Spirodecanone refers to a class of spirocyclic ketones, often studied for their potential applications in medicinal chemistry. One notable example is 1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-one, which has been investigated as a metabolite of neuroleptic agents like Fluspirilene. It has a molecular formula of C13H17N3O and a melting point of 188-191 °C.
Synthesis
The original synthesis was first disclosed by Paul Janssen,[1] and was covered by Daniel Lednicer in one of his books.[2]
A recent synthesis of spirodecanone is disclosed:[3][4]
The Strecker-like condensation between N-benzyl-4-piperidone [3612-20-2] (1), aniline and TMSCN [7677-24-9], gives 4-anilino-1-benzylpiperidine-4-carbonitrile [968-86-5] (2). Acid catalyzed partial hydrolysis of the nitrile to the amide afforded 4-anilino-1-benzylpiperidine-4-carboxamide [1096-03-3] (3). Reaction with DMF-DMA [de] forms the spiroimidazolidone ring giving 8-benzyl-1-phenyl-1,3,8-triazaspiro[4.5]dec-2-en-4-one [974-42-5] (4). The imine bond is reduced with sodium borohydride giving 8-benzyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one [974-41-4] (5). Catalytic hydrogenation then removes the benzyl group (6).
It is noteworthy to mention that intermediate 4 finds dual use in the synthesis of some highly potent fentanyl analogs.[5]
Applications
Listed in alphabetical order:
Fluspiperone is similar but with additional para-fluoro.
^Janssen Paul Adriaan Jan, US3155669, US3155670, US3161644 & US3238216 (1964, 1964, 1964 & 1966 all to Research Laboratorium C Janssen NV).
^Strategies for Organic Drug Synthesis and Design, second edition, by Daniel Lednicer (page 335).
^Morciano, G., Preti, D., Pedriali, G., Aquila, G., Missiroli, S., Fantinati, A., Caroccia, N., Pacifico, S., Bonora, M., Talarico, A., Morganti, C., Rizzo, P., Ferrari, R., Wieckowski, M. R., Campo, G., Giorgi, C., Trapella, C., Pinton, P. (23 August 2018). "Discovery of Novel 1,3,8-Triazaspiro[4.5]decane Derivatives That Target the c Subunit of F 1 /F O -Adenosine Triphosphate (ATP) Synthase for the Treatment of Reperfusion Damage in Myocardial Infarction". Journal of Medicinal Chemistry. 61 (16): 7131–7143. doi:10.1021/acs.jmedchem.8b00278. hdl:11392/2397146. PMID30060655.
^盛春泉, et al. CN113480536 (2021 to Second Military Medical University SMMU).
^Walz, A. J., Hsu, F.-L. (January 2014). "Synthesis of 4-anilinopiperidine methyl esters, intermediates in the production of carfentanil, sufentanil, and remifentanil". Tetrahedron Letters. 55 (2): 501–502. doi:10.1016/j.tetlet.2013.11.058.
^Alberati, D., Hainzl, D., Jolidon, S., Kurt, A., Pinard, E., Thomas, A. W., Zimmerli, D. (August 2006). "4-Substituted-8-(1-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-one as a novel class of highly selective GlyT1 inhibitors with superior pharmacological and pharmacokinetic parameters". Bioorganic & Medicinal Chemistry Letters. 16 (16): 4321–4325. doi:10.1016/j.bmcl.2006.05.063. PMID16762550.
^Röver, S., Adam, G., Cesura, A. M., Galley, G., Jenck, F., Monsma, F. J., Wichmann, J., Dautzenberg, F. M. (6 April 2000). "High-Affinity, Non-Peptide Agonists for the ORL1 (Orphanin FQ/Nociceptin) Receptor". Journal of Medicinal Chemistry. 43 (7): 1329–1338. doi:10.1021/jm991129q.
