5224 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21
Kim et al.
were measured by LC-MS/MS (Waters 2790) using positive mode
electrospray ionization. Elemental analyses (C, H, N/F) were
performed by Midwest Microlab, IN; analytical results were within
(0.4% of the theoretical values for the formula given unless
1-Adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}-
urea (15). To a solution of diethylene glycol monoethyl ether (13.0
g, 95 mmol) in THF (150 mL) was added portionwise triph-
enylphosphine (27.6 g, 0.11 mol) and carbon tetrabromide (35.0 g,
0.11 mol) at 0 °C. After stirring for 12 h at room temperature,
hexane (100 mL) was added to the reaction mixture. This crude
mixture was filtered to get rid of triphenylphospine oxide, and the
organic solvent dissolving the product was washed with water (100
mL), dried over MgSO4, and concentrated. The residue was purified
using silica gel column chromatography (hexane only and hexane/
ethyl acetate ) 3:1) to give brominated product II as an oil (16.4
g, 87%). Product II (10.4 g, 53 mmol) was added dropwise to a
suspension of 60% sodium hydride (2.83 g, 70mmol) and compound
7 (9.9 g, 35 mmol) in DMF (70 mL) at 0 °C. After stirring for 12
h, water (150 mL) was poured into the reaction mixture, and the
product was extracted with ether (100 mL × 2). The organic
solution was dried over MgSO4 and concentrated. The residue was
purified using silica gel column chromatography (hexane/ethyl
1
otherwise indicated. H and 13C NMR spectra were recorded on a
QE-300 spectrometer, using tetramethylsilane as an internal stan-
dard. IR spectra were recorded on a Thermo Nicolet IR100
spectrometer. Synthetic methods are described for representative
compounds.
1-Adamantan-1-yl-3-(5-hydroxypentyl)urea (7). To a solution
of adamantyl isocyanate (0.20 g, 1.13 mmol) in DMF (15 mL) was
added a solution of 5-amino-1-pentanol (0.17 g, 1.69 mmol) in DMF
(15 mL) at 0 °C. After stirring for 12 h, an aqueous solution of 1
N HCl (40 mL) was added into the reaction at 0 °C, and the mixture
was stirred for 30 min. The crystalline solid product was filtered
and washed with water (40 mL) and ethyl acetate (20 mL). The
resulting solid was dried in the vacuum oven to give 7 as a white
1
solid (0.75 g, 100%). H NMR δ (CDCl3) 1.37-1.42 (2H, m),
1
acetate ) 3:1) to afford 15 (52%) as a solid. H NMR δ (CDCl3)
1.46-1.53 (2H, m), 1.57-1.62 (2H, m), 1.66 (6H, brs), 1.96 (6H,
brs), 2.06 (3H, brs), 3.13 (2H, q, J ) 6.9 Hz), 3.65 (2H, t, J ) 6.9
Hz), 4.14 (1H, s), 4.39 (1H, s). LC-MS (ESI) m/z calcd for
C16H28N2O2 [M + H]+, 281.22; found [M + H]+, 281.33; mp
220 °C; Anal. (C16H28N2O2) C, H, N.
1.22 (3H, t, J ) 6.9 Hz), 1.37-1.43 (2H, m), 1.46-1.53 (2H, m),
1.56-1.61 (2H, m), 1.67 (6H, brs), 1.97 (6H, brs), 2.07 (3H, brs),
3.11 (2H, q, J ) 6.9 Hz), 3.46 (2H, t, J ) 6.9 Hz), 3.48-3.67
(10H, m), 4.21 (1H, s), 4.26 (1H, s). 13C NMR δ (CDCl3) 15.12,
23.36, 29.05, 29.53, 29.68, 36.43, 40.00, 42.51, 50.74, 66.64, 69.78,
69.97, 70.57, 70.60, 71.01, 157.2. IR 1631 cm-1, 3299 cm-1, 3379
cm-1. LC-MS (ESI) m/z calcd for C22H40N2O4 [M + H]+, 397.30;
found [M + H]+, 397.31; mp 78 °C; Anal. (C22H40N2O4) C, H, N.
Compound 19 was synthesized with the same procedure used
for the preparation of 15 using 3-morpholinopropyl bromide
prepared from the corresponding alcohol instead of 2-(ethoxy-
ethoxy)-ethyl bromide.
Compounds 1, 3, 5, and 9 were synthesized with the same
procedure used for the preparation of 7 using the corresponding
aminoalkanol instead of 5-amino-1-pentanol.
1-Adamantan-1-yl-3-(5-butoxypentyl)urea (8). To a suspension
of 60% sodium hydride (21 mg, 0.53 mmol) and 7 (150 mg, 0.53
mmol) in DMF (20 mL) was added dropwise 1-bromobutane (90
mg, 0.64 mmol) at room temperature. After stirring for 12 h, water
(40 mL) was poured into the reaction mixture, and the product was
extracted with ether (40 mL). The organic solution was dried over
MgSO4 and concentrated. The residue was purified using silica gel
column chromatography (hexane/ethyl acetate ) 3:1) to give 8 (80
mg, 45%) as a solid. 1H NMR δ (CDCl3) 0.92 (3H, t, J ) 6.9 Hz),
1.35-1.38 (4H, m), 1.53-1.77 (12H, m), 1.946 (6H, brs), 2.06
(3H, brs), 3.10 (2H, q, J ) 6.9 Hz), 3.36-3.43 (4H, m), 4.14 (1H,
s), 4.26 (1H, s). LC-MS (ESI) m/z calcd for C20H36N2O2 [M +
H]+, 337.28; found [M + H]+, 337.32; mp 71 °C; Anal.
(C20H36N2O2) C, H, N.
1-Adamantan-1-yl-3-(5-{2-[2-(2,2,2-trifluoroethoxy)ethoxy]-
ethoxy}pentyl)urea (16). To a solution of 60% sodium hydride
(1.71 g, 42.8 mmol) and 2,2,2-trifluoroethanol (7.20 g, 71.4 mmol)
in DMF (40 mL) was added di-(2-bromoethyl) ether (9.20 g, 35.7
mmol) at room temperature. The reaction mixture was stirred for
3 h, and water (50 mL) was poured into the reaction. The product
was extracted with ether (30 mL × 2), and the organic layer was
washed with water (30 mL × 2), dried over MgSO4, and evaporated
to give 2-(2,2,2-trifluoroethoxyethoxy)ethyl bromide in a crude
mixture (∼60% yield). Without further purification, this bromide
intermediate was directly used for the next reaction. To a suspension
of 60% sodium hydride (3.83 g, 95.7 mmol) and 7 (10.0 g, 39.3
mmol) stirred for 20 min in DMF (40 mL) was added this alkylated
2-bromoethyl ether intermediate at room temperature. After stirring
overnight, the product was extracted with ether (50 mL × 2), and
the organic layer was washed with water (80 mL), dried over
MgSO4, and evaporated. The residue was purified using column
chromatography eluting with hexane and ethyl acetate (1:1) to
provide 16 (0.36 g, 45%) as a solid. This purified product was
further recrystallized in hexane and dried in the vacuum oven for
Compounds 2, 4, 6, and 10 were synthesized with the same
method used for the preparation of 8 using the corresponding
1-bromoalkane instead of 1-bromobutane.
1-Adamantan-1-yl-3-[5-(1-methylpentyloxy)pentyl]urea (11).
To a solution of 7 (1.02 g, 3.64 mmol) in DMF (40 mL) was added
portionwise triphenylphosphine (1.05 g, 4.01 mmol) and carbon
tetrabromide (2.00 g, 4.01 mmol) at 0 °C. After stirring for 12 h,
the product was extracted with ether (60 mL), and the ether solution
was washed with water (60 mL), dried over MgSO4, and concen-
trated. The residue was purified using silica gel column chroma-
tography (hexane/ethyl acetate ) 3:1) to give 1-adamantan-1-yl-
3-(5-bromopentyl)urea I (1.08 g, 87%) as a solid. This bromide
(0.10 g, 0.29 mmol) was added portionwise to a suspension of 60%
sodium hydride (12 mg, 0.29 mmol) and 2-hexanol (41 mg, 0.35
mmol) in DMF (15 mL) at room temperature. After stirring for 12
h, water (30 mL) was poured into the reaction mixture, and the
product was extracted with ether (40 mL). The organic solution
was dried over MgSO4 and concentrated. The residue was purified
using silica gel column chromatography (hexane/ethyl acetate )
1
2 days to provide very pure compound. H NMR δ (CDCl3) 1.40
(2H, quint, J ) 6.9 Hz), 1.50 (2H, quint, J ) 6.9 Hz), 1.55 (2H,
quint, J ) 6.9 Hz), 1.65 (6H, brs), 1.95 (6H, brs), 2.05 (3H, brs),
3.09 (2H, t, J ) 6.9 Hz), 3.45 (2H, t, J ) 6.9 Hz), 3.57 (2H, t, J
) 6.9 Hz), 3.64 (2H, t, J ) 6.9 Hz), 3.68 (2H, t, J ) 6.9 Hz), 3.78
(2H, t, J ) 6.9 Hz), 3.90 (2H, q, J ) 6.9 Hz), 4.23 (1H, s), 4.32
(1H, s). 13C NMR δ (CDCl3) 23.36, 29.20, 29.38, 29.52, 29.63,
29.92, 36.41, 40.07, 42.49, 50.71, 69.10, 69.97, 70.56, 70.70, 71.19,
71.89, 122.8, 157.3. IR 1631 cm-1, 2909 cm-1, 3352 cm-1. LC-
MS (ESI) m/z calcd for C22H37F3N2O4 [M + H]+, 451.27; found
[M + H]+, 451.27; mp 34 °C; Anal. (C22H37F3N2O4) C, H, N, F.
Compound 17 was synthesized with the same procedure used
for the preparation of 16 using 4-ethylphenol instead of 2,2,2-
trifluoroethanol.
1
3:1) to afford 11 (5.8 mg, 52%) as a solid. H NMR δ (CDCl3)
0.89 (3H, t, J ) 6.9 Hz), 1.12 (3H, d, J ) 6.9 Hz), 1.30-1.40 (4H,
m), 1.48-1.68 (14H, m), 1.96 (6H, brs), 2.06 (3H, brs), 3.09 (2H,
q, J ) 6.9 Hz), 3.32-3.35 (2H, m), 3.48-3.50 (1H, m), 4.12 (2H,
brs). LC-MS (ESI) m/z calcd for C22H40N2O2 [M + H]+, 365.31;
found [M + H]+, 365.31; mp 45-48 °C; Anal. (C22H40N2O2) C,
H, N.
N-{5-[5-(3-Adamantan-1-yl-ureido)pentyloxy]pentyl}-
methanesulfonamide (21). To a solution of 5-amino-1-pentanol
(0.59 g, 5.7 mmol) in acetonitrile (20 mL) was added methane-
sulfonic anhydride (0.50 g, 2.9 mmol) at room temperature. After
stirring for 5 h, the solvent was evaporated. To this residue ethyl
acetate (30 mL) and water (30 mL) were poured and partitioned.
Compounds 12 and 18 were synthesized with the same procedure
used for the preparation of 11 using 2-methyl-1-pentanol for 12
and triethylene glycol monomethyl ether for 18, respectively, instead
of 2-hexanol.