Solid-state properties of 1,2-epoxy-3-(2-cyanophenoxy)propane, a conglomerate-forming chiral drug precursor

Article abstract of DOI:10.1070/MC2006v016n05ABEH002388

Both enantiomers of 1,2-epoxy-3-(2-cyanophenoxy)propane 1a were obtained and converted into enantiomeric bunitrolol hydrochlorides 3 to confirm the configuration of the formers; racemic 1a undergoes spontaneous resolution upon crystallization and could be resolved into individual enantiomers by a preferential crystallization with low efficiency.

Full text of DOI:10.1070/MC2006v016n05ABEH002388

Mendeleev Commun., 2006, 16(5), 245–247
Solid-state properties of 1,2-epoxy-3-(2-cyanophenoxy)propane,
a conglomerate-forming chiral drug precursor
Alexander A. Bredikhin,* Zemfira A. Bredikhina, Dmitry V. Zakharychev, Flyura S. Akhatova,
Dmitry B. Krivolapov and Igor A. Litvinov
A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Centre of the Russian Academy of Sciences,
420088 Kazan, Russian Federation. Fax: +7 8432 73 2253; e-mail: baa@iopc.knc.ru
DOI: 10.1070/MC2006v016n05ABEH002388
Both enantiomers of 1,2-epoxy-3-(2-cyanophenoxy)propane 1a were obtained and converted into enantiomeric bunitrolol hydro-
chlorides 3 to confirm the configuration of the formers; racemic 1a undergoes spontaneous resolution upon crystallization and
could be resolved into individual enantiomers by a preferential crystallization with low efficiency.
Racemic arylglycidyl ethers 1 are customary intermediates in the
industrial production of racemic β-blocker drugs 2 (Scheme 1).
For (S)-1a, Nicola et al.6 reported a positive sign for specific
rotation in ethanol. Sayyed et al.8 also reported a positive sign
for specific rotation for the same enantiomer but in chloroform.
We found that epoxide 1a, as well as o-methoxy derivative 1b,
belongs to uncommon compounds changing the sign of rotation
with the change of solvent. The sample of (S)-1b with [a]D20 +13.0
(c 0.6, EtOH) manifests [a]D20 –4.9 (c 0.6, CHCl3). The sample
of 1a with [a]D20 +18.1 (c 1.0, EtOH) simultaneously demonstrates
[a]D20 –5.0 (c 1.0, CHCl3) or [a]D20 –14.5 (c 0.65, CCl4).
To establish the absolute configuration for 1a, we transformed
both enantiomers of the compound into β-blocker bunitrolol 3
(Scheme 2).‡
O
O
ArOH +
Cl
ArO
– HCl
1
NH2Alk
Alk
ArO
N
H
HO
H
2
Scheme 1
1,2-Epoxy-3-(2-cyanophenoxy)propane 1a has an obvious
structural similarity with and can be used as an intermediate in
the synthesis of β-adrenoblockers bunitrolol 3 and epanolol 4.1
Levorotary bunitrolol hydrochloride was obtained from dextro-
rotary (in ethanol) epoxide, as well as dextrorotary 3·HCl derives
†
Racemic 1a was prepared from racemic epichlorohydrin and 2-hydroxy-
benzonitrile by a known procedure,5 bp 120–122 °C at 0.05 Torr, mp 66–
67 °C (colourless needles from diethyl ether) [lit.,5 mp 65 °C (diethyl
ether)]. 1H NMR (400 MHz, CDCl3) d: 2.83 [dd, 1H, C(1)H2, 2J –4.8 Hz,
CN
CN
OH
O
O
O
NHBut
3J 2.7 Hz], 2.92 [dd, 1H, C(1)H2, J –4.8 Hz, J 4.2 Hz], 3.34–3.39 [m,
1H, C(2)H], 4.08 [dd, 1H, C(3)H2, 2J –11.6 Hz, 3J 5.4 Hz], 4.37 [dd, 1H,
C(3)H2, 2J –11.6 Hz, 3J 3.1 Hz], 6.99–7.02 [m, C(4A)H, C(6A)H], 7.44–
7.53 [m, C(3A)H, C(5A)H]. 13C NMR (100.6 MHz, CDCl3) d: 44.53
[C(1)], 49.89 [C(2)], 69.58 [C(3)], 102.45 [C(2A)], 112.89 [C(6A)],
116.29 [C(4N)], 121.49 [C(4A)], 133.88 [C(3A)], 134.47 [C(5A)], 160.22
[C(1A)].
2
3
1a
Bunitrolol, 3
OH
CN
OH
O
O
NH
N
H
(R)-1a was obtained from (S)-epichlorohydrin {[a]D20 +32.5 (c 4.3,
MeOH), op 98%; 5.5 g, 0.06 mol} and 2-hydroxybenzonitrile (2.4 g,
0.02 mol) by the same procedure as for the racemic compound.5 The
crude (R)-1a (3.1 g) was repeatedly crystallised from diethyl ether and a
mixture of diethyl ether and methanol to give colourless needles {1.4 g
(39%); mp 90–91 °C; [a]D20 –17.5 (c 0.8, EtOH), ee 98.0% by d.s.c.}
{lit.,6 [a]D25 –16 (c 1, EtOH)}.
Epanolol, 4
For the family of β-adrenoblockers and for bunitrolol parti-
cularly, it has been shown that (S)-enantiomers are eutomer com-
ponents of the racemic drug, whereas (R)-enantiomers (distomers)
usually display other (often undesirable) activity.2,3 Therefore,
interest in preparative procedures and the properties of scalemic
aryl glycidyl ethers as the precursors of single enantiomer drugs
is understandable. We have disclosed recently the conglomerate
nature of 1,2-epoxy-3-(2-methoxyphenoxy)propane 1b, another
valuable aryl glycidyl ether.4 Here, we consider the solid-state
properties, namely, IR spectra, thermal behaviour, and X-ray
structure of epoxide 1a, as well as some comments on the pos-
sibility of spontaneous resolution of racemic 1a.
Rac-, (R)- and (S)-1a have been prepared uniformly through
the reaction of rac-, (S)- and (R)-epichlorohydrin and 2-hydroxy-
benzonitrile.† Some comments must be done on the configura-
tion ascribing to scalemic 1a samples. We believe that, in our
case, the configuration of resulting epoxides 1a is predominantly
inverted as against the configuration of the starting epichloro-
hydrine as it has happened to be in a similar reaction with
guaiacol.4 Generally, C(3)-activated 1,2-epoxypropanes do not
react with nucleophiles in an unambiguous fashion: alongside
the normal attack on the C(3) atom occurs an attack on the C(1)
atom with the opening and subsequent closure of the oxirane
ring.7 The first direction is accompanied by conservation of
starting material configuration, whereas the other direction leads
to an opposite enantiomer as a product, and on the whole the
nucleophilic substitution with epichlorohydrine can lead to any
stereochemical results.
(S)-1a was synthesised analogously from (R)-epichlorohydrin. colour-
less needles; mp 90–91 °C (diethyl ether–methanol), [a]D20 +18.1 (c 1.0,
EtOH), [a]D20 –5.0 (c 1.0, CHCl3), ee 99.92% by d.s.c.; {lit.,6 mp 88–
89 °C, [a]D25 +17.69 (c 1, EtOH); lit.,8 gum, [a]D25 +2.3 (c 2.3, CHCl3)}.
The NMR spectra for both enantiomers coincide completely with the
spectra for rac-1a.
‡
(R)-(+)-1-(2-Cyanophenoxy)-3-tert-butylaminopropan-2-ol hydro-
chloride; (R)-bunitrolol hydrochloride; (R)-3·HCl. (R)-1a {0.76 g,
4.3 mmol, [a]D20 –17.0 (c 0.5, EtOH)} and 4.6 ml (43 mmol) of ButNH2
were heated under reflux for 5–7 h. The reaction was monitored by TLC.
After disappearance of the starting epoxide, the mixture was evaporated
to dryness and the residue was dissolved in diethyl ether; dry HCl was
passed through the solution until saturation. The solid hydrochloride
was filtered off (yield 87%); after two successive crystallizations from
EtOH (R)-3·HCl was isolated in 66% yield, mp 188–191 °C, [a]D20 +29.1
1
(c 0.9, EtOH). H NMR (600 MHz, CDCl3) d: 1.54 (s, 9H, Me), 3.29
(dd, 1H, CH2N, 2J –18.5 Hz, 3J 9.5 Hz), 3.40 (dd, 1H, CH2N, 2J –18.5 Hz,
2
3
3J 8.6 Hz), 4.25 (dd, 1H, CH2O, J –9.5 Hz, J 5.1 Hz), 4.29 (dd, 1H,
CH2O, 2J –9.5 Hz, 3J 4.0 Hz), 4.72 (m, 1H, CH), 5.50 (s, 1H, OH), 7.03–
7.06 [m, C(4A)H, C(6A)H], 7.53–7.56 [m, C(3A)H, C(5A)H], 8.29 (s,
1H, NH), 9.62 (s, 1H, NH). 13C NMR (150.864 MHz, CDCl3) d: 25.91
(Me), 45.28 (NCH2), 58.01 (CMe3), 65.58 (CHOH), 70.82 (OCH2), 102.36
[C(2A)], 113.04 [C(6A)], 116.27 (CN), 121.50 [C(4A)], 133.43 [C(3A)],
134.50 [C(5A)], 160.14 [C(1A)]. The numbering of atoms in the aromatic
part is shown in Figure 3.
(S)-3·HCl was obtained from (S)-1a and ButNH2 following the above
procedure; mp 188–191 °C, [a]D20 –29.2 (c 0.7, EtOH).
Mendeleev Commun. 2006 245

Mendeleev Commun., 2006, 16(5), 245–247
1
CN
OH
CN
NaOH
+
Cl
O
H
O
O
H
(R)-epichlorohydrin
(S)-1a
i, ButNH2
ii, HCl
CN
But · HCl
0
O
NH
H
OH
(S)-3 · HCl
Scheme 2
500
1000
1500
2000
4000
n/cm–1
Figure 1 Experimental IR spectra of racemic (solid line) and scalemic
(dotted line) 1,2-epoxy-3-(2-cyanophenoxy)propanes 1a as well as dif-
ference curve (beneath).
from levorotary 1a. For the (+)-3·HCl R configuration was
established unambiguously by the Bijvoet method.§ The revealed
correspondence between the sign of optical rotation and the
absolute configuration is typical of the family of aryloxypropanol-
amine β-blockers where (S)-isomers both as free base and espe-
cially as salts with achiral acids always dispose negative rotation
in proton solvents.9
Figure 1 shows the IR spectra of both racemic and highly
enantiomerically enriched crystalline samples¶ of 1a in KBr
pellets, along with the normalised difference curve between
individual spectra. Excepting very minor discrepancies, the
spectra are identical. This is a good but not definitive diagnostic
for racemic conglomerate formation.
1a) the entropy of mixing in the liquid state ∆Slm and the free
energy of formation ∆G0 of racemic compound in the solid
state.10,11 Table 1 represents experimental†† and calculated thermo-
dynamic parameters for epoxide 1a. The calculated entropy of
mixing is equal to 5.32 J K–1 mol–1, which is very close to an ideal
value of 5.77 J K–1 mol–1 (Rln2) for conglomerates. The near-
zero value of ∆G0 points to the same crystallization peculiarity.
From the d.s.c. data for samples of different enantiomeric
purity the melting temperature against composition diagram
(binary phase diagram) was drawn (Figure 2). Experimental
points in Figure 2 form an obvious single eutectic V-shape
curve typical of a racemic conglomerate.10 Figure 2 also
presents the theoretical liquidus curve (dashed line) deduced for
conglomerate from the simplified Schröder–Van Laar equation
ln x = (∆HAf /R)(1/TAf – 1/Tf). Both experimental and theoretical
sets correlate quite well, and the calculated eutectic melting point
(Teu = 64.9 °C) is very close to the experimental value of TRf .
The above evidences that epoxide 1a crystallises as a con-
glomerate. Thus, the resolution of the racemic mixture via a
classical entrainment procedure has been tested.‡‡
Valuable information on a chiral substance can be obtained
by differential scanning calorimetry (d.s.c.). With a knowledge
of the temperature and enthalpy of fusion for racemic and
enantiopure samples, it is possible to calculate (for enantiomeric
§
X-ray diffraction data for (+)-3·HCl: C14H21ClN2O2, M = 284.78,
orthorhombic, space group P212121, a = 8.815(2), b = 12.510(3) and
c = 13.750(3) Å, V = 1516.3(6) Å3, Z = 4, dcalc = 1.25 g cm–3; 1773
independent reflections (1501 with I ³ 2s); T = 20 °C. The final residuals
were R(obs) = 0.046 and Rw(obs) = 0.113, R(tot) = 0.059 and Rw(tot) = 0.123,
GOF = 1.021. Flack parameter –0.07(3) (absolute structure was estab-
lished as R).
For 1a: C10H9NO2, M = 175.18, at 20 °C, orthorhombic, space group
P212121, a = 4.245(1), b = 7.834(2) and c = 26.989(6) Å, V = 897.4(4) Å3,
Z = 4, dcalc = 1.30 g cm–3; 1000 independent reflections (825 with I ³ 2s).
The final residuals were R(obs) = 0.031 and Rw(obs) = 0.070, R(tot) = 0.049,
and Rw(tot) = 0.077, GOF = 0.999. Flack parameter –0.1(5) (absolute
structure was not established).
Nominally, such a resolution takes place, i.e., the weight of
individual (R)- or (S)-1a obtained after two beginning cycles was
more than common weight of initial excess of corresponding
Table 1 D.s.c. measured melting point Tf and enthalpy of fusion ∆Hf of
racemic (subscript R) and (S)-1a (subscript A), as well as calculated
thermodynamic characteristics of 1,2-epoxy-3-(2-cyanophenoxy)propane.
Parameter
Value
Cell parameters and intensities for single or single like crystals were
measured on an Enraf-Nonius CAD-4 diffractometer in the w/2q-scan
mode, q £ 74.9°, using CuKα radiation with a graphite monochromator.
Absorption correction was not applied for 1a and was applied for 3·HCl
[m(Cu) = 22.3 cm–1]. The structures were solved by a direct method using
the SIR15 program and refined by the full matrix least-squares using the
SHELXL97 program.16 All non-hydrogen atoms were refined anisotro-
pically. The positions of the hydrogen atoms at OH and NH2 groups
were located from difference Fourier maps and refined isotropically, at C
atoms were idealised. All calculations were performed on a PC using the
WinGX program.17 Cell parameters, data collection and data reduction
were performed on an Alpha Station 200 computer using the MolEN
program.18 The figure was made using the PLATON program.19
Atomic coordinates, bond lengths, bond angles and thermal param-
eters have been deposited at the Cambridge Crystallographic Data Centre
(CCDC). These data can be obtained free of charge via www.ccdc.cam.uk/
conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336 033; or deposit@ccdc.cam.ac.uk).
Any request to the CCDC for data should quote the full literature citation
and CCDC reference numbers 606995 and 613539 for 1a and 3·HCl,
respectively. For details, see ‘Notice to Authors’, Mendeleev Commun.,
Issue 1, 2006.
TAf /°C
90.5
65.7
27665
25392
–68
TRf /°C
∆HAf /J mol–1
∆HRf /J mol–1
∆G0/J K–1 mol–1
∆Slm/J K–1 mol–1
5.32
90
80
70
60
0.0
0.5
1.0
Mole fraction of (S)-enantiomer
Figure 2 Experimental (circles) and calculated (dashed lines) melting
point phase diagram of epoxide 1a.
¶
The IR spectra of the polycrystalline samples of rac-1a and (R)- or
(S)-1a in KBr pellets were recorded on a Bruker IFS-66v Fourier
transform spectrometer. The NMR spectra were recorded on Bruker
MSL-400 and Avance-600 spectrometers in CDCl3 with TMS or the
solvent as an internal standard. Optical rotations were measured on a
Perkin-Elmer model 341 polarimeter (concentration c is given as g per
100 ml). Melting points for general purposes were determined using a
Boëtius apparatus and are uncorrected.
†† The melting curves of the samples of 1,2-epoxy-3-(2-cyanophenoxy)-
propane were measured on a Setaram DSC-111 differential scanning
calorimeter in stainless steel cells with the rate of heating of 1 K min–1.
The mass of samples amounted to approximately 2.5 mg. Temperature
scale and heat flux were calibrated against the data for α-corundum
(sapphire), phenol and naphthalene. Experimental DSC curves were
treated according to Gallis et al.12
246 Mendeleev Commun. 2006

Mendeleev Commun., 2006, 16(5), 245–247
References
N(4)
C(4)
1
The Merck Index, 12th edn., ed. S. Budavari, Merck and Co., Inc.,
Whitehouse Station, 1996, 1514 (bunitrolol) and 3641 (epanolol).
R. Mehvar and D. R. Brocks, J. Pharm. Pharm. Sci., 2001, 4, 185.
(a) J. A. Nathanson, J. Pharmacol. Exp. Ther., 1988, 245, 94; (b)
S. Narimatsu, T. Mizukami, Y. Huang, Y. Masubuchi and T. Suzuki, J.
Pharm. Pharmacol., 1996, 48, 1185.
2
3
C(2A)
O(1)
O(3)
C(3A)
C(4A)
C(2)
C(3)
C(1A)
C(1)
4
5
A. A. Bredikhin, E. I. Strunskaya, D. V. Zakharychev, D. B. Krivolapov,
I. A. Litvinov and Z. A. Bredikhina, Tetrahedron: Asymmetry, 2005,
16, 3361.
K. Kopka, S. Wagner, B. Riemann, M. P. Law, C. Puke, S. K. Luthra,
V. W. Pike, T. Wichter, W. Schmitz, O. Schober and M. Schäfers,
Bioorg. Med. Chem., 2003, 11, 3513.
C(6A)
C(5A)
Figure 3 Molecular structure of epoxide 1a in a crystal.
6
7
M. Nicola, A. Depaoli and M. Inglesi, Gazz. Chim. Ital., 1990, 120, 393.
(a) D. E. McClure, B. H. Ariston and J. J. Baldwin, J. Am. Chem. Soc.,
1979, 101, 3666; (b) J. J. Baldwin, D. E. McClure, D. M. Gross and
M. Williams, J. Med. Chem., 1982, 25, 931.
I. A. Sayyed, V. V. Thakur, M. D. Nikalje, G. K. Dewkar, S. P. Kotkar
and A. Sudalai, Tetrahedron, 2005, 61, 2831.
enantiomer in mother liquor and seed added. But the general
degree of resolution is rather low. Furthermore, the investiga-
tion of the alterations in mother liquor optical rotation during
single enantiomer seed induced crystallization reveals that after
sign inversion this value never amounts to absolute magnitude
of starting solution. In practice, after the second run, the mother
liquor becomes racemic.
8
9
(a) The Merck Index, 12th edn., ed. S. Budavari, Merck and Co., Inc.,
Whitehouse Station, 1996, 1055 (befunolol), 5488 (levobunolol), 6347
(moprolol), 7209 (penbutolol), 7882 (practolol), 7917 (prenalterol) and
9585 (timolol); (b) Sigma Biochemicals and Reagents for Life Science
Research, 2004–2005; pp. 224 (atenolol), 1629 (pindolol) and 1696
(propranolol).
The existence of a stable conglomerate is a necessary but
insufficient condition for a practical entrainment effect. An
obstacle for the efficient resolution is the existence of a meta-
stable racemic compound.13 Another possible reason for a feebly
marked entrainment effect is the lamellar racemic twinning of
nascent crystals.14 We studied the crystals of 1a by XRD. Dif-
fraction experiments showed that for particularly all tested crys-
tals picked from racemic samples automatic indexation gives
unrealistic cell parameters (very high or very low cell volume,
large experimental errors of the cell parameters). Only manual
selections of registered reflections led to realistic values. This
means that the test crystals are epitaxies or random joint of
crystals of the individual crystal components, contrary to lamellar
twinning with ideal overlapping crystallographic axes of indi-
vidual components, discussed previously.14 The absence of the
lamellar twinning can be confirmed by visual control of small
racemic sample fusion. Whereas druses and large crystals melt
near 65 °C, tiny splinters having no contacts with bulk melt fuse
at 90 °C, the melting point of enantiopure sample. The last
observation implies that when crystal aglomerate grows from
the racemate solution its components consist of enantiomerically
individual material, though the particle as such can be racemic
or near racemic.
10 J. Jaques, A. Collet and S. H. Wilen, Enantiomers, Racemates, and
Resolutions, Krieger Publishing Co., Malabar, FL, 1994, pp. 32–57.
11 Z. J. Li, M. T. Zell, E. J. Munson and D. J. W. Grant, J. Pharm. Sci.,
1999, 88, 337.
12 H. E. Gallis, F. Bougrioua, H. A. J. Oonk, P. J. van Ekeren and J. C.
van Miltenburg, Thermochim. Acta, 1996, 274, 23.
13 (a) S. Houllemare-Druot and G. Coquerel, J. Chem. Soc., Perkin Trans. 2,
1998, 2211; (b) F. Dufour, G. Perez and G. Coquerel, Bull. Chem. Soc.
Jpn., 2004, 77, 79.
14 V. Yu. Torbeev, K. A. Lyssenko, O. N. Kharybin, M. Yu. Antipin and
R. G. Kostyanovsky, J. Phys. Chem. B, 2003, 107, 13523.
15 A. Altomare, G. Cascarano, C. Giacovazzo and D. Viterbo, Acta
Crystallogr., Sect. A., 1991, 47, 744.
16 G. M. Sheldrick, SHELXL97, University of Göttingen, 1997.
17 L. J. Farrugia, J. Appl. Crystallogr., 1999, 32, 837.
18 L. H. Straver, A. J. Schierbeek, MolEN Structure Determination System,
Nonius B.V., 1994.
19 A. L. Spek, Acta Crystallogr., Sect. A, 1990, 46, 34.
The cell parameters of crystals belonged to racemic crop
were measured, the useful array of reflection intensities was
obtained, and the structure of 1a was solved and refined. Single
crystals picked up from a racemic sample of 1a belong to the
‘chiral’ space group P212121, Z = 4. This fact confirms that, in
general terms, epoxide 1a crystallises as a racemic conglo-
merate. Another experiment was conducted with a single crys-
tal of enantiopure dextrorotary (in ethanol) 1a in an effort to
establish absolute configuration of this compound. It turned out
that enantiopure crystals are also joint of crystals or twins, but
required reflects can easily be sorted out during the procedure
of indexing of the crystal. The general experimental parameters
for racemic sample are just worse but similar to parameters for
scalemic one. Thus, only the last set was further used.§ Cell
parameters for the crystal of (+)-1a are identical to the cell
parameters of single crystals picked up from a racemic sample.
The molecular structure of 1a is shown in Figure 3.
This work was supported by the Russian Foundation for Basic
Research (grant nos. 06-03-32508 and 04-03-32156).
‡‡ Racemic 1a (1.32 g) and (R)-1a {0.14 g, [a]D20 –16.9 (c 1.0, EtOH),
op 94%} was dissolved in 48 ml of CCl4 at 40 °C. The solution was
cooled to 25 °C and seeded with finely pulverised (R)-1a {7 mg, [a]D20 –17.5
(c 0.8, EtOH)}. After stirring the mixture for 60 min at 24–25 °C, precipi-
tated (R)-1 was collected by filtration {0.21 g after drying; [a]D20 –16.1
(c 0.6, EtOH), op 89%}. The extra portion of rac-1a (0.21 g) was then
dissolved in the mother liquor at 40 °C; the resulting solution was cooled
to 25 °C. After addition of (S)-1a {7 mg, [a]D20 +18.1 (c 1.0, EtOH)} as
seed crystals to the solution, and stirring the mixture for 70 min at 24 °C,
(S)-1a {90 mg after drying; [a]D20 +10.7 (c 0.6, EtOH), op 59%} was
collected by filtration.
Received: 22nd May 2006; Com. 06/2733
Mendeleev Commun. 2006 247