Four stereoisomers of the novel -opioid receptor agonist tapenta-dol hydro-chloride

Article abstract of DOI:10.1107/S0108270111001727

The crystal and mol-ecular structures of four stereoisomers of tapenta-dol hydro-chloride [systematic name: 3-(3-hy-droxy-phenyl)-N,N,2-trimethyl-pentan-1- aminium chloride], C₁₄H₂₄NO⁺·Cl ^-, a novel analgesic ag

Full text of DOI:10.1107/S0108270111001727

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
The United States Food and Drug Administration (US
FDA) approved tapentadol hydrochloride in 2008 as an
immediate-release oral tablet for the relief of moderate to
severe acute pain, both cancer-related and other. Tapentadol
is manufactured by Janssen Ortho LLC, Gurabo, Puerto Rico,
USA, and was initially developed by Grunenthal GmbH,
Aachen, Germany, in conjunction with Johnson & Johnson
Pharmaceutical Research and Development. We report here
the crystal structures of four stereoisomers of tapentadol
hydrochloride, (I)–(IV), as part of our ongoing study of the
structural characterization of drug molecules (Ravikumar &
Sridhar, 2009, 2010).
ISSN 0108-2701
Four stereoisomers of the novel
l-opioid receptor agonist tapentadol
hydrochloride
Krishnan Ravikumar,a* Balasubramanian Sridhar,a Nitin
Pradhanb and Mayur Khuntb
aLaboratory of X-ray Crystallography, Indian Institute of Chemical Technology,
Hyderabad 500 007, India, and bResearch and Development Centre, Actavis
Pharmaceutical Development Centre Pvt. Ltd, Bangalore 560 034, India
Correspondence e-mail: sshiya@yahoo.com
Received 26 October 2010
Accepted 12 January 2011
Online 20 January 2011
The crystal and molecular structures of four stereoisomers of
tapentadol hydrochloride [systematic name: 3-(3-hydroxy-
phenyl)-N,N,2-trimethylpentan-1-aminium chloride], C14H24-
NO+ꢀClꢁ, a novel analgesic agent, have been determined by
X-ray crystal structure analysis. Resolution of the isomers was
carried out by reverse-phase and chiral high-performance
liquid chromatographic (HPLC) methods. Stereoisomers (I)
and (II) crystallize in the monoclinic space group P21, each
with two tapentadol cations and two chloride anions in the
asymmetric unit, while stereoisomers (III) and (IV) crystallize
in the orthorhombic space group P212121, with one tapentadol
cation and one chloride anion in the asymmetric unit. The
absolute configurations of the four enantiomers were deter-
mined unambiguously by X-ray crystallography. The crystal
structures reveal the stereochemistries at the 3-ethyl and
2-methyl groups to be R,R, S,S, S,R and R,S in stereoisomers
(I)–(IV), respectively. The ethyl and aminopropyl groups
adopt different orientations with respect to the phenol ring for
(I) and (IV). In all four structures, the chloride ions take part
in N—Hꢀ ꢀ ꢀCl and O—Hꢀ ꢀ ꢀCl hydrogen bonds with the
tapentadol molecules, resulting in one-dimensional helical
chains in the crystal packing in each case.
Resolution of the four isomers was carried out using
reverse-phase and chiral high-performance liquid chromato-
graphy (HPLC) methods; compounds (I)–(IV) showed good
resolution in HPLC analysis and diastereomeric isomer
separation in reverse-phase HPLC analysis. The purities of all
individual isomers were confirmed by both chiral and reverse-
phase HPLC. In the chiral method, isomers (I), (II), (III) and
(IV) eluted at retention times of 19.21, 24.56, 17.81 and
16.61 min, respectively (Fig. 1), whereas in the reverse-phase
method, the retention times were 17.00, 17.21, 15.58 and
Comment
Tapentadol is a novel centrally acting synthetic analgesic with
a unique profile of action for the treatment of moderate to
severe pain (Tzschentke et al., 2007). It acts in two ways, viz.
opioid (narcotic) and non-opioid. Tapentadol affects the brain
and body primarily by activating opioid receptors in the brain,
spinal cord and gastrointestinal tract. In addition, it inhibits
the re-uptake of the brain chemical norepinephrine which
possibly has an analgesic effect. Tapentadol is being developed
in immediate-release and extended-release formulations
(Etropolski et al., 2010).
Figure 1
Chiral HPLC profiles of the four stereoisomers of tapentadol hydro-
chloride, using a CHIRALPAK AD-3 (250 ꢂ 4.6 mm ꢂ 5 mm) column
and an 85:15 (v/v) hexane–tetrahydrofuran solvent system.
Acta Cryst. (2011). C67, o71–o76
doi:10.1107/S0108270111001727
# 2011 International Union of Crystallography o71

organic compounds
Figure 2
Comparative differential scanning calorimetric (DSC) thermographs for
the four stereoisomers of tapentadol hydrochloride.
15.48 min, respectively. It can be seen that isomers (I) and (II)
are one pair of enantiomers, and isomers (III) and (IV) are a
second pair, having similar retention times in reverse-phase
HPLC analysis.
Differential scanning calorimetric (DSC) measurements
were carried out using a Perkin–Elmer Diamond DSC appa-
ratus. Experiments were performed at a heating rate of
10.0 K minꢁ1 over a temperature range of 303–533 K under a
nitrogen flow of 50 ml minꢁ1. The DSC curves for (I)–(IV)
show sharp endothermic peaks, corresponding to melting
points, at 482, 480, 477 and 478 K for isomers (I)–(IV),
respectively (Fig. 2).
Tapentadol consists of a meta-substituted phenol ring
possessing an ethyl and an aminopropyl residue at C7. It has
two stereogenic centres, at C7 and C10, which results in four
possible diastereomers; the R,R isomer is currently the clini-
cally used form (Franklin et al., 2010). Tapentadol is structu-
rally the closest chemical relative of tramadol in clinical use.
Both tramadol and venlafaxine are racemic mixtures (Reeves
& Cox, 2008), whereas tapentadol represents only one stereo-
isomer, viz. (1R,2R). Structurally, tapentadol differs from
tramadol in being a phenol and not an ether. Also, both
tramadol and venlafaxine incorporate a cyclohexyl group
attached directly to the aromatic ring, while tapentadol lacks
this feature.
Figure 3
The crystal structures of isomers (I) and (II) are enantio-
morphs, crystallizing in the space group P21. Similarly, the
crystal structures of isomers (III) and (IV) are also enantio-
morphs, but crystallizing in the space group P212121. Thus, (I)/
(III) and (II)/(IV) are pairs of diastereomers. Unambiguous
determination of the absolute configurations of all four
structures was carried out by means of refinement of the Flack
parameter (Flack & Bernardinelli, 2000). It was therefore
assigned that (I) is the R,R enantiomer and (II) is the S,S
enantiomer, with melting points of 482–483 and 480–481 K,
respectively. It was also found that (III) is the S,R isomer and
(IV) is the R,S isomer, with melting points of 477–478 and 478–
479 K, respectively, from the above-mentioned DSC studies.
Each asymmetric unit in (I) and (II) comprises two tapentadol
Views of (a) (I) and (b) (II), showing the atom-numbering schemes.
Displacement ellipsoids are drawn at the 50% probability level. Dashed
lines indicate hydrogen bonds.
cations and two chloride anions (Fig. 3). In the case of (III)
and (IV), the asymmetric unit consists of one tapentadol
cation and one chloride anion (Fig. 4).
The geometric parameters of (I)–(IV) are similar. However,
there are significant angular variations observed between the
two independent molecules of (I) and (II) involving the chiral
atom C7, the differences being C7—C8—C9 = 2.5 (2) [in (I)]
and 2.7 (2)ꢃ [in (II)], and C8—C7—C10 = 2.1 (1) [in (I)] and
2.3 (2)ꢃ [in (II)] (Table 1). This may perhaps be attributed to
the syn/anti conformers found around the C8—C9 bond.
Four stereoisomers of C14H24NO+ꢀClꢁ
Acta Cryst. (2011). C67, o71–o76
ꢄ
o72 Ravikumar et al.

organic compounds
Figure 6
Part of the crystal packing for (I), showing the involvement of the
chloride ions in N—Hꢀ ꢀ ꢀCl and O—Hꢀ ꢀ ꢀCl hydrogen bonds with the
tapentadol molecules, resulting in a one-dimensional helical chain along
the a axis. Hydrogen bonds are shown as dashed lines and H atoms not
involved in hydrogen bonding have been omitted for clarity. Only atoms
involved in hydrogen bonding have been labelled. [Symmetry code: (i)
x ꢁ 1, y, z.]
Figure 4
Views of (a) (III) and (b) (IV), showing the atom-numbering schemes.
Displacement ellipsoids are drawn at the 50% probability level. Dashed
lines indicate hydrogen bonds.
The aminopropyl and ethyl groups are located on opposite
sides of the plane defined by the aromatic ring. The two
cations in asymmetric unit of (I), although constructed from
molecules with the same chirality, are paired around a
pseudocentre of symmetry at (14, 0.65, 34) and differ significantly
in the orientation of atom C9 of the ethyl group. The orien-
tation of the ethyl group with respect to the phenol ring can be
seen from the torsion angle C1—C7—C8—C9, which is cis in
molecule A of (I) and trans in molecule B, while in (III) it
adopts a cis orientation. The conformation of the aminopropyl
group can be defined from the C—C—C—C and C—C—C—N
torsion angles, and the conformation is cis–trans for both
molecules of (I), while it is trans–trans for (III) (Table 1). An
overlay of the tapentadol molecules, superimposing atoms
C1–C7 of the phenol ring system, reveals the differences in
orientation of both the ethyl and aminopropyl groups with
respect to the phenol ring (Fig. 5). It is interesting to note that
the ethyl group of (III) adopts a similar conformation to
molecule (IA), while the conformation of the aminopropyl
group is entirely different from (I). This difference might
influence the participation of the aminopropyl group in C—
Hꢀ ꢀ ꢀCl interactions in (III), which are absent in (I).
Figure 7
Part of the crystal packing for (III), showing the helical chains of
tapentadol molecules linked by the chloride ions via N—Hꢀ ꢀ ꢀCl and O—
Hꢀ ꢀ ꢀCl hydrogen bonds. Also shown are the helical chains interlinked by
C—Hꢀ ꢀ ꢀCl hydrogen bonds. Hydrogen bonds are shown as dashed lines
and H atoms not involved in hydrogen bonding have been omitted for
clarity. Only atoms involved in hydrogen bonding have been labelled.
Figure 5
Superposition of the molecular conformations of the tapentadol
molecules of (I) and (IV), showing the orientations of the ethyl and
aminopropyl groups with respect to the phenol ring. The overlay was
made by making a least-squares fit through the planar phenol ring (atoms
C1–C7) of tapentadol [molecules (IA) and (IB)] and (IV).
1
1
1
1
[Symmetry codes: (i) ꢁx + 2, y + , ꢁz + ; (ii) x + , ꢁy ꢁ , ꢁz.]
2
2
2
2
Four stereoisomers of C14H24NO+ꢀClꢁ o73
ꢄ
Acta Cryst. (2011). C67, o71–o76
Ravikumar et al.

organic compounds
383–388 K for 6 h. After cooling, water (50 ml) and aqueous
ammonia (100 ml) were added, and the mixture was filtered through
Hyflo and the organic layer separated. The aqueous layer was
extracted with toluene (100 ml). The combined organic layers were
washed with water (100 ml), dried over anhydrous sodium sulfate and
concentrated under vacuum at 323–328 K to obtain an oil. Propan-2-
ol (50 ml) and propan-2-ol–HCl (30 ml, pH 1–2) were added to this
oil and the mixture was stirred for 2 h at 273–278 K. The solid was
then filtered off, washed with propan-2-ol (10 ml), dried under
vacuum at 313–318 K for 2 h and recrystallized from butanone to
yield a white solid (m.p. 477–478 K). 1H NMR (D2O): ꢀ 0.60 (t, 3H, –
CH2—CH3), 0.75 (d, 3H, –CH—CH3), 1.57 (m, 2H, –CH2—CH3), 2.10
(m, 1H, –CH–Ethyl), 2.35 (p, 1H, –CH—CH3), 2.72 [s, 6H, –N(Me)2],
3.09 (dd, 2H, –CH2), 6.62 (d, 1H, Ar—H), 6.69 (dd, 2H, Ar—H), 7.13
(t, 1H, Ar—H); MS: m/z 221 (M+).
The crystal structures of the four stereoisomers, (I)–(IV),
feature N—Hꢀ ꢀ ꢀCl and O—Hꢀ ꢀ ꢀCl hydrogen bonds (Tables
2–5) between the chloride ions and the amino and hydroxy
groups of the tapentadol molecules. Each chloride ion accepts
two hydrogen bonds from the amino and hydroxy groups of
the tapentadol molecules and forms a one-dimensional helical
chain. In (I) and (II), the helical chain is along the a axis
(Fig. 6), while in (III) and (IV) it is along the b axis (Fig. 7).
Furthermore, in (III) and (IV) C—Hꢀ ꢀ ꢀCl interactions link the
helical chains to adjacent chains.
Experimental
(2R,3R)-3-(3-Hydroxyphenyl)-N,N,2-trimethylpentan-1-aminium
chloride, (I), was prepared as follows. (2R,3S)-1-Dimethylamino-3-(3-
hydroxyphenyl)-2-methylpentan-3-ol tartaric acid salt (35 g, 1 mol)
and water (150 ml) were placed in a round-bottomed flask and an
aqueous ammonia solution (30 ml) was added to obtain a basic pH,
followed by extraction into dichloromethane (150 ml) at 293–298 K.
The organic layer was separated, dried over anhydrous sodium
sulfate and concentrated under reduced pressure to afford an oil.
2-Methyltetrahydrofuran (300 ml) and trifluoroacetic anhydride
(50 ml) were added to this oil at 293–298 K. The mixture was trans-
ferred to an autoclave, Pd/C (9 g, 10% Pd, 50% wet) was added and a
hydrogen pressure (5 to 7 kg cmꢁ2; 1 kg cmꢁ2 = 98066.5 Pa) was
applied. The reaction mixture was heated to 318–323 K for 5 h. After
cooling, the reaction mass was filtered through Celite Hyflo Super Cel
and the filtrate was distilled under vacuum at 318–323 K to obtain an
oil, to which water (150 ml) and aqueous ammonia (30 ml) were
added. The aqueous layer was extracted using dichloromethane
(150 ml) and the organic layer was separated, dried over anhydrous
sodium sulfate and concentrated under vacuum at 308–313 K to
obtain an oil. Propan-2-ol (100 ml) and propan-2-ol–HCl (30 ml, pH
1–2) were added to this oil and the mixture stirred for 1 h at 293–
298 K. The resulting slurry was cooled to 273–278 K for 1 h. The solid
was filtered off and washed with propan-2-ol (30 ml), and then dried
in an air oven at 328 K for 10–12 h. The solid was then recrystallized
from butanone to yield a white solid. Purity by HPLC: 99.53%; m.p.
482–483 K; 1H NMR (D2O): ꢀ 0.54 (t, 3H, –CH2—CH3), 0.96 (d, 3H, –
CH—CH3), 1.42, 1.73 (m, 2H, –CH2—CH3), 2.04 (m, 1H, –CH–
Ethyl), 2.20 (m, 1H, –CH—CH3), 2.61 [s, 6H, –N(Me)2], 2.70, 2.74 (m,
2H, –CH2), 6.62 (d, 1H, Ar—H), 6.69 (dd, 2H, Ar—H), 7.13 (t, 1H,
Ar—H); MS: m/z 221 (M+).
(2S,3R)-3-(3-Hydroxyphenyl)-N,N,2-trimethylpentan-1-aminium
chloride, (IV), was prepared as follows. (2S,3R)-1-Dimethylamino-3-
(3-methoxyphenyl)-2-methylpentane (12 g, 1 mol) and aqueous HBr
(80 ml) were placed in a round-bottomed flask at 293–298 K. The
reaction mass was heated to 373 K for 15–16 h. After cooling, water
(200 ml), ice (200 g) and aqueous ammonia (200 ml) were added to
the reaction mass at 278–283 K. The product was extracted with
dichloromethane (400 ml) and the organic layer was separated, dried
over anhydrous sodium sulfate and concentrated under vacuum at
308–313 K to obtain an oil. Propan-2-ol (100 ml) and propan-2-ol–
HCl (20 ml, pH 1–2) were added to this oil and the mixture stirred for
2 h at 273–278 K. The solid was then filtered off, washed with propan-
2-ol (25 ml), dried in an air oven at 323–328 K and recrystallized from
butanone to yield a white solid (m.p. 478–479 K). 1H NMR (D2O): ꢀ
0.61 (t, 3H, –CH2—CH3), 0.75 (d, 3H, –CH—CH3), 1.59 (m, 2H, –
CH2—CH3), 2.10 (m, 1H, –CH–Ethyl), 2.36 (p, 1H, –CH—CH3), 2.73
[s, 6H, –N(Me)2], 3.09 (dd, 2H, –CH2), 6.63 (d, 1H, Ar—H), 6.69 (dd,
2H, Ar—H), 7.15 (t, 1H, Ar—H); MS: m/z 221 (M+).
HPLC analysis was performed with a Shimadzu LC 2010 series
HPLC system (EMPOWER software) equipped with a quaternary
pump and UV detector monitoring the range 200–400 nm. Isomers
were analysed on a CHIRALPAK AD-3 (250 ꢂ 4.6 mm ꢂ 5 mm)
column using the normal-phase method, while a reverse-phase HPLC
analysis was carried out using INERTSIL ODS-3 V (4.6 ꢂ 250 mm ꢂ
5 mm). The mobile phase was an 85:15 (v/v) mixture of hexane and
tetrahydrofuran, respectively.
Single crystals of all four isomers, (I)–(IV), suitable for X-ray
crystallography studies were obtained by cooling hot methanol
solutions.
(2S,3S)-3-(3-Hydroxyphenyl)-N,N,2-trimethylpentan-1-aminium
chloride, (II), was prepared as follows. Using (2S,3R)-1-dimethyl-
amino-3-(3-hydroxyphenyl)-2-methylpentan-3-ol tartaric acid salt,
(25 g, 1 mol), the above process was followed to obtain (II). It was
recrystallized from butanone to yield a white solid. Purity by HPLC:
99.85%; m.p. 480–481 K; 1H NMR (D2O): ꢀ 0.55 (t, 3H, –CH2—CH3),
0.97 (d, 3H, –CH—CH3), 1.45, 1.74 (m, 2H, –CH2—CH3), 2.06 (m, 1H,
–CH–Ethyl), 2.23 (m, 1H, –CH—CH3), 2.65 [s, 6H, –N(Me)2], 2.70,
2.78 (m, 2H, –CH2), 6.64 (d, 1H, Ar—H), 6.69 (dd, 2H, Ar—H), 7.15
(t, 1H, Ar—H); MS: m/z 221 (M+).
Stereoisomer (I)
Crystal data
C14H24NO+ꢀClꢁ
3
˚
V = 1461.1 (5) A
Z = 4
Mr = 257.79
Monoclinic, P21
Mo Kꢂ radiation
ꢃ = 0.25 mmꢁ1
T = 294 K
0.18 ꢂ 0.15 ꢂ 0.09 mm
˚
a = 7.1600 (15) A
˚
b = 11.688 (3) A
˚
c = 17.514 (4) A
ꢁ = 94.535 (3)ꢃ
(2R,3S)-3-(3-Hydroxyphenyl)-N,N,2-trimethylpentan-1-aminium
chloride, (III), was prepared as follows. Toluene (160 ml), aluminium
chloride (45.3 g) and thiourea (20 g) were placed in a round-
bottomed flask and stirred at 293–298 K for 30 min. (2R,3S)-1-
Dimethylamino-3-(3-methoxyphenyl)-2-methylpentane (20 g, 1 mol)
was dissolved in toluene (40 ml). This solution was added to the
above mixture at 293–298 K and the combined mixture heated at
Data collection
Bruker SMART APEX CCD area-
detector diffractometer
Absorption correction: multi-scan
(SADABS; Bruker, 2001)
Tmin = 0.955, Tmax = 0.976
14096 measured reflections
5135 independent reflections
4972 reflections with I > 2ꢄ(I)
Rint = 0.022
Four stereoisomers of C14H24NO+ꢀClꢁ
Acta Cryst. (2011). C67, o71–o76
ꢄ
o74 Ravikumar et al.

organic compounds
Table 1
Selected valence and torsion angles (ꢃ) for stereoisomers (I)–(IV).
Parameter
(I), molecule A
(I), molecule B
(II), molecule A
(II), molecule B
(III)
(IV)
112.78 (16)
112.95 (14)
59.4 (2)
C7—C8—C9
C8—C7—C10
C1—C7—C8—C9
C1—C7—C10—C12
C7—C10—C12—N1
112.48 (16)
118.80 (13)
63.8 (2)
63.21 (17)
171.87 (13)
114.95 (16)
113.89 (13)
170.38 (16)
65.15 (17)
177.09 (13)
112.59 (18)
111.66 (15)
ꢁ63.6 (2)
115.22 (19)
113.99 (15)
ꢁ170.38 (18)
ꢁ65.6 (2)
112.65 (17)
112.91 (13)
ꢁ59.4 (2)
ꢁ63.4 (2)
170.15 (16)
157.87 (17)
ꢁ170.03 (15)
ꢁ172.03 (15)
ꢁ176.92 (15)
ꢁ157.68 (17)
Refinement
Data collection
R[F2 > 2ꢄ(F2)] = 0.027
wR(F2) = 0.072
S = 1.06
5135 reflections
331 parameters
1 restraint
Áꢅmax = 0.14 e A
ꢁ3
˚
Bruker SMART APEX CCD area-
detector diffractometer
Absorption correction: multi-scan
(SADABS; Bruker, 2001)
Tmin = 0.963, Tmax = 0.986
13998 measured reflections
5139 independent reflections
4883 reflections with I > 2ꢄ(I)
Rint = 0.021
ꢁ3
˚
Áꢅmin = ꢁ0.12 e A
Absolute structure: Flack &
Bernardinelli (2000), with 2430
Friedel pairs
Flack parameter: 0.03 (4)
H atoms treated by a mixture of
independent and constrained
refinement
Refinement
R[F2 > 2ꢄ(F2)] = 0.031
wR(F2) = 0.075
S = 1.06
5139 reflections
331 parameters
1 restraint
H atoms treated by a mixture of
independent and constrained
refinement
Áꢅmax = 0.14 e A
ꢁ3
˚
ꢁ3
˚
Áꢅmin = ꢁ0.10 e A
Absolute structure: Flack &
Bernardinelli (2000), with 2431
Friedel pairs
Stereoisomer (II)
Flack parameter: ꢁ0.02 (4)
Crystal data
C14H24NO+ꢀClꢁ
3
˚
V = 1462.0 (11) A
Z = 4
Mo Kꢂ radiation
ꢃ = 0.25 mmꢁ1
T = 294 K
Mr = 257.79
Monoclinic, P21
˚
a = 7.160 (3) A
˚
b = 11.688 (5) A
˚
c = 17.526 (8) A
0.15 ꢂ 0.12 ꢂ 0.06 mm
Stereoisomer (III)
ꢁ = 94.570 (7)ꢃ
Crystal data
C14H24NO+ꢀClꢁ
3
˚
V = 1498.50 (17) A
Z = 4
Mo Kꢂ radiation
ꢃ = 0.24 mmꢁ1
T = 294 K
Mr = 257.79
Orthorhombic, P212121
Table 2
Hydrogen-bond geometry (A, ) for (I).
ꢃ
˚
˚
a = 8.8218 (6) A
b = 12.1304 (8) A
˚
c = 14.0031 (9) A
˚
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
0.17 ꢂ 0.14 ꢂ 0.09 mm
N1A—H1Nꢀ ꢀ ꢀCl1Bi
O1A—H1Oꢀ ꢀ ꢀCl1A
N1B—H2Nꢀ ꢀ ꢀCl1A
O1B—H2Oꢀ ꢀ ꢀCl1B
0.875 (19)
0.83 (3)
0.90 (2)
0.79 (3)
2.23 (2)
2.24 (3)
2.19 (2)
2.30 (3)
3.0569 (17)
3.0584 (17)
3.0506 (15)
3.0667 (17)
157 (2)
168 (2)
158 (2)
164 (2)
Data collection
Bruker SMART APEX CCD area-
detector diffractometer
Absorption correction: multi-scan
(SADABS; Bruker, 2001)
Tmin = 0.958, Tmax = 0.975
14552 measured reflections
2653 independent reflections
2540 reflections with I > 2ꢄ(I)
Rint = 0.022
Symmetry code: (i) x ꢁ 1; y; z.
Table 3
Hydrogen-bond geometry (A, ) for (II).
Refinement
ꢃ
˚
R[F2 > 2ꢄ(F2)] = 0.030
wR(F2) = 0.081
S = 1.03
2653 reflections
166 parameters
H atoms treated by a mixture of
independent and constrained
refinement
Áꢅmax = 0.20 e A
ꢁ3
˚
ꢁ3
˚
Áꢅmin = ꢁ0.13 e A
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
Absolute structure: Flack &
Bernardinelli (2000), with 1113
Friedel pairs
O1A—H1Oꢀ ꢀ ꢀCl1A
N1A—H1Nꢀ ꢀ ꢀCl1Bi
N1B—H2Nꢀ ꢀ ꢀCl1A
O1B—H2Oꢀ ꢀ ꢀCl1B
0.81 (3)
0.88 (2)
0.91 (3)
0.79 (3)
2.26 (3)
2.23 (2)
2.19 (3)
2.30 (3)
3.060 (2)
3.056 (2)
3.051 (2)
3.067 (2)
169 (3)
156.5 (18)
158.9 (19)
166 (3)
Flack parameter: ꢁ0.02 (7)
Symmetry code: (i) x þ 1; y; z.
Table 4
Hydrogen-bond geometry (A, ) for (III).
Table 5
Hydrogen-bond geometry (A, ) for (IV).
ꢃ
ꢃ
˚
˚
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
N1—H1Nꢀ ꢀ ꢀCl1
O1—H1Oꢀ ꢀ ꢀCl1i
C11—H11Aꢀ ꢀ ꢀCl1
C13—H13Cꢀ ꢀ ꢀCl1ii
0.97 (2)
0.79 (3)
0.96
2.13 (2)
2.32 (3)
2.75
3.0580 (15)
3.1083 (16)
3.620 (2)
160.5 (16)
174 (2)
151
N1—H1Nꢀ ꢀ ꢀCl1
O1—H1Oꢀ ꢀ ꢀCl1i
C11—H11Aꢀ ꢀ ꢀCl1
C13—H13Bꢀ ꢀ ꢀCl1ii
0.95 (2)
0.81 (3)
0.96
2.14 (2)
2.29 (3)
2.75
3.0536 (15)
3.1013 (15)
3.614 (2)
161.0 (16)
175 (2)
151
0.96
2.71
3.657 (3)
168
0.96
2.71
3.651 (3)
167
1
2
1
2
1
2
1
2
1
2
5
2
1
2
3
2
Symmetry codes: (i) ꢁx; y þ ; ꢁz ꢁ ; (ii) x ꢁ ; ꢁy þ ; ꢁz.
Symmetry codes: (i) ꢁx þ 2; y ꢁ ; ꢁz þ ; (ii) x þ ; ꢁy þ ; ꢁz þ 2.
Four stereoisomers of C14H24NO+ꢀClꢁ o75
ꢄ
Acta Cryst. (2011). C67, o71–o76
Ravikumar et al.

organic compounds
program(s) used to solve structure: SHELXS97 (Sheldrick, 2008);
program(s) used to refine structure: SHELXL97 (Sheldrick, 2008);
molecular graphics: DIAMOND (Brandenburg & Putz, 2005),
PLATON (Spek, 2009) and Mercury (Macrae et al., 2008); software
used to prepare material for publication: SHELXL97.
Stereoisomer (IV)
Crystal data
C14H24NO+ꢀClꢁ
3
˚
V = 1491.29 (17) A
Z = 4
Mo Kꢂ radiation
ꢃ = 0.24 mmꢁ1
T = 294 K
Mr = 257.79
Orthorhombic, P212121
˚
a = 8.8101 (6) A
b = 12.1094 (8) A
˚
c = 13.9784 (9) A
˚
The authors thank Dr J. S. Yadav, Director, IICT, Hyder-
abad, for his kind encouragement.
0.21 ꢂ 0.17 ꢂ 0.12 mm
Data collection
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: SF3144). Services for accessing these data are
described at the back of the journal.
Bruker SMART APEX CCD area-
detector diffractometer
Absorption correction: multi-scan
(SADABS; Bruker, 2001)
Tmin = 0.948, Tmax = 0.969
14415 measured reflections
2630 independent reflections
2548 reflections with I > 2ꢄ(I)
Rint = 0.019
References
Refinement
Brandenburg, K. & Putz, H. (2005). DIAMOND. Release 3.0c. Crystal Impact
GbR, Bonn, Germany.
Bruker (2001). SAINT (Version 6.28A), SMART (Version 5.625) and
SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.
Etropolski, M. S., Okamoto, A., Shapiro, D. Y. & Rauschkolb, C. (2010). Pain
Physician, 13, 61–70.
Flack, H. D. & Bernardinelli, G. (2000). J. Appl. Cryst. 33, 1143–1148.
Franklin, R., Golding, T. & Tyson, R. G. (2010). US Patent No. 2010/
0227921A1.
ꢁ3
R[F2 > 2ꢄ(F2)] = 0.030
wR(F2) = 0.083
S = 1.05
2630 reflections
166 parameters
H atoms treated by a mixture of
independent and constrained
refinement
Áꢅmax = 0.22 e A
˚
ꢁ3
˚
Áꢅmin = ꢁ0.13 e A
Absolute structure: Flack &
Bernardinelli (2000), with 1104
Friedel pairs
Flack parameter: 0.00 (6)
Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P.,
Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood,
P. A. (2008). J. Appl. Cryst. 41, 466–470.
Ravikumar, K. & Sridhar, B. (2009). Acta Cryst. C65, o502–o505.
Ravikumar, K. & Sridhar, B. (2010). Acta Cryst. C66, o97–o100.
Reeves, R. R. & Cox, S. K. (2008). South. Med. J. 101, 193–195.
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122.
Spek, A. L. (2009). Acta Cryst. D65, 148–155.
¨
Tzschentke, T. M., Christoph, T., Kogel, B., Schiene, K., Hennies, H. H.,
Englberger, W., Haurand, M., Jahnel, U., Cremers, T. I., Friderichs, E. & De
All N- and O-bound H atoms were located in a difference Fourier
density map and refined isotropically. All other H atoms were posi-
tioned geometrically and treated as riding on their parent C atoms,
˚
with C—H = 0.93–0.98 A, and with Uiso(H) = 1.5Ueq(C) for methyl or
1.2Ueq(C) for other H atoms. The methyl groups were allowed to
rotate but not to tip.
For all compounds, data collection: SMART (Bruker, 2001); cell
refinement: SAINT (Bruker, 2001); data reduction: SAINT;
Vry, J. (2007). J. Pharmacol. Exp. Ther. 323, 265–276.
Four stereoisomers of C14H24NO+ꢀClꢁ
Acta Cryst. (2011). C67, o71–o76
ꢄ
o76 Ravikumar et al.