A facile synthesis of [tetrahydrofuran-3H] terazosin

Article abstract of DOI:10.1081/SCC-120034171

An efficient synthesis of [³H] terazosin at high specific activity from prazosin is described.

Full text of DOI:10.1081/SCC-120034171

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A Facile Synthesis of [Tetrahydrofuran‐ H] Terazosin
a
a
a
Judith A. Egan , Steven M. Souza & Crist N. Filer
a
PerkinElmer Life and Analytical Sciences, Inc. , 549 Albany St., Boston, Massachusetts,
2118, USA
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Published online: 20 Aug 2006.
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To cite this article: Judith A. Egan , Steven M. Souza & Crist N. Filer (2004) A Facile Synthesis of [Tetrahydrofuran‐ H]
Terazosin, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:10, 1881-1884, DOI: 10.1081/SCC-120034171
To link to this article: http://dx.doi.org/10.1081/SCC-120034171
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SYNTHETIC COMMUNICATIONS
Vol. 34, No. 10, pp. 1881–1884, 2004
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A Facile Synthesis of [Tetrahydrofuran- H]
Terazosin
*
Judith A. Egan, Steven M. Souza, and Crist N. Filer
PerkinElmer Life and Analytical Sciences, Inc.,
Boston, Massachusetts, USA
ABSTRACT
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An efficient synthesis of [ H] terazosin at high specific activity from
prazosin is described.
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Key Words: Terazosin; Tritium; Tritium NMR; [ H] Terazosin.
INTRODUCTION
Adrenergic receptors have historically been divided into the alpha and
beta types with the former being further subdivided into alpha-1 and alpha-2
[1,2]
receptors based on biochemical and pharmacological evidence.
In particu-
lar, alpha-1 adrenergic receptors have been implicated as effective points of
intervention in such diverse conditions as cardiovascular disease as well as
*
Correspondence: Crist N. Filer, PerkinElmer Life and Analytical Sciences, Inc., 549
Albany St., Boston, MA 02118, USA; E-mail: crist.filer@perkinelmer.com.
1
881
DOI: 10.1081/SCC-120034171
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Egan, Souza, and Filer
urinary tract problems, and over the years agonists and antagonists of this
receptor class have been sought as potential drug candidates. With our long-
[3,4]
standing interest in preparing radioligands for the alpha adrenergic area,
we were asked to prepare a tritium labelled analogue of the alpha-1 antagonist
terazosin 1 for biological testing and now disclose a convenient method.
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Our objective was to prepare [ H] terazosin with a specific activity of at
least 20 Ci/mmol to be useful in receptor binding assay. Most reported synth-
eses of 1 involved the condensation of a dimethoxyquinazoline derivative with
a tetrahydrofuroylpiperzine intermediate. However, for scale and simplicity
advantages, we reasoned that prazosin 2 itself might serve as a useful precur-
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sor to [ H] terazosin via catalytic tritiation. Surprisingly, to our knowledge, the
hydrogenation of 2 to 1 had not been reported, but in our hands, the catalytic
3
tritiation of 2 to [tetrahydrofuran- H] terazosin was straightforward, affor-
ding radiochemically pure product in reasonable yield and high specific
activity over the course of several runs. The proton decoupled tritium NMR
(
Fig. 1) clearly indicated that all of the incorporated tritium resided in the
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Figure 1. Proton decoupled tritium NMR (CD OD) of [tetrahydrofuran- H]
terazosin.
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Synthesis of [ H] Terazosin
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tetrahydrofuran ring, displaying resonances in excellent agreement with the
corresponding proton NMR assignments.
EXPERIMENTAL SECTION
General
Evaporations were carried out on a Buchi rotary evaporator at bath tem-
peratures less than 408C. Analytical TLC was performed on Analtech
2
5
ꢀ 15 cm glass plates coated with silica gel. Autoradiography was per-
formed at 08C after spraying with PPO and exposing plates to x-ray film.
TLC plates were also scanned (ꢀ3 min) for applied radioactivity (ꢀ10 uCi).
Analytical HPLC was performed on a Waters instrument with peak detection
done simultaneously by UV (280 nm—Waters 440 UV detector) and liquid
scintillation flow monitor. NMR spectra were obtained on a Bruker
300 MHz instrument and chemical shift values are expressed in parts per
million (ppm) downfield from TMS. The mass spectrum was obtained on a
Finnigan LC Deca instrument with direct injection.
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Tetrahydrofuran- H] terazosin. A solution of precursor 2 HCl
.
[
20 mg, 0.05 mmol) in 3 mL of ethanol : water (8 : 1) was reduced with 60 Ci
(
of tritium gas using 20 mg of 5% Pd/C catalyst with rapid stirring at ambient
temperature overnight. After this time, the reaction was filtered and the cata-
lyst washed with 5 mL of ethanol after which labile tritium was removed by
several vacuum transfers of ethanol yielding 938 mCi of crude product. A por-
tion (460 mCi) of the material was purified by TLC on two 500 mm silica gel
plates developed with ethyl acetate : methanol : triethylamine (70 : 20 : 5) to
afford 290 mCi (a 31% radiochemical yield based on precursor 2) of product
that was .98% radiochemically pure on TLC (same system as above) and
reverse phase HPLC [0.02 M aq. potassium phosphate (pH 3) : acetonitrile
(
82 : 18)]. The product also co-chromatographed with authentic 1 in
these systems. The specific activity of the product was measured to be
7.4 Ci/mmol by mass spectrometry and it provided a proton decoupled
tritium NMR (CD OD) as shown in Fig. 1.
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ACKNOWLEDGMENTS
We wish to thank Drs. Puliyur Srinivasan and Mahendra Suryan of
PerkinElmer Life and Analytical Sciences for obtaining the various NMR
and mass spectra, respectively, and Dr. Scot Pounds for assistance with the
tritiation.
REFERENCES
1
2
. Civantos Calzada, B.; Aleixandre de Artinano, A. Alpha-adrenoreceptor
subtypes. Pharmacol. Res. 2001, 44, 195–208.
. Docherty, J.R. The pharmacology of alpha 1- and alpha 2-adrenoreceptors:
evidence for and against a further subdivision. Pharmacol. Ther. 1989, 44,
2
41–284.
3
3
. Filer, C.N.; Ahern, D.G. Synthesis and characterization of [phenyl- H]
clonidine hydrochloride at high specific activity. J. Labelled Cpd. Radio-
pharm. 2001, 44, 323–327.
4
. Egan, J.A.; Filer, C.N. Tritium labelling and characterization of the potent
3
imidazoline I1 receptor antagonist [5,7- H] (þ/2)-efaroxan at high
specific activity. Appl. Rad. Isot. 2003, 58, 675–677.
Received in the USA January 6, 2004

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