The chiral drug Albicar: Resolution of its racemate via complexation with BINOL

Article abstract of DOI:10.1039/b9nj00701f

Both enantiomers of the title drug (2,6-diethyl-4,8-dimethyl-glycoluril; 1) were prepared from their complexes with (R)- and (S)-BINOL in 59% ((+)-1) and 43% ((-)-1) yield from its racemate. The absolute configuration of (1R,5R)-(+)-1 was determined by an

Full text of DOI:10.1039/b9nj00701f

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LETTER
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The chiral drug Albicar: resolution of its racemate via complexation
with BINOLwz
Denis A. Lenev,*a Konstantin A. Lyssenkob and Remir G. Kostyanovsky*a
Received (in Montpellier, France) 23rd November 2009, Accepted 5th January 2010
First published as an Advance Article on the web 27th January 2010
DOI: 10.1039/b9nj00701f
Both enantiomers of the title drug (2,6-diethyl-4,8-dimethyl-
glycoluril; 1) were prepared from their complexes with (R)-
and (S)-BINOL in 59% ((+)-1) and 43% ((ꢀ)-1) yield from
its racemate. The absolute configuration of (1R,5R)-(+)-1 was
determined by an XRD study of the (R)-(+)-BINOL-(+)-1ꢁH2O
complex.
4-R and 4-S in an organic solvent in the presence of H2O (in
our case, we used wet ethyl acetate). Thus, (ꢂ)-1 was dissolved
in EtOAc and (R)-BINOL (99% ee) added to it. Complex 4-R
((R)-BINOL + (1R,5R)-(+)-1 + H2O) immediately started to
crystallize, and the mixture was left at 4 1C for a time sufficient
to obtain full crystallization of the complex. The mother
liquor, M, was separated. Thus, the obtained complex, 4-R,
contained (+)-1 in approximately 90% ee (optical rotation
data). It was therefore recrystallized from wet EtOAc to
increase the de to 495%. The complex was destroyed by the
action of aqueous 15% NaOH, and (+)-1 was extracted with
CH2Cl2 in 59% total yield. By the action of HCl on the
aqueous layer, (R)-BINOL was separated, filtered and
recycled. The mother liquor, M, was treated in the same
way to liberate (ꢀ)-1 in 90% ee, which was purified by the
crystallization of 4-S using (S)-BINOL. An alkaline work-up
gave (ꢀ)-1 in 495% ee and 43% yield.z (+)-1 and (ꢀ)-1
could also be purified by recrystallization in their uncom-
plexed form, as the melting point of the enantiomers is 430 1C
higher than that of the racemate,7c and therefore, outside a
certain small eutectic region of the binary phase diagram,
mixtures of (+)-1 and (ꢀ)-1 are optically enriched by
recrystallization. The constants of (+)-1 and (ꢀ)-1 were
similar to those previously reported.7c
The resolution of chiral drugs is one of the main industrial
routes for their production. One of the resolving agents that is
gaining increasing importance is BINOL, well-known in
asymmetric synthesis as a catalyst.1 It was found by Toda,
co-workers and other researchers, that BINOL forms crystalline
hydrogen-bonded diastereomeric complexes with chiral sulfoxides,
selenoxides, phosphinates, phosphinoxides, N-oxides and phos-
phonium salts.2 Recent work has shown the utility of this general
method to resolve omeprazol.3
BINOL has also been used in the resolution of the carbonyl
compound spiro[4.4]nonane-1,6-dione.4 However, it has not
been used so far to resolve ureas.
Racemic bicyclic bis-urea Albicar (1) is an original drug with
the properties of a day time tranquillizer and an antidepressant,5
and its (1R,5R)-(+)-enantiomer is more active in mice,6 with
an active dose of 75 mg kgꢀ1 being two times lower compared
to the racemate. Less active achiral prototype Mebicar (2) has
been produced for a long time by JSC ‘‘Olainfarm’’ (Olaine,
Latvia) and sold under the trade name Adaptols. Previously,
1 was prepared in enantiopure form by the spontaneous
resolution of its precursor.7 Due to the complicated technical
implementation of effective spontaneous resolution on a
laboratory scale, other efficient methods were needed. Kravchenko
et al. have developed the enantioseparation of 1 by chromato-
graphy on chiral phases.6,8 However, this method is not cost
effective; the reason why we studied the possibility resolving 1
using enantiopure BINOL.
Interestingly, in the absence of H2O (e.g. in toluene), no
optical resolution occurred; however, the complex between
(R)-BINOL and (ꢂ)-1 was readily formed.
Racemic Albicar, (ꢂ)-1, was synthesized by the alkylation of
its precursor, 3, with MeI in the presence of NaH in DMF
(Scheme 1) in a 70% yield.y The desired resolution of (ꢂ)-1
was achieved by the formation of diastereomeric complexes
The crystal structure of complex 4-R was elucidated by
XRD (Fig. 1).8 Besides the molecules of BINOL and Albicar,
a Semenov Institute of Chemical Physics, Russian Academy of Sciences,
4 ul. Kosygina, 119991 Moscow, Russia. E-mail: kost@chph.ras.ru;
Fax: +7 495-6512191; Tel: +7 499-1373227
b Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russia.
E-mail: kostya@xray.ineos.ac.ru; Fax: +7 499-1355085;
Tel: +7 499-1359214
w Dedicated to Fumio Toda on the occasion of his 75th birthday.
z CCDC reference number 712625. For crystallographic data in CIF
or other electronic format see DOI: 10.1039/b9nj00701f
Scheme 1
ꢃc
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115.44, 118.57, 122.13, 124.55, 125.63, 127.74, 128.19, 128.51, 134.25,
153.03 and 158.14.
8 X-Ray diffraction analysis at 100 K of crystals of 4-R: C30H34N4O5,
triclinic, space group P1, a = 9.0758(5), b = 9.2281(5), c = 9.3635(5) A,
a = 64.225(1), b = 81.697(1), g = 70.4350(1)1, V = 665.42(6) A3,
Z = 1, (Z0 = 1), FM = 530.61, dc = 1.324 g cmꢀ3, m(Mo-Ka) =
0.91 mꢀ1
, F(000) = 282. The intensities of 8160 reflections
were measured with a Bruker Smart APEX II CCD diffractometer
(l(Mo-Ka) = 0.71072 A, 2y o 581) and 3554 independent reflections
(Rint = 0.0193) were used in the further refinement. The structure was
solved by direct methods and refined using the full-matrix least-squares
technique against F2 in the anisotropic–isotropic approximation. The
hydrogen atoms were located from a Fourier density synthesis. The
refinement converged to wR2 = 0.0864 and GOF = 1.021 for all
independent reflections (R1 = 0.0321 was calculated against F for 3478
observed reflections with I 4 2s(I)). All calculations were performed
using SHELXTL PLUS 5.0.z
1 (a) J. M. Brunel, Chem. Rev., 2005, 105, 857–897; (b) Y.
Chen, S. Yekta and A. K. Yudin, Chem. Rev., 2003, 103,
3155–3211.
Fig. 1 A general view of 4-R.
2 (a) F. Toda, K. Tanaka and S. Nagamatsu, Tetrahedron Lett., 1984,
25, 4929–4932; (b) F. Toda and K. Mori, J. Chem. Soc., Chem.
Commun., 1986, 1357–1359; (c) F. Toda, K. Mori, Z. Stein and
I. Goldberg, J. Org. Chem., 1988, 53, 308–312; (d) F. Toda, K. Mori,
Z. Stein and I. Goldberg, Tetrahedron Lett., 1989, 30, 1841–1844;
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the crystal also contains one molecule of H2O per unit cell.
The absolute configuration of (1R,5R)-(+)-1 was deduced
from the known absolute configuration of R-(+)-BINOL.
Previously, the absolute configuration of (1R,5R)-(+)-1 was
determined by a covalent diastereomeric derivative of its
precursor with a chiral auxiliary of known configuration.7a
Thus, an efficient method for resolving 1 has been developed.
The more active (+)-enantiomer of 1 is now easily accessible on
a large scale for biological and clinical studies.
4 X. M. Feng, D. C. Zeng, Z. Li and Y. Z. Jiang, Chin. Chem. Lett.,
1999, 10, 559–562.
We are grateful to JSC ‘‘Olainfarm’’ (Olaine, Latvia) for
financial support. This work was also supported by the Russian
Foundation for Basic Research (grant 09-03-00537a) and the
Russian Academy of Sciences.
5 A. A. Prokopov, A. S. Berlyand and N. V. Kostebelov, Pharm.
Chem. J., 2001, 35, 533–534.
6 A. N. Kravchenko, Dr. Chem. Sci. thesis, Zelinsky Institute of
Organic Chemistry, Moscow, 2007.
7 (a) R. G. Kostyanovsky, K. A. Lyssenko, G. K. Kadorkina,
O. V. Lebedev, A. N. Kravchenko, I. I. Chervin and
V. R. Kostyanovsky, Mendeleev Commun., 1998, 8, 231–233;
(b) R. G. Kostyanovsky, K. A. Lyssenko, A. N. Kravchenko,
O. V. Lebedev, G. K. Kadorkina and V. R. Kostyanovsky, Mendeleev
Commun., 2001, 11, 134–136; (c) R. G. Kostyanovsky,
G. K. Kadorkina, K. A. Lyssenko, V. Yu. Torbeev,
A. N. Kravchenko, O. V. Lebedev, G. V. Grintselev-Knyazev and
V. R. Kostyanovsky, Mendeleev Commun., 2002, 12, 6–8;
(d) R. G. Kostyanovsky, V. R. Kostyanovsky, G. K. Kadorkina
and V. Yu. Torbeev, New routes to chiral drugs, in Nitrogen-
Containing Heterocycles and Alkaloids, ed. V. G. Kartsev and
G. A. Tolstikov, Iridium Press, Moscow, 2001, pp. 132–136.
8 (a) A. N. Kravchenko, A. C. Sigachev, E. Yu. Maksareva,
G. A. Gazieva, N. C. Trunova, B. V. Lozhkin, T. S. Pivina,
M. M. Il’in, K. A. Lyssenko, Yu. V. Nelyubina, V. A. Davankov,
O. V. Lebedev, N. N. Makhova and V. A. Tartakovsky, Izv. Akad.
Nauk, Ser. Khim., 2005, 680–692; (b) A. N. Kravchenko,
A. C. Sigachev, E. Yu. Maksareva, G. A. Gazieva,
N. C. Trunova, B. V. Lozhkin, T. S. Pivina, M. M. Il’in,
K. A. Lyssenko, Yu. V. Nelyubina, V. A. Davankov,
O. V. Lebedev, N. N. Makhova and V. A. Tartakovsky, Russ.
Chem. Bull., 2005, 54, 691–704.
References
y Compound (ꢂ)-1: (ꢂ)-3 (25.75 g, 0.13 mol) was dissolved in DMF
(400 ml) and NaH (60% suspension; 12.6 g, 0.315 mol) carefully
added. After stirring for 1 h, MeI (65 ml, 150 g, 1.05 mol) was slowly
added, the temperature rising to 80 1C. At this temperature, the
mixture was stirred for 3 h. The DMF was then evaporated in vacuo,
and the residue dissolved in H2O (100 ml) and extracted with chloro-
form (4 ꢄ 100 ml). The organic phase was dried and evaporated. The
residue was recrystallized from EtOAc–Et2O (1 : 1) to give (ꢂ)-1
(20.5 g, 70%). mp 114–116 1C.
z 4-R (495% de): mp. 147–162 1C; [a]20 (l) (c 1, MeOH): +20 ꢂ 2
(578), +27 ꢂ 2 (546), +108 ꢂ 2 (436) and +196 ꢂ 2 (406).
4-S (495% de): mp. 145–161 1C; [a]20 (l) (c 1, MeOH): ꢀ19 ꢂ 2
(578), ꢀ26 ꢂ 2 (546), ꢀ111 ꢂ 2 (436) and ꢀ195 ꢂ 2 (406).
1H NMR of 4-R (CD3OD): 1.15 (t, 6H, 2CH2Me, 3J = 7 Hz), 2.89
(s, 6H, 2Me), 3.27, 3.42 (m, 4H, 2CH2), 5.15 (s, 2H, 2CH), 7.00 (d, 2H,
HAr, 3J = 8 Hz), 7.14 (t, 2H, HAr, 3J = 8 Hz), 7.23 (t, 2H, HAr, 3J =
8 Hz), 7.27 (d, 2H, HAr, 3J = 8 Hz), 7.81 (d, 2H, HAr, 3J = 8 Hz) and
7.85 (d, 2H, HAr,
3J = 8 Hz). 13C NMR: 13.28, 29.9, 37.44, 69.59,
ꢃc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2010
404 | New J. Chem., 2010, 34, 403–404