5-(4-ammonio-2-oxopyrimidine-1(2H)-yl)-1,3-oxathiolane-2-carboxylate (lamivudine acid) Semihydrate: The six-fold symmetry created by hydrogen bond network

Article abstract of DOI:10.1007/s10870-010-9866-8

The title compound, C₈H₉N₃O₄S × 1/2(H₂O), which is an impurity found in a drug lamivudine, crystallizes in the hexagonal space group P6₂ with a = 10.208(1) A and c = 18.073(2) A. Such a rare packing is constructed by the hierarchical network of hydrogen bonds, which connect the molecules into chains, then into pairs of chains, and neighboring chains, oriented at the angle of 60°, make the final packing mode. The molecule exists in the crystal as the zwitterion, with negative charged carboxylate and positive ammonio groups. The oxathiolane ring is close to an envelope conformation, and both pyrimidine and carboxylate substituent are in the equatorial positions.

Full text of DOI:10.1007/s10870-010-9866-8

J Chem Crystallogr (2011) 41:214–218
DOI 10.1007/s10870-010-9866-8
ORIGINAL PAPER
5-(4-Ammonio-2-Oxopyrimidine-1(2H)-yl)-1,3-Oxathiolane-2-
Carboxylate (lamivudine acid) Semihydrate: The Six-Fold
Symmetry Created by Hydrogen Bond Network
•
Grzegorz Dutkiewicz C. S. Chidan Kumar
•
•
H. S. Yathirajan B. Narayana Maciej Kubicki
•
Received: 11 November 2009 / Accepted: 5 August 2010 / Published online: 22 August 2010
Ó The Author(s) 2010. This article is published with open access at Springerlink.com
Abstract The title compound, C8H9N3O4S 9 1/2(H2O),
which is an impurity found in a drug lamivudine, crystallizes
˚
in the hexagonal space group P62 with a = 10.208(1) A and
of Anti HIV drugs. It is an antiretroviral agent, which
belongs to a class of drugs called ‘‘nucleoside reverse
transcripts inhibitors’’ or ‘‘NRTIs’’. The drug is marketed
by GlaxoSmithKline with the brand names Zeffix, Hepto-
vir, Epivir, and Epivir-HBV. Lamivudine and its hydrate
have been studied [1]. The identification of lamivudine
conformers by Raman scattering measurements and quan-
tum chemical calculations is reported [2]. Lamivudine
acid—or 5-(4-amino-2-oxopyrimidine-1(2H)-yl)-1,3-oxa-
thiolane-2-carboxylic acid is an impurity which can be
present in the drug lamivudine. In view of the importance
of lamivudine, the paper reports the synthesis and crystal
structure of lamivudine acid, C8H9N3O4S, which turned out
to crystallize in a zwitterionic form, and additionally as a
hydrate (I, Scheme 1).
˚
c = 18.073(2) A. Such a rare packing is constructed by the
hierarchical network of hydrogen bonds, which connect the
molecules into chains, then into pairs of chains, and neigh-
boring chains, oriented at the angle of 60°, make the final
packing mode. The molecule exists in the crystal as the
zwitterion, with negative charged carboxylate and positive
ammonio groups. The oxathiolane ring is close to an enve-
lope conformation, and both pyrimidine and carboxylate
substituent are in the equatorial positions.
Keywords Oxathiolane ring ꢀ Hydrogen bonds ꢀ Crystal
packing ꢀ Lamivudine
Figure 1 shows the perspective view of the molecule,
and Table 1 lists the relevant geometrical parameters. In
the crystal structure the molecule of lamivudine acid exists
as the zwitterion, with carboxylate anionic and ammonio
cationic groups on the opposite ends of the molecule. This
is proven by the bond lengths pattern: almost equal C–O
bonds, short C9–N91 bond (cf. Table 1). The bond lengths
and angles pattern is similar to that found in the structure of
Lamivudine saccharinate [3], which might be regarded as
an additional proof for the protonation site in the six-
membered ring.
Results and Discussion
Lamivudine (which is a common name for 4-amino-1-(2R,
5S)-[2-(hydroxymethyl)-l,3-oxathiolan-5-yl]pyrimidin-2(1H)-
one) is a reverse transcriptase inhibitor used in the treatment
of HIV infection alone or in combination with other class
G. Dutkiewicz ꢀ M. Kubicki (&)
The conformation of the oxathiolane ring is close to an
envelope, with four atoms: S1, C2, O3 and C5 almost
coplanar (maximum deviation from the least-squares plane
Department of Chemistry, Adam Mickiewicz University,
´
Grunwaldzka 6, 60-780 Poznan, Poland
e-mail: mkubicki@amu.edu.pl
˚
of 0.033(2) A) while the fifth atom (C4) is significantly, by
˚
0.608(5) A out of this plane. Also the asymmetry param-
C. S. Chidan Kumar ꢀ H. S. Yathirajan
Department of Studies in Chemistry, University of Mysore,
Manasagangotri 570 006, Mysore, India
eter [4], which describes the deviation from the ideal
symmetry (in this case Cs), has relatively low value of 8.8°.
Similar conformation was observed in the majority of the
structures with not fused oxathiolane rings found in the
B. Narayana
Department of Studies in Chemistry, Mangalore University,
Mangalagangotri 574 199, India
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J Chem Crystallogr (2011) 41:214–218
215
˚
0.010(2) A) occupies the equatorial position with respect to
the oxathiolane ring (C2–O3–C4–N6 torsion angle is 172.9
(3)°, S1–C5–C4-N6—160.8 (3)°), the position of carbox-
ylate group is also close to the equatorial one (C4–O3–C2–
C21—149.6(3)°, C5–S1–C2–C21—125.3(3)°).
Compound 1 crystallizes in a rather uncommon space
group P62—in the CSD there are only 61 structures in
either P62 or P64 space groups, of which 26 are of organic
compounds. The crystal packing is determined mainly
by an extensive network of hydrogen bonds (Table 2), both
strong (N-HꢀꢀꢀO(carboxylate), O(water)–HꢀꢀꢀO(carboxylate))
and weak (C–HꢀꢀꢀO(water, carbonyl)). Theorganizationofthe
three-dimensional network may be analyzed as the step-
by-step construction of the six-fold screw symmetry. At
the first level, molecules are connected by means of two dif-
ferent hydrogen bonds: N8–H8ꢀꢀꢀO23(x, y - 1, z) and N91–
H91AꢀꢀꢀO22(x, y - 1, z) into the infinite chains expanding
along y direction (Fig. 2a). Using the graph-set notation [6, 7]
one could find, atthislevel, twoparallelchainsC(9) and C(11)
along y, which give rise to the second-order R22(8) ring. The
neighboring chains are connected by hydrogen bonds with
water molecules (which lie on the twofold axes) into the pairs
of antiparallel chains; the ‘‘linking’’ graph symbol is R46(30),
cf. Fig. 2b.
Scheme 1 The lamivudine acid
Fig. 1 Anisotropic ellipsoid representation of the compound
I together with atom labelling scheme [12]. The ellipsoids are drawn
at 50% probability level, hydrogen atoms are depicted as spheres with
arbitrary radii, hydrogen bond is shown as the dashed line
Then, at the next level, these double strands are linked
by means of N91–H91BꢀꢀꢀO23 (y, -x?y, z - 1/3) hydro-
gen bonds with the subsequent strands, which are oriented
at the angle of 60° to the former one (Fig. 2c). At this
level relatively short and directional C5–H5ꢀꢀꢀO1Wiii
hydrogen bonds also play their part, by linking the
neighbouring chains. Altogether, all these steps lead to the
hexagonal symmetry as seen in the packing diagram
(Fig. 3).
Table 1 Selected geometrical
˚
S1–C2
1.855(4)
1.817(4)
1.407(5)
1.428(4)
1.232(4)
1.272(4)
1.364(4)
1.397(5)
1.383(4)
1.359(5)
1.298(5)
91.69(18)
125.5(3)
4.6(3)
parameters (A, °)
S1–C5
C2–O3
O3–C4
C21–O22
C21–O23
N6–C11
Experimental
N6–C7
Preparation
C7–N8
N8–C9
L-menthyl-5-cytosin-1,3-oxathiolane-2-carboxylate(2.0 g,
5.2 mmol) was added to a solution of KOH (0.3 g,
6.0 mmol) in 20 ml of methanol (Scheme 2). The mixture
was stirred for 4 h. Methanol was distilled out and the res-
idue was diluted with water. Aqueous layer was extracted
with ethyl acetate. The pH of aqueous layer was adjusted to
four using acetic acid. The solid was collected by filtration
and further recrystallized from water (m.p.: 311–313 K).
C9–N91
C2–S1–C5
C7–N8–C9
C5–S1–C2–O3
S1–C2–O3–C4
C2–O3–C4–C5
O3–C4–C5–S1
C4–C5–S1–C2
-31.6(3)
50.7(4)
-43.7(3)
21.2(3)
Crystallography
Cambridge Structural Database [5], however different
atoms occupy the out-of-plane position. The pyrimidine
substituent (which is approximately planar, within
Colourless block-like crystal (0.2,0.1,0.1 mm) was used for
data collection. Diffraction data were collected at 100(1)K
123

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J Chem Crystallogr (2011) 41:214–218
Fig. 2 The construction of the
packing motifs. a the hydrogen
bonded chain along y; b the pair
of antiparallel chains; c the set
of strands giving the six-fold
symmetry
˚
Table 2 Hydrogen-bond geometry (A, °)
D–HꢀꢀꢀA
D–H
HꢀꢀꢀA
DꢀꢀꢀA
D–HꢀꢀꢀA
N8–H8ꢀꢀꢀO23i
0.88
0.88
0.88
0.99
0.85
1.81
2.01
2.01
2.34
2.06
2.681(4)
2.873(4)
2.870(4)
3.202(5)
2.885(3)
173
168
166
145
173
N91–H91AꢀꢀꢀO22i
N91–H91BꢀꢀꢀO23ii
C5–H5AꢀꢀꢀO1 Wiii
O1 W–H1W1ꢀꢀꢀO22
Symmetry codes: (i) x, y - 1, z; (ii) y, -x?y, z - 1/3; (iii)
-x?y ? 1, -x?1, z ? 1/3
by the x-scan technique up to 2h = 60°, on an Xcalibur
diffractometer [8] with graphite-monochromatized MoKa
˚
Fig. 3 The packing diagram as seen along c-direction [13]
radiation (k = 0.71073 A). The temperature was controlled
123

J Chem Crystallogr (2011) 41:214–218
217
Scheme 2 Synthesis of the
lamivudine acid
by an Oxford Instruments Cryosystems cooling device. The
data were corrected for Lorentz-polarization and absorption
effects [8]. Accurate unit-cell parameters were determined
by a least-squares fit of 2307 reflections of highest intensity,
chosen from the whole experiment. The structures were
solved with SIR92 [9] and refined with the full-matrix least-
squares procedure on F2 by SHELXL97 [10]. Scattering
factors incorporated in SHELXL97 were used. The function
Rw(jFoj -jFcj ) was minimized, with w-1=[r2(Fo)2 ?
0.0951ꢀP2 ? 0.2763ꢀP] (P = [Max (Fo2, 0) ? 2F2c]/3). All
non-hydrogen atoms were refined anisotropically, hydrogen
atoms were put in the idealized positions (only that from
water molecule was found in the difference Fourier map),
and refined as riding model. Their isotropic thermal
parameters were set at 1.2 times Ueq’s of appropriate carrier
atoms. There are cavities on the two-fold axis which
appeared to be filled by highly disordered water molecule;
relatively satisfactory results were obtained with half
occupancy, but the displacement parameters were very
large. Therefore, we decided that the disorder is so severe
that in fact it is smeared-out electron density. As an alter-
native strategy, the SQUEEZE function of PLATON [11]
was used to eliminate the contribution of the electron density
in the solvent region from the intensity data. The use of this
strategy and the subsequent solvent-free model produced
better refinement parameters and more precise geometric
parameters, than the model with the disordered water mol-
ecule. Relevant crystal data are listed in Table 3, together
with refinement details.
2
2 2
CCDC-753804 contains supplementary crystallographic
data for this paper. These data can be obtained free
of charge via www.ccdc.cam.ac.uk/data_request/cif, by
e-mailing data_request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK.
Table 3 Crystal data, data collection and structure refinement
Formula
C8H9N3O4S ꢀ 1/2H2O
Formula weight
Crystal system
Space group
167.67
Hexagonal
P62
˚
a (A)
10.208(1)
18.073(2)
1631.0(3)
6
Acknowledgments CSC thanks University of Mysore for research
facilities.
˚
c (A)
3
˚
V (A )
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
Z
Dx(g cm-3
F (000)
)
1.56
798
l (mm-1
)
0.31
H range (°)
hkl range
3.22–24.99
-10 B h B12
-12 B k B7
-21 B l B21
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