166
Y. ZHAO ET AL.
compound as a white solid (0.72 g, 76%). M.p. 168.5–1708C; 1H NMR (CDCl3) d
(ppm) 2.49 (s, 6H, S–CH3) and 6.8–7.3 (m, 7H, Aryl H).
N-methyl-(2-chloro-5-methylthio)aniline (8). To a solution of (2-chloro-5-
thiomethyl)aniline (0.599 g, 3.75 mmol) in THF (10 ml) cooled in an ice-bath
was slowly added 1 equivalent of n-butyllithium (1 M hexanes, 3.75 mmol)
under stirring. After 15 min methyl iodide (0.532 g, 3.75 mmol) was added
dropwise and the resulting solution was allowed to reach room temperature
over a period of 1 h. Solvents were evaporated and the residue separated
between water (50 ml) and diethyl ether (50 ml). The organic phase was dried
(MgSO4), filtered and concentrated under reduced pressure. The resulting
crude product was purified by means of flash chromatography (silica, 1:1
dichloromethane/hexane) to give the title compound 8 (0.556 g, 79%) as a
colourless oil. 1H NMR (CDCl3) d 2.53 (s, 3H, S-Me), 2.96 (s, 3H, N-Me), 4.40
(br s, 1H, NH), 6.59 (dd, 1H, Aryl H, J ¼ 2:2 and 8.4 Hz), 6.65 (d, 1H, Aryl H,
J ¼ 2:2 Hz), 7.19 (d, 1H, Aryl H, J ¼ 8:4 Hz). The corresponding hydro-
chloride salt was prepared by treating an ice-cold solution of 8 in diethyl ether
(5 ml/mmol 8) with a 2-fold molar excess of HCl in diethyl ether (anhydrous,
2 M). Filtration provided the salt as a bright white solid (0.621 g, 94%).
N-(2-chloro-5-methylthiophenyl)-N0-(3-methylthiophenyl)-N-methylguanidine HCl
(9). To N-methyl-(2-chloro-5-methylthio)aniline (8) hydrochloride (0.100 g,
0.45 mmol) was added 3-methylthiophenylcyanamide (4) (0.074 g, 0.45 mmol),
toluene (0.5 ml) and dichloromethane (0.5 ml) under an inert nitrogen
atmosphere. The reaction mixture was heated to 1208C and concentrated by
allowing the dichloromethane solvent to be removed from the reaction mixture
by distillation. After 12 h the mixture was cooled to room temperature and the
residue purified by column chromatography (silica, chloroform/methanol
gradient, 0–10%). The resulting colourless oil was taken up in a minimum of
chloroform and 9.HCl was precipitated by addition of diethyl ether. The
1
product was isolated by filtration as a white solid (0.054 g, 31%). H NMR
(d6-DMSO) d 2.48 (s, 3H, S-Me), 2.52 (s, 3H, S-Me), 3.38 (s, 3H, N-Me),
7.14–6.97 (br m, 2H, Aryl H), 7.16 (m, 1H, Aryl H), 7.34 (m, 2H, Aryl H), 7.55
(m, 2H, Aryl H).
Cold methylation of N-(2-chloro-5-methylthiophenyl)-N0-(3-methylthiophenyl)-
guanidine (7). To the desmethyl precursor 7 (1.4 mg, 4.14 mmol) added
sodium hydride (4.0 mg, 0.17 mmol) and acetonitrile (0.6 ml). After stirring for
several minutes, methyl iodide (1 ml, 16.06 mmol) was added and the mixture
stirred for a further 10 min. The reaction mixture was diluted with
(NH4)2HPO4 (aq) (10 mM, 0.5 ml) and subjected to semi-preparative HPLC
using a C18 mBondapak column (7.8 ꢁ 300 mm, Waters) with a (NH4)2HPO4
(10 mM)/acetonitrile 50/50 (v/v) solvent system (3 ml/min, l ¼ 254 nm).
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 163–170