Brief Articles
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1777
(5) U.S. Food and Drug Administration, Center for Veterinary Medicine.
NADA 141-258 Zilmax (Zilpaterol Hydrochloride) Type A Medicated
fda.gov/cvm/FOI/141-258o08102006.pdf (accessed Nov 10, 2008).
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in the formation of a precipitate. The precipitate was collected,
washed with diethyl ether, and dried under reduced pressure to
provide 57 g (191.5 mmol, 81% over two steps and >99% ee) of
(+)-1·HCl as a colorless solid. [R]2D0 +33 (c 1.01, water); mp 195
°C (dec); m/z, 262.0 (M + H)+; HRMS, m/z, 262.1548 (M + H)+.
Anal. (C14H20N3O2Cl) C, H, N.
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Broeck, J. V.; Janecka, A. Functional characterization of opioid
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(21) Miculka, C.; Meyer, T.; Kern, C.; Droux, S. Zilpaterol Enantiomer
Compositions and Methods of Making and Using Such Compositions.
International Patent Application PCT/EP2007/057036, 2007.
(22) Joseph, S. S.; Lynham, J. A.; Colledge, W. H.; Kaumann, A. J. Binding
of (-)-[3H]-CGP12177 at two sites in recombinant human ꢀ1-
adrenoceptors and interaction with beta-blockers. Naunyn-Schmiede-
berg’s Arch. Pharmacol. 2004, 369, 525–532.
(6R,7R)-4,5,6,7-Tetrahydro-7-hydroxy-6-[(1-methylethyl)ami-
no]imidazo[4,5,1-jk][1]benzazepin-2(1H)-one Hydrochloride ((-)-
1·HCl). Using the procedure described for (+)-1·HCl, an amount
of 90 g (227 mmol) of (-)-6 was converted into 55.4 g (186 mmol)
of (-)-1·HCl in 82% yield (over two steps), its spectroscopic data
being identical to the ones obtained for (+)-1·HCl. >99% ee; [R]D20
-33 (c 1.03, water); HRMS, m/z, 262.1548 (M + H)+. Anal.
(C14H20N3O2Cl) C, H, N.
Synthesis of (6R,7R)-1-[2-(4-Bromophenyl)-2-oxoethyl]-4,5,6,7-
tetrahydro-7-hydroxy-6-[(1-methylethyl)amino]imidazo[4,5,1-
jk][1] benzazepin-2(1H)-one (7). General method for the prepa-
ration of the free bases from the corresponding hydrochloride salts
of 1 on small scale is as follows: A 0.1 M solution of 1·HCl in
water was treated with Amberlite IRA-67 resin for 20 min at room
temperature and then filtered. The filtrate was freeze-dried, and the
free bases of 1 were obtained as white solids. Following the general
procedure for the preparation of the free bases, (-)-1 (750 mg,
2.87 mmol) was dissolved in dry DMF (15 mL) and NaH (172
mg, 4.3 mmol, 60% dispersion in mineral oil) was added. After 10
min, 2,4′-dibromoacetophenone (956 mg, 3.44 mmol) was added
and the resulting reaction mixture was stirred for 20 h at room
temperature. Water was then added, and the resulting solution was
extracted with diethyl ether (2×), and the combined organic layers
were washed with 5% NaHCO3 (3×). After drying over MgSO4,
the organic phase was evaporated to dryness, and the residue was
purified by column chromatography on silica gel (CH2Cl2/MeOH,
9:1 v/v). 7 was obtained as a bright-yellow solid (0.66 g, 1.14 mmol,
50%). Mp 169-170 °C (dec); [R]2D0 -27° (c 0.45, EtOH); m/z, 460.1
(M)+, 457.9; HRMS, m/z, 458.1068 (M + H)+.
Acknowledgment. The authors thank Tanja Schweisel for
the preparation of crystals for the X-ray study and Karl-Heinz
Grimm for performing the enantioselective HPLC analyses.
Supporting Information Available: Details of ꢀ2-adrenergic
receptor binding assay, µ-opioid receptor binding assay, ꢀ2-
adrenergic receptor agonist activity assay, and functional human
1
recombinant µ-opioid receptor activity assay; H and 13C spectra
and HRMS, elemental analysis, HPLC results of selected com-
pounds; and crystallographic data for 7. This material is available
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