Electron impact mass spectrometry of some neuroleptic amino alkyl thieno[β]cycloalkanones

Abstract

The mass spectrometric behaviour of seven neuroleptic amino alkyl thieno[b]cycloalkanones has been studied under electron ionization conditions and with the aid of metastable ion studies, low energy collisional experiments and accurate mass measurements. The most relevant fragmentation pathways are discussed and the power of the different methodologies for the characterization of structural isomers has been tested. # 1998 John Wiley & Sons, Ltd. Received 29 December 1997; Revised 22 April 1998; Accepted 24 April 1998 Since the discovery of chlorpromazine as an effective antipsychotic agent, a large number of potential neuroleptics have been synthesized. Despite this intense research activity, relatively few classes of compounds have shown a clinically confirmed antipsychotic activity. Haloperidol represents the prototype of the butyrophenone family, which is well known for its potent antipsychotic activity. 1 Pursuing our research in the area of butyrophenone analogues, we thought it of interest to develop the synthesis of a new series of amino alkyl thieno [b]cycloalkanones in which the benzene ring is replaced by the isosteric thiophene group.2 Analogously to the derivatives of the benzene series, most of the thiophene containing compounds have shown a remarkable antipsychotic activity, in both in vitro and in vivo assays. 3Mass spectrometry has already been shown to be a valuable analytical tool for the characterization of butyrophenones 4 and, in the present paper, we report on the mass spectrometric behaviour of a series of these compounds, namely: 1- [(4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)methyl]-4-(2'-pyridyl)piperazine (1) 2-Aminoethyl-4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophenes were prepared via DCC (dicyclohexylcarbodiimide) mediated coupling of the corresponding amines and ketoacids followed by amide reduction, while 3-aminomethyl-4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophenes were synthesized by acid mediated ring closure of the corresponding acyclic amine derivatives. The study was carried out in electron ionization conditions and with the aid of metastable ion 5 studies, low energy collision experiment 6 and accurate mass measurements. The investigation has led to a clear depiction of the main fragmentation patterns and to the characterization of the different structural isomer pairs. EXPERIMENTALElectron ionization (EI) mass spectra were obtained using a Micromass (Altrincham, UK) QMD 1000 mass spectrometer operating at 70 eV (200 mA) with an ion source temperature of 200°C. The samples were introduced directly into the source and heated to 170°C. Low-energy collisional experiments 6 performed on the M . ions were obtained by using a Micromass (Altrincham, UK) Quattro triple quadrupole instrument using 30 eV collision energy and N 2 (1 Â 10 À4 Torr) as collision gas. Metastable ion studies were carried out by mass analysed ion kinetic energy (MIKE) 5 spectroscopy performed using a Micromass (Altrincham, UK) ZAB2F instrument.Accurate mass measurements were obtained using the same instrument...