Chiral drugs related to guaifenesin: synthesis and phase properties of methocarbamol and mephenoxalone

Article abstract of DOI:10.1016/j.tetasy.2007.05.019

The muscle relaxant methocarbamol 2 and tranquilizer mephenoxalone 3, as well as intermediate cyclic carbonate 4, have been prepared in enantiopure form by starting from enantiopure guaifenesin 1 easily available by an entrainment resolution procedure. Th

Full text of DOI:10.1016/j.tetasy.2007.05.019

Tetrahedron: Asymmetry 18 (2007) 1239–1244
Chiral drugs related to guaifenesin: synthesis and phase properties
of methocarbamol and mephenoxalone
Alexander A. Bredikhin,* Zemfira A. Bredikhina, Dmitry V. Zakharychev
and Alexander V. Pashagin
A.E. Arbuzov Institute of Organic and Physical Chemistry, Russian Academy of Sciences, Arbuzov St., 8,
Kazan 420088, Russian Federation
Received 19 April 2007; accepted 21 May 2007
Abstract—The muscle relaxant methocarbamol 2 and tranquilizer mephenoxalone 3, as well as intermediate cyclic carbonate 4, have been
prepared in enantiopure form by starting from enantiopure guaifenesin 1 easily available by an entrainment resolution procedure. Ther-
mal investigations reveal that 2 is probably a conglomerate forming substance, 3 forms a stable racemic compound, and 4 occupies an
intermediate position. The enantiomeric excess of a binary phase eutectic point for these substances comprises 0%, 85%, and 10%,
respectively.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
OH
*
O
OH
O
OH
O
O
NH2
Recently we have described1 a very practical entrainment
procedure for the direct resolution of 3-(2-methoxyphen-
oxy)-1,2-propanediol 1, the chiral drug guaifenesin.2a,3a
This compound can be treated as a typical New Chiral Pool
representative taking into account the easiness of both
enantiomer production and wide possibilities to transform
the framework of guaifenesin to other useful substances. In
the previous paper we reported the conversion of scalemic
1 to single enantiomer b-blockers levomoprolol and levo-
tensin.1 The obvious structural similarity is also present be-
tween guaifenesin and the skeletal muscle relaxant and
spasmolytic methocarbamol 22b,3b and tranquilizer
mephenoxalone 3.2c,3c
*
2
O
1
Methocarbamol
Guaifenesin
O
O
O
O
O
O
NH
O
O
*
4
*
3
Mephenoxalone
in experiments in mice.5 Bearing in mind a general ten-
dency for the replacement of racemic drugs by their single
enantiomer analogues, we wanted to represent herein the
synthesis and properties of scalemic 2 and 3, as well as a
valuable intermediate in the synthesis of 2 and undesirable
side product in the synthesis of 3 cyclic carbonate 4.
Methocarbamol is a popular remedy for different health
disorders. Recent investigations have shown that two
thirds of the prescriptions for muscle relaxants among indi-
viduals with back pain in the United States were attribut-
able to methocarbamol (along with cyclobenzaprine and
carisoprodol).4 Until now methocarbamol was used as a
racemate, yet rather different activities for racemic and
the individual (+)-2 enantiomer have been demonstrated
A chiral compound, due to the very fact of its chirality, re-
quires some additional characteristics for its description.
Data for the latter include the customary sign and value
of optical rotation power and the measure of enantiomeric
composition, the ee value. An important quantity in deter-
mining the method of resolution of such a compound and/
or the possibilities for its further enantioenrichment is the
composition of its eutectic point.6 The last is the special
*
Corresponding author. Tel.: +7 843 2727392; fax: +7 843 2731872;
e-mail: baa@iopc.knc.ru
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.05.019

1240
A. A. Bredikhin et al. / Tetrahedron: Asymmetry 18 (2007) 1239–1244
point on the binary or ternary phase diagram where the
three phases, liquid (melt or solution) and two solid (either
two individual enantiomers or enantiomer and racemic
compound) exist in equilibrium. If the enantiomeric excess
of the eutectic point (eutectic ee, eeeu) is exactly equal
to zero, we are dealing with a conglomerate forming
compound. For this compound, the direct resolution
approaches could be realized and the enantiomeric
composition of any scalemic (non-racemic) sample could
be enriched to any desirable degree by fractional crystalli-
zation. If the eutectic ee lies between 0 and 1 (0–100%),
we are dealing with a racemic compound forming sub-
stance. For this system, the direct resolution is impossible,
but if the ee of the starting sample is lower than the eutectic
ee, the predominant enantiomer can be enriched in the
liquid phase (mother liquor) to the eutectic ee extent,
whereas the precipitate will tend to be aracemate. If the
solution of the starting material has an ee higher than the
eutectic ee, a pure predominant enantiomer or mixtures
of enantiomers with an ee higher than the eutectic ee can
be crystallized out. Equilibrium crystallization of the sam-
ple with eutectic ee could not change its enantiomeric com-
position neither in the precipitate nor in the filtrate form.
The non-equilibrium crystallization method reminds us
that the well known ‘resolution by entrainment’ can be
used for enantioseparation in this case.7
2. Results and discussion
2.1. Chemistry
Guaifenesin enantiomers are easily available through our
previously described direct resolution procedure1 and were
used as starting materials for all the investigated products.
For the synthesis of racemate and both enantiomers of the
methocarbamol 2, we followed the scheme of Baizer et al.12
The synthesis the existing guaifenesin chiral center is bound
to conserve its configuration, meaning (R)-4 and (R)-2 have
to be obtained from (S)-1 and vice versa (configuration
descriptors are changing for formal reasons, because
C(O)NH2 group has higher rank than substituted phenyl
group in the CIP system).
rac-1
resolution
by entrainment
O
O
O
HO
OH
H
H
HO
O
O
OH
O
(R)-1
(S)-1
(EtO)2C=O
-EtOH
(EtO)2C=O
-EtOH
Until now, there are no firmly established interdependences
between binary and ternary phase diagram eutectic point
compositions. On the one hand, theoretical treatment
shows that the ternary eutectic ee is independent of the nat-
ure of achiral solvent(s) in dilute solution if no solvates are
formed.8 The same treatment also shows that eutectic ee
must vary with temperature: increasing the crystallization
temperature will decrease the eutectic ee. Although the
experimental evidence for the last statement remains very
scarce,8,9 Wang et al. have reported that it is misleading
to use a calculated or measured eutectic composition at
the binary eutectic temperature in place of the eutectic ee
at the temperature of interest.8 On the other hand, a thor-
ough investigation of the phase behavior for mandelic acid
has shown practical constancy of the eutectic composition
in the broad temperature range (0–115 ꢁC) and coincidence
of binary and ternary (water as a solvent) eutectics.10 The
close agreement between the melting and solubility (in eth-
anol and water system) phase diagram eutectics have been
shown for chiral drug ketoprofen.11
O
O
O
H
O
O
H
O
O
O
(R)-4
NH3
(S)-4
NH3
O
O
H OH
O
HO H
O
NH2 H2N
O
O
O
O
(R)-2
(S)-2
We are unaware of any published data for the chiroptical
properties of cyclic carbonate 4, and some uncertainties
concerning the absolute configuration and the sign of the
specific rotation for methocarbamol 2 existing in the avail-
able literature. Souri et al. have reported that the (R)-(+)-
enantiomer of methocarbamol is more biologically active.5
The authors did not mention the conditions for rotary
power determinations, but we know from our experience
that at least in alcohols and water, (R)-2 has a negative spe-
cific rotation. Demian13 reported that the signs of the spe-
cific rotation and the configuration descriptors (R or S) for
1 and 2 have not been combined in the unified name for
methocarbamol enantiomer. However on the sketched
chromatograms the author has used the same elution order
[namely, (S) after (R)] for enantiomers 1 and 2 under the
same conditions. Moreover, judging from the phrase ‘the
optical rotations of the methocarbamol enantiomers are
even lower (than that for guaifenesin enantiomers)’ the
author believes that the isomers of 1 and 2 which have
the same specific rotation signs, have the same spatial orga-
nization as well as CIP descriptors for their stereogenic
The building of a solubility (ternary) phase diagram and
the determination by this means of the eutectic ee is a
tedious and time consuming procedure. In addition, the
so-obtained quantities conserve their validity only for this
solvent and vary with temperature. Conversely, the con-
struction of a melting (binary) phase diagram by means
of differential scanning calorimetry (d.s.c.) is a relatively
straightforward and rapid procedure. The thus obtained
eutectic is characterized by a well-defined composition
and is ascribed to the definite temperature. As a result we
believe that a binary phase diagram eutectic ee of the chiral
substance can serve as a very useful starting point for those
concerned with the substance resolution and/or
purification.

A. A. Bredikhin et al. / Tetrahedron: Asymmetry 18 (2007) 1239–1244
1241
centers. We found that the enantiomers of guaifenesin and
methocarbamol that have the same spatial organization of
their stereogenic centers have opposite specific rotation
signs. As a result (S)-(+)-guaifenesin corresponds to (R)-
(ꢀ)-methocarbamol and vice versa.
The enantiomeric purities of products 2 and 4 were usually
equal to the enantiomeric purity of initial guaifenesin,
although there was no need to use an enantiopure starting
material to obtain highly enantioenriched methocarbamol.
As will become clear from the subsequent material, the low
value of the eutectic ee for intermediate carbonate 4 makes
it possible to obtain enantiopure product via simple crys-
tallization of the crude material. Moreover, methocarba-
mol 2 itself is most likely a conglomerate forming com-
pound and could be purified by subsequent crystallizations
to any desirable enantioenrichment from any starting one.
For the synthesis of the racemic and enantiomeric forms of
mephenoxalone 3 we followed the scheme reported by
Lunsford et al.14 (R)-Mephenoxalone was obtained from
(R)-guaifenesin, but the product was always contaminated
with carbonate 4.
O
O
O
O
OH
H
H
(NH2)2C=O
O
OH
O
NH
4
+
(R)-1
(
R)-3
In contrast to the case of 2, the eutectic ee for compound 3
is rather high, so almost enantiopure 1 must be used from
the start in order to obtain enantiopure 3.
2.2. IR spectroscopy
To investigate the type of crystallization for our com-
pounds, we compared the IR spectra of the racemic and
highly enantiomerically enriched crystalline samples of 2–
4 in KBr pellets, since the IR spectra of the optically active
and the racemic form should be identical for the conglo-
merate formation and different for the racemic compounds.
Figure 1. IR spectra of the crystalline samples of 2 (a), 3 (b), and 4 (c).
Red curves—racemates, blue curves—scalemates, black curves are differ-
ential curves.
Figure 1 shows a good coincidence between the pairs of
spectra for compounds 2 and 4 under visual comparison,
whereas the spectra of racemic and enantiopure crystalline
samples for 3 differ noticeably. A similar pattern was ob-
served for the differential curves: for compounds 2 and 4,
differences between the spectra of the racemate and enan-
tioenriched sample are slightly above the level of instru-
mental background, while they are rather substantial for
compound 3. This is in agreement with the assumption that
a racemic compound is formed upon crystallization of
racemic mephenoxalone, and the probability exists that
racemic conglomerates are formed by cyclic carbonate 4
and methocarbamol, although the latter cannot be consid-
ered as a conclusive decision.
To substantiate this comparison, the spectra were subjected
to a procedure of normalization and baseline correction.
For this purpose, coefficients that minimize the difference
As ꢀ [a0 + a1m + Ar(a2 + a3m)], where As and Ar are the
molar absorption coefficients of the scalemic and racemic
samples, respectively, m is the IR radiation frequency
corresponding to A, and an are the desired regression coef-
ficients, were selected by the least-squares method. It was
reasonable to introduce the regression a1m and Ara3m terms
to correct the spectral differences caused by the non-specific
(not related to particular absorption bands) interaction of
IR radiation with matter (probably by radiation scatter
on heterogeneities of the sample). It should be noted that
the use of polynomials of higher powers (quadratic and cu-
bic) for the generation of differential spectra does not im-
prove the statistical parameters characterizing regression.
The ratio between mean-square deviation of differential
curves and mean-square deviation of spectral curves for
racemate, that is, the ratio of error to variation (%), was
used as a quantitative characteristic for differential curves.
2.3. Thermochemical investigations
This part of the work deals with binary mixtures of (R)-
and (S)-compounds 2–4 using differential scanning
calorimetry (d.s.c.) as a research method. The temperature

1242
A. A. Bredikhin et al. / Tetrahedron: Asymmetry 18 (2007) 1239–1244
data were determined according to the method reported
by Ho¨hne et al.,15 and were treated as previously
described.16
The results obtained for the temperature and enthalpy of
fusion of the pure enantiomers and the pure racemates,
as well as the calculated6,17 values of entropy of mixing
for liquid enantiomeric compounds, DSml , and free energy
of formation for racemic compounds in the solid state,
DG0, are presented in Table 1. The calculated and experi-
mentally obtained eutectic melting temperatures and eutec-
tic compositions are presented in the same table.
The entropy of mixing for enantiomeric 2 in the liquid state
is equal to 5.23 J Kꢀ1 molꢀ1, which is slightly less but close
to the ideal value of 5.75 J Kꢀ1 molꢀ1 (Rln2) for conglo-
merates. The near zero value for DG0 also points on the
same peculiarity of chiral 2.17 The high negative value for
DG0 for mephenoxalone 3 is a good diagnostic for stable
racemic compound formation in the crystalline state.17
The intermediate DSlm and DG0 values for compound 4
are compatible with the assumption of unstable racemic
compound formation.
From the d.s.c. data, the melting temperature against com-
position diagrams were reconstructed and are depicted in
Figure 2. The binary phase diagram for compound 2 has
an obvious single eutectic V-shape typical to a racemic con-
glomerate.6 If the last is true, the eutectic ee for methocar-
bamol is equal to zero. The phase diagram for 3 is very
typical for a racemic compound. The eutectic ee for this
case found as mutual point(s) for Schro¨der–Van Laar
and Prigogine–Defay curves branches is equal to 85%, that
is, a sample with about 93% or more of one enantiomer ini-
tial content could only be enantioenriched by crystalliza-
tion (see however Wang et al.8). The phase diagram for 4
represents a rather conglomerate-like curve with a very
shallow plateau in the racemate region. The theoretical
eutectic ee for carbonate 4 is about 10%.
Figure 2. Experimental (circles) points and calculated (solid lines) binary
melting phase diagrams for compounds 2 (a), 3 (b), and 4 (c).
3. Conclusion
procedure for the direct resolution of guaifenesin enables
easy access to some other single enantiomer drugs. Ther-
mochemical investigations paying special attention to eu-
tectic enantiomeric composition make clear that only the
enantiopure starting material allows enantiopure mephen-
oxalone to be obtained, whereas the demands to enantio-
enrichment of raw material are not so critical for single
enantiomer methocarbamol production. Moreover, the
plausible assumption about the conglomerate forming nat-
ure of methocarbamol opens up the possibilities of the
direct resolution of this popular drug itself.
In conclusion, we are able to say that discovering the con-
glomerate nature and developing on this basis an effective
Table 1. d.s.c. measured melting point and enthalpy of fusion of racemic
(low index R) and enantiopure (low index A) compounds 2–4 and
calculated thermodynamic characteristics for these substances along with
calculated and measured eutectic fusion temperature and eutectic enan-
tiomeric composition
Compound
2
3
4
T0Af (ꢁC)
112.3
93.8
125.7
142.1
89.1
68.3
T0Rf (ꢁC)
DHfA (J molꢀ1
DHfR (J molꢀ1
)
)
42,800
37,450
35,190
39,120
29,420
26,900
4. Experimental
4.1. General
T0efu, calcd (ꢁC)
93.3
122.5
68.3
68.5
ꢁ10
4.73
ꢀ279
T0efu, exp. (ꢁC)
93.8
122.7
85
eeeu (%)
ꢁ0
DSml (J Kꢀ1 molꢀ1
DG0 (J molꢀ1
)
5.23
ꢀ3.68
The NMR spectra were recorded on a Bruker Avance-600
spectrometer in either CDCl3 or DMSO-d6 with TMS or
)
ꢀ65
ꢀ3844

A. A. Bredikhin et al. / Tetrahedron: Asymmetry 18 (2007) 1239–1244
1243
the signals of the solvent as the internal standard. The IR
spectra of the polycrystalline samples of rac- and scal-com-
pounds under investigations in KBr pellets were recorded
on a Bruker IFS-66v Fourier-transform spectrometer.
Optical rotations were measured on a Perkin–Elmer model
341 polarimeter (concentration c is given as g/100 mL).
Melting points for general purposes were determined using
a Boe¨tius apparatus and are uncorrected.
5.95 g (50 mmol) of diethyl carbonate. The mixture was
heated with stirring and the ethanol formed was distilled
at 79–84 ꢁC. When the internal temperature was 130 ꢁC,
heating was stopped, and 0.07 g (1.3 mmol) of ammonium
chloride added. The remainder of the ethanol and the ex-
cess diethyl carbonate were distilled in vacuo. The residue,
crude (S)-4 (5.92 g) was used without purification for the
next step. For analytical purposes, a small amount
(1.03 g) of the obtained crude product was crystallized
from ethyl acetate to yield 0.81 g (S)-4; mp 88–89 ꢁC
Melting curves were measured on a Perkin–Elmer Dia-
mond DSC differential scanning calorimeter in aluminum
pans with a rate of heating of 10 ꢁC minꢀ1. Mass of the
samples amounted to approximately 2.5 mg. Temperature
scale and heat flux were calibrated against the data for
indium, phenol, and naphthalene.
(EtOAc); 99.2% ee (HPLC; hexane/isopropanol = 60/40;
20
flow rate 0.4 ml/min; tR = 37.3 min); ½aꢂD ¼ ꢀ17:3 (c 1.0,
EtOH). 1H NMR (600 MHz, CDCl3) d = 3.80 (s, 3H,
2
3
CH3), 4.13 (dd, J = 11.0, J = 3.8 Hz, 1H, OCH2), 4.19
(dd, 2J = 11.0, 3J = 3.9 Hz, 1H, OCH2), 4.54 (d,
3J = 7.3 Hz, 2H, CH2), 4.94–5.00 (m, 1H, CH), 6.84–7.01
(m, 4H, Ar). 13C NMR (150.864 MHz, CDCl3) d = 55.81
(CH3), 66.13 (CH2), 69.25 (CH2), 74.66 (CH), 112.63
ðC3ArÞ, 116.50 ðCA6 rÞ, 120.92 ðCA4 rÞ, 123.19 ðCA5 rÞ, 147.51
ðC1ArÞ, 150.29 ðCA2 rÞ, 154.85 (C@O).
HPLC analyses were performed on a Shimadzu LC-20AD
system controller, and UV monitor 275 nm was used as a
detector. The column used, from Daicel, Inc., was Chiralcel
OD (0.46 · 25 cm). All experiments were run with a col-
umn temperature of 40 ꢁC.
4.2.6.
(R)-4-(2-Methoxyphenoxymethyl)-[1,3]dioxolan-2-
4.2. Synthesis
one, (R)-4. This was obtained by analogy with (S)-4
20
starting from (S)-1; mp 88–89 ꢁC (EtOAc); ½aꢂD ¼ þ17:7
Racemic guaifenesin, 3-(2-methoxyphenoxy)-propane-1,2-
diol, rac-1 is commercially available (Alfa Aesar,
A16827). (R)- and (S)-3-(2-methoxyphenoxy)-propane-
1,2-diol were prepared from the racemate by an entrain-
ment resolution method according to a previously de-
scribed protocol without modifications.1
(c 1.0, EtOH); 99.8% ee (HPLC; hexane/isopropanol =
60/40; flow rate 0.4 ml/min; tR = 38.9 min).
4.2.7. (S)-1-Carbamoyloxy-2-hydroxy-3-(2-methoxyphen-
oxy)propane, (S)-Methocarbamol, (S)-2. A solution of
0.86 g (50 mmol) of ammonia in 30 ml isopropyl alcohol
was added to a mixture of 10 ml isopropyl alcohol and
4.89 g of crude (S)-4 with stirring at room temperature.
The mixture was stirred overnight at room temperature
in a tightly stopped flask. At first, a dense almost unstirra-
ble precipitate formed, which dissolved and then re-precip-
itated. The isopropyl alcohol and excess ammonia were
removed in vacuo. The residue was recrystallized from
ethyl acetate and gave 2.64 g (53%) of (S)-2; mp 113–
114 ꢁC (EtOAc); 99.9% ee (HPLC; hexane/isopropa-
nol = 60/40; flow rate 0.4 ml/min; tR = 16.6 min);
4.2.1. (R)-3-(2-Methoxyphenoxy)-propane-1,2-diol, (R)-
20
1. Mp 97–99 ꢁC; ½aꢂD ¼ ꢀ9:4 (c 1.0, MeOH); 99.5% ee
(HPLC;
hexane/isopropanol/diethylamine = 80/20/0.1;
flow rate 1.0 ml/min; tR = 9.9 min).
4.2.2. (S)-3-(2-Methoxyphenoxy)-propane-1,2-diol, (S)-
20
1. Mp 97–99 ꢁC; ½aꢂD ¼ þ9:5 (c 1.0, MeOH); 99.9% ee
(HPLC;
hexane/isopropanol/diethylamine = 80/20/0.1;
flow rate 1.0 ml/min; tR = 17.4 min).
20
22
½aꢂD ¼ þ0:8 (c 1.1, MeOH); (lit.13 ½aꢂD ¼ þ0:5 (c 1,
1
4.2.3. rac-1-Carbamoyloxy-2-hydroxy-3-(2-methoxyphen-
oxy)propane, rac-methocarbamol, rac-2. Mp 94–95 ꢁC
(lit.12 mp 95–96.5 ꢁC); 1H NMR (600 MHz, CDCl3)
d = 3.33 (br s, 1H, OH), 3.87 (s, 3H, CH3), 4.04 (dd,
2J = 9.9, 3J = 6.3 Hz, 1H, OCH2), 4.11 (dd, 2J = 9.9,
3J = 4.7 Hz, 1H, OCH2), 4.23–4.28 (m, 2H, CH, 1CH2O),
MeOH)). H NMR (600 MHz, DMSO-d6) d = 3.42 (br s,
1H, OH), 3.76 (s, 3H, CH3), 3.87–4.04 (m, 5H, CH2OAr,
CH2OCO, CH), 6.48 (br s, 2H, NH2), 6.83–6.91 (m, 3H,
Ar), 6.96–6.99 (m, 1H, Ar). 13C NMR (150.864 MHz,
DMSO-d6) d = 56.09 (CH3), 65.39 (CH2), 67.81 (CH2),
70.78 (CH), 113.05 ðC6ArÞ, 114.43 ðCA3 rÞ, 121.26 ðCA4 rÞ,
121.72 ðC5ArÞ, 148.66 ðCA1 rÞ, 149.76 ðCA2 rÞ, 157.21 (C@O).
2
3
4.32 (dd, J = 11.0, J = 3.7 Hz, 1H, 1OCH2), 4.77 (br s,
2H, NH2), 6.92–7.01 (m, 4H, Ar).
4.2.8. (R)-1-Carbamoyloxy-2-hydroxy-3-(2-methoxyphen-
oxy)propane, (R)-Methocarbamol, (R)-2. This was pre-
pared from (S)-1 (9.91 g, 50 mmol) as described for (S)-2;
yield 7.45 g (68%); mp 113–114 ꢁC (EtOAc); 99.8% ee (chi-
4.2.4.
rac-4-(2-Methoxyphenoxymethyl)-[1,3]dioxolan-2-
one, rac-4. This [mp 68–69 ꢁC (lit.12 mp 68.4–69.0 ꢁC);
1H NMR (600 MHz, CDCl3) d = 3.86 (s, 3H, CH3), 4.24
3
(d, J = 3.8 Hz, 2H, CH2), 4.60–4.65 (m, 2H, CH2), 4.50–
ral HPLC analysis; hexane/isopropanol = 60/40; flow rate
20
0.4 ml/min; tR = 28.8 min); ½aꢂD ¼ ꢀ0:6 (c 1.0, MeOH)
22
5.03 (m, 1H, CH), 6.90–7.05 (m, 3H, Ar), 7.27–7.30 (m,
1H, Ar)] was prepared according to Baizer et al. without
modifications.12
{lit.13 ½aꢂD ¼ ꢀ0:8 (c 1, MeOH)}.
4.2.9. (rac)-5-(2-Methoxyphenoxymethyl)-oxazolidin-2-one,
(rac)-Mephenoxalone, (rac)-3. This was prepared from
8.0 g (40 mmol) of rac-1 and 4.85 g (80 mmol) of urea
according to Lunsford et al., method A without modifica-
tions.14 Yield 6.61 g (67%); mp 141–142 ꢁC (ethanol)
4.2.5.
(S)-4-(2-Methoxyphenoxymethyl)-[1,3]dioxolan-2-
one, (S)-4. To 5.0 g (25 mmol) of molten (100 ꢁC) (R)-3-
(2-methoxyphenoxy)-propane-1,2-diol (R)-1 was added,
with stirring, 0.07 g (1.3 mmol) of sodium methylate and

1244
A. A. Bredikhin et al. / Tetrahedron: Asymmetry 18 (2007) 1239–1244
(lit.14 mp 143–145 ꢁC). 1H NMR (600 MHz, DMSO-d6)
Acknowledgements
2
3
d = 3.36 (dd, J = 8.8, J = 7.7 Hz, 1H, NCH2), 3.61 (dd,
3
2J = 8.8, J = 8.8 Hz, 1H, NCH2), 3.76 (s, 3H, CH3), 4.07
The authors thank the Russian Fund of Basic Research for
financial support (Grant Nos. 06-03-32508 and 07-03-
12070).
(dd, 2J = 11.0, 3J = 6.0 Hz, 1H, OCH2), 4.12 (dd,
2J = 11.0, 3J = 3.2 Hz, 1H, OCH2), 4.98–5.05 (m, 1H,
CHO), 6.98–7.03 (m, 1H, Ar), 7.04–7.13 (m, 3H, Ar),
7.56 (s, 1H, NH). 13C NMR (150.864 MHz, DMSO-d6)
d = 41.54 (CH2N), 55.67 (CH3), 69.81 (CH2O), 73.76
(CH), 112.75 ðCA3 rÞ, 114.56 ðCA6 rÞ, 120.82 ðCA4 rÞ, 121.86
ðCA5 rÞ, 147.80 ðCA1 rÞ, 149.41 ðCA2 rÞ, 158.68 (C@O).
References
1. Bredikhina, Z. A.; Novikova, V. G.; Zakharychev, D. V.;
Bredikhin, A. A. Tetrahedron: Asymmetry 2006, 17, 3015–
3020.
2. Negwer, M.; Scharnow, H.-G.. Organic-Chemical Drugs and
Their Synonyms, 8th ed.; Wiley-VCH: Weinheim, 2001; (a)
2327; (b) 2900; (c) 2760.
3. The Merck Index, 12th ed.; Budavari, S., Ed.; Merck and Co.,
Inc.: Whitehouse Station, 1996 (a) 4582; (b) 6060; (c) 5896.
4. Luo, X.; Pietrobon, R.; Curtis, L. H. c.; Hey, L. A. Spine
2004, 29, E531–E537.
5. Souri, E.; Sharifzadeh, M.; Farsam, H.; Gharavi, N. J.
Pharm. Pharmacol. 1999, 51, 853–855.
6. Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates
and Resolutions; Krieger Publishing Company: Malabar,
Florida, 1994, 447 pp.
7. Lorenz, H.; Polenske, D.; Seidel-Morgenstern, A. Chirality
2006, 18, 828–840.
8. Wang, Y.; LoBrutto, R.; Wenslow, R. W.; Santos, I. Org.
Process Res. Dev. 2005, 9, 670–676.
9. Klussmann, M.; White, A. J. P.; Armstrong, A.; Blackmond,
D. G. Angew. Chem., Int. Ed. 2006, 45, 7985–7989.
10. (a) Lorenz, H.; Seidel-Morgenstern, A. Thermochim. Acta
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Morgenstern, A. J. Chem. Eng. Data 2002, 47, 1280–1284.
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22, 1595–1599.
4.2.10. (R)-5-(2-Methoxyphenoxymethyl)-2-oxazolidinone,
(R)-Mephenoxalone, (R)-3. A mixture of 8 g (40 mmol)
(R)-1 and 4.85 g (80 mmol) of urea was heated in a flask
equipped with a thermometer and an air condenser. The
mixture was heated rapidly to the range of 180–200 ꢁC by
immersing the flask in a Wood’s metal-bath, which had
previously been heated to 190 ꢁC. Heating in this tempera-
ture range was continued for 5 h and then the reaction mix-
ture was poured into 50 ml of water and extracted with
chloroform. The chloroform extract was dried over sodium
sulfate, filtered, and concentrated. The residue was crystal-
lized from ethanol, and 5.3 g of (R)-3 collected. Yield
20
59%; mp 125–127 ꢁC (CHCl3); ½aꢂD ¼ ꢀ34:4 (c 1.3, EtOH);
20
½aꢂD ¼ ꢀ37:2 (c 1.1, MeOH); ee >99.9% (HPLC; hexane/
isopropanol = 60/40; flow rate 0.4 ml/min; tR = 22.4 min).
1H NMR (600 MHz, CDCl3) 3.63 (dd, 2J = 8.5,
2
3
3J = 7.6 Hz, 1H, NCH2), 3.75 (dd, J = 8.5, J = 8.8 Hz,
1H, NCH2), 3.83 (s, 3H, CH3), 4.14 (dd, 2J = 10.5,
3J = 5.7 Hz, 1H, OCH2), 4.20 (dd, J = 10.5, J = 4.8 Hz,
1H, OCH2), 4.94–5.00 (m, 1H, CHO), 6.31 (s, 1H, NH),
6.87–7.01 (m, 4H, Ar).
2
3
13. Demian, I. Chirality 1993, 5, 238–240.
14. Lunsford, C. D.; Mays, R. P.; Richman, J. A.; Murphey,
R. S. J. Am. Chem. Soc. 1960, 82, 1166–1171.
4.2.11. (S)-5-(2-Methoxyphenoxymethyl)-oxazolidin-2-one,
(S)-Mephenoxalone, (S)-3. This was obtained from 0.8 g
(4 mmol) of (S)-1 by analogy with the (R)-isomer of (S)-3
15. Ho¨hne, G. W. H.; Cammenga, H. K.; Eysel, W.; Gmelin, E.;
Hemminger, W. Thermochim. Acta 1990, 160, 1–12.
16. Bredikhin, A. A.; Strunskaya, E. I.; Zakharychev, D. V.;
Krivolapov, D. B.; Litvinov, I. A.; Bredikhina, Z. A.
Tetrahedron: Asymmetry 2005, 16, 3361–3366.
was collected. Yield 0.43 g (47.4 %); mp 124–126 ꢁC
20
(CHCl3); ½aꢂ ¼ þ33:7 (c 1.0, EtOH); 99.8% ee (HPLC;
hexane/isoprDopanol = 60/40; flow rate 0.4 ml/min;
tR = 36.6 min). NMR spectra were close to the above de-
scribed for enantiomer and racemate.
17. Li, Z. J.; Zell, M. T.; Munson, E. J.; Grant, D. J. W. J.
Pharm. Sci. 1999, 88, 337–346.