Molbank 2005, M453 |
Synthesis of Benzyl 2-(4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperazin-1-yl)acetate
Department of Medicinal Chemistry, Victorian
381
Royal Parade, Parkville, Victoria, 3052, Australia.
Tel. +61 3 9903 9556; Fax +61
3 9903 9582 e-mail: [email protected]
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Keywords: clozapine, amidine, benzyl ester, N-alkylation, dibenzodiazepine.
As part of our research programme, we have synthesized the title
compound as an intermediate for the preparation of a zwitterionic
analogue of the atypical antipsychotic, clozapine.
The starting material, desmethylclozaine, 1 was synthesized in accordance with a
previously reported literature procedure [1]. Subsequent treatment of 1 with benzyl 2-bromoacetate (2) afforded the title compound 3 in very good yield.
To a solution of desmethylclozapine (1, 503 mg, 1.61 mmol)
and anhydrous triethylamine (0.451 mL, 3.23 mmol) in
anhydrous 1,2-dimethoxyethane
(25 mL) was added benzyl 2-bromoacetate (2, 0.287 mL,
1.81 mmol) via
syringe. The reaction mixture was stirred at room temperature for 3 hours, filtered
and then evaporated to dryness. The residue was treated with distilled water
(10 mL) and extracted with dichloromethane (4 ´ 50 mL).
The combined organic fractions were dried with anhydrous sodium sulfate, filtered, then evaporated
to dryness. The resulting residue was purified using flash chromatography
(silica gel 230-400 mesh, ethyl acetate:hexane,
1:1). The fractions containing product were combined and evaporated to dryness
affording a yellow oil that solidified on standing. Recrystallisation from dichloromethane-hexane gave the
title compound 3 as bright yellow
prisms (536 mg, 72%).
Melting Point: 182-183˚C
TLC: Rf (silica; ethyl acetate:hexane, 1:1) 0.35.
Elemental Analysis: Calculated
for C26H25ClN4O2: C, 67.75%; H, 5.47%;
N, 12.15%. Found: C, 67.62%; H, 5.51%; N, 12.17%.
IR (KBr, cm-1): 3320, 1728, 1600, 1558.
UV ((EtOH; λmax nm; log10e): 209 (4.55), 228 (4.43),
260 (4.28), 297 (4.09).
1H-NMR (300 MHz, CD2Cl2):
d= 7.39-7.25 (m, 7 H, H1'',
H3'', H2'''', H3'''', H4'''', H5'''', H6''''); 7.05-7.00 (m, 2 H, H2'', H4'');
6.87-6.81 (m, 2 H, H7'', H9''); 6.65 (d, J
= 8.5 Hz, 1 H, H6''); 5.17 (s, 2 H, H1'''); 5.05 (s, 1 H, H5''); 3.46 (m, 4
H, H3', H5'); 3.33 (s, 2 H, H2); 2.67 (m, 4 H, H2', H6').
13C-NMR (75 MHz, CD2Cl2):
d= 170.6 (C=O); 163.4 (Cq); 153.4 (Cq);
142.6 (Cq); 141.2 (Cq);
136.6 (Cq); 132.5 (CH); 130.8 (CH); 129.3
(Cq); 129.1 (CH); 128.8 (CH); 127.0 (CH);
124.0 (Cq); 123.6 (CH); 123.4 (CH); 120.7
(CH); 120.7 (CH); 120.6 (CH); 66.8 (CH2); 59.8 (CH2);
53.2 (CH2); 47.8 (CH2).
MS ESI (m/z, %): 463.2 (M[37Cl]H+, 32%); 461.2 (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.
Sample Availability: Available from the author.
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