88
M. Macchia et al. / Il Farmaco 58 (2003) 85Á89
/
silica gel (MachereyÁ
/
Nagel Silica Gel 60 Art. no.
4H), 10.20 (br, 1H, D2O exchangeable), 10.45 (br, 1H,
D2O exchangeable). MS (EI, 70 eV): m/z 380 (Mꢁ).
Compound 1e: 859 mg, 2.18 mmol, 31% yield (two
815381). Sodium sulfate was always used as the drying
agent. Evaporations were performed in vacuo (rotating
evaporator). Synthesis and characterization data of
compounds 1a and 2a have already been published [9].
C2-ceramide was purchased from Sigma, St. Louis, MO.
1
steps). M.p. 58Á
0.88 (t, 3H, Jꢀ
24H), 2.31Á2.46 (m, 4H), 8.92 (br, 1H, D2O exchange-
/
60 8C. H NMR (CDCl3, 200 MHz) d
/
6.5 Hz), 1.06 (s, 9H), 1.16Á1.36 (m,
/
/
able), 9.37 (br, 1H, D2O exchangeable). MS (EI, 70 eV):
m/z 394 (Mꢁ).
Compound 1f: 903 mg, 2.11 mmol, 30% yield (two
4.1.1. Synthesis of thiouracil derivatives 1bÁf
/
A solution obtained by dissolving 2.0 g of ethyl
palmitate (7.0 mmol) in 5 ml of anhydrous THF was
added drop by drop, at a temperature of 0 8C under an
argon gas atmosphere, to 4.2 ml of a 2 M solution of
LDA in anhydrous THF. After 30 min of stirring at
0 8C, the reaction mixture was added to a solution
containing 8.5 mmol of the appropriate acyl chloride
1
steps). M.p. 100Á
d 0.88 (t, 3H, Jꢀ
2.96 (m, 6H), 7.18Á
/
102 8C. H NMR (CDCl3, 200 MHz)
/
6.3 Hz), 1.11Á
/
1.40 (m, 24H), 2.27Á
/
/7.34 (m, 5H), 9.65 (br, 1H, D2O
exchangeable), 9.72 (br, 1H, D2O exchangeable). MS
(EI, 70 eV): m/z 428 (Mꢁ).
(4bÁf) in 10 ml of anhydrous THF. The resulting
/
mixture was stirred at room temperature (r.t.) for 12
h, then added to a saturated solution of NH4Cl. The
organic solvent was removed under a vacuum and the
remaining aqueous phase was extracted with diethyl
ether. The combined organic phase was washed with a
saturated aqueous solution of NaCl, dried over anhy-
drous Na2SO4 and then concentrated under a vacuum to
provide a crude residue composed almost exclusively of
4.1.2. Synthesis of uracil derivatives 2bÁ
The appropriate thiouracil derivative 1bÁ
/
f
/
f (0.45
mmol) was treated with a 10% aqueous solution of
chloroacetic acid (11 ml) and the mixture was refluxed
for 16 h. The resulting precipitate was then collected by
suction filtration, washed with absolute ethanol and
diethylether. The crude product so obtained was pur-
ified by silica gel column chromatography using an n-
b-ketoester (5bÁ/f), which was used in the next step
hexaneÁ
uracils 2bÁ
Compound 2b: 52 mg, 0.15 mmol, 33% yield. M.p.
132Á
134 8C. 1H NMR (CDCl3, 200 MHz) d 0.87 (t, 3H,
Jꢀ 6.4 Hz), 1.01 (t, 3H, Jꢀ 7.3 Hz), 1.25 (br, 26H), 2.32
(t, 2H, Jꢀ 7.5 Hz), 2.42 (t, 2H, Jꢀ 7.7 Hz), 8.81 (br,
/EtOAc mixture as the eluant, to afford pure
without further purification. The crude residue was
dissolved in 40 ml of absolute ethanol and then treated
with 8.02 g of thiourea (52.8 mmol) and 14.4 g of
sodium ethoxide (106 mmol). The resulting mixture was
stirred at 90 8C for 1 h, after which time it was cooled to
r.t. and filtered. The filtrate was evaporated under a
vacuum; the residue thus obtained was dissolved in a
10:1 mixture of water and THF. The resulting solution
was cooled to 0 8C and acidified to pH 2 with
concentrated HCl; the precipitate that developed due
to acidification was collected by suction filtration and
washed with small quantities of acetone, providing a
crude residue which was purified by silica gel column
/f.
/
/
/
/
/
1H, D2O exchangeable), 9.74 (br, 1H, D2O exchange-
able). MS (EI, 70 eV): m/z 350 (Mꢁ).
Compound 2c: 57 mg, 0.16 mmol, 35% yield. M.p.
116Á
Jꢀ 6.6 Hz), 0.96 (t, 3H, Jꢀ
28H), 2.32 (t, 2H, Jꢀ 7.8 Hz), 2.43 (t, 2H, Jꢀ
/
120 8C. 1H NMR (CDCl3, 200 MHz) d 0.87 (t, 3H,
/
/
7.1 Hz), 1.16Á
/
1.46 (m,
/
/
7.6 Hz),
8.72 (br, 1H, D2O exchangeable), 9.53 (br, 1H, D2O
exchangeable). MS (EI, 70 eV): m/z 364 (Mꢁ).
Compound 2d: 53 mg, 0.14 mmol, 32% yield. M.p.
chromatography using an n-hexaneÁ
the eluant, to afford pure thiouracils 1bÁ
Compound 1b: 644 mg, 1.76 mmol, 25% yield (two
/EtOAc mixture as
/f.
105Á
Jꢀ 6.4 Hz), 0.99 (d, 6H, Jꢀ
24H), 1.93Á2.03 (m, 1H), 2.31Á
/
108 8C. 1H NMR (CDCl3, 200 MHz) d 0.88 (t, 3H,
1
/
/
6.6 Hz), 1.14Á
/
1.40 (m,
2.36 (m, 4H), 9.08 (br,
steps). M.p. 128Á
d 0.87 (t, 3H, Jꢀ
(br, 26H), 2.35 (t, 2H, Jꢀ
/
130 8C. H NMR (CDCl3, 200 MHz)
6.4 Hz), 1.03 (t, 3H, Jꢀ 7.2 Hz), 1.25
7.4 Hz), 2.43 (t, 2H, Jꢀ 7.5
/
/
/
/
1H, D2O exchangeable), 9.91 (br, 1H, D2O exchange-
able). MS (EI, 70 eV): m/z 364 (Mꢁ).
Compound 2e: 63 mg, 0.17 mmol, 37% yield. M.p.
/
/
Hz), 9.73 (br, 2H, D2O exchangeable). MS (EI, 70 eV):
m/z 366 (Mꢁ).
Compound 1c: 642 mg, 1.69 mmol, 24% yield (two
1
98Á
/
100 8C. H NMR (CDCl3, 200 MHz) d 0.88 (t, 3H,
1
Jꢀ
/
6.3 Hz), 1.00 (s, 9H), 1.15Á
/
1.40 (m, 24H), 2.33Á2.45
/
steps). M.p. 124Á
d 0.87 (t, 3H, Jꢀ
1.10Á1.48 (m, 28H), 2.34 (t, 2H, Jꢀ
/
126 8C. H NMR (CDCl3, 200 MHz)
(m, 4H), 8.37 (br, 1H, D2O exchangeable), 8.85 (br, 1H,
D2O exchangeable). MS (EI, 70 eV): m/z 378 (Mꢁ).
Compound 2f: 72 mg, 0.18 mmol, 39% yield. M.p.
/
6.8 Hz), 0.96 (t, 3H, Jꢀ
/
7.2 Hz),
7.5 Hz), 2.46 (t, 2H,
/
/
Jꢀ 7.6 Hz), 10.12 (br, 2H, D2O exchangeable). MS (EI,
/
118Á
Jꢀ 6.3 Hz), 1.13Á
7.21Á7.32 (m, 5H), 8.79 (br, 1H, D2O exchangeable),
/
120 8C. 1H NMR (CDCl3, 200 MHz) d 0.88 (t, 3H,
1.37 (m, 24H), 2.23Á2.92 (m, 6H),
70 eV): m/z 380 (Mꢁ).
Compound 1d: 748 mg, 1.97 mmol, 28% yield (two
/
/
/
1
/
steps). M.p. 102Á
d 0.87 (t, 3H, Jꢀ
1.12Á1.39 (m, 24H), 1.93Á
/
104 8C. H NMR (CDCl3, 200 MHz)
/
6.4 Hz), 1.00 (d, 6H, Jꢀ
/
6.6 Hz),
2.38 (m,
9.93 (br, 1H, D2O exchangeable). MS (EI, 70 eV): m/z
412 (Mꢁ).
/
/
2.03 (m, 1H), 2.31Á
/