G.A. Pinna et al. / Il Farmaco 55 (2000) 553–562
559
filtrate evaporated and the oily residue purified by flash
chromatography (eluent: CH2Cl2:(CH3)2CO, 9:1) to
give the desired 1a–g and 2a–g as oils; when the stable
corresponding hydrochloride was obtained: see Table 4
for data.
(41 ml) was refluxed for 18 h, and the solvent evaporated.
The oily residue was heated at 170°C for 4 h removing
methanol by distillation to provide crude 8 which was
dissolved in dry ethanol (40 ml) and dry Et2O (40 ml) and
treated at 0–5°C with ethereal hydrochloric acid to
separate 2,4-dioxo-3,9-dibenzyl-3,9-diazabicyclo[3.3.1]-
nonane (8) hydrochloride as a white solid (3.64 g, 40%),
m.p. 173–175°C. The solid crystallized from ethanol as
white needles, m.p. 175–176°C.
6.3. Dimethyl h,h%-dibromopimelate (6)
A mixture of pimelic acid (5) (50 g, 312 mmol) in
thionyl chloride (55 ml) was heated at 40°C for 18 h.
To the irradiated (300 W lamp) solution, bromine
(117.3 g, 733 mmol) was slowly added (ꢀ8 h) under
stirring at 95°C. After the addition of Br2 was complete,
the brown solution was heated at the same temperature
for a further hour and cooled to room temperature (r.t.).
Methanol (180 ml) was added and the resulting reaction
mixture was poured into ice-water (180 ml) and the whole
solution concentrated and extracted with Et2O three
times. The combined organic extracts were washed with
2% NaHSO3, 5% NaHCO3 and H2O, then dried
(Na2SO4), filtered, and concentrated to a yellow oil
(102.78 g, 95.6%, b.p. 96–98°C/0.2) [4] which was used
in the next step without further purification.
Rf 0.58 (petroleum ether 50–70:ethyl acetate, 8:2); IR
(nujol mull, cm−1) w: 1680 (CꢀO), 2200–2400 (N+H);
1
UV umax (log m): 196.7 (4.21), 242.1 (2.86); H NMR
(CDCl3) lH: 1.20–1.50 (m, 1H), 1.80–1.95 (m, 1H),
2.02–2.20 (m, 2H), 2.80–3.02 (m, 2H), 4.11 (br s, 4H),
5.07 (s, 2H), 7.15–7.55 (m, 10H); Anal. C21H23ClN2O2
(C, H, Cl, N).
6.6. 2,4-Dioxo-3-benzyl-3,9-diazabicyclo[3.3.1]nonane
(9)
A solution of 8 · HCl (8.9 g, 24.1 mmol) in ethanol
(215 ml) was hydrogenated at 60 psi at r.t. for 2 h with
10% Pd–C (0.89 g).
The catalyst was filtered off and the solution was
concentrated to afford 9 · HCl (6.75 g, 100%) as white
powder, m.p. 180–182°C.
1
Rf 0.66 (benzene); IR (film, cm−1) w: 1740 (CꢀO); H
NMR (CDCl3) lH: 1.32–1.85 (m, 2H), 1.98–2.20 (m,
4H), 3.79 (s, 6H), 4.24 (t, 2H, J=70 Hz).
Analytical sample was crystallized from ethanol, m.p.
182–184°C.
6.4. Dimethyl cis- and trans-N-benzyl-2,6-
piperidinedicarboxylate (7)
Rf 0.20 (petroleum ether 50–70:ethyl acetate, 6:4); IR
(nujol mull, cm−1) w: 1690 (CꢀO), 2300–2600 (N+H); 1H
NMR (CDCl3) lH: 1.12–1.42 (m, 1H), 1.70–1.88 (m,
1H), 2.01–2.20 (m, 2H), 2.30–2.55 (m, 2H), 4.57 (br s,
2H), 4.95 (s, 2H), 6.80–8.01 (m, 7H).
A solution of 6 (1.50 g, 4.3 mmol) and benzylamine
(1.47 g, 13 mmol) in benzene (5.5 ml) was refluxed for
24 h. After cooling, the salts were filtered off, the solvent
evaporated and the oily residue was distilled at 114–
150°C/0.01–0.1 to give 7 as a yellowish oil (0.61 g, 64%)
[4]. Flash chromatography with 20% ethyl acetate in
petroleum ether afforded in the order trans-7 (0.21 g,
22.8%), as an oil; Rf 0.58 (petroleum ether 50–70:ethyl
The free base 9 was isolated from the HCl salt with
10% Na2CO3 (16 ml) and extracted with CH2Cl2. Evap-
oration of the solvent led to a viscous oil which on
standing solidified, m.p. 92–94°C. Analytical sample:
m.p. 94–96°C (ethyl ether–petroleum ether) [4].
Rf 0.24 (petroleum ether 50–70:ethyl acetate, 6:4); IR
(nujol mull, cm−1) w: 1670 (CꢀO), 3240, 3300 and 3360
acetate, 8:2); IR (film, cm−1) w: 1740 (CꢀO); H NMR
1
(CDCl3) lH: 1.50–1.62 (m, 2H), 1.75–1.98 (m, 4H), 3.65
(q, 2H, J=13.4 Hz), 3.72 (s, 6H), 3.87 (t, 1H, J=5 Hz),
3.90 (t, 1H, J=5Hz), 7.26–7.41 (m, 5H); 13C NMR
(CDCl3) lC: 19.16, 28.36, 51.34, 56.76, 59.02, 127.10,
128.11, 128.93, 137.98, 174.39; and cis-7 (0.33 g, 35.4%),
as a wax; Rf 0.45 (petroleum ether 50–70:ethyl acetate,
1
(NH); H NMR (CDCl3) lH: 1.25–1.50 (m, 1H), 1.65–
1.82 (m, 1H), 1.82–2.05 (m, 4H), 2.50 (br s, 1H, exch with
D2O), 3.79 (br s, 2H), 4.97 (s, 2H), 7.23–7.51 (m, 5H).
6.7. 3-Benzyl-3,9-diazabicyclo[3.3.1]nonane (10)
8:2); IR (nujol mull, cm−1) w: 1740 (CꢀO); H NMR
1
(CDCl3) lH: 1.20–1.50 (m, 2H), 1.75–1.95 (m, 4H),
3.15–3.30 (m, 2H), 3.60 (s, 6H), 3.85 (s, 2H), 7.20–7.40
(m, 5H); 13C NMR (CDCl3) lC: 20.27, 28.47, 51.19,
58.64, 62.01, 126.90, 127.71, 129.15, 136.81, 173.25.
To a stirred mixture of lithium aluminium hydride (7.9
g, 210 mmol) in dry Et2O (269 ml) at 0°C a solution of
9 (7.04 g, 29 mmol) in dry benzene (101 ml) was added
dropwise. The reaction mixture was refluxed for 6 h, then
cooled at 5°C, decomposed with water (27 ml) and kept
at r.t. for 1 h. The salts were filtered off and the filtrate
was dried (Na2SO4) and evaporated to leave a dark oil.
The oil was purified by distillation at 170–178°C/0.8 [4]
to afford the desired compound 10 (5.48 g, 88%) as a
brown oil.
6.5. 2,4-Dioxo-3,9-dibenzyl-3,9-diazabicyclo-
[3.3.1]nonane (8) hydrochloride
A solution of 7 (as a cis+trans mixture, 19.45 g, 67
mmol) and benzylamine (7.15 g, 767 mmol) in toluene