8-Chloro-11-[4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11yl)piperazino]-5H-dibenzo[b,e][1,4]diazepine

A method to synthesize desmethylclozapine, 3, is reported. The procedure afforded the target compound in 69% yield. A by-product, isolated from the reaction mixture in 11% yield, proved to be the title compound, 4.


Introduction
Clozapine is an atypical antipsychotic drug used clinically to treat schizophrenia.Unlike other drugs used to treat this condition, clozapine is virtually devoid of movement disorders.Clozapine, however, has been found to induce the blood disorder agranulocytosis that can, in some cases, be fatal.The major metabolite of clozapine, desmethylclozapine (3), has been implicated in this serious blood dyscrasia [1].
Upon work-up and column chromatography, a by-product, 4, was isolated and characterized (Scheme 1).

Results and Discussion
A high R f component initially thought to be unreacted lactam 1 was discovered by TLC when UV light was used as a visualizing aid.Removal of the lactam from the target compound 3 was achieved with an ethyl acetate wash of the acidic aqueous phase.Subsequent basification of the aqueous phase followed by extraction with ethyl acetate isolated the target compound 3 and the high R f component.
The original lactam and the organic layer were analysed by TLC.Visualization with iodine vapor revealed an orange coloration for the reaction extract as opposed to green for the lactam.This component was separated from desmethylclozapine chromatographically.The 1 H NMR spectrum showed aromatic hydrogen resonances consistent with the tricyclic nucleus of desmethylclozapine.A broad singlet at δ 3.54 ppm displayed a relative integral of four protons.This resonance, in addition to the overall integration pattern, suggested a symmetrical structure.The presence of a solitary methylene carbon resonance at δ 48.20 ppm in the 13 C NMR spectrum also supported this.ESI mass spectral analysis confirmed the presence of two chlorine atoms in the molecule with the major protonated molecular ion peak at m/z 539, and was evidence for the structural integrity of 4. Microanalysis, in conjunction with low and high resolution ESI-MS, confirmed a molecular formula of C 30 H 24 Cl 2 N 6 .

Conclusion
We have presented the isolation and structural determination of a by-product 4 from an alternative route for the synthesis of desmethylclozapine.The title compound 4 is easily separated from the desired compound 3 using column chromatography.The target compound 3 was obtained in moderate yield.

General
The melting point was determined on a Reichert Micro-melting point apparatus and is uncorrected.Thin-layer chromatography (TLC) was carried out on silica gel 60 F 254 pre-coated plates (0.25 mm, Merck, ART.5554).Elemental analysis was carried out on a sample dried under vacuum over phosphorus pentoxide at 30 o C for 24 h.The UV-VIS spectrum was recorded on a Pharmacia Biotech Ultraspec 2000 UV-VIS spectrophotometer.The IR spectrum was recorded on a Hitachi 270-30 Infra-Red spectrophotometer. 1 H and 13 C NMR spectra were obtained using a Bruker Avance DPX 300 spectrometer and were recorded at 300.13 and 75.4 MHz respectively.The low resolution electrospray ionization (ESI) mass spectrum was determined in positive ion mode using a Micromass Platform II Mass Spectrometer at the specified cone voltage.The high resolution electrospray ionization (ESI) mass spectrum was determined using a Bruker BioApex II FTICR Mass Spectrometer.