Synthesis of 11-(Piperazin-1-yl)-5H-dibenzo[b,e] [1,4]diazepine
1748
Experimental
All solvents and reagents were purchased from the suppliers and used without further
purification. Thin layer chromatography was performed on Merck precoated Silica-gel
60F254 plates. Mass spectra were obtained on Perkin Elmer Turbomass spectrometer.
1H-NMR spectra were recorded in CDCl3 using 300 MHz, on a Jeol-300 NMR spectrometer.
The chemical shifts were reported in δppm relative to TMS. The IR spectra were recorded in a
solid state as KBr dispersion using Perkin Elmer FT-IR spectrophotometer. Melting points were
obtained by using the open capillary method and are uncorrected.
N-(2-Nitrophenyl) anthranilic acid (3)
In a 20 liter RBF, equipped with a sealed mechanical stirrer and a reflux condenser, a
mixture of 1-fluoro-2-nitrobenzene (3.4 kg, 24.1mol) 1, anthranilic acid (3 kg, 21.89 mol) 2,
30 gm Cu powder and K2CO3 (3 kg, 21.58 mol) in 5 liter DMF was refluxed for 12 h. After
completion the reaction mixture was poured into 6 liter ice cold water and neutralised with
glacial acetic acid maintaining the temperature below 250c. Orange colored solid was
separated by filtration and recrystallized using glacial acetic acid. (4.8 kg, 85%); m.p.: 217-
219 0c (lit. 219 0c)9; TLC Rf (silica, EtOAc) 0.56; IR (KBr, cm−1): 3337 (NH), 1500 (NO2).
N-(2-Aminophenyl)anthranilic acid (4)
In a 5 liter stainless steel hydrogenation kettle, a solution of 1.5 kg of N-(2-
nitrophenyl)anthranilic acid 3 in 2 liter DMF was hydrogenated for 2 h using 75 gm Raney
Nickel W-2 as a catalyst at 70 psi pressure. The reaction mixture was filtered on bed of
celite and DMF was evaporated under vacuum. Recrystallization from methanol gave
0
methyl N-(2-aminophenyl)anthranilic acid. (1.1 kg, 83%). m.p.: 87-89 c; IR (KBr, cm-1):
3367, 3268 (NH2).
5H-dibenzo[b,e][1,4]diazepine-11(10H)-one (5)
To a solution of 2 kg of N-(2-aminophenyl) anthranilic acid 4 in 5 liter of DMF was added
10 ml of concentrated H2SO4 and refluxed for 7-8 h after which reaction mixture was
0
poured in ice cold water, solid was obtained which was filtered, dried in oven at 100 C.
This product is used without further purification for the next step. (1.5 kg, 81%); m.p.: 251-
30c (lit. 254-55 0C)1; TLC: Rf (silica, EtOAc) 0.86; IR (KBr, cm-1) 3634, 3017, 1659, 1215.
11-Piperazinyl-5H-dibenzo[b,e][1,4]diazepine (7)
To a solution of piperazine 6 (1.6 kg, 18.6 mol) in 7 liter anisole under nitrogen was added a
solution of titanium tetrachloride (0.40 kg, 2.12 mol) in anisole and an immediate
yellow/brown coloration was observed (titanium tetrakisamine complex). The mixture was
warmed to 50-55 0C and a solution of 5H-dibenzo[b,e][1,4]diazepine-11(10H)-one 5 (1.5 kg,
7.14 mole) in anisole (3 liter) was added. The mixture was heated at 1100c for 7-8 h and
was filtered while hot. The filtrate was concentrated under vacuum to remove 80% of
anisole. The concentrated filtrate was allowed to come at room temperature then cooled
0
to 4 C for 1 h. The green colored solid obtained which was filtered and recrystallized using
methanol. (1.33 kg, 63%). TLC: Rf (Hexane : EtOAc, 1:9) 0.66; m.p.: 230-34 0C; IR (KBr,
cm-1): 3328, 1604, 1515, 1245; 1H NMR (CDCl3) (δ ppm): 1.60 (s, 8H, aliphatic CH2), 5.55
(bs, 1H, Ar-NH-Ar), 6.7 (d, 1H, NH), 6.88-7.0 (m, 3H, aromatic), 7.3 (t, 1H, aromatic),
7.5 (bs, 1H, NH), 7.9 (d, 1H, aromatic); MS (m/z): 278 [M+]; 249 (2), 222 (50), 193 (64),
209 (100). Anal. Cald. For C17H18N4: C, 73.35; H, 6.52; N, 20.13. Found: C, 73.31; H,
6.54, N, 20.14
Kalhapure, Rahul S.
