A. Balsamo et al. / European Journal of Medicinal Chemistry 37 (2002) 11–22
19
water (18 mL). The separated aq. layer was extracted
with CH2Cl2 and the combined organic extracts were
washed with water, dried and evapored to yield a solid
that was crystallised from EtOAc to afford 14 (0.95 g,
66%): m.p. 118–119 °C; IR w 1660 cm−1(CONH);
1H-NMR l 1.50–2.06 (m, 4H), 2.36–2.51 (br, 1H),
2.56–2.90 (m, 2H), 3.40–3.76 (m, 2H), 4.05 (s, 2H),
5.01 (s, 2H), 5.13 (s, 2H), 6.83–7.53 (m, 12H).
C27H28ClNO4 (C, H, N).
filtered and the solid washed with ether. The organic
solvents were dried and evaporated to give an oil
1
consisting of 18 (0.56 g, 96%): H-NMR l 1.56–1.88
(m, 4H), 2.13–3.12 (m, 6H), 3.48–4.12 (m, 2H), 5.00 (s,
2H), 5.16 (s, 2H), 6.94 (d, 1H, J=8.80 Hz), 7.12–7.60
(m, 11H).
The resulting oil 18 was dissolved in a mixture of
Et2O–MeOH (8:2) and added of a solution of H2C2O4
in the same mixture. The resulting oxalate salt was
filtered and recrystallised from MeOH–Et2O to give
18·H2C2O4; m.p. 153–155 °C. C29H31NO7 (C, H, N).
8.1.2. 1-Hydroxy-1-(chloroacetaminomethyl)-6,7-
dibenzyloxy-1,2,3,4-tetrahydronaphthalene (15)
This compound was prepared from 13 [21] (1.10 g,
2.82 mmol) following the same procedure described
above for the preparation of compound 14. The crude
product was an oil consisting essentially of 15 (1.10 g,
84%) which was used for the following reaction without
further purification; IR w 1660 cm−1 (CONH); 1H-
NMR l 1.56–2.46 (m, 5H), 2.53–2.85 (m, 2H), 3.33–
3.70 (m, 2H), 4.05 (s, 2H), 5.15 (s, 4H), 6.70 (s, 1H),
7.16 (s, 1H), 7.43 (br, 10H). C27H28ClNO4 (C, H, N).
8.1.6. (6,7-Dibenzyloxy)-3,4-dihydrospiro[naphthalene-
1(2H)-2%,5%-morpholine] oxalate (19·H2C2O4)
Reduction of the morpholone 17 (0.66 g, 1.53 mmol)
with LiAlH4 as described above for 18 gave the desired
morpholine 19 as an oil (0.58 g, 90%): 1H-NMR l
1.50–2.16 (m, 4H), 2.56–3.16 (m, 6H), 3.50–4.23 (m,
2H), 5.25 (s, 2H), 5.31 (s, 2H), 6.80 (s, 1H), 7.43 (s,
1H), 7.50–7.83 (m, 10H).
Compound 19 was converted to the oxalate salt and
after recrystallisation from MeOH–Et2O yielded
19·H2C2O4; m.p. 186–188 °C. C29H31NO7 (C, H, N).
8.1.3. (5,6-Dibenzyloxy)-3,4-dihydrospiro-
[naphthalene-1(2H)-2%,5%-morpholin-4%-one] (16)
KOt-Bu (1.20 g, 10.70 mmol) was added portionwise
over 1 h to a stirred solution of the chloroacetamide 14
(0.95 g, 2.04 mmol) in anhydrous C6H6 (46 mL). The
reaction mixture was stirred at r.t. for 1.5 h, and then
diluted with water. The separated organic layer was
washed with H2O, dried and evaporated to give a solid
that was crystallised from EtOAc to yield 16 (0.50 g,
57%): m.p. 192–194 °C; IR w 1670 cm−1 (CONH);
1H-NMR l 1.63–2.96 (m, 6H), 3.33–3.73 (m, 2H), 4.26
(s, 2H), 5.02 (s, 2H), 5.13 (s, 2H), 6.76–7.56 (m, 12H).
C27H27NO4 (C, H, N).
8.1.7. (5,6-Dihydroxy)-3,4-dihydrospiro[naphthalene-
1(2H)-2%,5%-morpholine] oxalate (10a·H2C2O4)
A solution of 18·H2C2O4 (0.20 g, 0.40 mmol) in
MeOH (20 mL) was hydrogenated at r.t. and atmo-
spheric pressure in the presence of 10% Pd on charcoal
(0.07 g). When the absorption stopped the catalyst was
removed by filtration and the resulting solution was
concentrated and anhydrous Et2O was added. The re-
sulting precipitate was filtered and then crystallised
from MeOH–Et2O to give 10a·H2C2O4 (0.08 g, 62%):
m.p. 180–183 °C (dec.); 1H-NMR l 1.58–2.08 (m,
4H), 2.25–3.40 (m, 6H), 3.90–4.37 (m, 2H), 6.86 (d,
1H, J=8.77 Hz), 7.10 (d, 1H, J=8.77 Hz). C15H19NO7
(C, H, N).
8.1.4. (6,7-Dibenzyloxy)-3,4-dihydrospiro-
[naphthalene-1(2H)-2%,5%-morpholin-4%-one] (17)
The chloroacetamide 15 (0.90 g, 1.93 mmol) was
converted to the spiromorpholone 17 as described
above for preparation of compound 16. The crystallisa-
tion of the crude solid from AcOEt gave 17 (0.66 g,
80%): m.p. 171–173 °C; IR w 1670 cm−1 (CONH);
1H-NMR l 1.50–2.83 (m, 6H), 3.20–3.60 (m, 2H), 4.31
(s, 2H), 5.18 (s, 4H), 6.63 (s, 1H), 7.16 (s, 1H), 7.36 (br,
10H). C27H27NO4 (C, H, N).
8.1.8. (6,7-Dihydroxy)-3,4-dihydrospiro[naphthalene-
1(2H)-2%,5%-morpholine] oxalate (11a·H2C2O4)
This compound was prepared from 19·H2C2O4 (0.25
g, 0.60 mmol) dissolved in a mixture of MeOH (10 mL)
and CH2Cl2 (3 mL) following the same procedure de-
scribed for compound 10a·H2C2O4. The crude product
was purified by crystallisation from MeOH–Et2O to
yield 11a·H2C2O4 (0.20 g, 66%): m.p. 164–167 °C.
1H-NMR l 1.54–2.09 (m, 4H), 2.30–3.51 (m, 6H),
3.85–4.27 (m, 2H), 6.69 (s, 1H), 7.10 (s, 1H).
C15H19NO7 (C, H, N).
8.1.5. (5,6-Dibenzyloxy)-3,4-dihydrospiro[naphthalene-
1(2H)-2%,5%-morpholine] oxalate (18·H2C2O4)
A solution of the morpholone 16 (0.60 g, 1.40 mmol)
in anhydrous THF (15 mL) was added dropwise to a
stirred suspension of LiAlH4 (0.21 g, 5.54 mmol) in
anhydrous THF (9 mL). The reaction mixture was
heated at reflux for 3 h and then cooled to 10 °C. The
excess of LiAlH4 was destroyed by careful addition of
H2O, 10% NaOH solution, H2O. The mixture was
8.1.9. (5,6-Dibenzyloxy)-3,4-dihydro-5%-N-isopropyl-
spiro[naphthalene-1(2H)-2%,5%-morpholine] oxalate
(20·H2C2O4)
A suspension of 18 (0.35 g, 0.84 mmol), 2-bromo-
propane (0.35 mL, 3.7 mol) and KOH (0.09 g, 6.2