Preparation of specifically‐labelled buspirone ‐¹⁴C and buspirone ‐ ¹⁵N₂

Abstract

SUMMARYBuspirone 1 is a novel, clinically effective anxiolytic agent which is devoid of the sedative, anticonvulsant or muscle relaxant properties normally associated with the benzodiazepines. Buspirone labelled with both radioactive (14C) and stable (15N) isotopes was required in order to investigate the metabolism of the compound. The synthesis of both labelled compounds beginning with either urea -14C or urea -15N2 is described.

Solution Structure and Reagent Binding of the Zinc Alkoxide Catalyst in the Soai Asymmetric Autocatalytic Reaction

“…The magnetic equivalence of the two aryl hydrogen atoms in the ambient‐temperature 1 H NMR spectrum of all the mixtures of reactant 1 or alkoxide 4 with added i Pr 2 Zn requires that any N‐association is dynamic. To investigate this further, the synthesis of 15 N‐labeled pyrimidinal 1 d was carried out (Scheme ) 14. Association of reactant 1 d with varying i Pr 2 Zn concentration was conveniently studied at 213 K by 13 C, 1 H, and 15 N NMR spectroscopy, the latter by means of heteronuclear multiple‐bond correlation (HMBC) spectra; at this temperature the aldehyde reacted only slowly with i Pr 2 Zn.…”

Synthesis of the anxiolytic agent [14C] 6‐hydroxy‐buspirone for use in a human ADME study

“…Analytical characterization of the oil was consistent with 8-(4-bromobutyl)-8azaspiro[4.5]decane-7,9-dione). 16 Without purification, anhydrous piperazine (25.3 g, 294 mmol), potassium carbonate (16.3 g, 118 mmol), and acetonitrile (130 ml) were added to the reaction flask. The mixture was mechanically stirred while heating at reflux for 22 h. The mixture was hot filtered through a bed of celite and the cake rinsed with hot methanol.…”

“…A labeled synthesis existed for the preparation of the [ 14 C]1-PP variant of buspirone from the reaction of 2-Chloro-[2-14 C]pyrimidine with 8-(4-piperazinylbutyl)-azaspiro[4.5]decane-7,9dione. 16,17 Labeling the azaspiro portion of the molecule and the subsequent hydroxylation to prepare the [ 14 C]6-hydroxy-buspirone product had not been reported.…”

“…Synthesis of the [ 14 C]1-PP analog, 1a (Scheme 1), was accomplished in five steps from commercially available [ 14 C]urea. 16 The isotopic activity of the labeled urea (53 mCi/mmol) was diluted to accommodate scale, and it was reacted with malonaldehyde bis(dimethyl acetal) to give [ 14 C]2-hydroxy pyrimidine. The pyrimidine product was further reacted with POCl 3 , and the resulting radiolabeled chloride coupled with 8-(4-piperazinylbutyl)-azaspiro[4.5]decane-7, 9-dione affording 1a in an overall radiochemical yield of 17%.…”

A general synthetic method suitable for the introduction of deuterium or tritium in buspirone type anxiolytic agents

“…These properties, including freedom from benzodiazepine-related side effects, such as abuse potential and interactions with alcohol, have engendered much research into the mechanism of action of such agents and to the clinical investigation of a number of related derivatives@, 6). To this end, syntheses of specifically labelled 4Cand 5N-buspirone (7) , tetradeuterated buspirone (8) and Vitiated ipsapirone (9) have been reported. In the process of similar studies in our laboratories, it became of interest to study the receptor binding properties of compounds of this type and thus to synthesize agents specifically labelled with tritium at a known site for this purpose.…”