pharmaceuticals and natural products
Table 1
Experimental details.
Crystal data
Chemical formula
13 2
C H17NO
M
r
219.28
Crystal system, space group
Temperature (K)
1
Monoclinic, P2 /n
100
13.495 (3), 5.6335 (12), 15.721 (4)
109.368 (8)
1127.5 (4)
4
Mo Kꢀ
0.09
˚
a, b, c (A)
ꢄ
ꢂ ( )
˚
3
V (A )
Z
Radiation type
ꢁ1
ꢃ (mm
Crystal size (mm)
)
0.14 ꢅ 0.05 ꢅ 0.02
Data collection
Diffractometer
Absorption correction
Bruker APEXII CCD diffractometer
Multi-scan (SADABS; Bruker, 2006)
0.988, 0.998
Figure 3
The molecular structure of (ꢀ)-threo-2, with displacement ellipsoids
Tmin, Tmax
No. of measured, independent and
observed [I > 2ꢄ(I)] reflections
10280, 2603, 1482
drawn at the 50% probability level for non-H atoms.
R
int
0.097
0.652
˚
ꢁ1
)
(sin ꢅ/ꢆ)max (A
(piperidin-2-yl)acetate (methyl phenidate; 151 mg, 0.64 mmol)
and a tetrahydrofuran–water (7.5:1 v/v) mixture (1 ml) was
added followed by lithium hydroxide monohydrate (105 mg,
Refinement
2
2
2
R[F > 2ꢄ(F )], wR(F ), S
No. of reflections
No. of parameters
0.065, 0.143, 1.12
2603
213
All H-atom parameters refined
2.5 mmol). The resulting heterogeneous mixture was allowed
to stir for a further 19.3 h, during which time the mixture
formed two phases. After this time, the THF was removed and
the crude mixture was diluted with water (1 ml) and treated
with hydrochloric acid (4 M, aqueous) to adjust the pH to 7.
After ca 5 min, a precipitate started to form. Colourless prisms
were collected, washed with ice-cold water and dried to afford
the title compound (yield 50.8 mg, 0.23 mmol, 36%). These
crystals were used for the crystal structure analysis.
H-atom treatment
˚
ꢁ3
)
Áꢇmax, Áꢇmin (e A
0.27, ꢁ0.28
Computer programs: APEX2 (Bruker, 2006), SAINT (Bruker, 2006), SHELXS97
Sheldrick, 2008), OLEX2 (Dolomanov et al., 2009), SHELXL97 (Sheldrick, 2008),
PLATON (Spek, 2009), ORTEPIII (Johnson Burnett, 1996) and SHELXTL
(
&
(Sheldrick, 2008).
(
m, 2H, Ph), 3.61 (d, J = 9.3 Hz, 1H, H7) 3.55 (ddm, J = 2.8,
9
3
1
.3 Hz, 1H, H2), 3.47 (dm, J = 12.8 Hz, 1H, H6e), 3.04 (td, J =
.2, 12.8 Hz, 1H, H6a), 1.87–1.80 (m, 2H, H5 and H4), 1.63–
2.2. Refinement
13
.61 (m, 2H, H3 and H5), 1.46–1.40 (m, 2H, H3 and H4);
C
Crystal data, data collection and structure refinement
NMR (D O, 100 MHz): ꢁ 178.1 (0, C14), 136.8 (0, C8), 129.1 (1,
2
details are summarized in Table 1. All atoms could be loca-
lized and refined with reliable geometry, i.e. non-H atoms
anisotropically and H atoms isotropically.
2
5
2
5
1
1
C, C9 and C13), 128.4 (1, 2C, C10 and C12), 127.8 (1, C11),
9.2 (1, C2), 56.6 (1, C7), 44.9 (2, C6), 26.6 (2, C3), 22.0 (2, C5),
1
1.4 (2, C4). H NMR (NaOD/D O, 400 MHz): ꢁ 7.34–7.25 (m,
2
H, Ph), 3.22 (d, J = 10.3 Hz, 1H, H7), 2.95 (ddm, J = 2.3,
0.4 Hz, 2H, H2 and H6e overlapped), 2.59 (td, J = 2.8,
1.9 Hz, 1H, H6a), 1.60–1.49 (m, 2H, H4 and H5), 1.35–1.22
3. Results and discussion
(
m, 1H, H5), 1.20–1.07 (m, 2H, H3 and H4), 0.94–0.81 (m, 1H,
1
The crystal structure of (ꢀ)-threo-1ꢂHCl is reported to be
3
H3); C NMR (NaOD/D O, 100 MHz): ꢁ 180.5 (0, C14), 139.1
2
challenging due to the significant atomic disorder observed
(
1
0, C8), 128.6 (1, 2C, C9 and C13), 128.4 (1, 2C, C10 and C12),
27.0 (1, C11), 61.6 (1, C7), 58.5 (1, C2), 45.8 (2, C6), 28.6 (2,
C3), 24.6 (2, C5), 23.7 (2, C4).
.1.2. Method B. A round-bottomed flask at ambient
temperature and open to air was charged with methyl
1
(
Glaser et al., 1998) also by us , and other salts of (ꢀ)-threo-1
and its derivatives have been reported (Froimowitz et al., 1998;
Glaser et al., 1998; Steinberg et al., 2011). We recently needed a
sample of clinically relevant (ꢀ)-threo-2 and in the course of
its preparation we performed X-ray diffraction and NMR
solution-state analysis which we now report.
2
2
0
-phenyl-2-(piperidin-2-yl)acetate (methyl phenidate; 104 mg,
.44 mmol) and ethanol (absolute, 0.95 ml). The hetero-
The synthesis of (ꢀ)-threo-2 has been described previously
geneous mixture was treated with aqueous KOH (20 wt%,
.95 ml) to give a clear mixture which was allowed to stir for a
(
Frigerio et al., 2006) and it was accomplished in four steps
0
from commercially available benzonitrile and 2-bromo-
pyridine employing Rh-catalyzed reduction of the pyridine
ring. For our purposes, commercially available amide and the
methyl ester were obtained and the synthesis was envisioned
further 19.3 h, after which time the EtOH was removed and
the crude mixture treated with hydrochloric acid (4 M,
aqueous) dropwise until the precipitate started to form at pH
5
. The precipitate was washed with ice-cold water and dried to
1
afford the title compound (yield 39.5 mg, 0.18 mmol, 40%) as
colourless prisms.
2.1.3. Method C. A round-bottomed flask at ambient tem-
perature and open to air was charged with methyl 2-phenyl-2-
In our laboratory, we obtained crystals of (ꢀ)-threo-1ꢂHCl from MeOH
˚
, a = 20.781, b = 9.198, c = 7.378 A); disorder and twinning
(
space group Pna2
1
did not allow satisfactory refinement of the structure. The structure was
deposited with the Cambridge Structural Database under the deposition
number 956413.
ꢃ
1
226 Wyss et al.
13
C H17NO
2
Acta Cryst. (2013). C69, 1225–1228