C. Li et al.
1H NMR and 13C NMR spectra were recorded on a Bruker of 3 (662mg, 4 mmol, 6.7mCi) and 4 (754mg 4.1mmol) in
AM-400 (400 MHz) spectrometer. The chemical shifts were anhydrous ethanol (9mL) was refluxed for 8 h affording a clear
recorded in CDCl3 or dimethyl sulfoxide (DMSO-d6) and were yellow solution. The solvent was removed in vacuo after cooling
relative to TMS as the internal standard. Mass spectrometry to ambient temperature. The crude product was purified by
(MS) spectra were determined using a MicroMass GCT CA 055 silica gel chromatography using dichloromethane: acetone
instrument under electron impact (70 eV) (Agilent Technologies, (4:1, v/v) as eluant to give a white power (735 mg, 4.8 mCi)
1
Palo Alto, USA). The analytical HPLC system used was an Agilent (72% yield). H NMR (400 MHz, DMSO-d6): d 8.91 (s, 1H), 8.38
Model 1100 with a diode array detector, column: Diamonsil, (d, J = 1.9 Hz, 1H), 7.79 (dd, J1 = 8.2, J2 = 2.2 Hz, 1H), 7.55 (d,
C18 (2) 5u, 250 ꢀ 4.6 mm; isocratic elution: H2O/MeCN; flow: J = 8.2 Hz, 1H), 6.78 (s, 1H), 4.50 (s, 2H), 3.71–3.59 (m, 2H), 3.54
1.0 mL/min; UV 325 nm; column: DAICEL CHIRALPAK IC, (dd, J1 = 13.3 Hz, J2 = 5.6 Hz, 2H) ppm; 13C NMR (100 MHz,
0.46 ꢀ 15 cm; isocratic elution: EtOH= 100% (v); flow: 0.8 mL/min; DMSO-d6): d 159.0, 150.0, 149.7, 139.7, 131.9, 124.8, 96.3, 48.4,
UV 325 nm. The preparative HPLC system used was a Shimadzu 45.6, 42.9 ppm.1
Model LC 20 with a SPD-20A UV detector, column: DAICEL
1-((6-Chloropyridin-3-yl)methyl)-7-methyl-[14C]8-nitro-
1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridine-5-ol (5)
CHIRALPAK IC, 30 ꢀ 250mm; isocratic elution: EtOH= 100% (v);
flow: 20 mL/min; UV 325 nm. Melting points were recorded on
Büchi B540 apparatus (Büchi Labortechnik AG, Flawil, Switzerland).
Radioactivity was measured on WinSpectral-1414 liquid scintilla- A mixture of [14C]6-Cl-PMNI (735 mg, 2.9 mmol, 4.8 mCi), anhy-
tion spectrometer (PerkinElmer, Wallac, Finland).
drous acetonitrile (6 mL), crotonaldehyde (0.4 mL, 4.4 mmol),
and acetic acid (0.12 mL) was stirred at 40ꢂC–45ꢂC for 26 h, and
the solvent was removed in vacuo. The crude product was puri-
fied by using silica gel chromatography using dichloromethane:
acetone (1:2, v/v) to afford 580 mg (3.0 mCi) of 5 (62% yield).
Melting point = 171.1ꢂC–175.6ꢂC; 1H NMR (400 MHz, DMSO-d6):
d 8.34 (d, J = 2.1 Hz, 1H), 7.80 (dd, J1 = 8.3 Hz, J2 = 2.4 Hz, 1H),
7.49 (d, J = 8.2 Hz, 1H), 6.29 (br d, J = 6.2 Hz, 1H), 4.83–4.79 (m,
1H), 4.73 (d, J = 15.5 Hz, 1H), 4.59 (d, J = 15.5 Hz, 1H), 3.74–3.58
(m, 4H), 3.16–3.11 (m, 1H), 1.95–1.88 (m, 1H), 1.75–1.69 (m, 1H),
1.03 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (100 MHz, DMSO-d6): d
158.5, 149.6, 149.6, 139.7, 132.6, 74.4, 109.3, 76.0, 51.9, 49.8,
45.2, 38.6, 28.3, 20.1 ppm; high-resolution MS(ESI+) calculated
(calcd) for C14H17N4O335Cl (M+), 324.0989; found, 324.1014. Calcd
for C14H17N4O337Cl (M+), 326.0960; found, 326.0964. Analytic
Calcd for C14H17ClN4O3: C, 51.78; H, 5.28; N, 17.25; found: C,
51.91; H, 5.15; N, 16.95.1
Synthesis of N-2(chloro-5-pyridylmethyl)ethylenediamine (4)
2-Chloro-5-chloromethylpyridine (1.61 g, 10 mmol) in acetonitrile
(50 mL) was slowly added dropwise to a solution of ethylenedia-
mine (6.7 mL, 100 mmol) in acetonitrile (20 mL) cooled in salt
water ice bath (ꢁ15ꢂC to ꢁ10ꢂC), by using a pressure equalizer
funnel under argon. The mixture was warmed to ambient
temperature and reacted overnight. To the resulting solution
was added water (50 mL) followed by extraction with dichloro-
methane (30 mL ꢀ 5); the combined organic layers were dried
over anhydrous Na2SO4 and evaporated under reduced pressure
to produce 4 (81% yield). Gas Chromatography-Mass Spectro-
metry (GC-MS) (m/z): 185(6) M+, 155(50), 126(100), 90(11).1
Synthesis of potassium 2-nitro[2-14C]ethene-1,1-bis(thiolate) (2)
[14C]Nitromethane (20 mCi with a specific activity of 59 mCi/
mmol) was initially diluted to 6 mmol by adding nitromethane.
Then, a solution of potassium hydroxide (1.24 g, 22 mmol) in
anhydrous ethanol (15 mL) was added dropwise to a mixture of
[14C]nitromethane (366 mg, 6 mmol, 20 mCi) and carbon disulfide
(1.14 g, 15 mmol) in anhydrous ethanol (2mL) at 35ꢂC. The mixture
was stirred for 5 h at this temperature. The precipitate product was
filtered, washed with a small amount of anhydrous ethanol, and
dried in vacuum oven to give crude product (870mg, 13.6 mCi)
as a brown powder (68% yield), which was used for the next step
without additional purification.
1-((6-Chloropyridin-3-yl)methyl)-7--methyl-[14C]8-nitro-5-
propoxy-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridine
([14C]paichongding)
To 5 (580 mg, 1.8 mmol, 3.0 mCi) in dichloromethane (20 mL) was
added propan-1-ol (2.0 mL, 27 mmol) and hydrochloric acid
(0.2 mL); the mixture was refluxed for 36h. The solvent was
removed, and the residue was purified by column chromatogra-
phy (dichloromethane:acetone = 4:1, v/v) affording 400 mg
(2.1 mCi) pure yellow solid (61% yield). Melting point = 130.2
ꢂC-131.9 ꢂC; 1H NMR (400 MHz, CDCl3): d 8.33–8.31 (m, 1H),
7.86 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 0.5H), 7.82 (dd, J1 = 8.2 Hz,
J2 = 2.4 Hz, 0.5H), 7.33 (dd, J1 = 1.2 Hz, J2 = 0.8 Hz, 0.5H), 7.31
(dd, J1 = 1.2 Hz, J2 = 0.8 Hz, 0.5H), 4.88 (d, J = 15.2 Hz, 0.5H), 4.82
(d, J = 15.2 Hz, 0.5H), 4.67–4.61 (m, 1H), 4.55 (dd, J1 = 6.0 Hz,
J2 = 3.6 Hz, 0.5H), 4.50 (t, J = 3.6 Hz, 0.5H), 4.02–3.95 (m, 0.5H),
3.86–3.81 (m, 0.5H), 3.72–3.64 (m, 1H), 3.59–3.35 (m, 5H), 2.21–
2.14 (m, 0.5H), 2.01–1.99 (m, 1H), 1.82–1.75 (m, 0.5H), 1.65–1.54
(m, 2H), 1.25 (d, J = 6.8 Hz, 1.5H), 1.23 (d, J = 6.8 Hz, 1.5H), 0.95
(t, J = 6.2 Hz, 1.5H), 0.92 (t, J = 6.2 Hz, 1.5H) ppm; high-resolution
MS(ESI+) calcd for C17H23N4O335Cl (M+)+, 366.1459; found,
366.1487.1
1,1-Dimethylthio-2-nitro[2-14C]ethene (3)
Iodomethane (1 mL, 20 mmol) in anhydrous methanol (10 mL)
was added dropwise to a solution of 2 (870 mg, 4.1 mmol,
13.6 mCi) in anhydrous methanol (8 mL). The resulting mixture
was stirred for 5 h at room temperature and then concentrated
under reduced pressure. The residue was purified by silica gel
flash chromatography eluting with dichloromethane to provide
golden solid 3 (331 mg, 6.7 mCi) (49% yield). GC-MS (m/z): 165(31)
M+, 148(17), 104(66), 86(100), 72(93), 57(20).1
The retention times were 9.21 and 12.99 min, respectively,
over 98% purities, as determined by HPLC, and the ratio of two
peaks was 9 : 11 (area). [14C]Paichongding (400 mg) was sepa-
2-Chloro-5-(([14C]2-(nitromethylene)imidazolidin-1-yl)
methyl)pyridine ([14C]6-Cl-PMNI)
Compound 3 was initially diluted by adding equivalent amount rated into four diastereoisomers (a, b, c, and d: 70.2, 78.8, 72.2,
(331 mg, 2 mmol) 1,1-dimethylthio-2-nitroethene. Then a mixture and 71.3 mg, respectively), the ratio of the diastereoisomers
Copyright © 2011 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 775–779