A. J. Bojarski et al. / Bioorg. Med. Chem. 10 (2002) 87–95
93
Experimental
2.7–3.1 (m, 4H), 3.1–3.4 (m, 2H, CH2N), 3.7 (s, 2H,
CH2), 6.2 (br. s, 1H, NH), 6.9 (s, 1H, arom.), 7.0 (s, 2H,
Chemistry
arom). Mp (salt) 158–159 ꢀC. Anal. (C25H36N2O
.
.
C4H4O4 H2O) C, H, N.
Melting points were determined using an Electro-
thermal Digital Melting Point IA9000 apparatus and
were uncorrected. H NMR spectra were obtained with
1
2-[4-(1-Adamantoylamino)butyl]-8-bromo-5-methoxy-
1,2,3,4-tetrahydroisoquinoline (21). Oil, yield 39%. 1H
NMR 1.4–2.1 (m, 19H), 2.4–3.0 (m, 6H), 3.2–3.5 (m,
2H, CH2N), 3.6 (s, 2H, CH2), 3.8 (s, 3H, OCH3), 6.1 (br
s, 1H, NH), 6.7 (d, J=8 Hz, 1H, arom.), 7.4 (d, J=8
Hz, 1H, arom). Mp (salt) 164–165 ꢀC. Anal.
a Varian EM-360L (60 MHz) in a CDCl3 solution with
TMS as an internal standard; the values of chemical
shifts (d) are given in ppm. The starting R-substituted
1,2,3,4-tetrahydroisoquinolines were obtained according
to the published procedure, that is compounds 3–7,12
814 and 9, 10.13 Methods describing preparation of
compounds 11–193 and 20–2810 had been previously
published.
.
(C25H35BrN2O2 C4H4O4) C, H, N.
2-[4-(1-Adamantoylamino)butyl]-5-chloro-1,2,3,4-tetrahy-
1
droisoquinoline (22). Oil, yield 55%. H NMR 1.4–2.1
(m, 19H), 2.4–3.0 (m, 6H), 3.2–3.5 (m, 2H, CH2N), 3.7 (s,
2H, CH2), 6.0 (br s, 1H, NH), 7.0–7.6 (m, 3H, arom). Mp
General procedure for preparation of compounds 11–19
ꢀ
.
(salt) 241–243 C. Anal. (C24H33ClN2O HCl) C, H, N.
A mixture of N-(2-chloroethyl)- or N-(4-bromobutyl)-
phthalimide (3 mmol), substituted 1,2,3,4-tetra-
hydroisoquinoline 3–10 (0.4 g, 3 mmol), and n-butanol
(30 mL) was refluxed for 13 h. Then the reaction
mixture was filtered off, and the solvent was evapo-
rated to give a crude product, which was purified by
crystallization.
2-[4-(1-Adamantoylamino)butyl]-6-chloro-1,2,3,4-tetrahy-
1
droisoquinoline (23). Oil, yield 70%. H NMR 1.4–2.2
(m, 19H), 2.4–3.0 (m, 6H), 3.1–3.5 (m, 2H, CH2N), 3.7
(s, 2H, CH2), 6.0 (br s, 1H, NH), 7.0–7.3 (m, 3H, arom).
ꢀ
.
Mp (salt) 160–162 C. Anal. (C24H33ClN2O C4H4N4) C,
H, N.
A solution of phtalimide derivative (free bases, 1.2
mmol) and hydrazine (0.5 mL, 12 mmol) in 99.8% eth-
anol (15 mL) was refluxed for 1 h. The reaction mixture
was cooled down and treated with an additional
amount of 99.8% ethanol (15 mL) and concentrated
HCl (1.3 mL). Then the reaction mixture was refluxed
for 4 h and left overnight in a refrigerator. The pre-
cipitate was filtered off, and the solvent was evaporated.
The residue was treated with n-hexane (20 mL) and
NH3 (aqueous, 15 mL). The solution was extracted with
CHCl3 (3Â15 mL). the organic layer was dried over
anhydrous K2CO3, and the solvents were evaporated to
give a product (11–19) which was used without further
purification.
2-[4-(1-Adamantoylamino)butyl]-7-chloro-1,2,3,4-tetrahy-
1
droisoquinoline (24). Oil, yield 70%. H NMR 1.4–2.2
(m, 19H), 2.4–2.9 (m, 6H), 3.1–3.5 (m, 2H, CH2N), 3.6
(s, 2H, CH2), 6.1 (br s, 1H, NH), 7.1 (s, 3H, arom). Mp
(salt) 154–156 ꢀC. Anal. (C24H33ClN2O C4H4N4 0.5
H2O) C, H, N.
.
.
2-[4-(1-Adamantoylamino)butyl]-7-nitro-1,2,3,4-tetrahy-
1
droisoquinoline (25). Oil, yield 25%. H NMR 1.4–2.3
(m, 19H), 2.5–3.3 (m, 6H), 3.3–3.8 (m, 2H, CH2N), 3.7
(s, 2H, CH2), 5.8 (br s, 1H, NH), 7.3 (d, J=7 Hz, 1H,
arom), 7.4 (s, 1H, arom), 8.1 (d, J=7 Hz, 1H, arom).
ꢀ
.
Mp (salt) 117–119 C. Anal. (C24H33N3O3 C4H4O4) C,
H, N.
General procedure for preparation of compounds 20–28
2-[4-(1-Adamantoylamino)butyl]-6-methoxy-1,2,3,4-tetra-
1
1-Adamantanecarboxylic acid (1.5 mmol) was dissolved
in methylene chloride (3 mL) and triphenylphosphine
(1.5 mmol) was added on stirring. After 5 min N-
bromo-succinimide (NBS 1.6 mmol) was added in por-
tions and after that the mixture was stirred for 0.5 h at
room temperature. Then the solution of N-(o-ami-
noalkyl)-1,2,3,4-tetrahydroisoquinoline (11–19) (1.4
mmol) and triethylamine (1.7 mmol) in methylene chlo-
ride (1 mL) was added dropwise. The reaction mixture
was stirred for 3 h at room temperature and left over-
night. Then it was diluted with CHCl3 (10 mL) and
washed with 20% aqueous NaOH (5 mL), water (5 mL)
and dried over anhydrous MgSO4. The inorganic pre-
cipitate was filtered off, the solvents were evaporated
and the amides (20–28) were separated bycolumn
hydroisoquinoline (26). Oil, yield 65%. H NMR 1.5–
2.2 (m, 19H), 2.3–3.1 (m, 6H), 3.1–3.5 (m, 2H, CH2N),
3.5 (s, 2H, CH2), 3.8 (s, 3H, OCH3), 6.0 (br s, 1H, NH),
6.5–7.0 (m, 3H, arom). Mp (salt) 193–195 ꢀC. Anal.
.
.
(C25H36N2O2 HCl H2O) C, H, N.
2-[4-(1-Adamantoylamino)butyl]-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (27). Oil, yield 37%. 1H NMR
1.5–2.2 (m, 19H), 2.5–2.7 (m, 2H), 2.7–3.0 (m, 4H), 3.2–
3.5 (m, 2H, CH2N), 3.6 (s, 2H, CH2), 3.9 (s, 6H, 2OCH3),
6.1 (br s,ꢀ1H, NH), 6.6 (d, J=4 Hz, 2H, arom). Mp (salt)
.
.
188–190 C. Anal. (C26H38N2O3 C4H4O4 0.5H2O) C, H,
N.
2-[2-(1-Adamantoylamino)ethyl]-8-bromo-5-methoxy-
1,2,3,4-tetrahydroisoquinoline (28). Oil, yield 30%. 1H
NMR 1.5–2.2 (m, 15H), 2.5–3.2 (m, 6H), 3.2–3.5 (m,
2H, CH2N), 3.6 (s, 2H, CH2), 3.8 (s, 3H, OCH3), 6.2
(br s, 1H, NH), 6.6 (d, J=8 Hz, 1H, arom), 7.3 (d,
J=8 Hz, 1H, arom). Mp (salt) 226–228 ꢀC. Anal.
chromatographyusing SiO
CHCl3–MeOH, 95:5.
and CHCl3 followed by
2
2-[4-(1-Adamantoylamino)butyl]-7-methyl-1,2,3,4-tetra-
1
hydroisoquinoline (20). Oil, yield 60%. H NMR 1.4–
2.1 (m, 19H), 2.2 (s, 3H, CH3), 2.4–2.7 (m, 2H, CH2),
. .
(C23H31BrN2O2 C4H4O4 H2O) C, H, N.