Synthesis of [3H] dapsone

Article abstract of DOI:10.1081/SCC-200039492

An efficient synthesis of [³H] dapsone at high specific activity is described.

Full text of DOI:10.1081/SCC-200039492

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Synthesis of [3H] Dapsone
Judith A. Egan a , Scot Pounds a & Crist N. Filer a
a PerkinElmer Life and Analytical Sciences, Inc. ,
549 Albany St., Boston, 02118, USA
Published online: 10 Jan 2011.
To cite this article: Judith A. Egan , Scot Pounds & Crist N. Filer (2004) Synthesis
of [3H] Dapsone, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:23, 4417-4420, DOI: 10.1081/
SCC-200039492
To link to this article: http://dx.doi.org/10.1081/SCC-200039492
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 23, pp. 4417–4420, 2004
Synthesis of [3H] Dapsone
*
Judith A. Egan, Scot Pounds, and Crist N. Filer
PerkinElmer Life and Analytical Sciences, Inc., Boston, USA
ABSTRACT
An efficient synthesis of [3H] dapsone at high specific activity is
described.
Key Words: Dapsone; Tritium; Tritium NMR; Bromination;
Dehalogenation.
4,40-Sulfonylbisbenzeneamine (dapsone 1) is a truly intriguing com-
pound, possessing both valuable industrial polymer[1] and pharmaceutical
applications. With regard to the latter, 1 has been successfully employed for
leprosy[2] and is also the treatment of choice for dermatitis herpetiformis.
Recently, it has been broadly prescribed in the treatment of Pneumocystis
carinii in AIDS patients.[3] We were required to label 1 with tritium and
now report a useful method.
*
Correspondence: Crist N. Filer, PerkinElmer Life and Analytical Sciences, Inc., 549
Albany St., Boston, 02118, USA; Fax: þ617-350-9696; E-mail: crist.filer@
perkinelmer.com.
4417
DOI: 10.1081/SCC-200039492
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4418
Egan, Pounds, and Filer
Although no report of the bromination of 1 was found in the literature, the
mild preparation of dibromo analogues 2 was straightforward for us, as seen in
Scheme 1. Product 2 appeared to be a mixture of bromine isomers substituted
in large part ortho to the amines and also contained some tri- and tetrabromo
analogues. These were anticipated not to interfere in the subsequent tritiation
and even elevate product specific activity. Precursor mixture 2 was used
without further purification and was smoothly converted to [3H] dapsone 3
at high specific activity by catalytic tritium dehalogenation followed by
high-performance liquid chromatography (HPLC) purification. Product 3 was
found to be radiochemically homogeneous by HPLC and afforded the proton
decoupled tritium nuclear magnetic resonance (NMR) as seen in Fig. 1,
documenting the exclusive tritium incorporation into the phenyl positions
ortho to the amines.
EXPERIMENTAL
General
Evaporations were carried out on a Buchi evaporator at bath temperatures
less than 408C. Analytical thin-layer chromatography (TLC) was performed on
Analtech 5 ꢀ 15cm glass plates coated with silica gel and developed with
chloroform:methanol : ammonium hydroxide (10:1:0.1). Autoradiography
was performed at 08C after spraying with 2,5-diphenyloxazole (PPO) and
exposing the plates to x-ray film. The TLC plates were also scanned
Scheme 1. Synthesis of 3.

Synthesis of [3H] Dapsone
4419
(ꢀ3 min) for applied radioactivity (ꢀ10mCi). Analytical HPLC was performed
on a Waters instrument with peak detection done simultaneously by ultraviolet
(UV) (280nm- 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 downfield from tetramethylsilane
(TMS). All chemicals used were reagent grade.
Bromodapsone Mixture 2
To a three-neck, 100 mL round-bottom flask was added 1 (300 mg,
1.2 mmol) and 40 mL of acetic acid, followed by the drop-wise addition of
bromine (0.25 mL, 4.8 mmol) in 5 mL of acetic acid. After stirring overnight
at ambient temperature, the resulting solid was filtered, washed with water,
and vacuum dried to yield 507 mg (74% yield) of 2 (TLC, Rf 0.75), which
proved to be mostly a mixture of dibromodapsone isomers 2a and 2b by
mass spectral analysis (M þ 1: m/e 407) and 1H NMR (acetone-d6):
complex multiplet from 6.9–8.0 ppm.
[3H] Dapsone 3
To a 5 mL round-bottom flask was added 15 mg (0.026 mmol) of 2 and
2 mL of THF with 0.05 mL of triethylamine and 15 mg of 10% Pd/C catalyst.
Figure 1. Proton decoupled tritium NMR (CD2OD) of 3.

4420
Egan, Pounds, and Filer
The reaction was stirred at ambient temperature overnight with 60 Ci of
tritium gas. After evacuation of the tritium gas, catalyst filtration and
several vacuum evaporations of methanol, a radioassay revealed 2205 mCi
of crude product. A portion (544 mCi) of this was purified by reverse-phase
HPLC [10 mmol aqueous triethylammonium acetate (pH 4):acetonitrile
(70 : 30)] to afford 119 mCi of 3 (an extrapolated 22% radiochemical yield
based on precursor 2), which was 97% radiochemically pure and cochromato-
graphed with authentic 1 on HPLC (same system as above) and TLC. The
specific activity of 3 was measured to be 81.9 Ci/mmol by UV (ethanol)
assay (where E296 ¼ 29,399 for 1), and it provided the proton decoupled
tritium NMR of Fig. 1.
REFERENCES
1. Kagathara, V.M.; Parsania, P.H. Thermal Analysis of Cured Chloro Epoxy
Resins and Epoxy-Acrylate-Styrene Copolymers. Polymer Testing 2002,
21, 659–663.
2. Kataria, H.C.; Gupta, S.S. More Potential Drugs for Leprosy and Activity
of Diaminodiphenyl Sulfones and Other Drugs and Dosages. Oriental
Journal of Chemistry 1994, 10, 59–62.
3. Watson, J. Pneumocystis Carinii: Where Are We Now? Journal of HIV
Therapy 2002, 7, 8–12.
Received in the USA July 30, 2004