68
A. HINSCHBERGER ET AL
(1 g, 60%); mp 80ꢀC. IR (KBr) n: 3447, 2942, 1609,
1578, 1535, 1400, 1333, 1211, 1146, 1018, 903,
1
755 cmÀ1; H NMR (d6-DMSO) d: 8Á12 (1H, d,
H10), 8Á06 (1H, s, NH), 7Á66 (2H, m, H7 and H8),
7Á49 (1H, m, H9), 3Á44 (2H, m, H2), 2Á72 (2H, t, H4),
1Á91 (2H, m, H3); MS m=z 3 3 2 (M), 199, 183, 171.
Calculated for C13H11N2O3SF3: C, 46Á99; H, 3Á34; N,
8Á43; found: C, 46Á95; H, 3Á48; N, 8Á45%.
Figure 1. The structure of DR 4004.
5-N-Benzylpiperazino-1,2,3,4-tetrahydrobenzo[h]-
[1,6]naphthyridine difumarate (7a). N-Benzyl-
piperazine (0Á18 mL, 1Á08 mmol) was added to a
solution of 5- tri¯uoromethylsulphonyl- 1,2,3,4-
tetrahydrobenzo[h][1,6]naphthyridine 5a (0Á3g,
0Á9 mmol) and potassium carbonate (0Á25 g,
1Á8 mmol) in N,N-dimethylformamide (5 mL).
After stirring for 3h under re¯ux, the solvent was
removed. The residue was dissolved in ether
(100 mL) and washed with water (2 6 70 mL).
The organic layer was dried over magnesium sul-
phate, treated with charcoal and evaporated to
dryness to give an oil that was dissolved in iso-
propanol (3mL). This solution was heated under
re¯ux with fumaric acid (1Á17 mmol) for 3min.
After cooling, the precipitate was ®ltered and
dried to give 7a as a yellow powder (0Á1 g, 20%);
mp 210ꢀC. IR (KBr) n: 3258, 2995, 2862, 1702,
1640, 1591, 1556, 1349, 1279, 1184, 1165, 983,
for C13H14N2O: C, 72Á82; H, 6Á54; N, 13Á07;
found: C, 73Á08; H, 6Á25; N, 12Á82%.
1,2,3,4,5,6-Hexahydrobenzo[h][1,6]naphthyridin-
5-one (4a). Potassium iodide (0Á90 g, 5Á60 mmol)
was added to a solution of 5-methoxy-1,2,3,4-
tetrahydrobenzo[h][1,6]naphthyridine 2a (1 g,
4Á67 mmol) in glacial acetic acid (35 mL) and the
mixture was heated at 110ꢀC for 3h. After evapora-
tion of the solvent the residue was dissolved in
water and extracted with chloroform (2 6 60 mL).
The organic layer was washed with aqueous
sodium hydrogen carbonate (2 6 100 mL) and
iodine was removed with an aqueous solution of
sodium thiosulphate (3 6 100 mL). The organic
layer was then evaporated in-vacuo and the solid
residue was recrystallized from ether to give 4a as a
white powder (0Á75 g, 80Á3%); mp > 260ꢀC. IR
(KBr) n: 3285, 2953, 1640, 1600, 1541, 1472, 1413,
1
965 cmÀ1; H NMR (d6-DMSO) d: 7Á93(1H, d,
H10), 7Á58 (1H, d, H7), 7Á48 (1H, t, H8), 7Á35 (5H,
m, Hphenyl), 7Á26 (2H, m, NH and H9), 3Á59 (2H, s,
1
1207 cmÀ1; H NMR (d6-DMSO) d: 10Á80 (1H, s,
0
CH2benzyl), 3Á39 (2H, t, H2), 3Á18 (4H, m, H2 and
H6, NH), 7Á78 (1H, d, H10), 7Á37 (1H, t, H8), 7Á19
(1H, d, H7), 7Á07 (1H, t, H9), 6Á92 (1H, s, H1, NH),
3Á40 (2H, t, H2), 2Á45 (2H, t, H4), 1Á79 (2H, m, H3);
13C NMR (d6-DMSO) d: 164Á6, 147Á4, 132Á5,
128Á0, 118Á2, 117Á6, 113Á8, 112Á9, 107Á2, 37Á0,
0
0
0
H6 ), 2Á67 (2H, t, H4), 2Á57 (4H, m, H3 and H5 ),
1Á76 (2H, m, H3); MS m=z 358 (M ), 212, 199,
183, 146. Calculated for C31H35N4O8Á5: C, 62Á04;
H, 5Á83; N, 9Á33; found: C, 62Á07; H, 5Á78; N,
9Á46%.
36Á8, 13Á2; MS m=z 200 (M ), 181, 162. Calculated
for C12H12N2O: C, 71Á98; H, 6Á04; N, 13Á99; found:
C, 72Á13; H, 5Á76; N, 13Á96%.
6-(4-Bromobutyl)-2,3,4,5-tetrahydro-1H-benzo[h]-
[1,6]naphthyridin-5-one (6a). Sodium hydride
(0Á45 g, 15 mmol) was added to a suspension of
1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthyridin-5-
one 4a (2 g, 10 mmol) in dry N,N-dimethylforma-
mide (40 mL). The mixture was stirred for 15 min
(approx.) at room temperature before addition of
1,4-dibromobutane (1Á3mL, 11 mmol). Stirring
was then continued for 19 h at room temperature.
This mixture was poured into water (150 mL)
and extracted with diethyl ether (2 6 150 mL).
The organic layer was washed with water
(2 6 100 mL), dried over magnesium sulphate and
evaporated under reduced pressure to give 6a as an
oily residue which was puri®ed by chromatography
on silica gel with ethyl acetate±cyclohexane
(50 : 50 v=v) as eluent to give solid 6a (0Á73g,
22%); mp 122ꢀC. IR (KBr) n: 3308, 2929, 2844,
5-Tri¯uoromethylsulphonyl-1,2,3,4-tetrahydrobenzo-
[h][1,6]naphthyridine (5a). Tri¯uoromethanesul-
phonyl anhydride (1Á5 mL, 9 mmol) was added
dropwise to a suspension of 1,2,3,4,5,6-hexahydro-
benzo[h][1,6]naphthyridin-5-one 4a (1 g, 5 mmol)
cooled to 0ꢀC in dry pyridine (12 mL). The mixture
was stirred at room temperature overnight under
argon. Water (50 mL) was added and the solution
was extracted with dichloromethane (3 6 40 mL),
washed with water (3 6 50 mL), and the organic
layer was dried over magnesium sulphate, treated
with charcoal and ®ltered through celite. Evapora-
tion of the solvents furnished 5a as an oil that was
triturated in petroleum ether until crystallization