Russian Journal of Bioorganic Chemistry, Vol. 31, No. 4, 2005, pp. 378–382. Translated from Bioorganicheskaya Khimiya, Vol. 31, No. 4, 2005, pp. 420–424.
Original Russian Text Copyright © 2005 by Shevchenko, Nagaev, Kuznetsov, Polunin, Zozulya, Myasoedov.
A Synthesis of Tritium-Labeled Olanzapine
1
V. P. Shevchenko, I. Yu. Nagaev, Yu. V. Kuznetsov, E. V. Polunin,
A. A. Zozulya, and N. F. Myasoedov
Institute of Molecular Genetics, Russian Academy of Sciences, pl. akademika Kurchatova 2, Moscow, 123182 Russia
Received September 24, 2004; in final form, February 3, 2005
Abstract—A synthesis of olanzapine, 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiaz-
epine, was carried out and the conditions for its tritium labeling were optimized to obtain a tritium-labeled olan-
zapine preparation with a specific radioactivity of 12 Ci/mmol.
Key words: olanzapine, synthesis, tritium
1
INTRODUCTION
Reduction of (III) with SnCl in HCl and simultaneous
2
cyclization led to 4-amino-2-methyl-10ç-thieno[2,3-
b][1,5]benzodiazepine hydrochloride (IV). Its boiling
with N-methylpiperazine in a DMSO–toluene mixture
for 24 h gave the target olanzapine (I) in 65% yield.
Physicochemical characteristics of (I) coincided with
those described in patent [3]. More than 2 g of olanza-
pine (I) were obtained in this way, and it was used for
the optimization of conditions for the incorporation of
tritium label into olanzapine.
Olanzapine, 2-methyl-10-(4-methyl-1-piperazinyl)-
4
ç-thieno[2,3-b][1,5]benzodiazepine (I), is one of the
most potent neuroleptics (antipsychotics) of a new gen-
eration. The characteristic features of these drugs are its
efficiency in reducing both positive and negative symp-
toms of schizophrenia, lack of side effects incidental to
the dysfunction of extrapyramidal system, and the
mechanism of action related to their ability to bind to
serotonin, dopamine, and other receptors [1, 2].
The labeled olanzapine with the retention of native
structure of the unlabeled precursor can be obtained
only by the method of isotope exchange. The exchange
reaction is most often carried out using the liquid-phase
procedure (viz., the reaction between the solute and tri-
tiated water) or a solid phase procedure (the reaction
between gaseous tritium and the compound applied
onto a catalyst surface) [5].
N
N
N
NH
S
(I)
The goal of this study was the synthesis of tritium-
labeled olanzapine. Unlabeled olanzapine (I) required
for the preparation of the labeled compound was syn-
thesized according to the modified procedure [3] and
subsequently used for the optimization of the condi-
tions for tritium incorporation into this compound.
The generation of tritiated water directly in the reac-
tion ampoule is considered to be the most efficient pro-
cedure for the isotope exchange with tritiated water. To
this end, PdO, the starting compound, and a catalyst
(
usually, a palladium catalyst applied onto the surface
of an inert support: Al O , activated charcoal, BaSO ,
2
3
4
CaCO , etc.) are placed in a reaction ampoule, which is
then filled with gaseous tritium and kept at 70°ë for
3
RESULTS AND DISCUSSION
1
0–15 min. PdO is completely reduced under these
Olanzapine (I) was synthesized as proposed previ-
ously [3] starting from 2-amino-5-methylthiophene-3-
carbonitrile (II) obtained by the Gewald reaction [4]
conditions with the formation of tritiated water. The
ampoule contents (the tritiated water formed, the com-
pound, and the activated catalyst) are then frozen with
liquid nitrogen, and the ampoule is evacuated for the
removal of gaseous tritium and filled with argon. After
the addition of a dioxane solution of triethylamine in
the ampoule, it is sealed to prevent the influx of the tri-
tium water vapor into the atmosphere and then kept
under stirring either at room temperature (for 16 h in
the case of olanzapine) or at an elevated temperature
(100–170°ë) in a thermostat.
(
Scheme 1). While retaining the sequence of stages
described in patent [3], we improved the procedures for
isolation of intermediates and modified the ratios of
reagents and reaction times.
Nitrile (III) was obtained by coupling (II) with o-
fluoronitrobenzene in the presence of NaH in THF.
1
Corresponding author; fax: +7 (095) 196-0221; e-mail:
068-1620/05/3104-0378 © 2005 Pleiades Publishing, Inc.