Synthesis of carbon-14 labelled 1,5 diaryl-[5- 14C]-1,2,3-triazolines

Article abstract of DOI:10.1002/jlcr.794

Two 1,2,3-triazoline anticonvulsants, 1-(4-methylsulphone-phenyl)-5-(4-methoxy-phenyl)-1,2,3-triazoline and 1-(4-methylsulphone-phenyl)-5-phenyl-1,2,3-triazoline, both labelled with carbon-14 in the 5-position, have been synthesized as part of a 5-step sequence. Copyright

Full text of DOI:10.1002/jlcr.794

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2004; 47: 31–36.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.794
Note
Synthesis of carbon-14 labelled l,5 diaryl-[5-14C]-
l,2,3-triazolines
Hojatollah Matloubi1,*, Abbas Shafiee2, Nader Saemian1, Gholamhossein
Shirvani1 and Fariba Johari Daha1
1 Nuclear Research Center/AEOI, Chemical Division P.O. Box 11365-3486,
Tehran, Iran
2 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of
Medical Sciences, Tehran, Iran
Summary
Two 1,2,3-triazoline anticonvulsants, 1-(4-methylsulphone-phenyl)-5-(4-methoxy-
phenyl)-1,2,3-triazoline and l-(4-methylsulphone-phenyl)-5-phenyl-1,2,3-triazoline,
both labelled with carbon-14 in the 5-position, have been synthesized as part of a
5-step sequence. Copyright # 2003 John Wiley & Sons, Ltd.
Key Words: triazoline; Schiff base; anticonvulsant; carbon-l4
Introduction
1,5-Diaryl-1,2,3-triazolines frequently exhibit anticonvulsant properties1 and
compare favourably with prototype antiepileptic drugs such as phenobarbitol,
phenytoin, etc.2 The presence of the methylsulphone group at the para-
position of one of the phenyl rings has led to compounds with good anti-
inflammatory properties.3–6 To further elucidate the mechanism of action and
to support on-going metabolism studies7 the need arose to synthesise the
corresponding carbon-14 compounds, with the label situated in a biologically
stable site. In this paper we report the synthesis of two 1,5-diaryl-[5-14C]-1,2,3-
triazolines (la,b).
*Correspondence to: H. Matloubi, Nuclear Research Center/AEOI, Chemical Division P.O. Box 11365-3486,
Tehran, lran. E-mail: hmatloubi@aeoi.org.ir
Copyright # 2003 John Wiley & Sons, Ltd.
Received 14 July 2003
Revised 26 September 2003
Accepted 5 October 2003

32
H. MATLOUBI ET AL.
The desired product 1, was synthesized as part of a 5-stage sequence8–12
(Scheme 1).
Scheme 1.
Experimental
Barium [14C]-carbonate was purchased from Amersham Pharmacia Biotech
(Amersham Place, Little Chalfont, Buckinghamshire, England HP7 9NA) and
converted to potassium [14C]-cyanide according to the standard procedure.13
1
IR spectra were recorded on a Bruker FT-IR instrument and the H-NMR
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 31–36

SYNTHESIS OF CARBON-14
33
spectra on a Bruker DRX 500 (500 MHz) spectrometer. Radioactivity was
determined using a Beckman LS6500 liquid scintillation spectrometer.
Copper(I) [14C] cyanide
Copper(II) sulphate pentahydrate (1246 mg, 5 mmol) and water (3 ml) were
stirred at 458C. The resulting solution was treated with a solution of sodium
metabisulphite (257 mg, 1.35 mmol) in water (1.5 ml). A solution of potassium
hydroxide (115 mg, 2.05 mmol) and potassium [14C]-cyanide (26 mCi, 260 mg,
4 mmol) in water (1.26 ml) was added dropwise over the course of 5 min. The
resulting suspension was stirred at 458C for 1 h, followed by 30 min at 238C.
The suspension was filtered, washed with water (4 Â 4.5 ml), ethanol
(2 Â 4.5 ml), and ether (2 Â 1.5 ml) and was dried under vacuum to give the
title compound as a solid (23.74 mCi, 3.69 mmol, 332 mg) (yield: 91.3%).
4-Methoxy-benzonitrile-[cyano-14C] 3a
A mixture of 4-iodo-anisole 2a (700 mg , 3 mmol) and copper(I) [14C] cyanide
(9.65 mCi, l.5 mmol, 135 mg) in N,N-dimethylformamide (5.8 ml) was stirred at
reflux for 7 h. The solution was allowed to cool to room temperature and
extracted with ethyl acetate (30 ml). The extract was washed with water
followed by brine and dried over anhydrous sodium sulphate. Concentration
under reduced pressure and purification by column chromatography on silica
gel using (20%) ethylacetate: hexane as eluant gave (8.55 mCi, 1.33 mmol,
177 mg) of the title compound (yield: 88.56%). IR(KBr): 3085, 2980, 2230,
1600, 1510, 1460, 1160 CmÀ1, 1H-NMR (CDCl3, TMS): d 7.6, d, 2H; d 6.9, d,
2H; d 3.9, s, 3H.
Benzonitrile-[cyano-14C] 3b
The benzonitrile-[cyano-14C] 3b was prepared according to the above
described procedure by heating iodo-benzene 2b (610 mg, 3 mmol) and
copper(I) [14C] cyanide (9.65 mCi, l.5 mmol, 135 mg) in pyridine (yield:
79.6%). IR(KBr): 3092, 2240, 1600, 1490, 1450 CmÀ1
.
4-Methoxy-benzaldehyde-[carbonyl-14C] 4a
4-Methoxy-benzonitrile-[cyano-14C] 3a (8.35 mCi, 1.3 mmol, 173 mg) was
converted to 4-methoxy-benzaldehyde-[carbonyl-14C] 4a by refluxing with
Raney-Ni (173 mg) in 75% formic acid (2.6 ml) for 1 h. The product was
purified by distillation under vacuum, to give (7.73 mCi, 1.2 mmol, 163 mg) of
the title compound (yield: 92.6%), IR(KBr): 3083, 2960, 2860, 2740, 1680,
1600 CmÀ1
.
Copyright # 2003 John Wiley & Sons, Ltd.
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H. MATLOUBI ET AL.
Benzaldehyde-[carbonyl-14C] 4b
The benzonitrile-[carbonyl-14C] 4b was prepared according to the above
described procedure (yield: 94.3%). IR(KBr): 3095, 2840, 2740, 1720,
1450 CmÀ1
.
4-Methylsulphone-N-(4-methoxy-benzylidene)-aniline-[azomethine-14C] 6a
The title compound was obtained by warming a mixture of 4-methoxy-
benzaldehyde-[carbonyl-14C] 4a (6.44 mCi, 1 mmol, 136 mg) and 4-methylsul-
phone aniline (l mmol, 171 mg) in ethanol (0.5 ml) and acetic acid (0.3 ml) for
15 h. Recrystallization from THF/hexane (1:10) gave the title product
(4.26 mCi, 0.66 mmol, 191 mg) in 66.15% yield. IR(KBr): 3040, 2950, 1630,
1
1570, 1510, 1305, 1140 CmÀ1, H-NMR (DMSO-d6): d 8.56, s, 1H; d 7.9, m,
4H; d 7.46, m, 2H; d 7.15, m, 2H; d 3.85, s, 3H; d 3.22, s, 3H.
4-Methylsulphone-N-(benzylidene)-aniline-[azomethine-14C] 6b
The 4-methylsulphone-N-(benzylidene)-aniline-[azomethine-14C] 6b was pre-
pared according to the above described procedure by warming a mixture of
benzaldehyde-[carbonyl-14C] 4b (7.35 mCi, 1.14 mmol, 121 mg) and 4-methyl-
sulphone aniline 5 (1.14 mmol, 195 mg) in ethanol (0.4 ml) and THF (0.4 ml)
for 15 h. Recrystallization from THF/hexane (1:10) gave the title product
(5.98 mCi, 0.93 mmol, 241 mg) in 81.3% yield. IR(KBr): 3090, 2940, 1640,
1
1580, 1310, 1150 CmÀ1, H-NMR (DMSO-d6): d 8.65, s, lH; d 7.96, m, 4H; d
7.56, m, 3H; d 7.45, m, 2H; d 3.2, s, 3H.
Diazomethane
N-nitroso, N-methyl urea (2.5 g) was added in small portions and with shaking
to a mixture of 1,4-dioxane (25 ml) and 40% potassium hydroxide solution
(7.5 ml) kept at 8–108C. The mixture was then carefully introduced into a
separatory funnel and the lower alkaline layer was separated off. The dioxane
layer was deep yellow in colour and contained approximately 0.7 g of
diazomethane which was used immediately in the triazoline synthesis.
1-(4-Methylsulphone-phenyl)-5-phenyl-1,2,3-triazoline-[5-14C] 1b
4-Methylsulphone-N-(benzylidene)-aniline-[azomethine-14C] 6b (5.38 mCi,
0.84 mmol, 217 mg) was added with shaking to a cold freshly prepared
solution of diazomethane (3 mmol) in dioxane (4.5 ml) contained in an
Erlenmeyer flask. The reaction mixture was allowed to stand at room
temperature for 5 days. At the end of this period, the mixture was filtered,
cooled, and diluted with cold water (4.5 ml) with shaking, until a precipitate
formed. Recrystallization from ethanol provided the title compound
(4.41 mCi, 0.69 mmol, 208 mg). (yield: 82%).1H-NMR (DMSO-d6): d 7.78,
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 31–36

SYNTHESIS OF CARBON-14
35
m, 2H; d 7.28 À7.37, m, 5H; d 7.18, m, 2H; d 5.34, q, 1H; d 4.95, q, 1H; d 4.38,
q, 1H; d 3.1, s, 3H.
1-(4-Methylsulphone-phenyl)-5-(4-methoxy-phenyl)-1,2,3-triazoline-[5-14C] 1a
4-Methylsulphone-N-(4-methoxy benzylidene)-aniline-[azomethine-14C] 6a
(3.87 mCi, 0.6 mmol, 174 mg) was converted to the title compound according
to the above described procedure by using (8 ml) of diazomethane solution.
After 5 days, the mixture was worked up. Recrystallization using acetone/
petroleum ether (l : 10), gave the title compound. (1.85 mCi, 0.29 mmol, 96 mg)
in 47.8% yield.
1H-NMR(DMSO-d6): d 7.81, m, 2H; d 7.4, m, 4H; d 6.9, m, 2H; d 5.3, q,
1H; d 4.9, q, 1H; d 4.35, q, 1H; d 3.85, s, 3H; d 3.22, s, 3H.
Acknowledgements
We gratefully acknowledge Mr. H.R. Bijanzadeh (Tarbiat Modares Uni-
1
versity) and Mr. N. Ali-RezaZadeh (AEOI) for H-NMR spectroscopy and
radioactivity determination of the synthesized samples, respectively.
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