 a highly potent, orally active, long acting,
M1/M3 selective antagonist with lower side effects and
as such is being investigated for the treatment of COPD.
Our groups have engaged in the synthesis and biological
activity studies of anticholinergic drugs for many years.6
And in this process, we found that penehyclidine hydro-
chloride (8018), a new anticholinergic drug, had both
antimuscarinic and antinicotinic activities and retained
potent central and peripheral anticholinergic activities.7
Recently, the clinic results demonstrated that 8018 had
good curative effect for the pesticides poison of organic
phosphorus and soman. Other than the anticholinergic
effects to soman, 8018 could accelerate the elimination
of P(À)soman in the rabbits blood and reduced the dis-
tribution of P(À)soman in the mice diaphragm. More-
over, it could significantly increase bound [3H]soman
distribution in small intestine as well as in plasma.8
The receptor binding assay showed that this compound
had far greater selectivity for M3 over M1 receptor sub-
type, which makes it has potentially use in the treatment
of respiratory disorders such as COPD. Similarly, this
kind of racemic compound has also exhibited side effects
as classical antimuscarinic drugs in clinical.
Differing from the majority of muscarinic receptor
antagonists9 composed of a tertiary a-hydroxy acid ester
bond, 8018 is composed of an ether bond as a linkage
that connected the two parts, that is, tertiary a-hydroxyl
structure and the azepine base substituent (Fig. 1).
Keywords: Asymmetric; Epoxidation; Isomers; Penehyclidine
hydrochloride.
*
Corresponding author. Tel.: +86 1066874612; e-mail addresses:
han_xiangyu@yahoo.com.cn; bohuazhong@yahoo.com
Tel.: +86 1066931639.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.02.071

1980
X.-Y. Han et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1979–1982
2. Results and discussion
OH
O
The retrosynthetic route for the synthesis of 8018 optical
isomers is shown in Scheme 1 ((S,S)-1 as an illustration,
other isomers could be obtained in the similar way). Chi-
ral epoxide 2, the important intermediate for the synthe-
sis of target molecules, could be obtained by the
intramolecular Williamson ether synthesis from the
mono-sulfonated product of (S)-diol 5. The component
(S)-3 required for the (S,S)-1 synthesis could be easily
obtained through chemical resolution from racemic
quinuclidinol 3.
N
Figure 1. The structure of 8018.
There are two chiral carbon atoms in 8018 that should
have four optical isomers. Preliminary biological results
suggested that the four enantiomers have significant dif-
ference in cell toxicity on HepG2and HK-2cells, and
the pharmacology study performed recently showed that
the R-1a isomer in which the two chiral carbon atoms
have R-configuration displayed an improved therapeutic
profile compared to its racemic counterpart (pre-investi-
gated in our institute, unpublished data). Therefore, the
synthesis of enantioisomer pure compounds is very
important to study the different pharmacological behav-
ior of each optical isomer, to explore new suitable symp-
toms of these compounds and to reduce side effects that
its racemic counterparts have.
The synthesis of epoxide 2 started from chiral cyclopentyl
phenyl hydroxyl acetic acid 611 as illustrated in Scheme
2.
Compound 6 was treated with LiAlH4 in THF to give the
reductive product diol 5 in quantitative yield. The abso-
lute configuration of diol 5 should be in accordance with
6 because the reduction did not involve the stereocenter,
and this suggestion was confirmed from %ee of the target
isomers of 8018 in this paper. Recently, Gupta et al.
described the Sharpless asymmetric dihydroxylation of
a-cyclohexylstyrene, of which the (S)-cyclohexylphenyl-
1,2-diol could be obtained with only 92% ee.12 Therefore,
in this paper, we did not adopt this dihydroxylated meth-
od but adopted the method shown in Scheme 2. The
mono-sulfonation of compound 5 with p-TsCl in CH2Cl2
under ice-bath condition to give the crude product,
which recrystallized from petroleum ether afforded the
pure mono-sulfonated product 4 in 79% yield.13 The sub-
sequent intramolecular Williamson ether synthetic meth-
od from 4 in order to obtain the optical pure epoxide 2
was unsuccessful with NaH and catalytic amount of
DMSO in THF,14 of which the ee value of the epoxide
2 only reached 20–30%, while the mono-sulfonate 4 pro-
ceeded intramolecular ring closing reaction with K2CO3
in MeOH15 could give epoxide S-2 in quantitative yield.
The four optical isomers of 8018 were usually synthe-
sized by combining the racemic epoxide 2 and (R)- or
(S)-quinuclidinol 3 to produce a mixture of diastereo-
mers (R-1a) and (R-1b) or (S-1a) and (S-1b), then each
pair of diastereomers were usually prepared by TLC
method,10 which was a tedious work and the yields were
often relatively low. Therefore, a practical and direct
asymmetric synthetic method for the optical isomers
should be developed.
Herein, we report a new and enantioselective synthetic
method for the four isomers of 8018 through optical
epoxide 2 by employing the asymmetric intramolecular
SN2process of mono-sulfonate 4 as the key step.
The compound S-3 was resoluted according to the meth-
od10,16 shown in Scheme 3. The racemic 3-quinuclidinol
was reacted with (CH3CO)2O at 160 °C for 3 h to give
acetate 7, which reacted with D-(À)-tartaric acid to form
OH
HO
O
O
N
N
(S)-2
OH
(S,S)-1
OH
(S)-3
OH
OAc
OH
b, c
a
OH
N
3
OH
OH
OTs
N
7
N
(S)-3
O
Scheme 3. Reagents and conditions: (a) (CH3CO)2O, reflux, 3 h, 81%;
(b) D-(À)-tartaric acid and 80% EtOH; (c) 2N NaOH, 70 °C, 1 h,
K2CO3, extracted with benzene at 70 °C, 63%.
(S)-5
(S)-4
(S)-6
Scheme 1. Retrosynthetic route to (S,S)-1.
OH
OH
OH
O
OH
a
b
c
OH
OTs
O
(S)-2
(S)-4
(S)-6
(S)-5
Scheme 2. Reagents and conditions: (a) LiAlH4, THF, reflux, 1 h, quant; (b) TsCl, anhydrous CH2Cl2, Et3N, 0–5 °C, 79%; (c) K2CO3, MeOH, rt,
30 min, quant.

X.-Y. Han et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1979–1982
Table 1. Synthetic results of the four isomers17 of 8018
1981
Entry
2
3
1
%Eea
100
Yieldb (%)
HO
OH
1
75
N
O
N
O
S-1a
OH
HO
HO
HO
O
2
3
4
100
99
72
76
70
N
N
R-1a
OH
O
N
O
N
S-1b
OH
O
99
N
N
R-1b
a The ee is determined by HPLC (Chiradex Cartridge, mobile phase 30% acetonitrile/70% 0.05 M KH2PO4/0.3% Et3N at pH 6.0, and the tS-1a
42.8 min, tR-1b = 47.9 min).
b Yield of the reaction between epoxide 2 and 3.
=
tartaric acid salt. After recrystallized in 80% EtOH for
three times, the S-quinuclidinol tartaric acid salt was ob-
tained in 60% yield. The salt reacted with 2N NaOH at
70 °C for 1 h, then the solution was saturated with anhy-
drous K2CO3 and extracted with benzene at 70 °C to
give S-quinuclidinol 3 in 63% yield. Similarly, the com-
pound R-3 could be obtained with D-(+)-tartaric acid as
resolution agent.
References and notes
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The final step involved the ring opening of chiral epox-
ide 2 with alcohol 3, which could readily be performed
by simple nucleophile substitution with NaH10 in
DMSO, and the results are shown in Table 1. The data
in Table 1 show that the enantiopure isomers of 8018
were obtained in moderate yields with high ee values
by using our synthetic method.
In summary, we developed a facile and efficient proce-
dure to prepare the isomers of 8018 by employing the
asymmetric epoxidation of mono-sulfonate 4 for the
first time as the key step. The synthetic strategy can be
further extended to the asymmetric synthesis of other re-
lated C–S and C–N bonds analogs. Currently studies are
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Acknowledgements
Project supported by the National Natural Science
Foundation of China (No. 32813251).
Supplementary data
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2005.02.071.

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17. Analytical data of 8018 isomers: S-1a and R-1b: Colorless
liquid. IR (KBr): 3575, 1450, 1095 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d 7.20–7.44 (m, 5H), 3.71 (d, 1H,
J = 9 Hz), 3.59 (d, 1H, J = 9 Hz), 3.38–3.40 (m, 1H), 2.93–
2.96 (m, 1H), 2.85 (s, –OH, 1H), 2.52–2.77 (m, 5H), 2.26–
2.32 (m, 1H), 1.98–1.99 (m, 1H), 1.20–1.73 (m, 13H);
EIMS (m/z): 315 (M+). Compounds S-1b and R-1a:
Colorless liquid. IR (KBr): 575, 1450, 1097 cmÀ1 1H
;
NMR (400 MHz, CDCl3): d 7.29–7.42 (m, 5H), 3.71 (d,
J = 9 Hz, 1H), 3.58 (d, J = 9 Hz, 1H), 3.35–3.38 (m, 1H),
2.89–2.95 (m, 1H), 2.84 (s, –OH, 1H), 2.52–2.77 (m, 5H),
2.26–2.32 (m, 1H), 1.96–1.99 (m, 1H), 1.23–1.75 (m, 13H);
EIMS (m/z): 315 (M+).