Synthesis of some tolperisone metabolites in racemic and optically active form

Article abstract of DOI:10.1016/S0957-4166(02)00025-3

1-(4′-Carboxyphenyl)-2-methyl-3-(piperidine-1-yl)-propan-1-one M3, erythro-1-(4′-carboxyphenyl)-2-methyl-3-(piperidine-1-yl)-propan-1-ol M4 and threo-1-(4′-carboxyphenyl)-2-methyl-3-(piperidine-1-yl)-propan-1-ol M5, metabolites of the muscle relaxant tolp

Full text of DOI:10.1016/S0957-4166(02)00025-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3417–3422
Synthesis of some tolperisone metabolites in racemic and
optically active form
Jo´zsef Ba´lint,a Gabriella Egri,a,* Imre Markovits,a Ma´tya´s Czugler,b Katalin Marthi,c
d
e
a
´
Ada´m Demeter, Krisztina Temesva´ri-Taka´cs and Eleme´r Fogassy
aDepartment of Organic Chemical Technology, Budapest University of Technology and Economics, H-1521 Budapest,
PO Box 91, Hungary
bInstitute of Chemistry, Chemical Research Centre, Hungarian Academy of Sciences, H-1525 Budapest, PO Box 17, Hungary
cResearch Group for Technical Analytical Chemistry Hungarian Academy of Sciences,
Institute of General and Analytical Chemistry Budapest University of Technology and Economics, H-1521 Budapest,
PO Box 91, Hungary
dSpectroscopic Research Division, Gedeon Richter Ltd, H-1475 Budapest 10, PO Box 27, Hungary
eTechnological Development I., Chromatography Laboratory, Gedeon Richter Ltd, H-1475 Budapest 10, PO Box 27, Hungary
Received 4 January 2002; accepted 15 January 2002
Abstract—1-(4%-Carboxyphenyl)-2-methyl-3-(piperidine-1-yl)-propan-1-one M3, erythro-1-(4%-carboxyphenyl)-2-methyl-3-(pip-
eridine-1-yl)-propan-1-ol M4 and threo-1-(4%-carboxyphenyl)-2-methyl-3-(piperidine-1-yl)-propan-1-ol M5, metabolites of the
muscle relaxant tolperisone were synthesized in racemic and optically active forms. © 2002 Elsevier Science Ltd. All rights
reserved.
1. Introduction
methyl-3-(piperidine-1-yl)propan-1-one M3, erythro-1-
(4%-carboxyphenyl)-2-methyl-3-(piperidine-1-yl)propan-
1-ol M4 and threo-1-(4%-carboxyphenyl)-2-methyl-3-
(piperidine-1-yl)propan-1-ol M5 is presented herein.
This paper is the third part of a series of papers
presenting our work on the tolperisone metabolites. As
known, tolperisone is a widely used muscle relaxant.
The
D
-enantiomer is mainly responsible for the muscle
-tolperisone has bronchodilatory
relaxing effect, while
L
and peripheral vasodilatory activity.1 Following the
metabolic pathway described by Japanese researchers2
we aimed to produce all of the major human metabo-
lites on preparative scale for pharmacological purposes.
Following on from the synthesis of 3%-hydroxy-4%-
methylphenyl)-2-methyl-3-(piperidine-1-yl)propan-1-
one, M13 and 1-(4%-hydroxymethylphenyl)-2-methyl-
3-(piperidine-1-yl)propan-1-one M24 the preparation of
racemic and optically active 1-(4%-carboxyphenyl)-2-
2. Results and discussion
It was assumed that racemic M3 could be synthesized
from 4-propionyl-benzoic acid via the Mannich reac-
tion. However, known methods for producing 4-propi-
onylbenzoic acid 2 are complicated reactions, often
with low yield.5 We obtained the acid 2 in a workable
yield from (4%-hydroxymethylphenyl)propan-1-one4 by
KMnO4 oxidation of the benzyl alcohol 1 (Fig. 1).
Figure 1. Preparation of ( )-M3.
* Corresponding author. Fax: +36 1 4633648; e-mail: egrig@ella.hu
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00025-3

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J. Ba´lint et al. / Tetrahedron: Asymmetry 12 (2001) 3417–3422
Normal Mannich reaction (ethanol/paraformaldehyde
or water/formaldehyde systems) failed to yield M3, but
the previously reported solvent-free method3,4 proved
to be efficient: thus, compound 2 was heated with
paraformaldehyde and a catalytic amount of ethanolic
hydrogen chloride without solvent, and ( )-M3 was
produced in a few hours (Fig. 1).
tiomer see Fig. 3; (R)-M3 was obtained from (R)-M2
the same way).
As reduction of M3 with sodium borohydride resulted
in almost complete racemization, another method was
sought. We found that catalytic hydrogenation did not
affect the enantiomeric purity. Hydrogenation of (S)-
and (R)-M3 resulted in an 80:20 mixture of M4 and M5
(For (1S,2S)-M5 and (1R,2S)-M4 see Fig. 4) (R)-M3
yields (1S,2R)-M4) and (1R,2R)-M5. As in this case the
starting M3 was homochiral, the reaction mixture con-
tained only two stereoisomers from the four possible.
As the two products have a diastereoisomeric relation-
ship (erythro- and threo-), they should be separated
without further chiral effect. In fact, M4 could be
obtained in an enantiopure form by fractional crystal-
lization from methanol, but we could obtain pure M5
only by chromatographic separation.
The carbonyl group of M3 can be reduced with sodium
borohydride (Fig. 2). As 1-(4%-carboxyphenyl)-2-methyl-
3-(piperidine-1-yl)propan-1-ol (M4 and M5) has two
asymmetric centers, the reaction mixture will contain all
of the four possible stereoisomers: the (1S,2R)- and
(1R,2S)-isomers are of erythro-configuration, while the
(1S,2S)- and (1R,2R)-isomers are of threo-configura-
tion (M4 and M5, respectively). The M4/M5 ratio is
about 65:35, as determined by HPLC (see Section 3).
M4 and M5 can be separated by fractional crystalliza-
tion and preparative HPLC.
2.1. Absolute configurations
Attempts at the resolution of M3 using several resolv-
ing agents failed. To eliminate difficulties due to the
amphotherism of the molecule, the M3 ethyl ester was
also subjected to resolution experiments, but these were
also unsuccessful. Finally, (S)-M3 and (R)-M3 were
synthesized from the corresponding enantiomers of the
previous metabolite M2 by oxidation (for the (S)-enan-
The configuration of M2 has already been established4
and as the oxidation (M2 to M3) does not influence the
stereogenic center, the configuration of M3 can be
deduced. As for M4 and M5, when starting from
homochiral M3, the absolute configuration at the 2-
position remains the same and the two stereoisomers
Figure 2. Synthesis of racemic 1-(4%-carboxyphenyl)-2-methyl-3-(piperidine-1-yl)propan-1-ol ( )-M4 and ( )-M5.
Figure 3. Synthesis of (S)-M3.

J. Ba´lint et al. / Tetrahedron: Asymmetry 12 (2001) 3417–3422
3419
Figure 4. Synthesis of enantiopure M4 and M5.
Figure 5. X-Ray structure model of (+)-(1R,2S)-M4 hydrochloride.
are formed around C(1). The erythro and threo rela-
Bruker WM250 spectrometer as well as on a Varian
UNITYINOVA spectrometer at 300 and 500 MHz.
Chemical shifts are given relative to lTMS=0.00 ppm.
Chemical shift values are expressed in ppm values on
the l scale. IR spectra of KBr samples were taken on a
Perkin–Elmer 1600 Series FT-IR spectrophotometer.
Optical rotations were determined on a Perkin–Elmer
241 polarimeter. Chemicals were purchased from
Aldrich Chemical Company. All solvents used were
freshly distilled.
1
tionships were determined by the H NMR coupling
constants (see Section 3), allowing us to assign the
absolute configuration, which was confirmed by single
crystal X-ray crystallography of (+)-M4 (Fig. 5).
The crystal structure of (+)-(1R,2S)-M4 hydrochloride
has been determined by single crystal X-ray diffraction.
Its absolute configuration has been established based
on the absolute structure parameter of 0.00(3).6 Fig. 57
shows the configuration and the conformation (1R,2S)-
M4 cation adopts in the crystal lattice. Two cations
related by a two-fold screw axis are hydrogen bond
donors to the same chloride ion. The same two cations
are hydrogen bonded with an NꢀH···O(ꢁC) hydrogen
bond as well, giving rise to a 12-membered ring motif
Analytical HPLC conditions for M4/M5 ratios were as
follows: column: Macherey–Nagel nucleosil 100–5 C18
5 mm 125×4 mm; eluent: acetonitrile:McIlvain buffer
38:62, containing 0.01 M sodium lauryl sulfate (McIl-
vain buffer: 98 mL of 0.1 M citric acid, 2 mL of 0.2 M
Na2HPO4, 900 mL of HPLC grade water, pH adjusted
to 2.2 by H3PO4); flow rate 0.5 mL/min; detector: UV,
u1=254 nm and u2=235 nm; injected volume: 20 mL;
temperature: rt.
2
with three donor and two acceptor atoms (R3 (12)).
The cation chains run parallel to the b axis and are
linked by weaker CꢀH···O hydrogen bonds.
1
3. Experimental
The enantiomeric purity of M2 was determined by H
NMR using (R)-(−)-1-(9-anthryl)-2,2,2-trifluoroethanol
as described in our previous paper.4 For assessing the
enantiomeric purity of M4 and M5 we developed the
following NMR method.
3.1. Materials and methods
1H NMR spectra were recorded at 250 MHz on a

3420
J. Ba´lint et al. / Tetrahedron: Asymmetry 12 (2001) 3417–3422
Racemic M4 (1 mg) and b-cyclodextrin (7 mg) were
dissolved in D2O (1 mL) and the pH was adjusted to
pH 13.1 by adding NaOD (30 mL of 40 m/m%) to the
solution. In the presence of b-cyclodextrin, applied as a
chiral additive, the aromatic protons and the methyl
group of the respective enantiomers showed distinct sets
2940, 2674, 2553, 1686, 1570, 1504, 1427, 1413, 1321,
1294, 1127, 1114, 954, 760. Calcd for C10H10O3: C,
67.41; H, 5.66; found C, 67.36; H, 5.68%.
3.3. Racemic 1-(4%-carboxyphenyl)-2-methyl-3-(pipe-
ridine-1-yl)propan-1-one ( )-M3
1
of signals in the H NMR spectrum. From a quantita-
To a mixture of 4-carboxypropiophenone 2 (8.0 g,
0.045 mol), piperidine hydrochloride (8.8 g, 0.072 mol)
and paraformaldehyde (2.7 g), was added ethanolic
hydrogen chloride (1.5 mL). The mixture was stirred at
100–110°C for 2.5 h. After cooling, ethyl acetate (20
mL) was added to the solid mass. The resulting crystals
were filtered, washed with acetone, dried and recrystal-
lized from hot water: white crystalline 1-(4%-car-
boxyphenyl) - 2 - methyl - 3 - (piperidine - 1 - yl)propan - 1-
one·HCl·2H2O (M3·HCl·2H2O, 6.76 g, 19.4 mmol,
43%), mp: 166–168°C; 1H NMR (300 MHz, DMSO-d6):
l 1.20 (d, 3H, CH3, 7.3 Hz), 1.30–2.00 (br, 6H, pipe-
tive analysis point of view the aromatic doublets res-
onating at 7.35 ppm [(1R,2S)-(+)-M4] and 7.39 ppm
[(1S,2R)-(−)-M4] proved to be the most feasible as
they exhibited the largest enantiomeric separation
(Dl(1S,2R)-(1R,2S)=26.6 Hz at 500 MHz). In the case of
optically pure M4 samples only one signal set corres-
ponding to the respective enantiomer could be detected.
Based on the NMR results, (1R,2S)-(+)-M4 and (1S,
2R)-(−)-M4 are assumed to be enantiopure (e.e. >99%).
The enantiomeric purity of M5 was assessed from a
mixture of M4 and M5 using the b-cyclodextrin method
as described above. However, due to a substantial
signal overlap of the aromatic protons of M4/M5, the
enantiomeric purity of M5 was determined using the
CHꢀCH3 methyl signal resonating at 0.62 ppm
[(1S,2S)-(−)-M5] and 0.66 ppm [(1R,2R)-(+)-M5]
(Dl(1R,2R)-(1S,2S)=18.6 Hz at 500 MHz). Note that the
methyl signals of M4 appear at 0.82 ppm [(1R,2S)-(+)-
M4] and 0.85 ppm [(1S,2R)-(−)-M4], respectively. The
observed separation (Dl(1S,2R)-(1R,2S)=11.4 Hz at 500
MHz) is still sufficient for the e.e. measurement of M4
in the M4/M5 mixture. In the 1H NMR spectrum of the
M4/M5 mixture, only one methyl signal corresponding
to a single enantiomer was observed for both M4 and
M5 when the reaction was carried out from enan-
tiomerically pure M3. Therefore M5 is assumed to be
enantiomerically pure (e.e. >99%)
2
ridine-CH2), 3.13 (dd, 1H, Hx-CH2, J=13.2 Hz and
2
3J=4.2 Hz), 3.60 (dd, 1H, Hy-CH2, J=13.2 Hz and
3J=7.3 Hz), 2.70–3.70 (br, 4H, piperidine-CH2+
exchangeable protons), 4.26–4.41 (m, 1H, CH), 8.06–
8.21 (m, 4H, Ar-H), 10.4 (br s, 1H, exchangeable
proton); FT-IR (KBr, cm−1): 3401, 3180, 1941, 2754,
1679, 1571, 1410, 1276, 1081, 967, 719, 549. Calcd for
C16H26ClNO5: C, 55.25; H, 7.53, N, 4.03; found C,
55.32; H, 7.93; N, 4.02%.
3.4. Racemic erythro-1-(4%-carboxyphenyl)-2-methyl-3-
(piperidine-1-yl)propan-1-ol ( )-M4
To
a solution of racemic 1-(4%-carboxyphenyl)-2-
methyl - 3 - (piperidine - 1 - yl)propan - 1 - one·HCl·2H2O
(M3·HCl·2H2O, 10.0 g, 28.75 mmol) in methanol (50
mL) was added NaOH solution (2.3 g, 57 mmol in 5
mL of water). The resulting crystalline suspension was
treated by slow addition of sodium borohydride (1.2 g,
31.7 mmol). The clear solution was stirred for 10 min at
room temperature and then stirred under reflux for 5
min. After cooling, aqueous 37% HCl solution (14 mL)
was added and the solvent was evaporated in vacuo.
After adding methanol (50 mL) and bringing the mix-
ture to boil, inorganic impurities were removed by
filtration. To the solution diethyl ether (100 mL) was
added and the crystals were filtered to give a mixture of
M4 and M5 (ca. 65:35) as a white crystalline solid (5.75
g), which was recrystallized from methanol (11.5 mL)
to yield erythro-1-(4%-carboxyphenyl)-2-methyl-3-(pipe-
ridine-1-yl)propan-1-ol·HCl (M4·HCl, 2.62 g, 8.35
mmol, 29%), mp: 236–238°C; 1H NMR (500 MHz,
Due to the fact that at basic pH M3 underwent rapid
racemization, the developed b-cyclodextrin method
could not be applied for assessing the enantiomeric
purity of M3. At neutral pH the observed slight enan-
tiomeric separation of the signals was insufficient for
quantitative e.e. determination. However, since the
reaction mixture of M4/M5 was neither recrystallized
nor treated in other ways that would affect e.e., the
enantiomeric purity of M3 follows indirectly from the
results obtained in the M4/M5 mixture.
3.2. 4-Carboxypropiophenone 2
To a suspension of (4%-hydroxymethyl-phenyl)-propio-
phenone (1, 4.1 g, 0.025 mol) in water (20 mL) contain-
ing phase-transfer catalyst TEBA (0.1 g), was added
KMnO4 (4.0 g, 0.025 mol) slowly at 10–15°C. After the
color of KMnO4 disappeared, the MnO2 precipitate
was filtered off. The filtrate was acidified with cc. HCl
to pH 3. During this addition white crystals precipi-
tated. The mixture was filtered, and the filter cake
washed with water and dried to afford 4-carboxypro-
piophenone 2 (3.29 g, 18.5 mmol, 74%), mp: 153–154°C
3
DMSO-d6): l 0.70 (d, 3H, CH3, J=6.8 Hz), 1.30–2.10
(br m, 6H, piperidine-CH2), 2.30–2.41 (m, 1H, CH),
2.80–3.05 (m, 2H, piperidine-CH2), 2.89 (dd, 1H, Hx-
CH2, 2J=13.0 Hz and 3J=6.0 Hz), 3.23 (dd, 1H,
2
3
Hy-CH2, J=13.0 Hz and J=7.0 Hz), 3.30–3.60 (br,
2H, piperidine-CH2), 5.07 (d, 1H, CH, 3J=2.7 Hz),
3
5.69 (br s, 1H, OH), 7.56 (d, 2H, Ar-H, J=8.5 Hz),
7.92 (d, 2H, Ar-H, 3J=8.5 Hz), 10.42 (br s, 1H,
exchangeable proton), 12.80 (br s, 1H, exchangeable
proton); FT-IR (KBr, cm−1): 3441, 3100–2400, 1704,
1611, 1476, 1397, 1237, 1100, 1053, 961, 880, 841, 748,
675, 559. Calcd for C16H24ClNO3: C, 61.24; H, 7.71; N,
4.46; found C, 61.35; H, 7.73; N, 4.47%.
1
(lit.:8 157–158°C); H NMR (250 MHz, CDCl3): l 1.23
3
3
(t, 3H, CH3, J=7.3 Hz), 3.03 (q, 2H, CH2, J=7.3
Hz), 8.05 (d, 2H, Ar-H, 3J=7.7 Hz), 8.19 (d, 2H, Ar-H,
3J=8.2 Hz); FT-IR (KBr, cm−1): 3430, 3069, 2979,

J. Ba´lint et al. / Tetrahedron: Asymmetry 12 (2001) 3417–3422
3421
3.5. (S)-1-(4%-Carboxyphenyl)-2-methyl-3-(piperidine-1-
yl)propan-1-one (S)-M3
3.8. (1S,2R)-1-(4%-Carboxyphenyl)-2-methyl-3-(piperid-
ine-1-yl)propan-1-ol (1S,2R)-M4
(S) - 1 - (4% - Hydroxymethylphenyl) - 2 - methyl - 3 - (pipe-
ridine-1-yl)propan-1-one (M2, 4.7 g, 18.0 mmol,
[h]2D5=+28.8 [c=1, methanol]) was suspended in acet-
one (47 mL) and modified Jones’ reagent† (7 mL) was
added dropwise. The mixture was stirred at 40–45°C
for 0.5 h, then further Jones reagent (2.4 mL) was
added. After an additional stirring of 20 min, more
Jones reagent (1.3 mL) was added and the mixture
was stirred for a further 10 min. The solvent was
decanted from the thick, green, slurry and the solid
was washed with acetone (2×5 mL). To the superna-
tant liquid, diethyl ether (75 mL) and isopropanolic
hydrogen chloride (4 mL, 17 g HCl/100 mL) was
added. The crystallizing mixture was allowed to stand
at room temperature for 1 h then at −78°C for a
further hour. The crystals were collected by filtration,
washed with acetone:water (1:1) and then washed with
acetone and dried to afford (S)-1-(4%-carboxyphenyl)-
2-methyl-3-(piperidine-1-yl)propan-1-one·HCl·H2O (S)-
HCl·H2O, (3.57 g, 10.8 mmol, 60%), [h]2D5=+42.8
(c=1, methanol), mp: 120–123°C. NMR, IR and EA
data were identical within experimental error to those
of the racemate.
Starting from (R)-1-(4%-carboxyphenyl)-2-methyl-3-
(piperidine-1-yl)propan-1-one·HCl·H2O (R)-HCl·H2O
(5.56 g, 16.86 mmol), [h]2D5=−43.2 (c=1, methanol),
and proceeding as described above, crystalline
(1S,2R)-1-(4%-carboxyphenyl)-2-methyl-3-(piperidine-1-
yl)propan-1-ol·HCl (1S,2R)-M4·HCl, 1.88 g, 5.99
mmol, 36%), [h]2D5=−16.2 (c=1, methanol), mp: 218–
221°C was obtained. NMR, IR and EA data were
identical within experimental error to those of the
racemate.
3.9. Threo-1-(4%-carboxyphenyl)-2-methyl-3-(piperidine-
1-yl)propan-1-ol M5: racemic and optically active
M5 can be obtained by preparative HPLC from the
mother liquor of the recrystallization of the M4–M5
mixtures. Preparative HPLC conditions were as fol-
,
lows: Column: Waters Preppack Cartridge C18 125 A
55–105 mm, 300×47 mm (WAT 025876); eluent:
methanol:water 15:85 and 0.5 mL 37% aqueous HCl
solution added to each litre of eluent; detector: UV,
u=254 nm; flow rate: 40 mL/min; sample preparation:
dissolving in eluent (1–2 g of sample, dissolved in 100
mL); three subsequent separation steps were carried
out to result in a final purity of ]95%.
3.6. (R)-1-(4%-Carboxyphenyl)-2-methyl-3-(piperidine-1-
yl)propan-1-one (R)-M3
1
Starting
from
(R)-1-(4%-hydroxymethylphenyl)-2-
( )-M5 mp: 233–236°C; H NMR (500 MHz, DMSO-
3
methyl-3-(piperidine-1-yl)propan-1-one M2 (2.5 g, 9.57
mmol), [h]2D5=−28.1 (c=1, methanol), proceeding as
described above, (R)-1-(4%-carboxyphenyl)-2-methyl-3-
(piperidine-1-yl)propan-1-one·HCl·H2O (R)-HCl·H2O,
1.64 g, 4.97 mmol, 52%), [h]2D5=−43.3° (c=1,
methanol), mp: 120–123°C was obtained. NMR, IR
and EA data were identical within experimental error
to those of the racemate.
d6): l 0.87 (d, 3H, CH3, J=6.8 Hz), 1.30–2.05 (br m,
6H, piperidine-CH2), 2.25–2.33 (m, 1H, CH), 2.67–
3.00 (br m, 2H, piperidine-CH2), 2.92 (dd, 1H, Hx-
CH2, 2J=13.2 Hz and 3J=7.7 Hz), 3.18 (dd, 1H,
Hy-CH2, J=13.2 Hz and J=4.4 Hz), 3.21–3.50 (br
m, 2H, piperidine-CH2), 4.46 (d, 1H, CH, J=7.5 Hz),
2
3
3
3
5.97 (br s, 1H, OH), 7.50 (d, 2H, Ar-H, J=8.5 Hz),
7.92 (d, 2H, Ar-H, 3J=8.5 Hz), 9.99 (br s, 1H,
exchangeable proton), 12.87 (br s, 1H, exchangeable
proton); FT-IR (KBr, cm−1): 3700–2200, 2952, 1710,
1612, 1578, 1458, 1421, 1108, 1016, 972, 778, 708, 655.
Anal. calcd for C16H24ClNO3: C, 61.24; H, 7.71; N,
4.46. Found C, 61.14; H, 7.70; N, 4.47%.
3.7. (1R,2S)-1-(4%-Carboxyphenyl)-2-methyl-3-(pipe-
ridine-1-yl)propan-1-ol (1R,2S)-M4
To a solution of (S)-1-(4%-carboxyphenyl)-2-methyl-3-(pi-
peridine-1-yl)propan-1-one·HCl·H2O (S)-M3·HCl·H2O,
7.0 g, 21.22 mmol, [h]D25=+42.8 (c=1, methanol) 10%
Pd–C catalyst (SQ-6,9 0.7 g) and the mixture was
hydrogenated for 45 min at room temperature and
atmospheric pressure. Hydrogen uptake was 465 cm3.
After filtering off the catalyst and removing the
methanol 6.77 g of an amorphous foam was obtained:
about 80:20 mixture of M4 and M5. It was recrystal-
lized twice from methanol (7 and 4 mL, respectively) to
yield a white crystalline solid of (1R,2S)-1-(4%-carboxy-
phenyl)-2-methyl-3-(piperidine-1-yl)-propan-1-ol·HCl
(1R,2S)-M4·HCl, 2.12 g, 6.76 mmol, 32%), [h]2D5=
+16.2 (c=1, methanol), mp: 218–221°C. NMR, IR
and EA data were identical within experimental error
to those of the racemate.
(1R,2R)-M5: Oily amorphous solid, [h]2D5=+24.6 (c=
1, methanol); NMR, IR and EA data were identical
within experimental error to those of the racemate.
(1S,2S)-M5: Oily amorphous solid, [h]2D5=−24.4 (c=1,
methanol); NMR, IR and EA data were identical
within experimental error to those of the racemate.
3.10. X-Ray crystallography
(+)-M4 (50 mg) was dissolved in warm methanol (0.2
mL) and acetone (2 mL) was added. After seeding and
standing for 48 h suitable crystals formed. A crystal of
(+)-(1R,2S)-M4 hydrochloride was mounted on a glass
fiber. Cell parameters were determined by least-squares
of the setting angles of 25 (19.075q519.93°)
reflections.
† Modified Jones’ reagent: CrO3 (6.75 g) and 96% H2SO4 (5.75 mL)
made up with distilled water to a total volume of 25.0 mL.

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J. Ba´lint et al. / Tetrahedron: Asymmetry 12 (2001) 3417–3422
Crystal data, experimental and refinement details.
Empirical formula: C16H24ClNO3, formula weight:
313.81, colorless, block crystals, size: 0.55×0.45×0.40
mm, crystal system: monoclinic, space group P21, unit
Hydrogen atoms were included in structure factor cal-
culations but they were not refined. The isotropic dis-
placement parameters of the hydrogen atoms were
approximated from the U(eq) value of the atom they
were bonded to.
cell dimensions: a=7.201(1), b=14.958(1), c=7.792(1)
3
,
,
A, i=90.43(1)°, V=839.27(17) A , T=295(2) K, Z=2,
F(000)=336, Dx=1.242 Mg/m3, v=0.237 mm−1.
Acknowledgements
Intensity data were collected on a Enraf–Nonius CAD4
diffractometer (graphite monochromator; Mo Ka radi-
,
ation, u=0.710730 A) at 295(2) K in the range 2.725
The Hungarian OTKA Foundation (Project No’s:
T29251) is gratefully acknowledged for financial sup-
port. J.B. thanks the Zolta´n Magyary Foundation and
OTKA (D 32705) for a postdoctoral fellowship. G.E.
thanks the OTKA (D 29445) for a postdoctoral fellow-
ship. The Gedeon Richter Ltd is acknowledged for
financial support.
q534.95° using ꢀ/2q scans. Backgrounds were
measured one half the total time of the peak scans. The
intensities of three standard reflections were monitored
regularly (every 60 min). The intensities of the standard
reflections indicated a crystal decay of 4% (the data
were corrected for decay).
A total of 7876 reflections were collected of which 6915
were unique [R(int)=0.0092, R(|) =0.0127]; intensities
of 6140 reflections were greater than 2| (I). Complete-
ness to q=0.938.
References
1. Furuta, Y.; Nakamura, K.; Tashiro, Y.; Taka, S.;
Nagashima, T.; Japan. Kokai 78 40,779; CA 89, 10918m,
1978
2. Miyazaki, H.; Ishibashi, M.; Takayama, H.; Abuki, H.;
Idzu, G.; Morishita, N.; Ando, M. Proceedings of the 4th
Symposium on Drug Metabolism and Action; 1972 (Pub.
1973); pp. 154–164.
A psi-scan absorption correction was applied to the
data (the minimum and maximum transmission factors
were 0.489 and 1.00).
The initial structure model was obtained by direct
methods.10
3. Ba´lint, J.; Hell, Z.; Markovits, I.; Pa´rka´nyi, L.; Fogassy,
E. Tetrahedron: Asymmetry 2000, 11, 1323–1329.
4. Ba´lint, J.; Markovits, I.; Egri, G.; Tuza, Z.; Fogassy, E.;
Pa´rka´nyi, L. Tetrahedron: Asymmetry 2001, 12, 719–724.
5. Camps, P.; Gimez, S.; Farres, X.; Mauleon, D.; Cargam-
ico, G. Liebigs Ann. Chem. 1993, 641–644.
Anisotropic full-matrix least-squares refinement11 on F2
for all non-hydrogen atoms yielded R1=0.0305 and
wR2=0.0805 for 6140 [I>2|(I)] and R1=0.0369 and
wR2=0.0832 for all (6915) intensity data, (number of
parameters=194,
goodness-of-fit=1.023,
absolute
structure parameter x=0.00(3), the maximum and
mean shift/esd is 0.007 and 0.001).
6. Flack, H. D. Acta Crystallogr. 1983, A39, 876–881.
7. PLATON: Spek, A. L. Acta Crystallogr. 1990, A46, C34.
8. Piper, J. R.; Johnson, C. A.; Otter, G. M.; Sirotnak, F.
M. J. Med. Chem. 1992, 16, 3002–3006.
9. Ma´the´, T.; Tungler, A.; Petro´, J. Hung. Pat. 177860
10. SHELXS. Sheldrick, G. M. SHELXS-97 Program for
Crystal Structure Solution; University of Go¨ttingen: Ger-
many, 1997.
The maximum and minimum residual electron density
−3
,
in the final difference map was 0.362 and −0.182 e A .
(The applied weighting scheme was w=1/[|2(Fo )+
2
(0.0630P)2+0.0000P] where P=(Fo +2Fc )/3.)
2
2
11. Sheldrick, G. M. SHELXL-97 Program for Crystal
Structure Refinement; University of Go¨ttingen: Germany,
1997.
Hydrogen atomic positions were calculated from
assumed geometries except those of the OH group and
salt proton, which were located in difference maps.