Chiral drugs via the spontaneous resolution

Article abstract of DOI:10.1070/MC2002v012n01ABEH001521

The psychotropically active drug Albicar 1 has been prepared for the first time in both enantiomerically pure forms starting from the (+)-2 and (-)-2 precursors obtained by spontaneous resolution; the crystal structures of (-)-1 and (±)-1 have been solved by X-ray diffraction study.

Full text of DOI:10.1070/MC2002v012n01ABEH001521

Mendeleev Commun., 2002, 12(1), 6–8
Chiral drugs via the spontaneous resolution
Remir G. Kostyanovsky,*a Gul’nara K. Kadorkina,a Konstantin A. Lyssenko,b Vladimir Yu. Torbeev,a
Angelina N. Kravchenko,c Oleg V. Lebedev,c Gennadii V. Grintselev-Knyazevb and Vasily R. Kostyanovskya
a N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 938 2156, e-mail: kost@center.chph.ras.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 5085, e-mail: kostya@xrlab.ineos.ac.ru
c N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 5328
10.1070/MC2002v012n01ABEH001521
The psychotropically active drug Albicar 1 has been prepared for the first time in both enantiomerically pure forms starting from
the (+)-2 and (–)-2 precursors obtained by spontaneous resolution; the crystal structures of (–)-1 and ( )-1 have been solved by X-ray
diffraction study.
A perfect medicine (‘the Erlich magic bullet’) should match a
biological target. The latter is inherently a chiral species; there-
fore, the racemate and both enantiomers of the medicinal com-
pound may differ strongly in activity, toxicity and side effects
(for example, both enantiomers of the chiral drug Thalidomid
exhibit sedative action but only one of them is teratogenic).1
That is why in the last decade the world pharmacy intensively
turned to the production of enantiomerically pure medicines.2
The simplest ways for obtaining enantiomers are spontaneous
crystallization resolution and absolute asymmetric synthesis (i.e.,
crystallization under conditions of the fast enantiomerization in
a solution or melt that gives rise to the complete transformation
of a racemate into one enantiomer).2(b)–(e),3(b) The ability of a
racemate for crystallization in the form of a conglomerate (i.e.,
a mixture of homochiral crystals of the enantiomers) is a critical
requirement in both methods.3(a)–(d) Recently, data on the spon-
taneous crystallization resolution of the pseudo-racemates3(e) (in
their crystals, the relative positions of the enantiomers are sta-
tistically disordered3(a)) were reported.
Scheme 1 Reagents and conditions: i, resolution by an internal entrainment
In this work, we describe the synthesis of both enantiomers
procedure; ii, (MeO)2SO2 and KOH in H2O, 3 h at 70–75 °C, neutralization
of the psychotropically active medicine Albicar,4 2,6-diethyl-
with HCl at 20 °C, extraction with CH2Cl2 at 20 °C, chromatography on
4,8-dimethylglycoluril 1. Albicar has passed pre-clinical tests
and was recommended for clinical tests as a tranquilizer and a
remedy for treating vegetative neuroses.
According to the qualitative concepts for constructing con-
glomerates developed previously,5 there were the chiral glycol-
urils that seemed to be the most promising objects. Indeed,
whereas the Albicar itself is crystallised as a racemate (space
group P21/a, Z = 4)4(c) its possible precursors, 2,6-dialkylglycol-
urils, both do form conglomerates [R = Me (space group P212121,
silica (eluent CH2Cl2), and crystallization from Et2O.
Z = 4),5(b) R = Et, 2 (space group P41212, Z = 4)6] and undergo
spontaneous resolution by crystallization from water under nor-
mal conditions.5(a),(b)
It should be noted that in some instances crystallization in
the form of a conglomerate occurs only under high pressures
or elevated temperatures;3(a)–(c) sometimes, the conglomerates do
not undergo spontaneous resolution due to epitaxy.5(b)
By a comparative analysis of the crystal properties of Albicar
precursors, the advantage of 2 was shown;5(b) therefore, its spon-
taneous resolution into enantiomers was completed using an inter-
nal entrainment procedure (the novel method including applying
a single crystal as the seed from primary racemic conglomerate;7
early resolution by mechanical sorting of crystals was de-
scribed5(a)). Among the known methods for the N-alkylation
of glycolurils,4(b),8–11 we have selected the simplest one7 and
found conditions to provide quantitative yields of the product.
The obtained enantiomers of 1 have been purified by crys-
tallization from diethyl ether until the constancy of melting
points and optical rotation angles, and characterised by 1H NMR
(Figure 1) and CD spectra (Figure 2).† The absolute configura-
tion of the enantiomers of 1 is apparent from those established
earlier5(a) for precursors 2 (Scheme 1). The purity of (–)-1
exceeds 95% as it is evident from the absence of the signals due
to MeN, CH2O, and HC relating to another enantiomer and
observed for the racemate in 1H NMR spectrum in the presence
of the chiral shift reagent Eu(tfc)3 (Figure 1). It should be noted
that the melting points of the enantiomers are higher than that
of the racemate by 25 °C.† This uncommon case3,12 may indicate
to a metastable state of the racemate.3 However, crystallization
of ( )-1 from toluene at an elevated temperature (80–100 °C)
4.6
4.4
3.4
3.2
d/ppm
3.0
2.8
2.6
4.5
4.0
3.5
d/ppm
3.0
2.5
Figure 1 Partial 1H NMR spectra of ( )-1 (400 MHz) in C6D6; below:
normal spectrum; above: in the presence of the chiral shift reagent Eu(tfc)3.
– 6 –

Mendeleev Commun., 2002, 12(1), 6–8
10
8
6
1
4
a0
c
2
0
–2
–4
–6
–8
–10
2
200
220
l/nm
b
Figure 2 CD spectra (MeOH) of (1) (1S,5S)-(–)-1 and (2) (1R,5R)-(+)-1.
led to lower melting racemic crystals. In order to compare the
peculiarities of the crystal structures of enantiomerically pure
and racemic 1, the X-ray investigation of both crystals (grown
from Et2O at 20 °C) was carried out.‡ The geometries of 1 in
homo- and heterochiral crystals are similar (Figure 3). The con-
formations of the five-membered rings are slightly different.
Thus, in (–)-1 both five-membered rings are characterised by the
envelope conformation with the deviations of the N(2) and N(4)
by 0.11 and 0.13 Å, respectively, while in ( )-1 the maximum
Figure 4 The intermolecular C–H···O contacts in (–)-1. The parameters of
the C–H···O contacts are: C(2)–H(2)···O(1') (–x, –1/2 + y, 1/2 – z) {H(2)···O(1')
2.43 Å, ÐC(2)H(2)O(1') 155°, C(2)···O(1') 3.435(6) Å}; C(4)–H(4)···O(2')
(1/2 – x, –y, 1/2 + z) {H(4)···O(2') 2.41 Å, ÐC(4)H(4)O(2') 141°, C(4)···O(2')
3.309(6) Å}. C–H distances in (–)-1 are normalised to the ideal values
1.07 Å.
deviations of atoms from the mean square planes are less than
0.05 Å. The angles between planes in both structures are similar
and, in average, equal to 121°.
C(6)
C(7)
C(5)
The comparison of the crystal packings has revealed that in
accordance with the greater value of the mp of (–)-1 its density
(1.217 g cm–3) at room temperature is slightly higher than the cor-
responding value in ( )-1 (1.188 g cm–3). However, the C–H···O
contacts (cf. ref. 13), which are observed in both crystals, are
shorted in ( )-1. In (–)-1, the C–H···O contacts of the hydrogen
atoms attached to the C(2) and C(4) atoms assemble molecules
into a three-dimensional framework and with the C···O distances
from 3.309(6) to 3.435(6) Å (Figure 4). While in ( )-1 the
molecules are assembled into layers with hydrophobic coatings
(Et groups) parallel to the bc crystallographic plane by the
C–H···O contacts with the C···O distances varying in a range
of 3.214(4)–3.345(4) Å (Figure 5). Taking into account that the
C–H···O contacts play a great role in the formation of crystals,
the above shortening of the C–H···O contacts can be responsible
N(2)
N(1)
C(1)
O(2)
C(2)
C(4)
C(3)
O(1)
N(3)
C(8)
C(9)
N(4)
C(10)
Figure 3 The general view of (–)-1.
†
The NMR spectra were measured on a Bruker WM-400 spectrometer
1
(400.13 MHz for H), optical rotation was measured on a Polamat A
polarimeter, and CD spectra were recorded on a JASCO-J500A instrument
with a DP-500N data processor.
( )-1, obtained from ( )-2 by Scheme 1, mp 112–114 °C (Et2O) (lit.,4(b)
mp 108–110 °C). 1H NMR (C6D6) d: 0.85 (t, 6H, 2MeCH2, 3J 7.4 Hz),
2.5 (s, 6H, 2MeN), 3.05 (m, 4H, 2CH2N, ABX3 spectrum, ∆n 152 Hz,
2J –14.8 Hz, 3J 7.4 Hz), 3.99 (s, 2H, 2HC). When adding the chiral shift
reagent in the molar ratio 1/Eu(tfc)3 = 20 a low-field shift of all the
signals and splitting some of the signals of the enantiomers are observed
(∆n/Hz), 1H NMR [C6D6 + Eu(tfc)3] d: 0.99, 2.69 (4.4), 3.07, 3.42 (2.8),
4.3 (1.2), upon adding an amount of Eu(tfc)3 the signal of MeN moves to
2.8 ppm (∆n 23.1 Hz), and the signal of HC, to 4.58 ppm (∆n 12.7 Hz).
(1S,5S)-(–)-2 and (1R,5R)-(+)-2, upon complete crystallization of ( )-2
from H2O, a racemic mixture of the well-formed crystals was obtained;
two crystals of the opposite optical rotation signs were selected, rubbed
to powder and used as seeds for resolution of ( )-2 by an internal
entrainment procedure.7 Repeated crystallization of the enantiomerically
enriched products resulted in preparing enantiomerically pure samples
[cf. ref. 5(a)]. Starting from 5 g of ( )-1, 2.3 g of (–)-2 (91.4%) and 2.1 g
of (+)-2 (84%) were obtained.
‡
Crystallographic data for (–)-1 and ( )-1: at 295 K, the crystals of
C10H18N4O2 (–)-1 are orthorhombic, space group P212121, a = 9.460(3) Å,
b = 11.225(4) Å, c = 11.626(4) Å, V = 1234.6(7) Å3, Z = 4, M = 226.28,
dcalc = 1.217 g cm–3, m(MoKα) = 0.87 cm–1, F(000) = 488; ( )-1 mono-
clinic, space group P21/c, a = 10.042(2) Å, b = 11.022(2) Å, c = 11.950(2) Å,
b = 106.963(4)°, V = 1265.1(4) Å3, Z = 4, M = 226.28, dcalc = 1.188 g cm–3,
m(MoKα) = 0.85 cm–1, F(000) = 488. Intensities of 6917 and 12096 re-
flections were measured with a Smart 1000 CCD diffractometer at 295 K
[l(MoKα) = 0.71073 Å, w-scans with a 0.3° step in w and 30 and 15 s
per frame exposure, 2q < 50°, 2q < 60° for (–)-1 and ( )-1, respectively],
and 2123 and 3627 independent reflections were used in a further refine-
ment. The structures were solved by a direct method and refined by the
full-matrix least-squares technique against F2 in the anisotropic–isotropic
approximation. Due to high libration of the ethyl group C(5)–C(6) in
(–)-1, it was refined with the constrained bond lengths (C–C of 1.55 Å
and N–C of 1.44 Å). Hydrogen atoms were located from the Fourier
synthesis and refined using a riding model in (–)-1 and an isotropic
approximation in ( )-1. The refinement converged to wR2 = 0.1218 and
GOF = 1.006 for all independent reflections [R1 = 0.0625 was calculated
against F for 799 observed reflections with I > 2s(I)] for (–)-1 and to
wR2 = 0.1101 and GOF = 0.957 for all independent reflections [R1 = 0.0465
was calculated against F for 1399 observed reflections with I > 2s(I)]
for ( )-1. All calculations were performed using SHELXTL PLUS 5.1
on IBM PC AT. Atomic coordinates, bond lengths, bond angles and
thermal parameters have been deposited at the Cambridge Crystallographic
Data Centre (CCDC). For details, see ‘Notice to Authors’, Mendeleev
Commun., Issue 1, 2002. Any request to the CCDC for data should quote
the full literature citation and the reference number 1135/103.
(1S,5S)-(–)-1, obtained from (1S,5S)-(–)-25(a) (Scheme 1), yield 96%,
mp 137.5–139 °C (Et2O). 1H NMR spectrum (C6D6) is similar to that for
( )-1; when adding Eu(tfc)3 gradually until the low-field shift of the
signals at 2.74 (MeN) and 4.5 ppm (HC) the splitting was not observed;
20
578
20
546
20
436
20
406
[a] –17.3°, [a] –20.9°, [a] –40.8°, [a] –47.1° (c 0.38, MeOH);
CD spectrum (c 3.76×10–3 M MeOH), ∆e (l/nm): 5.8 (207.5), 0.0 (202),
–10.0 (196).
(1R,5R)-(+)-1, obtained from (1R,5R)-(+)-25(a) (Scheme 1), yield 96.5%,
1
mp 137.5–138 °C (Et2O). H NMR spectrum (C6D6) is similar to those
20
578
20
546
20
436
20
406
for ( )-1; [a]
+18.3°, [a]
+21.0°, [a]
+39.3°, [a]
+44.5°
(c 0.38, H2O); CD spectrum (c 9.3×10–3 M MeOH), ∆e (l/nm): –5.8
(207.5), 0.0 (202), +10.0 (196).
– 7 –

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b
Figure 5 The intermolecular C–H···O contacts in ( )-1. The parameters of
the C–H···O contacts are C(2)–H(2)···O(1') (x, 1/2 – y, –1/2 + z) {H(2)···O(1')
2.34 Å, ÐC(2)H(2)O(1') 155°, C(2)···O(1') 3.3452(4) Å}; C(4)–H(4)···O(2')
(2 – x, –1/2 + y, 1/2 – z) {H(4)···O(2') 2.17 Å, ÐC(4)H(4)O(2') 165°, C(4)···O(2')
3.213(4) Å}. C–H distances in ( )-1 are normalised to the ideal values
1.07 Å.
8
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This work was supported by the Russian Academy of Sciences,
Russian Foundation for Basic Research (grant nos. 00-03-32738
and 00-03-81187Bel), and INTAS (grant no. 99-00157).
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Received: 21st September 2001; Com. 01/1847
– 8 –