|
Molbank 2005, M475 |
Corrections
This is the corrected version of Molbank 2005, M454
Synthesis
of
8-Chloro-11-(4-(3-(p-tolyloxy)propyl)piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine
Ben Capuano*, Ian T. Crosby,
Sean E. K.
Lim, Edward J. Lloyd and Elizabeth Yuriev
Department
of Medicinal Chemistry, Victorian
Tel. +61 3 9903
9556; Fax +61 3 9903 9582 e-mail: [email protected]
Received:
Keywords: clozapine, amidine, p-tolyloxypropyl
analogue, dibenzodiazepine.
As part of our ongoing
research programme in the area of anti-schizophrenia therapeutics, we
have
synthesized the title compound based on the structural hybridization of
the two
prominent antipsychotic drugs, clozapine
and haloperidol.
The starting tricyclic lactam,
1, was synthesized according to previously described literature
procedures [1, 2, 3]. Subsequent treatment
of 1
with the titanium-amine complex [4] formed from the addition of
titanium
tetrachloride to the monosubstituted piperazine, 2, furnished the title
compound 3
in respectable yield.
To a solution of 1‑(3‑(p‑tolyloxy)propyl)piperazine (2) (1.20 g,
5.14 mmol) in anhydrous anisole (5 mL)
under nitrogen was added a solution of titanium tetrachloride in
toluene (1.0
M, 1.10 mL, 1.10 mmol).
The
mixture was warmed to 50-55oC and a hot solution of
8‑chloro-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11-one
(1) (250 mg, 1.02 mmol) in
anhydrous anisole
(10 mL) was then added via
syringe. The
mixture was heated at reflux for 4 h after which time it was cooled and
then
evaporated to dryness in vacuo. The brown coloured residue was
partitioned between ethyl acetate (50 mL)
and aqueous
sodium hydroxide (2 M, 30 mL), the mixture
filtered
under vacuum and the residue washed with ethyl acetate (20 mL).
The organic layer was separated and the aqueous phase extracted with
ethyl
acetate (2 ´ 50 mL). The
organic fractions were combined, washed with water
(2 ´ 30 mL),
dried (anhydrous sodium sulfate), evaporated to dryness and the
resulting
residue purified using flash column chromatography (silica gel 230-400 mesh, ethyl acetate:hexane,
4:1). The fractions corresponding to the major product were pooled and
evaporated to dryness producing a yellow oily residue. Recrystallisation
from a methanol-water gave the title compound 3 as bright
yellow prisms
(252 mg, 53%).
Melting Point: 154.4156.8ēC.
TLC: Rf
(silica; ethyl acetate:hexane,
4:1) 0.30.
Elemental Analysis: Calculated
for C27H29ClN4O: C, 70.34%; H, 6.34%;
N,
12.15%. Found: C, 70.36%; H, 6.36%; N, 12.24%.
IR (KBr,
cm-1): 3292, 2920, 2852, 1598, 1558.
UV ((EtOH; λmax nm; log10e): 217 (4.54), 225
(4.55), 261 (4.26), 297
(4.08).
1H-NMR (300 MHz, d6-acetone):
d=
7.367.26
(m, 2 H); 7.086.99 (m, 4 H); 6.96 (m, 1 H); 6.886.75
(m, 4 H); 6.52 (s, 1 H, H5); 4.02 (t, J = 6.5 Hz, 2 H, H3''); 3.41 (m, 4 H, H2', H6'); 2.602.50 (m, 6 H, H1'', H3', H5'); 2.23 (s, 3 H, CH3);
1.93 (m, J = 6.5 Hz, 2 H, H2'').
13C-NMR (75 MHz,
d6-acetone): d= 164.0 (Cq);
158.1 (Cq); 154.9 (Cq);
143.4 (Cq); 142.9 (Cq);
132.7 (CH); 130.9 (CH); 130.6 (CH); 130.1 (Cq);
128.5 (Cq); 126.9 (CH); 124.6 (Cq); 123.40 (CH); 123.35 (CH); 121.3
(CH); 121.1
(CH); 115.2 (CH); 66.8 (CH2); 55.7 (CH2); 53.8 (CH2);
48.2 (CH2); 27.6 (CH2); 20.5 (CH3).
MS ESI (m/z, %): 463.3 (M[37Cl]H+,
36%); 461.3 (M[35Cl]H+, 100%).
Acknowledgment
The
authors gratefully acknowledge financial support from
References
1. Capuano, B.; Crosby, I. T.; Lloyd, E. J.; Taylor D. A. Aust. J. Chem. 2002, 55, 565.
2.
3. Hunziker, F.; Lauener, H.; Schmutz, J. Arzneimittelforschung
1963, 13, 324.
4. Schneider, J. Neues verfahren zur
ilerstellung von organischen verbindungen.
Sample
Availability:
Available from the author.
Š 2006 MDPI. All rights reserved.