Synthesis of a new doxazosin-related compound

Article abstract of DOI:10.1080/00397910601039135

A simple procedure for the synthesis of 1-[4-(2,3-dihydro-1, 4-benzodioxin-2-yl) amide-6, 7-dimethoxy-2-quazolinyl]-4-(1,4-bensodioxan-2-yl- carbonyl) piperazine is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601039135

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Synthesis of a New Doxazosin‐Related
Compound
Irina Tsyskovskaia a , Mustapha Kandil a & Yves Beaumier a
a Pharmascience , Saint‐Laurent, Quebec, Canada
Published online: 06 Feb 2007.
To cite this article: Irina Tsyskovskaia , Mustapha Kandil & Yves Beaumier (2007) Synthesis of a New
Doxazosin‐Related Compound, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 37:3, 447-450, DOI: 10.1080/00397910601039135
To link to this article: http://dx.doi.org/10.1080/00397910601039135
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Synthetic Communicationsw, 37: 447–450, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601039135
Synthesis of a New Doxazosin-Related
Compound
Irina Tsyskovskaia, Mustapha Kandil, and Yves Beaumier
Pharmascience, Saint-Laurent, Quebec, Canada
Abstract: A simple procedure for the synthesis of 1-[4-(2,3-dihydro-1, 4-benzodioxin-2-
yl) amide-6, 7-dimethoxy-2-quazolinyl]-4-(1,4-bensodioxan-2-yl-carbonyl) piperazine is
described.
Keywords: doxazosin, related compounds, synthesis, HPLC
4-Amino-2-[4-(1,4-benzodioxan-2-ylcarbonyl) piperazin-1-yl]-6,7-dimethox-
yquin azoline 5 (doxazosin mesylate) is an important new member of the qui-
nazoline family of drugs used for the treatment of hypertension.[1–3]
Moreover, the compound has recently attracted more attention because of
its efficient treatment of benign prostatic hyperplasia.[4–8] It is believed that
doxazosin is a selective blocker of the a-adrenergic receptor.
Several procedures have been developed for the synthesis of doxazosin.
The most recent one is based on the conversion of acid 1 to the corresponding
acid chloride, followed by the reaction with piperazine to give the benzodiox-
ane 2, which is coupled with the quinazoline 3 to provide doxazosin hydro-
chloride 4, which is then converted into doxazosin mesylate 5 (Figure1).[9]
Two major impurities have been reported in the synthesis of doxazosin
mesylate 5. The first one is the symmetrical bis-amide 6 arising from the
bicoupling reaction of the acide chloride with piperazine. The second one
was piperazine 8. Herein, we report the synthesis of compound 8.
Moreover, it can be employed as a reference in the process of controlling
the impurities of doxazosin mesylate 5.
Received in the USA May 18, 2006
Address correspondence to Yves Beaumier, Pharmascience, 6625 Abrams, Saint-
Laurent, Quebec, Canada H4S 1X9. E-mail: ybeaumier@pharmascience.com
447

448
I. Tsyskovskaia, M. Kandil, and Y. Beaumier
Figure 1. Synthesis of doxazosin mesylate.
Doxazosin mesylate 5 was coupled with 1,4-benzodioxane-2-carbonyl
chloride 7 to obtain compound 8 (Fig. 2). The product was obtained in
88% yield after purification by flash chromatography and was characterized
by NMR, mass spectrometry (MS) spectroscopy, and analytical high-
performance liquid chromatography (HPLC).
EXPERIMENTAL
NMR spectra were recorded on a 400-MHz Bruker instrument. Mass spectra
were performed on a Micromass Autospec-TOF spectrometer. Microanalysis
was performed on an EA 1108 CHNS model analyzer. For thin-layer chrom-
atography (TLC) of analytical samples, silica-gel 60F254 precoated aluminum
sheets were used (Merck Art. No. 5554).
Figure 2. Synthesis of related compound (8).

Synthesis of a New Doxazosin-Related Compound
High-Performance Liquid Chromatography
449
Liquid chromatography was performed using a HPLC system composed of an
Agilent model G1311A pump, equipped with a ternary gradient controller and
an Agilent model G1315A diode array detector, wavelength 275 nm. The
computer is equipped with Agilent LC3D Chemstation for Analytical
program, Revision A:09.03. A 250-mm ꢀ 4.6-mm, 5-mm Waters spherisorbs
CN column was used for determination of degradation products. A mobile
phase consisting of a buffer solution (25 mM NH4H2PO4) and acetonitrile
was delivered at a rate of 1 mL/min, holding the composition at 95:5 for
20 min, then as a linear gradient to 40:60 in 20 min. A post time of 7.5 min
is added.
1,4-Benzodioxan-2-carbonyl Chloride 7
Thionyl chloride (0.49 mL, 6.6 mmol) was added dropwise to a solution of
1,4-benzodioxanecarboxylic acid (1.00 g, 5.5 mmol) in dichloromethane
(10 mL). The mixture was stirred for 14 h at room temperature, at which
point TLC analysis showed that the reaction was completed. After evaporation
of solvent and the excess of thionyl chloride, the crude was employed for the
next step without further purification.
1-[4-(2,3-Dihydro-1,4-benzodioxin-2-yl) Amide-6,7-dimethoxy-
2-quazolinyl]-4-(1,4-benzodioxan-2-yl-carbonyl) Piperazine 8
Triethylamine (1.4 mL, 10.06 mmol) was added to a stirred suspension of
doxazosin mesylate (2.75 g, 5.03 mmol) in dichloromethane (15 mL).
Stirring continued at room temperature until a clear solution was obtained.
This solution was treated dropwise with a solution of 1,4-benzodioxane-2-
carbonyl chloride 7 (1.00 g, 5.03 mmol) in dichloromethane (10 mL).
After 12 h of stirring at room temperature, the reaction mixture was
washed with water, dried with anhydrous sodium sulfate (Na2SO4), filtered,
and evaporated. The solid residue was purified by silica-gel chromatography
using chloroform as eluent to give the product as a yellow solid. The yield
evaluated by HPLC is 88%, and the purity is 98.6%. Mp: 99–1008C.
1NMR (CDCl3) d: 8.75 (s, 1H); 7.25 (s, 1H); 7.1 (t, 1H); 6.98–6.84
(m, 8H); 6.76 (s, 1H); 5.05 (t, 1H); 4.9 (dd, 1H); 4.6–4.44 (m, 3H);
4.4–4.37 (m, 1H); 4.19–4.04 (m, 2 H); 3 (s, 3H); 4.01–3.81 (m, 3H);
3.9 (s, 3H); 3.81–3.77 (m, 1H); 3.64–3.57 (m, 2H); 1.61 (s, 2H). (Mþ)
.
.
M/z ¼ 614. C32H31N5O8 HCl 2.5 H2O calc. C, 55.9%; H, 4.84%; N,
10.2%; found C, 55.93%; H, 4.71%; N, 9.76%.

450
I. Tsyskovskaia, M. Kandil, and Y. Beaumier
REFERENCES
1. Flack, J. M. Int. J. Clin. Pract. 2002 (7), 527–530.
2. Joung, R. A.; Brogden, R. N. Drugs 1998, 35 (5), 525–541.
3. Elliot, H. L.; Meredith, P. A.; Reid, J. L. Am. J. Cardiol. 1987, 59, 79.
4. Baez, M. A.; Gary, D. C.; Jellad, N. S.; Weidler, D. J.; British, J. Clin. Pharm. 1986,
21, (Sup. 1), 63S–67S.
5. Kirby, R. S.; Andersen, M.; Gratzke, P.; Dahlstrand, C.; Hoye, K. BJU International
2001, 87 (3), 192–200.
6. Kirby, R. S. Int. J. Clin. Pract. 1998, 52, 402.
7. Guthrie, R. M.; Siegle, R. L. Clin. Ther. 1999, 21, 1732–1748.
8. Campbell, S. F.; Davey, M. J.; Hardstone, D.; Levis, B. N.; Palmer, M. J. J. Med.
Chem. 1987, 30, 49–57.
9. Fang, Q. K.; Grover, P.; Han, Z.; McConvill, F. X.; Rossi, R. F.; Olsson, D. J.;
Kessler, W.; Wald, S. A.; Senanayake, C. Tetrahedron: Asymmetry 2001, 12,
2169–2174.