Synthesis and crystal structure of 3-quinuclidinyl α-(cyclopentyl-1- ene)-α-hydroxy-α-phenylacetate

Article abstract of DOI:10.1007/s10870-008-9395-x

The title compound 3-quinuclidinyl α-(cyclopentyl-1-ene)-α- hydroxy-α-phenylacetate was obtained by the reaction of methyl α-(cyclopentyl-1-ene)-α-hydroxy-α-phenylacetate with 3-quinuclidinol in n-heptane. Its structure was characterized by ¹H,

Full text of DOI:10.1007/s10870-008-9395-x

J Chem Crystallogr (2008) 38:491–494
DOI 10.1007/s10870-008-9395-x
COMMUNICATION
Synthesis and Crystal Structure of 3-Quinuclidinyl
a-(Cyclopentyl-1-ene)-a-hydroxy-a-phenylacetate
Yu-min Liu Æ He Liu Æ Yong-qi Hu
Received: 21 January 2006 / Accepted: 2 April 2008 / Published online: 16 April 2008
Ó Springer Science+Business Media, LLC 2008
Abstract The title compound 3-quinuclidinyl a-(cyclopen-
tyl-1-ene)-a-hydroxy-a-phenylacetate was obtained by the
reaction of methyl a-(cyclopentyl-1-ene)-a-hydroxy-a-
phenylacetate with 3-quinuclidinol in n-heptane. Its struc-
years [2]. Recently we synthesized a potent muscarinic
receptor antagonist, 3-quinuclidinyl a-(cyclopentyl-1-ene)-
a-hydroxy-a-phenylacetate. The biological tests suggest that
the title compound displays more effective treating centric
and peripheral choline dysfunctions [3]. The title compound
was obtained by the reaction of methyl a-(cyclopentyl-
1-ene)-a-hydroxy-a-phenylacetate with 3-quinuclidinol in
n-heptane. Crystals of the title compound suitable for X-ray
structure determination were obtained from the filtrate by
slow evaporation of the CH2Cl2 solution.
1
ture was characterized by H, 13C NMR, MS and X-ray
single-crystal
diffraction
techniques:
C20H25NO3,
Mr = 327.41, orthorhombic, space group P212121 with
˚
a = 8.547(2), b = 11.428(4), c = 18.288(5) A, V =
3
1786.3(9) A , Z = 4. The title compound comprises a ter-
˚
tiary a-hydroxy acid and a bicyclo[2.2.2]octan moiety. The
crystal structure shows the presence of the intermolecular
O(1)–H(1)ÁÁÁN(1) hydrogen bonds.
Experimental
Keywords Anticholinergic drug Á Tertiary a-hydroxy
acid Á Crystal structure
Materials and Synthesis
All reagents were commercially available and used without
further purification or purified by standard methods prior to
use. Melting points were determined using a RY-1 apparatus
Introduction
1
Over the past century classical anticholinergic drugs have
been widely used for the treatment of certain diseases, such
as chronic obstructive pulmonary diseases, Alzheimer’s
disease and urinary incontinence. Most of the muscarinic
receptor antagonists comprise of a tertiary a-hydroxy acid as
a key component [1]. We have engaged in the synthesis and
biological activity study of anticholinergic drugs for many
and are uncorrected. H NMR spectra were recorded on
Varian UNITY INOVA 600 MHz and JNM-ECA-400
400 MHz instrument in the solvent indicated below.
Chemical shift values are reported in parts per million (ppm)
relative to those for tetramethylsilane used as an internal
reference standard. Spectral splitting patterns are designated
as follows: s, singlet; br, broad; d, doublet; t, triplet; m,
multiplet. Mass spectra were obtained from Micromass
ZabSpec and API3000 instruments. Elemental analysis was
carried at the CarloErba-1106. Methyl a-(cyclopentyl-
1-ene)-a-hydroxy-a-phenylacetate was synthesized as
described in the literature [4]. The synthetic pathway for the
title compound is outlined in Scheme 1.
Y.-m. Liu Á Y.-q. Hu
College of Chemical and Pharmaceutical Engineering, Hebei
University of Science and Technology, Shijiazhuang 050016,
People’s Republic of China
H. Liu (&)
Methyl a-(cyclopentyl-1-ene)-a-hydroxy-a-phenylacetate
(2.6 g, 11.2 mmol) and 3-quinuclidinol (1.3 g, 10.2 mmol)
were dissolved in anhydrous n-heptane (100 mL) and NaH
No. 7 Department, Beijing Institute of Pharmacology and
Toxicology, Beijing 100850, People’s Republic of China
e-mail: liuhe@nic.bmi.ac.cn
123

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J Chem Crystallogr (2008) 38:491–494
Scheme 1 Procedure of
preparing the title compound
OH
O
OH
O
NaH
n-heptane, reflux
HO
OCH3
+
N
O
N
(0.5 g assay 80%) was added. Then the solution was refluxed
for 3 h. After the solvent was removed under reduced pres-
sure, the residue was dissolved in ether (150 mL), washed
with water and brine, dried over anhydrous sodium sulfate,
and concentrated to dryness. The product was purified by
flash-chromatography (chloroform/methanol, 9:1) and the
title compound was isolated as a white solid (2.51 g, 76%).
Crystallographic data and experimental details for struc-
tural analyses are summarized in Table 1. The selected
bond distances and angles are listed in Table 2, respec-
tively. Figure 1 shows the molecular structure of the title
compound and molecular packing together with the
hydrogen bonds.
The X-ray ORTEP structure of the title compound with
atomic labeling is shown in Fig. 1a. X-ray structure analyt-
ical data show that the title compound is composed of a 3-
quinuclidinol structure and a tertiary hydroxy acid moiety.
The three six-membered rings of the bicyclo[2.2.2]octan
structure have twist boat conformations along C(16)ÁÁÁN(1)
axis. The torsion angles of N(1)–C(20)ÁÁÁC(16)–C(19) =
7.6°, N(1)–C(15)ÁÁÁC(16)–C(14) = 6.0° and N(1)–
C(18)ÁÁÁC(16)–C(17) = 8.4° are similar to those found in
some monosubstituted quinuclidine compound [7]. In the
quinuclidine ring system the C–N distances (N(1)–
C(15) = 1.456(4), N(1)–C(18) = 1.467(4) and N(1)–C(20)
1
m.p.: 183–185 °C. H-NMR (ppm, CDCl3, 25 °C) d: 7.55
(2H, m), 7.33 (3H, m), 4.91 (1H, s), 3.93 (s, 1H), 3.24 (m, 1H),
2.76 (m, 5H), 2.41 (m, 4H), 2.05 (s, 1H), 1.92 (m, 3H), 1.64
(m, 1H), 1.52 (m, 1H), 1.26 (m, 2H). 13C-NMR d (CDCl3):
173.91, 144.48, 140.07, 127.93, 127.80, 126.46, 78.25, 73.65,
55.07, 47.08, 46.20, 32.52, 32.05, 25.24, 24.26, 23.48, 19.47.
ESI-MS: 328.2(M + 1). Anal. Calcd. (%)ForC20H25NO3: C,
73.37; H, 7.70; N, 4.28. Found (%): C, 73.28; H, 7.61; N, 4.32.
Crystallographic Study
A colorless crystal of the title compound with dimensions of
0.28 9 0.24 9 0.20 mm3 was mounted on a glass fiber in a
random orientation. The data were collected by a Bruker CCD-
1000 diffractometer with a graphite-monochromated MoKa
Table 1 Crystallographic data and structure refinement summary for
the title compound
˚
radiation (k = 0.71073 A) by using a x scan mode in the
CCDC deposit no.
Empirical formula
Molecular weight
Temperature (K)
Crystal system
245331
20H25NO3
range of 2.23 B h B 26.51° at 293(2) K. The structure was
solved by direct methods with SHELXL-97 program [5] and
all data were corrected by using semi-empirical (SADABS)
method [6]. Unit cell dimensions were obtained with least-
squares refinements. A total of 10,442 reflections were col-
lected with 2,125 unique ones (Rint = 0.0486), of which 1558
with I [2r(I) were considered as observed and used in the
succeeding refinements. All the other non-hydrogen atoms
were located in successive difference Fourier syntheses. The
final refinement was carried out by full-matrix least-squares
methods with anisotropic thermal parameters for non-hydro-
gen atoms on F2. The hydrogen atoms were added
theoretically, and allowed to ride on the concerned atoms and
refined with fixed thermal factors. The final refinement gave
R = 0.0518 and wR = 0.1228 for 2,125 observed reflections
(w = 1/[r2(Fo)2 + (0.0788P)2 + 0.2078P], where P =
C
327.41
293(2)
Orthorhombic
P212121
Space group
˚
a (A) = 8.547(2)
Unit cell dimensions
˚
b (A) = 11.428(4)
˚
c (A) = 18.288(5)
3
Volume, V (A )
˚
1786.3(9)
Z
4
Calculated density (mg m-3
)
1.217
Absorption coefficient (mm-1
)
0.081
F (000)
Crystal size (mm3)
704
0.20 9 0.20 9 0.18
10,442/2,125
1.0000 and 0.9841
2125/0/235
Reflections collected/unique
Max. and min. transmission
Data/restraints/parameters
Rint
(F2o + 2F2c)/3), S = 1.021, (D/r)max = 0.000, (Dq)max
0.341 and (Dq)min = -0.226 e/A .
=
3
˚
0.0486
Goodness of fit on F2
Final R indices [I [ 2r(I)]
R indices (all data)
1.029
Results and Discussion
R1 = 0.0518, wR2 = 0.1228
R1 = 0.0793, wR2 = 0.1360
0.341 to -0.226
The 1H, 13C NMR, MS and elemental analysis for the
product are in good agreement with the title compound.
-3
)
˚
Largest diff. peak and hole (eA
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J Chem Crystallogr (2008) 38:491–494
493
˚
Table 2 Selected bond lengths (A) and bond angles (°)
Bond
Distance
Bond
Distance
Bond
Distance
O(1)–C(7)
O(2)–C(13)
O(3)–C(13)
O(3)–C(14)
N(1)–C(15)
N(1)–C(18)
1.412(3)
1.195(4)
1.337(4)
1.447(4)
1.456(5)
1.466(5)
N(1)–C(20)
C(1)–C(2)
C(1)–C(6)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
1.470(4)
1.373(7)
1.378(6)
1.381(8)
1.350(8)
1.400(6)
C(5)–C(6)
1.361(5)
1.525(4)
1.328(5)
1.497(5)
1.531(5)
1.546(5)
C(6)–C(7)
C(8)–C(12)
C(8)–C(9)
C(17)–C(18)
C(19)–C(20)
Angle
(°)
Angle
(°)
Angle
(°)
C(13)–O(3)–C(14)
C(15)–N(1)–C(18)
C(15)–N(1)–C(20)
C(18)–N(1)–C(20)
C(2)–C(1)–C(6)
C(1)–C(2)–C(3)
C(4)–C(3)–C(2)
C(3)–C(4)–C(5)
117.5(2)
C(6)–C(5)–C(4)
C(5)–C(6)–C(1)
C(5)–C(6)–C(7)
C(1)–C(6)–C(7)
O(1)–C(7)–C(8)
O(1)–C(7)–C(6)
C(8)–C(7)–C(6)
O(1)–C(7)–C(13)
121.3(4)
118.4(4)
122.6(3)
118.8(3)
110.4(3)
106.4(2)
114.5(2)
109.3(2)
N(1)–C(15)–C(14)
C(14)–C(16)–C(19)
C(14)–C(16)–C(17)
C(19)–C(16)–C(17)
C(16)–C(17)–C(18)
N(1)–C(18)–C(17)
C(16)–C(19)–C(20)
N(1)–C(20)–C(19)
112.0(3)
107.3(2)
109.5(3)
108.7(3)
108.7(3)
111.2(3)
108.5(3
110.8(3)
108.9(3)
108.6(3)
109.9(3)
121.0(4)
119.7(5)
120.3(5)
119.3(4)
˚
1.468(3) A) are slightly shorter compared with cinchonine
alkaloid [8]. No significant difference was found in the bond
lengths, but the bond angle of C(18)–N(1)–C(20)(110.0(2)°)
was slightly larger than C(15)–N(1)–C(18)(108.7(2)°) and
C(15)–N(1)–C(20) (108.5(2)°) because of the 3-substituted
ester group.
As shown in Fig. 1b, a zig-zag one-dimensional linear
structure is formed through NÁÁÁH–O hydrogen bonds in
which the O atom of hydroxyl groups link the N atom of
3-quinuclidinol in the adjacent molecule. The NÁÁÁO sepa-
˚
˚
ration is 2.761 A with the HÁÁÁN separations of 1.954 A,
and the bond angles are 167.50°, falling into the normal
range of NÁÁÁO separation for hydrogen bonds [9].
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Fig. 1 (a) Molecular structure of the title compound with the 50%
probability of the thermal ellipsoids; (b) Molecular packing in a unit
cell showing the one-dimensional structure with hydrogen bonds
123

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J Chem Crystallogr (2008) 38:491–494
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