222 P. R. CONLON AND W. F. KIESMAN
visualized with UV lamp or phosphomolybdic acid
(PMA). Mass spectra were measured by electrospray
pos. at 60 V with a Micromass VG Platform MS. 1H and
13C NMR spectra (CDCl3 or DMSO-d6) were measured
with on a Bruker AVANCE 400 MHz spectrometer, peak
positions are given in ppm (d) downfield from TMS as an
internal standard. Column chromatography was done
with EM Science 230–400 mesh silica gel.
1-Iodopropane-d7 was purchased from CDN Isotopes
with isotopic purity of 99.3% D. Unless otherwise
specified, reactions were run under a nitrogen atmo-
sphere in oven-dried glassware.
ester 6 as a white solid (4.16 g, 49% yield). 1H NMR
(CDCl3) d: 1.28–1.33 (m, 6H); 1.60–1.69 (m, 6H); 3.16
(s, 2H); 3.51 (s, 3H) ppm.
4-Formyl-bicyclo[2.2.2]octane-1-carboxylic acid methyl
ester, (7). Dess–Martin periodinane (10.6 g, 0.025 mol)
was added to a stirred solution of 6 (4.16 g, 0.021 mol)
in CH2Cl2 (100 mL) at rt After 2 h the reaction mixture
was treated with 1 N sodium sulfite (50 mL) and stirred
for 1 h. The mixture was diluted with 100 mL of CH2Cl2,
washed twice with 1 N sodium sulfite (50 mL) and twice
with saturated NaCl. The organic layer was separated,
dried over Na2SO4 and concentrated in vacuo. The
resultant crude oil was purified by flash chromatogra-
phy (EtOAc–hexanes 1:5) to afford aldehyde 7 as a
white solid (1.53 g, 37% yield). 1H (CDCl3) d: 1.62–1.68
(m, 6H); 1.79–1.84 (m, 6H); 3.63 (s, 3H); 9.38 (s,
1H) ppm.
(6-Amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-
5-yl)-carbamic acid tert-butyl ester, (2). A suspension
of 5,6-diamino-3-propyl-1H-pyrimidine-2,4-dione hy-
drochloride7 (25.0 g, 0.113 mol) in dioxane (225 mL)
and water (110 mL) was treated with 3.2 N NaOH
(35 mL, 0.113 mol). The resulting solution was cooled
to 108C and di-t-butyl dicarbonate (24.6 g, 0.124 mol)
and 3.2 N NaOH (35 mL, 0.113 mol) was added and
allowed to stir at rt for 18 h. The resulting precipitate
was washed with cold water and toluene to give 2
(19.1 g, 60% yield) as a pink solid. 1H NMR (DMSO-d6)
d: 0.82 (t, 3H); 1.41 (s, 9H); 1.42–1.54 (sextet, 2H); 3.65
(t, 2H); 6.3 (b, 2H); 7.3 (s, 1H) ppm.
4-Formyl-bicyclo[2.2.2]octane-1-carboxylic acid, (8).
Lithium hydroxide (0.65 g, 0.027 mol) was added with
stirring to a rt solution of 7 (1.5 g, 0.0077 mol) in THF
(5 mL) and water (3 mL) After 16 h, the mixture was
concentrated in vacuo, diluted with 15 mL of water and
washed thrice with 15-mL portions of CH2Cl2. The
aqueous phase was acidified with 2 N HCl (10 mL) and
washed twice with CH2Cl2. The combined organic
fractions were dried over Na2SO4 and concentrated in
vacuo to give carboxylic acid 8 as a white solid (1.25 g,
89% yield) 1H (DMSO d6) d: 1.68–1.73 (m, 12H); 9.42 (s,
1H) ppm.
(6-Amino-2,4-dioxo-1-2H7-propyl-3-propyl-1,2,3,4-tetra-
hydro-pyrimidin-5-yl)-carbamic acid tert-butyl ester,
(3). Compound 2 (7.5 g, 0.026 mol), anhydrous potas-
sium carbonate (7.5 g, 0.054 mol) and 1-iodopropane-
d7 (5.0 g, 0.029 mol) were heated at 708C for 18 h in
anhydrous DMF (25 mL). The reaction mixture was
concentrated under reduced pressure and the residue
purified by flash chromatography (EtOAc–hexanes 1:1)
to afford 3 as a yellow solid (4.7 g, 56% yield), m=z ¼
334 (MH+).
4-(2-Methoxycarbonyl-vinyl)-bicyclo[2.2.2]octane-1-
carboxylic acid, (9). To an ice cold solution of 0.5 M
KHMDS in toluene (44 mL, 0.022mol) was added
dropwise
trimethylphosphonoacetate
(2.35 mL,
0.014 mol) over 10 min. A THF (1 mL) solution of
compound 8 (1.25 g, 0.0069 mol) was added over
30 min at 08C. The reaction mixture was allowed to
warm to rt, stirred an additional 16 h, and acidified
with 2 N HCl (15 mL). After concentration under
reduced pressure, the residue was taken up in EtOAc
(50 mL), washed twice with 2 N HCl (20 mL) and twice
with brine (20 mL). The organic layer was dried over
Na2SO4 and evaporated to give a white solid. Purifica-
tion by flash chromatography (EtOAc–hexanes 1:3)
afforded 9 as a white solid (0.525 g, 40% yield). 1H
(CDCl3) d: 1.55–1.60 (m, 6H); 1.75–1.80 (m, 6H); 3.68
(s, 3H); 5.75 (d, 1H); 6.85 (d, 1H) ppm.
5,6-Diamino-1-2H7-propyl-3-propyl-1H-pyrimidine-2,4-
dione hydrochloride, (4). Compound
3
(550 mg,
1.65 mmol) was dissolved in 4 N HCl-dioxane (5 mL)
and after 30 min the reaction mixture was concentrated
in vacuo to afford the HCl salt as white solid (365 mg,
95% yield), m=z ¼ 234 (MH+).
4-Hydroxymethyl-bicyclo[2.2.2]octane-1-carboxylic acid
methyl ester, (5). To a solution of bicyclo[2.2.2]octane-
1,4-dicarboxylic acid monomethyl ester10(9.15 g,
0.043 mol) in anhyd. THF (100 mL) was added dropwise
1M BH3–THF complex (86 mL, 0.086 mol). The solution
was stirred for 16 h at rt and a 5% HCl in methanol
solution (50 mL) was added. Concentration in vacuo
gave a colorless oil which when purified by flash
chromatography (EtOAc–hexanes 1:3) gave hydroxy
4-(2-Methoxycarbonyl-ethyl)-bicyclo[2.2.2]octane-1-
carboxylic acid, (10). To a degassed solution of 9
(0.50 g, 0.0021 mol) in EtOAc (20 mL) was added 10%
Pd/C (25 mg). The reaction mixture was charged with
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 219–223
DOI: 10.1002.jlcr