ORIGINAL ARTICLES
Table 4: Reaction conditions and ratio of compounds B and C
in reactions 3.2.3 a-c
2H), 2.13 (quintet, J = 6.4 Hz, 2H), MS (EI): found m/z = 314 and 316
(intensity 1:0.9) [M+], for C17H16NBr calcd. 315. FTIR (film) ν = 3019,
2960, 2850, 1592, 1570, 1435, 1238, 1115, 790, 761 cm−1
.
◦
Compound C: 5-(3-Chloropropyl)-5H-dibenzo[b,f]azepine; m.p. 63.5–
65 ◦C (methanol at low temperature) (lit. 67 ◦C (Geigy, Patent 1962)); 1H
NMR: ␦ = 7.29–7.26 (m, 2H), 7.09–7.07 (m, 2H), 7.05–6.99 (m, 4H), 6.74
(s, 2H), 3.90 (t, J = 6.35 Hz, 2H), 3.63 (t, J = 6.3 Hz, 2H), 2.01 (quintet,
J = 6.4 Hz, 2H), MS (EI): found m/z = 269 and 271 (intensity 1:0.3) [M+],
for C17H16NCl calcd. 269.5. FTIR (film) ν = 2954, 2922, 2850, 1592, 1484,
Reaction
Temp. [ C]
Time [h]
Yield [%]
%B; %C [mol/mol]
a
b
c
80
50
rt
6
24
48
43
40
25
43; 57
25; 75
10; 85
1460, 1436, 1297, 1239, 1115, 1046, 789, 763 cm−1
.
Compound D: 1,3-Bis(5H-dibenzo[b,f]-azepin-5-yl)-propane; m.p.164–
166 ◦C (2-propanol) (lit. 163–166 ◦C (Kawashima et al. 1976)); 1H NMR:
␦ = 7.15 (t, J = 7.8 Hz, 4H); 7.00 (d, J = 7.3 Hz, 4H); 6.95 (t, J = 7.3 Hz, 4H);
6.86 (d, J = 8.3 Hz, 4H); 6.53 (s, 4H); 3.85 (t, J = 6.3 Hz, 4H); 1.81 (quintet,
J = 6.3 Hz, 2H); MS (EI): found m/z = 426; calcd. for C31H26N2 426; FTIR
3.2.3. Synthesis of compounds B and C. Iminostilbene reactions
with 1-bromo-3-chloropropane
a-c) A stirred mixture of iminostilbene (2.50 g, 13 mmol), 1,3-bromo-
chloropropane (5.3 mL, 50 mmol), K2CO3 (11 g, 79 mmol) and tetra-
n-butylammonium iodide (0.5 g) in DMF (11 mL), was reacted under
conditionsgiveninTable4. Themixturewasdilutedwithwaterandextracted
with ethyl acetate. The products separated by column chromatography using
methylene chloride-hexane (1:3) gave a mixture of compounds B and C in
different ratios (see Table 4).
d) A mixture of iminostilbene (2.50 g, 13 mmol), 1,3-bromochloropropane
(5.3 mL, 50 mmol), Na2CO3 (5.3 g, 50 mmol) and tetra-n-butylammonium
iodide (0.75 g) in ethanol (25 mL) was stirred under reflux for 4 h. To the
cooled mixture methylene chloride (50 mL) was added. The deposit was
separated, washed with methylene chloride and discarded. The filtrate was
concentrated and separated on a column using methylene chloride-hexane
(1:3) mixture. Yield 1.42 g (40%) of a product consisting of >90% C and
< 10% B.
(nujol)ν = 1591; 1329; 1279; 1235; 1125; 903; 789; 758; 461 cm−1
.
Compound H: 2-(5H-Dibenzo[b,f]azepin-5-yl)-acridine-9-carbaldehyde;
m.p. 210–211 ◦C (acetone/water); 1H NMR: ␦ = 11.17 (s, 1H), 8.75
(d, J = 8,8 Hz, 1H), 8.21 (d, J = 8,3 Hz, 1H), 8.0 (d, J = 9,2 Hz, 1H),
7.68–7.59 (m, 6H), 7.53 (d, J = 7,2 Hz, 2H), 7.45–7.46 (m, 3H),
7,12 (dd, J1 = 9,2 Hz, J2 = 1,6 Hz, 1H), 6.90 (s, 2H). MS (EI): found
m/z = 398 [M+]; calcd. for C28H18N2O 398. FTIR (film) ν = 1678, 1625,
1607,1593, 1486, 1336, 1309, 1241, 1151, 1306, 755 cm−1. UV-Vis (ace-
tonitrile): 1 = 211 nm (1 = 2.75 × 104), 2 = 250 nm (2 = 2.38 × 104),
3 = 282 nm (3 = 3.49 × 104), 4 = 388 nm (4 = 4.55 × 103), 5 = 500 nm
(5 = 5.74 × 103). Fluorescence: ex = 282 nm, em = 610 nm.
Compound I: 5H-Dibenzo[b,f]azepine-5-carbaldehyde m.p. 130–132 ◦C
(lit. 135–136 ◦C (Querner et al. 2004))
1H NMR: ␦ = 6.87 (d, J = 11.7 Hz, 1H), 6.93 (d, J = 11.7 Hz, 1H), 7.31 (d,
J = 7.1 Hz, 1H), 7.34–7.50 (m, 7H), 8.34 (s, 1H). MS (EI): found m/z = 221
[M+], calcd. for C15
H11NO 221.
3.2.4. Synthesis of N-(3-hydroxypropyl)-5H-dibenzo[b,f]azepine,
compound K
FTIR (nujol)ν = 1697, 1569, 1492, 1337, 1300, 1152, 792, 768, 729 cm−1
.
Compound K: 5-(3-Hydroxypropyl)-5H-dibenzo[b,f]azepine, m.p. 116–
117 ◦C (dichloromethane/hexane) (lit. 117 ◦C (Ohta et al. 1981)); 1H NMR:
␦ = 7.33 (t, J = 7.3 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 7.10 (d, J = 8.3 Hz,
2H,), 7.06 (t, J = 7.3 Hz, 2H,), 6.84 (s, 2H), 3.92 (t, J = 6.3 Hz, 2H), 3.70 (t,
J = 5.9 Hz, 2H), 3.10 (s, 1H), 1.82 (m, 2H). MS (EI): found m/z = 251 [M+],
calcd. for C17H17NO 251. FTIR (nujol)ν = 3405, 1308, 1231, 1207, 1120,
A mixture of 5-(3-bromopropyl)-5H-dibenzo[b,f]azepine (compound B)
(1.20 g) and sodium acetate (0.45 g) in DMF (15 mL) was heated at 120 ◦C
overnight. The mixture was diluted with water and extracted with hexane-
ethyl acetate (4:1) mixture. The solvent was evaporated and the residue was
hydrolyzed with 5 mL conc. NaOH solution in methanol. After 2.5 h the
mixture was diluted with water and extracted with chloroform. After evap-
oration of the solvent, the residue was purified by column chromatography
using hexane-methylene chloride (3:1), (1:1) and finally with methylene
chloride as eluent. It was obtained 0.62 g (65%) of compound K.
1035, 971, 806, 769, 722, 568, 450 cm−1
.
Compound N: N-(3-Hydroxypropyl)-9(10H)-acridone; m.p. 205–208 ◦C
(chloroform/hexane) (lit. 209–210 ◦C (Ohta et al. 1981)); 1H NMR: ␦ = 8.62
(d, J = 8.3 Hz, 2H), 7.75 (t, J = 8.3 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 7.32 (t,
J = 7.8 Hz, 2H), 4.60 (t, J∼6 Hz, 2H), 3.92 (t, J = 5.8 Hz, 2H), 3.10 (s, 1H),
1.81 (quintet, J = 5.9 Hz, 2H). MS (EI): found m/z = 253 [M+], calcd. for
3.2.5. Synthesis of N-(3-hydroxypropyl)-9(10H)-acridone,
compound N
C16H15NO2 253. FTIR (nujol)ν = 3394, 1608, 1260, 1078, 1040, 751 cm−1
.
A mixture of 9(10H)-acridone (0.70 g, 3.6 mmol), 3-bromo-1-propanol
(0.33 mL, 3.6 mmol), K2CO3 (0.5 g, 3.6 mmol) and DMF (15 mL) was
stirred at 60 ◦C for 4 h and the reaction mixture was then diluted with
water. The solid was collected by filtration and washed with chloroform. The
organic solution was evaporated and the residue was purified by preparative
TLC using chloroform-methanol (20:1) mixture. Yield 24% of compound
N.
3.4. HPLC analysis
The mobile phase consisted of an acetonitrile-buffer (55:45, v/v) mixture at a
flow rate of 1 ml/min. Buffer composition: 5 ml triethylamine was dissolved
in 1000 ml water and the mixture was adjusted to pH 11.2 with phospho-
ric acid. When pure acetonitrile was the mobile phase the flow rates were
1 ml/min or 0.7 ml/min. All samples for HPLC analysis were dissolved in
acetonitrile-water (37:63, v/v) mixture using 1 mg substance per 1 ml sol-
vent. The injection volume was fixed at 10 l. All analyses were carried out
at room temperature using UV detection at 256 nm.
3.2.6. Synthesis of compounds G, H, I and J by oxidation
of iminostilbene with PCC
To pyridinium chlorochromate (PCC) (10.0 g) in methylene chloride
(50 mL), an iminostilbene suspension (4.8 g, 25 mmol) in methylene chlo-
ride (50 mL) was added in portions. The mixture was stirred at room
temperature for 24 h. The reaction mixture was filtered through an alu-
minium oxide layer under vacuum and the filter bed was washed with
methylene chloride until the filtrate was colorless. The concentrated fil-
trate was chromatographed as soon as possible by preparative TLC using
dichloromethane. Yield: 15% G, 13% I, 12% J and 4% H.
3.5. X-ray structural analysis of compound H
Single crystals of compound H were grown by slow evaporation of a solution
in dichloromethane (red prisms).
X-Ray measurements were carried out on KM4CCD kappa-geometry
diffractometer equipped with a Sapphire-2 CCD detector. Enhanced X-ray
MoK␣ radiation source with a graphite monochromator was used. Determi-
nation of the elemental cell and data collection were carried out at 120K.
The preliminary calculations were made using CrysAlis software package
(Oxford Diffraction, 2008). The structure was solved by direct method
and refined by full-matrix least squares procedure based on F2. Empiri-
cal absorption correction using spherical harmonics was implemented in
SCALE3 ABSPACK scaling algorithm. Non-hydrogen atoms were refined
with anisotropic displacement parameters. Final calculations were carried
out using the SHELX-97 program package (Sheldrick 2008). Supplemen-
tary data: cif file for compound H was deposited with the Cambridge
Crystallographic Data Center as supplementary publication number CCDC
748029 (CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK; E-mail:
deposit@ccdc.cam.ac.uk).
3.3. Characteristics of potential impurities of opipramol (mainly for
those not commercially available or not fully characterized in the
literature)
Compound A: 5-Allyl-5H-dibenzo[b,f]azepine; m.p. 29–30 ◦C (lit. 40–
42 ◦C (Sadashiva et al. 2005)); 1H NMR: ␦ = 7.27 (t, J = 7.6 Hz, 2H), 7.10
(dd, J1 = 7.3 Hz, J2 = 1.4 Hz, 2H), 6.99–7.03 (m, 4H), 6.79 (s, 2H), 5.87–
5.78 (m, 1H), 5.34 (dd, J1 = 17.1 Hz, J2 = 1.5 Hz, 1H), 5.14 (dd, J1 = 10.4,
J2 = 1.5 Hz, 1H), 4.45 (d, J = 5.4 Hz, 2H). FTIR (film) ν = 3071, 3018, 2979,
2838, 1643, 1593, 1572, 1484, 1458, 1437, 1414, 1355, 1298, 1234, 1117,
1051, 984, 919, 789, 715, 644 cm−1
Compound B:
.
5-(3-Bromopropyl)-5H-dibenzo[b,f]azepine;
m.p.
77–78.5 ◦C (crystallized from methanol at low temperature); 1H
NMR: ␦ = 7.35–7.31 (m, 2H), 7.14 (dd, J1 = 7.3 Hz, J2 = 1.5 Hz, 2H),
7.09–7.05 (m, 4H), 6.81 (s, 2H), 3.94 (t, J = 6.4 Hz, 2H), 3.54 (t, J = 6.8 Hz,
Acknowledgments: The authors thanks Dr. Jarosław Chojnacki for X-ray
measurements which were undertaken at Department of Inorganic Chem-
istry, Chemical Faculty, Gdansk University of Technology.
Pharmazie 65 (2010)
243